Correspondence
We read with great interest the meta-analysis on adjuvant chemotherapy after preoperative (chemo) radiotherapy for patients with rectal cancer by Anne Breugom and colleagues.1 However, we are concerned that the methodology has some shortcomings and that the conclusions of the meta-analysis may not be entirely justified. The primary endpoint of the analysis was overall survival, which is understandable because all four studies included in the meta-analysis provided data for this endpoint. However, in all modern studies of adjuvant treatment of colorectal cancer, disease-free survival is regarded as a more suitable primary endpoint because overall survival is heavily affected by subsequent treatments and a relatively long follow-up is needed to observe an effect of new treatment strategies.2,3 The authors should also explain in more detail why so many patients were excluded from the metaanalysis (eg, 398 of 634 were excluded in the I-CNR-RT trial,4 and 538 of 1011 patients were excluded in the EORTC 22921 trial5) because this might have caused significant selection bias. On this basis, it is unclear whether the authors did a per-protocol analysis or an intentionto-treat analysis. Why patients with ypTNM0 and ypTNM1 disease were excluded is another question, since these patients were included in the two largest trials in the meta-analysis and possibly benefit from adjuvant treatment the most.6 Around a third of the patients included in the meta-analysis are derived from an analysis of the prematurely terminated PROCTORSCRIPT study.7 In this study, randomisation was done after surgery, with the inherent potential bias of surgeons allocating low-risk patients to the study but selecting high-risk patients for chemotherapy outside of the trial. Whether patients receiving nonstandard treatment (45 Gy without www.thelancet.com/oncology Vol 16 April 2015
concurrent chemotherapy) should be included in the analysis is also highly debatable. If this group of patients were omitted, there certainly does seem to be an effect of adjuvant chemotherapy on disease-free survival. Calculation of the hazard ratio for disease-free survival from the published 95% CI of the five doses of 5 Gy and the radio(chemo)therapy pretreated groups gives a hazard ratio of 0·85 (95% CI 0·70–1·03).8 The conclusion of the meta-analysis is that fluorouracil-based chemotherapy does not improve disease-free survival or overall survival. However, as also referred to by the authors, results of both the ADORE trial9 and the CAO/ARO/AIO-04 trial10 trials showed a significant advantage of combined fluorouracil and oxaliplatinbased adjuvant chemotherapy disease-free survival, compared with fluorouracil alone. The authors argue that because neither of these two trials have an observational group, whether adjuvant combination therapy provides a benefit remains unknown. Formally, this might be correct, but the ADORE and CAO/ARO/AIO-04 studies suggest otherwise. Moreover, findings of an exploratory phase 3 trial analysis11 showed that perioperative capecitabine was associated with better disease-free survival than was bolus fluorouracil, which was the standard treatment for the overwhelming majority of patients included in this meta-analysis. This casts severe doubts on whether the conclusion of the meta-analysis by Breugom and colleagues, which is based preferably on suboptimum fluorouracil regimens, are appropriate. Finally, as the authors correctly pointed out, only about half of the patients, at best, actually received the full dose of adjuvant chemotherapy. Taking into account that individual patient data were available for the analysis, it seems remarkable that no analysis on the effect of adherence to chemotherapy and of dose intensity on outcomes was done, especially in view
of the suboptimum bolus fluorouracil regimens used in the majority of patients. It would have been interesting to see how patients who received all or at least a substantial number of scheduled cycles compared to the remainder. CR declares grants and personal fees from Roche and Sanofi-Aventis and grants from Merck-KGaA. R-DH, IB, and PK declare no competing interests.
Ralf-Dieter Hofheinz, Claus Rödel, Iris Burkholder, *Peter Kienle Interdisziplinäres Tumorzentrum, Universitätsmedizin Mannheim, Universität Heidelberg, Germany (R-DH, PK); Klinik für Strahlentherapie, Universitätsklinikum Frankfurt, Johann-Wolfgang Goethe Universität Frankfurt, Germany (CR); and Hochschule für Technik und Wirtschaft des Saarlandes, Saarbrücken, Germany (IB) 1
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4
5
6
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8
Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015; 16: 200–07. Sargent DJ, Patiyil S, Yothers G, et al. End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 2007; 25: 4569–74. Sargent D, Shi Q, Yothers G, et al. Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803. Eur J Cancer 2011; 47: 990–96. Sainato A, Cernusco LNV, Valentini V, et al. No benefit of adjuvant fluorouracil leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): long term results of a randomized trial (I-CNR-RT). Radiother Oncol 2014; 113: 223–29. Bosset JF, Calais G, Mineur L, et al. Fluorouracilbased adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014; 15: 184–90. Maas M, Nelemans PJ, Valentini V, et al. Adjuvant chemotherapy in rectal cancer: Defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients. Int J Cancer 2014; published online Nov 22. DOI:10.1002/ ijc.29355. Breugom AJ, van den Broek CBM, van Gijn W, et al. The value of adjuvant chemotherapy in rectal cancer patients after preoperative radiotherapy or chemoradiation followed by TME-surgery: the PROCTOR/SCRIPT study. Eur J Cancer 2013; 49 (suppl 3): S1. Parmar M, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statist Med 1998; 17: 2815–34.
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Hong YS, Nam BH, Kim KP, et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol 2014; 15: 1245–53. Rödel C, Liersch T, Fietkau R, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: results of the German CAO/ARO/AIO-04 randomized phase III trial. Proc Am Soc Clin Oncol 2014; 32 (suppl): 3500 (abstr). Hofheinz RD, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012; 13: 579–88.
Authors’ reply We thank the various correspondents for their interest in our systematic review and meta-analysis of studies of adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer.1 Bujko proposed an interesting hypothesis to explain the absence of an effect of adjuvant chemotherapy after preoperative (chemo) radiotherapy and surgery for patients with rectal cancer: that enhanced toxicity of chemotherapy by previous radiation causes an increased rate of non-cancer deaths, especially in elderly patients. To examine this, we compared the effect of adjuvant chemotherapy on overall survival in relation to age, with age categories based on quartiles. The hazard ratio for overall survival when receiving adjuvant chemotherapy was 1·25 (95% CI 0·81–1·93, p=0·313) in patients younger than 55 years, 0·79 (95% CI 0·52–1·22; p=0·293) in patients aged 55–60 years, 1·12 (95% CI 0·83–1·51, p=0·477) in patients aged 61–69 years, and 0·68 (95% CI 0·46–1·00, p=0·049) in patients 70 years or older (pinteraction=0·165). The improved overall survival in patients aged 70 years or older treated with adjuvant chemotherapy contradicts Bujko’s hypothesis, although we think this association is probably the e155
result of selection rather than a real effect of adjuvant chemotherapy. Unfortunately, we were not able to analyse the cumulative incidence of non-cancer deaths, with cancer death as a competing risk, because we did not have information on cause of death. Hofheinz and colleagues are right that disease-free survival is an excellent surrogate of overall survival. However, overall survival was the primary endpoint of all trials included in the meta-analysis, with a combined median follow-up of 7·0 years. As suggested by Hofheinz and colleagues, we omitted patients who received preoperative longcourse radiotherapy and compared the effect of adjuvant chemotherapy on overall survival and disease-free survival. The hazard ratio for overall survival was 1·00 (95% CI 0·79–1·25, p=0·966). In subgroup analyses, we recorded no significant differences in overall survival. For disease-free survival, the hazard ratio was 0·86 (95% CI 0·71–1·04, p=0·117). In subgroup analyses, patients with a tumour between 10–15 cm from the anal verge who received adjuvant chemotherapy had improved diseasefree survival (hazard ratio 0·50, 95% CI 0·33–0·76, p=0·001). We agree with Petrelli and colleagues, You and colleagues, and Hofheinz and colleagues that compliance with adjuvant chemotherapy was relatively low. In general, trials include fit patients without clinically significant comorbidity. We are concerned that the suggestion to assess the effect of adjuvant chemotherapy in patients who completed all cycles of adjuvant chemotherapy will not be of clinical value and that outcome of such an analysis will have no or restricted clinical implications. Even with patients eligible for participation in trials and who are thus deemed fit enough for adjuvant chemotherapy, compliance was between 43% and 73%.1 This relatively low compliance
shows the difficulty in selecting patients who will complete all adjuvant chemotherapy cycles. The limitations that Petrelli and colleagues and Hofheinz and colleagues highlight are related to study design and eligibility criteria of the individual trials. However, sensitivity analysis of all 2195 patients included in the individual trials showed that adjuvant chemotherapy provided no significant benefit in overall survival compared with observation. Indeed, it would be interesting to investigate the effect of adjuvant chemotherapy in patients with ypT0–2N0M0 rectal cancer. We do not think that definitive conclusions can be based on the meta-analyses2,3 of mostly retrospective studies; bias due to confounding by indication cannot be excluded. However, we do agree with Petrelli and colleagues that intensified preoperative therapy is a promising treatment strategy. Randomised trials with preoperative systemic therapy, such as the RAPIDO trial,4 are in progress, and these results are awaited. We declare no competing interests.
Anne J Breugom, Marloes Swets, *Cornelis J H van de Velde [email protected] Leiden University Medical Centre, Department of Surgery, 2300 RC Leiden, The Netherlands 1
2
3
4
Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo) radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015; 16: 200–07. Petrelli F, Coinu A, Lonati V, Barni S. A systematic review and meta-analysis of adjuvant chemotherapy after neoadjuvant treatment and surgery for rectal cancer. Int J Colorectal Dis 2014; published online Nov 30. DOI:10.1007/s00384-014-2082-9. Maas M, Nelemans PJ, Valentini V, et al. Adjuvant chemotherapy in rectal cancer: Defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients. Int J Cancer 2014; published online Nov 22. DOI:10.1002/ ijc.29355. Nilsson PJ, van Etten B, Hospers GA, et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial. BMC Cancer 2013; 13: 279.
www.thelancet.com/oncology Vol 16 April 2015
We read with great interest the meta-analysis on adjuvant chemotherapy after preoperative (chemo) radiotherapy for patients with rectal cancer by Anne Breugom and colleagues.1 However, we are concerned that the methodology has some shortcomings and that the conclusions of the meta-analysis may not be entirely justified. The primary endpoint of the analysis was overall survival, which is understandable because all four studies included in the meta-analysis provided data for this endpoint. However, in all modern studies of adjuvant treatment of colorectal cancer, disease-free survival is regarded as a more suitable primary endpoint because overall survival is heavily affected by subsequent treatments and a relatively long follow-up is needed to observe an effect of new treatment strategies.2,3 The authors should also explain in more detail why so many patients were excluded from the metaanalysis (eg, 398 of 634 were excluded in the I-CNR-RT trial,4 and 538 of 1011 patients were excluded in the EORTC 22921 trial5) because this might have caused significant selection bias. On this basis, it is unclear whether the authors did a per-protocol analysis or an intentionto-treat analysis. Why patients with ypTNM0 and ypTNM1 disease were excluded is another question, since these patients were included in the two largest trials in the meta-analysis and possibly benefit from adjuvant treatment the most.6 Around a third of the patients included in the meta-analysis are derived from an analysis of the prematurely terminated PROCTORSCRIPT study.7 In this study, randomisation was done after surgery, with the inherent potential bias of surgeons allocating low-risk patients to the study but selecting high-risk patients for chemotherapy outside of the trial. Whether patients receiving nonstandard treatment (45 Gy without www.thelancet.com/oncology Vol 16 April 2015
concurrent chemotherapy) should be included in the analysis is also highly debatable. If this group of patients were omitted, there certainly does seem to be an effect of adjuvant chemotherapy on disease-free survival. Calculation of the hazard ratio for disease-free survival from the published 95% CI of the five doses of 5 Gy and the radio(chemo)therapy pretreated groups gives a hazard ratio of 0·85 (95% CI 0·70–1·03).8 The conclusion of the meta-analysis is that fluorouracil-based chemotherapy does not improve disease-free survival or overall survival. However, as also referred to by the authors, results of both the ADORE trial9 and the CAO/ARO/AIO-04 trial10 trials showed a significant advantage of combined fluorouracil and oxaliplatinbased adjuvant chemotherapy disease-free survival, compared with fluorouracil alone. The authors argue that because neither of these two trials have an observational group, whether adjuvant combination therapy provides a benefit remains unknown. Formally, this might be correct, but the ADORE and CAO/ARO/AIO-04 studies suggest otherwise. Moreover, findings of an exploratory phase 3 trial analysis11 showed that perioperative capecitabine was associated with better disease-free survival than was bolus fluorouracil, which was the standard treatment for the overwhelming majority of patients included in this meta-analysis. This casts severe doubts on whether the conclusion of the meta-analysis by Breugom and colleagues, which is based preferably on suboptimum fluorouracil regimens, are appropriate. Finally, as the authors correctly pointed out, only about half of the patients, at best, actually received the full dose of adjuvant chemotherapy. Taking into account that individual patient data were available for the analysis, it seems remarkable that no analysis on the effect of adherence to chemotherapy and of dose intensity on outcomes was done, especially in view
of the suboptimum bolus fluorouracil regimens used in the majority of patients. It would have been interesting to see how patients who received all or at least a substantial number of scheduled cycles compared to the remainder. CR declares grants and personal fees from Roche and Sanofi-Aventis and grants from Merck-KGaA. R-DH, IB, and PK declare no competing interests.
Ralf-Dieter Hofheinz, Claus Rödel, Iris Burkholder, *Peter Kienle Interdisziplinäres Tumorzentrum, Universitätsmedizin Mannheim, Universität Heidelberg, Germany (R-DH, PK); Klinik für Strahlentherapie, Universitätsklinikum Frankfurt, Johann-Wolfgang Goethe Universität Frankfurt, Germany (CR); and Hochschule für Technik und Wirtschaft des Saarlandes, Saarbrücken, Germany (IB) 1
2
3
4
5
6
7
8
Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015; 16: 200–07. Sargent DJ, Patiyil S, Yothers G, et al. End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 2007; 25: 4569–74. Sargent D, Shi Q, Yothers G, et al. Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803. Eur J Cancer 2011; 47: 990–96. Sainato A, Cernusco LNV, Valentini V, et al. No benefit of adjuvant fluorouracil leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): long term results of a randomized trial (I-CNR-RT). Radiother Oncol 2014; 113: 223–29. Bosset JF, Calais G, Mineur L, et al. Fluorouracilbased adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014; 15: 184–90. Maas M, Nelemans PJ, Valentini V, et al. Adjuvant chemotherapy in rectal cancer: Defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients. Int J Cancer 2014; published online Nov 22. DOI:10.1002/ ijc.29355. Breugom AJ, van den Broek CBM, van Gijn W, et al. The value of adjuvant chemotherapy in rectal cancer patients after preoperative radiotherapy or chemoradiation followed by TME-surgery: the PROCTOR/SCRIPT study. Eur J Cancer 2013; 49 (suppl 3): S1. Parmar M, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statist Med 1998; 17: 2815–34.
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Hong YS, Nam BH, Kim KP, et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol 2014; 15: 1245–53. Rödel C, Liersch T, Fietkau R, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: results of the German CAO/ARO/AIO-04 randomized phase III trial. Proc Am Soc Clin Oncol 2014; 32 (suppl): 3500 (abstr). Hofheinz RD, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012; 13: 579–88.
Authors’ reply We thank the various correspondents for their interest in our systematic review and meta-analysis of studies of adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer.1 Bujko proposed an interesting hypothesis to explain the absence of an effect of adjuvant chemotherapy after preoperative (chemo) radiotherapy and surgery for patients with rectal cancer: that enhanced toxicity of chemotherapy by previous radiation causes an increased rate of non-cancer deaths, especially in elderly patients. To examine this, we compared the effect of adjuvant chemotherapy on overall survival in relation to age, with age categories based on quartiles. The hazard ratio for overall survival when receiving adjuvant chemotherapy was 1·25 (95% CI 0·81–1·93, p=0·313) in patients younger than 55 years, 0·79 (95% CI 0·52–1·22; p=0·293) in patients aged 55–60 years, 1·12 (95% CI 0·83–1·51, p=0·477) in patients aged 61–69 years, and 0·68 (95% CI 0·46–1·00, p=0·049) in patients 70 years or older (pinteraction=0·165). The improved overall survival in patients aged 70 years or older treated with adjuvant chemotherapy contradicts Bujko’s hypothesis, although we think this association is probably the e155
result of selection rather than a real effect of adjuvant chemotherapy. Unfortunately, we were not able to analyse the cumulative incidence of non-cancer deaths, with cancer death as a competing risk, because we did not have information on cause of death. Hofheinz and colleagues are right that disease-free survival is an excellent surrogate of overall survival. However, overall survival was the primary endpoint of all trials included in the meta-analysis, with a combined median follow-up of 7·0 years. As suggested by Hofheinz and colleagues, we omitted patients who received preoperative longcourse radiotherapy and compared the effect of adjuvant chemotherapy on overall survival and disease-free survival. The hazard ratio for overall survival was 1·00 (95% CI 0·79–1·25, p=0·966). In subgroup analyses, we recorded no significant differences in overall survival. For disease-free survival, the hazard ratio was 0·86 (95% CI 0·71–1·04, p=0·117). In subgroup analyses, patients with a tumour between 10–15 cm from the anal verge who received adjuvant chemotherapy had improved diseasefree survival (hazard ratio 0·50, 95% CI 0·33–0·76, p=0·001). We agree with Petrelli and colleagues, You and colleagues, and Hofheinz and colleagues that compliance with adjuvant chemotherapy was relatively low. In general, trials include fit patients without clinically significant comorbidity. We are concerned that the suggestion to assess the effect of adjuvant chemotherapy in patients who completed all cycles of adjuvant chemotherapy will not be of clinical value and that outcome of such an analysis will have no or restricted clinical implications. Even with patients eligible for participation in trials and who are thus deemed fit enough for adjuvant chemotherapy, compliance was between 43% and 73%.1 This relatively low compliance
shows the difficulty in selecting patients who will complete all adjuvant chemotherapy cycles. The limitations that Petrelli and colleagues and Hofheinz and colleagues highlight are related to study design and eligibility criteria of the individual trials. However, sensitivity analysis of all 2195 patients included in the individual trials showed that adjuvant chemotherapy provided no significant benefit in overall survival compared with observation. Indeed, it would be interesting to investigate the effect of adjuvant chemotherapy in patients with ypT0–2N0M0 rectal cancer. We do not think that definitive conclusions can be based on the meta-analyses2,3 of mostly retrospective studies; bias due to confounding by indication cannot be excluded. However, we do agree with Petrelli and colleagues that intensified preoperative therapy is a promising treatment strategy. Randomised trials with preoperative systemic therapy, such as the RAPIDO trial,4 are in progress, and these results are awaited. We declare no competing interests.
Anne J Breugom, Marloes Swets, *Cornelis J H van de Velde [email protected] Leiden University Medical Centre, Department of Surgery, 2300 RC Leiden, The Netherlands 1
2
3
4
Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy after preoperative (chemo) radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015; 16: 200–07. Petrelli F, Coinu A, Lonati V, Barni S. A systematic review and meta-analysis of adjuvant chemotherapy after neoadjuvant treatment and surgery for rectal cancer. Int J Colorectal Dis 2014; published online Nov 30. DOI:10.1007/s00384-014-2082-9. Maas M, Nelemans PJ, Valentini V, et al. Adjuvant chemotherapy in rectal cancer: Defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients. Int J Cancer 2014; published online Nov 22. DOI:10.1002/ ijc.29355. Nilsson PJ, van Etten B, Hospers GA, et al. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial. BMC Cancer 2013; 13: 279.
www.thelancet.com/oncology Vol 16 April 2015
