# 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)

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/metastatic-anal-cancer/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/metastatic-anal-cancer/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/metastatic-anal-cancer/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/metastatic-anal-cancer/#finding-it [5 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/metastatic-anal-cancer/#treating-it [4 settings, 2 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/metastatic-anal-cancer/#evidence [3 trials, 5 key papers, 3 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/metastatic-anal-cancer/#science [2 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/metastatic-anal-cancer/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/metastatic-anal-cancer/#living-with-it [17 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/metastatic-anal-cancer/coming/ [6 medicines, 3 trials, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/metastatic-anal-cancer/data/ [29 connected records]

## 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/), [InterAACT](https://onco.cc/trials/interaact/), [POD1UM-303/InterAACT-2](https://onco.cc/trials/pod1um-303/))
- 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/), [NCI9673](https://onco.cc/trials/nci9673/))
- 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-carboplatin-paclitaxel-advanced-anal-cancer-rao-jco-2020/), [NCI9673 part B: randomised phase 2 study of nivolumab with or without ipilimumab in refractory metastatic anal cancer](https://onco.cc/key-papers/paper-nci9673-part-b-nivolumab-ipilimumab-anal-cancer-morris-jco-2026/), [NCI9673: nivolumab for previously treated unresectable metastatic anal cancer](https://onco.cc/key-papers/paper-nci9673-nivolumab-metastatic-anal-cancer-morris-lancet-oncol-2017/), [POD1UM-303/InterAACT-2: retifanlimab with carboplatin and paclitaxel for locally recurrent or metastatic anal squamous cell carcinoma](https://onco.cc/key-papers/paper-pod1um-303-retifanlimab-anal-cancer-rao-lancet-2025/)
- trials: [InterAACT](https://onco.cc/trials/interaact/), [NCI9673](https://onco.cc/trials/nci9673/), [POD1UM-303/InterAACT-2](https://onco.cc/trials/pod1um-303/)

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JSON: https://onco.cc/api/v1/entities/metastatic-anal-cancer.json