Classical Endocrine Therapy: Tamoxifen - Current Status
For 20+ years, the antiestrogen (more precisely, categorized as a SERM (selective estrogen receptor modulator)) agent Tamoxifen (Nolvaldex), with both antagonist properties (on breast tissue) and agonist (on other tissues such as endometrium and bone), actively blocking estrogen activity by binding to the estrogen receptor, has been the most widely deployed adjuvant endocrine therapy for all early breast cancer patients, both premenopausal and postmenopausal, and formally approved as such adjuvant therapy to reduce the risk of recurrence. It exhibits a confirmed efficacy in women with either hormone ER-positive or unknown breast cancer of decreasing annual risk of recurrence by 47% and annual mortality risk by 26%, observable independent of age, menopausal status, lymph node status, or chemotherapy use. On the other hand, in women with ER-negative there is no conclusive data on survival or contralateral breast cancer (CBC) to support treatment with tamoxifen (Swain, J Clin Oncol (2001): Tamoxifen for Patients With Estrogen Receptor–Negative Breast Cancer).

Long-term Benefits of Tamoxifen Therapy
It has been thought until recently that trials of tamoxifen given for 5 years compared with longer terms (Stewart et al, J Natl Cancer Inst (2001): Scottish Adjuvant Tamoxifen Trial: a Randomized Study Updated to 15 Years; Fisher et al., J Natl Cancer Inst (2001): Five Versus More Than Five Years of Tamoxifen for Lymph Node-Negative Breast Cancer: Updated Findings From the National Surgical Adjuvant Breast and Bowel Project B-14 Randomized Trial) suggest that the longer therapy might be less beneficial. (See also the recent ESMO Consensus (European Society for Medical Oncology) from the ninth St Gallen (Switzerland) expert consensus meeting in January 2005 (Goldhirsch et al. (2005): Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005).)

EBCTCG 2005
However, the recently reported (Lancet (2005): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials - Early Breast Cancer Trialists' Collaborative Group (EBCTCG)) long term findings of the The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which coordinated the world's largest collaborative analysis of cancer trials, have shown that (1) the types of chemotherapy and hormonal therapy long deployed (since the 1980's) for the prevention of breast cancer recurrence have much greater effects on 15-year than on 5-year survival, and (2) where both chemotherapy and hormonal therapy are appropriate they can approximately halve the 15-year risk of death from breast cancer. The regimens examined were:
(1) CMF chemotherapy
    (cyclophosphamide, methotrexate, fluorouracil)
(2) Anthracyline-based chemotherapy combinations
(3) Tamoxifen
(4) Ovarian ablation (ovaries removal) or suppression.

This landmark EBCTCG study found that anthracycline-based treatment was significantly more effective than CMF-based treatment at reducing the annual breast cancer death rates (six months of anthracycline-based chemotherapy decreased the annual breast cancer death rate by 38% for women who younger than 50 years of age when diagnosed), and by 20% for those were between 50 and 69 years of age when diagnosed), and five years of tamoxifen therapy, regardless of whether or not they had chemotherapy - decreased the annual breast cancer death rate by 31% for women with estrogen receptor positive tumors. But ovarian ablation or suppression significantly decreased breast cancer mortality only in the absence of other treatments.

Thus, middle aged women aged 69 and under diagnosed with estrogen-positive breast cancer can cut their mortality rate in half over the 15 years following their diagnosis by undergoing six months of anthracycline-based chemotherapy and then taking tamoxifen for five years, strengthening significantly the case for following surgery and radiation with chemotherapy and hormonal (endocrine) therapy when treating early-stage breast cancer, with evidence that anthracycline-based therapies should be used over CMF-based therapies, and that chemotherapy should be followed by tamoxifen in women with estrogen-positive tumors. The true surprise of these findings is that the true effect of these treatments may not be realized until 15 years later, at which point rates of cancer recurrence and mortality were significantly lower than at five years! Given that these findings are based on therapies tested in the 1980’s, and hence not folding in potential benefits of third generation aromatase inhibitors, monoclonal antibodies and other newer agents, there may now be possible even further improvements in long term survival via leveraging these new generations of anticancer agents. See also the commentaries of Chia et al. (Lancer (2005): The 2000 EBCTCG overview: a widening gap), Thus, after decades long debate, the noted divergence of the survival curves for breast cancer over time suggest that adjuvant systemic therapies would appear to actually cure some significant proportion of women with early-stage breast cancer, not just delay recurrence. Indeed, as Michaud has recently pointed out (Am J Health Syst Pharm (2005): Adjuvant use of aromatase inhibitors in postmenopausal women with breast cancer), the longevity of tamoxifen’s beneficial effects appears to extend long after its discontinuation, an advantage not to date demonstrated with aromatase inhibitors.

Thus, at present tamoxifen is well established as (1) an effective therapy for patients with all stages of hormone receptor-positive breast cancer, and more recently as (2) a breast cancer preventive.

Although tamoxifen is the most widely used SERM for breast cancer treatment and prevention, raloxifene (Evista) is another SERM originally developed as a breast cancer treatment, but now marketed as an anti-osteoporotic agent since it failed to demonstrate any clear and clinically substantive advantage over tamoxifen.

Adverse Effects of Tamoxifen
However, its partial agonist activity introduces some unsettling side effects: when tamoxifen is used long-term, its weak agonist activity can, rarely, cause endometrial cancer and thromboembolism. See the review and appreciation by Gradishar (Oncologist (2004): Tamoxifen - What Next?). Clinically, tamoxifen is deployed in three distinct settings: (1) as adjuvant treatment for women with early-stage estrogen receptor positive breast cancer; (2) as a so-called preventive agent to reduce the breast cancer risk for women at high risk of breast cancer; and (3) as a treatment for advanced (metastatic) hormone-sensitive breast cancer.

Most common side effects include hot flashes, vaginal discharge or bleeding, menstrual irregularities, with some women experiencing hair loss or skin rashes, and rarely but most seriously, endometrial cancer and thromboembolism. On the matter of endometrial cancer, the study of Swerdlow & Jones for the British Tamoxifen Second Cancer Study Group (J Natl Cancer Inst (2005): Tamoxifen Treatment for Breast Cancer and Risk of Endometrial Cancer: A Case–Control Study) found an increasing risk of endometrial cancer associated with longer tamoxifen treatment, extending well beyond 5 years, for both premenopausal and postmenopausal women. In addition, Decensi et al. (Circulation (2005): Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial) caution that women with conventional risk factors for atherosclerosis have a higher risk of venous thromboembolic events (VTE) during tamoxifen therapy, and this information needs be integrated into any counseling directed at women on the risk-benefit ratio of tamoxifen, especially in the prevention setting. Finally, tamoxifen resistance, both de novo and acquired, is a well-documented clinical issue (see the review of Ring & Dowsett, Endocr Relat Cancer (2004): Mechanisms of tamoxifen resistance).

In connection with these serious adverse effects, Breast Cancer Watch finds intriguing the speculation of Andrea Decensi, director of the chemopreventive division of the European Institute of Oncology that the increased risk of endometrial cancer associated with tamoxifen could be managed by dose reduction (possible combined with anastrozole), and at least the preliminary results of a cooperative Italian Norwegian study show that reducing the standard amount of tamoxifen (20 mg) by three quarters still retained efficacy in reducing the incidence of breast cancer (as reported by J Lyall, Cancer World (2005): Has tamoxifen had its day? [pdf]).

Tamoxifen: Breast Cancer Watch Summary

• A selective (partial) estrogen agonist
  antagonistic actions in breast cancers
  agonist actions on endometrium, lipids, and bone
• Efficacy maximal at 20 mg/day
• Effective in all age groups, and
  in premenopausal and postmenopausal women
• Maximal efficacy when given for five years but no longer (rather than two years)
• Adjuvant tamoxifen for 5 years:
  annual breast cancer mortality rate reduced by 31%
  (independent of age and chemotherapy use)
  with same proportional reductions over 15 years
  at 15 years: cumulative mortality reduction 2x that at 5 years
  
• Adjuvant tamoxifen for 5 years:
  
• Reduces risk of contralateral breast cancer by 40-50%
• May be less effective against HER2 positive tumors
• Is more effective when given sequentially after chemotherapy (when indicated) rather than concurrently.

Issues in Tamoxifen Endocrine Therapy

• Tamoxifen + Radiotherapy: Concurrent or Sequential?
• Tamoxifen Failure in ER-Negative Tumors
• Tamoxifen in the ER-/PR+ Context
• The ER+/PR- Context
• The ER-/PR+/HER2+ Context
• Tamoxifen, Endocrine Resistance and HER2+
• Hope Against Endocrine Resistance:
  STIs (Signal Transduction Inhibitors)
  
  [for complete coverage click on links above]
  
  
  
  Toremifene (Fareston)
  Toremifene is a chlorinated derivative of tamoxifen, which is approved in the United States as an alternative to tamoxifen in the first-line treatment of hormone-responsive metastatic breast cancer, and appears as effective as tamoxifen in the adjuvant setting.
  

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Fulvestrant (Faslodex) Endocrine Therapy
[for complete coverage click on link above]

  Aromatase Inhibitors

But in the last analysis, in something of a clinical revolution in oncology, the aromatase inhibitors (third generation) have steadily established consistent superiority over tamoxifen in both the metastatic and adjuvant settings (see Michaud's clinical review, Am J Health Syst Pharm (2005): Adjuvant use of aromatase inhibitors in postmenopausal women with breast cancer), and have even demonstrated superiority in the neoadjuvant setting. As Freedman et al. (Cancer Treat Rev (2005): Using aromatase inhibitors in the neoadjuvant setting: evolution or revolution?) have recently summarized, neoadjuvant endocrine treatment with aromatase inhibitors were introduced originally as little more than an experimental effort to palliate women with LABC (locally advanced breast cancer) found unsuitable for surgery or chemotherapy, but have evolved as viable, possibly preferred, alternatives for postmenopausal women with hormone receptor positive large humors or LABC (Howell, Curr Opin Obstet Gynecol (2005): Selective oestrogen receptor modulators, aromatase inhibitors and the female breast; Howell et al., Best Pract Res Clin Endocrinol Metab (2004): The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer; Brueggemeie et al., Endocr Rev (2005): Aromatase inhibitors in the treatment of breast cancer); and Kudachadkar & O'Regan (CA Cancer J Clin (2005): Aromatase Inhibitors as Adjuvant Therapy for Postmenopausal Patients With Early Stage Breast Cancer; and Tobias, Ann Oncol (2004): Recent advances in endocrine therapy for postmenopausal women with early breast cancer: implications for treatment and prevention). See also Jonat et al. (Cancer Chemother Pharmacol (2005): The use of aromatase inhibitors in adjuvant therapy for early breast cancer) who note that anastrozole (Arimidex) is the only aromatase inhibitor with mature adjuvant data to date.

Aromatase Inhibitors (AIs) deplete estrogen through the inhibition of aromatase, the enzyme responsible for synthesizing estrogen from androgens, converting testosterone to estradiol and androstenedione to estrone. As such, AIs are effective breast cancer therapies only in postmenopausal women whose humors express hormonal (estrogen or progesterone) receptors. Despite relatively distinct individual pharmacologies, as a class, aromatase inhibitors all cause a state of estrogen deprivation greater even than that consequent to surgical removal of the ovaries, starving tumor cells of the critical growth stimulus provided by estrogen to ultimately effect cancer-cell death.

Three generations of AIs are distinguished, but first generation (aminoglutethimide) and second generation (formestane, fadrozole) are no longer clinically deployed. The third generation AIs currently in use at this time are the non-steroidal, triazole compounds anastrozole (Arimidex) and letrozole (Femara) active by competitively inhibiting aromatase to significantly lower estrogen levels, and the steroidal exemestane (Aromasin), active by binding irreversibly to the aromatase enzyme, requiring increased aromatase production to overcome the inhibition..

Two recent guidelines are clinically authoritative in this context:
(1) the ASCO Technology Assessment Status Report (ASCO Panel, J Clin Oncol (2005): American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors As Adjuvant Therapy for Postmenopausal Women With Hormone Receptor–Positive Breast Cancer: Status Report 2004) which concluded that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen.
(2) the NCCN (National Comprehensive Cancer Network) guidelines (NCCN (2005): Practice Guidelines in Oncology - v.1.2006: Breast Cancer [pdf]) whose panel recommends the use of adjuvant endocrine therapy in women with hormone receptor-positive breast cancer regardless of menopausal status, age, or HER2/ status, with the exception of patients with lymph node-negative cancers less than or equal to 0.5 cm or 0.6 to 1.0 cm in diameter with favorable prognostic features.

See also the recent ESMO Consensus (European Society for Medical Oncology) from the ninth St Gallen (Switzerland) expert consensus meeting in January 2005 (Goldhirsch et al. (2005): Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005).

The cumulative evidence to date therefore shows that tamoxifen, exemestane and fulvestrant have activity in patients who have progressed on non-steroidal AIs, and given the apparent lack of cross-resistance between non-steroidal and steroidal AIs, non-steroidal AIs could also be effective following steroidal AI failure (Dodwell et al., Breast (2006): Postmenopausal advanced breast cancer: Options for therapy after tamoxifen and aromatase inhibitors).

Adverse Effects of Aromatase Inhibitors
Side effects of aromatase inhibitors are typically mild: hot flashes, joint pain and muscle aches, but a more major concern given their reduction of estrogen levels, is the potential for higher risk of osteoporosis (although modest and clinically manageable: see Shapiro, J Clin Oncol (2005): Aromatase Inhibitors and Bone Loss: Risks in Perspective).

Cardiovascular
And as reduced estrogen levels may also affect blood lipid levels, there is concern for increased risk of cardiovascular disease: the first results of the an open, randomized, multicenter, phase I pharmacodynamic Letrozole, Exemestane, and Anastrozole Pharmacodynamics (LEAP) study showed a small but significant increase in LDL-C/HDL-C in patients treated with exemestane (McCloskey et al., 28th San Antonio Breast Cancer Symposium (SABCS), December (2005): Initial results from the LEAP study: the first direct comparison of safety parameters between aromatase inhibitors in healthy postmenopausal women); however, Lonning et al., J Clin Oncol (2005): Effects of Exemestane Administered for 2 Years Versus Placebo on Bone Mineral Density, Bone Biomarkers, and Plasma Lipids in Patients With Surgically Resected Early Breast Cancer) found that one aromatase inhibitor, exemestane, only modestly enhanced bone loss from the femoral neck without significant influence on lumbar bone loss, and that except for a 6% to 9% drop in plasma high-density lipoprotein cholesterol, no major effects on serum lipids, coagulation factors, or homocysteine were discovered. In addition, AIs increase in gonadotropin secretion in premenopausal women, and hence cause ovarian stimulation, potentially resulting in ovarian cysts, and are for this and other reasons not recommended in women with functioning ovaries.

[new] However, the LEAP study did find that the ratio of apolipoprotein B to apolipoprotein A–I, considered an indicator of increased coronary heart disease risk, was elevated with exemestane (Aromasin), but in contrast remained normal with anastrozole and letrozole (Femara).

However, Chow et al. (Biomed Pharmacother (2005): Serum lipid profiles in patients receiving endocrine treatment for breast cancer-the results from the Celecoxib Anti-Aromatase Neoadjuvant (CAAN) Trial) investigated the efficacy and side effects, including changes in lipid profiles, of combining aromatase inhibitor therapy and a COX-2 inhibitor (celecoxib 400 mg twice-daily) preoperatively in hormone sensitive postmenopausal breast cancers, noting that the COX-2 inibitor celecoxib has both apoptotic and antiangiogenic activities, and may be of use in treatment of breast tumors which overexpress the COX-2 enzyme. They found that the addition of the COX-2 inhibitor was associated with beneficial effects on the serum lipid profiles, with a progressive drop in cholesterol levels and significantly lowered cholesterol and LDL levels.

Cognitive Function
And some concern about adverse impact on cognitive function: the research of Tralong & Di Mari (J Clin Oncol (2005): Cognitive Impairment, Aromatase Inhibitors, and Age) suggests that the evidence supports the hypothesis that cognitive impairment could also be a late side effect of adjuvant hormonal therapy.

Cost
The AIs are typically all more than $200 per month in cost to the patient, while in contrast generic tamoxifen is approximately $30 per month.

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Aromatase Inhibitors: Breast Cancer Watch Summary

• Activity = inhibition of estrogen synthesis
• Non-steroidal agents: anastrozole (Arimidex) and
  letrozole (Femara)
• Steroidal agent: exemestane (Aromasin)
• Only effective only in postmenopausal women
• Greater DFS (disease free survival) and
  MFS (metastatic free survival) than tamoxifen
• Improve DFS (disease-free survival)
  if patients are switched after 2 or 3 years of tamoxifen
  instead of continuing on tamoxifen
• Reduce the risk of recurrence
  when used as extended adjuvant therapy
  after 5 years of tamoxifen
• Improve survival in node positive patients
• Reduce the risk of contralateral breast cancer
  by a further 40-50% when given instead of, or after, tamoxifen
• May be more effective than tamoxifen against HER2+ tumors.
• [new] Women who are premenopausal, and patients with 4 positive lymph nodes, receive the greatest absolute benefit, namely of >3% in the 10-year EFS (event-free survival) rate from extended therapy with aromatase inhibitors (Freedman et al., Cancer (2006): Identifying breast cancer patients most likely to benefit from aromatase inhibitor therapy after adjuvant radiation and tamoxifen).
• [new] There is highly preliminary phase I data (McCloskey et al., 28th San Antonio Breast Cancer Symposium (SABCS), December (2005): Initial results from the LEAP study: the first direct comparison of safety parameters between aromatase inhibitors in healthy postmenopausal women) that exemestane (Aromasin) may have a greater adverse event potential on cardiovascular / coronary heart disease risk that letrozole (Femara) or anastrozole (Arimidex).
  

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Aromatase Inhibitors and Bone Loss
Estrogen's bone-protective effects is well-known, exhibiting stimulatory activity on new bone formation and inhibitory activity on bone resorption. In natural and induced estrogen deficiency states, bone resorption outruns new bone formation resulting in net bone loss. Such estrogen deficiency states may be consequent to (1) natural menopause, or consequent to cancer-related therapies, that is, cancer-treatment-induced bone loss (CTIBL) (Pfeilschifter & Diel, J Clin Oncol (2000): Osteoporosis Due to Cancer Treatment: Pathogenesis and Management): (2) chemotherapy-induced ovarian failure, (3) therapy with gonadotropin-releasing hormone agonists (luteinizing hormone-releasing hormone (LHRH) analogs), or (4) therapy with aromatase inhibitors: given that the conversion of androgens to estrogens via the aromatase enzyme is for postmenopausal women the principle source of endogenous estrogen, then the class effect of aromatase inhibitors in lowering endogenous estrogen levels is undesirable bone loss (Shapiro, J Clin Oncol (2005): Aromatase Inhibitors and Bone Loss: Risks in Perspective), putting patients at substantially increased risk for fractures from AI cancer-treatment-induced bone loss.

This contrasts dramatically with tamoxifen, with its tissue-specific estrogen agonist effects in the bone of postmenopausal women, allowing tamoxifen to act as a weak estrogen with a consequent preservation of bone mineral density (BMD) and possible decrease in fracture risk and actual fractures. Studies have shown that rates of bone loss in women receiving adjuvant hormonal therapy with aromatase inhibitors or ovarian ablative therapies for breast cancer (oophorectomy or CRA (chemotherapy-related amenorrhea from, for instance, cyclophosphamide), are at least twice those exhibited during early menopause (typically the period when natural bone loss is most profound (Lipton, J Clin Oncol (2004): Toward New Horizons: The Future of Bisphosphonate Therapy)).

It has until recently been widely held that all aromatase inhibitors (AIs) adversely impact bone health through their promotion of bone loss; however, recent studies suggest that although all AIs have similar effects on bone resorption, the steroidal AI exemestane (Aromasin) exhibits a statistically significant increase in bone formation marker (Subar et al., ASCO Annual meeting (2004): Effects of steroidal and nonsteroidal aromatase inhibitors (AIs) on markers of bone turnover and lipid metabolism in healthy volunteers) compared 6 months of 25 mg of exemestane versus 2.5 mg of letrozole daily on bone formation and resorptive markers in non-osteoporotic postmenopausal women, finding that although bone resorption increased from all three AIs, exemestane caused a presumptive androgenic increase in bone formation markers). This is consonant with the findings of Lonning et al. (J Clin Oncol (2005): Effects of Exemestane Administered for 2 Years Versus Placebo on Bone Mineral Density, Bone Biomarkers, and Plasma Lipids in Patients With Surgically Resected Early Breast Cancer) who reported that exemestane modestly enhanced bone loss from the femoral neck without significant influence on lumbar bone loss (see also Lonning & Geisler, J Clin Oncol (2005): In Reply:).


Treating Bone Pain and Bone Metastasis
Studies have shown that zoledronic acid (Zometa), pamidronate (Aredia), clodronate (Bonefos), and ibandronate (Boniva/Bondronat) are effective bone therapies in patients with breast cancer, with all demonstrating transient palliation of bone pain. And there is some suggestion (Journe et al., Breast Cancer Res (2004): Additive growth inhibitory effects of ibandronate and antiestrogens in estrogen receptor-positive breast cancer cell lines) that ibandronate inhibits breast cancer cell growth, both in the presence and absence of estrogenic stimulation, may have additive effects with antiestrogens, supporting their combined use for the treatment of bone metastases from breast cancer, cross-confirmed by Journe et al. (Breast Cancer Res (2005): Additive growth inhibitory effects of ibandronate and antiestrogens in estrogen receptor-positive breast cancer cell lines) who found in vitro evidence for additive effects between ibandronate and antiestrogens, suggesting combined use for the treatment of bone metastases from breast cancer.

Similarly, zolendronic acid has demonstrated potent anti-tumor activity in vitro and in vivo (Croucher et al., Breast (2003): The anti-tumor potential of zoledronic acid); Philippe Clézardin (Cancer Treat Rev (2005): Anti-tumour activity of zoledronic acid); and Budman & Calabro (Oncololgy (2006): Zoledronic Acid (Zometa®) Enhances the Cytotoxic Effect of Gemcitabine and Fluvastatin: In vitro Isobologram Studies with Conventional and Nonconventional Cytotoxic Agents) found that zoledronic acid with both gemcitabine and fluvastatin demonstrated global cytotoxic synergy across 7 of 8 cell lines, suggesting that these combinations may have a therapeutic role in treatment of bone metastasis of selected malignancies. See also Clézardin et al. (Cancer Res (2005): Bisphosphonates and Cancer-Induced Bone Disease: Beyond Their Antiresorptive Activity), Graham Russell (Ann N Y Acad Sci (2006): Bisphosphonates: From Bench to Beside) who documents the potential underlying pathways by which bisphosphonates induce apoptosis, and similarly Anke Roelofs and colleagues (Roelofs et al., Clin Cancer Res (2006): Molecular Mechanisms of Action of Bisphosphonates: Current Status ) from the University of Aberdeen have clarified the molecular basis of their antitumor activity.

However, zoledronic acid appears to be more effective than pamidronate, and it demonstrates both significant and sustained pain reduction and a significantly lower incidence and longer time to onset of SREs (skeletal-related events) compared with placebo. It was also until recently the only bisphosphonate (now clodronate appears to have similar activity) to found effective against bone metastases from a variety of other solid tumors (lung cancer and renal cell carcinoma). At this time therefore it is well-established that bisphosphonates effectively reduce skeletal complications in patients with bone metastases from breast cancer, with zoledronic acid demonstrating the broadest clinical activity in a wide variety of tumor types (P. Conte, Oncologist (2004): Optimizing Bisphosphonate Therapy in Oncology; R. Coleman, Oncologist (2004): Bisphosphonates: Clinical Experience; Conte & Guarneri, Oncologist (2004): Safety of Intravenous and Oral Bisphosphonates and Compliance With Dosing Regimens); Mystakidou et al., Cancer Treat Rev (2005): Approaches to managing bone metastases from breast cancer: The role of bisphosphonates; Pavlakis et al., Cochrane Database Syst Rev (2005): Bisphosphonates for breast cancer).

And several studies have evaluated the newly released (March 2005) oral form of ibandronate (Boniva): Lichinitser et al. (28th San Antonio Breast Cancer Symposium (SABCS), December (2005): Non-inferiority of oral ibandronate to intravenous zoledronic acid for reducing markers of bone turnover in metastatic breast cancer patients) in an open-label multicenter, randomized, parallel-group trial found ibandronate (oral administration at 50mg/daily) non-inferior to zoledronic acid (Zometa), IV-administered at 4mg infusion over 15 minutes every 4 weeks, in reducing bone turnover markers, and the same researchers (Bergstrom et al., 28th San Antonio Breast Cancer Symposium (SABCS), December (2005): Intravenous ibandronate 15-minute infusion followed by daily oral ibandronate for metastatic bone disease: bone marker data) found in a phase III trial that rapid 15-minute infusion of intravenous ibandronate (6mg) followed by daily oral ibandronate (50mg) was associated with a marked decrease in bone turnover markers.

Furthermore, in the specific breast cancer context, the Greek research team of Heras et al. (28th San Antonio Breast Cancer Symposium (SABCS), December (2005): Efficacy and safety of intravenous ibandronate 6mg infused over 15 minutes: results from a 2-year study of breast cancer patients with metastatic bone disease) conducted a cohort trial which evaluated the efficacy and safety of an ibandronate infusion over 15 minutes in breast cancer patients with metastatic bone disease, finding that ibandronate reduced the proportion of patients who experienced an skeletal-related events (SREs), and decreased the median time to both first SRE, and the SRE risk, with no evidence of renal toxicity compared with placebo; Breast Cancer Watch notes in this connection that the renal safety of ibandronate has been independently well established (see especially Guarneri et al., cited above, Oncologist (2005): Renal Safety and Efficacy of i.v. Bisphosphonates in Patients with Skeletal Metastases Treated for up to 10 Years), R. von Moos, Oncologist (2005): Bisphosphonate Treatment Recommendations for Oncologists, GH Jackson, Oncologist (2005): Renal Safety of Ibandronate, R Bell, Oncologist (2005): Efficacy of Ibandronate in Metastatic Bone Disease: Review of Clinical Data ).

However, Breast Cancer Watch notes that there is some controversy concerning the relative renal safety of zoledronic acid compared to other bisphosphonates, including ibandronate: see Zohno et al., J Clin Oncol (2005): Zoledronic Acid Significantly Reduces Skeletal Complications Compared With Placebo in Japanese Women With Bone Metastases From Breast Cancer: A Randomized, Placebo-Controlled Trial, and Conte & Guarneri, Oncologist (2005): In Response to Jackson Letter to the Editor Regarding "Safety of Intravenous and Oral Bisphosphonates and Compliance with Dosing Regimens", and BA Chabner, Oncologist (20050: Late Toxicities of Drugs: Bisphosphonates.

Finally, the same American researchers ((Body et al., 28th San Antonio Breast Cancer Symposium (SABCS), December (2005): Safety of oral ibandronate and intravenous zoledronic acid in breast cancer patients with metastatic bone disease) conducted an open-label, multicenter, parallel-group study of breast cancer patients comparing ibandronate directly with zoledronic acid, finding that a high proportion of the zoledronic acid group reported adverse events associated with an acute-phase response following initial treatment, whereas gastrointestinal adverse events were slightly higher for oral ibandronate than intravenous zoledronic acid. However, despite this observation by the researchers, Breast Cancer Watch notes that the higher proportion of adverse events (other than GI-related) found in the zoledronic group were indeed acute-phase and of narrow duration (with the first three days), of the kind typical observed with infusion-consequent administration of zoledronic acid, not long-term, so although tolerability in terms of administration mode may be more favorable with an oral administered bisphosphonate like ibandronate, we cannot conclude that overall tolerability across all phases of adverse events are superior for this agent and further studies of higher methodological rigor than these open-label trials are required to be determinative on this issue.



New Hope and Options for Bone Pain and Metastasis:
Anti-osteolytic Bisphosphonates
Given the hypothesis that a bone resorptive phase precedes the development of osteoblastic metastases, the use of bisphosphonates to inhibit this resorptive phase has the potential to significantly reduce the development of osteoblastic metastases, and anti-osteolytic agents including bisphosphonates
have indeed been shown to prevent the development of bone
metastases in various animal models (see Padalecki et al., Breast Cancer Res (2002): The role of bisphosphonates in breast cancer: Actions of bisphosphonates in animal models of breast cancer; and Woodward et al., Anti-Cancer Drugs (2005): Preclinical evidence for the effect of bisphosphonates and cytotoxic drugs on tumor cell invasion who conclude from the preclinical data that bisphosphonates not only induce tumor cell apoptosis, but might also affect tumor cell invasion in vitro, and the component processes of adhesion, migration and degradation).

Thus bisphosphonates appear to exhibit a variety of anti-tumor activities: apoptosis induction, inhibition of cell growth, inhibition of invasive behavior and inhibition of angiogenic factors, as well as the potential to enhance the anti-tumour activity of known cytotoxic drugs (Neville-Webbe et al, Cancer Treat Res (2002): The anti-tumour activity of bisphosphonates). Taken together these findings confirm that oral clodronate significantly improve the 5 year bone relapse free survival when used as supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer.

The antiresorptive agent zoledronic acid (Zometa) and the chemotherapeutic agents doxorubicin (Adriamycin) and paclitaxel (Taxol) have been shown to synergistically increase apoptosis in breast cancer cells in vitro (Michailidou et al., Breast Cancer Res (2006): Effects of combined treatment with Zometa and Taxol on endothelial cells in vitro; Holen et al., Breast Cancer Res (2006): Woodward et al., ; Benefits of combined treatments using antiresorptive agents and cytotoxic drugs), and based on this researchers at the University of Sheffield (Ottewell et al., Breast Cancer Res (2006): Synergistic effects of cytotoxic drugs and antiresorptive agents in vitro and in vivo) conducted a study to determine potential in vivo activity, finding that the combination treatment with doxorubicin followed serquentially by zoledronic acid resulted in a significant reduction of tumour growth compared with control mice or mice treated with either agent alone.

It is essential to note that sequencing here may be critical: invasion of MCF7 cells treated with zoledronic acid and doxorubicin was significantly reduced when compared with control, but the effect was dependent on drug sequence (Woodward et al., Anti-Cancer Drugs (2005): Combined effects of zoledronic acid and doxorubicin on breast cancer cell invasion in vitro), and in another study by Helen Neville-Webbe and the University of Sheffield team (Neville-Webbe et al., Int J Cancer (2004): Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells), it was found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence- and schedule-dependent apoptosis of breast and prostate cancer cells, requiring for maximal apoptosis that cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr., thus showing a clear cell cycle phase-specific synergistic effect. The same sequence-dependency was seen for paclitaxel, where maximal levels of apoptosis were achieved when cells are treated with paclitaxel followed by zoledronic acid, as opposed to the reverse sequence or simultaneous treatment, and with hormone independence, mutated p53 status and presence of BRCA1 gene being associated with higher levels of apoptosis (Neville-Webbe et al., TumorBiology (2006): Mechanisms of the Synergistic Interaction between the Bisphosphonate Zoledronic Acid and the Chemotherapy Agent Paclitaxel in Breast Cancer Cells in vitro).

Furthermore, zoledronic acid (Zometa) is reported to have antiangiogenic properties in vivo, and so Santini and collegaues (Oncol Rep (2006): Changes in bone resorption and vascular endothelial growth factor after a single zoledronic acid infusion in cancer patients with bone metastases from solid tumours [pdf]) investigated the correlations between changes in the proangiogenic cytokine, vascular endothelial growth factor (VEGF), and markers of bone resorption in a cohort of patients with metastatic bone disease, following a single infusion of zoledronic acid, finding a statistically significant correlation exists between circulating levels of VEGF and ßCTX (a measure of bone resorption) concentration 1 day after a single infusion of zoledronic acid, which persisted for 21 days after infusion. The demonstarted benefit is hypothesized to be consequent to the fact that metastatic tumor stimulates bone turnover and bone turnover in turn promotes local tumor growth (Reddi et al., J Bone Miner Res (2003): Mechanisms of Tumor Metastasis to the Bone: Challenges and Opportunities) and as a consequence, the zoledronic-induced
inhibition of bone turnover may lead to inhibition of tumor growth in the bone environment, as well as by direct zoledronic-induced angiogenesis inhibition, although it appears that the biological response to ZOL is not the same in all patients, with some seen as non-responders (Reddi, above).

Given in addition that bisphosphonates exert their anti-osteolytic effects by inhibiting osteoclast activity, this mechanism is hypothesized to be the mechanism for metastasis prevention. The findings of placebo-controlled trials demonstrate that oral clodronate (Paterson et al., J Clin Oncol (1993):Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer), oral ibandronate (Tripathy et al., Ann Onc (2004): Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial) or intravenous pamidronate (Hortobagyi et al., J Clin Oncol (1998): Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group, and Theriault et al., J Clin Oncol (1999): Pamidronate Reduces Skeletal Morbidity in Women With Advanced Breast Cancer and Lytic Bone Lesions: A Randomized, Placebo-Controlled Trial) will reduce the skeletal complications in patients with metastatic breast cancer (see also the commentary of GN Hortobagyi (J Clin Oncol (2005): Progress in the Management of Bone Metastases: One Continent at a Time?).

Oral clodronate has also been shown to reduce the
incidence of bone metastases in both (1) women with advanced breast cancer (Kanis et al., Bone (1996): Clodronate decreases the frequency of skeletal metastases in women with breast cancer) and (2) in women with primary breast cancer (Diel et al., N Engl J Med (1998): Reduction in New Metastases in Breast Cancer with Adjuvant Clodronate Treatment). And more recently, Powles et al. (Breast Cancer Res (2006): Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]) conducted a randomized, double-blind, placebo-controlled study to determine if oral clodronate (1,600 mg daily) for 2 years when combined with standard adjuvant therapy could reduce the incidence of bone metastases in patients with primary, stageI-III breast cancer, finding that the addition of oral clodronate to adjuvant breast cancer therapy significantly reduced the risk of bone metastases by 45% during the 2-year treatment period, and 31% over the 5 year study period, with only 6% of patients with stage I disease developing bone metastasis, and a significant reduction in mortality during the clodronate treatment period (see also Powles et al., J Clin Oncol (2002): Randomized, Placebo-Controlled Trial of Clodronate in Patients With Primary Operable Breast Cancer). Clodronate - as a non-nitrogen containing bisphosphonate - has not demonstrated an potential for osteonecrosis of the Jaw (ONJ).

New Hope and Options for Bone Pain and Metastasis:
Radiopharmaceuticals
Radiopharmaceuticals are a group of drugs with radioactive elements, which are injected into a vein, settling in areas of bone containing cancer, and whose emitted radiation kills the cancer cells as well as relieves some of the pain caused by bone metastases. Radiopharmaceutical therapy may be preferable to external beam radiation (EBRT) in cases in which cancer has spread to many bones, as EBRT would require trying to aim at each affected bone. it may be the case that radiopharmaceuticals work best when the metastases are osteoblastic: that is, when the cancer has stimulated the bone cells (osteoblasts) to form new areas of bone. The major side effect of radiopharmaceutical therapy is a lowering of blood cell counts, with potential increased risk for infections or bleeding, but this is within manageable range. See Siegel et al. (J Am Acad Orthop Surg (2004): Advances in Radionuclide Therapeutics in Orthopaedics).

Radiopharmaceuticals provide several advantages over conventional external beam radiotherapy (EBRT):

• they can treat multiple diffuse sites with mild bone marrow depression;
• they can be administered intravenously;
• they cause fewer adverse effects, such as nausea, vomiting, diarrhea, and tissue damage;
  

In patients with bone metastases, radiopharmaceuticals may be used as an alternative or adjunct to external beam radiation therapy. These agents are not useful in spinal cord or peripheral nerve invasion by adjacent metastases, for acute pathologic fractures, or for pure osteolytic lesions. Because the adverse effects of radiopharmaceuticals can include bone marrow suppression, patients with preexisting bone marrow suppression or those who are expected to soon receive other myelosuppressive therapies are not candidates for this treatment, and the risk-benefit ratio of using radiopharmaceuticals needs to be weighed for each individual patient (Smith et al., Medscape (2005): Skeletal Complications Across the Cancer Continuum: Bone Metastases and Bone Loss).

Strontium-89 (Metastron), also referred to as samarium-153-EDTMP, is already well-established as effective in the palliation of the metastatic bone pain of prostate cancer, refractory to conventional analgesia; it "imitates" the activity of calcium: it is taken up and incorporated into bone, with a preferential retention in metastatic lesions compared to normal bone; it is also been used in sclerotic metastases from primaries cancer such as breast cancer. Fuster et al. (Nuc Med Commun (2000): Usefulness of strontium-89 for bone pain palliation in metastatic breast cancer patients) evaluated its usefulness for bone pain palliation in breast cancer patients, finding that breast cancer patients with metastatic bone pain can benefit from therapy with strontium-89 in terms of performance status, pain and analgesia. Later studies have confirmed and extended these early results: Robinson et al. (JAMA (2004): Strontium 89 therapy for the palliation of pain due to osseous metastases found that as many as 80% of selected patients with painful osteoblastic bony metastases from breast or prostate cancers may experience some pain relief following strontium-89 administration, with as many as 10% or more becoming pain free; they observed a duration of clinical response averaging 3 to 6 months in some cases, with pain relief usually appearing within 1–3 weeks after treatment, and with only mild hemotoxicity (see also Rao & Chen, J Natl Cancer Inst (2004): Symptom Management in the Elderly Cancer Patient: Fatigue, Pain, and Depression, but note that the authors mis-identify strontium-89 as "strontium-80"). Patients treated with strontium-89 appear to develop fewer new sites of pain, with improved median overall survival (Bauman et al., Radiother Oncol (2005): Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic review). Toxicity is limited to temporary myelosuppression.

Similar positive results have been obtained for another radiopharmaceutical samarium-153 (Quadramet). Samarium-153 is complexed with ethylenediaminetetramethylene phosphonic acid to form 153Sm-EDTMP, a phosphonate complex which concentrates in the skeleton, in proportion to osteoblastic activity. The Therapeutic Radiopharmaceuticals Guidelines Group (Cancer Care Ontario (2004): Radiopharmaceuticals for the Palliation of Painful Bone Metastases Practice Guideline Report #14-1 [pdf]) concluded that the available evidence would suggest both radiopharmaceuticals are useful palliative interventions for patients with pain secondary to multiple sites of bone metastases. See also Sapienza et al. (Rev Hosp Clin Fac Med Sao Paulo (2004): Retrospective evaluation of bone pain palliation after samarium-153-EDTMP therapy) who found that with samarium-153 pain was reduced to less than 50% of basal levels in 76% of cases typically with reduction or elimination of opiates for pain seen in all patients (Anderson et al., J Clin Oncol (2002): High-Dose Samarium-153 Ethylene Diamine Tetramethylene Phosphonate: Low Toxicity of Skeletal Irradiation in Patients With Osteosarcoma and Bone Metastases), and with no distinction as to the primary tumor (breast or prostate), and studies in prostate cancer suggest a trend toward improved survival (Collins et al., J Nucl Med (1993): Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial). Like strontium-89, there may be a "pain flare" phenomenon within the first 2 - 3 days of treatment, but this is usually mild, self-limited, and controlled with analgesics. The main adverse effects observed during follow-up was a transitory mild to moderate medullary depression, leukopenia in 71.2% of the patients, and thrombocytopenia in 53.4%;but most of the patients had recovered at the end of the eighth week.

Baranauskas et al. (Merdicina (Kaunas) (2006): Use of strontium-89 in the analgesic treatment of cancer patients with bone metastases [pdf]) found that 80% of patients with pain from bone metastasis secondary to prostate or breast cancer experienced significant pain relief via administration of strontium-89, with only mild levels of hematotoxicity, and the duration of pain relief in some cases exceeded 3-6 months. They conclude that use of single-agent radiopharmaceuticals like strontium-89 and samarium-153 should be considered as a possible option for the palliation of multiple sites of bone pain from metastatic cancer where pain control with conventional analgesic regimens is unsatisfactory. See also Falkmer et al. (Acta Oncol (2003): A Systematic Overview of Radiation Therapy Effects in Skeletal Metastases).

More promising still are two recent findings:
(1) the effectiveness of these radiopharmaceuticals can be enhanced by combining them with chemotherapeutic agents;
(2) some studies indicate a reduction of hot spots on bone scans in up to 70% of patients, and this suggests a possible tumoricidal action independent of any concommitant chemotherapy (Finlay et al., Lancet Oncol (2005): Radioisotopes for the palliation of metastatic bone cancer: a systematic review); this is also confirmed in the review of EB Silberstein (Semin Nucl Med (2005): Teletherapy and radiopharmaceutical therapy of painful bone metastases) who found that strontium-89 (Metastron) exhibits availability to reduce the incidence of new bone metastases and when combined with chemotherapy, to prolong patient survival.

New Hope and Options for Bone Pain and Metastasis:
COX-2 Inhibitors
I have already noted elsewhere that the COX-2 inhibitor (celecoxib 400 mg twice-daily) preoperatively in hormone sensitive postmenopausal breast cancers exhibits both apoptotic and antiangiogenic activities, and may be of use in treatment of breast tumors which overexpress the COX-2 enzyme, and both pre-clinical breast cell studies (Ono et al., J Bone Min Res (2002): Involvement of cyclo-oxygenase-2 in osteoclast formation and bone destruction in bone metastasis of mammary carcinoma cell lines) and clinical research in prostate cancer (Gamradt et al., Anticancer Res (20050: The effect of cyclooxygenase-2 (COX-2) inhibition on human prostate cancer induced osteoblastic and osteolytic lesions in bone) suggest the potential to limit the progression of osteoblastic metastases by COX-2 inhibitors, in addition to the remarkable breast cancer risk reduction of COX-2 inhibitors (Harris et al., BMC Cancer (2006): Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors) which found that both celecoxib and rofecoxib induce a 71% reduction in the risk of human breast cancer. It appears that cyclooxygenase-2 (COX-2), the rate-limiting enzyme of prostaglandin synthesis, is implicated in invasiveness and distant metastases of cancer, so Hiraga et al. (Cancer Res (2006): Stimulation of cyclooxygenase-2 expression by bone-derived transforming growth factor-beta enhances bone metastases in breast cancer) examined the surgical specimens of bone metastases from patients with various types of cancers by using immunohistochemistry, observing evident COX-2 expression in these bone metastases. Their study found that bone-derived TGFbeta (of the most abundant growth factors stored in bone) up-regulates COX-2 expression in breast cancer cells, thereby increasing prostaglandin E2 production, which in turn, stimulates osteoclastic bone destruction, leading to the progression of bone metastases, and that COX-2 inhibitors significantly suppressed bone metastases with decreased osteoclast number and increased apoptosis in human breast cancer cells, strongly suggesting COX-2 as a potential therapeutic target for bone metastases in breast cancer.



New Hope and Options for Breast Cancer Liver Metastasis
We know that survival in breast cancer patients with liver-only metastases or with liver and bone metastases is typically longer than that in patients with metastases to other sites (Zinser et al., J Clin Oncol (1987): Clinical course of breast cancer patients with liver metastases). One challenge of oncotherapy for breast cancer with liver metastasis is that since CT (chemotherapy) agents are dependent on the liver for their essential metabolism, the concern is that CT efficacy and metabolism may be impaired by virtue of the liver metastasis.

Although surgical intervention is not always possible depending on nature and extent of non-hepatic metastases and degree of hepatic involvement, nontheless in carefully selected patients such intervention may yield significant gains: researchers from the Department of Surgical Oncology, at M. D. Anderson Cancer Center (Vlastos et al., Ann Surg Oncol (2004): Long-term Survival After An Aggressive Surgical Approach in Patients With Breast Cancer Hepatic Metastases) demonstrated that n selected patients with liver metastases from breast cancer, an aggressive surgical approach, consisting of liver resection with or without radiofrequency ablation (RFA), is associated with favorable long-term survival, cocluding that hepatic resection should be considered a component of multimodality treatment of breast cancer in these patients; this extends the somewaht earlier review of another team of researchers from M. D. Anderson Cancer Center (Singletary et al., Oncologist (2003): A Role for Curative Surgery in the Treatment of Selected Patients with Metastatic Breast Cancer) who reviewed the role of surgery in the treatment of single or multiple metastatic lesions restricted to one site, mainly in the context of isolated hepatic metastases treated with surgery, in the form of resection and/or radiofrequency ablation with curative intent.

As to liver metastasis treatment, many local therapies (ie, percutaneous ethanol injection, radiofrequency (RF) ablation, microwave ablation, and/or ultrasound ablation) have been deployed for the treatment of primary liver carcinoma, ands some of these have also been effective in the treatment of breast cancer liver metastasis: so, Livraghi et al (Radiology (2001): Percutaneous Radio-frequency Ablation of Liver Metastases from Breast Cancer: Initial Experience in 24 Patients) found percutaneous RF ablation (P-RFA) to be a simple, safe, and effective treatment for focal liver metastases in selected patients with breast cancer, and a valid alternative to surgery; they speculate that the higher rate of local control observed in their study, as compared with colorectal cancer liver metastases, suggests that occult invasion of surrounding liver tissue may be less frequent, or absent, in breast cancer metastasis.

A related intervention L-RFA (laproscopic radiofrequency ablation) has also some some promise: Berber et al. (Surg Endosc (2005): Laparoscopic radiofrequency thermal ablation for unusual hepatic tumors: operative indications and outcomes) found that laparoscopic radiofrequency ablation can safely and effectively treat breast hepatic metastasis, and concluded that patients, selected for their unusual presentation of liver-exclusive disease, may benefit from cytoreduction of their tumor by L-RFA when other treatment methods have failed.

[new] Liver Metastases: Surgery = Increased Survival
Finally, recent evidence suggests that even in patients with multiple or bilobar metastases, hepatectomy may offer longer survival, with neither the operative procedure nor the size of the surgical margin having any influence on post-hepatectomy survival, with an increased survival benefit from by repeat hepatectomy for recurrent hepatic metastases (Hirai et al., Hepatogastroenterology (2006): Surgical management for metastatic liver tumors); in addition, preoperative portal embolization extended the indication for hepatectomy and provided postoperative safety. This is also supported by the french research team of Rene Adam and colleagues (Ann Surg (2006): Is Liver Resection Justified for Patients With Hepatic Metastases From Breast Cancer?) who found that hepatic resection is safe and may provide a significant survival benefit over medical therapy alone for patients with breast cancer liver metastases, and concluded that favorable outcomes can be achieved even in patients with medically controlled or surgically resectable extrahepatic disease, thus suggesting that hepatic resection surgery should be considered more frequently in the multidisciplinary care of patients with liver metastases from breast cancer.

For an overview presentation (pdf version of Powerpoint slides) of various ablation interventions for breast cancer, see American College of Surgeons, 33rd Annual Spring Meeting (2005): Ablative Options for Breast Cancer [pdf] and for a comparable presentation on surgical interventions, see S. Curely, American College of Surgeons, 33rd Annual Spring Meeting (2005): Surgical Treatment of Breast cancer Liver Metastases [pdf].

New Hope and Options for Breast Cancer Liver Metastasis
Using 5-FU Prodrugs: S-1 and Gemcitabine
A new anticancer drup, S-1, which is an oral fluoropyrimidine derivative, has been used predominantly in Japan, along with some scattered use alos in Europe, with some promising success for breast cancer liver metastasis. However, S-1 is not currently available in the US or Canada.

However, Breast Cancer Watch notes that is a prodrug of 5-fluorouracil (5-FU) a well-established agent with demonstrated antitumor activity against epithelial malignancies arising in the gastrointestinal tract (especially CRC - colorectal cancer) and breast as well as the head and neck. 5-FU itself has been used in breast cancer liver metastasis setting by German researchers Loibi et al. (ASCO (American Society of Clinical Oncology) Annual Meeting (2003): Mitomycin-C, folinic acid, 5-FU (Mi-Fo-Fu) as salvage chemotherapy for hepatic failure due to liver metastases in breast cancer) who found that Mi-Fo-Fu (Mitomycin C 8mg/m2 on day 1, 5-Fluorouracil (5-FU) 750mg/m2 and Folinate 300mg/m2 on day 1and 2 every four weeks) could control the disease in 40% of the patients, was a tolerable regimen and therefore a therapeutic option for heavily pretreated patients with liver metastasis and impaired liver function.

And it is therefore of interest to further note that there are two other prodrugs of 5-FU that are increasingly deployed in MBC (metastatic breast cancer) settings, namely capecitabine (Xeloda) and gemcitabine (Gemzar). And as one would perhaps expect, both of these agents have been found of potential benefit in breast cancer liver metastasis (see Martino & Martino, Oncologist (2002): Clinical Studies of Three Oral Prodrugs of 5-Fluorouracil (Capecitabine, UFT, S-1): A Review). And Modi et al. at Memorial Sloan-kettering Cancer Center (Clin Breast Cancer (2005): A Phase II Trial of Gemcitabine in Patients with Metastatic Breast Cancer Previously Treated with an Anthracycline and Taxane) found that gemcitabine was active and well tolerated as monotherapy given (800 mg/m2 on days 1, 8, and 15 of a 28-day cycle) in heavily pretreated patients with MBC, including a patient with liver metastasis, after anthracyclines and taxanes.

New more experimental options are being aggressively pursued: Max Sung at Mt. Sinai Medical Center in New York is conducted a clinical trial (Clinical Trials (2006): Biological Therapy in Treating Women With Breast Cancer That Has Spread to the Liver) evaluating biological therapy using a gene-modified virus that can make interleukin-12. And Steven A Curley, S Eva Singletary, Jean-Nicolas Vauthey and other members of the Department of Surgical Oncology at the M.D. Anderson Cancer Center are pursuing still other interventions for breast cancer liver metastasis (see their Radiofrequency Ablation of Malignant Liver Tumors).

New Hope and Options for Breast Cancer Liver Metastasis:
TACE (Transcatheter Arterial Chemoembolization)

Now although we know that cytotoxic chemotherapy can result in regression of tumor lesions and a decrease in symptoms in liver metastases from breast cancer (BCLM), another viable optiuon is transcatheter arterial chemoembolization (TACE).

TACE is most frequently performed by intra-arterially injecting an infusion of antineoplastic agents mixed with iodized oil (Lipiodol) in order to treat of large hepatocellular carcinoma (HCC) tumors, with the goal to renders the tumor ischemic, depriving it of nutrients and oxygen. The foundation for this TACE approach is that although liver cells normally receive approximately 60% of the blood from the portal vein and 40% from the hepatic arteries, in liver tumors over 95% of the blood supplied to a tumor in the liver comes from the hepatic arteries. Thus, by injecting substances that occlude, or block the hepatic arterial blood supply to a tumor, it is possible to kill portions of the tumor by "starving" it of its oxygen and nutrient supply. Additionally, by adding chemotherapy (CT) drugs to the mixture - by intra-arterially injection of an infusion of CT agents - that blocks the blood vessels, it is possible to deliver a high dose of chemotherapy drug directly into the tumor. Potential advantages of this are that a higher dose of CT agent(s) is placed into the tumor, with the drug residing in the tumor for a longer period because of the decreased blood flow, and in addition, the side effects of the chemotherapy drugs are reduced because more of the CT agent remains in the liver tumor.

Overall, mixed metastatic lesions treated with chemoembolization are associated with a 60%–75% objective response rate and median patient survival times of 8–11 months (J Vasc Interv Radiol (2006): Society of Interventional Radiology Position Statement on Chemoembolization of Hepatic Malignancies). And Li et al. (World J Gastroenterol (2005): Treatment for liver metastases from breast cancer: results and prognostic factors) found that TACE treatment of liver metastases from breast cancer may prolong survival in certain patients, with response and survival rates significantly better in TACE group than in chemotherapy group, offering new promise for the curative treatment of the patients with metastatic breast cancer (MBC), and although they further found that variables significantly associated with survival were the lymph node status of the primary cancer, the clinical stage of liver metastases, the Child-Pugh grade, loss of weight, with no reference to hormone receptor status, this appears to be in error: see the commentary of Altundag et al. (World J Gastroenterol (2005): Hormone receptor status of primary tumor as a prognostic factor in patients with liver metastases from breast cancer treated with transcatheter arterial chemoembolization) which suggests that survival in patients with positive hormone receptor status is significantly better than in those with negative hormone receptor status. (See alsoGiroux et al., J Vasc Interv Radiol (2004): Chemoembolization of Liver Metastasis from Breast Carcinoma).

New Hope and Options for Breast Cancer Liver Metastasis:
LITT (Laser-induced Interstitial Thermotherapy)
Laser-induced interstitial thermotherapy (LITT) uses lasers to induce hyperthermia in interstitial (between organ) areas of the body near a tumor, with the consequent heat increases tumor temperature, thereby achieving (partial) cytoreduction, and hence damaging, or wholly destroying the contained cancer cells.

Such magnetic resonance (MR) imaging-guided LITT yields high local tumor control and survival rates for patients with liver metastases from breast cancer: Mack et al. (Radiology (2004): Breast cancer metastases in liver: laser-induced interstitial thermotherapy--local tumor control rate and survival data) in their prospective trial found that breast cancer patients with liver metastasis treated with LITT had a mean survival rate of 4.9 years from the date of diagnosis of the metastases treated with LITT, or 4.2 years after the first LITT treatment, and median survival in general was 4.3 years, with a remarkable 96% survival at one year, 80% at two years, 63% at three years, and 41% at five years; and as they correctly observe, LITT is both less expensive and considerably less invasive than surgery, easily performed with local anesthesia in an outpatient setting with low complication rates, and moreover does not preclude the simultaneous or subsequent use of other therapies like endocrine therapy and/or chemotherapy. Nor did the presence or absence of bone metastases significantly impact survival.

New Findings on AIs and Bone/Joint Symptoms
Women with AI-induced joint symptoms may have lowered vitamin D levels and vitamin D supplementation improved some of these joint symptoms: Rastelli et al. (27th San Antonio Breast Cancer Symposium (SABCS), December (2004): Incidence of 25-OH vitamin D deficiency in patients with a history of breast cancer who have musculoskeletal symptomatology) found a high proportion of symptomatic patients have inadequate vitamin D levels, suggesting the importance of assessing vitamin D levels to reduce musculoskeletal morbidities. Vitamin D deficiency induces osteomalacia, a disorder associated with musculoskeletal pain and stiffness, secondary hyperparathyroidism, bone loss, osteopenia, osteoperosis, and increased risk of fracture. Note furthermore in this connection that vitamin D utilizes the cytochrome P450 enzyme system. Therefore breast cancer populations confront multiple etiologies for bone disorders: (1) vitamin D deficiency, (2) premature menopause and low levels of circulating estrogen, and (3) by possible increased vitamin D requirements from prescribed drugs via inhibition of isoforms of the the cytochrome P450 enzyme system.

In addition, although in the ATAC trial (see below) arthralgia was significantly higher in anastrozole-treated patients: 35.6% of patients on anastrozole as opposed to 29.4% of patients on tamoxifen at the 68-month followup, most arthralgia incidences occurred early in both treatment arms (75% in the first 33 months) and were primarily mild to moderate in intensity. In essential agreement, Dr. Michael Baum pointed out (Patterns of Care in Medical Oncology (2005): Adjuvant Systemic Therapy) that as patients come off anastrozole, the fracture rate returns to that of patients on tamoxifen, and more reassuringly still, so far no difference has occurred in fractures of the neck or hip, of the greatest concern (and Dr. Chlebowski observes is no difference in hip fractures after 68 months with anastrozole and tamoxifen), the latter in particular given associated high rates of morbidity and mortality.

As to bone loss reversal, Dr. Michael Gnant, investigator of the ABCSG-12 trial, reported that the researchers found (Patterns of Care in Medical Oncology (2005): Adjuvant Systemic Therapy) that although a significant bone loss occurs (close to 15 percent on the average) in premenopausal women treated with endocrine therapy with goserelin and with tamoxifen or anastrozole, the bone loss could be prevented completely with zoledronic acid (Zometa) given twice a year (Gnant et al., 27th San Antonio Breast Cancer Symposium (SABCS), December (2004): Zoledronic acid effectively counteracts cancer treatment induced bone loss (CTIBL) in premenopausal breast cancer patients receiving adjuvant endocrine treatment with goserelin plus anastrozole versus goserelin plus tamoxifen - bone density subprotocol results of a randomized multicenter trial); and in keeping with the findings of Brufsky et al. (27th San Antonio Breast Cancer Symposium (SABCS), December (2004): Zoledronic acid (ZA) for prevention of cancer treatment-induced bone loss (CTIBL) in postmenopausal women (PMW) with early breast cancer (BCa) receiving adjuvant Letrozole (Let): Preliminary results of the Z-FAST trial) that at 6 months, AI-induced bone loss as indicated in a decrease in BMD (bone mineral density) was prevented by upfront zoledronic acid.




Breast Cancer Watch Warning:
Bisphosphonates and Jaw Osteonecrosis
There have been questions raised concerning the renal safety of long-term bisphosphonate use and a recent study of Guarneri et al. (Oncologist (2005): Renal Safety and Efficacy of i.v. Bisphosphonates in Patients with Skeletal Metastases Treated for up to 10 Years) is reassuring: they found that renal function is maintained in patients receiving multiple cytotoxic therapies along with prolonged treatment administration of bisphosphonates; however, there appears to be increased incidence of osteonecrosis of the jaw (ONJ) with prolonged bisphosphonate administration. Bamias et al. (J Clin Oncol (2005): Osteonecrosis of the Jaw in Cancer After Treatment With Bisphosphonates: Incidence and Risk Factors) found that the incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months, with the cumulative hazard significantly higher with zoledronic acid (Zometa) compared with pamidronate (Aredia) alone or pamidronate and zoledronic acid sequentially.

And Guarneri et al. (cited above) found that jaw osteonecrosis occurred in 5% of the study population, although they correctly note that a causal relationship between bisphosphonate therapy and jaw osteonecrosis has not to date been proven. Previous dental procedures may be a precipitating factor, and it may be prudent that such at-risk patients might also receive appropriate prophylactic attention to maintain oral health, including careful assessment of dental status, and exercising extra precautions when carrying out dental surgery procedures in patients on bisphosphonate therapy, such as strict aseptic techniques, performing atraumatic surgery, and achieving primary wound closure when possible (Guarneri et al., cited above). See Ficara et al., J Clin Periodontol (2005): Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment who also found that jaw osteonecrosis appears to be associated with the intravenous use of bisphosphonates, with all affected patients showing a history of extraction of periodontally hopeless teeth preceding the onset of osteonecrosis, and with duration of bisphosphonate therapy at presentation ranged from 10 to 70 months. But although a large proportion of cases are associated with tooth extractions (approx. 70%), some affected patients have no history of dental manipulation. And Migliorati et al. (Cancer (2005): Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone) confirmed this association, while finding that the most common clinical presentations of osteonecrosis were infection and necrotic bone in the mandible, with associated events included dental extractions, infection, and trauma, although we note that here too two patients are reported to have developed disease spontaneously, without any clinical or radiographic evidence of local pathology. See also Schirmer et al. (Mund Kiefer Gesichtschir (2005): Bisphosphonates and osteonecrosis of the jaw [in German]) and Markiewicz et al., J Am Dent Assoc (2005): Bisphosphonate-associated osteonecrosis of the jaws: A review of current knowledge).

Furthermore, researchers at the Tel Aviv Sourasky Medical Center (Shlomi et al., Harefuah (2005): Avascular necrosis of the jaw bone after bisphosphonate therapy [in Hebrew]) found that maxillary and mandibular osteonecrotic foci accompanied by pain, inconvenience and purulent exudates in patients who were taking pamidronate, zoledronate or alendronate; affected patients were all treated under the osteomyelitis protocol, with variable response to therapy: several weeks to many months, with some cases requiring repeat surgical intervention (curettage or sequestrectomy). Interestingly, the Israeli researchers note that all affected patients also had a recent dental extraction. Typical presenting lesions are either a nonhealing extraction socket or an exposed jawbone, refractory to conservative debridgement and antibiotic therapy (Ruggiero et al., J Oral Maxillofac Surg (2004): Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases). And Lenz et al. (J Craniomaxillofac Surg (2005): Does avascular necrosis of the jaws in cancer patients only occur following treatment with bisphosphonates?) have confirmed ONJ associated with the still another bisphosphonate, ibandronate (Boniva) so it would now appear that all bisphosphonates as a class share this same adverse propensity.

Breast Cancer Watch notes that prior to these findings, it was thought that the association was restricted to IV-administered bisphosphonates like zoledronic acid and pamidronate, but it now appears that alendronate (Fosamax) exhibits similar adverse potential for maxillary / mandibular / jaw osteonecrosis. And Breast Cancer Watch has found reports suggesting that the problem may extend to other oral bisphosphonates like risedronate (Actonel): see Carter et al. (Med J Aust (2005): Bisphosphonates and avascular necrosis of the jaw: a possible association), and Purcell & Boyd (Med J Aust (2005): Bisphosphonates and osteonecrosis of the jaw) reporting the records of the Adverse Drug Reactions Advisory Committee (ADRAC) in Australia, involving a total of 129 reported cases, with seven implicating oral alendronate (Fosamax) or risedronate (Actonel).

Presenting symptoms included localized pain, numbness and altered sensation, exposed bone in the oral cavity, soft tissue infection, loosening of several teeth, and a dental abscess after radiotherapy, with all reports describing the osteonecrosis as occurring in the jaw, four specifically in the mandible, and two in the maxilla. There is currently no wholly effective treatment for the condition, and it is therefore advised (Purcell & Boyd, above) that when intravenous or high-dose oral bisphosphonates are administered, it may be prudent to refer patients for full dental assessment and treatment before the start of therapy and once bisphosphonate therapy has begun, there should be regular clinical monitoring of oral health. They further note that avoiding tooth removal and dental implants, non-surgical control of periodontal disease, and use of soft liners on dentures also seem prudent, and major debridgement surgeries should be avoided if at all possible. In established cases of osteonecrosis, the primary goals are palliation and control of osteomyelitis. In most cases, progression can be controlled with long-term or intermittent courses of dicloxacillin or cephalexin for the treatment of any secondary infection, chlorhexidine mouthwash (Peridex, Corsodyl, Savacol), and periodic minor debridgement of soft-textured sequestrating bone and wound irrigation.

And Wooltortan (CMAJ (2005): Patients receiving intravenous bisphosphonates should avoid invasive dental procedures) summarizes the major recommendations in this connection: "Patients who are to receive intravenous bisphosphonates should be warned of this potential effect. If time permits before the drug therapy is initiated, a dental examination may detect and allow treatment of tooth or gum problems that could predispose a patient to osteonecrosis. Proper denture fit should be ensured and good dental hygiene reinforced. The oral hard and soft tissues of patients taking these drugs should be examined every 3 months or so. Invasive procedures that may require bone to heal, such as tooth extractions and bone biopsies, should be avoided if possible. When dental surgery is required, it is uncertain whether cessation of bisphosphonate therapy decreases the risk of necrosis. Prompt referral to a dentist or oral maxillofacial surgeon is recommended for patients with facial symptoms of osteonecrosis, although surgery in the affected area may exacerbate or prolong the condition. Conservative management includes culturing any lesions and using antibiotics as appropriate, and recommending an antiseptic oral rinse that contains chlorhexidine gluconate", although they note that unfortunately, some affected patients may ultimately require the resection of portions of their jaw.

Note that this side effect had not been detected in the clinical trials carried out prior to marketing of IV-administered bisphosphonates, and it was not until September 2004 when the manufacturer Novartis, confronted with an increasing number of adverse reports and the FDA issued a warning communication and modified the recommendations for use of Zometa and Aredia, including osteonecrosis among the potential side effects (under “Postmarketing experience” and “Precautions for use”), with studies initiated to explore the relationship between bisphosphonate therapy and osteonecrosis (Jimenez-Soriano & Bagan, Med Oral Patol Oral Cir Bucal (2005): Bisphosphonates, as a new cause of drug-induced jaw osteonecrosis: an update (pdf) [in Spanish and English]). Unfortunately, no comparable warning or modification of recommendations has been issued for the oral bisphosphonates that Breast Cancer Watch believes are now also implicated. The FDA also issued a "Dear Dentist Letter" in conjunction with Novartis (Novartis Pharmaceuticals Co (May 5, 2005): Important drug precaution for dental health professionals with patients being treated for cancer [letter to dentists]. Rockville (MD): US Food and Drug Administration [pdf]) recommending that recommends that "cancer patients receive a dental examination prior to initiating therapy with intravenous bisphosphonates (Aredia and Zometa), and avoid invasive dental procedures while receiving bisphosphonate treatment. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition". However, Breast Cancer Watch notes that this warning is in error, as it (1) it is incorrectly narrowly constrained to cancer patients (on the weight of the research we cite above, incidence includes cases outside the oncology sphere), and (2) it is incorrectly narrowly constrained to intravenous bisphosphonates, but on the weight of the research cited above, incidence with oral bisphosphonates is attested, and although to date only with the oral agents alendronate (Fosamax) and risedronate (Actonel), Breast Cancer Watch has no reason to believe that the potential for comparable adverse events does not also apply to other oral bisphosphonates.

Breast Cancer Watch Practice Guideline
Therefore, until evidence to the contrary arises, patients should be advised and warned of the potential for all bisphosphonates, both in the normal osteoporotic therapy setting, and in the oncology setting, to lead to jaw osteonecrosis, and that furthermore, all at-risk patients using bisphosphonates receive prophylactic attention for the maintenance of optimal oral health, including regular clinical assessment of dental status and oral health, with observed extra precautions under dental surgery procedures (including but not limited to strict aseptic techniques and atraumatic surgery if feasible, avoidance wherever possible of tooth removal and dental implants and major debridgement surgeries, and non-surgical periodontal disease control, antiseptic oral rinse with chlorhexidine-based mouthwash, among other appropriate precautions and interventions. Finally, as Wooltortan, and the advice of the official guidelines, note it is uncertain whether discontinuation would ameliorate ONJ symptomology, although most observers have failed to see a benefit on termination; however, since bisphosphonates become part of the bone matrix and therefore have long-term residency of months to possible years, then (1) it is unlikely that discontinuation could benefit ONJ symptoms at least in the short term, although we don't know whether it may ultimately either benefit or at least not advance the condition in the long term as no trials have studied this possibility; (2) the effects or benefit of substitution, rather than termination, of the bisphosphonate, optimally with a non-nitrogen-containing bisphosphonate like clodronate (Bonefos) although presently unknown is, on the weight of our current understanding of the condition, unlikely to be detrimental.

See also Zarychanski et al. (Am J Hematol (2006): Osteonecrosis of the jaw associated with pamidronate therapy) who observed that discontinuation of pamidronate therapy has not helped reverse the presence of osteonecrosis, and surgical manipulation of the involved site appears to worsen the underlying bone pathology); also Badros et al. (J Clin Oncol (2006): Osteonecrosis of the Jaw in Multiple Myeloma Patients: Clinical Features and Risk Factors) who conclude that trials addressing the benefits/risks of continuing bisphosphonate therapy are needed. However, against this Farrugia et al. (Laryngscope (2006): Osteonecrosis of the Mandible or Maxilla Associated with the use of New Generation Bisphosphonates) who conclude that "most patients can be treated with conservative surgical debridgement and cessation of bisphosphonate therapy, whereas a few may require radical surgical intervention". Note also that although exact figures are not known, Abu-ld et al. (Mund Kiefer Gesichtschir (2006): Bisphosphonate-associated osteonecrosis of the jaw [in German]) have estimated that the incidence in cancer patients with pamidronate and zoledronate therapy is 4%–10%.

New Clues
(1) Ardine et al. (Ann Oncol (2006): Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw?) who speculate that hypocalcemic coupled with elevated PTH serum levels may be a predisposing factor for ONJ in MBC patients).
(2) Hansen et al. (J Oral Pathol Med (2006): Osteonecrosis of the jaws in patients treated with bisphosphonates – histomorphologic analysis in comparison with infected osteoradionecrosis) examined the histologic findings of ONJ cases, comparing to that of infected osteoradionecrosis (IORN), finding that in all cases, Actinomyces - a gram positive bacterium and frequently opportunistic pathogen, especially of the oral cavity, and often associated with IUD use - attached to the necrotic bone tissue. Indeed, Breast Cancer Watch, noting:

(1) the consistent association of ONJ and pathogens of the physiological flora of the oral cavity, especially Actinomyces, inducing aggressive infection in the bone, and
(2) the dramatic relief in symptomology secondary to local and systematic anti-bacterial therapy, with patients often becoming wholly asymptomatic,

now believes that we can no longer consider bisphoosphonates alone as causative of ONJ, but rather must acknowledge the joint role of oral pathogens in the complex pathogenesis of ONJ. In confirmation of this, Christine Dannemann of the Department of Cranio-Maxillofacial Surgery at the University Hospital of Zurich and her colleagues (Dannemann et al., Swiss Med Wkly (2006): Clinical experiences with bisphosphonate-induced osteochemonecrosis of the jaws [pdf]) who observed that even after successful surgery in some patients, dehiscence of the bone occurred subsequently, but patients became asymptomatic after undergoing anti-bacterial therapy, consisting of both antibiotics and anti-bacterial rinsing, which also suggests a potential role for antibiotic prophylaxis if any invasive dental treatment is necessitated during bisphosphonate therapy.

Breast Cancer Watch has investigated this further and notes:
(1) that penicillin and clindamycin are the mainstay of treatment, yet Zarychanski et al. (above) observed that treatment with an extended course of clindamycin at any rate conferred no clinical benefit, although penicillin (and perhaps also doxycycline) may still be effective; and
(2) oral rinsing with chlorhexidine (Peridex, Corsodyl, Savacol) even at a relatively low concentration is effective: see Young et al. (Clin Oral Implants Res (2002): The effects of an immediately pre-surgical chlorhexidine oral rinse on the bacterial contaminants of bone debris collected during dental implant surgery) using 0.1% chlorhexidine digluconate mouthrinse. Note that in the case reports of Pastor-Zuazaga et al. (Med Oral Patol Oral Cir Bucal (2006): Osteonecrosis of the jaws and bisphosphonates. Report of three cases [pdf]) the authors used a combination of antibiotic therapy (amoxicilline, clarythromycin, with possible alternative use of penicillin or erythromycin, and both chlorhexidine gel and rinse application, to achieve favorable evolution, with some limited debridgement as needed, providing significant pain relief and at least partial healing. And these researchers, against the customary advice of many others and most major promulgated guidelines, stand in agreement with R Marx (J Oral Maxillofac Surg (2005):Bisphosphonate-Induced Exposed Bone (Osteonecrosis/Osteopetrosis) of the Jaws: Risk Factors, Recognition, Prevention, and Treatment) and (J Oral Maxillofac Surg (2003): Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic) agree with RE Marx's recommendation of a two months interruption of bisphosphonates. And note that Marx has found that who concluded that effective control to a pain free state without resolution of the exposed bone is 90.1% effective using a regimen of antibiotics along with 0.12% chlorohexidine antiseptic mouth.

And Breast Cancer Watch has further discovered that two non-prescription agents are also active and effective against various forms of orally resident Actinomyces:
(i) a baking soda toothpaste (see Zambon et al. (Compend Contin Educ Dent Suppl (1996): A microbiological and clinical study of the safety and efficacy of baking-soda dentifrices) who found that both a dentifrice containing 52% baking soda and 3% sodium percarbonate (Arm & Hammer PeroxiCare) as well as another dentifrice containing 65% baking soda (Arm & Hammer Dental Care) resulted in statistically significant reductions in the levels of Actinomyces species); and
(ii) the antimicrobial mouth rinse Listerine completely eradicated a broad spectrum of oral microorganisms in 10 to 30 seconds, including Actinomyces viscosus (as well as methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, and even Candida albicans, among many others), and may even be effective in providing some significant analgesia, probably the investigators speculated, due to a decrease in oral bacteria by the antimicrobial action of Listerine, leading to lowering the inflammatory response of the host (Okuda et al., Bull Tokyo Dent Coll (1998): The efficacy of antimicrobial mouth rinses in oral health care).

Breast Cancer Watch also observes that to date all instances of ONJ have been associated with third generation nitrogen-containing bisphosphonates (such as pamidronate (Aredia), zoledronic acid (Zometa), ibandronate (Boniva), alendronate, risedronate (Actonel)), with no documented incidence of ONJ associated with non-nitrogen-containing bisphosphonates (no nitrogen ring) such as clodronate (Bonefos) and etidronate (Didronel).

Breast Cancer Watch further notes that etidronate is effective only in vertebral, but not in nonvertebral bone activity and fracture, which to our mind both severely limits and deprecates its value as a non-ONJ-promoting bisphosphonate, in contrast to clodronate with activity in both vertebral and nonvertebral domains. Therefore, one viable alternative to the ONJ-promoting bisphosphonates that effectively obviates the issue is deployment of clodronate (Bonefos), although clodronate is to date only available in Canada and Europe.

---

Breast Cancer Watch finally urges all oncology and oral health professionals, as well as patients now or to be on bisphosphonate therapy to consult the just released guidance:

Practical Guidelines for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaw in
Patients With Cancer
[click to download as PDF]

developed by a panel of experts representing oral and maxillofacial surgery, oral medicine, endocrinology, and medical oncology, provding clinical guidelines for the prevention, early diagnosis, and multidisciplinary treatment of ONJ in patients with cancer.

Also just released is the Position Paper on BON (bisphosphonate-associated osteonecrosis, aka OJN) from the American Academy of Oral Medicine in association with the American Dental Association (ADA):

Migliorati et al., J Am Dent Assoc (2006): Managing the care of patients with bisphosphonate-associated osteonecrosis - An American Academy of Oral Medicine position paper
[click to downlaod as PDF]

Trials of AIs in Early Breast Cancer

• ATAC
  The double-blinded ATAC (Arimidex, Tamoxifen Alone or in Combination) trial compared anastrozole therapy with tamoxifen therapy, and with the combination of tamoxifen plus anastrozole over 5 years in 9366 women, with two findings reporting, first at a median follow-up of 33.3 months and more recently at 68 months. The first reporting found improved disease-free survival with anastrozole, but evidenced no difference between combination therapy and tamoxifen alone (Baum et al., Lancet (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial). At the final analysis, Anastrozole maintained its advantage in disease-free survival (Cuzick et al., Lancet (2005): Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer). The FDA has, on the basis of the results of the ATAC trial, approved anastrozole for the adjuvant treatment of hormone receptor-positive breast cancer (HRP-BC) in postmenopausal women.
  
  Breast Cancer Watch Commentary: ATAC
  Three points concerning the ATAC findings however should be noted: (1) the disease-free survival curves for tamoxifen and anastrozole do not significantly diverge before the third year of therapy, with only a 1.7% absolute difference in disease recurrence, (2) after a median follow-up period of 47 months, anastrozole showed statistically significant benefits over tamoxifen in all efficacy endpoints that were compared: DFS (disease-free survival), TTR (time to recurrence), and CLBC (incidence of contralateral breast cancer), along with a favorable tolerability profile, but distant disease-free survival between the two arms is not evidenced as significant until the final 68-month report, (3) toxicity experience to date found fewer endometrial carcinomas, thromboembolic events, and menopausal adverse events (hot flashes and vaginal symptoms) with anastrozole over tamoxifen, (4) nonetheless, to date no analysis has demonstrated convincingly any difference between anastrozole and tamoxifen in overall survival. However, even if further trials fail to demonstrate a decisive efficacy superiority of anastrozole compared with tamoxifen, it is nonetheless the case that anastrozole appears to have the more favorable toxicity profile for better overall long-term outcomes.
  
  Dowsett (San Antonio Breast Cancer Symposium (2003):Analysis of time to recurrence in the ATAC (Arimidex, tamoxifen, alone or in combination) trial according to estrogen receptor and progesterone receptor status) on behalf of the ATAC Trialists' Group reported on a retrospective evaluation of the ATAC Trial conducted to ascertain whether PR status influences the relative benefit of anastrozole versus tamoxifen, given that in tamoxifen-treated patients previous adjuvant studies have found PR status to be prognostic. The retrospective analysis examined time to recurrence in the four possible receptor subgroups: ER positive, ER negative, PR positive, and PR negative, finding that although anastrozole is moderately more effective than tamoxifen in patients whose breast tumors are both ER+/PR+ (18% reduction in relative risk of relapse after adjustment), the drug's advantages become far more pronounced in disease that is ER+ but PR- (52% reduction).
  
  On the weight of these considerations, the current NCCN (National Comprehensive Cancer Network) guidelines (v.2.2005 at the time of this writing) have been revised (NCCN (2005): Practice Guidelines in Oncology - v.2.2005: Breast Cancer [pdf]) concerning ET (endocrine therapy) of postmenopausal women with early breast cancer, now allowing for the use of an aromatase inhibitor as either initial adjuvant therapy, sequential with tamoxifen, or as extended therapy in those situations where ET is to be utilized, further noting that in postmenopausal women, the use of tamoxifen alone for 5 years should be limited to those who decline or who have a contraindication to aromatase inhibitors. (AIs of course are not active in women with functioning ovaries, and AI use in premenopausal women should be deployed only in the clinical trial setting).
  
  
• BIG 01-98
  BIG 01-98 (Breast International Group) trial (Thurlimann, BIG 1-98 Collaborative Group (2005): Letrozole vs tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor positive breast cancer. BIG 1-98: a prospective randomized double-blind phase III study. Proceedings of the St Gallen Primary Therapy of Early Breast Cancer 2005 [pdf]) accrued 8028 women, randomly assigned to receive tamoxifen for 5 years, letrozole for 5 years, or alternate sequencing of the two agents. The first analysis reported at a median follow-up of 25.8 months, revealing only the letrozole versus tamoxifen results of 91.2% v 89.3%( P = 0.004) disease-free survival, with no difference in overall survival.
  Breast Cancer Watch Commentary: BIG
  One needs to be aware of the rather unexpected finding in the BIG study of increased deaths in the letrozole arm from myocardial infarction (3.6 percent in patients on letrozole versus 2.5 percent in patients on tamoxifen, 26 versus 13 myocardial deaths, respectively). Further (pending) studies are needed to clarify any essential differences between the major aromatase inhibitors with respect to adverse cardiovascular disease.
  
  
• ABCSG-8 & ARNO-95
  Both the ABCSG-8 (Austrian Breast Cancer Study Group) and the ARNO-95 (German Adjuvant Breast Cancer Group) trials assessed a switch to anastrozole after 2 years of adjuvant tamoxifen therapy chemotherapy-naive women (all hormone-receptor-positive). Recurrence-free survival favored the switch to anastrozole (95.2% v 92.8% (P < 0.0018) in a combined analysis (Jakesz et al., San Antonio Breast Cancer Symposium (2004): Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: Combined results from 3,123 women enrolled in the ABCSG Trial 8 and the ARNO 95 Trial) of 3224 women with a median follow-up of 28 months.
  Breast Cancer Watch Commentary: ABC/ARNO
  It should be noted that despite 26% of the patients having positive axillary nodes, no adjuvant chemotherapy was given, for reasons unclear to this researcher.
  
  
• ITA
  In another switching trial (Boccardo et al, San Antonio Breast Cancer Symposium (2003): Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment), the ITA trial (Italian Trial of Anastrozole), 426 postmenopausal patients with early breast cancer node-positive disease were randomly assigned after 2 years of tamoxifen therapy to either continue taking tamoxifen or switch to anastrozole for a total of 5 years of therapy. event-free survival favored anastrozole at a median follow-up of 24 months (95.2% v 88.1% (P = 0.006)). Recently, the trial reported (Boccardo et al., J Clin Oncol (2005): Switching to Anastrozole Versus Continued Tamoxifen Treatment of Early Breast Cancer: Preliminary Results of the Italian Tamoxifen Anastrozole Trial) at a median follow-up of 36 months, finding that disease-free and local recurrence-free survival were significantly longer in the anastrozole group, and although overall, more adverse events were recorded in the anastrozole group than in the tamoxifen group, more events were life threatening or required hospitalization in the tamoxifen group than in the anastrozole group.
  
  
• IES
  In the International Exemestane Study (IES) trial (Coombes et al. N Engl J Med (2004): A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer), 4742 patients were randomly allocated to receive either exemestane or tamoxifen after 2–3 years of adjuvant tamoxifen therapy. Patients receiving exemestane showed a 4.7% absolute benefit in disease-free survival (92.3% v 88.8% (P = 0.001) at a median follow-up of 30.6 months, and incidence of contralateral, endometrial and other primary cancers was also lower in the exemestane group, although there was no difference in overall survival.
  
  
• MA-17
  The MA-17 trial (Goss et al, N Engl J Med (2003): A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer) was coordinated by NCICCG (the National Cancer Institute of Canada Clinical Trials Group) and randomly allocated 5187 women who had completed 4.5–6 years of adjuvant tamoxifen therapy to receive either letrozole or placebo for 5 more years. Two reportings have been made, one at a median follow-up of 26.8 months, and another at 2.5 years (Goss et al., Proc Am Soc Clin Oncol (2004): Updated analysis of the NCIC CTG MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer), the first showing a statistically significant difference in disease-free survival favoring letrozole, this advantage in disease-free survival being maintained in the longer term (96.4% v 94.0% (P = 0.0004)). Although an intention-to-treat analysis showed no survival benefit, there was a statistically significant survival advantage in the node-positive subgroup: the calculated reduction in recurrence risk or new breast cancer development in the letrozole group was 43% less than that in the placebo (highly statistically significant).
  
  
• Breast Cancer Watch Commentary: Switching
  Although the ATAC, ITA and IES trials all demonstrated a clear and consistent improvement in disease-free survival among women who received an aromatase inhibitor (as opposed to those randomized to a control arm or not receiving an aromatase inhibitor, only the MA-17 demonstrated a survival advantage conferred by an aromatase inhibitor to node-positive patients; MA-17 found:
  (1) a 39% (statistically significant) mortality reduction for letrozole compared with placebo in postmenopausal women with early breast cancer;
  (2) a 40% reduction in risk of distant metastases;
  (3) and a 43% reduction in risk of overall recurrence and local recurrence.
  In addition, these findings suggest that a reduction from 5 years of tamoxifen therapy to 2 or 3 years may minimize the increase in blood clotting disorders associated with tamoxifen. (See also Pritchard's editorial (J Clin Oncol (2005): Aromatase Inhibitors in Adjuvant Therapy of Breast Cancer: Before, Instead of, or Beyond Tamoxifen)
  
  
• Optimal Sequencing of Tamoxifen and AIs
  In an interview Dr Rowan T Chlebowski observed (Patterns of Care in Medical Oncology (2005): Adjuvant Systemic Therapy) that when beginning with tamoxifen, more patients will have relapsed after two and a half, three or five years, than on an aromatase inhibitor, and a substantial number of those patients may be irretrievable - that is,have incurable disease - so in a sense the oncologist is banking on being able to capture more patients later, but there is no real data for such an assumption. In his opinion, there is no reason not to start with the most effective therapy, namely an aromatase inhibitor followed by tamoxifen or a nonsteroidal aromatase inhibitor alone. In essential agreement with this, Dr. Maura N Dickler (Patterns of Care in Medical Oncology (2005): Adjuvant Systemic Therapy) noted that in breast cancer, the highest risk of recurrence is typically within the first two to three years post-surgery so that if tamoxifen id deployed first, patients are not only lost to an early breast cancer recurrence in the first two to three years, but also some women are lost to tamoxifen-induced adverse events. Her clinical practice therefore is to offer anastrozole (Arimidex) to the majority of postmenopausal patients with receptor-positive tumors after surgery and chemotherapy, and if the patient has already been on two to three years of tamoxifen, consideration is made of switching them to an aromatase inhibitor, with letrozole (Femara) being considered at the end of five years of tamoxifen. This sentiment is shared by Dr. Baum (Patterns of Care in Medical Oncology (2005): Adjuvant Systemic Therapy) of the ATAC Trialists' Group who also observes that the strongest argument for starting adjuvant endocrine therapy with an aromatase inhibitor is that anastrozole if one waits two to three years, although the effects are impressive, meanwhile lost are those patients who will relapse and ultimately die in those first two years.
  
  At present, as Dr. William J Gradishar has observed (Patterns of Care in Medical Oncology (2005): Adjuvant Systemic Therapy), the latest NCCN guidelines see selection of which aromatase inhibitor to be used as based on the design of the study, with anastrozole (Arimidex) for firstline therapy, exemestane (Aromasin) for those patients already on tamoxifen, and letrozole (Femara) after five years of tamoxifen.
  
  It is certainly the case that the 68-month follow-up of the ATAC Trial (ATAC Trialists' Group, Lancet (2005): Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer) suggests that it is inappropriate to wait five years to start an aromatase inhibitor: the higher rates of recurrence, especially in the first three years, and the increased numbers of adverse events and treatment withdrawals associated with tamoxifen lend support to the approach of offering the most effective and well-tolerated therapy at the earliest opportunity.
  
  Approved Indications of AIs:
  - Based on the ATAC trial, anastrozole (Arimidex) is approved as up-front therapy,
  
  - Based on the IES study, exemestane (Aromasin) is approved for cross-over treatment (or switching) in women who have already undergone 2 - 3 years of tamoxifen, and
  
  - Based on the MA.17 trial, letrozole (Femara) is approved in the extended adjuvant setting after 5 years of tamoxifen.
  
  Consensus
  The consensus of opinion, threfore, among leading oncologists appears to be that five years of anastrozole (Arimidex) should now be considered as the preferred initial adjuvant endocrine treatment for postmenopausal women with hormone receptor-positive localized breast cancer.
  
  However, one leading oncologist, Dr. Stephen E. Jones is somewhat in dissent, reasoning that the preliminary findings of the ABCSG Trial 8 [Austrian Breast and Colorectal Cancer Study Group] suggest that there weren't many events during the first 2 years, so that probably not much is lost by deploying a tamoxifen-first cross-over strategy, starting with tamoxifen which is less expensive -- and then switching to an AI. But Breast Cancer Watch notes that this view is at least in part economical, and while it is true as observed by Dr. Jones that aggregate number of events in the first 2 years is not absolutely high, nonetheless it is indisputable that there are higher rates of early breast cancer recurrence and that there will inevitably be in the first two to three years some non-trivial number of patients lost to either relapse or tamoxifen-induced adverse events, and that these are in the final analysis and in a very real sense, irretrievable on any tamoxifen-first strategy. Furthermore, if economic considerations argue against the high cost of AIs to the patient, Breast Cancer Watch still does not agree that this in itself agrues for a tamoxifen-first strategy, since as we have substantiated above, the antiestrogen fulvestrant (Faslodex) is at least as effective as tamoxifen and hence remains a viable and in many ways for the reasons we document, an attractive alternative. Thus, all in all, we don not find the perspective put forward by Dr. Jones compelling, and conclude, as above, that an AI (anastrozole) -first strategy of five years in duration should be currently regarded as the preferred initial adjuvant endocrine treatment for HR+ postmenopausal women with localized breast cancer.
  

  Chemotherapy (CT): State of the Art

  Common Classical Chemotherapy Regimens

• AC: doxorubicin + cyclophosphamide
  
• AC ---- > paclitaxel
  
• AFM: doxorubicin + (5-)fluorouracil + methotrexate
  
• CAF (FAC): cyclophosphamide + fluorouracil + doxorubicin
  
• CEF: cyclophosphamide +epirubicin + and (5-)fluorouracil
  
• CMF: cyclophosphamide + methotrexate + (5-)fluorouracil
  
• Doxorubicin ---- > CMF
  
• EC: epirubicin + cyclophosphamide
  
• FEC: (5-)fluorouracil+ epirubicin + cyclophosphamide
  
• TAC: docetaxel + doxorubicin + cyclophosphamide
  
  For a comprehensive list, see Chemotherapy Drugs - Acronyms.
  

  Optimal CT Regimens

• The Classical CMF Chemotherapy Regimen
  See our dedicated discussion at:
  Principles of Chemotherapy, Part 1:
  CMF - Optimal Deployment, Place in Current Chemotherapeutics
  
  Doxorubicin- vs Non-doxorubicin-based Chemotherapy
  The next development in adding precision to our knowledge of the efficacy of adjuvant chemotherapy regimens in the non-metastatic setting was head-on comparison of the CMF standard against anthracycline-containing regimens. The Early Breast Cancer Trialists' overview of polychemotherapy (Lancet (1998): Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group) has established that anthracycline-containing regimens were superior to CMF, with a 12% further reduction in the annual odds of recurrence and an 11% further reduction in the annual odds of death on the anthracycline-containing regimens, and on this basis, the panel issued the statement that anthracycline-containing regimens are preferred for node-positive patients.
  
  Dealing with Doxorubicin (Adriamycin) Induced Cardiotoxicity
  One widely noted clinical limitation with doxorubicin is induced cardiotoxicity. There are three viable ways to address this issue.
  (1) Epirubicin (at doses equivalent to doxorubicin) has been shown to be as efficacious as doxorubicin but less toxic than doxorubicin (Findlay & Walker-Dilks, Cancer Prev Control (1998): Epirubicin, alone or in combination chemotherapy, for metastatic breast cancer. Provincial Breast Cancer Disease Site Group and the Provincial Systemic Treatment Disease Site Group);
  
  (2) Use of dexrazoxane (Zinecard, Cardioxane), a cyclic derivative of the chelating agent EDTA: this cardioprotective agent has been demonstrated to reduce the risk of anthracycline-associated cardiotoxicity when given from first dose of anthracycline (Cvetkovic & Scott, Drugs (2005): Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy). And although a recent Cochrane Review (van Dalen et al., Cochrane Database Syst Rev (2005): Cardioprotective interventions for cancer patients receiving anthracyclines) expressed concern over some suggestion that patients treated with dexrazoxane might have a lower anti-tumour response rate, recent studies have not found any anti-tumor response compromise:
  so in a recent RCT dexrazoxane significantly reduced the occurrence and severity of anthracycline-induced cardiotoxicity even in patients at increased risk of cardiac dysfunction due to previous anthracycline treatment, yet without compromising the antitumor efficacy of the chemotherapeutic regimen (Marty et al., Ann Oncol (2006): Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane®) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy); similarly P Pouillart (Cancer Treat Rev (2004): Evaluating the role of dexrazoxane as a cardioprotectant in cancer patients receiving anthracyclines).
  
  (3) A recent study by Kim et al. (J Cardiovasc Pharmacol (2005): Modulation by Melatonin of the Cardiotoxic and Antitumor Activities of Adriamycin) have shown that given melatonin's oncolytic activity (on this see our discussion of melatonin on Breast Cancer Prevention Watch), the combination of adriamycin and melatonin improved the antitumor activity of adriamycin, as indicated by an increase in the number of long-term survivors as well as decreases in body-weight losses resulting from adriamycin treatment, suggesting that melatonin not only protects against adriamycin-induced cardiotoxicity but also enhances its antitumor activity and further suggesting that a melatonin and adriamycin combination represents a potentially useful regimen for the treatment of human neoplasms, by virtue of the fact that it allows the use of lower doses of adriamycin, thereby avoiding the toxic side effects associated with this drug. And the review of Mills et al. (J Pineal Res (2005): Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis) found that melatonin reduced the risk of death across a variety of cancer types (also confirmed by the animal study of Oz et al. (Mol Cell Biochem (2006): Prevention of doxorubicin-induced cardiotoxicity by melatonin).
  
  (4) A fourth agent that can potentially be used to address doxorubicin (Adriamycin), as well as daunorubicin (Cerubidine), induced cardiotoxicity is CoQ10: both preclinical and clinical studies suggest that such anthracycline-induced cardiotoxicity can be prevented by administering coenzyme Q10 during cancer chemotherapy, and preventing cardiotoxicity might allow for escalation of the anthracycline dose to enhance antitumor effect, with one limited clinical investigation (KA Conklin, Integr Cancer Ther (2005): Coenzyme Q10 for Prevention of Anthracycline-Induced Cardiotoxicity) finding that a cumulative dose of doxorubicin of up to 900 mg/m2 (and possibly higher) can be administered safely during chemotherapy if coenzyme Q10 is administered concurrently. Furthermore, and critically studies further suggest that coenzyme Q10 does not interfere with the antineoplastic action of anthracyclines, possibly even enhancing their anticancer effects.
  
  
  Errors in Current Breast Cancer Therapy:
  Overdeployment of Doxorubicin / Underdeployment of Epirubicin
  Doxorubicin (Adriamycin) has been and continues to be the dominant anthracycline in the US-based clinical chemotherapeutic approach to breast cancer, especially in the form of the standard four-cycle doxorubicin-based regimen. However, as noted above, epirubicin (Ellence, Pharmorubicin), used in Europe and Canada since 1980, and receiving US FDA approval in 1999 - at doses equivalent to doxorubicin - has been shown to be as efficacious as doxorubicin but less toxic than doxorubicin (Findlay & Walker-Dilks, Cancer Prev Control (1998): Epirubicin, alone or in combination chemotherapy, for metastatic breast cancer. Provincial Breast Cancer Disease Site Group and the Provincial Systemic Treatment Disease Site Group); in addition, compared with doxorubicin, epirubicin was associated with less nausea and vomiting), less neutropenia and less cardiotoxicity, including a trend toward fewer episodes of congestive heart failure. Burdette-Radoux & Muss (Clin Breast Cancer (2003): Optimizing the Use of Anthracyclines in the Adjuvant Treatment of Early-Stage Breast Cancer) found epirubicin, compared to doxorubicin, to have a better toxicity profile and can be escalated to higher doses than doxorubicin with better outcomes associated with those higher dose levels. HT Mouridsen (Clin Breast Cancer (2000): Rationale and use of epirubicin-based therapy in the adjuvant setting) found that while the two drugs exhibit similar activity in advanced breast cancer, the toxicity data favor epirubicin, and that CEF (cyclophosphamide / epirubicin / fluorouracil) was significantly superior to CMF in terms of recurrence-free survival and overall survival in the treatment of premenopausal and perimenopausal patients with early breast cancer. The concerns with CEF are potentially more acute toxicity, primarily in terms of alopecia and chemotherapy-induced amenorrhea, and there has been some concern that epirubicin may be associated with an increased risk of acute leukemia. However, they concluded that the prognostic benefits outweigh the acute and late toxicities. And note that on a milligram-per-milligram basis, epirubicin causes less cardiotoxicity than doxorubicin (Hershman DL, Neugut AI. Anthracycline cardiotoxicity: one size does not fit all! J Natl Cancer Inst 2008 Aug 6; 100(15):1046-7; also Ryberg M, Nielsen D, Cortese G, Nielsen G, Skovsgaard T, Andersen PK. New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J Natl Cancer Inst (2008) 100(15):1058–1067 [pdf]; Ryberg M, Nielsen D, Cortese G, et al. New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J Natl Cancer Inst 2008 Aug 6; 100(15):1058-67). 
  
  Thus, as the review of epirubicin by Stefan Glück concluded, epirubicin may have particular advantages over doxorubicin in terms of cardiotoxicity and likely also in terms of efficacy, especially when used in combination with docetaxel (Glück S. Adjuvant chemotherapy for early breast cancer: optimal use of epirubicin. Oncologist 2005 Nov-Dec; 10(10):780-91).
  
  Kummel et al. (Crit Rev Oncol Hematol (2005): Dose-dense adjuvant chemotherapy for node-positive breast cancer in women 60 years and older: Feasibility and tolerability in a subset of patients in a randomized trial) evaluate the feasibility and tolerability of dose-dense adjuvant chemotherapy for older patients with node-positive breast cancer, finding that a dose-dense regimen combining epirubicin and paclitaxel can be administered to patients >/=60 years of age with a tolerable safety profile. Namer et al. (Ann Oncol (2006): Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials) found that the addition of FEC50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2, cyclophosphamide 500 mg/m2, six cycles every 21 days) adjuvant chemotherapy to tamoxifen significantly improves long-term DFS in N1–3, ER+ and postmenopausal women, and so that chemoendocrine therapy seems to be more effective than tamoxifen in terms of long-term survival. Langley et al. (J Clin Oncol (2005): Phase III Trial of Epirubicin Plus Paclitaxel Compared With Epirubicin Plus Cyclophosphamide As First-Line Chemotherapy for Metastatic Breast Cancer: United Kingdom National Cancer Research Institute Trial AB01) compared the effectiveness and tolerability of epirubicin and paclitaxel (EP) with epirubicin and cyclophosphamide (EC) as first-line chemotherapy for metastatic breast cancer, finding that in terms of progression-free survival and overall survival, there was no evidence of a difference between EP and EC, while EP patients had more grade 3 and 4 mucositis and grade 3 and 4 neurotoxicity compared with EC patients, so that there is no additional advantage to using EP instead of EC as first-line chemotherapy for MBC in taxane-naive patients.
  
  Epirubicin in Node-Positive and Node-Negative Disease
  Several critical trials, including FASG (French Adjuvant Study Group) 05 and NCIC (National Cancer Institute of Canada) MA.5 demonstrated the that optimal dosing of epirubicin in combination chemotherapy regimens achieves superior long-term 10-year survival in node-positive breast cancer patients at high relapse risk, and that for node-negative patients ECMF (optimal-dose epirubicin at 100 mg/m2 followed by CMF), compared to the classical CMF regimen, produced significantly better RFS (relapse free survival) and OS (overall survival), irrespective of nodal status. These positive findings in node-negative disease had been also earlier found by the Danish Breast Cancer Group (Moridsen et al. (1999 ASCO Annual Meeting): Adjuvant anthracycline in breast cancer. Improved outcome in premenopausal patients following substitution of methotrexate in the CMF combination with epirubicin) who compared CEF (cyclophosphamide, epirubicin, and fluorouracil) to CMF, finding that 93% of the node-negative patients who received CEF (with 60 mg/m2 epirubicin) had 6 year survival compared with 83% of those who received CMF. (See also the review of S Gluck, Oncologist (2005): Adjuvant Chemotherapy for Early Breast Cancer: Optimal Use of Epirubicin) which noted that extended follow-up has confirmed that higher-dose combination chemotherapy regimens containing epirubicin improve therapeutic efficacy for both node-positive and node-negative early breast cancer patients).
  
  Epirubicin + Taxanes
  Researchers (Roche et al., 27th SABCS (Annual San Antonio Breast Cancer Symposium) (2004): Five years analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) for the adjuvant treatment of node positive breast cancer) evaluated three cycles of standard FEC100 followed by docetaxel 100 mg/m2 every 3 weeks for three cycles n women <= 65 years with node-positive breast cancer, finding (1) that sequential use of FEC100 followed by docetaxel produced significantly better DFS and OS, and (2) that although women under the age of 50 years receiving FEC100 and docetaxel did not gain a survival benefit, they did experienced fewer side effects (less neutropenia, use of G-CSF, cardiotoxicity) than those receiving six cycles of FEC100, (3) while women between 50 – 65 years of age experienced benefits both in longer survival and fewer adverse events, suggesting that a FEC100–docetaxel regimen may be the most effective yet least toxic among all regimens containing anthracycline and taxane components (S Gluck, Oncologist (2005): Adjuvant Chemotherapy for Early Breast Cancer: Optimal Use of Epirubicin).
  
  Furthermore, the addition of the biological anti-HER2 monoclonal antibody trastuzumab (Herceptin) to epirubicin-containing chemotherapy appears both effective and relatively safe, whereas it is known that doxorubicin and trastuzumab combination induces as high as 29% rate of cardiotoxicity. And although there has been a concern of increased risk of acute leukemia with epirubicin, large-scale studies and meta-analyses have suggested that epirubicin-based regimens have no more risk - and possibly a trend toward a lower risk - of producing secondary leukemia than doxorubicin-based regimens, and the balance of the evidence to date suggests that epirubicin may have particular advantages over doxorubicin in terms of cardiotoxicity and also efficacy when used in combination with docetaxel.
  
  Epirubicin Summary
  The extensive systematic review of Gluck concluded that more than a decade of anthracycline therapy research in breast cancer clearly favor epirubicin as the anthracycline of choice across the entire spectrum of patients: (1) it exhibits a superior safety profile compared with doxorubicin in terms of both cardiotoxicity and secondary leukemia, (2) it is tolerated at higher doses than doxorubicin, resulting in significantly better efficacy, with superior results for both long-term DFS and OS, the significant improvement in survival being seen across the spectrum of patient subsets independently of hormone receptor status, including patients who are node-negative, node-positive, HER-2–expressing, elderly, and undergoing neoadjuvant treatment.
  
  For these reasons, Breast Cancer Watch concludes that the continued dominance and overdeployment of doxorubicin compared to epirubicin is clinically and methodologically in error and represents a serious and unnecessary compromise in delivering optimal therapy to breast cancer populations both in terms of efficacy and safety / tolerability.
  
  Escalating Anthracycline versus Taxane Addition
  Henderson et al. (J Clin Oncol (2003: Improved Outcomes From Adding Sequential Paclitaxel but Not From Escalating Doxorubicin Dose in an Adjuvant Chemotherapy Regimen for Patients With Node-Positive Primary Breast Cancer) sought to determine whether increasing the dose of doxorubicin in a standard adjuvant breast cancer chemotherapy regimen (AC: cyclophosphamide + doxorubicin), or adding paclitaxel to that same regimen would prolong time to recurrence and survival, finding that the addition of four cycles of paclitaxel upon completion of a standard course of AC improved disease-free and overall survival. Escalation of the doxorubicin dose failed to improve either the disease-free or overall survival of patients with stage II breast cancer, while substantially increasing hematologic toxicity, stomatitis and long-term cardiotoxicity.
  
  In this connection, given the proven value of taxanes in the metastatic breast cancer setting, Gimenez Poderos et al. (Farm Hosp (2005): Taxanes in the adjuvant therapy of breast cancer with positive nodes: a meta-analysis [in Spanish]), sought to assess their efficacy in non-metastatic breast cancer both in the adjuvant and neoadjuvant setting, finding that chemotherapy regimens including a taxane in the adjuvant therapy setting for breast cancer with positive nodes provide a significant improvement regarding increased disease-free survival and overall survival at 5 years.
  
  Comparing Taxane-based Regimens: FAC v. TAC
  Martin et al. (NEJM (2005): Adjuvant Docetaxel for Node-Positive Breast Cancer) compared two chemotherapy regimens, TAC (docetaxel plus doxorubicin and cyclophosphamide) and FAC (fluorouracil plus doxorubicin and cyclophosphamide), as adjuvant chemotherapy for operable node-positive breast cancer, finding TAC, as compared with FAC, significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer.
  
  [new] Comparing CEF and Dose-dense EC - T v. AC - T
  Burnell et al. (SABCS (2006): A randomized trial of CEF versus dose dense EC followed by paclitaxel versus AC followed by paclitaxel in women with node positive or high risk node negative breast cancer, NCIC CTG MA.21: Results of an interim analysis) for the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) MA.21 conducted an interim analysis of phase III randomized study to evaluate benefit of adding a taxane to an epirubicin-containing regimen and to compare epirubicin-based regimen including a taxane with other standard regimens, and to directly compare AC - T with CEF. They found that relapse-free survival (RFS) rates were higher for CEF and dose-dense EC - T adjuvant regimens compared with AC - T in women with operable breast cancer. Outcomes for CEF and dose-dense EC - T arms were comparable, suggesting that taxane therapy may not be required for all women, although the data was still too premature to detect a difference between dose intense (CEF) and dose-dense epirubicin-based treatment approaches.
  
  Optimizing Taxane Schedules
  Traditionally, the taxanes paclitaxel and docetaxel have been given on an every 3 week schedule; however, nonclassic schedules may favorably affect the therapeutic ratio: weekly lower dose taxanes showed a more favorable toxicity profile, and were associated with a lower incidence of febrile neutropenia, myelosuppression was substantially less, with lower overall toxicity, while maintaining efficacy (see the review of Crown et al., Oncologist (2004): Docetaxel and Paclitaxel in the Treatment of Breast Cancer: A Review of Clinical Experience). To date, it appears that fatigue is the common primary toxicity associated with weekly docetaxel. And as has been noted by Hainsworth (Oncologist 2004): Practical Aspects of Weekly Docetaxel Administration Schedules), other side effects are like excessive tearing, nail changes, and alopecia appear to be cumulative toxicities, with most of these side effects manageable or minimizable by effecting relatively minor changes in the docetaxel dose or schedule. (See also Estevez & Gradishar, Clin Cancer Res (204): Evidence-Based Use of Neoadjuvant Taxane in Operable and Inoperable Breast Cancer)
  
  Comparing Taxane-based Regimens: Docetaxel v. Paclitaxel
  Although docetaxel appears to be the more active taxane (see the review of Crown, above), the findings are largely drawn from the MBC (metastatic breast cancer) setting, and furthermore the widely cited single study of Jones/Ravdin purporting to establish docetaxel as superior in efficacy over paclitaxel is not wholly compelling on the issue, as the paclitaxel regimen deployed appears to have been sub-optimal: as J Bonneterre (Medscape (2003): Advances in the Treatment of Breast Cancer: Continual Attempts at Improving Outcomes) has pointed out, a higher dose and/or a longer duration of infusion, or a weekly regimen would likely have found for equi-efficacy (at the expense of increased side effects incidence). In the light of this consideration, and the absence of further studies showing a convincing advantage of docetaxel over paclitaxel, clinicians should consider these two taxanes equi-efficacious in the treatment setting.
  
  CMF Responsiveness and HER2 Overexpression
  However, these findings did not examine the potential influence of HER2/ expression level, an issue within the broader context of intense interest in biologic markers able to predict the response of cancer patients to therapy. It is already well established that HER2 overexpression is a potential indicator of positive responsiveness to doxorubicin and to paclitaxel, and of unresponsiveness to tamoxifen in patients with breast carcinoma, but the influence, if any, of HER2 overexpression in responsiveness to the CMF (cyclophosphamide, methotrexate, and fluorouracil) regimen has remained unclear. Several trials have examined this issue: Menard et a. (J Clin Oncol (2001: Response to Cyclophosphamide, Methotrexate, and Fluorouracil in Lymph Node–Positive Breast Cancer According to HER2 Overexpression and Other Tumor Biologic Variables) investigated this issue in the first CMF controlled clinical trial with a 20-year follow-up, finding that patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, concluding hopefully that the poor prognosis typically associated with HER2 overexpression could be completely overcome by CMF chemotherapy.
  
  Building on this, Moliterni et al. (J Clin Oncol (2003): HER2 Overexpression and Doxorubicin in Adjuvant Chemotherapy for Resectable Breast Cancer) examined whether therapy regimens including CMF + doxorubicin (ADM) versus CMF alone have the same therapeutic effect in patients with HER2+ and HER2- tumors in terms of relapse-free survival (RFS) and overall survival (OS), finding a clear therapeutic benefit of doxorubicin treatment in patients with HER2+ breast carcinoma, further confirming the conclusions from other studies suggesting that doxorubicin activity is restricted to the subset of breast carcinomas overexpressing the HER2 oncogene (the latest NCCN guidelines have added a footnote stating that doxorubicin-based chemotherapy may be superior to non-doxorubicin-containing regimens in the adjuvant treatment in patients whose tumors exhibit HER2 overexpression: see NCCN (2005): Practice Guidelines in Oncology - v.2.2005: Breast Cancer [pdf]). Their conclusions therefore demonstrate that the subset of HER2+ tumors seems to be more responsive to doxorubicin + CMF than to CMF alone, an advantage not observed in the subset of patients with HER2- tumors, where doxorubicin treatment did not significantly increase the therapeutic benefit achieved with CMF alone. This contrasts starkly with the fact that in metastatic disease, no direct association between HER2 overexpression and response to chemotherapy has been observed to date.
  
  Optimal Sequencing of Anthracycline-containing Regimens
  These important findings however leave open the question optimal sequencing of doxorubicin + CMF, a matter addressed in the study of Bonadonna et al. (J Clin Oncol (2004): Clinical Relevance of Different Sequencing of Doxorubicin and Cyclophosphamide, Methotrexate, and Fluorouracil in Operable Breast Cancer) in the case of operable breast cancer patients at risk of relapse; they found (1) that in patients with one to three involved nodes, there was no significant difference in the effectiveness of intravenous (IV) CMF given every 3 weeks for 12 courses versus eight courses of the same CMF regimen followed by four courses of full-dose doxorubicin; (2) in patients with more than three involved nodes, four courses of full-dose doxorubicin sequentially followed by eight courses of IV CMF significantly reduced the risk of disease relapse and of death compared with the alternating regimen in which two courses of the same CMF regimen was alternated with one course of doxorubicin for a total of 12 courses.
  
  Note therefore that despite the fact that both regimens included the same drugs, at the same doses, and for identical treatment duration, with the received dose-intensity for all drugs being identical in both regimens, this study clearly confirms the superiority of the sequential delivery of doxorubicin as first treatment for four cycles followed by IV CMF compared with the alternating delivery of the same regimens, and suggests that doxorubicin sequentially followed by CMF represents a recommended treatment option for moderate- to high-risk patients with operable breast cancer, in whom the significant improvement in the reduction of the odds of recurrence and death is not counterbalanced by an increased risk of life-threatening sequelae, most notably congestive heart failure (CHF).
  
  The CEF/FEC Chemotherapy Regimen
  Comparable results have obtained for another anthracycline-containing adjuvant chemotherapy regimen, CEF [aka FEC] (cyclophosphamide, epirubicin, and fluorouracil) over CMF in women with early-stage breast cancer: Levine at al. (J Clin Oncol (2005): Randomized Trial Comparing Cyclophosphamide, Epirubicin, and Fluorouracil With Cyclophosphamide, Methotrexate, and Fluorouracil in Premenopausal Women With Node-Positive Breast Cancer: Update of National Cancer Institute of Canada Clinical Trials Group Trial MA5) found that CEF, with the anthracycline epirubicin, was associated with improved relapse-free survival (RFS) and overall survival (OS) compared with the classic CMF regimen in women with early-stage breast cancer.
  
  
  The Issue of Chemotherapy and Cognition
  Since the late 1980s, following adjuvant chemotherapy for breast cancer mild cognitive impairment (MCI), often casually referred to as ''chemobrain'' or "chemofog''' (Matsuda et al., Breast Cancer (2005): Mild cognitive impairment after adjuvant chemotherapy in breast cancer patients - evaluation of appropriate research design and methodology to measure symptoms; see also Shilling et al., Breast Cancer Res Treat (2005): The (mis)classification of chemo-fog - methodological inconsistencies in the investigation of cognitive impairment after chemotherapy). Some studies examining the effect of chemotherapy, especially HDCT (high-dose chemotherapy) on cognitive functioning in breast cancer patients suggest that at least a subset of women may exhibit chemotherapy-related cognitive / neuropsychological impairment or dysfunction. Sherwath et al. (Ann Oncol (2006): Neuropsychological function in high-risk breast cancer survivors after stem-cell supported high-dose therapy versus standard-dose chemotherapy: evaluation of long-term treatment effects) evaluated the impact of high-dose versus standard-dose chemotherapy on late neuropsychological outcome in high-risk breast cancer survivors, finding that global cognitive impairment was observed in 8% of high-dose versus 13% of standard-dose compared with 3% of early-stage breast cancer patients, concluding from this that five years after treatment, standard-dose patients were slightly, but not significantly, more impaired in cognitive performance than high-dose patients. Eberhardt et al. (Support Care Cancer (2005): Medium-term effects of chemotherapy in older cancer patients) found that chemotherapy has no negative effects on cognitive functions after the first six months following the onset of treatment. It was demonstrated that complete recovery of cognitive functions is independent of the patient's age. Falleti (Brain Cogn (2005): The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: a meta-analysis of the current literature) undertook a meta-analysis with assessed the severity and nature of cognitive impairment associated with adjuvant chemotherapy, finding that although cognitive impairment occurs reliably in women who have undergone adjuvant chemotherapy for breast cancer, the magnitude of impairment depends on the type of design that was used (i.e., cross-sectional or prospective), so that more prospective studies are required before definite conclusions about the effects of adjuvant chemotherapy on cognition can be made.
  
  Bender et al. (Psychooncology (2005): Cognitive impairment associated with adjuvant therapy in breast cancer) found that adjuvant chemotherapy in women with breast cancer may be associated with deterioration in memory and this may persist over time, and that furthermore the addition of tamoxifen may lead to more widespread memory deficits [Breast Cancer Watch note: however, this study failed to examine what would typically be considered long-term effects, namely in periods over one year postchemotherapy, stopping as it did at one year].
  
  Fan et al. (J Clin Oncol (2005): Fatigue, Menopausal Symptoms, and Cognitive Function in Women After Adjuvant Chemotherapy for Breast Cancer: 1- and 2-Year Follow-Up of a Prospective Controlled Study) evaluated fatigue, menopausal symptoms, and cognitive dysfunction in patients receiving adjuvant therapy for breast cancer and matched healthy women at base and then 1 and 2 years later, finding that these adverse events improve in most patients, and in particular the incidence of moderate-severe cognitive dysfunction decreased in patients from 16% (on chemotherapy) to 4.4% and 3.8% at 1 and 2 years, respectively; there were minimal differences between estrogen receptor–positive patients who started hormonal therapy (mainly tamoxifen) after chemotherapy and estrogen receptor–negative patients who did not. Donovan et al. (Cancer (2005): Cognitive functioning after adjuvant chemotherapy and/or radiotherapy for early-stage breast carcinoma) examined whether there are differences in cognitive performance and cognitive complaints between women treated with and without chemotherapy for TNM Stage 0 to II breast carcinoma; their findings failed to confirm previous reports suggesting that adjuvant chemotherapy is associated with problems in cognitive functioning among women who receive treatment for Stage 0 to II breast carcinoma.
  
  Massa et al. (Crit Rev Oncol Hematol (2005): Evaluation of the effectiveness of treatment with erythropoietin on anemia, cognitive functioning and functions studied by comprehensive geriatric assessment in elderly cancer patients with anemia related to cancer chemotherapy) examined the relationship of changes in hemoglobin levels following recombinant human erythropoietin (rHuEPO) (also known as Epoetin, commercially as as Epoetin Alfa (Epogen, Procrit) or an alternate formulation, Darbepoetin Beta (Arenesp)) treatment to changes in cognitive functioning in elderly cancer patients undergoing chemotherapy treatment, finding support for the hypothesis that significant increases in hemoglobin over the course of chemotherapy supplemented with rHuEPO ([epoetin] Epogen) administration would be accompanied by significant improvement in cognitive performance over the same interval (see also J O'Shaughnessy, Clin Breast Cancer (2005): Effect of Epoetin Alfa on Cognitive Function, Mood, Asthenia, and Quality of Life in Women with Breast Cancer Undergoing Adjuvant Chemotherapy) on erythropoetin as a potent, endogenous neuroprotective agent, following up their earlier RCT of O'Shaughnessy et al., ASCO Annual Meeting (2002): Effects of epoetin alfa (Procrit) on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy: a double-blind, randomized, placebo-controlled trial). Tesch et al. reported on the results of the Epolym trial (9th Congress of the European Hematology Association, Geneva Palexpo, Switzerland, 10 – 13 June, 2004: Evaluation of the cognitive effects of once-weekly epoetin alfa in anemic patients with hematologic cancers receiving chemotherapy: preliminary results of the epolym trial), a prospective, international, multicenter, open-label, Phase IIIB trial in anemic patients receiving chemotherapy, finding improved cognitive function in anemic chemotherapy patients, the improvement being associated with an increase in Hb level achieved with once-weekly epoetin alfa; epoetin alfa therapy was initiated at a dose of 40,000 IU once-weekly administered subcutaneously, with dosage adjustments (increases or decreases) to be made based on clinical response (target Hb, 11.5-13.0 g/dL). These results were confirmatory with those reported by Dammacco et al. on quality-of-life (QOL) parameters from the same epolym trial (9th Congress of the European Hematology Association, Geneva Palexpo, Switzerland, 10 – 13 June, 2004: Epoetin alfa improves hemoglobin levels and quality of life parameters in anemic patients with hematologic malignancies receiving chemotherapy: interim results from the epolym trial) who similarly found that treatment with epoetin alfa resulted in improved QOL parameters and cognitive function in anemic chemotherapy patients. See also A. Snively, Spotlight on Symposia from the ONS 30th Annual Congress in Orlando, FL, 2005: Current Topics in Cancer, Quality of Life: Fatigue, Cognitive Dysfunction, and Cachexia [pdf]).
  
  The efficacy of erythropoietin / epoetin on cognition appears to be mediated by its favorable activity on anemia via increasing hemoglobin (Hb): Mancuso et al. (Ann Oncol (2005): Correlation between anemia and functional/cognitive capacity in elderly lung cancer patients treated with chemotherapy) who found (1) that Chemotherapy-related anemia is associated with impairment of functional status and cognitive functions, and (2) that higher Hb values were significantly associated with more favorable values of all indexes measuring mental and functional capacity, depression and comorbidities.
  
  Comparison of the several recombinant human erythropoietin (rHuEPO) commercial products has been conducted by B Reichardt (9th Congress of the European Hematology Association, Geneva Palexpo, Switzerland, 10 – 13 June, 2004: Evidence-based, novel comparison between epoetin alfa, epoetin beta, and darbepoetin alfa based on drug use, efficacy and treatment costs in daily oncological clinical practice) who found that darbepoetin alfa leads to longer treatment duration and/or dosage increase resulting in an overall increased cost of therapy, and Borg et al. (9th Congress of the European Hematology Association, Geneva Palexpo, Switzerland, 10 – 13 June, 2004: Differences in treatment practice, response rates and cost of epoetin alfa and darbepoetin alfa treatment for anemic cancer patients: a retrospective analysis from sweden) found that epoetin alfa was associated with a higher hematopoietic response rate, a significantly faster Hb response, and significantly higher increase in Hb levels compared with darbepoetin alfa, as used clinically. However, Breast Cancer Watch notes that these findings are not dispositive of the issue, as Glaspy et al. (ASCO Annual Meeting (2005): Final results of a phase 3, randomized, open-label study of darbepoetin alfa 200 mcg every 2 weeks (Q2W) versus epoetin alfa 40,000 U weekly (QW) in patients with chemotherapy-induced anemia (CIA)) in their in a large, randomized phase 3 study found, against these earlier results, for the non-inferiority with respect to incidence of transfusion between darbepoetin alfa (200 micrograms every two weeks) compared with epoetin alfa (40,000 units weekly) . Similar efficacy was seen for Hb, PRO and safety endpoints. Less frequent dosing of darbepoetin alfa offers potential benefits for pts, caregivers, and healthcare providers.
  
  Furthermore, Jansen et al. (Cancer (2005): A metaanalysis of studies of the effects of cancer chemotherapy on various domains of cognitive function) in a recent meta-analysis sought to estimate the effect sizes for the effect of chemotherapy on each domain of cognitive function, finding that data from this review supported the hypothesis that chemotherapy can have a negative impact on cognitive function, but with most deficits in this study ranged from small to moderate and were nonsignificant. Buckwater et al. (Int J Neurosci (2005): Cognitive performance of older women who have survived cancer) conducted a cross-sectional comparison finding that the difference between cancer survivors and those with no history of cancer on a screening test of global cognitive functioning to be insignificant, with similarly no differences on a subtest of the global test that assesses verbal memory.
  
  Breast Cancer Watch Conclusions:
  The Issue of Chemotherapy and Cognition
  On the balance of the evidence, Breast Cancer Watch concludes that
  (1) that the adverse effect of chemotherapy on cognitive function, if any, appears to be mild to moderate at worst and in the preponderance fails to reach statistical significance; we also note that many studies purporting to find more adverse cognitive impact are subject to a serious methodological compromise: it is known that pre-systemic therapy, 35% of women in the current cohort exhibited cognitive impairment; verbal learning (18%) and memory function (25%) were impaired significantly more frequently relative to normative expectations, and although the impairments were not significant in the women who were examined, nonverbal memory (17%), psychomotor processing speed and attention (13%), confrontational naming (13%), visuoconstruction (13%), and upper-extremity fine motor dexterity (12%) were impaired more frequently than was expected, therefore given cognitive impairment frequently is observed before the administration of systemic chemotherapy, investigations purporting to measure chemotherapy-induced cognitive dysfunction must employ study designs that incorporate prechemotherapy baseline assessments to accurately detect changes in cognitive function that are attributable to chemotherapy (Wefel et al., Cancer (2004): 'Chemobrain' in breast carcinoma?: a prologue).
  (2) that the adverse impact of chemotherapy, if any, on cognitive function appears to be both temporally limited and transient, and significant improvement appears to occur initiating at latest one year forward.
  (3) that the adverse impact of chemotherapy, if any, on cognitive function - wholly transient - appear to be wholly reversible in in the short-term, via several distinct interventions:
  
  
  (a) recombinant human erythropoietin (Epogen) but only if clinical a clinical anemia state is observed (given the unresolved mortality question surrounding erythropoietic agents): in the BEST trial (Breast Cancer Erythropoietin Survival Trial) reported by Leyland-Jones et al. (J Clin Oncol (2005): Maintaining Normal Hemoglobin Levels With Epoetin Alfa in Mainly Nonanemic Patients With Metastatic Breast Cancer Receiving First-Line Chemotherapy: A Survival Study) higher mortality in the group treated with epoetin alfa led to early trial termination; as the researchers note, in this trial the use of epoetin alfa to maintain high Hb (hemoglobin) targets (in the range of 12 to 14 g/dl ) in women with metastatic breast cancer, most of whom did not have anemia at the start of treatment, was associated with decreased survival. And although another RCT trial in SCLC (small-cell lung cancer) found that epoetin alfa neither affected tumor response to chemotherapy or survival, as the researchers themselves note the early trial closure makes these conclusions preliminary. The BEST trial findings were consonant with earlier results by Henke et al. in the ENHANCE trial (Lancet (2003): Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial) which found in anemic head and neck cancer patients receiving radiotherapy that locoregional progression-free survival was unexpectedly poorer with epoetin beta treatment than with placebo (therapeutic goal was normalization of Hb (> 14 g/dl in women, > 15 g/dl in men). One observation in connection with the BEST and ENHANCE trials is that a higher Hb target was used than in most other cancer patient studies, leading to the speculation that the toxicity profile of erythropoietin at higher Hb levels may be distinct. But as Steensma & Loprinzi observe (J Clin Oncol (2005): Erythropoietin Use in Cancer Patients: A Matter of Life and Death?), at least three other studies of erythropoietic agents, not looking specifically at survival as an end point, in cancer patients with a normal or near-normal goal Hb, have been terminated because of higher thromboembolic risk in the active therapy arm, effectively disputing the widespread acceptance of the safety of erythropoietin. Given this, Breast Cancer Watch believes it prudent for patient safety that erythropoietin deployment in oncology settings use only the lower 12 g/dl Hb target in conformance with ASCO/AHS (American Society of Clinical Oncology / American Society of Hematology) evidence-based guidelines (Rizzo et al., Blood (2002): Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology).
  
  In the aftermath of these studies showing mortality compromise in erythropoietin oncology patients, the FDA's MedWatch safety information program (August 2004) announced a letter addressed to oncologists, hematologists, and other health care professionals on the safety of epoetin alfa (Procrit), with new prescribing information recommending that the target Hb level in patients with cancer should be individualized and not to exceed 12 g/dl, with epoetin alfa doses withheld if the Hb level is 13 g/dl or higher (along with new recommendation about the rate of Hb increase, with dosing interruption and modification also advised if the rate of Hb increase exceeds 1 g/dl during a 2-week period. Similar warnings were added to labels for darbepoetin alfa (Aranesp) later that same year (December 2004) as a precaution, although Breast Cancer Watch and other researchers believe these warnings should apply to all erythropoietic agents (Steensma & Loprinzi, J Clin Oncol (2005): Erythropoietin Use in Cancer Patients: A Matter of Life and Death?).
  
  Breast Cancer Watch further observes that other recent research suggests potential thromboembolic risks with erythropoietic agents, as well as a potential stimulation of tumor cell growth, given that erythropoietin receptor is expressed in several cancer cell lines (Stasi et al., Oncologist (2005): Management of Cancer-Related Anemia with Erythropoietic Agents: Doubts, Certainties, and Concerns).
  
  Given these serious unresolved safety and mortality concerns, Breast Cancer Watch concludes that the balance of the evidence for both the efficacy and safety of erythropoietic agents in the treatment of chemotherapy-induced anemia is to date not compelling, and we further observe that it is often overlook that a viable alternative of blood transfusion is essentially highly reliable, yielding prompt hemoglobin increases in most patients treated with minimal mortality concerns. We finally advise all oncology clinicians to consult the full FDA Briefing Document on this issue (FDA Oncologic Drugs Advisory Committee (May, 4, 2004): Safety Concerns Associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, L.P., for the Treatment of Anemia Associated with Cancer Chemotherapy)
  
  (b) acetyl)cholinesterase inhibitor (AChEI) agents (even the over-the-counter agent galantamine, and
  
  (c) possibly also with the herbal Ginkgo biloba in the form of pharmaceutical grade EGb 761), among others.
  
  (4) although adverse impact in the case of traditional chemotherapeutic agents has been suggested, there are to date no reported cases implicating solely taxane-based (paclitaxel (Taxol) and docetaxel (Taxotere) regimens.
  

  Chemotherapy (CT): Breast Cancer Watch Summary

• Benefits are greatest in younger women
  but are still significant up to 70 years
  
• Absolute benefit increases
  with increasing adverse prognostic factors:
  • number of involved nodes
  • ER- tumor
  • tumor with poor histological grade + lymphovascular invasion
  • increasing tumor size,
  • young age (especially <35 years),
    
  • HER2+ tumor

  which determine if chemotherapy should be deployed

• does not appear to produce substantial benefits in postmenopausal women with grade I or II breast cancer that is
  ER rich and HER2-, who receive appropriate endocrine therapy
• anthracycline-containing regimens using
  doxorubicin (Adriamycin) or epirubicin (Ellence)
  are more effective than CMF
• adding taxanes (paclitaxel (Taxol), docetaxel (Taxotere))
  to anthracyclines improves survival further in node positive disease
• dose dense) CT given every two weeks with hemopoietic support from G-CSF (granulocyte colony stimulating factor)
  may improve survival further in node positive disease
• five year survival in women with node positive cancer:
  ~ 65% without treatment
  ~ 70% with CMF to around
  ~ 85% with modern anthracycline-taxane combinations.
  
  Table:
  Estimated Effects of 6 Months of Anthracycline based Chemotherapy or 5 Years of Tamoxifen,
  or both, on Breast Cancer Mortality
  

Dose-dense and Dose-intense Therapies
It is critical at this juncture to clarify some concepts in dosing regimens, which involves components of doe level and dose scheduling (interval frequency): the terms dose-dense and dose-intense chemotherapy are often confused and/or misunderstood. With dose-dense chemotherapy (aka "accelerated therapy"), an agent is given more often at lower doses, as opposed to dose-intense chemotherapy where higher doses are given at less frequent intervals. In addition, there is high-dose chemotherapy which, when differentiated explicitly from dose-intense chemotherapy, also involves higher doses but with no reduction in interval frequency.

Given that the primary limitation of dose-intensity and dose-density is the development of hematologic toxicities, such as neutropenia and anemia due to myelosuppression, and leukopenia and thrombocytopenia, the clinical deployment of biotechnology derived drugs is commonly leveraged to enable further increases in dose-intensity and dose-density. The growth factor cytokine G-CSF/filgrastim (Neupogen) is commonly used in this way to treat chemotherapy induced neutropenia and thereby allow for dosing to be scheduled more frequently. Thus, Citron et al. in the CALGB trial 9741 (J Clin Oncol (2003): Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741) compared dose-dense four-cycle AC chemotherapy followed by four cycles of paclitaxel (Taxol) in dose-dense intervals with conventional 3-week intervals in node-positive patients, finding that the dose-dense regimen produced significantly better DFS (disease free survival), with less frequent observation of severe neutropenia in patients receiving G-CSF support with the dose-dense chemotherapy schedule, the regimen being otherwise well tolerated.

However, the results the GONO-MIG trial (Gruppo Oncologico Nord Ovest-Mammella InterGruppo) reported by Venturini et al. (J Natl Cancer Inst (2005): Dose-Dense Adjuvant Chemotherapy in Early Breast Cancer Patients: Results From a Randomized Trial) appear to diverge from the CALGC trial 9741 of Citron et al. (cited above): they compared outcomes with the same fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapeutic regimen administered every 3 weeks (FEC21) or administered every 2 weeks (FEC14) along with G-CSF support using filgrastim in patients with lymph node–positive or high-risk lymph node–negative breast cancer, finding that at a median follow-up of 10.4 years, no statistically significant difference in the hazard of death or recurrence between FEC14 and FEC21 groups, so that the dose-dense therapy (in which the chemotherapy dose per cycle and total number of cycles was held constant, and only the interval between doses varied) was not after all associated with improved outcome.

Nonetheless, even in the GONO-MIG trial, there was a trend toward improved event-free and overall survival for women who received the every-14-day regimen (FEC14), and as Lin et al. (J Natl Cancer Inst (2005): Dose Density in Breast Cancer: A Simple Message?) sensibly observe, from a practical standpoint, it is often the case that both clinicians and patients would nonetheless consider a smaller risk reduction to be therapeutically meaningful, especially under the circumstance of a dosing regimen involving the same drugs at identical doses, and in addition the GONO-MIG trial did observe improved 10-year event-free survival for patients with HER2-positive tumors in the arm receiving dose-dense therapy, compared with the arm receiving standard therapy. As Lin et al. further noted, if increasing dose density improves outcomes by killing more cancer cells as they regrow after the previous cycle of therapy, then it would be reasonable to hypothesize that the interval between chemotherapy cycles of may be most critical in high-grade rapidly proliferating tumors, and they therefore conclude that In our view, the totality of evidence supports the concept that dose density has at least a modest impact on the outcome of unselected patients with early-stage breast cancer, with compelling reason to believe that the benefits of dose-dense therapy will be greater in specific subsets of patients with breast cancer.

Turning to the matter of tolerability, although most toxicities were largely transient, the dose-dense FEC14 regimen of the GONO-MIG trial was nonetheless - as would be expected - associated with more toxicity than the FEC21 regimen, consistent with results of the CALGB 9741 trial: a reduction in the interval between cycles to 2 weeks (FEC14) yielded a greater incidence of anemia, and a statistically significantly increase in asthenia, bone pain, and psychologic distress when compared with FEC21.

In sum, therefore, from these and several other trial data, that the weight of the evidence demonstrates that using dose-dense therapies can both decrease the risk of disease recurrence as well as improve overall survival.

Optimizing Anthracycline: Doxorubicin vs. Epirubicin
Breast Cancer Watch observes in this connection that the Levine study (cited above) used epirubicin 60 mg/m2, and it is instructive to know that further benefit may be had by using a high(er)-dose regimen of epirubicin 100 mg/m2 (FEC 100): as Bonneterre et al. (J Clin Oncol (2005): Epirubicin Increases Long-Term Survival in Adjuvant Chemotherapy of Patients With Poor-Prognosis, Node-Positive, Early Breast Cancer: 10-Year Follow-Up Results of the French Adjuvant Study Group 05 Randomized Trial) found, treatment with adjuvant FEC 100 demonstrated superior DFS and OS versus FEC 50 at 10 years of follow-up, a survival advantage not offset by long-term complications (such as cardiac toxicity and second malignancy). Given the risk-benefit ratio, FEC 100 may be a more optimal regimen for long-term survival in patients with poor prognosis, a finding in keeping with the earlier results of the the French Adjuvant Study Group (French Adjuvant Study Group, J Clin Oncol (2001): Benefit of a High-Dose Epirubicin Regimen in Adjuvant Chemotherapy for Node-Positive Breast Cancer Patients With Poor Prognostic Factors: 5-Year Follow-up Results of French Adjuvant Study Group 05 Randomized Trial) who found that after 5 years of follow-up, higher epirubicin dose (100 mg/m2) led to a significant benefit in terms of DFS and OS, with a high survival rate among patients with poor-prognosis breast cancer.

Breast Cancer Watch Warning
Boltgon-Maggs & Flagin (BMJ (2005): Epirubicin for breast cancer may cause considerable venous sclerosis [pdf]) pain and restriction of movement of the arm due to venous sclerosis after having infusions of epirubicin, a complication not previously reported, suggesting that venous sclerosis may be more extensive and troublesome than previously recognized.

AC v. CMF Chemotherapy
Another head-on comparison of different chemotherapy regimens was undertaken by Bang et al. (Cancer (2000): Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma). This study found no difference between AC and CMF with respect to both disease free and overall survival rates in premenopausal women with axillary lymph node positive breast carcinoma, and a complimentary study by Fisher et al. (J Clin Oncol (2001): Tamoxifen and Chemotherapy for Axillary Node-Negative, Estrogen Receptor–Negative Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-23) reconfirmed the finding of no significant difference in the outcome of patients who received AC or CMF, adding the new finding that tamoxifen with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.

FAC v. CMF Chemotherapy
Kuru et al. (J Exp Clin Cancer Res (2005): ) compared the results of adjuvant FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy on DFS (disease-free survival), OS (overall survival) and LFS (loco-regional recurrence-free survival) for node positive breast carcinoma treated with mastectomy in a non-randomised setting, finding that adjuvant FAC was improved DFS, OS and LFS, all of which were longer at 5-years for patients treated with FAC as compared to CMF.

Reassessing High-dose Chemotherapy: Trouble in Paradise
Zander et al. (J Clin Oncol (204): High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Support Compared With Standard-Dose Chemotherapy in Breast Cancer Patients With 10 or More Positive Lymph Nodes: First Results of a Randomized Trial) reported their findings that although there was a trend in favor of high-dose chemotherapy (HD-CT) with respect to event-free survival, this was without statistical significance; although the trial was closed prematurely because of insufficient accrual, the available results provide no evidence supporting a survival benefit from HD-CT, and no significant reduction in risk of recurrence.

Furthermore, a review of the 10 high-dose chemotherapy randomized adjuvant trials that have reported findings to date, none has shown a significant survival difference, and only one, the French Pegase Group trial, showed a significant improvement in the three-year disease-free survival rate (Viens et al., Cancer Control (2003): High-dose chemotherapy for breast cancer: the French PEGASE experience [pdf]). And it is well established that the morbidity rate of high-dose chemotherapy is high, exceeding that observed with standard-dose adjuvant chemotherapy regimens Zander, above reports neutropenic fever in 87% of patients, definite infections in 22%, along with other less frequent serious adverse effects, and treatment-related deaths in 2% of patients, and on the basis of these and similar findings, G Hortobagyi (J Clin Oncol (2004): What Is the Role of High-Dose Chemotherapy in the Era of Targeted Therapies?) concludes that "there is no role today for high-dose chemotherapy in the standard management of primary breast cancer, even in subgroups at high risk", especially when considered against the advent of newer anthracycline-taxane–containing regimens, and endocrine therapies, among other emergent developments. (We note however that Zander & Kroger (Acta Haematol (2005): High-dose therapy for breast cancer - a case of suspended animation) suggest that the failure of these studies to achieve an improvement in overall survival may be secondary to the low power of the studies, so that it is thus necessary to perform a meta-analysis of all these studies).

Note: These negative findings on high-dose chemotherapy are not relevant to the issue of the clinical value of dose-dense chemotherapy: as Seidman has noted (Cancer Chemother Pharmacol (2005): Current status of dose-dense chemotherapy for breast cancer), phase III data now demonstrates the advantages of dose-dense chemotherapy regimens in the adjuvant treatment of breast cancer and suggests that the dose intensity, dose density, and treatment duration may exert as much influence as the specific antitumor agents deployed, especially when the delivery of has been made safe and feasible by the use of hematopoietic GFS (growth factor support) - in particular, filgrastim (Neupogen), pegfilgrastim (Neulasta) and darbepoetin alfa (Aranesp); see Burstein et al. (J Clin Oncol (2005): Efficacy of Pegfilgrastim and Darbepoetin Alfa As Hematopoietic Support for Dose-Dense Every-2-Week Adjuvant Breast Cancer Chemotherapy) who note that dose-dense, every-2-week adjuvant chemotherapy using doxorubicin/cyclophosphamide (AC; 60/600 mg/m2 every 2 weeks x four cycles) followed by paclitaxel (175 mg/m2 every 2 weeks x four cycles), has been shown to improve survival compared with every-3-week treatment schedules, but requires filgrastim on days 3 through 10 of each cycle and is associated with greater risk of RBC transfusion (13%); they found that pegfilgrastim and darbepoetin alfa are effective and safe in facilitating every-2-week AC ---> paclitaxel, minimizing rates of febrile neutropenia and RBC transfusion.

Breast Cancer Watch - Clinical Practice Guideline
On the basis of these and other studies we critically appraised in systematic review (Aug, 2005), Breast Cancer Watch recommends against any further deployment of high-dose chemotherapy (HD-CT) even in high risk populations, given its lack of demonstrated survival or other significant clinical benefit coupled with its high rate of morbidity.

  Efficacy of CPM (Contralateral Prophylactic Mastectomy)

McDonnell et al. (J Clin Oncol (2001): Efficacy of Contralateral Prophylactic Mastectomy in Women With a Personal and Family History of Breast Cancer) found that incidence of contralateral breast cancer appears to be reduced significantly (model-estimated >= 90% reduction in the risk of second breast cancer events) after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer; the researchers soberly noted in conclusion that consideration must also be given to the woman’s risk of recurrence from her first breast cancer and her ovarian cancer risk, and that ipsilateral breast conservation and tamoxifen represent acceptable alternatives. McDonnell's findings have been more recently replicated in the collaborative investigation of Herrinton et al. (J Clin Oncol (2005): Efficacy of Prophylactic Mastectomy in Women With Unilateral Breast Cancer: A Cancer Research Network Project) where CPM was again found protective against the development of contralateral breast cancer (97% risk reduction) and also was associated with decreased breast cancer mortality.

However, the true reduction in mortality directly attributable to CPM is less clear that suggested by these investigators: women who underwent CPM were healthier overall, and hence less likely to die from all causes compared with other women with breast cancer, suggesting a potential strong selection bias for those women who would be advised to undergo such a prophylactic procedure, a bias addressed but we think not wholly satisfactorily resolved by the investigators; see Helzlsouer (J Clin Oncol (2005): Contralateral Prophylactic Mastectomy: Quantifying Benefits and Weighing the Harms) who sensibly notes that although women should be informed of CPM's potential benefit, this must placed in the broader context of (1) drawing attention to the fact of the rarity of this event, known to affect less than 3% of women; (2) the existence of other options that effectively reduce the risk of contralateral breast cancer: hormonal/endocrine therapy using SERMS and aromatase inhibitors; and (3) that there is one advantage of prophylactic surgery over hormonal interventions: for estrogen receptor–negative tumors, where such interventions have not to date demonstrated significant efficacy.

This is an important point, as we now know from the Breast Cancer Linkage Consortium findings (Lakhani et al., J Clin Oncol (2004): The Pathology of Familial Breast Cancer: Predictive Value of Immunohistochemical Markers Estrogen Receptor, Progesterone Receptor, HER-2, and p53 in Patients With Mutations in BRCA1 and BRCA2) that the vast majority of breast cancers developing in BRCA1 carriers are ER–negative yet there is no compelling evidence to date that tamoxifen reduces the risk of estrogen receptor–negative breast cancer, in either adjuvant or prevention settings (Fisher et al., J Natl Cancer Inst (2004): Treatment of Axillary Lymph Node–Negative, Estrogen Receptor–Negative Breast Cancer: Updated Findings From National Surgical Adjuvant Breast and Bowel Project Clinical Trials; also Hartmann et al., J Clin Oncol (2004): Prophylactic Mastectomy for BRCA1/2 Carriers: Progress and More Questions; and the commentary of K Albain, J Natl Cancer Inst (2004): Adjuvant Chemotherapy for Lymph Node–Negative, Estrogen Receptor–Negative Breast Cancer: A Tale of Three Trials).



Breast Cancer Watch Commentary: Mastectomy

• Prophylactic Mastectomy
  A recent Cochrane systematic review (Lostumbo et al., Cochrane Database Syst Rev (last update: 23 July 2004): Prophylactic mastectomy for the prevention of breast cancer) of both contralateral prophylactic mastectomy (CPM) and bilateral prophylactic mastectomy (BPM) concluded (1) that with respect to CPM, while it appeared to reduce the incidence of cancer in the contralateral breast, there was insufficient evidence about whether, and for whom, CPM actually improved survival; (2) with respect to BPM, while published observational studies demonstrate it to be effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies (ideally randomized trials) are needed to be fully dispositive of the issue, especially in the light of the fact that all studies reviewed (23) had methodological limitations.
  
  
• (Treatment-Oriented) Mastectomy
  As to treatment-oriented mastectomy, numerous studies have established that that more extensive surgery (supraradical, radical, and total mastectomy) did not improve outcomes compared with less extensive surgery (breast conservation) in women with early invasive breast cancer (providing that all local disease was excised). The review of Poggi et al (Cancer (2003): Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy
  The National Cancer Institute randomized trial) examining findings after 18+ years of follow-up concluded that there was no detectable difference in overall survival or disease-free survival in patients with early-stage breast carcinoma who were treated with mastectomy compared with those treated with breast conservation therapy (BCT), although for BCT patients, long-term in-breast failures continued to occur throughout the duration of follow-up; they also found that there was no statistically significant difference in the incidence of contralateral breast carcinoma between the two treatment groups.
  
  Note, however, that we know that even after surgical resection with microscopically clear margins, solid malignant tumors recur locally in up to 50% (Hockel & Dornhofer, Cancer Res (2005): The Hydra Phenomenon of Cancer: Why Tumors Recur Locally after Microscopically Complete Resection). And although the effect of a local tumor recurrence on the overall survival appears to be quite low in breast carcinoma, affected patients may naturally be apprehensive of both such recurrence and of the burden of the secondary treatment for the recurrence.
  
  
  
  
• Immediate vs. Delayed Breast Reconstruction
  It is generally well-established that breast reconstruction after mastectomy represents an improvement in the quality of life of breast cancer patient, and recently immediate reconstruction has become increasingly popular as a result of better aesthetic outcome, reduction of total hospitalisation and avoidance of delayed surgery, although concern voiced has been regarding possible delay in radiotherapy and chemotherapy due to surgical complications of reconstruction procedure (Petit et al, Oncol Haematol (2001): Breast reconstructive techniques in cancer patients: which ones, when to apply, which immediate and long term risks?).
  
  Now although the safety of immediate breast reconstruction for patients treated with initial surgery is further well-establised, some concerns exist after neoadjuvant chemotherapy, given that this sequence is typically deployed for patients with large tumors and for whom adjuvant therapies are considered the standard of care. Addressing this issue, Gouy et al. (Ann Surg Oncol (2005): Immediate Reconstruction After Neoadjuvant Chemotherapy: Effect on Adjuvant Treatment Starting and Survival) sought to determine whether reconstruction after neoadjuvant chemotherapy and mastectomy for large operable breast cancer may affect (1) the interval between surgery and adjuvant treatment, and (2) survival. They found that immediate breast reconstruction did not delay the start of adjuvant therapy and had no significant effect on local relapse–free or distant disease–free survival; survival was not different in patients treated with immediate reconstruction compared with those with mastectomy alone. This is in agreement with the TRAM-specific findings of Foster et al. (Arch Surg (2005): Safety of Immediate Transverse Rectus Abdominis Myocutaneous Breast Reconstruction for Patients With Locally Advanced Disease) who found that immediate transverse rectus abdominis myocutaneous (TRAM) breast reconstruction followed by radiation therapy is safe, with minimal morbidity, no significant change in tissue volume, and with complications tending to be minor, not delaying adjuvant therapy.
  
  With respect to mastectomy defects repair, Kronowitz et al. (J Plast Reconstr Aesthet Surg (2006): Radiation effects on the cosmetic outcomes of immediate and delayed autologous breast reconstruction: an argument about timing) found that immediate repair of partial mastectomy defects with local tissues results in a lower risk of complications and better aesthetic outcomes than immediate repair of partial mastectomy defects with a latissimus dorsi flap.
  
  There has been considerable further controversy however concerning the optimal timing of radiotherapy in relation to autologous tissue breast reconstruction (which includes pedicled or free transverse rectus abdominis muscle (TRAM) flap, deep inferior epigastric artery perforator (DIEP) flap, latissimus dorsi musculocutaneous flap with or without implant, superior gluteal free flap and other relatively uncommonly used free flaps, as opposed to non-autologous techniques which include silicon or saline prosthetic expander/implants). Although there are to date no RCTs that are dispositive on this issue, Javaid et al. (J Plast Reconstr Aesthet Surg (2006): Radiation effects on the cosmetic outcomes of immediate and delayed autologous breast reconstruction: An argument about timing) conducted a systematic review, and concluded that the current evidence suggests that radiation has a deleterious effect on autologous flap reconstruction and there are long term effects of radiation on the reconstructed breast, so that until better methods of radiation delivery can be devised to minimise the long term radiation sequelae in irradiated tissue, delayed reconstruction until after radiotherapy seems to be a safe option in most of the cases.
  
  
• Mastectomy v. BCT (Breast Conservation Therapy)
  Breast-conservation therapy (BCT) consists of breast-conserving surgery (BCS) and postoperative radiation therapy (RT), with breast conserving surgery being also known as lumpectomy, partial mastectomy, and segmental mastectomy, and the incidence and election of BCT has been increasing over approximately the last two decades. Early reviews over ten years from 1979 to 1987 (Jacobson et al., Ten-Year Results of a Comparison of Conservation with Mastectomy in the Treatment of Stage I and II Breast Cancer) have shown that in the management of stage I and II breast cancer, breast conservation with lumpectomy and radiation offers results at 10 years that are equivalent to those with mastectomy. These and other similar findings led to a consensus statement issued at the National Institutes of Health Consensus Development Conference on Treatment of Early-Stage Breast Cancer in 1990, adopted by NCI, that "breast conservation treatment is an appropriate method of primary therapy for the majority of women with Stage I and II breast cancer and is preferable because it provides survival equivalent to total mastectomy and axillary dissection while preserving the breast" (NIH Consensus Development Conference Statement (1991): Treatment of Early-Stage Breast Cancer)
  
  Some 15+ years later, researchers reported on a 20 year follow-up (Fisher et al., N Engl J Med (2002): Twenty-Year Follow-up of a Randomized Trial Comparing Total Mastectomy, Lumpectomy, and Lumpectomy plus Irradiation for the Treatment of Invasive Breast Cancer), concluding that lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor. This confirms the findings of Obedian et al. (J Clin Oncol (2000): Second Malignancies After Treatment of Early-Stage Breast Cancer: Lumpectomy and Radiation Therapy Versus Mastectomy) which concluded that there seems to be no increased risk of second malignancies in patients undergoing lumpectomy and radiation therapy (LRT) using modern techniques, compared with mastectomy.
  
  BCT Guidelines
  These findings have led to the revision of relevant guidelines, including those under promulgated by the American Cancer Society (ACS) for two distinct settings, DCIS (ductal carcinoma in situ) on the one hand (Morrow et al., CA Cancer J Clin (2002): Standard for the Management of Ductal Carcinoma In Situ of the Breast (DCIS)), and invasive breast carcinoma on the other (Morrow et al., CA Cancer J Clin (2002): Standard for Breast Conservation Therapy in the Management of Invasive Breast Carcinoma).
  
  For DCIS, the guidelines stipulate these
  indications for BCT (BCS + RT):
  
  
  • DCIS detected mammographically or by physical exam that is localized (without evidence of gross multicentricity or diffuse malignant calcifications);
    
    
  • The extent of DCIS should be less than or equal to 4 cm, as there are little data to support breast conservation’s effectiveness in larger lesions (the difficulty in measuring the size of DCIS makes definitive recommendations difficult).
    
    

  and these
  indications for mastectomy:
  

  • Women with two or more primary tumors in the breast or with diffuse malignant-appearing microcalcifications;
    
    
  • Persistent positive margins after reasonable surgical attempts.
    
    

  For invasive breast carcinoma,
  the guidelines stipulate these
  absolute contraindications for BCT (BCS + RT):
  

  • Pregnancy is an absolute contraindication to the use of breast irradiation. However, in many cases, it may be possible to perform breast-conserving surgery in the third trimester and treat the patient with irradiation after delivery;
    
    
  • Women with two or more primary tumors in separate quadrants of the breast or with diffuse malignant-appearing microcalcifications are not considered candidates for breast conservation treatment;
    
    
  • A history of prior therapeutic irradiation to the breast region that would require retreatment to an excessively high total-radiation dose to a significant volume is another absolute contraindication;
    
    
  • Persistent positive margins after reasonable surgical attempts. The importance of a single focally positive microscopic margin needs further study and may not be an absolute contraindication.
    

For invasive breast carcinoma,
the guidelines stipulate these
relative contraindications for BCT (BCS + RT):

• A history of collagen vascular disease is a relative contraindication to breast conservation treatment because published reports indicate that such patients tolerate irradiation poorly. Most radiation oncologists will not treat patients with scleroderma or active lupus erythematosus, considering it an absolute contraindication. In contrast, rheumatoid arthritis is not a relative or an absolute contraindication;
  
  
• The presence of multiple gross tumors in the same quadrant and indeterminate calcifications must be carefully assessed for suitability because studies in this area are not definitive;
  
  
• Tumor size is not an absolute contraindication to breast conservation treatment, although there is little published experience in treating patients with tumor sizes greater than four to five cm. However, a relative contraindication is the presence of a large tumor in a small breast in which an adequate resection would result in significant cosmetic alteration. In this circumstance, preoperative chemotherapy should be considered;
  
  
• Breast size can be a relative contraindication Treatment by irradiation of women with large or pendulous breasts is feasible if reproducibility of patient setup can be assured and the technical capability exists for greater than or equal to six MV photon beam irradiation to obtain adequate dose homogeneity.

The latest NCCN breast cancer guidelines (NCCN (2005): Practice Guidelines in Oncology - v.2.2005: Breast Cancer [pdf]) note that although mastectomy provides maximum local control, the long-term, cause specific survival with mastectomy appears to be equivalent to that with excision and whole breast irradiation, and therefore "for the vast majority of patients with more limited disease and in whom negative margins are achieved with the initial excision or with re-excision, breast-conserving therapy or total mastectomy are appropriate treatment options". And although the NCCN patient guidelines (NCCN (2004): Breast Cancer Treatment Guidelines for Patients - v.VI 2004 [pdf]) for DCIS correctly note that mastectomy provides the most certain local control of DCIS, they observe that studies have shown that women with DCIS who are treated with lumpectomy and radiation are in no greater danger of dying of breast cancer than those who have a mastectomy, although they do have a risk of the cancer coming back in the breast that would require a mastectomy. NCCN recommends a mammogram after lumpectomy to ensure that the entire tumor has been removed. In neither case do the lymph nodes under the arm need to be removed. In addition, comparable guidelines (Recht et al., J Clin Oncol (2000): Postmastectomy Radiotherapy: Clinical Practice Guidelines of the American Society of Clinical Oncology) were adopted earlier by ASCO (American Society of Clinical Oncology).

These findings are confirmed by the recent Singletary et al. (Ann Surg (2005): Treatment Trends in Early-Stage Invasive Lobular Carcinoma: A Report From the National Cancer Data Base) survey of treatment for ILC (invasive lobular carcinoma) over 15 years from 1989 - 2001 where it was found that despite the fact that the use of breast conversation therapy (BCT) increased almost threefold during the study period, local recurrence rates were very low and disease-free survival rates were correspondingly high in both treatment groups (those electing BCT, and those undergoing mastectomy) for all diagnosis years and across all pathologic tumor size/lymph node status designations. Thus in the case of ILC, less invasive treatment options yielded outcomes equivalent to those seen with more aggressive treatment.

Chen et al. (J Clin Oncol (2004): Breast Conservation After Neoadjuvant Chemotherapy: The M.D. Anderson Cancer Center Experience) explored the feasibility and outcome efficacy of exploiting the most established advantage of neoadjuvant chemotherapy, namely its ability to convert patients initially ineligible for BCT into candidates for this treatment strategy, concluding that BCT after neoadjuvant chemotherapy yields acceptably low rates of local-regional recurrence (LRR) and ipsilateral breast tumor recurrence (IBTR) in appropriately selected patients, even with T3 or T4 disease. Their guidelines in this context stipulate that advanced nodal involvement at diagnosis, residual tumor larger than 2 cm, multifocal residual disease, and lymphovascular space invasion would predict higher rates of LRR and IBTR. Further, patients who had any of the following factors after neoadjuvant chemotherapy were not considered BCT candidates: residual tumor size in excess of 5 cm, residual skin edema, direct skin involvement, or chest-wall fixation, diffuse microcalcifications, multicentric disease, or medical contraindications to the use of radiotherapy.

One fundamental association that is attested and established by these and many others studies is that between young age and risk of recurrence: so Arriagada et al. (Ann Oncol (2003): Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients) found that late breast recurrences were more frequently observed in younger patients treated with breast-conserving treatment than those undergoing to mastectomy; see Roukos et al. (Ann Surg Oncol (2003): Perspectives and Risks of Breast-Conservation Therapy for Breast Cancer) and Voogd & Tienhoven (Ann Oncol (2004): Breast conservation in patients of 35 years or younger).



Critical Role of Radiotherapy
Note the critical role played by radiotherapy (RT) in the success of BCT was explored by in the review of Vinh-Hung et al. (J Natl Cancer Inst (2004): Breast-Conserving Surgery With or Without Radiotherapy: Pooled-Analysis for Risks of Ipsilateral Breast Tumor Recurrence and Mortality) where it was concluded that omitting radiotherapy is associated with a large increase in risk of ipsilateral breast tumor recurrence and with a small risk increase in patient mortality. This was later reconfirmed in the recent review of Whelan (J Clin Oncol (2005): Use of Conventional Radiation Therapy As Part of Breast-Conserving Treatment) which concluded that breast irradiation substantially both reduces the risk of local recurrence and prevents the need for subsequent mastectomy, and appears to remains effective in the absence or presence of systemic therapy. This is in keeping with the early finding by the EBCTCG (Early Breast Cancer Trialists' Collaborative Group at Oxford, Lancet (2000): Favorable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials) that RT reduces local recurrence by about 70%, both after mastectomy or breast-conserving surgery (BCS). Even more impressively, when systemic therapy is combined with RT, there is a significant decrease in distant metastases coupled with an improvement in survival (Whelan et al., J Clin Oncol (2000): Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis). See also the thoughtful editorial and commentary by Harris (J Clin Oncol (2005): Radiation Therapy for Invasive Breast Cancer: Not Just for Local Control).

Furthermore the systematic review of PMRT (postmastectomy radiotherapy ) in the presence of adjuvant (or neoadjuvant) systemic therapy by Pierce (J Clin Oncol (2005): The Use of Radiotherapy After Mastectomy: A Review of the Literature) has clarified and reaffirmed guidelines (NIH Consensus Panel on Adjuvant Therapy of Operable Breast Cancer, ASTRO (American Society of Therapeutic Radiology and Oncology), ACR (American College of Radiology), ASCO (American Society of Clinical Oncology), and Health Canada ) on PMRT: that PMRT is well-motivated on the balance of the evidence for patients with four positive axillary nodes, T3 or T4 lesions, and/or tumor invading the skin or adjacent musculature. All groups found insufficient evidence to recommend PMRT in patients with one to three positive nodes (or high-risk node-negative disease). In addition, Ragaz et al. (J Natl Cancer Inst (2005): Locoregional Radiation Therapy in Patients With High-Risk Breast Cancer Receiving Adjuvant Chemotherapy: 20-Year Results of the British Columbia Randomized Trial) found in their 20-year review that for high-risk breast cancer patients treated with modified radical mastectomy, radiation therapy (schedule of 16 fractions) and adjuvant chemotherapy led to better survival outcomes than chemotherapy alone, reducing isolated locoregional recurrence, distant recurrence, deaths due to breast cancer, and overall mortality, while being well tolerated, and with acceptable long-term toxicity; these findings prompted the NCI to issue a clarifying Memo to the Media (Zielinski, J Natl Cancer Inst (2005): Adding Radiation Therapy to Chemotherapy Improves Survival in Patients With High-Risk Breast Cancer). See also the editorial by Whelan & Levine (J Natl Cancer Inst (2005): More Evidence That Locoregional Radiation Therapy Improves Survival: What Should We Do?).

And Genski et al. (J Natl Cancer Inst (2005): Survival Effects of Postmastectomy Adjuvant Radiation Therapy Using Biologically Equivalent Doses: A Clinical Perspective) note that although it is incontrovertible that postmastectomy radiation therapy (PMRT) reduces locoregional recurrence among women with operable breast cancer (with a relative risk reduction that is now known to be about 70%), the question of whether it also significantly improves survival has been well settled; they reanalyzed the results from 36 unconfounded trials where addition of radiation therapy was the sole discriminant between treatments being compared, finding that adjuvant radiation therapy with an optimal biologically equivalent dose (BED) of 40–60 Gy in 2-Gy fractions and appropriate target volume (irradiation of chest wall and regional lymph nodes) was statistically significantly associated with improved survival for up to 10 years. See also the commentary by Prosnitz & Marks (J Natl Cancer Inst (2005): Postmastectomy Radiotherapy: Quality Counts!) who conclude that "the evidence is now strong for survival benefits for both postmastectomy radiation therapy and postlumpectomy radiation therapy", as well as the commentaries of J Cuzick ((J Natl Cancer Inst (2005): Radiotherapy for Breast Cancer), Vallis & Tannock (J Natl Cancer Inst (2005): Postoperative Radiotherapy for Breast Cancer: Growing Evidence for an Impact on Survival), and Whelan & levine (J Natl Cancer Inst (2005): More Evidence That Locoregional Radiation Therapy Improves Survival: What Should We Do?).

Breast Cancer Watch Commentary: BCT Underuse
From the above systematic review undertaken by Breast Cancer Watch, we conclude that (1) despite the oncological safety and efficacy of BCT, and its well-established survival equivalence with mastectomy, BCT continues to be underutilized in the US (Morrow et al., J Clin Oncol (2001): Factors Predicting the Use of Breast-Conserving Therapy in Stage I and II Breast Carcinoma); (2) although the slow adoption and low deployment of BCT was originally considered to be a result of surgical professionals favoring mastectomy procedures, we now know that this is not a major influencing factor, and that indeed patient choice appears to be driving the decisions yielding BCT underuse (see Katz et al. (2005): Patient Involvement in Surgery Treatment Decisions for Breast Cancer who found that more patient involvement in the decision making was actually associated with greater use of mastectomy; also Nattinger's thoughtful editorial on this issue (J Clin Oncol (2005): Variation in the Choice of Breast-Conserving Surgery or Mastectomy: Patient or Physician Decision Making?); (3) clearer and more effective efforts need to be made at educating patients on how to navigate through the complex decision process of weighing BCT versus mastectomy, and on what the research findings have already established.

The Real Issue: Locoregional Recurrence
Although overall survival outcome is comparable between BCS (lumpectomy) and mastectomy, this is not the whole of what is critical to know about BCS versus mastectomy as a decision facing many breast cancer patients.
(1) For it is incontrovertible that BCS (breast-conserving surgery) like lumpectomy has a significantly higher incidence and likelihood of locoregional recurrence, especially IBTR (ipsilateral breast tumor recurrence), and locoregional recurrence occurs in 10%-20% of patients treated with breast-conserving surgery for stage I-II breast cancer (Fatouros M, Roukos DH, Arampatzis I, Sotiriadis A, Paraskevaidis E, Kappas AM. Factors increasing local recurrence in breast-conserving surgery. Expert Rev Anticancer Ther. 2005 Aug;5(4):737-45).
(2) In addition, such locoregional failure post-BCS is associated with poor prognosis in terms of lower survival via increased risk of distant metastasis and mortality (Nottage MK, Kopciuk KA, Tzontcheva A, et al. Analysis of incidence and prognostic factors for ipsilateral breast tumour recurrence and its impact on disease-specific survival of women with node-negative breast cancer: a prospective cohort study. Breast Cancer Res. 2006; 8(4):R44): IBTR is significantly associated with distant metastasis, with almost two-thirds of patients who develop invasive local recurrence following BCS going on to develop distant metastases (Voogd AC, Rutgers EJ, van Tienhoven G. The long-term prognosis of locally recurrent breast cancer after breast conserving treatment [in Dutch]. Ned Tijdschr Geneeskd. 2006 Jan 7;150(1):29-33), and although without radiotherapy (RT), the rate of IBTR is approximately 17%, even with RT it remains a significant 8.5% (Komoike Y, Akiyama F, Iino Y, et al. Ipsilateral breast tumor recurrence (IBTR) after breast-conserving treatment for early breast cancer: risk factors and impact on distant metastases. Cancer. 2006 Jan 1; 106(1):35-41); young age, positive surgical margin, and omission of RT all favor IBTR.
(3) For a large number of women, weighing on the one hand the prospect of locoregional recurrence and the associated distressful interventions to address the recurrence, against the equivalence of overall survival from BCS and mastectomy procedures on the other, nonetheless leads a significant proportion of women to elect non-BCS mastectomy. Fear of breast cancer recurrence and the understandable impulse to avoid associated pre-event anxieties continues to be a powerful motivator behind the continued election of mastectomy and the underutilization of BCS to this day.
(4) And as pointed out above,more patient involvement in the surgical decision making process is in fact associated with greater use of mastectomy (Katz et al. (2005): Patient Involvement in Surgery Treatment Decisions for Breast Cancer).

  Neoadjuvant versus Adjuvant Systemic Therapy

Until recently, the primary appeal of neoadjuvant (preoperative) systemic therapy has been, as we discussed above, to reduce the extent of local surgery required and in certain cases thereby allow or facilitate breast conservation therapy (BCT), typically consisting of breast conserving surgery (BCS) + radiotherapy (RT).

In an important recent contribution, Mauri et al. (J Natl Cancer Inst (2005): Neoadjuvant Versus Adjuvant Systemic Treatment in Breast Cancer: A Meta-analysis) conducted a metaanalysis of randomized trials that compared neoadjuvant with adjuvant therapy, finding no statistically or clinically significant differences between the two on the endpoints of overall survival, disease progression, or distant disease recurrence. This finding prompted the NCI to issue a clarifying Memo to the Media (Zielinski, J Natl Cancer Inst (2005): Neoadjuvant and Adjuvant Systemic Therapy for Breast Cancer Give Equivalent Survival, Study Finds)

However, the researchers found a statistically significant increased risk of loco-regional disease recurrences (with a local failure rate of approx. 22%) for neoadjuvant therapy compared with adjuvant therapy, although this increase in risk was largely attributable to neoadjuvant trials where patients showing a complete clinical response after neoadjuvant therapy received radiotherapy without surgery (see Davidson & Morrow, J Natl Cancer Inst (2005): Editorial - Sometimes a Great Notion—An Assessment of Neoadjuvant Systemic Therapy for Breast Cancer) who conclude consequentially to these findings that (1) surgery continues to be an essential part of the management of early breast cancer, even under the scenario of the apparent eradication of all grossly evident disease via systemic therapy and (2) "for women who are BCT candidates at presentation, neoadjuvant therapy does not offer any significant benefit for local control, possibly making it harder to determine the appropriate extent of resection.

Given this, it would appear therefore that neoadjuvant systemic therapy is a reasonable alternative, and attains its strongest motivation, in the case of patients with palpable cancers who require mastectomy.



pCR and Survival Outcome
pCR (pathological complete response) is defined as the absence of residual invasive cancer both in breast and axilla. Several trials first lent credence to the general belief that pCR to neoadjuvant chemotherapy appears to be associated with improved long-term outcome: the best known and widely cited is EORTC 10902 (van der Hage et al., J Clin Oncol (2001): Preoperative Chemotherapy in Primary Operable Breast Cancer: Results From the European Organization for Research and Treatment of Cancer Trial 10902), as well as NSABP B-18 (Fisher et al., Cancer (2002): Pathobiology of preoperative chemotherapy: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-1), and Chollet et al. (Br J Cancer (2002): Prognostic significance of a complete pathological response after induction chemotherapy in operable breast cancer). The cumulative import of these and similar trials was to suggest that breast pCR is the best available surrogate for elimination of microscopic metastatic disease, evidenced by long-term survival findings.

However, it is still indeterminate to what degree an improved pCR rate brought effected by some neoadjuvant therapy will translate into a true improvement in overall survival: so, NSABP B27 (Bear et al., J Clin Oncol (2003): The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Cyclophosphamide: Preliminary Results From National Surgical Adjuvant Breast and Bowel Project Protocol B-27) in the initial report of this trial documented a rough doubling in pCR from approximately 14% to 26% via the addition of docetaxel to a doxorubicin + cyclophosphamide combination chemotherapy (at a three-year point), but a later report of the same trial showed that the docetaxel addition was not associated with a statistically significant increase either in disease-free or overall survival (median follow-up of 5 years), confirming the observation of various researchers and clinicians that in RCTs a difference in pCR does not always nor necessarily translate into an outcome improvement (Beruti et al, J Clin Oncol (2005): Is Pathologic Complete Response a Valid Surrogate Parameter of Treatment Efficacy in HER2 Positive Breast Cancer Patients Undergoing Primary Chemotherapy Plus Trastuzamab?). And Buzdar et al. in their reply to Beruti et al. acknowledge that the existence of and the degree of correlation between pCR and survival (or disease-free survival) are still open questions, so that we cannot assume that a pCR benefit translates into a survival benefit (Buzdar et al., J Clin Oncol (2005): In Reply).

Indeed, some studies suggest that pCR is even in its narrower role an imperfect and not particularly"fine" indicator: Gadjos et al. (J Surg Oncol (2002): Relationship of clinical and pathologic response to neoadjuvant chemotherapy and outcome of locally advanced breast cancer" found little evidence that measurable clinical or pathologic changes attributable to chemotherapy predicted survival. Axillary lymph node status, associated with young age, was the most important prognostic indicator in these patients.

Given that a small percentage of breast cancer patients with pCR do subsequently experience recurrence, Gonzalez-Angulo et al. (J Clin Oncol (2005): Factors Predictive of Distant Metastases in Patients With Breast Cancer Who Have a Pathologic Complete Response After Neoadjuvant Chemotherapy) sought to identify what precise clinicopathological factors are predictive of distant metastasis in patients achieving pathologic complete response after neoadjuvant chemotherapy, finding that (1) clinical stages IIIB, IIIC, and IBC (exhibiting locally advanced disease and suboptimal axillary node evaluation), and (2) premenopausal status, predicted for distant metastasis.

This highlights the clinical reality that it appears that therapies need to have large and very substantial effects on end points such as pCR before they might significantly alter long-term survival, and the fact that pCR is not synonymous with cure as some risk of metastatic disease remains despite the lack of detectable carcinoma.

So researchers cautiously now say that pCR has the power to identify women with a relatively better outcome no matter which chemotherapy they received, but this only confirms a much quoted medical oncology adage that responders fare better than non-responders in general, not a particularly earthshaking finding. So in the end using pCR as a prognostic marker does not at present lead to a consistent, confirmable, quantification of the degree of benefit .

(5) pCR in Invasive Lobular Carcinoma (ILC)
And most radically, reversing generations of accepted clinical wisdom Cristofanilli and Carcinoma at MD Anderson Cancer Center sought to assess the prognostic value of pCR: their retrospective study (Cristofanilli et al., J Clin Oncol (2005): Invasive Lobular Carcinoma Classic Type: Response to Primary Chemotherapy and Survival Outcomes) of six clinical trials found that in the case of ILC (invasive lobular carcinoma) a poor response to chemotherapy in terms of measured pCR did not correlate with a poorer prognosis, as the study demonstrated that whether or not patients with ILC achieved a complete response, they nonetheless tended to have a more favorable prognosis even compared with hormone receptor positive invasive ductal carcinomas, typically a better prognosis group. So women with ILC had a poorer response to primary (neoadjuvant) chemotherapy yet better overall survival, with five-year survival significantly higher (91%) compared with women with invasive ductal carcinoma (72%) despite the fact that the latter exhibited higher pCR. It appears therefore that ILC patients achieved a clinical and pathological response to standard neoadjuvant chemotherapy significantly less frequently compared to women with ductal malignancy without necessarily being accompanied by an unfavorable prognosis. (See also the commentary on this study by Katz (J Clin Oncol (2005): Does Neoadjuvant/Adjuvant Chemotherapy Change the Natural History of Classic Invasive Lobular Carcinoma?) and the reply by Cristofanilli et al. (J Clin Oncol (2005): In Reply:).

Endocrine Therapy for MBC: Aromatase Inhibitors
In the MBC setting, endocrine therapy (ET) is primarily deployed for hormone-sensitive non-life-threatening MBC when the risk of rapid disease progression is low. Minimally, choice of optimal ET regimen must take into account menopausal status, the type of adjuvant ET received, and thromboembolic disease history, assuming positive estrogen receptor (ER+) and/or progesterone receptor (PR+) status of primary tumor. For reasons we have already articulated in our discussion of ET in the non-metastatic breast cancer setting, currently third generation aromatase inhibitors (AIs) have established themselves as the new gold standard for first-line ET in postmenopausal MBC patients.

The third generation AIs currently in use at this time are the non-steroidal, triazole compounds anastrozole (Arimidex) and letrozole (Femara) active by competitively inhibiting aromatase to significantly lower estrogen levels, and the steroidal exemestane (Aromasin) , active by binding irreversibly to the aromatase enzyme, requiring increased aromatase production to overcome the inhibition.

• Endocrine Therapy for Premenopausal MBC Patients
  For premenopausal women with ER- and/or PR-positive MBC, endocrine therapy options are:

• suppression of ovarian function via
  (a) surgery,
  (b) radiotherapy, or
  (c) LHRH analogues;
• tamoxifen;
• combination of ovarian function suppression + tamoxifen
• combination of LHRH analogues + aromatase inhibitor

• Suppression of Ovarian Function:
  Ovarian Ablation (OA) via Oophorectomy (OO)
  Ovarian Suppression (OS) via LHRH/GnRH Analogs


• Suppression of Ovarian Function
• OS (Ovarian Suppression via LHRH / GnRH) + Tamoxifen
• OS (Ovarian Suppression) via LHRH / GnRH) + AI (Aromatase Inhibitor)
• Ovarian Ablation (OA) and Ovarian Suppression (OS) versus Chemotherapy
• Ovarian Suppression (OS) and Ablation (OA): Breast Cancer Watch Summary

For complete coverage click on links above, but below for convenience we provide a brief summary:

[new] The LHRH-Agonist Overview Group Meta-Analysis of Adjuvant Ovarian Suppression
This has been further confirmed in the recently reported findings of the LHRH-Agonist Overview Group's meta-analysis of 13 randomized studies on adjuvant LHRH agonists in premenopausal patients with hormone receptor-positive breast cancer (LHRH-agonists in Early Breast Cancer Overview group, Cuzick J, Ambroisine L, Davidson N, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet. 2007 May 19;369(9574):1711-23).  The LHRH-Agonist Overview Group meta-analysis found:

(1) That in terms of women receiving an LHRH agonist versus no treatment, there was approximately a 30% reduction of recurrence and mortality.

(2) In terms of LHRH agonist versus chemotherapy, where most of the chemotherapy was CMF, with some anthracycline-based regimens also evaluated, the evidence suggested the two modalities were essentially equally effective, and although it is commonly objected that the chemotherapy like CMF is representative of an older generation of agents, in fact, the investigators were unable to find any real difference between anthracycline-based and CMF-based chemotherapy; this suggests that in women with low-risk disease LHRH agonists can be a reasonable alternative to chemotherapy, but in women with higher-risk disease, many clinicians would maintain that chemotherapy followed by tamoxifen should continue as the standard approach, with the addition of an LHRH agonist a reasonable option for those who remain premenopausal, as observed in an accompanying editorial by Nicholas Wilcken and Martin Stockler at the University of Sydney.
 
(3) One novel finding highlighted by the LHRH-Agonist Overview Group is the benefit of LHRH agonists after chemotherapy in premenopausal women younger than 40 years, but not in older premenopausal women, where in this group of younger than 40 women, chemotherapy is known to be less likely to induce permanent amenorrhea than in older women, and it must also be remembered that with modern non-CMF chemotherapy permanent amenorrhea occurs far less often.

(4) This leaves open the important question whether the addition of an LHRH agonist is clinical benefit only when amenorrhea is not induced by chemotherapy, given that some previous trials found worse outcomes after chemotherapy in such non-amenorrheic women, suggesting that this  would be the group who would benefit most from adding an LHRH agonist.

(5) in terms of the addition of an LHRH agonist to either chemotherapy, tamoxifen, or both, there was a modest effect of 12.7% improvement in recurrence and 15.1% in mortality, and effect that held whether the LHRH agonist was added to tamoxifen, chemotherapy or both. 

• The Steroidal Aromatase Inhibitor Exemestane
  Recent studies have in particular established exemestane as a safe and highly active steroidal aromatase inactivator, superior to tamoxifen in the treatment of metastatic breast cancer (with significantly longer median PFS (progression free survival)), viable as a first line therapy in hormone responsive MBC, and with a safety profile allowing for realistic deployment in adjuvant and preventive settings (Paridaens, J Clin Oncol (2004): First line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts) - A randomized phase III trial of the EORTC Breast Group).
  
  Selective Estrogen Receptor Downregulators: Fulvestrant
  A new anti-estrogen, fulvestrant (Faslodex), the first and currently the only member in a new class of endocrine agents, the class of selective estrogen receptor downregulators (SERDs), has been recently approved: fulvestrant operates as an estrogen receptor (ER) antagonist lacking partial agonist activity, but exhibits activity not only on breast tissue but also on the endometrium and bone. It has poor oral bioavailability, being given in monthly intramuscular injections.
  
  Fulvestrant is now being assessed in patients who do not respond to aromatase inhibitors. Fulvestrant should also be explored in premenopausal ER-positive patients where aromatase inhibitors cannot be used, or for prevention of breast cancer in high-risk patients. As noted by Weinberg et al. (Drug Resist Updat (2005): New approaches to reverse resistance to hormonal therapy in human breast cancer), fulvestrant - due to its unique mode of action, downregulating cellular levels of estrogen receptor with no agonist activity - may be an ideal candidate for combination treatment with inhibitors targeted to growth factor receptor signaling pathways.
  
  The study of Howell et al. (J Clin Oncol (2004): Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial) was the first RCT comparing the efficacy and tolerability of fulvestrant with tamoxifen in postmenopausal women with advanced predominantly ER/PR-positive, breast cancer and who had not received prior hormonal or cytotoxic therapy. Overall tolerability was similar in both groups (fulvestrant as a single monthly gluteal intramuscular injection), with however hot flush incidence significantly lower in the fulvestrant group. Time to tumor progression, the primary endpoint, was not significantly different between the two treatment groups and the general finding of the study showed no superiority of fulvestrant over tamoxifen.
  
  In advanced breast cancer, Howell et al. (Cancer (2005): Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma) examined the role of fulvestrant in the treatment of postmenopausal women with advanced breast carcinoma who had disease progression after receipt of previous endocrine treatment, finding that fulvestrant was similar to anastrozole with respect to overall survival in the second-line treatment, but was associated with a significantly lower incidence of joint disorders compared with anastrozole. Fulvestrant is currently being evaluated As a first-line treatment for metastatic disease in combination with anastrozole versus anastrozole alone in two phase III trials (Gradishar & Sahmoud, Clin Breast Cancer (2005): Current and Future Perspectives on Fulvestrant).

Chemotherapy (CT) in MBC: State of the Art

General Principles
The treatment of metastatic breast cancer has entered a new era where prolongation of survival and improvements in time to progression and duration of response, has become for the first time a realistic goal in the metastatic setting, largely to the advent of both new agents and new more targeted regimens, allowing more MBC patients to live longer with fewer disease-related symptoms. At present, three systemic treatment modalities are deployed: endocrine therapy (ET), chemotherapy (CT), and biologic targeted therapy (BT). And although the benefit of first-line chemotherapy for MBC is unquestionable, there is considerable controversy surrounding the value of second-lines chemotherapy, especially in terms of significant survival benefit (Cardoso et al, Ann Oncol (2002): Second and subsequent lines of chemotherapy for metastatic breast cancer: what did we learn in the last two decades?).

Taxane-containing v Non-taxane-containing Chemotherapy
Ghersi et al. (Cochrane Database Syst Rev., last update 02/03/2005: Taxane containing regimens for metastatic breast cancer (Cochrane Review); also Gheresi et al., Br J Cancer (2005): A systematic review of taxane-containing regimens for metastatic breast cancer) reviewed 21 randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing taxanes in women with metastatic breast cancer, finding (1) that taxane-containing regimens appear to improve overall survival, time to progression and overall response in women with metastatic breast cancer, and (2) taxane-containing regimens are more effective than some, but not all non-taxane-containing regimens; (3) taxane-based combination chemotherapy was associated with more neurotoxicity and alopecia than nontaxane based regimens.

Docetaxel (Taxotere) v Paclitaxel (Taxol)
The widely cited study of Jones et al. (Eur J Cancer Suppl. 2003): Phase III comparison of docetaxel (D) and paclitaxel (P) in patients with metastatic breast cancer (MBC) [editor note: also sometimes cited as Ravdin et al.]) as the first head-to-head comparison of these two taxanes (in MBC patients after anthracycline failure), where docetaxel was found to be statistically superior in terms of median time to tumor progression (TTP), but not overall response rate (RR). And we know independently that patients aged 65 years and greater appear to be more sensitive to docetaxel-induced neutropenia (ten Tije et al., J Clin Oncol (2005): Prospective Evaluation of the Pharmacokinetics and Toxicity Profile of Docetaxel in the Elderly).

Breast Cancer Watch - Clinical Practice Guideline
We do not find however this single study of Jones/Ravdin wholly compelling on the issue, as the paclitaxel regimen deployed appears to have been sub-optimal: as J Bonneterre (Medscape (2003): Advances in the Treatment of Breast Cancer: Continual Attempts at Improving Outcomes) has pointed out, a higher dose and/or a longer duration of infusion, or a weekly regimen would likely have found for equi-efficacy (at the expense of increased side effects incidence). Indeed, the tested dose of paclitaxel has been demonstrated to be clinically inferior to other taxane regimens in several randomized trials: Seidman et al. (J Clin Oncol (1998): Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer [pdf]) obtained highly favorable results with paclitaxel administered as a 1-hour infusion on weekly basis, finding this weekly paclitaxel regimen well tolerated and exhibiting a remarkable lack of overall and cumulative myelosuppression, with no febrile neutropenia observed, and more recently Del Mastro et al. (Ann Oncol (2005): Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano DI Oncologia Geriatrica (GIOGer)) likewise found weekly paclitaxel to be highly active in elderly advanced breast cancer patients (see also Winer et al., J Clin Oncol (2004): Failure of Higher-Dose Paclitaxel to Improve Outcome in Patients With Metastatic Breast Cancer: Cancer and Leukemia Group B Trial 9342) who found no benefit from higher doses (above 175 mg/m2) of paclitaxel administered as a 3-hour infusion in the metastatic breast cancer setting), and the sober remarks of Hudis (J Clin Oncol (2005): Testing Chemotherapy for Breast Cancer: Timing Is Everything) who like us questions at this juncture the clinical relevance of the Jones finding given the advances in superior paclitaxel administration schedules than that tested by Jones et al. (175 mg/m2 during 3 hours every third week).

---

• Breast Cancer Watch Summary: Choosing a Taxane
  Paclitaxel (Taxol) versus Docetaxel (Taxotere)
  On the basis of these (above) considerations, therefore, Breast Cancer Watch does not find sufficient compelling evidence to suggest that the two major taxanes, docetaxel and paclitaxel, are significantly different in clinical efficacy and the widely cited Jones et al. study cannot be viewed as dispositive on the issue, for the reasons we have presented. Recent evidence reported at the 28th Annual SABCS (San Antonio Breast Cancer Symposium) further validates our conclusion: the ECOG 1199 trial (Sparano et al., 28th Annual San Antonio Breast Cancer Symposium (2005): Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer: results of North American Breast Cancer Intergroup Trial E1199) compared AC (doxorubicin + cyclophosphamide) followed by either paclitaxel or docetaxel, given either weekly or every 3 weeks in 5000 women, with data presented with nearly 4 years of follow-up, and found that the primary study comparisons demonstrated equivalence, with neither paclitaxel nor docetaxel emerging as superior with respect to DFS (disease-free survival), and in the aggregate nor was the weekly regimen different from every-3-weeks regimen, However, there were significant differences in the feasibility of therapy, with weekly docetaxel the least feasible regimen, and every-3-weeks docetaxel associated with the most myelotoxicity (presenting as febrile neutropenia), although it was this every-3-weeks docetaxel regimen along with weekly paclitaxel that were associated with the best clinical outcomes from the vantage point of DFS.
  
  Clinical Question:
  Every-3-Week vs Every-2-Week Paclitaxel (Dose-dense)
  An update, with median follow-up of 6.5 years, of CALGB 9741 (Hudis et al., 28th Annual San Antonio Breast Cancer Symposium (2005): Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective) which defined the every-2-weeks was presented by C Hudis at the 28th Annual SABCS (San Antonio Breast Cancer Symposium), continuing to show an advantage for the dose-dense every-2-weeks chemotherapy compared with every-3-weeks AC paclitaxel, with respect to both DFS and overall survival, the dose-dense regimen demonstrating reduced hazards of recurrence. The major difference in outcome with the dose-dense scheduling is seen in women with ER-negative tumors, with the difference among patients with ER-positive tumors less clear, according to exploratory subset analyses. It was reassuring to learn that the risk of acute myeloid leukemia / myelodysplastic syndrome was not increased with the dose-dense arms of treatment. Thus dose-dense every-2-weeks AC paclitaxel is clinically superior to every-3-weeks AC paclitaxel.
  

Comparison of Taxanes:

• Docetaxel (Taxotere) exhibits higher incidence of treatment-related hematologic and nonhematologic toxicities than paclitexal (Taxol).
  
• Paclitaxel (Taxol) is more likely to produce dose-limiting neurotoxicity and myalgias / arthralgias.
  
• Docetaxel (Taxotere) is more likely to be associated with cumulative fluid retention.
  
• However, QOL (quality-of-life scores) are not statistically different between these two taxanes over time.

---

Nanoparticle Albumin-Bound Paclitaxel (Nab-Paclitaxel)
(ABI-007 (Abraxane))
There has recently been aggressive development of several new taxane formulations, such as the cremophor-free, polymeric micelle formulated paclitaxel (Genexol-PM), and paclitaxel is bound to nanoparticles of albumin, the natural occurring vehicle for hydrophobic molecules (from APP as Abraxane). A recent phase III trial by Gradishar et al. (J Clin Oncol (2005): Superior Efficacy of Albumin-Bound Paclitaxel, ABI-007, Compared With Polyethylated Castor Oil-Based Paclitaxel in Women With Metastatic Breast Cancer: Results of a Phase III Trial) compared nanoparticle albumin-bound paclitaxel to conventional paclitaxel (Taxol) for women with metastatic breast cancer. Using 3-week cycles, conventional paclitaxel was administered at the licensed dose of 175 mg/m2 with steroid premedication, while nanoparticle albumin-bound paclitaxel was administered at 260 mg/m2. Both the primary endpoint, overall response rate, and the secondary endpoint, time to progression, were superior for patients assigned to nanoparticle albumin-bound paclitaxel. Note however that overall survival did not differ significantly in the intent-to-treat population for the two groups, although for the subgroup who received therapy as second or third line, nanoparticle albumin-bound paclitaxel was superior to convention paclitaxel. But a dramatic difference was exhibited in the toxicity profiles of the two drugs, with grade 4 neutropenia significantly lower in the nanoparticle albumin-bound paclitaxel group, with no severe hypersensitivity reactions despite the absence of steroid premedication, and with the higher incidence of sensory peripheral neuropathy being relatively short-term and reversible, and manageable through treatment interruption and dose reduction. The authors therefore underline this clear advantage in terms of lower incidence of myelosuppression of nanoparticle albumin-bound paclitaxel over conventional paclitaxel.

Nyman et al. (J Clin Oncol (2005): Phase I and Pharmacokinetics Trial of ABI-007, a Novel Nanoparticle Formulation of Paclitaxel in Patients With Advanced Nonhematologic Malignancies) evaluated the nab-paclitaxel (Abraxane) in patients with advanced nonhematologic malignancies without premedication at dose levels from 80 to 200 mg/m2 as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle), with partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with standard paclitaxel (containing polyoxyethylated castor oil) in the formulation, with dose-limiting toxicities of grade 4 neutropenia and grade 3 peripheral neuropathy, demonstrating that weekly nab-paclitaxel (Abraxane) can be administered at doses exceeding those typically used for polyoxyethylated castor oil containing paclitaxel.

[new] Abraxane + Avastin: Nab-paclitaxel + Bevacizumab (Avastin)
More recently, Link et al. (SABCS (2006): Bevacizumab (Avastin) and albumin bound paclitaxel (Abraxane) treatment in metastatic breast cancer) found in a pilot study of nab-paclitaxel (Abraxane) that the combination of nab-paclitaxel with bevacizumab demonstrated clinical benefit for heavily pretreated women with metastatic breast cancer. And Schwartzberg et al. (SABCS (2006): Phase II trial of nanoparticle albumin-bound paclitaxel (ABX) + capecitabine (XEL) in first-line treatment of metastatic breast cancer (MBC): interim results) conducted a multicenter, open-label, phase II interim analysis of first-line therapy with weekly nab-paclitaxel 125 mg/m2 Days 1 and 8 (no premedications, reduced to 100 mg/m2) plus daily capecitabine, (825 mg/m2 twice daily days 1-14, reduced to either 650 mg/m2 or 550 mg/m2 as needed), in 3 week cycles, finding the regimen active and well tolerated, with over 50% of patients achieving at least a partial response, and with prolonged progression-free survival and relatively low incidence of grade 3/4 adverse events.

Breast Cancer Watch Commentary on ABI-007/Abraxane
Despite these positive findings, there are several methodological issues that constrain an impulse to shift in clinical therapy:
(1) for various reasons, there has been a broad significant shift in clinical practice, especially in the MBC (metastatic breast cancer) setting toward docetaxel (Taxotere) as the reference standard over paclitaxel (Taxol);
(2) as we document below, on the basis of the critical appraisal in our systematic review, the 3-weekly schedule appears on the weight of the evidence to be suboptimal compared to weekly taxane schedules.

[new] Nonetheless, it now appears on the balance of the evidence that weekly nab-paclitaxel (Abraxane) yields the highest response rates when compared with every 3 week nab-paclitaxel or docetaxel (Taxotere), and that response rates are comparable between weekly low-dose and weekly high-dose nab-paclitaxel; in addition all nab-paclitaxel arms produced lower rate of neutropenia and mucositis in comparison with docetaxel (Gradishar et al., SABCS (San Antonio Breast Cancer Symposium) 2006: A randomized phase 2 trial of qw or q3w ABI-007 (ABX) vs. q3W solvent-based docetaxel (TXT) as first-line therapy in metastatic breast cancer (MBC). As Robert Livingston of the Arizona Cancer Center pointed out, in terms of response rate and time to progression the magnitude of improvement demonstrated by nab-paclitaxel to paclitaxel on an every three-week schedule for metastatic breast cancer (Gradishar et al., J Clin Oncol (2005): Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil–Based Paclitaxel in Women With Breast Cancer) is comparable to the magnitude of difference that was demonstrated in ECOG-E2100 between paclitaxel alone and paclitaxel with bevacizumab (Miller et al., J Clin Oncol (2005): Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer); as he remarked:

[new] "The paclitaxel with bevacizumab trial was accepted with great enthusiasm - legitimately - and presented in a fairly frenzied special oral session at ASCO, while the trial involving nab paclitaxel versus paclitaxel was basically disregarded - in my own practice, I’m prescribing patients paclitaxel because of the cost differential. If cost were not an issue, I would stop administering paclitaxel today and substitute it with nab paclitaxel"
(Breast Cancer Update, V.5, Issue 8 (2006): Conversations with Oncology Investigators: Bridging the Gap between Research and Patient Care).


Breast Cancer Watch Taxane Guidance
(1) nab-paclitaxel (Abraxane) over paclitaxel (Taxol), in any cases when the cost can be managed;
(2) a weekly administration schedule of both docetaxel and paclitaxel over once-every-3-weeks administration; the latter schedule should be disfavored due to
(a) its lack of evidence of superior antitumor efficacy;
(b) the inferior antitumor efficacy vis a vis pCR (pathologic complete response) rates in the case of paclitaxel;
(b) its less favorable toxicity profiles, with higher incidence of febrile neutropenia and myelosuppression.

Mono-Chemotherapy v Poly-Chemotherapy
Until recently, a standard assumption of therapy in the metastatic breast cancer setting has been that combining agents will yield regimens with superior response rates, improved palliative efficacy, disease-free survival, and overall survival (Fossati et al., J Clin Oncol (1998): Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women [pdf]). But currently the clinical medical oncology community is in a schism over of this issue of treating ER/PR-negative MBC patients either by (1) combination CT regimens (poly-CT) in all endocrine-resistant patients, or by (2) single agents deployed in sequence (mono-CT), unless symptoms or signs of life-threatening disease exist, with sub-questions concerning the optimal administration schedule for chemotherapy in MBC: concurrent versus sequential. Prior to the advent of paclitaxel (Taxol), the chemotherapeutic agent considered to exhibit the greatest single-agent activity was the antitumor antibiotic doxorubicin (Adriamycin).

Anthracyclines (Doxorubicin) + Taxanes
Addressing some of these issues is the pivotal trial of Sledge et al. (J Clin Oncol (2003): Phase III Trial of Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193)) which compared single-agent doxorubicin, single-agent paclitaxel, and the combination of doxorubicin and paclitaxel as front-line therapy for patients with metastatic breast cancer, reasoning plausibly that this combination might result in superior therapeutic activity; three critical findings were established:
(1) doxorubicin and paclitaxel have equivalent activity;
(2) the doxorubicin + paclitaxel combination results in superior overall response rates and time to TTF (Median time to treatment failure ); and
(3) despite these results, combination therapy with doxorubicin + paclitaxel did not improve either survival or quality of life compared to sequential single-agent therapy.

Note that earlier, Chan et al. (J Clin Oncol (1999): Prospective Randomized Trial of Docetaxel Versus Doxorubicin in Patients With Metastatic Breast Cancer) compared doxorubicin and docetaxel, finding docetaxel to produce a significantly higher rate of objective response than did doxorubicin, being significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (and resistance to prior chemotherapy, although median overall survival was similar in the two groups; toxicity profiles differed, with febrile neutropenia and severe infection, cardiac toxicity, nausea, vomiting, and stomatitis occurring more frequently in the doxorubicin group, and diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel. And Cresta et al. (Ann Oncol (2004): A randomized phase II study of combination, alternating and sequential regimens of doxorubicin and docetaxel as first-line chemotherapy for women with metastatic breast cancer) explored this doxorubicin + docetaxel administered either as a combination, an alternating regimen, or a sequential regimen in women with metastatic breast cancer, finding that doxorubicin and docetaxel yielded therapeutic results independently of the schedule of administration, although the therapeutic window of the combination was worse than that of the alternating and sequential regimens due to significantly more hematological (grade 4 neutropenia and febrile neutropenia) and cardiac toxicity (congestive heart failure only occurred in the combination arm), most likely due to the higher total dose of delivered doxorubicin. A valuable side benefit of the study was the fact that prophylaxis with ciprofloxacin did not reduce the incidence of febrile neutropenia or infection.

Nabholtz et al. (J Clin Oncol (2003) looked a combination anthracycline + taxane regimen, namely doxorubicin coupled with docetaxel (Taxotere) in their study (J Clin Oncol (2003): Docetaxel and Doxorubicin Compared With Doxorubicin and Cyclophosphamide as First-Line Chemotherapy for Metastatic Breast Cancer: Results of a Randomized, Multicenter, Phase III Trial), establishing that doxorubicin + docetaxel significantly improved TTP (time to treatment failure ) and ORR (overall response rate) compared with AC (doxorubicin + cyclophosphamide) in patients with MBC, but without a difference in OS (overall survival). And we now know that the addition of cyclophosphamide to doxorubicin + docetaxel regimen can extend to efficacy even to a survival benefit: this was established by Martin et al. (NEJM (2005): Adjuvant Docetaxel for Node-Positive Breast Cancer) who compared two chemotherapy regimens, TAC (docetaxel plus doxorubicin and cyclophosphamide) and FAC (fluorouracil plus doxorubicin and cyclophosphamide), as adjuvant chemotherapy for operable node-positive breast cancer, finding TAC, as compared with FAC, significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer.

Note however that in contrast to the positive results reported for sequential docetaxel after AC (doxorubicin and cyclophosphamide), the findings of Evans et al,, (J Clin Oncol (2005): Phase III Randomized Trial of Doxorubicin and Docetaxel Versus Doxorubicin and Cyclophosphamide As Primary Medical Therapy in Women With Breast Cancer: An Anglo-Celtic Cooperative Oncology Group Study) do not suggest a benefit for simultaneous doxorubicin + docetaxel over AC.

Breast Cancer Watch Warning: We note however in this connection that there have been recent disturbing findings concerning the doxorubicin and docetaxel regimen: the open-label trial of Brain et al. (JAMA (2005): Life-Threatening Sepsis Associated With Adjuvant Doxorubicin Plus Docetaxel for Intermediate-Risk Breast Cancer) found a high risk of life-threatening sepsis complications associated with the doxorubicin-docetaxel regimen, with the incidence of febrile neutropenia significantly higher than with the doxorubicin-cyclophosphamide regimen. The researchers caution therefore that the doxorubicin-docetaxel combination should only be considered as an alternative to the doxorubicin-cyclophosphamide regimen within the context of carefully designed studies that include primary prophylaxis for febrile neutropenia. A regimen of sequential doxorubicin and docetaxel (A--->T) would appear deployable and equi-efficacious in the alternative: in a randomized, multicenter, phase III trial Alba et al. (J Clin Oncol (2004): Multicenter Randomized Trial Comparing Sequential With Concomitant Administration of Doxorubicin and Docetaxel As First-Line Treatment of Metastatic Breast Cancer: A Spanish Breast Cancer Research Group (GEICAM-9903) Phase III Study) evaluated whether sequential doxorubicin and docetaxel (AT) reduced hematological toxicity, especially febrile neutropenia, compared with concomitant (AT) administration as first-line chemotherapy in metastatic breast cancer (MBC), finding in the affirmative, that sequential A--->T significantly reduced febrile neutropenia compared with concurrent AT in MBC patients while maintaining comparable antitumoral efficacy.

Breast Cancer Watch - Clinical Practice Guideline
On the basis of the potential life-threatening sepsis / febrile neutropenia associated with the concurrent doxorubicin + docetaxel regimen, the sequential A--->T regimen, with comparable antitumoral efficacy but reduced hematological toxicity, especially febrile neutropenia, should replace concurrent doxorubicin + docetaxel in all but highly controlled settings incorporating and assuring primary prophylaxis for febrile neutropenia. To date, it appears that the risk of febrile neutropenia can be effectively reduced by:
(1) deployment of a sequential doxorubicin ---> docetaxel regimen over a concurrent regimen,
(2) deployment of a weekly administration schedule of docetaxel over once-every-3-weeks administration; note it appears that for both taxanes the dose limiting toxicity for 3-weekly taxanes, severe neutropaenia, is generally very limited in weekly regimens (Wildiers & Paridaens, Cancer Treat Res (2004): Taxanes in elderly breast cancer patients);
(3) addition of the protein cytokine biologic response modifier, pegfilgrastim (Neulasta);
(4) switching from docetaxel (Taxotere) to paclitaxel (Taxol), since the use of docetaxel provokes a greater incidence (a least 3x greater) and severity of neutropenia (Luis-Fernandez et al., Invest Clin (2005): Neutropenia induced by taxoids and its control with granulocyte colony-stimulating factor).


Chemotherapy-induced Neutropenia
Furthermore, as we noted above, patients aged 65 years and greater appear to be more sensitive to docetaxel-induced neutropenia (ten Tije et al., J Clin Oncol (2005): Prospective Evaluation of the Pharmacokinetics and Toxicity Profile of Docetaxel in the Elderly). Vogel et al. (J Clin Oncol (2005): First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study) evaluated the efficacy of pegfilgrastim (Neulasta), a protein cytokine biologic response modifier used to the neutrophils (white blood cells) in the blood after chemotherapy and hence decrease the risk of infection, to reduce the incidence of febrile neutropenia associated with docetaxel in breast cancer patients, finding that first and subsequent cycle use of pegfilgrastim (pegfilgrastim 6 mg subcutaneously on day 2 of each 21-day chemotherapy cycle of 100 mg/m2 docetaxel) in this context markedly reduced febrile neutropenia, febrile neutropenia–related hospitalizations, and IV anti-infective use, with pegfilgrastim generally well tolerated and safe. Papaldo et al. (J Clin Oncol (2005): Impact of Five Prophylactic Filgrastim Schedules on Hematologic Toxicity in Early Breast Cancer Patients Treated With Epirubicin and Cyclophosphamide) evaluated the comparative efficacy of varying intensity schedules of filgrastim support in preventing febrile neutropenia in early breast cancer patients on a relatively high-dose EC (epirubicin plus cyclophosphamide) regimen, finding that the frequency of prophylactic G-CSF administration could be reduced to just two administrations (days 8 and 12) without altering outcome on incidence of neutropenic fever. However, as Djulbegovic et al. (J Clin Oncol (2005): Acting on Imperfect Evidence: How Much Regret Are We Ready to Accept?) validly observe, this a nonrandomized observational trial and hence on its own insufficient to motivated changes in clinical practice.
In sum, given its efficacy and once-per-cycle administratio, pegfilgrastim is widely usew to support delivery of dose-dense chemotherapy, stem cell mobilization, and stem cell transplantation after high-dose chemotherapy in patients with non-myeloid or myeloid malignancies.

Clark et al. (J Clin Oncol (2005): Colony-Stimulating Factors for Chemotherapy-Induced Febrile Neutropenia: A Metaanalysis of Randomized Controlled Trials) conducted a comprehensive metaanalysis to evaluate the safety and efficacy of the CSFs in patients with febrile neutropenia, concluding that CSFs in patients with established chemotherapy-induced febrile neutropenia reduces the time spent in hospital as well as the neutrophil recovery period, but finding that the question of the possible influence of the CSFs on infection-related mortality requires further investigation. Note however that MA Fridrik, J Clin Oncol (2005): Is the Statistical Difference Clinically Relevant?) observe that the Clark et al. presentation is only of relative reduction, not absolute reduction numbers (see the response by Clark et al., J Clin Oncol (2005): In Reply:).

In addition, Frampton et al. (BioDrugs (2005): Spotlight on Pegfilgrastim in Chemotherapy-Induced Neutropenia) evaluated pegfilgrastim (Neulasta), the sustained-duration form of filgrastim (Neupogen), both being recombinant human granulocyte colony-stimulating factors (G-CSFs) approved for the reduction of the incidence of febrile neutropenia (fever with concomitant reduction in their white blood cells with associated susceptibility to infection) consequent to myelosuppressive chemotherapy; they found that a single subcutaneous injection of pegfilgrastim once per chemotherapy cycle used as an adjunct to moderately myelosuppressive chemotherapy for breast cancer was more effective than placebo, and non-inferior to daily injections of filgrastim. Pegfilgrastim also provides effective support for dose-dense chemotherapy, and offers a convenient alternative to daily filgrastim.

Breast Cancer Watch - Clinical Practice Guideline
Given therefore pegfilgrastim's general safety and tolerability, it would appear prudent to deploy it in populations at higher risk of febrile neutropenia associated with myelosuppressive chemotherapy with docetaxel and docetaxel-containing regimens, especially in the elderly 65 years and older.

Breast Cancer Watch:
Warnings for Filgrastim (Neupogen) & Pegfilgrastim (Neulasta)
(1) Rare Splenic Rupture and Allergic Reactions:
The manufacturer, Amgen, warns that rare cases of splenic rupture and allergic reactions, including anaphylaxis, have been reported in postmarketing experience with pegfilgrastim. Rarely, these allergic reactions recurred within days after discontinuing anti-allergic treatment. The potential for such rare adverse events must be balanced against the potential for more likely serious development of life-threatening sepsis / febrile neutropenia in such higher risk populations.
Note: We also know from Cresta et al. (Ann Oncol (2004): A randomized phase II study of combination, alternating and sequential regimens of doxorubicin and docetaxel as first-line chemotherapy for women with metastatic breast cancer) cited above, that attempted prophylaxis with ciprofloxacin does not reduce the incidence of febrile neutropenia or infection.
(2) Bone Pain:
Bone pain is a common side effect of G-CSF therapy with filgrastim (Neupogen), and it appears that this is also true for the pegylated long-acting filgrastim analogue, pegfilgrastim (Neulasta), typically administered once per chemotherapy cycle: Kubista et al. Clin Breast Cancer (2003): Bone Pain Associated with Once-Per-Cycle Pegfilgrastim Is Similar to Daily Filgrastim in Patients with Breast Cancer) found no statistically significant difference of bone pain incidence, severity, or duration between patients once-per-cycle pegfilgrastim and those receiving daily filgrastim, with bone pain incidence and severity significantly greater in cycle 1 for both regimens. Among patients experiencing bone pain, there was a trend towards earlier onset with pegfilgrastim compared with filgrastim, but this was not associated with increased bone pain severity or duration, and in patients receiving a fixed 6-mg dose of pegfilgrastim, the overall bone pain incidence was similar when analyzed by body weight, with no patients withdrawing due to bone pain.

Optimizing Taxanes in MBC
The taxanes differentiate with respect to their efficacy:toxicity ratio in relation to dose and schedule: the recommended dosing for paclitaxel is 175 mg/m2 as a 3-h i.v. Infusion every 3 weeks, whereas docetaxel is recommended at 60–100 mg/m2 as a 1-h i.v. Infusion every 3 weeks, unless administered in combination with an anthracycline, in which case the recommended docetaxel dose is 75 mg/m2. Weekly taxane schedules are being explored to optimize dose intensity and avoid tumor regrowth between cycles, with the potential for improved tolerability through dosing well below the maximum tolerated dose. And preliminary results from a Phase II randomized trial of single-agent docetaxel in MBC have confirmed similar antitumor efficacy for patients receiving either weekly or 3-weekly treatment, but with different toxicity profiles (Climent et al., Proc Am Soc Clin Oncol (2002): Preliminary results of a phase II randomized trial of docetaxel (taxotere) as a single agent chemotherapy (CT) administered weekly or 3-weekly in patients (pts) with metastatic breast cancer (MBC)). This early finding has more recently been confirmed and extended in the study of Tabernero et al. in the metastatic breast cancer setting (Ann Oncol (2004): A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer) where it was found that weekly docetaxel (docetaxel 40 mg/m2 weekly for 6 consecutive weeks followed by 2 weeks without treatment) exhibited comparable efficacy to 3 weekly docetaxel (100 mg/m2 on day 1 every 3 weeks), with a more favorable toxicity profile, although both schedules were well tolerated overall.

This has also been confirmed more recently for the other major taxane, paclitaxel in the study of Del Mastro et al. (Ann Oncol (2005): Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano DI Oncologia Geriatrica (GIOGer)) who found weekly paclitaxel to be highly active in elderly advanced breast cancer patients; however, they note that cardiovascular complications indicate the need for a careful and rigorous monitoring of patient cardiac function before and during chemotherapy. And the study of Green et al. (J Clin Oncol (2005): Weekly Paclitaxel Improves Pathologic Complete Remission in Operable Breast Cancer When Compared With Paclitaxel Once Every 3 Weeks) examined the impact a change in schedule of paclitaxel administration from once every 3 weeks (followed by four cycles of fluorouracil / doxorubicin / cyclophosphamide (FAC) in standard doses every 3 weeks) to weekly administration (for a total of 12 doses of paclitaxel) would have on the pathologic complete response (pCR) rate in the breast and lymph nodes in patients with invasive breast cancer treated with primary systemic chemotherapy (PST). They found that patients receiving weekly paclitaxel had a higher pCR (pathologic complete response) rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%), with improved breast conservation rates, and thus significantly improving the eradication of invasive cancer in the breast and lymph nodes.

Furthermore, weekly lower dose taxanes showed a more favorable toxicity profile, and were associated with a lower incidence of febrile neutropenia and myelosuppression, with lower overall toxicity, while maintaining efficacy (see the review of Crown et al., Oncologist (2004): Docetaxel and Paclitaxel in the Treatment of Breast Cancer: A Review of Clinical Experience). To date, it appears that fatigue is the common primary toxicity associated with weekly docetaxel. And as has been noted by Hainsworth (Oncologist 2004): Practical Aspects of Weekly Docetaxel Administration Schedules), other side effects are like excessive tearing, nail changes, and alopecia appear to be cumulative toxicities, with most of these side effects manageable or minimizable by effecting relatively minor changes in the docetaxel dose or schedule.

Breast Cancer Watch - Clinical Practice Guideline
On the basis of these and other studies we critically appraised in systematic review (Aug, 2005), Breast Cancer Watch recommends weekly administration schedules of both docetaxel and paclitaxel over once-every-3-weeks administration; the latter should be disfavored due to (1) its lack of evidence of superior antitumor efficacy; (2) the inferior antitumor efficacy vis a vis pCR (pathologic complete response) rates in the case of paclitaxel; (3) its less favorable toxicity profiles, with higher incidence of febrile neutropenia and myelosuppression. A critical caution however is careful and rigorous monitoring of cardiac function, as weekly taxanes administration may result in somewhat higher cardiotoxicity.

Anthracyclines (Epirubicin) + Vinorelbine
Building on the finding that epirubicin (at doses equivalent to doxorubicin) has been shown to be equally efficacious and less toxic than doxorubicin (Findlay & Walker-Dilks, Cancer Prev Control (1998): Epirubicin, alone or in combination chemotherapy, for metastatic breast cancer. Provincial Breast Cancer Disease Site Group and the Provincial Systemic Treatment Disease Site Group), Ejlertsen et al. (J Clin Oncol (2004): Phase III Study of Intravenous Vinorelbine in Combination With Epirubicin Versus Epirubicin Alone in Patients With Advanced Breast Cancer: A Scandinavian Breast Group Trial (SBG9403)) sought to determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer, finding that vinorelbine + epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.
Note: Although FDA-approved for treatment of early breast cancer, epirubicin is not currently approved for use in the metastatic breast cancer setting, although used and approved throughout the European community for MBC treatment.



• New and Emerging Chemotherapies:
  Capecitabine Regimens
  
  Capecitabine + Paclitaxel
  The tumor-activated oral fluoropyrimidine capecitabine (Xeloda) exhibits consistently high antitumor efficacy, achieving a high tumor control rate in heavily pretreated patients with metastatic breast cancer, with a favorable safety profile, good tolerability, and convenient oral administration allowing for outpatient therapy (Reichardt et al, Ann Oncol (2003): Multicenter phase II study of oral capecitabine (Xeloda") in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy). It has further been observed that both docetaxel and capecitabine show high single-agent antitumor efficacy in metastatic breast cancer, as well as synergy of activity in preclinical studies. Pursuing this, Gradishar (J Clin Oncol (2004):Capecitabine Plus Paclitaxel As Front-Line Combination Therapy for Metastatic Breast Cancer: A Multicenter Phase II Study) conducted a multicenter, open-label phase II study to evaluate this combination therapy (using capecitabine and the taxane paclitaxel) in patients with metastatic breast cancer (MBC), finding the combination therapy highly active and generally well-tolerated regimen for first-line treatment of MBC. More recently, Costanzo et al. (Ann Oncol (2005): Weekly paclitaxel plus capecitabine in advanced breast cancer patients: dose-finding trial of GOIRC and GOL) found that paclitaxel and capecitabine demonstrate a synergetic effect and significant antitumor activity in patients with advanced breast cancer, and that weekly paclitaxel plus capecitabine is a safe and active chemotherapy in previously treated metastatic breast cancer.
  
  Note also that more RCTs are needed to fully place capecitabine within the menu of available chemotherapy options, as many of the studies suffer from poor methodological quality: see Jones et al., Health Technol Assess (2004): ).Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda®) for locally advanced and/or metastatic breast cancer.
  
  Optimizing the Capecitabine Schedule
  O’Shaughnessy et al (J Clin Oncol (2002): Superior Survival With Capecitabine Plus Docetaxel Combination Therapy in Anthracycline-Pretreated Patients With Advanced Breast Cancer: Phase III Trial Results) conducted a phase III trial comparing the efficacy and tolerability of capecitabine + docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC, finding that the combination regimen (21-day cycles of oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 plus docetaxel 75 mg/m2 on day 1) resulted in significantly superior efficacy in time to disease progression (TTP), objective tumor response rate, and overall survival compared to single agent docetaxel, concluding that docetaxel + capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.
  Breast Cancer Watch notes here that although in the O’Shaughnessy study the FDA-approved 1,250 mg/m2 twice daily dose of capecitabine, the earlier Gradishar study used a lower 825 mg/m2 twice daily dose.
  
  As we have noted above, in the O’Shaughnessy study, capecitabine was used at the FDA-approved dose (2500 mg/m2/day) which clinical experience suggests may result in unacceptable toxicity. Researchers at the MD Anderson Cancer Center in a retrospective analysis (Hennessy et al., Ann Oncol (2005): Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature) tested lower dose capecitabine regimens and on the basis of their findings recommend a starting dose of 2000 mg/m2/day because of its superior therapeutic index, without leading to poorer response rates or shorter time to progression; and this finding is cross-verified by Bajetta et al. (J Clin Oncol (2005): Safety and Efficacy of Two Different Doses of Capecitabine in the Treatment of Advanced Breast Cancer in Older Women) where capecitabine was tested in elderly breast cancer patients (median age, 73 years; range, 65 to 89 years), comparing oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 every 21 days versus capecitabine 1,000 mg/m2 twice daily (this regimen was a fallback after two toxic deaths (out of 30 patients)); the researchers concluded that lower-dose capecitabine dose (1,000 mg/m2 twice daily) merits consideration as "standard" for older patients who do not have severely impaired renal function.
  
  [new] Low-dose Capecitabine (Xeloda)
  In addition, the study of Leonard and international coresearchers (Ann Oncol (2006): Detailed analysis of a randomized phase III trial: can the tolerability of capecitabine plus docetaxel be improved without compromising its survival advantage?) found that the simultaneous reduction of capecitabine and docetaxel (to 950 mg/m2 and 55 mg/m2, respectively), yielded fewer cycles (17%) with grade 3/4 adverse events compared with the full doses (34%), with time to progression and overall survival similar in patients starting the second cycle with these reduced doses of capecitabine/docetaxel and those who continued to receive full doses for at least the first four cycles. It is clear from these cited studies in the aggregate that capecitabine (Xeloda) dosing flexibility permits considerable side-effects management without compromise to efficacy.
  
  
  To further address the problem of capecitabine's propensity to induce hand-foot syndrome (HFS) and gastrointestinal toxicity, in particular diarrhea, in higher doses, including at or somewhat under the official FDA approval dose (2500 mg/m2/day), various modified schedules have been tested sucessfully, including as above 1000mg/m2 twice daily. Recently, the Japanese researchers Saeki et al. (Breast Cancer (2006): A Pilot Phase II Study of Capecitabine in Advanced or Recurrent Breast Cancer [pdf]) tested an intermittent capecitabine therapy consisting of 828 mg/m2 twice daily for 3 weeks followed by a 1-week rest period, finding it to be both effective (overal response 45.5%) and well tolerated as second-line treatment for advanced or recurrent breast cancer. Only 35% of the patients (8 patients) experienced treatment- related events that required temporary
  interruptions oftherapy or decrease in dosage, with most of these (5 of 8 patients) were as a result of HFS. And Gynne-Jones et al. (Ann Oncol (2006): The integration of oral capecitabine into chemoradiation regimens for locally advanced rectal cancer: how successful have we been?) found in their review, continuous oral administration of capecitabine (825 mg/m2 twice daily for 7 days/week) is an effective regimen with similar tolerability to the less dose-intensive intermittent regimens of capecitabine given 5 days/week followed by 2 day's rest or 14 days followed by 7 day's rest as used in systemic chemotherapy for patients with colorectal or breast cancer. Similarly, El-Hewl & Coleman (Breast (2005): Reduced dose capecitabine is an effective and well-tolerated treatment in patients with metastatic breast cancer) used reduced dose capecitabine 1 g/m2 twice daily for 14 days repeated every 3 weeks after failure of a number of chemotherapy regimens or hormonal treatment, achieving overall objective response rate of 28% (2% complete response rate and 26% partial response), with the most common treatment-related adverse events being hand-foot syndrome (HFS) (32%), nausea (21%) and diarrhoea (19%), and dose limiting toxicities, especially HFS being rare; they concluded that this reduced dose of capecitabine appears as effective for advanced breast cancer as full dose capecitabine with a lower incidence of toxicity.
  
  Capecitabine (Xeloda) vs. Vinorelbine (Navelbine)
  In addition, there are beginning to emerge some comparative outcomes of post-anthracycline and/or post-taxane therapies involving capecitabine. Two large Canadian cancer centers (Verma et al., Breast Cancer Treat Res (2004): Survival differences observed in anthracycline and taxane refractory metastatic breast cancer treated with capecitabine when compared to vinorelbine, as summarized by Verma et al. J Clin Oncol (2005): What Is the Best Chemotherapy Treatment Option for Anthracycline and Taxane Pretreated Metastatic Breast Cancer?) evaluated the efficacy of capecitabine, vinorelbine, or both agents sequentially in anthracycline and taxane refractory MB, finding median overall survival time was significantly higher (almost double) in the capecitabine group than in vinorelbine group and 6.3 months, and higher still (almost double the capecitabine result, and almost four times the vinorelbine results) in patients who received both agents in sequence (median overall survival of 13 months); survival at 1 year was 15.6% for the vinorelbine group, 28.4% for the capecitabine group, and 46.4% for the sequential group.
  
  Vinorelbine (Navelbine) vs. Taxane
  The recent FinHER study (Joensuu et al., N Engl J Med (2005): Adjuvant Docetaxel or Vinorelbine with or without Trastuzumab for Breast Cancer) found that adjuvant treatment with docetaxel, as compared with vinorelbine, improves recurrence-free survival in women with early breast cancer: (recurrence-free survival at three years was better with docetaxel (taxotere) than with vinorelbine (Navelbine). Furthermore, the same researchers presented additional confirming data from the same trial at SABCS (28th Annual San Antonio Breast Cancer Symposium (SABCS, 2005): Trastuzumab in combination with docetaxel or vinorelbine as adjuvant treatment of breast cancer: the FinHer Trial) in which they found that using a constant CEF regimen (cyclophosphamide, epirubicin and 5-fluorouracil) in two arms of the study, one arm with docetaxel (three 3-weekly cycles of docetaxel (100 mg/m2)) preceding CEF, the other with vinorelbine (eight weekly cycles of vinorelbine (25 mg/m2)) preceding CEF, in adjuvant treatment of HER2-positive early breast cancer, yielded the result that single-agent docetaxel/CEF was more effective than vinorelbine/CEF as adjuvant treatment of BC, in terms of distant, or locoregional recurrence, or contralateral BC. (See also the remarks of Dr. Sandra M. Swain (Chief, Cancer Therapeutics Branch, Center for Cancer Research (NCI)) in interview: "However, I would not recommend vinorelbine. The FinHer study showed that docetaxel had a better outcome compared to vinorelbine" (Breast Cancer Update, V.5/Issue 2 (2006): Conversations with Oncology Research Leaders (Neil Love, Editor)).
  
  Vinorelbine (Navelbine) in Refractory MBC
  It appears that in the refractory metastatic breast cancer (MBC) setting, recurrent disease within the breast, lymph nodes, skin, or soft tissues is particularly sensitive to vinorelbine treatment, whereas bone lesions are not (Andrew D. Seidman (Program Directror) & Edith A. Perez (Faculty), Clinical Care Options - Oncology (2005): Treatment Options After Hormone, Anthracycline, and Taxane Therapy in Advanced/Metastatic Breast Cancer).
  
  Capecitabine + Vinorelbine
  Capecitabine has also been deployed successfully in various combination regimen. Nole et al. (Ann Oncol (2005): Dose-finding and pharmacokinetic study of an all-oral combination regimen of oral vinorelbine and capecitabine for patients with metastatic breast cancer) found that the all-oral regimen of oral vinorelbine (60 mg/m2/week) and capecitabine (2000 mg/m2/day days 1–14 every 3 weeks) as first-line chemotherapy in patients with MBC yielded a response rate of 40.9%, and results from the pharmacokinetic study demonstrated the absence of mutual pharmacokinetic interactions when both drugs were co-administered; see also Tubiana-Mathieu et al. (SABCS (2006): Phase II study of an all-oral combination of oral vinorelbine (NVBo) and capecitabine (X) in HER2-negative metastatic breast cancer (MBC): first results of an international phase II trial).
  
  Capecitabine + Cisplatin
  Donadio (Oncology (2005): Weekly Cisplatin plus Capecitabine in Metastatic Breast Cancer Patients Heavily Pretreated with both Anthracycline and Taxanes) evaluated the activity and safety of a combination of cisplatin (20 mg/m2 every week for 6 weeks, followed by 1 week of rest) and capecitabine (1,000 mg/m2 twice daily for 14 days, followed by a 7-day rest period) in patients with anthracycline- and taxane-pretreated metastatic breast cancer, Objective response was obtained in 14 patients (35.9%), with complete remission in 3 (7.7%), with leucopenia being the dose-limiting toxicity for the regimen, while gastrointestinal discomfort was the most frequent cause of capecitabine reduction or delay; this combination regimen seems to be non-cross resistant to anthracyclines and taxanes.
  
  Capecitabine + Gemcitabine
  Andres et al. (Clin Breast Cancer (2005): Gemcitabine/capecitabine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes) conducted a phase II trial of gemcitabine (2000 mg/m2 on day 1 every 3 weeks) / capecitabine (2500 mg/m2 daily (divided into 2 doses) on days 1–14 every 3 weeks) in patients with disease progression after treatment with anthracyclines and taxanes, finding a response rate of 48.7%; all patients received concomitant oral pyridoxine 300 mg twice daily to prevent hand-foot syndrome (HFS).
  
  [new] Capecitabine and Brain Metastasis
  Italian researchers at the Regina Elena National Cancer Institute (Fabi et al., Cancer Investigation (2006): Dramatic Regression of Multiple Brain Metastases from Breast Cancer with Capecitabine: Another Arrow at the Bow?) document a case of breast cancer brain metastasis regression with capecitabine (Xeloda) montherapy prior to brain irradiation therapy.
  
  [new] CMX: Capecitabine + Cyclophosphamide / Methotrexate
  Gabriella Mariani and colleagues (Clin Breast Cancer (2006): Capecitabine/Cyclophosphamide/Methotrexate for Patients with Metastatic Breast Cancer: A Dose-Finding, Feasibility, and Efficacy Study) conducted a feasibility study in which the 5-FU of the CMF regimen (cyclophosphamide/methotrexate/5-FU) was substituted with capecitabine to yield a CMX regimen, with a capecitabine schedule of dose of 1850 mg/m2 orally on days 1 - 14 every 28 days, finding an overall response rate of 44% (13% complete response rate + 31% partial response rate).
  
  
• [new] Triple Negative BC: Cisplatin (platinum-based) Chemotherapy
  Garber et al. (SABCS (2006): Neo-adjuvant cisplatin (CDDP) in “triple-negative” breast cancer (BC)) conducted a nonrandomized, phase II trial of neoadjuvant cisplatin (75 mg/m2 every 3 weeks for 4 cycles prior to definitive surgery) in triple-negative breast cancer, finding it active, with rate of pathologic complete response (pCR) similar to that reported with multiagent chemotherapy, and with such response significantly associated with age; cisplatin demonstrated clinical activity in one half of patient population, with greater than 20% achieving pCR (including both patients with germline BRCA1 mutations).
  
  
  
  
  Biological Therapy (BT)

Encouraging findings have emerged of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single-agent activity in breast cancer, including (taxanes, capecitabine , gemcitabine, and vinorelbine, among others, as well as part of various triplet drug regimens.

Furthermore, Brufsky et al. (Clin Breast Cancer (2005: Hormone receptor status does not affect the clinical benefit of trastuzumab therapy for patients with metastatic breast cancer have recently established that hormone receptor (HR) status did not affect the clinical benefit of trastuzumab whether given as a single agent, or combined with chemotherapy. Thus adding trastuzumab to chemotherapy provides an improved clinical benefit compared with chemotherapy alone, regardless of HR status.



Trastuzumab (Herceptin): As Monotherapy
As monotherapy, the recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) produces antitumor response, probably through induction of apoptosis (Moshin et al., J Clin Oncol (2005): Neoadjuvant Trastuzumab Induces Apoptosis in Primary Breast Cancers) in patients with HER-2-amplified/overexpressing metastatic breast cancer that has progressed after chemotherapy (anthracyclines and taxanes) (Cobleigh et al., J Clin Oncol (1999): Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease; also Vogel et al, J Clin Oncol (2002): Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer; see also the recent review of Osborne et al., Oncologist (204): Oncogenes and Tumor Suppressor Genes in Breast Cancer: Potential Diagnostic and Therapeutic Applications).

These studies and several large sufficiently powered trials have assessing the role of trastuzumab in addition to adjuvant chemotherapy for patients with HER2 positive tumors, consistently finding that trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among these women with HER2-positive breast cancer (Piccart-Gebhart et al., N Engl J Med (2005): Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer). A BMJ editorial (Dent & Clemons, BMJ (2005): Adjuvant trastuzumab for breast cancer ) on these cumulative studies notes that the most impressive finding from these trials is the enormity of the hazard ratios, citing that in the combined trial of B-31 and N9831, the hazard ratio for breast cancer recurrence in the group receiving trastuzumab with chemotherapy, compared with chemotherapy alone, was 0.48 (48% relative risk reduction).

Issues of Absolute versus Relative Risk Reduction, and Cost
However, McClaren (BMJ (2005): Letter: Adjuvant trastuzumab for breast cancer) legitimately takes issue with reporting only of the hazard ratio of a treatment without any reference to the absolute reduction in recurrence observed? McClaren computes (from the original paper of Piccart-Gebhart et al., above) that in fact the absolute reduction in recurrence rate at one year with trastuzumab would be 5.5%, translating as they observe "that out of 100 patients given the drug, 94 will have been exposed to the (not insignificant) side effects without any effect on their outcome at one year". In addition, the original editorial and several of the associated Letters raise the issue of the high cost of trastuzumab therapy, and in one of these Kell & Power also note that at least 1 out 5 patients with positive Immunohistochemical results will be truly negative for HER2/neu gene amplification, and so not not benefit from trastuzumab (BMJ (2005): Letter: Adjuvant trastuzumab for breast cancer: Assessing HER2/neu status incurs more costs for treatment, based on the original findings of Ross et al. (Oncologist (2003): The HER-2/neu Gene and Protein in Breast Cancer 2003: Biomarker and Target of Therapy).

Optimizing Trastuzumab Administration:
3-Weekly Schedule
Trastuzumab therapy is typically considered for breast cancer patients with tumors that demonstrate 3+ overexpression by the IHC (immunohistochemistry) technique, or 2+ IHC along with a FISH (fluorescence in situ hybridization)-positive test. Until recently the standard schedule of administration has been weekly intravenous infusion dose of 2 mg/kg after a loading dose of 4 mg/kg. However, it has been noted that this drug has a prolonged half-life (approximately 28 days), so an alternate dosing regimen has been explored using a loading dose of 8 mg/kg followed by a maintenance dose of 6 mg/kg given every 3 weeks: Baselga et al., J Clin Oncol (2005): Phase II Study of Efficacy, Safety, and Pharmacokinetics of Trastuzumab Monotherapy Administered on a 3-Weekly Schedule) determined that three-weekly trastuzumab is a convenient alternative to weekly administration which did not compromise the efficacy and safety of trastuzumab in women with HER2-positive MBC.

Trastuzumab + Taxane Chemotherapy
In women whose tumors overexpress the HER2/neu oncogene, standard chemotherapy plus trastuzumab as first line treatment increased the time to disease progression, objective response, duration of response, and overall survival, with a 20% reduction in the risk of death, compared with standard chemotherapy alone: Slamon et al. (N Engl J Med (2001): Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2). More recently, Marty et al. (J Clin Oncol (2005): Randomized Phase II Trial of the Efficacy and Safety of Trastuzumab Combined With Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Administered As First-Line Treatment: The M77001 Study Group) explored combination therapy of trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression) + the taxane docetaxel (six cycles at 100 mg/m2 every 3 weeks), finding it superior in all end points to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of response rate, response duration, time to progression, time to treatment failure, and overall survival, with little additional toxicity.



The Issue of Trastuzumab Cardiotoxicity
It is now well-accepted that trastuzumab therapy requires diligent cardiac monitoring due to known risk of cardiotoxicity via decrease in left ventricular ejection fraction (LVEF), more acutely when other risk factors are present such as prior anthracycline exposure (Seidman et al., J Clin Oncol (2002): Cardiac Dysfunction in the Trastuzumab Clinical Trials Experience) and advanced age, and for this reason evaluation of LVEF is currently recommended every 3 months for patients undergoing trastuzumab therapy (Baselga et al., Proc Am Soc Clin Oncol( 2003): Changes in left ventricular ejection fraction (LVEF) during trastuzumab therapy: A pooled analysis of four trials).
It was the seminal study of Slamon cited above which found that the most serious adverse effect observed was an unexpectedly high level of cardiac dysfunction which occurred in 27% of the group given an anthracycline, cyclophosphamide, and trastuzumab, and although the cardiotoxicity was potentially severe and, in some cases, life-threatening, symptoms generally improved with standard medical management. Despite this, such trastuzumab-induced cardiotoxicity has led to the NCCN panel recommendation (NCCN (2005): Practice Guidelines in Oncology - v.2.2005: Breast Cancer [pdf]) to avoid concomitant anthracycline (doxorubicin/cyclophosphamide) use with trastuzumab outside the confines of a prospective clinical trial.
Interestingly, trastuzumab-induced cardiac dysfunction appears to be qualitatively different than anthracycline cardiotoxicity, as it is not cumulative dose-dependent, often improving after treatment withdrawal and allowing for retreatment (Youssef & Links, Am J Cardiovasc Drugs (2005): The Prevention and Management of Cardiovascular Complications of Chemotherapy in Patients with Cancer). See also Yeh et al. (Circulation (2004): Cardiovascular Complications of Cancer Therapy: Diagnosis, Pathogenesis, and Management)

Breast Cancer Watch Commentary: Trastuzumab Cardiotoxicity
On the basis however of our Breast Cancer Watch systematic review, we find trastuzumab-induced cardiac dysfunction as a contraindication (as per NCCN 2005 guidelines, cited above) to combination therapy with anthracyclines not as convincingly established as suggested by the NCCN disjunction: Buzdar et al. (J Clin Oncol (2005): Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer) found that paclitaxel followed by an epirubicin-containing regimen when administered with concurrent trastuzumab resulted in a 65% pathologic complete response (pCR) rate with no cardiotoxicity in the form of clinical congestive heart failure. It is however important to note that the anthracycline used here was epirubicin, not doxorubicin, and we know, as cited above, that epirubicin (at doses equivalent to doxorubicin) is equally efficacious to but less toxic than doxorubicin (Findlay & Walker-Dilks, Cancer Prev Control (1998): Epirubicin, alone or in combination chemotherapy, for metastatic breast cancer. Provincial Breast Cancer Disease Site Group and the Provincial Systemic Treatment Disease Site Group), and it may be the NCCN disjunction is valid narrowly to doxorubicin/cyclophosphamide regimens but not at least to the epirubicin + trastuzumab combination.

Breast Cancer Watch Commentary:
Limiting the Scope of Trastuzumab Cardiotoxicity
Furthermore, Breast Cancer Watch believes that trastuzumab-induced cardiotoxicity even in the case of AC (doxorubicin and cyclophosphamide) is less clearly established than suggested in the latest NCCN guidelines. In 2000 the North Central Cancer Treatment Group (NCCTG) began a phase III randomized study, NCCTG N9831, to evaluate the safety and efficacy of (1) Arm A: adjuvant AC followed by weekly paclitaxel only; or (2) Arm B: adjuvant AC followed by weekly paclitaxel plus sequential trastuzumab (in patients with HER2-overexpressing early-stage breast cancer); or (3) Arm C: adjuvant AC followed by weekly paclitaxel and concurrent trastuzumab (in patients with HER2-overexpressing early-stage breast cancer), and Perez et al. (J Clin Oncol (2005): Interim cardiac safety analysis of NCCTG N9831 Intergroup adjuvant trastuzumab trial) have recently issued an interim analysis of cardiac safety in this NCCTG N9831 trial. They acknowledge an increase in cardiac toxicity on trastuzumab note that it remains less than the threshold (4%) prospectively designated as a stopping rule, and by that criteria, both Arms A (there were no cardiovascular events at all in Arm A) and B manifests acceptable cardiac safety data in the adjuvant treatment setting, suggesting that the problematic arm is Arm C with concurrent - rather than sequential - docetaxel + trastuzumab, and indeed of 20 patients in arm C who developed cardiovascular events, 19 had confirmed congestive heart failure (CHF), with one death from cardiac failure. At this point, we know that less than 4% of the patients receiving trastuzumab developed CHF or died from cardiac events, and we await the long-term follow-up of this trial for the full impact determination of adverse cardiovascular events.

In addition, the Breast International Group (BIG) began in late 2001 the HERA (Herceptin Adjuvant) phase III study to evaluate the efficacy of trastuzumab after initial adjuvant chemotherapy versus observation, with patients were randomized to receive trastuzumab 6 mg/kg (8-mg/kg loading dose) every 3 weeks for either 1 or 2 years, or no other treatment. Subsequent analysis (Piccart-Gebhart, 41st Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, FL (2005):