Andrew J Kaufman & Harvey IPass. Expert Review of Anticancer Therapy. Volume 8, Issue 2. February 2008.
Malignant pleural mesothelioma (MPM) is a locally aggressive cancer that arises from the multipotential mesothelial cells of the pleura. Over the next two decades, there will be an estimated 72,000 new cases of MPM diagnosed in the USA alone, with similar increases projected for Western Europe, South Africa and Australia. MPM has a uniformly poor prognosis, with a median survival from diagnosis of 9-12 months. Limited treatment options are available for those diagnosed with MPM, or at risk for developing MPM from past or ongoing asbestos exposure. While rare, MPM is responsible for approximately 0.6% of all cancer-related deaths; MPM poses an increasing public health, medical and economic problem. This is due to the peak commercial use of asbestos in industrialized countries from the 1930s to the 1960s, and the latency in developing MPM from the time of first exposure that ranges from 15-40 years. In addition, asbestos continues to pose a public health hazard throughout the world owing to the need for its disposal and its current and increasing use in industrializing nations. Recent estimates report an expected incidence of 2000-3000 cases per year in the USA, 1950-2450 cases per year in Great Britain and 250,000 deaths caused by MPM in Western Europe over the next few decades. In addition to the direct costs to the healthcare system, defendant companies in the USA have already paid US$54 billion in legal claims, and are expected to face upwards of $200 billion in future liabilities, thus representing a significant socio-economic burden. Interestingly, only 5% of asbestos mine workers who have experienced heavy exposure to asbestos go on to develop malignant pleural mesothelioma, a fact that illustrates the complex relationship between environment, biology and genetics in MPM. In addition, the characteristically long latency time for developing malignant pleural meso-thelioma suggests that the multiple chromosomal abnormalities common in MPM accumulate within the mesothelial cells over time, and contribute substantially to the pathogenesis of MPM. Recent research has implicated multiple molecular pathways and genetic loci that are abnormal in MPM and has increased our understanding of the pathogenesis of MPM. These insights may provide possible therapeutic targets for treatment and prevention.
In 1960, Wagner was the first to report a causal association between asbestos exposure in South African mine workers and the development of malignant pleural mesothelioma. Since this time, there have been many epidemiologic studies that have proved the causative role of asbestos exposure in MPM. Asbestos is a naturally occurring silicate fiber consisting of two mineralogical subtypes, amphibole and serpentine. Amphibole asbestos includes crocidolite (blue asbestos), amosite (brown asbestos), tremolite, anthophyllite and actinolite. Serpentine asbestos, represented mainly by chrysotile fibers (white asbestos) is the most commonly produced form of asbestos for commercial use. The role of amphibole asbestos in the development of MPM has been firmly established by multiple epidemiologic studies, and crocidolite (blue asbestos), in particular, is considered to be the most oncogenic form of asbestos. Chrysotile, which accounts for more than 90% of the world’s asbestos production, combined with cigarette smoking predisposes people to the development of bronchogenic lung cancer. Researchers have debated whether chrysotile may also cause MPM. A systematic review of the literature has been unable to address this hypothesis. Heavy exposure to asbestos is occupationally related to and seen most often in workers from asbestos mines, industrial shipyards, automotive production and automotive parts production, the insulation and construction industries and now, more commonly, in plumbing and demolition work. Most MPM cases are seen in geographic areas with a concentration of these industries. The peak age of diagnosis of MPM is in the 60s, and MPM develops in men five-times more frequently than in women.
Endemic MPM has been described in Cappadocia, in central Turkey, where inhabitants of three separate villages experienced long-term exposure to erionite, an asbestos-like silicate fiber. MPM was responsible for over 50% of deaths in these villages, and the age at diagnosis was much younger than commonly seen with industrially related MPM. Interestingly, while all of the villagers lived in houses constructed from the same erionite-containing stone, MPM cases were concentrated among specific families. Pedigree analysis revealed an autosomal dominant pattern of susceptibility; MPM developed only in predisposed individuals exposed to erionite, but not in predisposed individuals living in different villages. These data suggest that the epidemic of MPM in Cappadocia was caused by erionite exposure in genetically susceptible individuals.
Genomic and molecular analyses have elucidated multiple cytogenetic and molecular abnormalities that contribute to the development of MPM. It is commonly believed that asbestos inhalation leads to deposition of fibers deep in the lung parenchyma and eventual migration and implantation of fibers in the pleural lining. Repeated episodes of inflammation and healing, oxygen-free radical production from inflammatory cells and the iron moiety within asbestos, and direct damage to DNA by the fibers are generally accepted pathogenic features of asbestos exposure. Karyotype and comparative genomic hybridization (CGH) analyses of primary MPM tumors and cell lines detected frequent deletions, duplications and translocations with genomic losses more commonly than gains. Deletions within chromosomes 1p, 3p, 4p, 4q, 6q, 9p, 13q, 14q and 22q are common and notable for the loss of the tumor suppressor genes p16 /CDKN2A, p53 and NF2, located within these loci. Testa and colleagues demonstrated that heterozygous Nf2 +/- mice exposed to asbestos exhibited frequent homozygous deletions of the Cdkn2a /Arf and Cdkn2b loci, and activation of Akt with rapid development of MPM, suggesting that these molecular events may be critical to tumorigenesis. In addition, the Wilms’ tumor gene (WT1 ), which encodes a transcription factor that represses the transcription of a number of growth factors and proto-oncogenes, is often mutated in both MPM primary tumors and cell lines. Loss of tumor-suppressor gene activity may be a key to the transformation into malignant mesothelioma.
Interestingly, the dose-dependent cytotoxicity of asbestos is not lethal to the asbestos-sensitive mesothelial cells. In fact, a recent paper has illustrated the critical role of TNF-α and NF-κB signaling in the survival of damaged mesothelial cells. The inflammatory response to asbestos deposition in the pleura is mediated by macrophages and mesothelial cells, with both cell types secreting TNF-α, and the mesothelial cell expressing TNF-α receptor-1 (TNF-R1), in an autocrine and paracrine interaction. TNF-α then stimulates the NF-κB pathway, which regulates prosurvival cellular mechanisms and may allow asbestos-induced DNA damaged cells to divide rather than undergo apoptosis. This response imparts a survival advantage that permits the asbestos-injured cells to transform and progress into malignant mesothelioma.
Other cytokines and growth factors produced by malignant mesothelial cells are associated with asbestos carcinogenesis. PDGF-A chain and C-sis, an oncogene that encodes for the PDGF-β chain, are overexpressed in cell lines derived from primary and metastatic MPM, whereas C-sis expression is virtually nonexistent in normal mesothelial cells. In addition, TNF-β is a growth-regulatory and immunomodulatory cytokine expressed in high levels in MMP cell lines. TNF-β may play a role in PDGF receptor expression in MMP. Pleural fluid from MPM patients also shows increased levels of IL-6 and -8; both important cytokines involved in angiogenesis. It has been shown that increased expression of IL-6 results in higher levels of VEGF and a greater degree of thrombocytosis in MPM patients.
Asbestos also causes direct activation of cell-signaling pathways. Crocidolite fibers can stimulate autophosphorylation of the EGF receptor (EGFR) which activates extracellular-regulated kinase (ERKs)1 and 2. ERK1/2 activation in turn increases activator protein (AP)-1 activity with subsequent increased mitosis of the mesothelial cells. Recent work by Jablons and colleagues has implicated the Wnt pathway in the development of MPM, and has recently shown that promoter hypermethylation of Wif-1 results in constitutive activation of Wnt signaling, suggesting a mechanism for the inhibition of apoptosis in abnormal mesothelial cells.
Considerable controversy regarding the role of simian virus 40 (SV40) in the pathogenesis of MPM persists today. SV40 is a rhesus monkey DNA virus, likely introduced into humans from contaminated Salk polio vaccines produced between 1955 and 1978. SV40 has been associated with the development of MPM in humans and animal models. SV40 produces two oncogenic proteins: the large T antigen that binds p53 and pRb proteins; and the small t antigen that inhibits phosphatase 2A, a protein important for microtubule-associated kinase component dephosphorylation. However, not all research has supported the association between SV40 and MPM, as some laboratories have failed to find SV40 in MPM samples. Recent work has suggested that SV40 positivity in many but not all human tumor specimens, was a result of sample contamination and not actual SV40 infection. Lopez-Rios et al. described their experience with plasmid contamination and found that a majority of their positive cases were in fact due to contamination, while only a small minority of samples had true SV40 positivity. However, Comar and colleagues have demonstrated that almost 16% of tumor samples tested with real-time quantitative PCR were SV40 positive, with SV40 detected in some distant tissue, suggesting that in their geographic cohort, SV40 may play a role in MPM development. In addition, animal models and in vitro studies with human mesothelial cells, utilizing an attenuated strain of SV40, showed that asbestos and SV40 may act as co-carcinogens. Together, they are able to induce ERK1/2 phosphorylation, AP-1 activity and produce MPM in 90% of animals co-exposed, whereas the less oncogenic strain of SV40 alone caused none, and asbestos alone caused MPM in only 20% of subject animals. This further suggests that individuals may have varying degrees of susceptibility to asbestos-induced MPM, based on their SV40 status. Furthermore, Robinson and colleagues have shown that SV40 copy number plays a significant role in the malignant transformation of mesothelial cells, with high-copy mice displaying more rapid development of mesothelioma and more invasive mesotheliomas after exposure to asbestos. A recent paper suggests that SV40 oncoprotein expression in murine mesothelial cells enhances both spontaneous and asbestos-induced DNA double-strand breaks, and may achieve this via p53 inhibition. Overall, the role of SV40 in MPM remains an active and controversial topic.
Most commonly, a person with MPM will be male, in his 60s-70s, and report a significant history of asbestos exposure. The most common presenting symptoms include dyspnea and chest pain. The average time from onset of symptoms to diagnosis is 2-3 months, and upwards of 25% of patients will have had symptoms for 6 months or more before seeking medical attention. Interestingly, the right side of the chest is affected in approximately 60% of cases, compared with 40% for left-sided disease, likely due to the increased volume of the right chest.
Physical findings are directly related to the extent and natural progression of disease; 80% of patients will present with a pleural effusion and dyspnea, and 95% of patients will develop an effusion at some point during the course of their disease. Progression of disease, and increasing tumor volume, will invariably lead to increased dyspnea and pain, which can become unremitting if the lung becomes entrapped by tumor. Without resection, the tumor can enlarge to a point of complete encasement of the lung, with obliteration of the pleural space. Extension of the tumor through the diaphragm can result in malignant ascites.
Laboratory Analysis & Serum Markers
Laboratory findings are generally nonspecific, and can include hypergammaglobulinemia, an elevated erythrocyte sedimentation rate, anemia and, most strikingly, thrombocytosis (>400,000), which is seen in upwards of 30-40% of patients. Recent research has identified serum mesothelin-related protein (SMRP) and osteopontin as promising new serum markers for identifying and following patients with MPM. In the past, serum markers such as hyaluronic acid and CA-125 have been of limited use owing to overall poor sensitivity. SMRP is the freely circulating form of mesothelin, a cell surface protein important for mesothelial cell adhesion and cell signaling that may be translated from an alternatively spliced variant of meso-thelin mRNA. In a study of 44 patients with mesothelioma, 68 healthy adults (28 nonasbestos exposed and 40 asbestos exposed) and 160 patients with other nonmesothelioma, inflammatory or malignant lung and pleural diseases, SMRP had a sensitivity of 84% and a specificity of 95% in detecting MPM. These data have been validated by two other studies, which further documented that changes in SMRP levels correlate with tumor progression/size and that SMRP is elevated in 75% of patients at the time of diagnosis. More recent studies have further illustrated the utility of SMRP as both a surveillance marker and prognostic marker for MPM. A mesothelin ELISA (MesoMark(TM)) is currently available for clinical use in Europe, Australia and through reference laboratories in the USA.
Osteopontin is a glycoprotein that is overexpressed in several cancers and mediates cell-matrix interactions and cell signaling by binding with integrin and CD44 receptors. DNA microarray analysis of human MPM, and animal models with asbestos-induced MPM, revealed that osteopontin levels are upregulated. In addition, osteopontin expression profiles could predict survival and recurrence patterns. In a study comparing patients with MPM to individuals exposed to asbestos, but without MPM, serum osteopontin levels were significantly higher in the MPM cohort (p < 0.001). They also showed comparatively higher levels as the duration of asbestos exposure increased (p = 0.02), and were higher as the degree of radiographic abnormality (plaques and fibrosis vs lesser findings) increased (p = 0.004). The same authors, utilizing a cut-off value of 48.3 ng/ml, demonstrated that serum osteopontin has a sensitivity of 77.6% and a specificity of 85.5% comparing asbestos exposed individuals without MPM with MPM patients. The most important distinction of this study was that serum osteopontin levels could distinguish between individuals exposed to asbestos who have yet to develop MPM and those who already have the disease.
Standard chest radiography is able to show both pleural effusions seen with early disease, and pleural thickening and nodularity associated with later disease. In cases of locally advanced disease, tumor volume can involve the entire hemithorax, the pericardium and mediastinum, with mediastinal shift and compression of the contralateral lung. Computed tomography (CT) of the chest remains the most useful imaging study in MPM. CT can identify pleural changes associated with asbestos exposure and MPM, such as pleural thickening, calcified plaques and pleural effusions. MPM can also appear as a localized nodular mass with pleural effusion on CT. In 60% of cases, CT will show intrapulmonary nodules. In addition, CT may show infiltration into the fissure, and hilar and mediastinal lymphadenopathy. CT is also especially useful for determining the extent of pericardial involvement, which is critical for staging and surgical planning. Yet CT is not sensitive in diagnosing chest wall or diaphragmatic involvement. MRI has recently proved to be more sensitive in diagnosing chest wall invasion and diaphragmatic invasion. Interestingly, tumor volume, as seen on CT, has been found to be prognostic, with volumes less than 100 ml associated with a mean survival of 22 months compared with 11 months for volumes greater than 100 ml. The same study indicated that larger tumor volume correlated with a higher American Joint Commission on Cancer (AJCC) stage, and predicted a greater likelihood of lymph node metastasis. However, CT and MRI remain imperfect diagnostic modalities and are inaccurate in determining resectability; upwards of 25% of patients are found to be unresectable at the time of surgery.
PET has been used at multiple centers in the USA, and early data suggest that PET is helpful in distinguishing between benign and malignant pleural disease (MPM in particular) in asbestos-exposed individuals. PET may be useful in determining the extent of distant metastatic disease, but had a sensitivity of only 11% in detecting metastatic lymph node disease . However, the same study found that a high standard uptake value (SUV) correlated with N2 disease at the time of resection. More recently, research from the same institution showed that an SUV value of greater than or equal to 10 correlated with a significantly shorter survival time and a 3.3-times greater risk of dying compared with SUV levels below 10. This suggests that PET results may help to stratify patients for different treatments according to their metabolic activity. Integrated CT-PET imaging combines the anatomic data from CT with the functional data of PET, and may be able to increase the diagnostic accuracy and staging of MPM patients. In a study of 29 MPM patients, integrated CT-PET correctly assigned the overall stage in 72% of cases, showed increased sensitivity for T4 disease, 67 versus 19% for PET alone, identified seven patients with extrathoracic disease missed by conventional radiographic studies, and identified 12 patients who would have been precluded from surgical resection based on conventional studies.
Both CT and PET are useful for evaluating the progression of disease or the response to therapy. CT can identify irregularities in the pleura, lymphadenopathy in the mediastinum, or the development of diaphragmatic disease and ascites that may signify progression or recurrent disease. A modified Response Evaluation Criteria in Solid Tumors Group (RECIST) protocol has been used to evaluate response to chemotherapy in MPM patients. Measurements of tumor thickness are taken at two sites and three different levels on CT, and response or progression documented. Similarly, PET can determine the metabolic activity of residual disease, with longer survival seen in patients with greater metabolic response to therapy.
MPM is an aggressive malignancy with a dismal prognosis. However, there are other benign and malignant pleural tumors that must be distinguished from MPM for obvious therapeutic and prognostic reasons. In contradistinction to malignant mesothelioma, localized mesothelioma, also referred to as localized fibrous tumor of the pleura (FTP), is generally a benign tumor more similar in appearance to other fibrous tumors than to MPM. FTP can be distinguished from MPM by immunohistochemical analysis. FTP stains positive for the nonmesothelial cell marker CD34 and negative for the mesothelial cell marker cytokeratin. In approximately 10% of cases, FTP can develop into a malignant variant. Complete surgical resection offers a 5-year survival rate as high as 97%. Since pleural effusion is such a common presenting sign in MPM, thoracentesis is routinely the first diagnostic procedure attempted, and succeeds in diagnosing approximately 30-50% of cases. Video-assisted thoraco-scopy (VATS) is useful when thoracentesis results are negative, it can provide a diagnosis in 80% of patients and provides excellent visualization of the extent of disease. When tumor volume precludes thoracoscopy, open biopsy should be done in an intercostal space that can later be excised with a more definitive operation. The routine diagnostic approach for MPM utilizes immunohistochemical analysis of surgically obtained specimens, either from VATS or open surgical procedures. There are three main histologic subtypes of MPM. Epithelial tumors account for 50-60% of MPMs and carry a better prognosis. Sarcomatoid MPMs comprise 10% of cases and are the most resistant to therapy, with a mean survival less than 1 year. Mixed, or biphasic tumors, account for 35% of MPMs. There is also a rare undifferentiated subtype. MPM can resemble adenocarcinoma both macroscopically and microscopically. It is therefore necessary to distinguish between primary MPM and metastatic adenocarcinoma to the pleura with immunohistochemical staining. MPM is generally positive for cytokeratin, calretinin, WT1 and negative for CEA, CD15, TTF-1 and B72.3. It is generally accepted that positive staining for cyto-keratin and calretinin with negative staining for three epithelial markers is sufficient to make the diagnosis of MPM. In difficult diagnostic circumstances, such as determining between epithelial and biphasic mesothelioma, electron microscopy (EM) remains the gold standard. EM is also useful in distinguishing sarcomatoid MPM from other spindle cell tumors of the pleura.
Historically, staging for MPM used nonstandardized criteria that resulted in substantial differences in the reported rates of survival and treatment efficacy. In response, the International Mesothelioma Interest Group (IMIG) published their guidelines for the staging of MPM, which more accurately documented the progression of disease and the importance of nodal involvement. The AJCC has adopted these guidelines, and the current Tumor, Node, Metastasis (TNM) staging system used is generally accepted. Staging is essential for operative planning. Patients with stage I-III disease are candidates for surgical cytoreduction. In an effort to stratify patients for survival, Cancer and Leukemia Group B (CALGB) and European Organisation for Research and Treatment of Cancer (EORTC) studies found that performance status is the best predictor of survival, while age, histologic subtype and gender are other important prognostic factors. Most patients will succumb to their disease owing to respiratory failure or pneumonia. Metastatic disease to the liver and contralateral lung are the most common sites, although distant metastases, which commonly remain asymptomatic, are found in 33-49% of patients. Molecular analysis using DNA microarray technology has developed a four-gene expression ratio that accurately predicted outcomes independent of histologic subtype. A new 27-gene chip array predicted time to progression with 95% accuracy, and data from another group showed that Aurora kinase A and B expression correlated with a more aggressive phenotype. However, none of the microarray data have been validated by other investigators to date.
Preoperative evaluation aims to delineate the resectability and extent of disease, and adequately determine the patient’s ability to tolerate major surgery. CT of the chest and abdomen, PET and diagnostic thoracoscopy are routinely performed. If CT or PET suggests mediastinal lymphadenopathy, mediastino-scopy is recommended. Diagnostic laparoscopy may be necessary if CT suggests diaphragmatic invasion and possible intraperitoneal disease. Advanced age, with concomitant comorbidities at presentation, is a common reason for unresectability. In general, patients have multiple pulmonary issues related to the tumor itself; asbestos-associated parenchymal disease and smoking-related lung disease. Relative contraindications to surgery include a forced expiratory volume in 1 s (FEV 1 ) less than 1000 cc/s, a pO2 less than 55 mm Hg, and a pCO2 greater than 45 mm Hg. Patients with a FEV1 less than 2 l, or a predicted FEV1 less than 1.2 l after pneumonectomy, should undergo ventilation/perfusion scans to determine postoperative pulmonary reserve. Cardiac status must also be evaluated and patients with an ejection fraction (EF) less than 45% or a myocardial infarction within the last 3 months, are not eligible for surgery involving pneumo-nectomy owing to the large amount of expected blood loss and perioperative stress.
To date, there are no generally accepted or published treatment guidelines for MPM. Recently, the standard treatment regimen for unresectable MPM has been cisplatin and pemetrexed. This followed a well-powered Phase III trial demonstrating longer median survival time and longer time to progression with combined therapy versus cisplatin alone. For these patients, control of pleural effusions can be accomplished by thoracoscopic or chest-tube pleurodesis with 90% efficacy. Pleurex catheters can be used for poor surgical candidates or recurrent effusions. The main goals of treatment are to control local disease, treat symptoms and prevent progression and metastasis. Surgery, radiation, chemotherapy and immunotherapy, generally in combination, have become the common treatment strategies.
The role of surgery in the management of MPM is perhaps the most controversial area in the treatment of this disease. The relatively small numbers of MPM cases, the aggressive nature of the disease with short median survival times and the nonstandardized staging systems used in the past have precluded randomized controlled studies and made comparisons between studies difficult. As a result of the lack of randomization, the current level of evidence regarding surgical management remains low. The common operations used to treat MPM include thoracoscopy for diagnosis or symptomatic control, extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD) for curative intent, and cytoreduction for adjuvant therapy. Significant debate exists regarding whether EPP or PD offer any survival advantage when compared with each other, or other treatments. No randomized controlled trials comparing EPP to PD, or surgery to nonsurgical treatments, have been performed; however, recent data from Flores et al. point to the efficacy of PD in early-stage mesothelioma when compared with EPP. The Mesothelioma and Radical Surgery (MARS) trial in the UK, which randomizes patients after chemotherapy to either EPP with radiation, or to nonsurgical therapy, currently aims to determine whether EPP offers any survival advantage. EPP is an en bloc resection of pleura, underlying lung parenchyma, ipsilateral hemidiaphragm and peri-cardium. PD attempts to remove all pleural disease without underlying lung, and may also include the ipsilateral hemi-diaphragm and pericardium in the resection. Two important studies compared EPP and PD in prospective, noncontrolled studies. Rusch et al. reported on 231 patients who underwent EPP for locally advanced disease or PD for minimal disease. This study demonstrated median survival and mortality of 14.7 months and 5% for EPP, respectively, and 18.5 months and 3% for PD, respectively. Pass et al. also compared EPP and PD in 48 patients and showed median survival of 11 and 22 months for EPP and PD, respectively. Mortality was 4% in the EPP cohort and 6% in the PD cohort. However, in this study no real survival benefit can be attributed to PD because patients from this group had significantly lower tumor volumes compared with the EPP group. For both studies, the rate of local recurrence was high and patients relapsed soon after treatment. Pass et al. described a recurrence rate of 69% for EPP and 79% for PD over 3 years. Four other studies have looked at EPP or PD in a retrospective fashion. One retro-spective study of 111 patients who either received EPP, PD, or EPP with chemotherapy demonstrated zero mortality and 14-month median survival for the PD cohort, and 9.1% mortality and 13-month median survival in the EPP group. The three other retrospective studies examined the results of PD alone. In two studies, median survival was 16-17 months, and in the third study the median survival was 9.2 months. Rusch et al. published prospective data on 28 patients, 23 of whom completed treatment that included PD with intrapleural chemotherapy followed by systemic chemotherapy, and reported a median survival time of 17 months and a 3.7% postoperative mortality. Overall, these results established the dismal prognosis for MPM and surgery alone, and heralded the need for multimodality treatment to prevent recurrence and increase median survival time.
Thoracic radiotherapy for MPM is limited mainly by the radiosensitivity of the surrounding vital structures of the chest and by the volume of tumor. Curative doses (>60 Gy) pose a serious risk to normal tissues, including the neighboring lung, heart, esophagus and spinal cord. Several studies have shown that definitive radiotherapy does not increase median survival past 10 months.
Historically, anthracyclines, platinum agents and antimetabolites have been used as single agents against MPM with poor response rates ranging from 30-40%, and median survival times of less than 1 year. Combination chemotherapies have had marginally better response rates and median survival times. Platinum-based regimens demonstrated the best response and survival results, and cisplatin was found to be the most active single agent. Symptomatic relief was seen in 40-50% of patients treated with a combination of mitomycin c, vinblastine and cisplatin. Recently, studies using the antimitotic vinca alkaloid vinorelbine have shown it to have a similar benefit as a single agent. Significant progress has been made with combination cisplatin and antifolate therapy. Pemetrexed is a novel antifolate that showed extensive antitumor activity in Phase I and II trials. A large Phase III trial enrolled 456 chemotherapy-naive patients to receive either cisplatin or cisplatin in combination with pemetrexed. The combined regimen proved superior, with a 3-month longer average survival time and an almost 2 month increase in disease-free interval, both statistically significant. In addition, the same study noted that vitamin B12 and folate supplementation provided better tolerance and decreased side-effect profile, and thus a better response rate. Similarly, a randomized controlled trial in patients with advanced MPM compared single-agent cisplatin therapy to the combination of cisplatin with raltitrexed. In this study, the combined therapy arm had a better response rate and overall median survival when compared with cisplatin alone (23.6 vs 13.6% and 11.4 vs 8.8 months, respectively). The authors noted no difference in quality of life scores between the two treatment arms, and achieved these results without B12 or folate supplementation. In an attempt to limit the side effects encountered with cisplatin therapy, a recent Phase II trial has studied combination pemetrexed-carboplatin as first-line treatment in 102 MPM patients, and demonstrated an 18.6% response rate and a median overall survival time of 12.7 months. These results are comparable to cisplatin-antifolate regimens and suggest that the carboplatin combination could be an alternative treatment regimen.
Ribonuclease inhibitors, such as ranpirnase, are a novel chemotherapeutic approach to MPM treatment. Cytotoxic ribonucleases specifically target tumor cell tRNA, resulting in inhibition of protein synthesis and cell cycle arrest at the G1 phase. A Phase III trial comparing single-agent ranpirnase to conventional doxorubicin that enrolled 154 patients with MPM resulted in better overall and 2-year survival in a subset of low-risk patients treated with ranpirnase. These results suggest that a select group of individuals may benefit from ranpirnase therapy; a large international Phase III trial comparing doxorubicin to combination doxorubicin and ranpirnase is currently ongoing.
The most promising survival data have been generated in studies that combined surgery with radiation, chemotherapy or all three modalities. In the largest study of EPP, which also included adjuvant chemoradiation, Sugarbaker and colleagues reported that negative surgical margins were obtained in 66 of 183 patients. Those patients with negative margins, epithelial histology and node-negative disease had remarkable 2- and 5-year survival rates of 68 and 46%, respectively. Patients with epithelial histology had 52 and 21% survival at 2 and 5 years respectively; while sarcomatous patients had a 2-year survival of 16% and no survivors at 5 years. Overall survival rates of 38 and 15% were achieved for all patients at 2 and 5 years, respectively, and the postoperative mortality was only 3.4%. In a separate study, Rusch et al. concluded that lymph node status and disease stage had the most prognostic importance. In this study, the 2- and 5-year survival for stage I patients, 16 out of 131 patients, was 65 and 30%, respectively. More recently, de Perrot and colleagues demonstrated that survival was significantly worse in patients with N2 disease who underwent EPP with postoperative radiation; survival was 10 months compared with 29 months for node-negative patients (p < 0.005). These studies confirmed that durable survival could be achieved in early-stage patients without nodal disease, and that EPP could be performed with acceptable operative mortality. Another benefit of EPP is that postoperative radiation therapy can be given without concern for ipsilateral pulmonary toxicity. In a Phase II trial of EPP followed by radiation, completed at the Memorial Sloan-Kettering Cancer Center, Rusch and colleagues demonstrated that some patients could have a durable survival, 27% at 3 years, and decreased local recurrence of only 13%. In an effort to boost the amount of radiation delivered to the post-operative field, researchers have utilized intensity-modulated radiation therapy (IMRT). Initial studies suggested an improved survival and decreased recurrence; however, fatal pneumonitis developed in six patients who received higher doses of radiation. Intrapleural chemotherapy at the time of surgery is an intriguing method of treatment that has yet to show any improvement in local control or survival rates.
Recently, several studies have reported encouraging results using induction chemotherapy. In a small pilot study, Weder et al. showed that neoadjuvant chemotherapy with cisplatin and gemcitabine followed by EPP and postoperative radiation could produce a median survival of 23 months. The 1- and 2-year survival rates were 79 and 37%, respectively. Flores et al. in another small study found that early-stage MPM patients successfully completing a course of neoadjuvant chemo-therapy with cisplatin and gemcitabine, followed by EPP and 54 Gy of radiotherapy, had a median survival of 33.5 months. A more recent Swiss, multicenter Phase II trial of induction therapy followed by EPP and radiation, that included 61 patients, reported the same 23-month median survival in those patients who underwent EPP. These data suggest that induction therapy may prolong survival compared with upfront surgery. Postoperative morbidity was 62% and mortality was 3.2%, which is comparable to the Brigham experience. A multicenter US trial of neoadjuvant pemetrexed and cisplatin, followed by EPP and hemithoracic radiation for resectable MPM that included 77 patients, illustrated that trimodality therapy was feasible and that chemotherapy could be successfully delivered to patients in a neoadjuvant setting. However, preliminary median survival was only 16.6 months, which is below the median survival reported in the aforementioned single-institution studies. However, these results could be explained by the high censorship rates experienced early in this study.
EGFR, VEGF and PDGF are important growth factors involved in MPM pathogenesis that are currently being treated with targeted therapy in several studies. Unfortunately, trials with the EGFR tyrosine kinase inhibitors erlotinib and gefitinib have shown no efficacy. In addition, imatinib mesylate, an inhibitor of tyrosine kinase activity, has had similar treatment failure. Recently, a multicenter, double-blinded, randomized, placebo-controlled Phase II trial that included gemcitabine and cisplatin with either bevacizumab (Avastin reg; ), an anti-VEGF receptor monoclonal antibody, or placebo, concluded that the addition of bevacizumab did not affect progression-free survival or median overall survival. Other studies with antiangiogenic therapies, including thalidomide and PTK787, have had no clinical benefit.
Expert Commentary & Five-Year View
MPM continues to impart a dismal prognosis to those diagnosed with the disease. Currently, no standard therapy or consensus exists regarding treatment. The number of MPM cases will probably increase over the next two decades and clinicians specializing in thoracic malignancies will be increasingly called upon to treat these patients. For nonsurgical candidates, cis-platin and pemetrexed is now considered the standard of care. Based on the previous success of radical surgery and adjuvant chemoradiation, current trimodality therapy has focused on induction therapy followed by surgery and radiation. The encouraging results of this treatment strategy warrant larger confirmatory trials. The utilization of newer technologies, such as PET and gene expression microarray, may enable better staging and risk stratification of patients and, thus, appropriately directed therapies. Basic science and translational research has led to substantial advances in understanding MPM patho-genesis and its molecular mechanisms. The use of proteomics and serum analysis may lead to earlier diagnosis of MPM, earlier treatment and, thus, better survival.
- A significant increase in malignant pleural mesothelioma (MPM) is expected throughout the industrialized world over the next two decades.
- Increased understanding of the genetics and molecular biology of MPM will lead to new diagnostic, therapeutic, and prognostic capabilities.
- Current randomized trials will help determine the role of radical surgery for MPM.
- Trimodality therapy with neoadjuvant chemotherapy, followed by surgery and radiotherapy, has produced substantial gains in median survival.
- In the next 5 years, microarray expression analysis, serum markers and PET scanning will help stratify patients for different modes of treatment.
- Several targeted therapies have not been successful in treating MPM; however, newer agents are currently being tested.