Optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II

Reporter: Annemarie Fernandes
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2012

Presenter: Robert Glynne-Jones, MD
Presenter's Affiliation: Mount Vernon Centre for Cancer Treatment, Middlesex, United Kingdom


  • Localized anal cancer is typically treated with definitive chemoradiotherapy (CRT).
  • Patients with persistent or locally progressive disease after treatment require salvage surgical resection, which typically involves a resection with colostomy placement.
  • In the ACT I trial, relapse-free survival was improved with chemoradiotherapy compared to radiotherapy alone, but the complete response (CR) rate at 6 weeks was similar (39% CRT, 30% RT alone; p=0.08).
  • Most studies assess CR between 6 and 12 weeks following completion of CRT.
  • The preliminary results of ACT II were presented at ASCO 2009. With a median follow-up of 3 years, there was no difference in CR rates between MMC and Cisplatin with or without maintenance chemotherapy.
  • This ACT II study investigates the association between observation of CR at 3 different time-points and progression-free and overall survival (PFS, OS), to determine the optimal time to assess this early endpoint.

Materials and Methods

  • This is a multicenter, randomized factorial trial that enrolled patients between June 2001- December 2008 and compared Cisplatin (60mg/m2 on d1+ d29) versus MMC (12mg/m2 on d1 only) when combined with 5-FU (1000mg/m2 d1-4 +d29-32) concurrent chemoradiotherapy, and two cycles of maintenance chemotherapy versus no maintenance.
  • Radiation therapy was delivered with 3D conformal radiation therapy with parallel-opposed fields. The whole pelvis was treated to 3060 cGy (in 180 cGy daily fractions) with a cone-down to the primary tumor to a total dose of 5040 cGy).
  • Patients were excluded if assessment was not done/ missing at one or more time points.
  • CR (complete absence of tumor and node negative) was assessed by digital rectal exam or exam under anesthesia at
    • 11 weeks (or 4 weeks after end of CRT)
    • 18 weeks (10-11 weeks after CRT and pre-maintenance)
    • 26 weeks (19 weeks after CRT and 4 weeks post-maintenance)
  • At 26 weeks, response assessment also included a CT of the abdomen/pelvis and chest X-ray


  • 940 patients MMC (N=472), Cisplatin (N=468), maintenance (N=448), no maintenance (N=446) were enrolled on the ACT II study.
  • 245 patients were excluded and 695 patients were analyzed.
  • Median follow-up= 5 years
  • Pt characteristics (of all 940):
    • median age 58 years
    • tumour site - canal (84%), margin (14%)
    • stage T1-T2 (52%), T3-T4 (46%); N+ (32%), N0 (62%).
  • Similar to results presented in 2009, Cisplatin (compared to MMC) did not improve OS (HR: 0.96, p=0.89) or PFS (HR: 0.85, p=0.43) and rates of grade 3/4 overall toxicity were also similar.
  • 90% compliance was seen in the MMC and Cisplatin arms
  • Complete response rates at 26 weeks were:
    • 83% and 84% in the primary tumor and lymph nodes in the MMC and Cisplatin arms, respectively (p=NS)
    • 82% and 85% in the primary tumor and lymph nodes in the no maintenance and maintenance arms, respectively (p=NS)
  • Complete response at 11 weeks, 18 weeks and 26 weeks was associated with statistically significant improvement in progression-free survival (for example, 11 weeks: 3-yr PFS: 80% CR vs. 72% no CR, p=0.02; 26 weeks 3-yr PFS: 83% CR vs. 45% no CR, p<0.001) and overall survival (26 weeks: 3-yr OS: 93% CR vs. 61% no CR, p<0.001).

Author's Conclusions

  • Excellent CR rate were observed at 6 months- 83% and 84% for MMC and cisplatin, respectively
  • The majority (60%) of pts not in CR at 11 weeks achieved CR at 26 weeks.
  • The authors recommend response assessment at 26 weeks in future trials.

Clinical Implications

  • Because many patients who did not achieve complete response at 11 weeks had complete regression of their tumor at 26 weeks, response assessment at 26 weeks will prevent many patients from undergoing unnecessary salvage surgery
  • It is important to note that while response assessment at 26 weeks benefits late responders to therapy, earlier response assessment at 11-18 weeks is still necessary to identify patients with progressive disease.
  • Interestingly, maintenance therapy did not impact the increased rate of complete response at 26 weeks vs. 11 weeks.
  • The administration of MMC on day 1 only (compared to prior RTOG studies that administered MMC on day 1 and 28) may explain the similar toxicity profiles and compliance rates seen in this study

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