Design and rationale of a single-arm phase II study of neoadjuvant Durvalumab and Gemcitabine associated with Cisplatin or Carboplatin for upper urinary tract urothelial cancer: the iNDUCT trial (NCT04617756).

BACKGROUND: Upper urinary tract urothelial carcinoma (UTUC) is often locally advanced at initial diagnosis and is associated with high recurrence and mortality rates after radical nephroureterectomy (RNU). Adjuvant platinum-based chemotherapy has shown a recurrence-free survival benefit in a randomised phase III trial, while neoadjuvant treatment seems promising in retrospective series. On the contrary, little is known about the role of perioperative immunotherapy and its combination with chemotherapy for UTUC patients, although initial positive results have been published for muscle-invasive bladder cancer. STUDY DESIGN AND ENDPOINTS: Against this backdrop, we are running a multi-centre single-arm phase 2 trial of neoadjuvant Durvalumab, a monoclonal antibody targeting programmed cell death ligand 1, combined with Gemcitabine and Cisplatin or Carboplatin for high-risk UTUC patients. The primary outcome is pathological complete response rate at RNU. Secondary endpoints include the partial pathological response rate, safety, as well as disease-free and overall survival. A biomarker analysis is also planned. PATIENTS AND INTERVENTIONS: Included patients must have a good performance status and harbour a non-metastatic UTUC, considered at high risk of progression, defined as either biopsy-proven high-grade disease or invasive features at imaging with or, more recently, without high-grade cytology at the multidisciplinary team discretion, as specified in the latest amendment. Enrolled patients receive 3 cycles of neoadjuvant immuno-chemotherapy before RNU, and the standard of care thereafter. The trial is registered as NCT04617756 and is supervised by an independent data monitoring committee.

The role of perioperative chemotherapy for upper tract urothelial carcinoma patients treated with radical nephroureterectomy.

PURPOSE: To summarize evidence regarding the use of neoadjuvant (NAC) and adjuvant chemotherapy (AC) among patients treated with radical nephroureterectomy (RNU). METHODS: A comprehensive literature search of PubMed (MEDLINE), EMBASE and the Cochrane library was performed to identify any original or review article on the role of perioperative chemotherapy for UTUC patients treated with RNU. RESULTS: With regards to NAC, retrospective studies consistently suggested that it may be associated with better pathological downstaging (pDS) ranging from 10.8 to 80% and complete response (pCR) ranging from 4.3 to 15%, while decreasing the risk of recurrence and death as compared to RNU alone. Even higher pDS ranging from 58 to 75% and pCR ranging from 14 to 38% were observed in single-arm phase II trials. With regards to AC, retrospective studies provided conflicting results although the largest report from the National Cancer Database suggested an overall survival benefit in pT3-T4 and/or pN + patients. In addition, a phase III randomized controlled trial showed that the use of AC was associated with a disease-free survival benefit (HR = 0.45; 95% CI = [0.30-0.68]; p = 0.0001) in pT2-T4 and/or pN + patients with acceptable toxicity profile. This benefit was consistent in all subgroups analyzed. CONCLUSIONS: Perioperative chemotherapy improves oncological outcomes associated with RNU. Given the impact of RNU on renal function, the rational is stronger for the use of NAC which impacts final pathology and potentially prolongs survival. However, the level of evidence is stronger for the use of AC that has been proven to decrease the risk of recurrence after RNU with a potential survival benefit.

Features and management of men with pN1 cM0 prostate cancer after radical prostatectomy and lymphadenectomy: a systematic review of population-based evidence.

PURPOSE OF REVIEW: To investigate the features and optimal management of pN+ cM0 prostate cancer (PCa) according to registry-based studies. RECENT FINDINGS: Up to 15% of PCa patients harbor lymph node invasion (pN+) at radical prostatectomy plus lymph node dissection. Nonetheless, the optimal management strategy in this setting is not well characterized. SUMMARY: We performed a systematic review including n = 13 studies. Management strategies comprised 13 536 men undergoing observation, 11 149 adjuvant androgen deprivation therapy (aADT), 7,075 adjuvant radiotherapy (aRT) +aADT and 705 aRT. Baseline features showed aggressive PCa in the majority of men. At a median follow-up ranging 48-134months, Cancer-related death was 5% and overall-mortality 16.6%. aADT and aRT alone had no cancer-specific survival or overall survival advantages over observation only and over not performing aRT, respectively. aADT plus aRT yielded a survival benefit compared to observation and aADT, which in one study, were limited to certain intermediate-risk categories. Age, Gleason, Charlson score, positive surgical margins, pathological stage, and positive nodes number, but not prostate specific antigen, were most relevant prognostic factors. Our work further confirmed pN+ PCa is a multifaceted disease and will help future research in defining its optimal management based on different risk categories to maximize survival and patient's quality of life.

Cabazitaxel schedules in metastatic castration-resistant prostate cancer: a review.

Cabazitaxel (25 mg/m2 every 3 weeks) is the standard second-line chemotherapy for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel. It is associated with a risk of neutropenic complications, which may be a barrier to its use in daily clinical practice, particularly in frail elderly patients. Here the authors reviewed key studies conducted with cabazitaxel (TROPIC, PROSELICA, AFFINITY, CARD and the European compassionate use program) and pilot studies with adapted schedules. Based on this review, the use of prophylactic granulocyte colony-stimulating factor from cycle 1 appears crucial to maximize the benefit-risk ratio of cabazitaxel in metastatic castration-resistant prostate cancer. Preliminary data with alternative schedules look promising, especially for frail patients. Results of the ongoing Phase III CABASTY trial (ClinicalTrials.gov: NCT02961257) are awaited.

Pharmaceutical consultation to detect drug interactions in patients treated with oral chemotherapies: A descriptive cross-sectional study.

OBJECTIVE: The development of oral chemotherapy (OC) has led to the recent establishment of multidisciplinary programmes involving pharmacists. We evaluated the utility of our local programme for detecting potential interactions with OCs, particularly drug-drug interactions (DDIs) and herbal-drug interactions (HDIs). METHODS: We performed a single-centre retrospective descriptive study of patients on OC attending a pharmaceutical consultation (PC) during a seven-month period. These consultations included the use of various complementary tools/databases to search for interactions. RESULTS: We analysed 308 treatments taken by 42 consecutive patients. Fifty-four potential interactions with OCs were detected in 26% (n = 79) of the treatments taken by patients: 46 DDIs (32 minor, 12 major, 2 contraindicated) and eight HDIs. Five interventions associated with interactions were suggested by pharmacists during the consultations (4 were taken into account by oncologists). The total mean time spent on each PC for an individual patient was 80 minutes (36 minutes of preparation, 44 minutes with the patient). CONCLUSION: This pilot study highlights the importance of studying interactions in such patients, and of the expertise of pharmacists for detecting interactions, which were found in more than one in four treatment lines. The further development of such activities, which already take up considerable amounts of time, is therefore warranted.

Pharmaceutical interventions to improve safety of chemotherapy-treated cancer patients: A cross-sectional study.

PURPOSE: Cancer chemotherapy is a high-risk process. To improve patient safety, a systematic pharmaceutical analysis of chemotherapy prescriptions is performed in our institution. The aim of this study was to assess the impact of pharmaceutical interventions (PIs) on the safety of patient chemotherapy prescriptions. METHODS: This prospective cross-sectional study was conducted in an 800-bed university hospital with oncology departments. All chemotherapy prescriptions were included and PIs were collected prospectively during one month. The clinical impact of PIs was scored by an expert panel of oncologists and pharmacists, using the Hatoum scale. Univariate and multivariate analysis were conducted to identify factors associated with a higher frequency of PIs. RESULTS: Of 1346 prescriptions included, 129 required a PI (9.6% (95% CI: 8.1-11.4)). Most PIs were scored as having at least a significant impact for patient safety (69.8% (95% CI: 60.4-76.9)). The frequency of PIs was significantly associated with tumour site (p = 0.04) and weekday of prescription (p = 0.005). Multivariate analysis identified factors independently associated with PI performance, including pancreas and biliary tract cancers (odds ratio = 2.8 (95% CI: 1.4-5.3)), ovary cancers (odds ratio = 2.4 (95% CI: 1.2-4.8)) and head and neck cancers (odds ratio = 2.4 (95% CI: 1.1-5.1)) and the day 1 of the protocol with a cytotoxic agent (odds ratio = 3.7 (95% CI: 1.1-11.1)). CONCLUSIONS: Oncology pharmacists have a critical role in the safety of chemotherapy prescriptions. The coordination between healthcare professionals and access to patient data seem essential to improve the PIs' relevance and their clinical impact on patient safety.

Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer.

OBJECTIVES: To evaluate the safety and efficacy of a 2-weekly cabazitaxel schedule in patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: During the period October 2013 to February 2016, 43 patients with mCRPC were treated with cabazitaxel (16 mg/m2 , on days 1 and 15 of a 4-week cycle) together with prophylactic granulocyte colony-stimulating factor (G-CSF). The safety profile and efficacy (prostate-specific antigen [PSA] response; biological, clinical or radiological progression-free survival [PFS] and overall survival [OS]) of the treatment were analysed. RESULTS: All patients had received prior docetaxel and 79.1% abiraterone acetate. At inclusion, 46.5% were aged >70 years and 27.9% had an Eastern Cooperative Oncology Group performance status ≥2. Six patients stopped treatment because of toxicity. Grade ≥3 toxicities were: asthenia (16.3%); neutropenia (11.6%); thrombocytopenia (9.3%); diarrhoea (7%), anaemia (4.7%), febrile neutropenia (4.7%) and haematuria (2.3%). In all, 52.4% achieved a ≥30% PSA response and 40.5% had a ≥50% PSA response. The median OS was 15.2 months. CONCLUSION: This prospective pilot study suggests that cabazitaxel 16 mg/m² given 2-weekly has a manageable toxicity profile in docetaxel- and abiraterone acetate-pretreated patients with mCRPC. A prospective phase III trial comparing this regimen with the standard cabazitaxel regimen is planned to confirm these results.

Base-Position Error Rate Analysis of Next-Generation Sequencing Applied to Circulating Tumor DNA in Non-Small Cell Lung Cancer: A Prospective Study.

BACKGROUND: Circulating tumor DNA (ctDNA) is an approved noninvasive biomarker to test for the presence of EGFR mutations at diagnosis or recurrence of lung cancer. However, studies evaluating ctDNA as a noninvasive "real-time" biomarker to provide prognostic and predictive information in treatment monitoring have given inconsistent results, mainly due to methodological differences. We have recently validated a next-generation sequencing (NGS) approach to detect ctDNA. Using this new approach, we evaluated the clinical usefulness of ctDNA monitoring in a prospective observational series of patients with non-small cell lung cancer (NSCLC). METHODS AND FINDINGS: We recruited 124 patients with newly diagnosed advanced NSCLC for ctDNA monitoring. The primary objective was to analyze the prognostic value of baseline ctDNA on overall survival. ctDNA was assessed by ultra-deep targeted NGS using our dedicated variant caller algorithm. Common mutations were validated by digital PCR. Out of the 109 patients with at least one follow-up marker mutation, plasma samples were contributive at baseline (n = 105), at first evaluation (n = 85), and at tumor progression (n = 66). We found that the presence of ctDNA at baseline was an independent marker of poor prognosis, with a median overall survival of 13.6 versus 21.5 mo (adjusted hazard ratio [HR] 1.82, 95% CI 1.01-3.55, p = 0.045) and a median progression-free survival of 4.9 versus 10.4 mo (adjusted HR 2.14, 95% CI 1.30-3.67, p = 0.002). It was also related to the presence of bone and liver metastasis. At first evaluation (E1) after treatment initiation, residual ctDNA was an early predictor of treatment benefit as judged by best radiological response and progression-free survival. Finally, negative ctDNA at E1 was associated with overall survival independently of Response Evaluation Criteria in Solid Tumors (RECIST) (HR 3.27, 95% CI 1.66-6.40, p < 0.001). Study population heterogeneity, over-representation of EGFR-mutated patients, and heterogeneous treatment types might limit the conclusions of this study, which require future validation in independent populations. CONCLUSIONS: In this study of patients with newly diagnosed NSCLC, we found that ctDNA detection using targeted NGS was associated with poor prognosis. The heterogeneity of lung cancer molecular alterations, particularly at time of progression, impairs the ability of individual gene testing to accurately detect ctDNA in unselected patients. Further investigations are needed to evaluate the clinical impact of earlier evaluation times at 1 or 2 wk. Supporting clinical decisions, such as early treatment switching based on ctDNA positivity at first evaluation, will require dedicated interventional studies.

Radiation Therapy for Locally Advanced Prostate Cancer: How Do We Treat Patients with cN1 Disease?

Radiotherapy (RT) for high-risk localized prostate cancer (HRLPC) can be controversial in the context of increasing detection of suspicious lymph nodes via advanced imaging techniques. The EORTC 22683 trial initially established RT with androgen deprivation therapy (ADT) as the standard of care for HRLPC, but many patients remain uncured. GETUG-AFU-12 showed that addition of docetaxel and estramustine to ADT improved relapse-free survival but not overall survival. STAMPEDE later demonstrated that abiraterone acetate with ADT and RT significantly improved failure-free survival and overall survival. Ongoing trials such as ENZARAD, ATLAS, DASL-HiCap, and GETUG-P17 ALADDIN are investigating the efficacy of new androgen receptor pathway inhibitors combined with RT and ADT. These studies aim to refine treatment strategies for HRLPC, particularly in the context of advanced imaging and patient upstaging. PATIENT SUMMARY: Addition of newer medications to standard radiation therapy has shown promise in improving survival for men with high-risk prostate cancer. Ongoing studies are testing these options to find the best combination. The aim is to increase the chances of curing prostate cancer, especially as advanced scan techniques are detecting more cases.

Management of patients with muscle-invasive bladder cancer with clinical evidence of pelvic lymph node metastases.

Identification of clinically positive pelvic lymph node metastases (cN+) in patients with muscle-invasive bladder cancer is currently challenging, as the diagnostic accuracy of available imaging modalities is limited. Conventional CT is still considered the gold-standard approach to diagnose lymph node metastases in these patients. The development of innovative diagnostic methods including radiomics, artificial intelligence-based models and molecular biomarkers might offer new perspectives for the diagnosis of cN+ disease. With regard to the treatment of these patients, multimodal strategies are likely to provide the best oncological outcomes, especially using induction chemotherapy followed by radical cystectomy and pelvic lymph node dissection in responders to chemotherapy. Additionally, the use of adjuvant nivolumab has been shown to decrease the risk of recurrence in patients who still harbour ypT2-T4a and/or ypN+ disease after surgery. Alternatively, the use of avelumab maintenance therapy can be offered to patients with unresectable cN+ tumours who have at least stable disease after induction chemotherapy alone. Lastly, patients with cN+ tumours who are not responding to induction chemotherapy are potential candidates for receiving second-line treatment with pembrolizumab.

Adverse myocardial and vascular side effects of immune checkpoint inhibitors: a prospective multimodal cardiovascular assessment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can induce cardiovascular toxicities. OBJECTIVES: To prospectively assess the incidence of major cardiovascular events (MACE) on ICIs in solid cancer patients: myocarditis, pericarditis, acute coronary syndrome, heart failure, high-degree conduction abnormalities or sustained ventricular arrhythmias, or cardiovascular death at 6 weeks (early MACE), including asymptomatic clinical changes by an independent adjudication committee using current recommended diagnostic criteria. The secondary objective was the incidence of the above-mentioned events adding atrial fibrillation (AF) at 6 months (late MACE). RESULTS: Participants underwent pre-ICIs and repeated multimodality cardiac imaging (echocardiogram, cardiac magnetic resonance (CMR)), serum biomarkers (ultrasensitive troponin I), and rhythm surveillance (ambulatory ECG monitoring) at 6 weeks and 6 months. Forty-nine patients (38 (77.6%) male; mean age 64.3 (SD 11.0) years old) were included (June 2020-December 2021). Early MACE were observed in 9 (18.4%) patients at mean 40.1 (SD 5.9) days, with heart failure (HF) in 5 (10.2%), ventricular arrhythmias, or new conduction disorders in 4 (8.2%) patients. History of AF (HR 4.49 (CI 1.11-18.14), P = 0.035) predicted early MACE. At 6 months follow-up, 18 MACE were observed in 15/49 (31%) patients, with 6 (12.2%) HF events, 5 (10.2%) significant ventricular arrhythmias, or conduction disorders, and 4 (8.2%) AF. There was a significant decline in LVEF (P < 0.001) in patients with no MACE (P = 0.003) or HF (P = 0.0028). Higher creatinine at inclusion (HR 0.99 [0.98-1.00], P = 0.006) predicted HF on multivariate analysis. There were no significant T1 or T2 mapping changes in our study cohort on repeated CMR. CONCLUSIONS: Cardiotoxicity on ICIs is more frequent than previously described when using a thorough detection strategy, consisting mainly in HF and asymptomatic rhythm disorders.

Safety and efficacy of nivolumab in elderly patients with metastatic clear cell renal cell carcinoma: Analysis of the NIVOREN GETUG-AFU 26 study.

INTRODUCTION: Immune checkpoint inhibitors are standard of care in metastatic renal cell carcinoma but their activity and safety in elderly patients is insufficiently explored. We evaluated outcomes of elderly patients with mRCC treated with nivolumab in the GETUG-AFU 26 NIVOREN phase 2 trial (NCT03013335) and conducted exploratory circulating biomarker analyses. METHODS: Patients with mRCC were treated with nivolumab after at least one antiangiogenic therapy. The main endpoint of this analysis was safety in patients ≥ 70 years old (y.o), as per the rate of treatment-related grade 3-5 events (TRAE). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival. Exploration of candidate biomarkers associated with aging included baseline circulating cytokines involved in inflammation, adhesion, immune checkpoints, angiogenesis (IL6, IL7, IL8, BAFF, CXCL13, VCAM-1, 4-1BB, VEGF). RESULTS: Of 720 patients, 515 were < 70 y.o and 205 ≥ 70 y.o. Patients ≥ 70 y.o exhibited numerically less IMDC poor risk disease (21.0% vs 26.9%), sarcomatoid component (4.9% vs 9.8%) or brain metastases (5.9% vs. 14.7%), but more previous treatment lines (≥ 2 in 54.1% vs 48.5%). TRAE were higher in patients ≥ 70 y.o (24.9% vs. 17.9%, p = 0.033). Respective ORR (19.2% vs. 22.1%) and median PFS (4.5 versus 3.0 months, HR 0.97 [95%CI 0.81-1.15]) were similar. Overall survival was shorter in patients ≥ 70 y.o (19.3 versus 26.9 months, HR 1.26 [95%CI 1.04-1.51]), but not significantly in a competitive risk model. Only V-CAM1 and 4-1BB were found to be increased in patients ≥ 70 y.o. CONCLUSIONS: Nivolumab displayed higher grade 3/4 TRAE but manageable toxicity in elderly patients, with sustained activity. Elderly patients did not display specific inflammatory or angiogenic circulating profiles.

Innovation in Radionuclide Therapy for the Treatment of Prostate Cancers: Radiochemical Perspective and Recent Therapeutic Practices.

Prostate cancer represents the second cause of death by cancer in males in western countries. While early-stage diseases are accessible to surgery and/or external radiotherapy, advanced metastatic prostate cancers are primarily treated with androgen deprivation therapy, to which new generation androgen receptor antagonists or taxane-based chemotherapies are added in the case of tumor relapse. Nevertheless, patients become invariably resistant to castration with a median survival that rarely exceeds 3 years. This fostered the search for alternative strategies, independent of the androgen receptor signaling pathway. In this line, radionuclide therapies may represent an interesting option as they could target either the microenvironment of sclerotic bone metastases with the use of radiopharmaceuticals containing samarium-153, strontium-89 or radium-223 or tumor cells expressing the prostate-specific membrane antigen (PSMA), a protein found at the surface of prostate cancer cells. This review gives highlights the chemical properties of radioligands targeting prostate cancer cells and recapitulates the clinical trials evaluating the efficacy of radionuclide therapies, alone or in combination with other approved treatments, in patients with castration-resistant prostate tumors. It discusses some of the encouraging results obtained, especially the benefit on overall survival that was reported with [177Lu]-PSMA-617. It also addresses the specific requirements for the use of this particular class of drugs, both in terms of medical staff coordination and adapted infrastructures for efficient radioprotection.

[Collecting duct carcinoma and renal medullary carcinoma in the age of new therapies]. / Tumeurs de Bellini et carcinomes médullaires rénaux à l'ère des nouvelles thérapies.

Collecting duct carcinoma (also known as Bellini tumour) and renal medullary carcinoma are two extremely rare and aggressive renal cancers. They are both less responsive to conventional treatments used in clear cell renal carcinoma. There are very few studies evaluating their optimal management and currently, at the metastatic stage, polychemotherapy based on platinum salts remains the most widely used. The emergence of new treatments such as anti-angiogenic TKIs, immunotherapy or treatments targeting specific genetic abnormalities, opens up a new field of possibilities in the management of these cancers. The evaluation of the response to these treatments is therefore essential. In this article, we will review the status of their management and the various studies that have evaluated recent treatments in these two cancers.

[Antibody drug conjugates (ADC) and bispecific antibodies in oncology - report of the 2022 Saint Louis day]. / Anticorps monoclonaux conjugués et bispécifiques en cancérologie ­ compte rendu de la Journée de Saint Louis 2022.

Antibody Drug Conjugates (ADC) and bispecific antibodies are booming and were the subject of the scientific event proposed by the French Society of Oncological Pharmacy, October 13, 2022. An ADC is composed of the antibody targeting a receptor expressed on the tumor cell, the spacer making it possible to attach the cytotoxic to the antibody and to control its distribution in the body, and the cytotoxic. Therapeutic antibodies, monoclonal and conjugated, have particular pharmacokinetics. Unlike monoclonal antibodies for which the standard dose is most often fixed, this is expressed in mg/m2 (or mg/kg) and capped at 2m2 (or 100kg) for conjugates. The linked cytotoxics are powerful cytotoxics: mitotic spindle poisons (emtansine, monomethyl auristatin E or vedotin), topoisomerase I inhibitors (deruxtecan, SN 38) or antibiotics (ozogamicin). In senology, trastuzumab deruxtecan (anti-HER2) and sacituzumab govitecan (anti-Trop 2) are now modifying treatment standards for patients with metastatic breast cancer, respectively HER2 3X or HER2 low and triple negative. In metastatic bladder cancer, enfortumab vedotin (anti-nectin 4) is positioned as the 2nd line of treatment. Bispecific antibodies, on the other hand, are able to target two epitopes, an antigen specific to a tumor cell and one to an immune cell, allowing a bridge between the killer immune cells and the tumor cells. For lymphoma proliferation, many bispecific antibodies are in development. The most advanced are glofitamab, epcoritamab and mosunetuzumab, which target the CD20 of B lymphocytes and the CD3 of T lymphocytes. Bispecific antibodies are also emerging in the treatment of myeloma with teclistamab and elranatamab (anti-CD3 and anti-BCMA) or talquetamab (anti-GPRC5D and anti-CD3). Conjugated antibodies, and more recently bispecific antibodies, are potential game changers in cancer treatment and researchs are needed to improve their efficacy and safety.

Metastatic Sites' Location and Impact on Patient Management After the Introduction of Prostate-specific Membrane Antigen Positron Emission Tomography in Newly Diagnosed and Biochemically Recurrent Prostate Cancer: A Critical Review.

CONTEXT: The introduction of prostate-specific membrane antigen positron emission tomography (PSMA-PET) had a substantial impact on the management of prostate cancer (PCa) patients with a stage migration phenomenon and consequent treatment changes. OBJECTIVE: To summarise the role of PSMA-PET to define the burden of disease through an accurate location of metastatic site(s) in PCa patients, describing the most common locations at PSMA-PET in the primary staging and recurrence setting, and to assess the clinical impact in the decision-making process. EVIDENCE ACQUISITION: A comprehensive nonsystematic literature review was performed in April 2022. Literature search was updated until March 2022. The most relevant studies have been summarised, giving priority to registered clinical trials and multicentre collaborations. EVIDENCE SYNTHESIS: PSMA-PET showed higher diagnostic accuracy than conventional imaging both in newly diagnosed PCa and in recurrent disease. This greater accuracy led to a migration of a higher proportion of patients identified with metastatic disease. Bone metastases were reported as the most frequent site of metastatic spread in staging (up to 17%) and restaging (up to 18%). In staging, considering the suboptimal sensitivity in lymph node metastasis detection prior to radical surgery, PSMA-PET should be performed in patients with high risk or unfavourable intermediate risk only, and it is not recommended to routinely avoid pelvic lymph node dissection in case of a negative scan. In case of prostate-specific antigen relapse, PSMA-PET had higher diagnostic accuracy than other diagnostic procedures in the early detection of the sites of recurrence, thus influencing the therapy decision-making process. CONCLUSIONS: PSMA-PET detects a higher number of lesions than conventional imaging or other PET radiotracers, especially metastatic lesions unseen with other modalities. The high diagnostic accuracy of PSMA-PET leads to a significant patient upstage and thus an impact in clinical management, even if the overall impact on cancer mortality is still to be assessed. PATIENT SUMMARY: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) identifies metastatic lesions with higher accuracy than conventional imaging, both in primary prostate cancer and during disease recurrence. Skeletal metastasis and extrapelvic lymph nodes are the most common sites of metastatic spread. The high accuracy of PSMA-PET in the detection of metastatic disease led to a significant impact on patient management, even if the overall impact on cancer mortality is still to be assessed.

Efficacy and safety of cabozantinib rechallenge in metastatic renal cell carcinoma: A retrospective multicentric study.

BACKGROUND: Despite metastatic renal cell carcinoma (mRCC) expanded treatment options, disease progression ultimately occurs for most patients. Rechallenge may be a compelling strategy in a refractory setting. Cabozantinib is the standard of care in first and later lines of therapy, but its activity in rechallenge is unknown. METHODS: This retrospective study assessed the efficacy and safety of cabozantinib rechallenge, as defined by a second exposure after an interval of ≥3 months without treatment or ≥1 other treatment line, in patients with mRCC. The primary endpoint was median progression-free survival (PFS) at rechallenge. Secondary endpoints included overall survival, objective response rate, and safety at rechallenge. RESULTS: We included 51 mRCC patients who received cabozantinib in a rechallenge setting between 2017 and 2022. Median age at diagnosis was 54 years, 78% were male, 90% had clear cell mRCC, and 92% had prior nephrectomy. 15 patients (29%) were rechallenged after a pause in treatment, whereas 36 (70.6%) had ≥1 other treatment lines between first cabozantinib exposure (CABO-1) and rechallenge (CABO-2). Median PFS was 15.1 months (mo, 95% Confidence interval 11.2-22.1) at CABO-1 and 14.4mo (95%CI 9.8-NR) at CABO-2. Median overall survival was 67.6mo for CABO-1 (95% CI 52.2-NR) and 27.4mo for CABO-2 (95%CI 17.2-NR); objective response rate was 70.6% for CABO-1 and 60% for CABO-2. CABO-2 PFS was higher for patients with CABO-1 PFS > 12 months, and for those who discontinued CABO-1 because of toxicity, without statistical significance. There were no unexpected adverse events. CONCLUSIONS: Cabozantinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients.