By Hedy L. Kindler, MD
The American Society of Clinical Oncology (ASCO) has issued its first-ever clinical practice guidelines on the management of patients with malignant pleural mesothelioma (MPM), based on a systematic review of the medical literature.1 This comprehensive guideline consists of 63 recommendations on the diagnosis, staging, chemotherapy treatment, surgical cytoreduction, and radiotherapy treatment of MPM.
The ASCO mesothelioma guidelines were developed by a multidisciplinary expert panel, co-chaired by myself and Raffit Hassan, MD, with experts in medical oncology, thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy. The panel conducted a literature search that included systematic reviews, meta-analyses, and randomized controlled trials, as well as prospective and retrospective comparative observational studies published from 1990 through 2017. Some phase II studies were also included to address clinical questions for chemotherapy management. The 222 studies identified comprised the evidentiary basis for the guideline recommendations. These recommendations were crafted, in part, using the Guidelines Into Decision Support (GLIDES) methodology and accompanying BridgeWiz software.2 Ratings for the type and strength of recommendation and evidence quality were provided with each recommendation.
Five overarching clinical questions relevant to the management of patients with MPM were addressed:
- What is the optimal approach to obtain an accurate diagnosis?
- What initial assessment is recommended before initiating therapy?
- What is the appropriate first and second-line systemic treatment?
- What is the appropriate role of surgical cytoreduction?
- When should radiation be recommended?
Panel Recommendations and Insights
The panel emphasized that mesothelioma should always be reported as epithelial, sarcomatoid, or biphasic because these subtypes have a clear prognostic signifi-cancer. Thus, for patients in whom antineoplastic treatment is planned, a thoracoscopic biopsy is recommended to allow for histologic confirmation of diagnosis and to enable more accurate determination of the pathologic subtype. Cytologic evaluation of pleural fluid is not considered sufficiently sensitive. It was recommended that histologic examination be supplemented by immunohistochemistry using selected markers expected to be positive or negative in MPM, along with other markers that address the differential diagnosis.
The panel recommended a CT scan of the chest and upper abdomen with intravenous contrast for initial staging and a PET/CT for those being considered for surgery. The indications for additional staging procedures including dedicated abdominal imaging, mediastinoscopy, endobronchial ultrasound, contralateral thoracoscopy, and laparoscopy were reviewed. Identifying measurement sites on CT per modified RECIST for mesothelioma3 was deemed the optimal approach to tumor measurement.
The guideline panel recommended that chemotherapy be offered to patients with MPM because it improves survival and quality of life. However, in asymptomatic patients with epithelial MPM and a low disease burden who are not surgical candidates, a trial of expectant observation may be an initial option. In the absence of a clinical trial, pemetrexed plus platinum-based chemotherapy is the recommended first-line treatment, and bevacizumab may be added if there are no contraindications. For those unable to tolerate cisplatin, carboplatin may be substituted. Retreatment with pemetrexed-based chemotherapy may be offered if durable disease control with first-line therapy is achieved. Pemetrexed maintenance was not recommended due to insufficient evidence to support its use. Given the very limited activity of second-line chemotherapy, participation in clinical trials was encouraged.
The surgical recommendations addressed selected patients with early-stage disease who should be considered for maximal surgical cytoreduction and those who should not (including patients with sarcomatoid histology). Lung-sparing surgery (such as extended pleurectomy/decortication) was deemed the first choice due to decreased operative and long-term risk, whereas extrapleural pneumonectomy could be offered to highly selected patients at centers of excellence. Because surgical cytoreduction is not expected to yield an R0 resection, multimodality therapy with pre or postoperative chemotherapy and/or radiation was advised.
The panel recommended that prophylactic irradiation of intervention tracts should not generally be offered to prevent tract recurrences, unless resected tracts were histologically positive. Radiation therapy was considered effective for palliation of symptoms. Adjuvant radiation could be offered to patients who underwent maximal cytoreduction, as it might be associated with a decreased local recurrence risk; this complex treatment approach should be confined to experienced centers of excellence.
It is hoped that these ASCO recommendations and the accompanying comprehensive literature review will enable more optimal treatment of patients with this relatively uncommon malignancy. ✦
About the Author: Dr. Kindler is a professor of medicine in the Section of Hematology/ Oncology, University of Chicago.
1. Kindler HL, Ismaila N, Armato S, et al. Treatment of malignant pleural mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(13):1343-1373.
2. Shiffman RN, Michel G, Rosenfeld RM, Davidson C. Building better guidelines with BRIDGEWiz: development and evaluation of a software assistant to promote clarity, transparency, and implementability. J Am Med Inform Assoc. 2012;19(1):94-101.
3. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol. 2004;15(2):257-260.
Perspective: Patient Care in Egypt
By C.A.I.R.O Journal Club Executive Board
The one thing we know for sure about MPM is that very little is known about this disease entity. This malignancy poses a major challenge to thoracic oncologists because of limited effective treatment options. The incidence of MPM in Egypt is one of the highest in the world, and the incidence rate is rapidly increasing.1
We believe that the general approach of the ASCO recommendations does not apply well to low-resource settings like Egypt. First, some practice settings in Egypt lack expert pathologists who can confidently establish a MPM diagnosis. In addition, some recommended systemic therapies are not reimbursed by public health insurance in Egypt. Moreover, the clinical and epidemiologic characteristics of patients with MPM in Egypt are a bit different from Western countries; thus, clinicians in Egypt must tailor these recommendations wisely for patients with MPM. We believe that one of the priorities of MPM management in Egypt should include establishing a strong awareness program for both patients and general physicians, which might help with diagnosing MPM at an earlier stage and better performance status, thereby enabling patients to benefit more from complex multimodal treatment strategies. Moreover, designing nationwide clinical trials that focus on innovative approaches for early diagnosis and better treatment is essential for optimizing care of patients with MPM in Egypt.
1. Gaafar RM, Eldin NH. Epidemic of mesothelioma in Egypt. Lung Cancer. 2005;49 Suppl 1:S17-20.
Perspective: Patient Care in Europe
The 2018 ASCO guidelines for MPM are the first guideline this year to give a clear overview of the latest developments in the field. Compared to the MPM guidelines published by the European Respiratory Society and the European Society of Thoracic Surgeons in 20101 and those published by the European Society for Medical Oncology in 2015,2 there are some differences.
Regarding the diagnosis of MPM, the European guidelines underscore the need for a tissue biopsy, which is not a focus of the ASCO guideline. This is partly because of the requirements for reimbursement for asbestos victims, which vary by country. The ASCO guidelines correctly focus in depth on the genomic sequencing data, and they state that some mutations can be found in higher incidence in MPM (i.e., BAP1, TP53, NF2, and SETD2). The major differences in guidelines are related to the ASCO recommendation of the use of surgical resections, whereas the European guidelines recommend a stricter approach because of the lack of phase III data showing an OS benefit to surgery. It is not expected that the rate of surgical resections for MPM in Europe will be altered by the ASCO guidelines.
Considering all the new guidelines in this era of immuno-oncology, it is unfortunate that no randomized studies have yet been reported.
The guidelines from the British Thoracic Oncology Group and the European Respiratory Society will be published soon.
1. Scherpereel A, Astoul P, Baas P, et al. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J. 2010;35(3):479-495.
2. Baas P, Fennell D, Kerr KM, et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep;26 Suppl 5:v31-39.
About the Author: Dr. Baas is a professor of Thoracic Malignancies and chief of the department of Thoracic Oncology of the Netherlands Cancer Institute, Amsterdam.
Perspective: Patient Care in China
By Renhua Guo, MD
The ASCO guideline provides clinicians in China with detailed methods for diagnosis of MPM including thoracentesis, core needle biopsy, or thoracoscopic biopsy. These recommendations are both practical and affordable.
Regarding treatment, chemotherapy has been shown to improve patient survival and quality of life. The recommended first-line chemotherapy for patients with mesothelioma is pemetrexed plus platinum. Only vinorelbine is offered in the guidelines as second-line therapy, but is this the only option? Is maintenance therapy required for patients with a performance status of 0 to 2 and either partial response or stable disease? For a few of the patients with MPM whom I have treated, pemetrexed plus a platinum agent was used as first-line therapy followed by second-line chemotherapy with gemcitabine plus Endostar (a recombinant human endostatin). Patients with partial response and/or stable disease were offered maintenance treatment. One patient, who presented with advanced disease, has survived more than 9 years without recurrence.
The overall treatment response for patients with MPM remains poor. Whether the tumor genome has been sequenced, the related driver genes/mutations and the tumor mutation burden are poorly understood.
About the Author: Dr. Guo is deputy director of the Department of Oncology at the Hospital of Nanjing Medical University (Jiangsu Provincial People’s Hospital).
By Dr. Jiuwei Cui
MPM is rare but highly aggressive malignancy associated with asbestos exposure. Its incidence has peaked in the United States and will continue to increase over the next few decades in Asia, due to ongoing asbestos exposure in many countries and a long latency period. Given the rarity of this malignancy, there are relatively few reports on treatment of patients with MPM in Asia. The recently released ASCO guidelines should provide updated evidence-based therapeutic options and provoke awareness among the public to improve the care quality of the patients with MPM in Asia, as well as in other countries in which MPM incidence is increasing.
The guideline will help clinicians in China to inform patients about appropriate treatment options and to protect them from potentially harmful or useless therapies on an individual basis. It also calls for more clinical trials to test new treatment technologies, as well as improved patient communication regarding participation in these trials. Future management of MPM will emphasize both locoregional and systemic control. Therefore, inclusion of patients in clinical trials evaluating multimodality treatment should be encouraged. In addition, multinational cooperation regarding translational research is essential to obtain meaningful answers regarding unsolved questions in a timely manner.
About the Author: Dr. Cui is chief, Cancer Center, the First Hospital of Jilin University.