Therapeutic Advances in Medical Oncology最新文献

Background: Immune checkpoint inhibitor (ICI)-based combination therapy has transformed the therapeutic landscape of advanced hepatocellular carcinoma (aHCC). However, durable clinical benefit remains limited to a subset of patients, highlighting the need for approaches that enhance efficacy.

Objectives: The MONTBLANC study presents a novel investigational strategy utilizing triple immunotherapy through the combination of the anti-programmed cell death ligand 1 antibody durvalumab, the anti-cytotoxic T-lymphocyte-associated antigen-4 tremelimumab, and the anti-vascular endothelial growth factor bevacizumab in patients with aHCC.

Methods and analysis: This randomized, open-label, phase II clinical trial examines two distinct therapeutic regimens through parallel study arms: upfront triple-agent administration or doublet therapy with durvalumab and tremelimumab, followed by the addition of bevacizumab upon disease progression or lack of objective radiological response. The primary endpoint is the overall response rate. Secondary endpoints include overall survival, progression-free survival, safety, and patient-reported outcomes.

Ethics: The ethics review boards of all participating sites have approved the study protocol. The trial will be performed in accordance with the Declaration of Helsinki, Good Clinical Practice Standards, and the applicable laws and regulations. All patients must provide written informed consent.

Discussion: The MONTBLANC study aims at guiding the design of future trials in aHCC by assessing efficacy signals of upfront triple or response-adapted treatment escalation with durvalumab, tremelimumab, and bevacizumab.

Trial registration: The MONTBLANC clinical trial is registered at the US National Institutes of Health (ClinicalTrials.gov, NCT05844046) and the European Union Drug Regulating Authorities Clinical Trials Database (clinicaltrialsregister.eu, 2022-001201-48).

Background: Concurrent chemoradiotherapy (cCRT) is essential for stage III unresectable non-small cell lung cancer (NSCLC) but increases the risk of radiation pneumonitis (RP), especially with immunotherapy (IO). Induction chemotherapy (ICT) controls tumor progression but damages lung tissue, raising RP risk. Research on the RP risk from ICT, cCRT, and IO consolidation is poorly investigated.

Objectives: We evaluated whether ICT increases RP incidence and affects survival in the IO era.

Design: This was a retrospective analysis conducted at a single cancer center.

Methods: Retrospective data from stage III unresectable NSCLC patients treated with cCRT and IO between 2018 and 2024 were analyzed. Patients were divided into cCRT without ICT (N = 55) and ICT before cCRT groups (N = 103). The cumulative incidence of RP was evaluated using competing risk analysis (Gray's test and Fine-Gray models), with death as a competing risk. Multivariable Cox regression was used to analyze overall survival, progression-free survival, and RP risk among ICT regimen subgroups.

Results: The ICT before cCRT group showed a higher incidence of ⩾Grade 2 RP compared to the cCRT without ICT group (Gray's test, SHR = 1.964, 95% confidence interval (CI): 1.137-3.394, p = 0.013), with no survival benefit. Subgroup analysis based on ICT regimens, compared with the Etoposide + Platinum regimen, Pemetrexed + Platinum regimen (hazard ratio (HR): 0.277, 95% CI: 0.090-0.854, p = 0.025), Paclitaxel + Platinum regimen (HR: 0.294, 95% CI: 0.094-0.926, p = 0.037), and Docetaxel + Platinum regimen (HR: 0.059, 95% CI: 0.010-0.356, p = 0.002) were associated with a lower incidence of ⩾Grade 2 RP.

Conclusion: ICT followed by cCRT showed a higher incidence of ⩾Grade 2 RP compared to cCRT alone in patients with unresectable stage III NSCLC receiving consolidation immunotherapy.

Background: The current standard-of-care chemotherapy for treatment-naïve epithelial ovarian cancer is paclitaxel plus carboplatin.

Objectives: To compare the efficacy and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin versus paclitaxel plus carboplatin as first-line treatment in patients with epithelial ovarian cancer.

Design: This was an investigator-initiated, multicenter, open-label, randomized, noninferiority trial.

Methods: This trial with a prespecified noninferiority margin (HR₀) of 1.2, was conducted in 20 clinic centers in China. Eligible patients were randomly assigned in a 1:1 ratio to receive either PLD (30 mg/m² on day 1) plus carboplatin (area under the curve (AUC) 5 on day 1; experimental group) or paclitaxel (175 mg/m² on day 1) plus carboplatin (AUC 5 on day 1; control group) for up to six cycles. The primary endpoint was progression-free survival (PFS). The key secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.

Results: Between March 21, 2019, and December 8, 2021, 395 eligible patients were enrolled, of whom 195 were randomly assigned to receive PLD-carboplatin and 196 received paclitaxel-carboplatin. Median PFS was 35.3 months (95% confidence interval (CI), 23.7-46.9) in the experimental group and 35.0 months (95% CI, 26.9-43.1) in the control group (hazard ratio = 0.99, 95% CI, 0.73-1.35; p = 0.94). There were no statistically significant differences between the two groups in median ORR (80.5% vs 79.2%), DCR (90.2% vs 83.3%), 2-year OS rate (96.2% vs 92.4%), or 4-year OS rate (87.6% vs 82.4%; all p > 0.05). In the experimental and control groups, 165 (84.6%) and 169 (86.2%) patients experienced at least one adverse event (AEs). Alopecia (9.2% vs 28.1%, p < 0.001), peripheral sensory neuropathy (2.1% vs 17.9%, p < 0.001), and febrile neutropenia (1.0% vs 6.1%, p = 0.01) were less common in the PLD-carboplatin group compared to the paclitaxel-carboplatin group.

Conclusion: The superior tolerability and comparable efficacy of PLD plus carboplatin over paclitaxel plus carboplatin as a first-line treatment for epithelial ovarian cancer suggest that substituting paclitaxel with PLD is both feasible and potentially more beneficial.

Trial registration: This trial is registered with ClinicalTrials.gov, NCT03794778.

Background: Brentuximab vedotin (BV) and polatuzumab vedotin (PV), CD30-specific and CD79b-specific monoclonal antibody conjugates, respectively, are used in the treatment of hematologic cancers. Both have been observed to cause gastrointestinal adverse events (GI AEs).

Objectives: We aimed to assess the clinical characteristics, disease course, treatment, and outcomes of patients who developed GI AEs following treatment with BV or PV.

Design: We retrospectively identified 879 adult cancer patients who received BV or PV therapy between March 1, 2016, and March 31, 2023, at our tertiary cancer center. Patients with alternate diagnoses were excluded.

Methods: Clinical characteristics, management, and outcomes of GI AEs were retrospectively evaluated and statistically analyzed.

Results: Sixty-four patients were included, and the median duration from therapy initiation to GI AE onset was 37 days. GI AEs occurred in the lower gastrointestinal tract (78%), upper gastrointestinal tract (45%), hepatobiliary system (11%), and pancreatic system (4.3%). Common symptoms were diarrhea (77%), nausea (61%), and abdominal pain (52%). Some patients had Common Terminology Criteria for Adverse Events grade ⩾3 toxicity (19% with diarrhea and 2.7% with colitis symptoms). Most patients (81%) received supportive care alone, and three received corticosteroids. Most patients (93%) achieved symptom resolution following treatment. Symptoms recurred in 37% of patients, and 41% of patients stopped BV/PV therapy due to GI AE.

Conclusion: GI AEs following the use of targeted antibody-drug conjugates can involve various gastrointestinal systems. In our patient cohort who received BV or PV, GI AEs were typically low grade and managed with supportive care or corticosteroids. Nonetheless, some patients experienced high-grade AEs or symptom recurrence and stopped BV/PV therapy. Future studies may provide clarification and guide clinical practice.

Background: Monocarboxylate transporters (MCTs) facilitate lactate transfer and support cancer cell survival and metastasis. MCT1 and MCT4 expression has been associated with poor prognosis and resistance to therapy with tyrosine kinase inhibitors.

Objectives: This pilot study examined the relevance of MCT1 and MCT4 expression in circulating tumour cells (CTCs) isolated from non-small cell lung cancer (NSCLC) patients during osimertinib treatment through single-cell analysis.

Design: Fifty-three NSCLC patients were enrolled at three different time points: baseline (n = 53), post-first cycle (n = 20) and progressive disease (PD; n = 21), to evaluate MCT1 and MCT4 expression in patients' samples.

Methods: CTCs were isolated with the ISET platform. MCT1/MCT4 expression was assessed using immunofluorescence triple staining experiments and confocal laser scanning microscopy.

Results: CTCs were detected in 75% (40/53), 40% (8/20) and 29% (6/21) of patients at baseline, post-first cycle and PD, respectively. Among cytokeratin (CK)-positive patients, MCT1 was overexpressed at all time points in a significant percentage: 67% (18/27) at baseline, 57% (4/7) at post-first cycle and 50% (2/4) at PD. Similarly, MCT4 was overexpressed in 55% (16/29), 50% (2/4) and 60% (3/5) of cases, respectively. Statistical analysis revealed that the (CK+MCT1-CD45-) phenotype was associated with worse progression-free survival [PFS; log rank, p = 0.041, hazard ratio (HR) = 1.971] and overall survival (log rank, p = 0.028; HR = 2.288) of the patients. Conversely, the presence of ⩾3 MCT4+ CTCs was correlated with poorer PFS (log rank, p = 0.042, HR = 4.189). Significant inverse correlations were observed between MCT1 and MCT4 expression, implying their distinct biological roles.

Conclusion: MCT1 and MCT4 are overexpressed in CTCs from NSCLC patients, supporting their potential as prognostic biomarkers and therapeutic targets.

Background: Spontaneous tumor rupture is a unique and life-threatening presentation of hepatocellular carcinoma (HCC). The optimal postoperative management of patients with spontaneously ruptured HCC (srHCC) remains controversial. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed to reduce peritoneal dissemination, but its clinical benefit in srHCC is uncertain.

Objectives: This study aimed to evaluate the survival benefit and safety of postoperative HIPEC combined with hepatic resection in patients with srHCC.

Design: A retrospective multicenter cohort study was conducted, including patients with srHCC who underwent curative hepatectomy with or without postoperative HIPEC between 2018 and 2024.

Methods: A total of 208 srHCC patients from 4 institutions were enrolled and categorized into the resection group (R) and the resection plus HIPEC group (R-HIPEC). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were applied to minimize baseline differences. The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was overall survival (OS). Survival outcomes were assessed using Kaplan-Meier analysis, Cox proportional hazards models, and subgroup analysis.

Results: Across the primary, PSM, and IPTW cohorts, patients in the R-HIPEC group achieved significantly longer median RFS (mRFS) and OS than those in the R group. The median OS was 45.6 versus 26.4 months in the primary cohort (p = 0.025), 48.2 versus 26.4 months in the PSM cohort (p = 0.025), and 42.9 versus 26.5 months in the IPTW cohort (p = 0.012). The mRFS was 15.5 versus 7.7 months (p = 0.002), 18.2 versus 8.3 months (p = 0.002), and 14.7 versus 7.4 months (p = 0.014), respectively. Subgroup analysis indicated that patients with Barcelona Clinic Liver Cancer stage 0/A derived significantly greater RFS benefit from HIPEC than those with stage B/C (interaction p = 0.0264). For OS, a significant interaction was observed with postoperative immunotherapy (interaction p = 0.0054). The R-HIPEC group showed a lower incidence of peritoneal implantation metastasis, without an increase in perioperative complications.

Conclusion: HIPEC combined with resection for srHCC can effectively prolong survival time. Resection combined with HIPEC and targeted therapy may be a promising strategy for srHCC.

Background: Platinum-based chemotherapy is the first-line treatment choice for advanced thymic epithelial tumors (TETs), with the expected objective response rate (ORR) ≈of 50% in thymoma and ≈20% in thymic carcinoma.

Objective: To evaluate the impact of relative dose intensity (RDI) on first-line treatment outcomes in TET patients.

Design: Retrospective cohort referred between 2016 and 2022 at the University of Naples Federico II, Italy.

Methods: Advanced TETs treated with first-line platinum chemotherapy; RDI calculated as delivered/planned dose intensity and categorized as low (<85%) or high (⩾85%). Outcomes: ORR, time to next treatment (TTNT), overall survival (OS).

Results: Thirty-three patients (15 thymoma, 18 carcinoma); 22 low RDI, 11 high RDI. RDI was not associated with ORR. High RDI showed longer TTNT (6.6 vs 5.0 months; p = 0.042) and numerically longer OS (86.4 vs 32.2 months; p = 0.361).

Conclusion: Maintaining ⩾85% RDI during first-line platinum chemotherapy may offer clinical benefits and warrants further validation in larger cohorts.

Mesothelioma is a rare cancer that carries a poor prognosis. This malignancy has had few therapeutic advances prior to the introduction of immune checkpoint inhibitors. Immunotherapy is now a cornerstone of first-line treatment for pleural mesothelioma and has been shown to provide clinical benefit for relapsed or refractory patients treated with prior chemotherapy. This review article will discuss key immunotherapy trials in the scientific literature, along with challenges in the application of this therapy. We will also discuss future areas of immunotherapy research in the treatment of mesothelioma.

Background: The spleen, the largest secondary lymphoid organ, plays an essential role in systemic immune regulation. Its function in tumor progression and treatment response has gained increasing attention.

Objectives: This study aimed to evaluate the prognostic value of spleen volume (SV) change in patients with extensive-stage small-cell lung cancer (ES-SCLC) receiving first-line chemo-immunotherapy (CIT) and to explore its associations with tumor-infiltrating lymphocytes (TILs) and peripheral immune parameters.

Design: A single-center retrospective cohort study.

Methods: A total of 292 ES-SCLC patients who received first-line CIT were retrospectively analyzed. SV was measured on baseline and post-treatment CT scans, and the relative change was used to classify patients into increased or decreased SV groups. Cox proportional hazards regression models were used to assess the effects of SV metrics, immune-related indices, and clinicodemographic factors on overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR) differences were tested using the chi-square test, and immune parameters were compared using Wilcoxon rank-sum tests and correlation analyses.

Results: Multivariate analysis identified increased SV after CIT as an independent adverse prognostic factor for both OS (hazard ratio (HR) = 1.561, 95% confidence interval (CI), 1.193-2.041, p = 0.001) and PFS (HR = 1.411, 95% CI, 1.106-1.800, p = 0.006). Patients with increased SV exhibited significantly shorter OS and PFS and a lower ORR (all p < 0.005). Increased SV was also associated with markedly lower total, CD4+, and CD8+ TIL densities and, at the systemic level, lower absolute lymphocyte count (ALC), and higher neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) (all p < 0.0001), indicating both local and systemic immune suppression.

Conclusion: SV change reflects both local and systemic immune remodeling during CIT in ES-SCLC. As a noninvasive and measurable imaging biomarker, SV change holds translational potential for immune monitoring and treatment response assessment.