Is There an Opportunity to De-Escalate Treatments in Selected Patients with Metastatic Hormone-Sensitive Prostate Cancer?

The treatment landscape for metastatic hormone-sensitive prostate cancer continues to evolve, with systemic treatment being the mainstay of current treatment. Prognostic and predictive factors such as tumour volume and disease presentation have been studied to assess responses to different treatments. Intensification and de-escalation strategies arouse great interest, so several trials are being developed to further personalize the therapy in these populations. Is there an optimal sequence and a possible option to de-intensify treatment in selected patients with a favourable profile? This and other goals will be the subject of this review.

Urinary Organs at Risk for Prostate Cancer External Beam Radiation Therapy: Contouring Guidelines on Behalf of the Francophone Group of Urological Radiation Therapy.

PURPOSE: The occurrence of genitourinary (GU) toxicity is a common adverse event observed after external beam radiation therapy (EBRT) for prostate cancer (PCa). Recent findings suggest that the dose delivered to specific urinary organs at risk (OARs) such as the ureters, bladder trigone, and urethra is involved in the development of GU toxicity. METHODS AND MATERIALS: A multidisciplinary task force including 3 radiation oncologists, a uroradiologist, and a urologist was created in 2022. First, OARs potentially involved in GU toxicity were identified and discussed. A literature review was performed, addressing several questions relative to urinary OARs: anatomic and radiological definition, radiation-induced injury, and dose-volume parameters. Second, results were presented and discussed with a panel of radiation oncologists and members of the "Francophone Group of Urological Radiation Therapy." Thereafter, the "Francophone Group of Urological Radiation Therapy" experts were asked to answer a dedicated questionnaire, including 35 questions on the controversial issues related to the delineation of urinary OARs. RESULTS: The following structures were identified as critical for PCa EBRT: ureters, bladder, bladder neck, bladder trigone, urethra (intraprostatic, membranous, and spongious), striated sphincter, and postenucleation or posttransurethral resection of the prostate cavity. A consensus was obtained for 32 out of 35 items. CONCLUSIONS: This consensus highlights contemporary urinary structures in both the upper and lower urinary tract to be considered for EBRT treatment planning of PCa. The current recommendations also propose a standardized definition of urinary OARs for both daily practice and future clinical trials.

PARP inhibitors in prostate cancers, is it time for combinations?

Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular BRCA2. More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection.

Organ at risk dose-volume metrics in a series of hypofractionated breast radiotherapy with integrated boost.

Dose and volume metrics to organs at risk are used for evaluation and optimization in radiotherapy planning. However, the numerous choices of metrics can be confusing. In a series of patients treated with hypofractionation and an integrated boost for breast cancer, we aim to determine if a parsimonious selection of representative metrics can be identified. The dosimetries of 42 patients receiving 42 Gy to the breast, with or without nodal irradiation, and 51 Gy integrated boost to tumor bed in 15 fractions were reviewed. For each organ-heart, lungs, and contralateral breast-cumulative dose-volume histograms were used to extract values for 3 basic metric classes: Two additional classes were considered: Pearson correlation coefficient R was calculated between pairs of values within each basic class and with the 2 additional classes for each organ. The interquartile ranges of correlations for D.yy, Vrel.xx, and Vabs.xx were as follows: The mean dose correlated with all basic classes for the heart and lungs, and with dose D.yy and volumes at Vrel.10-Vabs.10 for the contralateral breast. The standard deviation correlated with Vrel.xx and Vabs.xx for the heart and lungs (R ≥ 0.70). Among the D.yy, D.50 (median dose) correlated with the mean and standard deviation for all organs (R = 0.65-0.96). The mean, standard deviation, and median doses were the preeminent correlators. These statistics appear to be parsimonious representatives of doses to organs. Further studies with other radiotherapy series will be necessary to validate these observations.

Stereotactic body radiation therapy for primary renal cell carcinoma: A review on behalf of the CC-AFU.

INTRODUCTION: The incidence of localized renal cell carcinoma (RCC) is on the rise among individuals aged 70 and older. While the gold standard for treatment remains surgical resection, some elderly and frail patients with comorbidities are not eligible for this procedure. In selected cases, percutaneous thermal ablation, such as cryotherapy, microwave and radiofrequency, offers less invasive options. General anesthesia is sometimes necessary for such treatments, but most of the procedures can be conducted using mild or deep conscious sedation. This approach is preferably recommended for small cT1a tumors situated at a distance from the renal hilum and/or ureter. Active surveillance remains an alternative in the case of small low grade RCC although it may induce anxiety in certain patients. Recent research has highlighted the potentials of stereotactic ablative body radiotherapy (SABR) as a noninvasive, well-tolerated, and effective treatment for small renal tumors. This narrative review aims to explore recent advances in SABR for localized RCC, including appropriate patient selection, treatment modalities and administration, as well as efficacy and tolerance assessment. MATERIAL AND METHODS: We conducted a literature review using the terms [kidney cancer], [renal cell carcinoma], [stereotactic radiotherapy], [SBRT], and [SABR] in the Medline, PubMed, and Embase databases, focusing on prospective and relevant retrospective studies published in English. RESULTS: Studies report local control rates ranging from 70% to 100% with SABR, highlighting its efficacy in treating RCC. The decline in glomerular filtration rate (GFR) is approximately -5 to -17mL/min over the years following SABR. Common toxicities are rare, primarily CTCAE grade 1, include fatigue, nausea, chest or back pain, diarrhea, or gastritis. CONCLUSION: Stereotactic ablative body radiotherapy (SABR) may be considered as a viable option for patients with localized RCC who are not suitable candidates for surgery with a high local control rate and a favorable safety profile. This approach should be discussed in a multidisciplinary meeting and results from ongoing clinical trials are awaited.

The current landscape of stereotactic body radiation therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: The onset of castration-resistance is associated with dismal outcomes in patients with prostate cancer (PCa). Metastasis directed therapy has been investigated in multiple disease settings and may improve outcomes in selected patients. Our systematic review aims to summarize evidence with stereotactic body radiotherapy (SBRT) in castration-resistant prostate cancer (CRPC). METHODS: The literature search was performed on March 2024, on Pubmed, using the keywords "SBRT" AND "CRPC", and "stereotactic ablative radiotherapy (SABR)" AND "CRPC". This search retrieved a total of 108 articles, 19 were included. RESULTS: The literature is largely dominated by retrospective series. In men with metachronous oligoprogression, SBRT with androgen receptor pathway inhibitor significantly increased progression-free survival (PFS) including biochemical progression-free survival in a randomized phase II trial (hazard ratio of 0.35, p < 0.001). In patients continuing ADT, the bPFS ranged between 9.5 months to 17.9 months, and next systemic treatment-free survival (NEST-FS) reached up to 2 years. In men with induced oligoprogression, SBRT enabled NEST-FS up to 3 years. SBRT was well tolerated, with less than 5% grade 3 toxicity reported across studies. CONCLUSION: In the population of patients with oligometastatic CRPC, SBRT enables long-term biochemical response and PFS. In the oligoprogressive setting, SBRT could be integrated to prolong the duration and efficacy of systemic therapies. Nevertheless, the level of evidence remains very low and inclusion within prospective trials remain the preferred option for this population of patients.

The testosterone replacement therapy for prostate cancer patients: Time to take the leap?

The advent of new systemic therapies resulted in a significant decrease in prostate cancer (PCa) death in the past decades. It comes at the cost of an increase in the proportion of men living with long-term treatment-induced hypogonadism. In a population of men with no history of PCa, the testosterone replacement therapy (TRT) proved its ability to both improve erectile function and reduce cardiovascular morbidity, translating into an improved overall survival. Whether TRT is safe and efficient in PCa patients remains an open question. Here, we present an overview on the safety of TRT for PCa patients and discuss the optimal population eligible for TRT after the PCa treatment.

Combination of Abiraterone Acetate, Prostate Bed Radiotherapy, and Luteinizing Hormone-releasing Hormone Agonists in Biochemically Relapsing Patients After Prostatectomy (CARLHA): A Phase 2 Clinical Trial.

BACKGROUND: The relevance of next-generation hormone therapies and circulating tumor cells (CTCs) are not elucidated in biochemical recurrence after prostatectomy. OBJECTIVE: To evaluate the combination of abiraterone acetate plus prednisone (AAP), prostate bed radiotherapy (PBRT), and goserelin in biochemically relapsing men after prostatectomy, and to investigate the utility of CTCs. DESIGN, SETTING, AND PARTICIPANTS: In this single-arm multicenter phase 2 trial, 46 biochemically relapsing men were enrolled between December 2012 and January 2019. The median follow-up was 47 mo. INTERVENTION: All patients received AAP 1000 mg daily (but 750 mg during PBRT), salvage PBRT, and goserelin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 3-yr biochemical recurrence-free survival (bRFS) when prostate-specific antigen (PSA) levels were ≥0.2 ng/ml. The secondary outcomes included alternative bRFS (alt-bRFS) when PSA levels were ≥0.5 ng/ml and safety assessment. CTC count was assessed. RESULTS AND LIMITATIONS: The 3-yr bRFS and alt-bRFS were 81.5% (95% confidence interval or CI [66.4-90.3%]) and 95.6% (95% CI [83.5-98.9%]), respectively. The most common acute radiotherapy-related adverse effect (AE; all grades was pollakiuria (41.3%). The most common late AE (all grades) was urinary incontinence (15.2%). Grade 3-4 acute or late radiotherapy-related AEs were scarce. Most frequent AEs nonrelated to radiotherapy were hot flashes (76%), hypertension (63%), and hepatic cytolysis (50%, of which 20% were of grades 3-4). Of the patients, 11% had a CTC count of ≥5, which was correlated with poorer bRFS (p = 0.042) and alt-bRFS (p = 0.008). The association between CTC count and higher rates of relapse was independent of the baseline PSA level and PSA doubling time (p = 0.42 and p = 0.09, respectively). This study was nonrandomized with a limited number of patients, and few clinical events were reported. CONCLUSIONS: Adding AAP to salvage radiation therapy and goserelin resulted in high bRFS and alt-bRFS. AEs remained manageable, although a close liver surveillance is advised. CTC count appears as a promising biomarker for prognosis and predicting response to treatment. PATIENT SUMMARY: Our study was a phase 2 clinical trial that exhibited the efficacy and tolerance of a novel androgen-receptor targeting agent (abiraterone acetate plus prednisone) in patients with prostate cancer who experienced rising prostate-specific antigen after radical prostatectomy, in combination with prostate bed radiotherapy. The results also indicated the feasibility and potential value of circulating tumor cell detection, which constitutes a possible advance in managing prostate cancers.

Short-term Darolutamide (ODM-201) Concomitant to Radiation Therapy for Patients with Unfavorable Intermediate-risk Prostate Cancer: The Darius (AFU-GETUG P15) Phase 2 Trial Protocol.

BACKGROUND: Combination of androgen deprivation therapy (ADT) with external beam radiation therapy (EBRT) is a standard of care for patients with intermediate-risk prostate cancer (PCa). However, 6 months of ADT generates multiple side effects impacting quality of life (QoL). Darolutamide (an androgen receptor targeting agent [ARTA]) is associated with low blood-brain barrier penetrance and less drug-drug interaction. OBJECTIVE: To assess the efficacy of a combination of 6 months of darolutamide with EBRT to treat patients with unfavorable intermediate-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: The DARIUS trial is a multicenter randomized non comparative phase 2 trial, randomizing the 6-months darolutamide + EBRT arm versus 6-months ADT + EBRT in patients with unfavorable intermediate-risk PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint is a biological response defined as prostate-specific antigen ≤0.1 ng/ml at month six of darolutamide or ADT. The key secondary endpoints are biochemical recurrence-free survival, disease-free survival, safety, and QoL. Ancillary studies using radiomics and genomic classifier are planned. Sixty-two patients will be included. RESULTS AND LIMITATIONS: In this population of patients requiring ADT combined with EBRT, the use of an ARTA alone, such as darolutamide, may demonstrate antitumoral efficacy while minimizing toxicity and maintaining QoL. Limitations are mainly inherent to the open-label design of this study. CONCLUSIONS: Six months of darolutamide + EBRT compared with 6 months of ADT + EBRT may be efficient in terms of a biological response, avoiding toxicity and altered QoL attributable to ADT in patients with unfavorable intermediate-risk PCa. PATIENT SUMMARY: The ongoing DARIUS clinical trial assesses short-term (6 months) darolutamide treatment in association with external beam radiation therapy in men with localized prostate cancer. The trial investigates whether single-agent darolutamide can improve the biological response while maintaining a favorable tolerability profile.

Long-term Outcomes and Patterns of Relapse Following High-dose Elective Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Nodes in Prostate Cancer: OLIGOPELVIS (GETUG-P07).

Androgen deprivation therapy (ADT) is a mainstay of treatment for metastatic prostate cancer, while additional salvage radiotherapy may offer prolonged remission for patients with regional node relapses. We report 5-yr outcomes from OLIGOPELVIS (GETUG-P07), an open-label phase 2 trial assessing long-term outcomes and patterns of relapse after 6-mo ADT and elective nodal radiotherapy (ENRT) in men with pelvic nodal oligorecurrence (<6 lesions) of prostate cancer. Progression was defined as two consecutive prostate-specific antigen (PSA) levels above the level at inclusion and/or clinical progression according to Response Evaluation Criteria in Solid Tumors v1.1 and/or death from any cause. Sixty-seven patients were recruited. Median follow-up was 6.1 yr (95% confidence interval 5.9-6.3). Rates of grade 2+ toxicities among patients without progression at 3, 4, and 5 yr were 15%, 9%, and 4% for genitourinary toxicities, and 2%, 3%, and 4% for gastrointestinal toxicities, respectively. The 5-yr progression-free, biochemical relapse-free, and ADT-free survival rates were 39%, 31%, and 64%, respectively. In total, 45 patients experienced progression, which was PSA-only progression in seven cases. Among the other 38 patients, local clinical progression occurred in 18%, progression to N1 stage in 29%, to M1a stage in 50%, to M1b stage in 32%, and to M1c stage in 11%. Finally, combined ENRT and ADT appeared to prolong tumor control with limited toxicity. At 5 yr, one-third of the patients had not experienced biochemical relapse. The major site of relapse was the para-aortic lymph nodes. PATIENT SUMMARY: We evaluated long-term results for high-dose radiotherapy in patients with recurrence of prostate cancer in pelvic lymph nodes. We found that this treatment provided prolonged tumor control without significant toxicity. One-third of the patients were still in complete remission after 5 years.

Radiotherapy Combined with a Radiosensitizer for Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Carcinoma In Situ Bladder Cancer: An Open-label, Single-arm, Multicenter, Phase 2 European Organisation for Research and Treatment of Cancer Trial.

Radical cystectomy with pelvic lymph node dissection and urinary diversion is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). However, many patients are unwilling or unable to undergo such major surgery associated with high morbidity and a negative impact on quality of life. Chemoradiotherapy is an established treatment option for muscle-invasive bladder cancer. However, it has not been investigated adequately in NMIBC until now. The European Organisation for Research and Treatment of Cancer (EORTC) 2235 study (NCT06310369) is designed as a multicenter, prospective, international, phase 2 trial of moderate hypofractionated radiotherapy combined with a radiosensitizer in BCG-unresponsive NMIBC patients with carcinoma in situ (CIS) who are not eligible for or declined to undergo radical cystectomy. Patients who have received nadofaragene firadenovec or TAR-200 are eligible. The primary endpoint is the 6-mo complete response (CR) rate defined by the absence of CIS proven by a control biopsy of the bladder. The secondary endpoints include overall survival, progression-free survival, durability of CR, grade 3-4 adverse events rate, patients' quality of life, and organ preservation rate. PATIENT SUMMARY: Intravesical instillation of bacillus Calmette-Guérin is the standard treatment of non-muscle-invasive, also coined as superficial, bladder cancer. In case the cancer recurs, even superficially, there is no other proven treatment than a radical cystectomy-the surgical removal of the bladder. Although the surgical technique has improved dramatically over the past few years, it remains contraindicated in patients with severe comorbidities. In addition, because it affects the quality of life, patients may reject this option. This study will assess the efficacy of external beam radiotherapy, a robust alternative to surgery in muscle-invasive bladder cancer. Radiotherapy will be administered 5 d a week for 4 wk. It will be associated with a "radiosensitizer," an intravenous or oral drug, during the radiotherapy treatment. The study will measure the proportion of patients remaining recurrence free at 6 mo and thereafter. It will also evaluate the safety of the treatment and its impact on quality of life.

Emergency radiation therapy in modern-day practice: Now or never, or never again ?

Radiation therapy plays a fundamental role in oncological emergencies such as superior vena cava syndrome (SVCS) and metastatic epidural spinal cord compression (MESCC). These are two examples of critical complications of metastatic cancer in terms of pain and functional impact (respiratory and/or neurological). The aim of this review is to explore the current indications, treatment options and outcomes for emergency radiotherapy regarding to these complications.Regarding SVCS, studies are mostly retrospective and unanimously demonstrated a beneficial effect of radiotherapy on symptom relief. Spinal cord compression remains an indication for urgent radiotherapy, and should be combined with surgery when possible. The innovative stereotactic body radiotherapy (SBRT) showed promising results, however this technique requires small volumes and more time preparation and therefore is often unsuitable for SVCS and MESCC emergencies.This review concluded that radiotherapy has a central role to play within a multimodal approach for SVCS and MESCC treatment. Further prospective studies are needed to confirm the effectiveness of radiation and establish the criteria for selecting patients to benefit from this treatment option.

Role of Radiotherapy and Hormone Therapy in Patients with Node-Positive Locally Advanced Prostate Cancer.

BACKGROUND: New-generation imaging techniques and the increasing use of surgery in high-risk prostate cancer (PCa) allow us to detect many cases of nodal disease at initial diagnosis or after resection. The treatment of PCa with pathologic regional nodes has evolved from the exclusive use of systemic therapy to its combination with locoregional treatment. It can also represent a benefit in the overall survival. However, the evidence from randomised studies is limited. Thus, we review the most relevant results in this scenario. MATERIALS AND METHODS: A literature search was conducted in MEDLINE, PubMed, EMBASE, Clinical-Trials.gov and Web of Science on January 2023 to review node-positive PCa by considering the relevant literature on this topic published with no restrictions on date and language. The search keywords used were "Prostatic Neoplasms" (MeSh) and "Node-positive" (Text Word) and "Radiotherapy" (MeSh) and ("Androgen Antagonists" (MeSh) or "Antineoplastic Agents, Hormonal" (MeSh)), which are indexed within the Medical Subject Headings database. RESULTS: The management of node-positive PCa has no clear definitive consensus at the initial disease diagnosis or after surgery. However, in this review, we summarise the existing literature for the management of these patients in both scenarios, considering imaging tests, radiotherapy, hormone therapy and second-generation hormonal treatments. CONCLUSIONS: The combination of radiotherapy and androgen-deprivation therapy is the treatment of choice. The addition of second-generation hormone therapy, plus the intensification of radiotherapy schedules, will likely change the treatment paradigm for these patients.