Efficacy of National Comprehensive Cancer Network Guidelines in Identifying Pathogenic Germline Variants Among Unselected Patients with Prostate Cancer: The PROCLAIM Trial.

BACKGROUND: Prostate cancer (PCa) patients with pathogenic/likely pathogenic germline variants (PGVs) in cancer predisposition genes may be eligible for U.S. Food and Drug Administration-approved targeted therapies, clinical trials, or enhanced screening. Studies suggest that eligible patients are missing genetics-informed care due to restrictive testing criteria. OBJECTIVE: To establish the prevalence of actionable PGVs among prospectively accrued, unselected PCa patients, stratified by their guideline eligibility. DESIGN, SETTING, AND PARTICIPANTS: Consecutive, unselected PCa patients were enrolled at 15 sites in the USA from October 2019 to August 2021, and had multigene cancer panel testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Correlates between the prevalence of PGVs and clinician-reported demographic and clinical characteristics were examined. RESULTS AND LIMITATIONS: Among 958 patients (median [quartiles] age at diagnosis 65 [60, 71] yr), 627 (65%) had low- or intermediate-risk disease (grade group 1, 2, or 3). A total of 77 PGVs in 17 genes were identified in 74 patients (7.7%, 95% confidence interval [CI] 6.2-9.6%). No significant difference was found in the prevalence of PGVs among patients who met the 2019 National Comprehensive Cancer Network Prostate criteria (8.8%, 43/486, 95% CI 6.6-12%) versus those who did not (6.6%, 31/472, 95% CI 4.6-9.2%; odds ratio 1.38, 95% CI 0.85-2.23), indicating that these criteria would miss 42% of patients (31/74, 95% CI 31-53%) with PGVs. The criteria were less effective at predicting PGVs in patients from under-represented populations. Most PGVs (81%, 60/74) were potentially clinically actionable. Limitations include the inability to stratify analyses based on individual ethnicity due to low numbers of non-White patients with PGVs. CONCLUSIONS: Our results indicate that almost half of PCa patients with PGVs are missed by current testing guidelines. Comprehensive germline genetic testing should be offered to all patients with PCa. PATIENT SUMMARY: One in 13 patients with prostate cancer carries an inherited variant that may be actionable for the patient's current care or prevention of future cancer, and could benefit from expanded testing criteria.

Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy: A Randomized Clinical Trial.

Importance: Hypofractionated radiation therapy (RT) for prostate cancer has been associated with greater acute grade 2 gastrointestinal (GI) toxic effects compared with conventionally fractionated RT. Objective: To evaluate whether a hyaluronic acid rectal spacer could (1) improve rectal dosimetry and (2) affect acute grade 2 or higher GI toxic effects for hypofractionated RT. Design, Setting, and Participants: This randomized clinical trial was conducted from March 2020 to June 2021 among 12 centers within the US, Australia, and Spain, with a 6-month follow-up. Adult patients with biopsy-proven, T1 to T2 prostate cancer with a Gleason score 7 or less and prostate-specific antigen level of 20 ng/mL or less (to convert to µg/L, multiply by 1) were blinded to the treatment arms. Of the 260 consented patients, 201 patients (77.3%) were randomized (2:1) to the presence or absence of the spacer. Patients were stratified by intended 4-month androgen deprivation therapy use and erectile quality. Main Outcomes and Measures: For the primary outcome, we hypothesized that more than 70% of patients in the spacer group would achieve a 25% or greater reduction in the rectal volume receiving 54 Gy (V54). For the secondary outcome, we hypothesized that the spacer group would have noninferior acute (within 3 months) grade 2 or higher GI toxic effects compared with the control group, with a margin of 10%. Results: Of the 201 randomized patients, 8 (4.0%) were Asian, 26 (12.9%) Black, 42 (20.9%) Hispanic or Latino, and 153 (76.1%) White; the mean (SD) age for the spacer group was 68.6 (7.2) years and 68.4 (7.3) years for the control group. For the primary outcome, 131 of 133 (98.5%; 95% CI, 94.7%-99.8%) patients in the spacer group experienced a 25% or greater reduction in rectum V54, which was greater than the minimally acceptable 70% (P < .001). The mean (SD) reduction was 85.0% (20.9%). For the secondary outcome, 4 of 136 patients (2.9%) in the spacer group and 9 of 65 patients (13.8%) in the control group experienced acute grade 2 or higher GI toxic effects (difference, -10.9%; 95% 1-sided upper confidence limit, -3.5; P = .01). Conclusions and Relevance: The trial results suggest that rectal spacing with hyaluronic acid improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Rectal spacing should potentially be considered for minimizing the risk of acute grade 2 or higher toxic effects for hypofractionated RT. Trial Registration: ClinicalTrials.gov Identifier: NCT04189913.

Epidemiology, diagnosis, and optimal management of glioma in adolescents and young adults.

Neoplasms of the central nervous system (CNS) are the most frequently encountered solid tumors of childhood, but are less common in adolescents and young adults (AYA), aged 15-39 years. Gliomas account for 29%-35% of the CNS tumors in AYA, with approximately two-thirds being low-grade glioma (LGG) and the remaining being high-grade glioma (HGG). We review the epidemiology, work-up, and management of LGG and HGG, focusing on the particular issues faced by the AYA population relative to pediatric and adult populations. Visual pathway glioma and brainstem glioma, which represent unique clinical entities, are only briefly discussed. As a general management approach for both LGG and HGG, maximal safe resection should be attempted. AYA with LGG who undergo gross total resection (GTR) may be safely observed. As age increases and the risk factors for recurrence accumulate, adjuvant therapy should be more strongly considered with a strong consideration of advanced radiation techniques such as proton beam therapy to reduce long-term radiation-related toxicity. Recent results also suggest survival advantage for adult patients with the use of adjuvant chemotherapy when radiation is indicated. Whenever possible, AYA patients with HGG should be enrolled in a clinical trial for the benefit of centralized genetic and molecular prognostic review and best clinical care. Chemoradiation should be offered to all World Health Organization grade IV patients with concurrent and adjuvant chemotherapy after maximal safe resection. Younger adolescents with GTR of grade III lesions may consider radiotherapy alone or sequential radiotherapy and chemotherapy if unable to tolerate concurrent treatment. A more comprehensive classification of gliomas integrating pathology and molecular data is emerging, and this integrative strategy offers the potential to be more accurate and reproducible in guiding diagnostic, prognostic, and management decisions.

Prognostic significance of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in patients treated with selective internal radiation therapy.

BACKGROUND: Elevated neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) may represent markers of a suboptimal host immune response to cancer and have been shown to correlate with prognosis in multiple tumor types across different treatment modalities, including radiation therapy. Limited data suggest that NLR may predict for survival and disease control in patients receiving selective internal radiation therapy (SIRT). The correlation between clinical outcomes and change in NLR and PLR after SIRT has not been evaluated. METHODS: We retrospectively reviewed 339 consecutive patients with primary (n=37) or metastatic (n=79) liver cancer treated with SIRT from 2006 to 2014. Complete blood counts with differential were available for 116 patients both before and after (median, 29 and 20 days, respectively) SIRT. Survival and progression were calculated from date of initial SIRT. Patient and tumor characteristics evaluated for ability to predict overall survival (OS) and progression free survival (PFS) included pre- and post-treatment neutrophil, platelet, and lymphocyte counts (LCs), as well as NLR, PLR, and relative change in NLR and PLR. Cutoff values were determined for variables that were significant on multivariate analysis (MVA) for OS and/or PFS. RESULTS: Median follow-up of surviving patients was 12 months. Median OS was 8 months from SIRT and 20 months from date of liver metastasis diagnosis. Significant factors on univariate analysis (UVA) for both lower OS and PFS included higher post-treatment neutrophil count (NC), higher post-treatment NLR, higher liver tumor volume, higher percentage liver tumor burden, and worse Eastern Cooperative Oncology Group (ECOG) performance status. Significant factors on MVA for lower OS and PFS were ECOG performance status ≥2, higher liver tumor volume, higher pretreatment PLR, and increase in PLR after SIRT. Post-treatment increase in PLR >3-fold was the most predictive early marker for increased risk of death when compared with those whose PLR did not increase or increased <3-fold. Pretreatment PLR >78 was the most predictive serum marker associated with improved OS prior to therapy. CONCLUSIONS: This is the largest study to evaluate the association between NLR and PLR with clinical outcomes in patients receiving SIRT, with results that confirm that pre- and/or post-treatment NLR and/or PLR are predictive of clinical outcomes. The largest increase in risk of death as well as local and extrahepatic disease progression was related to change in PLR, a datum not well reported in the literature. The impact of SIRT on blood count changes and the underlying implications of these ratios should be further characterized in a prospective study.

Should we irradiate a brain tumor in a patient with parkinsonism? A case report and literature review.

PURPOSE: Parkinson's disease (PD) is the second most common neurodegenerative disorder; the safety and effects of radiation therapy on PD are not well established. We report a patient with PD and a brain tumor referred for radiation therapy and review the literature on this topic focusing on the incidence of cancer and brain tumors in PD, brain tumors and radiation therapy as independent causes of PD, and the safety and effect of radiation therapy, including functional radiosurgery, in patients with PD. METHODS AND MATERIALS: A PubMed literature review focusing on all English language publications from 1940 to 2014 identified 146 relevant articles, of which 91 discussed functional radiosurgery for PD, 49 discussed "neoplastic parkinsonism," 4 discussed radiation-induced parkinsonism, and 2 discussed the safety of fractionated radiation therapy in patients with PD. RESULTS: Odds ratios of 0.4 to 0.88 have been reported for the development of cancer in general among patients with PD, whereas the incidence ratios of PD patients developing a brain tumor relative to the general population range from 0.9 to 1.61. Parkinsonian symptoms thought to arise as a sequelae of tumor growth have been described in 49 papers dating to 1953. We identified 4 reports of parkinsonian syndromes that arose after radiation therapy, comprising a total of 7 patients, including 5 adults and 2 pediatric patients. Pediatric patients showed a mixed response to dopamine agonist therapy, whereas adults had little symptom improvement. Reports of PD patients irradiated in conventional fractionation for a variety of indications do not appear to indicate increased sensitivity to radiation therapy or exacerbated PD symptoms after irradiation. Radiosurgery performed for management of refractory tremor in PD patients results in up to an 88% favorable outcome, with the onset of symptom improvement ranging from 3 days to 1 year and minimal toxicity (not exceeding the toxicities observed for the same stereotactic radiosurgery procedure performed for essential tremor in nonparkinsonian patients). CONCLUSIONS: Patients with PD do not harbor an increased risk for the development of cancer in general and have similar incidence of brain tumors as the general population. Tumor-induced parkinsonism is a rare entity. Parkinsonism as a side effect of brain radiation is an uncommon phenomenon, even after high doses, but is associated with limited response to medical management. Rare cases in children, typically associated with bilateral imaging changes, have been described, which suggests possible uncommon genetic predisposition. There are no convincing reports that suggest that pre-existing parkinsonism is worsened by radiation therapy, although a mechanistic possibility for this exists. Functional radiosurgery for management of refractory tremor in PD patients is safe and effective. Radiation therapy, either fractionated or stereotactic radiosurgery, appears to be safe when used judiciously for patients with PD, for the treatment of either tumors or PD itself.