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constantine kaniklidis |
| : : : : Breast Cancer Watch Digest |
issue
2 | aug 30, 2011
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CNS (Brain and Leptomeningeal) Metastasis from Breast Cancer - A Review
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Brain
Metastasis in Breast Cancer
Molecular and Biological Issues Despite the well known compromised survival associated with CNS metastasis, it should be remembered that not all patients with developed metastases to the CNS necessarily have equally poor prognosis132-136 . In this connection it should be pointed out that there is some evidence from Nancy Lin and colleagues254 at Dana-Farber that patients with initial CNS metastases had significantly shorter survival than did those with initial extra-CNS metastases. They found that the age-adjusted and race-adjusted rate of death for patients who first presented with a CNS metastasis was 3.4 times (range: 1.9-6.1 times) that of patients without an initial CNS lesion at the time of first metastatic presentation; survival rates for patients with extra-CNS metastases were 61.6% at 1 year, 21.8% at 2 years, and 14.4% at 3 years. And Carsten Nieder and colleagues255 have clarified the importance of radiosensitive tumor histology to remission attainment: complete remission occurred in 35% of patients with breast cancer metastases, compared to 37% in those with small cell carcinoma metastases, 25% in those with squamous cell carcinoma metastases, and 14% with non-breast adenocarcinoma metastases, with small tumor volume and absence of necrosis being favorable factors, as seen by the fact that the rate of remission being 52% for metastases <0.5 cm3 compared to 0% for those >10 cm3. Small tumor volume and absence of necrosis also were important, as the complete response rate was 52% for metastases less than 0.5 cm3 and 0% for those greater than 10 cm3.
We also noted that the
immunohistochemical (IHC) profiles (including ER, PgR, and
HER2/neu) of the primary tumor and the brain metastasis can
differ, as they did in 29.2% of patients studied by the Japanese
team of Kan Yonemori and colleagues201, suggesting
that FISH testing in the primary breast tumor but not IHC
testing is highly predictive of the receptor status of the
CNS metastases202,203,173. However, in the narrower
HER2 context, concordance even under IHC appears to be more
consistent, and with a high degree of agreement in HER-2 status
between the primary tumors and the metastatic foci to the lung,
liver and brain as confirmed at autopsy, as found by Shegeya
Kyoda and colleagues204 in Japan but we noted that
our review has found the data even on this issue inconsistent:
so for example, against the Kyoda data finding for high
concordance between primary and metastatic tumor on HER2 status,
Elizabeth Mittendorf and her colleagues205 from MD
Anderson reporting at ASCO 2008 found that approximately
one-third of HER2-amplified patients not achieving a pCR after
with taxane and anthracycline-based chemotherapy with
concomitant trastuzumab in the neoadjuvant setting were found to
have converted to HER2-negative disease, suggesting that
residual tumor identified at the time of surgery should be
reassessed for HER2 status. Of course this is residual tumor,
not the same as distal metastatic tumor, but it does suggest
that the phenomenon of receptor shifting may be far more common
than previously thought, and it suggests to us that reassessment
of both residual tumor and metastatic tumor, including CNS
metastasized, may be prudent especially by FISH assay. Indeed,
we could hypothesize that at least some lack of response or
progression on trastuzumab therapy may appear to be consequent
to multidrug resistance (MDR) but may in fact be attributable to
receptor shift.
WBRT: Whole-Brain Radiotherapy Standard treatment for brain metastases to prevent or delay progression of neurologic deficits and avoid steroid dependency is WBRT, sometimes deferred until the brain metastases become symptomatic. WBRT monotherapy is common in patients with low performance (KPS) scores and progressive systemic disease, while those with high KPS scores + controlled systemic disease undergo WBRT upon new or recurrent lesions following resection or radiosurgery2, but note that for at least selected patients with resectable single brain metastases WBRT + resection favors survival over WBRT monotherapy (as per our discussion below). Adverse events associated with WBRT are typically manageable (mild-to-moderate fatigue, headache, nausea / vomiting, ear blockade, temporary hair loss, and skin hyperpigmentation). Recently, the viability of short-course WBRT has been explored, and retrospective data suggests that a short WBRT regimen of with 5 fractions of 4 Gy each resulted in survival and local control comparable to longer programs in breast cancer patients with brain metastases65,66. In sum, the weight of the evidence suggests that optimal radiotherapy of brain metastases consists of a multimodal approach involving a combination of surgery or SRS (see below) with WBRT, the conservative component of WBRT serving to improve local control and delay intracranial recurrence91. But increasingly, we are recently seeing the radical emergence of chemotherapy as a vital aspect of the broad spectrum of interventions against brain metastases (see below). And other modalities may prove feasible: Kim Huang at UCSF and colleagues200 found that permanent iodine-125 brachytherapy for brain metastasis resection cavities, without WBRT, provides excellent local control for patients with symptomatic or large newly diagnosed or recurrent brain metastases, although we note the high risk (23%) of radiation necrosis over time. In addition there may be an appreciable potential benefit of a radiation boost in patients treated with whole brain radiation therapy (WBRT): Avi Assouline and colleagues328 in France conducted a retrospective analysis 232 patients with secondary brain metastases from lung cancer, breast cancer and melanoma, via a subgroup analysis of whether an additional radiation boost, delivered via conventional linear accelerator, could potentially improve outcome in patients who presented with less than three metastases, and with performance status <2, and who were unresected. They found that the radiation boost more than doubles median overall survival (8.9 months, compared to 4.0 months in patients with no radiation boost). The WBRT Decision In evaluating and weighing the option of WBRT with patients it is therefore important to note that despite often only a narrow margin of survival benefit good performance cases, WBRT can provide a significant benefit in reduced distant brain tumor recurrence, and that in cases where WBRT is motivated or compelled due to ineligibility to other modalities, WBRT can provide rapid attenuation of many neurological symptoms, improve quality of life, especially for patients whose brain metastases are surgically inaccessible or surgery is not a viable option for other considerations. Adjuvant WBRT following resection or radiosurgery is effective for improving local control of brain metastases, and thus decreasing the likelihood of neurological death. And it need be also noted as the data suggests that the majority of patients who achieve local tumor control die from progression of extracranial disease, in contrast to patients with recurrent brain metastases in whom the cause of death is most often due to CNS disease and WBRT can moreover effectively improve neurologic function and symptoms for patients with minimal co-morbidity206,219,250-252. Jing LI and colleagues250 at the University of Wisconsin Comprehensive Cancer Center found that good responders experienced a significantly improved survival and that in long-term survivors, tumor shrinkage significantly correlated with preservation of executive function and fine motor coordination, concluding that (1) WBRT-induced tumor shrinkage correlates with improved survival and preservation of neurocognitive function (NCF), (2) NCF is stable or improved in long-term survivors, and (3) tumor progression adversely affects NCF more than WBRT does. In this prospective study therefore, results demonstrate WBRT-related improved control of intracranial disease is associated with neurocognitive function stabilization and improvement, supporting the conclusions that (1) the beneficial effect of WBRT-induced tumor regression on cognition outweighs its potential harm, and (2) CNS disease progression is the main contributor to neurologic decline, in agreement with the results of the study conducted by Christina Meyers at MD Anderson and coresearchers251 who found that neurocognitive decline correlates with tumor growth but was not statistically correlated with the number of brain metastases, suggesting that NCF is more affected by tumor burden than by number of lesions. Thus multiple studies suggest that WBRT at a 30 Gy in 10 fractions yields more neurocognitive benefit than harm256;250-252. And it should be recognized that a survival end point may have limited value in the assessment of the clinical benefit derivable from a new treatment for brain metastases, since mortality in such patients is predominantly secondary to systemic, extracranial, disease progression. In addition, Kazuhiko Ogawa and colleagues253 in Japan conducted a 20 year (1985 - 2005) review of treatment results for patients with brain metastases from breast cancer. Treatment modality, performance status (KPS), and administration of systemic chemotherapy were significant prognostic factors in multivariate analysis. They found that in all eight patients who survived for more than 2 years, post-diagnosis treatment included surgical resection and/or systemic chemotherapy in addition to WBRT, and that in addition for the 45 patients treated with solely with WBRT without systemic chemotherapy, improvements in neurological symptoms were observed in 78% of these patients. Finally, it should be borne in mind that there is potential for significant improvements in cognitive functioning from cognitive deficit interventions, and there is evidence that these cognitive rehabilitation programs in patients with CNS disease are both feasible and can yield both short-term and long-term positive effects; these have been comprehensively reviewed by Karin Gehring at Tilburg University and colleagues329. Surgical Intervention / Resection Surgery, and postoperative irradiation, continue to be important treatment modalities for for brain metastases from breast cancer especially under favorable prognostic factors (performance, single brain metastasis, and controlled systemic disease). It's been established by the landmark trial of Roy Patchell and colleagues3 that selected patients with resectable single brain metastases undergoing resection and WBRT survived longer than those on WBRT alone. And certainly the addition of resection to WBRT can improved survival, local control at the original metastatic site, and control within the entire brain in patients with a single brain metastasis, although it does not necessarily prevent the development of new brain metastases distant to the original site104. Although many clinicians question the role of surgery in the multiple brain metastases scenario, the seminal retrospective review at MD Anderson by Rajesh Bindal and his colleagues4 found that patients with multiple metastases who underwent resection of all lesions had a significantly longer survival than those with multiple metastases remaining not resected. Also the recent review of Moksha Ranasinghe and Jonah Sheehan5 who noted that with proper patient selection and operative / postoperative management, surgery has a positive effect on survival and quality of life, and Frederick Lange and colleagues6 reinforced these positive findings, concluding that "the presence of multiple brain metastases does not automatically contraindicate surgery". SRS: Stereotactic Radiosurgery Stereotactic radiosurgery involves the use of high dose noninvasive radiation focused to the brain tumors by a linear accelerator (called LINAC-SRS) or by gamma knife surgery (GKS), or by cyberknife (a robotic version of the gamma knife), to the brain metastases, and has established itself, with or without WBRT, as a treatment option for patients with metastatic brain disease. A primary goal of SRS plus WBRT is the eradication of both local (particularly at the site of surgical resection) and distant micrometastases, and as a substitute for surgical intervention in patients with lesions less than 3cm diameter70. SRS technology is characterized by the sharp dose fall off at the target edges, delivering a clinically insignificant dose to the surrounding normal brain tissue, and its primary advantages are lower risk of hemorrhage, infection and tumor seeding. For patients harboring two to four metastases SRS combined with WBRT is superior to WBRT monotherapy7, and the radiosurgery technique - linear accelerator (LINAC) versus gamma knife surgery (GKS) - appears to have no significant impact on outcome8. Current clinical practice treats SRS and resection as overlapping and complementary therapies, with single, large, and superficial lesions in noneloquent brain regions - that is, in regions in which injury does not result in any disabling neurologic deficits, as opposed to eloquent brain regions such as the sensorimotor, language, and visual cortex, and others in which trauma typically induces such deficits - in patients with favorable prognostic factors typically being resected, while multiple deep lesions in medically frail patients being treated by SRS8. In terms of tumor size, SRS is commonly used for single small to moderate tumors (less than 3.5 to 4.0 cm) that are located in surgically inaccessible areas, and for patients who are not surgical candidates, while either SRS or resection may be used for small tumors (< 3.5 - 4.0 cm) causing minimal edema which are surgically accessible9,10. The Treatment Mix: SRS with or without WBRT Advantages of GKS / SRS over WBRT are briefer hospitalization, higher control rates, better symptom palliation, treatability of all MRI-detected lesions, no need to postpone other treatments (e.g., radiotherapy), repeatability of gamma knife irradiation, lower incidence of dementia secondary to radionecrosis, and a greater number of tumors treatable in one session11. One open issue remains: whether or not WBRT is needed after SRS105. From our review, Breast Cancer Watch does not regard this issue as settled dispositively, but one option is to reserve WBRT for numerous metastases, or delayed until recurrence12, especially as we now know that repeated SRS is both viable and effective, with relatively long survival in some patients associated with a low risk of radiation-induced injury13. As noted, we have limited data on the value of SRS added to WBRT, largely from one randomized trial conducted by Douglas Kondziolka and colleagues71 at the University of Pittsburgh which compared SRS + WBRT to WBRT monotherapy in patients with multiple brain metastases, with the trial was stopped early (after 27 patients accrued) due to an observed 100% local failure rate at 1 year in the WBRT monotherapy arm, compared with 8% in the SRS + WBRT combination arm. And in this connection, a recent meta-analysis and systematic review by Tania Stafinski and colleagues at the University of Alberta of three RCTs and one cohort study found no difference in survival between patients treated with WBRT+SRS and those treated with WBRT among patients with multiple metastases but a statistically significant difference favoring those treated with the WBRT + SRS combination among patients with one metastasis; in addition, rates of local tumor control at 24 months were significantly higher in the WBRT + SRS treatment arm, regardless of the number of metastases. Thus, adding SRS to WBRT improves survival in patients with one brain metastasis, also the conclusion of the recent review by Falk Müller-Riemenschneider and colleagues212 across 16 included studies. Combining SRS and WBRT in general (independent of one versus 1+ nodes) improves local tumor control and functional independence in all patients, and it should be noted in connection with issues of QoL under WBRT that although some studies show that certain parameters of Qol deteriorate after WBRT, others show that QoL in patients with better prognosis is actually improved after WBRT, as found by the recent review of Jennifer Wong, Edward Chow and colleagues at the Odette Cancer Centre / Sunnybrook (Toronto)113.. In addition, Dirk Rades and colleagues196 at University Medical Center in Hamburg compared in a retrospective matched-paired analysis the results of whole-brain radiotherapy plus stereotactic radiosurgery (WBRT+SRS) with those of surgery plus whole-brain radiotherapy and a boost (OP+WBRT+boost) to the metastatic site or patients with one or two brain metastases, finding that although treatment outcomes were not significantly different after the two interventions, given that WBRT+SRS is less invasive than OP+WBRT+boost, it may be preferable for patients with one or two brain metastases. And Samuel Chao and colleagues197 at the Cleveland Clinic examined the records for overall survival (OS) and time to local failure (LF) of 111 patients who received salvage stereotactic radiosurgery (SRS) for recurrent brain metastases after initial management that included whole-brain radiation therapy (WBRT), finding these patients had good local control and survival after SRS, with those with a longer time to failure after WBRT having significantly longer survival after SRS. suggesting the viability of SRS salvage of post-WBRT recurrence. However there continue to
be serious concerns: a randomized trail found the risk of neurocognitive decline
(48%) at 4 months, with respect to learning and memory, to be twice as
high among cancer patients with brain metastases who undergo
stereotactic radiosurgery SRS) and whole brain radiotherapy (WBRT)
compared to those
who undergo SRS alone (20% decline), as reported at the at the
American Society for Therapeutic Radiology and Oncology’s 50th
Annual Meeting by Eric Chang at MD Anderson and colleagues199b,
from which the authors conclude that the preferred intervention
would be SRS alone as the upfront, initial therapy for patients with
up to three brain metastases, followed be close monitoring for
recurrence. The trial was halted by the independent data monitoring
committee after interim results showed a high 96.4% statistical
probability that patients randomized to SRS alone would continue to
perform better than SRS+WBRT counterparts. However, the
patient stratification was controversial: graded prognostic
assessment was well balanced, but patients were not stratified
according to their baseline neurocognitive function. Moreover, the
primary end point (neurological function at 4 months) was debatable
since most patients with terminal cancer experience neuro cognitive
impairment.
It should be noted that the MD Anderson team
was surprised to discover that WBRT also had a negative impact on
overall survival (OS): there was an OS of 5.6 months compared to
15.2 months for SRS alone), with one-year survival being 19% for the
WBRT arm compared to 61% for the SRS only arm. These survival
results - as opposed to their primary endpoint results on
neurocognitive function (NCF) - however are not wholly convergent
with the literature, and although learning and memory were
negatively affected to a greater degree by toxicity from initial
WBRT than by increased progression of distant brain metastases
resulting from omission of WBRT, we nonetheless note that the trial
found that one-year local freedom from progression (FFP) was 67% in
SRS alone and 100% in SRS + WBRT (p=0.012) while one-year distant
FFP was 45% for SRS and 73% for WBRT+SRS.
Hence, the combination treatment (WBRT+SRS was
superior at halting cancer progression, with complete 100%
freedom from progression with respect to brain metastases at one
year, and in addition, only 2 patients among those treated initially
with SRS plus WBRT went on to receive more SRS, while in contrast
for those treated initially only with SRS, 4 went on to receive more
SRS, 9 went on to receive surgery, and 6 went on to receive WBRT,
and given these observations we are not as sanguine as the trial
authors in concluding that the risks of learning dysfunction
outweigh the benefits of freedom from progression, and tip the
scales in favor of using SRS alone (according to Dr. Chang), and we
believe that the choice is complex and should be left to the
patient in consultation with their oncology professionals as at
least some patients may still elect freedom from progression over
the risk of neurocognitive decline, a decision at least in part
by the recent findings from the EORTC 22952-26001323 trial
that suggest that although adjuvant WBRT significantly reduces the
risk for intracranial relapse, nonetheless neither overall survival
nor the time of functional independence is increased, and hence the
intracranial risk reduction does not translate into real gains in
either patient functional independence or clinically significant
survival outcome.
With tumor control rates obtainable from SRS being superior to those
from WBRT and equal or better than those from surgery plus WBRT
evidenced in most studies14, we are finally seeing that
with such modalities as SRS, extended survival of several years
is now possible even in patients with multi-organ disease, and with
selected patients with effective intracranial and extracranial care
capable of having prolonged and good-quality survival15,16. The Issue of Tumor Necrosis and SRS New Appreciation of Multiple Brain Metastases Thus, Yang and colleagues found that gamma knife (radio)surgery (GKS) was an effective treatment modality for local tumor control while maintaining normal brain function even for a large number - up to 25 - of brain metastases treated at different times and without side effects. Similarly, Beatriz Amedola's team at the University of Miami Bengst Karlsson at the West Virginia University and colleagues tested this in a long-term retrospective study with a large patient cohort, hypothesizing that (1) primary disease control is more critical to survival than the number of brain metastases treated, and that (2) repeated stereotactic radiosurgery (SRS) - in the form of gamma knife surgery (GKS) - is more effective than the addition of WBRT. Both hypotheses were confirmed in their conclusions: (1) primary tumor control and patient age were found to be the decisive factors for survival in patients with brain metastases, suggesting that the number of brain metastases is an invalid criterion for determining who will benefit from SRS (as GKS) and who will not; (2) among patients with multiple brain metastases there are long-term survivors; (3) micrometastases are a limited clinical problem and their presence does not warrant prophylactic treatment, and regular follow-up imaging after SRS, along with management of any potential new lesions with the best treatment options then available are recommended instead. Note in connection with these recent (Feb 2009) results that although some investigators failed to find age as a significant factor in survival217,218,219, others on the other hand have found it to be a significant survival factor220-224, although Karlsson et al.224 found that in general survival was unrelated to age in younger patients up to ~ 60 years, after which median survival time appears to decrease linearly by approximately 1 month for every 10 years of age.
As to number of brain
metastases, since there is a strong relationship between this number
on the one hand and both survival as well as primary tumor control
on the other, the parameters of
controlled primary disease and number of brain metastases are
therefore
covariates - uncontrolled primary disease in a patient increases the
likelihood of harboring a larger number of brain lesions, but at
least these provisional results suggest that primary tumor control is more important for
ultimate survival time than the number of brain metastases.
These findings222,224,230,235,236,237 collectively suggest the feasibility of GKS in the treatment of multiple brain metastases in patients with various types of advanced cancer, and that furthermore if there is any significant disadvantage to the omission of WBRT, it is very limited224. This is in contrast with LINAC radiosurgery where there is an upper limit to how many lesions can be safely treated, while with GKS Masaaki Yamamoto's team has shown that the integral dose is acceptable even if > 10 lesions are treated225. And other data support long-term survivors from brain metastasis, such as Chao et al.227 and Lutterbach and colleages228, and it is therefore fortunate that GKS does not cause any long-term intellectual sequelae24, in contrast to WBRT6.New Dimensions: The Emerging Role of Chemotherapy Although it has been assumed that the blood-brain barrier (BBB) is largely impermeable to chemotherapeutic drugs, it is now recognized that the microcirculation of cerebral, especially macroscopic, metastases differs substantially from that of the normal blood-brain barrier, being to some extent disrupted in patients with brain metastases, allowing for opportunities for select chemotherapy of brain metastases, and although it is likely still to be the case that water-soluble agents and macromolecules may not be capable of sufficient penetration to achieve therapeutic concentrations, a new generation of chemotherapeutic agents appear to have to ability to cross even an intact / physiologically normal BBB. But effective chemotherapy hinges on tumor sensitivity to the mechanisms of the agent as well as sufficient drug exposure levels, and possibly also sufficient tumor size, as animal models suggest that only after microscopic metastatic foci reach at least 1 mm2 does an intact BBB tend to fail as a barrier; here the best experimental evidence suggests that the BBB is intact in and around brain metastases smaller than 0.20 - 0.25 mm in diameter, but is functionally leaky in larger metastases as Isaiah Fidler and colleagues130 at MD Anderson have found, although larger metastases (>0.4 mm2) may still exclude therapeutic drugs as NCI scientists Diane Palmieri and Patricia Steeg and coresearchers have suggested in their review of the biology of metastases to sanctuary sites131. Indeed, current opinion has shifted to the view that although the BBB may still have some importance in harboring microscopic tumor foci, the overall impediment of the BBB on treatment failure is questionable at best18,98,100-103. In addition, it is important to realize in assessing chemotherapy efficacy that neurologic progression-free survival - or even quality of life - might be more relevant endpoints than overall survival, given that mortality is typically from extracranial, rather than intracranial, disease progression278. Thus, survival from brain metastases depends not only on performance status but also on he use of systemic treatment281. And in leptomeningeal metastasis, as noted by neuro-oncology experts in review, high-dose systemic - as opposed to intra-CSF/intrathecal - therapy may not only benefit selected patients with breast-related leptomeningeal metastasis but may indeed obviate the need for intra-CSF chemotherapy280. The Chemotherapy Spectrum Many chemotherapeutic regimens have been documented with significant activity against CNS metastases from breast cancer, including:
among others, and although
the preponderance of clinical practice continues to reserve
chemotherapy for those patients whose CNS disease has progressed
despite WBRT and/or SRS, the emerging data is beginning to support a
more critical role for chemotherapy, possibly concurrently with
traditional anti-CNS-metastatic modalities like SRS and WBRT.
In addition, Kan Yonemori and colleagues258 at the
National Cancer Center Hospital in Tokyo have demonstrated that in
contrast to brain metastases of HER2-positive breast cancer which
tend to preserve the blood-brain barrier - and hence represent an
obstacle to effective cross-BBB chemotherapy - brain metastases of
triple negative or basal breast cancers are
negatively correlated with glucose
transporter 1 (GLUT!) and breast cancer resistance protein (BCRP)
expression in intratumor microvessels, and often disrupt the BBB, potentially facilitating passage of
therapeutic agents to the brain. These and other findings we
have presented suggest that triple negative and basal breast
cancers exhibit a distinctly different pattern of brain metastasis
development and brain tissue affinity in comparison with
HER2-positive breast cancer. Indeed, the
same team under Makiko Ono259 reported at ASCO 2008 that
in triple negative breast cancer patients, the BBB was
entirely absent in 28% out of the 29 patients with brain metastases
studied.
Cyrus Chargari and
colleagues234 with the Institut Curie Breast Cancer Study
Group retrospectively assessed the use of capecitabine (Xeloda,
median dose 1,000 mg/m2 twice daily for 14 days) concurrently with
whole-brain radiotherapy (WBRT), aka the WBRT-X regimen, in 5
patients with brain metastases from breast cancer, finding that one
patient achieved a complete response, two achieved partial response,
including one with local control lasting until most recent
follow-up, and one patient had stable disease. And
the Turkish researcher team of Kurt Mevlüt
and colleagues234
evaluated retrospectively
103 metastatic breast cancer (MBC) patients treated with
capecitabine (Xeloda)
mainly as 3rd line therapy at 2500
mg/m2/day for 14 days, with 3 weeks of intervals between cycles
every 3 weeks, in 20 patients (19.4%) with brain metastasis, which
yielded an overall response rate (ORR) of 48.6% (3.9% complete
response plus 44.7% partial response), with 28.2% stable
disease; dose reductions were required in 29% of patients, however
no decrease in efficacy was observed after dose reduction due to HFS
(hand-foot syndrome). As to survival, the capecitabine
monotherapy yielded a median OS of 17.1 months, with a range of
11.5-22.7 months, and note further that the mean OS was
significantly higher in the group of patients with grade 3 HFS (29.4
months vs 16.0 months, p= 0.023) compared to those with lower grade
HFS, suggesting that HFS occurrence during capecitabine treatment is
a good prognostic factor for assessment of capecitabine efficacy.
Median PFS was 7.3 months in patients with brain metastasis (with a
wide range of from 1.8 to 26.7 months), with no significant PFS or
OS related differences between patient groups with and without brain
metastasis.
Liposomal Anthracyclines
Endocrine Therapy A Place for Bevacizumab? The Safety of Anti-VEGF Therapy in CNS
Metastasis Finally, two recent reviews are more
decisive on the question: in 2008 Peter Carden and colleagues195
at Royal Marsden Hospital reviewed the available data from 57 trials
in a
total of 10,598 patients
to investigate
the risk of intracranial bleeding with anti-VEGF therapy in the
presence and absence of CNS metastases, finding the rate of
intracranial bleeding to be negligible, and concluding that
there is no trial evidence that anti-VEGF therapy confers an
increased risk of intracranial bleeding, even in the presence of CNS
metastases, suggesting that future trials of anti-VEGF therapy
should not exclude patients with controlled CNS metastases at
enrollment. And Benjamin Besse and colleagues276 at the Institut
Gustave Roussy (France) conducted a retrospective exploratory
analysis using datasets from 13 randomized controlled phase II/III
trials, two open-label single-arm safety trials, and two prospective
studies comprising > 12,000 patients, concluding
that patients with CNS metastases are at similar risk of developing
cerebral hemorrhage, independent of bevacizumab therapy, for
patients with CNS metastases from advanced/metastatic breast cancer,
non–small cell lung carcinoma NSCLC), and renal (RCC) and colorectal
cancer (CRC), and on the basis of
these findings, the European Medicines Agency (EMA) has recently
rescinded the contraindication as no longer justified. Hence,
administration of bevacizumab should no longer be
contraindicated based solely on the presence of CNS metastasis, and
furthermore based on the aggregated data to date, there is no evidence that anti-VEGF therapy
in general, including sorafenib (Nexavar) and sunitinib (Sutent) as
well as bevacizumab (Avastin),
confers an increased risk of cerebral hemorrhage, regardless of the
presence of CNS metastases195, and none of the four cases of breast cancer patients treated for CNS metastases with bevacizumab reported tumor-associated cerebral hemorrhage245. Israeli researchers Isac Schnirer and colleagues260 at the Baruch Padeh Medical Center reported at ASCO 2010 on their use of the E2100 regimen, consisting of paclitaxel (175 mg/m2) + bevacizumab (15 mg/kg) every 3 weeks to treat HER2/neu negative patients with widely disseminated metastatic breast cancer (30% of which were triple negative, obtaining an overall response of 80% including one patient with leptomeningeal and brain metastases who achieved complete response (CR) without any radiation therapy to the meninges or brain, and remaining disease free for 8 months, a remarkable finding given that there are few reports documenting complete remission of leptomeningeal and metastatic brain lesions without radiotherapy.
A Role for HER-Targeted Therapy in
TNBC Brain Metastases? Buttressing this, for patients with metastatic breast cancer without HER2 amplification but who express the transmembrane HER3 ligand neuregulin (NRG), transmembrane NRG expression is associated with objective clinical response to trastuzumab (Herceptin), and it is known that an alternative mode of HER-2 receptor activation is the presence of neuregulins ligands which can be released as soluble factors via cell surface protease activity, with expression of NRG in the mammary gland favoring metastatic spread of breast cancer cells. HER2 receptor activation via transmembrane NRG is highly sensitive to trastuzumab even in the absence of HER-2 overexpression291. Precisely this issue was addressed by Atanasio Pandiella's team292 in Salamanca who analyzed NRG expression in samples from breast cancer patients and retrospectively studied the potential correlation between transmembrane NRG expression (NRG+) and clinical response, finding that in the absence of HER-2 amplification, NRG+ is associated with objective clinical response to trastuzumab and hence a marker of trastuzumab sensitivity. Transmembrane neuregulins may also be attractive therapeutic targets, as they eliminate the possibility of neuregulin signaling through all HER receptors, not just HER2293. Tellingly in this connection, the HER3/HER2 heterodimerization inhibitor pertuzumab (Omnitarg) can inhibit tumor growth in non-HER2 over-expressing xenograft models of prostate and breast cancer294..
Building on these results, Sunil Lakhani's team295 in Australia has demonstrated that deregulated HER family receptors, particularly neuregulin/HER3 activation, and their downstream pathways are implicated in brain metastasis colonization including triple negative and basal-like metastases,
suggesting that anti-HER family inhibitors may even be effective in the absence of HER2 amplification (as in TNBC/basal tumors), and further confirming the possibility that tumors with low HER2 expression may respond to either or both
traditional anti-HER2 therapies (trastuzumab, lapatinib) or combinations of HER family receptor inhibitors, given that even basal levels may enhance signaling through homo/hetero-dimerization of the other HER family receptors. For the first time,
Sunil Lakhani and colleagues have identified somatic mutations in genes related to the AKT/MAPK
signaling pathways (in particular EGFR, PIK3CA, KRAS, HRAS and NRAS) in brain
metastases of both breast cancer and other malignancies, and this
further suggests that in addition to HER-targets, complete treatment response may require targeting of additional actionable downstream targets (such as PI3 kinases, GRB2, ERK1/2, JNK1/2, ERK5, and p38, among others), given the potential of cancer cells to evade and resist targeted therapies such as HER2 and EGFR by acquiring oncogenic mutations in downstream pathways.
Vinorelbine-based Regimens
Temozolomide (TMZ) Monotherapy
Salvatore Siena at the Istituto
Nazionale Tumori
(Milan) and colleagues249 had investigated
in a Phase II trial a dose-intense regimen of temozolomide monotherapy (150 mg/m2/d on days 1-7 and 15-21
every 28 days, until disease progression or for 1 year)in 63
patients with advanced non-small cell lung cancer (NSCLC), breast
cancer, and melanoma, 21 of whom had breast cancer,
finding in the 62 evaluable patients a disease control rate (partial
responses plus stable disease) of 24%, with 19% for breast
cancer brain metastasis.
Following up this study, the same team266 (Salvatore Siena and
colleagues), evaluated the efficacy of single-agent TMZ
[150 mg/m2/day (days 1–7 and 15–21 every 28-
or 35-day cycle] in an alternating weekly, dose-dense schedule, in
pretreated patients with brain metastases prospectively
stratified by primary tumor type (51 with breast cancer), but
response rates were only modest, unsurprising we note given TMZ
monotherapy; in contrast, combining TMZ with WBRT yields response
rates ranging from 55% to 96% as documented below. The
authors correctly concluded that single-agent TMZ is likely not
optimal in BC therapy against CNS disease, although not without some
appreciable activity.
TMZ + WBRT or SRS
More recently, Carlos
Gamboa-Vignolle and colleagues262 at the Instituto Nacional de
Cancerologia in Mexico tested in an open label Phase II randomized
trial reported at ASCO 2010, an innovative combination chemoradiotherapy regimen of WBRT
(whole brain radiotherapy) + temozolomide (TMZ, Temodar/Temodal),
with TMZ at fixed oral dose of 200 mg on Monday, Wednesday, Friday;
300 mg on Tuesday, and Thursday, before each one of 10 WBRT
sessions, and WBRT at 30 Gy/2 weeks total dose, achieving an overall
response rate of 78.6%
in the WBRT + TMZ arm compared to 48.1% in the WBRT-only arm,
suggesting that concurrent WBRT + TMZ is feasible and improves
response significantly, while also extending BM-PFS (brain
metastasis-progression free survival).
Other combinations include:
TMZ + vinorelbine
(Navelbine):
Laura Abrey's team297 at Memorial Sloan-Kettering (MSK) conducted a
phase I study of TMZ + vinorelbine (Navelbine) in 21 patients
(18 evaluable) with recurrent or progressive brain metastasis (6
patients with breast cancer) using an alternating
week-on/week-off TMZ schedule (28-day cycles of 150 mg/m2, days
1–7 and 15–21) with vinorelbine chemotherapy on days one and
eight at escalating doses from 15 mg/m2, with increments of 5
mg/m2 for each cohort of 3–6 patients until MTD (30 mg/m2); 30
mg/m2 of vinorelbine was recommended going forward). The regimen
was well tolerated: grades 3/4 toxicities were neutropenia (6
pts), lymphopenia (9), and thrombocytopenia (6), with all other
toxicities being rare and no dose-limiting toxicities
observed. Two patients had a radiographic response (one partial,
one minor). Disease was stable in 6 of 18 patients and the
median survival was 27 weeks. In the six patients with breast
cancer, one had a partial response, with an additional patient
having stable disease. TMZ Dose/Schedule
Optimization and Pharmacokinetics
Regimen
Chemotherapy (CT)
TMZ
CDDP-TMZ
CDDP (cisplatin):
150mg/m2/d pretreated
IRI-TMZ
irinotecan:
100 mg/m2
week-on/weak-off
PLD-TMZ
Doxil:
200 mg/m2 days 1–5 each 28
VIN-TMZ
vinorelbine:
150 mg/m2
week-on/week-off each 28
X-TMZ
capecitabine:
start at 1800 mg/m2/d
daily starting at 75 mg/m2 Author's Conclusions
Dose-Dense TMZ (DD-TMZ) Taxanes: Promoters or Confounders Several studies have suggested that breast cancer patients who received taxane-based chemotherapy regimen(s) exhibited a significantly higher incidence of CNS metastases than those treated with taxane-free regimens125-128. This may be a confounding factor in part consequent to taxane efficacy in increasing survival although low BBB penetrance of taxanes could promote CNS as sanctuary site, however the failure of taxanes to penetrate an intact BBB promote CNS as sanctuary for the development of brain metastases, and this suggests that taxanes may have somewhat deprecated value in contexts of high CNS metastasis risk such as triple negative, HER2-positive, and BRCA1-mutated breast cancers, although the matter is as yet not dispositively settled as at least one recent study, that of Bernhard Pestalozzi and colleagues138, have failed to find evidence of an association between adjuvant taxane treatment with docetaxel (Taxotere) and an increased frequency of CNS relapse, at least for node-positive patients. Radiation Sensitization/Protection Given the continued vital role of radiotherapy in the treatment of brain metastases, considerable efforts have been expended to enhance the efficacy of radiation therapy through biologic agents - radiosensitizers - modulating reduction/oxidation reactions within tumor cells. It appears from the evidence base that novel radiosensitizers, such as efaproxiral (Efaproxyn, aka, RSR13) and motexafin gadolinium (Xcytrin, aka, gadolinium texaphyrin), have considerable potential in a multimodal approach to improve local control as well as overall survival, and to in addition reduce treatment-related adverse events, through their ability to increase tumor responsiveness to radiation27. Part of the breakthrough depends on the fact that a key mechanism affecting sensitivity to radiation is tumor oxygenation28: hypoxic tumor cells are simply more likely to be resistant to cell damage from ionizing radiation radiation, and also have a higher local failure rate after radiation therapy, consequently compromising prognosis, and the adverse effects may extend beyond just radiation therapy: poor oxygenation affects angiogenesis, apoptosis, and other processes treatment outcome-dependent processes. Hence the intense interest in radiosensitizers. In addition, radiosensitizers may also improve quality of life: efaproxiral (Efaproxyn) has been shown in a randomized trial to reduce the death rate by 46% when added to WBRT, with an accompanying improvement in QoL and quality-adjusted survival64. In addition, anemia - common in cancer populations and which increases in prevalence during radiation therapy - is suspected of contributing to intratumoral hypoxia: studies suggest that a low hemoglobin level before or during radiation therapy is an important risk factor for poor locoregional disease control and survival, suggesting a strong correlation between anemia and hypoxia, and furthermore early correction of mild-to-moderate anemia (hemoglobin range of 12-14 g/dl) may improve both locoregional control and possibly help delay the development or progression of intratumoral hypoxia29. Radiation Sensitization: Efaproxiral (Efaproxyn) Efaproxiral is a synthetic allosteric modifier of hemoglobin, is administered intravenously via a central access device, facilitating the release of oxygen from hemoglobin more readily into tissues, and hence decreasing tissue hypoxia through enhanced tumor oxygenation and radiation sensitivity. And in contrast to other radiosensitizers, efaproxiral doesn't have to enter cancer cells to increase tumor radiosensitivity because oxygen readily diffuses across the blood-brain barrier, thus decreasing tumor hypoxia. Efaproxiral has been shown to confer a significant survival benefit when used as a radiation enhancer in patients with breast cancer brain metastases, with a good safety profile, making efaproxiral advantageous over radiation monotherapy30,31. The REACH study, a randomized, open-label phase 3 trial, compared efaproxiral plus WBRT to WBRT alone in patients with solid tumors, including 107 patients with newly diagnosed brain metastases from breast cancer, finding that breast cancer patients who received efaproxiral for brain metastases as an adjunct to WBRT had a 40% reduction in the likelihood of death32,33. The multicenter team led by John Suh with the Cleveland Clinic Foundation was one of the largest phase III RCTs34 ever conducted in brain metastases. Although the primary analysis did not demonstrate a convincing survival advantage for patients in the efaproxiral arm overall, an exploratory subset analysis showed different treatment benefits observed by primary site, with a significant survival benefit benefit appearing to be restricted to the subgroup of patients with breast cancer to the extent that the death rate was reduced by 46% and improved quality of life, showing that quality-adjusted survival was statistically and significantly improved by the addition of efaproxiral to WBRT. There did not seem to be a treatment benefit in the NSCLC subgroup or in the subgroup tumor types other than breast cancer. The study found efaproxiral to be generally safe when administered to heavily pretreated cancer patients as an adjunct to WBRT, with the main adverse event being reversible hypoxemia (see also the insightful commentary on this study by Penny Sneed35). Thus as Gustavo Viani
and colleagues206 in Sao Paulo established in their
recent meta-analyses, radiosensitizers may be
helpful in specific subsets of
patients with brain metastases from lung and breast
cancers; see also the more guarded systematic review of Jeffrey
Olson and colleagues268.
In addition, Joachim Stemmler and colleagues43,44 performed a retrospective analysis of the incidence of brain metastasis in patients with HER2 overexpressing metastatic breast cancer to elucidate the relationship of such disease occurrence to the remission status of visceral disease during trastuzumab treatment, concluding that trastuzumab, although highly effective for treatment of liver- and lung metastasis in HER2 overexpressing patients, was apparently ineffective to treat or prevent brain metastasis, given that one third of these patients developed brain metastases despite effective trastuzumab therapy, suggesting inadequate concentrations of the large molecule trastuzumab in the central nervous system across the blood–brain barrier. But we note that there is some contrary data that despite the high incidence of CNS metastasis incidence in HER-2–positive MBC, nonetheless survival after CNS relapse in this population is longer than in patients unselected for HER-2 status, apparently consequent to the better control of extracranial disease provided by trastuzumab68. Thus for instance, Shaheenah Dawood and colleagues at MD Anderson170 found in their retrospective study of a cohort of patients with breast cancer and CNS metastases that patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients compared to both those with HER2-positive disease who had never received trastuzumab and patients with HER2-negative disease. And David Church and colleagues172 in Bristol found that patients with HER2 overexpressing MBC who received trastuzumab after diagnosis of BM survived approximately 3 times longer than expected compared to both patients with HER2-negative disease and to patients with HER2 overexpressing disease not treated with trastuzumab after development of brain metastasis. Finally, the evidence to date suggests that patients with brain metastases from a HER2-positive breast tumor still have a more favorable prognosis than those with brain metastases from a HER2-negative tumor215.
Trastuzumab Beyond
Progression (TBP)
It is telling that among patients who received trastuzumab
post-diagnosis of brain metastases, those with longer TTF (time to
treatment failure) than the median value (5.8 months) had a tendency
toward prolonged survival compared with other patients. Median survival of patients with continuation of trastuzumab after diagnosis of BM was longer than survival of patients with discontinuation of trastuzumab treatment after BM (18 vs. 3 months, p = 0.006).
This was the case also in the context of brain metastasis, where
for 75 HER2-positive patients treated with trastuzumab for MBC, Isabell Witzel and colleagues332
in Germany found that median survival of patients continuing
trastuzumab after diagnosis of brain metastasis (BM) was
longer than survival of patients discontinuing trastuzumab treatment
after emergence of brain metastasis (18 vs. 3 months). And Anna Niwińska and
colleagues332 in Poland investigated differences in
survival in patients with breast cancer brain metastases depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT),
finding that in the HER2-positive subtype, median survival
after chemotherapy with targeted therapy was 11 months,
compared to 3 months
without further treatment and 8 months after chemotherapy with
targeted therapy. Following up this Phase II lapatinib monotherapy trial, Nancy Lin at Dana-Farber and international colleagues216 conducted a multicenter Phase II study to assess the CNS activity of the small molecule EGFR/HER2 TKI lapatinib (Tykerb) in 242 HER2+ breast cancer patients with progressive brain metastases who were previously treated with trastuzumab and cranial radiotherapy (whole-brain or stereotactic radiosurgery), with the protocol later amended to allow patients progressing on lapatinib the option of lapatinib + capecitabine (Xeloda), finding CNS objective responses to single-agent lapatinib in 6% of patients. Furthermore an exploratory analysis found 21% of patients experiencing at least a 20% volumetric reduction in CNS lesions, there being observed an association between volumetric reduction and improvement in progression-free survival (PFS) and in neurologic signs and symptoms. There was additional activity in the 50 evaluable patients entering the lapatinib plus capecitabine study extension, with 20% experiencing a CNS objective response and 40% experiencing a 20% volumetric reduction in CNS lesions. Hence lapatinib (Tykerb) was found to induce modest antitumor activity in patients with recurrent HER2+ brain metastases, and as the authors conclude, the survival of HER2+ patients continues to improve even after diagnosis of CNS metastasis.
Giulio Metro and colleagues289,321 at the Regina
Elena National Cancer Institute (Rome) investigated retrospectively the efficacy of
lapatinib + capecitabine for brain metastases in 22 evaluable patients with HER2+
breast cancer, all of whom had received prior treatment with a taxane, an
anthracycline, and trastuzumab but were naïve for both
lapatinib and capecitabine reporting at ASCO
2010 that a significantly higher overall survival (OS) was observed in
favor of the LC-treated pts compared to
treated only with trastuzumab-based therapies beyond brain
progression, thus showing that using
lapatinib + capecitabine after the development of
brain metastases appears to improve OS
over receiving only trastuzumab-based therapy. And Stefan Glück and
colleagues330 at the UM Sylvester Comprehensive Cancer Center present a
case study of a HER2-positive / endocrine positive patient who later
developed multiple brain lesions and was treated with lapatinib (1250 mg/d continuous) plus capecitabine (2000 mg/m
on a 14/21 schedule). A brain CT shortly before death from systemic
disease progression confirmed near complete resolution of brain metastases. See also the review of Gianluca Tomasello and colleagues287, and Charles Vogel
and colleagues288.
Leptomeningeal Metastasis
Treatment for Leptomeningeal Metastasis
(1) Focal radiotherapy
(2)
Chemotherapy
Commonly used intra-CSF / intrathecal
chemotherapy regimens use drugs such as methotrexate, cytarabine,
thiotepa, and a sustained-release liposome-encapsulated form of
cytarabine (Depocyt, SkyePharma, London, UK). Systemic chemotherapy
can be effective given its ability to penetrate into bulky disease
seen on neuroimaging,
so patients with extensive bulky disease may
be best treated with systemic chemotherapy obviating the need for
intra-CSF therapy, while intrathecal chemotherapy may be reserved
for those with a positive CSF cytology but negative imaging140.
(3) A Role for Stereotactic Radiosurgery (SRS)?
Capecitabine Monotherapy for Leptomeningeal Metastasis
Therefore these findings suggest that capecitabine (Xeloda)
without concurrent radiotherapy and intraventricular/intrathecal
chemotherapy may be effective in treating leptomeningeal metastasis,
and we may hypothesize that diffuse leptomeningeal metastasis might
disrupt the blood-brain barrier (BBB) and the blood-CSF barrier,
allowing a higher concentration of capecitabine into the CSF,
enhancing penetration and response, and it is further possible
in growing micrometastases, up-regulation of angiogenic factors
yields new vasculature lacking the core physio-anatomic
features of
normal BBB
vessels, fostering the development of a disrupted barrier with
increased vessel permeability.
Clinical Trials in Breast Cancer Leptomeningeal Metastasis In addition, the H. Lee Moffitt Cancer Center and Research Institute (Tampa) is conducting, and hosting, a single arm pilot clinical trial274 of intrathecally (IT) administered DepoCyt + systemic sorafenib (Nexavar) [a multikinase inhibitor (MKI)] in the treatment of leptomeningeal metastasis from solid tumors. Finally, an MD Anderson sponsored and hosted clinical trial275 of is exploring the safety, tolerability and MTD of oral temozolomide (TMZ) using a 7 days on and 7 days off regimen combined with intrathecal liposomal cytarabine (IT DepoCyt) in patients with leptomeningeal metastasis from solid tumors and systemic lymphoma; this trial has recently completed and although findings have not yet been reported, results have been positive for this innovative 7/7 TMZ schedule + IT DepoCyt.
Trastuzumab + Capecitabine for Leptomeningeal Metastasis
Topotecan for Leptomeningeal Metastasis Topotecan' efficacy in leptomeningeal metastasis has also been confirmed in the earlier study of Susan Blaney at Baylor and colleagues268 who tested topotecan (recommended dose of o.4 mg) in 23 assessable patients received IT topotecan (administered by means of either lumbar puncture or an indwelling ventricular access device (Ommaya reservoir)), demonstrating the feasibility of administering a topotecan, to children and adults with refractory leptomeningeal meningitis. Thus, the topoisomerase inhibitor topotecan appears as effective as traditionally used intrathecal agents (MTX and DepoCyt), with little toxicity, making it potentially useful in combination with other agents, or as prophylaxis271,272 .
Complications of Intrathecal Chemotherapy
TMZ, traditionally associated with treatment of brain metastasis,
appears also to be some value in leptomeningeal disease, and TMZ may
provide benefit from both its intracranial as well as
systemic activity. Henry Friedman at
Duke University reports two patients with stable diseases after two
cycles of TMZ 266 and Pedro Pérez Segura and colleagues in Madrid264 conducted a Phase II trial of
first line TMZ ((100 mg/m2 daily) week-on, week-off) in 19 patients with solid tumors with leptomeningeal metastases (10 with breast cancer)), all of whom had received various prior
chemotherapy regimens (median 3) and with 14 previously receiving
radiotherapy. The median PFS was 80%, and TMZ therapy was well
tolerated; there was a 15.79% clinical benefit rate (2 partial
responses (PR), 1 stable disease (SD)), and quality of life (QoL)
was unaffected by TMZ treatment. We note of course that the
relatively low response rate is likely due to TMZ monotherapy.
Systemic Endocrine Therapy for Leptomeningeal Metastasis
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