The benefit of concurrent chemoradiation as a definitive treatment was first reported by Nigro et al. in 1974.r Two phase III randomised trials (UKCCCR ACT I and EORTC) compared radiation therapy alone to concurrent chemoradiation and reported superior local control in the concurrent chemoradiation arm.rr
The evidence supporting this chemoradiation protocol is provided by two phase III multicentre randomised trials: RTOG 9811 and ACT II.
RTOG 98-11 is a phase III randomised study of 5-fluorouracil, mitomycin and radiation therapy vs 5-fluorouracil, cisplatin and radiation therapy in patients with anal canal carcinoma.r Between October 1998 and June 2005, 341 patients were randomised to receive fluorouracil (1000 mg/m2 on days 1-4 and 29-32) plus mitomycin (10 mg/m2 on days 1 and 29) and radiation therapy (45-59Gy) and 341 patients were randomised to receive induction and concurrent chemotherapy: 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 radiation therapy (45-59Gy; start day = day 57). The primary end point was 5 year disease-free survival (DFS), and secondary end points were overall survival (OS) and time to relapse. All endpoints were superior for the mitomycin/fluorouracil arm (5 year DFS, 67.8% v 57.8%; P=0.006; 5 year OS, 78.3% v 70.7%; p=0.026). A trend towards statistical significance was reported for colostomy free survival (P=0.05), locoregional failure (p=0.087), and colostomy failure (p=0.074).
Figure 1: Impact of radiation therapy plus fluorouracil/mitomycin (RT + FU/MMC) versus radiation therapy plus fluorouracil/cisplatin (RT + FU/CDDP) on (A) disease-free survival (p=0.006) and (B) overall survival (p=0.026).r
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The ACT II trial, a large randomised multicentre trial, compared cisplatin with mitomycin and flurouracil based chemoradiation in improving responses with acceptable toxicity.r It was also designed to test whether maintenance chemotherapy improves survival. Primary endpoints were complete response, grade 3 and 4 acute toxicities and PFS. Secondary endpoints included colostomy-free survival, in-field recurrence rate, cause-specific survival and OS. Radiation therapy of 50.4 Gy was delivered in 28 daily fractions over 5.5 weeks with a two-phase technique. There were no significant differences in the complete responses (absolute difference -0.9%, 95% CI: -4.9 to 3.1; p=0.64) and grade 3 and 4 adverse events (71% vs 72%). The addition of maintenance treatment did not improve 3 year PFS (HR 0.95, 95% CI: 0.75–1.19; p=0.63) nor did it improve OS (HR 1.07, 95% CI: 0.81-1.41; p=0.65). Link to: Anal definitive mitomycin and fluorouracil chemoradiation and Anal definitive ciSplatin and fluorouracil chemoradiation.
Intensity-modulated radiation therapy (IMRT)
Multiple retrospective studies have assessed the efficacy and safety of IMRT for treatment of anal cancer. Many report similar local control rates, disease free survival, colostomy free survival and comparable or lower toxicity with IMRT compared to traditional planning techniques.rr
RTOG 0529, a prospective phase II study (n =63), evaluated dose-painted intensity modulated radiation therapy (DP-IMRT) in combination with fluorouracil and mitomycin-C for the reduction of ≥ grade 2 GI and GU adverse events in carcinoma of the anal canal.rOutcomes with IMRT in conjunction with fluorouracil and mitomycin C were comparable to those from the fluorouracil/mitomycin control arm of the RTOG 9811 trial in which radiation therapy was delivered using 2D/3D techniques.r
Prophylactic inguinal node irradiation
Ortholan et al. demonstrated an inguinal node failure rate of 12% in T1-2 tumours and 30% in T3-4 tumours in patients not receiving prophylactic inguinal irradiation.r A publication on the TROG 99.02 study similarly demonstrated a 12.5% failure rate in patients with clinical T1-T2 tumours without prophylactic inguinal irradiation.r A caveat with these 2 studies is staging did not include FDG-PET.
The Action Clinique Coordonees en Cancerologie Digestive (ACCORD-03) trial, investigated the use of neoadjuvant cisplatin-based chemotherapy and dose-escalation of the radiation therapy boost.r They compared 45 Gy in 25 daily fractions plus a 15 Gy boost after a gap of 3 weeks with a higher boost dose of 20–25 Gy. The trial failed to show any additional benefit in terms of PFS by escalating total radiation.