The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma
Introduction
Malignant pleural mesothelioma (MPM) is a rapidly lethal malignancy causally associated with exposure to asbestos with a prevalence that is set to increase significantly in Europe over the next decade [1], [2], [3], [4]. MPM is often refractory to cytotoxic treatment, which may be due to intrinsic apoptosis resistance [5]; a variety of single agents achieve low response rates of around 20% [6], [7], [8], [9].
No reported randomised trial has yet confirmed a benefit of chemotherapy over best supportive care although one trial, MS-O1 (active symptom control versus vinorelbine versus mitomycin/cisplatin/vinblastine) is due to report full data [10]. Two phase 3 randomised trials comparing either the ‘gold standard’ doublet pemetrexed (Alimta®) and cisplatin [8], [11], [12], or ralitrexed (Tomudex®) and cisplatin [13], [14] versus cisplatin alone, confirmed a survival advantage for both doublets [15].
The efficacy of radical surgery is not yet proven due to a lack of randomised evidence [16], and radical radiotherapy although providing palliative benefit, does not appear to improve overall survival (OS) [17].
There exists only a paucity of reports of second-line therapy for individuals with relapsed MPM. Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. We have recently published the use of the triplet irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy in the front line and second-line settings. In relapsed disease, progression-free survival (PFS) measured 7.3 months (95% CI: 3.4–11.2) and overall survival was also 7.3 months (95% CI: 4.8–9.8) [18].
Vinca alkaloids have known activity in MPM and vinflunine monotherapy has reasonable response rates in untreated individuals [19]. Vinorelbine has been used as part of a first-line triplet regimen in combination with cisplatin and gemcitabine in 12 patients [20] and we have studied its use in combination with oxaliplatin, a doublet that was found to be associated with significant toxicities with 18% of patients developing grade III or IV neutropenia [21]. A recent study evaluated gemcitabine–vinorelbine on days 1 and 8 of a 3 weekly cycle in 30 individuals pretreated with pemetrexed: a partial response (PR) was observed in 10% and stable disease (SD) occurred in 33.3% with grade III or IV neutropenia occurring in 10% of patients [22]. Overall, the gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM.
We have also previously studied weekly single-agent vinorelbine, in the first-line setting (n = 29), which was found to induce a partial response rate of 24%, a stable disease rate of 55% with 21% having disease progression during chemotherapy [23]. Although grade III or IV neutropenia occurred at least once in 62% of patients, only one patient experienced neutropenic sepsis requiring hospital admission and intravenous antibiotics. To investigate use of this regimen further, we wished to establish the efficacy and toxicity of weekly vinorelbine in 63 individuals with relapsed previously treated MPM.
Section snippets
Patients and methods
A total of 63 patients with MPM, previously treated with one chemotherapy regimen were enrolled onto a single-center trial of weekly vinorelbine. The study had appropriate institutional ethical review board approval, and all patients provided written, informed consent. All recruited individuals were required to have measurable, histologically confirmed, inoperable, MPM and to be >18 years old, with Eastern Cooperative Oncology Group (ECOG) performance statuses (PSs) of 0–2 and no uncontrolled
Results
Table 1 demonstrates the patient characteristics for the 63 individuals with relapsed MPM. The median age was 59 years (range 29–77), the majority (94%) were male and all patients had pleural ‘only’ MPM (no patients with peritoneal disease were included). Histology was available on all patients and the majority (62%) had epithelial histology, with more advanced IMIG staging (III or IV in 64%) although only 22% had an ECOG performance status of 2, the remainder having an ECOG performance status
Discussion
Weekly vinorelbine demonstrates useful clinical activity in the second-line treatment of MPM and appears well tolerated in the second-line setting; its use requires validation in prospective randomised studies.
It is surprising that the median overall survival on a salvage study was 9.6 months and the stable disease rate at 6 months was 68% though this may reflect the aggressive nature of MPM when progression does occur, often following cessation of cytotoxic chemotherapy. In our previous study
Conflict of interest
None.
Acknowledgment
We are grateful to the study participants and Linda Clarke for help with patient notes.
References (33)
- et al.
Survival from rare cancer in adults: a population-based study
Lancet Oncol
(2006) - et al.
Defective core-apoptosis signalling in diffuse malignant pleural mesothelioma: opportunities for effective drug development
Lancet Oncol
(2004) The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guidelines
J Thorac Oncol
(2006)- et al.
Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program
Clin Lung Cancer
(2005) - et al.
Systemic chemotherapy in the management of malignant peritoneal mesothelioma
Eur J Surg Oncol
(2006) - et al.
Surgical management of malignant pleural mesothelioma: a systematic review and evidence summary
Lung Cancer
(2005) - et al.
The role of radiation therapy in malignant pleural mesothelioma: a systematic review
Radiother Oncol
(2006) - et al.
Phase II trial of vinorelbine and oxaliplatin as first-line therapy in malignant pleural mesothelioma
Lung Cancer
(2005) A proposed new international TNM staging system for malignant pleural mesothelioma from the International Mesothelioma Interest Group
Lung Cancer
(1996)- et al.
Ralitrexed–oxaliplatin combination chemotherapy is inactive as second-line treatment for malignant pleural mesothelioma patients
Lung Cancer
(2005)
Intensity modulated radiotherapy to deliver hemithorax irradiation for mesothelioma for the Mars trial
Clin Oncol (Roy Coll Radiol)
The European mesothelioma epidemic
Br J Cancer
Advances in the systemic therapy of malignant pleural mesothelioma
Nat Clin Pract Oncol
Malignant mesothelioma resistance to apoptosis: recent discoveries and their implication for effective therapeutic strategies
Curr Med Chem
Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials
J Clin Oncol
Cited by (128)
EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study
2022, The Lancet OncologyCitation Excerpt :Additionally, this study did not collect information regarding time since initial diagnosis, which might have biased the cohort to those with more indolent disease. Although the response rate was modest in these patients with relapsed or refractory malignant pleural mesothelioma, the adverse event profile, as well as the evidence of prolonged disease control, compares favourably against traditional second-line cytotoxic agents used in this setting, such as gemcitabine and vinorelbine.10–14 The emerging data for checkpoint inhibitors,15,16 although not directly comparable, provide similar disease control rates: 12-week disease control rate of 44% (95% CI 31–58) with nivolumab and 50% (37–63) with nivolumab plus ipiliminumab in the MAPS2 trial17; 68% disease control rate (95% CI 51–81; median follow-up 16·8 months) with nivolumab in the Japanese study;15 and the survival advantage of nivolumab over placebo in the randomised CONFIRM study (median progression-free survival 3·0 months [95% CI 2·8–4·1] vs 1·8 months [1·4–2·6]; median overall survival 10·2 months [95% CI 8·5–12·1] vs 6·9 months [5·0–8·0]).18
Pleural mesothelioma (PM) – The status of systemic therapy
2021, Cancer Treatment ReviewsTumour Treating Fields for mesothelioma: controversy versus opportunity
2019, The Lancet Oncology