# Node-positive and metastatic penile cancer

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

## TL;DR

Node-positive penile cancer is squamous cell cancer of the penis that has reached the lymph nodes of the groin or pelvis, and it is where penile cancer becomes life-threatening. Treatment combines removal of the groin nodes with chemotherapy or chemoradiotherapy before or after surgery, the InPACT trial is testing the best order, and PD-1 antibodies are being added for advanced disease.

## Summary

Penile squamous cell carcinoma spreads in an orderly way from the primary to the superficial and deep inguinal nodes, then to the pelvic nodes and only later to distant sites, which is why inguinal lymphadenectomy can still cure patients with limited node disease. The 2023 EAU-ASCO guideline recommends radical inguinal lymphadenectomy for a positive sentinel node or a palpable, biopsy-proven node, with pelvic lymphadenectomy when two or more inguinal nodes are involved or a node shows extranodal extension. Survival falls steeply with the number of nodes, bilateral disease, extranodal extension and pelvic involvement, and lymphadenectomy itself carries high rates of wound breakdown and lymphoedema, which minimally invasive and robotic techniques aim to reduce.

Systemic therapy is borrowed from small trials. The TIP regimen (paclitaxel, ifosfamide and cisplatin) produced responses in half of 30 patients given it before lymphadenectomy in a phase 2 trial at MD Anderson (Journal of Clinical Oncology 2010) and became the guideline neoadjuvant regimen for bulky or fixed nodes; paclitaxel and cisplatin with or without fluorouracil are alternatives. Adjuvant chemotherapy or chemoradiotherapy is offered after lymphadenectomy for pelvic node disease or extranodal extension, but the order and value of these treatments has never been randomised, which is what the international InPACT trial (International Penile Advanced Cancer Trial) is designed to answer. For metastatic disease platinum chemotherapy gives short responses, and phase 2 trials of pembrolizumab or cemiplimab, alone or with chemotherapy (HERCULES, EPIC), have shown responses in a subset, especially HPV-positive or PD-L1-positive tumours; the TG4001 HPV 16 vaccine with avelumab is also being tested in HPV 16-positive recurrent cancers.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: Advanced penile squamous cell carcinoma; Inguinal node-positive penile cancer; Locally advanced penile cancer; Metastatic penile cancer
- Tags: subtype-page; genitourinary
- Group: genitourinary
- Burden: A minority of patients in high-income countries but the group in which most deaths occur; groin node involvement is the strongest predictor of survival.
- Subtypes: Single inguinal node metastasis without extranodal extension (pN1; lymphadenectomy alone); Multiple or bilateral inguinal node metastases (pN2; lymphadenectomy with adjuvant therapy considered); Pelvic node metastasis or extranodal extension (pN3; multimodal therapy); Bulky or fixed inguinal nodes (neoadjuvant TIP then surgery); Distant metastatic penile squamous cell carcinoma
- Biomarkers: Number, laterality and extranodal extension of inguinal nodes; Pelvic node involvement on CT or PET-CT; p16 immunohistochemistry and HPV DNA (prognostic, trial stratification); PD-L1 expression (investigational); TP53 and CDKN2A alterations in HPV-independent tumours

## 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/node-positive-penile-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/node-positive-penile-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/node-positive-penile-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/node-positive-penile-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/node-positive-penile-cancer/#treating-it [5 settings, 4 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/node-positive-penile-cancer/#evidence [2 trials, 2 key papers, 4 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/node-positive-penile-cancer/#science [1 target]
- 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/node-positive-penile-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/node-positive-penile-cancer/#living-with-it [20 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/node-positive-penile-cancer/coming/ [6 medicines, 2 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/node-positive-penile-cancer/data/ [25 connected records]

## Standard of care

- Positive sentinel node or resectable palpable nodes: Radical inguinal lymphadenectomy; pelvic lymphadenectomy when two or more inguinal nodes are involved or extranodal extension is found. ([Lymphadenectomy (lymph node dissection)](https://onco.cc/terms/lymphadenectomy/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/))
- Bulky or fixed inguinal nodes: Neoadjuvant TIP chemotherapy (paclitaxel, ifosfamide, cisplatin) followed by lymphadenectomy in responders; chemoradiotherapy as an alternative within InPACT. ([Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Ifosfamide](https://onco.cc/drugs/ifosfamide/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [InPACT](https://onco.cc/trials/inpact/))
- After lymphadenectomy with pelvic nodes or extranodal extension: Adjuvant chemotherapy or chemoradiotherapy, ideally within InPACT because the benefit is unproven. ([Cisplatin](https://onco.cc/drugs/cisplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [InPACT](https://onco.cc/trials/inpact/))
- Metastatic disease: Platinum-based chemotherapy (TIP, paclitaxel-cisplatin, or with fluorouracil); PD-1 antibodies in trials or later lines (pembrolizumab, cemiplimab). ([Cisplatin](https://onco.cc/drugs/cisplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Fluorouracil (5-FU)](https://onco.cc/drugs/fluorouracil/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Cemiplimab](https://onco.cc/drugs/cemiplimab/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/))
- HPV 16-positive recurrent disease: Trials of HPV-directed vaccines with checkpoint inhibition (TG4001 with avelumab). ([Phase Ib/II of TG4001 and Avelumab in HPV16 Positive R/M Cancers](https://onco.cc/trials/nct03260023/))

## State of the art

- Inguinal and pelvic lymphadenectomy still cures many men with limited node disease.
- TIP chemotherapy before surgery for bulky nodes is the accepted approach, on phase 2 evidence.
- InPACT is the first randomised trial to test the order of surgery, chemotherapy and radiotherapy.

## Open problems

- No randomised trial has ever shown that chemotherapy improves survival in penile cancer.
- Lymphadenectomy causes lymphoedema and wound complications in a large share of patients.
- Distant metastatic disease is rarely controlled for long.
- HPV-positive and HPV-independent tumours may need different systemic strategies but are treated alike.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Penile_cancer
- Neoadjuvant TIP phase 2 (JCO 2010): https://doi.org/10.1200/JCO.2010.29.5477
- InPACT (ISRCTN): https://www.isrctn.com/ISRCTN36516280
- Wikipedia: https://en.wikipedia.org/wiki/Penile_cancer

## Connected records

- cancers: [Localised penile cancer (organ-confined, node-negative)](https://onco.cc/cancers/localised-penile-cancer/), [Metastatic and recurrent anal squamous cell carcinoma](https://onco.cc/cancers/metastatic-anal-cancer/), [Penile cancer](https://onco.cc/cancers/penile/)
- technologies: [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Robotic & minimally invasive surgery](https://onco.cc/technologies/robotic-surgery/), [Sentinel lymph node biopsy](https://onco.cc/technologies/sentinel-node/)
- targets: [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Cemiplimab](https://onco.cc/drugs/cemiplimab/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Fluorouracil (5-FU)](https://onco.cc/drugs/fluorouracil/), [Ifosfamide](https://onco.cc/drugs/ifosfamide/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- terms: [HPV status (HPV-positive / HPV-negative)](https://onco.cc/terms/hpv-status/), [HPV-positive (p16) head and neck cancer](https://onco.cc/terms/hpv-p16/), [Lymphadenectomy (lymph node dissection)](https://onco.cc/terms/lymphadenectomy/)
- trials: [InPACT](https://onco.cc/trials/inpact/), [Phase Ib/II of TG4001 and Avelumab in HPV16 Positive R/M Cancers](https://onco.cc/trials/nct03260023/)
- key papers: [EAU-ASCO collaborative guideline on penile cancer, 2023 update](https://onco.cc/key-papers/paper-eau-asco-penile-cancer-guideline-eur-urol-2023/), [Neoadjuvant paclitaxel, ifosfamide and cisplatin (TIP) for penile cancer with bulky lymph node metastases](https://onco.cc/key-papers/paper-pagliaro-neoadjuvant-tip-penile-cancer-jco-2010/)

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JSON: https://onco.cc/api/v1/entities/node-positive-penile-cancer.json