# Radiotherapy for penile cancers: 2025 update

Geneviève Loos, Alexandre Escande, Sabrina Aziez, Vincent Marchesi, Paul

Sargos, Mario Terzilli, Igor Latorzeff, Stéphane Supiot, Verane Achard, J.

Le guevelou, et al.

► To cite this version:

Geneviève Loos, Alexandre Escande, Sabrina Aziez, Vincent Marchesi, Paul Sargos, et al. . Ra-diotherapy for penile cancers: 2025 update. Cancer/Radiothérapie, 2025, 29 (7-8), pp.104761. 10.1016/j.canrad.2025.104761 . hal-05409140

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Clinical practice guidelines

# Radiotherapy for penile cancers: 2025 update☆

## Radiothérapie des tumeurs de la verge : actualisation 2025

Geneviève Loos<sup>a, *,</sup> , Alexandre Escande<sup>b</sup> , Sabrina Aziez<sup>c</sup> , Vincent Marchesi<sup>d</sup> , Paul Sargos<sup>e, f</sup> , Mario Terzilli<sup>g</sup> , Igor Latorzeff<sup>h</sup> , Stéphane Supiot<sup>i</sup> , Vérane Achard<sup>e</sup> , Jennifer Le Guévelou<sup>k, l</sup> , Aude Flechon<sup>m</sup> , Jean-Michel Hannoun-Lévi<sup>n</sup> , Cyrus Chargari<sup>o</sup>

<figure><img src="image_3.png" /></figure>

## INFO ARTICLE

Keywords :

Radiotherapy
Penile cancer
Brachytherapy
Management
Surgery
Chemotherapy

Mots clés :

Radiothérapie
Cancer de la verge
Curiethérapie
Chirurgie
Chimiothérapie

## ABSTRACT

This article presents an update of the French national guidelines for the management of penile cancer, with recommendations on dose and volume for radiotherapy and brachytherapy. Multidisciplinary management and centralization in high-level of expertise centres is key for the management of this rare malignancy. For patients at high-risk of having micrometastatic disease (stage T1b or higher), a dynamic sentinel node biopsy should be offered as surgical staging and human papillomavirus status should be obtained. Organ-preservation with brachytherapy should be discussed whenever it is possible (tumours limited to the glans). For locoregionally advanced diseases, chemoradiotherapy as primary treatment could be discussed.

© 2025 The Authors. Published by Elsevier Masson SAS on behalf of Société française de radiothérapie oncologique (SFRO). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## RÉSUMÉ

Cet article présente une actualisation des recommandations françaises de radiothérapie pour le traitement des cancers de la verge en y détaillant les indications, les doses et les volumes de radiothérapie et de curiethérapie. La prise en charge de cette pathologie rare nécessite une centralisation dans les centres ayant un haut niveau d'expertise. Pour les patients sans atteinte ganglionnaire clinique (maladie de stade cN0) à haut risque d'avoir des micrométastases (maladie de stade T1b ou plus), la technique du ganglion sentinelle biopsie sentinelle doit être proposée. La recherche d'une infection par le papillomavirus humain est recommandée. La préservation d'organe en utilisant la curiethérapie devrait pouvoir être lorsque cela est possible (lorsque la tumeur est limitée au gland). Pour les tumeurs localement évoluées, la chimioradiothérapie définitive en première intention pourrait être discutée.

© 2025 Les Auteurs. Published par Elsevier Masson SAS au nom de Société française de radiothérapie oncologique (SFRO). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

<footnote><sup>a</sup> Département d'oncologie radiothérapie, centre Jean-Perrin, Clermont-Ferrand, France</footnote>

<footnote><sup>b</sup> Service de radiothérapie, centre Léonard-de-Vinci, Dechy, France</footnote>

<footnote><sup>c</sup> Radiation Oncology, hôpital Tenonn Assistance publique-hôpitaux de Paris, Sorbonne université, Paris, France</footnote>

<footnote><sup>d</sup> Service de physique médicale, institut de cancérologie de Lorraine, Vandœuvre-lès-Nancy, France</footnote>

<footnote><sup>e</sup> Department of Radiation Oncology, institut Bergonié, Bordeaux, France</footnote>

<footnote><sup>f</sup> Department of Radiotherapy, centre Charlebourg, La Garenne-Colombes, France</footnote>

<footnote><sup>g</sup> Department of Radiation Oncology, institut Gustave-Roussy, Villejuif, France</footnote>

<footnote><sup>h</sup> Clinique Pasteur, Toulouse, France</footnote>

<footnote><sup>i</sup> Institut de cancérologie de l'Ouest, centre René-Gauducheau, Saint-Herblain, France</footnote>

<footnote><sup>k</sup> Centre Eugène-Marquis, Rennes, France</footnote>

<footnote><sup>l</sup> LTSI, université de Rennes, avenue de la Bataille-Flandres-Dunkerque, Rennes, France</footnote>

<footnote><sup>m</sup> Centre Léon-Bérard, Lyon, France</footnote>

<footnote><sup>n</sup> Department of Radiotherapy, centre Antoine-Lacassagne, université Côte d'Azur, Nice, France</footnote>

<footnote><sup>o</sup> Radiation Oncology, hôpital Pitié Salpêtrière, Assistance publique-hôpitaux de Paris, Sorbonne université, Paris, France</footnote>

<footnote>☆ This article is part of the special issue RecoRad™, 4th edition on the 2025 update of the recommendations of the Société française de radiothérapie oncologique (SFRO) on external radiotherapy and brachytherapy procedures.</footnote>

<footnote>* Corresponding author: centre Jean-Perrin, Clermont-Ferrand, France.
Adresse e-mail : genevieve.loos@clermont.unicancer.fr (G. Loos).</footnote>
# 1. Introduction

## 1.1. Epidemiology, aetiology and pathology

More than 95 % of penile cancers are squamous cell carcinomas [1]. Human papillomavirus (HPV) infection is the main risk factor for developing penile cancer. Other risk factors have been identified, such as chronic penile inflammation, non-treated phimosis, poor hygiene, smoking, obesity, and low socioeconomic status [2]. Penile cancer is rare, particularly in industrialised countries, as well as in countries where circumcision is widely practiced [3].

In France, approximately 500 patients are diagnosed each year, of which one third is related to HPV infection [4]. The incidence increases with age, with a peak in the sixth decade. The new pathology classification separates HPV-related and non-HPV-related tumours. Block-type p16 immuno-histochemistry is the most practical and reliable method to separate HPV-associated from HPV-independent penile squamous cell carcinoma [5]. Similar to other HPV-related cancers, HPV-infected patients seem to have better outcomes and be more radiosensitive, but more data are needed [2,3].

## 1.2. Clinical presentation, extension and assessment of extension

In the majority of cases, the lesion is located in the glans. A large epidemiologic study revealed that 65.4 % of penile cancer cases are diagnosed as localized, 26.5 % as regional, and 3.5 % as distant disease [6]. The clinical examination with palpation should look for involvement of the corpora cavernosa and inguinal nodal involvement.

The primary staging consists of magnetic resonance imaging (MRI) or ultrasound performed by an expert radiologist with pharmacologically-induced erection to assess the extent of invasion of the corpora cavernosa and screening for signs of pelvic inguinal nodal extension [7,8]. The pathology report must specify: the histological type, the grade, the stage of local invasion, the presence or absence of lymphovascular and perineural invasion, the p16 status, and the surgical margin [9].

According to the American Joint Committee on Cancer (AJCC), poor prognosis factors are perineural invasion, lymphovascular invasion, and high grade [10]. The presence of any of these factors automatically classifies a tumour as pT1b. The prognosis of penile tumours is influenced by the Tumour Node Metastasis (TNM) stage, histological grade, and whether or not a sarcomatoid component is present [11]. Risk groups are categorized as follows [9]:

* low-risk tumours (stages up to pT1a and well-differentiated, histological grade 1 [G1]);

* intermediate-risk tumours (stage pT1a G2);

* high-risk tumours (stage pT1b or higher, or G3, or sarcomatoid component).

## 1.3. Lymphatic and metastatic diagnosis

Lymphatic evaluation is essential in diagnosing penile cancer. About 25 % of patients with cN0 tumours of intermediate or higher risk will have lymph node metastases that are not clinically detectable, so additional staging is warranted [12,13]. Thus, early detection of lymphatic spread is essential. However, current non-invasive staging methods, such as computed tomography (CT) and positron-emission tomography (PET)-CT, are not reliable enough to identify micrometastatic disease and should not be routinely used in patients with cN0 disease [14,15]. Hence, surgical staging is recommended in patients with a high-risk tumour (stage T1b or higher) and clinically node-negative groins (cN0) [12]. Whenever it is possible, dynamic sentinel lymph node biopsy is now recommended

as the preferred surgical diagnostic modality, as it is associated with less morbidity and higher accuracy compared with inguinal lymph node dissection [16,17]. Furthermore, it seems beneficial to centralize penile cancer management in high-volume centres that utilize the dynamic sentinel node biopsy technique, as these centres possess the necessary multidisciplinary expertise [9].

Nodal involvement is the main prognostic factor. An analysis of outcomes in 700 patients treated for penile cancer showed that 92 % of relapses occurred within 5 years after treatment of the primary disease. The probability of a regional relapse was 2.3 % for cancers of stage N° 19.1 % for those with nodal involvement and 9.1 % for those classified as Nx. In case of a regional relapse, the probability of 5 year specific survival was only 32.7 % [18]. Inguinal nodal involvement is found in almost 30 to 45 % of the cases at the time of diagnosis. Risk depends primarily on tumour size, existence of lymphovascular invasion, and ulcerative infiltrating histological type. Tumours which overexpress the protein p16 have a more favourable prognosis and appears to be more radiosensitive, probably related to the lack of TP53 mutations [19].

For patients with cancer classified as clinical node negative (stage cN0), a surgical lymph node staging should be offered to all patients at high-risk of having micrometastatic disease (stage T1b or higher), and the preferred method is dynamic sentinel node biopsy. If dynamic sentinel node biopsy is not available, surgical staging should be an inguinal lymph node dissection. Tumours staged up to pT1G1 have a favourable prognosis with a low risk of nodal involvement, whereas pT1G2 tumours present an intermediate risk (33 % nodal involvement). In contrast, pT1G3, pT2-3 G1-3 tumours are associated with a high risk of infraclinical nodal involvement, reaching up to 83 % of cases [20-22].

In case of clinically node positive (cN+), an image-guided biopsy should be obtained to confirm nodal metastasis before initiating treatment. The evaluation of the pelvis and metastatic staging using (18F)-fluorodeoxyglucose PET-CT is likely to be more accurate than CT alone for preoperative staging of pelvic lymph nodes with a sensitivity and specificity of 91 % and specificity of 100 %, respectively [20,23].

## 1.4. Classification

The eighth edition of the Union for International Cancer Control (UICC)/AJCC TNM classification is the system currently used for penile cancer and was last updated in 2017 (Table 1).

# 2. Disease management

## 2.1. Treatment of the primary tumour

The goal of treating the primary tumour is to achieve optimal oncological control while maximizing organ preservation [24]. There are no randomised control trials or observational comparative studies for any treatment options for localised penile cancer. Histological diagnosis and local staging must be obtained before non-surgical treatment option. Histology provides confirmation of the diagnosis before treatment and informs on the risk group of the primary tumour, which has important consequences for invasive staging of the groins. Treatment of the primary tumour and of the regional nodes can either be simultaneous or sequential. Circumcision is recommended for the Tis stage disease and mandatory for all other stages.

### 2.1.1. Treatment of superficial non-invasive disease (PeIN, Ta)

Stage Tis, Ta, or T1a can be treated with using superficial ablative, penile-sparing modalities such as topical therapies with imiquimod or 5-fluorouracil or laser ablation [25,26]. Surgery with glans resurfacing is an option, safe and effective, particularly in
<table><caption>**Table 1**
Tumour, node, metastasis (TNM) 2016 classification of penile cancers.</caption><thead><tr><th>Stage</th><th>Criteria</th></tr></thead><tbody><tr><td>Tumour</td><td></td></tr><tr><td>Tx</td><td>Not known</td></tr><tr><td>T0</td><td>No tumour</td></tr><tr><td>Tis</td><td>Lesion in situ</td></tr><tr><td>Ta</td><td>Non-invasive verrucous carcinoma</td></tr><tr><td>T1</td><td>Tumour invading the subepithelial connective tissue</td></tr><tr><td>T1a</td><td>Tumour with no lymphovascular invasion and not poorly differentiated</td></tr><tr><td>T1b</td><td>Tumour with lymphovascular invasion or poorly differentiated</td></tr><tr><td>T2</td><td>Tumour invading the corpus spongiosum</td></tr><tr><td>T3</td><td>Tumour invading the corpus cavernosum</td></tr><tr><td>T4</td><td>Tumour with invasion of the adjacent structures</td></tr><tr><td>Nodes</td><td></td></tr><tr><td>Nx</td><td>Not known</td></tr><tr><td>N0</td><td>No lymph node at clinical or paraclinical examination</td></tr><tr><td>N1</td><td>One palpable unilateral mobile inguinal lymph node</td></tr><tr><td>pN</td><td>Up to two palpable unilateral inguinal lymph nodes invaded</td></tr><tr><td>N2</td><td>Multiple lymph nodes or bilateral inguinal lymph node invasion</td></tr><tr><td>pN</td><td>More than two lymph nodes invaded unilaterally or bilaterally</td></tr><tr><td>N3</td><td>Fixed or pelvic lymph nodes</td></tr><tr><td>pN</td><td>Delvic nodes or extracapsular spread</td></tr><tr><td>Metastasis</td><td></td></tr><tr><td>Mx</td><td>Not known</td></tr><tr><td>M0</td><td>No distant lesion</td></tr><tr><td>M1</td><td>Distant lesion</td></tr><tr><td>Histological grade</td><td></td></tr><tr><td>Gx</td><td>Not known</td></tr><tr><td>G1</td><td>Well differentiated</td></tr><tr><td>G2</td><td>Intermediately differentiated</td></tr><tr><td>G3</td><td>Poorly differentiated</td></tr><tr><td>G4</td><td>Undifferentiated</td></tr></tbody></table>

case of recurrent disease after ablative or topical therapy [27]. Such early superficial lesions are usually not managed with brachytherapy though refractory or relapsed superficial tumours can be good candidates for brachytherapy. Surface mould-based high-dose rate brachytherapy can be considered for lesion thickness less than 3 mm, even for tumour larger than 4 cm in extent.

### 2.1.2. Treatment of invasive disease confined to the glans (cT1/T2)

Organ-sparing treatment should be offered for small invasive lesions. The aim of the resection is not only curative but also provides definitive pathological staging. In a systematic review involving 9578 men, the cumulative mean 5 year recurrence-free rates were 82.0 % for penile-sparing surgery, 83.9 % for amputative surgery. Even though the level of evidence is poor, these data support the notion that penile-sparing surgery is not inferior to amputative surgery and should be offered whenever possible [28].

#### 2.1.2.1. Glansectomy and partial penectomy
A glansectomy is recommended when the tumour involves more than the half of the glans. Partial amputative surgery is reserved for more advanced diseases. In two cases series after partial penectomy including men with T1 and T2 disease, the 5 year recurrence-free rates reported were 92 % and 95.4 % [28].

#### 2.1.2.2. Brachytherapy
Brachytherapy can be used as an alternative to surgery. Although higher local relapses are observed compared to radical surgery, most local relapses are salvaged by surgery and brachytherapy, therefore, can be proposed as an organ preservation strategy. Historically, low-dose rate brachytherapy has been the standard treatment and provided excellent oncological outcome and toxicity profile [28]. However, since 2014, this technique is no longer available, and more recently pulsed-dose rate is being abandoned in favour of the high-dose rate technique. High-dose rate brachytherapy has been increasingly used as a treatment strategy in replacement of the low-dose rate technique, with good local control and acceptable toxicity.

Brachytherapy showed better outcomes for lesions less than 4 cm, with penile preservation free of recurrence at 10 years for 83 % [29]. There is an increased risk of failure for tumour diameter greater than 4 cm, but brachytherapy still offers a reasonable chance of penile sparing for 50 % of patients at 10 years [29]. For localised tumours, results of brachytherapy are excellent with 10-year local control rate of over 75 % (95 % confidence interval [CI]: 68–84 %), and 74 % penile preservation rate (95 % CI: 66–83 %) [30–32]. Patients undergoing low-dose rate brachytherapy were mostly satisfied with their sexual functions after treatment [33]. Long-term outcomes for high-dose rate brachytherapy are expected to be comparable.

The risk of complications 10 years after low-dose rate brachytherapy is essentially painful ulceration (26 %) and stenosis (29 %), and is correlated to the treated volume, with a significant cut off at 22 cm³ [29]. Urethral stenosis is the most frequent late complication, and its occurrence is correlated with dosing to the distal part of the urethra. In a retrospective study, Achkar et al. reported 21.5 % of patients who experienced a grade 2 meatal stenosis [34]. Results for high-dose rate interstitial penile brachytherapy were summarised by Crook and Chargari (Table 2) [35]. However, this technique requires a high level of expertise, further justifying the centralization of care in specialized penile cancer centres and the referral of patients to high-volume centres [36–39].

#### 2.1.2.3. External beam radiotherapy
There is no place for first-line treatment with external radiotherapy without prior assessment of the feasibility of brachytherapy, which is the method of irradiation recommended for penile tumours limited to the glans [40]. In most of case, external beam radiotherapy is only palliative.

### 2.1.3. Locally advanced disease (stages T3/T4)

Patients with a tumour invading the corpora cavernosa (stage T3) will be managed by partial amputation (glansectomy, partial penectomy) or total penectomy since brachytherapy is contraindicated in this case. After surgical treatment, local recurrence is associated with poor survival. In order to make the functional deleterious impact more acceptable, patients should be informed that a wider resection provides a lower risk of local recurrence at the cost of functionality of the penis [41].

Radiotherapy for locally advanced penile lesions should be undertaken with concurrent chemotherapy. External beam radiotherapy has not been prominent in the treatment of penile cancer because of poorly reproducible results when used in the adjuvant setting. However, as with disease in the lymph nodes, traditional radiotherapy dosing recommendations are being reconsidered, with a need to deliver doses higher than 50 Gy for penile squamous cell carcinoma [42,43].

For non-resectable diseases, induction chemotherapy offers the ability to downstage disease [44]. Neoadjuvant chemotherapy with paclitaxel, ifosfamide, and cisplatin is preferred for patients with up to 4 cm inguinal lymph nodes (fixed or mobile), if the result of fine-needle aspiration biopsy is positive for metastatic penile cancer [45]. The alternative chemotherapy regimen could be 5-fluorouracil with cisplatin [46,47].

Few studies proposed multimodal treatment for patients with penile cancer. In a study on six patients with locally advanced lymph node-positive squamous cell carcinoma penile cancer who refused surgical treatment, four patients who received definitive chemoradiotherapy were free of recurrence at the median follow-up of 7.2 years [48]. More recently, a prospective study of chemoradiotherapy as primary treatment in 33 patients with locally advanced penile cancer showed that 73 % responded, including 39 % complete responses, and 27 % underwent salvage surgery. The treatment consisted of an external beam radiation with simultaneous integrated boost volumetric modulated arc therapy. A total
<table><caption>**Table 2**
Summary of results for high-dose rate interstitial penile cancer brachytherapy (reproduced from [35]).</caption><thead><tr><th>Reference</th><th>Number of patients</th><th>Follow-up (range)</th><th>Total dose</th><th>Daily dose</th><th>Local control rate</th><th>Cause-specific survival rate</th><th>Toxicity</th><th>Penile preservation rate</th></tr></thead><tbody><tr><td>Pohanková et al., 2022 [37]</td><td>26</td><td>87 (7–200) months</td><td>54 Gy</td><td>3 Gy × 2</td><td>77 % (83 % 5-year)</td><td>100 % (5-year)</td><td>Necrosis 4 % (amputation)</td><td>73 %</td></tr><tr><td>Sharma et al., 2014 [39]</td><td>14</td><td>22 (6–40) months</td><td>42–45 Gy</td><td>3 Gy × 2</td><td>12/14</td><td>83 % (3-year)</td><td>Grade 2 fibrosis: 29 % Hyperpigmentation: 14 %</td><td>93 %</td></tr><tr><td>Rouscoff et al., 2014 [71]</td><td>12</td><td>27 (5–83) months</td><td>36–39 Gy</td><td>4–4.34 Gy × 2</td><td>92 %</td><td>100 % (5-year)</td><td>Necrosis: 9 % Telangiectasia: 33 % Hyperpigmentation: 35 %</td><td>70 %</td></tr><tr><td>Kellas-Śłęczka et al., 2019 [81]</td><td>76</td><td>76 (7–204) months</td><td>49 (30–54) Gy</td><td>3–3.5 Gy × 2</td><td>73 %</td><td>100 % (5-year)</td><td>Necrosis: 3 % Stenosis: 1 % Hyperpigmentation: 35 %</td><td>70 %</td></tr><tr><td>Marbán et al., 2020 [82]</td><td>7</td><td>90 (11–106) months</td><td>38.4–53 Gy</td><td>3.12–3.75 Gy × 2</td><td>86 %</td><td>100 % (5-year)</td><td>Necrosis: 43 % Stenosis: 43 % Telangiectasia: 67 %</td><td>86 %</td></tr><tr><td>Martz et al., 2021 [38]</td><td>29</td><td>72 (3–147) months</td><td>35–39 Gy</td><td>3.89–4.3 Gy × 2</td><td>82 %</td><td>88 % (5-year)</td><td>Necrosis 10 %</td><td>79 %</td></tr></tbody></table>

radiation dose of 59.4 Gy was delivered in 33 daily fractions of 1.8 Gy to the primary tumour and involved lymph nodes, whereas the electively treated lymph nodes received a total dose of 49.5 Gy in 33 fractions of 1.5 Gy in the same overall treatment time of 6.5 weeks. Radiotherapy was combined with mitomycin C intravenous bolus injection (10 mg/m², maximum 15 mg) on day 1 and capexicabine tablets twice daily on radiation days (825 mg/m²) [49]. In comparison to perioperative chemotherapy studies, a conservative approach can be proposed to all patients irrespective of their performance status and age; while neoadjuvant chemotherapy is highly toxic and can only be offered to relatively fit patients.

## 2.2. Regional lymph node management

A systematic review for the management of lymph node-positive penile cancer has been published in 2024 [50]. The development of lymphatic metastases in penile cancer follows the route of anatomical drainage from the primary tumour to the superficial and then deep inguinal lymph nodes, followed by the ipsilateral pelvic lymph nodes. The presence of nodal involvement is singularly the most important prognostic factor in patients with penile cancer.

### 2.2.1. cN1-N2 disease: radical lymph node dissection

Radical lymph node surgery remains the cornerstone of management for early nodal disease (stages cN1–2) but is associated with significant morbidity. Historically, morbidity of the radical inguinal lymph node dissection has been reported to be up to 61 % [51]. A better understanding of pre-, per- and postoperative management has helped reduce morbidity rates in modern practice, now ranging between 21 % and 55 %. After a radical inguinal lymph node dissection, the number of positive inguinal lymph nodes (one to two versus three, or more with no extracapsular extension) was associated with positive pelvic lymph nodes in 0 to 6.5 % of patients compared to 33 to 67 % [45]. After a radical inguinal lymph node dissection and with pN1 disease, due to the lack of benefit and the morbidity associated, do not offer adjuvant radiotherapy.

### 2.2.2. Clinical N3 disease

2.2.2.1. Neoadjuvant chemotherapy. Neoadjuvant chemotherapy is an option for patients with stage cN3 disease, as a meta-analysis suggested that approximately 50 % of the patients with bulky

regional lymph node metastases from penile cancer respond to platinum-based neoadjuvant chemotherapy and approximately 16 % of patients achieve a pathological complete response [45]. However, toxicity comes at a significant cost, with a grade 3 or higher toxicity rate of 40 % (95 % CI: 19–64 %) and an overall mortality rate of 55 % (95 % CI: 40–70 %).

2.2.2.2. Primary chemoradiotherapy. Very few data are available, as it was not recommended to offer chemoradiotherapy for stage cN3 disease. However, it has been suggested that the classical dose of 50 Gy used in other squamous cell carcinoma might be insufficient to explain why radiation treatment has failed in older studies [43]. In case of patient who refuses or who is ineligible for surgery, the dose prescribed to macroscopic lymph nodes should be an equivalent dose in 2-Gy fractions (EQD2) of 66 to 70 Gy [30,52]. Furthermore, HPV-related penile squamous cell carcinoma, as other HPV-related malignancies, seems to be radiosensitive and a genome-based model for adjusting radiotherapy dose is currently under evaluation [19,53,54]. Therefore, using HPV status and biomarkers could help in the future for penile squamous cell carcinoma management. Results of two prospective studies have been published, using concomitant platinum-based chemotherapy or 5-fluorouracil and mitomycin C, with external beam radiotherapy [48,49]. These results suggest that chemoradiotherapy as a definitive treatment could be proposed as an option, with an organ-preserving approach.

2.2.2.3. Adjuvant postoperative radiotherapy. Adjuvant radiotherapy for node-positive penile cancer remains controversial, as most studies were retrospective and heterogeneous in selection, with doses delivered to microscopic diseases probably insufficient. Hence, the place of radiotherapy as adjuvant treatment for pelvic inguinal nodal involvement is still uncertain considering the lack of prospective data.

A recently published systemic review included 14 studies on adjuvant radiotherapy [19,43,51,55–65]. Adjuvant radiotherapy showed a superiority in disease-specific survival (median disease-specific survival 14.4 months) compared to observation (median disease-specific survival 8 months) (P=0.02) in patients with high-risk of recurrence (microscopic positive margins resection [R1] or with extranodal pelvic extension) [59]. Jaipura et al. reported results from 45 patients, including 25 who received adjuvant radio-
therapy and seven adjuvant chemotherapy with results in favour of the former (average overall survival 44 months versus 33 months respectively) [55]. HPV-related tumours had better outcomes when adjuvant radiotherapy was prescribed, with a 5 year overall survival rate of 70 % for HPV+ versus 30 % for HPV⁻ [19]. Ager et al. reported the outcomes of 146 patients with pN3 disease of whom 121 received adjuvant radiotherapy: 31.6 % of patients who received less than 50 Gy in postoperative settings had a local recurrence compared to 14.2 % who received more than 50 Gy [43].

Therefore, adjuvant external radiotherapy can be discussed in the following cases: multiple site histological involvement, extracapsular spread, or resection margins involved.

2.2.2.4. **Adjuvant postoperative chemoradiotherapy.** In a large multicentre retrospective study, adjuvant chemoradiotherapy seemed to provide a benefit in terms of overall survival for patients with pN3 disease associated with extranodal extension [57]. Khurud et al. analysed the impact of adjuvant treatment for pN3 penile cancer: 128 patients were treated [66]. A combined modality adjuvant treatment improved disease-free survival with an overall survival rate at 2 years of 28 % for patients without treatment compared to 75 % in patients who received multimodality treatment. Adjuvant radiotherapy or chemotherapy alone were similar in their impact; multimodality treatment with intensification using the combination of chemotherapy followed by chemoradiotherapy was associated with the best disease-free survival.

2.2.2.5. **Perspective with the InPact study.** The InPACT study (NCT02305654) is a prospective two sequential randomised study of 400 patients to determine the role for chemotherapy or chemoradiotherapy and the role of prophylactic pelvic lymph nodal dissection with chemoradiation compared to chemoradiation alone in high-risk inguinal lymph nodal disease and should provide better quality evidence to guide clinical practice [67].

# 3. Brachytherapy

## 3.1. Pretreatment assessment and management

Patients should have undergone pelvic MRI and surgical assessment of inguinal lymph nodes if indicated [68]. It is also essential to perform postectomy (for patients who have not previously undergone circumcision) prior to brachytherapy [31]. Postectomy enables to better defining the treatment volume and limits inflammatory processes and the risk of stenosis and phimosis. Healing should be achieved prior to brachytherapy (generally 2 to 4 weeks). At the same time as postectomy, surgical lymph node staging can be planned.

## 3.2. Implantation

The second edition of the handbook of brachytherapy by the Groupe européen de curiethérapie (Gec) of the European Society for Radiotherapy and Oncology (ESTRO) with technical considerations and results has been published in 2022 [35]. The use of contact brachytherapy with a bolus or use of a three-dimensional protective mould is possible only for very superficial pre-invasive tumours of less than 3 mm in thickness. For infiltrating tumours, interstitial implantation is necessary to treat the lesion with a minimum margin of 1 cm, if possible, in all dimensions considering the absence of an anatomical barrier in the glans [31,69,70]. In this case, implantation is usually done under general or spinal anaesthesia (or more rarely under a penile regional nerve block in case of implantation of limited volume) with placement of a Foley catheter.

Implantation of interstitial needles is done according to the Paris system, with spacing ranging from 12 to 15 mm, perpendicular to

the axis of the penis and avoiding the urethra. The use of a rigid perforated grid enables us to better comply with rules for application and maintenance of position of the catheters throughout the duration of treatment. Vector needles can be used or needles can be replaced by plastic catheters (taking into account the risk of oedema). It is possible to use a bolus dose if plesiotherapy catheters are used [69]. Placement of a spacer and/or of a testicular protection enables to decrease the dose to the scrotum and to the testes. It is also necessary to place a spacer with a gauze sponge in order to prevent the risk of epithelitis. After the implantation of the needles, with particular caution to the urethra, according to the Paris system, a CT simulation is performed for catheter reconstruction and dose calculation.

## 3.3. Dose and fractionation

Dose and fractionation are not consensual, as the technique is still evolving; the most commonly used prescription for high-dose rate brachytherapy is 42 to 45 Gy delivered in 12 to 14 fractions, twice daily [35].

For pulsed-dose rate treatments, the equivalent total dose delivered in 2 Gy fractions is 62 to 65 Gy. A better rate of local control has been demonstrated with a dose greater than 62 Gy for patients receiving low- or pulsed-dose rate brachytherapy [31]. Postoperatively, for treatment of close margins or in contact, the dose is approximately 55 to 60 Gy for low- or pulsed-dose rate treatments. Since iridium-192 sutures are no longer marketed in France, treatment can be performed with pulsed-dose rate or high-dose rate. Pulsed-dose rate is based on hourly pulses of 0.42 Gy. It has been shown that an hourly dose greater than 0.43 Gy per pulse was associated with more frequent complications [31].

Prescription for multicatheter high-dose rate brachytherapy has been previously described [71]. The prescribed dose was established according to multicatheter high-dose rate brachytherapy indications. For adjuvant multicatheter high-dose rate brachytherapy, 35 Gy was delivered in nine fractions over 5 days (7 Gy on day 1, then 3.5 Gy twice daily from days 2 to 5); for definitive treatment, 39 Gy was given with the same schedule, using 4 Gy fractions from days 2 to 5. Five years' clinical outcome analysis shows that multicatheter interstitial high-dose rate brachytherapy is efficient and late toxicity seems acceptable. With a median follow-up of 72.4 months, 29 patients were treated, mainly with stage T1 disease (75.9 %), 18 patients received multicatheter high-dose rate brachytherapy as definitive treatment. Six patients (20.7 %) experienced local relapse and underwent salvage penectomy. Six percent experienced grade 3 acute skin toxicity. Late skin complications were telangiectasia for five patients (17 %) and necrosis for three patients [38].

Another monocentric retrospective study was published in 2022 [37]. In that study, 31 patients, mostly with stage T1 disease (24 patients), received a dose of 54 Gy delivered in 18 fractions, twice daily. With a median follow-up of 117 months, penile sparing was achieved in 22 patients, and eight patients (25.8 %) developed a recurrence requiring salvage surgery (partial amputation). The probability of local control at 5 and 10 years was 80.7 % and 68.3 %, respectively, with penile-sparing rates of 80.6 % and 62.1 %, respectively. Only one case of radiation-induced necrosis was observed.

These results appear to demonstrate that high-dose rate brachytherapy could achieve results that are comparable to low-dose rate technique; prospective data from larger samples are needed.

## 3.4. Treatment volume

The target volume is defined by the clinical examination. The entire gross tumour volume is included in the treated volume with a margin of 1 cm in all three dimensions. Placement of fiducial mar-
<table><caption>**Table 3**
Indications of radiotherapy for penile cancers, and proposed doses and target volumes.</caption><thead><tr><th>Indication</th><th>Technique</th><th>Indication</th><th>Volume</th><th>Dose</th></tr></thead><tbody><tr><td>Localized cancer, &lt;4 cm, definitive setting</td><td>Brachytherapy</td><td>Conservative treatment</td><td>Minimum 1 cm margin around the lesion<br>Infiltrative or large lesions: whole glans<br>Excluding the urethra</td><td>High-dose rate: 42–45 Gy in 12–14 fractions, twice daily/39 Gy in 9 fractions<br>Pulsed-dose rate: 62 to 65 Gy (hourly pulses of 0.42 Gy)</td></tr><tr><td>Localized cancer, &lt;4 cm, adjuvant setting</td><td>Brachytherapy</td><td>Close margins/resection margins involved</td><td>Tumour bed</td><td>High-dose rate: 35 Gy in 9 fractions (7 Gy day 1, 3.5 Gy twice daily from day 2 to 5)<br>Pulsed-dose rate: 55–60 Gy (hourly pulses of 0.42 Gy)</td></tr><tr><td>Locally advanced (T3-T4) or node-positive, adjuvant setting</td><td>External beam radiotherapy</td><td>To be discussed in case of pN3 disease<br>To be discussed for pN1-pN2 disease in case of: - Multiple site histological involvement; - Extracapsular spread - Resection margins involved</td><td>CTV-T: GTV + 1 cm in craniocaudal axis/entire diameter of the penis<br>CTV-N: elective nodal radiotherapy (ipsilateral inguinal and external iliac node)</td><td>Chemoradiotherapy: weekly 30 mg/m² cisplatin<br>Radiotherapy alone: 50–54 Gy in 25–27 fractions</td></tr><tr><td>Locally-advanced (node-positive cN3), definitive setting</td><td>External beam radiotherapy</td><td>To be discussed in case of surgery refusal</td><td>CTV-T: GTV + 1 cm in craniocaudal axis/entire diameter of the penis<br>CTV-N: elective nodal radiotherapy (ipsilateral inguinal and external iliac nodes) + boost on involved nodes</td><td>Chemoradiotherapy (platinum-based/5-fluorouracil, mitomycin)<br>Primary tumour and involved nodes: 60–65 Gy in 25 fractions<br>Elective nodal radiotherapy: 45 Gy in 25 fractions<br>Radiotherapy alone<br>Primary tumour and involved nodes: up to 70 Gy EQD2 in 25 fractions<br>Elective nodal radiotherapy: 45 Gy in 25 fractions</td></tr><tr><td>Palliative</td><td>External beam radiotherapy</td><td>Pain relief, bleeding, etc.</td><td>Painful sites</td><td>30 Gy in 10 fractions<br>20 Gy in 5 fractions</td></tr></tbody></table>

CTV: clinical target volume; EQD2: equivalent dose in 2 Gy fractions; GTV: gross tumour volume; N: nodal; T: primary tumour.

kers can aid in visualisation of this volume in a dosimetric CT-scan. For very infiltrating or multifocal tumours, it is necessary to include the totality of the glans in the implanted volume (focal treatment of the lesion is not advisable). A dosimetry CT-scan is performed with millimetric sections without injection of contrast medium.

# 4. External radiotherapy

## 4.1. Dose and fractionation

### 4.1.1. Dose and fractionation in an adjuvant situation

Since the publication of the study by Ager et al., a minimal dose of 50 Gy should be prescribed to elective nodal area (Table 3) [43]. The recommended dose is 50 to 54 Gy delivered in 25 to 27 fractions.

### 4.1.2. Dose and fractionation in a neoadjuvant setting

Chemotherapy is actually the preferred neoadjuvant treatment, as InPact results are still awaited [67]. Should a patient be unfit for CT, preoperative radiotherapy could be proposed with a conventional daily fractionation delivering 45 to 50 Gy.

### 4.1.3. Dose and fractionation for exclusive radiotherapy

Old small retrospective studies were previously published, such as the work by Zouhair et al. who reported a dose to the nodal areas from 36 to 66 Gy given in 1.8 to 2 Gy fractions with parallel opposed lateral fields [72]. Nowadays, intensity-modulated whole pelvic radiotherapy allows better dosimetry constraints to organs at risk [73–75]. External beam radiotherapy to lymph nodes should deliver 45 Gy in 25 fractions, with a simultaneous boost to macroscopic disease to reach approximately 60 to 65 Gy to nodes and 65 Gy to the primary tumour (70 Gy EQD2 in a protocol without chemotherapy). A combination with weekly concomitant chemotherapy with

40 mg/m² cisplatin or carboplatin area under the curve (AUC2) is recommended. In case of a contraindication to platinum salts, it is possible to discuss chemotherapy with 5-fluorouracil in combination with mitomycin.

Another external beam radiotherapy prescription could be the Dutch chemoradiotherapy protocol previously prescribed for locally advanced anal carcinoma using simultaneous integrated boost-intensity-modulated radiation [76]. The largest prospective study of chemoradiotherapy as primary treatment for patients with locoregionally advanced penile carcinoma proposed an external beam radiotherapy that consisted of a dose of 49.5 Gy (delivered in 33 fractions of 1.5 Gy) on affected inguinal and pelvic areas combined with intravenous mitomycin C on day 1 and capecitabine on radiation days.

## 4.2. Treatment volumes

There is no standardisation nor level of evidence for external radiotherapy volumes for patients with penile cancer, whether for the primary tumour or nodal clinical target volumes (CTV-T, CTV-N). Recommendations have been published by Mittal et al., proposing inguinal clinical target volume delineation for penile cancer [77]. Technical considerations have also been analysed to optimise target volume for adjuvant radiation therapy [78].

### 4.2.1. Primary tumour clinical and planning target volumes

External radiotherapy of the primary tumour is a treatment to be considered only after ruling out possible brachytherapy and therefore, after advice from a brachytherapist with experience in penile cancer treatment. For patients who are inoperable and not eligible for brachytherapy, the clinical target volume of the primary tumour (CTV-T) corresponds to the macroscopic penile lesion with a margin
of 1 cm in the craniocaudal axis and the entire diameter of the penis with circumferential margin. The planning target volume (PTV-T) should be wide in light of difficulties in repositioning the penis, with uncertainty that can range up to 2 cm. These margins can be reduced if compression is used (with a surface mold). Moreover, in case of photon therapy, it is necessary to use a personalised bolus dose that covers the entire penis and enables treatment with the skin surface and increases the reproducibility of position.

### 4.2.2. Nodal clinical and planning target volumes

In an adjuvant setting, the nodal radiotherapy volumes are to be discussed on a case-by-case basis. When postoperative inguinal nodal involvement exists, the ipsilateral inguinal area affected is included in the nodal clinical target volume (CTV-N), as well as the upper nodal area (external iliac nodal area) [30]. The benefit of contralateral prophylactic irradiation is not demonstrated when the surgical assessment is negative. For extensive nodal involvement, the bilateral inguinal and pelvic nodal areas are included. It is necessary to include the peripubic fat in the treatment volume [30]. The margin to be applied in order to define the nodal planning target volume (PTV-N) depends on modalities of treatment and repositioning. Usually it is 10 mm, but can be reduced to 5 to 7 mm when positioning is verified daily by onboard imaging enabling to visualise soft tissues.

### 4.3. Treatment technique and image-guided radiotherapy

Even in the absence of clinical evidence, it is possible by analogy with other pelvic tumours to propose treatment with intensity modulation and daily image guidance. Image-guided radiotherapy should use imaging that enables good visualisation of soft tissues, considering the uncertainties in terms of repositioning of the penis while bony structures are used for repositioning nodal volumes. Three-dimensional (3D) printing has been increasingly studied and evaluated, particularly for making bolus and contentions systems for external radiotherapy, and could be used in the context of external beam radiotherapy with intensity modulation for penile squamous cell carcinoma [79,80].

### 4.4. Surveillance

Physical examination should be conducted every 3 months for the first 2 years, then extended to every 6 months for years 3 to 5 [24].

## 5. Conclusion

Penile cancer is a rare malignancy requiring highly specialized management. Accurate assessment and tailored treatment of nodal involvement is essential for prognosis. Organ preservation should be prioritized whenever feasible, with interstitial high-dose rate brachytherapy offering excellent local control and functional outcomes for tumours confined to the glans. For locally advanced or node-positive disease, multimodal strategies, including chemoradiotherapy, may be considered, although the level of evidence is still evolving and currently being addressed in prospective trials. Given the complexity of care, these patients must be managed in expert multidisciplinary centres.

## Funding

This work has not received any specific grant from public, commercial or not-for-profit funding bodies.

## Disclosure of interest

The authors did not disclose their relationships/activities/interests.

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