Treating Brain Mets

Margerie · 04-16-2007, 07:54 AM

Brain Metastasis in Breast Cancer
With (1) significant increases in median patient survival secondary to advances in oncotherapy, 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.

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).

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 WBRTsurvived longer than those on WBRT alone. 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) to the brain metastases, and has established itself, with or without WBRT, as a treatment option for patients with metastatic brain disease. 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 accessible^9,10.

Advantages of GKS 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 SRS? 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.

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 multiorgan disease, and with selected patients with effective intracranial and extracranial care capable of having prolonged and good-quality survival^15,16.

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 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 mm³ does an intact BBB tend to fail as a barrier¹⁷. 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. 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 progression¹⁸.

The questions remains how to 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, a case study reported a response brain metastases to capecitabine (Xeloda) monotherapy before brain irradiation²⁰. And the MD Anderson team of Edgardo Rivera and colleagues²¹ investigated the combination regimen of capecitabine plus 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 and good tolerability; see also our discussion of TMZ below. 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

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. Although one study under NCIC-CTG auspices failed to find TMZ of benefit in MBC²³, this was monotherapy and in addition was in a population of heavily pretreated women with extensive MBC. In contrast, Christos Christodoulou and colleagues with HeCOG (the Hellenic Cooperative Oncology Group)²⁴ evaluated the efficacy of temozolomide (TMZ) combined with cisplatin (CDDP), 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, and we have already documented above the significant antitumor activity of TMZ when combined with another chemotherapeutic agent, capecitabine²¹.
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 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.

Radiation Sensitization
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, 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 monotherapy^30,31. 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 death^32,33. 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; 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).

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 progression^36,37.

The HER2 / Trastuzumab (Herceptin) 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 high CNS involvement in young women with metastatic breast cancer women responding to trastuzumab-based therapies, has prompted some researchers^38,40-42 to suggest a defensive posture entertaining possible prophylactic cranial irradiation strategies, or to early detection in asymptomatic patients via CNS screening, to improve surgery or radiosurgery outcomes. In addition, Joachim Stemmler and colleagues^43,44 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.

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 factors. 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 evident⁴⁸.

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.

Breast Cancer Watch also found some preliminary evidence that a combination chemobiotherapy 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.

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.

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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 boswellia⁵⁴. This is consonant with previous demonstrations of boswellia exhibiting activity against brain tumors^55,56,57, 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. 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 trials^60,61. (Boswellic acids have also been found of clinical value in asthma, colitis ulcerosa, osteoarthritis, and inflammatory bowel diseases, as well as in brain tumors⁶²).

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 Inhibitors
In addition, as we noted in our discussion of the activity of the COX-2 inhibitor celecoxib (Celebrex) in brain metastases of breast cancer, standardized curcumin may therefore also be of benefit.

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, retrieving 580 citations, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include clinical trials from ClinicalTrials.gov and medical feed sources as returned from FeedNavigator provided by the National Library of Health Sciences - Terkko at the University of Helsinki. Unpublished studies were located via contextual search using Vivisimo, and scientific databases searched using COS Workbench from Community of Science. 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.
* [("brain metastasis" OR "brain metastases" OR "cerebral metastasis" OR "CNS metastasis" OR "metastasis to the brain") breast]

Coming Next:
Dr. Larry Norton's
Breast Cancer Update 2007
Breast Cancer Watch will report on and review the important recent presentation (3/8/07) on Advances in the Prevention and Cure of Breast Cancer delivered by eminent oncologist Dr. Larry Norton as part of Memorial Sloan-Kettering Cancer Center's (MSKCC) annual CancerSmart lecture series.

Coming Next:
Breast Cancer Q&A Series
Hereafter, each issue of Breast Cancer Watch Digest will present an anonymized query on breast cancer treatment and prevention selected from the hundreds received over the years, either directly or through Breast Cancer Watch.

Coming Soon:
Bone Metastasis - A Review
(and the Elizabeth Edwards Case)
The recently reported experience of Elizabeth Edwards's breast cancer recurrence and metastasis to the bone highlights the special problems of and issues in the treatment of bone metastases, and of ER+ / PR+ / HER2-negative breast disease, as well as underlining the importance of proactive screening - Elizabeth Edwards had regrettably failed to have a regular mammogram for four years prior to her diagnosis in 2004, resulting in an atypically large tumor at diagnosis of 9 cm., along with a presentation of significant metastatic bone pain. In addition, she presents with a not uncommon phenomenon of "receptor shift" being originally weakly endocrine (hormone)-responsive at diagnosis - and therefore receiving no prior endocrine therapy, only chemotherapy after standard surgery and radiation treatment - and now being strongly endocrine-responsive, for which her oncologist at UNC, Dr. Lisa Carey, will initiate AI (aromatase inhibitor) therapy in the form of letrozole (Femara) monotherapy + standard bisphosphonate bone therapy; at present no chemotherapy for this recurrence is being deployed. Her recurrence also teaches some important lessons concerning the recurrence "velocity" and pattern of breast cancer (her recurrence within 2 - 3 years of initial diagnosis is well within the norm in this scenario), intelligently acknowledged by her in describing MBC (metastatic breast cancer) as a chronic disease.

Breast Cancer Watch will review these and other related issues in our assessment of the state-of-the-art of bone metastasis therapy for breast cancer, with our customary look at emerging and frontier-edge developments as well as a critical appraisal of any well-evidenced CAM interventions, and will tie our findings where relevant back to the case of Elizabeth Edwards

Our Dedicated Topic Pages

Breast Cancer Prevention

Endocrine / TAM Therapy
Fulvestrant (Faslodex)

IBC Watch

Oncology Drug Interactions
Ovarian Suppression