Malignant Pleural Mesothelioma
So, what is mesothelioma? Malignant pleural mesothelioma is a very aggressive and almost always fatal type of cancer caused by exposure to Asbestos. Approximately 3000 Americans are diagnosed with this terrible disease each year. Because malignant pleural mesothelioma is caused by exposure to Asbestos, it was believed that the occurrence of this disease would decrease after the regulation and eventual bans on asbestos used were initiated in the 1970s and 80s. Malignant pleural mesothelioma is more common than Unfortunately, malignant pleural mesothelioma cases continue to be diagnosed at an alarming rate in the United States and across the globe.
Malignant pleural mesothelioma arises more frequently in males than females and the risk of this cancer increases with age. The average age for males diagnosed with mesothelioma is 72 and the range is typically between 45 and 85 years old. Malignant pleural mesothelioma arises at least 20 years and as long as 40 or 50 years after exposure to Asbestos.
Presently, there are no approved screening techniques for the early detection of malignant pleural mesothelioma. Scientists have, however, discovered two different markers which may be predictive of the recurrence of malignant pleural mesothelioma after surgical resection and to distinguish malignant pleural mesothelioma from benign pleural changes.
Malignant pleural mesothelioma is a very difficult and challenging cancer to treat. Typically, survival rates vary between 9 and 17 months. Conventional treatments for cancer such as surgery, radiation and chemotherapy have proven to be largely ineffective in treating malignant pleural mesothelioma. Studies and clinical trials for new and different treatments for this disease are ongoing and have shown promise.
RESECTABLE MESOTHELIOMA
Surgery for Pleural Mesothelioma
Surgery for Pleural Mesothelioma can affect mesothelioma prognosis. Surgical methods used in treating patients with malignant pleural mesothelioma include diagnostic video-assisted thoracoscopy, palliative pleurectomy/decortication (P/D), and extrapleural pneumonectomy. P/D includes an open thoracotomy; removal of the parietal pleura, pleura over the mediastinum, pericardium, and diaphragm; and 
Patients who get P/D alone typically experience local reoccurrence as the very first site of disease recurrence and, less frequently, remote recurrence. This is in contrast to extrapleural pneumonectomy alone, for which the remote recurrence rate is greater than that of local recurrence. Although extrapleural pneumonectomy might alter the pattern of reoccurrence with less locoregional recurrence, it remains a surgery that is associated with high morbidity, and its contribution toward total survival benefit is uncertain. The 30-day operative death rate for extrapleural pneumonectomy in experienced cancer surgical centers varies between 3.4% and 18%, and the 2-year survival rate is 10% to 37%.
The option of surgical resection strategy at this time is controversial. Previously, it was assumed that extrapleural pneumonectomy was the only treatment method that might increase long-lasting survival for patients with 
Recently, a large retrospective analysis comparing extrapleural pneumonectomy with P/D was performed; the researchers reported that P/D in conjunction with different multimodality treatments may also provide long-term survival advantage. This analysis revealed that females, patients with earlier phase illness, epithelioid histology, treatment with multimodality treatment and those who went through P/D had better survival results. After eliminating the operative deaths, multivariate analysis revealed that extrapleural pneumonectomy alone resulted in a lower survival rate than P/D.
Adjuvant Radiation Therapy
In malignant pleural mesothelioma, radiotherapy can be provided either prophylactically to prevent tumor seeding 
In the conclusive setting, adjuvant hemithoracic radiotherapy contributed to extrapleural pneumonectomy enhanced local control, with a 13% threat of regional recurrence and 64% incidence of distant metastasis. To date, the only treatment modality that reduces the threat of local recurrence after surgical resection is radiotherapy. High-dose radiotherapy with consecutive chemotherapy was reported to improve locoregional control over moderate-dose radiotherapy. Nevertheless, this outcome was not statistically significant, and the dose of radiotherapy did not predict for survival.
Alternative radiotherapy techniques, such as intensity-modulated radiation therapy, have resulted in early reports demonstrating a 95% possibility of disease control in the irradiated field and a locoregional control rate of 87%. However, intensity-modulated radiation therapy is not considered as a viable treatment modality as there have actually been reports of high toxicity and morbidity (ie, fatal pneumonitis) connected with its use.
Mesothelioma Chemotherapy
Chemotherapy can be given in the neoadjuvant or adjuvant settings, along with radiation.
Neoadjuvant mesothelioma chemotherapy
Owing to the small number of malignant pleural mesothelioma candidates for extrapleural pneumonectomy, few neoadjuvant trials have actually succeeded. All neoadjuvant regimens studied to date consist of platinum doublets in single-arm trials, with the average survival ranging in between 19 and 25 months. The largest of these potential trials administered platinum and pemetrexed and reported initial results of a typical time to recurrance of 13.1 months, general survival of 16.6 months, and 1-year overall survival rate of 67%. The reaction rate to induction chemotherapy was 29%, with 67% of the patients undergoing extrapleural pneumonectomy and just 56% continuing to adjuvant radiotherapy. The subgroup analysis suggested that patients with a complete or partial reaction to neoadjuvant chemotherapy trended toward extended general survival. Since the efficacy of neoadjuvant chemotherapy remains unverified, a neoadjuvant trial using dasatinib at The University of Texas M. D. Anderson Cancer Center (Houston, TX) is currently underway and will offer follow up dasatinib after surgery, adjuvant radiation, and adjuvant chemotherapy in patients with malignant pleural mesothelioma with a reaction to induction therapy.
Adjuvant mesothelioma chemotherapy
Adjuvant chemoradiotherapy is hard to administer after extrapleural pneumonectomy due to associated toxicities, and as a result, there are very few trials available to review. One of the biggest series assessed 183 patients who got extrapleural pneumonectomy followed by carboplatin and paclitaxel for two cycles, then thoracic radiation treatment with concurrent paclitaxel weekly, and then carboplatin and paclitaxel for 2 cycles. For the 176 patients who survived the extrapleural pneumonectomy, the 2-year-survival rate was 38%, the 5-year-survival rate was 15%, and the average total survival was 19 months. Patients with epithelioid histology, unfavorable resection margins, and no extrapleural lymph node transition had the best prognosis, with a mean total survival of 51 months. This series has been upgraded to include 496 patients. The 418 patients who underwent extrapleural pneumonectomy had a median total survival of 18.9 months and a 5-year total survival rate of 13.9%.
Unresectable Malignant Pleural Mesothelioma
Mesothelioma Chemotherapy
Historically, examining the clinical advantages of chemotherapy in patients with unresectable malignant pleural mesothelioma has been challenging. There are favorable clinical prognostic functions that include epithelioid histology, female sex, and no nodal metastasis; whereas patients with sarcomatoid histology, poor performance status, and elevated hematologic criteria have an even worse prognosis. However, understanding reaction assessments is restricted by the complexity of determining the uneven tumor growth. A system called the modified Reaction Examination Criteria in Strong Growths can be dependably utilized to examine growth response; however, these measurements do not always predict survival. The European Organization for Research Study and Treatment of Cancer (EORTC) has therefore proposed that progression-free survival rates at 3, 4, 5, and 6 months be used as the main end points in phase II trials to show the prospective survival advantage of cytostatic agents.
Prior to 2003, few mesothelioma chemotherapy agents had response rates higher than 20%. Researchers examined 119 trials and reported that combination chemotherapy had higher reaction rates than single agent chemotherapy. Platinum-containing programs had higher reaction rates compared with non-platinum-containing regimens, with cisplatin yielding better results than carboplatin. Platinum agents integrated with anthracyclines, gemcitabine or irinotecan had the highest action rates. When platinum representatives were combined with immunomodulator effectors, such as interleukin or interferon, the action rate was 12%. These data do have restrictions, as a many malignant pleural mesothelioma trials are single-arm stage II studies, owing to the small number of available patients to study.
Front-Line Mesothelioma Chemotherapy
As malignant pleural mesothelioma is more mesothelioma chemotherapy resistant than other tumor types, the Medical Research study Council conducted a randomized Stage III trial comparing active supportive care with two different chemotherapy regimens (mitomycin, vinblastine and cisplatin or weekly vinorelbine) and reported that chemotherapy did not significantly improve survival over active care. When examining the results from the single-agent vinorelbine arm, there was a trend toward survival that did not reach statistical significance since the research study was underpowered to identify this survival difference between the specific arms. Patients who received vinorelbine had a mean progression-free survival of 6.2 months and mean overall survival of 9.5 months. This suggests that certain chemotherapy agents do improve survival for patients with malignant pleural mesothelioma. In addition, subsequent randomized trials using more recent agents such as pemetrexed and raltitrexed integrated with platinum representatives verify the survival advantage over cisplatin alone.
Platinum and antifolates
The mix of cisplatin and pemetrexed given every 3 weeks was developed as a standard-of-care front-line regimen after the biggest phase III trial conducted in patients with chemotherapy-naïve malignant 
pleural mesothelioma showed a survival enhancement over cisplatin alone. The combination regimen had a 41.3% action rate, average time to progression of 5 months, and typical overall survival of 12 months. Patient lifestyle factors were also enhanced quickly, typically within the first 3 cycles of treatment with statistically significant enhancements frequently seen by week 15. This program is now the standard against which other front-line routines are compared.
Other antifolates have been examined but are less commonly utilized than pemetrexed. The EORTC reported that raltitrexed integrated with cisplatin improved the total action rate compared with cisplatin alone, without any reported distinction in lifestyle factors. However, although the reaction rate was not statistically significant, the median overall survival in patients getting raltitrexed plus cisplatin was increased to 11.4 months, and the 1-year survival rate was increased to 46%.
Other mix and maintenance programs under investigation have actually substituted carboplatin for cisplatin. Carboplatin plus pemetrexed yielded action rates of 6% to 22%, with development of 6.5 to 7 months, and mean general survival of 9.3 to 12.7 months. The International Extended Gain Access to Program trial carried out in 1,704 patients with chemotherapy-naïve or pretreated malignant pleural mesothelioma discovered that cisplatin with pemetrexed and carboplatin with pemetrexed had comparable reaction rates, time to progression and 1-year general survival rates. In the International Extended Access Program, single-agent pemetrexed accomplished reaction rates of 10.5% and 12.1% for chemotherapy-naïve and pretreated patients with malignant pleural mesothelioma, respectively.
The concept of upkeep or on-going therapy after front-line treatment remains under investigation. A study has actually revealed the feasibility of maintenance pemetrexed and demonstrated that reactions could happen even after 6 cycles of treatment. However, the function of maintenance therapy requires additional study in larger prospective trials before being utilized as typical practice. The Cancer and Leukemia Group B (CALGB) is preparing a randomized trial to study maintenance treatment.
Additional front-line mesothelioma chemotherapy agents
Gemcitabine as a single agent has response rates between 0% and 31%; combining gemcitabine with cisplatin leads to action rates between 12% and 48% and average overall survival times of 9.4 to 13 months. The efficacy of a carboplatin plus gemcitabine program has likewise been reported, with a 1-year survival rate of 53% and time to development of 40 weeks. Another study provided a retrospective Canadian series comparing platinum plus gemcitabine with platinum plus pemetrexed (n = 34) and reported no difference in total survival. An ongoing Eastern Cooperative Oncology Group trial in patients with good performance status is comparing carboplatin plus pemetrexed to gemcitabine plus pemetrexed. Another study reported a stage II trial in chemotherapy-naïve patients with malignant pleural mesothelioma utilizing two various schedules of pemetrexed and gemcitabine and reported a 17% to 26% reaction rate with average survival of 8.08 to 10.12 months.
Formerly, vinorelbine was the only vinca alkaloid that had single-agent activity in malignant pleural mesothelioma, with reaction rates of 24% and average overall survival of 10.6 months. In one front-line trial, cisplatin with vinorelbine improved the action rate to 29.6%, mean time to development to 7.2 months, and overall survival to 16.8 months. The most recent vinca alkaloid vinflunine, has actually revealed similar efficacy in chemotherapy-naïve patients. Vinflunine was administered intravenously every 3 weeks to 67 patients with malignant pleural mesothelioma, with a 13.8% action rate, a typical progression-free survival of 3.2 months, and an average overall survival of 10.8 months.
The Japanese have performed several irinotecan-based scientific trials for patients with unresectable malignant pleural mesothelioma. One pilot trial studied a three part routine of irinotecan and cisplatin followed by doxorubicin; the general reaction rate was 36%. A stage II trial used methotrexate, irinotecan and doxorubicin; a 21% partial action rate was reported and the rate in the chemotherapy-naïve patients was 24%. Although these three agent programs showed tolerance and effectiveness, irinotecan has not yet been accepted for malignant pleural mesothelioma in the United States. In the only United States trial of irinotecan for malignant pleural mesothelioma, CALGB studied single-agent irinotecan in chemotherapy-naïve patients; the program had a 0% reaction rate and substantial toxicity.
Second-Line Mesothelioma Chemotherapy
At this time, there is no extensively approved salvage regimen utilized for malignant pleural mesothelioma. However, there is growing evidence that if pemetrexed is not given as a front-line treatment, it ought to be administered in the salvage setting, either alone or with platinum agents. A study conducted a stage III trial comparing second-line pemetrexed with finest supportive care and reported that pemetrexed resulted in better growth reaction and progression-free survival but did not enhance overall survival for unselected patients. The subgroup analysis showed that patients who had responded to front-line chemotherapy had a pattern toward longer general survival with second-line pemetrexed. Gemcitabine plus vinorelbine was likewise found to have some efficacy as a salvage program in 28 patients who had failed to react to pemetrexed-based chemotherapy. The reaction rate was 7.4%, with stabilization of disease in an additional 37% of patients with a mean time to progression of 2.8 months. Single-agent vinorelbine has also been examined in a stage II trial, with a reported reaction rate of 16% and overall survival of 9.6 months.
Biologic Therapy
Biologic therapies that have been successful against other tumors are now being evaluated for malignant pleural mesothelioma. To date, in spite of preclinical information demonstrating overexpression of skin development element receptor and platelet-derived growth element receptor (PDGFR) on malignant pleural mesothelioma tumor cells, scientific trials have shown no substantial improvement in outcome from using single-agent inhibitors of the epidermal development aspect receptor or of the PDGFR. Nevertheless, many new targets and biologic representatives may have potential in the treatment of malignant pleural mesothelioma.
Antiangiogenic agents
Angiogenic inhibition with the monoclonal antibody bevacizumab offers a survival advantage in colorectal cancer and non-small-cell lung cancer. Patients with malignant pleural mesothelioma have high levels of plasma vascular endothelial growth aspect (VEGF), and, as in lung cancer, higher levels of serum VEGF are associated with a worse prognosis. However, a front-line stage II randomized trial using cisplatin and gemcitabine with or without bevacizumab did not show an increase in action rate or survival with the addition of bevacizumab. A subgroup analysis revealed that greater baseline plasma VEGF levels were correlated with a much shorter progression-free and total survival times. Patients with VEGF levels less than the typical had longer progression-free and overall survival when treated with bevacizumab. This suggests that antiangiogenic therapy might benefit some patients with malignant pleural mesothelioma and numerous ongoing malignant pleural mesothelioma research studies with bevacizumab may further define which patients might benefit from antiangiogenic treatment. One such trial is a front-line study of cisplatin, pemetrexed, and bevacizumab. In the salvage setting, a small bevacizumab with erlotinib trial recently reported no radiographic responses, with a mean time to development of 2.2 months and median general survival of 5.8 months.
It is possible that VEGF receptor (VEGFR) tyrosine kinase inhibitors or concomitant inhibition of other tumor or angiogenesis targets will be necessary to attain the best antitumor impact for malignant pleural mesothelioma. Numerous oral multikinase inhibitors that include VEGF/VEGFR path inhibition have been examined in malignant pleural mesothelioma. SU5416, or semaxanib, and thalidomide have been reported to produce clinical activity. Thalidomide as a single representative has been shown to accomplish disease stabilization in 25% of patients for more than 6 months and is under examination in a worldwide trial in which patients with malignant pleural mesothelioma receive 4 cycles of platinum with pemetrexed followed by thalidomide. In one stage II trial, vatalanib had an 11% reaction rate, a 66% stable-disease rate, average progression-free survival of 4.1 months, and mean general survival of 10 months. Sunitinib has been evaluated in a stage II single-arm trial in patients who had experienced treatment failure with one platinum plus pemetrexed regimen. Of 22 assessable patients, there was a 15% partial response rate and 55% stable illness rate by customized Response Assessment Criteria in Strong Tumors. In patients without a talc pleurodesis were assessed by fluorodeoxyglucose positron emission tomography and a 30% metabolic reaction was seen. The typical general survival was 5 months, and typical time to development was 3.5 months. There was one treatment-related death attributed to pulmonary infiltrates and respiratory failure. A phase II trial (CALGB 30307) utilizing sorafenib at 400 mg two times daily for chemotherapy-naïve malignant pleural mesothelioma that was previously treated with pemetrexed discovered grade 3 to 4 negative effects that consisted of tiredness in 25% of patients and hand-foot syndrome in 13%. The total response rate was just 4.4%, with a 38.8% disease-stabilization rate, typical failure-free survival of 4.1 months, and typical overall survival of 10.4 months. Chemotherapy-naïve patients had worse survival results than the previously studied patients.
Other ongoing antiangiogenic scientific trials include AZD2171 in pretreated patients (Southwest Oncology Group) and cisplatin, pemetrexed, and AZD2171 (Southwest Oncology Group) in chemotherapy-naïve patients; sunitinib in both front-line and salvage therapy settings (National Cancer Institute of Canada); and pazopanib, or GW786034 (North Central Cancer Treatment Group) . Although imatinib mesylate as a single agent did not demonstrate activity in malignant pleural mesothelioma, trials of mix regimens of cisplatin plus pemetrexed in chemotherapy-naïve patients with and with gemcitabine in pretreated patients are in progress (M. D. Anderson Cancer Center).
Ribonuclease inhibitors
Ranpirnase particularly targets tumor cell tRNA and hinders protein synthesis, resulting in cell cycle arrest at the G1 stage. The unfavorable effect profile includes hypersensitivity, kidney toxicity, tiredness and peripheral edema. Single-agent ranpirnase in a stage II malignant pleural mesothelioma trial showed a 5% reaction rate, a 43% steady illness rate, and a mean general survival of 6 months. A phase III trial compared ranpirnase with doxorubicin and showed no difference in total survival. However, patients with CALGB prognostic groups 1 to 4 and EORTC danger criteria had a 2-month survival benefit when treated with ranpirnase over doxorubicin. A worldwide phase III trial comparing doxorubicin with the mix of doxorubicin and ranpirnase is ongoing.
Histone deacetylase inhibitors
Histone acetylation manages gene expression by enabling transcription aspect access to genomic DNA. Deacetylation of histones results in cell cycle development and unattended growth. Histone deacetylase inhibitors (HDACIs) are representatives that prevent deacetylation and restore control over the cell cycle. Preclinical studies have shown that HDACIs prevent cell cycle development or cause tumor apoptosis. However, the exact antitumor nature of HDACIs is unknown, although caspase and bcl-xL might be involved. It is likewise thought that the antitumor effect of HDACIs might result from targeting nonhistone proteins, such as α-tubulin, p53, heat shock protein 90, and Ku70.
Suberoylanilide hydroxamic acid (SAHA), or vorinostat, an oral HDACI, was studied in an early stage I trial that included 13 patients with malignant mesothelioma. Single-agent SAHA given at 300 mg or 400 mg two times daily for 3 consecutive days per week yielded 2 partial actions in this small number of patients. The main toxicities were tiredness, anorexia, dehydration, nausea/vomiting, and diarrhea. A continuous randomized, placebo-controlled, phase III trial of SAHA plans to accumulate 660 patients with malignant pleural mesothelioma for whom prior treatments have not been beneficial. Belinostat, also called PDX101, is an additional HDACI under examination. It is a reversible hydroxamic acid, as is vorinostat.
Proteasome inhibitors
Proteasome complexes process ubiquitinated proteins and facilitate protein degradation. When proteasome activity is inhibited, nuclear factor-κB production is also inhibited, and tumor cells undergo apoptosis. Preclinical studies in cell lines and murine xenograft models showed antitumor activity against malignant pleural mesothelioma, and two European trials are underway using single-agent bortezomib (All Ireland Cooperative Oncology Research Group/Gruppo Italiano Mesotelioma) and the combination of cisplatin and bortezomib (EORTC).
Gene therapy
Early work with gene therapy used adenovirus vectors containing the herpes virus thymidine kinase (Ad-HSVtk) gene administered intrapleurally followed by intravenous ganciclovir. The premise for this work was to transduce viral thymidine kinase into the cancer cells and then administer the antiviral agent ganciclovir to selectively kill the tumor cells. Ganciclovir is metabolized to cytotoxic ganciclovir triphosphates by the thymidine kinase gene, which can potentially diffuse through the tumor and kill cells that are expressing the transgene. In addition to the direct anticancer effect, it was also presumed that an adenoviral-induced inflammatory response would stimulate the host immune system to attack the cancer cells. A phase I trial was therefore conducted using intrapleural Ad-HSVtk followed by 2 weeks of ganciclovir in 21 previously untreated patients with malignant pleural mesothelioma. This trial demonstrated feasibility, with 11 of 20 assessable patients having transfer of the HSVtk gene into superficial tumor layers and two patients reporting long-term survival of over 6.5 years. Analysis of these data suggested that the antitumor effect was more likely related to the immune modulatory effect from the Ad-HSVtk and ganciclovir rather than the direct anticancer effect for which it was originally designed. Therefore, a clinical trial using an adenoviral vector containing an immune stimulant interferon beta (IFN-β) was undertaken. This phase I trial injected adenoviral human interferon beta intrapleurally into 10 patients (seven had mesothelioma) and demonstrated successful gene transfer in seven patients. Three of the seven patients with mesothelioma had disease stability at 60 days. The main toxicities seen in the trial were transient hypoxia and reversible liver function value elevations. Further studies of gene therapy and immune modulation are ongoing.
Other Agents
In patients with deadly pleural mesothelioma, triggered Src kinase may be a prospective therapeutic target. Studies of archival tumor tissue show that overexpression of triggered Src kinase protein is associated with more advanced pleural mesothelioma cancer and that preclinical studies with dasatinib, a multitargeted Src tyrosine kinase inhibitor, can cause malignant pleural mesothelioma cancer cell cycle arrest, apoptosis, and impair the capability of the tumor cell to migrate and invade. Dasatinib is presently under examination in clinical trials for the neoadjuvant setting (M. D. Anderson) and also as a second-line agent through a stage II trial sponsored by CALGB. Antimesothelin representatives are presently in clinical trials for mesothelioma: SS1P (an immunotoxin), Morab009 (an antimesothelin monoclonal antibody) and CRS-207 (a Listeria monocytogene mesothelin vaccine). Both SS1P and Morab009 have undergone single-agent trials and are now being investigated in stage I/II trials in combination with cisplatin and pemetrexed; CRS-207 is being evaluated as a single agent in stage I trials. Possible future targets for malignant pleural mesothelioma therapy consist of the insulin-growth aspect pathway, MEK pathway, and the PI3K/AKT paths. Vaccines are also under investigation; the Memorial Sloan-Kettering Cancer Center just recently reported arise from a pilot trial of a Wilms’ tumor 1 peptide vaccine, which showed some activity against malignant pleural mesothelioma. An adjuvant medical trial utilizing the Wilms’ growth 1 vaccine is currently under advancement.
In conclusion, at this time, surgical resection and adjuvant radiation therapy remain the essential of treatment for patients with resectable malignant pleural mesothelioma. There is considerable evidence that systemic treatment is likewise required, as improvements in regional control have actually been accompanied by increased rates of distant transition. Unfortunately, the optimal multimodality management of these patients is still uncertain. Therefore, the use of systemic chemotherapy (neoadjuvant, intrapleural, and adjuvant) remains experimental, and it is encouraging that systemic treatment can be administered in the setting of clinical trials.
For the patient with unresectable malignant pleural mesothelioma, the antifolates or gemcitabine, given in addition to a platinum agent, have shown the most impressive clinical effect. More progress is needed, however, and recruitment of patients with malignant pleural mesothelioma into medical trials of unique restorative representatives must be emphasized. In addition to recognizing brand-new therapeutic targets, key issues requiring further investigation include understanding the function of immune modulation, determining whether upkeep therapy is indicated after front-line chemotherapy, differentiating the genomic profiles between the histologic subtypes to determine whether they must be dealt with in a different way, evaluating more accurate methods of measuring clinical reaction, and verifying surrogate blood-based markers for action. New strategies and target pathways under examination will hopefully supply better restorative alternatives for patients with malignant pleural mesothelioma in the future.
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