Since the early 1990s, postoperative adjuvant chemoradiotherapy was widely viewed as the main approach to treat patients with stage II and III rectal cancer. Over the past few years, significant efforts have shifted towards developing neoadjuvant approaches, which combine chemotherapy with radiotherapy prior to surgical resection.
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Dear Clinical Colleague:
I am pleased to introduce the first issue of E-Updates: Controversies in the Management of Rectal Cancer that will be available to you between now and the end of the year. The first part will focus on management with preoperative chemoradiation and the second part will explore novel chemoradiation regimens.
When you click on the link below, you will find the first issue “Controversies in Preoperative Chemoradiation for Rectal Cancer”. In this issue, the role of postoperative chemotherapy is addressed by Dr. Edward Chu, and I address whether novel chemoradiation regimens are more effective.
In the forthcoming issue, Dr. Philip Paty will address whether local excision is appropriate and Dr. Christopher Willett will examine 3D and IMRT radiation techniques.
I hope that you find these E-Updates timely, interesting, and informative.
Bruce Minsky, MD
Associate Dean and Professor of Radiation and Cellular Oncology
Pritzker School of Medicine, University of Chicago
Chief Quality Officer
University of Chicago Medical Center
Since the early 1990s, postoperative adjuvant chemoradiotherapy was widely viewed as the main approach to treat patients with stage II and III rectal cancer. Over the past few years, significant efforts have shifted towards developing neoadjuvant approaches, which combine chemotherapy with radiotherapy prior to surgical resection. The pivotal randomized study, performed in Germany and reported on in 2004, compared preoperative chemoradiotherapy with postoperative adjuvant chemoradiotherapy. Based on that study, neoadjuvant combined modality therapy has now become the standard of care in the United States for patients with locally advanced rectal cancer. The latest developments in neoadjuvant approaches are reviewed in greater detail by Dr. Bruce Minsky. This portion of the E-Update reviews the key clinical trials that focus on the role of chemotherapy in the adjuvant treatment of patients with rectal cancer following surgical resection.
By Edward Chu, MD
Professor of Medicine and Pharmacology
Chief, Section of Medical Oncology
Deputy Director, Yale Cancer Center
Yale University School of Medicine
New Haven, Connecticut
Several randomized phase III trials showed that chemotherapy when administered with concurrent radiation therapy after curative resection of rectal cancer decreased locoregional recurrence and improved survival. In the mid-1980s, the Gastrointestinal Study Group (GITSG) conducted GITSG 7175, which was a pivotal trial showing that adjuvant concurrent chemoradiation improved both local control and overall survival for patients with locally advanced rectal cancer, when compared with surgery alone or radiotherapy alone. After curative surgical resection of rectal cancer, patients (n = 202) were randomized to one of four treatment arms:
(1) no postoperative therapy;
(2) postoperative radiotherapy alone;
(3) postoperative chemotherapy alone with 5-fluorouracil (5-FU) and methyl-CCNU; or
(4) concurrent chemoradiation with 5-FU and methyl-CCNU.
Patients treated with concurrent chemoradiation had a much lower risk of recurrence (33%) compared to those who did not receive postoperative therapy (55%). Time to tumor recurrence was also significantly prolonged in the concurrent chemoradiation arm (P < .009). Overall survival (OS) did not differ significantly among the treatment groups. This study supported the incorporation of adjuvant chemoradiation as the standard of care for patients with Dukes stage B2 and C rectal cancer.
The National Surgical Adjuvant Breast and Bowel Project trial R-01 (NSABP R-01) investigated the role of adjuvant therapy in the management of Dukes B and C rectal cancer after curative surgical resection. Patients were randomized to one of three arms:
(1) no further treatment (n = 184);
(2) adjuvant MOF (methyl-CCNU, vincristine [Oncovin], 5-FU) chemotherapy (n = 187); or
(3) adjuvant radiation therapy alone (n = 184).
Patients treated with adjuvant chemotherapy experienced a significant increase in disease-free survival (DFS) (P = .006) and OS (P = .05) when compared to surgery alone. The use of adjuvant radiation therapy resulted in a reduction in locoregional recurrence in comparison to surgery alone (25% vs 16%, P = 0.6). Of note, no significant difference in DFS and OS was observed between radiation therapy and observation following surgical resection.
The North Central Cancer Treatment Group (NCCTG) trial 79-47-51 evaluated the role of adjuvant chemoradiation in the management of high-risk rectal cancer. A total of 2,004 patients were randomized to receive either adjuvant radiation alone or adjuvant radiation with concurrent 5-FU/methyl-CCNU combination chemotherapy. Patients receiving concurrent chemoradiation experienced significant reductions in disease recurrence (34% reduction, P = .0016), cancer-related deaths (36% reduction, P = .0071), and overall deaths (29% reduction, P = 0.025). This trial documented the clear superiority of concurrent chemoradiation over radiation alone in the adjuvant therapy of rectal cancer.
NSABP R-02 evaluated the role of radiation in addition to chemotherapy in the adjuvant setting. In this phase III randomized trial, 741 patients with Dukes B and C rectal cancer were randomized to receive adjuvant chemotherapy alone or adjuvant chemoradiation. Patients were stratified according to sex, number of positive lymph nodes, age, and institution. Male patients were randomized to one of four treatment arms:
(1) 5-FU/leucovorin weekly for 6 weeks followed by a 2-week rest period, given on an every 8-week cycle;
(2) infusional 5-FU/leucovorin plus radiotherapy;
(3) MOF (methyl-CCNU, vincristine [Oncovin], 5-FU at 325 mg/m2) on a 10-week cycle; or
(4) MOF plus radiotherapy given on a 10-week cycle.
Female patients were randomized to 5-FU/leucovorin alone or 5-FU/leucovorin plus radiotherapy. Patients treated with chemoradiation experienced a significant reduction in the cumulative incidence of locoregional relapse, from 13% to 8% at 5-year follow-up (P = .02). No differences in 5-year OS were observed between the MOF and 5-FU/leucovorin systemic chemotherapy arms in male patients (62% vs 65%, P = .17). This study confirmed that use of chemoradiotherapy in the adjuvant setting plays a key role in reducing the incidence of locoregional recurrence.
Bolus vs Infusional Fluorouracil
Fluorouracil-based chemotherapy has been the foundation of chemotherapy regimens in the adjuvant therapy of rectal cancer. In the early trials back in the 1980s and early 1990s, 5-FU was administered via bolus schedules. However, preclinical studies revealed that infusional 5-FU therapy was able to enhance antitumor activity and reduce overall toxicity when compared to bolus schedules. This finding stimulated the development of trials incorporating infusional 5-FU schedules.
O’Connell et al investigated the role of protracted venous infusion (PVI) 5-FU in combination with radiation in the adjuvant therapy of rectal cancer in 660 patients who had undergone potentially curative resection for stage II or III rectal cancer. Patients were randomized to one of four arms:
(1) bolus 5-FU (350 mg/m2 on days 1 to 5; 400 mg/m2 on days 36 to 40; 300 mg/m2 on days 134 to 138; and 350 mg/m2 on days 169 to 173) with methyl-CCNU (130 mg/m2 on day 1 and 100 mg/m2 on day 134) plus radiation therapy with concurrent bolus 5-FU;
(2) 5-FU/methyl-CCNU plus radiation therapy with concurrent PVI 5-FU (225 mg/m2/day for the entire radiation period);
(3) 5-FU (500 mg/m2 on days 1 to 5 and days 36 to 40; 450 mg/m2 on days 134 to 138 and days 169 to 173) plus radiation therapy with concurrent bolus 5-FU; or
(4) bolus 5-FU plus radiation therapy with concurrent PVI 5-FU.
Patients who received PVI 5-FU experienced significant decreases in the overall rate of tumor relapse compared to patients treated with bolus 5-FU/leucovorin combined with radiation therapy (47% vs 37%) and of distant metastasis (40% vs 31%). Although administration of PVI 5-FU did not result in a significant decrease in local recurrence, significant improvements in time to relapse and survival were observed when compared to bolus 5-FU treatment, with tumor-relapse decreased by 27% and death rates decreased by 31%.
This was a pivotal study as it showed for the first time that infusional 5-FU was superior to bolus 5-FU in the adjuvant chemoradiation treatment of early-stage rectal cancer. Moreover, this study provided the rational basis for using infusional schedules of 5-FU in the neoadjuvant preoperative setting.
Intergroup trial 0144 evaluated the role of infusional vs bolus schedules of 5-FU chemotherapy combined with radiation therapy in the adjuvant treatment of rectal cancer. After curative resection, patients (n = 1,917) were randomized to one of three treatment arms:
(1) bolus 5-FU in two 5-day cycles every 28 days before and after radiation in combination with PVI 5-FU at 225 mg/m2/day during radiation;
(2) PVI 5-FU for 42 days before and 56 days after radiation in combination with PVI 5-FU during radiation; or
(3) bolus 5-FU/leucovorin in two 5-day cycles before and after radiation in combination with bolus 5-FU/leucovorin.
After a median follow-up of 5.7 years, no significant differences in clinical efficacy between bolus vs PVI 5-FU were observed in terms of locoregional failure, DFS, and OS. However, PVI 5-FU was associated with an improved safety profile, as the incidence of grade 3/4 hematologic toxicity was markedly reduced, 4% vs 49% to 55% compared to bolus 5-FU.
European Organization for Research and Treatment of Cancer (EORTC) 22921 was a randomized trial to evaluate the role of concurrent chemoradiation in the neoadjuvant setting, along with the role of adjuvant chemotherapy in patients with resectable stage T3/4 rectal cancer. Patients (n = 1,011) were randomized to one of four treatment arms:
(1) preoperative radiation (45 Gy over 5 weeks) alone;
(2) preoperative radiation plus two 5-day courses of chemotherapy (5-FU at 350 mg/m
/day and leucovorin at 20 mg/m
/day in week 1 and 5 of radiation therapy);
(3) preoperative radiotherapy plus four postoperative courses of chemotherapy; or
(4) preoperative radiotherapy and chemotherapy plus postoperative chemotherapy.
The adjuvant chemotherapy used in this study was 5-FU (350 mg/m
/day) and leucovorin (20 mg/m
/day) given on days 1 to 5, and this regimen was given every 3 weeks for a total of 4 courses. Randomization was well-balanced with approximately 250 patients allocated to each treatment arm.
Patients treated with preoperative chemotherapy and radiotherapy experienced a higher pathologic complete response (pCR) rate of 13.7% vs 5.3% in patients treated with only preoperative radiotherapy. A lower pathologic stage of disease was observed in the combined chemoradiotherapy arm, as reflected by tumor and nodal substage. In addition, significant histologic changes were noted in the combined modality arm, with the number of tumors with venous, perineural, and lymphatic invasions markedly reduced in the preoperative combined treatment compared with the preoperative radiotherapy group. Patients treated with neoadjuvant chemoradiotherapy experienced a significantly reduced local failure rate when compared to radiotherapy alone (8% vs 17%,
This study provided further evidence for the benefit of combining chemotherapy with radiotherapy in the preoperative setting. At the time of the initial analysis, which was reported after a median follow-up of 5.4 years, adjuvant chemotherapy did not appear to confer benefit in terms of DFS or OS. However, there are two important points to note. The first is that only 43% of patients randomized to receive adjuvant chemotherapy actually received ≥ 95% of the planned dose of chemotherapy. The underlying reason(s) for this remain unclear, and could explain, at least, in part the lack of benefit to DFS or OS. Second, the survival curves for patients who received postoperative adjuvant chemotherapy begin to diverge after 2 years for DFS and after 4 years for OS, when compared to those who did not receive adjuvant chemotherapy, suggesting that further follow-up is required to determine whether these differences will continue.
An updated analysis was subsequently performed to determine the long-term results of the EORTC 22921 study. The goal of this exploratory multivariate analysis was to investigate whether a subgroup of patients could be identified who would benefit most from adjuvant chemotherapy in the long term. Adjuvant chemotherapy did not improve DFS or OS for all patients with resectable T3/4 rectal cancer. However, a subset analysis revealed that patients whose tumors were located higher up in the rectum (> 5 cm from the anal verge) and whose disease responded to neoadjuvant therapy, specifically those patients whose tumors were downstaged to ypT0-2 compared with stages ypT3-4 with preoperative therapy, experienced a survival benefit from adjuvant chemotherapy.
Fdration Francophone de la Cancrologie Digestive (FFCD) 9203 evaluated the potential survival benefit of concurrent chemoradiation in the neoadjuvant setting by randomizing patients to preoperative radiotherapy alone (n = 363) or concurrent neoadjuvant chemoradiation (n = 370). Patients treated on the concurrent chemoradiation arm received bolus 5-FU at 350 mg/m² and leucovorin at 20 mg/m² IV on days 1 to 5 in weeks 1 and 5 with concurrent radiation. In both arms, patients received four cycles of adjuvant 5-FU/leucovorin using a schedule of 5-FU at 350 mg/m² and leucovorin at 20 mg/m² IV on days 1 to 5 every 4 weeks, for a total of four cycles following surgical resection.
The pCR was significantly improved with the addition of chemotherapy from 3.7% to 11.7% (
< .05), although the sphincter-sparing rate was similar in the two arms (53% vs 52%). With a median follow up of 69.3 months, patients treated with neoadjuvant concurrent chemoradiotherapy experienced an improved 5-year local failure rate (8% vs 16.5%). Since patients received the same adjuvant chemotherapy in both study arms, the exact clinical benefit of postoperative 5-FU/leucovorin cannot be determined.
Eastern Cooperative Oncology Group (ECOG) 3201 was originally designed to compare the clinical efficacy of combination therapy vs 5-FU/leucovorin in stage II/III rectal cancer when used in the adjuvant setting. In this phase III study, patients were randomized to one of three treatment arms, which included infusional leucovorin/fluorouracil, FOLFOX (5-FU, leucovorin, oxaliplatin [Eloxatin]), and FOLFIRI (5-FU, leucovorin, irinotecan [CPT-11, Camptosar]). Unfortunately, this study was terminated after only 178 patients were randomized, in large part due to the report that FOLFIRI adjuvant chemotherapy was of no benefit in early-stage colon cancer and to the emerging role of bevacizumab (Avastin) in the treatment of colorectal cancer. Although no definitive conclusions could be made about the effects of adjuvant chemotherapy on clinical efficacy, an important conclusion of this study was that FOLFOX chemotherapy could be safely administered in patients following chemoradiation.
Ongoing Clinical Trials
Presently, the high priority adjuvant rectal cancer trial for the GI Intergroup is E5204, a randomized phase III study. The goal of this two-arm study is to determine whether combination postoperative adjuvant therapy can improve disease-free and overall survival. Patients are randomized to receive modified FOLFOX6 with or without the anti-vascular endothelial growth factor (anti-VEGF) antibody bevacizumab, given for 12 cycles.
In Europe, the Spanish are conducting the GCR-3 randomized phase II study. The efficacy of neoadjuvant CAPOX (capecitabine [Xeloda], oxaliplatin) chemotherapy followed by chemoradiotherapy and surgical resection with no further adjuvant chemotherapy is being compared with chemoradiotherapy using CAPOX followed by surgery and postoperative CAPOX chemotherapy.
Concerning the main question about whether there is a role for adjuvant chemotherapy following neoadjuvant combined modality therapy and surgical resection, the answer is simple-yes. However, the optimal adjuvant chemotherapy to be administered remains an ongoing issue. To date, there has been no definitive randomized study to identify the optimal postoperative adjuvant chemotherapy and the optimal duration of therapy. Despite the absence of such hard clinical data, the general recommendation is to give adjuvant chemotherapy for 4 months in patients with stage II and III rectal cancer. Fluoropyrimidine-based chemotherapy with infusional 5-FU/leucovorin, oral capecitabine, and FOLFOX are certainly all reasonable treatment options, depending on the stage of disease. This is similar to what is presently being recommended for the adjuvant therapy of stage II and III colon cancer.[12-14]
What about the situation in which a patient experiences a pathologic complete response to neoadjuvant chemoradiotherapy? Should this individual receive adjuvant chemotherapy? Again, while there is no study directly addressing this issue, the consensus view is to offer 4 months of therapy with FOLFOX for stage III and high-risk stage II disease, and fluoropyrimidine monotherapy with infusional 5-FU/leucovorin or oral capecitabine for patients with stage II disease.
We eagerly await the results of ongoing studies to determine the role of biologic agents in the adjuvant treatment of patients with surgically resected rectal cancer. The development of key clinical and pathologic factors as well as molecular biomarkers are critically important, since they will help identify which patients are at high risk for tumor recurrence and poor survival, as well as predict which patient subgroup will respond best to a particular treatment regimen and/or experience increased toxicity. Certainly, the goal moving forward is to begin to move away from empiric delivery of chemotherapy and to administer chemotherapy using an individually tailored approach.
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10. Gerard J, Conroy T, Bonnetain F, et al: Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203. J Natl Cancer Inst 24:4620-4625, 2006.
11. Benson AB, Catalan P, Meropol NJ, et al: ECOG E3201: Intergroup randomized phase III study of postoperative irinotecan, 5-fluorouracil (FU), leucovorin (LV) (FOLFIRI) vs oxaliplatin, FU/LV (FOLFOX) vs FU/LV for patients with stage II/III rectal cancer receiving either pre or postoperative radiation (RT)/FU (abstract 3526). J Natl Cancer Inst 24: 2006.
12. Benson AB: New approaches to assessing and treating early-stage colon and rectal cancers: Cooperative group strategies for assessing optimal approaches in early-stage disease. Clin Cancer Res 13(suppl 22): 6913s-6920s, 2007.
13. Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004.
14. Twelves C, Wong A, Nowacki MP, et al: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696-2704, 2005.