Patient-Derived Xenograft Establishment from Human Malignant Pleural Mesothelioma.

Purpose: Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with few therapeutic options. The tumor-stromal interface is important in MPM, but this is lost in cell lines, the main model used for preclinical studies. We sought to characterize MPM patient-derived xenografts (PDX) to determine their suitability as preclinical models and whether tumors that engraft reflect a more aggressive biological phenotype.Experimental Design: Fresh tumors were harvested from extrapleural pneumonectomy, decortication, or biopsy samples of 50 MPM patients and implanted subcutaneously into immunodeficient mice and serially passaged for up to five generations. We correlated selected mesothelioma biomarkers between PDX and patient tumors, and PDX establishment with the clinical pathologic features of the patients, including their survival. DNA of nine PDXs was profiled using the OncoScan FFPE Express platform. Ten PDXs were treated with cisplatin and pemetrexed.Results: A PDX was formed in 20 of 50 (40%) tumors implanted. Histologically, PDX models closely resembled the parent tumor. PDX models formed despite preoperative chemotherapy and radiotherapy. In multivariable analysis, patients whose tumors formed a PDX had significantly poorer survival when the model was adjusted for preoperative treatment (HR, 2.46; 95% confidence interval, 1.1-5.52; P = 0.028). Among 10 models treated with cisplatin, seven demonstrated growth inhibition. Genomic abnormalities seen in nine PDX models were similar to that previously reported.Conclusions: Patients whose tumors form PDX models have poorer clinical outcomes. MPM PDX tumors closely resemble the genotype and phenotype of parent tumors, making them valuable models for preclinical studies. Clin Cancer Res; 23(4); 1060-7. ©2016 AACR.

Phase 1/2 Study of the Addition of Cisplatin to Adjuvant Chemotherapy With Image Guided High-Precision Radiation Therapy for Completely Resected Gastric Cancer.

PURPOSE: Locoregional recurrence is common after surgery for gastric cancer. Adjuvant therapy improves outcomes but with toxicity. This phase 1/2 study investigated infusional 5-fluorouracil (5-FU) in combination with biweekly cisplatin delivered concurrently with image guided high-precision radiation therapy. METHODS AND MATERIALS: Eligible patients had completely resected stage IB to IV (Union for International Cancer Control TNM 6th edition) nonmetastatic gastric adenocarcinoma. Treatment constituted 12 weeks of infusional 5-FU (200 mg/m2/day) with cisplatin added in a standard 3 + 3 dose escalation protocol (0, 20, 30, and 40 mg/m2) during weeks 1, 3, 5, and 7, and an additional week 9 dose in the final cohort. Radiation therapy (45 Gy in 25 fractions) was delivered during weeks 3 to 7. Maximum tolerated dose (MTD) was determined in phase 1 and confirmed in phase 2. RESULTS: Among the 55 patients (median age, 54 years; range 28-77 years; 55% male), the median follow-up time was 3.0 years (range, 0.3-5.3 years). Five patients in phase 1 experienced dose-limiting toxicity, and MTD was determined as 4 cycles of 40 mg/m2 cisplatin. Twenty-seven patients were treated at MTD. Acute grade 3 to 4 toxicity rate was 37.0% at MTD and 29.1% across all dose levels. No treatment-related deaths occurred. Fourteen patients experienced recurrent disease. The 2-year overall survival (OS) and relapse-free survival were 85% and 74%, respectively. Median OS has not been reached. Quality of life (QOL) was impaired during treatment, but most scores recovered by 4 weeks. CONCLUSION: Cisplatin can be safely delivered with 5-FU-based chemoradiation therapy. Acute toxicity was acceptable, and patient-reported QOL showed the regimen was tolerable. Outcomes are encouraging and justify further study of this regimen.

A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: the "SMART" approach for resectable malignant pleural mesothelioma.

INTRODUCTION: We developed an innovative approach for malignant pleural mesothelioma (MPM) with a short accelerated course of high-dose hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP). This phase I/II study assessed the feasibility of Surgery for Mesothelioma After Radiation Therapy (SMART). METHODS: All resectable clinical T1-3N0M0 histologically proven, previously untreated MPMs were eligible. Patients received 25 Gy in five daily fractions during 1 week to the entire ipsilateral hemithorax with concomitant 5 Gy boost to areas at risk followed by EPP within 1 week of completing neoadjuvant IMRT. Adjuvant chemotherapy was offered to ypN2 patients on final pathologic findings. The primary end point was treatment-related mortality and secondary end points were overall survival, disease-free survival, treatment-related morbidity, and patterns of failure. RESULTS: Targeted accrual of 25 patients was completed between November 2008 and October 2012. All patients completed SMART. IMRT was well tolerated with no grade 3+ toxicities. EPP was performed 6 ± 2 days after completing IMRT without any perioperative mortality. Thirteen patients developed grade 3+ surgical complications. One patient (4%) died from treatment-related toxicity (empyema) during follow-up. All but one patient had stage III or IV disease on final pathologic findings. Five of 13 ypN2 patients received adjuvant chemotherapy. After a median follow-up of 23 months (range, 6-51), the cumulative 3-year survival reached 84% in epithelial subtypes compared with 13% in biphasic subtypes (p = 0.0002). CONCLUSIONS: SMART is feasible in resectable MPM patients. This innovative protocol presents encouraging results and supports future studies looking at long-term outcome in patients with epithelial subtypes.

A phase II and pharmacokinetic study of SB-715992, in patients with metastatic hepatocellular carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG IND.168).

Hepatocellular carcinoma (HCC) remains a lethal treatment-resistant cancer with a median survival of <6 months in patients not considered candidates for radical surgical treatments. SB-715992 is a novel cytotoxic agent implicated in the inhibition of mitotic kinesin spindle protein (KSP). Based on evidence from preclinical models and phase I trials, we conducted a phase II trial of SB-715992 in chemo-naïve patients with advanced HCC. A non-randomized, non-blinded multicentre two-stage phase II study was completed examining the efficacy, toxicity, and pharmacokinetics of SB-715992 at 18 mg/m2 IV q 3 weeks, in patients with measurable locally advanced, metastatic or recurrent HCC. The predictive value of KSP in archival tumour was assessed. Fifteen patients with metastatic HCC received a median of 3 cycles of SB-715992. The most common grade 3+ toxicities were granulocytopenia, leukocytopenia, diarrhea and liver transaminase rise. Overall confirmed response rate was 0%. Seven (46%) patients had a best response of stable disease at the 8-week evaluation (median duration 3.9 months) Median time to progression was 1.61 months (95%CI = 1.31-3.94 months) SB-715992 plasma concentrations were comparable to those observed in the phase I studies. Expression of KSP by immunohistochemistry was observed in only four of eight evaluable samples with strong expression reported in only two. No correlation was observed between intensity of KSP staining and clinical outcome. Among these patients with preserved hepatic function and good performance status, SB-715992 was generally well tolerated. However, no conclusive evidence of benefit was seen with SB-715992 monotherapy in HCC.

Use of the epidermal growth factor receptor inhibitors gefitinib and erlotinib in the treatment of non-small cell lung cancer: a systematic review.

INTRODUCTION: Inhibition of the epidermal growth factor receptor is a promising therapy in the treatment of non-small cell lung cancer (NSCLC). In this systematic review, we evaluated the role of the epidermal growth factor receptor inhibitors gefitinib and erlotinib in the treatment of patients with advanced NSCLC. METHODS: Relevant randomized trials published as articles or abstracts were identified through a systematic search of the literature from 1975 to November 2005 by two independent reviewers. RESULTS: Twelve randomized trials met the predefined eligibility criteria for this systematic review. Four large placebo-controlled trials demonstrated that the addition of gefitinib or erlotinib to platinum-based first-line chemotherapy did not significantly improve overall survival or time-to-disease progression. A large placebo-controlled trial revealed a clinically and statistically significant survival benefit for erlotinib therapy as second- or third-line systemic therapy. The results of a single placebo-controlled trial and two phase II trials suggest that modest tumor response rates and symptom control can be achieved with gefitinib as second-line or subsequent therapy; however, a statistically significant survival benefit was not found for gefitinib compared with placebo. CONCLUSION: There is strong evidence to recommend against the use of gefitinib or erlotinib in combination with chemotherapy or as maintenance therapy after chemotherapy and radiation as a first-line treatment for advanced NSCLC. Erlotinib monotherapy is an effective treatment that can prolong survival for patients with advanced NSCLC whose disease has relapsed or recurred after prior chemotherapy. Although a significant survival benefit has not been demonstrated for gefitinib in a placebo-controlled study, the two randomized phase II trials suggest that gefitinib may provide clinically important symptomatic benefits.

Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial.

PURPOSE: Biliary cancer has a poor prognosis, and chemotherapy has had little impact. The objectives of this trial were to determine the response rate, time to disease progression, survival, and safety profile of the combination of gemcitabine and capecitabine (GemCap) in patients with advanced biliary cancer. PATIENTS AND METHODS: Eligible patients had pathologically proven, locally advanced or metastatic adenocarcinoma arising from the intra- and extrahepatic bile ducts or gallbladder with no prior chemotherapy. Patients were treated on a 3-week cycle consisting of capecitabine at 650 mg/m(2) orally twice a day for 14 days and gemcitabine at a fixed dose of 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8. RESULTS: Forty-five patients were enrolled between July 2001 and January 2004. Fifty-three percent of patients had cholangiocarcinoma, 47% had gallbladder cancer, and 89% had metastatic disease. The overall objective response rate was 31%, with an additional 42% of patients with stable disease, for a disease control rate of 73%. The median overall survival time was 14 months (95% CI, 7.3 months to not available), and the median progression-free survival time was 7 months (95% CI, 4.6 to 11.8 months). This chemotherapy combination was generally well tolerated. Transient neutropenia, thrombocytopenia, fatigue, and hand-foot syndrome were commonly observed but were easily managed without discontinuing further treatment. CONCLUSION: The significant antitumor activity combined with a mild toxicity profile seen in this study argue that GemCap chemotherapy may benefit patients with advanced biliary cancer. This regimen warrants further evaluation in a randomized study with survival and quality of life end points.