Malignant pleural mesothelioma: when is radiation therapy indicated?

Malignant pleural mesothelioma is an aggressive tumor of serosal surfaces resistant to many current treatment options. This article will provide a comprehensive discussion of the latest developments in the treatment of malignant pleural mesothelioma, with a focus on radiation therapy. We will discuss the role of radiotherapy as a prophylactic, palliative and potentially curative treatment of malignant pleural mesothelioma. An update will be provided of the latest clinical trials including new treatment.     

A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma

A single 9-MeV electron treatment, following invasive thoracic procedures in patients with malignant pleural mesothelioma, was examined. In all, 58 sites were randomised to prophylactic radiotherapy or not. There was no statistically significant difference in tract metastasis. A single 10-Gy treatment with 9-MeV electrons appears ineffective.     

Irradiation préventive en une séance de 10 Gy des sites d’intervention pleurale des patients atteints de mésothéliome pleural malin : étude de cohorte rétrospective monocentrique

Purpose

Prophylactic radiotherapy to prevent procedure-tracts metastases from malignant pleural mesothelioma remains controversial and clinical practice varies. The purpose was to assess the efficacy of local radiotherapy in a single fraction of 10 Gy in preventing malignant seeding at intervention pleural site in patients with malignant pleural mesothelioma.

Prevention of malignant seeding at drain sites by hypofractionated radiotherapy in patients with pleural mesothelioma

Aim: Unlike most other malignancies, malignant pleural mesothelioma (MPM) has a tendency to recur along tracks of chest wall instrumentation. We investigated the efficiency of hypofractionated radiotherapy for prevention of malignant seeding. Methods: Twenty‐one (six female, 15 male) patients diagnosed with pleural mesothelioma who had chest wall instrumentation and were treated with prophylactic radiotherapy were investigated retrospectively. All patients underwent surgery or thoracoscopy and/or talc pleurodesis, for diagnosis, staging procedures or as a treatment. All were treated with electron (12 MeV) external beam radiation therapy (21 Gy in three fractions over 3 days), directed to the instrumentation pathway after the invasive procedure. After completion of radiotherapy, four of 21 patients had also undergone chemotherapy. Results: Nineteen of 21 patients were followed‐up for a median period of 13 months (1–24 months) and two patients were lost just after the first month of the follow‐up period. None of the followed patients had tumor progression in the treated area. Radiotherapy was well tolerated. The most common side‐effect was grade 1 erythema (Radiation Therapy Oncology Group [RTOG] scale), noted in 13 treated patients. Conclusion: Our experience showed that prophylactic radiotherapy to prevent malignant seeding in malignant mesothelioma at invasive procedure sites was effective and well tolerated in preventing malignant seeding, painful metastases after surgery or instrumentation in patients with pleural mesothelioma. Larger multicenter prospective trials are still needed to validate this treatment approach utility for it to be recommended routinely.     

The role of radiotherapy in the treatment of malignant pleural mesothelioma

Radiation therapy for the treatment of malignant pleural mesothelioma has historically been limited by its efficacy. However, the increasing incidence of this tumour and the emergence of new technologies present a number of opportunities and challenges for this treatment modality. Radiotherapy is used to palliate mesothelioma patients with chest wall pain. Responses of over 60% have been seen, although the duration of response is often disappointing. The optimum dose has not been shown and many of the previous studies were small retrospective studies. An improved response has been seen in several studies where hyperthermia was added to radiotherapy. However, further investigation of this technique, which is not widely available, is required. There has not been any comparison of radiotherapy with chemotherapy in the palliation of patients with malignant pleural mesothelioma. Prophylactic chest wall radiotherapy to intervention sites successfully reduces the incidence of malignant seeding along the intervention tracts. However, the optimum dose and timing of treatment are not clear. There is no role for radical radiotherapy alone, but the role of radiotherapy as part of multimodality therapy is discussed. There have been studies of intensity-modulated radiotherapy as part of multimodality therapy and this technique needs to be evaluated further.     

Mesothelioma: treatment and survival of a patient population and review of the literature

BACKGROUND: Our purpose was to evaluate the survival of patients with pleural and intraperitoneal malignant mesothelioma and, particularly, to estimate the efficacy of chemotherapy as well as radiotherapy and surgery. A review of the literature with respect to these parameters is included. PATIENTS AND METHODS: Thirty-five patients with malignant mesothelioma (28 with pleural and 7 with intraperitoneal) were enrolled. Twenty-eight patients underwent chemotherapy, 7/35 radiation and 9/35 surgery (2 with pleural and 7 with abdominal disease). Combination chemotherapy included cisplatin-gemcitabine, cisplatin (or carboplatin) with premetrexed and doxorubicin-cyclophosphamide. RESULTS: In 2/28 patients with pleural mesothelioma the tumor was excised and in 7 with intraperitoneal disease, surgical therapy was palliative and there was survival prolongation. Radiotherapy was only palliative. Chemotherapy produced a very low response: 2/28 (7.14%) patients achieved a partial response. The median survival was 17 months, 4-year survival, 24.4% and 5-year survival, 12.12%. No serious toxicity was observed. CONCLUSION: Malignant mesothelioma of the pleura and intraperitoneum is a slow-growing disease which is indicated by the long survival, despite the failure of chemotherapy, radiation therapy and surgery.     

Considerations for post-operative radiotherapy to the hemithorax following extrapleural pneumonectomy in malignant pleural mesothelioma

With growing interest in evaluating extrapleural pneumonectomy (EPP) and post-operative in selected patients with early stage malignant pleural mesothelioma, it is essential that clinical trials should be conducted using a clear and reproducible radiotherapy protocol. The considerations which have determined the policy of radiotherapy planning and treatment delivery for patients with mesothelioma in The Netherlands are given. As well as general considerations such as patient selection, target volume and critical organ delineation, a dose-fractionation scheme, constraints relating to normal tissue, treatment planning, the type of external beam equipment, treatment verification and radiation toxicity and scoring are all taken into account.     

A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma.

BACKGROUND AND PURPOSE: To assess the effectiveness of radiotherapy in preventing tumour seeding after chest drain or pleural biopsy in patients with malignant mesothelioma and to determine, if tract metastases appear, whether they are tender or troublesome to patients. PATIENTS AND METHODS: Patients with a histological diagnosis of pleural mesothelioma and an invasive procedure within the preceding 21 days were stratified by age, performance status and treatment centre. Randomisation was performed between immediate drain site radiotherapy 21Gy in three fractions (XRT arm) or best supportive care (BSC) with follow-up to 12 months. Patients were asked to complete questionnaires on treatment toxicity and on symptoms from any tract metastases detected. RESULTS: Sixty-one patients were recruited from two centres between 1998 and 2004; 56 men, 5 women, median age 70. 31 were allocated to drain site radiotherapy. Seven patients developed tract metastases associated with the drain site (four XRT arm, three BSC) and four developed metastases associated with subsequent procedures at other sites (three XRT, one BSC). Two patients each developed two tract metastases. Of the 12 metastases, nine overlay the previous drain site but three were adjacent to the site. No statistically significant difference was found in the risk of tract metastasis associated with the drain site between the arms (p=0.748). CONCLUSIONS: Prophylactic drain site radiotherapy in malignant pleural mesothelioma does not reduce the incidence of tumour seeding by the margin indicated by previous studies.     

预防性放疗降低恶性胸膜间皮瘤有创操作通道转移发生率的Meta分析

目的 系统评价预防性放疗能否降低恶性胸膜间皮瘤（MPM）有创操作通道转移（PTMs）发生率。方法 检索PubMed、Cochrane Library、Web of Science、Embase数据库，收集MPM有创操作通道进行预防性放疗的相关研究，由两位评价员独立筛选文献、提取资料并评价纳入研究的方法学质量后，采用RevMan5.3软件进行Meta分析。结果 共纳入7项研究，包括698例患者。Meta分析结果显示，预防性放疗不能降低所有MPM患者PTMs的发生率（OR=0.48, 95%CI: 0.22~1.07, P=0.07）。而进行亚组分析后发现预防性放疗能有效减少进行大口径操作的MPM患者（OR=0.39, 95%CI: 0.18~0.84, P=0.02），或上皮型MPM患者（OR=0.21, 95%CI: 0.11~0.69, P=0.006）医源性PTMs的发生。结论 预防性放疗能有效预防进行开胸手术、胸腔镜、留置胸壁引流管等大口径操作或病理类型为上皮型MPM患者医源性PTMs的发生。     

Prophylactic irradiation of intervention sites in malignant pleural mesothelioma

Background and purpose

To assess the effectiveness of prophylactic irradiation of intervention track (PIT) to prevent tumor seeding in patients with malignant pleural mesothelioma.

Materials and methods

A retrospective review was conducted of 171 patients with a histological diagnosis of pleural mesothelioma with some undergoing prophylactic irradiation of intervention sites.

Results

Forty-eight patients (28%) received PIT. A majority of patients were followed until death. Thoracoscopy (88%) was the procedure most often performed. Thirty-three percent of patients received chemotherapy. The median dose of PIT was 21 Gy in 3 fractions with electrons or 6 MV photons. The local progression free survival (LPFS) at the intervention site was significantly higher in the PIT group and was not influenced by chemotherapy. At 6 months, LPFS for the intervention sites was 91% with PIT and 74% without PIT (p = 0.002). During the follow-up, 6 patients (13%) in the PIT group had tumor invasion of the subcutaneous tissue compared to 40 patients (33%) in the group without PIT (p = 0.008).

Conclusions

This study suggests that PIT in mesothelioma reduces the incidence of procedure tract metastasis. Finally, chemotherapy does not seem to have an influence on the incidence of tract metastasis.     

Closed pleural biopsy to diagnose mesothelioma: Dead or alive?

This letter explores the role of closed pleural biopsy in the diagnosis of malignant mesothelioma. Through retrospective analysis of local data, we found that closed pleural biopsy had a sensitivity of 44% in the diagnosis of malignant mesothelioma. It should therefore still be considered as a first line investigation in suspected mesothelioma especially in centres where CT-guided or thoracoscopic pleural biopsy are not immediately available.     

Brain metastases in malignant pleural mesothelioma. Case report and review of the literature

Recent advances in pleural malignant mesothelioma include the sequential use of palliative surgery, perioperative radiation therapy, and systemic chemotherapy. Radical treatments may not only palliate but also improve survival in some patients. The latter may be associated with the appearance of metastases in unusual sites including the central nervous system. In malignant mesothelioma, brain metastases were previously reported in 19 patients at autopsy and in only 1 patient antemortem. We detail the clinical presentation in the second patient with pleural malignant mesothelioma thus far reported to develop brain metastases. The difficulties in diagnosis, the role of immunoperoxidase stains in malignant mesothelioma, excellent tolerance of different modalities of treatment, and a review of the literature of brain metastases in mesothelioma are discussed. Based on our report, the possibility of brain metastases should be investigated by careful clinical examination prior to a radical treatment in patients with progressive refractory mesothelioma.     

Analysis of the Effect of Radiotherapy on Malignant Pleural Mesothelioma when Given on Adjuvant or Palliative Basis

Background and objective This retrospective study was designed to evaluate the response and survival of malignant pleural mesothelioma to radiotherapy when delivered with surgery and chemotherapy and when delivered alone or with chemotherapy. Methods A study for 110 patients with malignant pleural mesothelioma who presented to radiotherapy department, National Cancer Institute, Cairo and received radiation therapy in the period from January 1999 to July 2007. Results Forty-six patients (41.8%) received trim...     

Explaining differences in incidence rates of pleural mesothelioma between Sweden and the Netherlands

In recent years in several countries a deceleration or leveling off of pleural mesothelioma rates has been observed. The impact of asbestos used was analysed by comparing a country with a relative modest incidence rate of mesothelioma (Sweden) and an early response to asbestos use with a country with one of the highest incidence rates of mesothelioma in Western Europe (The Netherlands). In Sweden the Cancer Register provided information on the annual incidence of pleural mesothelioma, whereas in The Netherlands mortality data were provided by Statistics Netherlands for the period 1969-2001. In The Netherlands among men the incidence rate was consistently higher (1.5-2 times) than in Sweden, whereas among women similar rates were observed. Assuming that none of the female cases was caused by occupational exposure to asbestos, minimum estimates of the etiologic fraction for occupational exposure to asbestos in men would be 82% in Sweden and 92% in The Netherlands. Possible explanations for the consistently higher incidence rates in the Netherlands than in Sweden include differences in exposure levels, the proportion of exposed subjects in the workforce and types of asbestos fibres used. Measures to decrease the exposure to asbestos seem to have decreased the risk of pleural mesothelioma in both countries among age groups below 60 years. This effect will result in a leveling off of the increase in pleural mesothelioma in both countries in the next decade.     

Thrombocytosis in patients with malignant pleural mesothelioma

Platelet counts were studied retrospectively in a series of 64 patients suspected of primary malignant pleural mesothelioma. Only platelet counts taken before chemotherapy and radiotherapy and surgery other than thoracocentesis were considered. Thirty-two patients had malignant pleural mesothelioma and 32 patients had other malignant disease in pleura. In both groups 34% had slightly elevated platelet counts. In a subgroup consisting of 18 patients with primary pulmonary adenocarcinoma 28% had thrombocytosis. The distribution of platelet counts did not differ in the diagnostic subgroups, and thrombocytosis had no differential diagnostic value in patients with malignant disease in any stage in the pleurae. The frequency of thromboembolic episodes was low.     

The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy.

Thirty-eight patients with malignant mesothelioma of the pleura were seen at Peter MacCallum Cancer Institute between 1981 and 1985. In 35 patients presenting with disease confined to one hemithorax, the following treatments were given: radical surgery, 13 patients: radical radiotherapy, 12 patients; palliative radiotherapy, 20 patients; chemotherapy, 9 patients; observation only, 2 patients. Median survival from time of diagnosis for all 38 patients was 9 months, with an estimated 2-year survival rate of 16%. Treatment did not significantly affect survival, although there was an indication that patients having radical surgery did better (median survival 17 months) than those who did not (median survival 9 months) (p = 0.13). Fifteen patients were given radiotherapy with radical intent but only 12 completed treatment (50 Gy). The median survival of the 12 patients completing radiotherapy was 17 months, with an estimated 2-year survival rate of 17%. Two patient deaths were attributable to radical radiotherapy (one radiation hepatitis, one radiation myelopathy). Twenty-one patients received 31 courses of palliative radiotherapy for various symptoms, predominantly pain. The results were assessable for 26 courses, with 17 (65%) being at least partly successful. In conclusion, radiotherapy appears to be ineffective in prolonging survival in malignant mesothelioma of the pleura, but has a useful role in palliation.     

Malignant pleural mesothelioma

Opinion statement Despite innumerable trials of surgery, radiotherapy, and countless chemotherapeutic drugs, it is unclear whether any intervention has had a significant impact on more than a few highly selected patients with malignant pleural mesothelioma. Because most patients die of respiratory failure from extensive disease progression in the thorax, treatment usually includes attempts at local control. Unfortunately, radiotherapy is associated with significant complications in pleural mesothelioma, and surgery is feasible in only a small percentage of patients. Although there have been several single-institution reports of combined-modality therapy with extrapleural pneumonectomy, postoperative radiation, and chemotherapy in which prolonged survival has been observed, most patients with malignant pleural mesothelioma have locally advanced disease, advanced age, or comorbid medical illnesses that preclude aggressive surgery. Therefore, the use of a systemic anticancer agent is the only treatment option for most patients with malignant pleural mesothelioma. Evaluation of effective chemotherapy regimens for this disease has been hampered by many factors. Because mesothelioma is an uncommon malignancy, most studies have enrolled small numbers of patients, and few trials have been randomized. The disease is heterogenous, yet until recently there was no single staging system that could reliably predict survival, nor is there a universally accepted set of prognostic criteria for selecting a uniform group of patients. Response assessment has been limited by the inherent difficulties of reproducibly measuring pleural-based disease. The real impact of systemic chemotherapy on the natural history of malignant mesothelioma is still uncertain because phase III trials comparing chemotherapy with best supportive care have not yet been completed. Although nearly every class of cytotoxic agent has been evaluated in mesothelioma, response rates of greater than 20% have not been consistently demonstrated for any drug. The most active drug classes are the antifolates, the anthracyclines, and the platinums. Doxorubicin has historically been considered the gold-standard chemotherapy, although its true response rate is likely only 15%. The most active commercially available drug for mesothelioma so far appears to be gemcitabine. Although gemcitabine has a limited role as a single agent, it is quite active in combination with a platinating agent. The impressive 48% response rate reported for the combination of gemcitabine with cisplatin in a single phase II study has made this regimen the new standard of care for off-protocol treatment of this disease, although this trial still requires validation. With the recent introduction of several new agents with definite activity in this disease, the therapeutic nihilism previously associated with malignant pleural mesothelioma is gradually being replaced by a cautious optimism. Early trials of angiogenesis inhibitors, gene therapy, and vaccines offer additional avenues for treatment. As we begin to incorporate these active new drugs with each other and in adjuvant and neoadjuvant treatment regimens, there is reason to believe that superior results for patients with malignant pleural mesothelioma can be achieved in the near future.     

Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients

Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.     

Up-regulation of thioredoxin and thioredoxin reductase in human malignant pleural mesothelioma

Thioredoxin (Trx) with a redoxactive dithiol together with NADPH and thioredoxin reductase (TrxR) is a major disulfide reductase regulating cellular redox state and cell proliferation and possibly contributing to the drug resistance of malignant cells. We assessed the Trx system in malignant pleural mesothelioma cell lines, in nonmalignant pleural mesothelium and in biopsies of malignant pleural mesothelioma. The mRNA and immunoreactive proteins of Trx and cytosolic and mitochondrial TrxR were positive in all four human mesothelioma cell lines investigated. Six cases of nonmalignant, histologically healthy pleural mesothelium showed no Trx or TrxR immunoreactivity, whereas immunohistochemistry on 26 biopsies of human malignant pleural mesothelioma showed positive Trx in all cases and positive TrxR in 23 (88%) of the cases. Moderate or strong immunoreactivity for Trx or TrxR was detected in 85% (22 cases) and 61% (14 cases) of the mesothelioma cases, respectively. Both Trx and TrxR staining patterns were mainly diffuse and cytoplasmic, but in 39% of the mesothelioma cases prominent nuclear staining could also be detected. Although staining for Trx and TrxR was seen in tumor cells, no significant association could be demonstrated between Trx or TrxR expression and tumor cell proliferation or apoptosis in the biopsies of mesothelioma. There was no significant association between the intensity of Trx or TrxR immunoreactivity and patient survival, which may possibly be related to moderate or intense Trx and TrxR reactivity in most of the cases. Although the Trx system may have an important role in the drug resistance of malignant mesothelioma, these studies also suggest that multiple factors contribute to the promotion, cell proliferation and apoptosis of malignant mesothelioma cells in vivo.