Paolo Andrea Zucali, Fabio De Vincenzo, Matteo Simonelli, Armando Santoro. Expert Review of Anticancer Therapy. Volume 9, Issue 4. April 2009.
Malignant pleural mesothelioma (MPM), the most common primary tumor of the pleura, is an aggressive tumor that usually has a poor prognosis. In fact, the median survival is less than 12 months. This tumor was once rare but its incidence has been increasing throughout most of the world as a result of widespread past exposure to asbestos, and it is predicted that it will rise in the next decades, especially in developing countries where the use of asbestos has not yet been banned. Approximately 80% of MPM cases can be attributed to asbestos fiber exposure; other potential carcinogenic factors are exposure to simian virus 40 (SV40), radiation and thorotrast.
The management of patients with MPM is controversial. Difficulty in diagnosing and staging the disease, especially in its early stages, has thwarted the development of a generally accepted stage-related approach. Moreover, MPM is a heterogeneous disease, often with different clinical courses. A number of prognostic factors have been described, and two major prognostic scoring systems have been published. The majority of patients (80%) are diagnosed in stage III/IV and are not candidates for surgical treatment. Systemic therapy is the only potential treatment option for the majority of these patients, but their poor performance status and the low chemo- and radio-sensitivity of this tumor induced a nihilistic attitude towards medical treatment in the past. Moreover, the relatively low incidence of the disease has made it difficult to conduct randomized controlled studies with adequate numbers of cases.
Recently, there have been several major developments in the management of MPM. Two Phase III randomized trials have set the combination of cisplatin with an antifolate as the reference regimen for first-line chemotherapy. In particular, the combination of pemetrexed plus cisplatin is considered the standard of care as a front-line chemotherapy in MPM patients because it was shown to improve response rates (RR), time to progression (TTP), overall survival (OS) and quality of life significantly when compared with cisplatin alone. Also, the combination of raltitrexed and cisplatin as first-line treatment was reported to improve RR, TTP and OS compared with cisplatin alone. However, these outcomes had borderline significance, probably due to the limited sample size of the trial.
A number of molecular alterations occurring in MPM have been reported, leading to a deeper understanding of its biology and the identification of new targets for therapy. Consequently, several biological agents have been explored or are currently under evaluation. More accurate staging and patient selection and improvements in surgical techniques and postoperative care have led to lower morbidity and mortality rates after radical surgery. Finally, new radiotherapy (RT) techniques, such as intensity-modulated radiation therapy (IMRT), have provided the potential to conform radiation doses tightly to target volumes, reducing normal tissue toxicity.
The principal goals of this review are to summarize the improvements in the management of MPM that have been achieved recently and outline the therapeutic approaches in development.
State of the Art
Diagnosis
Correlation between clinical, imaging and pathological findings is critical to a correct and rapid diagnosis. However, difficulty in diagnosing and staging the disease, especially in its early stages, has thwarted the development of a generally accepted stage-related approach.
Imaging
Correct staging is mandatory in the treatment of MPM. The computed tomography (CT) scan, MRI, PET, and often thoracoscopy and mediastinoscopy, should be considered as complementary to define the extent of disease, selecting the optimal patients for a multimodality approach and to assess the response to treatment. More than 70% of patients present with pleural effusion alone at the CT scan, and 92% present with pleural-based masses, with or without thickening of interlobular septa (86% of cases). CT scan is currently the most accurate noninvasive method to stage patients, to assess response to treatment and to detect recurrent disease postoperatively, but it is often inaccurate in diagnosing chest wall involvement or extension through the diaphragm. Tumor spread into the interlobular fissures, tumor invasion of the diaphragm and through the diaphragm and the invasion of the endothoracic fascia and bone structures seems to be shown more clearly by MRI. However, a study comparing CT scan and MRI for preoperative staging showed that MRI is not significantly better than CT in defining the local extent of tumor. Therefore, CT remains the standard imaging modality. Pass et al. observed that preoperative tumor volume assessed by volumetric CT tumor measurement is representative of tumor (T) status in MPM and can predict survival.
The use of 18 F-fluorodeoxyglucose (FDG) PET for the diagnosis of MPM has been described recently. PET has proved useful in detecting malignant pleural lesions and partially in assessing the extent of tumor involvement. In one study of 65 MPM patients, this imaging technique correctly detected extrathoracic metastases but failed to reliably identify the locoregional (tumor and mediastinal nodal) status of MPM; sensitivity was 19% for locally advanced disease (T4) and 11% for nodal metastases. Integrated CT-PET with coregistration of anatomic and functional imaging data increases the accuracy of MPM staging for T4 disease (sensitivity: 67%; specificity: 93%), while it remains inaccurate in the evaluation of nodal metastases (sensitivity: 38%; specificity: 78%), with high rates of false-positive and false-negative results. In addition to the benefit of identifying patients with stage IV disease, PET has prognostic significance and it is useful in assessing the response to treatment. However, response evaluation through PET scan alone has not yet been sufficiently standardized. In conclusion, both imaging and metabolic diagnostic modalities should afford the clinician the ability to define the most appropriate treatment options, and the combination of CT scan and PET is likely to be the optimal method for evaluating their efficacy in patients with MPM. Considering the suboptimal accuracy of radiological staging in MPM, some authors have advocated the need for extended surgical staging, such as mediastinoscopy, to evaluate the node (N) status in patients being evaluated for radical resection.
Histology
Three basic and distinct histological types of malignant mesothelioma can be identified by optic microscopy: epithelial, sarcomatoid and mixed (or biphasic). MPMs are exclusively epithelial in approximately 50-67% of cases, sarcomatoid in 7-21% and mixed in the remaining 24-35% of cases.
Cytologic evidence of malignant mesothelioma in the pleural fluid is found in 33-84% of cases. Moreover, for lesions presenting as chest wall or pulmonary lesions, or as a pleural encasement without effusion, or rarely as a metastatic deposit, fine-needle aspiration is needed to make a diagnosis. Percutaneous pleural biopsy yields a diagnosis of malignancy in up to a third of cases; however, it does not usually provide a large enough specimen for the immunohistochemical or electron microscopic studies that are critical for a definitive diagnosis.
In order to obtain tissue for histologic diagnosis and to facilitate staging, the investigation of choice is a thoracoscopic examination, by which excessive fluid can be drained, followed by pleurodesis. Thoracoscopy yields a diagnosis in at least 80% of patients without committing the patient to a major surgical procedure. Ideally, thoracoscopy and biopsy should be performed through a single port-site incision placed in the line of a potential future thoracotomy. Moreover, considering the advent of the targeted therapy era, thoracoscopy with biopsy should allow the availability of sufficient tumor tissue to perform biomarker analyses to select patients for target therapy.
The major difficulty in MPM diagnosis is the differential diagnosis (with a pleural diffusion) of a tumor originating elsewhere, usually an adenocarcinoma of various origin. However, there may also be difficulties in determining whether a pleural proliferation is benign or malignant. The determination of telomerase expression and the immunohistochemical staining for several markers are useful in making a diagnosis of MPM. In particular, MPM is characterized by the presence of staining for epithelial membrane antigen, the calcium-binding protein calretinin (exclusively expressed in the epithelial type but not in the sarcomatoid and mixed types), Wilms’ tumor 1 antigen, cytokeratin 5/6, HBME-1 (an antimesothelial cell antibody) or mesothelin (>85% of epithelioid malignant mesotheliomas are positive for mesothelin), and the absence of staining for antigens such as carcinoembryonic antigen, thyroid transcription factor-1, the tumor glycoproteins B72.3, MOC-31 and Ber-EP4, and the epithelial glycoprotein BG8. New markers under evaluation are D2-40 and podoplanin, which are detected in approximately 90% of epithelioid MPMs.
An alternative method for distinguishing between MPM and lung cancer could be a diagnostic test using gene-expression ratios. Gordon et al. observed that this molecular diagnosis is an accurate and inexpensive technique with direct clinical applicability.
Staging
The staging of MPM is difficult. However, the basal assessment of the disease extent can allow an accurate evaluation of response to the treatment, if any, at a later time. At present, the recommended classification for clinical use is the International Mesothelioma Interest Group (IMIG) Classification, based on a tumor-node metasitasis modification. This classification is mainly surgical-pathological and may not be completely applicable to cross-sectional imaging. Moreover, the lymphatic drainage of the pleura is quite complex and is not fully reflected in the IMIG system, in which the N classification mirrors that of lung cancer. The distinction between N1, N2 and N3 nodes is currently preserved in this staging system in order to facilitate further study of the prognostic implications of nodal metastasis. However, a recent study of 348 surgically resected patients observed longer survival for patients with N1 disease compared with patients with N2 disease, suggesting that this cohort of patients should be downstaged from stage III to stage II. Currently, a multi-institutional international effort is investigating pooled data from a dozen centers to identify variables correlating with survival to improve upon the current staging system.
Serum Markers
In an attempt to facilitate early diagnosis of cancer and early therapeutic intervention in patients with MPM, several serum markers were analyzed.
Serum mesothelin-related protein (SMRP) is a soluble form of mesothelin. More than 80% of MPM patients have elevated SMRP levels (>60% at the time of diagnosis). In particular, SMRP is elevated in patients with epithelial and biphasic MPM. The original immunohistochemical studies with the K1 monoclonal antibody revealed that mesothelin was expressed on all of 15 pleural epithelial cryopreserved MPM tumor samples but not in any of the four sarcomatous MPMs examined. In four cases of mixed or biphasic MPM, mesothelin staining was observed in regions of epithelial differentiation and not in sarcomatous regions. SMRP concentrations seemed to correlate with tumor size and to increase during tumor progression. Moreover, SMRP levels may prove useful in screening for malignant mesothelioma. Beyer et al. demonstrated that SMRP is a serum biomarker, with 83% sensitivity and 95% specificity. In a more recent study, SMRP was shown to be a promising marker for MPM in blood and pleural fluid.
Osteopontin is a glycoprotein regulated by proteins in cell-signaling pathways that are associated with asbestos-induced carcinogenesis. Sandhu et al. reported that osteopontin is upregulated in asbestos-induced tumors in a rat model of asbestos carcinogenesis and in cells exposed to asbestos in vitro. Serum osteopontin levels could be used to discriminate persons with exposure to asbestos who do not have early pleural mesothelioma from those with exposure to asbestos who have early pleural mesothelioma (higher serum osteopontin levels), regardless of the histologic type of the mesothelioma.
Prognosis
The median survival of patients with MPM from the time of diagnosis is 12 months, ranging from 8 months for stage IV patients to 40 months for stage I. The clinical course of these patients varies widely, ranging from slowly progressive, indolent disease to more aggressive, rapidly progressive disease. Two clinical prognostic scoring systems have been devised. Poor prognosis was associated with a poor performance status (according to Eastern Cooperative Oncology Group or Karnofsky scores), a high white cell count, a probable/possible histologic diagnosis of mesothelioma, male gender and having sarcomatous tissue as the histologic subtype. Taking these five factors into consideration, patients were classified by the European Organisation for Research and Treatment of Cancer (EORTC) into two groups: a good-prognosis group (1-year survival rate: 40%) and a poor-prognosis group (1-year survival: 12%). The Cancer and Leukemia Group B (CALGB) has reported that the key prognostic factors in MPM include performance status, age, hemoglobin, white blood cell count, chest pain and weight loss, and that these may be useful in predicting outcomes for chemotherapy-treated patients. As performance status, age and white blood cell count increase, survival decreases. Prospective validation of these prognostic groupings and, in particular, the worst prognostic CALGB cohorts has been reported.
Pass et al. observed that preoperative tumor volume assessed by volumetric CT tumor measurement is representative of T status in MPM and can predict survival. Median survival for preoperative tumor volume less than 100 cc was 22 versus 11 months for tumor volumes of greater than 100 cc (p = 0.03). Progressively higher stages were associated with higher median preoperative volume (stage I: 4 cc; stage II: 94 cc; stage III: 143 cc; stage IV: 505 cc; p = 0.007). Higher tumor volumes were also associated with a greater likelihood of lymph node metastasis. Therefore, CT seems to serve not only as a diagnostic but also as a prognostic tool.
18 F-fluorodeoxy-D -glucose-PET has a prognostic role in MPM. Recent studies have demonstrated that FDG uptake, measured at diagnosis by standardized uptake value (SUV), has independent prognostic value in this disease. There was a linear relationship between increasing SUV and poor median survival time in a cohort of 137 MPM patients who underwent PET scanning. The relative risk of death in patients with a SUV greater than 10, when compared with a SUV less than 10, was 3.3 (p = 0.03). These findings suggest that PET SUV predicts survival and can be used to stratify patients for treatment.
Treatment Approaches
Attitudes toward the treatment of MPM vary greatly, and range from supportive treatment only to aggressive surgery and combined modality treatment.
Surgery
The role of surgery in MPM is still controversial. Its results are difficult to interpret because of different patient selection, the relatively small number of patients, the lack of randomized trials and often the addition of another treatment modality to surgery. Nevertheless, in clinical practice, surgery is performed to make diagnosis, to palliate symptoms such as pain or dyspnea and to improve survival in a highly select group of patients. In general, patients with stage I and II disease should be considered candidates for radical surgery. Pleurectomy/decortication (P/D) and extrapleural pneumonectomy (EPP) are the two major types of operation. EPP usually involves an en bloc resection of lung, pleura, pericardium and diaphragm, while P/D involves resection of the parietal and visceral pleurae and the pericardium and diaphragm when necessary, but spares the lung.
Considering that sample sizes are too small for demonstrating statistically significant differences in survival, many studies have chosen end points such as TTP and patterns of recurrence to justify the preferred surgical procedure. While P/D is believed to be associated with fewer complications and lower mortality, EPP appears associated with lower rates of local recurrence. However, recurrence end points are unreliable because follow-up practices, definitions of progression of disease and the methods of documenting recurrence vary greatly, causing considerable difference in rates of progression-free survival (PFS) from OS.
To investigate the outcomes of EPP and P/D with OS as the primary end point, a large multicenter study was performed. Over a 16-year period, 663 consecutive patients underwent either EPP (n = 385) or P/D (n = 278). There was no significant difference in median survival for stage I and II patients having P/D (n = 98; 23 months) versus EPP (n = 96; 19 months; p = 0.07). Multivariate analysis demonstrated a hazard ratio (HR) of 1.2 for EPP (p = 0.04) controlling for stage (HR = 1.9; p < 0.001) and histology (HR = 1.5; p < 0.001). This study suggested that P/D had a marginally better survival than EPP. However, the role of P/D has not yet been universally considered as a curative approach. As a matter of fact, many authors consider P/D more a palliative than curative treatment. Thus, the choice of resection procedure should be tailored to the extent of disease identified at the time of operation, patient comorbidities and the type of multimodality therapy planned.
Radiotherapy
The role of RT in the management of MPM is still debated and RT alone probably has no major role in disease control and survival. RT is often used for palliation of pain and it has often been added to surgery in an attempt to improve local control and reduce local failure. However, the results of the published literature are difficult to interpret because RT was used as a component of multimodality treatment, because of the small number of patients reported in single studies and because of the lack of randomized trials.
The diffuse nature of the tumor, which often covers most of the lung and the interlobular fissures, is the principal limitation to RT. Although the tolerance is mitigated by fractionation, a very high radiation dose is usually required to treat the entire pleura. However, even when the affected lung is removed, the addition of postoperative RT has been limited because of the proximity of dose-limiting structures. Thus, the recent improvements in radiation treatment techniques, such as IMRT, have provided the potential to conform radiation doses tightly to target volumes, reducing normal tissue toxicity. The better sparing of the normal tissues gives IMRT the possibility of dose escalation to improve locoregional control and decrease local recurrences. Ahamad et al. showed how IMRT after EPP is feasible, with modest toxicity and excellent local control. However, in spite of a highly conformal dose distribution around the target volume and a steep dose gradient near the organs at risk, the IMRT technique may not adequately spare ipsilateral kidney, with a potential high toxicity. A novel therapy modality combining electrons and photon IMRT has recently been proposed; this technique exhibited, in a theoretical study on CT images of 11 MPM patients (six after EPP and five after P/D), an advantage in further reducing the doses to the liver, ipsilateral and contralateral kidney and heart.
Chemotherapy
For many years, a nihilistic attitude characterized the medical treatment of MPM. All chemotherapy studies using either single agents or combination regimens in the setting of small Phase II trials reported poor response rates (<20%), without any impact on median survival. In a meta-analysis of studies published between 1965 and 2001, cisplatin was found to be the most active single drug and polychemotherapy has been associated with higher RR, but not with longer survival.
There are few randomized data assessing the role of chemotherapy versus best supportive care (BSC). Sponsored by the British Thoracic Society and Cancer Research UK, a large three-arm Phase III trial comparing polychemotherapy (mitomycin, vinblastine and cisplatin [MVP] schedule) plus BSC versus vinorelbine plus BSC versus BSC alone started in 2000. This study did not show any significant advantage in terms of OS among the three arms. Although the study was not powered to detect a difference between chemotherapy arms, one may infer that the addition of inactive chemotherapy (MVP) does not improve survival or quality of life in mesothelioma patients, while the addition of an active drug, such as vinorelbine, may do so. Moreover, in this trial, BSC was compared with the ‘old’ chemotherapeutic schedule; no data are available about the actual standard treatment (cisplatin/antifolate combination) compared with BSC. Recently, O’Brien et al. observed how the early use of chemotherapy (MVP schedule) versus delay in the management of patients with stable symptoms, after control of any pleural effusion, provided an extended period of symptom control, and a trend to survival advantage.
Several new cytotoxic agents with definite activity in mesothelioma have recently been evaluated, including gemcitabine and the antifolates pemetrexed and raltitrexed. A single study reported a RR of 48% with gemcitabine combined with cisplatin, but additional Phase II studies have documented a lower level of efficacy. Recently, two randomized controlled trials comparing cisplatin alone versus its combination with an antifolate were reported. In a multicenter Phase III study involving 448 chemonaive patients, those treated with pemetrexed plus cisplatin had a longer median OS (12.1 months) than those treated with cisplatin alone (9.3 months) and had an objective RR (shrinkage of the tumor by at least 50%) of 41 versus 16.7%. Furthermore, the raltitrexed and cisplatin combination also improved OS compared with cisplatin alone in a population of 250 patients, confirming that cisplatin with an antifolate should be the reference regimen in patients with MPM. The magnitude of the survival benefit was similar in both studies: a 2.8-month increase in median survival in the pemetrexed study (from 9.3 to 12.1 months) and a 2.6-month increase in the raltitrexed study. However, in the pemetrexed trial, this difference was statistically significant, while, in the other study, the survival improvement had borderline significance, probably due to the limited sample size. Considering that many MPM patients are unfit to receive cisplatin-based chemotherapy, some combined schedules containing carboplatin instead of cisplatin were tested in an attempt to reduce toxicity maintaining the same survival outcomes. Moreover, considering that the incidence of MPM in elderly patients is increasing, no significant difference was observed in terms of overall disease control (60.4 vs 66.9%; p = 0.47), TTP (7.2 vs 7.5 months; p = 0.42) and survival (10.7 vs 13.9 months; p = 0.12) between age groups in a retrospective analysis of pooled data from two Phase II trials of pemetrexed and carboplatin as first-line therapy. Vinorelbine has one of the highest response rates of any single agent against mesothelioma, and recent Phase III data suggest that it may improve survival over BSC. Combination with cisplatin yielded a RR of 29.6% and a median survival of 16.8 months. The novel vinca alkaloid vinflunine achieved a RR of 13.8% and a median survival of 10.8 months. Despite this activity, the drug has not been developed further for MPM.
The role of second-line chemotherapy in MPM is not yet proven. However, there is increasing evidence from single-arm studies that chemotherapy in the second-line setting is not only feasible but also active. Moreover, patients who experience clinical benefit from such first-line chemotherapy are frequently still healthy when radiological progression of MPM is documented and commonly inquire about second-line therapy. Recently, a noteworthy activity of pemetrexed, both alone and combined with carboplatin, as second-line treatment following prior platinum-based chemotherapy was reported. In a randomized, multicenter Phase III study examining pemetrexed as second-line chemotherapy versus BSC, treatment with pemetrexed provided clinical benefit with a statistically significant improvement in TTP (3.8 vs 1.5 months), whereas improvement in OS was not seen, possibly owing to the influence of poststudy therapy on the BSC arm. However, because the cisplatin-pemetrexed regimen has recently become standard in the treatment of first-line MPM patients, second-line chemotherapy should focus on other compounds. In a retrospective analysis of patients treated in the Phase III pemetrexed trial, approximately 42% of all patients received some form of poststudy chemotherapy (PSC). This group of patients had a significantly prolonged survival. However, because PSC was not randomized, it is impossible to know whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival were able to receive more PSC. Very few prospective trials of second-line chemotherapy in pemetrexed-pretreated MPM patients have been performed (Table 1).
Combined Modality Treatment
Given the disappointing results of surgery alone, combined modalities have been attempted in order to reduce local recurrence and systemic spread. Surgery was employed in the form of P/D or EPP in combination with various forms of radiation treatment and chemotherapy. The aim of a surgical approach in MPM is to remove all gross disease. However, a complete resection (R0) with surgery alone is theoretically unattainable owing to the inability to eradicate residual microscopic disease, regardless of whether an EPP or a P/D is performed. Therefore, treatment has focused on surgery in combination with radiation and/or chemotherapy in a multimodality setting. To an extent, the choice of operation is also determined by the type of adjuvant therapy planned. For example, following EPP, high-dose hemithoracic radiation can be administered, which appears to lessen the chance of local tumor recurrence, whereas, because the lung is left in place after P/D, administration of therapeutic doses of radiation is not feasible because of the risk of severe pulmonary toxicity.
Surgical resection with intrapleural and systemic chemotherapy showed disappointing results with a high morbidity rate. EPP followed by high-dose external beam RT (54 cGy) achieved a median survival of 33.8 months in stages I and II compared with a median survival of 10 months in stages III and IV, demonstrating the best local control ever achieved in mesothelioma. The Dana Farber Cancer Center (MA, USA) have a great deal of experience with EPP combined with multi-agent chemotherapy and postoperative radiation. The median survival of 183 patients treated between 1980 and 1997 was 19 months with 2- and 5-year survival rates of 38 and 15%, respectively. The conclusion of this group was that this approach is safe and offers improved survival only for patients with epithelial cell type, lack of extrapleural nodal involvement and negative surgical margins, with a median survival approaching 5 years. The pattern-of-failure analysis showed that 54% of patients had recurrences and the site of recurrence was local in 35% of them. This and other studies indicate that more effective strategies should be sought to increase local control. Moreover, better staging procedures should be developed to accurately stage the patients preoperatively.
The best timing of chemotherapy with respect to surgery is still open to debate. In the neoadjuvant setting, chemotherapy seems to improve resectability rates and survival without altering surgery mortality rates. The Swiss pilot study administered three cycles of gemcitabine/cisplatin followed by EPP in 19 patients with stages I-III MPM. Induction therapy response rate was 32%. EPP was performed in 16 patients without perioperative mortality and 13 patients received postoperative RT. Median survival time was 23 months. The other neoadjuvant Phase II study using gemcitabine/cisplatin was performed at Memorial Sloan-Kettering (NJ, USA), but focused on patients with stage III and IV disease; induction therapy RR was 26%. All patients underwent postoperative external beam radiation therapy (54 cGy). The median survival of all patients with advanced-stage MPM entered on study was 19 months. Patients who underwent EPP had a median survival of 33.5 months, while patients who were unable to undergo resection had a median survival of 9.7 months (p = 0.01), suggesting that neoadjuvant chemotherapy is feasible and also helps to select patients who would benefit most from surgical resection. These results also led to the development of a Swiss trial and a multicenter US trial testing pemetrexed/cisplatin as induction therapy in patients with earlier-stage disease who are considered potential candidates for resection via EPP.
In conclusion, considering the literature, multimodality treatment is far from perfect, it has not been sufficiently validated and it should be studied further through clinical trials.
Future Directions
End Points for Efficacy Evaluation & Assessment of Tumor Response
Adequate response evaluation is a cornerstone for the identification of active drugs. Emerging data suggest that the survival outcomes faithfully reflect the drug’s activity and should represent the best treatment end points in MPM, considering the notable difficulty in radiological response assessment. Fennell et al. demonstrated how radiological responses did not appear to be correlated with survival improvement. A recent overview of the EORTC Lung Cancer Group has pointed out that replacement of the RR by TTP as the primary end point would allow a better selection of clinically active drugs, especially considering the advent of targeted therapy. The authors grouped ten trials into three categories according to the published RR: significant, moderate and poor clinical activity. Moreover, they calculated the PFS rate at fixed timepoints (3, 4, 5 and 6 months) in order to distinguish the treatment effect from the natural history of disease.
Assessment of the response with conventional criteria based on CT scan measurements is challenging, owing to the circumferential and axial pattern of growth of MPM. Several radiological response systems have been proposed, but neither WHO criteria, nor the more recent Response Evaluation Criteria In Solid Tumors (RECIST) unidimensional criteria, nor hybrid uni- and bi-dimensional criteria seem to apply to tumor measurement in this disease. Recently, modified RECIST criteria have been developed and validated by Byrne and Nowak. Although they are already being used in current clinical trials, they have been criticized based on the high grade of interobserver variability documented in the assessment of tumor response classification in MPM and on theoretical studies of mesothelioma growth according to nonspherical models. Furthermore, some morphological characteristics of MPM, such as growth in the axial direction or along the lung fissures, cannot be captured by any of the proposed CT-based response criteria. Therefore, alternative measurement modalities using direct measurement of tumor volume or metabolic imaging are being developed. FDG-PET seems to be useful to assess the response to treatment. In fact, there is growing evidence that therapy-induced changes in tumor FDG uptake might predict response and patient outcome early in the course of treatment. In a study of 22 patients evaluated by FDG-PET and CT imaging at baseline and after two cycles of therapy, eight out of 20 evaluable patients showed a decrease of 25% or more in tumor FDG uptake (as measured by SUV) and were defined as having a metabolic response. Metabolic response correlated to PFS, which was 14 months in responders and 7 months in nonresponders. By contrast, no correlation was found between PFS and the radiologic response evaluated by CT imaging. Patients with a metabolic response had a trend towards a longer OS. Other groups have reported similar observations. Based on these studies, the use of FDG-PET for prediction of response and, more importantly, of survival outcomes appears promising and warrants validation in larger prospective series of MPM patients. A total glycolytic volume (TGV) analysis of FDG-PET uptake could represent an interesting development in the assessment of response and prediction of patient outcome in MPM. In 17 MPM patients evaluated after two cycles of first-line chemotherapy with carboplatin and pemetrexed, the metabolic response, defined as any TGV reduction, was significantly correlated to TTP, with a median TTP for metabolic responders of 15.8 versus 5.6 months for nonresponders (p = 0.04). Moreover, patients with a metabolic response had a trend towards longer OS (mean OS: 25.4 vs 17.5 months), but this difference did not reach statistical significance (p = 0.20). The sensitivity of this method in comparison to a single-pixel evaluation (SUVmax ) should be evaluated in a larger prospective series.
Biomarkers
Elevated SMRP levels were recently found to be a significant negative prognostic marker in MPM patients. Paradoxically, tumors that strongly express mesothelin have a better prognosis, possibly reflecting the fact that tumor mesothelin is a differentiation marker, whereas SMRP is more related to tumor burden and destruction of mesothelin-expressing tumor cells. Preclinical SMRP and mesothelin expression in tumors were not correlated, supporting the notion that tumor burden is the most important contribution to SMRP elevation. However, the prognostic impact of SMRP in MPM is still inconclusive and needs further evaluation.
Several novel biomarkers are under evaluation as useful predictive or prognostic tools. However, thus far, no biomarkers have been successfully translated into the clinic. This is owing to the difficulty in defining a patient subpopulation in which single or multiple biological variables accurately predict sensitivity to therapy and prognosis by significantly adding to, or supplanting, clinical variables. Many biomarkers correlate certain biochemical pathways with specific clinical outcome, and provide a useful hypothesis generator for novel, early clinical trials. Data suggest the great importance of angiogenesis in mesothelioma, and high microvessel density was associated with poor survival. Proteins involved in regulating the angiogenic process have been implicated in the prognosis of MPM and can be indirectly assessed using immunohistochemistry and microvessel counting. The engine of angiogenesis is hypoxia. MPM exhibits high levels of expression of the surrogate marker of hypoxia, hypoxia-inducible factor 1-α. The reduced level of BAX , a tumor-suppressor gene downregulated by tumor hypoxia, has been associated with a poor outcome. The angiogenic factors, such as VEGF, the VEGF receptors (VEGFRs) FLT-1 (VEGFR1), KDR (VEGFR2), VEGF-C and VEGFR3, have been shown to be coexpressed in MPM. Moreover, FGF1, FGF2, TGF-b, thrombospondin 1, methionine aminopeptidases, IL-6 and IL-8 have been implicated in angiogenesis in MPM. High levels of VEGF and FGF2 or coexpression of TGF-b, VEGF, FGF1 and FGF2 have been found to be associated with a poor outcome.
The advent of microarray technology has been used to investigate different gene signatures that could be used to predict both survival and progression of MPM. A four-gene signature comprising KIAA097, GDP-dissociation inhibitor 1, cytosolic thyroid hormone-binding protein and an expressed sequence tag similar to the L6 tumor antigen, which correctly classified a training sample into good- and poor-prognostic groups, was able to predict the correct outcome in a significant number of cases, supporting the identification of novel disease-specific and treatment-specific prognostic molecular marker candidates. The presence of an 11-gene, oncogene-driven pathway signature, correlated with a stem cell-like expression profile, is associated with a poor prognosis in patients with MPM. In the same way, aurora kinases were identified and validated as predictive of outcome with a large gene-expression analysis. In fact, mitosis or proliferation, diploidy and S-phase fraction were identified as indices of significance, and increased expression of regulators of mitosis and cell-cycle control were observed in more-aggressive cancers. Further prospective studies are required to confirm these data and the detection of novel biomarkers will be one of the major fields of MPM research in the coming years.
Novel Therapeutic Strategies
Given the relative rarity of mesothelioma, it is surprising how many novel agents have been evaluated. Certainly, the better understanding of the biology of mesothelioma makes the assessment of a number of targeted agents particularly interesting (Table 2).
Malignant mesothelioma cells show an increased or dysregulated growth. The cells produce and respond to many autocrine growth factors, such as HGF, EGF, PDGF-A and -B, TGF-b and angiogenic factors, such as VEGF. The corresponding receptors to these growth factors activate the Akt/PI3K pathway, which has a crucial role in MPM cell survival and contributes to the antiapoptotic phenotype.
EGF Receptor Pathway Inhibitors
Although the EGF receptor (EGFR) is highly overexpressed in mesothelioma, and although the EGFR tyrosine kinase inhibitor gefitinib inhibits mesothelioma in vitro , minimal activity was observed in two Phase II trials of gefitinib and in one trial of erlotinib. The lack of the common EGFR mutations that confer sensitivity to gefitinib in non-small-cell lung carcinoma could explain the resistance to EGFR tyrosine kinase inhibitors in MPM. Moreover, the lack of phosphorylation of Akt and lack of PTEN expression in the Akt pathway downstream of EGFR observed in an immunohistochemical analysis of 64 patients treated with erlotinib may be a mechanism of the clinical resistance of MPM.
PDGF Receptor Pathway Inhibitors
PDGF is a potent mitogen for connective tissue cells; in vitro, mesothelial cells proliferate in a dose-dependent manner when exogenous PDGF is administered. PDGF receptors (PDGFRs) are differentially expressed in MPM cells compared with normal mesothelium. MPM cell lines express PDGFR-b, while normal mesothelial cells express PDGFR-α. Transduction of a hammerhead ribozyme against PDGFR-b mRNA in mesothelioma cell lines led to a significant reduction of cell growth and decreased expression of PDGFR-b. In vitro experiments demonstrated that imatinib can cause apoptosis and death via inhibition of the Akt/PI3K pathway in MPM cell lines, enhance sensitivity of MPM cell lines to chemotherapy and synergize with gemcitabine.
Despite preclinical data, early studies testing imatinib mesylate, a selective inhibitor of the PDGFR tyrosine kinase, failed to achieve any responses in four Phase II trials. The poor expression of c-Kit could be an explanation of resistance to imatinib in MPM patients. Several trials combining imatinib with chemotherapy are still ongoing.
VEGF Signaling Pathway Inhibition
The rationale for inhibition of VEGF signaling in MPM is quite strong. VEGF, VEGF-C and their receptors are overexpressed in MPM tissue, cell lines and pleural effusions. Furthermore, it has been recently demonstrated that SV40 can cause VEGF release in SV40-positive MPM cells, and that the entire viral genome is required for this effect. Neutralizing antibodies against VEGF receptors (VEGFRs) significantly reduced MPM cell growth in vitro and, in a nude mouse model, pretreatment with an anti-VEGFR antibody was able to reduce malignant pleural effusion in vivo. Mesothelioma patients have the highest VEGF levels of any solid-tumor patients. VEGF and VEGF-C expression in mesothelioma correlates with microvessel density and high microvessel density is associated with poor survival.
Thus, several antiangiogenic agents that target the vascular VEGF pathway, such as semaxanib (SU5416), vatalanib (PTK787), thalidomide, bevacizumab, sorafenib and sunitinib, were evaluated or are still under evaluation.
Phase II studies of semaxanib (SU5416), vatalanib (PTK787), thalidomide and sorafenib have demonstrated only modest single-agent activity, comparable to other single agents in this disease. Vatalanib, an inhibitor of PDGFR-b and all VEGFR tyrosine kinases, yielded an 11% RR, a 66% rate of stable disease (SD) and a 10-month median survival in a Phase II CALGB trial. There was no correlation between baseline VEGF or PDGF levels and response, PFS or survival. Although the study did not achieve the protocol-specified 3-month PFS of 75%, efficacy data compare favorably with other active single agents for MPM, and further research in this field is warranted. SD for longer than 6 months was achieved in 27.5% of the 40 patients in a Phase II Dutch study of thalidomide. On the basis of these data, the Phase III NVALT 5 trial evaluates maintenance thalidomide to assess TTP in responders or in SD after the completion of first-line pemetrexed-based chemotherapy. The CALGB studied sorafenib, an inhibitor of VEGFR2, PDGFR-b and raf kinase, in both chemonaive and previously treated patients. As a likely result of patient selection, median survival in the chemonaive patients was 5.2 months, compared with 14.3 months for the patients who were previously treated. An ongoing study of sunitinib in previously treated patients showed a 15% RR by conventional CT scan and a 30% RR by FDG-PET.
In a Phase II trial, 108 patients were randomized to evaluate the addition of the anti-VEGF monoclonal antibody bevacizumab to gemcitabine plus cisplatin. PFS, the primary end point, was 6.9 months for the bevacizumab arm and 6.0 months for placebo (HR = 0.93; p = 0.88). Median OS for bevacizumab and placebo, respectively, was 15.6 and 14.7 months (p = 0.91). Higher baseline plasma VEGF levels correlated with shorter PFS (p = 0.02) and OS (p = 0.0066). Bevacizumab-treated patients with low baseline VEGF levels had a longer OS. Several studies of bevacizumab in combination with pemetrexed and platinum are ongoing.
Another antiangiogenic drug, NGR-hTNF, is in development. The antivascular effects of TNF-α provided the rationale for developing a vascular targeting strategy aimed at increasing the local anti-tumor activity and enabling systemic administration of therapeutic doses. A recombinant fusion protein between human TNF-α and NGR peptide that binds specifically to the CD13 expressed on the tumor blood vessels of MPM was created. In a Phase II trial, NGR-hTNF administered at low dose (0.8 μg/m2 intravenously every 3 weeks) as second-line therapy in MPM patients yielded some efficacy in terms of PFS (2.8 months, 95% CI: 2.0-3.6; 3 months PFS rate: 43%, 95% CI: 26-59), with a good toxicity profile.
Targeting the mTOR
The Akt/PI3K pathway is activated by many growth factors and interacts with mTOR. mTOR, when activated, phosphorylates p70s6 kinase and releases the eLF-4 complex to allow efficient protein translation and subsequent cell growth. Singhal et al. found that eLF-4A1, eLF-4E and eLF-4G (all components of the eLF-4 complex, which is involved in the translation of mRNA) are upregulated 1.7- to 3.8-fold in MPM tissues. Rapamycin, a natural macrolide approved for human use to prevent allograft rejection, is a potent inhibitor of mTOR. Temsirolimus and everolimus are nonimmunosuppressive analogs of rapamycin that have shown activity in patients with metastatic renal cancer. Given the upregulation of eLF-4 in MPM tissues and the anticancer activity of these drugs, clinical evaluation in MPM seems to be very interesting.
HGF & Downstream Signaling Pathways
HGF/scatter factor (HGF/SF) is now recognized as a multifunctional growth factor that can induce many biologic functions that are critical to the malignant phenotype, including cell scattering, invasion, proliferation and morphogenesis. The c-Met receptor is a tyrosine kinase; it is the only known receptor for HGF/SF and it mediates all HGF/SF-induced biologic activities. Multiple signaling pathways are activated downstream of c-MET, including the Ras/Erk, Akt/PI3K and c-Src kinase pathways. An HGF/SF/c-Met autocrine loop has been demonstrated both in MPM cell lines and in MPM tissue samples, and their overexpression has been associated with an increased microvessel density, as well as with increased matrix metalloproteinase expression. HGF and c-Met play an important role in mesothelioma cell motility and invasion into extracellular stroma. SV40 infection of human mesothelial cells induces Met receptor activation via an autocrine loop. At present, no specific Met inhibitor has been tested in clinical trials.
Src is very frequently expressed and activated in mesothelioma. Src kinase activity is associated with advanced stage in mesothelioma and may contribute to invasiveness and metastatic spread. Dasatinib, a potent inhibitor of Src family kinases, inhibits migration and invasion of mesothelioma in preclinical models. The CALGB is currently testing dasatinib in previously treated patients.
Inhibition of Histone Deacetylases & the Proteasome/Ubiquitin Degradation Pathway
The limited effectiveness of cytotoxic drugs and RT in mesothelioma may implicate them in an important functional defect in apoptosis signaling.
The histone deacetylase inhibitors induce apoptosis in mesothelioma cells by a mechanism that involves downregulation of BCL-XL, a potent regulator of mitochondrial permeability. Suberoylanilide hydroxamic acid (SAHA), an oral inhibitor of class I and II histone deacetylases, is a potent inhibitor of mesothelioma growth in vitro. It is interesting that SAHA represses the gene for thymidylate synthase, the principal target of pemetrexed. SAHA yielded two objective responses in the 13 mesothelioma patients enrolled in a Phase I trial, inducing a decrease in dyspnea or pain in all patients with at least SD. At present, a randomized Phase III trial in 660 previously treated patients, with OS as a primary end point, is ongoing.
The proteasome inhibitors can reduce viability and cause apoptosis in neoplastic cells. Moreover, their combination with several chemotherapeutic compounds has a synergistic effect in tumor cells. Recently, it has been found that inhibition of the proteasome also counteracts angiogenesis. Bortezomib (Velcade®, PS-341) is the first proteasome inhibitor to be introduced into clinical practice, for its striking activity in multiple myeloma. It interferes with proliferation of tumor cells and angiogenesis and induces apoptosis in tumors via various pathways important for tumor progression, including p53 and nuclear factor (NF)-kB. In preclinical mesothelioma models, the proteasome inhibitor bortezomib inhibits constitutive activation of NF-kB and enhances the cytotoxicity of cisplatin and pemetrexed. Bortezomib, both as a single agent and in combination with cisplatin, is being evaluated in two European mesothelioma trials.
Targeting the p53-Retinoblastoma Protein Pathway
Functional inactivation of the p53 and retinoblastoma protein (pRB) pathways appears to be a critical requirement in the development of several human cancers. These pathways play key roles in apoptosis and cell cycle regulation. Homozygous deletion of the 9p21 region occurs in more than 70% of MPM cell lines. The INK4a/ARF locus within the 9p21 chromosome band plays a critical role in the regulation of both the pRB and p53 tumor-suppressor pathways. This locus encodes two distinct proteins, p16INK4a and p14ARF. p16INK4a exerts its tumor-suppressive effect by inhibiting the cyclin D-dependent kinases (CDKs), thus preventing CDK-mediated hyperphosphorylation and inactivation of pRB and leading to G1 -phase cell cycle arrest. In terms of prognosis, p16/CDKN2A loss is associated with a more aggressive clinical behavior of mesotheliomas. Also, the neurotrophin receptor, thropomyosin receptor kinase A (TRKA), plays a significant role in the biology of MPM. In fact, frequent expression of activated TRKA is frequently found in MPM and is predominantly seen in effusions and peritoneal lesions. PHA-848125 is a potent inhibitor of the kinase activity of the CDK2/cyclin A complex, showing activity also towards closely related CDKs (i.e., CDK1, CDK4 and CDK5) and TRKA, suggesting a role in the treatment of MPM. A Phase II study on PHA-848125AC, as second-line therapy of MPM patients, with the intent of prolonging the control of the disease and, ultimately, improving patient outcome, will be initiated.
Immune-Activation Strategies
Mesothelin, a membrane-bound glycosyl phosphatidylinositol-anchored glycoprotein, is overexpressed on the surface of MPM, ovarian and pancreatic cells and can elicit a humoral immune response in patients with MPM. Several agents with activity in preclinical models are being developed to target mesothelin: a recombinant immunotoxin (SS1P), a humanized monoclonal antibody (MORAb-009) and an attenuated listeria vector that encodes human mesothelin (CRS-207). SS1P and MORAB-009 have completed Phase I evaluation. Preclinical models have demonstrated significant synergy of these agents with cytotoxic chemotherapy, and trials that combine these drugs with pemetrexed and cisplatin are in development. Gene-delivery strategies offer an alternative method of immune activation. For example, intratumoral delivery of a recombinant adenovirus encoding the CD40 ligand can stimulate and recruit MPM-specific CD8 + T cells in immunocompetent mice, leading to anti-tumor effects. Delivery of an adenovirus expressing IFN-b achieves similar effects in nu/nu immunodeficient mice, and these approaches are, therefore, currently being tested in Phase I clinical trials. A pilot Phase II second-line clinical trial is currently evaluating the efficacy of cyclophosphamide and a vaccine against MPM cells treated with IFN-α, followed by granulocyte-macrophage colony-stimulating factor, in promoting an immune response.
Expert Commentary
Malignant mesothelioma is an aggressive tumor with a poor prognosis and an increasing incidence as a result of widespread exposure to asbestos. The results of the available therapeutic resources are poor. Surgery and RT have a limited role in highly selected patients. When the stage of the disease is amenable to surgical intervention, the combination of neoadjuvant chemotherapy with postoperative hemithorax RT could be a strategy to improve survival, but only in selected patients. Clinical trials are ongoing to quantify potential benefits and to monitor toxicities of combined-modality treatments. Systemic therapy is the only potential treatment option for the majority of patients. Despite some definite activity of the novel antifolates, such as pemetrexed and raltitrexed, only small steps forward were recently made possible. Pemetrexed and raltitrexed are now a recognized standard treatment. However, the results even in combination with platinating agents are still modest, with extensions of median survivals of only 3 months and with a median survival of approximately 1 year. An improvement in the knowledge of the molecular alterations that are specific for MPM will allow the discovery of biomarkers, a useful predictive or prognostic tool, and the development and testing of novel targeted agents in this disease in the future. In particular, there is a need to reach more precise criteria for selecting patients in terms of prognosis, to improve prognostication before definitive surgery and to identify new therapeutic targets. Gene-expression arrays offer the possibility of simultaneously analyzing the transcription of several thousands of genes in a semiquantitative manner, either as cDNA arrays or oligonucleotide arrays. Microarray-based global gene-expression analysis can be a powerful approach to addressing issues such as predictive factors for response to chemotherapy or prognostic factors. However, MPM still remains a rare disease and the steps forward in its management will derive from a multidisciplinary approach involving the medical oncologist, the surgeon and the radiation oncologist, bearing in mind the inputs from the laboratory. The tailor-made treatment derived from the biologic and genetic characterization of tissue will probably offer better outcomes against MPM in the future. Fortunately, pragmatism seems to have taken the place of nihilism regarding the management of this disease.
Five-Year View
In the next 5 years, it is reasonable to expect some advances in MPM management. An improvement in the current staging system is possible. Early results about the impact of the new standard of care pemetrexed/cisplatin as induction therapy in patients with earlier-stage disease who are considered potential candidates for resection via EPP could be available. The adjustment of new end points for efficacy evaluation and assessment of tumor response will offer more chances for the identification of active drugs. Many new target drugs are under clinical evaluation. In particular, the real impact of antiangiogenic therapy is yet to be defined, especially in combination with pemetrexed plus platinating agents. Several studies of bevacizumab in combination with pemetrexed and platinum are ongoing. The early evidence of clinical activity of chemotherapy in second-line settings is likely to grow in the next 5 years. Clinical prognostic scores provide tools for a priori identification of patients likely to do better or worse following a diagnosis of MPM. Several novel biomarkers are under evaluation as useful predictive or prognostic tools. It is likely that some biomarkers able to reliably identify chemoresistant subgroups could be translated into routine clinical practice in the near future.
Table 1
| Studies of second-line chemotherapy in pemetrexed-pretreated malignant pleural mesothelioma patients. DCR: Disease control rate; mSv: Median survival; NR: Not reported. |
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| Author | Regimen | Patients (n) | Response rate (%) | DCR (%) | Mean time to progression (months) | mSv (months) | |
| Serke et al. | Oxaliplatin with or without gemcitabine | 18 | 22 | 50 | NR | NR | |
| Zucali et al. | Vinorelbine plus gemcitabine | 30 | 10 | 43.3 | 2.8 | 10.9 | |
| Stebbing et al. | Weekly vinorelbine | 63 | 16 | 84 | NR | 9.6 | |
| Jackman et al. | Erlotinib plus bevacizumab | 24 | 0 | 50 | 2.2 | 5.8 | |
| Zucali et al. | NGR-hTNF | 43 | 2 | 42 | 2.8 | NR | |
Table 2
| Novel therapeutic strategies in malignant pleural mesothelioma. CDK: Cyclin-dependent kinase; EGFR: EGF receptor; PDGFR: PDGF receptor; TRKA: Thropomyosin receptor kinase A; VEGFR: VEGF receptor. |
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| Novel agent | Target | Setting |
| Gefitinib | EGFR | Phase II, second-line treatment |
| Erlotinib | EGFR | Phase II, second-line treatment |
| Erlotinib plus bevacizumab | EGFR, VEGF | Phase II, second-line treatment |
| Vatalanib | PDGFR-b, VEGFR1, 2 and 3 | Phase II, first-line treatment |
| Sorafenib | PDGFR-b, VEGFR2 and 3, RAF | Phase II, second-line treatment |
| Sunitinib | PDGFR-b, VEGFR1 and 3, KIT, RET | Phase II, second-line treatment |
| Thalidomide | VEGF, FGF, TNF-α | Phase III, maintenance chemotherapy |
| Bevacizumab plus cisplatin plus pemetrexed | VEGF | Phase II, first-line treatment |
| Bevacizumab plus carboplatin plus pemetrexed | VEGF | Phase II, first-line treatment |
| Bevacizumab plus cisplatin plus pemetrexed versus placebo plus cisplatin plus pemetrexed | VEGF | Phase II, III, first-line treatment |
| NGR-hTNF | CD13 | Phase II, second-line treatment |
| Imatinib plus gemcitabine | PDGFR-b, KIT | Phase II, second-line treatment |
| Imatinib plus cisplatin plus pemetrexed | PDGFR-b, KIT | Phase I, first-line treatment |
| Dasatinib | SRC | Phase I, induction chemotherapy |
| Dasatinib | SRC | Phase II, pretreated patients |
| Vorinostat versus placebo | Class I and II histone deacetylases | Phase III, second-line treatment |
| PHA-848125AC | CDKs, TRKA | Phase II, second-line treatment |
| Bortezomib | Proteosome inhibitor | Phase II, pretreated patients |
| Bortezomib plus cisplatin | Proteosome inhibitor | Phase II, first-line treatment |
| MORAb-009 plus cisplatin plus pemetrexed | Mesothelin | Phase I, first-line treatment |
| SS1P plus gemcitabine | Mesothelin | Phase II, second-line treatment |
Key Issues
- Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis and an increasing incidence in many countries.
- Surgery and radiotherapy have a limited role and only in highly selected patients. Systemic therapy is the only potential treatment option for the majority of patients.
- Despite the therapeutic plateau of the past 20 years, randomized trials have now confirmed that combining antifolates with platinum-based therapy confers a survival benefit.
- No standard therapy has yet been defined in the second-line setting.
- Adequate response evaluation is a cornerstone for the identification of active drugs. The survival outcomes faithfully reflect the drug’s activity and should represent the best treatment end points in MPM, considering the notable difficulty in radiological response assessment.
- An improvement in the knowledge of the molecular alterations that are specific to MPM will allow the discovery of biomarkers as a useful predictive or prognostic tool and the development and testing of novel targeted agents in this disease in the future.