Reply to Letter to the Editor ‘Weekly oxaliplatin and pre-operative radiotherapy as a new neoadjuvant therapy for locally advanced rectal cancer’, by T. Watanabe et al. (Ann Oncol 2006; 17: 1173)
Authors: C. Aschele, M.L. Friso, P. Del Bianco, S. Pucciarelli
Journal: Annals of Oncology (2006)

The letter by Watanabe et al. regarding the report of our phase I–II study of weekly oxaliplatin and infused 5-fluorouracil combined with standard pre-operative radiotherapy for locally advanced rectal cancer, published in the July 2005 issue of Annals of Oncology [1.Aschele C. Friso M.L. Pucciarelli S. et al.A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer.Ann Oncol. 2005; 16: 1140-1146Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar], gives us the opportunity to define more clearly the surgical complications of this regimen. In summary, data on post-operative morbidity have been requested, concern has been raised on the re-operation rate and a relationship has been hypothesized between re-operations and the schedule of oxaliplatin administration.As to the first issue, post-operative complications were observed in 12 of 46 patients (26%). Of note, only seven of these patients (five with anastomotic leakage and one each with pelvic abscess and emoperitoneum) required a re-operation, had a prolonged hospital stay or required re-admission. This figure appears to be substantially lower compared to the complication rates approaching 40% recently reported for other pre-operative chemoradiation programs for locally advanced rectal cancer [2.Sauer R. Becker H. Hohenberger W. et al.Preoperative versus postoperative chemoradiotherapy for rectal cancer.N Engl J Med. 2004; 351: 1731-1740Crossref PubMed Scopus (4610) Google Scholar, 3.Rodel C. Grabenbauer G.G. Papadopoulos T. et al.Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.J Clin Oncol. 2003; 21: 3098-3104Crossref PubMed Scopus (262) Google Scholar]. The relevance of these results is increased considering the low location of the tumors (median distance from the anal verge 6 cm) and the conservative approach used in 90% of the patients. Both of these features are in fact associated with a high risk of anastomotic complications following surgery for rectal cancer.The concern raised on the re-operation rate appears to be based on a wrong interpretation of our results. The four patients requiring a second surgical procedure reported in our paper [1.Aschele C. Friso M.L. Pucciarelli S. et al.A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer.Ann Oncol. 2005; 16: 1140-1146Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar] are in fact referred to the whole population of 46 patients included in the study and not only to the cohort of 25 patients treated at the recommended dose level. The total re-operation rate is thus 8.7%. This figure compares well to the re-operation rates ranging from 6.5 to 17% reported for other regimens of pre-operative radiotherapy, with [3.Rodel C. Grabenbauer G.G. Papadopoulos T. et al.Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.J Clin Oncol. 2003; 21: 3098-3104Crossref PubMed Scopus (262) Google Scholar, 4.Gérard J.P. Chapet O. Nemoz C. et al.Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 Phase II Trial.J Clin Oncol. 2003; 21: 119-124Crossref Scopus (193) Google Scholar, 5.Machiels J.P. Duck L. Honhon B. et al.Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.Ann Oncol. 2005 Oct 11; (Epub ahead of print)Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar] or even without [6.Francois Y. Nemoz C.J. Baulieux J. et al.Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial.J Clin Oncol. 1999; 17: 2396-2402Crossref PubMed Google Scholar] the use of concomitant chemotherapy.Multiple arguments strongly argue against the hypothesized relationship between oxaliplatin scheduling and re-operations. As clearly outlined in the previous paragraph, the rate of re-operation in our study was lower than that assumed by Watanabe and coauthors and fully comparable to other, recently published, chemoradiation regimens for locally advanced rectal cancer [3.Rodel C. Grabenbauer G.G. Papadopoulos T. et al.Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.J Clin Oncol. 2003; 21: 3098-3104Crossref PubMed Scopus (262) Google Scholar, 4.Gérard J.P. Chapet O. Nemoz C. et al.Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 Phase II Trial.J Clin Oncol. 2003; 21: 119-124Crossref Scopus (193) Google Scholar, 5.Machiels J.P. Duck L. Honhon B. et al.Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.Ann Oncol. 2005 Oct 11; (Epub ahead of print)Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 6.Francois Y. Nemoz C.J. Baulieux J. et al.Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial.J Clin Oncol. 1999; 17: 2396-2402Crossref PubMed Google Scholar]. This leaves little room for a correlation between drug scheduling and this measure of surgical outcome. The re-operation rate observed with our weekly schedule of oxaliplatin administration compares then favourably to the 10% re-operation rate recently reported for a pre-operative chemoradiation regimen that uses oxaliplatin with a tri-weekly schedule [4.Gérard J.P. Chapet O. Nemoz C. et al.Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 Phase II Trial.J Clin Oncol. 2003; 21: 119-124Crossref Scopus (193) Google Scholar]. Of note, patients requiring a second surgical procedure in our study also appeared to be evenly distributed among the cohort treated at the recommended dose level and the cohorts treated at lower doses (2 out of 25, 8% and 2 out of 21, 9%, respectively), ruling out a major impact of chemotherapy on re-operations. Other factors, including tumor location and tumor size, radiotherapy dose and length of the interval between chemoradiation and surgery, extension and type of surgery and the use of a covering stoma in patients with low anastomoses, are likely to play a more important role on outcome and complications following rectal cancer surgery. On the other hand, weekly administration allows the delivery of doses of oxaliplatin potentially active systemically concomitant to radiation and may also result in increased radiosensitization and decreased acute toxicity [1.Aschele C. Friso M.L. Pucciarelli S. et al.A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer.Ann Oncol. 2005; 16: 1140-1146Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. Multiple reports by other authors [3.Rodel C. Grabenbauer G.G. Papadopoulos T. et al.Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.J Clin Oncol. 2003; 21: 3098-3104Crossref PubMed Scopus (262) Google Scholar, 5.Machiels J.P. Duck L. Honhon B. et al.Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.Ann Oncol. 2005 Oct 11; (Epub ahead of print)Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 7.Sebag-Montefiore D. Brown G. Rutten H. et al.An international phase II study of Capecitabine, Oxaliplatin, Radiotherapy and Excision (CORE) in patients with MRI-defined locally advanced rectal adenocarcinoma. Interim results.Eur J Cancer Supplements. 2005; 3: 170Crossref Google Scholar] have indeed confirmed the feasibility of incorporating weekly oxaliplatin in the pre-operative treatment of rectal cancer with promising results.In summary, we believe that these data on surgery-related adverse events provide further evidence of the feasibility of the proposed regimen, combining standard pre-operative radiotherapy, infused 5-fluorouracil and weekly oxaliplatin at the doses set in our original report and fully support its suitability for a neoadjuvant use in locally-advanced rectal cancer. Since this was a phase I–II study with an inherently small sample size, surgery-related morbidity as well acute toxicity and efficacy of the regimen should now be addressed in larger and controlled studies. The rapid accrual of an Italian randomized trial comparing our novel experimental regimen with a standard 5-fluorouracil-based chemoradiation program without oxaliplatin (STAR – Studio Terapia Adiuvante Retto) is reassuring at this regard. The letter by Watanabe et al. regarding the report of our phase I–II study of weekly oxaliplatin and infused 5-fluorouracil combined with standard pre-operative radiotherapy for locally advanced rectal cancer, published in the July 2005 issue of Annals of Oncology [1.Aschele C. Friso M.L. Pucciarelli S. et al.A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer.Ann Oncol. 2005; 16: 1140-1146Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar], gives us the opportunity to define more clearly the surgical complications of this regimen. In summary, data on post-operative morbidity have been requested, concern has been raised on the re-operation rate and a relationship has been hypothesized between re-operations and the schedule of oxaliplatin administration. As to the first issue, post-operative complications were observed in 12 of 46 patients (26%). Of note, only seven of these patients (five with anastomotic leakage and one each with pelvic abscess and emoperitoneum) required a re-operation, had a prolonged hospital stay or required re-admission. This figure appears to be substantially lower compared to the complication rates approaching 40% recently reported for other pre-operative chemoradiation programs for locally advanced rectal cancer [2.Sauer R. Becker H. Hohenberger W. et al.Preoperative versus postoperative chemoradiotherapy for rectal cancer.N Engl J Med. 2004; 351: 1731-1740Crossref PubMed Scopus (4610) Google Scholar, 3.Rodel C. Grabenbauer G.G. Papadopoulos T. et al.Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.J Clin Oncol. 2003; 21: 3098-3104Crossref PubMed Scopus (262) Google Scholar]. The relevance of these results is increased considering the low location of the tumors (median distance from the anal verge 6 cm) and the conservative approach used in 90% of the patients. Both of these features are in fact associated with a high risk of anastomotic complications following surgery for rectal cancer. The concern raised on the re-operation rate appears to be based on a wrong interpretation of our results. The four patients requiring a second surgical procedure reported in our paper [1.Aschele C. Friso M.L. Pucciarelli S. et al.A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer.Ann Oncol. 2005; 16: 1140-1146Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar] are in fact referred to the whole population of 46 patients included in the study and not only to the cohort of 25 patients treated at the recommended dose level. The total re-operation rate is thus 8.7%. This figure compares well to the re-operation rates ranging from 6.5 to 17% reported for other regimens of pre-operative radiotherapy, with [3.Rodel C. Grabenbauer G.G. Papadopoulos T. et al.Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.J Clin Oncol. 2003; 21: 3098-3104Crossref PubMed Scopus (262) Google Scholar, 4.Gérard J.P. Chapet O. Nemoz C. et al.Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 Phase II Trial.J Clin Oncol. 2003; 21: 119-124Crossref Scopus (193) Google Scholar, 5.Machiels J.P. Duck L. Honhon B. et al.Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.Ann Oncol. 2005 Oct 11; (Epub ahead of print)Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar] or even without [6.Francois Y. Nemoz C.J. Baulieux J. et al.Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial.J Clin Oncol. 1999; 17: 2396-2402Crossref PubMed Google Scholar] the use of concomitant chemotherapy. Multiple arguments strongly argue against the hypothesized relationship between oxaliplatin scheduling and re-operations. As clearly outlined in the previous paragraph, the rate of re-operation in our study was lower than that assumed by Watanabe and coauthors and fully comparable to other, recently published, chemoradiation regimens for locally advanced rectal cancer [3.Rodel C. Grabenbauer G.G. Papadopoulos T. et al.Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.J Clin Oncol. 2003; 21: 3098-3104Crossref PubMed Scopus (262) Google Scholar, 4.Gérard J.P. Chapet O. Nemoz C. et al.Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 Phase II Trial.J Clin Oncol. 2003; 21: 119-124Crossref Scopus (193) Google Scholar, 5.Machiels J.P. Duck L. Honhon B. et al.Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.Ann Oncol. 2005 Oct 11; (Epub ahead of print)Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 6.Francois Y. Nemoz C.J. Baulieux J. et al.Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial.J Clin Oncol. 1999; 17: 2396-2402Crossref PubMed Google Scholar]. This leaves little room for a correlation between drug scheduling and this measure of surgical outcome. The re-operation rate observed with our weekly schedule of oxaliplatin administration compares then favourably to the 10% re-operation rate recently reported for a pre-operative chemoradiation regimen that uses oxaliplatin with a tri-weekly schedule [4.Gérard J.P. Chapet O. Nemoz C. et al.Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: the Lyon R0-04 Phase II Trial.J Clin Oncol. 2003; 21: 119-124Crossref Scopus (193) Google Scholar]. Of note, patients requiring a second surgical procedure in our study also appeared to be evenly distributed among the cohort treated at the recommended dose level and the cohorts treated at lower doses (2 out of 25, 8% and 2 out of 21, 9%, respectively), ruling out a major impact of chemotherapy on re-operations. Other factors, including tumor location and tumor size, radiotherapy dose and length of the interval between chemoradiation and surgery, extension and type of surgery and the use of a covering stoma in patients with low anastomoses, are likely to play a more important role on outcome and complications following rectal cancer surgery. On the other hand, weekly administration allows the delivery of doses of oxaliplatin potentially active systemically concomitant to radiation and may also result in increased radiosensitization and decreased acute toxicity [1.Aschele C. Friso M.L. Pucciarelli S. et al.A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer.Ann Oncol. 2005; 16: 1140-1146Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. Multiple reports by other authors [3.Rodel C. Grabenbauer G.G. Papadopoulos T. et al.Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.J Clin Oncol. 2003; 21: 3098-3104Crossref PubMed Scopus (262) Google Scholar, 5.Machiels J.P. Duck L. Honhon B. et al.Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.Ann Oncol. 2005 Oct 11; (Epub ahead of print)Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 7.Sebag-Montefiore D. Brown G. Rutten H. et al.An international phase II study of Capecitabine, Oxaliplatin, Radiotherapy and Excision (CORE) in patients with MRI-defined locally advanced rectal adenocarcinoma. Interim results.Eur J Cancer Supplements. 2005; 3: 170Crossref Google Scholar] have indeed confirmed the feasibility of incorporating weekly oxaliplatin in the pre-operative treatment of rectal cancer with promising results. In summary, we believe that these data on surgery-related adverse events provide further evidence of the feasibility of the proposed regimen, combining standard pre-operative radiotherapy, infused 5-fluorouracil and weekly oxaliplatin at the doses set in our original report and fully support its suitability for a neoadjuvant use in locally-advanced rectal cancer. Since this was a phase I–II study with an inherently small sample size, surgery-related morbidity as well acute toxicity and efficacy of the regimen should now be addressed in larger and controlled studies. The rapid accrual of an Italian randomized trial comparing our novel experimental regimen with a standard 5-fluorouracil-based chemoradiation program without oxaliplatin (STAR – Studio Terapia Adiuvante Retto) is reassuring at this regard.