Approximately 80% of cases it is considered that due to occupational exposure or primary para occupational asbestos fiber types (hence the high demand numbers asbestos mesothelioma), or crocidolite, amosite and chrysotile in a ratio of 500:100:1, respectively, and less often by exposure to tremolite (which has little commercial value, and in limited quantities).
These are the cases of mesothelioma in relation to the majority of lawyers and claims across the country, a lawyer mesothelioma. According to the latest statistics from mesothelioma British Health and Safety Executive Epidemiology and Medical Statistics Unit, the odds seem to be higher among workers in the following major areas of use of asbestos: shipbuilding, railways and construction of locomotives and l " installation and maintenance of insulation in buildings and industrial installations.
The remaining 20% of cases no obvious reason and is considered in relation to etiologic factors, including contact with fibers as Erionite nonindustrial and exposure to Simian virus 40 (SV40), a DNA tumor virus of macaques affect Asia stocks contaminated polio vaccine used in the late 1950s/early 1960.
Epidemiological trends
Malignant mesothelioma develops after a long period, which means an average of 32 years. Proportionally more men than women are affected (ratio of about 3:1) and the incidence continues a pattern that is determined by age and date of birth, this model in addition to the exposure to trends and changes in consumption and industrial use of asbestos fibers throughout the 20th century. Between 1973 and 1999, for a total of 5266 cases of mesothelioma have been reported in the United States, with an average incidence of 0.97 per 100,000 people, and a higher incidence in men and women (1.8/100000 vs. 0.4 / 100,000 , respectively). Models similar to the rates of correct age, almost 50% higher in the period 1980-1984 compared with 1975-1979 period, with maximum effect cohort of men born between 1905 and 1909. Given the associations of the exhibition, the rate for women is not surprising, is flat, and the estimate of the risk of life of women is 2.5 per 10,000 people. Since the use of asbestos was banned in the United States since 1970, the number of male drop significantly in the next 50 years.
By contrast, during the same period when asbestos was banned in the United States, imports of asbestos peaked in the United Kingdom. This explains the increasing incidence of this, a current total of 1300 cases per year for a total of more than 3000 cases per year in 2021. In Western Europe - particularly Great Britain, France, Germany, Italy, Netherlands and Switzerland, representing 75% of all people in Western Europe - the use of asbestos remained high until 1980, and the amounts are still in use in many countries.
In Western Australia, crocidolite was mined commercially from 1937 to 1966 and the first cases of mesothelioma are reported in my work since 1962. New South Wales has continued to produce until 1983 chrysotile, and the country still imports about 2000 tonnes of chrysotile fiber per year. Consumption of asbestos in Australia peaked in 1975, which correlates with the increased incidence seen dramatically in the last 20 years. More than 6000 cases were reported between 1945 and 2000 with a total population of about 20 million and a further 600 cases were reported in 2001. In the next 20 years, the number of cases expected to triple to a total of 18,000 cases in 2020.
Forecast
The prognosis for malignant mesothelioma is poor with a median survival ranging from 8 to 14 months depending on the stage and the presentation of the disease and in clinical disease activity.
Diagnosis
A thorough history with a special emphasis on the professional and present signs and symptoms, together with computer tomography (CT) and pleural biopsy thorascopic, are generally effective for diagnosing the disease.
The role of surgery and radiotherapy
The role of surgery and radiotherapy (RT) in the management of mesothelioma is very limited. Neither is supported by data from randomized, controlled studies on the effectiveness as a form of therapy.
Surgery, while successfully used for the palliative control of symptoms has only a minimal effect on the median survival times when used as a radical treatment. Extrapleural pneumonectomy, defined as a "radical" is associated with a median survival of 15-24 months. Extrapleural pneumonectomy is resection of the pleura, lung, pericardium, and often, and the diaphragm. Debulking parietal pleurectomy is associated with minimal morbidity and 90% control of effusion in 12 months. Palliative thoracoscopy with pleurodesis is usually reserved for patients requiring pneumonectomy and other procedures (eg, pleural decortication, resection of the parietal / visceral pleura for the preservation of the lungs) is contraindicated.
RT has been studied only in a limited number of patients, and their usefulness is limited by the size of the tumor to treat the toxicity of normal tissue. As the operation, there may be a role for palliative RT, and that seems to be effective for pain. There are no data to suggest that RT improves survival compared with best supportive care.
Single agent chemotherapy
Because most patients with mesothelioma are not candidates for surgery or RT, chemotherapy or palliative care are often the only option. Until now, the only agent systems using commercially available cytotoxic agents such as cisplatin, Doxorubicin, trimetrexate, taxanes or paclitaxel or docetaxel are modest, with an average response of 10% to 20%. Although Doxorubicin is the most studied, the results of a recent meta-analysis suggests that cisplatin is the most active.
Single agent chemotherapy with new compounds, such as liposomal anthracyclines (eg Doxorubicin liposomal, daunorubicin), pemetrexed and gemcitabine, are also limited. While the first were the most inactive, phase 2 data with nucleoside analogues gemcitabine demonstrated response rates ranging from 0% to 31%, while the overall response was 14% to the pemetrexed antifolate.
The combination of chemotherapy
Until now, using a combination of traditional (eg Doxorubicin / cisplatin, Doxorubicin / cisplatin / cylophosphamide, cisplatin / etoposide, cisplatin / DHAC) have not much higher response rate to single agent regimens. [19] In contrast, the use of new cytotoxic agents such as pemetrexed doublet, gemcitabine and raltitrexed in combination with a platinum have shown more encouraging results.
Pemetrexed / cisplatin
Pemetrexed main action is inhibition of 3 enzymes involved in purine and pyrimidine synthesis: timidilato synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). While other drugs such as raltitrexed and 5-fluorouracil, also TS goal, no other agent is open for all 3 enzymes that are currently available.
Encouraging results of phase 1 and 2 clinical studies, up to 45% of patients evaluated pemetrexed / cisplatin experienced a partial response (PR), led to phase 3, the largest study ever conducted in patients with mesothelioma. Vogelzang and colleagues [35.36] 456 eligible patients randomized to pemetrexed 500 mg/m2 intravenous bolus over 10 minutes plus cisplatin 75 mg/m2 given every 3 weeks (n = 226) or as an agent at 75 mg / m 2 cisplatin more salt (to blindness), administered every 3 weeks (n = 222). Most patients had evidence of stage III or IV disease. Previous reports documented severe toxic effects (eg, grade 4 neutropenia and diarrhea) due to the high baseline serum homocysteine and methylmalonic acid folic acid and vitamin B12. Therefore, the 2 treatment groups were changed during the process in the first months of employment with supplementation with 350 to 1000 mcg folic acid and 1000 mcg per day by intramuscular injection of vitamin B12 every 9 weeks.
A statistically significant longer median survival was observed in all patients treated with combination therapy compared with patients treated with cisplatin alone (12.1 months versus 9.3 months, hazard ratio [HR] = 0, 77, P = .020).
The median time to progression of the disease was significantly higher for patients in the pemetrexed / cisplatin compared with cisplatin alone arm in the arm (5.7 months versus 3.9 months, HR = 0.68, P =, 001). Tumor response (PR only), as measured by CT was observed in 41.3% of patients in the pemetrexed / cisplatin arm against 16.7% of patients in the cisplatin alone arm (p <.001).
Although treatment with pemetrexed / cisplatin resulted in a higher incidence of drug-related serious adverse events (22.5% vs 7.2%, respectively) and grade 3 / 4 neutropenia, nausea and vomiting, supplementation with folic acid and vitamin B12 resulted in the reduction of toxicity. In fact, some significant differences in toxicity was observed in those who fully or partially completed and who has never been.
Finally, Gralla and colleagues analyzed the quality of life (QoL) parameters measured by the LCSS-meso instrument approximately 96% of patients (n = 448) enrolled in this process. In addition to the observed survival advantage Vogelzang, the pemetrexed / cisplatin combination was associated with statistically significant improvements in global QOL and relief of symptoms in most of the parameters at week 18, compared with cisplatin alone, there are improvements in pain, dyspnoea and cough at 15 weeks (P <.001). Significant improvements in QOL and symptoms within 6 to 9 weeks of treatment.
Gemcitabine / cisplatin
Gemcitabine is a pyrimidine anti-metabolites that is associated with cytosine arabinoside. Has shown to have a wide range of mesothelioma and other solid tumors. Although their activity is limited, as an agent, the response was generally higher when used in combination with cisplatin.
Byrne and his colleagues that a response rate of 47.6% between the 21 patients receiving cisplatin 100 mg/m2 intravenously on day 1 and gemcitabine 1000 m/m2 intravenously on days 1, 8 and 15 cycles of 28 days for 6 cycles. Ninety percent of patients experienced complete or substantial relief of symptoms. However, despite these positive results, the median survival was only 9.4 months. Toxicity is largely limited to systems gastroenterologic haematological grade 3 and nausea and vomiting in 33% of patients and leukopenia were at 38%, while grade 4 thrombocytopenia were at 19%.
New therapeutic pathways
Although relatively little is known about the biology of malignant mesothelioma, there is increasing interest in the multiplicity of factors involved in angiogenesis. One of the objectives of particular interest is the vascular endothelial growth factor (VEGF), via signal transduction. VEGF is considered the best characterized proangiogenic factor expression, binds to VEGF receptors on endothelial cells and a signaling cascade that stimulates the formation of new blood vessels. In vitro data indicate that VEGF is one of several autocrine growth factors that play an important role in the aggressive growth and metastasis of mesothelioma, so that VEGF, VEGF-C and its receptors are expressed by mesothelioma cell lines. [40] Note that, by means of the expression of VEGF receptor FLK-1 is correlated with micro vessel density, which in turn is associated with poor survival.
The presence of both VEGF and VEGF-C autocrine activity on mesothelioma cells suggests that the development of therapies that ultimately aim both to increased activity. Another possible way to the blockade of VEGF in the current cytotoxic regimens. Agents currently being investigated for possible anti-VEGF include SU5416, Thalidomide, PTK787/ZK222584, bevacizumab, and VEGF, vascular endothelial growth factor.
Several clinical studies are ongoing for the activity of thalidomide malignant mesothelioma. It believes that thalidomide inhibits VEGF, tumor necrosis-alpha, and basic growth factor, fibroblast-induced angiogenesis.
PTK787/ZK222584 is an inhibitor of tyrosine kinase receptor VEGF and platelet-derived growth factor tyrosine kinase receptor beta. In vitro data show a dose-dependent inhibition of malignant mesothelioma cell lines and cell lines of patients who are sensitive and resistant to conventional therapy. In addition PTK787/ZK222584 inhibits VEGF-induced migration of cells through the extracellular matrix. Phase 1 study of the data showed the stabilization of the disease to 50% of patients treated with 1000 mg per day. [45] There were no signs of toxicity observed. A review of phase 2 trial of the effectiveness of the malignant mesothelioma quickly open in the CALGB.
Bevacizumab is a monoclonal antibody that blocks VEGF binding to the receptors and is the first anti-angiogenesis agent to be effective in a phase 3 trial. In combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin), bevacizumab increased survival, progression-free survival and response rates and duration of 800 patients with metastatic colorectal cancer vs bolus IFL alone. A randomized phase 2 study, sponsored by the Consortium University of Chicago, is to test the effectiveness of gemcitabine / cisplatin with or without bevacizumab in 106 patients with malignant mesothelioma.
For epidermal growth factor receptor (EGFR), another angiogenic target of particular interest. His speech, which is activated by different signals and ligand binding has been reported in 68% of paraffin-embedded mesothelioma specimens and 4 of 4 cell lines of mesothelioma. However, Govindan and colleagues have shown that EGFR-targeted agent Gefitinib 500 mg per day was inactive in malignant mesothelioma and is not correlated with survival free of disability in patients who express EGFR.
Summary and conclusions
Although malignant mesothelioma is considered one of the most common cancers in the Western Hemisphere, a steady increase in the number of cases, especially in the United Kingdom, has an urgent need to find new therapies with less side effects and better control of symptoms, the increase in antitumour activity, improved survival, and in general a better QOL. Until recently, it remains difficult to achieve these objectives, and the strength of the evidence to support a method of treatment is weak.
Fortunately, the trend seems to be turning and a sense of nihilism in the treatment of mesothelioma is included. Very encouraging results of clinical studies suggest that combination chemotherapy with at least one new agent has a definitive role in the management of the disease. Currently, phase 3, the data show a significant improvement in survival, the favorable tolerance, a good antitumour activity and higher QOL support the use of pemetrexed and cisplatin as first-line treatment for malignant pleural mesothelioma. Other combinations, including gemcitabine with cisplatin or carboplatin and oxaliplatin raltitrexed more may also standard therapy in the near future.
If evidence indicates more firmly the role of combination chemotherapy, the researchers are beginning to infringe upon a better understanding of the biology of mesothelioma. In the final analysis, the new therapeutic targets new ideas and a means to improve the results.
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