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.

Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors: The CHEERS Phase 2 Randomized Clinical Trial.

Importance: Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs. Objective: To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors. Design, Setting, and Participants: This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023. Interventions: Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions). Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population. Results: Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred. Conclusions and Relevance: This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03511391.

Accuracy and reliability of a commercial treatment planning system in nontarget regions in modern prostate radiotherapy.

BACKGROUND: The currently available treatment planning systems (TPSs) are neither designed nor intended for accurate dose calculations in nontarget regions. The aim of this work is to quantify the accuracy and reliability of nontarget doses calculated by a commercially available TPS. METHODS: Nontarget doses calculated by the collapsed cone (CC) (v5.2) algorithm implemented in the RayStation (v6) TPS were compared to measured values. Different scenarios were investigated, from simple static fields to intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) treatment plans. Deviations and confidence limits (CLs) were calculated between results of calculations and measurements-applying both local (δ) and global (Δ) normalization-for various points of interest (POIs). Results were based on a single-institution experience for one clinical test case (prostate) and evaluated against internationally accepted criteria. RESULTS: Overall, the TPS underestimated the nontarget dose by an average of -17.7% ± 25.3% for IMRT. Quantitatively similar results were obtained for VMAT (-17.6% ± 21.2%). POIs receiving < 5% of the prescription dose were significantly underestimated by the TPS (p-value < 0.05 for both IMRT and VMAT). Dose calculation accuracy was also determined by the contribution of secondary radiation, with measured doses for out-of-field POIs being significantly different from calculated values (p-value < 0.01 for both IMRT and VMAT). Although the CLδ in nontarget regions failed the proposed tolerance criteria (40%) for both IMRT (68.8%) and VMAT (52.6%), the CLΔ was within the tolerance limit (4%) for both treatment techniques (1.9% for IMRT and 1.3% for VMAT). No action levels (7%) were exceeded. CONCLUSIONS: Based on the currently available benchmarks our TPS is considered acceptable for clinical use, although the dose in some POIs was poorly predicted by the CC algorithm. Some areas were pointed out where TPSs and linear accelerator control systems can be improved.

Dosimetric and Hematologic Implications of Prostate-Only Versus Whole Pelvic Radiotherapy: Results of the Multicentric Phase 3 PROPER Study.

Objectives: The aim is to evaluate the incidental dose to the lymphatic regions in prostate-only radiotherapy (PORT) and to compare hematological outcome between PORT and whole pelvic radiotherapy (WPRT) in node-positive prostate cancer (pN1 PCa), in the era of modern radiotherapy techniques. Methods: We performed a prospective phase 3 trial in which a total of 64 pN1 PCa patients were randomized between PORT (ARM A) and WPRT (ARM B) delivered with volumetric-modulated arc therapy (VMAT). The lymph node (LN) regions were delineated separately and differences between groups were calculated using Welch t-tests. Hematological toxicity was scored according to common terminology criteria for adverse events (CTCAE) version 4.03. To evaluate differences in the evolution of red blood cell (RBC), white blood cell (WBC), and platelet count over time between PORT and WPRT, 3 linear mixed models with a random intercept for the patient was fit with model terms randomization group, study time point, and the interaction between both categorical predictors. Results: Except for dose to the obturator region, the incidental dose to the surrounding LN areas was low in ARM A. None of the patients developed severe hematological toxicity. The change in RBC from time point pre-external beam radiotherapy (EBRT) to month 3 and for WBC from time point pre-EBRT to months 3 and 12 was significantly different with ARM B showing a larger decrease. Conclusion: The incidental dose to the lymphatic areas becomes neglectable when PORT is delivered with VMAT. Hematological toxicity is very low after WPRT with VMAT and when bone marrow constraints are used for planning, although WPRT causes a decrease in RBC and WBC count over time.

Impact of radiotherapy parameters on the risk of lymphopenia in urological tumors: A systematic review of the literature.

BACKGROUND: We investigated how radiotherapy (RT) parameters may contribute to the risk of lymphopenia in urological tumors and we discussed how this may impact clinical outcomes. MATERIAL & METHODS: A systematic review was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. The PubMed, Embase and ISI Web Of Knowledge databases were searched. Study quality was assessed according to the Newcastle-Ottawa Scale. RESULTS: Overall, 8 articles reporting on a total of 549 urological cancer patients met the inclusion criteria. The pooled mean incidence of acute severe lymphopenia (absolute lymphocyte count < 500 cells/µL) was 17.1%. Extended radiation volumes may lead to an increased risk of developing lymphopenia. Medium-high doses (≥ 40 Gy) to the whole pelvic (odds ratio (OR) = 1.01; 95% confidence interval (CI) 1.00-1.01; p = 0.025) and iliac (OR = 1.04; 95% CI 1.01-1.08; p = 0.009) bone marrow (BM) were associated with acute grade 3 and late grade 2 lymphopenia, respectively. CONCLUSION: Multiple studies reported high and severe incidences of lymphopenia. Minimizing radiation volumes and unintentional irradiation of pelvic BM may reduce the incidence of lymphopenia, potentially improving clinical outcomes. More research is needed to further elucidate these findings and effectively implement recently developed new risk assessment tools.