Cancer Chemotherapy and Pharmacology最新文献

Purpose: Capecitabine (CAP) side effect, a prodrug of 5-fluorouracil (5-FU), is hand-foot syndrome (HFS), a localized skin disorder of the hands and feet that is believed to induce a decrease in skin barrier function. Stratum corneum (SC) lipids play an important role in skin barrier function; therefore, this study compared the SC lipid structure and composition of healthy participants with those of patients with CAP-induced HFS.

Methods: Forty patients receiving a combination regimen of CAP and oxaliplatin as adjuvant chemotherapy for colorectal cancer were enrolled. All patients received 1,000 mg/m² twice daily on days 1-14. SC samples were obtained from 11 patients with CAP-induced HFS (CSC). The SC lipid structure was analyzed using synchrotron X-ray diffraction. SC lipid components, ceramides (CERs), free fatty acids (FFAs), CAP, and its metabolites in CSC samples were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

Results: In healthy SC (HSC), lipids formed two lamellar phases. Hexagonal and orthorhombic hydrocarbon chain packing was observed in lateral lipid organization. However, in CSC, these structures have almost disappeared. UPLC-MS/MS analysis revealed that the composition of CER and FFA differed between CSC and HSC, and that the carbon chain length of SC lipid components in CSCs was reduced compared to that in HSCs. 5-FU was detected in CSCs at 3.4 ± 1.4 ng/mg.

Conclusion: CAP induces changes in SC lipid structure due to changes in SC lipid composition and a decrease in carbon chain length in CSCs. CAP-induced HFS is associated with 5-FU accumulation in SC.

Purpose: Premedication with clemastine and dexamethasone is administered to prevent paclitaxel-induced hypersensitivity reactions (HSRs), which predominantly occur during the first two administrations. To reduce premedication and related adverse effects, our hospital implemented a policy to discontinue premedication after two paclitaxel doses if no HSR occurred. This study evaluated whether rescue medication use after the second dose was not substantially higher following the protocol change.

Method: We conducted a retrospective, observational, non-inferiority study, comparing patients receiving premedication for every paclitaxel administration (pre-policy change) with those discontinuing premedication after two HSR-free administrations (post-policy change). The primary outcome was the incidence of rescue medication use; non-inferiority was defined as the upper 95% confidence interval (CI) boundary below 4.0%.

Results: A total of 148 patients were included (74 per group). Baseline characteristics were comparable between the two groups. Rescue medication was required in 3/74 patients (4.1%; 95% CI: 0.8-11.4%) in the pre-policy change group and 8/74 (10.8%; 95% CI: 4.8-20.2%) in the post-policy change group, yielding a difference of 6.8% (95% CI: - 1.6-15.1%). Non-inferiority could not be demonstrated, due to insufficient power resulting from an underestimated baseline incidence of rescue medication use. This limitation precludes interpreting the findings as evidence of inferiority.

Conclusion: Discontinuing premedication after two paclitaxel doses increased the incidence of rescue medication use, although reactions were mild and manageable, with most patients completing treatment. These findings suggest that premedication may not be necessary for all patients. Further research is needed to assess the safety of discontinuing premedication.

Purpose: Prostate-specific membrane antigen (PSMA) has been identified as a therapeutic target for metastatic castration-resistant prostate cancer (mCRPC). The recent success of radioligands targeting PSMA spurred development of new PSMA-targeting agents including immunotherapy. JNJ-80038114 is a bispecific antibody that binds PSMA on tumor cells and CD3 on T cells to induce anti-tumor activity.

Methods: This was a phase 1, open-label, multicenter study of JNJ-80038114 in participants with mCRPC and ≥ 1 prior systemic therapy. JNJ-80038114 was administered subcutaneously every 3 weeks (Q3W), starting at 0.1 mg. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK), immunogenicity, and prostate-specific antigen (PSA).

Results: At final analysis, 39 participants received 0.1-180 mg JNJ-80038114 across 11 dose-escalation cohorts for a median of 9.3 weeks (range, 0.1-31.1). The most common treatment-related adverse events (TRAEs; ≥20%) included cytokine release syndrome (CRS, 51.3%, all Grade 1-2), injection-site reactions (46.2%), and fatigue (30.8%). Related Grade ≥ 3 TRAEs occurred in 51.3% of participants; dose-limiting toxicities occurred in 3 (7.7%). Four participants (10.3%) developed clinically significant neuropathies. In 37 PK-evaluable participants, mean exposure (C_max, AUC) increased with increasing doses. Anti-drug antibodies (ADA) were reported in 56.8% (21/37) participants. One participant had confirmed PSA decrease ≥ 50%. Three participants had radiological responses in the context of rapidly rising PSA. Following a review of data, the study was terminated.

Conclusions: This first-in-human study of JNJ-80038114 was discontinued early due to its lack of preliminary clinical activity, neurologic toxicities, high rates of CRS, and the development of ADAs impacting PK.

Clinicaltrial:

Gov information: NCT05441501, Registered July 1, 2022.

Purpose: Lung cancer treatment options have advanced, chemotherapy continues to play a central role in its management. However, the prognostic impact of individualized chemotherapy dose modifications remains uncertain. To examine the association between intravenous chemotherapy dose variations and disease-free survival (DFS) in lung cancer patients, and to identify factors influencing dose adjustment.

Methods: Lung cancer patients who received chemotherapy at Xiangya Hospital, Central South University from 2016 to 2021. Patients were classified into three groups based on deviation from the standard dose: dose reduction group, standard dose group, and dose increase group. Multivariable Cox proportional hazards models and inverse probability weighting (IPW) were used to evaluate the relationship between dose changes and DFS. Multivariate logistic regression was performed to identify factors associated with dose modification.

Results: Among 23,231 patients, 7673 received standard doses, 13,655 reduced doses and 1903 increased doses. After adjustment by multivariable Cox regression and IPW, dose reduction (HR 1.06, 95% CI 1.01-1.11; P = 0.015) and dose increase (HR 1.11, 95% CI 1.02-1.22; P = 0.022) were associated with shorter DFS; in the platinum-doublet subgroup, only dose reduction remained significant (HR 1.08, 95% CI 1.02-1.15; P = 0.007). Logistic regression identified age, sex, height, weight, pathology, TNM stage and use of targeted/immunotherapy as associated factors.

Conclusion: Dose reduction was associated with significantly shorter DFS. Individualized dosing strategies should be based on comprehensive clinical evaluation to improve outcomes. These findings provide evidence to support rational chemotherapy planning in lung cancer care.

Introduction: Selpercatinib is a selective inhibitor of rearranged during transfection (RET) kinase and is indicated for patients with RET fusion-positive non-small cell lung cancer, advanced RET fusion-positive solid tumors, and thyroid cancer. This report describes a patient who developed renal tubular damage resulting in renal loss of electrolytes and polyuria four weeks after the start of selpercatinib. To our knowledge, tubular damage is a rare selpercatinib-induced toxicity. This report contributes to the growing literature about selpercatinib-related adverse events and their management.

Case: A 74-year-old male with RET mutation-positive medullary thyroid cancer, presented with thirst, hyponatremia, hypomagnesemia, hypocalcemia, and polyuria. The hyponatremia deteriorated to symptomatic hyponatremia (112 mmol/L) and required intensive care unit admission. Selpercatinib treatment (160 mg bi-daily) was interrupted, and plasma was collected for therapeutic drug monitoring (TDM). The patient was hospitalized for fluid supplementation and correction of electrolytes. The association with selpercatinib seemed likely due to a Naranjo score of 9 (out of 13). Following dose interruption and supportive care, electrolyte disturbances and polyuria resolved. After recovery, selpercatinib was rechallenged at a dose of 80 mg bi-daily based on TDM. No recurrence of electrolyte disturbances or renal toxicity was observed, and the patient maintained stable disease.

Conclusion: Our report indicates an association between selpercatinib plasma concentration and renal tubular damage, and emphasizes the importance of recognizing selpercatinib-induced tubular injury. This report also provides guidance for the management of these renal manifestations and for rechallenge guided by TDM, highlighting a potential role for TDM in dose determinations after selpercatinib-induced renal toxicity.

Purpose: Plasma abemaciclib concentrations vary among individuals, and their association with hematologic toxicity has been reported in real-world settings. The incidence of interstitial lung disease (ILD), a serious adverse event of abemaciclib, is higher in clinical practice than in clinical trials. Here, to assess the potential usefulness of abemaciclib concentration monitoring, we conducted a prospective exploratory study of the association between plasma abemaciclib concentration, age, and the occurrence of adverse events in breast cancer patients.

Methods: Patients with hormone receptor-positive breast cancer who initiated abemaciclib with endocrine therapy between December 2022 and May 2025 were included. Plasma abemaciclib concentrations were measured using liquid chromatography-tandem mass spectrometry, and adverse events of grade ≥ 3 or those leading to treatment interruption were identified.

Results: A total of 322 plasma samples from 23 patients were analyzed. The median age was 52 years (range: 34-79), including four aged ≥ 65. Thirteen had metastatic disease, and six out of ten completed two-year adjuvant therapy. During a median follow-up of 344 days (range: 29-732), ILD occurred in five patients (21.7%). Abemaciclib concentrations on day 15 of cycle 1 were significantly higher in patients with ILD than in those without (p = 0.005, Mann-Whitney U test). A positive correlation was observed between age and concentration on day 15 of cycle 1 (Pearson's correlation coefficient = 0.54, p = 0.008), with increased variability in older patients.

Conclusion: Abemaciclib concentrations tend to be higher in elderly patients and may be associated with increased risk of ILD. These findings support the potential usefulness of abemaciclib concentration monitoring from a safety perspective in real-world practice.

Colorectal cancer (CRC) is a leading global cause of cancer-related deaths, influenced by both genetic predisposition and lifestyle factors. Inherited syndromes such as Lynch syndrome and Familial Adenomatous Polyposis account for a minority of cases, while modifiable risk factors like diet, obesity, smoking, and physical inactivity significantly contribute to incidence rates. Curcumin, a natural polyphenol derived from turmeric, has garnered interest due to its anti-inflammatory and anticancer properties, particularly in CRC prevention and therapy. Despite promising preclinical data, challenges such as poor bioavailability hinder its clinical translation. Innovative delivery systems are under development to enhance its therapeutic potential. This review explores CRC's epidemiology, risk factors, current treatments, and curcumin's emerging role in management strategies.

Purpose: Epithelial ovarian cancer (EOC) is associated with high recurrence and poor prognosis. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) offers a locoregional treatment strategy. However, the pharmacokinetics of cisplatin administered via HIPEC compared to intravenous (IV) infusion remain insufficiently characterized. This study aimed to compare local abdominal tissue concentrations and systemic exposure of cisplatin following HIPEC and IV administration in a healthy porcine model using microdialysis.

Methods: Sixteen healthy Danish Landrace pigs were divided into HIPEC (n = 8) and IV (n = 8) groups. The HIPEC group underwent CRS followed by 90-minute cisplatin-based HIPEC. The IV group received an equivalent cisplatin dose intravenously (100 mg/m²). Microdialysis catheters were placed in the liver, rectum, stomach (superficial and profound layers) and peritoneum. Free cisplatin concentrations were quantified using UPLC-MS/MS.

Results: Within the HIPEC group, cisplatin C_max and AUC_0 - last were significantly higher in the peritoneum compared to other abdominal tissues and plasma. The peritoneal-to-plasma AUC_0 - last ratio was 8.7 for HIPEC vs. 1.8 for IV infusion (ratio: 4.92, 95% CI: 3.12-7.78, p < 0.001). Compared to IV infusion, HIPEC achieved significantly higher peritoneal C_max, while peritoneal AUC_0 - last was comparable. In contrast, IV infusion resulted in significantly higher plasma and non-peritoneal tissue exposure. Plasma AUC_0 - last was 4.7-fold higher following IV administration compared to HIPEC (95%-CI: 3.0-7.3, p < 0.001).

Conclusion: HIPEC concentrates cisplatin within the peritoneum while minimizing systemic distribution, whereas IV administration leads to a broad systemic and less targeted exposure. These findings support the pharmacologic rationale for HIPEC in maximizing local cytotoxicity and minimizing systemic toxicity in EOC treatment.