The diagnosis of malignant pleural mesothelioma is very difficult because the disease may develop 30 to 40 years after asbestos exposure. To obtain an early and reliable diagnosis of malignant pleural mesothelioma, guidelines recommend that all suspected patients should undergo thoracoscopy, except in cases with contraindications to surgery and pleural adhesions.
In approximately 10% of cases, standard staining methods do not yield satisfactory results, so specific immunohistochemical markers should be used at the time of pleural biopsy.
The patient’s physical status and tissue subtype are the only, important clinical prognostic factors. Malignant pleural mesothelioma is highly resistant to chemotherapy and only some patients can undergo radical surgery.
Risk factors
Asbestos
Asbestos is the primary causative agent of malignant pleural mesothelioma and consists of six silicate minerals that form very fine fibers: ciliophorite, crocidolite, amosite, anthophyllite, tremolite, and actinolite. Fibrous serpentine, amosite and crocidolite are all widely used in industry. Most asbestos exposure is work-related.
Environmental mesothelioma is associated with natural exposures in some areas, such as asbestos being present in the soil as a geological component. In some areas, people were exposed by painting the walls of their houses with asbestos or by living in close proximity to asbestos mines or asbestos factories. Family members of asbestos workers often become ill from exposure to asbestos on the workers’ work clothes.
All individuals exposed to asbestos are at high risk. The average incubation period for malignant pleural mesothelioma is approximately 40 years (15 to 67 years) after asbestos exposure, with incubation periods greater than 15 years accounting for 99% of all cases. In most cases, pleural plaques are a sign of asbestos exposure, and a strong association with the risk of mesothelioma has been reported, but some studies have concluded that there is no correlation between the two. Overall, there is no clear evidence that pleural spots alone are associated with an increased risk of pleural mesothelioma.
In men with malignant pleural mesothelioma, more than 80% had a history of asbestos exposure, but in women, there was little history of asbestos exposure. There is a clear dose-dependent relationship between asbestos exposure and malignant pleural mesothelioma, but the disease can occur in people with low doses of asbestos exposure.
Malignant pleural mesothelioma occurs primarily through occupational exposure to asbestos, but can also occur through indirect occupational exposure or environmental exposure to asbestos. Most amphibole fibers, especially crocidolite, amosite, and tremolite, have a higher carcinogenic potential than fibrous serpentine fibers.
Other factors
In addition to asbestos, other potential causative or synergistic factors for malignant pleural mesothelioma include exposure to other natural fibers (e.g., grossular zeolite, fluorine amphibole) or man-made fibers (refractory ceramics), in addition to ionizing radiation and simian vacuolar virus 40 (SV40). In contrast, tobacco has no significant role in the development of mesothelioma.
There is no evidence that man-made fibers, such as mineral wool fibers (rock wool, glass wool, slag wool), are pleurotoxic in humans. Genetic factors may increase susceptibility and thus contribute to the formation of pleural mesothelioma.
Epidemiology
The incidence of malignant pleural mesothelioma varies considerably among different countries of the world, ranging from 7 per million (Japan) to 40 per million (Australia) per year, mainly related to the consumption of asbestos in these countries in the last decades. In Europe, the incidence of malignant pleural mesothelioma is around 20 per million.
Treatment
Surgical treatment
The aim of surgery is to relieve compression-induced atelectasis by removing tumor tissue from the visceral layer. Restrictive hypoventilation and chest wall pain can be relieved by removing the mural tumor tissue. This procedure can be accomplished by open-heart surgery or closed television-assisted thoracoscopic surgery (VATS), with VATS being preferred. partial pleurectomy/stripping does not achieve a cure but provides symptomatic relief, especially in patients in whom chemical pleural fixation has failed and who have a syndrome of pulmonary atelectasis.
Radical surgery is defined as the removal of all naked eye visible tumors from the hemithorax. This can be achieved by removing the entire pleura, lung, pericardium, diaphragm, and systemic lymph node dissection through extrapleural pneumonectomy. Studies have shown that the median survival of patients after radical surgery is 20 to 24 months, and the postoperative mortality rate is reduced to 5%, while the recurrence rate is high, about 50%.
Radiation therapy
The main purpose of palliative radiotherapy is to relieve pain, and it can be considered for patients with pain due to invasion of the chest wall. However, prophylactic radiotherapy remains controversial. In contrast, the data on postoperative radiotherapy are limited to retrospective studies. Radiation therapy is not recommended after pleurectomy or dissection. Further in-depth studies are needed on the role of radiation therapy in malignant pleural mesothelioma.
Chemotherapy
Only one randomized study has currently evaluated the efficacy of chemotherapy in malignant pleural mesothelioma. No survival difference was observed between the chemotherapy and placebo groups, except for a survival advantage found in the vincristine subgroup. Studies have shown that combination chemotherapy including cisplatin and anti-folate agents, pemetrexed or raltitrexed improves patient survival.
Median survival was significantly longer in the cisplatin combined with pemetrexed group (12.1 months) or cisplatin combined with retitrexed group (11.4 months) than usually reported in the literature (7 to 9 months) Other chemotherapy regimens were: cisplatin combined with etoposide, cisplatin combined with doxorubicin, cisplatin combined with gemcitabine, cisplatin combined with interferon, and oxaliplatin combined with retitrexed (or gemcitabine or vincristine). The optimal course of chemotherapy is not known. Patients can be treated with the same chemotherapy regimen again after first-line chemotherapeutic agents if clinical symptoms improve and the disease resolves and relapses.
Biomodulatory agents
Interferon and interleukins are the main experimental agents in the biologic treatment of malignant mesothelioma. Currently, no efficacy has been found for monotherapy with these two agents, and they are not recommended for use outside of clinical trials. Dosage, method of administration (intrapleural, subcutaneous, intramuscular and intravenous), drug type and disease stage vary among clinical trials, so the results of these studies need to be interpreted with caution.
Targeted therapies
Several biologically targeted therapies have shown efficacy in lung, colon, and breast cancers, but few studies have been applied to malignant mesothelioma. The drugs that have been tested include the following.
(i) Thalidomide (anti-angiogenic drug): clinical trials have shown >6 months of disease stabilization and a median survival of 230 days in patients receiving treatment.
②Bevacizumab (monoclonal antibody, vascular endothelial growth factor inhibitor): one study showed that treatment with cisplatin + gemcitabine did not improve the efficacy if combined with bevacizumab.
③ Gefitinib: Studies have shown that gefitinib is not effective in patients with malignant mesothelioma.
④ Imatinib: Available studies suggest that it is ineffective in malignant mesothelioma.
⑤ Erlotinib: No objective remission was observed in patients in phase II clinical studies.
Efficacy can be evaluated by clinical criteria (symptom control and quality of life), imaging criteria, and survival criteria (time to disease progression and overall survival).
Surgery alone cannot cure malignant mesothelioma because 1 to 2 cm of the inner pleural layer (especially in the pericardium and mediastinum) margin cannot be removed. Therefore, it is currently considered that in the treatment of malignant pleural mesothelioma, all surgical operations are R1 (with residual tumor at the cut edge), which is the theoretical basis for comprehensive treatment.
In addition, radiotherapy of the entire half of the chest wall is limited due to the presence of vital organs, such as bilateral lungs, liver, and especially the heart, in addition to the spinal cord and esophagus. Therefore, the implementation of irradiation with a total dose of more than 54 Gy for such a large volume is difficult, as it requires lean treatment techniques and requires orientation through what the surgeon and pathologist see.
Indications
Before undergoing any multimodal combination treatment, patients must undergo the following examinations and meet the appropriate conditions
(i) Physical examination: no signs of tumor growth in the rib cage or abdomen, while unilateral thoracic atrophy is a sign of advanced disease.
②Pulmonary function examination: the value of pulmonary function after pneumonectomy should meet the needs of normal life.
③There should be adequate cardiac function reserve without pulmonary hypertension and arrhythmia.
④Line examination: spread beyond the thorax to the diaphragm, spread to the contralateral side, and spread with multiple points of involvement can be excluded.
⑤ Histologic examination: the best prognostic histologic subtype of malignant mesothelioma is the epithelial type.
⑥Gender: There is no strong data to confirm how the treatment outcome differs between genders.
Symptom control
Pain management Pain caused by mesothelioma is usually the result of a combination of injurious pain, neuropathic pain and inflammatory factors. Pain control should follow the principles of cancer pain management. In addition to the use of opiates, patients often require adjunctive pain relief. For pain caused by small tumor nodules, the application of palliative radiotherapy is recommended.
Treatment of dyspnea
Repeated aspiration of pleural fluid should be avoided if pleural fixation was performed early in the disease or until the pleural fluid forms an inclusion and/or the lung is fixed and complete lung expansion is not possible. In patients with recurrent pleural effusions who are very weak, occasional repeated aspiration or intrathoracic drainage is the most practical management. Pleural fixation is effective in preventing recurrent pleural effusions and may be preferred to sterile talc. Pleural fixation is usually most effective when performed early in the course of the disease, but it should not be performed until sufficient tissue is obtained for diagnosis. Oral low-dose morphine is effective in reducing the sensation of dyspnea, as well as reducing associated anxiety. Oxygen may be helpful, but must be used only in the presence of decreased oxygen saturation.
Treatment of other symptoms
For cough, cough suppressants such as codeine syrup or forcodine should be used. It is important to rule out or treat co-morbidities such as lung infections or heart failure should be treated with high energy supplements, smaller meals, treatment of oral Candida infections, and avoidance of dehydration and constipation. For sweating, improvement can be obtained by increasing or decreasing clothing, using fans, and taking medications such as cimetidine. Dysphagia may be due to oral Candida infection or extrinsic compression of the esophagus by the tumor. Fluconazole is effective in treating Candida. Constipation is caused by inactivity and poor eating and is an unavoidable result of taking opiates. Laxatives should be used aggressively and regularly. Constipation is also a sign of tumor spread through the diaphragm into the peritoneal cavity. Due to chemotherapy side effects, patients may experience vomiting, which is effectively treated with antiemetics. Vomiting may also be caused by opioid analgesic side effects, and a change of medication may be effective.