Elsevier

Lung Cancer

Volume 84, Issue 3, June 2014, Pages 265-270
Lung Cancer

Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma

https://doi.org/10.1016/j.lungcan.2013.11.011Get rights and content

Abstract

Background

Pemetrexed-platinum chemotherapy is the standard first-line treatment of unresectable malignant pleural mesothelioma (MPM). At progression, patients are generally selected to experimental trials, when available, or, in every-day clinical practice, they are offered second-line chemotherapy. The optimal treatment has not yet been defined. The aim of this retrospective, single-center study was to evaluate the activity and toxicity of vinorelbine administered to a consecutive series of pemetrexed-pretreated MPM patients.

Methods

Vinorelbine 25 mg/m2 was administered intravenously as a single agent on days 1, 8 every three weeks, either as second-line (2L) or further-line (>2L) therapy. Treatment was repeated for a maximum of 6 cycles, until progression, or unacceptable toxicity.

Results

Fifty-nine patients were included in this analysis. Vinorelbine was given to 34 patients as 2L, and to 25 as >2L treatment. The median age was 69 years (range 45–80). Forty-two patients (71.2%) had a good EORTC prognostic score. Partial response was observed in 9 (15.2%) cases, stable disease in 20 (33.9%). The overall disease control rate (DCR) was 49.1%. Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.2 months, respectively. ECOG performance status (PS) (HR0 vs. 1–2 0.50; 95%CI: 0.3–0.8; p = 0.014) and PFS  6 months following first-line (FL) chemotherapy (HRFL-PFS>6ms vs. <6ms 0.50; 95%CI: 0.3–0.9; p = 0.031) were significantly associated to OS in multivariate analysis. No difference was observed in terms of DCR, PFS, and OS in relation to age, histology, sex, line of vinorelbine therapy, or response to FL treatment. Hematological toxicity was acceptable, with grade 3/4 neutropenia occurring in 5 (8.4%) patients, and there were no cases of febrile neutropenia. The main non-hematological toxicities were grade 2 fatigue in 17 (28.8%) and constipation in 7 (11.8%) patients.

Conclusions

Vinorelbine was moderately active in pemetrexed-pretreated MPM patients, with an acceptable toxicity profile, particularly in patients with ECOG-PS0 and FL-PFS ≥6 months.

Introduction

Most MPM patients receive chemotherapy during the course of their disease. The combination of pemetrexed with cisplatin is the current standard of care in the first-line setting [1], [2]. In patients unfit to receive cisplatin-based chemotherapy, pemetrexed alone or combined with carboplatin has been proposed in an attempt to reduce toxicity yet maintain the same survival outcomes [3], [4], [5], [6]. Unfortunately, nearly all MPM patients progress during or after first-line treatment. Second-line (SL) therapy is frequently administered, but its role in MPM is not yet established [7]. A number of single-arm and a few randomized studies have clearly shown that chemotherapy in the SL setting is feasible and may be active [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. A randomized, multi-center phase III study has shown a clinical benefit for single agent pemetrexed as compared to placebo in pemetrexed-naïve patients, with a statistically significant improvement in time to progressive disease. Improvement in overall survival has not been seen, possibly due to the influence of post-study chemotherapy on the BSC arm [15]. In pemetrexed-pretreated patients, no compound has demonstrated an improvement in survival outcomes [18]. In patients achieving a prolonged benefit from FL pemetrexed-based chemotherapy, retreatment with pemetrexed as a single agent or in combination with a platinum compound has shown relevant activity in small retrospective series [19], [20].

Vinca alkaloids are active in MPM. Vinorelbine has shown activity in the FL setting both as a single agent [21], [22], [23] and in combination with platinum compounds [24], [25], [26]. Studies with vinorelbine in the SL setting are scarce. In a single-center phase II study 63 pretreated patients achieved a response rate of 16% and a median OS of 9.6 months [27] with single agent vinorelbine; however, patients had been pretreated with several regimens, and the authors did not disclose what percentage of patients were treated with pemetrexed-based chemotherapy in the first-line setting. In another prospective trial, our group evaluated vinorelbine combined with gemcitabine on days 1 and 8 of a 3-weekly cycle in 30 pemetrexed-pretreated individuals [16]. A PR and SD were observed in 3 patients (10%), and 10 patients (33.3%), respectively. Median TTP and OS were 2.8 months and 10.9 months. As far as we know, there are no published data of single agent vinorelbine in pemetrexed-pretreated patients.

The aim of the current study was therefore to retrospectively assess the activity and toxicity profile of vinorelbine administered either as second-line (2L) or further-line (>2L) therapy in a consecutive series of pemetrexed-pretreated patients treated at our institution.

Section snippets

Patient selection

Patients progressing after pemetrexed-based chemotherapy and treated between January 2001 and July 2012 at the Humanitas Clinical and Research Center (Rozzano, Milan, Italy) with single agent vinorelbine either as 2L or >2L therapy were included in this analysis.

Treatment

Patients received intravenous vinorelbine at the dose of 25 mg/m2, given on days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles, until progression, or unacceptable toxicity. Dose adjustments at the start of a

Patients characteristics

Overall, 59 patients were included in the study. Patient characteristics are listed in Table 1. There were 38 males and 21 females. The median age was 69 years (range: 45–80 years). Most patients had an epithelial histological subtype (89.8%) and a good EORTC prognostic score (71.2%). All patients had previously received pemetrexed-based chemotherapy, achieving PR and SD in 20 (33.9%) and 29 cases (49.2%), respectively. A FL-PFS > 6 months after pemetrexed-based chemotherapy was observed in 33

Discussion

No standard option is available as second-line treatment for pemetrexed pretreated MPM patients. Nearly all studies in this setting had disappointing results, and prospective trials with new compounds are seldom available in clinical practice. Literature data show response rates of 7–11%, and DCR ranging from 33 to 65%. Median PFS and OS are in the range of 2.2–3.5 months, and 5.6–10.9 months, respectively [18]. Most studies have severe methodological limitations, with small numbers of patients

Conclusions

Our study confirms the feasibility of 2L chemotherapy in MPM patients. Considering the lack of a standard treatment in pemetrexed-pretreated patients, this remains an ideal field in which to test new agents. Patients should be encouraged to participate in clinical trials. When a trial is unavailable or patients are ineligible for an experimental approach, single agent chemotherapy with vinorelbine appears to be a reasonable palliative option, mainly in patients with ECOG PS 0 and with prolonged

Conflict of interest statement

We did not receive any financial, material, or specific funding for this work. All authors have no relevant financial interests in this manuscript.

Acknowledgements

Not applicable.

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