Correspondence
Adjuvant chemotherapy for rectal cancer The current standard of care for locally advanced rectal cancer is preoperative chemoradiation followed by radical resection. Irrespective of the final pathology, a full course of adjuvant chemotherapy is recommended. However, there is insufficient evidence to lend support to this strategy. Findings from a randomised trial exploring the benefit of chemotherapy given preoperatively or postoperatively for patients with rectal cancer receiving preoperative radiotherapy showed that postoperative adjuvant chemotherapy did not improve overall survival or diseasefree survival (DFS).1 The updated results of this trial2 confirm that, even after 10·4 years of follow-up, no improved oncological outcomes were seen in patients receiving adjuvant chemotherapy compared with those who did not. Is adjuvant chemotherapy therefore not beneficial for patients with locally advanced rectal cancer after preoperative chemoradiation? We believe further investigation is needed. We suggest that Bosset and colleagues do a subgroup analysis based on patients’ pathological N stage—a prognostic factor for patients with rectal cancer who received preoperative chemoradiation—even though their subgroup analysis based on ypT stage was negative. As for the management of patients with early stage rectal cancer (pT1–2N0), it might be that no further adjuvant treatment is needed after surgery because their prognosis is good. Similarly, the findings of a previous study showed that patients with rectal cancer with ypT0–2N0 after chemoradiation and surgery had a favourable outcome, especially those with ypT0N0 disease, who had a 5-year overall survival of about 93%.3 Results of retrospective studies suggest no benefit of adjuvant chemotherapy www.thelancet.com/oncology Vol 15 May 2014
for patients with ypN0 rectal cancer, especially for those with ypT0–2N0 disease.4,5 But what about patients with ypN+ or ypT3–4N0 disease? This subgroup showed poor response to preoperative chemoradiation.3–5 Whether they would benefit from adjuvant chemotherapy is unknown, although, in Bosset and colleagues’ trial, distant metastases were a major cause of death in patients with rectal cancer treated with preoperative chemoradiation, and systemic therapy is the main means to eradicate subclinical tumour micrometastases.2 A prospective study to compare outcomes with and without adjuvant chemotherapy for patients with ypN0 disease is needed. And for patients with ypN+ disease, further investigation is needed to establish the best practice for management of adjuvant treatment. We declare that we have no conflicts of interest.
KaiYun You, Rong Huang, YuanHong Gao* [email protected] Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China (KY, RH, YG) 1
2
3
4
5
Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355: 1114–23. 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. Park IJ, You YN, Agarwal A, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 2012; 30: 1770–76. Kiran RP, Kirat HT, Burgess AN, et al. Is adjuvant chemotherapy really needed after curative surgery for rectal cancer patients who are nodenegative after neoadjuvant chemoradiotherapy? Ann Surg Oncol 2012; 19: 1206–12. Govindarajan A, Reidy D, Weiser MR, et al. Recurrence rates and prognostic factors in ypN0 rectal cancer after neoadjuvant chemoradiation and total mesorectal excision. Ann Surg Oncol 2011; 18: 3666–72.
In The Lancet Oncology, Jean-François Bosset and colleagues1 presented an update of the EORTC 22921 randomised study that showed
no long-term benefit of adjuvant chemotherapy in patients with rectal cancer who had already received preoperative radiotherapy or chemoradiotherapy. In an unplanned analysis in their previous publication,2 which had a shorter follow-up (5·2 years), the researchers showed a survival benefit after adjuvant chemotherapy for those patients who were downstaged after preoperative radiotherapy to ypT0–2 disease or who had tumours located higher than 5 cm from the anal verge. No benefit was noted for patients with tumours not downstaged or those with low-lying tumours.2 The benefit previously shown for ypT0–2 disease was not sustained with longer followup (hazard ratio [HR] for overall survival 0·98, 95% CI 0·81–1·20; test for heterogeneity p=0·41).1 Unfortunately, the subgroup analysis comparing benefit of chemotherapy in relation to the location of the tumour within the rectum was not repeated; we ask the authors to provide these results. Of course, unplanned analyses of subgroups of patients can be used only to generate hypotheses. To be clinically applicable, results need to be validated. Findings from a Swedish population-based study3 suggest that for patients receiving neoadjuvant radiotherapy, adjuvant chemotherapy works for tumours located in the intraperitoneal rectum but not for those located in the extraperitoneal rectum.3 This study included 436 patients with stage III rectal cancer who were younger than 75 years. Most patients received preoperative short-course radiotherapy. Adjuvant chemotherapy with mainly fluorouracil and leucovorin was given to 185 (42%) of 436 patients. The investigators noted a statistically significant overall survival benefit for patients with high rectal cancer (HR 0·54, 95% CI 0·3–0·9; p
Adjuvant chemotherapy for rectal cancer The current standard of care for locally advanced rectal cancer is preoperative chemoradiation followed by radical resection. Irrespective of the final pathology, a full course of adjuvant chemotherapy is recommended. However, there is insufficient evidence to lend support to this strategy. Findings from a randomised trial exploring the benefit of chemotherapy given preoperatively or postoperatively for patients with rectal cancer receiving preoperative radiotherapy showed that postoperative adjuvant chemotherapy did not improve overall survival or diseasefree survival (DFS).1 The updated results of this trial2 confirm that, even after 10·4 years of follow-up, no improved oncological outcomes were seen in patients receiving adjuvant chemotherapy compared with those who did not. Is adjuvant chemotherapy therefore not beneficial for patients with locally advanced rectal cancer after preoperative chemoradiation? We believe further investigation is needed. We suggest that Bosset and colleagues do a subgroup analysis based on patients’ pathological N stage—a prognostic factor for patients with rectal cancer who received preoperative chemoradiation—even though their subgroup analysis based on ypT stage was negative. As for the management of patients with early stage rectal cancer (pT1–2N0), it might be that no further adjuvant treatment is needed after surgery because their prognosis is good. Similarly, the findings of a previous study showed that patients with rectal cancer with ypT0–2N0 after chemoradiation and surgery had a favourable outcome, especially those with ypT0N0 disease, who had a 5-year overall survival of about 93%.3 Results of retrospective studies suggest no benefit of adjuvant chemotherapy www.thelancet.com/oncology Vol 15 May 2014
for patients with ypN0 rectal cancer, especially for those with ypT0–2N0 disease.4,5 But what about patients with ypN+ or ypT3–4N0 disease? This subgroup showed poor response to preoperative chemoradiation.3–5 Whether they would benefit from adjuvant chemotherapy is unknown, although, in Bosset and colleagues’ trial, distant metastases were a major cause of death in patients with rectal cancer treated with preoperative chemoradiation, and systemic therapy is the main means to eradicate subclinical tumour micrometastases.2 A prospective study to compare outcomes with and without adjuvant chemotherapy for patients with ypN0 disease is needed. And for patients with ypN+ disease, further investigation is needed to establish the best practice for management of adjuvant treatment. We declare that we have no conflicts of interest.
KaiYun You, Rong Huang, YuanHong Gao* [email protected] Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China (KY, RH, YG) 1
2
3
4
5
Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355: 1114–23. 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. Park IJ, You YN, Agarwal A, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 2012; 30: 1770–76. Kiran RP, Kirat HT, Burgess AN, et al. Is adjuvant chemotherapy really needed after curative surgery for rectal cancer patients who are nodenegative after neoadjuvant chemoradiotherapy? Ann Surg Oncol 2012; 19: 1206–12. Govindarajan A, Reidy D, Weiser MR, et al. Recurrence rates and prognostic factors in ypN0 rectal cancer after neoadjuvant chemoradiation and total mesorectal excision. Ann Surg Oncol 2011; 18: 3666–72.
In The Lancet Oncology, Jean-François Bosset and colleagues1 presented an update of the EORTC 22921 randomised study that showed
no long-term benefit of adjuvant chemotherapy in patients with rectal cancer who had already received preoperative radiotherapy or chemoradiotherapy. In an unplanned analysis in their previous publication,2 which had a shorter follow-up (5·2 years), the researchers showed a survival benefit after adjuvant chemotherapy for those patients who were downstaged after preoperative radiotherapy to ypT0–2 disease or who had tumours located higher than 5 cm from the anal verge. No benefit was noted for patients with tumours not downstaged or those with low-lying tumours.2 The benefit previously shown for ypT0–2 disease was not sustained with longer followup (hazard ratio [HR] for overall survival 0·98, 95% CI 0·81–1·20; test for heterogeneity p=0·41).1 Unfortunately, the subgroup analysis comparing benefit of chemotherapy in relation to the location of the tumour within the rectum was not repeated; we ask the authors to provide these results. Of course, unplanned analyses of subgroups of patients can be used only to generate hypotheses. To be clinically applicable, results need to be validated. Findings from a Swedish population-based study3 suggest that for patients receiving neoadjuvant radiotherapy, adjuvant chemotherapy works for tumours located in the intraperitoneal rectum but not for those located in the extraperitoneal rectum.3 This study included 436 patients with stage III rectal cancer who were younger than 75 years. Most patients received preoperative short-course radiotherapy. Adjuvant chemotherapy with mainly fluorouracil and leucovorin was given to 185 (42%) of 436 patients. The investigators noted a statistically significant overall survival benefit for patients with high rectal cancer (HR 0·54, 95% CI 0·3–0·9; p
