Jama Oncology最新文献

Importance: Immune checkpoint inhibitors have transformed the treatment landscape for metastatic renal cell carcinoma; however, the failure of first-line therapeutic strategies remains a considerable challenge. Currently, clinicians face various issues, such as managing cases in patients who progress during treatment or relapse after adjuvant immunotherapy.

Observations: This review evaluates different strategies for treating patients with advanced kidney cancer previously exposed to immunotherapy. Evidence from other malignant neoplasms suggests potential effectiveness for rechallenging with immune checkpoint inhibitors. The most important available data are presented, including retrospective, prospective, and randomized clinical trials, to explore the role of immunotherapy in patients with renal cell carcinoma who have experienced prior failure of immune checkpoint inhibitors.

Conclusions and relevance: Although retrospective data suggest modest effectiveness of an immunotherapy rechallenge treatment, larger phase 3 trials failed to demonstrate substantial benefit in progression-free survival and overall survival. Currently, no randomized evidence supports the use of agents targeting conventional immune checkpoints in patients with renal cell carcinoma who have previously received immunotherapy.

Importance: Neoadjuvant systemic therapy (NST) has been associated with pathologic complete response (pCR) in up to 60% of breast cancers (BCs). The findings of this trial question the necessity of surgery.

Objective: To report preplanned 5-year efficacy outcomes evaluating radiotherapy alone without breast surgery in patients selected with image-guided vacuum assisted biopsy (VAB).

Design, setting, and participants: This single-arm, prospective, phase 2 nonrandomized clinical trial was conducted at 7 US medical centers and included women 40 years or older with cT1-2N0-1M0 ERBB2-positive (formerly HER2-positive) or triple-negative invasive BC who showed residual breast lesions after NST of less than 2 cm on imaging. Enrollment was from March 6, 2017, to November 9, 2021. Data analysis was from October to December 2024.

Intervention: Image-guided VAB of the tumor bed (9G with a minimum of 12 cores) was performed after standard NST. Patients with clinically node-negative disease at diagnosis and no residual cancer in the breast on post-NST VAB underwent whole-breast radiotherapy with a boost without breast or axillary surgery. Patients with initial documented nodal disease and a breast pCR on VAB underwent targeted axillary dissection, while those with residual cancer when undergoing VAB had standard breast and axillary surgery. Patients were monitored with physical examinations and mammography every 6 months.

Main outcome measures: The primary outcome was ipsilateral breast tumor recurrence.

Results: Fifty patients (median [IQR] age, 62 [55-77] years) were enrolled and underwent post-NST VAB. Twenty-nine (58%) and 21 (42%) patients had ERBB2-positive and triple-negative invasive BC, respectively. Breast pCR on VAB was identified in 31 patients (62%; 95% CI, 47.2%-75.34%), and axillary pCR was identified among all 8 patients with initial nodal metastases and breast pCR on VAB who underwent targeted axillary dissection. At a median follow-up of 55.4 (IQR, 44.0-63.5) months, the ipsilateral breast tumor recurrence rate was 0%, and disease-free and overall survival rates were 100% for patients without breast surgery.

Conclusions and relevance: The results of this nonrandomized clinical trial that reported preplanned 5-year outcomes suggest that omission of breast surgery in select patients after NST may be feasible, with no recurrences seen. More confirmatory studies are necessary before this new approach alters surgical practice.

Trial registration: ClinicalTrials.gov Identifier: NCT02945579.

Importance: Neoadjuvant immunotherapy in human papillomavirus (HPV)-negative locoregionally advanced (LA) head and neck squamous cell carcinoma (HNSCC) appears promising, yet its role in nonsurgical treatment for head and neck cancer remains undefined. Neoadjuvant nivolumab plus chemotherapy followed by response-stratified de-escalated chemoradiation therapy (CRT) in HPV-negative LA stage IVa/b HNSCC may improve treatment efficacy while reducing treatment-related toxic effects.

Objective: To determine the deep response rate and tolerability of neoadjuvant nivolumab plus chemotherapy followed by response-stratified CRT in nonvirally mediated stage IVa/b HNSCC.

Design, setting, and participants: In this investigator-initiated phase 2 nonrandomized clinical trial conducted at a single academic center, patients with stage IVa/b (American Joint Committee on Cancer Tumor Classification, 8th edition) HPV-negative LA HNSCC were enrolled between 2019 and 2022. Data were analyzed from February 2023 to January 2024.

Interventions: The DEPEND trial evaluated neoadjuvant nivolumab plus carboplatin and paclitaxel, followed by response-stratified CRT. Patients with 50% or greater reduction per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 received de-escalated CRT to 66 Gy with elimination of elective nodal volumes; patients with less than 50% reduction received standard CRT to 70 to 75 Gy. Adjuvant nivolumab was administered for 9 cycles.

Main outcomes and measures: The primary end point was deep response rate (DRR; 50% or greater shrinkage per RECIST version 1.1) following neoadjuvant nivolumab plus chemotherapy. Secondary end points included progression-free survival (PFS), overall survival (OS), locoregional control, and distant control. Exploratory end points included acute toxic effects in patients who received response-adapted de-escalated CRT.

Results: Of 36 included patients, 28 (78%) were male, and the median (range) age was 58.9 (27-77) years. All patients started treatment and were available for analysis. The median (range) follow-up was 20 (13-40) months. The primary end point was met, with a DRR following neoadjuvant nivolumab/chemotherapy of 53% (95% CI, 35-70). The objective response rate was 86% (95% CI, 71-95). A total of 19 received de-escalated CRT and 16 received standard CRT. PFS and OS at 2 years were 66% (95% CI, 34-76) and 73% (95% CI, 52-86), respectively. The most common treatment-emergent adverse events for de-escalated and standard CRT were mucositis (14 of 19 [74%] and 15 of 16 [94%], respectively), radiation dermatitis (13 of 19 [68%] and 14 of 16 [88%], respectively), and dry mouth (7 of 19 [37%] and 10 of 16 [63%], respectively).

Conclusions and relevance: In this phase 2 nonrandomized clinical trial, neoadjuvant nivolumab/chemotherapy led to deep respon

Importance: The lifetime risk of aging-related diseases among survivors of childhood cancer, accelerated by cancer treatment exposures, is unknown. Understanding this risk can provide a more comprehensive assessment of long-term health across the lifespan of survivors and guide adult care.

Objective: To estimate the lifetime risks of 8 treatment-related cancers and cardiovascular conditions among childhood cancer survivors and compare them with the general population.

Design, setting, participants: Using data from the Childhood Cancer Survivor Study and national databases, this simulation modeling study projected long-term outcomes for 5-year survivors diagnosed between 1970 and 1999 based on treatment exposures and age-related risks. The general population comparator was simulated using age-, sex-, and calendar year-matched individuals who faced only age-related risks.

Exposures: Treatment era (1970s, 1980s, 1990s), original cancer diagnosis, radiation treatment for primary diagnosis (any, none).

Main outcomes and measures: Estimated lifetime risks of 8 health conditions (breast cancer, colorectal cancer, glial tumors, sarcomas, heart failure, coronary heart disease/myocardial infarction, stroke, and valvular disease). Risks were projected and compared with the general population, stratified by radiation exposure.

Results: In the general population, 20% developed at least 1 health condition by age 65.0 years; in 5-year survivors this threshold was reached at age 47.3 years, representing a 17.7-year (95% uncertainty interval [UI], 14.0-21.0) acceleration in disease onset. By age 65 years, 55% of survivors were projected to develop at least 1 condition, indicating a 2.7-fold (95% UI, 2.2-3.5) higher relative risk and 34.2% (95% UI, 28.3-42.5) absolute excess risk compared with the general population. Risks were higher among those treated with radiation therapy for childhood cancer (22.0 years earlier onset [95% UI, 18.0-25.0]; 37.3% excess risk [95% UI, 31.6%-44.7%]) but still elevated for those without radiation exposure (13.5 years earlier onset [95% UI, 10.0-16.0]; 31.0% excess risk [95% UI, 23.9%-40.3%]). Reaching middle age was still associated with increased health risks. Compared with the general population, survivors who reached age 40 years had a 6.2-fold higher risk (95% UI, 4.8-9.4) of developing a new condition within 10 years.

Conclusions and relevance: This study found that survivors of childhood cancer experience accelerated onset of aging-related diseases, regardless of prior radiation exposure. These findings underscore the importance of prioritizing cancer and cardiovascular disease prevention among survivors decades earlier than for the general population.