Efficacy
The benefit of concurrent chemoradiation (CRT) 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 CRT and reported superior local control in the concurrent chemoradiation arm.rr
The evidence supporting this CRT protocol is provided by two phase III multicentre randomised trials: RTOG 98-11 and ACT II.rr
RTOG 98-11
RTOG 98-11 is a phase III randomised study of 5-fluorouracil, mitomycin and radiation therapy versus 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 plus mitomycin and radiation therapy (45-59 Gy) and 341 patients were randomised to receive induction and concurrent chemotherapy: fluorouracil plus cisplatin and radiation therapy (45-59 Gy). The primary end point was 5-year disease-free survival, and secondary end points were overall survival and time to relapse. All endpoints were superior for the mitomycin/fluorouracil arm, 5-year disease-free survival 67.8% versus 57.8% (p = 0.006) and 5-year overall survival 78.3% versus 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 versus radiation therapy plus fluorouracil/cisplatin on (A) disease-free survival and (B) overall survival
RT + FU/MMC = radiation therapy plus fluorouracil/mitomycin; RT + FU/CDDP = radiation therapy plus fluorouracil/cisplatin.
© J Clin Oncol 2012r
ACT II
ACT II, a large randomised multicentre trial, compared cisplatin or mitomycin combined with fluorouracil-based CRT in improving responses with acceptable toxicity.r It also tested whether maintenance chemotherapy improved survival. Primary endpoints were complete response, grade 3 and 4 acute toxicities and progression-free survival. Secondary endpoints included colostomy-free survival, in-field recurrence rate, cause-specific survival and overall survival. Radiation therapy of 50.4 Gy was delivered in 28 daily fractions over 5.5 weeks, using a two phase technique. There were no significant differences in complete responses (absolute difference -0.9%, 95% CI: -4.9-3.1; p = 0.64) and grade 3 and 4 adverse events (71% versus 72%). The addition of maintenance treatment did not improve 3-year progression-free survival (HR = 0.95, 95% CI: 0.75-1.19; p = 0.63) or overall survival (HR = 1.07, 95% CI: 0.81-1.41; p = 0.65). See chemotherapy protocols 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 in combination with fluorouracil and mitomycin-C for the reduction of grade ≥2 gastrointestinal and genitourinary adverse events in carcinoma of the anal canal.r Outcomes with IMRT in conjunction with fluorouracil and mitomycin C were comparable to those from the fluorouracil/mitomycin control arm of the RTOG 98-11 trial in which radiation therapy was delivered using 2D/3D techniques.r
Prophylactic inguinal node irradiation
In patients not receiving prophylactic inguinal irradiation, Ortholan et al. demonstrated an inguinal node failure rate of 12% in T1-2 tumours, and 30% in T3-4 tumours.r A publication on the TROG 99.02 study demonstrated a similar failure rate of 12.5% in patients with clinical T1-T2 tumours and without prophylactic inguinal irradiation.r A caveat with these 2 studies is that staging did not include FDG-PET.
Dose escalation
The Action Clinique Coordonees en Cancerologie Digestive (ACCORD 03) and KANAL 2 trial, investigated the use of neoadjuvant cisplatin-based chemotherapy and dose-escalation of the radiation therapy boost.r These studies compared 45 Gy in 25 daily fractions plus a 15 Gy boost (after a 3 week gap), to a higher boost dose of 20-25 Gy. A pooled analysis has potentially shown benefits of escalating dose to 60 Gy or higher to improve colostomy-free survival, but was dependent on treatment time.
In select cases, dose escalation to 59.4 Gy may be considered for bulky tumours. There is an ongoing PLATO trial (incorporating anal cancer trials ACT IV and V) comparing 53.2 Gy in 28 fractions to two dose escalated arms.r
Adjuvant immunotherapy
Of note, results are pending from the RADIANCE trial comparing mitomycin/5-fluorouracil in combination with radiation therapy with an experimental arm receiving durvalumab.r