Results of a pivotal Radiation Oncology Therapy Group (RTOG) phase II trial indicate that dose-painted intensity-modulated radiation therapy (IMRT) has similar efficacy to two- or three-dimensional (3D) radiation therapy in treating anal cancer when combined with standard chemotherapy, but causes fewer acute side effects. In this trial of 52 patients with stage II or III anal cancer (RTOG 0529), researchers found that patients who received dose-painted IMRT with fluorouracil (5-FU) and mitomycin had similar 2-year outcomes but fewer significant acute toxicities, compared with patients on the RTOG 9811 phase III trial, who received standard radiotherapy and 5‑FU/mitomycin.

Dose-painted IMRT allows dose distributions to be "painted" in such a way that their 3D shape agrees with the shape of the targets. Because it spares patients acute toxicity, dose-painted IMRT will be used as the platform and may allow for the investigation of novel agents and radiation dose escalation in future RTOG anal cancer trials, said lead researcher Lisa Kachnic MD, Chair of Radiation Oncology at Boston University. Dr. Kachnic presented the results of the dose-painted IMRT anal cancer phase II trial at this year's Gastrointestinal Cancers Symposium.¹

Toxicity Sparing

In the trial, dose-painted IMRT with 5-FU and mitomycin for anal cancer was associated with significant sparing of grade 3 or higher dermatologic and gastrointestinal acute toxicity, Dr. Kachnic reported. About 20% of patients experienced grade 3+ gastrointestinal acute toxicities in the dose-painted IMRT trial compared to 35% on the 5‑FU/mitomycin arm of RTOG 9811 (P = .0082). The researchers also observed a striking difference between the two groups in occurrence of grade 3+ acute dermatologic toxicities: Slightly over 20% of patients in the dose-painted IMRT trial had grade 3+ acute skin toxicities, compared with just under 50% for those on the RTOG 9811 trial (P < .0001). Patients on the dose-painted IMRT trial also experienced fewer grade 2+ hematologic toxicities (P = .032).

After a median follow-up of 26.7 months, the 2-year disease-free survival rate in the dose-painted IMRT trial was 77% and the overall survival rate was 86%. Although significantly more patients in the dose-painted IMRT trial had node-positive disease, their survival outcomes as well as local-regional failure, colostomy failure, and distant failure rates were similar to those in the 5-FU/mitomycin treatment arm of the RTOG 9811 trial. After 2 years, patients in the 5-FU/mitomycin arm of the RTOG 9811 trial had a disease-free survival of 75% and an overall survival of 91%.

Patients and Objectives

With the exception of the number of patients with node-positive disease, the investigators noted few differences between those treated in the dose-painted IMRT trial and those on the 5-FU/mitomycin arm of the RTOG 98-11 trial in terms of gender, performance status, histology, and tumor size. About 70% of patients in both the dose-painted IMRT trial and 5-FU/mitomycin arm of the RTOG 9811 trial had tumors ≤ 5 cm, Dr. Kachnic said.

The researchers' primary objective was to reduce the combined acute grade 2+ gastrointestinal and genitourinary toxicities by 15%, a goal they did not meet. Secondary endpoints were patient outcomes after follow-up, acute adverse events, IMRT feasibility and compliance as well as duration and treatment breaks. Of the 52 patients in the trial, 51 completed dose-painted IMRT as planned, and 84% completed the planned two cycles of chemotherapy. The median dose-painted IMRT duration was significantly lower than in the 5-FU/mitomycin arm of the RTOG 9811 trial (43 vs 49 days), and there were fewer treatment breaks, according to Dr. Kachnic. "That's important because we've seen from other studies that the longer the duration, the more chance there is for having a local recurrence," Dr. Kachnic said.

Planning Revisions

All of the radiation plans received real-time quality assurance, prior to the patients being treated, Dr. Kachnic said. All radiation plans were reviewed by Dr. Kachnic or her co-investigators.

Approximately 81% of patients required planning revisions since the investigators were more accustomed to performing prostate IMRT, and avoiding the rectum and mesorectum, rather than targeting these organs for anal cancer IMRT, Dr. Kachnic said. To aid the investigators, Dr. Kachnic and fellow researchers produced a radiation planning atlas to help with drawing the target volumes, she said.

"On final radiation review, we found that most of the investigators were able to achieve the rigid tumor, nodal, and normal tissue radiation prescription constraints we had prescribed," Dr. Kachnic said. "Dose-painted IMRT for anal cancer is feasible, but with rigorous quality assurance and continued education," she said. ■

Financial Disclosure: Dr. Kachnic has disclosed that she is an uncompensated consultant for Dor Biopharma.

Reference

1. Kachnic LA, Winter KA, Myuerson RJ, et al: Two-year outcomes of RTOG 0529: A phase II evaluation of dose-painted IMRT in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Gastrointestinal Cancers Symposium. Abstract 368. Presented January 22, 2011.