Carboplatin Plus Pemetrexed as First-line Treatment of Patients with Malignant Pleural Mesothelioma: A Phase II Study

Nikolaos Katirtzoglou; Ioannis Gkiozos; Nektaria Makrilia; Emilia Tsaroucha; Aggeliki Rapti; Grigorios Stratakos; Georgios Fountzilas; Konstantinos N. Syrigos

Disclosures

Clin Lung Cancer. 2010;11(1):30-35. 

In This Article

Abstract and Introduction

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a rapidly progressive tumor that is increasing in frequency worldwide. Treatment options are limited, and response to chemotherapy is poor. The aim of this phase II study was to evaluate the activity of the carboplatin/pemetrexed combination as first-line chemotherapy in patients with unresectable MPM.
Patients and Methods: Chemotherapy-naive patients with histologically confirmed MPM and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled. Treatment consisted of pemetrexed 500 mg/m2 and carboplatin area under the concentration-time curve of 5 mg/mL/min, both administered on day 1 of a 21-day cycle. The treatment continued until 6 cycles were completed or until unacceptable toxicity or disease progression were observed.
Results: A total of 62 patients were enrolled. Of these patients, 18 (29%) had a confirmed partial response, whereas the disease remained stable in 34 patients (54.9%) and progressed in 10 patients (16.1%). The median overall survival (OS) was estimated at 14 months (95% CI, 11.8–16.2 months), and the median time to progression was 7 months (95% CI, 5.8–8.2 months). The difference in median OS between the epithelial histologic subtype (16 months) and the sarcomatoid subtype (11 months) was statistically significant.
Conclusion: This study confirmed the activity of the carboplatin/pemetrexed combination in the first-line treatment of patients with MPM. It is a viable option, especially in cases in which side effects are generally anticipated.

Introduction

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a median survival of less than a year.[1,2] MPM is causally associated with asbestos exposure, but the latency period after exposure can last for several decades. It arises from the mesothelial surfaces of the pleural cavity, and it is locally invasive. The incidence of MPM has been increasing in industrialized countries, and it is thought that it will continue to increase in the future.[3] Very few patients are eligible for curative surgical resection, and no randomized evidence exists to support its efficacy.[4] Radiation therapy has also demonstrated poor results, rendering chemotherapy the treatment of choice. Nevertheless, MPM is often refractory to chemotherapeutic agents, and treatment intent is mostly palliative.[5]

A study by Ellis et al demonstrated overall response rates (ORRs) of < 10% and < 12% for single-agent therapy and nonplatinum combinations, respectively, whereas this rate for platinum-based chemotherapy was 25%.[6] Standard chemotherapeutic regimens in MPM are therefore platinum based.[6,7] A meta-analysis by Berghmans et al proved cisplatin to be the most active monotherapy agent in mesothelioma.[8] Pemetrexed monotherapy in previously untreated patients has exhibited a 14.5% RR,[9] which can reach 16% when vitamin supplementation is added.[10] Survival has been shown to improve when pemetrexed is combined with platinum agents.[11,12]

Two phase III studies have demonstrated benefit from the combination of cisplatin and an antifolate. The landmark trial of Vogelzang et al, which was the largest randomized trial, showed significant advantage in terms of survival and RRs with pemetrexed plus cisplatin when compared with cisplatin monotherapy.[1] Median overall survival (OS) was 2.8 months longer in the combination arm (12.1 months vs. 9.3 months in the cisplatin arm), and median time to progression (TTP) was also longer with the doublet (5.7 months vs. 3.9 months). Additionally, the combination of raltitrexed and cisplatin showed a 2.6-month improvement in OS, and 1-year survival was improved when raltitrexed was added to cisplatin monotherapy.[2] Recently, an international expanded-access program (EAP) single-arm open-label study was conducted in the United States examining the cisplatin/pemetrexed regimen and showed a 20.5% RR and a 45.4% 1-year survival rate.[13] These rates were slightly higher in the European EAP study.[14] The cisplatin/pemetrexed combination is currently considered the gold-standard doublet in MPM, as it was approved by the US Food and Drug Administration in February 2004 and by the European Medicines Agency for patients with advanced unresectable disease or who are not eligible candidates for surgery.[15]

Lee et al conducted a cohort review of practice in British Columbia and concluded that cisplatin and carboplatin appear to have comparable efficacy.[16] The carboplatin/pemetrexed combination has been studied in 2 phase II trials[17,18] and by a retrospective review[19] that showed a median OS ranging from 12.7 months to 14 months. With respect to other chemotherapeutic agents, results have been poor. Two studies concerning the gemcitabine/cisplatin combination showed median OS of 10 months and 11.2 months, respectively.[20,21] Several other cisplatin combination regimens have been attempted, with RRs of 24% to 26%.[22–24] Oxaliplatin-based combinations have shown an ORR of 20%-40%.[25–27] Bevacizumab has also been studied in combination with other regimens, but no improvement in OS has been observed.[28] The multimodality approach has been attempted, but further research is needed to identify groups of patients that would benefit.[29]

Following these results, we designed a phase II study to evaluate the activity of pemetrexed and carboplatin as first-line chemotherapy in patients with nonresectable MPM. This regimen was chosen because cisplatin is associated with severe neurotoxicity as well as ototoxicity and renal toxicity,[1] and carboplatin is preferred in its place when patients are elderly or have poor performance status (PS). In addition, it should be taken into account that chemotherapy in MPM is mostly palliative, and adverse events are to be avoided as much as possible.

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