RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal

Abstract

Purpose: A multi-institutional phase 2 trial assessed the utility of dose-painted intensity modulated radiation therapy (DP-IMRT) in reducing grade 2+ combined acute gastrointestinal and genitourinary adverse events (AEs) of 5-fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer by at least 15% compared with the conventional radiation/5FU/MMC arm from RTOG 9811.

Methods and materials: T2-4N0-3M0 anal cancer patients received 5FU and MMC on days 1 and 29 of DP-IMRT, prescribed per stage: T2N0, 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs) in 28 fractions; T3-4N0-3, 45 Gy elective nodal, 50.4 Gy ≤ 3 cm or 54 Gy >3 cm metastatic nodal and 54 Gy anal tumor PTVs in 30 fractions. The primary endpoint is described above. Planned secondary endpoints assessed all AEs and the investigator's ability to perform DP-IMRT.

Results: Of 63 accrued patients, 52 were evaluable. Tumor stage included 54% II, 25% IIIA, and 21% IIIB. In primary endpoint analysis, 77% experienced grade 2+ gastrointestinal/genitourinary acute AEs (9811 77%). There was, however, a significant reduction in acute grade 2+ hematologic, 73% (9811 85%, P=.032), grade 3+ gastrointestinal, 21% (9811 36%, P=.0082), and grade 3+ dermatologic AEs 23% (9811 49%, P<.0001) with DP-IMRT. On initial pretreatment review, 81% required DP-IMRT replanning, and final review revealed only 3 cases with normal tissue major deviations.

Conclusions: Although the primary endpoint was not met, DP-IMRT was associated with significant sparing of acute grade 2+ hematologic and grade 3+ dermatologic and gastrointestinal toxicity. Although DP-IMRT proved feasible, the high pretreatment planning revision rate emphasizes the importance of real-time radiation quality assurance for IMRT trials.

Figure 1

Figure 1a. DP-IMRT Target Volumes and Doses A representative image of target volumes and doses in a cT3N3M0, stage IIIB case. The primary tumor PTV receives 54 Gy (red colorwash), and the elective nodes 45 Gy (blue colorwash). An involved right-sided inguinal node was dose-painted to 50.4 Gy (orange colorwash). Figure 1b. Mesorectal Contouring An illustration of incorrect (red colorwash) and correct (green line) investigator contouring of the mesorectum. The rectum with its surrounding lymphatic tissue is an important elective target.

Figure 1

Figure 1a. DP-IMRT Target Volumes and Doses A representative image of target volumes and doses in a cT3N3M0, stage IIIB case. The primary tumor PTV receives 54 Gy (red colorwash), and the elective nodes 45 Gy (blue colorwash). An involved right-sided inguinal node was dose-painted to 50.4 Gy (orange colorwash). Figure 1b. Mesorectal Contouring An illustration of incorrect (red colorwash) and correct (green line) investigator contouring of the mesorectum. The rectum with its surrounding lymphatic tissue is an important elective target.