Malignant pleural mesothelioma (MPM) is an aggressive cancer that is somewhat rare, with only approximately 3,000 new diagnoses each year in the U.S. MPM is a disease that affects the pleural lining of the chest walls and lungs; however, mesotheliomas can also occur in the peritoneum or the pericardium. The main risk factor for contracting MPM is exposure to asbestos fibers.
Patients with MPM have a 5-year survival rate of approximately 5-10 percent. One reason for this low survival rate is the fact that in many instances, a proper diagnosis of MPM is not given until the patient is at an advanced disease stage. The symptoms for MPM, which include chest pain, coughing, shortness of breath, fatigue, and unwanted weight loss, are somewhat vague and often mirror those for a number of other ailments. Once a patient receives an MPM diagnosis, there are a number of treatment options available to them, including chemotherapy, radiation therapy, surgery, or a combination of these.
Although there have been some clinical trials that have focused on the treatment of MPM, there is a dearth of real-world data on the treatment patterns for MPM patients. To gain further insight into this patient population, Marjorie G. Zauderer, MD, MS, Co-Director, Mesothelioma Program, Memorial Sloan Kettering Cancer Center, New York City, and colleagues conducted a retrospective trial that sought to evaluate comorbidities, patterns of referrals, treatments, and resource utilization in U.S.-based MPM patients. Their findings were presented at the 2017 ASCO Annual Meeting (Abstract 8554).
MPM Treatment Options
There are a few surgical options for MPM patients. One of the more extensive techniques is extrapleural pneumonectomy, in which the entire lung on the side of the cancer and many of the surrounding tissues are removed. A less radical procedure is pleurectomy/decortication (P/D), in which the pleural lining covering the chest wall and the lung on the affected side, as well as the linings of mediastinum and the diaphragm, are all removed. Another procedure is the partial pleurectomy, in which as much of the mesothelioma is removed as possible. This last technique is even less extensive than P/D, as more unaffected tissue is not removed.
Since the early 2000s, the standard chemotherapy regimen for MPM has been cisplatin-pemetrexed doublet therapy, largely based on the results obtained in a phase III trial that evaluated the use of cisplatin alone or in combination with the antifolate pemetrexed (J Clin Oncol 2003;21:2636-2644). In that study, chemotherapy-naïve MPM patients who were not eligible for curative surgery were randomized in an approximately 1:1 ratio to receive either 75 mg/m2 cisplatin (day 1, i.v.; q3w) or 75 mg/m2 cisplatin plus 500 mg/m2 pemetrexed (day 1, i.v.; q3w). Analysis showed patients in the cisplatin/pemetrexed arm had a median overall survival of 12.1 months, as compared to 9.3 months for those in the cisplatin monotherapy arm. Subsequently, in February 2004, the FDA approved the use of cisplatin/pemetrexed for MPM patients with unresectable disease or who are not candidates for curative surgery.
Recently, the vascular endothelial growth factor (VEGF)-targeting monoclonal antibody bevacizumab has begun to be used in combination with pemetrexed or platinum-based chemotherapy regimens. A phase III French trial evaluated the use of cisplatin/pemetrexed (PC arm) versus bevacizumab/cisplatin/pemetrexed (PCB arm) (The Lancet 2016;387;1405-1414). These researchers found there was a significantly longer median OS associated with the PCB arm (18.8 months) than for the PC arm (16.1 months). Based on that data, the investigators concluded that the addition of bevacizumab to cisplatin/pemetrexed should be considered as a reasonable treatment for MPM.
In this study, the MarketScan insurance claims database was used to identify patients who were 18 or older with a MPM diagnosis between January 2004 and December 2015. Among the key inclusion criteria were a valid MPM diagnosis, a diagnosis code of “malignant neoplasm of the pleural,” two claims in the database at least 1 week apart, and data for 1 year prior to and a minimum of 3 months after the diagnosis index date. Key exclusion criteria were diagnosis with non-MPM cancer (except lung cancer), an additional diagnosis of MPM within 1 year before the index date, non-pleural mesothelioma, and enrollment in a clinical trial.
When asked why the retrospective study utilized an insurance claims database instead of the National Cancer Database, Zauderer replied, “By using the insurance claims database, we were able to get a clearer picture of a patient's history before their MPM diagnosis. For example, during the pre-diagnosis baseline period, we could see what comorbidities were present, what diagnoses were given prior to the one for MPM, how long the MPM diagnosis took, as well as track the patient's referral pathway. In the follow-up period after the index date, we could track a patient's treatment patterns as well as their health resource utilization.”
There were 1,869 patients included in this study, with a median age of 71 years (range—61-79 years). Of these, 65.4 percent were male and 34.6 percent were female. Geographically, the largest number of patients came from the North Central part of the U.S. (n = 714, 38.2%) followed by the South (n = 578, 30.9%). Additionally, 692 patients (37.0%) were included in the commercial portion of the database and 1,177 (63.0%) were included in the Medicare portion of the database.
The comorbidities most frequently noted during the baseline period (pre-diagnosis index date) included chronic pulmonary disease (20.7%), metastatic solid tumor (17.5%, a majority of which were ‘secondary malignant neoplasm of the pleura’), and diabetes (15.4%).
Across the full analysis time frame (2004-2015), radical surgery was utilized by only 4.1 percent of all MPM patients in this study and, of those, 43 (55.8%) underwent radiation therapy and 21 (27.3%) received chemotherapy within 90 days.
Of the patients who did not undergo radical surgery, 15.6 percent received first-line chemotherapy within 90 days, 33.2 percent received radiation therapy plus first-line chemotherapy, 11.7 percent received only radiation therapy, and 39.5 percent did not receive radiation or chemotherapy. As first-line chemotherapies, the two most commonly-used were carboplatin/pemetrexed (11.2%) and cisplatin/pemetrexed (10.9%). Interestingly, more than half of the patients included in this study (51.2%) had no chemotherapy.
To gauge the recent trends in therapies for MPM, the entire analysis period was split into two segments—2004-2009 and 2010-2015. When done like this, clear trends emerge regarding the treatments utilized. For example, those patients having radical surgery fell to 2.6 percent in 2010-2015 from 5.8 percent in 2004-2009. Similarly, the use of radiation therapy decreased from 14.0 percent in 2004-2009 to 9.7 percent in 2010-2015. Conversely, there was an increase in the use of chemotherapy among those patients not undergoing radical surgery; that usage rose from 45.3 percent in 2004-2009 to 51.9 percent in 2010-2015. Additionally, the use of bevacizumab in combination with pemetrexed or platinum-based therapies increased from 3.4 percent in 2004-2009 to 4.5 percent from 2010 to 2015.
Of the patients who did not undergo radical surgery, 99.8 percent had an outpatient doctor visit and 77.3 percent required hospitalization. Overall, 73.4 percent of patients required an ER visit during follow-up; in 51.2 percent of these cases, that visit was a result of lung-related issues and in 12.0 percent of the cases, a MPM-related emergency.
When results for health care resource utilization are dichotomized into the same 2004-2009 and 2010-2015 time frames used for treatments, some trends are easily seen. The number of ER visits increased from 54.3 percent of patients in 2004-2009 to 62.4 percent of patients in 2010-2015. However, the proportion of patients requiring hospitalizations decreased from 80.2 percent (669 of 835 patients) in 2004-2009 to 74.9 percent (717 of 957 patients) in 2010-2015.
For 45.2 percent of the patients in this study, their first lung-related baseline visit was with their primary care physician. The most common diagnoses delivered at first lung-related visits included pleural effusion (16.6%), chest pain (10.7%), shortness of breath (9.6%), and cough (8.5%). The median time between first lung-related visit and MPM diagnosis was 77 days, with times ranging from 23 days to 258 days. For most patients, a correct diagnosis of MPM was obtained after visits to two distinct health care providers.
In addressing some of the difficulties diagnosing MPM, Zauderer had the following observations: “In many instances, the most common symptom is pleural effusion, often a benign condition and, as a consequence, patients are often treated for an infection. Further complicating the diagnosis of MPM is the fact that few if any malignant cells are present in the fluid drained from the pleural cavity.”
When asked about recent trends in treatment, Zauderer noted, “There has been an increase in the use of the monoclonal antibody bevacizumab in combinations with pemetrexed and/or platinum-based therapies. At the same time, there have been decreases in the use of radiotherapy and radical surgery. Particularly in the case of surgery, there definitely seems to be a geographical component to this factor; some regions favor a radical pneumonectomy, in which the entire lung is removed, while in other regions, less extensive pleurectomies, which entails removal of the lining and affected portions of the lungs, are more frequently utilized.
“There were a number of surprises in reviewing this data,” Zauderer noted. “We were surprised to note that over the entire analysis period more than half of the patients received no chemotherapy. While we were not surprised by the number of referrals to pulmonologists, we did not expect so many different specialists to be involved in an individual's MPM diagnosis.”
In discussing the large amount of patients having had no chemotherapy, Zauderer explained, “In many instances, because when a diagnosis is made the patient's disease is at an advanced stage, there is a sort of nihilism with regards to treatment at that point; patients are also reluctant to endure the significant side effects that often accompany chemotherapy.
“A significant problem with this disease is the delay that often occurs in properly diagnosing it. This is not a frequently-encountered disease; its symptoms often mimic those of benign conditions, and additionally, the fluid which is drained from pleural effusion has few, if any cancer cells present for identification. More scrutiny should be given to those patients having recurrent pleural effusions.”
Richard Simoneaux is a contributing writer.