NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016

These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.

Abstract

These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.

NCCN: Continuing Education

Accreditation Statement

This activity has been designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-16-007-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/79123; and 4) view/print certificate.

Release date: July 10, 2016; Expiration date: July 10, 2017

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to NCCN Guidelines for Malignant Pleural Mesothelioma

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Malignant Pleural Mesothelioma

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NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016

Version 3.2016 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 7; 10.6004/jnccn.2016.0087

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Mesothelioma is a rare cancer that is estimated to occur in approximately 2,500 people in the United States every year.1,2 These NCCN Guidelines Insights focus on malignant pleural mesothelioma (MPM), which is the most common type; mesothelioma can also occur in the lining of other sites, such as the peritoneum, pericardium, and tunica vaginalis testis. Histologic subtypes of mesothelioma include epithelioid (most common), sarcomatoid, and biphasic (mixed) epithelioid and sarcomatoid (see MPM-2, above).24 Patients with epithelioid histology have better outcomes than those with either sarcomatoid or biphasic (mixed) histologies. MPM is difficult to treat, because most patients have pleural dissemination at presentation. Median overall survival for MPM is approximately 1 year; cure is rare.57 MPM occurs mainly in older men (median age at diagnosis, 72 years) who have been exposed to asbestos, although it occurs decades after exposure (20–40 years

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NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016

Version 3.2016 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 7; 10.6004/jnccn.2016.0087

later).810 Reports of MPM have also been described following radiation therapy (RT) for other malignancies, including breast cancer and Hodgkin lymphoma.1113 Patients with suspected MPM often have dyspnea and chest pain; they may also have pleural effusion, fatigue, insomnia, cough, chest wall mass, loss of appetite, and weight loss.1416 Patients with MPM often have a high symptom burden; therefore, supportive care is important for patients, especially management of pleural effusions.14,1721 A phase III randomized trial is currently assessing whether early palliative care will improve survival in patients with MPM.22 The NCCN panel recommends palliative RT for chest pain, bronchial or esophageal obstruction, or other symptomatic sites (see MPM-D, pages 830 and 831).14,23,24

The NCCN Guidelines recommend that patients with MPM be managed by a multidisciplinary team with experience in MPM. Treatment options for patients with MPM include surgery, RT, and/or chemotherapy2; select patients with clinical stages I–III disease who are medically operable and have good performance status (PS) are candidates for multimodality therapy.2529 These NCCN Guidelines Insights focus on systemic therapy regimens and surgical controversies for MPM. Surgery for MPM is controversial, because sufficient data from randomized controlled trials are limited.14,3033 Some surgical procedures, such as extrapleural pneumonectomy (EPP), are associated with greater morbidity than others, such as pleurectomy/decortication (P/D); therefore, EPP is are not recommended for patients with MPM who have sarcomatoid histology. When comparing EPP with P/D, it is not clear which surgical procedure will yield better oncologic outcomes.14

Systemic Therapy

Many patients with MPM receive systemic therapy either alone or as part of multimodality therapy. Because most patients present with unresectable or medically inoperable MPM, they are not candidates for surgery, although a board-certified thoracic surgeon with experience

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NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016

Version 3.2016 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 7; 10.6004/jnccn.2016.0087

in multimodality mesothelioma management should make the decision regarding resectability (see “Surgery,” page 831). The NCCN Guidelines currently recommend 4 combination systemic therapy options for patients with MPM, depending on clinical characteristics such as PS, histology, and whether patients are medically operable or inoperable. Three of the combination regimens are recommended as first-line therapy options for patients with unresectable clinical stage IV, sarcomatoid histology, or medically inoperable MPM or for those who refuse surgery (see MPM-B, page 828). The 3 combination regimens include (1) cisplatin/pemetrexed (category 1), (2) carboplatin/pemetrexed, and (3) cisplatin/gemcitabine.3445 Pemetrexed-based regimens are typically used, with gemcitabine recommended only for patients who cannot receive pemetrexed. These 3 combination regimens can also be used as adjuvant therapy for patients as part of multimodality therapy.46 Several regimens can also be used as induction therapy as part of a modality regimen, including cisplatin/pemetrexed.46 The fourth combination regimen is bevacizumab/cisplatin/pemetrexed, which is only recommended for patients with unresectable disease and should only be considered for patients who are candidates to receive bevacizumab.47 For patients with clinical stage IV MPM, sarcomatoid histology, or medically inoperable MPM who are asymptomatic and have a minimal burden of disease, observation may be considered if chemotherapy is planned at the time of symptomatic or radiographic progression (see MPM-2, page 827).48,49 Best supportive care is recommended for patients with PS 3 to 4 who have clinical stage IV MPM, sarcomatoid histology, or medically inoperable MPM.

The NCCN panel recommends cisplatin/pemetrexed (category 1) based on a phase III randomized trial and FDA approval.50 The phase III trial assessed cisplatin/pemetrexed versus cisplatin alone in patients who were not candidates for surgery; the combined regimen increased survival by 2.8 months

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NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016

Version 3.2016 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 7; 10.6004/jnccn.2016.0087

compared with cisplatin alone (12.1 vs 9.3 months; P=.02). Patients receiving cisplatin/pemetrexed had less pain and dyspnea than those receiving cisplatin alone. Other recommended first-line combination chemotherapy options include (1) pemetrexed/carboplatin, which was assessed in 3 large phase II studies (median survival, 12.7, 14, and 14 months, respectively) and a large expanded access nonrandomized study34,5153; or (2) gemcitabine/cisplatin, which was assessed in phase II studies (median survival, 9.6–14.7 months).35,36,40,54,55 The carboplatin/pemetrexed regimen is a better choice for patients with poor PS or comorbidities.51 Gemcitabine/cisplatin is only recommended for patients who cannot take pemetrexed. First-line single-agent options include pemetrexed or vinorelbine, which are recommended only for patients who cannot receive platinum-doublet therapy.48,56,57 New agents are being assessed in the frontline setting for MPM.43,5861

A recent multicenter phase III randomized trial assessed the addition of bevacizumab to cisplatin/pemetrexed (with maintenance bevacizumab) compared with cisplatin/pemetrexed alone for patients 75 years of age or younger with unresectable MPM and PS 0 to 2 who did not have significant cardiovascular history, including history of stroke or transient ischemic attack.47 Most patients (97%) were PS 0 to 1. Overall survival was increased in the bevacizumab plus chemotherapy arm by 2.7 months when compared with chemotherapy alone: bevacizumab triplet arm (median, 18.8 months; 95% CI, 15.9–22.6) compared with cisplatin/pemetrexed (16.1 months; 95% CI, 14.0–17.9; hazard ratio, 0.77; 95% CI, 0.62–0.95; P=.0167). Grade 3 to 4 adverse events were reported in 71% of patients (158 of 222) receiving the bevacizumab regimen when compared with 62% (139 of 224) of those receiving cisplatin/pemetrexed alone. More grade 3 or higher hypertension (23% vs 0%), grade 3 proteinuria (3.1% vs 0%), and grade 3 to 4

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NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016

Version 3.2016 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 7; 10.6004/jnccn.2016.0087

thrombotic events (6% vs 1%) were observed in patients receiving the triplet arm. Based on this trial, the NCCN panel added a recommendation (category 2A) in 2015 (Version 2) for the bevacizumab/cisplatin/pemetrexed regimen.

Recommended second-line chemotherapy options include pemetrexed (if not administered first-line) (category 1), vinorelbine, or gemcitabine (see MPM-B, page 828).57,58,6267 If patients experienced a good response to first-line pemetrexed, data suggest that repeating pemetrexed is effective, especially in those who achieved a treatment-free interval of at least 3 months.58,6870 Several agents are in clinical trials.58,61,68,7173 Preliminary data suggest that immune checkpoint inhibitors and agents targeting mesothelin may be useful in MPM.7479

Surgery

For patients with MPM, the goals of surgery may differ depending on the needs of the patient. Surgery will be recommended in select patients with good PS and epithelioid or mixed histology if a complete gross cytoreduction can be achieved, with the goal to increase survival.46,80 However, palliative surgery and/or RT may be recommended to relieve pain, free a trapped lung, decrease pleural effusions, and/or improve respiration.14 As previously mentioned, most patients with MPM are not candidates for surgery because they present with unresectable or medically inoperable disease. Board-certified thoracic surgeons with expertise in managing MPM should decide whether a patient has unresectable or resectable MPM and should perform the surgical resection if indicated. Surgery is not usually recommended for patients with anticipated short-term survival and/or at high risk of morbidity and mortality, poor PS, or comorbidities, as well as unfavorable oncologic outcomes due to unfavorable histology such as sarcomatoid.5,8183 The NCCN Guidelines do not recommend surgery for patients with clinical stage IV MPM who have locally advanced unresectable tumors (T4), N3 disease, and/or distant metastases (see Table 1 in the complete version of these guidelines, available at NCCN.org). In addition, patients with N2 disease, mixed histology, or sarcomatoid histology should not routinely be resected outside of a clinical trial and in a center with MPM experience (see MPM-C, page 829).

Surgical resection for patients with MPM can include either P/D (also known as total pleurectomy or lung-sparing surgery), which is complete removal of the involved pleura and all gross tumor, or EPP, which is en bloc resection of the involved pleura, lung, ipsilateral diaphragm, and often the pericardium.84 Extended P/D refers to the resection of the diaphragm and pericardium in addition to total pleurectomy.84 Mediastinal nodal dissection is recommended in patients with either P/D or EPP; at least 3 nodal stations should be obtained.

Trimodality therapy—chemotherapy, EPP, and hemithoracic RT—has been shown to benefit select patients with epithelioid histology, good PS, and low-volume disease on the basis of single-arm phase II studies at centers with experience.14,2528,46 Median survival of up to 20 to 29 months has been reported for patients who complete trimodality therapy.26,46 Lung-sparing options, such as P/D, decrease the risk for perioperative mortality and yield either equal or better long-term survival than nonsurgical therapy in patients with more advanced disease.85,86 However, the choice of surgery for MPM is controversial, because data from randomized controlled trials are not available.14,3033

A retrospective analysis (n=663) suggested that survival was greater after P/D than EPP, but this may have been confounded by patient selection.2,80 A recent meta-analysis suggested a trend in favor of overall survival for extended PD when compared with EPP.30 The Mesothelioma and Radical Surgery (MARS) trial assessed whether patients treated with induction chemotherapy would accept randomization either to EPP with hemithoracic radiation or to no further treatment; 112 were patients enrolled in the trial, and 50 patients were randomized.87 In this trial, overall 30-day mortality was 18.7% (3 of 16 patients). Median survival was 14.4 months in the EPP arm and 19.5 months in the no-EPP arm. The authors concluded that EPP was not beneficial because of the high rate of surgical mortality when compared with chemotherapy alone treatment. However, these results were controversial because survival was not the primary outcome of the study, the sample size was small, and the surgical mortality was higher than expected.88

Neither P/D nor EPP will achieve an R0 resection2,85,89; it is not clear which surgical procedure will yield better oncologic outcomes.14 When compared with P/D, EPP is associated with more morbidity and more short-term mortality.30,9092 Some surgeons prefer to use P/D, because they feel it is a safer procedure.33,80,90,9397 Some surgeons mainly use P/D for palliation.14

The surgical goal for MPM is cytoreductive surgery to achieve macroscopic complete resection by removing all visible or palpable tumors.84,98,99 If macroscopic complete resection is not possible, such as in patients with multiple sites of chest wall invasion, then surgery should be aborted. However, to help with postoperative management, surgery should be continued if most of the gross disease can be removed and if there will be a minimal impact on morbidity (see MPM-C, page 829). The NCCN panel feels that P/D and EPP are both reasonable surgical options that should be considered in select patients to achieve complete gross cytoreduction.30,80,87,91,100 For patients having surgery, either preoperative chemotherapy or postoperative chemotherapy (with or without adjuvant hemithoracic RT, depending on which surgical procedure is used) is recommended in the NCCN Guidelines.14,46 Surgical procedures can also be done to obtain diagnostic samples and to provide palliative benefit.14 Palliative surgical procedures include pleurodesis to decrease pleural effusions and P/D to debulk the tumor with the goals of relieving pain and decreasing pleural effusions.14,20,101 Video-assisted thoracic surgery (VATS) has a diagnostic role and a palliative role (eg, pleurodesis) in patients with MPM, but it is not an accepted technique for P/D.84

Summary

These NCCN Guidelines Insights discuss surgical controversies and systemic therapy regimens for MPM. The NCCN Guidelines recommend that patients with MPM be managed by a multidisciplinary team with experience in MPM. Patients with suspected MPM often have dyspnea and chest pain; they may also have pleural effusion, fatigue, insomnia, cough, chest wall mass, loss of appetite, and weight loss. Patients with MPM often have a high symptom burden; therefore, supportive care is important for patients, especially management of pleural effusions. The NCCN panel recommends palliative RT for chest pain, bronchial or esophageal obstruction, or other symptomatic sites. Treatment options for patients with MPM include surgery, RT, and/or chemotherapy; select patients with clinical stages I to III disease who are medically operable and have good PS are candidates for multimodality therapy. Board-certified thoracic surgeons with expertise in managing MPM should decide whether a patient has resectable MPM and should perform the surgical resection if indicated. Surgery is not usually recommended for patients with anticipated short-term survival and/or at high risk of morbidity and mortality, poor PS, or comorbidities, as well as unfavorable oncologic outcomes because of unfavorable histology such as sarcomatoid. The choice of surgery for MPM is controversial, because data from randomized controlled trials are not available. Neither P/D nor EPP will achieve an R0 resection; it is not clear which surgical procedure will yield better oncologic outcomes. The NCCN panel feels that P/D and EPP are both reasonable surgical options that should be considered in select patients to achieve complete gross cytoreduction.

The NCCN Guidelines currently recommend 4 combination systemic therapy options for patients with MPM. Three of the combination regimens are recommended as first-line therapy for patients with unresectable, metastatic, sarcomatoid histology, or medically inoperable MPM or those who refuse surgery. The 3 regimens include (1) cisplatin/pemetrexed (category 1), (2) carboplatin/pemetrexed, and (3) cisplatin/gemcitabine. The NCCN panel now also recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. Observation may be considered if chemotherapy is planned at the time of symptomatic or radiographic progression for select patients with clinical stage IV, sarcomatoid histology, or medically inoperable MPM who are asymptomatic and have a minimal burden of disease.

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