- Email: [email protected]
Surgery versus SABR for resectable non-small-cell lung cancer
Correspondence
9
10
Tournoy KG, Keller SM, Annema JT. Mediastinal staging of lung cancer: novel concepts. Lancet Oncol 2012; 13: 221–29. Shingyoji M, Nakajima T, Yoshino M, et al. Endobronchial ultrasonography for positron emission tomography and computedt tomography-negative lymph node staging in non-small cell lung cancer. Ann Thorac Surg 2014; 98: 1762–88.
In their pooled analysis of two randomised trials that each closed early due to inadequate accrual, Joe Chang and colleagues1 compared stereotactic ablative radiotherapy (SABR) with lobectomy for stage I non-small-cell lung cancer. Their conclusion, that “SABR is better tolerated—and might lead to better overall survival—than surgery for operable clinical stage I non-small cell lung cancer”, should be interpreted with caution because it is based on an unjust comparison of modern SABR techniques to outdated surgical approaches, and due to methodological limitations of the pooled data. Although advanced SABR techniques were used in the radiotherapy group, most lobectomies were undertaken using a thoracotomy. In fact, thoracotomy was done in 19 (79%) of 24 patients who underwent lobectomy. Open lobectomy, although a time-honoured procedure, should not be thought to be a standard of care for stage I non-small cell lung cancer. Compared with open lobectomy, thoracoscopic lobectomy is associated with lower (and ever improving) postoperative morbidity2,3 and mortality,4 without impairing oncological outcomes.5 When the comparison group is best possible radiotherapy, the conclusion that lobectomy is associated with increased procedural morbidity and mortality misrepresents the evolving surgical standard for patients with stage I disease. Furthermore, the conclusions of the investigators regarding procedural mortality refers to one perioperative death in the surgical group, compared with no deaths in the SABR group. On the basis of data from large national datasets, www.thelancet.com/oncology Vol 16 August 2015
the cumulative procedure-related mortality from SABR (0·7%) is similar to the operative (30 day or hospital discharge) mortality of thoracoscopic lobectomy (0·8%).4 The methodological limitations of this study cannot be understated when considering its conclusions. Both the STARS and ROSEL trials closed early owing to poor patient accrual. The 28 sites in the STARS trial randomised only 36 patients, and the ten sites in the ROSEL study randomised only 22 patients. Owing to the obvious lack of statistical power and short follow-up (median survival was not reached in either group), conclusions pertaining to overall survival outcomes are not interpretable. Additionally, in the ROSEL study, biopsy confirmation of non-small cell lung cancer was not mandatory, and could have inflated the survival advantage of SABR. In this study, one patient in the surgical group underwent surgical resection for benign disease but the number of patients with benign disease who underwent SABR cannot be established. The report by Chang and colleagues was underpowered to study overall survival and it was also underpowered to evaluate recurrence-free survival. The rate of locoregional recurrence (lung and nodal) in this report was four times greater in patients undergoing SABR (16·1%) than in patients undergoing lobectomy (4·1%). How such data would translate into cancer-specific survival outcomes in a trial that was properly designed to examine this variable is unknown. Last, the investigators stated in the Methods section that “the analyses were exploratory in nature”, yet they made a bold conclusion that SABR is better tolerated. We agree that a multi-institutional randomised controlled trial is needed. However, future randomised trials should be designed to make fair comparisons between best radiotherapy and best surgical therapy.
The authors declare no competing interests.
Masatsugu Hamaji, Shawn S Groth, David J Sugarbaker, *Bryan M Burt [email protected] Department of Thoracic Surgery, Kyoto University Hospital, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan (MH); Division of Thoracic Surgery, Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, USA (SSG, DJS, BMB) 1
2
3
4
5
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; 16: 630–37. Falcoz PE, Puyraveau M, Thomas PA, et al. Video-assisted thoracoscopic surgery versus open lobectomy for primary non-small-cell lung cancer: a propensity-matched analysis of outcome from the European Society of Thoracic Surgeon database. Eur J Cardiothorac Surg 2015; published online April 26. DOI:10.1093/ejcts/ezv154. Nwogu CE, D’Cunha J, Pang H, et al. VATS lobectomy has better perioperative outcomes than open lobectomy: CALGB 31001, an ancillary analysis of CALGB 140202 (Alliance). Ann Thorac Surg 2015; 99: 399–405. Burt BM, Kosinski AS, Shrager JB, Onaitis MW, Weigel T. Thoracoscopic lobectomy is associated with acceptable morbidity and mortality in patients with predicted postoperative forced expiratory volume in 1 second or diffusing capacity for carbon monoxide less than 40% of normal. J Thorac Cardiovasc Surg 2014; 148: 19–28. 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.
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 trials were halted early because of slow recruitment. We welcome the much needed evidence from randomised controlled trials (RCTs) and agree with the Comment2 by Tom Treasure and colleagues that evidence is needed as a basis for treatment selection. Nevertheless, we believe that the evidence from these two trials should be placed in a balanced perspective and rated according to a reliable and internationally recognised grading system. For this purpose, we will e372
Correspondence
use the GRADE approach,3 a grading system used by over 80 organisations including WHO and the American College of Physicians. For the outcome of overall mortality, we assume a high quality of evidence because RCTs are thought to provide unbiased estimates of treatment effects. The STAR and ROSEL trials seem to be well designed and we see no reason to downgrade the quality of evidence because of a presumed risk of bias. However, since the two trials showed different results and since the pooled effect estimate is imprecise, we suggest downgrading the quality of the evidence by minus two points, to low quality. Additionally, in view of the small sample size, it is likely that the groups were not well balanced in terms of patient prognosis and that patients with an increased risk of mortality were by chance randomised to the surgery group, which might explain at least partly the excessive mortality in this groups. A mortality of 3·7% is very unusual for elective lobectomies and unacceptable by modern surgical standards, as confirmed by more recent references than the ones provided in the Discussion. In fact, 30day mortality figures for lobectomy in RCTs ranges between less than 1% and 1–1·5% even in patients with marginal pulmonary function.4 Another misleading factor might be the low rate of histologically verified tumours in the radiotherapy group, which is only as high as 27% in the ROSEL trial. Much larger trials are needed to achieve balanced treatment groups. In the analysis by Chang and colleagues, discrepancy exists between the p value shown in figure 2 (p=0·037) and the 95% CI (0·017–1·190) for the hazard ratio of 0·14, which does not imply a real statistically significant effect. Because of this, and because of falsenegative effects often detected in small trials, uncertainty surrounds the evidence from these two trials. e373
We suggest that the quality of evidence is very low and likely to change as new evidence becomes available. Finally, the authors refer to equal efficacy in the two treatment modalities. However, we would like to highlight that these trials were not designed as non-inferiority or equivalence trials. In summary, we believe that no conclusions can be made from these trials that will affect clinical practice of stage I lung cancer. However, the paper by Chang and colleagues serves the purpose of emphasising the need for larger RCTs. AB reports grants from Medela Healthcare, outside the submitted work. IO, GR, GV, GM, and WW declare no competing interests.
*Isabelle Opitz, Gaetano Rocco, Alessandro Brunelli, Gonzalo Varela, Gilbert Massard, Walter Weder, on behalf of the European Society of Thoracic Surgeons [email protected] Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland (IO and WW); Division of Thoracic Surgery, Istituto Nazionale Tumori, Fondazione Pascale, IRCCS, Naples, Italy (GR); Department of Thoracic Surgery, St. James’s University Hospital, Leeds, UK (AB); Cirugia Toracica, Hospital Universitario de Salamanca, Salamanca, Spain (GV); and Department of Thoracic Surgery, Centre Hospitalier, Strasbourg, France (GM) 1
2
3
4
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; 16: 630–37. Treasure T, Rintoul RC, Macbeth F. SABR in early operable lung cancer: time for evidence. Lancet Oncol 2015; 16: 597–98. Guyatt GH, Oxman AD, Schuneman HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol 2011; 64: 380–82. Taylor MD, LaPar DJ, Isbell JM, Kozower BD, Lau CL, Jones DR. Marginal pulmonary function should not preclude lobectomy in selected patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 2014; 147: 738–44.
The pooled analysis of two independent phase 3 trials by Joe Chang and colleagues1 has shown the potential to use stereotactic ablative radiotherapy (SABR) for operable stage I non-small-cell lung cancer.
Such an analysis was necessary because of the early closure of the studies analysed due to slow accrual. There are several recent examples showing the difficulties of performing traditional clinical trials with new health technologies.2 We therefore commend National Health Service (NHS) England for announcing an investment of £15 million to fund SABR to treat patients with oligometastases, hepatocellular carcinoma, and reirradiation of the pelvis or spine as a Commissioning through Evaluation (CtE) programme. This follows the progress of an ongoing CtE initiative to assess selective internal radiotherapy (SIRT) for patients with metastatic colorectal cancer and intrahepatic cholangiocarcinoma. The concept underpinning CtE is that patients should gain access to promising treatments and technologies that are not routinely commissioned. This innovative funding model allows rapid evaluation of new treatments in a so-called real-world setting to inform future commissioning,1 overseen by the National Institute for Health and Care Excellence and NHS England. Although similar concepts are being applied to accelerate licensing of drugs,3,4 CtE is the first hybrid fundingevaluation model to accelerate the adoption of emerging technologies. The CtE model has some advantages over traditional trial designs in situations in which it is difficult to run a randomised trial, or where CtE can assess feasibility of recruitment to inform future trial design. Relatively small numbers of patients might be required to address specific gaps in the evidence base. Recruitment is likely to be faster since there is no control or comparator group. The model also allows for highly specialist treatments to be developed safely with appropriate quality assurance at centres selected by NHS England to provide equity of access throughout the country. www.thelancet.com/oncology Vol 16 August 2015
9
10
Tournoy KG, Keller SM, Annema JT. Mediastinal staging of lung cancer: novel concepts. Lancet Oncol 2012; 13: 221–29. Shingyoji M, Nakajima T, Yoshino M, et al. Endobronchial ultrasonography for positron emission tomography and computedt tomography-negative lymph node staging in non-small cell lung cancer. Ann Thorac Surg 2014; 98: 1762–88.
In their pooled analysis of two randomised trials that each closed early due to inadequate accrual, Joe Chang and colleagues1 compared stereotactic ablative radiotherapy (SABR) with lobectomy for stage I non-small-cell lung cancer. Their conclusion, that “SABR is better tolerated—and might lead to better overall survival—than surgery for operable clinical stage I non-small cell lung cancer”, should be interpreted with caution because it is based on an unjust comparison of modern SABR techniques to outdated surgical approaches, and due to methodological limitations of the pooled data. Although advanced SABR techniques were used in the radiotherapy group, most lobectomies were undertaken using a thoracotomy. In fact, thoracotomy was done in 19 (79%) of 24 patients who underwent lobectomy. Open lobectomy, although a time-honoured procedure, should not be thought to be a standard of care for stage I non-small cell lung cancer. Compared with open lobectomy, thoracoscopic lobectomy is associated with lower (and ever improving) postoperative morbidity2,3 and mortality,4 without impairing oncological outcomes.5 When the comparison group is best possible radiotherapy, the conclusion that lobectomy is associated with increased procedural morbidity and mortality misrepresents the evolving surgical standard for patients with stage I disease. Furthermore, the conclusions of the investigators regarding procedural mortality refers to one perioperative death in the surgical group, compared with no deaths in the SABR group. On the basis of data from large national datasets, www.thelancet.com/oncology Vol 16 August 2015
the cumulative procedure-related mortality from SABR (0·7%) is similar to the operative (30 day or hospital discharge) mortality of thoracoscopic lobectomy (0·8%).4 The methodological limitations of this study cannot be understated when considering its conclusions. Both the STARS and ROSEL trials closed early owing to poor patient accrual. The 28 sites in the STARS trial randomised only 36 patients, and the ten sites in the ROSEL study randomised only 22 patients. Owing to the obvious lack of statistical power and short follow-up (median survival was not reached in either group), conclusions pertaining to overall survival outcomes are not interpretable. Additionally, in the ROSEL study, biopsy confirmation of non-small cell lung cancer was not mandatory, and could have inflated the survival advantage of SABR. In this study, one patient in the surgical group underwent surgical resection for benign disease but the number of patients with benign disease who underwent SABR cannot be established. The report by Chang and colleagues was underpowered to study overall survival and it was also underpowered to evaluate recurrence-free survival. The rate of locoregional recurrence (lung and nodal) in this report was four times greater in patients undergoing SABR (16·1%) than in patients undergoing lobectomy (4·1%). How such data would translate into cancer-specific survival outcomes in a trial that was properly designed to examine this variable is unknown. Last, the investigators stated in the Methods section that “the analyses were exploratory in nature”, yet they made a bold conclusion that SABR is better tolerated. We agree that a multi-institutional randomised controlled trial is needed. However, future randomised trials should be designed to make fair comparisons between best radiotherapy and best surgical therapy.
The authors declare no competing interests.
Masatsugu Hamaji, Shawn S Groth, David J Sugarbaker, *Bryan M Burt [email protected] Department of Thoracic Surgery, Kyoto University Hospital, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan (MH); Division of Thoracic Surgery, Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, USA (SSG, DJS, BMB) 1
2
3
4
5
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; 16: 630–37. Falcoz PE, Puyraveau M, Thomas PA, et al. Video-assisted thoracoscopic surgery versus open lobectomy for primary non-small-cell lung cancer: a propensity-matched analysis of outcome from the European Society of Thoracic Surgeon database. Eur J Cardiothorac Surg 2015; published online April 26. DOI:10.1093/ejcts/ezv154. Nwogu CE, D’Cunha J, Pang H, et al. VATS lobectomy has better perioperative outcomes than open lobectomy: CALGB 31001, an ancillary analysis of CALGB 140202 (Alliance). Ann Thorac Surg 2015; 99: 399–405. Burt BM, Kosinski AS, Shrager JB, Onaitis MW, Weigel T. Thoracoscopic lobectomy is associated with acceptable morbidity and mortality in patients with predicted postoperative forced expiratory volume in 1 second or diffusing capacity for carbon monoxide less than 40% of normal. J Thorac Cardiovasc Surg 2014; 148: 19–28. 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.
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 trials were halted early because of slow recruitment. We welcome the much needed evidence from randomised controlled trials (RCTs) and agree with the Comment2 by Tom Treasure and colleagues that evidence is needed as a basis for treatment selection. Nevertheless, we believe that the evidence from these two trials should be placed in a balanced perspective and rated according to a reliable and internationally recognised grading system. For this purpose, we will e372
Correspondence
use the GRADE approach,3 a grading system used by over 80 organisations including WHO and the American College of Physicians. For the outcome of overall mortality, we assume a high quality of evidence because RCTs are thought to provide unbiased estimates of treatment effects. The STAR and ROSEL trials seem to be well designed and we see no reason to downgrade the quality of evidence because of a presumed risk of bias. However, since the two trials showed different results and since the pooled effect estimate is imprecise, we suggest downgrading the quality of the evidence by minus two points, to low quality. Additionally, in view of the small sample size, it is likely that the groups were not well balanced in terms of patient prognosis and that patients with an increased risk of mortality were by chance randomised to the surgery group, which might explain at least partly the excessive mortality in this groups. A mortality of 3·7% is very unusual for elective lobectomies and unacceptable by modern surgical standards, as confirmed by more recent references than the ones provided in the Discussion. In fact, 30day mortality figures for lobectomy in RCTs ranges between less than 1% and 1–1·5% even in patients with marginal pulmonary function.4 Another misleading factor might be the low rate of histologically verified tumours in the radiotherapy group, which is only as high as 27% in the ROSEL trial. Much larger trials are needed to achieve balanced treatment groups. In the analysis by Chang and colleagues, discrepancy exists between the p value shown in figure 2 (p=0·037) and the 95% CI (0·017–1·190) for the hazard ratio of 0·14, which does not imply a real statistically significant effect. Because of this, and because of falsenegative effects often detected in small trials, uncertainty surrounds the evidence from these two trials. e373
We suggest that the quality of evidence is very low and likely to change as new evidence becomes available. Finally, the authors refer to equal efficacy in the two treatment modalities. However, we would like to highlight that these trials were not designed as non-inferiority or equivalence trials. In summary, we believe that no conclusions can be made from these trials that will affect clinical practice of stage I lung cancer. However, the paper by Chang and colleagues serves the purpose of emphasising the need for larger RCTs. AB reports grants from Medela Healthcare, outside the submitted work. IO, GR, GV, GM, and WW declare no competing interests.
*Isabelle Opitz, Gaetano Rocco, Alessandro Brunelli, Gonzalo Varela, Gilbert Massard, Walter Weder, on behalf of the European Society of Thoracic Surgeons [email protected] Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland (IO and WW); Division of Thoracic Surgery, Istituto Nazionale Tumori, Fondazione Pascale, IRCCS, Naples, Italy (GR); Department of Thoracic Surgery, St. James’s University Hospital, Leeds, UK (AB); Cirugia Toracica, Hospital Universitario de Salamanca, Salamanca, Spain (GV); and Department of Thoracic Surgery, Centre Hospitalier, Strasbourg, France (GM) 1
2
3
4
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; 16: 630–37. Treasure T, Rintoul RC, Macbeth F. SABR in early operable lung cancer: time for evidence. Lancet Oncol 2015; 16: 597–98. Guyatt GH, Oxman AD, Schuneman HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol 2011; 64: 380–82. Taylor MD, LaPar DJ, Isbell JM, Kozower BD, Lau CL, Jones DR. Marginal pulmonary function should not preclude lobectomy in selected patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 2014; 147: 738–44.
The pooled analysis of two independent phase 3 trials by Joe Chang and colleagues1 has shown the potential to use stereotactic ablative radiotherapy (SABR) for operable stage I non-small-cell lung cancer.
Such an analysis was necessary because of the early closure of the studies analysed due to slow accrual. There are several recent examples showing the difficulties of performing traditional clinical trials with new health technologies.2 We therefore commend National Health Service (NHS) England for announcing an investment of £15 million to fund SABR to treat patients with oligometastases, hepatocellular carcinoma, and reirradiation of the pelvis or spine as a Commissioning through Evaluation (CtE) programme. This follows the progress of an ongoing CtE initiative to assess selective internal radiotherapy (SIRT) for patients with metastatic colorectal cancer and intrahepatic cholangiocarcinoma. The concept underpinning CtE is that patients should gain access to promising treatments and technologies that are not routinely commissioned. This innovative funding model allows rapid evaluation of new treatments in a so-called real-world setting to inform future commissioning,1 overseen by the National Institute for Health and Care Excellence and NHS England. Although similar concepts are being applied to accelerate licensing of drugs,3,4 CtE is the first hybrid fundingevaluation model to accelerate the adoption of emerging technologies. The CtE model has some advantages over traditional trial designs in situations in which it is difficult to run a randomised trial, or where CtE can assess feasibility of recruitment to inform future trial design. Relatively small numbers of patients might be required to address specific gaps in the evidence base. Recruitment is likely to be faster since there is no control or comparator group. The model also allows for highly specialist treatments to be developed safely with appropriate quality assurance at centres selected by NHS England to provide equity of access throughout the country. www.thelancet.com/oncology Vol 16 August 2015