RTOG 0529: A Phase II Evaluation of Dose-painted IMRT in Combination with 5-Fluorouracil and Mitomycin-C for Reduction of Acute Morbidity in Carcinoma of the Anal Canal

Article Outline

• Purpose/Objective(s)
• Materials/Methods
• Results
• Conclusions
• Copyright

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Purpose/Objective(s) 

Definitive 5-Fluorouracil (5-FU) and mitomycin-C (MMC) chemoradiation for anal cancer is an effective treatment strategy, but is associated with significant acute morbidity. Dose-painted IMRT (DP-IMRT), allowing for the simultaneous delivery of escalated doses to gross tumor and lower doses to normal tissues, has potential for reducing this toxicity.

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Materials/Methods 

A multi-institutional Phase II trial in T2–4N0-3M0 anal canal cancer evaluated DP-IMRT as follows - T2N0: 42 Gy, 1.5 Gy/fx to elective nodal and 50.4 Gy, 1.8 Gy/fx to anal tumor PTVs; T2N1–3, T3–4N0–3: 45 Gy, 1.5 Gy/fx elective nodes, 50.4 Gy, 1.68 Gy/fx to ≤3 cm, 54 Gy to >3 cm metastatic nodes, and 54 Gy anal tumor. All patients received 5-FU (1,000 mg/m²/day, 96 hours CI) and MMC (10 mg/m² i.v. bolus) Days 1 and 29 of RT. The primary endpoint was to determine if the combined rate of ≥ Grade 2 GI and GU acute adverse events (AEs) with DP-IMRT was decreased by 15% as compared to the RTOG 9811 MMC arm (9811MMC); 59 evaluable patients required. An important secondary endpoint was to assess the ability of investigators to perform DP-IMRT within the guidelines delineated; 42 evaluable patients required. If fewer than 5 cases had major deviations, DP-IMRT would be considered feasible.

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Results 

Of 63 accrued patients, 51 were analyzable. Median age 58 years; 42 (82%) female; 27 (53%) Stage II; 13 (25%) IIIA; and 11 (22%) IIIB. Thirty-nine patients (76%) experienced ≥ Grade 2 GI/GU acute AEs; equivalent to the rate from 9811MMC. There was a statistically significant reduction in ≥ Grade 3 GI/GU AEs, 11/51 (22%) vs. 117/324 (36%) 9811MMC, p = 0.014; ≥ Grade 2 dermatologic AEs, 35 (69%) vs. 264 (81%) 9811MMC, p = 0.039, and ≥ Grade 3 dermatologic AEs, 10 (20%) vs. 153 (47%) 9811MMC, p < 0.0001. Real-time QA was performed on all DP-IMRT plans; 79% required re-contouring prior to treatment. On final case review, there were no major deviations concerning tumor and nodal PTVs, and only 3 cases with major deviations for exceeding small bowel (3) and femoral head (1) tolerance. Median RT duration was 42.5 days (range, 32–59); 49 days (range, 0–102) on 9811MMC. At 8 Weeks, 34/51 (67%) of patients experienced complete clinical responses; 7 (14%) persistent but not progressive disease; 1 clinically suspicious progression, and no evaluations performed in 9 (18%).

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Conclusions 

Dose-painted IMRT in combination with 5-FU and MMC for the treatment of anal canal cancer are feasible in a multi-institutional setting, with significant sparing of Grade 2+dermatologic and Grade 3+GI/GU acute toxicity. Early clinical complete response rates appear encouraging, and further analysis of outcomes and late morbidity will be required to validate this approach.