Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: Highlights of the ASCO Guideline

Introduction:
This summary presents the key points of the American Society of Clinical Oncology (ASCO) guideline on systemic therapy for patients with stage I-III anal squamous cell carcinoma (SCC). The guideline’s objectives are to offer evidence-based recommendations that support clinicians in selecting radiosensitizing chemotherapy, dosage regimens, treatment strategies, the use of induction chemotherapy, and the use of ongoing adjuvant chemotherapy. This guidance focuses on optimizing chemoradiation (CRT) to improve oncologic outcomes while minimizing toxicities, particularly the myelosuppression that can limit therapy tolerability. Patients who are immunosuppressed and those with comorbidities receive special consideration.

Key Recommendations:

Radiosensitizing Chemotherapy

• Mitomycin-C (MMC) + Fluoropyrimidine: The standard radiosensitizing combination is MMC with fluorouracil (FU). Radiosensitizing means making the cancer cells more sensitive to radiation therapy. MMC with capecitabine (an oral alternative to FU) may also be offered, especially when infusion access is a concern. However, MMC is linked to higher hematologic toxicity, so its use demands vigilant monitoring.
• Cisplatin + FU: An alternative option for radiosensitization. This combination demonstrated noninferiority to MMC + FU in the ACT-II trial. The guideline states that the preferable regimen for patients with immunosuppression is cisplatin and FU, due to the myelosuppression associated with MMC. However, this regimen is not limited to this population. Cisplatin is unsuitable for individuals with renal impairment, significant neuropathy, or hearing loss, and there is no evidence supporting carboplatin substitution.

Dose and Schedule

• MMC + FU: Common regimens include MMC 10 mg/m^2 on days 1 and 29 (with caution on the second dose) or a single dose of 12 mg/m^2 on day 1, along with continuous-infusion FU (1,000 mg/m^2) on days 1–4 and 29–32. Clinicians should note that there is ongoing discussion about giving one versus two MMC doses, given the additional hematologic toxicity and radiation breaks often observed with two cycles.
• MMC + Capecitabine: MMC (single or divided dose as above) plus capecitabine (825 mg/m^2 orally twice daily on radiation days) is often used in practice, although large randomized trial data are lacking.
• Cisplatin + FU: Most commonly, cisplatin 60 mg/m^2 on days 1 and 29, with continuous-infusion FU (1,000 mg/m^2) on days 1–4 and 29–32, can be used. Weekly cisplatin regimens (20 mg/m^2 plus FU 300 mg/m^2) are another acceptable approach, though based on a lower level of evidence.

Single-Agent FU
For patients deemed unable to tolerate combination chemotherapy (e.g., poor performance status), single-agent FU with concurrent radiation may be offered.

Induction and Adjuvant Chemotherapy
No survival or disease-control benefit was observed with adding induction chemotherapy before CRT, nor with additional chemotherapy after CRT for localized anal cancer. Hence, routine use of induction or ongoing adjuvant therapy is not recommended.

Conclusion:
The guideline’s recommendations are based on moderate-quality evidence. These recommendations reinforce the longstanding role of MMC plus FU as the preferred radiosensitizing regimen for stage I-III anal SCC, with cisplatin-based or capecitabine-based options for specific patient needs. The guideline highlights that there are disparities in anal cancer incidence and outcomes, with higher rates among Black men and MSM. These disparities are further complicated by social determinants of health, such as smoking rates, HPV vaccination coverage, and access to screening and treatment. Limiting treatment toxicity—especially myelosuppression—remains critical to preserve treatment adherence and minimize breaks in radiation. Clinicians should tailor therapy to each patient’s comorbidities and performance status. Meanwhile, ongoing trials—such as ECOG-ACRIN 2165 (NCT03233711)—are investigating immunotherapy approaches for higher-risk locally advanced anal cancer, potentially informing future guideline updates.

Reference: Morris VK, Kennedy EB, Amin MA, et al. “Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline.” Journal of Clinical Oncology. https://doi.org/10.1200/JCO-24-02120