Pleural Mesothelioma: Little Evidence, Still Time to do Trials

Tom Treasure, Artyom Sedrakyan
Lancet 2004; 364: 1183-85

Cardiothoracic Unit, Guy's Hospital, London SE1 9RT, UK (Prof T Treasure MD); and School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA (A Sedrakyan MD) Tom.Treasure@ukgateway.net

Chemotherapy
Surgery
Radiotherapy
Conclusion

Context The incidence of malignant pleural mesothelioma is increasing throughout most of the world. This cancer is uniformly fatal, and characterised by progressive breathlessness and unremitting pain in the chest wall. From the onset of symptoms, survival is from a few weeks to a few years. Desperation by patients and doctors has driven a search for effective treatments. Clinical benefits are marginal and evidence of a good quality is lamentably lacking.

Starting point David Sugarbaker is the world's leading proponent of extrapleural pneumonectomy (EPP), an operation in which all the pleura is removed with the lung, pericardium, and diaphragm. He has recently reported the complications of this radical surgery in a series of 496 operations (J Thorac Cardiovasc Surg 2004; 128: 138-46). Although EPP as part of trimodality therapy (preoperative chemotherapy and postoperative radiation) is thought to be the best that can be offerred and is regarded as the standard of care for selected patients given the morbidity associated with it, evidence for benefit is needed to justify its wider use.

Where next? With the increase in the number of cases there is increasing awareness of the disease, leading to earlier diagnosis, and an expectation that something must be done. Survival is short and the treatments on offer are onerous. The only responsible approach from a scientific, compassionate, or economic view (and why not combine all three?) is to find evidence of effectiveness to avoid futile and distressing treatment when possible.

The worldwide epidemic of malignant mesothelioma (table 1)1-4 is predicted to peak in the UK between 2011 and 2015, at 1950-2450 deaths a year.5 Most cases are a direct consequence of asbestos exposure 30-40 years earlier. The causative link between asbestos and mesothelioma is beyond dispute, with a relative risk for the main commercial types of asbestos, chrysotile, amosite, and crocidolite, broadly in the ratio 1:100:500.6 Predictions from asbestos imports of the scale of the problem are robust.7

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Countries Incidence in men Incidence in women

UK and Netherlands1 7·4-8·8 0·8-1·3
Western Europe1* 2·9-4·2 0·7-1·3
Germany, Spain, and Ireland1 1·0-1·9 0·2-0·5
Eastern Europe1 0·6-1·0 0·3-0·5
United States2 1·5-2·2 0·3-0·4
South Africa3† >5·4 >2·3
Western Australia4 >4·8 >0·3

*Excludes Germany, Spain, and Ireland. †Reported to be six times higher than in UK. Incidence in European counties is only related to only-pleural mesothelioma, while in other counties all forms of mesothelioma are likely to be included in estimates.

Table 1: Incidence of pleural mesothelioma (per 100 000 population)

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Chemotherapy

Mesothelioma is relatively unresponsive to chemotherapy. Before-and-after CT images can be selected to show dramatic change, but it is a difficult disease in which to measure response8,9 because of the diffuse spreading nature of the cancer and the variable volumes of pleural fluid that obscure its actual extent. Berghmans et al10 systematically reviewed evidence for chemotherapy from 1965 to June, 2001, and found 83 studies with 88 treatment arms. Cisplatin was the most active single drug and cisplatin plus doxorubicin had the highest response rate (28·5%, 95% CI 21·3-35·7%). This combination was recommended as the control arm for subsequent trials. Since then a phase III randomised trial of cisplatin plus pemetrexed versus cisplatin alone has reported.11 The results in 456 assigned patients favoured the combination with longer median survival (12·1 vs 9·3 months; hazard ratio 0·77, p=0·02) and longer median time to progression (5·7 vs 3·9 months; 0·68, p=0·001). Response rates were the highest recorded in any chemotherapy trial: 41·3% (34·8-48·1%) for the combination versus 16·7% (12·0-22·2%) for the control arm, respectively above and below the cisplatin and doxorubicin combination.10

The statistics on response rates based on imaging might not parallel clinical effect. The survival gains are modest, as in many chemotherapy studies for advanced solid tumours; when adjusted for quality of life are they worth it? In the pemetrexed trial, folic acid and vitamin B12 were added in the second half of the study to combat toxicity. Put simply, chemotherapy may add life time for the minority who respond at the cost of impairing quality for many. Addressing this concern, Muers et al12 recently reported a feasibility study of a randomised trial of active symptom control with or without chemotherapy. Over a year, 109 patients were randomised (55% of eligible patients). The critical question was whether data on the burden of symptoms during the remaining months of life could be captured from quality-of-life questionnaires. Active symptom control alone achieved measurable and clinically relevant palliation. The question for the main trial,13 in which one arm receives active symptom control without chemotherapy, is whether chemotherapy contributes positively to the goal of maximising quality time.

Surgery

There are three distinct objectives in the surgical management of mesothelioma: palliation of breathlessness, debulking to increase efficacy of other treatments, and radical surgery to eradicate the disease. If there is breathlessness due to effusion and the lung is still mobile, breathlessness can be sustainably relieved by talc pleurodesis. A Cochrane systematic review14 of the randomised evidence for management of malignant pleural effusion concluded that talc is better than placebo or any other sclerosant, and that surgical videoassisted thoracoscopic surgery (VATS) resulted in better control of effusion than bedside pleurodesis. VATS also provides the best opportunity to get representative tissue to make the diagnosis.

A systematic review, up to October, 2001, of surgery was highly critical of the quality of the studies.15 Many of the 92 citations are of series of surgical resections. Survival times after surgery are given in isolation as if there is some gold standard of the natural history against which these can be compared, which is certainly not the case. Mesothelioma is a slowly progressing tumour that might have been present for years before presentation, and survival data vary between observational series.16 Survival times are susceptible to lead-time effect and, at least in earlier series, variability in pathological criteria for diagnosis. Reference to an expected average survival has no validity. There are no surgical outcome studies with an internal control group. Instead, the investigators analyse the predictors of survival within their study group. Factors that predict shorter survival include local and nodal advanced stage and histological type (sarcomatoid worse than epithelioid).17 The most favourable cases are selected for the preferred treatments, and when the patients survive longer than those not selected, this is given as evidence of benefit.18-20

The role of debulking (called cytoreductive therapy by advocates) is unproven. It is no more than parietal pleurectomy and stripping of cancer piecemeal off the lung. Debulking appears under various guises, often as part of multimodality therapy, or with further adjuncts such as intraoperative chemotherapy,21 hyperthermia, or photodynamic therapy.22 Van Ruth et al15 found just one randomised trial23 that compared surgical debulking alone (n=23) with surgery with photodynamic therapy (n=25): there was no survival or other advantage. Morbidity associated with surgery is frequent and sometimes severe. Without a formal measure of symptoms one can only speculate on whether debulking confers net benefit or harm compared with the course of the disease itself. If there is benefit, the surgical morbidity might be reduced with VATS24 rather than open thoracotomy. A randomised UK trial of debulking by VATS (called MesoVATS), with survival and quality of life as endpoints, is recruiting.13

The more radical operation of extrapleural pneumonectomy (EPP) has not so far been studied in a randomised trial, and in the best available analyses of outcome has not been shown to confer benefit over debulking or indeed no surgery.15,17 There were five series of EPP from 1974 to 1994 comprising 174 patients.15 With the increase in the incidence of mesothelioma, there has been renewed interest in EPP particularly within the context of trimodality therapy (table 2).18,20,25-29 Without evidence that EPP offers benefit over other management, the procedure has somehow acquired the sobriquet of the procedure of choice.22 The pemetrexed trial recruited patients "not eligible for curative surgery".12 Such references to EPP are powerful rhetoric for an unproven operation. David Sugarbaker is a powerful advocate of radical surgery, and recently reported30 complications in a series of 496 operations. Patients were young (median age 58 years), healthy (Karnofsky performance >70), and carefully selected. In-hospital mortality was 4%, but over 60% of patients had serious or noteworthy complications. Proof is needed, and not only survival time but also quality of life must be assessed. EPP is the subject of the MARS (mesothelioma and radical surgery) trial.13

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Study Number of Age Female (%) Epitheloid Treatment In-hospital Median patients (years) cancer (%) death (%) survival (months)
Sugarbaker et al, 199918 183 57 (mean) 23 56 EPP+chemotherapy+radiotherapy 3·8 19
Maggi et al, 200125 32 53 (median) 33 100 Mostly EPP+chemotherapy+radiotherapy 6·2 Not clear
Rusch et al, 200126 61 62 (median) 17 68 EPP+radiotherapy 7·9 17*
Aziz et al, 200220 51 <60 ·· 54 EPP+chemotherapy 9·1 35
Lee et al, 200227 26 69 (median) 19 73 EPP+chemotherapy+radiotherapy 6·9 18
Ahamad et al, 200328 28 59 (mean) 7 79 EPP+radiotherapy NA 24†
Stewart et al, 200429 53 57 (median) ·· 87 EPP+radiotherapy (not extensive) 7·5 17

*Demographics presented for 88 patients and survival calculated for 61 patients (surgery was not done in 21 patients, 1 dropped out, and 5 had pleurectomy and were not included in survival analyses). †Only patients surviving surgery were enrolled. EPP=extrapleural pneumonectomy. Chemotherapy was mostly cisplatin-based; radiation was on average around 54 Gy with some differences in techniques.

Table 2: Mesothelioma treatment

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Radiotherapy

Mesothelioma responds to radiotherapy. The problem is that the tumour's pattern of growth (surrounding the lung, coming close to the heart, spinal cord, and other organs; and its large surface area rather than localised bulk) makes it difficult to deliver sufficiently high doses and to avoid serious toxicity. Reports of efficacy for radiotherapy have therefore to be looked at in three specific contexts. First, after biopsy, aspiration, or drainage, this cancer has a propensity for seeding and growing down tracts to cause painful lumps under the skin. A small but widely accepted controlled trial supports the use of prophylactic radiotherapy in this context,31 although recent work showed no benefit at the dose under test.32 Second, radiotherapy for relief of pain is a therapeutic option for palliation.33 Third, radiotherapy is possible as adjuvant treatment after EPP as part of trimodality treatment. With the lung removed, along with the bulk of the disease, the radiotherapy target-volume is easier to define, the radiosensitive lung has been removed, and respiration-induced mobility no longer has to be accounted for. However, these advantages only ensue if appropriate surgical techniques, such as a low reconstruction of the pericardium and creation of a patch replacement of resected pericardium, have been used. Radiotherapy has been given in high doses in a phase II trial,26 and intensity-modulated radiotherapy is now proposed in this context.34

Conclusion

Malignant mesothelioma has largely defeated treatment. Radical treatments, occupying the 3 months after diagnosis, can take up the best 3 months that the patient might have had. The evidence to date is that we might only be able to make small gains in symptom control and survival. The available evidence does not rule out the possibility that well-intentioned radical treatments do more harm than good. With this disease we are in the unusual position of knowing how many cases we can expect over the next 20 years. In this era of evidence-based medicine we owe it to our patients to obtain evidence and to use treatments that have proven net health-gains. A portfolio of trials is open for recruitment.13

We declare that we have no conflict of interest.

References

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*** POSTED SEPTEMBER 27, 2004 ***