Treatment of Rectal Cancer
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The article by Bosset and colleagues (Sept. 14 issue)1 provides support for the use of adjuvant chemotherapy in patients with locally advanced rectal cancer. However, information on nodal status and the extent of mesorectal invasion would have helped to characterize the role of neoadjuvant therapy in these patients. Among patients with clinical stage T3 disease, both nodal status and the extent of mesorectal invasion affect the risk of recurrence.2,3 In addition, with the growing indication that adjuvant therapy for minimally invasive stage T3N0 tumors is unnecessary,4 characterization of the "overtreatment" response according to nodal status and the extent of T3 mesorectal invasion would have been helpful.
Gavin C. Harewood, M.D.
Beaumont Hospital
Dublin 9, Ireland
harewood.gavin@gmail.com
References
Bosset J-F, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114-1123.
Tang R, Wang JY, Chen JS, et al. Survival impact of lymph node metastasis in TNM stage III carcinoma of the colon and rectum. J Am Coll Surg 1995;180:705-712.
Harewood GC, Kumar KS, Clain JE, Levy MJ, Nelson H. Clinical implications of quantification of mesorectal tumor invasion by endoscopic ultrasound: all T3 rectal cancers are not equal. J Gastroenterol Hepatol 2004;19:750-755.
Mackay G, Downey M, Molloy RG, O'Dwyer PJ. Is pre-operative radiotherapy necessary in T-T rectal cancer with TME? Colorectal Dis 2006;8:34-36.
To the Editor: Bosset and colleagues conclude that in patients who receive preoperative radiotherapy for rectal cancer, "adding fluorouracil-based chemotherapy preoperatively or postoperatively has no significant effect on survival." This conclusion is consistent with the findings of the study, but we question this statement because it is not accompanied by the phrase "in the dose and schedule tested."1
Adherence to the protocol in the European Organization for Research and Treatment of Cancer trial (EORTC 22921) was very low, since less than 50% of the patients assigned to receive postoperative chemotherapy actually received it. Moreover, chemotherapy was given at a dose of only 350 mg of fluorouracil per square meter of body-surface area per day and 20 mg of leucovorin per square meter per day, and whether fluorouracil was given as a bolus or as an infusion is not stated.2,3,4 For these reasons, we question the generalization of the authors' conclusion.
Stefan Hoecht, M.D.
Wolfgang Hinkelbein, M.D.
Charité Campus Benjamin Franklin
D-12200 Berlin, Germany
stefan.hoecht@charite.de
References
Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 2004;22:1785-1796.
Wolmark N, Wieand HS, Hyams DM, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000;92:388-396.
O'Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502-507.
Rich TA, Shepard RC, Mosley ST. Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy. J Clin Oncol 2004;22:2214-2232.
To the Editor: A review of the data reported by Bosset et al. showed that 65 patients (13.5%) receiving preoperative chemoradiotherapy and 25 patients (5.0%) receiving radiotherapy alone preoperatively had a pathological complete response with respect to tumor stage (pT0). A pathological complete response to preoperative chemoradiotherapy results in markedly improved survival for patients with locally advanced rectal cancer, with 5-year recurrence-free and overall survival rates of 96% and 90%, respectively.1,2 We were disappointed to find no post hoc analysis of survival among patients with a pT0 tumor stage, given the magnitude of the increase in the number of patients with a pathological complete response after preoperative chemoradiotherapy, and we would look forward to the authors' analysis of survival in this group of patients.
John W. Cromwell, M.D.
Lourdes T. Santiago, M.D.
Jorge E. Marcet, M.D.
University of South Florida College of Medicine
Tampa, FL 33606
jcromwel@health.usf.edu
References
Stipa F, Chessin DB, Shia J, et al. A pathologic complete response of rectal cancer to preoperative combined-modality therapy results in improved oncological outcome compared with those who achieve no downstaging on the basis of preoperative endorectal ultrasonography. Ann Surg Oncol 2006;13:1047-1053.
Theodoropoulos G, Wise WE, Padmanabhan A, et al. T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival. Dis Colon Rectum 2002;45:895-903.
To the Editor: Bosset et al. report that their results are consistent with those of the German Rectal Cancer Study Group trial,1 which showed that neoadjuvant pelvic radiotherapy combined with fluorouracil and leucovorin chemotherapy improved local tumor control in patients with operable rectal cancer. In their discussion, the authors speculate that "given the high rate of local control obtained with preoperative chemoradiotherapy and the lack of effect on survival, it seems unnecessary to intensify this regimen." We disagree. Since a complete tumor response after neoadjuvant therapy for rectal cancer correlates with local tumor control and disease-free and overall survival, a current research strategy is to improve pathological complete response rates by adding other agents, such as oxaliplatin2 or bevacizumab,3 to fluorouracil or capecitabine and pelvic radiotherapy. Given that distant metastasis is the predominant pattern of treatment failure in rectal cancer, the development of more effective systemic therapy is a prerequisite to making further improvements in the treatment of this disease.
Giuseppe Curigliano, M.D.
Gianluca Spitaleri, M.D.
Giulia Zampino, M.D.
European Institute of Oncology
20133 Milan, Italy
giuseppe.curigliano@ieo.it
References
Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740.
Ryan DP, Niedzwiecki D, Hollis D, et al. A phase I/II study of preoperative oxaliplatin (O), 5-fluorouracil (5-FU), and external beam radiation therapy (XRT) in locally advanced rectal cancer: CALGB 89901. J Clin Oncol 2004;22:260-260.
Willett CG, Chung D, Sahani D, et al. Phase I study of neoadjuvant bevacizumab, 5-fluorouracil, and radiation therapy followed by surgery for patients with primary rectal cancer. J Clin Oncol 2004;22:267-267.
The authors reply: We agree with Harewood that assessment of the nodal status and the extent of disease spread into the mesorectum would have been helpful in interpreting our results. For pragmatic reasons, as in other trials in the 1990s, patients were selected on the basis of a clinical assessment of the local spread of the primary tumor. Magnetic resonance imaging (MRI) with high spatial resolution has recently been established as the most accurate method for identifying pretreatment prognostic factors and for predicting the status of the circumferential resection margin.1 MRI is more accurate than echoendoscopy and is recommended for use in ongoing trials. Hoecht and Hinkelbein point to suboptimal chemotherapy and moderate compliance as possible causes of the failure of chemotherapy. Sauer et al.2 also noted the low adherence to postoperative chemotherapy after preoperative chemoradiotherapy. Whether an "optimal" or "modern" adjuvant computed tomographic scheme would be better tolerated and more effective remains unproved.
Cromwell et al. underline the prognostic value of tumor sterilization (ypT0). We did not assess this subgroup of 90 patients. Rather, we investigated prognostic and predictive factors among all patients with an R0 resection and M0 disease (i.e., patients who had no microscopical evidence of remaining disease and who had no metastatic disease). We found that downstaging (ypTs0-2) predicts a long-term benefit from adjuvant chemotherapy.3 These findings may be useful for deciding on postoperative treatment in patients who have received preoperative chemoradiotherapy.
Curigliano et al. suggest that improving the ypT0 rate by using newer, possibly more active drugs would improve survival. We argue that the surrogacy of ypT0 — or more generally of tumor downstaging for survival — is unproved and that prognostic association is not causality. Thus, if more effective systemic treatment is needed, we think that restricting its delivery to the preoperative setting to improve pathological complete response rates (ypT0) will not suffice to control distant disease spread.
Jean-Fran?ois Bosset, M.D.
Laurence Collette, Ph.D.
Philippe Maingon, M.D.
European Organization for Research and Treatment of Cancer Data Center
B-1200 Brussels, Belgium
jean-francois.bosset@ufc-chu.univ-fcomte.fr
References
Brown G, Radcliffe AG, Newcombe RG, Dallimore NS, Bourne MW, Williams GT. Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic resonance imaging. Br J Surg 2003;90:355-364.
Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740.
Collette L, Calais G, Mineur L, et al. Patients with R0 resection of T3-4 cancer after preoperative radio or radiochemotherapy: does anybody benefit from postoperative LV/5-FU chemotherapy? Further results of EORTC trial 22921. Eur J Cancer 2005;3:170-170.
Gavin C. Harewood, M.D.
Beaumont Hospital
Dublin 9, Ireland
harewood.gavin@gmail.com
References
Bosset J-F, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114-1123.
Tang R, Wang JY, Chen JS, et al. Survival impact of lymph node metastasis in TNM stage III carcinoma of the colon and rectum. J Am Coll Surg 1995;180:705-712.
Harewood GC, Kumar KS, Clain JE, Levy MJ, Nelson H. Clinical implications of quantification of mesorectal tumor invasion by endoscopic ultrasound: all T3 rectal cancers are not equal. J Gastroenterol Hepatol 2004;19:750-755.
Mackay G, Downey M, Molloy RG, O'Dwyer PJ. Is pre-operative radiotherapy necessary in T-T rectal cancer with TME? Colorectal Dis 2006;8:34-36.
To the Editor: Bosset and colleagues conclude that in patients who receive preoperative radiotherapy for rectal cancer, "adding fluorouracil-based chemotherapy preoperatively or postoperatively has no significant effect on survival." This conclusion is consistent with the findings of the study, but we question this statement because it is not accompanied by the phrase "in the dose and schedule tested."1
Adherence to the protocol in the European Organization for Research and Treatment of Cancer trial (EORTC 22921) was very low, since less than 50% of the patients assigned to receive postoperative chemotherapy actually received it. Moreover, chemotherapy was given at a dose of only 350 mg of fluorouracil per square meter of body-surface area per day and 20 mg of leucovorin per square meter per day, and whether fluorouracil was given as a bolus or as an infusion is not stated.2,3,4 For these reasons, we question the generalization of the authors' conclusion.
Stefan Hoecht, M.D.
Wolfgang Hinkelbein, M.D.
Charité Campus Benjamin Franklin
D-12200 Berlin, Germany
stefan.hoecht@charite.de
References
Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 2004;22:1785-1796.
Wolmark N, Wieand HS, Hyams DM, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000;92:388-396.
O'Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502-507.
Rich TA, Shepard RC, Mosley ST. Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy. J Clin Oncol 2004;22:2214-2232.
To the Editor: A review of the data reported by Bosset et al. showed that 65 patients (13.5%) receiving preoperative chemoradiotherapy and 25 patients (5.0%) receiving radiotherapy alone preoperatively had a pathological complete response with respect to tumor stage (pT0). A pathological complete response to preoperative chemoradiotherapy results in markedly improved survival for patients with locally advanced rectal cancer, with 5-year recurrence-free and overall survival rates of 96% and 90%, respectively.1,2 We were disappointed to find no post hoc analysis of survival among patients with a pT0 tumor stage, given the magnitude of the increase in the number of patients with a pathological complete response after preoperative chemoradiotherapy, and we would look forward to the authors' analysis of survival in this group of patients.
John W. Cromwell, M.D.
Lourdes T. Santiago, M.D.
Jorge E. Marcet, M.D.
University of South Florida College of Medicine
Tampa, FL 33606
jcromwel@health.usf.edu
References
Stipa F, Chessin DB, Shia J, et al. A pathologic complete response of rectal cancer to preoperative combined-modality therapy results in improved oncological outcome compared with those who achieve no downstaging on the basis of preoperative endorectal ultrasonography. Ann Surg Oncol 2006;13:1047-1053.
Theodoropoulos G, Wise WE, Padmanabhan A, et al. T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival. Dis Colon Rectum 2002;45:895-903.
To the Editor: Bosset et al. report that their results are consistent with those of the German Rectal Cancer Study Group trial,1 which showed that neoadjuvant pelvic radiotherapy combined with fluorouracil and leucovorin chemotherapy improved local tumor control in patients with operable rectal cancer. In their discussion, the authors speculate that "given the high rate of local control obtained with preoperative chemoradiotherapy and the lack of effect on survival, it seems unnecessary to intensify this regimen." We disagree. Since a complete tumor response after neoadjuvant therapy for rectal cancer correlates with local tumor control and disease-free and overall survival, a current research strategy is to improve pathological complete response rates by adding other agents, such as oxaliplatin2 or bevacizumab,3 to fluorouracil or capecitabine and pelvic radiotherapy. Given that distant metastasis is the predominant pattern of treatment failure in rectal cancer, the development of more effective systemic therapy is a prerequisite to making further improvements in the treatment of this disease.
Giuseppe Curigliano, M.D.
Gianluca Spitaleri, M.D.
Giulia Zampino, M.D.
European Institute of Oncology
20133 Milan, Italy
giuseppe.curigliano@ieo.it
References
Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740.
Ryan DP, Niedzwiecki D, Hollis D, et al. A phase I/II study of preoperative oxaliplatin (O), 5-fluorouracil (5-FU), and external beam radiation therapy (XRT) in locally advanced rectal cancer: CALGB 89901. J Clin Oncol 2004;22:260-260.
Willett CG, Chung D, Sahani D, et al. Phase I study of neoadjuvant bevacizumab, 5-fluorouracil, and radiation therapy followed by surgery for patients with primary rectal cancer. J Clin Oncol 2004;22:267-267.
The authors reply: We agree with Harewood that assessment of the nodal status and the extent of disease spread into the mesorectum would have been helpful in interpreting our results. For pragmatic reasons, as in other trials in the 1990s, patients were selected on the basis of a clinical assessment of the local spread of the primary tumor. Magnetic resonance imaging (MRI) with high spatial resolution has recently been established as the most accurate method for identifying pretreatment prognostic factors and for predicting the status of the circumferential resection margin.1 MRI is more accurate than echoendoscopy and is recommended for use in ongoing trials. Hoecht and Hinkelbein point to suboptimal chemotherapy and moderate compliance as possible causes of the failure of chemotherapy. Sauer et al.2 also noted the low adherence to postoperative chemotherapy after preoperative chemoradiotherapy. Whether an "optimal" or "modern" adjuvant computed tomographic scheme would be better tolerated and more effective remains unproved.
Cromwell et al. underline the prognostic value of tumor sterilization (ypT0). We did not assess this subgroup of 90 patients. Rather, we investigated prognostic and predictive factors among all patients with an R0 resection and M0 disease (i.e., patients who had no microscopical evidence of remaining disease and who had no metastatic disease). We found that downstaging (ypTs0-2) predicts a long-term benefit from adjuvant chemotherapy.3 These findings may be useful for deciding on postoperative treatment in patients who have received preoperative chemoradiotherapy.
Curigliano et al. suggest that improving the ypT0 rate by using newer, possibly more active drugs would improve survival. We argue that the surrogacy of ypT0 — or more generally of tumor downstaging for survival — is unproved and that prognostic association is not causality. Thus, if more effective systemic treatment is needed, we think that restricting its delivery to the preoperative setting to improve pathological complete response rates (ypT0) will not suffice to control distant disease spread.
Jean-Fran?ois Bosset, M.D.
Laurence Collette, Ph.D.
Philippe Maingon, M.D.
European Organization for Research and Treatment of Cancer Data Center
B-1200 Brussels, Belgium
jean-francois.bosset@ufc-chu.univ-fcomte.fr
References
Brown G, Radcliffe AG, Newcombe RG, Dallimore NS, Bourne MW, Williams GT. Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic resonance imaging. Br J Surg 2003;90:355-364.
Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740.
Collette L, Calais G, Mineur L, et al. Patients with R0 resection of T3-4 cancer after preoperative radio or radiochemotherapy: does anybody benefit from postoperative LV/5-FU chemotherapy? Further results of EORTC trial 22921. Eur J Cancer 2005;3:170-170.