Therapeutic Advances in Medical Oncology最新文献

Background: Trastuzumab (Herceptin) can be administered intravenously (IV Herceptin) and subcutaneously, with similar efficacy and safety, but with differences in dosage and costs. Previous studies have evaluated the costs of both treatment approaches in the outpatient settings, but no study has compared the costs of IV Herceptin administered in outpatients with subcutaneous Herceptin administered at patients' homes (Homecare SC Herceptin).

Objectives: This study aimed to compare the per-patient costs of Homecare SC Herceptin versus IV Herceptin administered in a healthcare institution's outpatient setting in Singapore.

Designs: We performed a model-based cost-minimization analysis to estimate and compare the per-patient annual costs associated with each treatment modality from a societal perspective.

Methods: Direct cost comprised healthcare resources utilization: drug, consumables, manpower, facility and cardiac assessment. Indirect cost was valued using a human capital approach to account for productivity lost by patients. Monte Carlo simulations with 1000 iterations were performed to account for parameter uncertainties. Costs were reported in 2023 Singapore dollars.

Results: The annual societal cost per patient receiving IV Herceptin ranged from S$64,194 to S$65,135, while for Homecare SC Herceptin, it ranged from S$25,865 to S$26,807. Homecare SC Herceptin reduced the annual cost burden by 58.8% and 59.7%, per non-metastatic and metastatic breast cancer patient, respectively. The primary cost contributor was drug therapy, comprising more than 90% of the total cost. Even when excluding the cost of drugs, Homecare SC Herceptin remained cheaper by S$1912 annually. The cost reduction is approximately 60% compared to IV Herceptin regardless of disease status, with a 100% probability that the decision to adopt Homecare SC Herceptin leads to cost savings in Singapore.

Conclusion: Treatment of breast cancer with Homecare SC Herceptin is a cost-saving option compared to IV Herceptin.

Background: The efficacy of immune checkpoint inhibitors (ICIs) in cancer patients taking anti-hypertensive drugs is still not well established.

Objective: To elucidate the effect of anti-hypertensive drugs on the clinical outcome of cancer patients receiving immunotherapy.

Design: A retrospective cohort study and meta-analysis.

Method: We conducted a real-world retrospective study of cancer patients treated with immunotherapy at two tertiary centers between January 2019 and June 2023, with primary outcomes being overall survival (OS) and progression-free survival (PFS). In addition, we performed a meta-analysis to synthesize currently relevant clinical studies.

Results: A retrospective clinical study of 336 patients from 2 centers suggested that the use of anti-hypertensive drugs was related to a preferable OS (hazard ratio (HR) = 0.55, 95% confidence interval (CI): 0.33-0.90) compared to non-users. For PFS, no significant correlation was detected (HR = 0.71, 95% CI: 0.49-1.03). Further analysis revealed that renin-angiotensin system inhibitor (RASi) and calcium channel blocker (CCB) have a synergistic effect with ICIs. In addition, subgroup analysis found that the benefits of RASi or CCB in combination with ICIs are greater in women or patients ⩾65 years of age. There was better disease control in lung cancer patients using RASi, and a significantly longer OS was observed in patients with gastrointestinal tumors taking CCB. Meta-analysis suggested that anti-hypertensive drugs were associated with improved OS, but only the combination of RASi and immunotherapy showed a synergistic effect. No significant correlation with OS was found for other anti-hypertensive drugs, and there was no overall positive effect on PFS.

Conclusion: Our study found that use of anti-hypertensive drugs, particularly RASi or CCB, was associated with improved OS in patients undergoing immunotherapy. The synergistic effects of RASi or CCB with ICIs were more pronounced in females or elderly. RASi or CCB exhibited different benefits in various types of tumors. These findings provide valuable insights for treating cancer patients with hypertension.

Background: Cholangiocarcinomas (CCA) are a group of aggressive malignancies with poor prognosis. The distinct subtypes are related to different etiologies and genetic aberrations that are subject to targeted therapies. Mouse double minute 2 homolog (MDM2) is a potent inhibitor of tumor suppressor p53 and is proven to be altered in certain carcinomas. Novel targeted drugs, such as the MDM2-p53 antagonist Brigimadlin, have shown promising results for therapeutic efficacy in patients with MDM2 amplification and wild-type TP53.

Objectives: This study therefore aimed to characterize CCAs regarding their MDM2 status, compare the concordance between fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods, and elucidate the role of MDM2 amplification in prognosis and other clinicopathological characteristics.

Design: Retrospective cohort study.

Methods: All patients (n = 52) were diagnosed with CCA and received surgical resection with curative intention at the University Hospital of Cologne. Samples were analyzed retrospectively for MDM2 amplification with FISH and IHC. We correlated results with pre-existing molecular as well as clinical data.

Results: We included 52 patients with primary CCA, three of which showed positive MDM2 amplification (5.8%). MDM2 amplification was present only in the intrahepatic CCA type and all patients with positive MDM2 amplification exhibited normal p53 status. Among the large-duct subtypes of intrahepatic CCAs, patients with positive MDM2 amplification demonstrated better survival than patients with negative MDM2 amplification (p = 0.041). Of the patients with MDM2 amplification, two underwent adjuvant therapy post-surgery (66.7%). There was a strong correlation between MDM2 amplification and positive protein expression in IHC. There were no identifiable molecular co-alterations of MDM2 with FGFR2 or SWI/SNF complex alterations.

Conclusion: Real-world evidence in our Caucasian patient population confirmed that a significant number of intrahepatic CCAs showcase MDM2 amplification, qualifying for a personalized therapy option with Brigimadlin. MDM2 amplification must therefore be considered in the context of personalized molecular testing in CCA.

Background: Glioblastoma (GBM) is the most aggressive and lethal central nervous system (CNS) tumor. The treatment strategy is mainly surgery and/or radiation therapy, both combined with adjuvant temozolomide (TMZ) chemotherapy. Historically, methylation of MGMT gene promoter is used as the major biomarker predicting individual tumor response to TMZ.

Objectives: This research aimed to analyze genes and molecular pathways of DNA repair as biomarkers for sensitivity to TMZ treatment in GBM using updated The Cancer Genome Atlas (TCGA) data and validate the results on experimental datasets.

Methods: Survival analysis of GBM patients under TMZ therapy and hazard ratio (HR) calculation were used to assess all putative biomarkers on World Health Organization CNS5 reclassified TCGA project collection of molecular profiles and experimental multicenter GBM patient cohort. Pathway activation levels were calculated for 38 DNA repair pathways. TMZ sensitivity pathway was reconstructed using a human interactome model built using pairwise interactions extracted from 51,672 human molecular pathways.

Results: We found that expression/activation levels of seven and six emerging gene/pathway biomarkers served as high-quality positive (HR < 0.61) and negative (HR > 1.63), respectively, patient survival biomarkers performing better than MGMT methylation. Positive survival biomarkers were enriched in the processes of ATM-dependent checkpoint activation and cell cycle arrest whereas negative-in excision DNA repair. We also built and characterized gene pathways which were informative for GBM patient survival following TMZ administration (HR 0.18-0.44, p < 0.0009; area under the curve 0.68-0.9).

Conclusion: In this study, a comprehensive analysis of the expression of 361 DNA repair genes and activation levels of 38 DNA repair pathways revealed 13 potential survival biomarkers with increased prognostic potential compared to MGMT methylation. We algorithmically reconstructed the TMZ sensitivity pathway with strong predictive capacity in GBM.

Background: Stereotactic body radiation therapy (SBRT) in treating non-small-cell lung cancer (NSCLC) exhibits a remarkable therapeutic efficacy. However, its effectiveness in overcoming resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced EGFR mutations (EGFRm) NSCLC remains uncertain.

Objective: We aimed to analyze the effect of SBRT on patients with first-line EGFR-TKIs.

Design and methods: Eligible patients with advanced NSCLC initially diagnosed with EGFRm were enrolled. Patients in the EGFR-TKIs group received only the first-generation EGFR-TKIs until disease progression or death, while the others in the EGFR-TKIs + SBRT group received EGFR-TKIs and early SBRT (dose of 40-60 Gy/5-8 F) targeting the primary lung tumor at 1 month after EGFR-TKIs. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were treatment-related adverse effects, overall survival (OS), and sites of initial failure.

Results: A total of 184 advanced NSCLC patients with EGFRm were enrolled, including 39 patients in the EGFR-TKIs + SBRT group and 145 patients in the EGFR-TKIs group. The median PFS was 15.50 months in the EGFR-TKIs + SBRT group compared to 9.33 months in the EGFR-TKIs group (p = 0.0020). However, the median OS was 29.10 months in the EGFR-TKIs + SBRT group and 26.33 months in the EGFR-TKIs group, with no significant difference observed (p = 0.22). SBRT is an independent positive prognostic factor for PFS in advanced EGFRm NSCLC. EGFR exon 19 deletion mutation (16.33 vs 11.55 months, p = 0.0087) and fewer metastases (0-5) (31.94 vs 9.59 months, p = 0.0059) were associated with improved PFS in EGFR-TKIs + SBRT versus EGFR-TKIs. Combination therapy increased radiation pneumonitis mainly in Grades 1-2 (89.74% vs 0.0%). The EGFR-TKIs + SBRT group mainly had new site failure (57.10% vs 32.10%) rather than the original site failure.

Conclusion: Early SBRT for primary lung tumors may overcome targeted resistance in advanced EGFRm NSCLC patients combined with EGFR-TKIs without serious toxicities, especially for EGFR exon 19-del.

Trial registration: ChiCTR-OIN-17013920.

Background: The value of pretreatment baseline ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET)/computed tomography (CT) as a prognostic factor for survival of patients with non-small-cell lung cancer (NSCLC) receiving immunotherapy remained uncertain.

Objectives: To investigate the prognostic ability of baseline ¹⁸F-FDG PET/CT in patients with NSCLC receiving immunotherapy.

Design: A systematic review and meta-analysis.

Data sources and methods: We searched the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases until May 7, 2024, and extracted data related to patient characteristics, semiquantitative parameters of ¹⁸F-FDG PET/CT, and survival. We pooled hazard ratios (HRs) to evaluate the prognostic value of the maximum standardized uptake value (SUV_max), mean standardized uptake value (SUV_mean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for overall survival (OS) and progression-free survival (PFS).

Results: A total of 22 studies (1363 patients, average age range 30-88 years) were included. Baseline ¹⁸F-FDG PET/CT-derived MTV was significantly associated with both OS (HR: 1.124, 95% confidence interval (CI) 1.058-1.195, I ² = 81.70%) and PFS (HR: 1.069, 95% CI: 1.016-1.124, I ² = 71.80%). Other baseline ¹⁸F-FDG PET/CT-derived parameters, including SUV_max (OS: HR: 0.930, 95% CI: 0.718-1.230; PFS: HR: 0.979, 95% CI: 0.759-1.262), SUV_mean (OS: HR: 0.801, 95% CI: 0.549-1.170; PFS: HR: 0.688, 95% CI: 0.464-1.020), and TLG (OS: HR: 0.999, 95% CI: 0.980-1.018; PFS: HR: 0.995, 95% CI: 0.980-1.010), were not associated with survival. Sensitivity analyses by removing one study at a time did not significantly alter the association between MTV and PFS or between MTV and OS. There was no evidence of publication bias.

Conclusion: Pretreatment baseline ¹⁸F-FDG PET/CT-derived MTV might be a prognostic biomarker in NSCLC patients receiving immunotherapy. Further studies are needed to support routine use.

Background: Ascites is common in advanced gastrointestinal cancers with peritoneal metastases (PM) and negatively impacts patient survival. No study to date has specifically evaluated the relationship between ascites, PM and survival outcomes in metastatic colorectal cancer (mCRC) and metastatic gastric cancer (mGC).

Objectives: This study aims to investigate and elucidate the relationship between malignant ascites, PM and survival outcomes in both mCRC and mGC patients.

Design: This is a retrospective analysis of prospectively collected clinical trial data of mCRC and mGC patients with PM.

Methods: We performed two pooled analyses, firstly of two Italian randomized trials enrolling patients with mCRC eligible for systemic therapy (TRIBE2; VALENTINO), and secondly of gastric cancer and peritoneal metastasis (GCPM) patients who underwent bi-directional therapeutic treatment comprising systemic and peritoneal-directed therapies.

Results: Of 900 mCRC patients, 39 (4.3%) had PM with malignant ascites. Compared to the group without PM, median progression-free and overall survival were significantly inferior in the ascites group (hazard ratio (HR) for progression-free survival (PFS) 1.68, 95% confidence interval (CI): 1.21-2.35, p = 0.007; HR for overall survival (OS) 2.14, 95% CI: 1.57-3.01, p < 0.001), but not in the group of PM without ascites (HR for PFS 1.10, 95% CI: 0.91 - 1.34; HR for OS 1.04, 95% CI: 0.84 - 1.30). Of 170 patients with GCPM, those with ascites had higher median Peritoneal Cancer Index scores (23 vs 9, p < 0.001). Median OS was significantly inferior among those with ascites compared to those without (13.0 vs 21.0 months, HR 1.71, 95% CI: 1.16-2.52, p = 0.007).

Conclusion: Ascites identifies a subgroup of patients with PM and poor outcomes, for whom tailored research are needed.

Background: Alveolar soft-part sarcoma (ASPS) is a rare tumor driven by the ASPSCR1-TFE3 fusion protein, with a propensity for metastasis. Prognostic factors remain poorly understood, and traditional chemotherapies are largely ineffective. Recent interest lies in immune checkpoint inhibitors (ICIs), yet predictive biomarkers for treatment response are lacking. Previous studies have shown promising results with ICIs in ASPS, indicating a need for further investigation into biomarkers associated with immune response.

Objectives: To identify prognostic biomarkers in ASPS and to explore the role of immune-related markers, particularly L1CAM, in predicting patient outcomes.

Design: A retrospective cohort study of 19 ASPS patients registered in the GEIS database. The study involved the collection of clinical and histopathological data, followed by an analysis of immune markers and gene expression profiles to identify potential prognostic indicators.

Methods: Clinical and histopathological data were retrospectively collected from the GEIS-26 study cohort of 19 ASPS patients. Immunohistochemistry was performed to evaluate immune markers programmed death-1 ligand (PD-L1), programmed death-1, FAS, FASL, CD8, CD3, and CD4. An HTG ImmunOncology panel was conducted on formalin-fixed paraffin-embedded samples to explore gene expression. Effects of differentially expressed genes on survival were explored by Kaplan-Meier.

Results: PD-L1 positivity was widely observed (63%) in tumors, and CD8+ lymphocytic infiltration was common. High CD8 density correlated with greater overall survival (OS) while not statistically significant. No associations were found for other immune markers. L1CAM was identified as differentially expressed in patients with low CD8 infiltration and correlated negatively with OS.

Conclusion: High L1CAM expression correlated with poorer OS, highlighting its potential as a prognostic marker and therapeutic target in ASPS. Immunomodulatory interventions may hold promise, as evidenced by PD-L1 expression and CD8+ infiltration. Further research, including larger cohorts and international collaborations, is needed to validate these findings and explore therapeutic strategies targeting L1CAM in ASPS.

Background: Cholangiocarcinoma is a kind of malignant tumor that originates in the epithelium of the biliary tract. Although there are several options for second-line treatment for patients without specific genetic mutations, the overall treatment efficacy is disappointing. Second-line treatment which is composed of liposomal irinotecan plus fluorouracil and leucovorin significantly improved the treatment efficacy for advanced biliary tract cancer and extended patient survival. This study aims to evaluate the efficacy and safety of the combination of cadonilimab with liposomal irinotecan plus fluorouracil and leucovorin for advanced biliary tract cancer.

Objectives: The primary objective of this study is to determine the objective response rate. The second objectives of this study are overall survival, progression-free survival, disease control rate, and adverse event incidence rate.

Design: The study is a single-arm, prospective phase II clinical trial. In all, 51 patients who are diagnosed with locally advanced or metastatic bile tract cancer will be enrolled.

Methods and analysis: Eligible participants will receive cadonilimab at a dosage of 6 mg/kg on day 1 of each 21-day cycle combined with intravenous liposomal irinotecan at a dosage of 70 mg/m² for 90 min on day 1 plus leucovorin at a dosage of 400 mg/m² for 30 min on day 1 and fluorouracil at a dosage of 400 mg/m² for 46 h every 2 weeks.

Discussion: Previous studies have suggested that there is a synergistic effect between the two treatment modalities. However, the potential of cadonilimab in bile tract cancer has not been explored. Hence, this trial is the first to investigate its efficacy and toxicity. In addition, the trial is also willing to explore potential biomarkers in patients with locally advanced and metastatic bile tract cancer.

Trial registration: This study was registered on ClinicalTrials.gov with NCT06438822.

Ethics: This study protocol and amendments have been approved by the Ethics Committee of West China Hospital (2024(791)).

Background: Increasingly, more evidence has shown that inflammation stress and the tumor microenvironment pose a negative effect on targeted therapy. The neutrophil-to-lymphocyte ratio is considered to be a surrogate biomarker of inflammation and can predict pazopanib treatment effect in non-adipocytic soft-tissue sarcoma (STS). The role of the pan-immune-inflammation value (PIV) in STS is still yet to be determined.

Objectives: We sought whether the pre-treatment PIV could be applied to predict the response of pazopanib in STS.

Design: We conducted a retrospective analysis of 75 patients who had been treated with pazopanib for recurrent or metastatic non-adipocytic STS.

Methods: Our cohort was stratified into either a pre-treatment high PIV group with PIV ⩾310 (n = 45) or a low PIV group with PIV <310 (n = 30). We compared their clinical features and outcomes. Cox regression analysis was employed to determine the risk factors of disease progression and mortality. Kaplan-Meier survival curves were utilized to assess both the progression-free survival (PFS) and overall survival (OS).

Results: The results revealed that a pre-treatment high PIV (⩾310) is a risk factor for progression under pazopanib (hazard ratio: 1.91; 95% confidence interval: 1.08-3.36; p = 0.025). The median PFS and OS of the pre-treatment high PIV group were found to be significantly lower than the low PIV group (0.33 vs 0.75 years; p = 0.023, 0.46 vs 1.63 years; p = 0.025).

Conclusion: High pre-treatment PIV in STS patients may indicate an elevated risk of disease progression and mortality. Pre-treatment PIV reflects inflammation stress and acts as a practical biomarker for STS patients treated with pazopanib.