ASCO Guideline on Malignant Pleural Mesothelioma Calls for Subtyping, Clinical Trial Enrollment

ASCO Guideline on Malignant Pleural Mesothelioma Calls for Subtyping, Clinical Trial Enrollment

Dr. Raffit Hassan
Dr. Hedy Lee Kindler
ASCO recently released a new Clinical Practice Guideline on the management of malignant pleural mesothelioma.1 Malignant pleural mesothelioma is a rare cancer that begins in the pleural lining surrounding the lungs and affects approximately 3,000 people each year in the United States.1

“This disease is difficult to treat, and because of that patients have a poor prognosis with a median survival of about 12 months,” Raffit Hassan, MD, guideline co-chair, said. Dr. Hassan is also co-chief of the Thoracic and Gastrointestinal Oncology Branch at the National Cancer Institute.

Due to its rarity, many oncologists may see only one or two cases of mesothelioma each year.

“Because this disease is so uncommon, there are very few randomized trials,” Hedy Lee Kindler, MD, director of the Mesothelioma Program at the University of Chicago Medicine and guideline co-chair, said. “This guideline is the most authoritative compilation of the best evidence-based treatment algorithms for this disease that has been compiled anywhere.”

Evidence Review

To develop the guideline, ASCO convened an Expert Panel in medical oncology, thoracic surgery, radiation oncology, pulmonary oncology, pathology, imaging, and advocacy. A literature search of studies published between 1990 and 2017 was conducted. The search identified 222 relevant studies, including systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies, which were used to inform the guideline.

Using this evidence, the panel put forth more than 60 recommendations covering the diagnosis and staging of the disease, chemotherapy, surgical cytoreduction, and radiotherapy.

Dr. Hassan and Dr. Kindler agreed that one of the most important recommendations in the guideline is that mesothelioma should be reported as epithelial, sarcomatoid, or biphasic, because each disease subtype has a clear prognostic significance. The majority of patients with mesothelioma will have epithelial histology, which may grow more slowly and be more responsive to chemotherapy. According to Cancer.Net, between 7% and 15% of people diagnosed with mesothelioma will have the sarcomatoid subtype, which is generally more resistant to treatment. Mixed or biphasic mesothelioma, which occurs in 10% to 20% of patients, contains both epithelial and sarcomatoid types.

“Patients with sarcomatoid histology have a much shorter survival than the other subtypes, fail to benefit from surgery, and are less likely to respond to systemic therapy,” the guideline states. “Biphasic tumors have an intermediate prognosis between epithelial and sarcomatoid.”

“That means that it is essential to obtain a large enough sample to differentiate the pathologic subtype of the disease. The pathologist should not just call the diagnosis ‘malignant mesothelioma’ without specifying the subtype,” Dr. Kindler said.

The guideline also discusses the importance of taking an optimal approach to mesothelioma measurement using modified RECIST for mesothelioma criteria.

“Mesothelioma is a disease with very irregular borders that can be quite difficult to measure reproducibly,” Dr. Kindler said. “The standard modified RECIST for mesothelioma criteria uses the sum of up to six sites, measured perpendicular to the chest wall, to make that determination.”

Modified RECIST for mesothelioma requires calculating the sum of up to six measurement sites with at least 1 cm thickness measured perpendicular to the chest wall or mediastinum with no more than two sites on each of three CT sections separated by at least 1 cm axially.

“If done methodically, one can more accurately follow the disease over time,” Dr. Kindler said.

Treatment

In selected patients diagnosed with early-stage disease, the guideline strongly recommends maximal surgical cytoreduction. Lung-sparing options such as pleurectomy/decortication or extended pleurectomy/decortication should be the first choice because of the decreased operative and long-term risk to the patient.

However, maximal surgical cytoreduction as a single modality treatment is generally insufficient, according to the guideline. Additional antineoplastic treatment including chemotherapy and/or radiotherapy should be administered.

“Chemotherapy has been shown to improve survival and quality of life, and it should be offered to most patients with mesothelioma,” Dr. Kindler said. The current standard of care for malignant pleural mesothelioma is pemetrexed plus platinum.

“Bevacizumab may also be added to pemetrexed-based chemotherapy and does improve survival in selected patients who have no contraindications to its use,” Dr. Kindler said.

The guideline specifies that, “given the high frequency of cardiovascular comorbidity and hypertension among patients with malignant pleural mesothelioma, however, it is important to carefully select patients who might benefit from the addition of bevacizumab to chemotherapy.”

“In addition, retreatment with pemetrexed-based chemotherapy may be offered to patients with durable disease control after first-line pemetrexed,” Dr. Kindler added.

However, given the limited activity of second-line chemotherapy in patients with mesothelioma, it is recommended that enrollment into clinical trials be made available to all patients whose disease recurs.

“Clearly, the standard of care is not yet good enough,” Dr. Kindler said.

Radiotherapy

The guideline also addresses several issues related to the use of radiotherapy in patients with mesothelioma.

According to Dr. Kindler, although these tumors often track through sites of intervention, prophylactic irradiation of intervention tracts should generally not be offered to prevent these recurrences. However, adjuvant radiation should be offered to patients who have resection of intervention tracts found to be histologically positive.

The guideline also discusses the most relevant and up-to-date data on adjuvant and palliative radiation. 

Future Directions

“ASCO’s process for developing these guidelines is robust and incredibly thorough,” Dr. Kindler said. “This guideline should serve as a standard for defining the treatment of malignant pleural mesothelioma.”

According to the guideline, there have been significant, recent advances in understanding the biology of mesothelioma and identifying new targets for therapy.

“Ongoing clinical trials suggest promising activity of several new agents in malignant pleural mesothelioma, but they are not sufficiently mature to make treatment recommendations,” the guideline states. “These include clinical trials of mesothelin-targeted agents as well as antibodies against the immune checkpoints PD-1/PD-L1 and CTLA-4. Given the rarity of this disease, large randomized international clinical trials are vital to fully define the role of novel therapeutic drugs for the management of patients with malignant pleural mesothelioma.” 

–Leah Lawrence