Endocrine Therapy (ET): State of the Art
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
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.
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).
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): |
