Therapeutic Advances in Medical Oncology最新文献

Background: Induction chemotherapy (IC) regimens such as gemcitabine plus cisplatin (GP), docetaxel plus cisplatin plus fluorouracil (TPF), and paclitaxel plus cisplatin (TP) are optional clinical options for locoregionally advanced nasopharyngeal carcinoma (LA-NPC).

Objectives: This study aims to evaluate the efficacy and toxicity profiles of the GP, TPF, and TP induction regimens in LA-NPC.

Design: This was a retrospective study.

Methods: This multicenter retrospective study enrolled 722 patients with stage III-IVA LA-NPC who received GP, TPF, or TP IC. Propensity score matching (PSM) was performed before comparing survival outcomes and acute grades 3-4 toxicities among the three groups. Survival outcomes included the overall survival (OS), failure-free survival (FFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS).

Results: The original cohort comprised 722 patients (247 in the GP group, 240 in the TPF group, and 235 in the TP group). After PSM analysis, the GP group showed a better 3-year OS rate than the TP group (p = 0.019), while the 3-year OS rate revealed no difference between the GP group and TPF group and between the TPF group and TP group. There were no significant differences in the 3-year FFS, 3-year LRFS, and 3-year DMFS rates between and within the three groups. During the induction period, the toxicity of the three regimens was generally acceptable and manageable.

Conclusion: The GP induction regimen demonstrated superior efficacy in terms of OS, with its favorable safety profile. Compared with the TPF and TP regimens, the GP induction regimen represents a more clinically advantageous treatment option for LA-NPC.

Background: Circulating tumor DNA (ctDNA) is predictive of recurrence in resected stage III melanoma, yet its role in the neoadjuvant setting for clinical stage III (cSIII) is unclear.

Objective: Assess the association between ctDNA and outcomes following neoadjuvant immunotherapy (IO) + targeted therapy (TT) in cSIII melanoma.

Design: Patients in the NeoACTIVATE study were treated with neoadjuvant IO + TT, underwent lymphadenectomy, and received adjuvant immunotherapy.

Methods: Patients with ctDNA testing performed at baseline, pre- and post-operation were analyzed. Baseline positron emission tomography-computed tomography volumetrics and surgical, major pathological responses (MPR) were assessed.

Results: Thirteen patients had serial ctDNA, 10 (77%) were detectable at baseline, and 9/10 (90%) had ctDNA clearance. Seven (54%) achieved MPR, all with undetectable preoperative ctDNA, yet 3/7 (43%) had disease recurrence.

Conclusion: ctDNA and MPR are poor predictors of recurrence following neoadjuvant IO + TT for cSIII melanoma patients. Further studies are warranted to define the role of ctDNA in this setting.

Background: Postoperative early recurrence (PER) remains a major challenge to long-term survival after successful conversion therapy and curative resection for initially unresectable colorectal liver metastases (CRLM). Existing prediction models rely heavily on clinicopathological parameters and lack molecular biomarkers, limiting their predictive accuracy.

Objectives: To define the optimal recurrence-free survival (RFS) cutoff for PER and develop a comprehensive predictive nomogram incorporating molecular and clinical variables to predict PER in patients with initially unresectable CRLM who undergo curative resection following conversion therapy.

Design: Retrospective cohort study.

Methods: Clinicopathological and molecular data from 411 patients with initially unresectable CRLM undergoing curative resection after conversion therapy were analyzed. The minimum p value approach determined the optimal RFS cutoff for PER. Least absolute shrinkage and selection operator regression identified significant predictors, followed by multivariate logistic regression to build a nomogram. Model performance was assessed using the area under the curve (AUC), calibration curves, and decision curve analysis (DCA).

Results: PER was defined as recurrence within 4 months postoperatively. Independent predictors included dual preoperative positivity for CEA and CA19-9 (odds ratio (OR) = 2.437, p < 0.001), number of liver metastases (OR = 1.061, p < 0.001), tumor progression during the chemotherapy-to-surgery interval (OR = 2.837, p = 0.003), KRAS exon 2 mutations (OR = 1.927, p = 0.006), and BRAF V600E mutations (OR = 2.410, p = 0.002). An AUC of 0.703 (95% confidence intervals (CI): 0.650-0.756) was achieved, with an internal validation AUC of 0.697 (95% CI: 0.670-0.723). Calibration curves showed good agreement (p > 0.05), and DCA indicated clinical benefit at recurrence risk thresholds above 30%.

Conclusion: We identified 4 months as the optimal RFS threshold for PER and proposed a novel nomogram integrating molecular and clinical factors for perioperative decision-making in patients with initially unresectable CRLM.

Background: The benefit of adding immunotherapy to induction chemotherapy before definitive chemoradiotherapy (CRT) in older patients with unresectable stage III non-small-cell lung cancer (NSCLC) remains unclear.

Objectives: This real-world study aimed to evaluate the efficacy and safety of induction chemoimmunotherapy followed by CRT in this patient population.

Design: A real-world multicenter study.

Methods: In this retrospective, multicenter study, we enrolled patients aged ⩾65 years with unresectable stage III NSCLC who received CRT between January 2014 and June 2024. Patients were stratified into two groups: the induction chemoimmunotherapy group (I-CRT), who received PD-1/PD-L1 inhibitors plus chemotherapy before CRT, and the control group (Non-I-CRT), who received CRT without any prior immunotherapy. Propensity score matching (PSM) was used to balance baseline characteristics. The primary endpoints were progression-free survival (PFS) and overall survival (OS).

Results: Among 260 patients, 141 received I-CRT and 119 constituted the Non-I-CRT control group. After 1:1 PSM (97 patients per group), the I-CRT group showed significantly improved outcomes compared to the Non-I-CRT group: median PFS was 23.4 versus 11.6 months (p < 0.001), and median OS was 46.0 versus 24.4 months (p = 0.009). The incidence of Grade 3/4 adverse events was comparable between the matched groups (20.6% vs 28.9%, p = 0.52).

Conclusion: Induction chemoimmunotherapy before CRT is feasible in selected older NSCLC patients, offering survival benefits without significant safety concerns.

Early-stage (I-III) non-small cell lung cancer (NSCLC) can harbor oncogenic driver mutations that have critical implications for patient management and outcomes. Historically, molecular testing in resected NSCLC was limited, often focusing only on EGFR mutations or ALK rearrangements due to the lack of approved targeted therapies in the adjuvant setting until recently. However, with the advent of next-generation sequencing (NGS) and emerging evidence of actionable mutations in early-stage tumors, comprehensive genomic profiling is becoming increasingly relevant in this setting. Identifying these alterations is clinically significant: the presence of specific mutations can directly influence adjuvant treatment planning and refine the role of immunotherapy. Beyond guiding therapy selection, molecular profiles also provide prognostic insight: certain driver subtypes have been associated with higher recurrence risk in early-stage patients, suggesting a need for intensified surveillance. The expanding role of NGS enables personalized postoperative strategies, including tailored follow-up intervals and potential circulating tumor DNA monitoring to detect minimal residual disease. In summary, incorporating broad molecular testing in early-stage NSCLC empowers clinicians to optimize adjuvant treatment decisions and surveillance strategies, ultimately aiming to improve patient outcomes through precision oncology.

Locally advanced rectal cancer (LARC) presents a significant burden on lower gastrointestinal diseases, with current treatment strategies primarily involving neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery. However, patient responses to nCRT exhibit significant variability, highlighting the need for personalized therapeutic approaches. Emerging evidence suggests that the gut microbiota plays a critical role in influencing both treatment outcomes and toxicity in LARC patients. Intestinal dysbiosis has been linked to LARC progression and may affect the efficacy and adverse effects of nCRT. This narrative review critically evaluates the current literature on the relationship between gut microbiota and nCRT in LARC. Certain microbial taxa, such as Alistipes spp., Akkermansia muciniphila, and Faecalibacterium prausnitzii, have been associated with enhanced therapeutic responses, while others, such as Fusobacterium nucleatum and Enterotoxigenic Bacteroides fragilis, may contribute to treatment resistance and exacerbate adverse effects. We also discuss novel mechanisms by which specific gut microbiota and their metabolites modulate nCRT response distinct from conventional immune regulation, alongside emerging strategies for microbiota modulation, including dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation. Despite challenges in standardizing microbiota analysis and fully understanding the precise mechanisms, microbiota-targeted interventions offer a promising avenue for personalized treatment in LARC, with the potential to improve patient outcomes and quality of life.

Background: The effect of vulnerability on the outcomes of patients with locally advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemoradiotherapy (CCRT) remains unclear.

Objectives: To examine the impact of vulnerability on the outcomes in patients with locally advanced NSCLC undergoing CCRT.

Design: We analyzed data from the Japan Lung Cancer Society Integrated Clinical Trial Database, which included 1288 patients with locally advanced NSCLC treated with CCRT.

Methods: Vulnerability was defined as meeting one or more of the following: age ⩾75 years; history of chronic obstructive pulmonary disease (COPD) or emphysema; chronic kidney disease with at least one other comorbidity; or cancer cachexia (C-reactive protein >1.0 mg/dL and albumin <3.5 g/dL).

Results: Among 741 eligible patients, 283 (38.2%) were classified as vulnerable. Vulnerable patients had significantly shorter overall survival (OS; 19.7 vs 27.4 months, p = 0.003), whereas progression-free survival (PFS) did not differ significantly (8.8 vs 10.4 months, p = 0.151). In multivariate analysis adjusted for factors including cisplatin (CDDP) use, the association between vulnerability and OS was attenuated (hazard ratio = 1.221, 95% confidence interval: 0.959-1.555, p = 0.105). The vulnerable patients were significantly less likely to undergo subsequent therapies (60.4% vs 71.6%, p = 0.003). Among the vulnerability components, cachexia showed the strongest association with shorter PFS (8.0 vs 10.5 months, p = 0.009) and OS (16.5 vs 27.4 months, p < 0.001).

Conclusion: Clinical vulnerability was associated with poorer OS after CCRT, mediated by multiple factors, including reduced CDDP use, lower subsequent therapy rates, and cachexia. Individualized strategies that balance treatment intensity, supportive care, and access to post-CCRT are essential for improving outcomes.

Background: Head and neck squamous cell carcinoma (HNSCC) remains a global health challenge with rising incidence, especially in HPV-associated subtypes. The mismatch repair (MMR) system maintains genomic stability, and its deficiency has been linked to tumor immunogenicity and response to immunotherapy in several cancers. However, its role in HNSCC, particularly in the context of HPV status, remains poorly defined.

Objectives: The aim of this study was to compare the imbalance expression of MMR proteins and their association with clinical features and survival in HNSCC.

Design: A retrospective, clinicopathological correlation study.

Methods: We retrospectively analyzed 369 HNSCC specimens. Tissue microarrays were constructed and immunohistochemically stained for four key MMR proteins (MSH2, MSH6, PMS2, and MLH1) and p16 (as an HPV surrogate). Expression patterns were correlated with clinicopathological variables, immune cell infiltration, and survival outcomes.

Results: Among all HNSCC patients, MMR protein expression was preserved in all but one case. MSH2 and PMS2 showed consistently higher nuclear positivity than their partners, MSH6 and MLH1. These imbalances were more pronounced in p16-negative tumors (p < 0.001), whereas p16-positive tumors showed balanced expression. Expression patterns varied by sex, tumor site, drinking history, and AJCC stage. Moreover, MSH6 was significantly lower than MSH2 in nondrinkers (p = 0.039), and PMS2 was lower in advanced-stage patients (p = 0.023). Immunologically, MSH2 expression positively correlated with CD8⁺ T cells in nontumor tissue, while MSH6 and PMS2/MLH1 ratios were inversely correlated with CD4⁺ T cells in tumor tissue. Kaplan-Meier survival analysis revealed that lower MSH2 expression was significantly associated with improved overall survival (p = 0.030).

Conclusion: MMR protein expression in HNSCC varies by HPV status and demographic factors and is linked to differential immune infiltration. These findings suggest that MMR protein imbalance may influence tumor immunogenicity and could potentially serve as a biomarker to inform therapeutic strategies in the immunotherapy era, especially in p16-negative tumors.

Radioligand therapy (RLT) has reshaped the treatment landscape of advanced prostate cancer (PCa), offering a precision medicine approach that integrates molecular imaging with targeted radionuclide delivery, in which radioactive isotopes are bound to molecules that aim to selectively target cancer cells. The approval of ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA)-617 for metastatic castration-resistant prostate cancer marked a major milestone, with randomized trials (VISION, PSMAfore) demonstrating significant improvements in overall and progression-free survival compared to standard therapies. Beyond beta-emitting agents, next-generation alpha emitters such as actinium-225 and beta/Auger electron-emitting isotopes like terbium‑161 are in active development, aiming to overcome resistance and target micrometastases with greater potency. Combination approaches, pairing RLT with poly(ADP-ribose) polymerase inhibitors, immune checkpoint blockade, or androgen receptor pathway inhibitors, for example, are under intense investigation, with early phase data indicating potential efficacy. Technical advances in imaging, personalized dosimetry, and molecular diagnostics may enable more precise patient selection and adaptive treatment strategies, such as dose adjustment based on dosimetry or target expression. Emerging RLT platforms target additional tumor markers, including human kallikrein 2 and six-transmembrane epithelial antigen of the prostate-2 as well as bispecific ligands, addressing disease heterogeneity and expanding therapeutic reach. Nonetheless, challenges remain around long-term hematologic and renal safety, radionuclide supply, protocol standardization, and global accessibility. Ongoing and future multicenter trials, collaborative consortia, and innovations in theranostics will be critical to defining optimal patient selection, sequencing with existing therapies, and embedding RLT as a key pillar in the management of advanced PCa.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become a cornerstone in the treatment of HR+/HER2- advanced breast cancer. While their efficacy is well-established, emerging reports of nephrotoxicity warrant further investigation into its incidence, risk factors, and potential impact on survival outcomes.

Objectives: This study aimed to evaluate the incidence and risk factors for nephrotoxicity in patients receiving CDK4/6 inhibitors (palbociclib or ribociclib) and to analyze its association with progression-free survival (PFS) and overall survival (OS).

Design: This was a single-center, retrospective cohort study.

Methods: We reviewed the medical records of 120 patients with advanced breast cancer treated with palbociclib or ribociclib between October 2018 and July 2024. Nephrotoxicity was defined as a ⩾20% decline in creatinine clearance (CKD-EPI 2021) from baseline. Statistical analyses included descriptive statistics, chi-square tests, t-tests, Kaplan-Meier survival analysis, and Cox regression models.

Results: Nephrotoxicity occurred in 28 patients (23.3%). Older age (⩾65 years) and higher baseline urea and creatinine levels were significant risk factors (p < 0.001). Paradoxically, patients who developed nephrotoxicity showed a trend toward better survival outcomes: median PFS was 30 months versus 20 months (p = 0.188), and the 3-year OS rate was 77.9% versus 63.8% (p = 0.801), though these differences were not statistically significant. In multivariate Cox analysis, the development of nephrotoxicity showed a trend toward a 71% reduction in mortality risk (HR = 0.293, p = 0.078), but it was not statistically significant.

Conclusion: Nephrotoxicity is relatively common in patients treated with CDK4/6 inhibitors, particularly in older individuals and those with elevated baseline renal parameters. Contrary to conventional expectations, its occurrence may be associated with a trend toward improved survival, possibly reflecting higher drug exposure or effective target inhibition. These findings highlight the need for careful renal monitoring and suggest that nephrotoxicity could serve as a potential surrogate marker for treatment efficacy, warranting validation in larger prospective studies.