Prior studies suggest that proportional-hazards violations (PHVs) occur in oncology randomized controlled trials (RCTs) and may affect conclusions, but evidence has largely focused on initial reports rather than updated analyses. We examined PH testing practices, frequency, patterns, and statistical implications of PHVs in updated oncology RCTs. We focused on oncology RCTs supporting US Food and Drug Administration approvals. Phase II-III oncology RCTs supporting FDA approvals between 2006 and 2025 were identified. Individual patient data were reconstructed from Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. Treatment effects were analyzed with Cox proportional-hazards models, log-rank tests, MaxCombo, and restricted mean survival time difference (RMSD). Two hundred seventy endpoint comparisons (150 overall survival [OS], 120 non-OS) from 168 RCTs were included. PH testing dropped from 24.1% in initial reports to 11.5% in updates (McNemar p < 0.001). Although PH testing increased over the past decade in initial publications (Wald p < 0.001), no trend in updates (Wald p = 0.29). PHV frequency was numerically higher in updated than initial analyses (38.9% vs. 33.0%). Non-OS endpoints, metastatic settings, and immunotherapy or targeted-therapy regimens were associated with PHVs. Among updated analyses, nominal significance differences between PH-dependent and alternative methods were more frequent with PHVs (MaxCombo: 11.4% vs. 3.6%, chi-square p = 0.012; RMSD: 8.6% vs. 2.4%, chi-square p = 0.021). PHV patterns were diminishing effects (35.2%), delayed separation (27.6%), and crossing hazards (27.6%). PH testing declined in updated analyses despite numerically more frequent PHVs. Although updates are descriptive and do not invalidate original conclusions, unrecognized non-proportionality may affect long-term benefit interpretation, supporting PH diagnostics and prespecified complementary analyses.

Twenty-five percent of colon cancer patients having curative surgery will recur. Most of them will die from distant metastasis partly due to shortcomings of routine histopathological analysis, that is, undetected tumor cells in the regional lymph node field. We have developed ColoNode, an mRNA test in which five biomarkers are quantified and related to a house-keeping gene. Thereby, four different risk groups are defined from low to very high-risk of recurrence being highly valuable as various indicators of the risk of occult tumor cell dissemination and their aggressiveness. Here we report results of the 5-year survival analysis of a prospective study involving nine Swedish hospitals comparing ColoNode with routine histopathology. The study involves 186 colon cancer patients. The following four conclusions can be drawn: (1) ColoNode surpassed histopathology by identifying all 20 patients who were found by histopathology and an additional seven patients who recurred. Multivariate analysis provided a hazard ratio of 6.7 (p = 0.002) while histopathology lost its significance (HR: 1.3; p = 0.60). Only perineural invasion remained as an independent risk factor apart from ColoNode, with a hazard ratio of 2.7 (p = 0.038). (2) Patients belonging to medium-risk group apparently benefited from adjuvant chemotherapy treatment. (3) A total of 113 patients (≈60%) belonged to the low-risk group and can be considered cured by surgery alone. (4) Four patients were missed by both ColoNode and histopathology. Possible reasons for this are discussed. The results suggest that the ColoNode test should be added to the arsenal of prognostic tools, maybe even replacing histopathological lymph node analysis.

Neoadjuvant mitomycin C plus cisplatin (MP) previously demonstrated promising activity in high-grade serous ovarian cancer in a single-arm study of BRCA1 pathogenic variant (PV) carriers. This prospective, open-label, randomized Phase II trial (NCT04747717) compared MP with standard paclitaxel-carboplatin (TCbP) in women with germline BRCA1/2 PVs. Here, we report a per-protocol analysis of the BRCA1 subgroup involving 29 MP and 31 TCbP patients. Grade III-IV anemia and thrombocytopenia were more frequent with MP, while other adverse events showed similar distribution. RECIST v1.1 response rates did not differ between treatment arms. Surgery was undertaken for 25 MP and 28 TCbP patients. Complete cytoreduction was achieved in 20/25 (80%) MP and 19/28 (68%) TCbP cases. All MP patients underwent complete debulking after 3-4 neoadjuvant cycles, while six out of 19 women from the TCbP arm required more than 4 cycles to achieve surgical clearance of tumor lumps (p = 0.008). MP outperformed TCbP in the improvement of the peritoneal cancer index (p = 0.001). Complete absence of tumor cells in the omentum was documented in 4/25 (16%) MP patients and 6/28 (21%) TCbP patients (p = 0.73). Maintenance olaparib, complete cytoreduction, resolution of carcinomatosis, and TP53 mutation type (loss-of-function (LOF) versus non-LOF) were associated with improved disease-free interval (DFI). At a median follow-up of 44.8 months, multivariate analysis revealed no differences in progression-free survival or DFI between treatment arms. In conclusion, MP showed no significant efficacy advantage over TCbP but produced a rapid and profound reduction of tumor burden, thus warranting further evaluation. Trial Registration: ClinicalTrials.gov (identifier: NCT04747717).

Although colorectal cancer (CRC) is the fourth most common cancer in Vietnam, evidence on lifestyle factors associated with colorectal adenomas (CRA) remains limited. We conducted a case-control study to examine lifestyle factors associated with CRA. Conditional logistic regression (CLR) was performed using 845 matched case-control pairs. Structural equation modeling (SEM) and propensity score matching (PSM) analyses were conducted using the full sample of 847 cases and 1201 controls. CLR identified heavy alcohol consumption (OR 1.59, 95% CI: 1.13-2.23), current smoking (OR 1.88, 95% CI: 1.28-2.76), a personal history of colorectal polyps (OR 7.02, 95% CI: 4.02-12.27), and a sibling history of CRC (OR 3.33, 95% CI: 1.23-9.03) as risk factors for overall adenomas. A personal history of colorectal polyps was associated with both advanced and non-advanced adenomas, whereas current smoking and heavy alcohol consumption were associated with advanced but not non-advanced adenomas. SEM and PSM generally corroborated the CLR findings, with heavy alcohol consumption, current smoking, and a personal history of colorectal polyps associated with advanced adenomas. PSM additionally suggested a possible positive association between high meat consumption and advanced adenomas. CLR identified an inverse association between a beverage pattern characterized by coffee, black tea, and fruit juice consumption and adenoma prevalence; however, this finding was not confirmed in PSM. In conclusion, current smoking, heavy alcohol consumption, and a personal history of colorectal polyps were consistently associated with an increased risk of CRA, particularly advanced adenomas. These findings support lifestyle-focused prevention strategies and risk-stratified CRC surveillance in Vietnam.

Breast ductal carcinoma in situ (DCIS) is often overtreated due to a lack of robust prognostic and predictive tools. This study aimed to evaluate gene expression in a well-characterised DCIS cohort to determine their clinical utility as biomarkers for ipsilateral recurrence. RNA was extracted from microdissected tissues from primary DCIS. A 129-gene panel was analysed using NanoString in 174 DCIS cases (131 with no recurrence and 43 with recurrence). Association with recurrence was determined by Cox regression analyses. Validation was performed by immunohistochemistry. A new 7-gene panel (PBK, COL1A2, GSTM5, MMP2, MX1, SLC22A3 and ZEB1) was derived from the NanoString data but could not be validated in external datasets, including when stratified by radiotherapy treatment. Increased expression of ZEB1 alone was consistently significantly associated with longer recurrence-free survival in discovery and validation cohorts (hazard ratios 0.56-0.71). Correlation between mRNA and protein expression showed the strongest association with peri-ductal fibroblast expression. However, there was no association of ZEB1 protein expression in these cells with recurrence in an independent cohort. Existing multigene panels showed inconsistent associations with recurrence in the current cohort. Gene expression panels show limited reproducibility across cohorts, highlighting the need for prospective trials and context-specific validation. ZEB1 mRNA emerges as a potential biomarker warranting further investigation for its clinical utility in guiding management decisions in DCIS.

Proton pump inhibitors (PPIs) are commonly prescribed in patients with cancer. Prior studies suggest concomitant PPI use may reduce the efficacy of oral capecitabine through impaired absorption, with no interaction expected with intravenous 5-fluorouracil (5-FU). Using the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD), we identified patients with Stage III colon cancer diagnosed between 1 January 2006 and 31 December 2023. Concomitant PPI use during adjuvant chemotherapy was determined by chart review. We evaluated the prevalence of PPI use with fluoropyrimidine-containing adjuvant therapy and its association with recurrence-free survival (RFS) and overall survival (OS). A total of 459 patients were included as follows: 63 (14%) received 5-FU alone, 115 (25%) capecitabine alone, 148 (32%) FOLFOX and 133 (29%) CAPOX. High-risk disease (T4 and/or N2) was present in 203 patients (44%). Overall, 142 patients (31%) received a PPI during adjuvant chemotherapy, with similar rates across treatment groups (p = 0.952). Formal interaction testing did not demonstrate significant heterogeneity of PPI effect across treatment regimens (RFS: LR test p = 0.615; OS: LR test p = 0.143). However, in high-risk patients receiving CAPOX, PPI use was associated with reduced RFS (HR 3.07, 95% CI 1.38-6.84, p = 0.006) and OS (HR 4.11, 95% CI 1.44-11.74, p = 0.008). No impact was observed with capecitabine monotherapy, 5-FU, or FOLFOX. Concomitant PPI use is common in Australian patients with Stage III colon cancer. While formal interaction testing did not reach statistical significance, PPI use was associated with inferior survival outcomes in high-risk patients receiving CAPOX.

Chemotherapy-induced peripheral neuropathy (CIPN) is a potentially long-term consequence of oxaliplatin-based chemotherapy for colorectal cancer (CRC). Oxaliplatin dosing is based on body surface area (BSA), but lean body mass (LBM) may influence susceptibility to long-term CIPN. We examined associations between oxaliplatin treatment and CIPN up to 2 years post-treatment and whether LBM modified these associations. In a prospective cohort, we analysed 106 stage II-III CRC patients treated with adjuvant CAPOX. Data on oxaliplatin treatment were obtained from medical records. CIPN during treatment was graded with the CTCAE, and patient-reported CIPN was assessed by the EORTC QLQ-CIPN20 questionnaire at diagnosis and at 6 weeks and 6, 12, and 24 months post-treatment. LBM was derived from diagnostic CT scans, and sarcopenia was defined using sex-specific skeletal muscle index cut-offs. Longitudinal associations were analysed through confounder-adjusted linear mixed models. Effect modification by LBM and sarcopenia was examined by stratified analyses (median-split) and interaction tests. Higher cumulative oxaliplatin dose (β per 0.5 SD 2.91, 95% CI 1.22-4.59), relative oxaliplatin dose intensity (3.15, 1.2-5.25), and initial dose (2.21, 0.46-3.95) were longitudinally associated with higher CIPN summary scores. Patients with grade 2/3 CIPN had higher post-treatment CIPN scores (5.82; 0.63-11.01) than those with grade 1. Associations were generally stronger in patients with low LBM or sarcopenia, although interaction tests were not statistically significant. In conclusion, higher oxaliplatin exposure and CIPN during treatment were associated with greater long-term CIPN burden. Patients with low LBM or sarcopenia may be particularly vulnerable under current BSA-based dosing.

Long-term survival data for patients with locally advanced gastro-esophageal adenocarcinoma (GEA) treated with neoadjuvant chemoimmunotherapy are lacking. We describe the long-term disease-free survival (DFS) and overall survival (OS) outcomes of such patients treated with a novel neoadjuvant chemoimmunotherapy regimen, aDCF (avelumab with docetaxel/cisplatin/5-fluorouracil). The 50 patients included in the study were treated with 4 neoadjuvant cycles of aDCF followed by an en-bloc transthoracic resection after which 4 additional adjuvant cycles were planned to be given. An exploratory analysis of patients achieving major pathological response (MPR) was also performed. There were 50 patients included in the survival analysis. Clinical disease burden was high (cT3 44/50, 88%, N+ 31/50, 62%) with 49/50 (98%) completing neoadjuvant aDCF. All patients proceeded to surgery with MPR found in 9/50 (18%) patients. The median follow-up for the cohort was 71.5 months (range 43-105) with an estimated median DFS and OS of 61.0 months (95% CI not met) and 77.0 months (95% CI not met) corresponding to a 5-year DFS and OS of 50.0% and 60.0%. For patients with MPR, 5-year DFS and OS were 100%. There were no new safety signals. We conclude that aDCF is a feasible and novel regimen for patients with locally advanced esophagogastric adenocarcinoma providing durable survival outcomes. These outcomes seem enhanced among patients with MPR.

The treatment effect of neoadjuvant therapy (NAT) in esophageal squamous cell carcinoma (ESCC) may vary across individuals. We aimed to estimate individualized treatment effects (ITEs) to identify patients most likely to benefit from NAT to characterize postoperative benefit stratification. This was a cohort-based study for ITE estimation and treatment benefit prediction. The primary outcomes were 5-year overall survival (OS) and disease-free survival (DFS). We applied causal survival forests (CSF) to estimate ITEs, defined as the potential survival outcome differences under NAT before surgery and surgery alone. Patients were stratified into tertiles based on predicted ITEs. Survival outcomes were descriptively compared between patients whose actual treatment was concordant or discordant with the predicted treatment benefit pattern. A total of 838 patients were included, the predicted ITE ranged from -480 to 312 days for OS and from -435 to 442 days for DFS. Patients were stratified into lower, middle, and upper benefit groups. The C-for-benefit values were 0.532 for OS and 0.544 for DFS, and the AUTOC values were 34.86 and 89.49 days, respectively. IPTW-weighted survival curves showed more favorable OS and DFS among patients whose actual treatment was concordant with the predicted treatment benefit pattern than among those with discordant treatment patterns. Age, tumor size, and clinical N stage were the most influential variables. CSF-based ITE estimation suggested heterogeneity in NAT benefit and may support future individualized treatment research in ESCC, but external validation is needed before clinical implementation.

Human papillomavirus (HPV) is the necessary cause of cervical cancer and responsible for ~90% of anal, 78% of vaginal, 50% of penile, and 25% of vulvar cancers. In Costa Rica (CR), few studies have examined incidence trends of these cancers. We assessed age-standardized incidence rates (ASIRs) and trends of invasive anogenital cancers. Incidence data were obtained from the CR National Registry of Tumors and population estimates from the National Institute of Statistics and Census. ASIRs (1960-Segi World population) were calculated using Surveillance, Epidemiology, and End Results (SEER)*Stat, and trends and annual percent changes (APCs) using Joinpoint regression. During 1996-2022, 10,022 invasive anogenital cancer cases were included in the analysis; of which 8122 (81.0%) were cervical. Cervical cancer incidence declined significantly (APC: -3.2%, 95% confidence interval [CI]: -3.9, -2.5). Vaginal cancer showed a non-statistically significant increase (APC: 0.8%, 95% CI: -1.6, 4.1), while vulvar and penile cancers presented a non-statistically significant decrease (APC: -0.8, 95% CI: -1.9, 0.4, and -0.8, 95% CI: -2.1, 1.0, respectively). Anal cancer incidence remained stable (APC: 0.2, 95% CI: -0.9, 1.8) and was 1.4 times higher in females than males (5.3 and 3.7 per million, respectively). In males, penile cancer incidence was 3-times higher than anal cancer (10.9 vs. 3.7 per million). Non-cervical anogenital cancers were rare and showed varying trends. Cervical cancer remains a public health concern in CR, requiring stronger prevention. Research on vaccine-covered HPV genotypes and continued surveillance of anogenital cancers are needed to assess prevention impact.

Adjuvant chemotherapy can improve outcomes for patients who have undergone lung cancer resection, and perioperative rehabilitation may help maintain the physical condition necessary to receive adjuvant chemotherapy. This observational cohort study investigated the impact of perioperative rehabilitation on the administration of postoperative adjuvant chemotherapy, focusing on platinum-based chemotherapies, using a proprietary database of health claims and administrative data from over 450 acute care hospitals in Japan. Patients with Stage II-IIIB non-small cell lung cancer (NSCLC) who underwent surgery between 2017 and 2023 within 180 days of a record of lung cancer diagnosis were eligible. Primary outcome was the proportion of patients who initiated adjuvant platinum-based chemotherapy within 90 days after surgery. Adjusted risk differences were estimated using inverse probability of treatment weighted modified least-squares regression. A total of 8111 patients with Stage II-IIIB NSCLC were included in this study, of whom 5158 (median age: 73.0 years; 72.0% male) received perioperative rehabilitation and 2953 (72.0 years; 69.8% male) did not. Adjuvant chemotherapy (within 90 days of surgery; primary outcome) was initiated in 31.1% (1489/4794) of patients with rehabilitation versus 29.1% (788/2708) in patients without rehabilitation. The adjusted risk difference was 4.1% (adjusted risk difference estimate: 0.041 [95% confidence interval: 0.021, 0.062]; p < 0.001). This study demonstrated that perioperative rehabilitation was associated with more frequent initiation of adjuvant platinum-based chemotherapy within 90 days after surgery in patients with Stage II-IIIB NSCLC. Additional research is warranted to confirm the clinical benefits of the broader implementation of perioperative rehabilitation.

Immune checkpoint inhibitors (ICIs) frequently cause thyroid immune-related adverse events (irAEs). Permanent hypothyroidism, the clinically most relevant phenotype, requires lifelong hormone replacement. We investigated its incidence, course, risk factors, and prognostic relevance under pembrolizumab. This retrospective single-center study included patients from the Departments of Gynecology and Dermatology who received ≥ 3 cycles of pembrolizumab between 2018 and 2024. Permanent hypothyroidism occurred in 30/188 patients (16.0%). Thyrotoxicosis was observed in 46/188 (24.5%) and de novo hypothyroidism in 33/188 (17.6%). Overt thyrotoxicosis progressed to permanent hypothyroidism in 71% of cases. Nearly all permanent cases were overt at first detection (29/30), and most patients were asymptomatic. Permanent hypothyroidism developed earlier than transient courses (median 15 vs. 26 weeks), and no new permanent events occurred beyond 50 weeks. Prior chemotherapy was strongly associated with permanent hypothyroidism (33% vs. 11%; p = 0.001), whereas age, sex, tumor stage, treatment setting, and other systemic therapies were not. Permanent hypothyroidism was not associated with progression-free survival, recurrence-free survival, or overall survival. Permanent hypothyroidism is a common pembrolizumab-related irAE, typically occurring within the first 6 months but occasionally up to 12 months after treatment initiation. Prior chemotherapy emerged as an independent predictor of permanent hypothyroidism. Most cases were mild and manageable with oral levothyroxine. These findings suggest that cycle-based thyroid monitoring may warrant continuation through the first 12 months of ICI therapy, with heightened attention to patients with prior chemotherapy exposure.