Clinical perspectives from ongoing trials in oligometastatic or oligorecurrent prostate cancer: an analysis of clinical trials registries.

PURPOSE: Thanks to the introduction of more sensitive/specific imaging and minimally invasive treatment techniques, the oligometastatic state in prostate cancer (PCa) has attracted the interest of the uro-oncological community. We aim to identify and analyze trials across five registries to gain insights into the directions this field is moving. METHODS: A systematic review of trials on oligometastatic PCa registered on ClinicalTrials.gov, ANZCTR, ISRCTN, Netherlands and UMIN Clinical Trials Registries was performed using the following keywords: 'prostate cancer' and 'oligo'. Data were extracted from ongoing/completed trials, with an unreported primary endpoint in a peer-reviewed journal, as of May until August, 2018. RESULTS: We identified 41 trials on oligometastatic PCa. Twenty-four trials are conducted in North America and 14 in Europe. Up to 70% are phase I or II trials and < 10% (n = 4) are in phase III. Less than 50% (n = 17) are randomized controlled trials. Oligometastases are PET detected in 25 trials. Studies on synchronous oligometastatic (n = 12; 29%) or oligorecurrent (n = 14; 34%) PCa are equally represented, the remainder focus on mixed states (n = 15; 37%). The majority (n = 39; 95%) of trials investigate local treatment options (RP: 5; RT: 9; RP ± RT: 7; metastasis-directed therapy: 28) with (72%) or without (28%) systemic treatment. The remaining two are imaging studies. Progression-free (PFS; 17/41; 41%) or overall survival (OS; 3/41; 7%) is defined as primary endpoint in half of all trials, others are 'safety/toxicity' or 'PSA response'. CONCLUSIONS: With 41 ongoing trials, there is great interest in oligometastatic PCa. Most trials address local ablative treatments both for prostate and/or metastases, typically by radiotherapy, and several attempts to determine the benefit of adding systemic therapy. The field will hopefully have definitive answers after completion of four ongoing phase III trials.

Discovery and validation of a serum microRNA signature to characterize oligo- and polymetastatic prostate cancer: not ready for prime time.

PURPOSE: Patients with oligometastatic prostate cancer (PC) may benefit from metastasis-directed therapy (MDT), delaying disease progression and the start of palliative systemic treatment. However, a significant proportion of oligometastatic PC patients progress to polymetastatic PC within a year following MDT, suggesting an underestimation of the metastatic load by current staging modalities. Molecular markers could help to identify true oligometastatic patients eligible for MDT. METHODS: Patients with asymptomatic biochemical recurrence following primary PC treatment were classified as oligo- or polymetastatic based on 18F-choline PET/CT imaging. Oligometastatic patients had up to three metastases at baseline and did not progress to more than three lesions following MDT or surveillance within 1 year of diagnosis of metastases. Polymetastatic patients had > 3 metastases at baseline or developed > 3 metastases within 1 year following imaging. A model aiming to prospectively distinguish oligo- and polymetastatic PC patients was trained using clinicopathological parameters and serum-derived microRNA expression profiles from a discovery cohort of 20 oligometastatic and 20 polymetastatic PC patients. To confirm the models predictive performance, it was applied on biomarker data obtained from an independent validation cohort of 44 patients with oligometastatic and 39 patients with polymetastatic disease. RESULTS: Oligometastatic PC patients had a more favorable prognosis compared to polymetastatic ones, as defined by a significantly longer median CRPC-free survival (not reached versus 38 months; 95% confidence interval 31-45 months with P < 0.001). Despite the good performance of a predictive model trained on the discovery cohort, with an AUC of 0.833 (0.693-0.973; 95% CI) and a sensitivity of 0.894 (0.714-1.000; 95% CI) for oligometastatic disease, none of the miRNA targets were found to be differentially expressed between oligo- and polymetastatic PC patients in the signature validation cohort. The multivariate model had an AUC of 0.393 (0.534 after cross-validation) and therefore, no predictive ability. CONCLUSIONS: Although PC patients with oligometastatic disease had a more favorable prognosis, no serum-derived biomarkers allowing for prospective discrimination of oligo- and polymetastatic prostate cancer patients could be identified.

Prevalence and prognosis of low-volume, oligorecurrent, hormone-sensitive prostate cancer amenable to lesion ablative therapy.

OBJECTIVES: To describe the anatomical patterns of prostate cancer (PCa) recurrence after primary therapy and to investigate if patients with low-volume disease have a better prognosis as compared with their counterparts. MATERIALS AND METHODS: Patients eligible for an 18-F choline positron-emission tomography (PET)-computed tomography (CT) were enrolled in a prospective cohort study. Eligible patients had asymptomatic biochemical recurrence after primary PCa treatment and testosterone levels >50 ng/mL. The number of lesions was counted per scan. Patients with isolated local recurrence (LR) or with ≤3 metastases (with or without LR) were considered to have low-volume disease and patients with >3 metastases to have high-volume disease. Descriptive statistics were used to report recurrences. Cox regression analysis was used to investigate the influence of prognostic variables on the time to developing castration-resistant PCa (CRPC). RESULTS: In 208 patients, 625 sites of recurrence were detected in the lymph nodes (N1/M1a: 30%), the bone (18%), the prostate (bed; 11%), viscera (4%), or a combination of any of the previous (37%). In total, 153 patients (74%) had low-volume recurrence and 55 patients (26%) had high-volume recurrence. The 3-year CRPC-free survival rate for the whole cohort was 79% (95% confidence interval 43-55), 88% for low-volume recurrences and 50% for high-volume recurrences (P < 0.001). Longer PSA doubling time at time of recurrence and low-volume disease were associated with a longer time to CRPC. CONCLUSIONS: Three out of four patients with PCa with a 18-F choline PET-CT-detected recurrence have low-volume disease, potentially amenable to local therapy. Patients with low-volume disease have a better prognosis as compared with their counterparts. Lymph node recurrence was the most dominant failure pattern.

Evaluation of chest CT-scans following lung stereotactic ablative radiotherapy: Challenges and new insights.

Stereotactic ablative radiotherapy (SABR) is increasingly used for the treatment of early-stage non-small cell lung cancer (ES-NSCLC) and for pulmonary metastases. In patients with ES-NSCLC, SABR is highly successful with reported 5-year local control rates of approximately 90%. However, the assessment of local control following lung SABR can be challenging as radiological changes arising from radiation-induced lung injury (RILI) can be observed in up to 90% of patients. These so-called 'benign' radiological changes evolve with time and are often asymptomatic. Several radiological and metabolic features have been explored to help distinguish RILI from local recurrences (LR). These include the Response Evaluation Criteria for Solid Tumors (RECIST), high-risk features (HRF's) and maximum standardized uptake value (SUVmax) on FDG-PET-CT. However, use of some of these approaches have poor predictive values and low specificity for recurrence. A proposed new workflow for the evaluation of post-lung SABR radiological changes will be reviewed which uses the presence of so-called 'actionable radiological features' to trigger changes to imaging schedules and identifies the need for a multidisciplinary board review. Furthermore, this critical review of post-lung SABR imaging will highlight current challenges, new insights, and unknowns in this field.

Disease Control and Late Toxicity in Adaptive Dose Painting by Numbers Versus Nonadaptive Radiation Therapy for Head and Neck Cancer: A Randomized Controlled Phase 2 Trial.

PURPOSE: Local recurrence remains the main cause of death in stage III-IV nonmetastatic head and neck cancer (HNC), with relapse-prone regions within high 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)-signal gross tumor volume. We investigated if dose escalation within this subvolume combined with a 3-phase treatment adaptation could increase local (LC) and regional (RC) control at equal or minimized radiation-induced toxicity, by comparing adaptive 18F-FDG-PET voxel intensity-based dose painting by numbers (A-DPBN) with nonadaptive standard intensity modulated radiation therapy (S-IMRT). METHODS AND MATERIALS: This 2-center randomized controlled phase 2 trial assigned (1:1) patients to receive A-DPBN or S-IMRT (+/-chemotherapy). Eligibility: nonmetastatic HNC of oral cavity, oro-/hypopharynx, or larynx, needing radio(chemo)therapy; T1-4N0-3 (exception: T1-2N0 glottic); KPS ≥ 70; ≥18 years; and informed consent. PRIMARY OUTCOMES: 1-year LC and RC. The dose prescription for A-DPBN was intercurrently adapted in 2 steps to an absolute dose-volume limit (≤1.75 cm3 can receive >84 Gy and normalized isoeffective dose >96 Gy) as a safety measure during the study course after 4/7 A-DPBN patients developed ≥G3 mucosal ulcers. RESULTS: Ninety-five patients were randomized (A-DPBN, 47; S-IMRT, 48). Median follow-up was 31 months (IQR, 14-48 months); 29 patients died (17 of cancer progression). A-DPBN resulted in superior LC compared with S-IMRT, with 1- and 2-year LC of 91% and 88% versus 78% and 75%, respectively (hazard ratio, 3.13; 95% CI, 1.13-8.71; P = .021). RC and overall survival were comparable between arms, as was overall grade (G) ≥3 late toxicity (36% vs 20%; P = .1). More ≥G3 late mucosal ulcers were observed in active smokers (29% vs 3%; P = .005) and alcohol users (33% vs 13%; P = .02), independent of treatment arm. Similarly, in the A-DPBN arm, significantly more patients who smoked at diagnosis developed ≥G3 (46% vs 12%; P = .005) and ≥G4 (29% vs 8%; P = .048) mucosal ulcers. One arterial blowout occurred after a G5 mucosal toxicity. CONCLUSIONS: A-DPBN resulted in superior 1- and 2-year LC for HNC compared with S-IMRT. This supports further exploration in multicenter phase 3 trials. It will, however, be challenging to recruit a substantial patient sample for such trials, as concerns have arisen regarding the association of late mucosal ulcers when escalating the dose in continuing smokers.

Microbiome and metabolome dynamics during radiotherapy for prostate cancer.

BACKGROUND: Prostate cancer patients treated with radiotherapy are susceptible to acute gastrointestinal (GI) toxicity due to substantial overlap of the intestines with the radiation volume. Due to their intimate relationship with GI toxicity, faecal microbiome and metabolome dynamics during radiotherapy were investigated. MATERIAL & METHODS: This prospective study included 50 prostate cancer patients treated with prostate (bed) only radiotherapy (PBRT) (n = 28) or whole pelvis radiotherapy (WPRT) (n = 22) (NCT04638049). Longitudinal sampling was performed prior to radiotherapy, after 10 fractions, near the end of radiotherapy and at follow-up. Patient symptoms were dichotomized into a single toxicity score. Microbiome and metabolome fingerprints were analyzed by 16S rRNA gene sequencing and ultra-high-performance liquid chromatography hybrid high-resolution mass spectrometry, respectively. RESULTS: The individual α-diversity did not significantly change over time. Microbiota composition (ß-diversity) changed significantly over treatment (PERMANOVA p-value = 0.03), but there was no significant difference in stability when comparing PBRT versus WPRT. Levels of various metabolites were significantly altered during radiotherapy. Baseline α-diversity was not associated with any toxicity outcome. Based on the metabolic fingerprint, no natural clustering according to toxicity profile could be achieved. CONCLUSIONS: Radiation dose and treatment volume demonstrated limited effects on microbiome and metabolome fingerprints. In addition, no distinctive signature for toxicity status could be established. There is an ongoing need for toxicity risk stratification tools for diagnostic and therapeutic purposes, but the current evidence implies that the translation of metabolic and microbial biomarkers into routine clinical practice remains challenging.

Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

A Trial-Based Cost-Utility Analysis of Metastasis-Directed Therapy for Oligorecurrent Prostate Cancer.

The optimal management of patients with oligorecurrent prostate cancer (PCa) is unknown. There is growing interest in metastasis-directed therapy (MDT) for this population. The objective was to assess cost-utility from a Belgian healthcare payer's perspective of MDT and delayed androgen deprivation therapy (ADT) in comparison with surveillance and delayed ADT, and with immediate ADT. A Markov decision-analytic trial-based model was developed, projecting the results over a 5-year time horizon with one-month cycles. Clinical data were derived from the STOMP trial and literature. Treatment costs were derived from official government documents. Probabilistic sensitivity analyses showed that MDT is cost-effective compared to surveillance (ICER: €8393/quality adjusted life year (QALY)) and immediate ADT (dominant strategy). The ICER is most sensitive to utilities in the different health states and the first month MDT cost. At a willingness-to-pay threshold of €40,000 per QALY, the cost of the first month MDT should not exceed €8136 to be cost-effective compared to surveillance. The Markov-model suggests that MDT for oligorecurrent PCa is potentially cost-effective in comparison with surveillance and delayed ADT, and in comparison with immediate ADT.

Nodal Oligorecurrent Prostate Cancer: Anatomic Pattern of Possible Treatment Failure in Relation to Elective Surgical and Radiotherapy Treatment Templates.

BACKGROUND: Patients with biochemical recurrence following primary prostate cancer (PCa) treatment often experience relapse in the lymph nodes (LNs). Both salvage LN dissection (sLND) and elective nodal radiotherapy (ENRT) are potential treatment options. OBJECTIVE: To describe anatomic patterns of nodal oligorecurrent PCa in relation to different surgical and radiotherapy templates. DESIGN, SETTING, AND PARTICIPANTS: Patients with biochemical recurrence following primary PCa treatment were eligible for 18F-choline positron emission tomography/computed tomography (CT). Patients with five or fewer LN recurrences (N1/M1a) were eligible for the current retrospective analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All LN recurrences were mapped on a reference patient CT, as well as different surgical templates (limited to superextended) and an adapted version of the PIVOTAL ENRT template, blinded for the recurrences. Descriptive statistics were used to report recurrences in relation to the different templates and to compare LN coverage between templates. RESULTS AND LIMITATIONS: In total, 158 LN recurrences (N1: 88; M1a: 70) in 82 patients (median age: 67yr; prostate-specific antigen [PSA]: 3.1ng/ml; PSA doubling time of 7.8mo at the time of clinical recurrence) were mapped. In 49% of patients, recurrences were exclusively located in the true pelvis, followed by the common iliac LN (10%), retroperitoneal/inguinal LN (10%), or a combination (31%). There was up to 40% volume overlap between ENRT and the surgical templates. Theoretically, with ENRT more patients are fully covered (p<0.02) and the total number of covered lesions is higher (p<0.001) when compared to all types of sLND, except for superextended sLND, which is comparable to ENRT (patient-level: p=0.6; lesion-level: p=0.09). With 22% of all 158 lesions located outside all templates (N1: 7%; M1a: 15%), at least 31% of all 82 patients would not be salvaged using any of the templates. CONCLUSIONS: More than half of nodal recurrences are located outside the true pelvis. Limited or standard extended sLND is considered insufficient as a salvage treatment approach and is thus not recommended for use. To maximize treatment outcomes for nodal recurrences, ENRT or superextended sLND should be preferred. PATIENT SUMMARY: We compared two possible treatment options, elective nodal radiotherapy and salvage lymph node dissection, for patients with prostate cancer recurrence limited to five or fewer lymph nodes and reported the nodal distrubution. Radiotherapy and surgery cover different areas with possible different outcomes.

Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial.

Purpose Retrospective studies suggest that metastasis-directed therapy (MDT) for oligorecurrent prostate cancer (PCa) improves progression-free survival. We aimed to assess the benefit of MDT in a randomized phase II trial. Patients and Methods In this multicenter, randomized, phase II study, patients with asymptomatic PCa were eligible if they had had a biochemical recurrence after primary PCa treatment with curative intent, three or fewer extracranial metastatic lesions on choline positron emission tomography-computed tomography, and serum testosterone levels > 50 ng/mL. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions (surgery or stereotactic body radiotherapy). Surveillance was performed with prostate-specific antigen (PSA) follow-up every 3 months, with repeated imaging at PSA progression or clinical suspicion for progression. Random assignment was balanced dynamically on the basis of two factors: PSA doubling time (≤ 3 v > 3 months) and nodal versus non-nodal metastases. The primary end point was androgen deprivation therapy (ADT)-free survival. ADT was started at symptomatic progression, progression to more than three metastases, or local progression of known metastases. Results Between August 2012 and August 2015, 62 patients were enrolled. At a median follow-up time of 3 years (interquartile range, 2.3-3.75 years), the median ADT-free survival was 13 months (80% CI, 12 to 17 months) for the surveillance group and 21 months (80% CI, 14 to 29 months) for the MDT group (hazard ratio, 0.60 [80% CI, 0.40 to 0.90]; log-rank P = .11). Quality of life was similar between arms at baseline and remained comparable at 3-month and 1-year follow-up. Six patients developed grade 1 toxicity in the MDT arm. No grade 2 to 5 toxicity was observed. Conclusion ADT-free survival was longer with MDT than with surveillance alone for oligorecurrent PCa, suggesting that MDT should be explored further in phase III trials.