- Email: [email protected]
SABR in early operable lung cancer: time for evidence
Comment
Another successful trial done in refractory metastatic colorectal cancer has been completed.5 The RESOURCE trial was a placebo-controlled, phase 3 study of TAS-102, a nucleoside analogue combined with a thymidine phosphorylase inhibitor, which showed an improvement in overall survival similar to that of regorafenib (HR 0·68 [95% CI 0·58–0·81]; median survival 7·1 months with TAS-102 vs 5·3 months with placebo; p<0·0001). The toxicity profile was mild, with the most common adverse events being haematological (grade 3 or 4 neutropenia in 22% of patients and anaemia in 18%). Once TAS-102 receives regulatory approval outside of Japan where it is already registered, the question of which drug to give first—TAS-102 or regorafenib—needs to be addressed. In the RESOURCE trial, 18% of patients received regorafenib before TAS-102, and the HR for overall survival was 0·69 (previous regorafenib 95% CI 0·45–1·05; no previous regorafenib 0·57–0·83), irrespective of previous regorafenib exposure.5 One could argue that because TAS-102 is better tolerated than regorafenib is, it could be offered to frail, heavily pretreated patients first because its efficacy is not affected by previous regorafenib use. On the other hand, regorafenib could arguably be used before TAS-102 because it might be more active in less heavily pretreated patients whose
disease is less refractory. But, so far, the right order has not been established. In view of the enormous unmet need in the setting of refractory metastatic colorectal cancer, the rational goal of a treatment strategy would be to allow patients to benefit from both drugs. Rachel Riechelmann, *Axel Grothey Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil (RR); and Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA (AG) [email protected] RR reports grants and personal fees from Bayer during the conduct of this study and personal fees from Roche outside the submitted work. The Mayo Clinic Foundation received research funding and honoraria for consulting activities by AG from Bayer, Eisai, Eli-Lilly, Genentech, and Pfizer. 1
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5
Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 2010; 28: 453–59. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2013; 381: 303–12. Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; published online May 14. http://dx.doi.org/10.1016/S1470-2045(15)70156-7 Dienstman R, Guinney J, Delorenzi M, et al. Colorectal Cancer Subtyping Consortium (CRCSC) identification of a consensus of molecular subtypes. Proc Am Soc Clin Oncol 2014; 32: 5s (abstr 3511). Yoshino T, Mayer R, Falcone A, et al. Results of a multicenter, randomised, double-blind, phase III study of TAS-102 vs. placebo, with best supportive care (BSC), in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies (RECOURSE). Ann Oncol 2014; 25: 105 (abstr O0022).
In The Lancet Oncology, Joe Chang and colleagues1 report the combined results of two randomised trials (STARS and ROSEL) comparing stereotactic ablative radiotherapy (SABR) with surgery for early-stage non-small-cell lung cancer, both of which were halted early because of slow recruitment. We congratulate the investigators for publishing the results and for being prepared to merge their data in an attempt to answer this question. We suspect that much valuable information in “invisible and abandoned trials”2 could, if brought to light, inform practice, avoid time wasted in repetition, or at least refine the research questions. Although findings from non-randomised studies had previously suggested that SABR might be as effective as surgery, these results are the first from randomised trials. However, even after combining the two trials, there were only 58 patients, imposing a limitation on the strength www.thelancet.com/oncology Vol 16 June 2015
of any inferences drawn. Nevertheless, the results suggest that SABR is not inferior to surgery, with a hint that it might be better in terms of clinical effectiveness. The findings cast doubt over the superiority of lobectomy, sufficient to suggest group equipoise (a prerequisite for future randomised trials), and the investigators state that further trials in this setting are warranted. We would put it more strongly. In an era when evidence is expected for treatments, the fact that these interventions have still not been properly assessed is shameful. The difficulty in evaluating the benefit of innovations is summed up in what has become known as Buxton’s law: “It is always too early [for rigorous evaluation] until suddenly it’s too late”.3 If a proper evaluation is not done now, we risk technology creep. To avoid a turf war between opposing camps, the claims for lobectomy and those for ablation should
Astier-CHRU Lille/Science Photo Library
SABR in early operable lung cancer: time for evidence
Published Online May 14, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70225-1 See Articles page 630
597
Comment
both be considered carefully. Chang and colleagues state that lobectomy with dissection or sampling of mediastinal lymph nodes (ie, intraoperative dissection of whole lymph nodes, either all that are accessible or those in specified anatomical locations) is the standard of care for operable, stage I, non-small-cell lung cancer.1 However, after surgical lobectomy— when all mediastinal nodes can be looked at under the microscope—some cases will be identified as non-stage-I cancers.4 But, in a cohort of patients treated with SABR, these cases would remain, thus systematically defeating the intention-to-treat principle and providing a golden opportunity to bias the analysis in favour of lobectomy.5 The clinical effectiveness of the addition of lymphadenectomy to lobectomy has not been proven. The notion runs counter to the evidence gained in breast cancer, in which the historical justification for axillary node dissection and clearance has been reversed.6 In lung cancer, lymphadenectomy is being promoted without evidence of efficacy in an era in which such changes in standards of care should be tested with randomised controlled trials.7 The opportunity of a fair test should be given to less invasive treatments.8 With an average age of 67 years, the patients in Chang and colleagues’ study were not particularly elderly, but cancer treatments are being offered to ever-older patients who might not feature in trials and for whom improved evidence is needed. SABR is not the only candidate procedure that might reduce the harms of lung cancer treatment without loss of effectiveness. The uptake of videothoracoscopy, for example, has been resisted by surgeons, but the accumulating case series and registry evidence suggest that oncological effectiveness is not sacrificed by moving away from thoracotomy.9 The VIOLET trial in the UK seeks to test that question in a randomised controlled trial.
Clinicians have an ethical imperative to obtain evidence rather than continue to perpetrate needless harm through ignorance. “Trust me, I’m your doctor” does not have the ring of truth when different doctors claim to know what is best while consistently failing to encourage trials to put their beliefs to the test, as evidenced by poor recruitment into studies. Patients, too, have a societal duty to participate in carefully planned and monitored trials. However, evidence suggests that patients are not the main obstacle to trial recruitment;10 many are willing to participate in studies for various motives, including altruism. *Tom Treasure, Robert C Rintoul, Fergus Macbeth Clinical Operational Research Unit, University College London, London WC1H 0BT, UK (TT); Department of Thoracic Oncology, Papworth Hospital, Cambridge, UK (RCR); and Wales Cancer Trials Unit, Cardiff, UK (FM) [email protected] We declare no competing interests. 1
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5 6 7
8 9
10
Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 2015; published online May 14. http://dx.doi.org/10.1016/S1470-2045(15)70168-3. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013; 346: f2865. Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT. Statistical assessment of the learning curves of health technologies. Health Technol Assess 2001; 5: 1–79. Wu Y, Huang ZF, Wang SY, Yang XN, Ou W. A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer. Lung Cancer 2002; 36: 1–6. Blackstone EH, Lauer MS. Caveat emptor: the treachery of work-up bias. J Thorac Cardiovasc Surg 2004; 128: 341–44. Berwick DM. The science of improvement. JAMA 2008; 299: 1182–84. Treasure T, Russell C, Morton D, Macbeth F, Utley M. Surgical resection of lung cancer in England: more operations but no trials to test their effectiveness. Thorax 2012; 67: 759–61. Russell RCG, Treasure T. Counting the cost of cancer surgery for advanced and metastatic disease. Br J Surg 2012; 99: 449–50. Paul S, Isaacs AJ, Treasure T, Altorki NK, Sedrakyan A. Long term survival with thoracoscopic versus open lobectomy: propensity matched comparative analysis using SEER-Medicare database. BMJ 2014; 349: g5575. Department of Health. Cancer patient experience survey 2011/12. National report. https://www.gov.uk/government/uploads/system/uploads/ attachment_data/file/212860/Cancer-Patient-Experience-SurveyNational-Report-2011-12.pdf (accessed May 1, 2015).
Effect of PALB2 status on breast cancer precision medicine Published Online May 8, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70182-8 See Articles page 638
598
PALB2 is a key protein in the regulation of DNA repair. Through its interaction with BRCA1 and BRCA2, it not only acts as a major effector of both interstrand crosslink and homologous recombination repair but also functions as a tumour suppressor.1 Biallelic germline
mutations in PALB2 cause Fanconi’s anaemia, whereas monoallelic mutations have been associated with increased breast cancer risk.2,3 In a study undertaken at genetic and breast cancer clinics, Antoniou and colleagues estimated the familial risk of breast cancer www.thelancet.com/oncology Vol 16 June 2015
Another successful trial done in refractory metastatic colorectal cancer has been completed.5 The RESOURCE trial was a placebo-controlled, phase 3 study of TAS-102, a nucleoside analogue combined with a thymidine phosphorylase inhibitor, which showed an improvement in overall survival similar to that of regorafenib (HR 0·68 [95% CI 0·58–0·81]; median survival 7·1 months with TAS-102 vs 5·3 months with placebo; p<0·0001). The toxicity profile was mild, with the most common adverse events being haematological (grade 3 or 4 neutropenia in 22% of patients and anaemia in 18%). Once TAS-102 receives regulatory approval outside of Japan where it is already registered, the question of which drug to give first—TAS-102 or regorafenib—needs to be addressed. In the RESOURCE trial, 18% of patients received regorafenib before TAS-102, and the HR for overall survival was 0·69 (previous regorafenib 95% CI 0·45–1·05; no previous regorafenib 0·57–0·83), irrespective of previous regorafenib exposure.5 One could argue that because TAS-102 is better tolerated than regorafenib is, it could be offered to frail, heavily pretreated patients first because its efficacy is not affected by previous regorafenib use. On the other hand, regorafenib could arguably be used before TAS-102 because it might be more active in less heavily pretreated patients whose
disease is less refractory. But, so far, the right order has not been established. In view of the enormous unmet need in the setting of refractory metastatic colorectal cancer, the rational goal of a treatment strategy would be to allow patients to benefit from both drugs. Rachel Riechelmann, *Axel Grothey Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil (RR); and Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA (AG) [email protected] RR reports grants and personal fees from Bayer during the conduct of this study and personal fees from Roche outside the submitted work. The Mayo Clinic Foundation received research funding and honoraria for consulting activities by AG from Bayer, Eisai, Eli-Lilly, Genentech, and Pfizer. 1
2
3
4
5
Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 2010; 28: 453–59. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2013; 381: 303–12. Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; published online May 14. http://dx.doi.org/10.1016/S1470-2045(15)70156-7 Dienstman R, Guinney J, Delorenzi M, et al. Colorectal Cancer Subtyping Consortium (CRCSC) identification of a consensus of molecular subtypes. Proc Am Soc Clin Oncol 2014; 32: 5s (abstr 3511). Yoshino T, Mayer R, Falcone A, et al. Results of a multicenter, randomised, double-blind, phase III study of TAS-102 vs. placebo, with best supportive care (BSC), in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies (RECOURSE). Ann Oncol 2014; 25: 105 (abstr O0022).
In The Lancet Oncology, Joe Chang and colleagues1 report the combined results of two randomised trials (STARS and ROSEL) comparing stereotactic ablative radiotherapy (SABR) with surgery for early-stage non-small-cell lung cancer, both of which were halted early because of slow recruitment. We congratulate the investigators for publishing the results and for being prepared to merge their data in an attempt to answer this question. We suspect that much valuable information in “invisible and abandoned trials”2 could, if brought to light, inform practice, avoid time wasted in repetition, or at least refine the research questions. Although findings from non-randomised studies had previously suggested that SABR might be as effective as surgery, these results are the first from randomised trials. However, even after combining the two trials, there were only 58 patients, imposing a limitation on the strength www.thelancet.com/oncology Vol 16 June 2015
of any inferences drawn. Nevertheless, the results suggest that SABR is not inferior to surgery, with a hint that it might be better in terms of clinical effectiveness. The findings cast doubt over the superiority of lobectomy, sufficient to suggest group equipoise (a prerequisite for future randomised trials), and the investigators state that further trials in this setting are warranted. We would put it more strongly. In an era when evidence is expected for treatments, the fact that these interventions have still not been properly assessed is shameful. The difficulty in evaluating the benefit of innovations is summed up in what has become known as Buxton’s law: “It is always too early [for rigorous evaluation] until suddenly it’s too late”.3 If a proper evaluation is not done now, we risk technology creep. To avoid a turf war between opposing camps, the claims for lobectomy and those for ablation should
Astier-CHRU Lille/Science Photo Library
SABR in early operable lung cancer: time for evidence
Published Online May 14, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70225-1 See Articles page 630
597
Comment
both be considered carefully. Chang and colleagues state that lobectomy with dissection or sampling of mediastinal lymph nodes (ie, intraoperative dissection of whole lymph nodes, either all that are accessible or those in specified anatomical locations) is the standard of care for operable, stage I, non-small-cell lung cancer.1 However, after surgical lobectomy— when all mediastinal nodes can be looked at under the microscope—some cases will be identified as non-stage-I cancers.4 But, in a cohort of patients treated with SABR, these cases would remain, thus systematically defeating the intention-to-treat principle and providing a golden opportunity to bias the analysis in favour of lobectomy.5 The clinical effectiveness of the addition of lymphadenectomy to lobectomy has not been proven. The notion runs counter to the evidence gained in breast cancer, in which the historical justification for axillary node dissection and clearance has been reversed.6 In lung cancer, lymphadenectomy is being promoted without evidence of efficacy in an era in which such changes in standards of care should be tested with randomised controlled trials.7 The opportunity of a fair test should be given to less invasive treatments.8 With an average age of 67 years, the patients in Chang and colleagues’ study were not particularly elderly, but cancer treatments are being offered to ever-older patients who might not feature in trials and for whom improved evidence is needed. SABR is not the only candidate procedure that might reduce the harms of lung cancer treatment without loss of effectiveness. The uptake of videothoracoscopy, for example, has been resisted by surgeons, but the accumulating case series and registry evidence suggest that oncological effectiveness is not sacrificed by moving away from thoracotomy.9 The VIOLET trial in the UK seeks to test that question in a randomised controlled trial.
Clinicians have an ethical imperative to obtain evidence rather than continue to perpetrate needless harm through ignorance. “Trust me, I’m your doctor” does not have the ring of truth when different doctors claim to know what is best while consistently failing to encourage trials to put their beliefs to the test, as evidenced by poor recruitment into studies. Patients, too, have a societal duty to participate in carefully planned and monitored trials. However, evidence suggests that patients are not the main obstacle to trial recruitment;10 many are willing to participate in studies for various motives, including altruism. *Tom Treasure, Robert C Rintoul, Fergus Macbeth Clinical Operational Research Unit, University College London, London WC1H 0BT, UK (TT); Department of Thoracic Oncology, Papworth Hospital, Cambridge, UK (RCR); and Wales Cancer Trials Unit, Cardiff, UK (FM) [email protected] We declare no competing interests. 1
2
3
4
5 6 7
8 9
10
Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 2015; published online May 14. http://dx.doi.org/10.1016/S1470-2045(15)70168-3. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013; 346: f2865. Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT. Statistical assessment of the learning curves of health technologies. Health Technol Assess 2001; 5: 1–79. Wu Y, Huang ZF, Wang SY, Yang XN, Ou W. A randomized trial of systematic nodal dissection in resectable non-small cell lung cancer. Lung Cancer 2002; 36: 1–6. Blackstone EH, Lauer MS. Caveat emptor: the treachery of work-up bias. J Thorac Cardiovasc Surg 2004; 128: 341–44. Berwick DM. The science of improvement. JAMA 2008; 299: 1182–84. Treasure T, Russell C, Morton D, Macbeth F, Utley M. Surgical resection of lung cancer in England: more operations but no trials to test their effectiveness. Thorax 2012; 67: 759–61. Russell RCG, Treasure T. Counting the cost of cancer surgery for advanced and metastatic disease. Br J Surg 2012; 99: 449–50. Paul S, Isaacs AJ, Treasure T, Altorki NK, Sedrakyan A. Long term survival with thoracoscopic versus open lobectomy: propensity matched comparative analysis using SEER-Medicare database. BMJ 2014; 349: g5575. Department of Health. Cancer patient experience survey 2011/12. National report. https://www.gov.uk/government/uploads/system/uploads/ attachment_data/file/212860/Cancer-Patient-Experience-SurveyNational-Report-2011-12.pdf (accessed May 1, 2015).
Effect of PALB2 status on breast cancer precision medicine Published Online May 8, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70182-8 See Articles page 638
598
PALB2 is a key protein in the regulation of DNA repair. Through its interaction with BRCA1 and BRCA2, it not only acts as a major effector of both interstrand crosslink and homologous recombination repair but also functions as a tumour suppressor.1 Biallelic germline
mutations in PALB2 cause Fanconi’s anaemia, whereas monoallelic mutations have been associated with increased breast cancer risk.2,3 In a study undertaken at genetic and breast cancer clinics, Antoniou and colleagues estimated the familial risk of breast cancer www.thelancet.com/oncology Vol 16 June 2015