Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma
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.
References (35)
- et al.
Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM)
Ann Oncol
(2008) - et al.
Pemetrexed plus cisplatin or pemetrexed plus carbolatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program
J Thorac Oncol
(2008) - et al.
Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma
Ann Oncol
(2005) - et al.
Phase II trial of ZD0473 as second-line therapy in mesothelioma
Eur J Cancer
(2002) - et al.
Raltitrexed–oxaliplatin combination chemotherapy is inactive as second-line treatment for malignant pleural mesothelioma patients
Lung Cancer
(2005) - et al.
Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program
J Thorac Oncol
(2006) - et al.
Pemetrexed as second-line treatment in malignant pleural mesothelioma (MPM) after platinum-based first-line treatment
J Thorac Oncol
(2007) - et al.
Second-line treatment for malignant pleural mesothelioma
Cancer Treat Rev
(2010) - et al.
Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma
Lung Cancer
(2011) - et al.
Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial
Lancet
(2008)
Phase II trial of vinorelbine and oxaliplatin as first-line therapy in malignant pleural mesothelioma
Lung Cancer
The efficacy and safety of weekly vinorelbina in relepsed malignant pleural mesothelioma
Lung Cancer
Modified RECIST criteria for assessment of response in malignant pleural mesothelioma
Ann Oncol
A note on quantifying follow-up in studies of failure time
Control Clin Trials
Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas
Eur J Cancer
Future developments in the management of malignant pleural mesothelioma
Expert Rev Anticancer Ther
Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma
J Clin Oncol
Cited by (43)
Long-term benefit of lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma (MPM): final efficacy and translational data of the SAKK 17/16 study
2022, ESMO OpenCitation Excerpt :In this updated analysis of the SAKK 17/16 phase II trial, lurbinectedin continues to result in prolonged OS when administered in second- or third-line therapy in a subset of patients with advanced MPM. Almost half of the patients (47%) had a median OS of ≥12 months, which compares favorably with historical trials showing OS of <9 months.15-18 Importantly, we observed a clinically meaningful subgroup of patients (19%) who experience long-term benefit from lurbinectedin and continue to be alive ≥18 months.
Pleural mesothelioma (PM) – The status of systemic therapy
2021, Cancer Treatment ReviewsCitation Excerpt :In patients who have progressed on first-line platinum-pemetrexed, choice of second-line chemotherapy is not standardised and benefit unproven. Subsequent-line chemotherapy with gemcitabine, vinorelbine and anthracyclines have shown modest ORR, up to 16% in single arm trials or retrospective analyses.[31–37] The randomized phase 3 trial of pemetrexed versus best supportive care in pre-treated patients with PM without pemetrexed exposure, demonstrated an improved PFS, but no difference in OS, likely influenced by increased rate of post discontinuation chemotherapy use for the BSC arm, particularly pemetrexed.[36]
Immune checkpoint inhibitors a new player in the therapeutic game of mesothelioma: New reality with new challenges
2021, Cancer Treatment ReviewsCitation Excerpt :In patients with advanced MPM who progressed on previous platinum-based chemotherapy, the guidelines recommend different strategies such as retreatment with pemetrexed (specially in patients with progression at least 6 months after the first-course of pemetrexed), vinorelbine or gemcitabine [9]. However, this resulted in limited outcomes with a response rate (RR) ranging from 9.8% to 19%, median PFS from 2.3 to 3.3 months, and median OS below to 10 months [28–30]. In the most recent phase 2 VIM trial, active symptom control (ASC) plus vinreolbine in second line (80 mg/m2 [60 mg/m2 in the first cycle] on days 1, 8, and 15 of each 3-weekly) significantly improved the PFS compared with ASC alone (4.2 vs. 2.8 months, HR 0.60; 95% CI: 0.41–00,86, p = 0.002), without improving the OS (9.3 vs. 9.1 months, HR 0.79; 95%CI: 0.53–0.71, p = 0.24) [31].
A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma
2020, Lung CancerCitation Excerpt :Unfortunately, as for whole population, the characteristics of these patients are not sufficiently specific to be considered as potential biomarkers predictive of response to the combination of IM–GEM. In previous studies, we evaluated the activity of vinorelbine alone and combined with GEM in not selected population in the same setting [22,23]. The 3-month PFS rates were 47.5 % for patients treated with vinorelbine as monotherapy and 44.8 % for patients treated with vinorelbine combined with GEM compared with 39.1 % for patients treated with the combination of IM–GEM.