- Email: [email protected]
Ipilimumab in patients with melanoma and brain metastases
Correspondence
Ipilimumab in patients with melanoma and brain metastases Kim Margolin and colleagues1 addressed the issue of systemic treatment in patients with malignant melanoma and brain metastases. Such treatment is a crucial component of care because most of these patients have metastases outside the brain that restrict survival after successful local management (ie, surgical resection or radiotherapy, or both). In their openlabel, phase 2 study of ipilimumab,1 they reported that some patients responded and that the toxicity profile was similar to those from other investigations.2,3 The feasibility of such treatment is good news. However, the study had several limitations. In cohort A (asymptomatic patients not receiving concomitant corticosteroid treatment), 39 (76%) of 51 patients had progressive brain metastases after 12 weeks (assessed with modified WHO criteria) and median brain progression-free survival was 1·5 months (median overall survival 7·0 months). Only 21 (41%) patients in this cohort had undergone previous brain radiotherapy. Together with the apparent disconnect between progression-free survival and overall survival, one might speculate that many patients might have been subsequently irradiated. The use and potential effect of such salvage treatment was not reported by Margolin and co-workers.1 Additionally, further information about the cause of death (brain metastases vs extracranial progression) would be interesting because the main effect of ipilimumab could be improved extracranial control. Eight (16%) patients in cohort A achieved partial responses in the brain after 12 weeks, with no complete responders. Details about these patients were not provided. Patients who had completed brain radiotherapy at least 14 days before the start of ipilimumab could be included in the trial.1 If such patients www.thelancet.com/oncology Vol 13 July 2012
were among those who responded, the prevailing cause of response might in fact have been radiotherapy. Da Silva and colleagues4 reported that 22·6% of melanoma metastases decreased in volume by more than 15% within 30 days of radiosurgery, and that imaging response could continue well beyond the first month. Another radiosurgery study5 showed that 14% of patients had complete responses and 42% partial responses. Therefore, such highly efficacious treatment should be part of routine management of patients with few small brain metastases and good performance status (only patients with ECOG performance status of 0 or 1 and index lesions ≤3 cm were included by Margolin and co-workers1). In cohort B (symptomatic metastases controlled with corticosteroids; only 24% had had previous brain radiotherapy), 19 (90%) of 21 patients had progressive brain metastases after 12 weeks and median brain progression-free survival was 1·2 months (median overall survival 3·7 months).1 With the high cost of ipilimumab, the short and provocative interpretation of these results could be that such treatment is difficult to justify. Additional, unreported prognostic factors—eg, number of brain metastases and serum lactate dehydrogenase concentration6,7—could help to identify the few patients with fairly favourable survival prognosis who might be candidates for ipilimumab treatment. Further information about baseline parameters and salvage treatment, particularly in responders, could contribute to an improved understanding of ipilimumab’s effects in patients with brain metastases. Effective systemic treatment is urgently needed in this patient population. I declare that I have no conflicts of interest.
Carsten Nieder [email protected] Department of Oncology and Palliative Medicine, Nordland Hospital, 8092 Bodø, Norway; and Institute of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
1
2
3
4
5
6
7
Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012; 13: 459–65. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–23. Lebbe C, McDermott DF, Robert C, et al. Ipilimumab improves survival in previously treated, advanced melanoma patients with poor prognostic factors: subgroup analyses from a phase III trial. Ann Oncol 2010; 21 (suppl 8): 401–07. Da Silva AN, Nagayama K, Schlesinger D, Sheehan JP. Early brain tumor metastasis reduction following gamma knife surgery. J Neurosurg 2009; 110: 547–52. Gaudy-Marqueste C, Regis JM, Muracciole X, et al. Gamma-Knife radiosurgery in the management of melanoma patients with brain metastases: a series of 106 patients without whole-brain radiotherapy. Int J Radiat Oncol Biol Phys 2006; 65: 809–16. Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008; 70: 510–14. Nieder C, Marienhagen K, Geinitz H, Grosu AL. Can current prognostic scores reliably guide treatment decisions in patients with brain metastases from malignant melanoma? J Cancer Res Ther 2011; 7: 47–51.
Authors’ reply We thank Carsten Nieder for his thoughtful comments about our report. The first concern was that patients in cohort A had long survival times, although a high proportion had progressive disease, which is possibly caused by the use of radiotherapy in patients after they had not benefited from ipilimumab in the study. Although we did not formally analyse data for treatments given after the study, most, if not all, patients who progressed in the brain were probably referred for stereotactic or rarely whole brain radiotherapy. However, patients in cohort A were a selected group: they were asymptomatic, did not need steroids for treatment of peritumoral oedema, and were good candidates for immunotherapy.1 Therefore, their median overall survival of 7 months does not seem extraordinary to us. Our methods did not allow for reliable attribution of the cause of death to CNS versus extracranial disease, but the consistency of e277
Ipilimumab in patients with melanoma and brain metastases Kim Margolin and colleagues1 addressed the issue of systemic treatment in patients with malignant melanoma and brain metastases. Such treatment is a crucial component of care because most of these patients have metastases outside the brain that restrict survival after successful local management (ie, surgical resection or radiotherapy, or both). In their openlabel, phase 2 study of ipilimumab,1 they reported that some patients responded and that the toxicity profile was similar to those from other investigations.2,3 The feasibility of such treatment is good news. However, the study had several limitations. In cohort A (asymptomatic patients not receiving concomitant corticosteroid treatment), 39 (76%) of 51 patients had progressive brain metastases after 12 weeks (assessed with modified WHO criteria) and median brain progression-free survival was 1·5 months (median overall survival 7·0 months). Only 21 (41%) patients in this cohort had undergone previous brain radiotherapy. Together with the apparent disconnect between progression-free survival and overall survival, one might speculate that many patients might have been subsequently irradiated. The use and potential effect of such salvage treatment was not reported by Margolin and co-workers.1 Additionally, further information about the cause of death (brain metastases vs extracranial progression) would be interesting because the main effect of ipilimumab could be improved extracranial control. Eight (16%) patients in cohort A achieved partial responses in the brain after 12 weeks, with no complete responders. Details about these patients were not provided. Patients who had completed brain radiotherapy at least 14 days before the start of ipilimumab could be included in the trial.1 If such patients www.thelancet.com/oncology Vol 13 July 2012
were among those who responded, the prevailing cause of response might in fact have been radiotherapy. Da Silva and colleagues4 reported that 22·6% of melanoma metastases decreased in volume by more than 15% within 30 days of radiosurgery, and that imaging response could continue well beyond the first month. Another radiosurgery study5 showed that 14% of patients had complete responses and 42% partial responses. Therefore, such highly efficacious treatment should be part of routine management of patients with few small brain metastases and good performance status (only patients with ECOG performance status of 0 or 1 and index lesions ≤3 cm were included by Margolin and co-workers1). In cohort B (symptomatic metastases controlled with corticosteroids; only 24% had had previous brain radiotherapy), 19 (90%) of 21 patients had progressive brain metastases after 12 weeks and median brain progression-free survival was 1·2 months (median overall survival 3·7 months).1 With the high cost of ipilimumab, the short and provocative interpretation of these results could be that such treatment is difficult to justify. Additional, unreported prognostic factors—eg, number of brain metastases and serum lactate dehydrogenase concentration6,7—could help to identify the few patients with fairly favourable survival prognosis who might be candidates for ipilimumab treatment. Further information about baseline parameters and salvage treatment, particularly in responders, could contribute to an improved understanding of ipilimumab’s effects in patients with brain metastases. Effective systemic treatment is urgently needed in this patient population. I declare that I have no conflicts of interest.
Carsten Nieder [email protected] Department of Oncology and Palliative Medicine, Nordland Hospital, 8092 Bodø, Norway; and Institute of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
1
2
3
4
5
6
7
Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012; 13: 459–65. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–23. Lebbe C, McDermott DF, Robert C, et al. Ipilimumab improves survival in previously treated, advanced melanoma patients with poor prognostic factors: subgroup analyses from a phase III trial. Ann Oncol 2010; 21 (suppl 8): 401–07. Da Silva AN, Nagayama K, Schlesinger D, Sheehan JP. Early brain tumor metastasis reduction following gamma knife surgery. J Neurosurg 2009; 110: 547–52. Gaudy-Marqueste C, Regis JM, Muracciole X, et al. Gamma-Knife radiosurgery in the management of melanoma patients with brain metastases: a series of 106 patients without whole-brain radiotherapy. Int J Radiat Oncol Biol Phys 2006; 65: 809–16. Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008; 70: 510–14. Nieder C, Marienhagen K, Geinitz H, Grosu AL. Can current prognostic scores reliably guide treatment decisions in patients with brain metastases from malignant melanoma? J Cancer Res Ther 2011; 7: 47–51.
Authors’ reply We thank Carsten Nieder for his thoughtful comments about our report. The first concern was that patients in cohort A had long survival times, although a high proportion had progressive disease, which is possibly caused by the use of radiotherapy in patients after they had not benefited from ipilimumab in the study. Although we did not formally analyse data for treatments given after the study, most, if not all, patients who progressed in the brain were probably referred for stereotactic or rarely whole brain radiotherapy. However, patients in cohort A were a selected group: they were asymptomatic, did not need steroids for treatment of peritumoral oedema, and were good candidates for immunotherapy.1 Therefore, their median overall survival of 7 months does not seem extraordinary to us. Our methods did not allow for reliable attribution of the cause of death to CNS versus extracranial disease, but the consistency of e277