scholarly journals Meta-Analysis of Survival and Development of a Prognostic Nomogram for Malignant Pleural Mesothelioma Treated with Systemic Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2186
Author(s):  
Rupesh Kotecha ◽  
Raees Tonse ◽  
Muni Rubens ◽  
Haley Appel ◽  
Federico Albrecht ◽  
...  
Keyword(s):  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Systemic Chemotherapy ◽  
Meta Analysis ◽  
Performance Status ◽  
Locally Advanced ◽  
Phase Iii ◽  
Pleural Mesothelioma ◽  
Prognostic Variables ◽  
Phase Ii Studies

(1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. (2) Methods: Using PRISMA guidelines, a systematic review and meta-analysis was performed of MPM studies published from 2002–2019 obtained from the Medline database evaluating systemic therapy combinations for locally advanced or metastatic disease. Weighted random effects models were used to calculate survival estimates. The influence of proportions of known prognostic factors on overall survival (OS) were evaluated in the creation of a prognostic nomogram to estimate survival. The performance of this model was evaluated against data generated from one positive phase II study and two positive randomized trials. (3) Results: Twenty-four phase II studies and five phase III trials met the eligibility criteria; 2534 patients were treated on the included clinical studies. Ten trials included a platinum-pemetrexed-based treatment regimen, resulting in a pooled estimate of progression-free survival (PFS) of 6.7 months (95% CI: 6.2–7.2 months) and OS of 14.2 months (95% CI: 12.7–15.9 months). Fifteen experimental chemotherapy regimens have been tested in phase II or III studies, with a pooled median survival estimate of 13.5 months (95% CI: 12.6–14.6 months). Meta-regression analysis was used to estimate OS with platinum-pemetrexed using a variety of features, such as pathology (biphasic vs. epithelioid), disease extent (locally advanced vs. metastatic), ECOG performance status, age, and gender. The nomogram-predicted estimates and corresponding 95% CIs performed well when applied to recent randomized studies. (4) Conclusions: Given the rarity of MPM and the aggressive nature of the disease, innovative clinical trial designs with significantly greater randomization to experimental regimens can be performed using robust survival estimates from prior studies. This study provides baseline comparative values and also allows for accounting for differing proportions of known prognostic variables.

scholarly journals Nintedanib Plus Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Phase II Results From the Randomized, Placebo-Controlled LUME-Meso Trial

2017 ◽  
Vol 35 (31) ◽  
pp. 3591-3600 ◽  
Author(s):  
Federica Grosso ◽  
Nicola Steele ◽  
Silvia Novello ◽  
Anna K. Nowak ◽  
Sanjay Popat ◽  
...  
Keyword(s):  
Overall Survival ◽  
Placebo Group ◽  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
Pleural Mesothelioma ◽  
Double Blind

Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade ≥ 3 adverse event (AE; nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Conclusion Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.

Phase I Clinical and Pharmacokinetic Study of Pemetrexed and Carboplatin in Patients With Malignant Pleural Mesothelioma

2002 ◽  
Vol 20 (16) ◽  
pp. 3533-3544 ◽  
Author(s):  
Andy Hughes ◽  
Paula Calvert ◽  
Ashraf Azzabi ◽  
Ruth Plummer ◽  
Rob Johnson ◽  
...  
Keyword(s):  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Intravenous Infusion ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
World Health ◽  
Pleural Mesothelioma ◽  
Time Curve ◽  
Phase Ii Studies ◽  
Carboplatin Auc

PURPOSE: To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated. PATIENTS AND METHODS: Twenty-seven patients (23 male, four female) with MPM were treated on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m2 (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL·min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m2, carboplatin AUC 6 mg/mL·min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10). RESULTS: The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m2, carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days. CONCLUSION: The MTD was pemetrexed 500 mg/m2 and carboplatin AUC 6 mg/mL·min. The recommended phase II dose of the combination is pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL·min. The combination is both active and well tolerated in MPM and deserves further exploration.

scholarly journals A Review of Docetaxel: Its Use in the Treatment of Gastric Cancer

2010 ◽  
Vol 2 ◽  
pp. CMT.S5191
Author(s):  
Alessandro Inno ◽  
Michele Basso ◽  
Alessandra Cassano ◽  
Carlo Barone
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Poor Performance ◽  
Phase Iii ◽  
Poor Performance Status ◽  
Phase Ii Studies ◽  
Combination Regimens

Docetaxel, a member of the taxane family, promotes cell death by binding β-tubulin and has demonstrated activity against several human malignancies, both as a single agent and in combination therapy. It has been approved in Europe and the US as front-line treatment for advanced gastric cancer in combination with cisplatin and fluorouracil (DCF regimen). This approval was based on the results of a pivotal study (V325) which demonstrated that the addition of docetaxel to the reference regimen of cisplatin and fluorouracil improves overall survival and progression-free survival with a better quality of life despite increased toxicity (mainly haematological). Modifications of DCF regimen have been successfully investigated as a means of making the treatment more tolerable and suitable also for elderly patients or patients with poor performance status. Emerging data from several phase II studies suggest that other docetaxel-based combination regimens with anthracyclines or irinotecan have interesting activity with acceptable toxicity profiles, but the true efficacy of these regimens needs to be assessed in large randomized phase III studies. Thus, the best docetaxel-containing regimen has yet to be identified. Docetaxel also represents a good candidate for combination with novel molecular target agents. In light of the high response rates observed in phase II-III studies, a docetaxel-based chemotherapy regimen might also be considered a treatment option as perioperative or adjuvant therapy in potentially curable gastric cancer and further studies with or without biological agents are eagerly awaited in this setting.

Meta-analysis and systematic review of the cardiotoxicity of TAS-102.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16053-e16053 ◽  
Author(s):  
Carlos Alberto Lopez ◽  
Elham Azimi-Nekoo ◽  
Su Yun Chung ◽  
James Newman ◽  
Janice Shen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systematic Review ◽  
Phase I ◽  
Phase Ii ◽  
Literature Search ◽  
Meta Analysis ◽  
Phase Iii ◽  
Cardiac Events ◽  
Phase Ii Studies ◽  
Increased Risk

e16053 Background: Fluoropyrimidines such as 5-FU and capecitabine are known to be cardiotoxic drugs. TAS-102 (trifluridine-tipiracil) is a novel oral fluoropyrimidine that was recently FDA approved to treat gastric and colon cancer. However, the incidence of cardiac related events of TAS-102 is not fully ascertained. We performed a meta-analysis and systematic review to determine the incidence of cardiotoxic events associated with TAS-102. Methods: We performed a literature search through PubMed, Embase, and Web of Science to identify any publications in any language up to December 31st, 2019 where TAS-102 (and equivalent terms such as “trifluridine-tipiracil” and “Lonsurf”) was used. These were then manually reviewed to identify any publications reporting cardiac events. Randomized controlled trials (RCTs) were included for meta-analysis to determine the incidence of cardiotoxic events, which were summarized as pooled odds ratios (OR) when compared to placebo. Non-randomized, non-controlled clinical trials (phase I and phase II studies) were included in the systematic review but excluded from the pooled OR calculation. Results: 869 publications were identified in the initial literature search, of which 17 trials (3 Phase III studies, 6 Phase II studies, and 8 phase I studies) met inclusion criteria. A total of 1,877 patients among 4 RCTs were included in the meta-analysis. Compared with placebo, TAS-102 did not increase the risk of myocardial infarction (OR 1.97 95% CI [0.22-17.89]), hypertension (OR 0.73 95% CI [0.37, 1.44]), palpitations (OR 1.51 95% CI [0.30, 7.56]), cardio-pulmonary arrest (OR 0.83 95% CI [0.11-6.32]), or syncope (OR 1.50 95% CI [0.06-37.14]). Among the 1,252 patients receiving TAS-102, the overall incidence of cardiovascular events was low, with hypertension being the most common side effect (21 events), followed by palpitations (6 events), cardiopulmonary arrest (2 events), and myocardial infarction (3 events), though there was no statistically significant increased risk compared to placebo. No deaths were reported. Conclusions: Unlike other fluoropyrimidines, TAS-102 appears to be a cardiogentle drug, with no increased risk of cardiac events compared to placebo. Since fluoropyrimidines remain the backbone of treatment for gastrointestinal malignancies, TAS-102 can offer an alternative to patients who developed cardiotoxicities from other agents. Prospective studies with consideration of cardiac risk factors are required.

Phase III Randomized Comparison of Gemcitabine Versus Gemcitabine Plus Capecitabine in Patients With Advanced Pancreatic Cancer

2009 ◽  
Vol 27 (33) ◽  
pp. 5513-5518 ◽  
Author(s):  
David Cunningham ◽  
Ian Chau ◽  
Deborah D. Stocken ◽  
Juan W. Valle ◽  
David Smith ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Meta Analysis ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Primary Outcome Measure ◽  
Phase Iii ◽  
Open Label

PurposeBoth gemcitabine (GEM) and fluoropyrimidines are valuable treatment for advanced pancreatic cancer. This open-label study was designed to compare the overall survival (OS) of patients randomly assigned to GEM alone or GEM plus capecitabine (GEM-CAP).Patients and MethodsPatients with previously untreated histologically or cytologically proven locally advanced or metastatic carcinoma of the pancreas with a performance status ≤ 2 were recruited. Patients were randomly assigned to GEM or GEM-CAP. The primary outcome measure was survival. Meta-analysis of published studies was also conducted.ResultsBetween May 2002 and January 2005, 533 patients were randomly assigned to GEM (n = 266) and GEM-CAP (n = 267) arms. GEM-CAP significantly improved objective response rate (19.1% v 12.4%; P = .034) and progression-free survival (hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P = .004) and was associated with a trend toward improved OS (HR, 0.86; 95% CI, 0.72 to 1.02; P = .08) compared with GEM alone. This trend for OS benefit for GEM-CAP was consistent across different prognostic subgroups according to baseline stratification factors (stage and performance status) and remained after adjusting for these stratification factors (P = .077). Moreover, the meta-analysis of two additional studies involving 935 patients showed a significant survival benefit in favor of GEM-CAP (HR, 0.86; 95% CI, 0.75 to 0.98; P = .02) with no intertrial heterogeneity.ConclusionOn the basis of our trial and the meta-analysis, GEM-CAP should be considered as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.

A phase II trial of nintedanib in recurrent malignant pleural mesothelioma (MPM).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20061-e20061
Author(s):  
Antoinette J. Wozniak ◽  
Bryan J. Schneider ◽  
Gregory Peter Kalemkerian ◽  
Robert Michael Daly ◽  
Wei Chen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Malignant Pleural Mesothelioma ◽  
Stable Disease ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Unmet Need ◽  
Small Subset ◽  
Pleural Mesothelioma ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

e20061 Background: Malignant pleural mesothelioma (MPM) is a disease that is resistant to chemotherapy and there remains an unmet need for better therapeutic options. Nintedanib (BIBF 1120) is an oral multikinase inhibitor impacting VEGFR, FGFR, PDGFR, and other kinase activity such as TGFß signaling pathways. VEGF, FGF, and TGFβ are commonly expressed in MPM. We conducted a phase II trial in patients with recurrent MPM after platinum-based chemotherapy. Methods: Patients (pts) with MPM previously treated with platinum-based chemotherapy, performance status (PS) 0-1, adequate organ function, and no contraindications to anti-angiogenic therapy were eligible for treatment. Nintedanib 200 mg twice per day was administered until disease progression or unacceptable toxicity. The primary endpoint was the 4-month progression-free survival (PFS). A two-stage design was used and > 4 pts had to have a PFS of ≥4 months to proceed to the second stage. Results: Twenty pts. were enrolled. The median age was 70 yrs. (32-81), 90% were male, and 80% were PS = 1. The histology was 70% epithelioidal, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up is 16.4 mo. A median of 2 treatment cycles (range 1-18) were delivered. There were no responses but 40% had stable disease. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the PFS rate at 4 mo. was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the OS rate at 4 mo. was 55%. Toxicities were usually grade 1-2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea. Conclusions: The activity of nintedanib in previously treated MPM pts. was modest. The trial did not meet the primary PFS endpoint. However, there was a small subset of pts. that had prolonged stable disease for > 4 months thus potentially deriving some clinical benefit from treatment. Supported by Boehringer Ingelheim. Clinical trial information: NCT02568449.

scholarly journals Consensus Report of the National Cancer Institute Clinical Trials Planning Meeting on Pancreas Cancer Treatment

2009 ◽  
Vol 27 (33) ◽  
pp. 5660-5669 ◽  
Author(s):  
Philip A. Philip ◽  
Margaret Mooney ◽  
Deborah Jaffe ◽  
Gail Eckhardt ◽  
Malcolm Moore ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Locally Advanced ◽  
Evaluation Criteria ◽  
Predictive Biomarkers ◽  
Steering Committee ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Phase Ii Studies ◽  
Planning Meeting

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.

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