Therapeutic Advances in Medical Oncology最新文献

Background: The emergence of new antileukemic drugs, including Bruton tyrosine kinase inhibitors (BTKis), phosphoinositide 3-kinase inhibitors (PI3Kis), and B-cell lymphoma 2 antagonists (BCL-2a), has significantly improved the outcomes for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Despite advances in treatment efficacy, the comprehensive safety profile of these novel agents versus traditional chemotherapy and immunotherapy has not been adequately explored, and there have been few direct comparisons.

Objectives: This study aimed to compare the safety profiles of novel therapeutic agents, chemotherapy, and immunotherapy in patients with relapsed/refractory CLL using a Bayesian network meta-analysis (NMA).

Methods: A systematic literature review was conducted to identify randomized clinical trials on relapsed/refractory CLL. The search encompassed major medical databases (MEDLINE, Embase, and CENTRAL) and gray literature, with the aim to integrate the findings into a Bayesian NMA framework for safety outcome assessment.

Design: Systematic literature review with Bayesian NMA.

Results: The systematic search identified 14 randomized trials that formed networks for the comparison of safety outcomes. No differences were shown between therapies in terms of overall adverse events (AEs). However, bendamustine + rituximab had a more favorable safety profile for grade ⩾3 AEs when compared with ibrutinib (risk ratio 0.62 (95% credible interval 0.40-0.86)), acalabrutinib (0.69 (0.45-0.94)), zanubrutinib (0.64 (0.42-0.91)), and venetoclax + rituximab (0.87 (0.79-0.96)). The frequency of grade ⩾3 AEs, serious AEs, and treatment discontinuations and deaths due to AEs was comparable between acalabrutinib, zanubrutinib, and venetoclax + rituximab. There were no significant differences in the safety profiles regarding hematological events, events affecting the quality of life, and infections for most comparisons of venetoclax + rituximab with BTKis. Among BTKi-specific events, zanubrutinib was associated with a higher risk of hypertension (2.96 (1.74-5.16)) and bleeding (1.38 (1.06-1.81)) than acalabrutinib. No differences in the risk of atrial fibrillation were found between acalabrutinib and zanubrutinib (1.56 (0.74-3.34)).

Conclusion: Our findings showed that venetoclax + rituximab, acalabrutinib, and zanubrutinib have acceptable safety profiles, which indicates that they may be the preferred therapeutic options in the setting of relapsed/refractory CLL.

Trial registration: PROSPERO CRD42022304330.

Background and objectives: To evaluate the prognostic value of an integrated model consisting of tumour response to induction chemotherapy (IC) and gross tumour volume (GTV) after IC in nasopharyngeal carcinoma (NPC) and elucidate optimal cumulative cisplatin dose (CCD) in concurrent chemoradiotherapy (CCRT) for different subgroups.

Design and methods: This retrospective study enrolled 896 patients with NPC diagnosed from 2010 to 2017 receiving IC plus radiotherapy. The primary endpoint was disease-free survival (DFS). Cut-off points for GTV were combined with IC response to develop an integrated model. Propensity score matching (PSM) was used to adjust for potential confounders. Survival outcomes and acute toxicity were compared between the different CCD groups.

Results: Unsatisfactory IC response and large GTV after IC were correlated with poor survival outcomes; the AUC increased to 0.668 when these factors were incorporated. The integrated model classified patients into three groups. After PSM, radiotherapy alone and CCRT demonstrated similar efficacy in the low-risk group (complete response (CR)/partial response (PR) and GTV <68 cm³ after IC). In the intermediate-risk group (CR/PR but GTV ⩾68 cm³), CCD of >200 mg/m² and 101-200 mg/m² increased the 5-year DFS rates (83.7% vs 81.1% vs 65.3%, p = 0.042). In the high-risk group (stable disease/progressive disease and any GTV), the use of different CCDs did not result in significantly different survival outcomes (p = 0.793). Additionally, high CCD was significantly associated with increased incidence of grade 1-4 acute toxicity.

Conclusion: The integrated model incorporating IC response and GTV after IC demonstrates satisfactory value in risk stratification and the potential to guide individualised decision-making in CCD selection. Balancing toxicity and efficacy, RT alone seems to be the optimal treatment for patients in low-risk groups and 200 mg/m² might be the optimal dose for intermediate-risk groups. Moreover, increasing CCD does not benefit patients in high-risk groups, and treatment options for these patients require further consideration.

The assessment of response to therapy in prostate cancer (PCa) patients is an ongoing, open issue. Prostate-specific antigen has limitations, especially in advanced metastatic PCa, which often displays intratumor variability in terms of response to therapy. Conventional imaging (i.e. computerized tomography and bone scan) is of limited use for its low sensitivity and specificity. Positron-emission tomography (PET) with prostate-specific membrane antigen (PSMA) demonstrated higher sensitivity and specificity, and novel PSMA-based criteria have been recently proposed for treatment response, with promising results in different scenarios, from chemotherapy to radioligand therapy. PSMA-based criteria have been found to outperform the current RECIST 1.1 and Prostate Cancer Working Group 3 frameworks in describing the behavior of PCa, precisely assessing tumor phenotypes through molecular-imaging-derived parameters. This review critically explores the current evidence about the role of PSMA PET/computed tomography in the assessment of treatment response.

Background: Many studies show that camrelizumab combination therapy can significantly improve progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC). However, the time of camrelizumab to market is short, and there is no systematic evaluation of camrelizumab-based comprehensive treatment of NSCLC.

Objectives: To systematically evaluate the efficacy and safety of camrelizumab in comprehensively treating NSCLC.

Design: A systematic review and meta-analysis.

Data sources and methods: Databases, including PubMed, Web of Science, Embase, and Cochrane, were searched by computer before August 2023 based on Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, and reports on the efficacy and safety of camrelizumab-based treatment for NSCLC were collected, and RevMan 5.4 software was employed for meta-analysis finally.

Results: Totally, 5 RCTs, 2 cohort studies, and 12 single-arm studies were included. The meta-analysis results revealed that, compared with the treatment without camrelizumab, the camrelizumab-based combination treatment considerably extended the OS (hazard ratio (HR) = 0.60, 95% confidence interval (CI): (0.44-0.82), p < 0.01), PFS (HR = 0.42, 95% CI: (0.28-0.63), p < 0.01), and event-free survival (EFS) (HR = 0.55, 95% CI: (0.44-0.68), p < 0.01). The median objective response rate in single-arm studies was 41% (95% CI: 28%-53%), and the disease control rate was 84% (95% CI: 78%-89%). Furthermore, in terms of the occurrence of grades 3-5 adverse events, the incidence of neutropenia was lower in the camrelizumab combination group than in the control group, while the incidence of leukopenia and rash was higher than in the combination group, and no significant difference was revealed in the incidence of other adverse events. Among single-arm studies, the incidence of grades 3-5 adverse events did not exceed 10%.

Conclusion: Treatment combined with camrelizumab can effectively prolong OS, PFS, and EFS in NSCLC patients with good safety, camrelizumab combined with chemotherapy is an effective treatment option for NSCLC patients.

Pancreatic cancer (PC) is an aggressive disease that is challenging to treat and is associated with a high mortality rate. The most common type of PC is pancreatic ductal adenocarcinoma (PDAC), and the existing treatment options are insufficient for PDAC patients. Due to the complexity and heterogeneity of PDAC, personalized medicine is necessary for effectively treating this illness. To achieve this, it is essential to understand the mechanism of PDAC carcinogenesis. Targeted therapies are a promising strategy to improve patient outcomes. Aberrant activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a crucial role in PC pathogenesis, from initiation to progression. This review provides a comprehensive overview of the current state of knowledge regarding the PI3K pathway in PDAC, summarizes clinical data on PI3K pathway inhibition in PDAC, and explores potential effective combinations that are a promising direction requiring further investigation in PDAC.

Background: Neoadjuvant (NE), adjuvant (AD), and perioperative (PE) immunotherapies have gained validation in early-stage non-small cell lung cancer (NSCLC) trials. However, a comprehensive assessment of their comparative efficacy and safety is lacking.

Objectives: To compare the efficacy and safety of NE, AD, and PE immunotherapies in early-stage NSCLC.

Design: A systematic review and network meta-analysis using a Bayesian framework.

Data sources and methods: We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCTs) of immune checkpoint inhibitors plus chemotherapy (CT) for early-stage NSCLC. Hazard ratios (HRs) and odds ratios (ORs) for binary endpoints with 95% confidence intervals (CIs) were calculated.

Results: We included 10 RCTs involving 5569 NSCLC patients, categorized as NE, PE, or AD immunotherapy. Indirect comparisons highlighted differences in efficacy between PE and AD immunotherapy, specifically in event-free survival (EFS)/disease-free survival (DFS) (HR = 0.72, 95% CI: 0.53-0.96). NE/PE immunotherapies improved pathologic complete response (pCR) (OR = 7.56, 95% CI: 5.24-10.92), major pathologic response (MPR) (OR = 5.46, 95% CI: 3.97-7.51), and EFS (HR = 0.58, 95% CI: 0.52-0.65), while AD immunotherapy enhanced DFS (HR = 0.78, 95% CI: 0.69-0.90). Overall survival (OS) benefits were seen only with PE immunotherapy (HR = 0.66, 95% CI: 0.55-0.81). PE treatment improved EFS across various subgroups (PD-L1 < 1%, IIIB, squamous, female, without MPR/pCR, epidermal growth factor receptor (EGFR) mutant-negative), except EGFR mutant-positive NSCLC (HR = 0.54, 95% CI: 0.21-1.43). AD (OR = 1.81, 95% CI: 1.20-2.73) and PE (OR = 1.28, 95% CI: 1.10-1.50) immunotherapies were associated with higher grade ⩾3 adverse events.

Conclusion: In the three treatment modalities, PE immunotherapy appears to be more effective than AD immunotherapy, with PE showing significant advantages in certain subgroups that NE does not. NE and PE immunotherapy significantly improved pCR, MPR, and EFS, while AD immunotherapy significantly improved DFS in NSCLC patients compared to the control group. However, only PE immunotherapy significantly improved OS. Differences in efficacy between NE and PE across the entire population of resectable NSCLC remain to be explored in additional studies.

Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown.

Design: Retrospective cohort study.

Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations.

Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens.

Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p < 0.001) regimens. The survival benefit of ASP/GEM-based regimens over other ASP-based regimens was substantial across risk-stratified and advanced-stage subgroups. The survival benefits of a combination of RT, ASP, and GEM were consistent after adjustment for confounding factors by IPTW.

Conclusion: These results suggest that combining ASP/GEM with RT for ENKTCL is an efficacious and feasible therapeutic option and provides a rationale and strategy for developing combination therapies.

Radioembolization is a locoregional transarterial therapy that combines radionuclide and micron-sized beads to deliver radiation internally to the target tumors based on the arterial blood flow. While initially developed as a palliative treatment option, radioembolization is now used for curative intent treatment, neoadjuvant therapy, and method to downstage or bridge for liver transplant. Radioembolization has become increasingly utilized and is an important therapeutic option for the management of hepatocellular carcinoma and liver metastasis. This article provides an overview of the techniques, challenges, and novel developments in radioembolization, including new dosimetry techniques, radionuclides, and new target tumors.

Among women, breast cancer is the most prevalent form of a malignant tumour. Among the subtypes of breast cancer, hormone receptor (HR) positive and human epidermal growth factor receptor (HER2) negative kinds make up the biggest proportion. The advent of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, which are dependent on cell cycle proteins, has greatly enhanced the prognosis of patients with advanced HR+/HER2- breast cancer. This is a specific treatment that stops the growth of cancer cells by preventing them from dividing. Nevertheless, the drug resistance of the disease unavoidably impacts the effectiveness of treatment and the prognosis of patients. This report provides a thorough analysis of the current research advancements about the resistance mechanism of CDK4/6 inhibitors in HR+/HER2- breast cancer. It presents an in-depth discussion from numerous viewpoints, such as aberrant cell cycle regulation and changes in signalling pathways. In response to the drug resistance problem, subsequent treatment strategies are also being explored, including switching to other CDK4/6 inhibitor drugs, a combination of novel endocrine therapeutic agents, an optimal combination of targeted therapies and switching to chemotherapy. An in-depth study of the resistance mechanism can assist in identifying creative tactics that can overcome or postpone drug resistance, alleviate the problem of restricted treatment strategies following drug resistance and enhance the prognosis of patients.

Background: In Part 1 of the phase III RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer (EC), dostarlimab plus carboplatin-paclitaxel (CP) significantly improved progression-free survival and overall survival compared with CP alone. Limited safety data have been reported for the combination of immunotherapies plus chemotherapy in this setting.

Objectives: The objective of this analysis was to identify the occurrence of treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) and to describe irAE management in Part 1 of the RUBY trial.

Design: RUBY is a phase III, randomized, double-blind, multicenter study of dostarlimab plus CP compared with CP alone in patients with primary advanced or recurrent EC.

Methods: Patients were randomized 1:1 to dostarlimab 500 mg, or placebo, plus CP every 3 weeks for 6 cycles, followed by dostarlimab 1000 mg, or placebo, every 6 weeks for up to 3 years. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events, version 4.03.

Results: The safety population included 487 patients who received ⩾1 dose of treatment (241 dostarlimab plus CP; 246 placebo plus CP). Treatment-emergent AEs were experienced by 100% of patients in both arms. TRAEs occurred in 97.9% of the dostarlimab arm and 98.8% of the placebo arm.The most common TRAEs occurred at similar rates between arms and were mostly low grade. IrAEs occurred in 58.5% of patients in the dostarlimab arm and 37.0% of patients in the placebo arm. Dostarlimab- or placebo-related irAEs were reported in 40.7% of patients in the dostarlimab arm and 16.3% of the placebo arm.

Conclusion: The safety profile of dostarlimab plus CP was generally consistent with that of the individual components. Dostarlimab plus CP has a favorable benefit-risk profile and is a new standard of care for patients with primary advanced or recurrent EC.

Trial registration: NCT03981796.