<figure><img src="image_1.png" /></figure>

HAL
open science

# Updated 2025 French guidelines for renal cell carcinoma

Pierre Bigot, Zine-Eddine Khene, Romain Boissier, Laurence Albiges, Jean-Christophe Bernhard, Olivier Chapet, Jean-Michel Correas, Stéphane de Vergie, Nicolas Doumerc, Matthieu Ferragu, et al.

► To cite this version:

Pierre Bigot, Zine-Eddine Khene, Romain Boissier, Laurence Albiges, Jean-Christophe Bernhard, et al. Updated 2025 French guidelines for renal cell carcinoma. French Journal of Urology, 2025, 35 (12), pp.103007. 10.1016/j.fjurol.2025.103007. hal-05380402

HAL Id: hal-05380402

https://hal.science/hal-05380402v1

Submitted on 3 Dec 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Recommendations

Updated 2025 French guidelines for renal cell carcinoma

Cancer du rein : actualisation des recommandations françaises 2025

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

Check for
updates

Pierre Bigot Ⓐª,ᵇ,*, Zine-Eddine Kheneª,ᶜ, Romain Boissierª,ᵈ, Laurence Albigesª,ᵉ,
Jean-Christophe Bernhardª,f, Olivier Chapetª,g, Jean-Michel Correasª,h,
Stéphane De Vergie Ⓐª,ᵢ, Nicolas Doumercª,ⱼ, Matthieu Ferraguª,ᵇ, Alexandre Ingelsª,ₖ,
Gaëlle Margue Ⓐª,f, Yann Neuzilletª,ᵢ, Idir Ouzaïdª,ₘ, Caroline Pettenatiª,ₙ,
Nathalie Rioux-Leclercq Ⓐª,'o, Thibaut Waeckel Ⓐª,ₚ, Philippe Barthelemyª,q,
Morgan Rouprêtª,r

ARTICLE INFO

Keywords:

Renal carcinoma

Nephrectomy

French recommendations

Epidemiology

Surveillance

Treatment

ABSTRACT

The 2025 update of the French guidelines for localized renal cell carcinoma highlights several major advances. Renal biopsy reaffirms its central role in guiding therapeutic decisions and reducing overtreatment, with growing evidence supporting a broader “biopsy-all” strategy. Active surveillance is now established as a safe and effective option for small renal masses, including selected complex cystic lesions, providing oncological outcomes comparable to immediate intervention. Among alternative approaches, stereotactic body radiotherapy has emerged as a credible and well-tolerated treatment for medically inoperable patients. In hereditary syndromes, progress includes improved characterization of BAP1-TPDS-associated RCC and the expanding role of belzutifan in von Hippel-Lindau disease. From an organizational standpoint, the center-volume effect is confirmed, supporting the centralization of renal cancer surgery within authorized, high-volume centers. Novel biomarkers such as KIM-1, urinary glycosaminoglycans, and circulating DNA represent promising tools for postoperative surveillance and personalized treatment planning. In the event of metastatic progression after adjuvant pembrolizumab, enrolment in a clinical trial remains the preferred strategy. For early relapse (during or within six months after adjuvant therapy), TKI monotherapy should be prioritized, whereas recurrence between six and twelve months may justify the reintroduction of immunotherapy. Beyond twelve months after pembrolizumab, standard first-line PD-1-based combinations remain the recommended approach. Finally, for localized or oligometastatic recurrences, local treatments should be considered within a multidisciplinary tumour board.

<footnote>ªComité de cancérologie de l'Association française d'urologie, groupe rein, Maison de l'urologie, 11, rue Viète, 75017 Paris, France</footnote>

<footnote>ᵇDepartment of Urology, Angers University Hospital, Angers, France</footnote>

<footnote>ᶜDepartment of Urology, Rennes University Hospital, Rennes, France</footnote>

<footnote>ᵈDepartment of Urology and Kidney Transplantation, Aix-Marseille University, AP-HM, Conception University Hospital, Marseille, France</footnote>

<footnote>ᵉDepartment of Cancer Medicine, Gustave-Roussy, Paris Saclay University, Villejuif, France</footnote>

<footnote>fDepartment of Urology, Hôpital Pellegrin, Bordeaux University Hospital, Bordeaux, France</footnote>

<footnote n="8">⁸Department of Radiation Oncology, centre hospitalier Lyon Sud, Pierre-Bénite, France</footnote>

<footnote>hDepartment of Adult Radiology, Hôpital Necker, AP-HP Centre, Université de Paris, Paris, France</footnote>

<footnote>Department of Urology, Nantes University Hospital, Nantes, France</footnote>

<footnote>Department of Urology and Renal Transplantation, Toulouse University Hospital, Toulouse, France</footnote>

<footnote>Department of Urology, UPEC, hôpital Henri-Mondor, Créteil, France</footnote>

<footnote n="1">¹Department of Urology, Hopital Foch, University of Versailles-Saint-Quentin-en-Yvelines, 40, rue Worth, 92150 Suresnes, France</footnote>

<footnote>Department of Urology, Bichat University Hospital, AP-HP, Paris, France</footnote>

<footnote>Department of Urology, Hôpital Franco-Britannique, Cognacq-Jay Foundation, Levallois-Perret, France</footnote>

<footnote>Department of Pathology, Rennes University Hospital, Rennes, France</footnote>

<footnote>Department of Urology, Caen University Hospital, Caen, France</footnote>

<footnote n="4">⁴Medical Oncology, Institut de Cancérologie Strasbourg Europe, Strasbourg, France</footnote>

<footnote>Sorbonne University, GRC 5, Predictive Onco-Urology, AP-HP, Hôpital Pitié-Salpêtrière, Urology, 75013 Paris, France</footnote>

<footnote>* Corresponding author at: Service d'Urologie, CHU d'Angers, 4, rue Larrey, 49000 Angers, France.</footnote>

<footnote>E-mail address: pibigot@chu-angers.fr (P. Bigot).</footnote>
## RÉSUMÉ

L'actualisation 2025 des recommandations françaises sur le carcinome rénal localisé met en avant plusieurs avancées majeures. La biopsie rénale confirme son rôle central pour affiner la stratégie thérapeutique et limiter le sur-traitement, avec des données renforçant une approche « biopsy-all ». La surveillance active s'impose comme une option sûre pour les petites masses rénales, y compris certaines lésions kystiques complexes, avec des résultats oncologiques comparables à ceux d'un traitement immédiat. Parmi les alternatives, la radiothérapie stéréotaxique émerge comme une option efficace et bien tolérée chez les patients inopérables. Concernant les formes héréditaires, les progrès portent sur la meilleure caractérisation des RCC liés au syndrome BAP1-TPDS et sur l'efficacité du belzutifan dans la maladie de von Hippel-Lindau. Sur le plan organisationnel, l'effet centre est confirmé, justifiant la concentration des chirurgies dans des établissements autorisés et à haut volume. De nouveaux biomarqueurs, tels que KIM-1, les glycosaminoglycanes urinaires et l'ADN circulant, ouvrent des perspectives prometteuses pour le suivi et la personnalisation des prises en charge. En cas de progression métastatique après un traitement adjuvant par pembrolizumab, l'inclusion dans un essai clinique reste à privilégier. Si la rechute survient pendant l'immunothérapie ou dans les six mois suivant son arrêt, un traitement par inhibiteur de tyrosine kinase en monothérapie est recommandé. Une progression entre six et douze mois permet de discuter une reprise d'immunothérapie, tandis qu'au-delà de douze mois, une première ligne standard à base d'anti-PD1 est préconisée. Enfin, pour les rechutes localisées ou oligométastatiques, une prise en charge locale doit être discutée en RCP multidisciplinaire.

**Mots clés:**

Cancer du rein

Néphrectomie

Recommandations françaises

Épidémiologie

Surveillance

Traitement

# 1. Epidemiology, aetiology and screening

Global projections indicate a 72% increase in kidney cancer incidence (approximately 745,800 new cases) and a 96% rise in mortality (around 304,900 deaths) by 2050, mainly driven by population ageing and demographic growth [1,2]. The overall 5-year survival rate varies considerably across regions, ranging from 40–63% in Africa, 66% in Europe, 67% in North America, 75% in Oceania, 69% in Asia, and up to 86% in Latin America [3].

Approximately 5–8% of cases are linked to a genetic predisposition, involving in particular the VHL, ELOC, TSC1/2, MET, FLCN, FH, BAP1 and SDH genes. Non-modifiable risk factors include age, male gender, ethnicity and family history. Modifiable factors include obesity, diabetes/insulin resistance, high blood pressure, chronic kidney disease, smoking, and certain environmental exposures [4].

To date, systematic population-based screening for renal cell carcinoma is not recommended [5]. However, targeted screening strategies based on individual risk profiles are under evaluation. The Yorkshire Kidney Screening Trial (YKST) investigated the feasibility of adding a non-contrast abdominal CT scan to low-dose CT lung screening in high-risk smokers and ex-smokers. Among the 4,019 participants included, 82 renal abnormalities were identified, including 10 histologically confirmed renal carcinomas (0.25%). The number needed to screen was 18 to detect a serious abdominal abnormality, 93 for a suspicious renal lesion, and 402 for a confirmed renal carcinoma. These results demonstrate that while the integration of opportunistic kidney screening is technically feasible and allows for the detection of cancers at a potentially curable stage, its yield remains low, with uncertain cost-effectiveness [6,7].

# 2. Renal biopsy

Renal biopsy (RB) plays an increasingly important role in the management of localized renal masses. While surgery remains the first-line treatment in most cases, nearly 15–20% of patients who undergo surgery are found to have a benign tumor upon definitive histological analysis, leading to a risk of overtreatment and unnecessary morbidity. In a recent analysis of the French UroCCR database, including 9283 patients who underwent surgery for a renal tumour, only 17% had undergone a preoperative biopsy. Biopsy was associated with a significant reduction in the risk of surgery for benign tumors (7.5% vs. 11.4%, P < 0.001). This effect was even more pronounced for tumors smaller than 4 cm, where a systematic biopsy

strategy prevented one unnecessary surgery for every 13 biopsies performed [8].

A major advance has come from the simulation study by Belladelli et al., which modelled a “biopsy-all” strategy in 1729 patients with cT1–2 renal masses. This approach avoided 6.7% of unnecessary surgeries, reduced overall complications by 3% and severe complications (Clavien ≥ III) by 0.5%, while saving an average of USD 840 per patient. The benefit was even greater in T1a tumours, with a 7.3% reduction in unnecessary interventions [9].

These new data support the idea that a broader biopsy strategy could optimize the benefit-risk ratio, reduce overtreatment and improve the economic efficiency of the care pathway.

**Recommendation (expert opinion):** The CCAFU reaffirms its position and recommends performing a renal biopsy in the following situations: before medical treatment in the absence of a histological diagnosis; before focal treatment (radiofrequency, brachytherapy or radiotherapy); before radical nephrectomy for localized tumors if partial nephrectomy is not feasible (cT1, cT2); before partial nephrectomy for tumors of high surgical complexity and risk of conversion to radical surgery; in cases of imperative indication, single kidney and bilateral tumours; in situation of diagnostic uncertainty (lymphoma, metastasis from other cancers, urothelial carcinoma, sarcoma).

# 3. Geriatric assessment and renal carcinoma

Renal carcinoma is increasingly common in elderly patients. In these patients, chronological age alone is not sufficient to guide treatment decisions: frailty is the factor that determines treatment tolerance and long-term outcomes.

The Comprehensive Geriatric Assessment (CGA) is the standardized reference tool for evaluating elderly patients, encompassing functional, nutritional, cognitive, psychological, and social domains. It allows clinicians to identify fit patients who may benefit from curative interventions, frail patients requiring treatment adaptation, and dependent patients for whom a palliative or conservative approach is more appropriate.

A recent review by Pecoraro et al. confirmed the prognostic value of frailty in patients with renal carcinoma [10]. The integration of CGA into multidisciplinary tumour board discussions improves patient selection, optimizes the risk–benefit balance of treatment, and promotes shared decision-making. Simple screening tools such as G8 or VES-13 may be used to identify patients who require a full geriatric evaluation.
**Recommendation (strong):** All elderly patients (≥ 70 years) or those suspected of frailty should undergo screening using the G8 or VES-13 tool.

If any abnormal results are identified, a comprehensive geriatric assessment (CGA) should be incorporated into the multidisciplinary treatment discussion to adapt management to the patient's geriatric profile.

## 4. Genetic predispositions and hereditary renal carcinomas

Hereditary renal carcinomas account for approximately 3–5% of all renal cell carcinomas (RCC) and include several genetic predisposition syndromes, including von Hippel-Lindau disease (VHL) and BAP1 tumor predisposition syndrome (BAP1-TPDS).

Von Hippel-Lindau disease is characterized by a germline mutation in the VHL tumour suppressor gene. Nearly 70% of patients develop RCC during their lifetime, often multifocal and bilateral. In a longitudinal cohort of 244 patients followed for more than 10 years, 63% had tumour progression at 5 years despite close monitoring, with 76% requiring at least one surgery and 44% two or more procedures, resulting in chronic kidney disease in 41% of cases [11].

These results highlight the limitations of an exclusively surgical strategy and the need to develop alternative therapies. The HIF-2α inhibitor belzutifan represents a major therapeutic advance in this setting. In the LITESPARK-004 trial, which included 61 patients with VHL-associated RCC, the objective response rate (ORR) reached 67%, with a median follow-up of 50 months, confirming sustained and durable antitumour activity. Clinical benefit was also observed in other VHL-related manifestations, including central nervous system haemangioblastomas, pancreatic neuroendocrine tumours (pNETs), cystic lesions, and ocular involvement [12]. Belzutifan is currently available on an early-access basis as monotherapy for adult patients with VHL-associated RCC, CNS haemangioblastomas, or pNETs not amenable to local therapy.

BAP1 tumour predisposition syndrome (BAP1-TPDS), linked to pathogenic germline variants of BAP1, confers an increased risk of mesothelioma, melanoma and RCC. In the largest multi-institutional series published to date (34 patients), 70% of RCCs were clear cell type: 43% were low grade and 84% were localised at stages pT1–2, with a high proportion of multifocal forms (35%). Unlike sporadic RCCs with somatic loss of BAP1, which are often aggressive, these hereditary forms have a more heterogeneous course. Diagnoses were made as early as 27 years of age, and 25% of patients had RCC before the age of 37. These data suggest initiating renal surveillance at 20–25 years of age, or 10 years before the age of the youngest affected relative [13].

## 5. Centre effect and the need to comply with authorisations for renal oncological surgery

Recent clinical data and the latest recommendations confirm the importance of concentrating renal oncological surgery in authorized centers. A systematic review by the EAU shows that high-volume hospitals achieve superior results: fewer complications, shorter hospital stays, lower rates of positive surgical margins, and fewer blood transfusions [14].

Previous studies report that nephrectomy performed in high-volume centers reduces first-year mortality by approximately 36% [15], and that overall mortality is reduced by ~24% in centers with expertise in the surgical management of renal tumours with vena cava thrombus [16].

In France, Decree No. 2022-689 requires that oncological surgery facilities have authorization, a complete technical platform, imaging resources to manage complications, and perform ≥ 30 urological

oncological procedures per year [17]. A referral multidisciplinary team meeting is required for grade B surgeries, such as nephrectomy with caval thrombectomy.

**Recommendations:** Any partial nephrectomy performed for suspected kidney tumour should be considered an oncological procedure, even in the absence of preoperative pathology. In France, complex procedures, such as nephrectomy with caval thrombectomy, are subject to an appeal multidisciplinary team meeting and be centralized in expert centers authorized for grade B surgery.

## 6. Active surveillance

Active surveillance (AS) is now recognized as the preferred strategy for the management of small renal masses (≤ 2 cm). Updated data from the prospective DISSRM registry, with 12 years of follow-up and more than 950 patients included, confirm that there is no significant difference in cancer-specific mortality between AS and immediate treatment (surgery or ablation) [18]. The progression rate under active surveillance is estimated at 15%, 22% and 26% at 1, 2 and 3 years, reaching 36% at 8 years. The crossover rate to deferred intervention remains low (15%), with oncological results equivalent to those observed after initial treatment. Tumour growth is not correlated with the presence of aggressive histology, unlike tumour size, suggesting that the role of growth rate as a criterion for triggering deferred treatment should be reviewed.

Furthermore, a recent study conducted at the Fox Chase Cancer Centre on 387 radiologically confirmed renal cystic masses showed that 23% of lesions had high-grade histology, despite their cystic appearance [19]. Nevertheless, AS applied to these masses demonstrated high oncological safety, with specific survival identical to that observed after immediate treatment (99% vs. 100% at 5 years). These results support the use of AS for complex cystic lesions, subject to rigorous selection and close follow-up.

**Recommendations:** Active surveillance should be offered as a first-line strategy for small renal masses ≤ 2 cm, and may be considered for masses up to 4 cm in selected patients. It is also a safe option for certain complex cystic lesions, subject to rigorous selection and close follow-up. The decision to delay treatment should be based primarily on tumour size (> 4 cm) or radiological signs of progression, rather than on growth rate alone.

## 7. Role of stereotactic radiotherapy

Historically considered radioresistant, renal tumours have benefited from advances in stereotactic radiotherapy (RT), which allows high doses to be administered per fraction and overcomes this resistance. The results of the FASTRACK-1 and FASTRACK-2 prospective trials confirmed the efficacy and tolerability of RT in localized RCC in inoperable patients, with local control greater than 90% and satisfactory preservation of renal function at one year [20,21].

More recently, a multicenter analysis from the international IROCK consortium evaluated 211 histologically confirmed RCC cases, including non-clear cell subtypes (papillary, chromophobe, and collecting duct). After a median follow-up of four years, the five-year local failure rate was 1.5% for chromophobe RCCs and 2.4% for non-clear cell RCCs, with no significant difference between histologies [22]. The 5-year specific survival rate was 96%, and less than 3% of patients required dialysis. Treatment tolerance was excellent, with 7.6% of grade ≥ 2 adverse events, mainly mild to moderate fatigue.

A recent meta-analysis comparing ablation modalities (radio-frequency, cryoablation, microwave and SABR) showed similar oncological efficacy for small renal masses (< 3 cm), but superiority of RT for tumours ≥ 4 cm, with a local control rate of 94% at 5 years [23].
**Recommendations:** RT is a credible, non-invasive alternative for treating T1a tumors in frail, elderly or inoperable patients, as well as for T1b tumors when surgery is not feasible. The decision must remain multidisciplinary, and surgery remains the standard of care for operable patients.

## 8. Follow-up after curative treatment of localized renal carcinoma

Follow-up after curative treatment of localized renal carcinoma remains a major challenge in terms of early detection of recurrence and prevention of long-term complications.

Combined analyses of the prospective SORCE and ASSURE trials (3542 patients) showed that the time to recurrence and sites of recurrence vary according to histological subtype. The median time to recurrence was 1.78 years for clear cell carcinomas, 1.34 years for papillary carcinomas (PC), 2.72 years for chromophobe carcinomas (CCC) and only 0.74 years for sarcomatoid carcinomas, reflecting the aggressiveness of the latter [24]. Patients with chromophobe carcinomas have a risk of later recurrence, sometimes beyond 5 years. These data suggest that the intensity and duration of follow-up should be adapted to the histology, with closer monitoring during the first two years for papillary and sarcomatoid carcinomas.

Furthermore, a recent meta-analysis of 27 studies confirmed that patients who have had RCC have an increased risk of second primary cancer (SPC) compared to the general population (overall SIR = 1.32, 95% CI: 1.19–1.48). The risk is particularly high for the contralateral kidney (SIR = 3.68), thyroid (3.05), bladder (2.15), but also for haematological, colorectal, skin and prostate cancers [25]. These results call for increased vigilance during follow-up, including appropriate screening and patient information about this risk.

Finally, follow-up must also take renal function into account. The loss of nephrons after nephrectomy promotes the development or worsening of chronic kidney disease (CKD), which is a major determinant of cardiovascular mortality. Risk factors for CKD (high blood pressure, diabetes, obesity, smoking, proteinuria) are common in this population and are exacerbated by the loss of nephron mass. Radical nephrectomy exposes patients to an average 30% decrease in glomerular filtration rate, and the risk of renal failure is significantly higher than that observed after conservative treatment [26].

**Recommendations:** The monitoring schedule after treatment for non-metastatic kidney cancer should be tailored to the risk of recurrence and the patient's life expectancy.

The risk of recurrence can be assessed using validated predictive nomograms.

The prevention of chronic kidney disease must be a central objective, justifying early and systematic collaboration with a nephrologist, both pre- and postoperatively.

## 9. Recent advances and prospects in prognostic and predictive biomarkers

Recent advances have highlighted several potential biomarkers.

Kidney Injury Molecule-1 (KIM-1) has emerged as an attractive candidate. Overexpressed by carcinomas arising from the proximal tubular epithelium, it is detectable in both plasma and urine. Elevated KIM-1 levels are associated with an increased risk of RCC diagnosis, sometimes several years before clinical detection [27]. In the post-nephrectomy setting, high concentrations are correlated with poorer recurrence-free survival and overall survival, and its inclusion improves existing prognostic models such as SSIGN or UISS. Furthermore, post hoc analyses of large adjuvant trials (ASSURE, CheckMate 914, IMmotion010) suggest that dynamic changes in KIM-

1 levels could predict response to immune checkpoint inhibitors (ICIs), particularly by identifying subgroups more likely to benefit from adjuvant immunotherapy.

Urinary glycosaminoglycans (GAGomes) represent another innovative biomarker approach. A prospective multicentre study (AURORAX-0087A) demonstrated that the GAGome score detects recurrences of non-metastatic clear cell RCC with high sensitivity (90%) and a negative predictive value of 97%, anticipating radiological detection by approximately four months [28].

The analysis of circulating tumour DNA (ctDNA) offers new perspectives for screening, early detection, and risk stratification in RCC.

At the diagnostic level, a machine learning model combining copy number variation, fragment size distribution, and nucleosomal footprinting successfully distinguished RCC patients from non-cancer controls with excellent accuracy (AUC: 0.95–0.97) and > 90% sensitivity for early-stage disease [29].

Beyond diagnosis, personalised ctDNA assessment in postoperative cohorts demonstrates a prognostic and potentially predictive role. In a single-centre study of patients who underwent curative nephrectomy, ctDNA positivity before or after surgery was strongly associated with recurrence risk (HR: 2.7 and 3.2, respectively), with a positive predictive value of 100% when detected postoperatively [30]. Conversely, the persistent absence of ctDNA identified a subgroup of patients at low risk of relapse, suggesting potential utility in selecting candidates for adjuvant therapy and in post-treatment monitoring.

**Recommendations:** In the absence of external validation and confirmation in large independent cohorts, these biomarkers should not be used to guide therapeutic decisions in routine clinical practice. Their use should currently be limited to clinical and translational research.

## 10. Management of metastatic progression after adjuvant treatment with pembrolizumab

Metastatic progression following adjuvant pembrolizumab (KEY-NOTE-564) represents a new clinical scenario that was not addressed in phase III trials establishing current first-line standards for metastatic RCC. Immunotherapy rechallenge strategies have been evaluated in a population of metastatic patients without demonstrated benefit: the CONTACT-03 trial (atezolizumab + cabozantinib vs cabozantinib alone) showed no improvement in progression-free survival or overall survival [31], and the TiNivo-2 trial (tivozanib ± nivolumab) confirmed that there was no benefit in reintroducing anti-PD-1 in patients who had already been exposed to immunotherapy [32]. These results suggest that immediate reintroduction of an ICI does not provide clinical benefit after recent failure of immunotherapy.

A retrospective multicenter study including 94 patients with CRC who had relapsed after adjuvant treatment with ICI reported heterogeneous management strategies [33]. Approximately 25% of patients received local treatment (surgery or radiotherapy), while the others received systemic treatment: TKI monotherapy (46%), ICI + TKI combinations (30%) or ICI-based regimens alone or in combination (17%). The objective response rate (ORR) was 39%, the 18-month PFS was 45%, and the 18-month OS was 85%. No significant difference in response was observed according to the type of systemic treatment.

In the subgroup of patients treated with adjuvant pembrolizumab (n = 23), a numerical difference was observed according to time to relapse: the ORR was 44% in patients relapsing after completion of adjuvant therapy, compared with 29% in those relapsing during treatment, suggesting that time to recurrence may reflect distinct resistance mechanisms.
<figure><img src="image_4.png" /><figcaption>Fig. 1. Proposed management for metastatic recurrence after adjuvant immunotherapy.</figcaption></figure>

## Pharmacology and duration of effect

Pembrolizumab has a plasma half-life of 14 to 27 days, and antibody elimination occurs at 5 times the half-life, or approximately 6 months [34]. However, its biological effect is more prolonged: PD-1 receptor occupancy is maintained for several months, and durable responses and delayed immune-induced toxicities are reported well after treatment discontinuation [35,36]. In the absence of definitive pharmacokinetic data defining “residual exposure time,” most experts use a pragmatic six-month threshold to differentiate true immunotherapy-refractory disease from a setting comparable to ICI-naïve disease.

**Recommendations** (Fig. 1): Inclusion in a clinical trial should be prioritized for patients with metastatic progression after adjuvant pembrolizumab (strong recommendation).

In the absence of an available trial, progression occurring during adjuvant therapy or within six months of discontinuation should be considered refractory to immunotherapy; in this setting, treatment should rely on TKI monotherapy (expert opinion).

Conversely, progression occurring more than six months after discontinuation may be managed as immunotherapy-naïve disease; first-line IO-based combinations (IO + IO or IO + TKI) can be considered according to patient characteristics (expert opinion).

Beyond 12 months after pembrolizumab completion, a standard first-line PD-1-based regimen is recommended (expert opinion).

For localized or oligometastatic relapse, local therapy (surgery or stereotactic body radiotherapy) should be discussed within a multidisciplinary tumour board (expert opinion).

## Disclosure of interest

Pierre Bigot : Ipsen, MSD, BMS, Merck-Pfizer, Novartis, Pfizer, Pierre-Fabre. Philippe Barthelemy : Aucun déclaré. Romain Boissier : Ipsen, Janssen, BMS, MSD, Astra Zeneca. Zine-Eddine Khene : Aucun déclaré. Caroline Pettenati : Ipsen, MSD, Janssen. Jean-Christophe Bernhard : Aucun déclaré. Jean-Michel Correas : Aucun déclaré. Nicolas Doumerc : Intuitive Surgical, Pierre Fabre, MSD, Ipsen. Pierre

Gimel : Ipsen, BMS, MSD. Alexandre Ingels : Aucun déclaré. Idir Ouzaïd : Janssen, MSD, BMS, Astellas, Astra-Zeneca, IPSEN, Boston Scientific. Nathalie Rioux-Leclercq : Astra zeneca, BMS, Ipsen, Merck-Pfizer. Laurence Albiges : Aucun déclaré. Olivier Chapet : Aucun déclaré. Morgan Rourprêt : Janssen, Ipsen, Astellas, Ferring, Astra-Zeneca, Bayer, Merck-Pfizer, MSD, BMS.

## Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.fjurol.2025.103007.

## References

[1] Cancer Today n.d. https://gco.iarc.who.int/today/ [accessed 29 September 2025].

[2] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63, http://dx.doi.org/10.3322/caac.21834

[3] Larcher A, Campi R, Bex A, Bray F, Bukavina L, Jonasch E, et al. Epidemiology of renal cancer: incidence, mortality, survival, genetic predisposition, and risk factors. Eur Urol. 2025;88:341–58, http://dx.doi.org/10.1016/j.eururo.2025.06.005

[4] Bukavina L, Bensalah K, Bray F, Carlo M, Challacombe B, Karam JA, et al. Epidemiology of renal cell carcinoma: 2022 update. Eur Urol. 2022;82:529–42, http://dx.doi.org/10.1016/j.eururo.2022.08.019

[5] Rossi SH, Klatte T, Usher-Smith J, Stewart GD. Epidemiology and screening for renal cancer. World J Urol. 2018;36:1341–53, http://dx.doi.org/10.1007/s00345-018-2286-7

[6] Usher-Smith JA, Godoy A, Kitt J, Farquhar F, Waller J, Sharp SJ, et al. Short-term psychosocial outcomes of adding a non-contrast abdominal computed tomography (CT) scan to the thoracic CT within lung cancer screening. BJU Int. 2024;133:539–47, http://dx.doi.org/10.1111/bju.16260

[7] Stewart GD, Godoy A, Farquhar F, Kitt J, Cartledge J, Kimuli M, et al. Abdominal noncontrast computed tomography scanning to screen for kidney cancer and other abdominal pathology within community-based computed tomography screening for lung cancer: results of the Yorkshire Kidney Screening Trial. Eur Urol. 2025;87:561–70, http://dx.doi.org/10.1016/j.eururo.2024.08.029

[8] Proye P, Gondran-Tellier B, Michel F, Bensalah K, Bigot P, Audenet F, et al. Renal mass biopsy prior to surgical excision: practice, diagnostic performance, and impact on management in the UroCCR Registry (Ancillary Study No. 118). Eur Urol Open Sci. 2025;73:60–7, http://dx.doi.org/10.1016/j.euros.2025.01.016
[9] Belladelli F, Rosiello G, Salerno L, Musso G, Cei F, Re C, et al. Biopsy-all strategy in patients with a renal mass: simulation of a randomised controlled trial. BJU Int. 2025;136:930-6, http://dx.doi.org/10.1111/bju.16885

[10] Pecoraro A, Testa GD, Marandino L, Albiges L, Bex A, Capitanio U, et al. Frailty and renal cell carcinoma: integration of comprehensive geriatric assessment into shared decision-making. Eur Urol Oncol. 2025;8:190-200, http://dx.doi.org/10.1016/j.euo.2024.09.001

[11] Linehan WM, Pinto CA, Liu Y, Choo K, Gautam R, Fox C, et al. Longitudinal evaluation of clear-cell renal cell carcinoma in von Hippel-Lindau Disease. Eur Urol. 2025;88:56-63, http://dx.doi.org/10.1016/j.eururo.2025.03.002

[12] Srinivasan R, Iliopoulos O, Beckermann KE, Narayan V, Maughan BL, Oudard S, et al. Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study. Lancet Oncol. 2025;26:571-82, http://dx.doi.org/10.1016/S1470-2045(25)00099-3

[13] Posada Calderon L, Dawidek MT, Tang C, Kim M, Zong G, Bandlamudi C, et al. Defining the histopathological, clinical, and genetic characteristics of familial BAP1-associated renal cell carcinoma. Eur Urol. 2025, http://dx.doi.org/10.1016/j.eururo.2025.08.007 [S0302283825004841].

[14] Marconi L, Kuusk T, Hora M, Klatte T, Dabestani S, Capitanio U, et al. Hospital volume as a determinant of outcomes after partial nephrectomy: a systematic review by the european association of urology renal cell carcinoma guidelines panel. Eur Urol Oncol. 2025;8:616-22, http://dx.doi.org/10.1016/j.euo.2025.01.013

[15] Hsu RCJ, Barclay M, Loughran MA, Lyratzopoulos G, Gnanapragasam VJ, Armitage JN. Impact of hospital nephrectomy volume on intermediate- to long-term survival in renal cell carcinoma. BJU Int. 2020;125:56-63, http://dx.doi.org/10.1111/bju.14848

[16] Henning GM, Deol ES, Vasdev R, Basourakos SP, Roberson DS, McLeay MT, et al. Characterising the hospital caseload-outcome relationship for radical nephrectomy with inferior vena cava tumor thrombectomy: analysis from the National Inpatient Sample. Urology. 2025, http://dx.doi.org/10.1016/j.urology.2025.05.048 [S0090429525005126].

[17] Decree No. 2022-689 of 26 April 2022 on the conditions for establishing cancer treatment activities. 2022.

[18] Alkhatib KY, Cheaib JG, Pallauf M, Alam R, Patel HD, Wlajnitz T, et al. Active surveillance vs. primary intervention for clinical T1a kidney tumours: 12-year experience of the delayed intervention and surveillance for small renal masses prospective comparative study. J Urol. 2025;214:197-209, http://dx.doi.org/10.1097/JU.00000000000004583

[19] Lee RA, Uzzo RG, Anaokar J, Thomas A, Wei S, Ristau BT, et al. Pathological and clinical outcomes in a large surveillance and intervention cohort of radiographically cystic renal masses. J Urol. 2023;209:686-93, http://dx.doi.org/10.1097/JU.00000000000003158

[20] Siva S, Bressel M, Sidhom M, Sridharan S, Vanneste BGL, Davey R, et al. Stereotactic ablative body radiotherapy for primary kidney cancer (TROG 15.03 FASTRACK II): a non-randomised phase 2 trial. Lancet Oncol. 2024;25:308-16, http://dx.doi.org/10.1016/S1470-2045(24)00020-2

[21] Siva S, Pham D, Kron T, Bressel M, Lam J, Tan TH, et al. Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial. BJU Int. 2017;120:623-30, http://dx.doi.org/10.1111/bju.13811

[22] Ali M, Correa RJM, Pryor D, Higgs B, Sridharan S, Sidhom M, et al. Efficacy of SABR in uncommon subtypes of primary kidney cancer: an analysis from the International Radiosurgery Oncology Consortium of the Kidney. Int J Radiat Oncol Biol Phys. 2025, http://dx.doi.org/10.1016/j.ijrobp.2025.08.043 [S0360301625061929].

[23] Huang RS, Chow R, Benour A, Chen D, Boldt G, Wallis CJD, et al. Comparative efficacy and safety of ablative therapies in the management of primary localised

renal cell carcinoma: a systematic review and meta-analysis. Lancet Oncol. 2025;26:387-98, http://dx.doi.org/10.1016/S1470-2045(24)00731-9

[24] Oza B, Frangou E, Eisen T, Stewart GD, Bex A, Harrison D, et al. Determining the impact of histology on the incidence, pattern, and timing of recurrences in patients with Renal Cell Carcinoma: A pooled analysis from the SORCE and ASSURE trials. Eur Urol Open Sci. 2025;79:19-26.

[25] Tundelalao S, Okunlola P, Titiloye T, Mayungbo B, Adegbesan A, Sajja A, et al. Risk of developing a second primary cancer following a renal cell carcinoma: a systematic review and meta-analysis. Int Urol Nephrol. 2025, http://dx.doi.org/10.1007/s11255-025-04794-7

[26] Tillquist K, Shringi S, Chang A, Hu SL. The nephrologist's perspective in evaluation and management of localised renal masses: core curriculum 2025. Am J Kidney Dis. 2025, http://dx.doi.org/10.1053/j.ajkd.2025.05.014 [S0272638625009734].

[27] Steiner C, Machaalani M, Bonventre JV, McDermott DF, Choueiri TK, Xu W. KIM-1 as a prognostic marker in renal cell carcinoma. Eur Urol Focus. 2025, http://dx.doi.org/10.1016/j.euf.2025.06.012 [S240456925001798].

[28] Dabestani S, Azawi NH, Campi R, Järvinen P, Nisen H, Capitanio U, et al. Urine Glycosaminoglycan Scores for Surveillance of recurrence in intermediate- and high-risk nonmetastatic clear cell renal cell carcinoma—An observational prospective multicentre diagnostic test cohort study. Eur Urol Oncol. 2025, http://dx.doi.org/10.1016/j.euo.2025.07.011 [S2588931125002044].

[29] Peng YL, Yu B, Huang TX, Zhou ZH, Zhang H, Tang WXF, et al. Early detection of renal cell carcinoma: a novel cell-free DNA fragmentomics-based liquid biopsy assay. ESMO Open. 2025;10:105323, http://dx.doi.org/10.1016/j.esmoop.2025.105323

[30] Correa AF, Kalashnikova E, Wu H-T, Winters RM, Balcioglu M, Sudhaman S, et al. Association of circulating tumour DNA with patient prognosis in surgically resected renal cell carcinoma. Oncologist. 2024;29:887-93, http://dx.doi.org/10.1093/oncolo/oyae180

[31] Pal SK, Albiges L, Tomczak P, Suárez C, Voss MH, de Velasco G, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402:185-95, http://dx.doi.org/10.1016/S0140-6736(23)00922-4

[32] Choueiri TK, Albiges L, Barthélémy P, Iacovelli R, Emambux S, Molina-Cerrillo J, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study. Lancet. 2024;404:1309-20, http://dx.doi.org/10.1016/S0140-6736(24)01758-6

[33] El Zarif T, Semaan K, Xie W, Eid M, Zarba M, Issa W, et al. First-line systemic therapy following adjuvant immunotherapy in renal cell carcinoma: an international multicenter study. Eur Urol. 2024;86:503-12, http://dx.doi.org/10.1016/j.eururo.2024.07.016

[34] Centanni M, Moes DJAR, Trocóniz IF, Ciccolini J, van Hasselt JGC. Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet. 2019;58:835-57, http://dx.doi.org/10.1007/s40262-019-00748-2

[35] Hu Y, Liu S, Wang L, Liu Y, Zhang D, Zhao Y. Treatment-free survival after discontinuation of immune checkpoint inhibitors in mNSCLC: a systematic review and meta-analysis. Front Immunol. 2023;14:1202822, http://dx.doi.org/10.3389/fimmu.2023.1202822

[36] Durbin SM, Zubiri L, Perlman K, Wu CY, Lim T, Grealish K. et al. Late-onset immune-related adverse events after immune checkpoint inhibitor therapy JAMA Netw. Open. 2025;8e252668, http://dx.doi.org/10.1001/jamanetworkopen.2025.2668