# Metastatic and recurrent anal squamous cell carcinoma

Source: https://onco.cc/cancers/metastatic-anal-cancer/  
OnCo record `metastatic-anal-cancer` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Metastatic anal cancer is squamous cell anal cancer that has spread to the liver, lungs or distant lymph nodes, or come back where surgery can no longer remove it. Carboplatin with paclitaxel became the standard first treatment after the InterAACT trial, the PD-1 antibody retifanlimab was added to it in 2025 after POD1UM-303, and nivolumab or pembrolizumab are options after chemotherapy.

## Summary

Anal squamous cell carcinoma that has spread beyond the pelvis was for decades treated with cisplatin and fluorouracil on the strength of small series alone. InterAACT (Journal of Clinical Oncology 2020), the first randomised trial in advanced anal cancer, compared that regimen with carboplatin and paclitaxel in 91 patients: response rates were similar, carboplatin and paclitaxel caused fewer serious adverse events and was associated with longer survival, and it became the reference first-line regimen in the NCCN and ESMO guidelines. Because almost all these tumours are HPV-driven and carry PD-L1, checkpoint inhibitors were tested early: the NCI9673 trial of nivolumab (Lancet Oncology 2017) reported responses in 24 percent of 37 previously treated patients, and pembrolizumab showed durable responses in the KEYNOTE-028 and KEYNOTE-158 anal cohorts, so both are guideline options after chemotherapy.

POD1UM-303, also called InterAACT 2 (Lancet 2025), randomised 308 patients with inoperable locally recurrent or metastatic disease to carboplatin and paclitaxel with retifanlimab or placebo and lengthened progression-free survival from 7.4 to 9.3 months, with overall survival favouring the antibody; the United States approved retifanlimab with carboplatin and paclitaxel in May 2025, the first drug approval specific to anal cancer. Oligometastatic disease is sometimes treated with resection or stereotactic radiotherapy of liver or lung metastases, and isolated pelvic recurrence after chemoradiotherapy is treated by salvage surgery rather than as metastatic disease. Circulating HPV DNA is being studied to follow response, and trials of HPV-directed T-cell therapies and vaccines enrol anal cancer alongside cervical and oropharyngeal cancer.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: Advanced anal cancer; Stage IV anal squamous cell carcinoma; Inoperable recurrent anal cancer; Metastatic SCAC
- Tags: subtype-page; gastrointestinal
- Group: gastrointestinal
- Burden: A minority of patients present with distant spread or relapse beyond the pelvis after chemoradiotherapy; the liver, lungs and distant nodes are the usual sites.
- Subtypes: Synchronous metastatic anal squamous cell carcinoma (liver, lung, distant nodes); Metachronous relapse after chemoradiotherapy; Inoperable locally recurrent anal cancer; Oligometastatic anal cancer (local treatment considered); HPV-negative metastatic anal squamous cell carcinoma
- Biomarkers: HPV and p16 status; PD-L1 (not required for retifanlimab); Circulating HPV DNA (investigational monitoring); HIV status and CD4 count; Mismatch repair and tumour mutational burden (rarely relevant)

## Standard of care

- First line: Carboplatin and paclitaxel with retifanlimab (POD1UM-303, approved 2025); carboplatin and paclitaxel alone (InterAACT) where the antibody is unavailable or contraindicated. ([Carboplatin](https://onco.cc/drugs/carboplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Retifanlimab](https://onco.cc/drugs/retifanlimab/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/))
- After platinum chemotherapy: Nivolumab (NCI9673) or pembrolizumab (KEYNOTE-158) if no prior PD-1 antibody; fluorouracil-based or taxane chemotherapy otherwise. ([Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Fluorouracil (5-FU)](https://onco.cc/drugs/fluorouracil/))
- Oligometastatic disease: Resection or stereotactic radiotherapy of limited liver or lung metastases alongside systemic therapy, on a case basis. ([SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/))
- Isolated pelvic recurrence: Salvage abdominoperineal resection when the tumour is resectable; re-irradiation is rarely possible. ([Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/), [Re-irradiation](https://onco.cc/terms/re-irradiation/))

## State of the art

- Retifanlimab with carboplatin and paclitaxel is the first regimen approved specifically for anal cancer.
- InterAACT gave the disease its first randomised first-line standard.
- PD-1 antibodies produce durable responses in a minority after chemotherapy.

## Open problems

- Median survival remains under two years even with a PD-1 antibody added to chemotherapy.
- No second-line standard exists after chemo-immunotherapy.
- Whether local treatment of oligometastases improves survival has never been randomised.
- HPV-directed cell therapies and vaccines are promising but early.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Anal_cancer
- InterAACT (JCO 2020): https://doi.org/10.1200/JCO.19.03266
- POD1UM-303 (Lancet 2025): https://doi.org/10.1016/S0140-6736(25)00631-2
- Wikipedia: https://en.wikipedia.org/wiki/Anal_cancer

## Connected records

- cancers: [Anal cancer (squamous cell carcinoma)](https://onco.cc/cancers/anal/), [Anal high-grade squamous intraepithelial lesions (precursor)](https://onco.cc/cancers/anal-hsil-precursor/), [Localised anal squamous cell carcinoma (stage I to III)](https://onco.cc/cancers/localised-anal-cancer/), [Node-positive and metastatic penile cancer](https://onco.cc/cancers/node-positive-penile-cancer/), [Recurrent or metastatic cervical cancer](https://onco.cc/cancers/recurrent-metastatic-cervical-cancer/)
- technologies: [Circulating tumour HPV DNA (ctHPV-DNA)](https://onco.cc/technologies/cthpv-dna/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/)
- targets: [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Fluorouracil (5-FU)](https://onco.cc/drugs/fluorouracil/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Retifanlimab](https://onco.cc/drugs/retifanlimab/)
- terms: [HPV-positive (p16) head and neck cancer](https://onco.cc/terms/hpv-p16/), [Re-irradiation](https://onco.cc/terms/re-irradiation/)
- key papers: [ESMO Clinical Practice Guideline on anal cancer: diagnosis, treatment and follow-up](https://onco.cc/key-papers/paper-esmo-anal-cancer-guideline-ann-oncol-2021/), [InterAACT: cisplatin and fluorouracil versus carboplatin and paclitaxel in advanced anal cancer](https://onco.cc/key-papers/paper-interaact-anal-cancer-carboplatin-paclitaxel-jco-2020/)

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