NCCN Guidelines® Insights: Prostate Cancer, Version 3.2024.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Body composition and mortality in men receiving prostate radiotherapy: A pooled analysis of NRG/RTOG 9406 and NRG/RTOG 0126.

PURPOSE: To validate the association between body composition and mortality in men treated with radiation for localized prostate cancer (PCa). Secondarily, to integrate body composition as a factor to classify patients by risk of all-cause mortality. MATERIALS AND METHODS: Participants of NRG/Radiation Therapy Oncology Group (RTOG) 9406 and NRG/RTOG 0126 with archived computed tomography were included. Muscle mass and muscle density were estimated by measuring the area and attenuation of the psoas muscles on a single slice at L4-L5. Bone density was estimated by measuring the attenuation of the vertebral body at mid-L5. Survival analyses, including Cox proportional hazards models, assessed the relationship between body composition and mortality. Recursive partitioning analysis (RPA) was used to create a classification tree to classify participants by risk of death. RESULTS: Data from 2066 men were included in this study. In the final multivariable model, psoas area, comorbidity score, baseline prostate serum antigen, and age were significantly associated with survival. The RPA yielded a classification tree with four prognostic groups determined by age, comorbidity, and psoas area. Notably, the classification among older (≥70 years) men into prognostic groups was determined by psoas area. CONCLUSIONS: This study strongly supports that body composition is related to mortality in men with localized PCa. The inclusion of psoas area in the RPA classification tree suggests that body composition provides additive information to age and comorbidity status for mortality prediction, particularly among older men. More research is needed to determine the clinical impact of body composition on prognostic models in men with PCa.

Prostate Cancer, Version 4.2023, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel's discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer.

Background Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity. Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230 mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging. Results 34 subjects were screened, 23 treated and 21 remained on study for ≥12 weeks. The median PSA was 6.4 ng/ml (range 1.7-80.1); doubling-time 6.2 months (range 1.4-36.6) and baseline testosterone 319.1 ng/ml (range 2.5-913.7). Median duration of therapy was 6.5 months (2.6-14.0). CTCs (median 48.5 cells/4 ml (range 15-268) at baseline) decreased a median of 65.3% in 18 of 19 patients. For patients who achieved an absolute CTC nadir count of <10 cells/4 ml (n = 10), disease control was 100% i.e. no metastases or PSA progression, while on trial (p = 0.005). PSA fell by ≥50% in 4.3% (1 subject). No patients developed metastatic disease while on treatment (metastases free survival =100%). There were no treatment-related adverse events (AEs) and quality of life was unchanged from baseline on the EORTC QLQ-C30 and QLQ-PR25. Testosterone levels rose slightly on SM-88 and were unrelated to efficacy or toxicity. Conclusions Use of SM-88 was associated with disease control while maintaining QOL. SM-88 may delay the need for ADT and the associated hormonal side effects. Larger trials are planned.Trial registration number, date of registration - NCT02796898, June 13, 2016.

Clinical recommendations in the management of advanced prostate cancer: International Gastrointestinal, Liver and Uro-oncology (IGILUC 2019) experts.

PURPOSE: Advancements in the diagnosis and treatment of prostate cancer (PC) have rapidly progressed through the past years. Various factors should be taken into account while treating individual patients to ensure optimal and careful decision making. The purpose of this consensus review is to summarize the current practice patterns when managing patients with advanced prostate cancer (APC) as there is still a lack of or very limited evidence on its clinical management in some areas. METHODS: Pre-defined questions were shared with experts prior to the consensus session that took place in Cairo, Egypt in April 2019 during the 8th International gastrointestinal, liver and uro-oncology conference (IGILUC). Voting was based mainly on the expert opinions of the panel after a thorough discussion and review of available evidence from guidelines or best evidence available concerning the topic at hand. RESULTS: A strong consensus or unanimity was reached on 47% of the proposed questions. Notably, the panelists reached consensus on several topics based on high-level expert opinion. These findings contribute in several ways to our understanding of the management of PC and provide a basis for future recommendations. There was also a lack of consensus on other several topics, which suggests the need for further supporting data addressing these knowledge gaps. CONCLUSION: This review offers a thorough understanding of APC practice and offers insight on the various opinions shared amongst experts in the field that can serve as guidance regionally and deepens our understanding of disease management globally.

Development of Treatments for Localized Prostate Cancer in Patients Eligible for Active Surveillance: U.S. Food and Drug Administration Oncology Center of Excellence Public Workshop.

PURPOSE: The following is a summary of discussion at a United States FDA (Food and Drug Administration) public workshop reviewing potential trial designs and end points to develop therapies to treat localized prostate cancer. MATERIALS AND METHODS: The workshop focused on the challenge that drug and device development to treat localized prostate cancer has been limited by the large trial sizes and lengthy timelines required to demonstrate an improvement in overall or metastasis-free survival and by the lack of agreed on alternative end points. Additionally, evolving treatment paradigms in the management of localized prostate cancer include the widespread use of active surveillance of patients with low and some intermediate risk prostate cancer, and the availability of advances in imaging and genomics. RESULTS: The workshop addressed issues related to trial design in this setting. Attendees discussed several potential novel end points such as a delay of morbidity due to radiation or prostatectomy and pathological end points such as Gleason Grade Group upgrade. CONCLUSIONS: The workshop provided an open forum for multiple stakeholder engagement to advance the development of effective treatment options for men with localized prostate cancer.

Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial.

BACKGROUND: The NRG/RTOG 9413 study showed that whole pelvic radiotherapy (WPRT) plus neoadjuvant hormonal therapy (NHT) improved progression-free survival in patients with intermediate-risk or high-risk localised prostate cancer compared with prostate only radiotherapy (PORT) plus NHT, WPRT plus adjuvant hormonal therapy (AHT), and PORT plus AHT. We provide a long-term update after 10 years of follow-up of the primary endpoint (progression-free survival) and report on the late toxicities of treatment. METHODS: The trial was designed as a 2 × 2 factorial study with hormonal sequencing as one stratification factor and radiation field as the other factor and tested whether NHT improved progression-free survival versus AHT, and NHT plus WPRT versus NHT plus PORT. Eligible patients had histologically confirmed, clinically localised adenocarcinoma of the prostate, an estimated risk of lymph node involvement of more than 15% and a Karnofsky performance status of more than 70, with no age limitations. Patients were randomly assigned (1:1:1:1) by permuted block randomisation to receive either NHT 2 months before and during WPRT followed by a prostate boost to 70 Gy (NHT plus WPRT group), NHT 2 months before and during PORT to 70 Gy (NHT plus PORT group), WPRT followed by 4 months of AHT (WPRT plus AHT group), or PORT followed by 4 months of AHT (PORT plus AHT group). Hormonal therapy was combined androgen suppression, consisting of goserelin acetate 3·6 mg once a month subcutaneously or leuprolide acetate 7·5 mg once a month intramuscularly, and flutamide 250 mg twice a day orally for 4 months. Randomisation was stratified by T stage, Gleason Score, and prostate-specific antigen concentration. NHT was given 2 months before radiotherapy and was continued until radiotherapy completion; AHT was given at the completion of radiotherapy for 4 months. The primary endpoint progression-free survival was analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769548. The trial has been terminated to additional follow-up collection and this is the final analysis for this trial. FINDINGS: Between April 1, 1995, and June 1, 1999, 1322 patients were enrolled from 53 centres and randomly assigned to the four treatment groups. With a median follow-up of 8·8 years (IQR 5·07-13·84) for all patients and 14·8 years (7·18-17·4) for living patients (n=346), progression-free survival across all timepoints continued to differ significantly across the four treatment groups (p=0·002). The 10-year estimates of progression-free survival were 28·4% (95% CI 23·3-33·6) in the NHT plus WPRT group, 23·5% (18·7-28·3) in the NHT plus PORT group, 19·4% (14·9-24·0) in the WPRT plus AHT group, and 30·2% (25·0-35·4) in the PORT plus AHT group. Bladder toxicity was the most common grade 3 or worse late toxicity, affecting 18 (6%) of 316 patients in the NHT plus WPRT group, 17 (5%) of 313 in the NHT plus PORT group, 22 (7%) of 317 in the WPRT plus AHT group, and 14 (4%) of 315 in the PORT plus AHT group. Late grade 3 or worse gastrointestinal adverse events occurred in 22 (7%) of 316 patients in the NHT plus WPRT group, five (2%) of 313 in the NHT plus PORT group, ten (3%) of 317 in the WPRT plus AHT group, and seven (2%) of 315 in the PORT plus AHT group. INTERPRETATION: In this cohort of patients with intermediate-risk and high-risk localised prostate cancer, NHT plus WPRT improved progression-free survival compared with NHT plus PORT and WPRT plus AHT at long-term follow-up albeit increased risk of grade 3 or worse intestinal toxicity. Interactions between radiotherapy and hormonal therapy suggests that WPRT should be avoided without NHT. FUNDING: National Cancer Institute.

Clinical trials involving carbon-ion radiation therapy and the path forward.

To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials (median, 47 participants) involving CIRT identified from the US clinicaltrials.gov trial registry and the World Health Organization International Clinical Trials Platform Registry. The objectives were to evaluate the potential for these trials to define the role of this modality in the treatment of specific cancer types and identify the major challenges and opportunities to advance this technology. A significant body of literature suggested the potential for advantageous dose distributions and, in preclinical biologic studies, the enhanced effectiveness for CIRT compared with photons and protons. In addition, clinical evidence from phase I/II trials, although limited, indicated the potential for CIRT to improve cancer outcomes. However, current high-level phase III randomized clinical trial evidence does not exist. Although there has been an increase in the number of trials investigating CIRT since 2010, and the number of countries and sites offering CIRT is slowly growing, this progress has excluded other countries. Several recommendations are proposed to study this modality to accelerate progress in the field, including: 1) increasing the number of multinational randomized clinical trials, 2) leveraging the existing CIRT facilities to launch larger multinational trials directed at common cancers combined with high-level quality assurance; and 3) developing more compact and less expensive next-generation treatment systems integrated with radiobiologic research and preclinical testing.

Prostate Cancer, Version 1.2016.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.

Impact of biochemical failure classification on clinical outcome: a secondary analysis of Radiation Therapy Oncology Group 9202 and 9413.

BACKGROUND: Biochemical failure (BF) after radiation therapy is defined on the basis of a rising prostate-specific antigen (PSA) level (A1 failure) or any event that prompts the initiation of salvage androgen-deprivation therapy without PSA failure (A2). It was hypothesized that A2 failure may have a different prognosis. METHODS: Data for 2799 eligible patients from Radiation Therapy Oncology Group (RTOG) 9202 and RTOG 9413 were analyzed. BF was defined according to the 1997 American Society for Therapeutic Radiology and Oncology consensus definition as A1 for PSA failure or as A2 for the start of salvage hormone therapy before 3 consecutive PSA rises. RESULTS: Rates of all-cause mortality (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.5-2.0; P < .0001) and distant metastasis (DM; HR, 1.6; 95% CI, 1.3-2.0; P < .0001) were greater with A2 failure. The 5-year overall survival (OS) rates were 88.2% and 74.6% for A1 and A2, respectively (P < .0001), and the DM rates were 15.7% and 29.0%, respectively (P < .0001). The DM rate was greater at 5 years for A2 patients with DM as the first sign of failure versus patients with other A2 failures (87.3% vs 11.7%, P < .001), and this also correlated with worse OS at 5 years: 81.1% for A2 failure without DM and 52.8% with DM (P < .001). After the removal of patients with DM, the difference between A1 and A2 BF persisted for OS (P = .002) but not for DM (P = .16) CONCLUSIONS: These results suggest that patients with rising PSA levels alone have less risk than those with A2 failures; although DM was the largest contributor of adverse risk to A2 failure, it did not account for all excess risk in A2 failure.

Patterns of Local Failure following Radiation Therapy for Prostate Cancer.

PURPOSE: Little is known about patterns of local failure following radiation therapy for prostate cancer. We aimed to characterize post-radiation biopsy findings, including the treatment effect and the zonal distribution of recurrent disease after radiation therapy, in men experiencing biochemical recurrence. MATERIALS AND METHODS: We identified patients who received post-radiation biopsy in the setting of biochemical recurrence following primary radiation for localized disease. Histological post-radiation biopsy results were categorized by the absence of tumor, demonstration of radiation treatment effect, failure (recurrent cancer) or a combination of treatment effect and failure. We described patterns of histological failure and compared them to the diagnostic biopsy findings. RESULTS: A total of 284 men underwent mapped post-radiation biopsy for biochemical recurrence. Mean age at initial diagnosis was 63 years and median prostate specific antigen was 8.2 ng/ml. Of the men 33%, 32% and 35% were classified at low, intermediate and high risk based on clinical CAPRA (Cancer of the Prostate Risk Assessment) categories. Median time to post-radiation biopsy was 61 months after treatment. Findings were negative in 4% of cases while we noted a treatment effect in 31%, failure in 45% and a combination in 20%. Failure rates were similar across sextants. Of 140 patients with mapped pretreatment and posttreatment biopsies 4% demonstrated cancer in a new location previously identified as negative. Gleason upgrading occurred in 43% of cases with 85% upgraded to 4 + 3 or higher. CONCLUSIONS: Men with rising prostate specific antigen after radiotherapy for prostate cancer most often experience recurrence in dominant tumor sites. Whether failure is due to inadequate targeting, dosing or intrinsic radiation resistance remains unknown to our knowledge. Further study is warranted.

Postoperative radiation therapy for patients at high-risk of recurrence after radical prostatectomy: does timing matter?

OBJECTIVE: To evaluate among radical prostatectomy (RP) patients at high-risk of recurrence whether the timing of postoperative radiation therapy (RT) (adjuvant, early salvage with detectable post-RP prostate-specific antigen [PSA], or 'late' salvage with a PSA level of >1.0 ng/mL) is significantly associated with overall survival (OS), prostate-cancer specific survival or metastasis-free survival, in a longitudinal cohort. PATIENTS AND METHODS: Of 6 176 RP patients in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), 305 patients with high-risk pathological features (margin positivity, Gleason score 8-10, or pT3-4) who underwent postoperative RT were examined, either in the adjuvant (≤6 months after RP with undetectable PSA levels, 76 patients) or salvage setting (>6 months after RP or pre-RT PSA level of >0.1 ng/mL, 229 patients). Early (PSA level of ≤1.0 ng/mL, 180 patients) or late salvage RT (PSA level >1.0 ng/mL, 49 patients) was based on post-RP, pre-RT PSA level. Multivariable Cox regression examined associations with all-cause mortality and prostate cancer-specific mortality and/or metastases (PCSMM). RESULTS: After a median of 74 months after RP, 65 men had died (with 37 events of PCSMM). Adjuvant and salvage RT patients had comparable high-risk features. Compared with adjuvant, salvage RT (early or late) had an increased association with all-cause mortality (hazard ratio [HR] 2.7, P = 0.018) and with PCSMM (HR 4.0, P = 0.015). PCSMM-free survival differed by further stratification of timing, with 10-year estimates of 88%, 84%, and 71% for adjuvant, early salvage, and late salvage RT, respectively (P = 0.026). For PCSMM-free survival and OS, compared with adjuvant RT, late salvage RT had statistically significantly increased risk; however, early salvage RT did not. CONCLUSION: This analysis suggests that patients who underwent early salvage RT with PSA levels of <1.0 ng/mL may have comparable metastasis-free survival and OS compared with adjuvant RT; however, late salvage RT with a PSA level of >1.0 ng/mL is associated with worse clinical outcomes.