Treating Brain Mets

[Margerie]

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 accessible9,10. 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 survival15,16. 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 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; 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 progression36,37. 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 researchers38,40-42 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 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. 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. References 1. Chang EL, Lo S. Diagnosis and Management of Central Nervous System Metastases from Breast Cancer. Oncologist, Oct 2003;8:398 - 410. 2. Chang SD, Adler JR. Current treatment of patients with multiple brain metastases. Neurosurg Focus. 2000 Aug 15;9(2):e5. 3. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494-500. 4. Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg. Aug 1993;79(2):210-6. 5. Ranasinghe MG, Sheehan JM. Surgical management of brain metastases. Neurosurg Focus. Mar 2007; 22 (3):E2. 6. Lang FF, Wildrick DM, Sawaya R. Management of Cerebral Metastases: The Role of Surgery. Management of Cerebral Metastases: The Role of Surgery. Cancer Control. 1998;5(2):124-129. 7. Andrews DW, Scott C, Sperduto PW. Phase III randomized trial comparing whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Results of the RTOG 9508 trial. Lancet 2004;63:1665-73. 8. Smith ML, Lee JYK. Stereotactic radiosurgery in the management of brain metastasis. Neurosurg Focus. Mar 2007;22 (3):E5. 9. Peacock KH, Lesser GJ. Current therapeutic approaches in patients with brain metastases. Curr Treat Options Oncol. Nov 2006;7(6):479-89. 10. Mehta MP, Tsao MN, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys. Sep 1 2005;63(1):37-46. 11. Yamamoto M. Radiosurgery for Metastatic Brain Tumors. Prog Neurol Surg. 2007;20:106-28. 12. Deinsberger R, Tidstrand J. LINAC Radiosurgery as Single Treatment in Cerebral Metastases. J Neurooncol. 2006 Jan;76(1):77-83. 13. Shuto T, Fujino H, Inomori S, Nagano H. Repeated gamma knife radiosurgery for multiple metastatic brain tumours. Acta Neurochir (Wien). Sep 2004;146(9):989-93; discussion 993. Epub 2004 Jun 28. 14. Flickinger JC. Radiotherapy and radiosurgical management of brain metastases. Curr Oncol Rep. Nov 2001;3(6):484-9. 15. Kondziolka D, Martin JJ, Flickinger JC, et al. Long-term survivors after gamma knife radiosurgery for brain metastases. Cancer. 2005;104(12):2784-91 16. Bartsch R, Fromm S, Rudas M, et al. Intensified local treatment and systemic therapy significantly increase survival in patients with brain metastases from advanced breast cancer - a retrospective analysis. Radiother Oncol. Sep 2006;80(3):313-7. 17. Lesser GJ: Chemotherapy of cerebral metastases from solid tumors. Neurosurg Clin North Am. 1996; 7:527-536. 18. Nieder C, Grosu LA, Astner S, Thamm R, Molls M. Integration of chemotherapy into current treatment strategies for brain metastases from solid tumors. Radiat Oncol. Jun 2006;27;1:19. 19. Fine RL, Chen J, Balmaceda C, et al. Randomized Study of Paclitaxel and Tamoxifen Deposition into Human Brain Tumors: Implications for the Treatment of Metastatic Brain Tumors. Oct 2006;1;12(19):5770-6 20. Fabi A, Vidiri A, Felici A, et al. Dramatic Regression of Multiple Brain Metastases from Breast Cancer with Capecitabine: Another Arrow at the Bow? Cancer Invest. June-July 2006;466-468. 21. Rivera E, Meyers C, Groves M, et al. Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Cancer. Cancer. Sep 2006;15;107(6):1348-54. 22. Madhupa R, Kirtia S, Bhatta MLB, Srivastavaa PK, Srivastavaa M, Kumarb S. Letrozole for brain and scalp metastases from breast cancer—a case report. Breast. 2006;15(3):439-441. 23. Trudeau ME, Crump M, Charpentier D. Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada – Clinical Trials Group (NCIC-CTG). Ann Oncol. Jun 2006;17(6):952-6. Epub 2006 Mar 24. 24. Christodoulou C, Bafaloukos D, Linardou H, et al. Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study. J NeuroOncol. Jan 2005;71(1):61-5. *25. Addeo R, Caraglia M, Faiola V, et al. Concomitant treatment of brain metastasis with Whole Brain Radiotherapy [WBRT] and Temozolomide [TMZ] is active and improves Quality of Life. BMC Cancer. Jan 2007;25;7:18. 26. Addeo R, Montella L, Guarrasi R, Dello Russo A, Faiola V, Del Prete S. Temozolomide (TMZ) and radiation (XRT) for brain metastasis of solid tumors. J Clin Oncol. ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2006;24(18S June 20 Suppl):1543. 27. Milker-Zabel S. Radiosensitizers in Brain Cancer: Clinical Experience to Date. Am Journal Cancer. 2006;5(6):363-370. 28. Rosenberg A, Knox S. Radiation sensitization with redox modulators: a promising approach. Int J Radiat Oncol Biol Phys. Feb 1 2006;64(2):343-54. 29. Harrison LB, Chadha M, Hill RJ, Hu K, Shasha D. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist. 2002;7(6):492-508. 30. Charpentier MM. Efaproxiral: A Radiation Enhancer Used in Brain Metastases from Breast Cancer. Ann Pharmacother. Dec 2005;39(12):2038-45. Epub 2005 Oct 25. 31. Engel RH, Kaklamani VG. Role of efaproxiral in metastatic brain tumors. Expert Rev Anticancer Ther. Apr 2006;6(4):477-85. 32. Stea B, Suh J, Shaw E, et al. Efaproxiral (EFAPROXYN) as an adjunct to whole brain radiation therapy for the treatment of brain metastases originating from breast cancer: updated survival results of the randomized REACH (RT-009) study. 27th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 8–11 December 2004. 33. Stea B, Shaw E, Pinter T, et al. Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases. Br J Cancer. Jun 2006;19;94(12):1777-84. 34. Suh JH, Stea B, Nabid A, et al. Phase III Study of Efaproxiral As an Adjunct to Whole-Brain Radiation Therapy for Brain Metastases. J Clin Oncol. Jan 1 2006;24(1):106-14. Epub 2005 Nov 28. 35. Sneed P. Efaproxiral: Should We Hold Our Breath? J Clin Oncol. Jan 1 2006;24(1):13-5. Epub 2005 Nov 28. 36. Carde P, Timmerman R, Mehta MP, et al. Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases. J Clin Oncol. APR 1, 2001;19(7):2074-83. 37. Mehta MP, Shapiro WR, Glantz MJ, et al. Lead-In Phase to Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation for Patients With Brain Metastases: Centralized Assessment of Magnetic Resonance Imaging, Neurocognitive, and Neurologic End Points. J. Clin. Oncol., August 15, 2002; 20(16): 3445 - 3453. 38. Gabos Z, Sinha R, Hanson J, et al. . Prognostic significance of HER-2/neu over-expression on the incidence of brain metastasis in newly diagnosed breast cancer. J Clin Oncol. ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2006;24(18 suppl). 39. Yau T, Swanton C, Chua S, et al. Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab. Acta Oncol. 2006;45(2):196-201. 40. Puente Vazquez J, Lopez-Tarruella Cobo S, Garcia-Saenz JA, et al. Brain metastases in metastatic breast cancer patients receiving trastuzumab-based therapies. Clin Transl Oncol. Jan 2006;8(1):50-3. 41. Kristiansen C, Enevoldsen K, Langkjer ST. Cerebral metastasis in advanced breast cancer and the significance of HER2 status. 29th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 14–17 December 2006. 42. Souglakos J,1 Vamvakas L, Apostolaki S, et al. Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status. Breast Cancer Res. 2006; 8(4): R36. 43. Stemmler J, Kahlert S, Siekiera W, et al. Brain metastases (BM) in patients treated with trastuzumab for HER2 overexpressing metastatic breast cancer (MBC): incidence and survival. J Clin Oncol. ASCO Annual Meeting Proceedings. 2005;23(16 suppl). 44. Stemmler J, Schmitt M, Willems A et al. Brain metastases in HER2-overexpressing metastatic breast cancer: comparative analysis of trastuzumab levels in serum and cerebrospinal fluid. J Clin Oncol. ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2006;24(18 suppl). 45. Ferretti G, Felici A, Pino M, et al. Incidence of brain metastases after first line chemotherapy in breast cancer patients treated with or without trastuzumab. J Clin Oncol. ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2006;24(18 suppl). 46. Crivellari D, Pagani O, Veronesi A, et al. High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel. Ann Oncol. Mar 2001;12(3):353-6. 47. Freilich RJ, Seidman AD, DeAngelis LM. Central nervous system progression of metastatic breast cancer in patients treated with paclitaxel. Cancer. Jul 1995;15;76(2):232-6. 48 Miller KD, Weathers T, Haney LG, et al. Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol. Jul 2003;14(7):1072-7. 49. Lin NU, Carey LA, Liu MC et al. Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition). .2006;24 (18 suppl). 50. Morabito A, Longo R, Gattuso D, et al. Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpressing metastatic breast cancer. Oncol Rep. Aug 2006;16(2):393-8. 51. Cerchietti LC, Bonomi MR, Navigante AH, Castro MA, Cabalar ME, Roth BM. Phase I/II study of selective cyclooxygenase-2 inhibitor celecoxib as a radiation sensitizer in patients with unresectable brain metastases. J Neurooncol. Jan 2005;71(1):73-81. 52. Takada Y, Bhardwaj A, Potdar P, Aggarwa BB. Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-B activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene. Dec 9 2004;23(57):9247-9258. 53. BabaT, Chio CC, Black KL. The effect of 5-lipoxygenase inhibition on blood-brain barrier permeability in experimental brain tumors. J Neurosurg. 1992;77:403-406. 54. Flavin DF. A lipoxygenase inhibitor in breast cancer brain metastases. J Neurooncol. Mar 2007;82(1):91-3. Epub 2006 Sep 26. 55. Glaser T, Winter S, Groscurth P, et al. Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity. Br J Cancer 1999;80:756–65. 56. Winking, M., S. Sarikaya, A. Rahmanian, A. Jodicke, D. K. Boker. 2000. Boswellic acids inhibit glioma growth: a new treatment option?. J. Neurooncol. 46: 97-103. 57. Hostanska K, Daum G, Saller R. Cytostatic and apoptosisinducing activity of boswellic acids toward malignant cell lines in vitro. Anticancer Res. 2002;22(5):2853-2862. 58. Takada Y, Ichikawa H, Badmaev V, Aggarwal BB. Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression. J Immunol. Mar 1 2006;176(5):3127-40. 59. Boeker DK, Winking M. Die Rolle von Boswellia-Säuren in der Therapie maligner Gliome. Deutsches Aerzteblatt. 1997;94:A1197- A1199. Translated Page: The role of boswellic acids in the therapy of malignant glioma.. 60. Streffer JR, Bitzer M, Schabet M, Dichgans J, Weller M. Response of radiochemotherapy-associated cerebral edema to a phytotherapeutic agent, H15. Neurology. 2001;56(9):1219-1221. 61. Janssen G, Bode U, Breu H, et al. Boswellic acids in the palliative therapy of children with progressive or relapsed brain tumors. Klin Padiatr. 2000;212(4):189-195. 62. Pöckel D. Pharmacological actions and targets of boswellic acids in human leukocytes and platelets [dissertation]. Frankfurt am Main: Johann Wolfgang Goethe-Universität; 2006. 63. Gramaglia A, Loi GF, Mongioj V, Baronzio GF. Increased survival in brain metastatic patients treated with stereotactic radiotherapy, omega-3 fatty acids and bioflavonoids. Anticancer Res. 1999;19(6C):5583-5586.

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[img]aoladp://MA16403868-0044/multiple-brain-mets.jpg[/img] 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 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. 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. (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

* subscribe * | * contact us * | * unsubscribe * | * previous issue *

Copyright © 2007. Constantine Kaniklidis. All rights reserved.

[Margerie]

The above was in a newsletter from Constantine- a medical researcher, emphasis on CAM treatments. Find his discussions very interesting. You can email him and subscribe to get the e newsletters. He covers many topics. His breast cancer page:

http://brcaprevention.evidencewatch.com/

[gdpawel]

The initial approach to using radiation postoperatively to treat brain metastases, used to be whole brain radiation, but this was abandoned because of the substantial neurological deficits that resulted, sometimes appearing a considerable time after treatment. Whole brain radiation was routinely administered to patients after craniotomy for excision of a cerebral metastasis in an attempt to destroy any residual cancer cells at the surgical site. However, the deleterious effects of whole brain radiation, such as dementia and other irreversible neurotoxicities, became evident.

This raised the question as to whether elective postoperative whole brain radiation should be administered to patients after excision of a solitary brain metastasis. Current clinical practice, at a number of leading cancer centers, use a more focused radiation field (Radiotherapy) that includes only 2-3cm beyond the periphery of the tumor site. This begins as soon as the surgical incision has healed.

Many metastatic brain lesions are now being treated with stereotactic radiosurgery. In fact, some feel radiosurgery is the treatment of choice for most brain metastases. There are a number of radiation treatments for therapy (Stereotatic, Gamma-Knife, Cyber-Knife, Brachyradiation and IMRT to name a few). These treatments are focal and not diffuse. Unlike surgery, few lesions are inaccessible to radiosurgical treatment because of their location in the brain. Also, their generally small size and relative lack of invasion into adjacent brain tissue make brain metastases ideal candidates for radiosurgery. Multiple lesions may be treated as long as they are small.

The risk of neurotoxicity from whole brain radiation is not insignificant and this approach is not indicated in patients with a solitary brain metastasis. Observation or focal radiation is a better choice in solitary metastasis patients. Whole brain radiation can induce neurological deterioration, dementia or both. Those at increased risk for long-term radiation effects are adults over 50 years of age. However, whole brain radiation therapy has been recognized to cause considerable permanent side effects mainly in patients over 60 years of age. The side effects from whole brain radiation therapy affect up to 90% of patients in this age group. Focal radiation to the local tumor bed has been applied to patients to avoid these complications.

Aggressive treatment like surgical resection and focal radiation to the local tumor bed in patients with limited or no systemic disease can yield long-term survival. In such patients, delayed deleterious side effects of whole brain radiation therapy are particularly tragic. Within 6 months to 2 years patients can develop progressive dementia, ataxia and urinary incontinence, causing severe disability and in some, death. Delayed radiation injuries result in increased tissue pressure from edema, vascular injury leading to infarction, damage to endothelial cells and fibrinoid necrosis of small arteries and arterioles.

The studies performed by Dr. Roy Patchell, et al, were thought to have been the difference between surgical excision of brain tumor alone vs. surgical excision & whole brain radiation. It was a study of whole brain radiation of a brain tumor alone vs. whole brain radiation & surgical excision. The increased success had been the surgery. And they measured "tumor recurrence", not "long-term survival". Patients experiencing any survival could have been dying from radiation necrosis, starting within two years of whole brain radiation treatment and documented as "complications of cancer" not "complications of treatment". There may have been less "tumor recurrence" but not more "long-term survival".

Patchell's studies convincingly showed there was no survival benefit or prolonged independence in patients who received postoperative whole brain radiation therapy. The efficacy of postoperative radiotherapy after complete surgical resection had not been established. It never mentioned the incidence of dementia, alopecia, nausea, fatigue or any other numerous side effects associated with whole brain radiation. The most interesting part of this study were the patients who lived the longest. Patients in the observation group who avoided neurologic deaths had an improvement in survival, justifying the recommendation that whole brain radiation therapy is not indicated following surgical resection of a solitary brain metastasis.

An editorial to Patchell's studies by Drs. Arlan Pinzer Mintz and J. Gregory Cairncross (JAMA 1998;280:1527-1529) described the morbidity associated with whole brain radiation and emphasized the importance of individualized treatment decisions and quality-of-life outcomes. The morbidity associated with whole brain radiation does not indicate whole brain radiation therapy following surgical resection of a solitary brain metastasis. Patients who avoided the neurologic side effects of whole brain radiation had an improvement in survival. His studies convincingly showed there was no survival benefit or prolonged independence in patients who received postoperative whole brain radiation therapy. There may have been some less tumor recurrence but not more long-term survival.

Had fatigue, memory loss and other adverse effects of whole brain radiation been considered, and had quality of life been measured, it might be less clear that whole brain radiation is the right choice for all patients. These patients do not remain functionally independent longer, nor do they live longer than those that have surgery alone, said researchers in a report in an issue of The Journal of the American Medical Association. Patchell's standard for proving the value (improving overall survival) of whole brain radiation fell short of this criteria.

The UCLA Metastatic Brain Tumor Program treats metastatic disease focally so as to spare normal brain tissue and function. Focal treatment allows retreatment of local and new recurrences (whole brain radiation is once and done, cannot be used again). UCLA is equipped with X-knife and Novalis to treat tumors of all sizes and shapes. For patients with a large number of small brain metastases (more than 5), they offer whole brain radiotherapy.

The results of a study at the University of Pittsburgh School of Medicine reported that treating four or more brain tumors in a single radiosurgery session resulted in improved survival compared to whole brain radiation therapy alone. Patients underwent Gamma-Knife radiosurgery and the results indicate that treating four or more brain tumors with radiosurgery is safe and effective and translates into a survival benefit for patients.

Sometimes, symptoms of brain damage appear many months or years after radiation therapy, a condition called late-delayed radiation damage (radiation necrosis or radiation encephalopathy). Radiation necrosis may result from the death of tumor cells and associated reaction in surrounding normal brain or may result from the necrosis of normal brain tissue surrounding the previously treated metastatic brain tumor. Such reactions tend to occur more frequently in larger lesions (either primary brain tumors or metastatic tumors). Radiation necrosis has been estimated to occur in 20% to 25% of patients treated for these tumors. Some studies say it can develop in at least 40% of patients irradiated for neoplasms following large volume or whole brain radiation and possibly 3% to 9% of patients irradiated focally for brain tumors that developed clinically detectable focal radiation necrosis. In the production of radiation necrosis, the dose and time over which it is given is important, however, the exact amounts that produce such damage cannot be stated.

Late effects of whole brain radiation can include abnormalities of cognition (thinking ability) as well as abnormalities of hormone production. The hypothalamus is the part of the brain that controls pituitary function. The pituitary makes hormones that control production of sex hormones, thyroid hormone, cortisol. Both the pituitary and the hypothalamus will be irradiated if whole brain radiation occurs. Damage to these structures can cause disturbances of personality, libido, thirst, appetite, sleep and other symptoms as well. Psychiatric symptoms can be a prominent part of the clinical picture presented when radiation necrosis occurs.

Again, whole brain radiation is the most damaging of all types of radiation treatments and causes the most severe side effects in the long run to patients. In the past, patients who were candidates for whole brain radiation were selected because they were thought to have limited survival times of less than 1-2 years and other technology did not exist. Today, many physicians question the use of whole brain radiation in most cases as one-session radiosurgery treatment can be repeated for original tumors or used for additional tumors with little or no side effects from radiation to healthy tissues. Increasingly, major studies and research have shown that the benefits of radiosurgery can be as effective as whole brain radiation without the side effects.

And, as reported in MD Anderson's OncoLog (below), in the past the only treatment for multiple metastases was whole brain radiation, which on its own had little effect on survival. There are now a variety of effective treatment modalities for people who have fewer than four tumors. Dr. Jeffrey Weinberg at the Department of Neurosurgery at MD Anderson has said "with a small, finite number of tumors, it may be better to treat the individual brain tumors themselves rather than the whole brain." Anderson is equipped with Linac Linear Accelerator. The critical idea is to focally treat all tumors.

http://cancerfocus.org/forum/showthread.php?t=526

[Believe51]

Pulling this up so I can find it to complete my list this week.>>Believe51

[Jackie07]

Thought I would attach the ABTA (American brain Tumor Association) brochure on metastatic brain tumor here. That particular brochure was dated 2004, a bit old, but gives a good overview on the topic. And the link has a date of 1/2009.

http://www.abta.org/siteFiles/SitePa...42670EC586.pdf

[gdpawel]

Reprinted from MDA OncoLog

Today, brain metastasis, even multiple metastases, is not an automatic death sentence, and its treatment, while still not to be taken lightly, has become safer, minimally invasive, and more effective than it was not many years ago.

"Multiple tumors in the brain do not have as bad a prognosis as one would think," said Jeffry Weinberg, M.D., assistant professor in the Department of Neurosurgery at The University of Texas M.D. Anderson Cancer Center. A study showed that a patient who has two or three lesions that can be removed actually has the same prognosis as someone who has only one brain tumor.

In the past, the only treatment for multiple metastases was whole brain radiation (WBR), which on its own had little effect on survival. While that is still the standard treatment for four or more brain tumors, there are now a variety of effective treatment modalities for people who have fewer than four tumors.

"With a small, finite number of tumors, it may be better to treat the individual brain tumors themselves rather than the whole brain when possible," Dr. Weinberg stated.

He explained that while whole brain radiation (WBR) has benefits such as treating micrometastases (individual cells that can eventually grow into brain tumors), today it is most often used in conjunction with other treatment modalities, such as surgery and radiosurgery.

"Surgery and radiosurgery allow treatment to be directed at the tumor itself," said Dr. Weinberg. "Because of technological advancements, both are now minimally invasive and have lower risks." At M.D. Anderson, multidisciplinary teams that include radiation oncologists and neurosurgeons design treatment plans tailored to the patient's individual situation.

Imaging Techniques Improve Precision

Computer-assisted surgery has made brain surgery faster, safer and more precise. Magnetic resonance imaging allows neurosurgeons to see beneath the skull before the incision is made and locate the tumor exactly. Ultrasound provides real-time imaging of the brain as the surgery is being performed. Because of the precision, surgeons can make smaller bone openings, approach the tumor more precisely, and more completely resect it.

Advanced operative and imaging technology also allows doctors to map and speech, motor and sensory areas of the brain before surgery and thereby preserve or avoid them during surgery. Furthermore, they can perform the surgery on patients who are awake if need be in order to better identify speech control areas of the brain.

"We've really perfected brain surgery to be relatively safe, even for many lesions that previously were considered unresectable," said Frederick Lang, M.D., associate professor in the Department of Neurosurgery.

While surgery now involves fewer risks and is less invasive, radiosurgery avoids the risks of a craniotomy altogether and requires only local anesthesia. This highly localized treatment is a same-day procedure.

At M.D. Anderson, radiosurgery is delivered by a team of neurosurgeons and radiation oncologists. Linear accelarators (Linac) are used in conjunction with stereotaxis that allows doctors to align exactly the correct angle and distance for directing radiation beams. The multiple low-dose beams converge from various angles, delivering to the tumor a very high dose of radiation. While radiosurgery does not actually remove the tumor, it damages the DNA so badly that the tumor is eradicated.

Weighing the Options

There is an ongoing debate about whether surgery or radiosurgery is the better option for treating brain metastasis and under what circumstances. In actuality, each has its own advantages and disadvantages.

Dr. Lang summarized the pros and cons: "The advantage of removing a tumor surgically is that it is taken out in one swoop and people tend to recover faster from swelling and neurocompromise. The disadvantage is that it requires invasive surgery."

"Radiosurgery is lot easier and avoids many of the problems of invasive surgery, but it does not eliminate the tumor immediately. It sometimes takes three or four months to shrink, causing the patient to deal with the tumor's symptoms longer and to possibly need steroids for a longer period. The follow-up can be more complicated with radiosurgery than with surgery because of the risk of destroying surrounding tissue."

Thanks to treatment advances, both surgery and radiosurgery are now minimally invasive and relatively safe

Radiosurgery is optimal for very small lesions, particularly those located deep in the brain, which are hard to find, much less excise surgically. It can't, however, be used on tumors larger than three centimeters because too large an area of brain tissue surrounding the tumor may be exposed to radiation.

Tumors that are between one and three centimeters can be treated with either approach. it's not yet clear which approach is optimal, but M.D. Anderson is working on finding out.

For people with more than one metastasis, M.D. Anderson physicians tend to take a more aggressive approach than many other treatment centers. Most patients with two or three tumors receive a combined surgery/radiosurgery treatment tailored to their particular situation.

"For example, we might take out one large lesion and give radiosurgery to two small ones," said Dr. Lang. "Tumors that can be removed are, and those that cannot are treated with radiosurgery. The critical idea is to focally treat all of the tumors, because if you lease one or two behind untreated, the patient is not going to do as well.

Today, brain metastasis can be regarded as another round in a person's fight against cancer, rather than the end of the battle. "There's a completely different perspective about it now," Dr. Lang said. "The chance of living through treatment fro brain metastasis today is very high. With these newer aggressive treatments and better outcomes, the focus can remain on trying to cure the underlying cause of metastatic disease."

You could also look into information from noted brain surgeon Dr. Christopher Duma

http://www.cduma.com/

[gdpawel]

When brain tumors are treated with radiation therapy, there is always a risk of radiation-induced necrosis of healthy brain tissue. Insidious and potentially fatal, radiation necrosis of the brain may develop months or even years after irradiation.

This poorly understood side effect can occur even when the most stringent measures are taken to avoid exposing healthy tissue to harmful levels of radiation. In most cases, radiation necrosis of the brain occurs at random, without known genetic or other predisposing risk factors. The only treatment options typically available for radiation necrosis of the brain are surgery to remove dead tissue and use of the steroid dexamethasone to provide limited symptom control. But clinicians have not found a way to stop the progression of necrosis, despite having tested a range of therapies including anticoagulants, hyperbaric oxygen, and high-dose anti-inflammatory regimens.

However, recent studies at M. D. Anderson have shown that the monoclonal antibody bevacizumab (Avastin) may be able to stop radiation necrosis of the brain and allow some of the damage to be reversed. Victor A. Levin, M.D., a professor in the Department of Neuro-Oncology and the senior researcher on the studies, said the findings suggest that radiation necrosis of the brain can be successfully managed—and perhaps even prevented—with bevacizumab or similar drugs.

The need for such a breakthrough is as old as radiation therapy for cancers in the brain. “No matter what we do or how good we do it, we know a small percentage of patients who receive radiation therapy to the central nervous system will suffer late-occurring radiation necrosis,” Dr. Levin said. “We used to think it was the dose that was causing problems. Then we did a study and found that there was little to no relation to radiation dose or radiation volume—the necrosis occurred simply by chance. So it is impossible to say which patients will develop this problem; we just have to monitor them and hope for the best.”

Like necrosis, the discovery that bevacizumab has an effect on necrosis can also be attributed to chance. Bevacizumab, a newer drug that prevents blood vessel growth in tumors by blocking vascular endothelial growth factor (VEGF), was originally approved in the United States for the treatment of metastatic colon cancer and non–small cell lung cancer. An M. D. Anderson group that included Dr. Levin decided to test the drug in patients who had VEGF-expressing brain tumors. “Some of these patients also had necrosis from prior radiation therapy, and we were struck by the positive response of those patients to bevacizumab,” Dr. Levin said. “We had never seen such a regression of necrotic lesions with any other drug like we did in those patients.” The observation prompted the researchers to design a placebo-controlled, double-blind, phase II trial sponsored by the U.S. Cancer Therapy Evaluation Program in which bevacizumab would be tested specifically for the treatment of radiation necrosis of the brain.

The trial is small, having accrued 13 of a planned 16 patients, and is limited to those with progressive symptoms, lower-grade primary brain tumors, and head and neck cancers. But the results have been unlike anything the researchers have seen before in radiation necrosis therapy. All of the patients receiving bevacizumab responded almost immediately to treatment, with regression of necrotic lesions evident on magnetic resonance images, while none of the patients receiving the placebo showed a response. The results were striking, and all of the patients who switched from placebo showed a response to bevacizumab as well. So far, responses have persisted over 6 months even after the end of bevacizumab treatment.

Side effects seen in the trial so far included venous thromboembolism in one patient, small vessel thrombosis in two patients, and a large venous sinus thrombosis in one patient. Dr. Levin is unsure whether the side effects were caused by therapy or the radiation necrosis itself. “We’re also not absolutely sure what is causing the positive effects against the radiation necrosis,” he said. “We presume it’s related to the release of cytokines like VEGF, since bevacizumab is very specific and only reduces VEGF levels. We think aberrant production of VEGF is involved with radiation necrosis of the brain, and the fact that even short treatment with bevacizumab seems to turn off the cycle of radiation damage further confirms the central role of VEGF in the process.”

The multidisciplinary research team has also postulated that radiation therapy damages astrocytes, a cell type involved in various brain functions, and causes them to leak VEGF. This leaked VEGF might then cause further damage to brain cells and further leakage of VEGF. “It gets to be a very vicious cycle,” Dr. Levin said. “The question is, is that all that’s going on?”

Dr. Levin hopes that the answers to that question and others may lead to preventive measures against radiation necrosis, beyond what is already done to control the development of radiation itself. Perhaps bevacizumab can be given in low doses before radiation or intermittently afterward to reduce VEGF levels and protect the brain from abnormally high levels of the protein. He hopes such approaches can be tested in future studies. “Just the fact that bevacizumab works has helped us understand so much more about what happens in radiation necrosis,” he said. “Everything we’ve tried up until now has been a brick wall.”

Source: OncoLog, May 2009, Vol. 54, No. 5

http://www2.mdanderson.org/depts/onc...ay/5-09-2.html

Visualizing the effects of Avastin (bevacizumab)

http://www2.mdanderson.org/depts/onc...5-may/pop.html

[gdpawel]

Avastin blocks VEGF and causes existing microcapillaries to die. This is what is measured with the AngioRx assay, death of existing endothelial cells of microcapillaries, and associated cells. Microcapillary blood vessels run throughout the brain in close proximity to brain cells.

Some clinical work on Avastin suggests that there could be several possible mechanisms for Avastin, including potentially decreasing the oncotic pressure within the center of a necrotic tumor, which can limit the ability of the drug it is given with to be delivered into the tumor.

The oncotic pressure (or colloid osmotic pressure) is a form of osmotic pressure exerted by proteins in blood plasma that usually tends to pull water into the circulatory system. Because "large" plasma proteins cannot easily cross through the capillary walls, their effect on the osmotic pressure of the capillary interiors will, to some extent, balance out the tendency for fluid to leak out of the capillaries (oncotic pressure tends to pull fluid into the capillaries).

A drop in vascular permeability induces trans-vascular gradients in oncotic and hydrostatic pressure iin blood vessels. The induced hydrostatic pressure gradient improves the penetration of large molecules (Avastin is a large molecule drug) into vessels.

Scientists from MD Anderson (and other institutions) have found out that they could treat radiation-induced necrosis of the brain with Avastin. Recent studies have shown that Avastin may be able to stop radiation necrosis of the brain and allow some of the damage to be reversed.

I can see where radiation can allow the lining of the brain to become permeable to VEGF, and VEGF can induce the brain cells to make more VEGF, and self-propagating brain damage ensues. And Avastin can disable VEGF.

The MD Anderson research team postulates that radiation therapy damages astrocytes, a cell type involved in various brain functions, and causes them to leak VEGF. This leaked VEGF might then cause further damage to brain cells and further leakage of VEGF. And the ultimate question is "is that all that's going on?"

With Hyperbaric Oxygen Therapy (HBOT), wound healing requires oxygen delivery to the injured tissues. Radiation damaged tissue has lost blood supply and is oxygen deprived. HBOT provides a better healing environment and leads to the growth of new blood vessels in a process called re-vascularization. HBOT acts as a drug when 100 percent oxygen is delivered at pressures greater than atmospheric (sea level) pressure to a patient in an enclosed chamber.

If this is the case, the judicious application of Avastin can normalize the vasculature by pruning the immature vessels and fortifying the remaining ones. Normalized vasculature is less tortuous and the vessels are more uniformally covered by pericytes (in capillaries which regulate the blood-brain barrier) and basement membrane (thin sheet of fibers which lines the interior surface of blood vessels).

Source: Cell Function Analysis