Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial

BackgroundAlmost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy.MethodsWe did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847.FindingsBetween March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6-8·7]) than in the supportive care group (3·2 months [2·8-4·1]; hazard ratio [HR] 0·48 [95% CI 0·33-0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33-0·72]; p=0·0002). Grade 3-4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection.InterpretationSwitch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma.FundingDutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies.Pathogenesis and treatment of chronic pulmonary disease

Energy balance in nonsmall cell lung carcinoma patients before and after surgical resection of their tumors.

BACKGROUND: The purpose of this study was to investigate whether surgical removal of a tumor influences energy balance, body weight, and body composition in lung carcinoma patients. METHODS: In 53 nonsmall cell lung carcinoma (NSCLC) patients, resting energy expenditure (REE, measured by ventilated hood), energy intake (EI, determined by diet history), body weight, and body composition (fat free mass [FFM], measured by bioelectrical impedance analysis) were all determined before tumor resection. In 39 of 53 patients, REE, EI, body weight, and body composition were also measured 3, 6, and 12 months after tumor resection. RESULTS: Thirty-six of 53 patients (68%) were found to be hypermetabolic. Fourteen patients were excluded from the repeated measurements. Patients with curative tumor resection (n = 30) showed an increase in body weight over a 1-year period, in contrast to patients with tumor recurrence (n = 9), who lost weight (+3.5 vs. -3.6 kg, P < 0.005). The weight gain was caused predominantly by an increase in fat mass (FM), while the weight loss was caused for more than half by a decrease in FFM. Body weight was increased in hypermetabolic patients (n = 20) as well as patients with normal metabolism (n = 10) 1 year after successful removal of their tumors. However, although EI/REE was significantly increased in hypermetabolic patients (from 106% to 140%, P < 0.05), it was not changed in patients with normal metabolism. CONCLUSIONS: Hypermetabolic NSCLC patients undergoing curative resection show an improvement in energy balance caused by both a decrease in REE and an increase in EI. This positive energy balance results in weight gain, which is caused predominantly by an increase in FM

Expression of E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in non-small-cell lung carcinoma.

Vascular cell adhesion molecules (VCAM) play an important part in the regulation of inflammation and are considered to be important in the process of malignant tumour growth. The present study describes the immunohistochemical staining patterns of E-selectin, intercellular adhesion molecule (ICAM)-1 and VCAM-1 on endothelial cells of the vessels in tumour stroma and other cell types in non-small-cell lung carcinoma (NSCLC; n = 43) in association with inflammatory cells. Expression of E-selectin was dominant on endothelial cells in the stromal areas of the tumour, especially at the borders, and was confined to endothelial cells. Moderate to strong staining for ICAM-1 was demonstrated on endothelial cell irrespective of size or localization of the vessels. Compared with ICAM-1, fewer vessels were positive for VCAM-1, and stained with lesser intensity. ICAM-1 expression was demonstrated on NSCLC cells, the basal cells of bronchial epithelium, type II pneumocytes, lymphocytes and fibroblasts. VCAM-1 was clearly expressed on NSCLC cells in 4 of the 43 cases and on lymphocytes and fibroblasts. The staining patterns observed on endothelial cells support the idea of an active status of NSCLC vessels. This phenotypic pattern looks similar to the vascular component of inflammation. The presence of ICAM-1 and VCAM-1 on NSCLC cells suggests a functional role in the process of chemotaxis for tumour cells

Analysis of the energy balance in lung cancer patients

Erratum in: Cancer Res 1995 Apr 15;55(8):1809. Analysis of the energy balance in lung cancer patients. Staal-van den Brekel AJ, Schols AM, ten Velde GP, Buurman WA, Wouters EF. Department of Pulmonology, University Hosital, Maastricht, The Netherlands. Previous studies have shown that an elevated resting energy expenditure (REE) frequently occurs in lung cancer patients. The aim of the present study was to assess the balance between REE and dietary intake and to analyze the contributing factors of elevated REE in newly detected lung cancer patients. One hundred newly detected lung cancer patients were evaluated. Measured values of REE were adjusted for the values predicted by the Harris-Benedict formula and for fat-free mass assessed by the bioelectrical impedance method. Dietary intake was measured using a dietary history. A substantial number of patients (30%) had a weight loss of 10% or more from their preillness stable weight. An elevated REE was found in 74% of the patients. Stratification by tumor localization revealed that patients with a central tumor had a significantly higher REE [121 +/- 13% (SD) versus 110 +/- 10% of predicted, P < 0.001] and significantly higher level of C-reactive protein (35 +/- 35 mg/liter versus 16 +/- 26 mg/liter, P = 0.006) compared with patients with a peripheral tumor. Dietary intake was significantly lower in the weight-losing group (1872 +/- 542 kcal/day versus 2169 +/- 782 kcal/day, P < 0.05) compared with the weight-stable group. We conclude that both elevated REE and decreased dietary intake contribute to weight loss in lung cancer patients. Tumor localization and inflammation were found to be contributing factors to the elevated RE

The enhanced inflammatory response in non-small cell lung carcinoma is not reflected in the alveolar compartment.

AbstractAn inflammatory response has been observed in lung cancer both locally and systemically. The aim of the present study was to investigate whether the alveolar compartment was involved in the inflammatory response in non- small cell lung carcinoma (NSCLC). Both inflammatory mediators in bronchoalveolar lavage fluid (BALF) and cytokines produced by alveolar macrophages (AM) were investigated. Twenty patients with newly detected NSCLC and nine control subjects were studied. The patients had not been treated with chemotherapy, radiotherapy or with systemic or inhaled corticosteroids. All patients and control subjects were current smokers or stopped smoking recently. BAL was performed in the affected lung as well as in the contralateral lung of NSCLC patients, and only unilaterally in control subjects. Comparable results were demonstrated for the levels of the inflammatory mediators TNF-α, Interleukin (IL)-6, IL-8, both soluble TNF receptors and the soluble adhesion molecules E-selectin and intercellular adhesion molecule (ICAM)-1 between the affected lung and the contralateral lung in the NSCLC population as well as between the NSCLC population and the control subjects. Moreover, no significant differences in cytokine profiles of AM were found between AM obtained from the affected lung and from the contralateral lung. Although BAL is a useful tool in the diagnostic procedure for NSCLC, the present findings suggest that BAL does not reflect the enhanced inflammatory state, as reported in plasma and in the interstitial compartment around the tumour cells in NSCLC

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer

Introduction Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC).Materials and methods Treatment-naive patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity.Results Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity.Conclusion Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity