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  : : : :   Breast Cancer Watch Digest  
issue 2   |  aug 30, 2011  
CNS (Brain and Leptomeningeal) Metastasis from Breast Cancer - A Review
 

Brain Metastasis in Breast Cancer
With (1) significant increases in median patient survival secondary to advances in oncotherapy, (2) the ability of more granular and higher accuracy radiological scans to detect increasingly smaller tumors, coupled with (2) the fact that the brain is found to be a viable place for metastatic colony formation and growth by breast tumor cells, experience confirms that more patients are living long enough to develop an increasing incidence of sanctuary brain metastasis from breast cancer.

Most present with headache or focal neurological deficits (muscle weakness, gait disturbances, visual field defects, aphasia). Medical management1, as opposed to disease treatment, includes tapered corticosteroids for metastasis-induced vasogenic edema, antibiotic prophylaxis for potential steroid-induced pneumonitis, anticonvulsant therapy if seizures present, and prophylactic anti-secretory therapy for steroid-induced GI and gastritis side effects.  And as to vasogenic / peritumoral edema, it should be noted that (1) significant preexisting edema did not affect the tumor response or clinical outcome, (2) although resolution of edema was not related to longer survival, it was related to improved quality of life for the patient, and (3) significant initial peritumoral edema should not be automatically considered an absolute contraindication to stereotactic radiosurgery213.

As to survival, despite well-documented compromised outcome in this challenging group, nonetheless the large retrospective review at MD Anderson undertaken by Kadri Altundag and colleagues333 of clinicopathologic characteristics and prognostic factors in 420 CNS-metastatic breast cancer patients  found that 19.5% (n=82) were alive at least 18 months after diagnosis of CNS metastasis, 30% (n=25) were HER-2-positive, with 18 patients (4.2%) alive at least 5 years (60 mo) after brain metastatic diagnosis. In addition, although it is commonly cited that the triple negative brreast cancer phenotype is associated with the shortest median survival time after CNS metastasis, statistically this was not significant (p = 0.3)333.

The Role of Anticonvulsant / Anti-epileptic Therapy
Note that we stated "anticonvulsant therapy if seizures present" as an as-necessary component of medical management, and this should not be misconstrued as anti-seizure premedication: prophylactic use of  antiepileptic drugs (AEDs) in brain tumor patients is not recommended, and the review of John Sirven and colleagues182 at the Mayo Clinic which concluded that no evidence supports AED prophylaxis in patients with brain tumors and no previous history of seizures, regardless of neoplastic type, and they called for more education on this issue for subspecialists who treat patients with brain tumors. In sum, prophylactic anticonvulsants / AED premedication are not effective and should not be used routinely because of their demonstrated lack of efficacy and potential for significant side effects178. Besides class I evidence of lack of efficacy, prophylactic AED therapy is furthermore problematic due to not only idiosyncratic and dose-related adverse effects (including memory problems, and dose-related neurotoxicity presenting as sedation, dizziness, diplopia, and ataxia), but also the potential for adverse pharmacokinetic drug interactions with cytochrome P-450 enzyme-inducing concomitant therapies, and variable patient compliance183

Indeed, the results of a retrospective review of a Tulane University team181 reported at ASCO 2004 actually found that, paradoxically, seizure development was more common in the group receiving AED premedication.  The guidelines suggested by Roberto Michelucci180 are prudent to heed as part of clinical practice: (1) use of phenytoin, and probably also phenobarbital and carbamazepine during cranial irradiation is associated with an increased risk for severe, potentially fatal, mucocutaneous reactions, and new AEDs with a very low potential for allergic cutaneous reactions may be preferred [although we note there is little robust support for this qualification], and (2) enzyme-inducing AEDs (phenytoin, phenobarbital, carbamazepine, among others) may increase the clearance and reduce the clinical efficacy of corticosteroids and anticancer agents metabolized by the cytochrome P450 system, suggesting the potential deployment, based on preliminary studies, of new  AEDs devoid of hepatic metabolism (levetiracetam (Keppra) and gabapentin (Neurontin).

Molecular and Biological Issues
In addition, there is evidence from the European Institute of Oncology that endocrine-unresponsive (hormone-negative) tumors (that is, ER- and PR) exhibit an increased risk, of borderline significance, of relapse with brain metastases, and this was regardless of HER2/neu overexpression status (and hence includes triple negative disease), and this suggests that patients with hormone-negative tumors may be candidates for additional monitoring, especially by MRI68

Moreover, in terms of pattern of metastatic migration, the distribution was 27% to the brain among the basal molecular class (defined as HER2- / ER- / PR- and CK 5/6+ and/or EGFR+), compared to 8% for Luminal A (defined as ER/PR+ and HER2- and Ki67 <19%), 13% for Luminal B (ER/PR+, and HER2- and Ki67 >19%), 17% for LuminalHER2 (Her2+ and ER/PR+), with the highest being 30% for HER2 (HER2+ and ER- and PR-), as per the recent analysis of 3,526 early stage breast cancer subjects referred to the British Columbia Cancer Agency (BCCA) from 1986 to 1992 reported at SABCS 2008 by Hagen Kennecke, Karen Gelmon and colleagues at BCCA (Vancouver)114.  And besides HER2 status, discussed below, other factors predictive for the occurrence of brain metastases are (1) hormone-negativity and (2) the presence of lung metastases, especially as the first site of relapse, as demonstrated by Kathy Miller at Indiana University and coresearchers123, Khemaies Slimane, Fabrice Andre and colleagues124 at the Institut Gustave Roussy, and Bernhard Pestalozzi and colleagues in Zurich137 among others, and (3) BRCA1-mutation status129.

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. 

Note
: However, patient stratification in this trial was methodologically questionable since patients were not stratified dependent on their baseline neurocognitive function, and in addition neurological function at 4 months as primary end point is somewhat problematic debatable since the preponderance of patients with advanced cancer independently may experience some neurocognitive impairment.


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. 

Hence,
patient stratification in this trial was methodologically questionable since patients were not stratified dependent on their baseline neurocognitive function, and in addition neurological function at 4 months as 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.
primary end point is somewhat problematic debatable since the preponderance of patients with advanced cancer independently may experience some neurocognitive 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.

Is SRS Limited by Number of Brain Metastases?
As to whether SRS is necessarily limited by the number of brain metastases, this has been addressed by Elizabeth Yan and colleagues72 at UCSF who reviewed of 183 patients with non-melanoma type brain metastases treated with SRS at their institution and found no difference in median survival by number of metastases, although given that this single institution finding is as yet not cross-validated, most clinicians would likely continue to limit SRS to patients with no more than three brain metastases and with controlled extracranial disease, and who exhibit adequate performance status. 

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.

Although the benefits of stereotactic radiosurgery (SRS) is well documented in patients with a single brain metastasis, and apparently, as we support here, also for patients with 2 to 3 metastases, the consensus until now has nonetheless been that SRS delivers minimal benefit if the number of brain lesions exceeds 3 or 4, with the unspoken rule of thumb that patients with greater than 4 brain metastases are typically referred to WBRT rather than SRS229.  However, the validity of a magic number of brain lesions, often cited as 3 or 4, as more prognostic than primary tumor(s) control is not satisfactorily established and has been recently disputed222,224,231, and it may be instead that the number of secondary brain lesions is primarily indicative of the aggressiveness of the primary disease itself. 

The Issue of Tumor Necrosis and SRS
Until recently, the influence of tumor necrosis on treatment efficacy of SRS in women with breast cancer metastatic to the brain is unknown, but the jstudy by Zhiyuan Xu and colleagues332 at the Brain Tumor & Neuro-Oncology Center of the Cleveland Clinic found that neuroimaging evidence of necrosis at the time of SRS does significantly diminish, but not eradicate,  the efficacy of therapy as to neurological survival (NS) and median survival after SRS: despite the decreases (32% and 27%, respectively) found, nonetheless still significant neurological median survival of 17 months and SRS median survival of 11 months were maintained, suggesting that tumor necrosis does not necessarily constitute an absolute contraindication to (further) 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. 

New Outlook for Multiple Brain Metastases
Yang, et al.235 found that up to 25 lesions can be safely treated with GKS without acute side effects, while Seung, et al.236 performed GKS to treat malignant melanoma patients, both those with a single brain metastasis and those with 1 to 7 multiple brain metastases, finding no statistically significant difference in survival time between the single versus multiple metastases groups, and observing, as  in the Amendola et al. series230, who also found that survival duration was found to be independent of the number of lesions treated in a group of patients with brain metastasis from breast cancer with up to 8 or  more lesions, that total intracranial tumor volume treated was of greater prognostic significance than absolute number of metastases.  And Bengt Karlsson and colleagues have found long-term survivors among patients who have undergone GKS who had 4 or more cerebral metastases who underwent GKS  without WBRT, and they failed to find any significant clinical disadvantage to MR imaging surveillance until evidence of metastatic lesions, then appropriate management of new lesions should they arise237, and view as minimal the clinically real risk from not implementing prophylactic WBRT to treat potential micrometastases from developing into radiosurgery-untreatable multiple new visible lesions, not having encountered it as a clinical problem in  their thirty year experience with GKS for brain224.

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:
  1. the three CMF-derived regimens74 of CFP (cyclophosphamide, fluorouracil, and prednisone) with 52% objective response, CMF-VP (cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone) with 54% objective response, and MVP (methotrexate, vincristine, and prednisone with 43% objective response;
  2. CMF and CAF75, with a 59% response rate and a 30 week median duration of neurologic remission for CMF therapy;
  3. cisplatin + etoposide (VP-16, Etopophos, Toposar, VePesid)76,88, with a 31 - 58% response rate, a median duration of combined complete plus partial response of 10 months, and with 55% of the patients alive at one year;
  4. the endocrine agents tamoxifen77,78,79, megesterol acetate80, anastrozole79, and letrozole81;
  5. bendamustine (Treanda)82, an alkylating agent (approved in the  hematological malignancies of CLL and B-Cell NHL), with regression of the liver metastases after two courses of bendamustine, and with two of the three brain metastases no longer detectable by CT, the third decreased compared to the time of diagnosis;
  6. temozolomide (TMZ, Temodar) monotherapy83,84, or as TMZ combined with WBRT85,86. One randomized Phase II study of RT (radiotherapy: 40-Gy fractionated conventional external-beam radiotherapy (2 Gy, 5 d/wk) for 4 weeks) + TMZ (75 mg/m2/d) for patients with brain metastasis from various solid tumors including 5 with breast cancer conducted by Dosia Antonadou and colleagues in Greece86 achieve an ORR (overall response rate) of 96% (nine (38%) with a complete response and 14 (58%) with a partial response) as opposed to 67% in the WBRT radiotherapy arm, and with marked neurological improvement and lower use of corticosteroid therapy in the TMZ arm; and note that this ORR of 96% is substantially higher than that previously reported chemoradiotherapy regimen. See our full TMZ discussion below for more information.
  7. capecitabine (Xeloda)20,69,87,92,93,99,234 which in one case study induced the dramatic regression of multiple brain metastases in a patient with CNS disease progression despite multiple therapies of paclitaxel, tamoxifen, procarbazine, lomustine, fluorouracil, and thalidomide; and in the combination of capecitabine + temozolomide21; see below for more information. 
  8. methotrexate (MTX) monotherapy in the form of rapid infusion of high-dose intravenous methotrexate (HD IV MTX), with 56% objective radiographic response and stable disease (and with one patient alive at 135.4 weeks)89;

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.  

Crossing the Blood-Brain Barrier (BBB)

The questions remains how do these agents and regimens bridge the blood-brain barrier (BBB) which partially mediates drug resistance in brain tumors. Part of the answer is founded on the fact that P-glycoprotein (Pgp) is a key component of the BBB and is is highly expressed in cerebral capillaries. One nontoxic inhibitor of Pgp, and the multidrug resistance phenotype, is tamoxifen, and so one critical investigation is whether tamoxifen could increase the disposition of certain chemotherapies, and Robert Fine and his colleagues19 recently explored just this issue with respect to differential paclitaxel (Taxol) deposition in primary and metastatic brain tumors under the influence of tamoxifen. Although they failed to find an increased paclitaxel deposition with tamoxifen (possibly due to low plasma tamoxifen concentrations due to concurrent use of P-450-inducing medications), they did find statistically higher paclitaxel deposition in the periphery of metastatic brain tumors indicating decreased P-glycoprotein expression in metastatic as opposed to primary brain tumors, suggesting that metastatic brain tumors may be responsive to paclitaxel if it exhibits clinical efficacy for the primary tumor's histopathology.

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. 

Capecitabine (Xeloda)

As we noted above, a case study reported a response brain metastases to monotherapy before brain irradiation20.  This is supplemented by the small retrospective review conducted at MSKCC69 on 7 patients with breast cancer brain metastases, with five of these seven patients had failed other treatment modalities before capecitabine (Xeloda). Three patients showed complete response (CR), another three stable disease (SD) after capecitabine therapy; the single patient with leptomeningeal disease did improve clinically, but refused repeat cerebrospinal fluid (CSF) studies. In addition, CNS involvement was well controlled by a chemoradiation regimen of oral capecitabine and WBRT with minimal toxicity in a woman who developed multiple brain and meningeal metastases92. and an Israeli case study found that capecitabine after cycle 10 of therapy showed complete resolution of cerebral and cerebellar metastases in a patient, who after continuation therapy for 30 cycles was free of cancer symptoms, with only grade 1-2 hand foot syndrome complaints. These studies collectively again suggests that capecitabine may achieve a complete response and provide long-term control in patients with CNS metastases from breast cancer (both leptomeningeal and parenchymal).  

Yee Lu-Tham and Richard Elledge121 at Baylor have reported on using  capecitabine (Xeloda) monotherapy in a woman for the long-term control for both brain and leptomeningeal metastases (brain metastasis were subjected to WBRT: whole-brain radiation therapy), with the patient remaining without neurologic symptoms or deficits, and no evidence of disease on neuroimaging studies (despite a persistent positive cytology), after 3.7 years, suggesting preliminarily that systemic chemotherapy - especially capecitabine (Xeloda) - can provide long-term complete responses for some patients with CNS metastases, in agreement also with findings from Meltem Ekenel and colleagues122 at Memorial Sloan-Kettering Cancer Center (MSKCC) who document several complete responses to capecitabine (Xeloda) therapy in CNS metastases.

The MD Anderson team of Edgardo Rivera and colleagues21 investigated the combination regimen of capecitabine + temozolomide (TMZ) in 24 patients with multiple brain lesions, 14 with newly diagnosed brain metastases and 10 with recurrent brain metastases, observing significant antitumor activity, with an objective benefit of 18% (1 complete, 3 partial responses) + 11 disease stabilization (50%), for an aggregate clinical benefit of 68%, and good tolerability; see also our discussion of TMZ below.

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.

Capecitabine Monotherapy for Brain Metastasis
And there are emerging findings that even capecitabine (Xeloda) monotherapy can be significantly effective against brain metastasis from breast cancer. So, David Naskhletashvili and colleagues at the Russian Cancer  Research Center235 have reported at ASCO 2009 the results of their evaluation of the efficacy of capecitabine (Xeloda)  monotherapy (1,000 mg/m2 bid on days 1-14 every 3 weeks) in 10 chemotherapy-pretreated (1 to 3 lines) advanced breast cancer patients with brain metastases, two of whom had metastases limited to the brain, with the remaining eight also having extracranial metastases. There were 6 partial responses (PR), and 3  patients with stable disease (SD), yielding an overall response rate of 60% and a clinical benefit rate (CBR = CR  +  PR + SD) of 90%, the remaining patient having disease progression as best response, and with 7 patients surviving  at time of reporting, median overall survival has therefore not yet been reached, these findings suggesting in this small series advanced pre-treated patients that capecitabine (Xeloda) monotherapy exhibits pronounced anticancer activity against brain metastases from breast cancer, and is associated with reasonable and expected tolerability, and outpatient ease of administration as oral therapy.

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.

Capecitabine Monotherapy for Leptomeningeal Metastasis
And capecitabine shows some potential benefit in the treatment of leptomeningeal metastasis also: Pierre Giglio and colleagues243 at MD Anderson reported a small case series with two cases of leptomeningeal metastasis (neoplastic meningitis) from breast carcinoma (a third was esophageal carcinoma), which responded to treatment with capecitabine.  In addition, as we discuss more fully below, Lisa Rogers and colleagues242 present another case report of a durable (12-month) response to capecitabine monotherapy in a patient with leptomeningeal metastasis from breast cancer who also had diffuse skull and vertebral metastasis. 

Liposomal Anthracyclines
It has been widely considered that anthracyclines like doxorubicin (Adriamycin) have limited penetration of the CNS but this appears not to be the case with liposomal encapsulated forms such as the pegylated liposomal doxorubicin (Doxil, Caelyx) which achieve augmented penetration of the BBB.  The Italian research team of Michelle Caraglia and colleagues90 administered a combination regimen of temozolomide (TMZ) and pegylated liposomal doxorubicin for treatment of brain metastases from solid tumors in 19 patients, mostly pretreated, patients, including 8 breast cancer patients who all had all had been previously  treated with WBRT. The TMZ + Doxil regimen yielded 3  complete responses (CR), all three being breast cancer patients with multiple brain lesions and extra-brain disease at different sites, and it should be noted that the duration of complete response was, impressively, over 23 months in one of these complete responders. There were 4 partial responses (PR) of which 2 were in breast cancer patients.  The overall response rate was 36.8%,  with breast cancer patients accounting for five of the seven responses, suggesting that given the limited activity of TMZ against breast cancer, liposomal doxorubicin in combination with TMZ has promising activity in mitigating cerebral metastatic BC. In addition, Micahael Koukourakis and colleagues331 in Greece tested Caelyx in 10 patients with metastatic brain tumors and five patients with brain glioblastoma undergoing radiotherapy.  Patients with metastatic brain lesions were treated with 10 consecutive fractions of radiotherapy (WBRT 3 Gy/fraction, day 1–12) followed by a booster dose of 9 Gy (3 Gy/fraction, day 21–23); Caelyx was given on day 1 and on day 21
at a dose of 25 mg mg–2 . They obtained complete response to PLD/Caelyx in 2 breast cancer patients (along with objective responses in glioma patients), based on data supporting the contention that liposomal technology may be of particular importance in overcoming the blood–brain barrier, with strong confirmation in the Koukourakis study of an intense accumulation of Caelyx in both patients with glioblastomas and with metastatic brain tumors (including from breast cancer), with an attractive tumor to normal brain count ratio showing a 7 –1 9-fold higher accumulation of the drug in tumoral as compared to normal brain tissue, hence establishing that liposomal drugs like Doxil/Caelyx selectively overcome the blood–brain barrier in tumoral areas. 

Endocrine Therapy
And it would appear that brain metastasis responsiveness is not limited to chemotherapy, but also to endocrine therapy: a recent case report22 documents a good response of intact breast carcinoma with brain as well as scalp metastasis to aromatase inhibitor therapy via letrozole (Femara) for a prolonged period of time; and as we noted above, other endocrine agents have shown promising efficacy in breast cancer brain metastases (
tamoxifen77,78,79, megesterol acetate80, anastrozole79).

A Place for the Epothilones?

There is also preclinical and provisional evidence that epothilones like ixabepilone (Ixempra) may also have significant cross-BBB activity (and David Peereboom at Case Comprehensive Cancer Center (Ohio) and Andrew Seidman at Memorial Sloan-Kettering Cancer Center (MSKCC) are evaluating in clinical trial new investigational epothilones for just this application, against brain metastases from breast cancer), and ixabepilone itself exhibits activity in pediatric brain tumor models (including broad spectrum activity in primary neuroblastoma), thus suggesting that epothilones may also cross the BBB, although here we need further robust data, pending from some in-progress clinical trials (such as: Epothilone B in Treating Women With CNS Metastases From Breast Cancer95, being conducted at the Memorial Sloan-Kettering and the Case Comprehensive cancer centers).

A Place for Bevacizumab?
There is preclinical motivation for a potential role of anti-angiogenic agents such as bevacizumab (Avastin) in breast cancer patients with brain metastases174.  Seiji Yano and colleagues166 at the MD Anderson Cancer Center found that expression of VEGF mRNA and protein directly correlated with angiogenesis and growth of brain metastasis in mice, suggesting that VEGF expression is necessary, but not sufficient, for the production of brain metastasis and that the VEGF inhibition inhibits brain metastasis, and hence that antiangiogenesis therapy targeting VEGF has particular therapeutic potential. Lee Su Kim in Seoul together with Janet Price and colleagues167 at MD Anderson found in a murine model specific for brain metastases from breast cancer that elevated expression (as VEGF-A) contributes to the ability of breast cancer cells to form brain metastases, with brain metastasis growth restricted by a VEGF TKI via induction of apoptosis and decreased angiogenesis. And VEGF appears to be contributory to the brain edema associated with brain metastases, and hence being a molecular source of considerable morbidity and mortality from peritumoral edema168

The Safety of Anti-VEGF Therapy in CNS Metastasis
VEGF has also been implicated in the development of brain edema, a significant source of the morbidity and mortality associated with brain metastasis, but there have been concerns expressed as to the  potential for increase in intracranial (intracerebral) hemorrhage (ICH) from the  use of the anti-VEGF / antiangiogenic agent bevacizumab (Avastin)192, but the two cases of symptomatic, life-threatening ICH in patients treated with bevacizumab reported by Ted Nyugen and Lauren Abrey192 at memorial Sloan-Kettering Cancer Center were treated concomitantly with full-dose low-molecular weight heparin (LMWH). However, in the retrospective review of Phioanh (Leia) Nghiemphu and colleagues193 at UCLA, anticoagulation did not lead to any major hemorrhages and hence did not appear to be a contraindication against bevacizumab therapy.  In addition, bevacizumab did increase the risk of ICH in patients with CNS malignancies, and although there was an increase in cerebrovascular infarct (CVA) prevalence, the risk was not statistically significant, so bevacizumab-based therapy appears to carry no appreciable increase in cerebrovascular risk in patients with CNS malignancies, as reported at ASCO 2008 in the retrospective analysis of 6674 patients by an MD Anderson Cancer center team194.

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?  
New research suggests that combination therapy targeting the HER family of receptors may be of clinical benefit for a larger proportion of breast cancer patients than strict standard IHC/FISH thresholds suggest, including those with HER2 negative disease, that is, even in the absence of HER2 over-expression or amplification, and may even be of benefit to brain metastasis from breast cancer295. This is earlier suggested in the NSABP B-31 trial where 161 of 1,662 (9.7%) subjects had neither gene amplification nor overexpression, yet there was observed consistent benefit from trastuzumab in every subset defined by IHC or FISH, including in patients with FISH-negative tumors and those who < 3+ staining intensity on HercepTest IHC290.

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
Vinorelbine + Cisplatin

Phillippe Cassier and colleagues198 at Edouard Herriot Hospital (Lyon, France) conducted a  study to determine the efficacy, tolerability, and safety of concurrent cisplatin (at a dose of 20 mg/m2/day, days 1-5) and vinorelbine (6-mg/m2 bolus on day 1 and 6 mg/m2/day continuous infusion on days 1-5) chemotherapy and concurrent radiotherapy (30-gray fractionated external-beam radiotherapy) in patients with previously untreated brain metastases from breast cancer. Chemotherapy was given at 3-week intervals for a total of 4 cycles.  Complete response in the brain was observed in 3 patients, and partial response was noted in 16 patients, yielding a 76% response rate in the brain, along with a 44% overall systemic response rate; overall toxicity was acceptable; nonhematologic grade 3-4 events were noted in 5 (20%) patients, and there were no toxic deaths. 
 
Metronomic Vinorelbine + TMZ

Liliana Montella and colleagues257 in Italy treated 19 breast cancer patients with brain metastases, using WBRT (3 Gy/d for weeks 1 - 2, total dose = 30Gy), and induction therapy with TMZ (75mg/m2/d) during this period, followed by 4 weeks off-therapy and subsequent original schedule with TMZ (75mg/m2 on days 1–21) and oral Vinorelbine (VNR, at 70mg/m2 fractionated in days 1, 3 and 5) using a wk-on/wk-off schedule (one week on, one week off), every four weeks up to 12 cycles. Response was impressive, with an objective response rate of 52%, comprised of  10% (2 pts) complete response (CR) and 42% (8 pts) partial response (PR), coupled with clinical benefit in other four patients (21%), for a total disease control rate of 73%, and 59% overall survival at 1 year.  The authors  concluded that some of the patients who received the full regimen achieved prolonged disease control and survival, with good tolerability.

The Role of Platinums
The Phillippe Cassier trial discussed above in connection with vinorelbine (Navelbine) regimens has  already shown the potential benefit of adding a platinum agent: the vinorelbine + cisplatin regimen yielded a 76% response rate in the brain, along with a 44% overall systemic response rate.  To this we can now add the trial of the Russian team of Gorbunova and colleagues261 who reported at ASCO 2010 on the efficacy of gemcitabine (GEM) [1,000 mg/m2 IV days 1, 8] + cisplatin (CIS) [50 mg/m2 IV days 1, 8] every 3 weeks in 14 heavily pretreated advanced breast cancer patients with progressive disease to the brain, already exposed to between 1 to three lines of previous chemotherapies and/or whole brain radiotherapy (WBRT), and with 12 patients having received prior salvage radiotherapy to the brain, finding pronounced, exceptionally high anticancer activity against CNS metastases, and also against extracranial (non-CNS) metastases: 2 patients (14.3%) achieved complete response in the brain and 1 patient (7.7%) achieved complete response in extracranial metastases, while 3 patients (21.4%) achieved a partial response in the brain and 3 patients (23.1%) achieved a partial response in the EM, along with 8 (57.1%) who showed disease stabilization in the brain and 7 (53.8%) who showed disease stabilization extracranially, This yields for CNS disease an overall response of 35.7% and a clinical benefit rate (with stable disease (SD)) of 92.8%, and for extracranial disease an overall response of 30.8% and a clinical benefit rate of 84.6%.  We note two noteworthy features of this small trial: (1) the separate response rates for CNS versus extracranial metastatic disease, rare in reported data, makes clear the activity - impressively high - of GEM + CIS in CNS metastases from breast cancer, and (2) it demonstrates that there can be effective targeting of both CNS and systemic (extracranial) disease in parallel, in an innovative regimen with acceptable toxicity. Although  a small trial, nonetheless it would appear that the GEM-CIS regimen constitutes another potential and powerful weapon against CNS disease from breast cancer, even for heavily pretreated patients.


Temozolomide (TMZ)
Temozolomide (TMZ), a new orally administered alkylating / imidazotetrazinone methylating agent already in use alone or in combination with radiotherapy in treating primary brain humors (malignant glioblastoma), appears to also have significant value in brain metastases. TMZ exhibits several unique attributes making it a favorable treatment modality in brain metastases: (1) high bioavailability after oral administration, with (2) excellent central nervous system penetration, as demonstrated by (3) therapeutic concentrations reaching the brain.

Temozolomide (TMZ) Monotherapy
Although one study under NCIC-CTG auspices failed to find temozolomide (TMZ, Temodar, Temodal) of benefit in MBC23, this was monotherapy and in addition was in a population of heavily pretreated women with extensive MBC. And there are some further data on TMZ monotherapy  in breast cancer brain metastasis:  Lauren Abrey and colleagues247 at Memorial Sloan-Kettering Cancer Center evaluated single-agent temozolomide in the treatment of recurrent or progressive brain metastases in 41 patients (median KPS 80)34 of whom were assessed for radiographic response, including 10 with breast cancer, on a schedule of temozolomide 150 mg/m2/day (200 mg/m3/day if no prior chemotherapy) for 5 days, of each  28 day treatment cycle, achieving a disease control rate of 50% (6% (2 patents) partial response in NSCLC, and 44% (15 other patients) with disease stabilization), with minimal toxicity.  In addition, Christos Christodoulou and colleagues248 with HeCOG (the Hellenic Cooperative Oncology Group) conducted a phase II trial of temozolomide monotherapy (150 mg/m2/day for five days every 28 days) in 27 heavily pretreated cancer patients with brain metastases from solid tumors including four with breast cancer, obtaining a 21% disease control rate (4% partial response and 17% disease stabilization)  (four of 27 patients had breast cancer). Also, Italian researcher Marco Danova and colleagues120 reported on the clinical activity of a dose-dense regimen of temozolomide (TMZ) in patients with brain metastases from advanced NSCLC, malignant melanoma, and breast cancer (51 patients), using oral TMZ 150 mg/m2/day on days 1–7 and 15–21 every 28 days for up to 15 months or until disease progression, findings partial response or stable disease in 19.6% of the BC patients with an acceptable safety profile. 

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.


Temozolomide (TMZ) Combination Therapy .  
As to TMZ combined with other modalities such as radiotherapy or  chemotherapy, Christos Christodoulou and colleagues with HeCOG (the Hellenic Cooperative Oncology Group)24 evaluated the efficacy of temozolomide (TMZ) combined with cisplatin (CDDP), and found that TMZ + CDDP was an active and well-tolerated regimen in patients with brain metastases from solid tumors, including partial response in six patients with breast cancer, yielding a response rate of 40%, and we have already documented above (Rivera et al.) the significant antitumor activity of TMZ when combined with another chemotherapeutic agent, capecitabine (Xeloda)21.  And as we discussed more fully below, TMZ has also been coupled with several other  chemotherapies in breast cancer: with irinotecan (Camptosar)94, with vinorelbine (Navelbine)297, with docetaxel (Taxotere)313, with pegylated liposomal doxorubicin/PLD (Doxil)90.

TMZ + WBRT or SRS
In addition the combination of WBRT + TMZ exhibits good objective response rate (45%), is well tolerated, and allows a significant improvement in quality of life25, further confirmed both by Addeo and colleagues26 who investigated WBRT + TMZ in 59 patients with solid tumors, including 21 with breast adenocarcinoma, finding clinical benefit in 44 patients, and by the phase II study of concomitant WBRT in patients with brain metastases from solid tumors by Kouvaris et al. which found favorable objective response and survival outcome67. In addition, Eugènia Verger and colleagues119 in Spain  in a randomized Phase II trial again compared WBRT (30 Gy) + TMZ (75 mg/m2/d) to WBRT alone, finding significantly better  progression-free survival (PFS) from brain metastasis at 90 days (72%) for WBRT + TMZ versus 54% for WBRT alone.  And we have already noted above the study of Dosia Antonadou and colleagues of radiotherapy (RT) + TMZ in a mixed solid tumor population of patients with brain metastasis achieve an impressive  ORR (overall response rate) of 96%, including (38% (nine patients) with a complete response, 58% (14) with a partial response) as opposed to 67% in the RT alone arm, and with marked neurological improvement and lower use of corticosteroid therapy in the TMZ arm, this ORR of 96% being substantially higher than that observed in any previous chemoradiotherapy regimen. 

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:

  1. TMZ + irinotecan (Camptosar): Michelle Melisko, Hope Rugo and colleagues94 at UCSF found that the  combination of irinotecan (Camptosar, CPT-11) and temozolomide (Temodar, TMZ) shows preliminary evidence of efficacy and is well tolerated in patients with progression of breast cancer brain metastases, although we observe nonetheless that the activity appears modest at best, and in this connection it should be remembered that the Mayo Clinic N0436 trial214 of irinotecan plus cetuximab in patients with metastatic breast cancer was close early because of the low response rate and the  rapid progression observed, so to Breast Cancer Watch the role of irinotecan (Camptosar, CPT-11) in metastatic breast cancer in general and in BC brain metastasis in particular remains questionable, and many of the non-irinotecan regimens we focus on here may be superior choices based on the evidence of higher response and slower rate of progression.
  2. TMZ + capecitabine (Xeloda): As noted above, TMZ + capecitabine (Xeloda), as per the results of Edgardo Rivera and colleagues21 at MD Anderson where in a Phase I study the combination regimen of demonstrated significant antitumor activity in patients with breast cancer brain metastases, with an objective benefit of 18% (including 1 complete, 3 partial responses) and an aggregate clinical benefit of 68% (11 disease stabilization (50%)). 
  3. 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.


Metronomic Temozolomide (TMZ)
The standard current administration of TMZ is is as a 5-day oral schedule every 4 weeks, but Rafaele Addeo and colleagues96 with Michelle Caraglia's team examined the efficacy and the safety profile of a new metronomic schedule of dose-intensified, protracted course TMZ regimen administered after whole-brain radiotherapy (WBRT) in 27 NSCLC and breast cancer patients, the findings of which were just reported this month.  The regimen consisted of 30 grays (Gy) of WBRT with concomitant TMZ (75 mg/m(2)/day) for 10 days, and followed by TMZ at a dose of 75 mg/m(2) per day for 21 days every 4 weeks, for up to 12 cycles, achieving 2wo complete responses (7.4%) and 11 partial responses (40.7%); the regimen was well-tolerated with only 2 patients with grade 3 toxicities. It appears that the metronomic protracted TMZ administration, even at relatively low daily doses, leads to significant and prolonged depletion of the AGAT (O6-alkylguaninae-DNA alkyltransferase) enzyme (also known as MGMT) activity known to be involved in DNA repair, which may enhance the antitumor activity of the agent. This confirms the earlier study by the same investigators97 reported out at ASCO  2007, where the same WBRT schedule was used, and an induction with TMZ 50 mg/m2/day during this period, following TMZ 50mg/m2 fractionated in 21 days every 28 days, for up to 12 cycles in 24 NSCLC and breast cancer patients, yielding an overall response rate was 45.5% and a disease control rate was 77%, with overall survival at 12 months of 64%. 

This is highly encouraging and the metronomic strategy utilizing a more intensive TMZ dosing schedule would permit the concomitant use of a second chemotherapeutic agent on the primary cancer (such as capecitabine (Xeloda) among others) while effecting prolonged AGAT depletion, given that the primary mechanism of resistance to temozolomide is a function of the activity of the DNA repair enzyme AGAT / MGMT110. And studies from malignant / refractory gliomas from GICNO106 and the GENOM Cooperative Group107, among others, suggests that metronomic q3wk TMZ administration may be able to revert previous tumor resistance to the drug, while in addition it has developed that alternative TMZ schedules may prove of superior efficacy to the standard schedule (SS: 200 mg/m2 for 5 days every 28 days = 1.0 g/m2 monthly dose, n=45), such as an extended schedule (ES: 150mg/m2, 7 on 7 off = 2.1 g/m2 monthly dose, n=35) or a daily schedule (DS: 75 mg/m2every day = 2.25 mg/m2 monthly dose, n=35), where both the extended and especially the daily schedule appear more effective108,109,111,112.

TMZ Dose/Schedule Optimization and Pharmacokinetics
Temozolomide (TMZ, Temodar/Temodal) is a second-generation imidazotetrazinone prodrug.  Pharmacokinetic studies of TMZ consistently demonstrate a linear pharmacokinetics with the AUC increasing in proportion to dose. TMZ does not require hepatic activation and after absorption is rapidly and spontaneously converted to the active metabolite MTIC (5-(3-methyl)1-triazen-1-yl-imidazole-4-carboxamide), and subsequently to the final degradation product AIC (5-aminoimidazole-4-carboxamide), with mean Tmax values for MTIC of 1.5 to 2.0 hours after single dose, and mean Tmax of AIC of 2.5 hours299. The cytotoxicity of MTIC is largely attributed to DNA alkylation at the O6 position of guanine, with DNA methylation considered to be the principal mechanism responsible for TMZ cytotoxicity.

Given the known effect of gastric pH and ingestion of food on the pharmacokinetic properties and oral bioavailability of TMZ298,299, administration with food results in a 33% decrease in Cmax and 9% decrease in AUC, and even without dispositive resolution on the true  clinical significance of such changes, it is prudent to administer TMZ in the fasting state. 

Dose-limiting toxicity mainly consists of myelosuppression predominantly in the form of grade 3/4 thrombocytopenia (incidence 8 - 17% across phase II and observational studies) and to a lesser extend neutropenia, with any limiting toxicity usually presenting in the first two treatment cycles, while platelet and neutrophil nadirs tending to occur late in the cycle with recovery usually observed within 1-2 weeks. These new alternative regimens can be associated with cumulative lymphopenia, suggesting vigilance as to opportunistic infections, but specific pneumocystis pneumonia (PCP) prophylaxis is typically required only during combined TMZ + concurrent radiotherapy), but TMZ therapy is nonetheless not associated with cumulative toxicity (unpredictable, severe myelosuppression prohibiting TMZ treatment continuation is exceeding rare. However, as concluded in the review by Van Anh Trinh and colleagues314 at MD Anderson, ll patients on TMZ therapy should be observed for lymphopenia and potential opportunistic infections, particularly when TMZ is combined with other immune suppressive therapies.

Alternative DD-TMZ Dosing Regimens
There has been intensive recent interest in alternative dose-dense (DD) TMZ regimens that use more extended periods of time, including 7/14 (week-on/week-off ( (21 out of 28 days), 6 out of 8 weeks, and several metronomic (commonly, 50 mg/m2/d although 75 mg/m2/d has also sometimes been deployed) or near-metronomic schedules, all of which allow  delivery of an increased cumulative dose yet retain acceptable toxicity compared to the classical 5/28 regimen, but data suggest that cumulative lymphocytopenia is a small but non-trivial potential with any dose-dense regimen using > 7 consecutive daily administration300. Note that lower doses are used in concomitant administration contexts: so for example, in TMZ + WBRT where some data
312 suggest that the maximum tolerated dose of daily TMZ + WBRT is 95 mg/m2 in the multiple brain metastases setting. In concurrent TMZ + chemotherapy settings, TMZ dose adjustment varies across various agents. 

Deconstructing the Capecitabine + TMZ Breast Cancer Study
Thus in the MD Anderson (Rivera et al.) study of X-TMZ21, that is, capecitabine plus TMZ, patients received capecitabine initially at 1800 mg/m2/day in 2 divided doses, with TMZ given orally once daily starting at 75 mg/m2/day, and concurrent dosing occurred on Days 1–5 and Days 8–12, with cycles repeated every 21 days until disease progression; sequential cohorts received X-TMZ at escalated doses:

   X: 1600 mg/m2    +    TMZ: 50 mg/m2
   X: 1800 mg/m2    +    TMZ: 75 or 100 mg/m2
   X: 2000 mg/m2    +    TMZ: 100 or 150 mg/m2 

For the 24 patients with multiple brain lesions (14 with newly diagnosed brain metastases and 10 with recurrent brain metastases), patients were treated until occurrence of unacceptable toxicity or evidence of progression of brain metastases. We found noteworthy that within the objective response rate of 18% (of 22 evaluable patients), the single complete response (CR) occurred at the base dosing level (aka, level 0: 1800 mg/m2 capecitabine + 75 mg/m2 TMZ), and interestingly, the 1 complete responder and 1 of the partial responders had never received WBRT.  In addition we note that there were objective (CR or PR) responses at both the
X: 1600 mg/m2 + TMZ: 50 mg/m2 level as well as the X: 1800 mg/m2 + TMZ: 75 or 100 mg/m2 level, but no responses were seen at  the most intense level (X: 2000 mg/m2 +TMZ: 150 mg/m2).  This suggests, admittedly limited to this study data, that in a concurrent X-TMZ regimen, capecitabine need not be escalated beyond 2000 mg/m2 and TMZ when coadministered with capecitabine should not exceed 100 mg/m2; finally the largest  number of minor responses or stable disease  were seen at the X: 2000 mg/m2 + TMZ: 100, although numbers are necessarily small. 

The most common hematologic adverse events were Grade 3/4 neutropenia (3 patients on X:1800/TMZ:75), 2 on X:2000/TMZ:100, and another 2 on X:2000/TMZ:150. There were nonetheless no episodes of neutropenic fever or sepsis.  Most reported adverse events were nonhematologic and generally mild to moderate in severity, with fatigue most common, but as noted hematologic toxicity was not a major DLT with this regimen.  And although in this study neurocognitive function was substantial pre-treatment, as in many comparable studies (particularly in the memory, executive function, cognitive processing speed, and motor function domains), the treatment had no negative impact on cognitive function or QoL, with a strong suggestion of a beneficial effect in those patients who had not progressed at the time of the neurocognitive assessment. In sum, advantages of X-TMZ therapy over conventional therapies for multiple brain metastases include the convenience of an all-oral self-administered regimen, plus durable responses, favorable time to progression (TTP), maintenance or improvement of neuropsychological function, favorable safety and tolerability and hence QoL, and thus X-TMZ offers a viable alternative to WBRT in patients who either have recurrent disease or refuse WBRT because of perceived risks of neurocognitive deficits (among these, brain atrophy, endocrine dysfunction, and dementia).

Other Combination TMZ Regimens in Breast Cancer
As we noted earlier above, the HeCOG  Phase II trial24 evaluated the efficacy of CDDP-TMZ (TMZ combined with cisplatin) in patients with brain metastases from solid tumors, including partial response in six patients with breast cancer, with a response rate of 40%, using the classical 5/28-TMZ schedule (150mg/m2/d for pretreated patients, 200 mg/m2/d for chemotherapy-naive patients) with good tolerability, but we not that platinum dosing was keep modest at 75mg/m2 on day 1, every 28 days.

In the previously discussed PLD(Doxil)-TMZ study of Michelle Caraglia and colleagues90 5 of 8 breast cancer patients with multiple brain lesions and extra-brain disease at different sites had responses, 3 complete responses (with one sustained long-term at 23+ months) and 2 partial responses, using a regimen of 5/28-TMZ (200 mg/m2 on days 1–5) under fasting conditions, and modestly-dosed pegylated liposomal doxorubicin (Doxil) at 35 mg/m2 day 1, every 28 days. The PLD-TMZ combination was able to rescue some patients who were refractory to conventional radiotherapy, and to induce some long-lasting responses in a subset of poor-prognosis patients (and with a highly promising median OS of 10.0 months), all with favorable safety and tolerability. (We note in this connection that an increase in the TMZ dose intensity can be achieved by deploying a 7/14-TMZ alternating regimen using TMZ at  125 mg/m2/d as implemented in another Phase I PLD(Caelyx)-TMZ trial conducted by Ahmad Awada's team315 at the Jules Bordet Institute in Brussels, but the applicability of these findings is limited as there were no responses reported in breast cancer patients who were not separately identified).   

The MSK Phase I study297 of VIN-TMZ (TMZ+ vinorelbine (Navelbine)) in 21 patients (18 evaluable) with recurrent or progressive brain metastasis (6 patients with breast cancer) used the 7/14-TMZ alternating week-on/week-off TMZ schedule with 28-day cycles of 150 mg/m2, and 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, and there were two patients with a radiographic response (one partial, one minor), and with stable disease in 6 of 18 patients, and median survival of 27 weeks; specifically in breast cancer patients, one had a partial response, with an additional patient having stable disease. Here again, as in PLD-TMZ and CDDP-TMZ studies just reviewed, the standard 5/28-TMZ regimen at 150mg/m2/d proved viable and tolerable.  


In the Cleveland Clinic DOC-TMZ trial (Ila Tamaskar and colleagues)313 the combination of docetaxel and TMZ was active and well tolerated, and the authors concluded that going forward in phase II trials, docetaxel in this regimen should be dosed at 35 mg/ m2 IV day 1, 8 and 15, with a 21/28-TMZ regimen of daily TMZ at 100 mg/ m2 day 1–21.

The IRI-TMZ trial conducted by Melinda Melisko and colleagues94 found efficacy and tolerability for irinotecan (125 mg/m2 i.v. every other week) plus 7-14-TMZ alternating dosing of 100 mg/m2 orally on days 1–7 and 15- 21, in patients with progression of breast cancer brain metastases (previous WBRT or SRS).


Summary of Chemotherapy + TMZ Regimens in Breast Cancer

Regimen

Chemotherapy (CT)

TMZ

 

 

 

CDDP-TMZ

CDDP (cisplatin):
75mg/m2 day 1, each 28

150mg/m2/d pretreated
200 mg/m2/d chemo-naive
days 1-5 each 28

IRI-TMZ

irinotecan:
125 mg/m2
week-on/weak-off

100 mg/m2 week-on/weak-off
each 28

PLD-TMZ

Doxil:
35 mg/m2 day 1 each 28

200 mg/m2 days 1–5 each 28

VIN-TMZ

vinorelbine:
start 15 mg/m2 days 1 & 8 escalating 5 mg/m2
until MLD (30 mg/m2)

150 mg/m2 week-on/week-off each 28

X-TMZ

capecitabine:

start at 1800 mg/m2/d

daily starting at 75 mg/m2
concurrent days 1–5 & 8–12, each 21


Author's Conclusions
From the above review of alternative DD-TMZ therapies in solid malignancy studies that included some breast cancer patients with brain metastasis, coupled with our discussion and dissection of the X-TMZ study (MD Anderson/Rivera et al.21), although not decisive and lacking stronger Phase III prospective data, we would conclude these TMZ combination dosing regimens are likely to be most optimal in this context:

  1. The classical 5/28-TMZ schedule at 150mg/m2/d Days 1-5 of each 28 day cycle, with the potential for escalating up to 200mg/m2/d if using low-dosed concurrent chemotherapy (such as PLD);
  2. The 7/14-TMZ alternating week-on/week-off TMZ schedule with 28-day cycles of 150 mg/m2, escalating down to 125mg/m2/d, and then 100mg/m2/d based on observed toxicity/tolerability in the first cycle;
  3. In the specifically capecitabine + TMZ (X-TMZ regimen) context, capecitabine may be started at 2000 mg/m2 (escalating down to 1800mg/m2/d if compelled), with TMZ at 100 mg/m2
  4. For this same X-TMZ context, a plausible and potentially more aggressive alternative would be the 7/14-TMZ alternating week-on/week-off TMZ schedule at TMZ dosing of 150 mg/m2, escalating down to 125mg/m2/d as compelled.
  5. We do  not find the safety of the 21/28-TMZ schedule convincing given the serious potential for prolonged myelosuppression, and at least some data from other  malignancies suggests it may be inferior in efficacy, further attractive if administered concurrently with chemotherapy also given on alternating 7/14 (week-on/week-off) schedule.
  6. Except in special contexts - in particular (1) in conjunction with WBRT or SRS, or (2) as maintenance therapy after securing disease stabilization, we find the data for a metronomic  schedule, at least in breast cancer, needs to mature further before clinical deployment can be viable. 

Dose-Dense TMZ (DD-TMZ)
Given that these dose-dense schedules entail a significant increase in dose intensity as well as deplete MGMT, a DNA repair system seen to be capable of reversing the lethal DNA-damage induced by TMZ at the O6 position and hence neutralizing TMZ cytotoxicity, thus the consideration is that such dose-density may mitigate a potential mechanism of TMZ resistance299,301-306, further suggested by the fact that  high levels of MGMT in the tumor are associated with resistance to both TMZ and several other alkylating agents; note that tumor cell levels of MGMT is frequently regulated by epigenetic silencing of the gene via hypermethylation of CpG islands within the MGMT gene promoter.  The critical question is therefore whether dose-dense and metronomic TMZ dosing regimens delivering a higher cumulative dose over a prolonged period can effectively deplete MGMT activity in the tumor and overcome or mitigate resistance, and a focal point of continued research remains the determination of the optimal TMZ schedule that most effectively depletes tumor cell-level MGMT and strikes the best balance between antitumor activity and hematologic toxicity. Finally, we note in this connection that accumulating evidence suggests potentiation of TMZ activity when administered concurrently with a PARP inhibitor: thus the Phase II trial just reported at ASCO 2010 found significant activity of veliparib administered concurrently with TMZ in metastatic breast cancer, including in patients with stable brain metastases311.

Clues from Other Malignancies: Alternative DD-TMZ Schedules
Although we lack dispositive data from prospective Phase III trials, provisional evidence from multiple malignancies, especially malignant gliomas and glioblastoma (GBM) in particular has helped shed some light on comparative benefits/harms of alternative TMZ dosing regimens. So results from a randomized trail reported at ESMO 2008307 including a secondary comparison of 5/28-TMZ versus 21/28-TMZ found that the 5/28-TMZ schedule was superior to the 21/28-TMZ schedule both as to  progression-free survival (PFS) and overall survival (OS), and furthermore reported clinical experience has found a subgroup of patients who develop a prolonged myelosuppression following the first treatment cycle, with  return of blood count normalization only after 12 weeks (reported experience of Bart Neyns at the Oncology Center of Universitair Ziekenhuis Brussel (Belgium)).  In addition, preliminary results of an early analysis from randomized phase II trial308 comparing dose-dense 7/14-TMZ to metronomic TMZ (50mg/m2 daily in 28 day cycles for 6 cycles) in 51 newly diagnosed GBM patients suggest that the dose-dense 7/14-TMZ regimen may be superior as to PFS to at least this instantiation of metronomic TMZ. 

Nonetheless, despite the substantial increase in dose density,
the evidence to date from extended dose-dense TMZ regimens (DD-TMZ) suggest that DD-TMZ regimens do not exhibit substantially different post-first-cycle prolonged myelosuppression may be of concern in the 21/28-TMZ, but not in the 7/14-TMZ, regimen.  Clinicians should consider therefore the potential deployment and benefit of pneumocystis pneumonia (PCP) prophylaxis against lymphocytopenia-induced susceptibility to this opportunistic fungal pulmonary infection in patients at  elevated risk (especially with total lymphocyte counts below 500/mm³ and even more critically, with CD4+ lymphocyte counts below 200/mm³).  First choice PCP prophylaxis is currently trimethoprim-sulfamethoxazole at 1 single-strength tablet daily or 1 double-strength tablet 3 times weekl, but pentamidine 300 mg monthly by aerosol is an excellent and highly  attractive alternative309.     



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.

Radiation Sensitization: Motexafin Gadolinium (Xcytrin)

Motexafin gadolinium (Xcytrin) is a redox mediator selectively targeting tumor cells and enhancing the effect of radiation therapy, and when administered with WBRT in a multi-institutional international clinical trial was associated with consistently high radiologic response rate and decreased deaths from brain metastasis progression36,37.


The HER2 Context: What We Know
Newly diagnosed HER-2/neu overexpressing breast cancer patients are at significantly increased risk for brain metastasis, as found in the population study of Bassam Abdulkarim and colleagues38 at the Cross Cancer Institute (Edmongton). In addition, as reported by Thomas Yau and his collegeagues39 at Royal Marsden Hospital, brain metastases are common in HER2+ advanced breast cancer patients receiving trastuzumab (Herceptin), potentially implicating the brain as a sanctuary site for early relapse in this HER2+ populations, and the reality of high CNS involvement in young women with metastatic breast cancer women responding to trastuzumab-based therapies, has prompted some researchers38,40-42 to suggest a defensive posture entertaining possible prophylactic cranial irradiation (PCI) strategies, or to early detection in asymptomatic patients via CNS screening, to improve surgery or radiosurgery outcomes.
On this issue of prophylactic cranial irradiation (PCI), Turkish researchers Pinar Saip and Irfan Cicin and colleagues169 conducted a study to identify the candidates for PCI among early and advanced-stage breast cancer patients, finding that isolated brain metastasis progression was related to the presence of the hepatic metastasis at first relapse and with HER-2 overexpression, with time to brain metastasis from the first extracerebral metastasis being  associated with high nuclear grade and with chemoresistance. PCI may be valuable (1) in early stage patients with high-grade, lobular/mixed type histology tumors and in those with a high degree of node-positivity, as these patients exhibit a tendency to early brain metastasis, and (2) in advanced stage chemosensitive patients with HER-2 over-expression and/or with hepatic metastasis at first relapse. See also the commentary by Fleur Huang and colleagues200 at McGill University who describe brain metastases occurring despite PCI and serious long-term neurobehavioral sequelae in PCI-treated high-risk stage IIIB/IV breast cancer patients.   

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)
Jungsil Ro and colleagues238 at the National Cancer Center (NCC) in Korea examined whether trastuzumab therapy beyond (TBP) or after the development of brain metastasis  was beneficial to HER2+ breast cancer patients with brain metastasis, finding that trastuzumab therapy after the onset of brain metastasis is associated with a significant survival benefit after brain metastasis diagnosis compared with patients never receiving or completing trastuzumab prior to such diagnosis.  The interval between the presentation of metastatic breast cancer and metastasis to the brain was twice as long in patients who received trastuzumab before BM was diagnosed than in those who did not receive trastuzumab until after BM was diagnosed, and in addition a significant prolongation of time to progression (TTP) in intracranial tumors was observed in patients who received trastuzumab after brain metastases were diagnosed, and it is speculated that WBRT might disrupt the blood–brain barrier and consequently make it possible to deliver trastuzumab into the CNS, something also suggested previously by Marco van Vulpen and colleagues in Utrecht239 among others.  

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.

It is also an interesting and important aside that despite the challenging survival outlook for patients with breast cancer brain metastasis , there were some long-term survivors. Eighty-two patients in this study (19.5%) were alive at least 18 months after diagnosis of brain metastasis. Of these 82 patients, 25 patients (30%) were human epidermal growth factor receptor 2 positive. Furthermore, 18 (4.2%) were alive at least 60 months after this diagnosis.
 
Taking everything into consideration, it is plausible that survival after BM diagnosis was prolonged in patients who received trastuzumab beyond brain progression due to better-controlled intra- as well as extracranial disease, a finding confirmed in the literature review of Brian Leyland-Jones284,285, as well as in the Korean retrospective review of Park and colleagues286 in Seoul. 

The HER2 Context: Open Questions

However, Breast Cancer Watch notes that these findings are nonetheless indeterminate: unresolved is whether (1) HER-2+ breast cancer has some intrinsic predilection for the brain as a sanctuary site of metastatic involvement, or (2) whether trastuzumab-based therapy itself has modulated the disease pattern by virtue of prolongation of survival, or some combination of these and other unidentified factors173. The issue of the role of trastuzumab itself has been recently clarified by Gianluigi Ferretti and colleagues45 at the Regina Elena Cancer Institute who compared the risk of brain metastases in patients treated with or without trastuzumab, finding that after first line chemotherapy, the use of trastuzumab did not affect the incidence of brain metastasis in HER2+ metastatic breast cancer patients, with on the other hand, HER-2-negativity appearing to predict a lower incidence of cerebral disease spread. In addition, we do not find wholly convincing the arguments for a true increase in incidence of brain metastases in HER2+ trastuzumab-treated metastatic breast cancer patients: similar increases of incidence of CNS involvement in patients with advanced breast cancer receiving anthracycline plus taxane chemotherapy have been reported46, as well as with taxane-only (paclitaxel) therapy47, suggesting that chemotherapy per se is unlikely to be the culprit, but rather that prolonged survival of patients after initial recurrence allows microscopic brain metastases to become clinically evident48Finally, it should be noted in  connection with the issue  of trastuzumab's cross-BBB capability, that under certain conditions, such as during radiotherapy for metastatic CNS disease, trastuzumab can cross the blood–brain barrier since the blood–brain barrier is impaired under such irradiation,43,44,281.

The HER2 Context: The Role of Lapatinib

For these reasons, research is exploring the small molecule dual (EGFR and HER2) TKI lapatinib (Tykerb). Nancy Lin and colleagues49 conducted a phase II trial with lapatinib (750 mg twice daily) for HER2-2-overexpressing breast cancer, including 39 patients who had developed brain metastases during trastuzumab treatment. Although preliminary, there was sufficient evidence of clinical effect to suggest that lapatinib can penetrate the BBB to influence CNS disease. Tolerability was high, with no grade 4 toxicities, and no grade 3 or 4 cardiac dysfunction, and only 4 of the 39 patients developing asymptomatic grade 2 LVEF (<50%); the most common grade 3 adverse events were diarrhea, fatigue, and headache. 

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 therapyAnd 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.  

The HER2 Context: Novel Combinations
Breast Cancer Watch also found some preliminary evidence that a combination chemobiological therapy regimen of trastuzumab coupled with gemcitabine (Gemzar) and vinorelbine (Navelbine) may have beneficial activity in brain metastasis: Italian researchers Alessandro Morabito and collegaues50 evaluated the safety and efficacy of H + GEM + VIN (trastuzumab, gemcitabine, vinorelbine) as second-line therapy for HER-2 overexpressing metastatic breast cancer, pretreated with anthracyclines and/or taxanes and/or trastuzumab, finding objective response in 571.% (4) of the 7 patients presenting with brain metastasis.


Leptomeningeal Metastasis
Leptomeningeal metastases represent the neoplastic infiltration of the meninges (consisting of the dura mater, arachnoid mater, and pia mater CNS layers of protective tissue) are characterized by the breach of malignant cells into the subarachnoid space, which are then disseminated throughout the central nervous system via the cerebrospinal fluid (CSF).  The incidence of leptomeningeal metastases appears to be increasing, due to, like brain metastases,
earlier detection by MRI and also because of the prolongation of survival from more effective therapies allowing the development of late-stage sequelae such as CNS metastases139.

Treatment for Leptomeningeal Metastasis
Treatment entails targeting one or more parts or the entire neural axis and involves:

(1) Focal radiotherapy
to symptomatic sites especially for cytoreduction of symptomatic and particularly bulky disease and as needed for CSF flow abnormality correction; such focal radiotherapy is via conventional external beam radiotherapy ias the classic form of spinal irradiation with hyperfractionation, with 20-40 Gy delivered to the spine and spinal cord over 5 - 20 daily fractionations, a limiting factor being the relatively low tolerance of the spinal cord in particular  to radiation.

(2) Chemotherapy
Either systemic or intra-CSF / intraventricular via intrathecal chemotherapy (directly into the CSF, often through a Ommaya reservoir surgically implanted into the lateral ventricle of the brain,
is the mainstay of entire neuraxis treatment . Less frequently, intralumbar administration (lumbar puncture) is also possible for patients considered poor candidates for intra-CSF therapy (as for instance because of hydrocephalus requiring a ventriculoperitoneal shunt (VPS), but intrathecal administration is safer, more patient-tolerable and more reliable in terms of achieving more rapid and higher uniformity of CSF space drug distribution and consistency of CSF levels, while with intralumbar delivery ventricular there is  considerable inter-patient variability of drug concentration despite similar doses152. Although it is widely held that intrathecal chemotherapy is rarely efficacious, hematopoietic neoplasms (leukemia, lymphoma) and breast cancer may be exceptions, with some patients responding well and with a substantial minority showing relatively longer survival140.  Thus Jordi Bruna and colleagues at the University of Barcelona found that intrathecal therapy was independently associated with longer overall survival in patients with leptomeningeal metastasis171.

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)?
Despite the primacy of external beam radiotherapy (EXBR) for the treatment of spinal metastasis, recent technological advances, such as  3-dimensional localization via image guidance, the advent of IMRT (intensity modulated radiation therapy) and higher accuracy for target dose conformation with sparing of normal surrounding tissue, have collectively enabled radiosurgery to be effectively extended to extracranial lesions. Thus researchers296 at the Korea Institute of Radiological and Medical Science found that cyberknife radiosurgery (CKS) in 129 (with 167 spinal metastases) was clinically effective and safe for spinal metastases, even in previously irradiated patients, with overall pain control rate of 91% and radiological tumor control rate of 90% at six months post-treatment, both of longer  duration than conventional radiotherapy, and with no neurological complications associated with radiosurgery.    


High Dose MTX (Methotrexate)
Florian Clatot and colleagues retrospectively analyzed clinical data and cerebrospinal fluid of 24 patients treated with intrathecal high-dose methotrexate (HD-MTX) for breast cancer leptomeningeal meningitis, finding cytologic response (CSF cytology without neoplastic cells after treatment) in 46% of the patients, with clinical symptoms improved in all patients who obtained a cytologic response and in another 54% without cytologic response. Importantly,  such cytologic response was associated with survival; in addition, suggesting  that  cytologic response may be of benefit in the management and evaluation of leptomeningeal metastasis.

Capecitabine Monotherapy for Leptomeningeal Metastasis 
In addition, there is some evidence that capecitabine (Xeloda) may have some efficacy in leptomeningeal metastasis: in a small case series, Pierre Giglio and colleagues243 at MD Anderson reported two cases of leptomeningeal metastasis (neoplastic meningitis) from breast carcinoma (a third was esophageal carcinoma), which responded to treatment with capecitabine.  And Lisa Rogers and colleagues242 present another case report of a durable (12-month) response to capecitabine monotherapy (1000 mg twice daily for 2 months, escalated to1500 mg twice daily) in a 42-year old woman patient with leptomeningeal metastasis from breast cancer who also had diffuse skull and vertebral metastasis.  Repeat CSF examination 2, 5, and 10 months after re-initiation of capecitabine demonstrated no malignant CSF cells,  and the patient's neurological symptoms resolved except for blurred vision in the right eye; neuraxis MRI showed complete disappearance of spinal meningeal enhancement and reduction in the optic nerve and brain enhancement except for the right frontal lobe. She was maintained on capecitabine therapy without requiring erythropoietin injections for the last 6 months of therapy; at the last follow-up at 1 year (in late 2003), the patient was fully active, with no complaints except for reduced right eye vision.

Meltem Ekenel and colleagues69 at Memorial Sloan-Kettering Cancer Center studied the benefit of capecitabine in seven patients with brain metastases from breast cancer (brain metastases alone in four patients, two patients with both brain and leptomeningeal metastases and one patient with leptomeningeal metastasis alone) with clinical improvement even in leptomeningeal disease, and with three patients obtaining complete response (CR) and three stable disease (SD) from capecitabine therapy. And in another case study, Yee-Lu Tham and colleagues121 at Baylor achieved long-term control of CNS disease in a breast cancer patient with both brain and leptomeningeal metastases who after 3.7 years of post-WBRT capecitabine therapy (initial capecitabine concurrent with WBRT was reduced dose at 1000 mg/m2 daily,, but as monotherapy was dosed at 2500 mg/m2 daily), remains absent of neurological symptoms or deficits, and despite a persistent positive cytology, has no evidence of disease on neuroimaging studies, and with minimal toxicity and no neurotoxicity during the near-four years of therapy;  the discordance re positive cytology shows that malignant cells can persist  in the CSF in the absence of evidence of radiological or clinical disease. In addition it should be noted that in responders, the average duration of response to capecitabine was over nine moths, substantially longer than from intrathecal chemotherapy, and the duration of response in this specific case study (> 43 months) was at least double of any previously reported in leptomeningeal disease.      
 

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.

Liposomal Cytarabine (DepoCyt)
DepoCyt, the sustained-release liposomal form of cytarabine is shown to provide cytotoxic cytarabine levels in the CSF for 10 to as long as 14 days177; when its biweekly administration was compared with twice weekly methotrexate (MTX), DepoCyt resulted in improved response rates, longer time to neurologic progression, and improved quality of life, in patients with leptomeningeal metastases from solid tumors (including 22 with breast cancer)141, and an increasing number of experts such as Marc Chamberlain142 at the H. Lee Moffitt Cancer Center & Research Institute, Michael Glantz141 at Brown University School of Medicine, and Kurt Jaeckle143 at the Mayo Clinic (Jacksonville, FL) among others, hold that DepoCyt should be considered the drug of first choice in the treatment of leptomeningeal metastases when appropriate clinical trials or experimental therapies are unavailable.  Note in addition that Dae-Young Kim and colleagues146 in Seoul found that the addition of ara-C (cytosine arabinoside) to methotrexate (MTX) showed greater efficacy than methotrexate monotherapy for intrathecal chemotherapy of solid tumor leptomeningeal metastases but as the authors themselves note, this was discordant with the results of previous randomized prospective studies, possibly due to either differences in the response criteria and/or  population characteristics. 

Other combinations may be plausible: in one case report from Martin Glas and colleagues176 at the University of Bonn evaluated WBRT + DepoCyt. And Paola Gaviani ande colleagues270 in Milan describe the case of a woman with a diagnosis of breast cancer leptomeningeal metastasis who presented cerebrospinal fluid CSF normalization and prolonged complete MRI response to intrathecal chemotherapy with liposomal cytarabine (DepoCyt).  In addition Herwig Strik's team320 in Germany presented a case studies of two HER2-positive women (42- and a 43-yrs) with leptomeningeal metastasis and disseminated CNS metastases who, after irradiation of the symptomatic sites, where given combination intrathecal liposomal Ara-C (every 2-4 weeks) + TMZ (100 mg/m2 day 1-5/7), finding that cerebrospinal fluid (CSF) cytology and neurological symptoms improved in both patients and stabilized for several months, with survival of  10 and 17 months post-diagnosis, and with no signs of neurological toxicity.

Clinical Trials in Breast Cancer Leptomeningeal Metastasis
An innovative (to our mind) phase II clinical trial273 is being sponsored by the Fred Hutchinson Cancer Research Center (Seattle) of high-dose methotrexate (MTX) + liposomal cytarabine (DepoCyt) in patients with CNS metastases (brain and/or leptomeningeal) from breast cancer.  During induction therapy (weeks 1-6):High-dose MTX IV over 4 hours on days 1, 15, and 29 and DepoCyt intrathecally (IT) over 5 minutes on days 8, 22, and 36. During consolidation therapy (weeks 7-11): patients achieving complete response (CR), partial response (PR), or stable disease (SD) then receive HD-MTX IV over 4 hours on days 43 and 57, along with liposomal cytarabine IT over 5 minutes on days 50 and 64. Finally, during maintenance therapy (weeks 13-37): patients achieving CR, PR, or SD receive HD-MTX IV over 4 hours once monthly, then beginning in week 15, patients receive DepoCyt IT over 5 minutes once monthly. Treatment repeats once monthly for 5-6 courses in the absence of disease progression or unacceptable toxicity.  Clinical trial centers are Dana-Farber (Boston, MA, Cleveland Clinic Foundation (Cleveland, OH), and the Fred Hutchinson Cancer Research Center (Seattle, WA). 

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 
In addition, aside from it's established use in HER2-positive disease, the combination regimen of trastuzumab (Herceptin)
plus capecitabine (Xeloda), the  regimen may benefit leptomeningeal metastasis from breast cancer, as a case study of Takashi Shigekawa's244 team in Japan who report a case of metastatic breast cancer with leptomeninges and multiple bone metastases that showed an excellent response to the trastuzumab + capecitabine combination as 6th-line therapy.  Indeed, it is just possible that this was a case of capecitabine monotherapy in disguise, as the investigators acknowledge that the patient was only 2+ (not 3+) by IHC on HER2 positivity, and moreover that trastuzumab had not been effective in previously in this patient's treatments.

Intra-CSF Trastuzumab for Leptomeningeal Metastasis
Dana Allison and colleagues246 at the University of Utah treated 15 patients with neoplastic meningitis (4 from breast cancer) and progressive neurologic deterioration with intra-CSF trastuzumab (20–60 mg per dose, weekly or every other week) for four treatments;  results found that two of the four patients with breast cancer (both HER-2/neu+) responded clinically and cytologically (time to response: 4 and 14 weeks), suggesting that trastuzumab can be safely administered into the CSF in patients with solid tumor leptomeningeal metastasis, with sustained clinical and cytologic responses in patients with breast cancer (and in those with primary brain tumors), and these findings confirmed previous results43,44,283 of trastuzumab activity in leptomeningeal metastasis.  Similarly, we have the case study from Malfalda Oliveira and colleagues235 in Portugal who administered trastuzumab (25 mg) weekly for 67  weeks directly into the cerebrospinal fluid (via lumbar puncture) of a 44 year  old HER2+ breast cancer patient with both leptomeningeal metastases and brain metastases previously treated without benefit from other intrathecal chemotherapy (node-positive, with  bone, lung, and liver metastases) and with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, systemic trastuzumab, and lapatinib. The patient showed marked clinical improvement and no adverse events, surviving for 27 months after leptomeningeal diagnosis, and achieving a complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy. 

Bevacizumab + Paclitaxel for Leptomeningeal Metastasis 
Recent data also suggest that the E2100 regimen (Kathy  Miller) of paclitaxel (Taxol) plus bevacizumab (Avastin) may have activity against leptomeningeal  metastasis from breast cancer.  Sana Labidi and  colleagues245 in France reported 4 CNS metastases patients treated with the E2100 regimen (all with previous WBRT, performance status 0-2, and radiographic evidence of progressive CNS metastases), with three patients having brain metastases, and 1 having meningeal lesions. The E2100 regimen demonstrated significant antitumor activity, with 1 complete response and 3 partial responses in the CNS metastases, and no patient having extra-CNS progression at the 9-month follow-up.  CSF VEGF levels fall and correlate with response in leptomeningeal metastasis responders280.   

Topotecan for Leptomeningeal Metastasis
In a phase II, open-label, nonrandomized, single-arm trial, Morris Groves at MD Anderson and colleagues267 tested intraventricular (IVent) topotecan (Hycamtin) [400 µg of topotecan [a topoisomerase I inhibitor] IVent twice weekly for 6 weeks] in 62  patients with leptomeningeal meningitis (LM), 19 with breast cancer LM; in absence of disease progression, patients were then treated with IVent topotecan weekly for 6 weeks, twice monthly for 4 months, and monthly thereafter.  Although, the authors found that the outcomes for patients treated with IVent topotecan were no better than those reported in three key randomized controlled trials that employed other IVent chemotherapies (MTX and DepoCyt - out of 40 patients (65%) completing the 6-week induction period, 21% had CSF clearance of malignant cells  - nonetheless as the authors note, given the mild side effect profile, combining IVent topotecan with other IVent or systemic interventions should be considered, and IVent topotecan's comparable efficacy and low toxicity offer another IVent chemotherapy alternative in those patients intolerant of other therapies or in whom the other IVent therapies have become ineffective.  As a follow-up, the same investigators presented at ASCO 2010 case studies from 5 patients who received IVent topotecan for leptomeningeal metastasis (2 with primary breast cancer), again finding IVent topotecan a well tolerated and viable treatment for patients with leptomeningeal metastasis originating from a variety of primary malignancies. 

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
However, there are a number of non-trivial complications144 of intrathecal chemotherapy due to either the implanted ventricular reservoir itself or secondary to administered chemotherapy: (1)  reservoir malposition (with a 3 - 12% incidence151), obstruction, and infection145 (the skin flora being a common site of infection, often by Staphylococcus epidermidis), with presentation of headache, neurologic status changes, or  fever. (2) cerebrospinal fluid pleocytosis (elevated CSF cell count); (3) myelosuppression, which can be mitigated by oral folinic acid / leucovorin rescue (10 mg every 6 hours for 24 hours) - with or without aminophylline148 - after MTX administration; (4) an inflammatory reaction known as chemical aseptic meningitis, presenting as fever, headache, nausea, vomiting, meningismus, and photophobia, outpatient-treatable with oral antipyretics, antiemetics, and corticosteroids; and (5) treatment-related neurotoxicity (rare) potentially resulting in symptomatic subacute leukoencephalopathy149 or myelopathy.  David Sandberg's team at Memorial Sloan-Kettering Cancer Center advise that reservoir-specific complications can be minimized by intraoperative fluoroscopic or endoscopic confirmation of catheter position, along with postoperative CT scans before initiation of intrathecal chemotherapy, and VPS procedure instead of Ommaya reservoir for those patients with elevated intracranial pressure154.

Systemic Chemotherapy for Leptomeningeal Metastasis 
Although intrathecal chemotherapy remains the preferred treatment leptomeningeal metastases, this raises the issue of whether intrathecal chemotherapy is compellingly motivated over systemic chemotherapy, proponents arguing that most systemically administered chemotherapeutic agents would fail to achieve adequate CSF penetration and therapeutic levels, although the improvement of outcome from intrathecal chemotherapy has itself been disputed by others arguing that systemic chemotherapy can achieve  access to subarachnoid deposits via their own vascular supply142,147. In support of this latter view, the retrospective study of Felix Bokstein and colleagues147 in Israel failed to find significant differences in response rates, median survival, or proportion of long-term survivors between patients treated with systemic chemotherapy and focal radiation plus intrathecal chemotherapy, in comparison to those not undergoing intrathecal chemotherapy. 
In addition, there are several distinct advantages of systemic chemotherapy over intra-CSF therapy: (1) intrathecal surgery for Ommaya reservoir placement is avoided, as are the need for and complications from lumbar puncture as an alternative; (2) the need to correct any CSF flow abnormality for patients with obstruction is bypassed, allowing also for more uniform drug distribution; (3) bulky disease may be made treatment-responsive since the systemically administered drug can reach leptomeningeal tumor deposits via their systemic vascular supply75,79,326,327.

 
And Michael Glantz141 and colleagues actually found response rates and survival to be significantly better in patients treated with systemic (intravenous) high-dose MTX therapy compared to those treated solely with intrathecal MTX; this has also been demonstrated in other malignancies (as in nasopharyngeal carcinoma with leptomeningeal metastasis, where Carole Fakhry and colleagues316 at Johns Hopkins document the case of a women with this disease treated with systemic HD-MTX and who remains asymptomatic and without clinical evidence of disease 6 years later). And the same investigator, Michael Glantz317  treated 16 patients with solid-tumor leptomeningeal metastases using one to four courses (mean, 2.3 courses) of systemic HD-MTX (8 g/m2 i.v. over 4 hours) plus leucovorin rescue, finding that cytotoxic CSF and serum MTX concentrations were maintained much longer than with intrathecal MTX dosing, yet toxicity was minimal, with  cytologic clearing  seen in 81% of patients compared with 60% of the MTX-intrathecally treated patients, and with a 6 fold survival advantage: median survival in the HD-MTX group was 13.8 months versus just 2.3 months in the intrathecal MTX group. There is also the suggestion that the IV route of administration is less likely to result in MTX-related neurotoxicity. 

Glantz and others note that the systemic MTX approach may also demonstrate other potential advantages over intrathecal therapy: intrathecally-administered agents  must diffuse into the tumor from the CSF-tumor interface, but tumor cells in areas of bulk disease and those that have penetrated deep into cerebral sulci are unlikely to be fully exposed to agents IT-administered drug must diffuse into the tumor from the CSF-tumor interface. Tumor cells in areas of bulk disease (common with nonleukemic meningeal malignancies), and cells that have penetrated deep into cerebral sulci are unlikely to be fully exposed to drugs administered
into the CSF intrathecally, in contrast to systemic administration where more drug will be delivered to more of the meningeal tumor volume when increased drug concentrations are maintained in both the CSF and the blood given diffusion-dependent penetration. In addition, only systemic therapy offers the potential of simultaneously treating CNS and extraneural tumors, and given this the possibility cannot be excluded that that recurrent seeding of the leptomeninges may be a source for the typical failure of intrathecal chemotherapy to produce sustained responses.

Systemic HD-MTX has also been used favorably in other contexts. Alberto Carmona-Bayonas318 treated a breast cancer patient with leptomeningeal metastases using an initial regimen of twice daily capecitabine (850 m/m2) + WBRT, and five doses of twice weekly intrathecal methotrexate and cytarabine, followed by four courses of high-dose (HD) methotrexate (8 g/m2) with further recovery and minimal toxicity (overall survival since whole-brain radiotherapy was 12 months with excellent QoL).

Merry Tetef and colleagues319 at City of  Hope National Medical Center  evaluated the pharmacokinetics and toxicity of systemic HD-MTX (
loading doses of 200–1500 mg/m2, followed by a 23-h infusion of 800–6000 mg/m2) with leucovorin rescue in 16 patients with leptomeningeal metastasis, 13 of these from breast cancer.  All HD-MTX treated patients  had CSF MTX concentrations above the target cytotoxic concentration (1 μM), the authors concluding that potentially cytotoxic CSF MTX concentrations (>1 μM) are delivered safely by less invasive systemic (i.v.) infusion, yielding a better distributed CSF therapy compared with intrathecal MTX, and that systemic HD-MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated leptomeningeal metastasis patients.

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 
In the endocrine context, Wilem Boogerd and colleagues150 at the Netherlands Cancer Institute present two case reports of good neurological response in two hormone-positive breast cancer patients with leptomeningeal metastases treated with endocrine therapy. The first patient was premenopausal and treated with ovarian ablation (goserelin (Zoladex), and later ovarian irradiation) and tamoxifen, later replaced with megestrol, with some intermittent systemic chemotherapy (epirubicin, cyclophosphamide), and although the patient ultimately died of progressive liver metastasis and cardiac failure, there was no recurrence of the symptoms or signs of leptomeningeal metastasis; the second patient was treated with  radiotherapy and continued hormonal therapy, first tamoxifen, later replaced by anastrozole (Arimidex), in turn replaced upon progression with megestrol, this patient being disease stable at last follow-up in October 1999, 14 months post-diagnosis.  In addition, Turkish researchers Mustafa Ozdogan and colleagues154 report the case of a premenopausal women with with leptomeningeal metastasis from breast cancer who obtained an excellent objective and subjective response to letrozole Femara) endocrine therapy, with an extended progression-free survival (PFS) of 16 months, after being first treated with whole brain radiotherapy and six doses of intrathecal methotrexate after radiotherapy. And describe the case of a woman with neoplastic meningitis from breast carcinoma who developed an excellent response to letrozole combined with intrathecal methotrexate, resulting in long-term survival of more than 36 months. And researchers in Greece279 describe the case of a woman with leptomeningeal metastasis from breast cancer who developed an excellent and durable response to letrozole combined with intrathecal methotrexate (IT-MTX), resulting in long-term survival of more than three years.



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  Multiple Brain Metastases
CAM Interventions: Boswellia  
The gum-resin of the Ayurvedic plant Boswellia serrata, otherwise known as Frankincense, and an active lipoxygenase (LOX) inhibitor with some clinical benefit in osteo- and rheumatoid arthritis and other inflammatory conditions, appears also to be of value in brain metastases, as the (arachidonate) LOX pathway is implicated in brain tumor growth, via the production of leukotrienes which are brain tumor stimulative as well as inductive of brain edema53: Dana Flavin at the Foundation for Collaborative Medicine and Research presents a case report of a breast cancer patient who had not shown improvement after standard therapy for multiple brain metastases, which were successfully reversed using boswellia (dosed at 3 x 800 mg/d orally; noted however that other studies with a different boswellia formulation used up to 3 x 1200 mg/d)54. This is consonant with previous demonstrations of boswellia exhibiting activity against brain tumors55,56,57, by it would appear the potentiation of apoptosis induced by TNF and chemotherapeutic agents, as well as by the inhibition of TNF-induced invasion and RANKL-induced osteoclastogenesis and suppression of NF-kB activation and consequent down-regulation of MMP-9 and adhesion proteins58.  From preclinical data it is known that it is the acetyl-11-keto-β-boswellic acid (AKBA) component that is the natural inhibitor of the proinflammatory transcription factor NF-kB184, NF-kB being a  transcriptional activator with potent antiapoptotic, angiogenic and proliferative functions implicated in oncogenesis and multidrug resistance (MDR), and it appears that oral intake of boswellia  extracts may indeed be sufficient to yield concentrations required for the inhibition of NF-kB signaling188. In addition, AKBA enhances apoptosis induced by cytokines and other chemotherapeutic agents, inhibits invasion, suppresses osteoclastogenesis through inhibition of NF-kB-regulated gene expression thus suggesting a potential benefit in bone metastases, inhibits IKK activation through suppression of Akt, and AKBA-induced inhibition of NF-kB-regulated gene transcription and NF-kB-regulated gene products includes those involved in (1) cell proliferation such as cyclin D1 and COX-2, (2) antiapoptosis such as  survivin, IAP1, XIAP, Bcl-2, and (3) invasion such as MMP-9 and VEGF191.
 
Pharmacokinetic studies have revealed poor bioavailability for AKBA185 suggesting a preference for use of standardized formulations rather than nonstandardized "raw" boswellia preparations, given that the comparatively low levels of AKBA  present (about 25%) are the constituents contributing entirely to the clinical efficacy and the most pronounced inhibition of 5-lipoxygenase product formation.

However, it  should be noted that although as we indicated above oral intake of boswellia extracts appear sufficient to yield concentrations required for NF-kB signaling inhibition, high bioavailability of boswellic acids strongly depends on concomitant food intake.  Vanessa Sterk and colleagues189 at the University of Ulm, Germany conducted a randomized, two-way crossover study where all 24 subjects received 3 capsules of BSE-018 extract, containing boswellic acids at 85% minimum (CPM Contract Pharma, Germany) equivalent to 786 mg dry extract of frankincense in a fasting state or together with a high-fat meal. Compared with treatment under fasting conditions, treatment with the extract  concomitant with a high-fat meal exerted a dramatic effect on the pharmacokinetic profile of boswellic acids, resulting in significant several-fold increases in the areas under the plasma concentration versus time curves for all beta-form boswellic acid components including AKBA, thus suggesting that the increase is due to improved absorption of boswellic acids in the presence of bile acids consequent to food intake189.    

Moreover, AKBA appears to act through a mechanism involving dual catalytic inhibition of topoisomerase activity (topoisomerases I and IIa), via competing with DNA for topoisomerase binding, hence suggesting that boswellic acids through their AKBA component are a new class of topoisomerase inhibitors186,190

In addition, high-dose boswellia (1800 to 3200 mg/daily) appears effective in the reduction (30%) of peritumoral edema and associated symptomology prior to resection for recurrence in patients with malignant glioma who were prohibited corticosteroids59, and this efficacy of boswellia in treating brain edema has been confirmed in other human trials60,61, with in addition all benefits with leukoencephalopathy benefiting significantly, and in animal studies confirming significant reduction on perifocal edema187, the delivery across the blood-brain barrier possibly secondary to the lipophilic nature of AKBA186.   (Boswellic acids have also been found of clinical value in asthma, colitis ulcerosa, osteoarthritis, and inflammatory bowel diseases, as well as in brain tumors62).

In addition, evidence from the Cytokine Research Laboratory at MD Anderson on the use of boswellic acid in other malignancies207 suggests that AKBA is a novel inhibitor of STAT3 activation, an important finding given that activation of STAT-3 signal transducers and activators has been linked with tumor cell survival, proliferation, and angiogenesis of tumor cells, as well as chemoresistance.  We find this has further importance is that leptin modulates the cell cycle and augments proliferation via activation of JAK/STAT-3 axis in breast cancer cells, including triple negative cells, and leptin-induced breast cancer cell growth stimulation involves recruitment of histone acetyltransferases and mediator complex to the Cyclin D1 promoter via activation of STAT-3208.  It furthermore appears from recent evidence that leptin is able to induce the growth of breast cancer cells via activation of the Jak/STAT-3, ERK1/2, and/or PI3K pathways, and to mediate angiogenesis by induction of VEGF expression, and the leptin-induced transactivation of ErbB-2 interacts in triple negative breast cancer cells with IGF-1 to transactivate EGFR, thus promoting invasion and migration209.  And we already know from that inhibition of the Src pathway reduced STAT-3 activity in breast cancer cell lines with elevated EGFR levels210,211, so the above consideration suggest a beneficial role for boswellic acids / AKBA as an additional STAT-3 inhibitor with some potential specific for triple negative breast cancer tumors themselves  influenced by STAT-3, Cyclin D1, EGFR and  VEGF expression.  

It should be noted that clinical practice re the treatment of cerebral edema differs between the United States and the European community, especially Western Europe where neurooncologists prefer treating brain tumor–induced edema and avoiding corticosteroid dependency as well as corticosteroid--induced adverse events by administering agent boswellic acids (also know as H15)168.

Omega-3 Fatty Acids
One RCT63 found that patients with stage IV cancers metastasized to the brain supplemented with omega-3 fatty acids from fish oils (2000mg EPA + 1000mg DHA) post-radiotherapy had 64% higher survival rates over a 2-year period compared to placebo-controls.

COX-2 Inhibition
We also find intriguing the results of Leandro Cerchietti's and colleagues51 phase I/II study of the COX-2 inhibitor celecoxib (Celebrex), 400 mg/day during entire course of radiotherapy, as a radiosensitizer, concomitant to radiotherapy to treat unresectable brain metastases, yielding 72% radiological responses (18 of 25 evaluable patients) including 5 complete responses; symptomatic responses were higher at 92.6% (in 25 of 27 patients). The use of celecoxib (Celebrex) as a radiosensitizer is additionally attractive given the established antiangiogenic, pro-apoptotic, and anti-proliferative activity of the COX-2 inhibitor, and the fact that curcumin exhibits the same beneficial range and is itself at least as antiproliferative in activity as celecoxib, as shown by Yasunari Takada and colleagues52 at Cytokine Research Laboratory of MD Anderson Cancer Center, suggests that standardized curcumin may also be a valuable adjunct radiosensitizer during radiotherapy. 

And recently,  nanoparticle-encapsulated curcumin has been used by investigators at Johns Hopkins322 to treat brain tumor cells (medulloblastoma and GBM) with evidence of dose-dependent-curcumin modulation of cell proliferation, survival and stem cell phenotype and reduction of the CD133-positive stem-like population, likely via down-regulation of the insulin-like growth factor pathway and the blocking of Hedgehog signaling.   

Additional Clinical Trials
As indicated above, temozolomide (TMZ) is widely deployed in the treatment of brain metastases, but the concern has been that the maximum TMZ dose is limited by low blood counts.  Therefore, a clinical trial at Tufts Medical Center115 (PI: Andreas Klein) is using hematopoietic stem cell rescue (autologous stem cell transplant (ASCT)) in order to to safely deliver very high TMZ doses - 350 mg to 1500 mg/m2 daily for 5 days (total dose 1750 to 7500 mg/m2 , daily for 5 days (total dose 1750 to 7500 mg/m2 - for the treatment of relapsed/refractory CNS malignancy, including malignant disease metastatic to the CNS. Another TMZ clinical trial sponsored by Schering-Plough in Italy118 is exploring TMZ (75 mg/m2/day, orally, for 6 weeks, every 8 weeks, for a total of 3 cycles) as prophylactic chemotherapy against recurrence of brain metastases 

Given that research has established the results of stereotactic radiosurgery (SRS) therapy are as good as surgical tumor removal, a Phase II clinical trial Memorial Sloan-Kettering (MSK) Cancer Center116 (PI: Kathryn Beal) is is studying the combination of these two techniques, surgical resection (SR) followed by SRS boost, in patients with 1-2 brain metastases to determine post-treatment tumor regrowth and treatment side effects. If a recurrence or any new metastases is detected, further treatment may be given (chemotherapy, surgery, whole brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS)). In addition, American College of Surgeons (ACS), Eastern Cooperative Oncology Group (ECOG), and Radiation Therapy Oncology Group (RTOG) along with NCI are sponsoring a phase III randomized clinical trial117 evaluating SRS and WBRT compared with SRS alone in treating patients with one to three cerebral metastases. And chemoradiotherapy is being explored in several clinical trials.  Baylor Breast Care Center is studying capecitabine (Xeloda) given concomitantly with WBRT (Whole Brain Radiotherapy) followed by capecitabine and sunitinib for CNS metastases in breast cancer155; this trial is not yet open for recruitment. 

The pegylated liposomal anthracycline Doxil is being evaluating in a Phase II clinical trial at the Johns Hopkins Singapore International Medical Center165 for in patients with brain metastasis from breast cancer, and as we noted in our discussion above, the results of Michelle Caraglia and colleagues90 with Doxil + TMZ help motivate and anticipate a favorable response, since in that study 5 of 8 breast cancer patients with multiple brain lesions and extra-brain disease at different sites had responses, 3 complete responses (with one sustained long-term at 23+ months) and 2 partial responses.

Duke University is exploring the potential contribution of anti-angiogenic activity via the anti-VEGF agent bevacizumab (Avastin) in breast cancer patients with brain metastases174.

There are two trials of epothilones for CNS mets in breast cancer: one at Memorial Sloan-Kettering and Case Comprehensive Cancer Center using patupilone156 and the other at Dana Farber Cancer Institute and the Beth Israel Deaconess Medical Center using ZK219477 / ZK-EPO157.

The Canadian biotechnology company Angiochem is sponsoring a Phase I multi-centre open-label dose-escalation study158 of the safety, tolerability, and pharmacokinetics of ANG1005, a conjugate constituted by a peptide bound together with three molecules of paclitaxel (Taxol), in patients with solid tumors, with or without brain metastases.  Preclinical data suggests that the peptide based drug delivery system underlying ANG1005 can be used to transport small drugs to the brain parenchyma for the treatment of brain cancers and brain metastases, via the low-density lipoprotein receptor-related protein (LRP) expressed on the surface of the BBB.  As to human clinical data, as of October 2008, 27 patients with advanced solid tumors (5 with breast cancer)  and/or brain metastases (18 patients) have received ANG1005, with safety and tolerability demonstrated to date, and preliminary response data suggest prolongation in time to progression (TTP) compared to current standard treatment159.

NCI is currently sponsoring a clinical trial at the City of Hope Comprehensive Cancer Center (Duarte, CA) of dasatinib plus (1) carboplatin, (2) the alkylating agent ifosfamide (Mitoxana), and (3) the topo II inhibitor etoposide (VP-16,  Vepesid, Etopophos) for the treatment of young patients With metastatic or recurrent malignant solid tumors160.  Dasatinib (Sprycel) is an oral small molecule multitargeted kinase inhibitor targeting several important oncogenic pathways including the Src family kinases and BCR-ABL, with basal-type / triple negative breast cancer cell lines appearing to be preferentially inhibited by, and highly sensitive to, dasatinib161-163. In addition, as the Src oncogenic pathway plays an important role downstream of VEGF signaling, preliminary evidence suggests that dasatinib may exert antiangiogenic activity, and Src appears to also play an important role in osteoclast function, suggesting possible activity in bone metastases, awaiting clinical confirmation, and there is finally some evidence from hematological malignancies that dasatinib cross the BBB164.


Methodology for this Review
A search of the PUBMED database was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include
just-in-time (JIT) medical feed sources as returned from Terkko FeedNavigator provided by the National Library of Health Sciences - Terkko at the University of Helsinki.  A "broad-spectrum" science search using  Scirus (410+ million entry database) was then deployed for resources not included in PUBMED.  Unpublished studies were located via contextual search, and  relevant dissertations were located via  NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software. Gratitude is expressed to the many health professionals who read the manuscript of this review and provided feedback.

Constantine Kaniklidis
Medical Researcher
Evidencewatch
Director, Medical Research,
No Surrender Breast Cancer Forum (NSBCF)
European Association for Cancer Research (EACR)


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