- Email: [email protected]
Adjuvant chemotherapy for rectal cancer – Authors' reply
Correspondence
Authors’ reply
See Online for appendix
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We read with great interest the correspondence generated by our Article.1 We thank the authors for their interest in our study and for the relevant questions that they raise. You and colleagues2 asked for a subgroup analysis by pathological T and N stage. For this analysis, we considered the subgroup of patients with R0 resection and no distant spread detected at surgery, which we used in the analysis shown in figure 4 of our Article. We now further split the patient groups by pN+ versus pN0, resulting in three groups: ypT0–2N0, ypT3–4N0, and ypN+. The forest plots in the appendix show the effect of adjuvant chemotherapy on diseasefree and overall survival from date of surgery in each of the three subgroups and by preoperative treatment. We note no statistically significant heterogeneity of the effect of adjuvant treatment according to this grouping. Within the pN+ subgroup, the adjuvant treatment hazard ratio for survival from surgery points in opposite directions for patients who had preoperative radiotherapy (hazard ratio 0·76, 95% CI 0·48– 1·19) compared with the effect in patients who had preoperative radiotherapy and chemotherapy (1·19, 95% CI 0·69–2·04), but neither of these effects are significant, nor are they different from one another (heterogeneity p=0·21). Bujko and Glimelius3 requested that we repeat the analysis of outcome after surgery according to tumour localisation, as presented in a previous study of ours.4 We provide the update of that analysis for progression-free and overall survival in the appendix. The data again suggest no significant heterogeneity of the effect according to the tumour localisation relative to the anal verge. Valsecchi5 requested an analysis by dose intensity of adjuvant chemotherapy effectively received, noting that such an analysis would lack statistical power. We are concerned
that this kind of analysis is inherently biased: the factors that explain why a patient could not receive the full dose of chemotherapy might also be prognostic factors for a worse outcome (be it overall or diseasefree survival). Even use of a landmark analysis—eg, assessing only the patients who survived disease-free for 22 weeks after surgery (22 weeks being 10 weeks maximum delay between surgery and the start of adjuvant chemotherapy, and four 3-week chemotherapy cycles)—would not eliminate all sources of bias in a comparison of completers versus non-completers in the adjuvant study group. Likewise, comparison of the subset of patients allocated adjuvant chemotherapy who were able to receive full adjuvant chemotherapy with the unselected group of patients allocated to no adjuvant treatment would also be a heavily biased comparison irrespective of use of a landmark analysis. Matching of the completers in the adjuvant treatment group to patients in the comparator group would diminish the bias only with perfect matching for all relevant prognostic factors (eg, preoperative chemotherapy, toxicity during preoperative treatment, tumour localisation, ypT, ypN, and performance status). However, our sample was too small to enable such matching, and, even if it were possible, the remaining sample size would be very limited and would provide very low power to detect any reasonable magnitude of effect. The situation would be even worse if preoperative treatment was accounted for. We thus argue that our study does not allow us to properly show if a more intense adjuvant chemotherapy might have improved patient outcome. Atkins suggests6 that intolerance to postoperative chemotherapy is probably due to preoperative radiation. This statement stems from a comparison with studies of colon cancer in which this problem is not
seen. Accordingly, in the Impact B2 trial done in resected colon cancer, the median dose-intensity of fluorouracilleucovorin (dose received divided by dose planned) was 90–98% despite higher doses of fluorouracil and higher numbers of completed chemotherapy courses.7 In our study, the proportion of patients who received the planned chemotherapy schedule among those who started was about 30% lower than usually seen in colon cancer trials. There are several possible explanations for this finding. First is the possible higher burden of rectal cancer surgery—abdominoperineal resection or ileostomy in case of conservative surgery—that can negatively affect tolerance to subsequent treatment. Second, the delivery of adjuvant chemotherapy in our trial could have been less aggressive than in other studies. In support of this presumption, findings from a comprehensive cancer network analysis done in patients with rectal cancer who received preoperative chemoradiotherapy in eight academic cancer centres in the USA showed that up to 70% of the patients who started postoperative chemotherapy were able to complete the treatment.8 Thornton and Rooney9 point out that the quality of surgery might have been suboptimal in the EORTC trial. They underline an unexpectedly high rate of abdominoperineal resection (39%) as well as a low rate of total mesorectal excision. In our study, the abdominoperineal resection rate significantly decreased during the study period, as did circumferential resection margin positivity,10 indicating that surgery improved over time. Nevertheless, the 24% abdominoperineal resection rate taken as reference by Thornton and Rooney as seen by the UK National Cancer audit programme, reported as a contemporary standard finding, was in fact seen in 2001–02, after our www.thelancet.com/oncology Vol 15 May 2014
Correspondence
trial had closed. Therefore, these data should not be used as a reference.11 Total mesorectal exicision became common practice only halfway through our study and its use was not planned in our protocol, therefore quality control of the procedure was not implemented either. Atkins, Thornton, and Rooney also point out a possible inaccurate staging of our patients. When the trial began in 1993, MRI accuracy for rectal cancer and access to equipment were poor. Therefore, we selected T3 or resectable T4 tumours identified by clinical examination, including rigid proctoscopy, and digital rectal examination as per UK recommendations.12,13 Total circumferential involvement or tumour fixity were important characteristics. For tumours inaccessible to digital rectal examination, the input of endorectal ultrasonography was taken into consideration.
www.thelancet.com/oncology Vol 15 May 2014
We declare that we have no competing interests.
6
Jean-François Bosset*, Laurence Collette
7
[email protected] Department of Radiation, Oncology, Besançon University, Hospital J Minjoz, Besançon, France (J-FB); and Department of Statistics, European Organisation forResearch and Treatment of Cancer, Brussels, Belgium (LC) 1
2
3 4
5
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. You, K, Huang R, Gao Y. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e194. Bujko K, Glimelius B. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e194. 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. Valsecchi ME. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e195.
8
9
10
11
12
13
Atkins CD. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e195. International multicentre pooled analysis of B2 colon cancer trials (IMPACT B2) investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol 1999; 17: 1356–63. Khrizman P, Niland JC, ter Veer A, et al. Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy : a national comprehensive cancer network analysis. J Clin Oncol 2013; 31: 30–38. Thornton M, Rooney PS. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e196. Den Dulk M, Collette L, van de Velde CJH, et al. Quality of surgery in T3-4 rectal cancer : involvement of circumferential resection margin not influenced by preoperative treatment. Results from EORTC 22921. Eur J Cancer 2007; 43: 1821–28. HSCIC. National bowel cancer audit. http:// www.hscic.gov.uk/bowel (accessed April 10, 2014). Nicholls RJ, York Mason A, Morson BC, Dixon AK, Kelsey Fry I. The clinical staging of rectal cancer. Br J Surg 1982; 69: 404–09. Williams NS, Jass JR, Hardcastle JD. Clinicopathological assessment and staging of colorectal cancer. Br J Surg 1988; 75: 649–52.
e198
Authors’ reply
See Online for appendix
e197
We read with great interest the correspondence generated by our Article.1 We thank the authors for their interest in our study and for the relevant questions that they raise. You and colleagues2 asked for a subgroup analysis by pathological T and N stage. For this analysis, we considered the subgroup of patients with R0 resection and no distant spread detected at surgery, which we used in the analysis shown in figure 4 of our Article. We now further split the patient groups by pN+ versus pN0, resulting in three groups: ypT0–2N0, ypT3–4N0, and ypN+. The forest plots in the appendix show the effect of adjuvant chemotherapy on diseasefree and overall survival from date of surgery in each of the three subgroups and by preoperative treatment. We note no statistically significant heterogeneity of the effect of adjuvant treatment according to this grouping. Within the pN+ subgroup, the adjuvant treatment hazard ratio for survival from surgery points in opposite directions for patients who had preoperative radiotherapy (hazard ratio 0·76, 95% CI 0·48– 1·19) compared with the effect in patients who had preoperative radiotherapy and chemotherapy (1·19, 95% CI 0·69–2·04), but neither of these effects are significant, nor are they different from one another (heterogeneity p=0·21). Bujko and Glimelius3 requested that we repeat the analysis of outcome after surgery according to tumour localisation, as presented in a previous study of ours.4 We provide the update of that analysis for progression-free and overall survival in the appendix. The data again suggest no significant heterogeneity of the effect according to the tumour localisation relative to the anal verge. Valsecchi5 requested an analysis by dose intensity of adjuvant chemotherapy effectively received, noting that such an analysis would lack statistical power. We are concerned
that this kind of analysis is inherently biased: the factors that explain why a patient could not receive the full dose of chemotherapy might also be prognostic factors for a worse outcome (be it overall or diseasefree survival). Even use of a landmark analysis—eg, assessing only the patients who survived disease-free for 22 weeks after surgery (22 weeks being 10 weeks maximum delay between surgery and the start of adjuvant chemotherapy, and four 3-week chemotherapy cycles)—would not eliminate all sources of bias in a comparison of completers versus non-completers in the adjuvant study group. Likewise, comparison of the subset of patients allocated adjuvant chemotherapy who were able to receive full adjuvant chemotherapy with the unselected group of patients allocated to no adjuvant treatment would also be a heavily biased comparison irrespective of use of a landmark analysis. Matching of the completers in the adjuvant treatment group to patients in the comparator group would diminish the bias only with perfect matching for all relevant prognostic factors (eg, preoperative chemotherapy, toxicity during preoperative treatment, tumour localisation, ypT, ypN, and performance status). However, our sample was too small to enable such matching, and, even if it were possible, the remaining sample size would be very limited and would provide very low power to detect any reasonable magnitude of effect. The situation would be even worse if preoperative treatment was accounted for. We thus argue that our study does not allow us to properly show if a more intense adjuvant chemotherapy might have improved patient outcome. Atkins suggests6 that intolerance to postoperative chemotherapy is probably due to preoperative radiation. This statement stems from a comparison with studies of colon cancer in which this problem is not
seen. Accordingly, in the Impact B2 trial done in resected colon cancer, the median dose-intensity of fluorouracilleucovorin (dose received divided by dose planned) was 90–98% despite higher doses of fluorouracil and higher numbers of completed chemotherapy courses.7 In our study, the proportion of patients who received the planned chemotherapy schedule among those who started was about 30% lower than usually seen in colon cancer trials. There are several possible explanations for this finding. First is the possible higher burden of rectal cancer surgery—abdominoperineal resection or ileostomy in case of conservative surgery—that can negatively affect tolerance to subsequent treatment. Second, the delivery of adjuvant chemotherapy in our trial could have been less aggressive than in other studies. In support of this presumption, findings from a comprehensive cancer network analysis done in patients with rectal cancer who received preoperative chemoradiotherapy in eight academic cancer centres in the USA showed that up to 70% of the patients who started postoperative chemotherapy were able to complete the treatment.8 Thornton and Rooney9 point out that the quality of surgery might have been suboptimal in the EORTC trial. They underline an unexpectedly high rate of abdominoperineal resection (39%) as well as a low rate of total mesorectal excision. In our study, the abdominoperineal resection rate significantly decreased during the study period, as did circumferential resection margin positivity,10 indicating that surgery improved over time. Nevertheless, the 24% abdominoperineal resection rate taken as reference by Thornton and Rooney as seen by the UK National Cancer audit programme, reported as a contemporary standard finding, was in fact seen in 2001–02, after our www.thelancet.com/oncology Vol 15 May 2014
Correspondence
trial had closed. Therefore, these data should not be used as a reference.11 Total mesorectal exicision became common practice only halfway through our study and its use was not planned in our protocol, therefore quality control of the procedure was not implemented either. Atkins, Thornton, and Rooney also point out a possible inaccurate staging of our patients. When the trial began in 1993, MRI accuracy for rectal cancer and access to equipment were poor. Therefore, we selected T3 or resectable T4 tumours identified by clinical examination, including rigid proctoscopy, and digital rectal examination as per UK recommendations.12,13 Total circumferential involvement or tumour fixity were important characteristics. For tumours inaccessible to digital rectal examination, the input of endorectal ultrasonography was taken into consideration.
www.thelancet.com/oncology Vol 15 May 2014
We declare that we have no competing interests.
6
Jean-François Bosset*, Laurence Collette
7
[email protected] Department of Radiation, Oncology, Besançon University, Hospital J Minjoz, Besançon, France (J-FB); and Department of Statistics, European Organisation forResearch and Treatment of Cancer, Brussels, Belgium (LC) 1
2
3 4
5
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. You, K, Huang R, Gao Y. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e194. Bujko K, Glimelius B. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e194. 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. Valsecchi ME. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e195.
8
9
10
11
12
13
Atkins CD. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e195. International multicentre pooled analysis of B2 colon cancer trials (IMPACT B2) investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol 1999; 17: 1356–63. Khrizman P, Niland JC, ter Veer A, et al. Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy : a national comprehensive cancer network analysis. J Clin Oncol 2013; 31: 30–38. Thornton M, Rooney PS. Adjuvant chemotherapy for rectal cancer. Lancet Oncol 2014; 15: e196. Den Dulk M, Collette L, van de Velde CJH, et al. Quality of surgery in T3-4 rectal cancer : involvement of circumferential resection margin not influenced by preoperative treatment. Results from EORTC 22921. Eur J Cancer 2007; 43: 1821–28. HSCIC. National bowel cancer audit. http:// www.hscic.gov.uk/bowel (accessed April 10, 2014). Nicholls RJ, York Mason A, Morson BC, Dixon AK, Kelsey Fry I. The clinical staging of rectal cancer. Br J Surg 1982; 69: 404–09. Williams NS, Jass JR, Hardcastle JD. Clinicopathological assessment and staging of colorectal cancer. Br J Surg 1988; 75: 649–52.
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