Annals of Oncology Advance Access originally published online on November 29, 2005
Annals of Oncology 2006 17(2):270-275; doi:10.1093/annonc/mdj073
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© 2005 European Society for Medical Oncology
A randomised trial in malignant mesothelioma (M) of early (E) versus delayed (D) chemotherapy in symptomatically stable patients: the MED trial
1 Royal Marsden Hospital, Sutton; 2 Kent Cancer Centre, Maidstone; 3 St George's Hospital, London, UK
* Correspondence to: Dr M. E. R. O'Brien, Lung Unit, Royal Marsden Hospital, Downs Road, Sutton SM2 5PT, UK. Tel: +44-20-8661-3278; Fax: +44-20-8643-0373; E-mail: mary.o'brien{at}rmh.nhs.uk
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Abstract |
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Background: Prior phase II trials have demonstrated the therapeutic activity of cytotoxic chemotherapy in mesothelioma. Currently there are few randomised data assessing the role of chemotherapy versus best supportive care (BSC) in the management of patients with stable symptoms after control of any pleural effusion. A policy of observation is often adopted over initial use of chemotherapy. In this prospective randomised trial we assess the use of early versus delayed cytotoxic therapy. The study opened in 1998, and closed in view of a competing national study (MSO 1) in 2003.
Methods: Eligible patients had a performance status 
2, life expectancy >3 months and had stable symptoms for at least 4 weeks prior to randomisation. Patients were randomised to receive immediate chemotherapy or initial BSC with the addition of chemotherapy at time of symptomatic progression. All patients received the same platinum-based chemotherapy regimen, MVP [mitomycin C 8 mg/m2 cycles 1, 2, 4 and 6, vinblastine 6 mg/m2, maximum 10 mg, and cisplatin 50 mg/m2 (or carboplatin AUC 5)], every 3 weeks for up to six cycles.
Results: A total of 43 patients were recruited, of which 21 were randomised to the early treatment group and 22 to the delayed treatment group. The median ages were 59 years (range 50–78) and 67 years (range 48–75), respectively (P = 0.1); other baseline parameters were well matched between the two groups. All 21 patients in the early group received chemotherapy versus 17 patients in the delayed group. Median time to symptomatic progression was 25 weeks in the early group compared with 11 weeks for the delayed group (P = 0.1). Median survival was 14 months (1-year survival 66%) for the early group compared with 10 months (1-year survival 36%) for the delayed group (P = 0.1). Quality of life was in general better maintained for early treatment and the health resources use was similar in both arms.
Conclusions: In this patient group, presenting with stable symptoms after control of pleural effusion, the early use of chemotherapy provided an extended period of symptom control, and in this small trial a trend to survival advantage.
Key words: randomised mesothelioma, chemotherapy, early, delayed
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introduction |
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Over the next decade we can expect to see a continuing rise in the incidence of malignant mesothelioma occurring in many parts of Europe [1
], Australia [2] and other industrialised nations. Mesothelioma remains a disease with limited therapeutic options, a majority of cases not being suitable for curative approaches to treatment, and therefore effective palliation of symptoms is the mainstay of management for most patients. Data from clinical trials have shown benefit from a number of chemotherapy regimens in providing patients with significant symptomatic relief despite relatively disappointing radiological response rates. Regimens have included MVP [3,15], vinorelbine [4], gemcitabine + cisplatin [5], and more recently cisplatin in combination with pemetrexed [6] and cisplatin in combination with raltitrexed [7]. The benefit in symptom control comes at the expense of potential treatment-related toxicities. Currently, there are no data regarding the relative benefit of any chemotherapy regimen over best supportive care (BSC) in malignant mesothelioma, but one trial is ongoing in the first-line setting [8].
The clinical course of patients with mesothelioma varies widely, ranging from slowly progressive, indolent disease to more aggressive, rapidly progressive disease. A number of prognostic factors have been described, with median survival varying from as little as 1.1 months in the worst group to 13.9 months in the best prognostic group [9–11]. However, some patients can remain asymptomatic or with minimum symptoms for extended periods of time, particularly after surgical control of any pleural effusion. A small group of 10 patients who were picked up when asymptomatic by chest X-ray have been described as having a median survival of 21 months [12]. In our own experience in a group of 33 asymptomatic patients, the median survival of the whole group was 20 months, the median time to deterioration of symptoms was 5 months and the median time to start chemotherapy was 9 months [13].
In view of the potential for treatment-related toxicities in delivering chemotherapy and the variable course of disease in individual patients, a period of initial observation with BSC is often considered, rather than the immediate use of chemotherapy in patients who are asymptomatic or have stable symptoms after control of any pleural effusion. In order to look at the effect of giving a course of chemotherapy at diagnosis in patients with mesothelioma who were asymptomatic or had stable symptoms, we designed a trial to compare the two treatment strategies, i.e. initial chemotherapy with BSC (early), versus initial BSC and observation followed by the introduction of chemotherapy at the time of symptomatic progression (delayed). In the symptomatic patient group, we have shown that MVP chemotherapy provides symptomatic benefit in patients with mesothelioma with an acceptable toxicity profile [3], and thus this regimen was the chosen regimen to be delivered within this trial.
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methods |
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study design and patients
Eligible patients had histologically proven malignant mesothelioma of the pleura or peritoneum, stable symptoms during the 4 weeks preceding randomisation, age
18 years, WHO performance status 2, life expectancy of 12 weeks, estimated glomerular filtration rate >35 ml/h and adequate haematological and liver function. Patients were excluded if they had received prior systemic therapy, had a serious concomitant medical illness or had worsening symptoms or a rapidly changing chest X-ray during the 4 weeks prior to study entry. Patients underwent pretreatment physical examination, and computed tomography (CT) or chest X-ray, and written consent was obtained. The presence of measurable disease was not a necessary entry requirement, nor was the use of assessment by CT scan essential. All patients were discussed at a multidisciplinary meeting with thoracic surgical oncology input and were not considered candidates for a radical surgical approach but had a surgical talc pleurodesis where appropriate.
Patients' symptomatic status was assessed at entry and during the study. Eligible patients with no or stable symptoms who were interested in possible study enrolment were given a further appointment for clinical review and chest X-ray after 4 weeks to ensure that they were free from worsening symptoms or rapidly progressive disease. Patients with symptomatic deterioration during this period were offered chemotherapy outside the trial. Patients with no or stable symptoms at the 4-week review appointment were consented to enter the study and randomised to either the early or delayed treatment group. Figure 1 illustrates the design of the study in the form of a CONSORT diagram.
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In both treatment groups symptoms were recorded by patients at study entry using a specific lung cancer checklist, with separate headings for recording pain, dyspnoea, cough, malaise and other symptoms [3
, 14]. Each symptom was graded on a three-point scale as: not present, mild/moderate or severe. In both treatment groups symptomatic assessment was undertaken at each cycle by a research nurse and a medical oncologist at each clinic review. Changes in symptoms were scored according to the following criteria: complete disappearance of symptoms, complete response; good improvement in symptoms, partial response; minor improvement or no change, stable disease; and worsening symptoms or progressive disease. In patients with multiple symptoms each symptom was scored individually; if significant worsening of any one symptom occurred the patient was classified as having progressive disease. Quality of life was assessed at baseline and then every 3 months using the EORTC 30 questions tool with added lung symptom assessments. Patients also filled in diaries on the use of resources, e.g. overnight hospital stay, visits to general practitioner (GP), antibiotics, etc. All patients received BSC and regular follow-up (3 weekly for first four visits).
MVP chemotherapy was delivered according to the following schedule: mitomycin C 8 mg/m2 intravenously day 1 (given on courses 1, 2, 4 and 6), vinblastine 6 mg/m2 (maximum 10 mg) intravenously day 1 and cisplatin 50 mg/m2 intravenously day 1, repeated every 21 days for up to six cycles. If the estimated creatinine clearance was 60 ml/min then carboplatin (AUC 5) was substituted for cisplatin. Standard pre- and post-treatment hydration was given to patients receiving cisplatin.
Following randomisation to the early treatment group commenced MVP chemotherapy as initial treatment. Treatment was continued for up to six cycles of chemotherapy or until symptomatic progression. Patients randomised to the delayed chemotherapy group received BSC measures to optimise symptom control, including the use of steroids and opiate analgesia. These patients were assessed when symptoms progressed and offered MVP chemotherapy for up to six cycles. All patients were reviewed in clinic every 3 weeks for the first 3 months and every 3 months thereafter.
The criteria used to define failure of BSC and for the initiation of chemotherapy were: worsening of symptoms (progressive disease on symptom scoring), increased analgesia requirements, continued weight loss and poor appetite, deterioration in performance status or if the patient wished to have treatment.
statistics
This study was designed as a pilot study to test the acceptability of the trial design and prediction of resources needed for a full trial. The primary outcome measure was time to symptom progression (TSP) and secondary measures were quality of life, overall survival and health resources use. From previous work using MVP chemotherapy in symptomatic patients, TSP was 4 months [15]. In this randomised study, we considered that it would be clinically significant if there was a reduction in the TSP of 3 months at the 5% significance level, i.e. the TSP in the delayed arm was 1 month. In order to do this, 42 patients (21 in each arm) were needed (power 90%). No interim analyses were planned.
Randomisation lists were generated by the trial statistician, using permuted blocks, and patients were stratified by centre. Treatment was allocated over the phone, by a central office at each centre after eligibility had been checked and consent obtained. The allocation was concealed until the treatment had been assigned but the nature of the trial precluded blindness after this.
TSP was measured from randomisation until documented progression of symptoms or death from disease and was censored at last follow-up. Survival curves were generated using the method of Kaplan and Meier [16] and compared using the log rank test. The Cox proportional hazards model was used to adjust overall survival for the influence of performance status.
Quality of life data were scored according to the EORTC QLQ-C30 scoring manual at baseline and every 3 months, and the scales were compared by means of the Mann–Whitney non-parametric test. The significance of changes in quality of life scores from baseline measurements were assessed by the Wilcoxon signed rank test. The protocol was reviewed and approved by the local ethics committees of both institutions.
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results |
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The pilot study was completed but recruitment was slow; 43 patients were recruited from two study centres between 1999 and 2003 with 21 patients in the early group and 22 in the delayed group. Patients' characteristics are shown in Table 1. Treatment groups were well matched for sex, performance status, haematological indices and histology. The median age of patients in the early group was lower, 59 versus 67 years, but this was not statistically significant (P = 0.1). In the early treatment group all 21 patients received chemotherapy for a median of three cycles (range one to six). Only 17 of the 22 patients in the delayed group received chemotherapy for a median of three cycles (range one to four) (Table 2). The median time to commencement of chemotherapy in the delayed group was 17 weeks (range 3–96).
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Median time to symptom progression was 25 weeks in the early group and 11 weeks in the delayed group (P = 0.1) (Figure 2). Each of the five patients in the delayed group who never received treatment died of progressive disease at 5, 9, 20, 30 and 40 weeks, respectively. Excluding the patients in the delayed arm who never received treatment exaggerates the symptom progression-free survival curve (Figure 3). No patients in the delayed group received second-line chemotherapy, while four in the early group did and for two of these patients this was pemetrexed. The most frequent symptoms reported at time of progression were pain (56%), dyspnoea (56%), cough (40%) and malaise (16%). The trial was not powered to detect a difference in overall survival, but the patients whose treatment was delayed had a marginally poorer survival (median 14 versus 10 months; P = 0.1) (Figure 4) even after adjusting for performance status (P = 0.1).
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Quality of life data, presented in Tables 3 and 4, show baseline data recorded in 31 patients and follow-up data in 20 patients who completed a follow-up questionnaire at least 3 months after randomisation (11 early and nine delayed). Of the nine delayed follow-up questionnaires, four were done before delayed chemotherapy and five after delayed chemotherapy. There were no differences in baseline quality of life data between the two groups (Table 3). In the follow-up data showing changes from baseline to follow-up there was a marginal worsening of fatigue (P = 0.07) and alopecia (P = 0.05) in those patients randomised to early chemotherapy, but no difference in any of the functional scales compared with baseline. In the patients randomised to delayed chemotherapy comparing baseline with follow-up scales, fatigue (P = 0.073) and alopecia (P = 0.05) were also marginally worse, but physical functioning became significantly worse (P = 0.008) and dyspnoea (P = 0.025) also deteriorated. There were no significant differences between early and delayed treatment arms (Table 4).
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The use of bed days was available for all 43 patients. Bed day use was largely influenced by days occupied having chemotherapy in the early arm, but was skewed by a few patients staying in hospital for long periods of time for symptom control (early median 4 days, range 0–12; late median 3 days, range 0–12). However, given the small numbers, overall there was no major difference in bed days used and extra use of GPs and specialist community services. From patient diaries, data on the number of visits to GPs were available for 12 patients in the early arm and eight in the delayed arm: median one (range none to six) and median one (range none to two), respectively. Other uses of resources were reported in small numbers and outside use associated with chemotherapy administration was not different.
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discussion |
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Our understanding of the relative benefit of palliative chemotherapy in mesothelioma in prolonging symptom control and survival has been hindered by an absence of randomised phase III trial data comparing chemotherapy to BSC alone, which has lead to inconsistencies in treating patients in both the UK and other countries. Some centres treat most patients at some time during the duration of their disease, while others never offer chemotherapy. The MESO 1 pilot study compared chemotherapy (MVP or single-agent vinorelbine) with active symptom control alone (no chemotherapy); the study started in the UK in 2000 and recruited 109 patients [8
]. This trial has now been extended and renamed the MSO 1 trial and is ongoing. Competition for recruitment was one of the reasons for not extending the MED trial despite the fact that the MED trial was focusing on patients with no or stable symptoms.
It is gratifying that the time to initiation of chemotherapy in the delayed arm is still around 5 months, as we reported earlier, suggesting that our local policy in this group of patients had not changed [13]. Therefore, we can compare this group with the group of symptomatic patients to whom we normally offer chemotherapy. The median survival in the early arm of the MED trial was 14 months (1-year survival 66%) and in the delayed arm was 10 months (1-year survival 36%), both of which are better than the median survival of 7 months (1-year survival 31%) that we have described overall in symptomatic patients [3, 15]. However, even within these data on symptomatic patients, the median survival for patients of performance status 0/1 was 13 months, and was 5 months for patients with a performance status of 2/3. It would appear that outcome is very dependent on the performance status of patients included in the trial and may be confounded by the duration and stability of symptoms present at trial entry.
The patient numbers in this study are small but the difference predicted was large (4 months versus 1 month for TSP). Other studies of chemotherapy versus no chemotherapy or delayed chemotherapy in other solid tumours (gastric, pancreas and colon cancer) have also been able to show a benefit in relatively small studies. Forty-three patients with unresectable advanced pancreatic cancer were randomised to receive chemotherapy using a combination of 5-fluorouracil, adriamycin and mitomycin or no chemotherapy [17]. Psychological measurements based on the Hospital Anxiety and Depression score were made in 31 patients. These showed significantly less depression but not anxiety in the treated group immediately after randomisation and following 2 months of chemotherapy. Median survival in the treated group was 33 weeks (range 9–80) compared with 15 weeks (range 1–62) in the untreated group (P < 0.002). Similarly, 40 previously untreated patients with advanced colorectal cancer were allocated randomly to receive chemotherapy or only supportive care in a ratio of 2:1 according to performance status, metastatic disease of the liver and weight loss in the 6 months before entering the study [18]. Chemotherapy consisted of 4-week cycles of intravenous leucovorin (200 mg/m2/day) followed by 5-fluorouracil (550 mg/m2/day) and cisplatin (20 mg/m2/day). Overall survival was significantly longer for patients given chemotherapy (11 months) than for those receiving supportive care alone (5 months) (P = 0.006). Despite common association of chemotherapy with mild to moderate gastrointestinal symptoms, there was no significant difference between the two groups in global or subgroup quality of life scores. Finally, a phase III randomised study, comparing treatment with fluorouracil, epidoxorubicin and methotrexate (FEMTX) with best supportive care, was conducted in 41 patients with unresectable or metastatic gastric cancer [19]. The median time to progression in the FEMTX group was 5.4 months [95% confidence interval (CI) 3.1–11.7], but only 1.7 months in the control group (95% CI 1.2–2.7) (P = 0.0013). Similarly, the FEMTX group displayed significantly prolonged survival compared with the control group (P = 0.0006), i.e. median survival 12.3 months (95% CI 7.1–15.6) versus 3.1 months (95% CI 1.6–4.6).
In this small randomised pilot study we compared two primary treatment strategies in patients with malignant mesothelioma presenting with stable symptoms. This group of patients would not normally have been offered chemotherapy until symptom progression in our practice. We demonstrated that the early initiation of chemotherapy provides a trend towards a longer period free from symptomatic progression with no extra deterioration in quality of life, and in this small study a trend towards improved survival. This study highlights the inherent risk in adopting a watch-and-wait policy viz. the patient's clinical state may deteriorate more rapidly than expected and the opportunity to instigate chemotherapy may be lost. In this study, five patients in the delayed treatment group died prior to receiving any chemotherapy. Our data support the early initiation of chemotherapy in patients with stable symptoms due to mesothelioma and suggest a possible survival advantage. Another interpretation of these data is that early initiation of chemotherapy in patients with stable symptoms does not appear to be detrimental.
This is the first study to support the early use of chemotherapy over a watch-and-wait policy in patients with asymptomatic or stable symptoms from mesothelioma, and adds further support to the role of chemotherapy in this disease.
Received for publication June 27, 2005. Revision received September 29, 2005. Accepted for publication October 10, 2005.
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References |
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TopAbstractintroductionmethodsresultsdiscussionReferences |
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1. Hodgson JT, McElvenny DM, Darnton AJ et al. The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050. Br J Cancer 2005; 92: 587–593.[Web of Science][Medline]
2. Leigh J, Davidson P, Hendrie L, Berry D. Malignant mesothelioma in Australia, 1945–2000. Am J Ind Med 2002; 41: 188–201.[CrossRef][Web of Science][Medline]
3. Andreopoulou E, Ross PJ, O'Brien MER et al. The palliative benefits of MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in patients with malignant mesothelioma. Ann Oncol 2004; 15: 1406–1412.
4. Steele JP, Shamash J, Evans MT et al. Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol 2000; 18: 3912–3917.
5. Byrne MJ, Davidson JA, Musk AW et al. Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 1999; 17: 25–30.
6. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21: 2636–2644.
7. Van Meerbeeck JP, Manegold C, Gaafar R et al. A randomized phase III study of cisplatin with or without raltitrexed in patients (pts) with malignant pleural mesothelioma (MPM): an intergroup study of the EORTC Lung Cancer Group and NCIC. J Clin Oncol 2004; 22 (14S): 622s (Abstr 7021).
8. Muers MF, Rudd RM, O'Brien ME et al. BTS randomised feasibility study of active symptom control with or without chemotherapy in malignant pleural mesothelioma: ISRCTN 54469112. Thorax 2004; 59: 144–148.
9. Edwards JG, Abrams KR, Leverment JN et al. Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax 2000; 55: 731–735.
10. Herndon JE, Green MR, Chahinian AP et al. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 1998; 113: 723–731.[CrossRef][Web of Science][Medline]
11. Curran D, Sahmoud T, Therasse P et al. Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol 1998; 16: 145–152.
12. Yates DH, Corrin B, Stidolph PN, Browne K. Malignant mesothelioma in south east England: clinicopathological experience of 272 cases. Thorax 1997; 52: 507–512.[Abstract]
13. O'Brien ME. Malignant mesothelioma—the UK experience. Lung Cancer 2004; 45 Suppl 1: S133–S135.
14. Smith IE, O'Brien ME, Talbot DC et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 2001; 19: 1336–1343.
15. Middleton GW, Smith IE, O'Brien ME et al. Good symptom relief with palliative MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in malignant mesothelioma. Ann Oncol 1998; 9: 269–273.
16. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[CrossRef][Web of Science]
17. Palmer KR, Kerr M, Knowles G et al. Chemotherapy prolongs survival in inoperable pancreatic carcinoma. Br J Surg 1994; 81: 882–885.[Web of Science][Medline]
18. Scheithauer W, Rosen H, Kornek GV et al. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 1993; 306: 752–755.
19. Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 1995; 71: 587–591.[Web of Science][Medline]
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