Correspondence
rectal cancer (0·97, 0·6–1·6; p=0·9). These findings should be interpreted with caution since adjuvant chemotherapy was not randomly allocated. Its delivery was associated with confounding factors such as age and comorbidity. Nonetheless, the association between tumour location and the effectiveness of adjuvant chemotherapy could be causal. Moreover, in colorectal cancer, molecular genetic changes are slightly different between intraperitoneal and extraperitoneal tumours.4 This finding can explain different effectiveness of adjuvant chemotherapy between low-lying and high tumours. We declare that we have no conflicts of interest.
Krzysztof Bujko*, Bengt Glimelius [email protected] Department of Radiotherapy, Maria SklodowskaCurie Memorial Cancer Centre, Warsaw 02-781, Poland (KB); and Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala S-75105, Sweden (BG) 1
2
3
4
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. 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. Tiselius C, Gunnarsson U, Smedh K, Glimelius B, Påhlman L. Patients with rectal cancer receiving adjuvant chemotherapy have an increased survival: a population-based longitudinal study. Ann Oncol 2013; 24: 160–65. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–37.
I read with interest the long-term results of EORTC 22921 by JeanFrançois Bosset and colleagues. 1 Findings from this study have certainly added more questions to the already controversial role of adjuvant chemotherapy in rectal cancer, especially after the use of neoadjuvant concurrent chemoradiotherapy. e195
However, as described by the authors, there are some limitations of the study that undermine its conclusions. One of those limitations is related to the fact that less than half of the patients received the chemotherapy as planned per protocol. It would be interesting—considering that findings from this study might lead to a change in practice—for the authors to present subgroup analyses of overall survival and disease-free survival by chemotherapy dose intensity received (eg, no adjuvant treatment, an incomplete course, and a full course with dose as originally planned), even though such an analysis would be hypothesis-generating only, given limited statistical power. Assuming that dose intensity is one of the most important determinants of the clinical effectiveness of chemotherapy,2,3 and considering that the post-surgical chemotherapy regimen used in EORTC 22921 might be suboptimal compared with others (eg, FOLFOX), it is unclear what the clinical outcome of patients who did not receive the full course of adjuvant chemotherapy would be. I declare that I have no conflicts of interest.
Matias E Valsecchi [email protected] Medical Oncology, Huntington Internal Medicine Group, Huntington, WV 25705, USA 1
2
3
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. Foote M. The importance of planned dose of chemotherapy on time: do we need to change our clinical practice? Oncologist 1998; 3: 365–68. Lyman GH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw 2009; 7: 99–108.
Bosset and colleagues present the long-term results of EORTC 2291,1 showing no survival advantage when fluorouracil-based chemotherapy is added to preoperative radiotherapy in patients with rectal cancer. The investigators rightly conclude that such practice is not lent support
by evidence. However, I think their suggestion that preoperative chemotherapy might be a better approach does not go far enough. Beets and Glimelius2 suggest that the problem is the inability of patients with rectal cancer to tolerate chemotherapy after surgery, but because this problem is not seen in patients with resected colon cancer, it is probably more likely that the intolerance is due to preoperative radiation. Another problem is the inaccurate staging associated with preoperative treatment. In Sauer and colleagues’ study of preoperative versus postoperative chemoradiation,3 69 (18%) of 384 patients in the postoperative group thought to have stage II or III disease had only stage I disease at surgery. These patients are being over-treated. Another 27 (7%) of 384 patients had stage IV disease, for which adjuvant treatment is the wrong approach. Also, patients with stage II disease are likely to receive little survival benefit from adjuvant chemotherapy. In Sauer and colleagues’ study,3 40% of patients in the postoperative group had stage II disease, for whom a survival benefit of only 2% (95% CI –2 to 4) would be expected from adjuvant chemotherapy, based on data from studies in colon cancer.4 This finding compares with an improvement in local relapse of only 7% for preoperative versus postoperative chemoradiation (without any survival improvement). So, to prevent local relapse in 7% of patients, 25% of patients now receive unnecessary radiation and almost 50% receive chemotherapy that will offer little or no benefit, or will be used with the wrong intent. Perhaps worse, fewer than 50% of patients complete adjuvant chemotherapy as planned, thus compromising the survival of the 40% of patients with pathological stage III disease. I propose that preoperative treatment of rectal cancer be offered only to patients who need it for www.thelancet.com/oncology Vol 15 May 2014
rectal cancer (0·97, 0·6–1·6; p=0·9). These findings should be interpreted with caution since adjuvant chemotherapy was not randomly allocated. Its delivery was associated with confounding factors such as age and comorbidity. Nonetheless, the association between tumour location and the effectiveness of adjuvant chemotherapy could be causal. Moreover, in colorectal cancer, molecular genetic changes are slightly different between intraperitoneal and extraperitoneal tumours.4 This finding can explain different effectiveness of adjuvant chemotherapy between low-lying and high tumours. We declare that we have no conflicts of interest.
Krzysztof Bujko*, Bengt Glimelius [email protected] Department of Radiotherapy, Maria SklodowskaCurie Memorial Cancer Centre, Warsaw 02-781, Poland (KB); and Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala S-75105, Sweden (BG) 1
2
3
4
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. 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. Tiselius C, Gunnarsson U, Smedh K, Glimelius B, Påhlman L. Patients with rectal cancer receiving adjuvant chemotherapy have an increased survival: a population-based longitudinal study. Ann Oncol 2013; 24: 160–65. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–37.
I read with interest the long-term results of EORTC 22921 by JeanFrançois Bosset and colleagues. 1 Findings from this study have certainly added more questions to the already controversial role of adjuvant chemotherapy in rectal cancer, especially after the use of neoadjuvant concurrent chemoradiotherapy. e195
However, as described by the authors, there are some limitations of the study that undermine its conclusions. One of those limitations is related to the fact that less than half of the patients received the chemotherapy as planned per protocol. It would be interesting—considering that findings from this study might lead to a change in practice—for the authors to present subgroup analyses of overall survival and disease-free survival by chemotherapy dose intensity received (eg, no adjuvant treatment, an incomplete course, and a full course with dose as originally planned), even though such an analysis would be hypothesis-generating only, given limited statistical power. Assuming that dose intensity is one of the most important determinants of the clinical effectiveness of chemotherapy,2,3 and considering that the post-surgical chemotherapy regimen used in EORTC 22921 might be suboptimal compared with others (eg, FOLFOX), it is unclear what the clinical outcome of patients who did not receive the full course of adjuvant chemotherapy would be. I declare that I have no conflicts of interest.
Matias E Valsecchi [email protected] Medical Oncology, Huntington Internal Medicine Group, Huntington, WV 25705, USA 1
2
3
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. Foote M. The importance of planned dose of chemotherapy on time: do we need to change our clinical practice? Oncologist 1998; 3: 365–68. Lyman GH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw 2009; 7: 99–108.
Bosset and colleagues present the long-term results of EORTC 2291,1 showing no survival advantage when fluorouracil-based chemotherapy is added to preoperative radiotherapy in patients with rectal cancer. The investigators rightly conclude that such practice is not lent support
by evidence. However, I think their suggestion that preoperative chemotherapy might be a better approach does not go far enough. Beets and Glimelius2 suggest that the problem is the inability of patients with rectal cancer to tolerate chemotherapy after surgery, but because this problem is not seen in patients with resected colon cancer, it is probably more likely that the intolerance is due to preoperative radiation. Another problem is the inaccurate staging associated with preoperative treatment. In Sauer and colleagues’ study of preoperative versus postoperative chemoradiation,3 69 (18%) of 384 patients in the postoperative group thought to have stage II or III disease had only stage I disease at surgery. These patients are being over-treated. Another 27 (7%) of 384 patients had stage IV disease, for which adjuvant treatment is the wrong approach. Also, patients with stage II disease are likely to receive little survival benefit from adjuvant chemotherapy. In Sauer and colleagues’ study,3 40% of patients in the postoperative group had stage II disease, for whom a survival benefit of only 2% (95% CI –2 to 4) would be expected from adjuvant chemotherapy, based on data from studies in colon cancer.4 This finding compares with an improvement in local relapse of only 7% for preoperative versus postoperative chemoradiation (without any survival improvement). So, to prevent local relapse in 7% of patients, 25% of patients now receive unnecessary radiation and almost 50% receive chemotherapy that will offer little or no benefit, or will be used with the wrong intent. Perhaps worse, fewer than 50% of patients complete adjuvant chemotherapy as planned, thus compromising the survival of the 40% of patients with pathological stage III disease. I propose that preoperative treatment of rectal cancer be offered only to patients who need it for www.thelancet.com/oncology Vol 15 May 2014
