Correspondence
We declare no competing interests.
Encouse B Golden, Samuel M Shin, Peter B Schiff, *Silvia C Formenti [email protected] Department of Radiation Oncology (EBG, SMS, PBS, SCF) and Department of Medicine (SCF), New York University School of Medicine, New York, NY, USA 1
2
3
4
5
Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 1999; 17: 2092–99. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007; 357: 664–72. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015; 385: 36–42. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol 2009; 10: 718–26. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 2013; 1: 365–72.
www.thelancet.com Vol 385 April 4, 2015
In their study of thoracic radiotherapy for treatment of extensivestage small-cell lung cancer (ES SCLC), Ben Slotman and colleagues1 concluded that thoracic radiotherapy should be considered for all patients with ES SCLC who respond to chemotherapy, even though the primary endpoint was not met. In an accompanying Comment, Jan van Meerbeeck and David Ball 2 were more cautious in their interpretation, suggesting that there might be a subset of patients that benefit from this approach. We have found shortcomings in their statistical analysis. Our power calculations show that the trial had only 71% power to detect a 10% difference in the overall survival rate at 1 year, using a two-sided type I error rate of 5%. The authors probably made additional assumptions, but did not describe them. The median follow-up was only 24 months, and so from a data-maturity standpoint, we find the comparison of the secondary 2-year overall survival endpoint questionable. A separation of the survival curves for patients in the radiotherapy group and control group happens at 9 months, and so it would be appropriate to identify factors that improved survival in patients who lived longer than 9 months. In other words, a prospectively specified subset analysis might identify which patients benefit from radiotherapy. The number needed to treat to avoid one death at 2 years was reported as 10·6 (95% CI 6·1–42·5) patients. This calculation was based only on 28 patients (5·6% of the study population) at risk at 24 months. Moreover, the authors did not address the issue of multiplicity for the many unspecified post-hoc analyses that were performed. The results from this trial are necessary but not sufficient to warrant the recommendation of thoracic radiotherapy for all patients with
some response to chemotherapy for ES SCLC. Many statistical nuances were not discussed by the authors, which might temper enthusiasm for the use of thoracic radiotherapy until results from the Radiation Therapy Oncology Group trial (NCT01055197) become available.
Dr P Marazzi/Science Photo Library
each associated with improved survival. Thus, it is plausible that some ES SCLC patients could derive additional benefit from upfront definitive chemoradiotherapy. Does concomitant use of radiotherapy contribute more than local control within the treatment field? Radiotherapy-induced immunogenic tumour-cell death can alert the immune system, and concurrent chemoradiotherapy might, at least in some patients, unleash an immune response that contributes to tumour rejection, thereby improving survival.4 Our data5 suggested that radiotherapy, when combined with immune checkpoint blocking agents, could activate these types of systemic responses in patients with metastases. The ongoing RTOG-0937 trial (NCT01055197), which compares cranial irradiation with and without radiotherapy to other areas of the body in chemotherapyresponsive patients with ES SCLC), will address the inclusion of sequential radiotherapy in the management of metastatic disease. Research is warranted to test upfront concurrent chemoradiotherapy in ES SCLC.
We declare no competing interests.
*Aaron Mansfield, Sumithra Mandrekar mansfi[email protected] Department of Medical Oncology (AM) and Department of Health Sciences Research (SM), Mayo Clinic, Rochester, MN 55905, USA 1
2
Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015; 385: 36–42. van Meerbeeck JP, Ball D. Small-cell lung cancer: local therapy for a systemic disease? Lancet 2015; 385: 9–10.
I read with interest the results of the trial of radiotherapy for extensive stage small-cell lung cancer (ES SCLC) by Ben Slotman and colleagues,1 and I would like to raise important issues that were not directly addressed by the authors. The authors note that the 2-year overall survival was improved in patients with ES SCLC who received thoracic radio therapy in addition to prophylactic cranial irradiation. This finding is potentially practicechanging. However, a caveat exists regarding this statement, also not addressed in the accompanying Comment.2 The trial allowed treatments of disease progression at the discretion of the participating treatment centres, and these uncontrolled interventions (or absence thereof) could have affected apparent disease survival, even if they were internally consistent at each centre (details of which the authors did not report). I suggest a more cautious interpretation of the post-recurrence data as a clear 2-year survival benefit to the thoracic radiotherapy group. Notwithstanding, subgroups within that patient cohort might in the future have a stronger survival effect than is evident in the whole patient group. 1291
We declare no competing interests.
Encouse B Golden, Samuel M Shin, Peter B Schiff, *Silvia C Formenti [email protected] Department of Radiation Oncology (EBG, SMS, PBS, SCF) and Department of Medicine (SCF), New York University School of Medicine, New York, NY, USA 1
2
3
4
5
Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 1999; 17: 2092–99. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007; 357: 664–72. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015; 385: 36–42. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol 2009; 10: 718–26. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 2013; 1: 365–72.
www.thelancet.com Vol 385 April 4, 2015
In their study of thoracic radiotherapy for treatment of extensivestage small-cell lung cancer (ES SCLC), Ben Slotman and colleagues1 concluded that thoracic radiotherapy should be considered for all patients with ES SCLC who respond to chemotherapy, even though the primary endpoint was not met. In an accompanying Comment, Jan van Meerbeeck and David Ball 2 were more cautious in their interpretation, suggesting that there might be a subset of patients that benefit from this approach. We have found shortcomings in their statistical analysis. Our power calculations show that the trial had only 71% power to detect a 10% difference in the overall survival rate at 1 year, using a two-sided type I error rate of 5%. The authors probably made additional assumptions, but did not describe them. The median follow-up was only 24 months, and so from a data-maturity standpoint, we find the comparison of the secondary 2-year overall survival endpoint questionable. A separation of the survival curves for patients in the radiotherapy group and control group happens at 9 months, and so it would be appropriate to identify factors that improved survival in patients who lived longer than 9 months. In other words, a prospectively specified subset analysis might identify which patients benefit from radiotherapy. The number needed to treat to avoid one death at 2 years was reported as 10·6 (95% CI 6·1–42·5) patients. This calculation was based only on 28 patients (5·6% of the study population) at risk at 24 months. Moreover, the authors did not address the issue of multiplicity for the many unspecified post-hoc analyses that were performed. The results from this trial are necessary but not sufficient to warrant the recommendation of thoracic radiotherapy for all patients with
some response to chemotherapy for ES SCLC. Many statistical nuances were not discussed by the authors, which might temper enthusiasm for the use of thoracic radiotherapy until results from the Radiation Therapy Oncology Group trial (NCT01055197) become available.
Dr P Marazzi/Science Photo Library
each associated with improved survival. Thus, it is plausible that some ES SCLC patients could derive additional benefit from upfront definitive chemoradiotherapy. Does concomitant use of radiotherapy contribute more than local control within the treatment field? Radiotherapy-induced immunogenic tumour-cell death can alert the immune system, and concurrent chemoradiotherapy might, at least in some patients, unleash an immune response that contributes to tumour rejection, thereby improving survival.4 Our data5 suggested that radiotherapy, when combined with immune checkpoint blocking agents, could activate these types of systemic responses in patients with metastases. The ongoing RTOG-0937 trial (NCT01055197), which compares cranial irradiation with and without radiotherapy to other areas of the body in chemotherapyresponsive patients with ES SCLC), will address the inclusion of sequential radiotherapy in the management of metastatic disease. Research is warranted to test upfront concurrent chemoradiotherapy in ES SCLC.
We declare no competing interests.
*Aaron Mansfield, Sumithra Mandrekar mansfi[email protected] Department of Medical Oncology (AM) and Department of Health Sciences Research (SM), Mayo Clinic, Rochester, MN 55905, USA 1
2
Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015; 385: 36–42. van Meerbeeck JP, Ball D. Small-cell lung cancer: local therapy for a systemic disease? Lancet 2015; 385: 9–10.
I read with interest the results of the trial of radiotherapy for extensive stage small-cell lung cancer (ES SCLC) by Ben Slotman and colleagues,1 and I would like to raise important issues that were not directly addressed by the authors. The authors note that the 2-year overall survival was improved in patients with ES SCLC who received thoracic radio therapy in addition to prophylactic cranial irradiation. This finding is potentially practicechanging. However, a caveat exists regarding this statement, also not addressed in the accompanying Comment.2 The trial allowed treatments of disease progression at the discretion of the participating treatment centres, and these uncontrolled interventions (or absence thereof) could have affected apparent disease survival, even if they were internally consistent at each centre (details of which the authors did not report). I suggest a more cautious interpretation of the post-recurrence data as a clear 2-year survival benefit to the thoracic radiotherapy group. Notwithstanding, subgroups within that patient cohort might in the future have a stronger survival effect than is evident in the whole patient group. 1291
