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
Correspondence
sphincter preservation, using chemotherapy first and chemoradiation only for salvage, thus affording patients with clinical or pathological stage III disease a greater likelihood of receiving full-dose adjuvant chemotherapy. Other patients should receive the benefit of accurate surgical staging, offering chemoradiation only to patients with stage II disease, adjuvant chemotherapy only to those with stage III disease, and palliative chemotherapy (or curative resection) to those with stage IV disease. Such practice would maximise survival and minimise unnecessary treatment. I declare that I have no conflicts of interest.
Carl D Atkins [email protected] St Peter’s Hospital, Albany, NY 12208, USA 1
2
3
4
Bosset J-F, 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: 184–190. Beets GL, Glimelius BL. Adjuvant chemotherapy for rectal cancer still controversial. Lancet Oncol 2014; 15: 130–31. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731–40. 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.
Bosset and colleagues1 question the current clinical thinking that patients with surgically resected rectal cancer who are treated with preoperative chemoradiotherapy should be routinely offered further postoperative fluorouracil-based adjuvant chemotherapy. There are, however, several important points to consider. First, in their study, staging was done clinically and by CT scan with or without endorectal ultrasound. We therefore regard the possibility of overstaging to be high, which might contribute to the absence of perceived benefit of adjuvant chemotherapy. Second, the reported rate of abdominoperineal www.thelancet.com/oncology Vol 15 May 2014
excision of the rectum of about 40% is high by contemporary standards— findings from the 2013 UK National Bowel Cancer Audit Programme2 showed abdominoperineal excision of the rectum being done for 24% of patients. This possible overestimation, together with a total mesorectal excision rate of 36·8% raises questions as to the oncological quality of surgery in the study.3 Third, 26·9% of patients randomised to receive adjuvant chemotherapy did not start treatment, and only 42·9% received more than 95% of the planned dose of fluorouracil within the scheduled timeframe.3 Any effect of adjuvant chemotherapy is therefore difficult to ascertain and the power of the study to identify a clinically meaningful benefit is reduced. Because many patients with locally advanced rectal cancer have ypN0 disease after preoperative chemoradiotherapy, a possible argument is that systemic therapy is not indicated in this setting. However, in rectal cancer, survival is mainly affected by distant metastases rather than local failure, and, therefore, efforts should be directed towards the prevention of systemic disease. Optimal treatment strategy should account for the risk of local recurrence and distant metastases. Identification of involvement of the circumferential resection margin on MRI, along with nodal disease, before preoperative chemoradiotherapy is associated with distant metastatic disease4 and decisions on delivery of adjuvant chemotherapy should be based on such involvement rather than postoperative nodal status. A good response to preoperative chemoradiotherapy, as indicated by successful downstaging, is a useful indicator of tumour biology. This is exactly the subgroup of patients who should be offered further fluorouracil-based adjuvant chemotherapy because the tumour has already shown chemosensitivity.
Findings from an unplanned subset analysis by Collette and colleagues5 lends support to this assumption. Conversely, adjuvant chemotherapy for patients who show less response to preoperative chemoradiotherapy needs to be different because this subgroup will be at higher risk of treatment failure and systemic relapse. The ideal modality of treatment for this group needs to be defined. Biomarker analysis on specimens from the PROCTOR/SCRIPT study (NTR552) is awaited and might identify potential predictive biomarkers that could inform personalised treatment in the future. Although findings from Bosset and colleagues’ study1 are a valuable contribution to the evidence base, we would not recommend a change in practice based on these results, and we would advocate that more and better chemotherapy—rather than less—is needed to improve survival from rectal cancer. We declare that we have no competing interests.
Michael Thornton, Paul S Rooney* [email protected] Departments of Surgery of the Royal Liverpool University Hospital, Liverpool L7 8XP, UK (MT, PSR) 1
2
3
4
5
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. Health Quality Improvement Partnership. National Bowel Cancer Audit Programme (NBOCAP). http://www.hqip.org.uk/nationalbowel-cancer-audit-programme-nbocap (accessed March 2, 2014). Bosset J-Fo, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355: 1114–23 Taylor FGM, Quirke P, Heald RJ, et al. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol 2014; 32: 34–43. 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.
e196
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
Correspondence
sphincter preservation, using chemotherapy first and chemoradiation only for salvage, thus affording patients with clinical or pathological stage III disease a greater likelihood of receiving full-dose adjuvant chemotherapy. Other patients should receive the benefit of accurate surgical staging, offering chemoradiation only to patients with stage II disease, adjuvant chemotherapy only to those with stage III disease, and palliative chemotherapy (or curative resection) to those with stage IV disease. Such practice would maximise survival and minimise unnecessary treatment. I declare that I have no conflicts of interest.
Carl D Atkins [email protected] St Peter’s Hospital, Albany, NY 12208, USA 1
2
3
4
Bosset J-F, 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: 184–190. Beets GL, Glimelius BL. Adjuvant chemotherapy for rectal cancer still controversial. Lancet Oncol 2014; 15: 130–31. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731–40. 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.
Bosset and colleagues1 question the current clinical thinking that patients with surgically resected rectal cancer who are treated with preoperative chemoradiotherapy should be routinely offered further postoperative fluorouracil-based adjuvant chemotherapy. There are, however, several important points to consider. First, in their study, staging was done clinically and by CT scan with or without endorectal ultrasound. We therefore regard the possibility of overstaging to be high, which might contribute to the absence of perceived benefit of adjuvant chemotherapy. Second, the reported rate of abdominoperineal www.thelancet.com/oncology Vol 15 May 2014
excision of the rectum of about 40% is high by contemporary standards— findings from the 2013 UK National Bowel Cancer Audit Programme2 showed abdominoperineal excision of the rectum being done for 24% of patients. This possible overestimation, together with a total mesorectal excision rate of 36·8% raises questions as to the oncological quality of surgery in the study.3 Third, 26·9% of patients randomised to receive adjuvant chemotherapy did not start treatment, and only 42·9% received more than 95% of the planned dose of fluorouracil within the scheduled timeframe.3 Any effect of adjuvant chemotherapy is therefore difficult to ascertain and the power of the study to identify a clinically meaningful benefit is reduced. Because many patients with locally advanced rectal cancer have ypN0 disease after preoperative chemoradiotherapy, a possible argument is that systemic therapy is not indicated in this setting. However, in rectal cancer, survival is mainly affected by distant metastases rather than local failure, and, therefore, efforts should be directed towards the prevention of systemic disease. Optimal treatment strategy should account for the risk of local recurrence and distant metastases. Identification of involvement of the circumferential resection margin on MRI, along with nodal disease, before preoperative chemoradiotherapy is associated with distant metastatic disease4 and decisions on delivery of adjuvant chemotherapy should be based on such involvement rather than postoperative nodal status. A good response to preoperative chemoradiotherapy, as indicated by successful downstaging, is a useful indicator of tumour biology. This is exactly the subgroup of patients who should be offered further fluorouracil-based adjuvant chemotherapy because the tumour has already shown chemosensitivity.
Findings from an unplanned subset analysis by Collette and colleagues5 lends support to this assumption. Conversely, adjuvant chemotherapy for patients who show less response to preoperative chemoradiotherapy needs to be different because this subgroup will be at higher risk of treatment failure and systemic relapse. The ideal modality of treatment for this group needs to be defined. Biomarker analysis on specimens from the PROCTOR/SCRIPT study (NTR552) is awaited and might identify potential predictive biomarkers that could inform personalised treatment in the future. Although findings from Bosset and colleagues’ study1 are a valuable contribution to the evidence base, we would not recommend a change in practice based on these results, and we would advocate that more and better chemotherapy—rather than less—is needed to improve survival from rectal cancer. We declare that we have no competing interests.
Michael Thornton, Paul S Rooney* [email protected] Departments of Surgery of the Royal Liverpool University Hospital, Liverpool L7 8XP, UK (MT, PSR) 1
2
3
4
5
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. Health Quality Improvement Partnership. National Bowel Cancer Audit Programme (NBOCAP). http://www.hqip.org.uk/nationalbowel-cancer-audit-programme-nbocap (accessed March 2, 2014). Bosset J-Fo, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355: 1114–23 Taylor FGM, Quirke P, Heald RJ, et al. Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol 2014; 32: 34–43. 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.
e196
