Oral versus intravenous vinorelbine: clinical safety profile

The availability of chemotherapeutic drugs administrable by oral route represents a step forward in the management of cancer patients. Among oral agents, vinorelbine is particularly interesting for its pharmacological characteristics and clinical efficacy. Oral vinorelbine is rapidly absorbed (1.5 – 3 hours) with an elimination half-life of ～ 40 hours. It shows a low level of binding to plasma proteins (13%), is highly bound to platelets (78%) and has a hepatic metabolism and an absolute bioavailability of 40% with a moderate and similar interpatient variability for the two forms. Food has no influence on the pharmacokinetic profile of oral vinorelbine even if nausea/vomiting is less frequent and less severe in the fed patients than in the fasting patients. Therefore, to ensure patient comfort, it is recommended that oral vinorelbine is administered with a snack. All the metabolites of oral vinorelbine have been identified and, among these, only deacetyl-vinorelbine presented activity demonstrating that for both oral and intravenous (i.v.) routes of administration the drug has the same metabolism pattern. Oral vinorelbine is eliminated mainly in a unconjugated form via the bile. In this process, the CYP 3A4 isoform of cytochrome P450 is mostly involved. Absorption of oral vinorelbine is not delayed in elderly patients. After oral administration, blood concentrations of vinorelbine in elderly patients are within the range of values observed in younger patients. The absolute bioavailability is close to 38% in elderly whereas it is close to 40% in younger patients. This difference is not significant. As compared to the intravenous drug, oral vinorelbine demonstrated linear pharmacokinetics as well an absolute bioavailability of ～ 40%, and a reliable dose-correspondence of 80 mg/m² oral form → 30 mg/m² i.v. and 60 mg/m² oral → 25 mg/m² i.v. Therefore, i.v. and oral forms show similar interindividual variability, same metabolism pattern, reproducible intra-patient blood exposure, and same pharmacokinetic–pharmacodynamic relationship. Oral vinorelbine has shown significant activity in advanced non-small cell lung cancer. Given at 60 mg/m²/week for the first 3 administrations and then increased to 80 mg/m²/week achieved the same efficacy as i.v. vinorelbine in terms of progression-free survival, overall survival, objective response. Mild-to-moderate gastrointestinal toxicity, easily manageable with standard treatment was recorded. Reproducible efficacy compared to previously reported results with vinorelbine i.v. Also, in advanced breast cancer, oral vinorelbine has shown significant activity with a good therapeutic index. Albeit no formal comparison between the oral and the intravenous formulations of vinorelbine has been made, however, the oral route seems to offer major advantages to patients who are faced with a clear decrease in the frequency of hospital admissions as compared to that needed to give intravenous chemotherapy.     

Prognostic and predictive biomarkers for targeted therapy in NSCLC: for whom the bell tolls?

Introduction: The discovery of molecular biomarkers and the advent of targeted therapies have led to a radical change in the treatment of several tumors, including NSCLC. In the last few years, the number of molecular biomarkers has rapidly increased, and a growing interest has been recently focused on their potential prognostic and predictive value in clinical settings.

Areas covered: This review describes all the molecular biomarkers with prognostic and predictive value in NSCLC, including both clinically approved biomarkers, and emerging biomarkers under investigation in clinical trials. Liquid biopsy and applications of circulating biomarkers are also described.

Expert opinion: The oncological research is currently focusing on the discovery and validation of molecular biomarkers in order to promote even more personalized treatment strategies. This paradigm of care will expand quickly thanks to the advent of new genotyping technologies, such as next-generation sequencing, making it possible to create a molecular-genomic profile of every patient’s tumor. Liquid biopsy and the use of circulating-biomarkers represent the new challenge of oncological research, with very promising implications in the management of patients.     

Naptumomab estafenatox: a new immunoconjugate

Importance of the field: New agents that specifically engage the immune system are being tested in a variety of malignancies. This review provides an overview of naptumomab, an immunotoxin, with encouraging clinical activity in Phase I trials.

Areas covered in this review: This review examines the preclinical and the published clinical data with regards to naptumomab.

What the reader will gain: This review provides the reader with an understanding of the mechanism of action, immunology, pharmacokinetics and clinical activity of this agent.

Take home message: Naptumomab has a unique mechanism of action and appears to be an active agent in the treatment of refractory solid tumors such as renal cell carcinoma.     

A phase II study of metronomic oral vinorelbine administered in the second line and beyond in non-small cell lung cancer (NSCLC): a phase II study of the Hellenic Oncology Research Group

Abstract

Introduction: Frequent administration of low doses of cytotoxic drugs (metronomic chemotherapy) has been suggested to suppress tumour growth possibly by inhibiting angiogenesis. We evaluated a metronomic regimen of oral vinorelbine in pre-treated patients with advanced non-small cell lung cancer (NSCLC).

Methods: Forty-six pre-treated NSCLC patients received oral vinorelbine at a fixed dose of 50 mg three times a week.

Results: Treatment was administered as second-line in 12 (26·1%) patients and as third- or further-line in 34 (73·9%). Grade 3–4 neutropenia was observed in 23·9% and febrile neutropenia in 10·9%. Grade 3 fatigue was the most common severe non-hematologic toxicity (10·9%). Response rate was 10·9%; 19·6% achieved disease stabilization. Median tumour progression (TTP) was 2·2 months, median overall survival 9·4 months and the 1-year survival rate was 30·1%.

Conclusion: The administration of metronomic oral vinorelbine is feasible and results in acceptable clinical efficacy associated with manageable toxicity in a population consisting mostly of heavily pre-treated NSCLC patients.     

培美曲塞治疗老年中晚期非小细胞肺癌的临床效果

目的：观察培美曲赛单药治疗老年中晚期非小细胞肺癌的疗效和不良反应。方法：总结分析于本院诊治2008—2009年26例老年（70～81岁）ⅢA-Ⅳ期非小细胞肺癌患者接受培美曲赛单药化疗2周期后行临床疗效和不良反应。结果：完全缓解（CR）0例，部分缓解（PR）6例，总有效率为23．08％，疾病稳定（SD）11例，疾病进展（PD）9例。全组毒性不良反应较轻，主要为骨髓抑制，可耐受。结论：培关曲赛治疗老年非小细胞肺癌疗效较好，不良反应轻，可明显改善老年患者生存质量。     

Feasibility study of metabolically supported chemotherapy with weekly carboplatin/paclitaxel combined with ketogenic diet,hyperthermia and hyperbaric oxygen therapy in metastatic non-small cell lung cancer

Background: Previous evidence suggests that metabolically supported chemotherapy (MSCT), ketogenic diet, hyperthermia and hyperbaric oxygen therapy (HBOT) could all target vulnerabilities of cancer cells. This study aimed to evaluate the efficacy and the tolerability of this combination therapy in the treatment of stage IV non-small cell lung cancer (NSCLC).

Methods: Forty-four NSCLC patients with distant metastasis that received MSCT (administration of chemotherapy regimen following induced hypoglycemia) plus ketogenic diet, hyperthermia and HBOT combination were included in this retrospective study. Survival and treatment response rates as well as toxicities were evaluated.

Results: Overall response rate (ORR, complete response plus partial response) was 61.4%; whereas, 15.9% and 22.7% of patients had stable disease (SD) and progressive disease (PD), respectively. Mean overall survival (OS) and progression-free survival (PFS) was 42.9?months (95% CI: 34.0–51.8) and 41.0?months (95% CI: 31.1–50.9), respectively. A higher Eastern Cooperative Oncology Group (ECOG) performance status (ECOG ≥2) was associated with worse OS and PFS. Patients received chemotherapy cycles with acceptable toxicity and adverse events. No problems were encountered due to fasting, hypoglycemia, ketogenic diet, hyperthermia or hyperbaric oxygen therapy.

Conclusions: Findings of this study suggest that MSCT combined with other modalities targeting multiple pathways and cellular vulnerabilities may bring about remarkable improvements in survival outcomes and treatment response rates in metastatic NSCLC, without additional safety concerns. Large comparative studies are warranted to draw robust conclusions.     

Assessment of Immune-Related Interstitial Lung Disease in Patients With NSCLC Treated with Immune Checkpoint Inhibitors: A Multicenter Prospective Study

IntroductionProgrammed cell death protein 1 immune checkpoint inhibitors (ICIs) have been reported to improve the survival of patients with NSCLC. On the expansion of clinical administration for a variety of cancers, immune-related adverse events have been typically recognized to be associated with ICIs, therefore, necessitating the monitoring and management of these patients. Among immune-related adverse events, immune-related interstitial lung disease (ir-ILD) is a serious complication that interrupts treatment and can occasionally be fatal. However, no prospective studies have investigated the incidence of ir-ILD and associated risk factors for its development in the clinical setting.MethodsThis is a prospective cohort study consisting of patients with NSCLC treated with ICIs. Baseline characteristics, including laboratory data, pulmonary function tests, daily symptoms of dyspnea defined by the modified Medical Research Council, and antitumor response were assessed.ResultsAmong the 138 patients with NSCLC who received anti–programmed cell death protein 1 monotherapy, 20 patients (14.5%) had ir-ILD within median 51.5 days (interquartile range: 29–147). This was approximately three times higher than those in clinical trials. A total of 11 patients (55.0%), including all eight patients with high-grade ir-ILD (≥grade 3), developed ir-ILD within 60 days. Impaired spirometry, decreased forced vital capacity and forced expiratory volume in 1 second, and daily symptoms of dyspnea measured using the modified Medical Research Council scale were identified as risk factors for ir-ILD development. In addition, combination assessment of forced vital capacity and forced expiratory volume in 1 second successfully classified patients at risk for ir-ILD development.ConclusionsThe incidence of ir-ILD was substantially higher in the clinical setting. Assessment of spirometry and daily dyspneic symptoms before ICI treatment may be useful in monitoring and managing patients with NSCLC.     

Stereotactic Ablative Radiotherapy as an Alternative to Lobectomy in Patients With Medically Operable Stage I NSCLC: A Retrospective,Multicenter Analysis

Background

Stereotactic ablative body radiation therapy (SBRT) has evolved as the standard treatment for patients with inoperable stage I non–small-cell lung cancer (NSCLC). We report the results of a retrospective analysis conducted on a large, well-controlled cohort of patients with stage I to II NSCLC who underwent lobectomy (LOB) or SBRT.