Jama Oncology最新文献

Importance: Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy.

Objective: To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone.

Design, setting, and participants: This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023.

Intervention: Personalized SBRT, 27.5 to 50 Gy in 5 fractions.

Main outcomes and measures: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life.

Results: Of 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77; 90% CI, 0.59-1.01; 1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72; 95% CI, 0.52-0.99; 2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P < .001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively (P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively.

Conclusions and relevance: In this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone.

Trial registration: ClinicalTrials.gov Identifier: NCT01730937.

Importance: Stereotactic body radiation therapy (SBRT) for spinal metastases improves symptomatic outcomes and local control compared to conventional radiotherapy. Treatment failure most often occurs within the epidural space, where dose is constrained by the risk of radiation myelitis (RM). Current constraints designed to prevent RM after spine SBRT are derived from limited data.

Objective: To characterize the risk of RM after spine SBRT and to update the dosimetric constraints for preventing it.

Design, setting, and participants: This cohort study was conducted in a single tertiary cancer care center with patients treated for spinal metastases from 2014 to 2023. All included participants had undergone spine SBRT, had a minimum of 1-month follow-up with magnetic resonance imaging (MRI), a maximal cord dose to a voxel (Dmax) greater than 0 Gy, and no overlapping prior radiotherapy. In all, 2051 patients received SBRT to 2835 spinal metastases (levels C1-L2) during the study period.

Exposures: Three-fraction spine SBRT to a prescription dose of 27 to 36 Gy.

Main outcomes and measures: RM defined as radiographic evidence of spinal cord injury in the treatment field, classified as grade (G) 1 to G4 or G3 to G4 per the Common Terminology Criteria for Adverse Events, version 5.0. Multiple dosimetric parameters of the true spinal cord structure were assessed for an association with risk of RM to determine the important covariates associated with this toxicity.

Results: The analysis included 1423 patients (mean [SD] age, 61.6 [12.9] years; 695 [48.8%] females and 728 [51.1%] males) who received SBRT for 1904 spinal metastases. Among them, 30 cases of RM were identified, 19 of which were classified as G3 to G4. Two years after SBRT, the rate of G1 to G4 RM was 1.8% (95% CI, 1.2%-2.5%) and the rate of G3 to G4 RM was 1.1% (95% CI, 0.7%-1.7%). The minimum dose to the 0.1 cm3 of spinal cord receiving the greatest dose (D0.1cc) was the most important covariate on univariable cause-specific hazards regression for RM (for G3 to G4: hazard ratio, 2.14; 95% CI, 1.68-2.72; P < .001). A true cord D0.1cc of 19.1 Gy and Dmax of 20.8 Gy estimated a 1.0% risk (95% CI, 0.3%-1.6% and 0.4%-1.6%, respectively) of G3 to G4 RM 2 years after SBRT.

Conclusions and relevance: The findings of this cohort study indicate that a cord (myelogram or MRI-derived) D0.1cc constraint of 19.1 Gy and a Dmax constraint of 20.8 Gy correspond with a 1.0% risk of G3 to G4 RM at 2 years.

Importance: Active surveillance is the preferred management strategy for patients with low- or favorable intermediate-risk prostate cancer (PCa); however, frequent health care visits can be costly and burdensome to patients. Identifying patients who may benefit from intensive vs passive surveillance could reduce these burdens.

Objective: To investigate associations between a polygenic risk score (PRS) and risk of upgrading and other prostate tumor features in patients receiving active surveillance.

Design, setting, and participants: This prospective multicenter cohort study across 10 US sites included 1220 patients from the Canary Prostate Active Surveillance Study (PASS) enrolled from July 2008 to November 2017, with follow-up (median, 5.3 years) through August 2022. Participants were those with clinically localized PCa (cT1-T2) receiving active surveillance. Analyses took place from January 2023 to April 2024.

Exposure: Multi-ancestry PRS of 451 PCa risk variants (PRS-451) and 400 PCa risk variants (PRS-400) after excluding prostate-specific antigen (PSA)-associated variants.

Main outcomes and measures: The primary outcome was PCa upgrading (any Gleason grade increase) vs no upgrading. Secondary outcomes included prostate volume, PSA, PSA density, percentage of biopsy cores with cancer, and Gleason grade group at diagnosis.

Results: The median (IQR) age at diagnosis of the 1220 patients receiving active surveillance was 63 (58-67) years. During follow-up, 470 patients upgraded; the 2- and 5-year risks of upgrading were 17.7% (95% CI, 15.5%-19.9%) and 33.3% (95% CI, 30.5%-36.3%), respectively. Each 1-SD unit increase in PRS-451 was associated with 23% increased hazard of upgrading (95% CI, 1.11-1.35; P < .001), whereas PRS-400 was associated with 27% increased hazard (95% CI, 1.15-1.39; P < .001) at any point in time during follow-up. Except for PSA, associations with remaining outcomes were similar or stronger using PRS-400. Higher PRS-400 was associated with smaller prostate volume, a higher percentage of biopsy cores with cancer, and higher PSA density. A model with clinical risk factors had a C-index of 0.64 (95% CI, 0.62-0.67); adding PRS-400 led to a C-index of 0.65 (95% CI, 0.63-0.68).

Conclusions and relevance: In this cohort study, among patients receiving active surveillance, high PRS was associated with risk of upgrading and possibly tumor multifocality. Excluding PSA variants from the PRS revealed an association with smaller prostate size, which has been previously associated with more aggressive tumors. Although PRS may inform active surveillance, it is yet to be seen whether they improve clinical decisions.

Importance: The commercialization of chimeric antigen receptor-T-cell (CAR-T) therapy has changed the landscape of treatment of hematological cancers. Numerous studies from the early 2000s paved the way for cell-based targeted therapeutics, which have been established as practice-changing therapies in lymphoma, leukemia, and multiple myeloma. However, there has been some recent concern about the risk for second primary cancers (SPCs).

Observations: Multiple cases of SPCs arising after CAR-T therapy have been reported to the US Food and Drug Administration. Most SPCs have been negative for the chimeric antigen receptor transgene, with rare reports of transgene-positive cancers. This review summarizes the most salient literature on epidemiology and pathobiology of SPCs after CAR-T therapy. Additionally, a discussion is provided on potential mitigation strategies for SPCs after CAR-T therapies.

Conclusions and relevance: The results of this review suggest that there are limited data to suggest that inadvertent transgene insertion is associated with SPCs in the post-CAR-T setting. Nonetheless, evidence-based practical solutions and scientific strategies for risk mitigation can be implemented. These include optimization of T-cell manufacturing, application of safer synthetic immunobiology, and implementation of high-fidelity genomic testing, including baseline screening for clonal hematopoiesis. These strategies may inform optimal design of the next generation of CAR-T products that confer minimal risk for SPCs such that the risk-benefit profile remains favorable to proceed with CAR-T administration for eligible patients.