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Options for Malignant Pleural MesotheliomaBy John LeBas
Malignant pleural mesothelioma (MPM) is a disease often misdiagnosed or mistreated at the outset. Almost universally caused by inhaled asbestos fibers embedded deep in the lungs, MPM takes decades to develop after initial exposure—and as a result may occur in patients with no obvious cancer risks. And while later-stage disease produces a painful, rind-like growth that can choke off the lungs or blood vessels, earlier-stage MPM may not appear to be cancer at all. “When patients are referred to us, they often have been diagnostic dilemmas,” said Anne S. Tsao, M.D., director of the Mesothelioma Program at The University of Texas M. D. Anderson Cancer Center. “Often, several months have passed since the onset of symptoms, and many of these patients have not yet been diagnosed with cancer. And too often, by the time the cancer is finally diagnosed, they are no longer candidates for surgery, which offers the best hope for a cure.” A cure? The notion may seem odd, given the generally poor prognosis of MPM and its widespread reputation as incurable. But in fact, while curing MPM happens very rarely, it is possible, and newer therapies are extending useful life even for patients with unresectable disease. Many challenges MPM is notoriously difficult to diagnose in its early stages, particularly if it is a slow-growing variety. It can appear to be adenocarcinoma, even on histologic evaluation, which can prompt therapy for the wrong disease type. Or, MPM may cause a pleural effusion, which can occur even before a tumor is detectable on imaging, leading to therapies aimed at curing the symptom but not the cause. Such difficult circumstances can have tragic implications for the patient, as delaying effective treatment can shorten the patient’s survival considerably. Even when a diagnosis of MPM has been confirmed, the disease’s long-standing reputation as incurable or even untreatable sometimes leads to clinical decisions aimed prematurely at palliation, Dr. Tsao said. For example, one common palliative approach, talc pleurodesis, is sometimes used when potentially life-extending surgery might still be an option. MPM is thus a disease best treated at a major cancer center that sees many cases, Dr. Tsao said. Physicians in the Mesothelioma Program at M. D. Anderson evaluate and treat more than 100 patients a year. Surgical treatment The only potentially curative treatment for MPM includes extrapleural pneumonectomy (EPP), an extensive surgery that removes the entire lung with the tumor, the pleura, the diaphragm, and the pericardium. The diaphragm and pericardium are reconstructed during the procedure. “If the disease has not spread outside the chest, to the lymph nodes, or into the chest wall and if we determine that the patient can tolerate EPP, then EPP is the best option,” said Dr. Reza Mehran, M.D., a professor in the Department of Thoracic and Cardiovascular Surgery and codirector of the Mesothelioma Program. Determining whether the disease has spread requires careful evaluation; all MPM patients undergo imaging studies with positron emission tomography–computed tomography (PET-CT); endobronchial ultrasound biopsy of mediastinal lymph nodes; mediastinoscopy; and diagnostic laparoscopy of regions that might harbor very small metastases. To undergo EPP, patients must have sufficient pulmonary reserve—that is, they must be able to have a good quality of life with their remaining lung. Their tumor must be resectable (for example, not involving a major blood vessel or other anatomical structure that would preclude surgery), and they also must be able to tolerate the 5-hour procedure and a recovery period that can last several months. And, of course, EPP can be performed only if MPM affects just one lung.
Despite the demands of the surgery itself, postoperative management often is the most difficult part of EPP, Dr. Mehran said. Complications occur in 40% of patients, and 8% die within 30 days of the surgery (including those who die during the procedure). The most dangerous complications are a lack of pulmonary sufficiency, which can be underestimated during the preoperative evaluation or compromised by some unforeseen event during or after the surgery, and pulmonary embolism. A surgical approach to primary treatment that is less favored at M. D. Anderson, according to Dr. Mehran, is pleurectomy/decortication (P/D), in which the surgeons peel away the pleura but leave the lung in place. P/D offers limited local control and, by itself, little chance of a cure because the lung itself is likely involved. If EPP is not an option but the patient is otherwise a surgical candidate, then M. D. Anderson surgeons will consider performing P/D, but only in combination with chemotherapy or radiation therapy to maximize disease control. In fact, said Dr. Mehran, “Surgery by itself, whether EPP or P/D, is not sufficient to cure the disease. You need to have surgery in combination with chemotherapy or radiation therapy to achieve the best results.” Radiation therapy The radiation therapy technique used at M. D. Anderson for MPM is a relatively new method called intensity-modulated radiation therapy (IMRT). IMRT, which uses multiple beams of radiation guided with imaging to deliver cancer-killing doses in the shape of the tumor, is particularly helpful in treating MPM because the disease occurs adjacent to the liver and other radiation-sensitive organs. Owing to its high level of precision, IMRT can kill residual tumor cells that cannot be removed surgically, and its efficacy in MPM has been shown by the changing patterns in disease recurrence. “Before we had IMRT, there was no option for postoperative local control of MPM. Traditional, 2-dimensional radiation therapy techniques are not appropriate because of the risk to surrounding tissues, and therefore most patients would experience local disease recurrence after surgery,” said Zhongxing Liao, M.D., an associate professor in the Division of Radiation Oncology and codirector of the Mesothelioma Program. “Now, distant metastases are more commonly where the disease recurs first. So that means IMRT has been effective at providing local control.” IMRT is not yet considered a standard of care for MPM; the technology has been commercially available for only about a decade and is still not widely used. But Dr. Liao, who helped develop IMRT for MPM therapy, is confident that will soon change. “IMRT is going to be so critical in treating this disease that it can’t be missed,” she said. “It will likely be almost as important as surgery in controlling the primary tumor and hopefully curing it.” Dr. Mehran agreed. “We have shown that when EPP is combined with IMRT, we can control the disease locally very well. But patients often come back with distant metastases. That tells us we still need more effective postoperative systemic chemotherapy, which would help reduce the chance of distant recurrence.” Chemotherapy Among available chemotherapy regimens, a combination of pemetrexed (Alimta) and cisplatin has yielded the best tumor response rates—around 40%. This combination is commonly given to patients who are not surgical candidates, as it provides symptom palliation and is associated with a median overall survival duration of 12 months. As Dr. Mehran said, postoperative systemic chemotherapy has not been proven to be effective at preventing distant metastases or to improve overall survival, but it remains under clinical investigation. Preoperative cisplatin-pemetrexed also has been studied in a large, multi-institutional phase II trial in which M. D. Anderson participated; radiation therapy was given postoperatively. Unfortunately, the median overall survival duration among trial participants was only 16.6 months. A drawback with preoperative systemic chemotherapy is that patients often have disease progression or develop toxicities that make them ineligible for later surgery. Therefore, the use of neoadjuvant chemotherapy is limited and is recommended only in clinical trial settings, Dr. Tsao said.
Clinical trials of novel targeted agents hold the best hope for more effective therapy. One such trial under way at M. D. Anderson uses dasatinib, a tyrosine kinase inhibitor, for both induction and maintenance therapy. Dasatinib, which was effective against MPM cells in the laboratory, interferes with the actions of the Src kinase family, which researchers believe has a role in regulating MPM. In the trial, patients receive 4 weeks’ treatment with dasatinib, followed by EPP or P/D (and sometimes radiation therapy). If imaging and histologic analysis show that the tumor responded to the dasatinib, participants can receive up to another 2 years’ treatment with the drug after definitive surgery. According to Dr. Tsao, dasatinib, an oral pill with limited side effects, is ideal to explore as a maintenance therapy for MPM—all other available chemotherapies are too toxic for long-term administration. Also, this trial is the first to test both initial and long-term response to dasatinib. In addition, researchers are collecting blood, tumor tissue, effusion samples, and platelets at two crucial times—before and after initial therapy—in hopes of identifying new therapeutic targets, such as proteins that cause drug resistance, or markers that predict response to treatment. (Please see Clinical Trials in Malignant Pleural Mesothelioma.) “In many ways, this trial holds significant promise for the future, as it will be the first clinical trial in patients with MPM to attempt neoadjuvant therapy using an oral targeted agent and it sets up a new infrastructure of specimen collection to conduct MPM research in the neoadjuvant setting,” Dr. Tsao said. Another experimental strategy in attacking MPM with chemotherapy is to make the tumor more susceptible to cytotoxic agents by first interfering with proteins that regulate cancer cells’ function or growth. For example, researchers have found that imatinib mesylate (Gleevec), which targets platelet-derived growth factor receptors, can induce increased uptake of cytotoxic chemotherapeutic agents. Imatinib mesylate is now being tested in conjunction with various agents as a front-line therapy for unresectable MPM. While results are preliminary, some patients with very aggressive tumors have experienced significant disease stabilization with regimens that include imatinib mesylate, Dr. Tsao said. AZD2171, another agent that may increase cytotoxic chemotherapy uptake and may also interfere with the tumor’s blood supply, will be tested in a multicenter Southwest Oncology Group trial that will open next year. Palliative treatment Unfortunately, because of the nature of MPM, many patients do require palliative care in lieu of definitive treatment or when primary treatment fails. P/D is commonly used for palliation of tumor bulk—removing tumor tissue reduces pain and shortness of breath, which commonly result from MPM. Other palliative options include talc pleurodesis, in which an infusion of talc into the pleura initiates a foreign-body reaction that closes off the cavity, preventing fluid accumulation; and the installation of a permanent chest drain. Still, Dr. Tsao stresses that such techniques should be used as a last resort and that careful staging and evaluation of patients for potentially curative surgical options should be made at facilities that are familiar with treating MPM. “Many people don’t know that there are effective therapies for MPM, and so some patients who may benefit from curative treatment don’t receive those therapies,” Dr. Tsao said. “All MPM patients should know about the best treatments that we have available today and should consider enrolling in clinical trials that hold the best hope for the future.” For more information, call Dr. Tsao at 713-792-6363 or visit http://www.mdanderson.org/diseases/mesothelioma. Other articles in OncoLog, November 2008 issue:
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