Correspondence
With these data in mind, the results of the meta-analysis by Breugom and colleagues1 need to be discussed. First, the patients included were not, or were only minimally, downstaged by fluorouracil-based (chemo)radiotherapy and so are representative of patients with more chemoresistant rectal cancers that might not benefit from adjuvant chemotherapy with the same drugs. Second, most patients underwent adjuvant bolus infusion fluorouracil therapy, a more toxic and less efficacious way of administration compared with continuous infusion. Third, compliance of postoperative treatment in the four trials was unsatisfactory. Only 48–73% of patients allocated to adjuvant chemotherapy arms received the complete or nearcomplete treatment programme. The choice of adjuvant therapy will continue to be dictated by clinical and perhaps pathological criteria (eg, site of rectal tumour), and the opportunity to offer more cycles of adjuvant or more intensified neoadjuvant therapy should still be kept in mind. The management of patients with pathological complete response remains a challenge because these tumours, even if they could be considered cured, still have a residual risk of relapse, depending on the initial clinical stage.6 In clinical practice, data translated from colon cancer trials and included in international guidelines suggest an overall duration of perioperative therapy of about 6 months.7 Systemic therapy after 5 weeks of fluorouracil-based neoadjuvant (chemo)radiotherapy is therefore an appealing option and advisable for fit patients with rectal cancer that responds to neoadjuvant treatment. Finally, we believe that for those patients with locally advanced (clinical stage III) disease who are at least partially downstaged, the addition of further cycles of fluorouracil-based chemotherapy after neoadjuvant (chemo)radiotherapy should be considered. e153
We declare no competing interests.
*Fausto Petrelli, Andrea Coinu, Sandro Barni [email protected] Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, 24047 Treviglio (BG), Italy 1
2
3
4
5
6
7
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 metaanalysis of individual patient data. Lancet Oncol 2015; 16: 200–07. Petrelli F, Coinu A, Lonati V, et al. 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. Collette L, Bosset JF, den Dulk M, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 2007; 25: 4379–86. Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014; 15: 184–90. Capirci C, Valentini V, Cionini L, et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 2008; 72: 99–107. National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Rectal cancer. http://www.nccn.org/professionals/ physician_gls/pdf/rectal.pdf (accessed Jan 29, 2015).
In their meta-analysis of individual patient data, Anne Breugom and colleagues1 show that there is no survival benefit of adjuvant chemotherapy in patients with rectal cancer treated with preoperative (chemo) radiotherapy. However, results of a Cochrane meta-analysis2 of randomised studies showed that a survival benefit exists after adjuvant chemotherapy in patients with rectal cancer treated without preoperative irradiation. Why, then, does adjuvant chemotherapy beneficially affect patients not
treated with preoperative irradiation, compared with patients who are? Adherence to postoperative chemotherapy has been shown to be lower in patients with rectal cancer treated with preoperative (chemo)radiotherapy3 compared with patients undergoing surgery alone.4 This difference might be at least partially explained by the post-radiation late damage to pelvic bone marrow and bowel, which could increase chemotherapyinduced toxicity. One can postulate that the putatively worse toxicity of chemotherapy by previous pelvic irradiation causes an increased rate of non-cancer deaths, especially for elderly patients—ie, adjuvant chemotherapy might take lives and save lives equally, with zero overall effect. I would thus suggest that Breugom and colleagues1 perform an additional subgroup analysis that can test this hypothesis; namely to assess the effect of chemotherapy on overall survival in relation to age, and to compare the cumulative incidence of non-cancer deaths between the chemotherapy and observational groups, with cancer death as a competing risk. I declare no competing interests.
Krzysztof Bujko [email protected] Department of Radiotherapy, Maria SklodowskaCurie Memorial Cancer Centre, Warsaw 02-781, Poland 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. Petersen SH, Harling H, Kirkeby LT, Wille-Jorgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 2012; 3: CD004078. Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014; 15: 184–90. Akasu T, Moriya Y, Ohashi Y, Yoshida S, Shirao K, Kodaira S. Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after mesorectal excision with selective lateral pelvic lymphadenectomy: a multicenter randomized controlled trial. Jpn J Clin Oncol 2006; 36: 237–44.
www.thelancet.com/oncology Vol 16 April 2015
With these data in mind, the results of the meta-analysis by Breugom and colleagues1 need to be discussed. First, the patients included were not, or were only minimally, downstaged by fluorouracil-based (chemo)radiotherapy and so are representative of patients with more chemoresistant rectal cancers that might not benefit from adjuvant chemotherapy with the same drugs. Second, most patients underwent adjuvant bolus infusion fluorouracil therapy, a more toxic and less efficacious way of administration compared with continuous infusion. Third, compliance of postoperative treatment in the four trials was unsatisfactory. Only 48–73% of patients allocated to adjuvant chemotherapy arms received the complete or nearcomplete treatment programme. The choice of adjuvant therapy will continue to be dictated by clinical and perhaps pathological criteria (eg, site of rectal tumour), and the opportunity to offer more cycles of adjuvant or more intensified neoadjuvant therapy should still be kept in mind. The management of patients with pathological complete response remains a challenge because these tumours, even if they could be considered cured, still have a residual risk of relapse, depending on the initial clinical stage.6 In clinical practice, data translated from colon cancer trials and included in international guidelines suggest an overall duration of perioperative therapy of about 6 months.7 Systemic therapy after 5 weeks of fluorouracil-based neoadjuvant (chemo)radiotherapy is therefore an appealing option and advisable for fit patients with rectal cancer that responds to neoadjuvant treatment. Finally, we believe that for those patients with locally advanced (clinical stage III) disease who are at least partially downstaged, the addition of further cycles of fluorouracil-based chemotherapy after neoadjuvant (chemo)radiotherapy should be considered. e153
We declare no competing interests.
*Fausto Petrelli, Andrea Coinu, Sandro Barni [email protected] Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, 24047 Treviglio (BG), Italy 1
2
3
4
5
6
7
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 metaanalysis of individual patient data. Lancet Oncol 2015; 16: 200–07. Petrelli F, Coinu A, Lonati V, et al. 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. Collette L, Bosset JF, den Dulk M, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol 2007; 25: 4379–86. Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014; 15: 184–90. Capirci C, Valentini V, Cionini L, et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 2008; 72: 99–107. National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Rectal cancer. http://www.nccn.org/professionals/ physician_gls/pdf/rectal.pdf (accessed Jan 29, 2015).
In their meta-analysis of individual patient data, Anne Breugom and colleagues1 show that there is no survival benefit of adjuvant chemotherapy in patients with rectal cancer treated with preoperative (chemo) radiotherapy. However, results of a Cochrane meta-analysis2 of randomised studies showed that a survival benefit exists after adjuvant chemotherapy in patients with rectal cancer treated without preoperative irradiation. Why, then, does adjuvant chemotherapy beneficially affect patients not
treated with preoperative irradiation, compared with patients who are? Adherence to postoperative chemotherapy has been shown to be lower in patients with rectal cancer treated with preoperative (chemo)radiotherapy3 compared with patients undergoing surgery alone.4 This difference might be at least partially explained by the post-radiation late damage to pelvic bone marrow and bowel, which could increase chemotherapyinduced toxicity. One can postulate that the putatively worse toxicity of chemotherapy by previous pelvic irradiation causes an increased rate of non-cancer deaths, especially for elderly patients—ie, adjuvant chemotherapy might take lives and save lives equally, with zero overall effect. I would thus suggest that Breugom and colleagues1 perform an additional subgroup analysis that can test this hypothesis; namely to assess the effect of chemotherapy on overall survival in relation to age, and to compare the cumulative incidence of non-cancer deaths between the chemotherapy and observational groups, with cancer death as a competing risk. I declare no competing interests.
Krzysztof Bujko [email protected] Department of Radiotherapy, Maria SklodowskaCurie Memorial Cancer Centre, Warsaw 02-781, Poland 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. Petersen SH, Harling H, Kirkeby LT, Wille-Jorgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev 2012; 3: CD004078. Bosset JF, Calais G, Mineur L, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014; 15: 184–90. Akasu T, Moriya Y, Ohashi Y, Yoshida S, Shirao K, Kodaira S. Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after mesorectal excision with selective lateral pelvic lymphadenectomy: a multicenter randomized controlled trial. Jpn J Clin Oncol 2006; 36: 237–44.
www.thelancet.com/oncology Vol 16 April 2015
