Chemoradiation Shows Responses Across Dose Levels in Anal Cancer

"[G]iven the improvements in compliance and tolerability of the de-escalated regimen in older patients, with preserved early cancer outcomes, this reduced-dose regimen could be considered a new treatment option for [patients who are] frailer [and] not fit for standard-dose chemoradiotherapy," according to the study authors.

Intensity-modulated radiotherapy (IMRT) demonstrated favorable 6-month complete clinical responses administered at a standard or reduced dose among patients with early-stage anal cancer, according to findings from the phase 2 PLATO-ACT4 trial (ISRCTN88455282) published in Lancet Oncology.1

At 6 months, a complete clinical response occurred in 84.4% (n = 135/160) of all evaluable patients, with respective rates of 84% (n = 46/55; 95% CI, 71.2%-92.2%) and 85% (n = 89/105; 95% CI, 76.4%-91.0%) with standard-dose IMRT (sd-IMRT) and reduced-dose IMRT (rd-IMRT). A confirmed clinical response was observed in 86% (n = 111/129) of patients with p16-positive disease and 100% (n = 8/8) of those with p16-negative disease.

Radiotherapy interruptions lasting 3 days or longer were needed for 26% (n = 14/55) of the sd-IMRT arm and 15% (n = 16/105) of the rd-IMRT arm. Investigators needed to modify chemotherapy delivery for 49% (n = 27/55) and 37% (n = 39/105) of each respective arm, with toxicity cited as the reason for modification in 36% (n = 20/55) and 25% (n = 26/105), respectively.

“[E]arly results from the ACT4 trial indicate there is a high complete clinical response rate at 6 months with reduced-dose chemoradiotherapy in early anal cancer. Although the 2 groups were not statistically compared, ACT4 suggests benefits in reduced acute toxicity and improved patient-reported sexual function for men and women with reduced-dose IMRT,” lead study author Alexandra Gilbert, FRCR, from Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, wrote with coauthors.1 “[G]iven the improvements in compliance and tolerability of the de-escalated regimen in older patients, with preserved early cancer outcomes, this reduced-dose regimen could be considered a new treatment option for [patients who are] frailer [and] not fit for standard-dose chemoradiotherapy.”

In the prospective, non-comparative phase 2 ACT4 trial, patients were randomly assigned 1:2 to receive sd-IMRT at 50.4 Gy in 28 fractions or rd-IMRT at 41.4 Gy in 23 fractions plus concurrent mitomycin (Mutamycin) and capecitabine (Xeloda).

The trial’s primary end point was 3-year locoregional failure. Secondary end points included acute toxicity, treatment compliance, 3-month and 6-month clinical response rates, disease-free survival, colostomy-free survival, progression-free survival, overall survival, and patient-reported outcomes (PROs).

PLATO is an integrated protocol that encompasses 3 individual trials—ACT3, ACT4, and ACT5—intended to optimize radiotherapy dosing in combination with chemotherapy for those with low-, intermediate-, and high-risk anal cancer.2 Eligibility for all trials included having histologically confirmed invasive primary squamous, basaloid, or cloacogenic carcinoma of the anus; being 16 years or older; and having adequate bone marrow, hepatic, and renal function. Additionally, patients needed to have an ECOG performance status of 0 or 1 to specifically enroll on the ACT4 trial.

Investigators noted that important prognostic factors were balanced across the sd-IMRT and rd-IMRT arms. The median age was 66.0 years (range, 35.0-87.0; IQR, 58.0-71.5). Additionally, 80% (n = 128/160) of patients had T2 tumors at a median tumor size of 2.5 cm (IQR, 2.0-3.0). A prior excision was noted for 40% (n = 14/35) of anal margin tumors.

Grade 3 or higher toxicities occurred in 46% (n = 25/55; 95% CI, 32%-60%) of the sd-IMRT arm and 35% (n = 37/105; 95% CI, 26%-45%) of the rd-IMRT arm. In the sd-IMRT and rd-IMRT arms, respectively, the most common grade 3 or higher adverse effects (AEs) included radiation dermatitis (13% vs 10%), diarrhea (7% vs 9%), and neutropenia (4% vs 6%). Additionally, 15% (n = 8/55) and 10% (n = 10/105) of patients in each arm experienced serious adverse reactions and serious AEs of interest. No patients had treatment-related deaths.

“PROs were similar during treatment and follow-up in both groups; however, better sexual function scores were observed for men and women at 6 months in the reduced-dose group, despite the dose constraints for organs at risk being standard for both groups,” the study authors noted.1

In the sd-IMRT arm, 36% (n = 5/14) of patients 70 years or older and 22% (n = 9/41) of those younger than 70 years required radiotherapy interruptions; these rates were 15% (n = 6/40) and 15% (n = 10/65), respectively, in the rd-IMRT arm. Any potential differences in radiotherapy or chemotherapy compliance between age groups did not confer a clear effect on complete clinical response rates.

Investigators are still awaiting 3-year locoregional failure data in the ACT4 study.

References

1. Gilbert A, Adams R, Webster J, et al. Standard versus reduced-dose chemoradiotherapy in anal cancer (PLATO-ACT4): short-term results of a phase 2 randomised controlled trial. Lancet Oncology. Published online May 4, 2025. doi:10.1016/S1470-2045(25)00213-X
2. PLATO - Personalising anal cancer radiotherapy dose. ISRCTN: The UK’s Clinical Study Registry. Updated January 24, 2025. Accessed May 7, 2025. https://tinyurl.com/3psfv98f