A chemoradiotherapy regimen containing Platinol (cisplatin) and 5-FU (fluorouracil) carcinoma was not associated in a phase III trial for anal canal cancer with improved survival researchers reported here. Overall and disease-free survival rates in the Radiation Therapy Oncology Group RTOG 98-11 study were similar for both the Platinol-based regimen and a chemoradiation regimen of mitomycin-C and 5-FU.

"Mitomycin, 5-FU and radiotherapy remain the standard of care for patients with anal canal carcinoma," concluded Jaffer Ajani, M.D., a professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston. Dr. Ajani said that Platinol should not be used for these patients considering the new data on colostomy risk, but he was concerned about hearing that as many as 80% of private oncologists are still using the Platinol-based regimen. "We've got to get this information out there," Dr. Ajani said, in a presentation here at the semi-annual RTOG meeting.

The problem with anal carcinoma and local control is that the higher the T stage, the more likely clinically node positive disease. With that in mind, this study used what Dr. Ajani called an unusual design, aimed at reducing the size of large tumors with induction chemotherapy and then giving directed chemoradiation for better local control. The primary objective was disease-free survival. Secondary endpoints were overall survival, cumulative rate of colostomy at two years, rate of loco-regional failure, and safety. The study's hypothesis was that Platinol-5-FU would reduce the hazard for disease-free survival by 33% compared with mitomycin-5-FU. Expressed another way, the investigators hoped the disease-free survival rate would increase from 63% in the control arm to 73% for the comparator at five years. For that, 215 events were necessary and an accrual of 650 patients was expected in five years, plus three years of follow-up.

From 632 randomly assigned patients, 322 in the control arm received radiotherapy plus 5-FU (1,000 mg/m² by continuous infusion on days one through four and 29 through 32) plus mitomycin (10mg/m² IV on days one and 29). The other 312 patients received radiotherapy plus 5-FU (1,000 mg/m² by continuous infusion on days one through four, 29 through 32, 57 through 60 and 85 through 88) plus Platinol (75 mg/m² on days one, 29, 57, and 85). The trial results, first presented at the 2006 annual meeting of the American Society of Clinical Oncology, showed a disease-free survival rate of 59 % for the mitomycin arm at five years and 53 % for the Platinol arm.

For overall survival, Dr. Ajani said 276 of 322 patients in the mitomycin group were alive at five years, compared with 250 of 312 patients in the Platinol group. This could be expressed as a hazard ratio of 1.29 for the mitomycin-containing regimen compared with the Platinol-based regimen. The colostomy-free survival rate at five years was 90% for mitomycin compared with 81% for Platinol but the difference was not statistically significant (P=0.12). "Treatment did not have an impact on overall survival but the colostomy rate favored the mitomycin-5-FU combination," Dr. Ajani said. Male gender, higher T stage and clinically node positive disease were all predictive of poor outcome. Although RTOG 98-11 identified the standard of care in conventional agents for patients with this disease, the mortality rate for anal canal carcinoma is still too high, Dr. Ajani said. "The future for treatment in anal canal cancer is in biologics, because we have 'hit the wall' with chemotherapy," he said.

Fluorouracil, Mitomycin, and Radiotherapy vs Fluorouracil, Cisplatin, and Radiotherapy for Carcinoma of the Anal Canal A Randomized Controlled Trial

Jaffer A. Ajani, MD; Kathryn A. Winter, MS; Leonard L. Gunderson, MD; John Pedersen, MD; Al B. Benson III, MD; Charles R. Thomas Jr, MD; Robert J. Mayer, MD; Michael G. Haddock, MD; Tyvin A. Rich, MD; Christopher Willett, MD
 

JAMA. 2008;299(16):1914-1921.

Context  Chemoradiation as definitive therapy is the preferred primary therapy for patients with anal canal carcinoma; however, the 5-year disease-free survival rate from concurrent fluorouracil/mitomycin and radiation is only approximately 65%.

Objective  To compare the efficacy of cisplatin-based (experimental) therapy vs mitomycin-based (standard) therapy in treatment of anal canal carcinoma.

Design, Setting, and Participants  US Gastrointestinal Intergroup trial RTOG 98-11, a multicenter, phase 3, randomized controlled trial comparing treatment with fluorouracil plus mitomycin and radiotherapy vs treatment with fluorouracil plus cisplatin and radiotherapy in 682 patients with anal canal carcinoma enrolled between October 31, 1998, and June 27, 2005. Stratifications included sex, clinical nodal status, and tumor diameter.

Intervention  Participants were randomly assigned to 1 of 2 intervention groups: (1) the mitomycin-based group (n = 341), who received fluorouracil (1000 mg/m² on days 1-4 and 29-32) plus mitomycin (10 mg/m² on days 1 and 29) and radiotherapy (45-59 Gy) or (2) the cisplatin-based group (n = 341), who received fluorouracil (1000 mg/m² on days 1-4, 29-32, 57-60, and 85-88) plus cisplatin (75 mg/m² on days 1, 29, 57, and 85) and radiotherapy (45-59 Gy; start day = day 57).

Main Outcome Measures  The primary end point was 5-year disease-free survival; secondary end points were overall survival and time to relapse.

Results  A total of 644 patients were assessable. The median follow-up for all patients was 2.51 years. Median age was 55 years, 69% were women, 27% had a tumor diameter greater than 5 cm, and 26% had clinically positive nodes. The 5-year disease-free survival rate was 60% (95% confidence interval [CI], 53%-67%) in the mitomycin-based group and 54% (95% CI, 46%-60%) in the cisplatin-based group (P = .17). The 5-year overall survival rate was 75% (95% CI, 67%-81%) in the mitomycin-based group and 70% (95% CI, 63%-76%) in the cisplatin-based group (P = .10). The 5-year local-regional recurrence and distant metastasis rates were 25% (95% CI, 20%-30%) and 15% (95% CI, 10%-20%), respectively, for mitomycin-based treatment and 33% (95% CI, 27%-40%) and 19% (95% CI, 14%-24%), respectively, for cisplatin-based treatment. The cumulative rate of colostomy was significantly better for mitomycin-based than cisplatin-based treatment (10% vs 19%; P = .02). Severe hematologic toxicity was worse with mitomycin-based treatment (P < .001).

Conclusions  In this population of patients with anal canal carcinoma, cisplatin-based therapy failed to improve disease-free-survival compared with mitomycin-based therapy, but cisplatin-based therapy resulted in a significantly worse colostomy rate. These findings do not support the use of cisplatin in place of mitomycin in combination with fluorouracil and radiotherapy in the treatment of anal canal carcinoma.