Pleural mesothelioma (PM) is a rare but highly malignant cancer of the pleural membrane. It originates on the mesothelial surface of the pleural cavity of the lungs, thus the name, pleural mesothelioma. PM is rapidly progressing and is associated with an aggressive character. Therefore, it is known as malignant pleural mesothelioma (MSM) in the medical community and there is no set treatment for pleural mesothelioma.
MSM has the worst prognosis in its peer group. It is one of the cancers with poor survival and higher mortality rates than the others. According to research by Jennifer Faig et al.1, median survival is merely 18.4 months after the diagnosis and survival rates at 1, 3, 5, and 10 years are just over 73%, a little short of 23%, 12, and 4.7% respectively.
Over the years, even the latest treatment advances have failed to improve this drastic outlook. Only a handful of carefully selected patients with relatively localized disease, when subjected to focused multimodality treatment, have slightly prolonged survival. Chemotherapy has been the mainstay of mesothelioma treatment. Along with surgical resection, it offered a ray of hope to a lot of patients. However, owing to the poor prognosis and increased morbidity, a dismal attitude has been prevalent among many physicians. Newer treatment therapies, which include Gene therapy, and immunotherapy, along with others, are showing promising results. This is encouraging scientists and the medical community to look out for innovative and newer treatment strategies to treat pleural mesothelioma.
Clinical Presentation and Patient Evaluation
A significant majority of patients belong to the geriatric group of the population. They typically present with gradual onset of chest problems such as shortness of breath, cough, and pain in the chest. This is understandable because mesothelioma requires prolonged asbestos exposure leading upwards of 10 years and more. Unfortunately, symptoms usually appear when cancer has already involved the lungs extensively. Metastasis is generally rare, but it can affect the brain, bones, and liver. Other more unusual symptoms the patients can present with include local invasion of vital structure in the vicinity, such as the brachial or cervical nerve plexus or some major muscles important for the movement. The treatment strategy, therefore, varies case to case where clinicians have to opt for patient-oriented therapies.
Differential Diagnosis and Choice of Therapy
Certain benign conditions can also imitate pleural mesothelioma. These may include inflammatory reactions in the lungs, such as chronic empyema. The difference is often apparent when a detailed pathologic examination is conducted.
Malignant conditions include distant metastasis of other lung cancers. Modalities of treatment, thus, need to be carefully selected.
Cancer staging evaluation is further performed to understand baseline disease load. On the other hand, pathological staging is a better and reliable tool to select patients where surgical resection can be helpful. Nearly all patients with malignant pleural mesothelioma receive drug treatment, which is also known as chemotherapy. It is further supplemented by surgical tumor debulking. Surgical debulking is technically known as cytoreduction.
Chemotherapy is the administration of certain drugs and pharmacologic chemicals against the cancerous tissue. Like other malignancies, it is the first line of medical intervention against mesothelioma. Researchers have been studying various chemotherapy regimens for long. In 1996, S T Ong et al.2, postulated that chemotherapeutic drugs like Detorubicin, high dose methotrexate, and Edatrexate have a response rate greater than 20%. They respectively showed a response rate of 26%, 37%, and 25%. However, none of the drugs performed consistently above 20% response rate.
It wasn’t until 2004 that the U.S Food and Drug Administration approved the first-ever chemotherapeutic regimen. Two drugs, namely, cisplatin and pemetrexed, finally came to the rescue. It is now the standard treatment for unresectable malignant pleural mesothelioma. In an EMPHACIS trial, this combination illustrated an improvement in median survival by 12.1 months.
This combination regimen, when administered with prophylactic folic acid and vitamin B12, proved to be highly beneficial. Systemic toxicity was significantly low, and therefore patients were better able to tolerate the toxic side effects. The addition of folic acid and vitamin B12 is not without an underlying mechanism. Most of the chemotherapeutic regimens disrupt folate enzymes and act by inhibiting nucleotide synthesis in cancerous cells. This, in turn, halts the cancerous growth in the body. However, to prevent depletion of the folic acid stores in the human body, exogenic folic acid is added prophylactically. As mentioned above, systemic toxicity is reduced, and more therapy cycles can be administered.
Newer Advances in Chemotherapy Drugs
The addition of bevacizumab in standard therapy, which includes cisplatin and pemetrexed, proved more effective in improving progression-free survival. After a randomized controlled phase 3 trial (MAPS)3 under the supervision of Prof. Gerard Zulcman et al., in France, it was recommended as a suitable addition in already prevalent regimens. This is now an accepted standard in France for treating pleural mesothelioma since 2016. As of now, it remains unapproved by the U.S Food and Drug Administration department.
Scientists are also exploring the realms of pharmacotherapy as well as genetic engineering to treat mesothelioma. Gene therapy falls under the ambit of gene engineering, and it involves the induction of a healthier gene in place of the defective gene in the genome of the patient. These genes are better able to fight off the cancerous cells.
Immunoglobulin antibodies are another emerging treatment option. In preliminary phase-3 trials, immunoglobulins such as PD-1 antibodies, pembrolizumab, and nivolumab are used as single agents or as a combination with cytotoxic T-cells lymphocyte antigen 4 (CTLA-) ipilimumab and have shown an improved outcome in Progression-Free Survival (PFS). Immunoglobulins are approved for off-label use, but more research is needed to prove their efficacy.
Scientists are working on another aspect of treating pleural mesothelioma. They are trying to make viruses work for humans. In the case of cancers, it’s the adenovirus. It is used as a vaccine to develop antibodies in human bodies. Mechanism of action of this “vaccine,” now known as ONCOS-102, is relatively simple. The adenovirus acts by stimulating the granulocyte-macrophage colony-stimulating factor (GMCSF), which is crucial in triggering a human immune response against “rogue” cells. Treatment with GMCSF resulted in increased infiltration of CD8+ T cells at the tumor sites and PD-L1 cell upregulation. The trial has paved the way for newer immunosensitizing agents to be included in combined treatments for cancers like pleural mesothelioma.
Surgical Treatment for Pleural Mesothelioma
Surgical resection is another primary curative modality in the treatment options for pleural mesothelioma. It is essential to know that not all stages of mesothelioma are a candidate for surgery. Surgery is usually reserved for those who have localized resectable cancerous lesions and are also at the early stage of the disease progression.
Various surgical procedures are available in practice to alleviate the symptoms and distress of mesothelioma patients. In some cases, if the disease hasn’t progressed extensively, surgery can prove to be curative. These procedures include 1) Extra-Pleural Pneumonectomy (EPP) and 2) Pleurectomy or Decortication.
Extra-Pleural Pneumonectomy is one of the first surgical techniques developed, and it is used in earlier stages of the mesothelioma. Preferably at stages 1 and 2, it involves the removal of affected lung entirely along with its pleura and some of the diaphragm. Dr. David Sugarbaker from Temple, Florida, is considered to be the pioneer of this technique.
Average hospitalization in the case of EPP is two weeks; however, patients generally need another 6-8 weeks to recover entirely outside the hospital.
Pleurectomy/Decortication is a more straightforward technique than the EPP, and it aims at preventing patients from losing a complete lung. This technique focuses on removing cancerous pleura only. Multiple types of research have proven this technique’s superiority to EPP. Mortality and disability is a significant problem encountered in EPP. Removal of an entire lung, its pleura, hemidiaphragm, and pericardium leads to significant cardio-pulmonary complications. Broncho-Pleural fistula is a considerable risk postoperatively in EPP, which further leads to Sepsis and multi-organ failure.
On the other hand, P/D’s main complication is prolonged air leak from the lungs. It is presumed to be associated with lung trauma while peeling off pleura from the lung. In the meta-analysis by Cao et al.4, it was concluded that decreased peri-operative morbidity is the hallmark of P/D.
P/D, EPP, or both, when combined with postoperative adjuvant chemotherapy, depicted enhanced survival and less morbidity. In the field of Medical Science, the concept of drug synchronicity is widely known. Most of the time, one form of treatment modality, when combined with the other one, can augment the effects of both. Each drug in the treatment supplement the other one. In the case of mesothelioma, surgical therapy, when carried in conjunction with chemotherapy, shows superior results.
Post Extra Pleural Pneumonectomy combined with chemotherapy and radiotherapy are instituted. Similarly, patients undergoing Pleurectomy/Decortication procedure receive radiation and chemotherapy before and after the process.
Although the above discussion may seem to reinforce the idea that adjunct chemotherapy is beneficial along with surgery, surgery alone in the case of limited disease progression has proved its value. Like every other treatment, medicine has its limitations. Prerequisites for operation include good patient tolerability, surgeon’s choice, and early diagnosis. Chemotherapy, on the other hand, can also be administered to unresectable and extensive tumors. Either way, it is a glaring reminder that Pleural Mesothelioma is a deadly incurable cancer, and every scientific effort should focus on finding a cure for this cancer.