The palliative benefits of MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in patients with malignant mesothelioma

E. Andreopoulou, P. J. Ross, M. E. R. O'Brien*, H. E. R. Ford, K. Priest, T. Eisen, A. Norton, S. Ashley and I. E. Smith

Lung Unit, Royal Marsden Hospital, Surrey, UK

* Correspondence to:Dr M. E. R. O'Brien, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-20-8661-3278; Fax: +44-20-8643 0373; Email: maryo{at}icr.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background: With the rising incidence of malignant mesothelioma (MM), it is important to optimise treatment to control symptoms, maintain quality of life and, if possible, prolong life. We have analysed prospectively collected data to evaluate a frequently used palliative chemotherapy regimen.

Patients and methods: Between October 1986 and May 2002 all patients with inoperable pleural mesothelioma were considered for treatment with MVP (mitomycin C 8 mg/m2 every 6 weeks, vinblastine 6 mg/m2 every 3 weeks and cisplatin 50 mg/m2 every 3 weeks) chemotherapy. Symptoms were assessed by physician assessment at baseline and after each cycle of chemotherapy.

Results: One hundred and fifty patients were treated with MVP for mesothelioma. Forty-three per cent had a performance status (PS) 2 or worse. The response rate was 15.3%, with 68.6% having stable disease. Sixty-nine per cent reported an improvement in symptoms; in particular there were good responses for pain (71%), cough (62%) and dyspnoea (50%). The most common grade 3/4 toxicity was neutropenia (22%). Median overall survival was 7 months, with 1-year survival 31% and 2-year survival 11%. Median survival for patients with PS 0/1 was 10 months, and was 6 months for patients with PS 2/3. Poor prognostic factors in univariate analysis included poor PS, weight loss, mixed or sarcomatoid histology, low haemoglobin and high white blood cell count. Excluding pathological subtype, the prognostic significance of poor PS and weight loss were retained in multivariate analysis.

Conclusions: Palliation of symptoms in MM is achievable with current cisplatin-based treatments.

Key words: mesothelioma, palliative chemotherapy, symptoms, MVP, survival


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
As the incidence of malignant mesothelioma (MM) is increasing [1Go], we are faced with the challenge of treating the previously untreatable. Most patients with MM have locally advanced disease at presentation. The natural history may involve aggressive local growth, invasion of vital mediastinal structures and death within 4–12 months without treatment [2Go–4Go]. However, there is also a type of disease that progresses slowly and with which patients may be asymptomatic for long periods [5Go].

The diffuse nature of the disease implies a limited role for both surgery and radiotherapy, but with modern techniques this is an area for future studies. Multimodality approaches that include surgery, radiation and chemotherapy have reported long survival in selected cases [6Go]; however, most patients with mesothelioma are not suitable for such an intensive approach to treatment. Radiotherapy has demonstrable palliative benefits [7Go–9Go]. The real impact of systemic chemotherapy on the natural history of MM is still uncertain, because trials comparing chemotherapy with best supportive care have not been completed; such a study has been started by the British Medical Research Council (MRC) [10Go]. Single-agent chemotherapy and combination regimens have been evaluated, but only a few have consistently demonstrated response rates of ~20%, with median survivals of 7–9 months [11Go, 12Go]. The most active classes of drugs are anthracyclines, platinum agents, vinca alkaloids and antifolates, with gemcitabine, vinorelbine and pemetrexed being the most active of the new generation of drugs [13Go–16Go]. Consequently, there is no internationally accepted standard treatment. Studies are increasingly showing that systemic therapy can provide significant palliative benefits [17Go–20Go].

Our institution uses the chemotherapy combination of mitomycin C, vinblastine and cisplatin (MVP) for the treatment of mesothelioma. We report here our experience with this combination of drugs in a large series of patients with mesothelioma in whom data were collected prospectively from the time of their first referral. This report is an update of the outcome of this group and an assessment of prognostic factors.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Patients with histologically confirmed MM were offered treatment with the MVP regimen. Histology was centrally reviewed for the majority of patients. Following an audit demonstrating accurate pathological diagnosis at referral, central review was not undertaken in all cases after April 1999. Histological subtyping was undertaken once the prognostic significance of this became apparent in the late 1990s [21Go, 22Go]. Patients were required to have adequate renal function (clearance >60 ml/min), normal haematological indices, no previous malignancy, and no serious medical or psychiatric illness. Patients underwent pre-treatment physical examination and computed tomography (CT) scan of thorax and abdomen, together with chest X-ray. All patients gave their written informed consent to receive treatment.

Treatment
All patients received the following regimen: mitomycin C 8 mg/m2 intravenously (i.v.) on day 1 (given on courses 1, 2, 4 and 6), vinblastine 6 mg/m2 (maximum 10 mg) i.v. on day 1 and cisplatin 50 mg/m2 i.v. on day 1, repeated every 21 days. Standard antiemetic therapy and intravenous pre- and post-treatment hydration was given with cisplatin [18Go]. Treatment continued until the development of progressive disease, unacceptable toxicity or to a maximum of six cycles (four cycles from late 1997) in patients achieving objective response and/or symptomatic benefit.

Response and toxicity
Response was evaluated clinically and radiologically. A chest X-ray was performed prior to each cycle of chemotherapy and CT scans of thorax and abdomen at baseline and after every two cycles of chemotherapy. Objective radiological response was assessed according to standard WHO criteria [23Go]. Tumour-related symptoms were recorded at the start of treatment under the following general headings: malaise, pain, cough, dyspnoea or ‘other’, which were then specified. Symptoms were assessed by the treating physician and graded as none, mild/moderate or severe, using the same methodology that has been used previously [24Go, 25Go]. Symptoms were reassessed following each course of treatment, with patients asked to grade changes in symptoms using simple descriptive criteria as follows: (i) complete disappearance of symptoms (complete response, CR); (ii) good improvement of symptoms (partial response, PR); (iii) minor or no change of symptoms (no change, NC); or (iv) worse (progressive disease, PD). Toxicity was assessed according to standard WHO criteria.

Statistics
Response duration and overall survival from the date of first treatment and survival curves were generated using the method of Kaplan and Meier [26Go], and compared by the log rank test [27Go]. Multivariate Cox's proportional hazards model [28Go] was used to calculate the relative risk of progression or death and to investigate the independent significance of prognostic variables. All P-values were two-sided.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient characteristics
Between October 1986 and May 2002, 244 patients were seen by the lung unit of The Royal Marsden Hospital with a diagnosis of MM. One hundred and fifty (61.5%) patients were treated with MVP and are the subject of this analysis. This group included 132 men with a median age of 62 years (Table 1). Five patients had received prior local radiation therapy. Seventeen patients received concurrent SRL172 (killed Mycobacterium vaccae suspension); these patients were included since SRL172 does not improve the efficacy of standard chemotherapy [29Go]. The WHO performance status (PS) of patients is described in Table 1.


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Table 1. Patient characteristics (n=150)

 
Response
A total of 131 patients were evaluable for response. There were no CRs and 21 patients demonstrated a PR, giving an overall response rate of 15.3% [95% confidence interval (CI) 9.3% to 21.4%], with a median duration of response of 35 weeks. Ninety-four patients (68.6%) had stable disease (SD). Twenty-two patients (16.1%) had PD.

Mesothelioma-related symptoms were documented in 147 patients at the start of chemotherapy, including dyspnoea, cough, chest pain and malaise. One hundred and one patients (69%) reported an improvement in symptoms during treatment. Two patients reported complete resolution of all symptoms. Although 22 patients were graded as having overall progression of symptoms, 11 of these had improvement in at least one specific symptom. Response rates to specific symptoms were as follows: dyspnoea, 66 of 123 (50%); cough, 56 of 91 (62%); pain, 87 of 112 (71%); and malaise, 39 of 82 (44%).

Nineteen (90.5%) of the 21 patients with an objective PR had a symptomatic response; a maximal symptom response was achieved after one cycle by 13 patients and the other six patients had incremental responses beyond this. One patient with an objective response had no change in symptoms, whilst one had progression of mesothelioma-related symptoms. Among patients with SD, 70 (74.5%) derived symptomatic benefit. Similarly, eight of 20 patients demonstrating objective PD derived symptomatic benefit.

Most patients (72 of 101) achieving a symptomatic response did so within one cycle, but symptomatic responses were also seen after two (22 of 101) or three (seven of 101) courses. Median time to symptom progression was 12 weeks (range 3–126) from the start of treatment. There was a difference in the duration of symptom response between patients achieving objective PR and those with SD (16 versus 14 weeks; P=0.02).

Toxicity
The median number of cycles per patient was three (range one to six). Treatment delays occurred in 11 (7.3%) patients, two (1.3%) patients required a dose reduction of 25% and 22 (14.7%) patients stopped treatment early due to toxicity.

Two patients died within 3 weeks of commencing chemotherapy, and for these patients no haematological toxicity data were available. Eighteen patients were not assessed for non-haematological toxicity, seven of whom died of progressive disease within 4 weeks of starting treatment. The treatment was well tolerated and toxicity data are presented in Table 2. The most frequent grade 3/4 toxicities were infection (12%), nausea/vomiting (8.8%) and constipation (4.8%). Infection was associated with grades 3/4 neutropenia in 13 patients: three with grade 1 infection, three with grade 2 infection and seven with grade 3 infection. The patient with grade 4 infection was not neutropenic.


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Table 2. Toxicity

 
Survival
At the time of analysis 127 patients had died. Follow-up of the 23 surviving patients ranged from 11 days to 6 years 7 months. Median survival was 7 months, with 1- and 2-year survivals of 31% (95% CI 24% to 39%) and 11% (95% CI 6% to 17%), respectively (Figure 1). Univariate analysis and the log rank test demonstrated that poor WHO PS (2/3), weight loss, mixed or sarcomatoid histology, low haemoglobin (<13 g/dl in males and <11.5 g/dl in females), high white blood cell count (≥8.3 x 109/l) and high absolute neutrophil count (≥5.0 x 109/l) were all found to be significant prognostic factors (Table 3). The superior median survival for patients with PS 0/1, epithelial histological subtype and patients without weight loss is illustrated in Figure 2.



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Figure 1. Overall survival. MVP, mitomycin C, vinblastine and cisplatin.

 

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Table 3. Univariate analysis: prognostic factors for survival

 


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Figure 2. Survival according to (A) performance status (PS), (B) pathological subtype and (C) the presence of weight loss. MVP mitomycin C, vinblastine and cisplatin.

 
Multivariate analysis was undertaken both including and excluding pathological subtype. When pathological subtype (n=82) was included, it was an independent prognostic factor (Table 4). Other independent prognostic factors included weight loss and anaemia. However, the usefulness of this analysis was limited because of the amount of missing data on pathological subtype (all patients did have a histological diagnosis of mesothelioma). Excluding pathological subtype (n=150) from the analysis, poor PS (relative risk 1.94; 95% CI 1.25–3.02; P=0.003) and weight loss at presentation (relative risk 2.02; 95% CI 1.26–3.23; P=0.004) were independent prognostic factors.


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Table 4. Multivariate analysis including pathology

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This is the largest series to have reported on the palliative benefits of a single chemotherapy regimen in patients with MM. More than two-thirds of patients experienced symptomatic improvement, with this being achieved after just one cycle of chemotherapy in the majority of patients. Improvement was most notable for pain and cough. Symptomatic benefit was observed in patients with both SD and PD, in addition to those demonstrating an objective response. PR was observed in 15% of patients, confirming the activity reported for the first 39 patients treated with MVP [18Go]. The median survival was 7 months.

The efficacy of both single-agent chemotherapy and combination chemotherapy reported from series including at least 15 patients has recently been reviewed [30Go]. Only vinorelbine [31Go], edatrexate [32Go], gemcitabine [33Go] and raltitrexed [34Go] as single agents have demonstrated response rates >20%. In two other studies, single-agent gemcitabine demonstrated response rates of 0% and 7%, respectively [35Go, 36Go]. Similarly, the majority of combination regimens demonstrate response rates between 10% and 20%. A number of combinations have reported higher response rates in small phase II studies, but the activity of all such regimens has yet to be confirmed in larger multicentre trials. The largest trial in MM randomised 456 patients with PS of 0 and 1 to cisplatin plus placebo or cisplatin plus pemetrexed [37Go]. A response rate of 17% was observed with cisplatin alone, compared with 41% with pemetrexed and cisplatin, and median survival improved from 9.3 to 12.1 months with cisplatin and pemetrexed (P=0.020).

Quality of life assessment has been reported in three studies [16Go, 31Go, 38Go]. Using the Rotterdam Symptom Checklist in 29 patients treated with single-agent vinorelbine, quality of life improved in 76% after one cycle of chemotherapy [31Go]. Lung-related symptoms and general physical symptoms improved in 48% and 41% of patients, respectively. Quality of life improvement was reported in patients with stable and responding disease. The improvement in symptom-related scores was approximately twice the objective response rate of 24%. In a study of 55 patients treated with cisplatin and gemcitabine there was no improvement in quality of life, as assessed by the European Organisation for Research and Treatment of Cancer QLQ-30 questionnaire. Patients with a response to chemotherapy demonstrated an improvement in global quality of life and physical function scores compared with non-responders. Using the QLQ-LC13 lung cancer module, cough and chest pain were observed to reduce in the group as a whole [16Go]. A phase II study of pemetrexed assessed a clinical benefit algorithm that included pain (pain intensity and analgesic consumption), dyspnoea and PS [39Go]. Clinical benefit was observed in 14 of 56 symptomatic patients; three of these patients had a PR and 11 had SD. It is not possible to compare directly the quality of life and clinical benefit data from these studies and the symptom response data we have reported here. A quality of life study using the LCSS-Meso instrument involving the 448 patients randomised between pemetrexed plus cisplatin and cisplatin alone demonstrated superior quality of life and symptom relief with the combination chemotherapy [38Go]. The difference was statistically significant for most parameters by week 15. Another study evaluating the cisplatin–gemcitabine combination demonstrated symptomatic benefit in patients with responding and stable disease [40Go]. These studies indicate that whilst symptomatic benefit is more frequent in patients achieving an objective response, many more patients may have improvement in symptoms from chemotherapy, and in fact it appears that symptomatic benefits occur approximately twice as often as radiological response. Symptomatic improvement most frequently occurs in lung-related symptoms of cough and pain, and this experience mirrors the results seen with MVP in the treatment of non-small-cell lung cancer (NSCLC) [25Go].

In the UK, survival from time of diagnosis with MM is typically 7–10 months [41Go–43Go], which is similar to that quoted in European and American series [44Go–46Go]. Our series with a median survival of 7 months included 38% of patients with a PS of 2 and 5% with a PS of 3. This contrasts with series with a lower incidence of patients with poor PS that have reported longer median survival of 10.8 months where 17% of the patients had a PS of 2 [31Go], and 9 months (cisplatin alone) or 12 months (cisplatin + pemetrexed) when all patients were PS 0/1 [37Go]. This observation, although not surprising, is of critical relevance because of the relatively high proportion of patients with pleural or pulmonary malignancies who have relatively poor PS at presentation, and again mirrors the findings in NSCLC, where a greater survival benefit from cisplatin-based therapy has been observed in patients with PS 0/1 [47Go].

The likelihood of reduced benefit from chemotherapy and increased risk of toxicity in patients with poor PS, combined with the high incidence of poor PS at presentation, makes it important to demonstrate that systemic chemotherapy results in a survival advantage and improved quality of life. Consequently, the results of the British MRC trial that randomises patients to active supportive care (ASC) plus MVP, ASC plus vinorelbine or ASC alone, and the trial comparing ASC plus pemetrexed with ASC alone, will further determine the role of chemotherapy in mesothelioma.

The poor prognostic features identified by univariate analysis were consistent with those from previously reported studies. Specifically, we confirmed that poor PS, weight loss, non-epithelial cell type, low haemoglobin and high white blood cell count were poor prognostic factors. Other investigators have demonstrated that thrombocytosis was also associated with a poorer outcome [43Go, 45Go, 46Go].

Multivariate analysis demonstrated that non-epithelial cell type, weight loss and low haemoglobin were independent predictors of a worse prognosis. In addition, when pathological subtype was not included in the multivariate analysis, PS and weight loss were the prognostic factors. Three other groups have recently reported prognostic factors from series of patients with mesothelioma (Table 5). In common with our results, PS and non-epithelial histopathological subtype were identified as poor prognostic features in all four studies. Three out of four studies identified leucocytosis as an additional prognostic factor.


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Table 5. Poor prognostic factors in malignant mesothelioma—recent publications

 
In conclusion, this is the largest series to have reported the palliative benefits of a single chemotherapy regimen in patients with MM. Symptomatic response was observed in approximately twice the number of patients demonstrating objective response, an observation also made in NSCLC. Survival in our series was modest, but was typical for a cohort that included patients with a poor PS. These results confirm that MVP is an active and well-tolerated regimen in patients with pleural mesothelioma, and is a suitable comparator for future studies.


    Acknowledgements
 
E.A. is a Registrar/Research Fellow at the Royal Marsden Hospital/Institute of Cancer Research, supported by an ESMO Fellowship.

Received for publication December 19, 2003. Revision received May 12, 2004. Accepted for publication May 12, 2004.


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 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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