- Email: [email protected]
Stereotactic radiosurgery alone for brain metastases
Comment
resistant prostate cancer if progression-free survival is a desired registration endpoint; comparator groups would be more meaningful if they consisted of other approved treatments such as enzalutamide or abiraterone. These considerations would provide a more meaningful context for changes in correlative biomarkers such as circulating tumour cells and PSA. Additionally, comprehensive trial designs that incorporate assessments of quality of life and pain progression could provide valuable corroborating data validating the effect of progression-free survival. Incorporating novel but validated imaging techniques would further strengthen analyses of progression-free survival. As we move forward, we must acknowledge that the proliferation of treatments for metastatic castrationresistant prostate cancer has created new opportunities for patients and new realities for clinical trial design.
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Ravi A Madan, *James L Gulley National Cancer Institute, National Institutes of Health, Center Drive, Bethesda, MD 20892, USA [email protected] We declare that we have no competing interests. 1
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Fizazi K, Jones R, Oudard S, et al. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol 2015; published online Jan 26. doi:10.1200/JCO.2014.56.5119. Basch E, Loblaw DA, Oliver TK, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol 2014; 32: 3436–48. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028–38. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424–33. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebocontrolled phase 3 study. Lancet Oncol 2015; 16: 152–60. D’Agostino RB Sr. Changing end points in breast-cancer drug approval— the Avastin story. N Engl J Med 2011; 365: e2. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasisfree survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: 39–46. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 2011; 29: 1252–60. Pivot X, Schneeweiss A, Verma S, et al. Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: results from AVADO. Eur J Cancer 2011; 47: 2387–95.
Saad F, Fizazi K, Jinga V, et al, for the ELM-PC 4 investigators. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castrationresistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol 2015; published online Feb 18. http://dx.doi.org/10.1016/S1470-2045(15)70027-6.
Stereotactic radiosurgery alone for brain metastases
www.thelancet.com/oncology Vol 16 March 2015
of cognitive scores with WBRT, thus strengthening the argument to avoid normal brain tissue radiation exposure. Nevertheless, some physicians might continue to advocate for adjuvant WBRT on the basis of its ability to reduce the risks of both local and distant brain failure,1 arguing subjectively that the benefits of maximising intracerebral control outweighs any disadvantages with respect to quality of life and neurocognitive scores. Furthermore, the evidence with respect to the effect of adjuvant WBRT on survival has been unclear.1 As a result, the choice between SRS alone, WBRT plus SRS, or even WBRT alone has been largely driven by physician or patient preference. An individual patient data meta-analysis9 of three randomised trials assessing SRS with or without WBRT has challenged our current understanding of the effect of adding WBRT. The investigators reported a survival advantage for SRS alone in those patients presenting with
Zephyr/Science Photo Library
Patients with limited brain metastases suitable for stereotactic radiosurgery (SRS) should be treated upfront with organ sparing SRS, and no longer with whole-brain radiation therapy (WBRT). In the past—and sometimes even today—WBRT was used indiscriminately for all patients with brain metastasis. But current class 1 evidence has shown that WBRT on its own does not durably control brain metastases,1,2 and can compromise survival in some patients when given without surgery or SRS.2,3 Contemporary randomised trials have focused on SRS, with or without WBRT, in patients with few brain metastases.1 Findings from these trials have shown that adjuvant WBRT has significant harmful effects on quality of life and cognition.4,5 Trials assessing prophylactic WBRT in patients with high risk non-small cell lung cancer,6 the use of neuroprotective drugs with WBRT,7 and WBRT hippocampal avoidance8 confirm the reduction
249
Comment
one to four metastases, Karnofsky performance status of 70 or higher, and age of 50 years or younger. In this group of patients, the expected reduction in the risk of new brain metastases with adjuvant WBRT was not noted. However, in older patients (aged >50 years), WBRT decreased the risk of new brain metastasis, as expected, but without affecting survival. The explanation of these findings is probably multifactorial; however, the authors postulate that exposure to the harms of adjuvant WBRT, without the benefit of increased distant brain control, could be one explanation for the survival advantage in younger patients treated with SRS. The findings from this metaanalysis must be considered in patient counselling and management decisions. Furthermore, this finding begs the question as to whether equipoise can still be claimed for ongoing phase 3 trials assessing brain metastasis management with WBRT and SRS, or simultaneous integrated WBRT boost. The noted benefits of WBRT avoidance in maintaining increased neurocognitive functioning, quality-of-life scores, and—now—extended survival do come at the expense of greater rates of intracranial relapse.1,9 This consequence highlights the importance of routine follow-up imaging and appropriate use of salvage therapies. Therefore, to be consistent with the evidence, it behooves us to routinely image all patients with brain metastases after treatment—local progression and new brain metastases can occur irrespective of what initial treatment is used. The American Society for Radiation Oncology (ASTRO) has recently recommended in their Choose Wisely campaign to not routinely add adjuvant WBRT to SRS for limited brain metastases.10 Although a major step forward, the recommendation falls short of clearly recommending SRS alone for patients presenting with limited brain metastases. The segregation of the recommendation to the adjuvant scenario might be taken by some to justify WBRT alone or simultaneous integrated WBRT boost despite the class 1 data showing WBRT’s inadequacies or toxic effects—which is central to the recommendation. We would support wording the recommendation as follows: for patients presenting with limited brain metastases, the preferred upfront therapeutic option is SRS alone. WBRT should be reserved as one of several possible salvage therapies. ASTRO’s recommendation is nevertheless a major statement both against the routine use of WBRT, and for 250
not specifying a number of presenting lesions. A landmark study of SRS alone for patients with one to ten metastases showed that risk of distant brain failure rates and survival do not vary for patients with two to four versus five to ten lesions.11 Metastasis counting is probably irrelevant if all tumours meet SRS criteria. Several decades of clinical trials now provide abundant class 1 evidence that we should provide individualised and customised brain metastasis treatments to maximise quality of life, neurocognitive function, and survival. The sun is setting on WBRT, and SRS alone is rising to be the standard of care. *Arjun Sahgal, David Larson, Jonathan Knisely Department of Radiation Oncology, University of Toronto, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada (AS); Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA (DL); and Department of Radiation Medicine, Hofstra North Shore-LIJ School of Medicine, NY, USA (JK) [email protected] AS has received honoraria for past educational seminars from Medtronic and Elekta AB, and research grants from Elekta AB. The other authors declare no competing interests. 1
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Tsao M, Xu W, Sahgal A. A meta-analysis evaluating stereotactic radiosurgery, whole-brain radiotherapy, or both for patients presenting with a limited number of brain metastases. Cancer 2012; 118: 2486–93. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004; 363: 1665–72. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494–500. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009; 10: 1037–44. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2010; 29: 134–41. Sun A, Bae K, Gore EM, Movsas B, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 2011; 29: 279–86. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol 2013; 15: 1429–37. Gondi V, Pugh SL, Tome W, Caine C, Corn B, Kanner A, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase 2 multi-institutional trial. J Clin Oncol 2014; published online Oct 27. DOI:10.1200/JCO.2014.57.2909. Sahgal A, Aoyama H, Kocher M, et al. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2015 (in press). Choose Wisely. ASTRO releases second list of five radiation oncology treatments to question, as part of national Choosing Wisely campaign. Sept 14, 2014. www.choosingwisely.org/astro-releases-second-list/ (accessed Dec 2, 2014). Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–95.
www.thelancet.com/oncology Vol 16 March 2015
resistant prostate cancer if progression-free survival is a desired registration endpoint; comparator groups would be more meaningful if they consisted of other approved treatments such as enzalutamide or abiraterone. These considerations would provide a more meaningful context for changes in correlative biomarkers such as circulating tumour cells and PSA. Additionally, comprehensive trial designs that incorporate assessments of quality of life and pain progression could provide valuable corroborating data validating the effect of progression-free survival. Incorporating novel but validated imaging techniques would further strengthen analyses of progression-free survival. As we move forward, we must acknowledge that the proliferation of treatments for metastatic castrationresistant prostate cancer has created new opportunities for patients and new realities for clinical trial design.
2
3
4
5 6
7 8
9
Ravi A Madan, *James L Gulley National Cancer Institute, National Institutes of Health, Center Drive, Bethesda, MD 20892, USA [email protected] We declare that we have no competing interests. 1
10
Fizazi K, Jones R, Oudard S, et al. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol 2015; published online Jan 26. doi:10.1200/JCO.2014.56.5119. Basch E, Loblaw DA, Oliver TK, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol 2014; 32: 3436–48. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028–38. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424–33. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebocontrolled phase 3 study. Lancet Oncol 2015; 16: 152–60. D’Agostino RB Sr. Changing end points in breast-cancer drug approval— the Avastin story. N Engl J Med 2011; 365: e2. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasisfree survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: 39–46. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 2011; 29: 1252–60. Pivot X, Schneeweiss A, Verma S, et al. Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: results from AVADO. Eur J Cancer 2011; 47: 2387–95.
Saad F, Fizazi K, Jinga V, et al, for the ELM-PC 4 investigators. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castrationresistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol 2015; published online Feb 18. http://dx.doi.org/10.1016/S1470-2045(15)70027-6.
Stereotactic radiosurgery alone for brain metastases
www.thelancet.com/oncology Vol 16 March 2015
of cognitive scores with WBRT, thus strengthening the argument to avoid normal brain tissue radiation exposure. Nevertheless, some physicians might continue to advocate for adjuvant WBRT on the basis of its ability to reduce the risks of both local and distant brain failure,1 arguing subjectively that the benefits of maximising intracerebral control outweighs any disadvantages with respect to quality of life and neurocognitive scores. Furthermore, the evidence with respect to the effect of adjuvant WBRT on survival has been unclear.1 As a result, the choice between SRS alone, WBRT plus SRS, or even WBRT alone has been largely driven by physician or patient preference. An individual patient data meta-analysis9 of three randomised trials assessing SRS with or without WBRT has challenged our current understanding of the effect of adding WBRT. The investigators reported a survival advantage for SRS alone in those patients presenting with
Zephyr/Science Photo Library
Patients with limited brain metastases suitable for stereotactic radiosurgery (SRS) should be treated upfront with organ sparing SRS, and no longer with whole-brain radiation therapy (WBRT). In the past—and sometimes even today—WBRT was used indiscriminately for all patients with brain metastasis. But current class 1 evidence has shown that WBRT on its own does not durably control brain metastases,1,2 and can compromise survival in some patients when given without surgery or SRS.2,3 Contemporary randomised trials have focused on SRS, with or without WBRT, in patients with few brain metastases.1 Findings from these trials have shown that adjuvant WBRT has significant harmful effects on quality of life and cognition.4,5 Trials assessing prophylactic WBRT in patients with high risk non-small cell lung cancer,6 the use of neuroprotective drugs with WBRT,7 and WBRT hippocampal avoidance8 confirm the reduction
249
Comment
one to four metastases, Karnofsky performance status of 70 or higher, and age of 50 years or younger. In this group of patients, the expected reduction in the risk of new brain metastases with adjuvant WBRT was not noted. However, in older patients (aged >50 years), WBRT decreased the risk of new brain metastasis, as expected, but without affecting survival. The explanation of these findings is probably multifactorial; however, the authors postulate that exposure to the harms of adjuvant WBRT, without the benefit of increased distant brain control, could be one explanation for the survival advantage in younger patients treated with SRS. The findings from this metaanalysis must be considered in patient counselling and management decisions. Furthermore, this finding begs the question as to whether equipoise can still be claimed for ongoing phase 3 trials assessing brain metastasis management with WBRT and SRS, or simultaneous integrated WBRT boost. The noted benefits of WBRT avoidance in maintaining increased neurocognitive functioning, quality-of-life scores, and—now—extended survival do come at the expense of greater rates of intracranial relapse.1,9 This consequence highlights the importance of routine follow-up imaging and appropriate use of salvage therapies. Therefore, to be consistent with the evidence, it behooves us to routinely image all patients with brain metastases after treatment—local progression and new brain metastases can occur irrespective of what initial treatment is used. The American Society for Radiation Oncology (ASTRO) has recently recommended in their Choose Wisely campaign to not routinely add adjuvant WBRT to SRS for limited brain metastases.10 Although a major step forward, the recommendation falls short of clearly recommending SRS alone for patients presenting with limited brain metastases. The segregation of the recommendation to the adjuvant scenario might be taken by some to justify WBRT alone or simultaneous integrated WBRT boost despite the class 1 data showing WBRT’s inadequacies or toxic effects—which is central to the recommendation. We would support wording the recommendation as follows: for patients presenting with limited brain metastases, the preferred upfront therapeutic option is SRS alone. WBRT should be reserved as one of several possible salvage therapies. ASTRO’s recommendation is nevertheless a major statement both against the routine use of WBRT, and for 250
not specifying a number of presenting lesions. A landmark study of SRS alone for patients with one to ten metastases showed that risk of distant brain failure rates and survival do not vary for patients with two to four versus five to ten lesions.11 Metastasis counting is probably irrelevant if all tumours meet SRS criteria. Several decades of clinical trials now provide abundant class 1 evidence that we should provide individualised and customised brain metastasis treatments to maximise quality of life, neurocognitive function, and survival. The sun is setting on WBRT, and SRS alone is rising to be the standard of care. *Arjun Sahgal, David Larson, Jonathan Knisely Department of Radiation Oncology, University of Toronto, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada (AS); Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA (DL); and Department of Radiation Medicine, Hofstra North Shore-LIJ School of Medicine, NY, USA (JK) [email protected] AS has received honoraria for past educational seminars from Medtronic and Elekta AB, and research grants from Elekta AB. The other authors declare no competing interests. 1
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Tsao M, Xu W, Sahgal A. A meta-analysis evaluating stereotactic radiosurgery, whole-brain radiotherapy, or both for patients presenting with a limited number of brain metastases. Cancer 2012; 118: 2486–93. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004; 363: 1665–72. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494–500. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009; 10: 1037–44. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2010; 29: 134–41. Sun A, Bae K, Gore EM, Movsas B, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 2011; 29: 279–86. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol 2013; 15: 1429–37. Gondi V, Pugh SL, Tome W, Caine C, Corn B, Kanner A, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase 2 multi-institutional trial. J Clin Oncol 2014; published online Oct 27. DOI:10.1200/JCO.2014.57.2909. Sahgal A, Aoyama H, Kocher M, et al. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2015 (in press). Choose Wisely. ASTRO releases second list of five radiation oncology treatments to question, as part of national Choosing Wisely campaign. Sept 14, 2014. www.choosingwisely.org/astro-releases-second-list/ (accessed Dec 2, 2014). Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–95.
www.thelancet.com/oncology Vol 16 March 2015