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Originally published as JCO Early Release 10.1200/JCO.2006.05.6754 on April 24 2006 © 2006 American Society of Clinical Oncology. Phase I/II Study of Preoperative Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy in Patients With Locally Advanced Rectal Cancer: Cancer and Leukemia Group B 89901
From the Massachusetts General Hospital Cancer Center; Dana-Farber Cancer Institute, Boston, MA; Cancer and Leukemia Group B Statistical Center; Duke University Medical Center, Durham, NC; University of North Carolina, Chapel Hill, NC; University of Missouri, Ellis Fischel Cancer Center, Columbia, MO; Weill Medical College of Cornell University, New York, NY Address reprint requests to David P. Ryan, MD, Massachusetts General Hospital, 100 Blossom St, Cox 640, Boston MA 02114; e-mail: dpryan{at}partners.org
PURPOSE: The addition of oxaliplatin to fluorouracil in patients with advanced colorectal cancer improves survival. This phase I/II study evaluated the addition of weekly oxaliplatin to preoperative continuous infusion fluorouracil (FU) and external-beam radiation therapy (RT) in patients with locally advanced rectal adenocarcinoma. PATIENTS AND METHODS: Patients with clinical T3/T4 rectal adenocarcinoma and no evidence of metastases were treated with weekly oxaliplatin, continuous infusion FU 200 mg/m2 intravenously, and RT. A total of 6 weekly doses of oxaliplatin were planned. RT dose was 1.8 Gy/fraction to a total dose of 50.4 Gy. In the phase I portion, oxaliplatin was escalated from 30 to 60 mg/m2. RESULTS: Forty-four patients were entered onto the study, 18 on the phase I portion and 26 on the phase II portion. The maximum-tolerated dose (MTD) for oxaliplatin was determined to be 60 mg/m2. At the MTD, 12 patients experienced grade 3 or 4 diarrhea, two patients experienced grade 3 neutropenia, and one patient experienced grade 3 thrombocytopenia. Fifty-six percent of patients entered at the MTD completed all 6 weeks of oxaliplatin. Eight (25%) of 32 patients enrolled at the phase II dose experienced a pathologic complete response. CONCLUSION: In this multicenter study, the addition of oxaliplatin to intravenous continuous infusion FU and RT for patients with locally advanced rectal cancer was associated with a high pathologic complete response rate but more toxicity than when FU is used alone. A regimen of weekly oxaliplatin, continuous infusion FU, and radiation therapy is now being evaluated by the National Surgical Adjuvant Breast and Bowel Project.
Surgery is the foundation of treatment for localized adenocarcinoma of the rectum. The standard surgical approach has changed over the last 20 years and sharp dissection of the total mesorectum (TME) is now the standard of care. Despite excellent local control with this technique, the Dutch Colorectal Cancer Group recently demonstrated that preoperative radiation improved local control for patients compared with the use of TME alone.1 For patients with pathologic T3 or T4 tumors, the use of adjuvant therapy with both chemoradiotherapy and chemotherapy has been associated with improved survival. Several centers have demonstrated that preoperative chemoradiotherapy can result in excellent rates of local control, better tolerance, and a higher likelihood of sphincter preservation.2-5 Recently, the German Rectal Cancer Study Group demonstrated in a randomized controlled trial that preoperative chemoradiotherapy was associated with improved local control and less toxicity when compared with postoperative chemoradiotherapy.6 Fluorouracil (FU) administered as a continuous infusion throughout the entire course of external-beam radiation is generally accepted in the United States as the standard chemoradiotherapy regimen for patients with T3, T4, or node-positive rectal cancer.7 When combined with FU, oxaliplatin improves the overall survival for patients with metastatic colorectal cancer and the rate of progression-free survival for patients with completely resected stage II and III colon cancer.8,9 In addition to improving the efficacy of systemic therapy for patients with colorectal cancer, oxaliplatin has radiation sensitization properties.10 In this study conducted by the Cancer and Leukemia Group B (CALGB), we combined oxaliplatin and continuous infusion FU in patients with clinically staged T3 or T4 rectal cancers. Our aims were to assess the safety of this combination in a phase I trial and to assess the efficacy and tolerability of this combination in a multi-institutional phase II trial, with the long-term goal of developing a treatment plan that would improve local control and sphincter preservation while managing systemic disease.
Eligibility Criteria Patients entering the study had histologically confirmed rectal adenocarcinoma beginning within 12 cm of the anal verge, as determined by endoscopy. The tumor had to be fixed on physical examination or have evidence of T3 or T4 disease by endoscopic ultrasound or magnetic resonance imaging. In addition, patients could have no evidence of metastatic disease by abdominal computed tomography scan and could have no history of neuropathy. We included patients with granulocytes  1,500/µL, platelets 1,500/µL, bilirubin  the upper limit of normal, AST or ALT 2.5xthe upper limit of normal, and creatinine 1.5 mg/dL or creatinine clearance 60 mL/min/1.73 m2. All patients signed written informed consent approved by the participating institution's institutional review board.
Evaluation
Treatment Chemotherapy. All patients received central venous access for chemotherapy. FU was administered by an infusion pump over a period of 24 hours each day of each treatment week and the dose was fixed at 200 mg/m2/d. FU was started simultaneously with oxaliplatin each week. Oxaliplatin was administered on day 1 of each 7-day treatment cycle as a 1-hour infusion. Patients were not allowed to receive more than six cycles of therapy. All patients were premedicated to minimize nausea and vomiting and the use of anti–5-HT3 medications was encouraged. Adjuvant treatment with FU and leucovorin was recommended for all patients following surgery.
During the phase II segment of the study, chemoradiotherapy was held for toxicities Surgery. It was recommended that patients undergo surgery after a 4-to-6 week rest period after completion of chemoradiotherapy. A total mesorectal excision was recommended. Pathology. The extent of residual tumor in the resected specimen was classified according to the TNM staging sytem of the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) using the prescript "y" to indicate that the tumor has been treated before surgical resection. Only histologically viable tumors were staged according to the residual tumor classification. A pathologic complete response was defined as the absence of viable tumor cells in the primary tumor and in the lymph nodes (ie, ypT0, ypN0).
Study Design
Phase II.
In addition to the six patients studied at the MTD in the phase I portion of the trial, 19 patients were to be enrolled at the MTD during phase II in order to estimate the true toxicity rate more accurately. With radiation therapy and concurrent FU, the pathologic complete response rate has typically been reported to be in the range of 10% to 15%. The trial was designed to detect the difference between a pathologic complete response rate of 0.10 and 0.30 with 91% power (Exact test one-sample binomial proportion, 1-sided Patient registration and clinical data capture were managed by the CALGB Statistical Center. All statistical analyses were conducted using SAS 9.1 (SAS Institute, Cary, NC) and S-Plus 7.0 (Insightful Corporation, Seattle, WA).
Patient Characteristics Between December 2000 and November 2003, 44 patients were enrolled onto the study; 18 during the phase I portion and 26 during the phase II portion. Patient characteristics are listed in Table 1.
Phase I Trial The phase I portion of the study enrolled 18 patients at four different dose levels (Table 2). No DLTs were observed at the first three oxaliplatin dose levels of 30, 40, and 50 mg/m2, although two patients had to be replaced because of an allergic reaction in one patient and obstruction after a barium enema in another. Seven patients were treated at the 60 mg/m2 dose level. One patient experienced grade 3 diarrhea that caused a more than 7-day interruption in therapy. An additional patient at this dose level was replaced for the phase I evaluation because of a disease-related bowel perforation, but is included in the phase II analyses. The 60 mg/m2 dose was determined to be the MTD for oxaliplatin.
Phase II Trial Toxicity. Twenty-six patients were enrolled onto the phase II portion of the study. The six patients treated at the MTD during phase I were also included in this toxicity analysis (n = 32). Diarrhea was the most common severe toxicity as 12 patients (38%) experienced grade 3 or 4 diarrhea (Table 3). Grade 3 nausea occurred in three patients and grade 3 vomiting occurred in one patient. Severe neurotoxicity was not observed, but 21 patients (66%) experienced grade 1 or 2 sensory neuropathy. Grade 3 fatigue occurred in six patients (19%). Myelosuppression was mild and grade 3 neutropenia and thrombocytopenia occurred in two patients and one patient, respectively.
Since dose reductions were not allowed, the oxaliplatin dose was discontinued if a delay in treatment of more than 7 days occurred due to toxicity, or oxaliplatin was discontinued at the investigator's discretion if moderate-to-severe toxicity was experienced. Of the 32 patients enrolled at the phase II dose, 18 patients (56%) completed six cycles of oxaliplatin. Twenty-three patients (72%) completed at least four cycles of therapy. In the phase II portion of the study, 19 patients underwent a low anterior resection and 11 patients underwent an abdominoperineal resection. Surgical morbidity is listed in Table 5. Two patients had colostomy/ileostomy ischemia. One patient had a wound infection and one patient had an anastomotic leak.
Efficacy. Eight (25%) of 32 patients (95% CI, 11% to 43%) enrolled at the phase II dose experienced pathologic complete responses, including two of five patients who had clinical T4 disease at study entry (Table 4). In addition, six patients had ypT2 disease and 23 patients (72%) were node negative after chemoradiotherapy. Of the eight pathologically complete responders, there has been one relapse in the pelvis and rectum at 9.1 months. Relapse-free times range from 9.9 to 26.1 months, with a median of 18 months in the remaining seven patients with complete responses. In all 32 patients enrolled at the phase II dose, there have been two additional relapses in the lung and liver, at 10.7 and 12.4 months, respectively. Two patients died at 15.5 and 20.5 months, and the current median follow-up time was 18.5 months.
Preoperative chemoradiotherapy with continuous infusional FU and external-beam radiation therapy has become the standard practice for patients with clinical T3, T4, and node-positive rectal adenocarcinoma in the United States. Preoperative therapy is associated with better local control and an improved toxicity profile when compared with postoperative chemoradiotherapy.6 Despite progress in surgical technique, and the use of adjuvant FU chemotherapy, many patients will experience a local and/or systemic recurrence.11 Integration of new agents such as oxaliplatin and irinotecan, which are associated with improved survival for patients with metastatic colorectal cancer, may improve local and systemic control for patients with stage II and II rectal cancer. Phase II studies have evaluated weekly administration schedules of oxaliplatin and FU and have demonstrated similar efficacy compared with once-every-2-weeks schedules.12,13 In preclinical studies, oxaliplatin has been associated with radiation sensitization.10 We evaluated weekly oxaliplatin with continuous infusion FU and external-beam radiation therapy in an attempt to maximize exposure to oxaliplatin. In this multi-institutional CALGB phase I/II study, we have demonstrated that the addition of oxaliplatin to continuous infusion FU is feasible and associated with moderate toxicity. Despite lowering the dose of continuous infusion FU from the standard 225 mg/m2 to 200 mg/m2, 32% of patients experienced grade 3 or 4 diarrhea when weekly oxaliplatin 60 mg/m2 was administered. Only 56% of patients were able to complete all six cycles of oxaliplatin. With dose reductions, it is possible that more patients could have completed six cycles of therapy. However, we did not want to compromise potentially curative therapy by having prolonged treatment delays and thus required investigators to discontinue oxaliplatin if there was a more than 7-day delay in therapy because of toxicity. It should also be noted that two patients experienced bowel obstruction during the phase I portion of the study. While these obstructions were related to a barium enema and metastases, respectively, it should also be noted that this regimen might have contributed to these events. This rate of toxicity is higher than that which other investigators have reported utilizing FU and radiation in multi-institutional settings. Administering FU 1,000 mg/m2 over 120 hours via continuous infusion during the first and fifth weeks of radiation therapy preoperatively, the German Rectal Cancer Study Group reported that 12% of 399 patients experienced grade 3 or 4 diarrhea.6 Using 5 days of bolus FU and leucovorin on the first and fifth week of radiation, the European Organisation for Research and Treatment of Cancer enrolled patients in a randomized trial of preoperative chemoradiotherapy versus preoperative radiation.14 They reported that 34% of patients experienced grade 2 or higher diarrhea in the chemoradiotherapy group but only 52 (13%) of 400 patients experienced a temporary suspension of chemoradiotherapy because of toxicity. Single-center or limited institutional studies evaluating the combination of oxaliplatin and a fluoropyrimidine with radiation therapy for patients with rectal cancer have not reported high toxicity rates. Gerard et al15 evaluated FU, leucovorin, and oxaliplatin 130 mg/m2 during weeks 1 and 5 of radiation therapy and reported grade 3 or 4 diarrhea in three of 40 patients. In another study that used a weekly oxaliplatin regimen, Rodel et al16 combined capecitabine (825 mg/m2 bid days 1 through 14 and days 22 to 35) and oxaliplatin (50 or 60 mg/m2 on days 1, 8, 22, and 29). Radiation therapy was delivered at 1.8 Gy/fraction up to a total dose of 50.4 Gy. Although two of six patients treated with 60 mg/m2 of oxaliplatin experienced grade 3 diarrhea, only two of 26 patients experienced grade 3 diarrhea at the 50 mg/m2 dose level. In the Rodel et al study, 89% of patients completed the full course of therapy compared with 56% patients in our study. However, the total dose of oxaliplatin over a period of 6 weeks was only 200 mg/m2 in the Rodel study compared with 360 mg/m2 in our trial. Despite the increased toxicity, 25% of patients experienced a pathologic complete response. Single-institution series of preoperative FU and radiation therapy have demonstrated pathologic complete responses of 5% to 29%, but may have been subject to selection bias of patients in earlier stages.2-5,17-22 Of these studies, only Grann et al5 used rectal ultrasound staging, and their pathologic complete response rate was 13%. Similarly, the German Rectal Cancer Study Group employed endorectal ultrasound for staging patients and reported a pathologic complete response of 8% in 415 patients undergoing preoperative chemoradiotherapy.6 In a preliminary report from a single-institution study, Aschele et al23 demonstrated a pathologic complete response in 29% of patients treated with preoperative continuous infusion FU, weekly oxaliplatin, and external-beam radiation therapy. The pathologic response rates of 25% in our series and 29% in the Ascele series suggest that the addition of oxaliplatin to fluorouracil and radiation may be associated with improved downstaging of tumors. In summary, the addition of weekly oxaliplatin to continuous infusion FU and external-beam radiation therapy as preoperative therapy of clinical T3 and T4 rectal cancer is feasible, but associated with more toxicity than when FU is used alone as a radiation sensitizer. Nevertheless, most patients completed therapy as planned and 72% of patients completed at least four cycles of weekly oxaliplatin for a total oxaliplatin dose of at least 240 mg/m2 over 6 weeks. The addition of oxaliplatin to standard chemoradiotherapy seems to be associated with a high pathologic complete response rate. A weekly regimen of oxaliplatin, continuous infusion FU, and radiation therapy is now being evaluated by the National Surgical Adjuvant Breast and Bowel Project as one of the experimental arms in their protocol NSABP R-04.
The following institutions participated in this study: CALGB Statistical Center, Durham, NC: Stephen George, PhD, supported by CA33601; Cancer Centers of the Carolinas, Greenville, SC: Jeffrey K. Giguere, MD, supported by CA29165; Dana-Farber Cancer Institute, Boston, MA: George P. Canellos, MD, supported by CA32291; Dartmouth Medical School - Norris Cotton Cancer Center, Lebanon, NH: Marc S. Ernstoff, MD, supported by CA04326; Kansas City Community Clinical Oncology Program CCOP, Kansas City, MO: Jorge C. Paradelo, MD; Massachusetts General Hospital, Boston, MA: Michael L. Grossbard, MD, supported by CA12449; Northern Indiana Cancer Research Consortium CCOP, South Bend, IN: Rafat Ansari, MD, supported by CA86726; Rhode Island Hospital, Providence, RI: William Sikov, MD, supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY: Ellis Levine, MD, supported by CA02599; Southeast Cancer Control Consortium Inc CCOP, Goldsboro, NC: James N. Atkins, MD, supported by CA45808; University of California at San Diego, San Diego, CA: Stephen L. Seagren, MD, supported by CA11789; University of Iowa, Iowa City, IA: Gerald Clamon, MD, supported by CA47642; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO: Michael C. Perry, MD, supported by CA12046; University of North Carolina at Chapel Hill, Chapel Hill, NC: Thomas C. Shea, MD, supported by CA47559; Vermont Cancer Center, Burlington, VT: Hyman B. Muss, MD, supported by CA77406; Wake Forest University School of Medicine, Winston-Salem, NC: David D. Hurd, MD, supported by CA03927; Washington University School of Medicine, St Louis, MO: Nancy Bartlett, MD, supported by CA77440; Weill Medical College of Cornell University, New York, NY: Scott Wadler, MD, supported by CA07968.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported in part by grants from the National Cancer Institute to the Cancer and Leukemia Group B (Grant No. CA31946; Richard L. Schilsky, MD, Chairman), as well as Grants No. CA12449 (D.P.R.), CA33601 (D.N. and D.H.), CA12046 (B.E.M.), CA07968 (S.W.), CA47559 (J.E.T. and R.M.G.), CA32291 (R.J.M.). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001 2. Rich TA, Skibber JM, Ajani JA, et al: Preoperative infusional chemoradiation therapy for stage T3 rectal cancer. Int J Radiat Oncol Biol Phys 32:1025-1029, 1995[CrossRef][Medline] 3. Chari RS, Tyler DS, Anscher MS, et al: Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 221:778-786, 1995[Medline] 4. Stryker SJ, Kiel KD, Rademaker A, et al: Preoperative "chemoradiation" for stages II and III rectal carcinoma. Arch Surg 131:514-518, 1996 5. Grann A, Feng C, Wong D, et al: Preoperative combined modality therapy for clinically resectable uT3 rectal adenocarcinoma. Int J Radiat Oncol Biol Phys 49:987-995, 2001[CrossRef][Medline] 6. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 7. 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 331:502-507, 1994 8. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 9. 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 10. Hess S, Blackstock AW: Oxaliplatin: In vitro and in vivo evidence of its radiation sensitizing activity: Preclinical observation relevant to ongoing clinical trials. Proc Amer Assoc Cancer Res 41, 2000 (abstr A335) 11. 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 22:1785-1796, 2004 12. Chiara S, Nobile MT, Gozza A, et al: Phase II study of weekly oxaliplatin and high-dose infusional 5-fluorouracil plus leucovorin in pretreated patients with metastatic colorectal cancer. Anticancer Res 24:355-360, 2004 13. Rosati G, Rossi A, Tucci A, et al: Phase I study of a weekly schedule of oxaliplatin, high-dose leucovorin, and infusional fluorouracil in pretreated patients with advanced colorectal cancer. Ann Oncol 12:669-674, 2001 14. Bosset JF, Calais G, Daban A, et al: Preoperative chemoradiotherapy versus preoperative radiotherapy in rectal cancer patients: Assessment of acute toxicity and treatment compliance—Report of the 22921 randomised trial conducted by the EORTC Radiotherapy Group. Eur J Cancer 40:219-224, 2004[CrossRef][Medline] 15. Gerard JP, 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 21:1119-1124, 2003 16. Rodel C, Grabenbauer GG, Papadopoulos T, et al: Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 21:3098-3104, 2003 17. Chan A, Wong A, Langevin J, et al: Preoperative concurrent 5-fluorouracil infusion, mitomycin C and pelvic radiation therapy in tethered and fixed rectal carcinoma. Int J Radiat Oncol Biol Phys 25:791-799, 1993[Medline] 18. Landry JC, Koretz MJ, Wood WC, et al: Preoperative irradiation and fluorouracil chemotherapy for locally advanced rectosigmoid carcinoma: Phase I-II study. Radiology 188:423-426, 1993 19. Chen ET, Mohiuddin M, Brodovsky H, et al: Downstaging of advanced rectal cancer following combined preoperative chemotherapy and high dose radiation. Int J Radiat Oncol Biol Phys 30:169-175, 1994[Medline] 20. Weinstein GD, Rich TA, Shumate CR, et al: Preoperative infusional chemoradiation and surgery with or without an electron beam intraoperative boost for advanced primary rectal cancer. Int J Radiat Oncol Biol Phys 32:197-204, 1995[Medline] 21. Minsky BD, Cohen AM, Enker WE, et al: Preoperative 5-FU, low-dose leucovorin, and radiation therapy for locally advanced and unresectable rectal cancer. Int J Radiat Oncol Biol Phys 37:289-295, 1997[CrossRef][Medline] 22. Nakfoor BM, Willett CG, Shellito PC, et al: The impact of 5-fluorouracil and intraoperative electron beam radiation therapy on the outcome of patients with locally advanced primary rectal and rectosigmoid cancer. Ann Surg 228:194-200, 1998[CrossRef][Medline] 23. Aschele C, Friso M, Pucciarelli S, et al: A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion, and preoperative radiotherapy in locally advanced rectal cancer. Proc Am Soc Clin Oncol:132a, 2002 (abstr 527) Submitted January 18, 2006; accepted March 15, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
=.1). The new regimen was to be considered worthy of further investigation if five or more pathologic complete responses were observed in the 25-patient cohort treated at the MTD. 
