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Originally published as JCO Early Release 10.1200/JCO.2008.19.0306 on October 6 2008 © 2008 American Society of Clinical Oncology.
Are Volumetric Changes of Brain Metastases the Best Evaluation of Efficacy?
Department of Radiation Oncology, AP-HP, Henri Mondor Hospital; Faculty of Medicine of Créteil, University of Paris XII, Paris, France
Division of Oncology, Rambam Health Care Campus, Haifa, Israel To the Editor: In metastatic breast cancer patients who overexpress HER2, trastuzumab combined with taxanes improves survival.1,2 In such a population, longer survival of patients with visceral metastasis control is associated with a higher rate of brain metastasis detection, suggesting low concentrations of trastuzumab in CNS tissue. Wardley et al3 was the first to report an increased rate of cerebral metastases in patients receiving trastuzumab in the metastatic setting in the trastuzumab era. The therapeutic release phenomenon of trastuzumab by brain and/or meningeal invasion seems as frequent as after conventional chemotherapy. Metastasis development may be due to the disease aggressiveness or the inability of trastuzumab to cross the blood-brain barrier (BBB). The CNS has been regarded as a sanctuary site in patients receiving chemotherapy, and it is not known whether trastuzumab crosses the BBB in humans. In a recent case report,4 the level of trastuzumab in the cerebrospinal fluid of a patient with meningeal spread was 300-fold lower than serum levels after intravenous infusion. This suggests a low penetration of trastuzumab across the BBB despite possible disruption of the barrier due to the spread of the disease. Clinical data support the hypothesis that the high rate of brain metastases may be due to the inability of trastuzumab to cross the BBB. The incidence of brain metastases in patients receiving trastuzumab for visceral metastatic disease ranged from 25% to 48%.5-10 In addition, patient cause of death is directly linked to the neurologic impact of metastases in 50% of patients.5 In most instances, death occurs as a consequence of neurologic alteration. Moreover, brain irradiation delivered secondary to confirmed metastases does not seem efficient in terms of disease control and does not increase survival. One of the potentially interesting approaches is the use of other HER1/2 target therapies that are administered systemically and are small enough to cross the BBB. Because the oncogenic activity of HER2 seems to function through the intracellular kinase domain, small molecules that cross the BBB and inhibit HER2 tyrosine kinase activity are attractive compounds to treat brain metastases from HER2-overexpressing breast cancer. In the Lin et al11 study, the authors evaluated lapatinib 750 mg orally twice a day in patients with HER-2–positive breast cancer who experienced CNS progression. Among the 39 patients who developed brain metastases while receiving trastuzumab, 37 experienced disease progression after prior radiation. One patient achieved partial remission in the brain with Response Evaluation Criteria In Solid Tumors, and seven patients (18%) were progression-free in both CNS and non-CNS sites at 16 weeks. The exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. In their conclusion, Lin et al reported that according to the volumetric changes observed in their exploratory analysis, additional studies are underway using volumetric changes as a primary end point. We do not share this conclusion. In this series the efficacy may be due to the lapatinib or the prior whole brain radiation therapy (WBRT) or the combination of both treatments. Thus, there is no rationale for using volumetric changes as a primary end point to evaluate efficacy of such combination. Our concern with these data and the conclusion is related to the fact that the authors have not discussed the potential delayed effect of radiation therapy (RT) during their 4 months of evaluation. Taking into account the fact that radiation effect could be delayed weeks after the completion of RT, brain metastasis control and volumetric changes cannot be attributed only to drug cytotoxicity. In addition, there are no data supporting the conclusion that volumetric changes could be predictive of increased survival, which remains one of the main objectives in brain metastasis studies. Radiotherapy is the mainstay of treatment for brain metastases from breast cancer. WBRT in patients displaying multiple brain metastases has been applied since the 1950s. It is still considered the principle treatment for patients with multiple brain metastases, to reverse neurologic deficits, and control disease progression in the brain. In the review by Kirsch and Loeffler12 focusing on studies of brain metastases of breast cancer published between 1969 and 2000, the median survival of the patients ranged from 1.2 to 18 months. In this large review, RT increased survival time significantly in patients with one or a low number of metastases, in patients who received RT after surgery, and those who had an increased KPS score. In the German experience,13 the median overall survival of the 145 patients who had WBRT was 26 weeks. Survival was dependent on the number of metastases and the radiation dose. In the study by Lin et al,11 the distribution of their patients was not presented according to these main prognostic factors of survival. They also did not present distribution of the imaging results of responding and nonresponding patients through the follow-up period. In the study from the Mahmoud-Ahmed et al,14 the rate of brain failure after WBRT was 50%. Half the patients had follow-up films because of rapid deterioration. The data describing stabilization and regression of tumors in that report were clearly taken from selected patients and are not representative of the entire group. Indeed, it can be assumed that many of the patients who did not have imaging follow-up would have shown progression. According to these issues, including the possible delayed RT response to WBRT, efficacy of RT in brain metastasis, the absence of objective evaluation of delayed response to WBRT, the absence of strong data showing curative effect of lapatinib on HER2 breast cancer metastases, we believe that Lin et al study does not provide a serious rationale for using volumetric changes as a primary end point for future studies. We believe that future investigations in this area must consider imaging and clinical efficacy, neurologic deterioration, and survival without symptoms as primary end points rather than volumetric changes. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on October 6, 2008 REFERENCES
1. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 2. Marty M, Cognetti F, Maraninchi D, et al: Efficacy and safety of trastuzumab combined with docetaxel in patients with HER2-positive metastatic breast cancer given as first-line treatment: Results of a randomized phase II trial (M77001). J Clin Oncol 23:4265-4274, 2005 3. Wardley AM, Danson S, Clayton AJ, et al: High incidence of brain metastases in patients treated with trastuzumab for metastatic breast cancer at a large center. Proc Am Soc Clin Oncol 21:61a, 2002 (suppl; abstr 241) 4. Pestalozzi BC, Brignoli S: Trastuzumab in CSF. J Clin Oncol 18:2349-2351, 2000 5. Bendell JC, Domchek SM, Burstein HJ, et al: Central nervous system metastases in women who receive trastzumab-based regimen for metastatic breast carcinoma. Cancer 97:2972-2977, 2003[CrossRef][Medline] 6. Brufsky AM, Cleary D, Fuchs C, et al: First-line chemotherapy for metastatic breast cancer (MBC) with docetaxel (T), carboplatin (C), and trastzumab (H) (TCH): A phase II trial. Proc Am Soc Clin Oncol 22:18, 2003 (suppl; abstr 71) 7. Clark GM, Sledge GW Jr, Osborne CK, et al: Survival from first recurrence: Relative importance of prognostic factors in 1015 breast cancer patients. J Clin Oncol 5:55-61, 1987[Abstract] 8. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanised anti-HER2 monoclonal antibody in women with HER2-overexpression metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639-2648, 1999 9. Crivellari D, Pagani O, Veronesi A, et al: High incidence of central nervous system involvement of patients in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel. Ann Oncol 12:353-356, 2001 10. Lai R, Dang CT, Malkin MG, et al: The risk of central nervous system metastases after Trastuzumab therapy in patients with breast carcinoma. Cancer 101:810-816, 2004[CrossRef][Medline] 11. Lin NU, Carey LA, Liu MC, et al: Phase II trial of Lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 26:1993-1999, 2008 12. Kirsch DG, Loeffler JS: Brain metastases in patients with breast cancer: New horizons. Clin Breast Cancer 6:115-124, 2005[Medline] 13. Lentzsch S, Reichardt P, Weber F, et al: Brain metastases in breast cancer: Prognostic factors and management. Eur J Cancer 35:580-585, 1999[CrossRef][Medline] 14. Mahmoud-Ahmed AS, Suh JH, Lee SY, et al: Results of whole brain radiotherapy in patients with brain metastases from breast cancer: A retrospective study. Int J Radiat Oncol Biol Phys 54:810-817, 2002[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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