Therapeutic Advances in Medical Oncology最新文献

Background: Hematoxylin and eosin (H&E) staining is routine in pathology but lacks cellular specificity. Multiplex immunofluorescence (mIF) captures spatial immune relationships in tumors, but cost and complexity limit clinical application. Novel approaches to yield similar information from readily available tumor histology are needed.

Objectives: Develop and validate a novel deep learning tool capable of translating standard H&E-stained histopathology images into high-fidelity synthetic mIF images that preserve immune cell information predictive of treatment response in breast cancer.

Design: Comparative model evaluation and predictive modeling in a retrospective breast cancer cohort.

Methods: Core-needle biopsies from 17 triple-negative breast cancer cases underwent mIF imaging. Hematoxylin and eosin and mIF images for DAPI (nuclei), pan-CK (tumor), CD3/CD4/CD8 (T-cells), and CD20 (B cells) were aligned. A pipeline outperforming standard Pix2Pix and CycleGAN image translation networks was developed, "multiplex Synthetic Immunofluoresence Generated through H&E Translation" (mSIGHT), which integrates a registration network to overcome misalignment between the input and target images. Generated images were evaluated with pixel-level metrics and biological metrics, including cell density and cell-to-cell adjacency. The pipeline was then applied to an external cohort to assess associations between predicted immune features and pathologic response to neoadjuvant chemotherapy.

Results: Generated images preserved immune cell distributions and proximity metrics correlated to the ground truth cell counts. In a cohort of 218 breast cancer cases treated with neoadjuvant chemotherapy, predicted density of CD8+ T cells was significantly associated with complete response (adjusted odds ratio 1.89, 95% confidence interval 1.23-2.80, p = 0.002), independent of receptor status, grade, and pathologist TIL annotations.

Conclusion: The mSIGHT pipeline enables translation of routine H&E slides into virtual mIF images with interpretable immune biomarkers, offering a scalable and affordable alternative to multiplex imaging. It also identifies immune features predictive of therapeutic response and has the potential to assist in the personalization of neoadjuvant therapy.

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Background: Soft tissue sarcomas (STS) are rare, heterogeneous tumors with poor prognosis, often characterized by high recurrence rates and limited response to conventional chemotherapy in advanced stages. Vascular-targeting agents (VTA) have shown promising efficacy for STS in numerous clinical trials; however, the optimal agent and combination strategies remain undetermined.

Objectives: This work aims to compare the clinical efficacy and adverse events of different VTA-containing regimens for patients with STS.

Design: This study is a systematic review and network meta-analysis.

Data sources and methods: We searched PubMed, Embase, and the Cochrane Library for eligible randomized clinical trials. All trials with VTA as monotherapy or VTA-included regimens in the experimental or control groups were selected, except for some specific histological subtypes. Pooled hazard ratios (HRs) for survival data and odds ratios for objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events with credible intervals were generated using R software. A Bayesian random-effects model was applied to rank different treatments based on the surface under the cumulative ranking curve (SUCRA) values.

Results: Seventeen articles covering 15 studies were included. Pairwise comparisons demonstrated prolonged progression-free survival (PFS) for tyrosine kinase inhibitor (TKI) versus placebo (HR 0.50, 95% confidence interval (CI) 0.32-0.83) and prolonged overall survival (OS) for monoclonal antibody plus chemotherapy versus placebo (HR 0.42, 95% CI 0.19-0.89). Vascular-disrupting agents (VDA) plus chemotherapy were ranked highest for OS (87.05%) and ORR (89.66%). TKI plus chemotherapy and TKI plus immunotherapy had higher SUCRA values for PFS (68.21%) and DCR (82.29%). TKI-based regimens were associated with higher incidences of hypertension, diarrhea, and elevated transaminase levels, whereas chemotherapy-based strategies resulted in higher incidences of hematological toxicity and constipation.

Conclusion: VTA-containing regimens showed promising activity and tolerability in patients with advanced STS. Combination regimens with TKI showed better efficacy for PFS and DCR. Novel VDA combined with chemotherapy showed potential to prolong OS and improve ORR.

Trial registration: PROSPERO website (registration number: CRD42024588134).

Background: Immunotherapy combinations like Pembrolizumab + Axitinib and Nivolumab + Ipilimumab have survival benefits over Sunitinib in advanced renal cell carcinoma (aRCC) first-line treatment. But their cost-effectiveness in the USA and China is unclear.

Objectives: To assess the cost-effectiveness of three first-line treatment regimens for untreated aRCC-Nivolumab plus Ipilimumab, Pembrolizumab plus Axitinib, and Sunitinib-from the perspective of national health service systems and indirect healthcare payers in China and the USA, with a focus on intent-to-treat (ITT) populations and International mRCC Database Consortium (IMDC) risk stratifications.

Design: Decision-tree and Markov models, based on KEYNOTE-426 and CheckMate 214 trials, simulated 5-year disease progression of eligible patients.

Methods: The model, constructed using TreeAge Pro 2022 (TreeAge Software, LLC, Williamstown, Massachusetts, USA), incorporated three health states: progression-free survival, progressive disease, and death. Economic parameters included direct medical costs (first-line and second-line treatments, adverse event management, monitoring), quality-adjusted life year (QALYs), and incremental cost-effectiveness ratios (ICERs). Probabilistic sensitivity analysis was performed to evaluate model uncertainty.

Results: Across favorable-risk, intermediate/poor-risk IMDC subgroups, and the ITT population, Nivolumab plus Ipilimumab sequential Cabozantinib demonstrated the optimal cost-effectiveness in both countries, with ICERs below the willingness-to-pay (WTP) thresholds. It was associated with lower costs and higher QALYs compared to the other two regimens. Pembrolizumab plus Axitinib sequential Cabozantinib was more cost-effective than sunitinib sequential Cabozantinib in both regions, with ICERs also below WTP thresholds.

Conclusion: In China and the USA, Nivolumab plus Ipilimumab is the most cost-effective first-line treatment for aRCC across different IMDC subgroups and the ITT population, followed by Pembrolizumab plus Axitinib, which outperforms sunitinib. These findings can guide clinical decision-making, though their generalizability is limited to China and the USA due to regional differences in drug pricing, payment systems, and market access.

Background: Despite advanced in systemic therapy for renal cell carcinoma (RCC), bone metastasis remains an adverse prognostic factor and major cause of mortality and morbidity. Orthopedic interventions may provide symptom relief, functional recovery, and survival benefit, yet the evidence is fragmented across heterogeneous studies.

Objectives: To systematically review the outcomes of orthopedic surgical interventions in patients with symptomatic bone metastases from RCC.

Design: Systematic literature review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Data sources and methods: A comprehensive search of Embase, MEDLINE, and the Cochrane Library was conducted for studies published between January 1, 2014, and January 30, 2024. Eligible studies included randomized controlled trials, prospective observational studies, and retrospective studies reporting on orthopedic interventions for RCC bone metastases. Primary outcomes included overall survival, reoperation rates, complication rates, and quality of life.

Results: Of 2208 studies screened, 15 met the inclusion criteria. All were retrospective series or case series, limiting the strength of the evidence. Six studies focused on appendicular skeleton metastases, five on axial skeleton involvement, and four on both regions. Results were primarily reported narratively, with limited statistical analyses. Orthopedic surgical interventions-particularly when combined with targeted systemic therapy-were associated with longer overall survival. Among surgical approaches, complete metastasectomy was most consistently associated with improved survival compared with intralesional curettage and stabilization-only procedures.

Conclusion: Although available data suggest that orthopedic surgery, particularly complete metastasectomy, may improve overall survival and quality of life in RCC patients with bone metastases, the evidence is limited to retrospective and narrative reports. Some studies also suggest that outcomes may be further enhanced when surgery is integrated with systemic therapy. Given the poor prognosis associated with bone involvement in RCC, prospective randomized studies are urgently needed to define optimal patient selection, standardize management strategies, and integrate surgery with systemic therapy in a multidisciplinary framework.

Background: As metastasis drives the majority of breast cancer-related deaths, improving outcomes for metastatic breast cancer (MBC) remains a crucial challenge. Observational studies using target trial emulation are increasingly applied to estimate treatment effects, providing insights when randomized trials are not viable.

Objectives: To estimate the effect of progression-free survival (PFS) of metronomic chemotherapy of weekly paclitaxel plus cisplatin (DP) compared with treatment of the physician's choice (TPC) for MBC.

Design: This analysis was designed as a retrospective cohort study according to STROBE criteria.

Methods: This retrospective cohort study compared metronomic chemotherapy of weekly DP versus TPC in MBC. The DP regimen included paclitaxel (80 mg/m²) on days 1, 8, 15, 22 and cisplatin (25 mg/m²) on days 1, 8, 15 in a 28-day cycle. Women aged ⩾18 years with MBC treated with at least one prior therapy between April 2014 and January 2023 at Renji Hospital were included. Propensity score matching (1:3) adjusted for confounding. The matched cohort subsequently underwent emulation of a randomized target trial, including cloning, censoring and weighting. The primary endpoint was PFS.

Results: Among 313 matched patients (83 on DP, 230 on TPC), DP showed a median PFS of 13.5 months (95% CI 10.3-16.6) versus 7.9 months (95% CI: 6.7-9.1) for TPC (hazard ratio (HR) 0.77, 95% CI 0.60-0.99). Target trial emulation further improved PFS in the DP arm to 14.1 months (95% CI: 13.3-16.6) versus 8.3 months (95% CI: 8.0-8.6) for TPC (HR 0.59, 95% CI: 0.54-0.64). Subgroup analysis and sensitivity analyses confirmed result robustness.

Conclusion: This study demonstrates that weekly metronomic DP chemotherapy reduces disease progression in MBC patients, particularly in first-line settings. These findings support its potential as a treatment option and warrant further study for broader application.

Background: The management of hormone receptor-positive (HR+), HER2-negative early breast cancer in young women presents unique challenges due to the absence of standardized guidelines and variability in clinical decision-making. In Latin America, these challenges are compounded by disparities in healthcare systems and limited access to genomic testing and supportive services.

Objectives: To evaluate current attitudes, diagnostic strategies, and treatment practices among Latin American oncologists regarding the care of young women with HR+ early breast cancer.

Design: A cross-sectional survey study targeting practicing oncologists across Latin America.

Methods: A 30-item online questionnaire was distributed to 329 oncologists from 17 Latin American countries. The survey explored physician demographics, access to diagnostic tools, treatment preferences, and availability of support services, including genetic counseling and fertility preservation.

Results: The findings revealed significant heterogeneity in clinical practices. Among patients with a Recurrence Score (RS) of 20-25, 53.8% of oncologists recommended adjuvant chemotherapy, while 23.4% considered additional clinicopathologic features. Fertility preservation counseling was inconsistently offered: 29.5% provided it routinely, whereas 12.5% never did. Ovarian function suppression (OFS) was universally recommended by 46.2% of respondents, with breast cancer specialists showing more nuanced use than non-specialists (p = 0.019). Access to genetic counseling was limited, with 12.5% reporting no access. Temporary interruption of endocrine therapy to pursue pregnancy was supported by 41.0% of respondents, though approaches varied. Female oncologists were more likely to recommend extended endocrine therapy (73.2% vs 60.8%, p = 0.019) and to refer patients for sexual health support (19.3% vs 8.7%, p = 0.05).

Conclusion: This study highlights considerable variability in the management of young women with HR+ early breast cancer across Latin America. Physician gender, specialty, and resource availability significantly influence treatment decisions. These findings underscore the urgent need for regionally tailored clinical guidelines and improved access to diagnostic and supportive care resources to ensure equitable and evidence-based care.

Background: Inflammatory breast cancer (IBC) is rare but aggressive, characterized by the rapid onset of diffuse skin erythema, edema, tenderness, induration, and fast metastasis. Both hormone receptor positive (HR+) and human epidermal receptor 2 positive (HER2+) are associated with inferior response after neoadjuvant systemic therapy (NAST) compared to non-IBC. Despite multimodal treatment approaches, the 3-year overall survival rate for stage III IBC remains low at approximately 74%, around 10% lower than the 83% for non-IBC.

Objectives: To evaluate whether the addition of neratinib, an irreversible pan-ErbB receptor small molecule tyrosine kinase inhibitor, improves the rate of pathological complete response in both HER2+ and HR+/HER2- IBC in neoadjuvant therapy, and to assess safety and explore biomarkers associated with response.

Design: This is a phase I/II (HER2+; cohort 1) and II (HR+/HER2-; cohort II trial conducted at a single center.

Methods: Pathological response was assessed using the pathological complete response (pCR) and residual cancer burden (RCB) criteria as the primary efficacy endpoint. Safety and biomarkers were assessed.

Results: In cohort 1, dose-limiting toxicities were Grade 2/3 diarrhea. Among the 10 evaluable patients from cohort 1 who underwent surgery, 5 achieved pCR (50%); in the intention-to-treat population of all 14 patients (counting drop-outs as nonresponders), the pCR rate was 36%. In cohort 2, 16 patients were enrolled, and 1 (6%) achieved pCR. Common adverse events (AEs) included Grade 2 alopecia, Grade 2/3 diarrhea, anemia, nausea, and neutropenia. High toxicity led to early closure of accrual. The median event-free survival in cohort 2 was 27.5 months, and was not reached for cohort 1 by data cutoff. Biomarker analysis showed that good responders (pCR + RCB-I) in both cohorts exhibited upregulation of immune-activating pathways, including interferon signaling and cytotoxic T-cell markers. By contrast, poor responders (RCB-II + RCB-III) showed immune-suppressive features, increased angiogenesis, proliferation, and anti-apoptotic gene expression.

Conclusion: The addition of neratinib to neoadjuvant therapy showed potential in improving the pCR rate in HER2+ IBC (36% in this study) but not in HR+/HER2- (6%), though high toxicity was a major limiting factor. Further research is needed to optimize the balance between efficacy and safety. Biomarker analysis uncovered interesting new hypothesis-generating data warranting future study in IBC.

Trial registration: ClinicalTrials.gov NCT03101748.

Background: Afatinib's efficacy and dose-adjustment strategies have been validated in clinical trials and increasingly supported by real-world evidence.

Objectives: This study aimed to provide additional real-world insights into afatinib use and to assess the impact of initial dosing and subsequent dose modifications on treatment outcomes and tolerability in patients with advanced epidermal-growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).

Design: We conducted a multicenter retrospective analysis of patients with advanced EGFR-mutated NSCLC who received first-line afatinib between April 2018 and June 2022.

Methods: Patients were categorized into four subgroups based on their starting and optimal afatinib doses. The primary endpoints were to analyze the association between afatinib dosing and time-to-treatment failure (TTF), overall survival (OS), and toxicity.

Results: A total of 343 patients were included. The most common starting afatinib dose was 30 mg (58.6%), followed by 40 mg (39.9%). The optimal dose maintained during treatment was 30 mg in 62.1% of patients, 40 mg in 33.2%, and 20 mg in 4.7%. Dose reductions due to toxicity occurred in 23.6% of cases. Regarding four subgroups: 53.1% of patients started and remained on <40 mg, 25.4% started and maintained 40 mg, 14.6% started at 40 mg but de-escalated to <40 mg, and 7.0% started <40 mg and escalated to 40 mg. After a median follow-up of 36.8 months, the median OS for all patients was 31.3 months (95% confidence interval: 29.3-33.1). Multivariate Cox regression analysis identified smoking status, Eastern Cooperative Oncology Group performance status, and EGFR mutation subtype as independent prognostic factors for OS. Notably, patients who initiated treatment at 40 mg but de-escalated to <40 mg had the longest median TTF and OS. In terms of safety, the highest incidence of adverse events was observed in this group, followed by those who started and remained at <40 mg.

Conclusion: In this real-world cohort, flexible afatinib dosing-either by initiating at 40 mg followed by dose reduction or starting at <40 mg with later escalation-was associated with favorable survival outcomes and manageable tolerability. These findings support the use of individualized afatinib dosing strategies to optimize both efficacy and safety in patients with EGFR-mutant NSCLC.