Role of Conservative (Palliative) Care-only in the Management of Advanced Malignant Pleural Mesothelioma

Discussion

Usually, MPM is classified into three broad histological subtypes: epithelioid (60%), sarcomatoid (20%), and biphasic (mixed, 20%). The epithelioid variant is the most common and is usually described as having a better outcome. On the other hand, according to the European Organisation for Research and Treatment of Cancer (EORTC) (8) and the Cancer and Leukaemia Group B (CALGB) (9), sarcomatous or mixed-histology MPM have poorer prognosis. It is also suggested that the histological subtype could be a finer independent prognostic factor in patients receiving best supportive care only. In 101 conservatively-treated patients, Merrit et al. reported that the median survival was 8.7, 8.6 and 2.7 months in epithelial, mixed and sarcomatous types, respectively (p=0.0016) (10). Moreover, Ak et al. showed that patients with an epithelial subtype of MPM had a good prognosis, even if they did not receive any treatment, while histological subtype was not related to the prognosis in patients undergoing chemotherapy (11). Prognostic factors defined by the EORTC and CALGB include Eastern Cooperative Oncology Group (ECOG) performance status score (PS), age, gender, chest pain, pleural effusion, fever of unknown origin, stage of disease, histology, and biological parameters (white blood cell and platelet count) (8, 9). Although neither of these patients belonged to the subgroup of MPM with an unfavourable outcome, clinicians pondered what was the best course of action. Although their expected median survival was only about a year, the first case survived longer than that period, prior to any specific treatment.

When there is no or only limited resection of disease, delivery of high-dose radiotherapy to the entire hemithorax in the setting of an intact lung is not the standard of care (12). Even with advanced technology (intensity-modulated radiotherapy), ionizing radiation to a large lung volume could result in significant toxicity, including radiation-induced pulmonary fibrosis, radiation pneumonitis, and bronchopleural fistula, without any survival benefit (13). It is unclear if case 2 actually benefited from palliative radiotherapy, or if alteration of her pulmonary function was in fact a side-effect of therapy. Due to the large volume required for re-irradiation, the patient received supportive care only.

For patients with advanced MPM, who are not candidates for locoregional therapy, combination of chemotherapy is the standard of care. In the randomized phase III trial reported by Vogelzang et al., the median time to progression was 1.8 months longer in the pemetrexed/cisplatin-treated arm (hazard ratio=0.77; p<0.01). This short-term survival benefit was also associated with high-grade hematological and gastrointestinal toxicities, despite supplementation with folic acid and vitamin B12 during therapy (5). Moreover, while toxicities may be increased for elderly patients (2, 9), the median age of patients with MPM typically ranges from 62 (in clinical trials) to 74 years (routine practice). As a matter of fact, Chapman et al. described that for 37% (54/146) patients declared suitable for chemotherapy, 52% declined (similarly to our case 1) this option and eventually only 18% of the total number of patients were randomized into chemotherapy trials (2).

Molecularly targeted agents are currently being evaluated for MPM. Unfortunately, while therapeutic benefits were observed in non-small cell lung cancer, (14) new clinical trials are still required to establish whether these high-cost agents will have a role in MPM management. Indeed, epidermal growth factor receptor and vascular endothelial growth factor pathway proteins are expressed in MPM. Nevertheless, in a phase II trial with previously untreated patients receiving the inhibitor erlotinib, no objective responses were observed (15). Monoclonal antibody to vascular endothelial growth factor bevacizumab, was also tested in combination with gemcitabine and cisplatin in a randomized phase II trial, but the addition of bevacizumab did not improve overall survival compared to chemotherapy alone (16).

Overtreatment of patients often occurs because doctors engage in defensive medicine, and can be justified by fear of malpractice suits, particularly for young patients. Of course, chemotherapy and high-tech irradiation have become standard practice in most developed countries. In the setting of an economic crisis that will impact on public health, these expansive practices with a limited benefit should be questioned. The quality-adjusted life-years (QALYs) gained are particularly doubtful in elderly patients. Financial constraints should force practitioners and policy makers to carefully analyze the true clinical benefit of treatment modalities, particularly in the palliative setting. Reasonable quality of life may be achieved with symptomatic care and it justifies thorough evaluation of the potential advantage of a planned specific-therapy for patients with advanced MPM.