Overall survival benefit of androgen suppression in addition to dose-escalated external beam radiotherapy for high-risk prostate cancer: Nationwide real-world data indicates a shift in men that benefit.

OBJECTIVE: To evaluate the real-world added value of androgen deprivation therapy (ADT) in addition to external beam radiotherapy (EBRT) in men with high-risk non-metastatic prostate cancer, in view of advances in radiotherapy and diagnostics. METHODS: All Dutch men diagnosed with high-risk non-metastatic prostate cancer (defined as: ≥cT2c-T3b N0M0, PSA ≥20-50 ng/ml, and/or Gleason score ≥8 (International Society of Urological Pathology [ISUP] grade ≥4)) from 2009 through 2019 and treated with EBRT with or without ADT were identified in the population-based Netherlands Cancer Registry. Propensity scores were used to match (1:1) men that received ADT to men that did not receive ADT. Subsequently, OS was compared. Analyses were also stratified by number of high-risk features, 1 (either ≥cT2c, PSA >20 ng/ml or Gleason score ≥8) versus ≥2 (out of ≥cT2c, PSA >20 ng/ml and Gleason score ≥8). RESULTS: A total of 14,773 men with high-risk non-metastatic prostate cancer were identified, 3,958 (27%) of which received EBRT alone. After matching, 3,427 men remained in both groups and baseline characteristics were well-balanced. After a median follow-up of 92 months, OS was better in men treated with EBRT and ADT compared to men treated with EBRT alone (10-year OS: 66.4% versus 61.8%; HR 0.88 [95%CI: 0.80-0.96]). There was no statistically significant difference in OS in the subgroup of men with only 1 high-risk feature (10-year OS 67.7% versus 64.9%; HR 0.95 [95%CI: 0.85-1.07]). CONCLUSIONS: In a contemporary cohort of men treated for high-risk non-metastatic prostate cancer with EBRT, an OS benefit of adding ADT was only observed in men with at least 2 high-risk features. These results suggest that improvements in diagnostics and treatment in recent decades have resulted in a stage shift of men benefiting from the addition of ADT to EBRT.

Radical prostatectomy versus external beam radiotherapy with androgen deprivation therapy for high-risk prostate cancer: a systematic review.

BACKGROUND: To summarize recent evidence in terms of health-related quality of life (HRQoL), functional and oncological outcomes following radical prostatectomy (RP) compared to external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for high-risk prostate cancer (PCa). METHODS: We searched Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Controlled Trial Register and the International Standard Randomized Controlled Trial Number registry on 29 march 2021. Comparative studies, published since 2016, that reported on treatment with RP versus dose-escalated EBRT and ADT for high-risk non-metastatic PCa were included. The Newcastle-Ottawa Scale was used to appraise quality and risk of bias. A qualitative synthesis was performed. RESULTS: Nineteen studies, all non-randomized, met the inclusion criteria. Risk of bias assessment indicated low (n = 14) to moderate/high (n = 5) risk of bias. Only three studies reported functional outcomes and/or HRQoL using different measurement instruments and methods. A clinically meaningful difference in HRQoL was not observed. All studies reported oncological outcomes and survival was generally good (5-year survival rates > 90%). In the majority of studies, a statistically significant difference between both treatment groups was not observed, or only differences in biochemical recurrence-free survival were reported. CONCLUSIONS: Evidence clearly demonstrating superiority in terms of oncological outcomes of either RP or EBRT combined with ADT is lacking. Studies reporting functional outcomes and HRQoL are very scarce and the magnitude of the effect of RP versus dose-escalated EBRT with ADT on HRQoL and functional outcomes remains largely unknown.

Impact of the COVID-19 outbreak on prostate cancer care in the Netherlands.

INTRODUCTION: The COVID-19 outbreak has affected care for non-COVID diseases like cancer. We evaluated the impact of the COVID-19 outbreak on prostate cancer care in the Netherlands. METHODS: Prostate cancer diagnoses per month in 2020-2021 versus 2018-2019 were compared based on preliminary data of the Netherlands Cancer Registry (NCR) and nationwide pathology network. Detailed data was retrieved from the NCR for the cohorts diagnosed from March-May 2020 (first COVID-19 wave) and March-May 2018-2019 (reference). Changes in number of diagnoses, age, disease stage and first-line treatment were compared. RESULTS: An initial decline of 17% in prostate cancer diagnoses during the first COVID-19 wave was observed. From May onwards the number of diagnoses started to restore to approximately 95% of the expected number by the end of 2020. Stage at diagnosis remainedstable over time. In low-risk localised prostate cancer radical prostatectomy was conducted more often in week 9-12 (21% versus 12% in the reference period; OR=1.9, 95% CI; 1.2-3.1) and less active surveillance was applied (67% versus 78%; OR=0.6, 95% CI; 0.4-0.9). In the intermediate-risk group, a similar change was observed in week 13-16. Radical prostatectomy volumes in 2020 were comparable to 2018-2019. CONCLUSION: During the first COVID-19 wave the number of prostate cancer diagnoses declined. In the second half of 2020 this largely restored although the number remained lower than expected. Changes in treatment were temporary and compliant with adapted guidelines. Although delayed diagnoses could result in a less favourable stage distribution, possibly affecting survival, this seems not very likely.

Prognostic importance of concomitant non-regional lymph node and bone metastases in men with newly diagnosed metastatic prostate cancer.

OBJECTIVES: To evaluate the prognostic importance of concomitant non-regional lymph node (NRLN) and bone metastases in men with synchronous metastatic hormone-sensitive prostate cancer (mHSPC), and to determine whether M1b/M1c is the most appropriate M-stage and evaluate the additional importance to the distinction in low/high volume disease. PATIENTS AND METHODS: All men diagnosed with synchronous mHSPC from 2010 to 2018 in the Netherlands were identified in the Netherlands Cancer Registry. Men were categorised as having NRLN (M1a), bone (M1b), NRLN and bone (M1c), or visceral metastases (M1c). For men diagnosed since October 2015 disease volume could be determined. Analyses were performed in this cohort (>5600 men) and repeated in the 2010-2018 cohort (>14 000 men). The primary outcome measure in this observational cohort study was overall survival (OS) and Cox regression was used to calculate hazard ratios (HRs). RESULTS: Compared to men with NRLN and bone metastases (reference group), OS of men with only NRLN (HR 0.70, 95% confidence interval [CI] 0.55-0.88) was better. This was also true for men with only bone metastases in the low-volume subgroup (HR 0.75, 95% CI0.58-0.98), but not in the high-volume subgroup (HR 0.99, 95% CI 0.84-1.18). In contrast, the OS of men with visceral metastases was worse (HR 2.20, 95% CI 1.75-2.77 + 0.97/month, 95% CI 0.96-0.98). CONCLUSION: In men with low-volume synchronous mHSPC, presence of concomitant NRLN and bone metastases (currently classified as M1c), is a poor prognostic sign. However, survival of men with visceral metastases (M1c) is worse. Implying that classifying concomitant NRLN and bone metastases as M1c or M1b is not appropriate. Adding a fourth M1-category to the ninth edition of the Tumour-Node-Metastasis classification should be contemplated. Furthermore, definitions of metastatic burden need to be re-evaluated.

Mathematical Models for Tumor Growth and the Reduction of Overtreatment.

Background To improve our understanding of the natural course of head and neck paragangliomas (HNPGL) and ultimately differentiate between cases that benefit from early treatment and those that are best left untreated, we studied the growth dynamics of 77 HNPGL managed with primary observation. Methods Using digitally available magnetic resonance images, tumor volume was estimated at three time points. Subsequently, nonlinear least squares regression was used to fit seven mathematical models to the observed growth data. Goodness of fit was assessed with the coefficient of determination ( R 2 ) and root-mean-squared error. The models were compared with Kruskal-Wallis one-way analysis of variance and subsequent post-hoc tests. In addition, the credibility of predictions (age at onset of neoplastic growth and estimated volume at age 90) was evaluated. Results Equations generating sigmoidal-shaped growth curves (Gompertz, logistic, Spratt and Bertalanffy) provided a good fit (median R 2 : 0.996-1.00) and better described the observed data compared with the linear, exponential, and Mendelsohn equations ( p < 0.001). Although there was no statistically significant difference between the sigmoidal-shaped growth curves regarding the goodness of fit, a realistic age at onset and estimated volume at age 90 were most often predicted by the Bertalanffy model. Conclusions Growth of HNPGL is best described by decelerating tumor growth laws, with a preference for the Bertalanffy model. To the best of our knowledge, this is the first time that this often-neglected model has been successfully fitted to clinically obtained growth data.

Clinical progression and metachronous paragangliomas in a large cohort of SDHD germline variant carriers.

Although it is well established that paternally transmitted germline variants in SDHD are associated with multifocal paragangliomas and lifelong follow-up is generally advised, the risk of metachronous lesions is presently unknown. In a large Dutch cohort of SDHD variant carriers, we studied the development of new paragangliomas, and the evolution of symptoms and cranial nerve impairment. Recurrent event analysis and the Kaplan-Meier product limit estimator were used to study the risk of new lesions. The relation between several predictors and development of new symptoms was assessed using logistic regression. Of the 222 SDHD variant carriers included, 65% presented with symptoms and 11% with cranial nerve dysfunction. Over a median period of 8 years, 42% reported new symptoms, and new cranial nerve impairment was observed in 11% of subjects. The estimated fraction of subjects that developed new HNPGL increased to 73% (95% CI: 52-85%) after 22 years of follow-up. Males were more likely to develop new HNPGL compared to females (HR: 1.63, 95% CI: 1.10-2.40), as were subjects that presented with symptoms, compared to subjects that were asymptomatic at baseline (HR: 1.61, 95% CI: 1.01-2.55). In addition, the risk of new lesions decreased with number of HNPGL present at first diagnosis (HR: 0.68 and 95% CI: 0.56-0.82). Carriers of a paternally inherited SDHD variant face a considerable risk for new HNPGL. In addition, nearly 50% of subjects reported new symptoms. However, new cranial nerve deficits were observed in only 11%, which is less than reported in surgical series. These risks should be taken into account when considering treatment strategies and counseling.

Age and Tumor Volume Predict Growth of Carotid and Vagal Body Paragangliomas.

Objective Treatment for head and neck paragangliomas (HNGPL) can be more harmful than the disease. After diagnosis, an initial period of surveillance is often indicated, and surgery or radiotherapy is reserved for progressive disease. With the aim to optimize this "wait and scan" strategy, we studied growth and possible predictors. Design A retrospective cohort study was conducted. Setting This study was conducted at a tertiary referral center for patients with HNGPL. Methods Tumor volume was estimated for 184 SDHD -related carotid and vagal body paragangliomas using sequential magnetic resonance imaging. Cox regression was used to study predictors of tumor growth. Results The estimated fraction of growing tumors ranged from 0.42 after 1 year of follow-up to 0.85 after 11 years. A median growth rate of 10.4 and 12.0% per year was observed for carotid and vagal body tumors, respectively. Tumor location, initial volume, and age ( p < 0.05) were included in our prediction model. The probability of growth decreased with increasing age and volume, indicating a decelerating growth pattern. Conclusions We created a prediction model (available online), enabling a more individualized "wait and scan" strategy. The favorable natural course of carotid and vagal body paragangliomas was confirmed; although with long follow-up growth will be observed in most cases.

No evidence for increased mortality in SDHD variant carriers compared with the general population.

Germline variants in subunit D of the succinate dehydrogenase gene (SDHD variants) are associated with an increased risk of developing paragangliomas. The aim of this study was to compare mortality rates and survival in a Dutch cohort of SDHD variant carriers with those in the general population. The study was conducted at the Leiden University Medical Center, a tertiary referral center for patients with paragangliomas. Included subjects all tested positive for SDHD variants before 1 July 2012 and visited the departments of Otorhinolaryngology or Endocrinology at least once or had a diagnosed paraganglioma and a SDHD variant-positive family history. Clinical data were retrieved from medical records, information on mortality was obtained from the Municipal Personal Records Database, and mortality rates for the Dutch population were obtained from the Dutch Central Bureau of Statistics, stratified by sex, age and date. SDHD variant carriers were followed from the date of first SDHD variant-related contact until death, emigration or 12 December 2012 and the standardized mortality ratio (SMR) was calculated. Two-hundred and seventy-five SDHD variant carriers were included in the study, of which 80% carried the c.274G>T, p.(Asp92Tyr) variant, had a mean duration of follow-up of 7.6 years, yielding 2242 person-years of observation for analysis. There were 18 deaths in the SDHD variant carrier group; two were paraganglioma related. The SMR for the whole cohort was 1.07 (95% confidence interval 0.67-1.73). In conclusion, mortality in SDHD variant carriers is not substantially increased. Additional studies are required to confirm these findings.

High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations.

Hereditary paraganglioma is a benign tumor syndrome with an age-dependent penetrance. Carriers of germline mutations in the SDHB or SDHD genes may develop parasympathetic paragangliomas in the head and neck region or sympathetic catecholamine-secreting abdominal and thoracic paragangliomas (pheochromocytomas). In this study, we aimed to establish paraganglioma risk in 101 asymptomatic germline mutation carriers and evaluate the results of our surveillance regimen. Asymptomatic carriers of an SDHD or SDHB mutation were included once disease status was established by MRI diagnosis. Clinical surveillance revealed a head and neck paraganglioma in 28 of the 47 (59.6%) asymptomatic SDHD mutation carriers. Risk of tumor development was significantly lower in SDHB mutation carriers: 2/17 (11.8%, P=0.001). Sympathetic paragangliomas were encountered in two SDHD mutation carriers and in one SDHB mutation carrier. In conclusion, asymptomatic carriers of an SDHD mutation are at a high risk for occult parasympathetic paraganglioma. SDHB carrier risk is considerably lower, consistent with lower penetrance of SDHB mutations. For both syndromes, the risk of symptomless sympathetic paragangliomas is small.