Łukasz Kwinta

Background: Metronomic chemotherapy (MCT), understood as continuous, low-dose cytotoxic administration without prolonged drug-free intervals, has become an established strategy in several solid tumors, acting primarily through antiangiogenic, immunomodulatory, and direct cytostatic mechanisms rather than replication-dependent cytotoxicity. Despite an expanding evidence base, including positive randomized trials, validated predictive biomarkers of response remain unavailable. Methods: We searched PubMed/MEDLINE, Embase, and ClinicalTrials.gov (January 2000 to July 2026) for phase II/III randomized trials, prospective cohorts, and selected retrospective analyses of MCT in breast cancer, head and neck squamous cell carcinoma, NSCLC, and mCRC, and extracted biomarker data from embedded translational substudies of eligible trials. Results: In breast cancer, phase III SYSUCC-001 (adjuvant metronomic capecitabine, improved DFS in TNBC) and MECCA (metronomic capecitabine plus aromatase inhibitor in HR+/HER2− disease) provide the strongest evidence, supported by randomized phase II data for the VEX regimen (METEORA-II) and MCT-anti-PD-1 combinations. TEMPO LUNG established metronomic vinorelbine as effective in platinum-unfit NSCLC, while CAIRO3 confirmed metronomic capecitabine–bevacizumab as an effective mCRC maintenance therapy. Most recently, the phase III TMC-I trial extended positive randomized evidence to head and neck cancer. Candidate biomarkers span angiogenic, immune, tumor proliferative, molecular, pharmacodynamic cytokine, on-treatment clinical (adverse-event-based), and gut–microbiome domains, with FOXC1, circulating endothelial cell kinetics, VEGF pathway markers, and regulatory T-cell dynamics among the most promising; however, none has been prospectively validated in a dedicated confirmatory trial. Conclusions: MCT has moved from empirical use to an evidence-based strategy across multiple tumor types, but the lack of validated predictive biomarkers limits informed patient selection. Future trials should incorporate biomarker-driven designs, particularly FOXC1, endothelial cell kinetics, and immune profiling as co-primary objectives. Defining an MCT-sensitive biological phenotype remains the key translational challenge for the field.

Background: Metronomic chemo-endocrine therapy combining fulvestrant with metronomic VEC (vinorelbine, cyclophosphamide, and capecitabine)—the FulVEC regimen—demonstrated promising activity in an initial cohort of 38 patients with advanced ER+/HER2− breast cancer (JCM 2023). Here, we present an extended analysis of 72 consecutive patients, with a focus on a novel hypothesis: that treatment-emergent adverse events (AEs) requiring dose modification serve as a surrogate for sufficient pharmacological exposure in metronomic combination chemotherapy. Methods: Retrospective analysis of 72 consecutive patients with metastatic ER+/HER2− breast cancer treated with FulVEC at Jagiellonian University Hospital between 2018 and 2024. Efficacy endpoints included progression-free survival (PFS), overall survival (OS), and biochemical response, as assessed by CA15-3 dynamics. Patients were stratified by AE severity requiring intervention (grade 0: no modification; grade 1: dose reduction; and grade 2: treatment delay). The association between AE grade and efficacy outcomes was assessed using Spearman’s correlation, the log-rank test, and the chi-square test. Results: The median PFS was 8.5 months, and the median OS was 18.0 months. The biochemical benefit rate (any CA15-3 decline) was 81.6%. No statistically significant differences in efficacy were observed according to prior exposure to CDK4/6 inhibitors, fulvestrant, or cytotoxic components of the FulVEC regimen. A monotonic dose–response relationship was observed across AE grade categories: non-progression rates increased from 73.2% (grade 0) to 84.2% (grade 1) and 91.7% (grade 2); biochemical benefit rates from 68.4% to 90.9% and 100.0%; and median CA15-3 reduction deepened from −34% to −44% and −52%, respectively (Spearman r = 0.258 and p = 0.043 for AE grade vs. treatment duration). Formal log-rank comparisons of PFS and OS across the three AE-grade categories did not reach statistical significance (p = 0.583 and p = 0.743, respectively), reflecting the limited size of the treatment-delay subgroup (n = 12); the dose–response signal should, therefore, be regarded as exploratory. No patient required permanent treatment discontinuation due to toxicity. Conclusions: The extended FulVEC cohort confirms durable activity and a reproducible, manageable safety profile in a heavily pretreated population, including CDK4/6i-refractory patients. The exploratory, hypothesis-generating observation of a dose–response gradient between AE severity and clinical outcomes raises the possibility that treatment-emergent AEs may, in some patients, reflect adequate pharmacological exposure to the metronomic regimen. Given confounding by treatment duration and survivor bias, and the absence of pharmacokinetic data, this hypothesis requires prospective validation and does not, at this stage, support any change to current treatment practice.

Background. Accurate prediction of pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in muscle-invasive urothelial bladder cancer (MIBC) remains an unmet clinical need. The neutrophil-to-platelet/hemoglobin-to-lymphocyte (NPLH) ratio, a composite hematologic index that reflects both systemic inflammation and nutritional oxygen-carrying capacity, has not been previously evaluated as a predictor of NAC response in this setting. Methods. We retrospectively analyzed 114 consecutive patients with MIBC (cT2–T4, N0–N3) who received accelerated MVAC (aMVAC) NAC followed by radical cystectomy at a single academic center. Pretreatment NPLH (calculated as [neutrophils × platelets]/[hemoglobin × lymphocytes]) was assessed as a predictor of pCR (ypT0N0) and tumor regression grade (TRG). Receiver operating characteristic (ROC) curve analysis, Mann–Whitney U test, and logistic regression were used. NPLH performance was compared to NLR and PLR. Results. pCR was achieved in 35 patients (30.7%). Median NPLH was significantly lower in pCR vs. non-pCR patients (33.9 [IQR 23.1–42.4] vs. 47.6 [IQR 30.7–90.4]; p = 0.0007). NPLH yielded an AUC of 0.700 (bootstrap 95% CI 0.596–0.794) for pCR prediction, numerically superior to NLR (AUC 0.645 [0.542–0.741]) and PLR (AUC 0.643 [0.533–0.747]); DeLong test: NPLH vs. NLR p = 0.079, NPLH vs. PLR p = 0.090. At the optimal cut-off of 44.5, NPLH demonstrated 80.0% sensitivity and 57.0% specificity. pCR rates declined progressively across NPLH quartiles: 48.3% (Q1) to 10.3% (Q4). On multivariate logistic regression, log-transformed NPLH was the only independent predictor of pCR (parsimonious model, OR 0.292, 95% CI 0.131–0.652; p = 0.003; EPV = 17.5). A positive correlation was observed between NPLH and TRG score (Spearman r = 0.284; p = 0.0022), with significant differences between TRG 1 and TRG 3 subgroups (p = 0.0036). Conclusions. Pretreatment NPLH is an independent predictor of pCR to aMVAC in MIBC and is numerically superior to NLR and PLR (DeLong p = 0.079). Consisting exclusively of standard complete blood count parameters, NPLH is readily available and inexpensive. This single-center exploratory study is hypothesis-generating and requires prospective external validation before clinical implementation.

Background: Breast cancer, with 2.3 million new cases and 0.7 million deaths every year, represents a great medical challenge worldwide. These numbers confirm that approx. 30% of BC patients will develop an incurable disease requiring life-long, palliative systemic treatment. Endocrine treatment and chemotherapy administered in a sequential fashion are the basic treatment options in advanced ER+/HER2- BC, which is the most common BC type. The palliative, long-term treatment of advanced BC should not only be highly active but also minimally toxic to allow long-term survival with the optimal quality of life. A combination of metronomic chemotherapy (MC) with endocrine treatment (ET) in patients who failed earlier lines of ET represents an interesting and promising option. Methods: The methodology includes retrospective data analyses of pretreated, metastatic ER+/HER2- BC (mBC) patients who were treated with the FulVEC regimen combining fulvestrant and MC (cyclophosphamide, vinorelbine, and capecitabine). Results: Thirty-nine previously treated (median 2 lines 1–9) mBC patients received FulVEC. The median PFS and OS were 8.4 and 21.5 months, respectively. Biochemical responses (CA-15.3 serum marker decline ≥50%) were observed in 48.7%, and any increase in CA-15.3 was observed in 23.1% of patients. The activity of FulVEC was independent of previous treatments with fulvestrant of cytotoxic components of the FulVEC regimen. The treatment was safe and well tolerated. Conclusions: Metronomic chemo-endocrine therapy with FulVEC regimen represents an interesting option and compares favorably with other approaches in patients’ refractory to endocrine treatments. A phase II randomized trial is warranted.