Correspondence
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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
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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
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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
