Stereotactic Body Radiotherapy and Liver Transplant for Liver Cancer: A Nonrandomized Controlled Trial.

Importance: Whether stereotactic body radiotherapy (SBRT) as a bridge to liver transplant for hepatocellular carcinoma (HCC) is effective and safe is still unknown. Objective: To investigate the feasibility of SBRT before deceased donor liver transplant (DDLT) for previously untreated unresectable HCC. Design, Setting, and Participants: In this phase 2 nonrandomized controlled trial conducted between June 1, 2015, and October 18, 2019, 32 eligible patients within UCSF (University of California, San Francisco) criteria underwent dual-tracer (18F-fluorodeoxyglucose and 11C-acetate [ACC]) positron emission tomography with computed tomography (PET-CT) and magnetic resonance imaging (MRI) with gadoxetate followed by SBRT of 35 to 50 Gy in 5 fractions, and the same imaging afterward while awaiting DDLT. Statistical analysis was performed on an intention-to-treat basis between October 1 and 31, 2023. Intervention: Patients received SBRT followed by DDLT when matched deceased donor grafts were available. Main Outcomes and Measures: Coprimary end points were progression-free survival (PFS) and objective response rates (ORRs) by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), modified RECIST (mRECIST), and PET Response Criteria in Solid Tumors (PERCIST). Secondary end points were local control rate, overall survival (OS), and safety. Results: A total of 32 patients (median age, 59 years [IQR, 54-63 years]; 22 men [68.8%]) with 56 lesions received SBRT. After a median follow-up of 74.6 months (IQR, 40.1-102.9 months), the median PFS was 17.6 months (95% CI, 6.6-28.6 months), and the median OS was 60.5 months (95% CI, 29.7-91.2 months). The 5-year PFS was 39.9% (95% CI, 19.9%-59.9%), and the 5-year OS was 51.3% (95% CI, 31.7%-70.9%). In terms of number of patients, ORRs were 62.5% ([n = 20] 95% CI, 54.2%-68.7%) by RECIST 1.1, 71.9% ([n = 23] 95% CI, 63.7%-79.0%) by mRECIST, and 78.1% ([n = 25] 95% CI, 73.2%-86.7%) by PERCIST. In terms of number of lesions, ORRs were 75.0% ([n = 42] 95% CI, 61.6%-80.8%) by RECIST 1.1, 83.9% ([n = 47] 95% CI, 74.7%-90.6%) by mRECIST, and 87.5% ([n = 49] 95% CI, 81.3%-98.6%) by PERCIST. Twenty patients with 36 lesions received DDLT, of whom 15 patients (75.0%) with 21 lesions (58.3%) exhibited pathologic complete response. Multivariable analyses revealed that pretreatment metabolic tumor volume (MTV) based on ACC (hazard ratio [HR], 1.06 [95% CI, 1.01-1.10]; P = .01) and complete metabolic response (CMR) by PERCIST (HR, 0.31 [95% CI, 0.10-0.96]; P = .04) were associated with PFS, while pretreatment MTV based on ACC (HR, 1.07 [95% CI, 1.03-1.16]; P = .01), total lesion activity based on ACC (HR, 1.01 [95% CI, 1.00-1.02]; P = .02), and CMR by PERCIST (HR, 0.21 [95% CI, 0.07-0.73]; P = .01) were associated with OS. Toxic effects associated with SBRT were reported for 9 patients (28.1%), with 1 grade 3 event. Conclusions and Relevance: This phase 2 nonrandomized controlled trial demonstrated promising survival and safety outcomes of SBRT before DDLT for unresectable HCC. Future randomized clinical trials are warranted.

Immune-Related Endocrine Dysfunctions in Combined Modalities of Treatment: Real-World Data.

The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) in cancer management. A retrospective analysis was conducted on consecutive patients ≥18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a university hospital in Hong Kong. Patients were reviewed up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis. A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) were included. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo + ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted + ICI). A significantly higher proportion of patients using targeted + ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (≥65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. This large, real-world cohort demonstrates that targeted + ICI has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is essential in older populations.

The addition of pretreatment plasma Epstein-Barr virus DNA into the eighth edition of nasopharyngeal cancer TNM stage classification.

The eighth edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage classification (TNM) for nasopharyngeal carcinoma (NPC) was launched. It remains unknown if incorporation of nonanatomic factors into the stage classification would better predict survival. We prospectively recruited 518 patients with nonmetastatic NPC treated with radical intensity-modulated radiation therapy ± chemotherapy based on the eighth edition TNM. Recursive partitioning analysis (RPA) incorporating pretreatment plasma Epstein-Barr virus (EBV) DNA derived new stage groups. Multivariable analyses to calculate adjusted hazard ratios (AHRs) derived another set of stage groups. Five-year progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS) were: Stage I (PFS 100%, OS 90%, CSS 100%), II (PFS 88%, OS 84%, CSS 95%), III (PFS 84%, OS 84%, CSS 90%) and IVA (PFS 71%, OS 75%, CSS 80%) (p < 0.001, p = 0.066 and p = 0.002, respectively). RPA derived four new stages: RPA-I (T1-T4 N0-N2 & EBV DNA <500 copies per mL; PFS 94%, OS 89%, CSS 96%), RPA-II (T1-T4 N0-N2 & EBV DNA ≥500 copies per mL; PFS 80%, OS 83%, CSS 89%), RPA-III (T1-T2 N3; PFS 64%, OS 83%, CSS 83%) and RPA-IVA (T3-T4 N3; PFS 63%, OS 60% and CSS 68%) (all with p < 0.001). AHR using covariate adjustment also yielded a valid classification (I: T1-T2 N0-N2; II: T3-T4 N0-N2 or T1-T2 N3 and III: T3-T4 N3) (all with p < 0.001). However, RPA stages better predicted survival for PS and CSS after bootstrapping replications. Our RPA-based stage groups revealed better survival prediction compared to the eighth edition TNM and the AHR stage groups.

Prognostication of serial post-intensity-modulated radiation therapy undetectable plasma EBV DNA for nasopharyngeal carcinoma.

Plasma Epstein-Barr virus (EBV) DNA titers have been used to monitor treatment response and provide prognostic information on survival for nasopharyngeal carcinoma (NPC). However, the long-term prognostic role of pretreatment and posttreatment titers after radical contemporaneous radiation therapy remains uncertain. We recruited 260 evaluable patients with non-metastatic NPC treated with radical intensity-modulated radiation therapy (IMRT) with or without adjunct chemotherapy. Plasma EBV DNA titers at baseline and then 8 weeks and 6 months after IMRT were measured. Cox regression models were employed to identify interaction between post-IMRT 8th week and 6th month undetectable titers and 3-year survival endpoints. Concordance indices (Ct) from time-dependent receiver-operating characteristics (TDROC) were compared between patients with post-IMRT undetectable and those with detectable titers. After a median follow-up duration of 3.4 years (range 1.4-4.6 years), patients with post-IMRT 8th week and 6th month undetectable plasma EBV DNA titers enjoyed longer 3-year survival endpoints than those who had detectable titers at the same time points. Post-IMRT 8th week, and more significantly, post-IMRT 6th month undetectable plasma EBV DNA were the only significant prognostic factors of 3-year survival endpoints. Ct values for all 3-year survival endpoints for both post-IMRT 8th week and 6th month undetectable plasma EBV DNA were significantly higher in those with stage IVA-IVB diseases compared to stage I-III counterparts. Early post-IMRT undetectable plasma EBV DNA titers were prognostic of 3-year survival endpoints in patients with non-metastatic NPC. Intensified treatment should be further explored for patients with persistently detectable titers after IMRT.