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Systemic treatment for unresectable malignant pleural mesothelioma

Systemic treatment for unresectable malignant pleural mesothelioma
Author:
Anne S Tsao, MD
Section Editors:
James R Jett, MD
Rogerio C Lilenbaum, MD, FACP
Deputy Editor:
Sadhna R Vora, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 29, 2021.

INTRODUCTION — Malignant mesothelioma is a rare neoplasm that arises most commonly from the mesothelial surfaces of the pleural cavity, less commonly from the peritoneal surface, and extremely rarely from the tunica vaginalis or pericardium. It often has an extremely poor prognosis; the median survival is 4 to 13 months for untreated patients [1] and 6 to 18 months for treated patients, regardless of the therapeutic approach [2-4].

The systemic treatment of unresectable malignant pleural mesothelioma (MPM) will be reviewed here, while the application of chemotherapy as a component of a combined-modality approach that includes definitive surgery is discussed separately. (See "Initial management of malignant pleural mesothelioma".)

Other related topics include:

(See "Pathology of malignant pleural mesothelioma".)

(See "Epidemiology of malignant pleural mesothelioma".)

(See "Initial management of malignant pleural mesothelioma".)

(See "Presentation, initial evaluation, and prognosis of malignant pleural mesothelioma".)

INITIAL EVALUATION — The presentation and initial evaluation of MPM is discussed elsewhere. (See "Presentation, initial evaluation, and prognosis of malignant pleural mesothelioma".)

FIRST-LINE TREATMENT

Nonepithelioid histology

Nivolumab plus ipilimumab — The combination of nivolumab plus ipilimumab is approved by the US Food and Drug Administration (FDA) for unresectable mesothelioma [5,6], and is our suggested initial option for patients with nonepithelioid tumors (algorithm 1). However, it is also acceptable to use front-line chemotherapy, reserving nivolumab plus ipilimumab as a subsequent-line option. (See 'Pemetrexed plus cisplatin' below.)

In a phase III trial including 605 patients with advanced, treatment-naïve mesothelioma, patients were assigned to nivolumab (3 mg/kg intravenously once every two weeks) plus ipilimumab (1 mg/kg intravenously once every six weeks) for up to two years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every three weeks for up to six cycles [7]. At a median follow-up of 30 months, the median overall survival (OS) for those in the nivolumab/ipilimumab group was 18 months, versus 14 months for those assigned to a platinum agent plus pemetrexed (hazard ratio [HR] 0.74, 96.6% CI 0.60-0.91). Two-year OS rates were 41 versus 27 percent, respectively. Subsequently reported three-year OS results were 23 versus 15 percent, respectively [8].

In subgroup analysis, improvements compared with chemotherapy were statistically significant among those with nonepithelioid histologies (18 versus 9 months for nivolumab plus ipilimumab versus chemotherapy [HR 0.46, 95% CI 0.31-0.68]), but not for epithelioid histology (19 versus 17 months, respectively [HR 0.86, 95% CI 0.69-1.08]). However, the trial was not powered to determine statistically significant differences within subgroups.

The presence of programmed cell death ligand 1 (PD-L1) also predicted improvement with nivolumab plus ipilimumab over chemotherapy (18 versus 13 months, respectively [HR 0.69, 95% CI 0.55-0.87]), but according to the authors of the study, PD-L1 results were descriptive only, precluding firm conclusions. Grade ≥3 treatment-related adverse events occurred in approximately one-third of patients in both groups, but 15 percent discontinued treatment due to toxicity in the immunotherapy group, versus 7 percent in the chemotherapy group.

Additionally, pembrolizumab monotherapy in the salvage setting as well as the combination of durvalumab, cisplatin, and pemetrexed in the front-line setting have shown promising activity in a phase II study of patients with unresectable mesothelioma (any histology) [9,10], but further investigation is necessary.

Epithelioid histology

Pemetrexed plus cisplatin — We suggest pemetrexed plus cisplatin for patients with unresectable malignant epithelioid mesothelioma (as for adjuvant or neoadjuvant therapy (algorithm 1)), although nivolumab plus ipilimumab represents a reasonable alternative, particularly for those who are unlikely to tolerate chemotherapy. (See 'Nivolumab plus ipilimumab' above.)

After completion of four to six cycles of a platinum-based doublet, some UpToDate experts treat patients with maintenance pemetrexed until progression (analogous to use in nonsquamous non-small cell lung cancer [NSCLC]), although data regarding maintenance pemetrexed in mesothelioma are preliminary and limited. The possible addition of bevacizumab is discussed below. (See 'Addition of bevacizumab' below.)

The combination of pemetrexed and cisplatin, incorporating prophylactic folic acid and vitamin B12, increased OS compared with single-agent cisplatin in patients with MPM whose disease was either unresectable or who were not otherwise candidates for potentially curative surgery. In the single-blinded EMPHACIS trial, 456 patients were treated with cisplatin (75 mg/m2) and randomly assigned to either pemetrexed (500 mg/m2) or placebo, given once every three weeks [11]. The median survival was improved for the combination (12.1 versus 9.3 months), as was the time to progression (5.7 versus 3.9 months) and the objective response rate (41 versus 17 percent). The EMPHACIS trial did not have a maintenance pemetrexed arm.

Differences in survival were most striking in patients who received supplementation with folic acid and vitamin B12 during therapy [11]. Furthermore, treatment-related toxicity was significantly less, and the mean number of administered cycles of therapy (both single-agent cisplatin as well as the combination) was significantly greater in supplemented compared with nonsupplemented patients [11,12].

In regards to pemetrexed maintenance, in preliminary data from a randomized trial of 49 patients with unresectable MPM and at least stable disease after four to six cycles of pemetrexed and platinum-based chemotherapy, median progression-free survival (PFS) between those assigned to pemetrexed maintenance versus observation was similar (3.4 versus 3 months) [13]. Median OS was 16.3 months with pemetrexed and 11.8 months with observation, a difference that was not statistically significant. Given that this trial was small and may not have identified a benefit even if it existed, and that the results are preliminary, some UpToDate experts continue to administer maintenance pemetrexed to patients who have not progressed after initial chemotherapy, although others do offer it, or use it only selectively. A separate trial suggested a PFS benefit with maintenance gemcitabine [14], but given the lack of OS benefit, this is not a recommended approach.

There are no recommended standard assays for predictive biomarkers. However, in a multivariate regression analysis of prognostic factors derived from EMPHACIS, factors predictive of longer OS were therapy group, vitamin supplementation group, Karnofsky performance status (90 to 100 versus 70 to 80 (table 1)), disease stage, epithelioid subtype, and white blood cell count (≥8200/microL versus lower values) [15]. Additionally, a retrospective study of 60 MPM patients correlated low thymidylate synthase levels with improved time to progression and OS on pemetrexed-based treatment [16]. Prospective trials to evaluate thymidylate synthase as a predictive biomarker for pemetrexed therapy are ongoing.

Additional considerations

Addition of bevacizumab — UpToDate contributors are divided in regards to their approach, with some not administering bevacizumab and others administering it to select patients with a good performance status. Specifically, if bevacizumab is being considered, patients should have no contraindications (eg, poorly controlled hypertension, deep venous thrombosis, proximity to surgery, or viscous perforation). Also, given the poorer prognosis in older adult NSCLC patients with bevacizumab treatment, this agent should be used with caution in patients over the age of 75.

The addition of bevacizumab to the pemetrexed-cisplatin regimen improved both PFS and OS compared with pemetrexed plus cisplatin without bevacizumab in a large phase III trial, but other trials evaluating the addition of antiangiogenic agents to chemotherapy have yielded discrepant results. Based on the results of the MAPS study discussed below, cisplatin-pemetrexed-bevacizumab is the accepted standard in France [17]. The National Comprehensive Cancer Network guidelines have included this regimen as an option for standard front-line therapy, although some insurance companies may not cover it until FDA approval is given.

In the MAPS trial, 448 patients were randomly assigned to pemetrexed-cisplatin plus bevacizumab or to pemetrexed-cisplatin alone. The trial was limited to patients with MPM, and only patients who were not eligible for radical surgery were included. Cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) were given on day 1 of each of six 21-day cycles. Bevacizumab was given at a dose of 15 mg/kg on day 1, and was continued as maintenance every three weeks following completion of six cycles of chemotherapy. No crossover was allowed.

Results were as follows [17]:

With a median follow-up of 39 months, PFS was increased with the bevacizumab combination compared with cisplatin-pemetrexed alone (median, 9.2 versus 7.3 months; HR 0.61, 95% CI 0.50-0.75).

OS was increased with the combination as well (median, 18.8 versus 16.1 months; HR 0.77, 95% CI 0.62-0.95).

These improvements are in contrast to a prior phase II trial, in which bevacizumab maintenance did not demonstrate the expected improvement in PFS relative to historical controls, although the chemotherapy backbone in this study was pemetrexed and carboplatin [18]. In a separate randomized trial, patients receiving cisplatin-pemetrexed with cediranib had a median PFS of 7.2 versus 5.6 months among those receiving the same chemotherapy with placebo (HR 0.71, 80% CI 0.59-0.95) [19]. OS was similar between the two groups, but toxicities among those receiving cediranib were greater (including more grade 3 and 4 diarrhea, dehydration, and weight loss).

Role for tumor-treating fields? — The FDA has approved a tumor-treating fields (TTF) delivery system for use in combination with pemetrexed plus platinum-based chemotherapy for the first-line treatment of patients with unresectable, locally advanced, or metastatic MPM [20]. However, given the availability only of limited observational data, as well as associated toxicities, we do not routinely use this therapy.

The system uses electric fields at specific frequencies to disrupt solid tumor cancer cell division. Its approval was based on results of a phase II trial in which 80 patients with unresectable, treatment-naïve MPM were treated with continuous 150 kHz TTF (≥18 hours/day) plus standard dosing of pemetrexed with either cisplatin or carboplatin [21]. The median OS (18 months) was longer than historic control (12 months). Median PFS was 7.6 versus 5.7 months in the historic control. TTF-related dermatitis was reported in 46 percent, and 5 percent had grade 3 dermatitis. Grade 3 to 4 adverse events were noted in 46 percent.

Alternatives

Pemetrexed plus carboplatin — Carboplatin has been substituted for cisplatin in conjunction with pemetrexed in an effort to decrease toxicity [22-24]. This approach is an appropriate alternative for patients who may not tolerate cisplatin, for example, those with baseline hearing deficits, in whom the potential for ototoxicity with cisplatin is less acceptable. Carboplatin is, however, associated with greater hematologic toxicity than cisplatin.

In the larger of two nonrandomized phase II studies, 102 patients were treated every 21 days with carboplatin (area under the curve 5) plus pemetrexed (500 mg/m2), with folic acid and vitamin B12 supplementation [22]. Objective responses were observed in 19 percent, with a median time to progression of 6.5 months and a median survival of 12.7 months. A secondary analysis of two of these trials based upon patient age found that the carboplatin-plus-pemetrexed regimen was well tolerated and had a similar level of activity in those ≥70 years of age compared with those who were younger [25].

These results are similar to those with the cisplatin-based combination, and pemetrexed plus carboplatin may be an alternative regimen if cisplatin toxicity is a particular concern. There are no data from large studies on the addition of bevacizumab to the pemetrexed-carboplatin regimen.

Other options

Gemcitabine plus platinum compoundsGemcitabine has been combined with platinum compounds, including cisplatin [26-30], carboplatin [31], and oxaliplatin [32]. Response rates for these combinations have ranged from 15 to 48 percent, with acceptable levels of toxicity. However, gemcitabine has not been compared with pemetrexed, and it is generally accepted that mesothelioma patients should receive pemetrexed-based therapy in the first-line setting. (See 'Pemetrexed plus cisplatin' above.)

The gemcitabine-plus-cisplatin regimen was evaluated in a multicenter phase II trial, in which 106 previously untreated patients were treated with gemcitabine plus cisplatin and randomly assigned to receive either bevacizumab or placebo [30]. The median survival was approximately 15 months on both treatment arms, consistent with the results seen with cisplatin plus pemetrexed [33]. No OS benefit was observed with the addition of bevacizumab in this regimen; however, a potential benefit may have been obscured by the use of pemetrexed as second-line therapy.

Other cisplatin-based combinationsCisplatin has also been combined with a number of older chemotherapy agents in phase II studies. These include anthracyclines (doxorubicin, epirubicin) [34-37]; the combination of fluorouracil, mitomycin, plus etoposide [34-36]; and the combination of methotrexate plus vinblastine [38,39].

The results from these studies do not suggest any advantage compared with combinations of cisplatin plus either pemetrexed or gemcitabine, and in fact may be somewhat inferior [39,40].

RESPONSE ASSESSMENT — For patients with unresectable malignant mesothelioma, response assessment typically includes computed tomography (CT) scans of the chest, abdomen, and pelvis, obtained for any change in clinical status, or routinely during every two to three cycles of treatment. Some UpToDate contributors prefer positron emission tomography combined with CT scanning (PET/CT) rather than CT alone. PET/CT can detect a decrease in metabolic activity in the tumor and may be a better predictor of time to progression rather than objective response as determined by CT alone [41]. However, the PET/CT endpoint has not been validated in phase III trials.

Measurement of serum levels of soluble mesothelin-related peptide has been suggested as a way of detecting recurrence of disease after surgical resection, but is not used in routine clinical care. It is not a US Food and Drug Administration-approved assay and does not reliably correlate with response to systemic treatment [42].

SUBSEQUENT-LINE TREATMENT — The decision to change therapy is often based on radiographic findings of progression (ie, new or worsening disease) and/or clinical deterioration with more symptoms of pain, shortness of breath, or weight loss. Patients who have significant side effects to treatment may also require a change in therapy.

There are no US Food and Drug Administration (FDA)-approved therapies for salvage treatment of mesothelioma. Our approach depends on the initial therapy administered.

For those initially treated with immunotherapy — For patients treated initially with immunotherapy, second-line treatment consists of chemotherapy (algorithm 1). For those who are appropriate candidates for combination chemotherapy, pemetrexed plus cisplatin would be the preferred option, with pemetrexed plus carboplatin as a reasonable alternative. (See 'Pemetrexed plus cisplatin' above and 'Pemetrexed plus carboplatin' above.)

However, for those who are unlikely to tolerate combination chemotherapy, single-agent chemotherapy (eg, cisplatin, pemetrexed, or gemcitabine) may be offered.

For those initially treated with chemotherapy — Our approach to such patients depends on whether or not progression occurred after a prolonged period off treatment (algorithm 1).

Progression >6 months after completion of platinum-based therapy — If patients developed disease progression in the setting of a prolonged treatment break from a platinum-pemetrexed-based regimen (>6 months), they can be rechallenged with the platinum-pemetrexed-based regimen before attempting further lines of single-agent therapy. (See 'First-line treatment' above.)

If a patient developed disease progression in the setting of a pemetrexed maintenance therapy (but >6 months from platinum-pemetrexed), a reasonable option would be cisplatin and gemcitabine, or participation in a clinical trial. (See 'Other options' above.)

Progression on or within 6 months of platinum-based therapy

Choosing between immunotherapy and chemotherapy — Several phase II studies have found that a number of agents lead to improved response rates in the second-line setting for mesothelioma, and, in general, either immunotherapy or single-agent chemotherapy is appropriate.

Although the most extensive data in the second-line setting are for pemetrexed (either alone or in combination with cisplatin) [43-48], many patients will have received pemetrexed in the front-line setting. If progression occurred on treatment or within six months of cessation of pemetrexed, we select an agent other than pemetrexed, with some UpToDate experts favoring immunotherapy over chemotherapy in this setting, particularly given that rapid deterioration is common among patients who have experienced progression after initial treatment for mesothelioma, and that immunotherapy may represent a more tolerable option for some.

However, other UpToDate experts feel that single-agent chemotherapy represents another appropriate option, including single-agent gemcitabine [49-51], vinca alkaloids [51-53], and anthracyclines [54-56]. (See 'Immunotherapy' below and 'Single-agent chemotherapy' below and "Toxicities associated with checkpoint inhibitor immunotherapy".)

Immunotherapy — Immunotherapy using checkpoint inhibitors offers a promising option for disease control [57,58]. The anti-programmed cell death protein 1 (PD-1) antibodies pembrolizumab and nivolumab as single agents, or nivolumab with the cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody ipilimumab, are appropriate options for MPM that have shown promising activity, and nivolumab plus ipilimumab has been approved by the FDA for unresectable mesothelioma [5,6]. Toxicities of these agents are discussed elsewhere. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

Single-agent immunotherapy

Pembrolizumab – In preliminary results of a phase III trial of 144 patients with advanced pretreated mesothelioma, pembrolizumab improved objective response rate relative to gemcitabine plus vinorelbine (22 versus 6 percent), but both progression-free survival (PFS; 2.5 and 3.4 months) and overall survival (OS; 10.7 and 11.7 months) for pembrolizumab versus chemotherapy, respectively, were similar [59]. In a separate study, treatment of 25 mesothelioma patients (88 percent with previous systemic therapy) with pembrolizumab resulted in five partial responses and 13 patients with stable disease, for an overall disease control rate of 72 percent [58]. All responding patients remained on therapy at the time of analysis. Additional clinical studies with pembrolizumab are being initiated.

Nivolumab – In a double-blind, placebo-controlled phase III trial, among 332 patients with platinum-refractory mesothelioma (95 percent with pleural mesothelioma), those assigned to nivolumab experienced improvements in both PFS (3.0 versus 1.8 months; hazard ratio [HR] 0.67, 95% CI 0.53-0.85) and OS (10.2 versus 6.9 months; HR 0.69, 95% CI 0.52-0.91) [60]. The most frequently reported grade ≥3 treatment-related adverse events were diarrhea (3 percent in the nivolumab group and 2 percent in the placebo group) and infusion-related reaction (3 versus 0 percent).

Preliminary results of a separate phase II trial including patients with previously treated and relapsed mesothelioma reported objective response rate and disease control rate of 18 and 40 percent, respectively, with single-agent nivolumab [57].

Nivolumab and ipilimumab – This same trial included a nivolumab-and-ipilimumab arm, in whom objective response rate and disease control rate were 24 and 52 percent, respectively, in an intention-to-treat population [57]. In a separate, single-arm phase II trial of patients with previously treated and relapsed mesothelioma, the response rate was 29 percent with nivolumab and ipilimumab, and 38 percent had stable disease [57,61]. Results for nivolumab plus ipilimumab among treatment-naïve patients are discussed above. (See 'Nivolumab plus ipilimumab' above.)

Other immunotherapies – Other immunotherapies, such as the CTLA-4 inhibitor tremelimumab, were studied in a randomized phase II trial of 571 patients (DETERMINE) but unfortunately showed no survival benefit beyond placebo (7.7 versus 7.3 months, respectively; HR 0.92, 95% CI 0·76-1·12) [62]. Tremelimumab has also been evaluated in combination with the anti-programmed cell death ligand 1 (PD-L1) antibody durvalumab in a phase II study, with some suggestion of activity, though randomized data are required [63]. Older immunotherapeutic approaches using interferons or interleukin-2, either alone or in combination with chemotherapy, did not offer substantive advantage [64-67].

Single-agent chemotherapy — Although single-agent chemotherapy has not been shown to prolong survival in previously untreated patients [33], an analysis of the phase III EMPHACIS trial identified second-line (poststudy) chemotherapy as a significant predictor of extended survival [11,48]. First-line therapy and further results of this study are discussed elsewhere. (See 'Pemetrexed plus cisplatin' above.)

Second-line chemotherapy options include single-agent gemcitabine [49-51], vinca alkaloids [51-53], and anthracyclines [54-56]. Given likely comparable efficacy among second-line agents, a choice among them must take into account the relative side effect profiles. Gemcitabine causes myalgias and flu-like symptoms, while vinorelbine is more frequently associated with neuropathy and requires a central line because of the risk of extravasation. Anthracyclines are associated with cardiotoxicity, which limits the acceptable duration of treatment. All can cause myelosuppression. Other agents with single-agent activity include methotrexate [68], edatrexate [69], and raltitrexed [70], and these may be options for later-line therapy.

Although a small, randomized trial (RAMES) showed a survival benefit with the addition of the angiogenesis inhibitor ramucirumab to gemcitabine (13.8 versus 7.5 months, respectively; HR 0.71, 90% CI 0.53-0.95) [71], further data are needed prior to routine use of this combination outside of a clinical trial.

For those who for whatever reason were not exposed to pemetrexed (or had a prolonged treatment-free interval), it remains an appropriate choice. In a study of 243 previously treated patients randomly assigned to pemetrexed or best supportive care, pemetrexed significantly increased the median PFS, time to progression, and time to treatment failure (3.6 versus 1.5, 3.7 versus 1.5, and 3.6 versus 1.5 months, respectively) [47]. However, pemetrexed did not improve median survival (8.4 versus 9.7 months with best supportive care). An OS benefit may have been obscured, since 52 percent of those assigned to best supportive care received systemic chemotherapy once disease progression was evident.

OTHER ASPECTS OF MANAGEMENT

Pleurodesis — Management of pleural effusions from MPM using pleurodesis is discussed elsewhere. (See "Initial management of malignant pleural mesothelioma", section on 'Pleural effusions'.)

Radiation — Radiation in unresectable MPM is discussed elsewhere. (See "Initial management of malignant pleural mesothelioma", section on 'Radiation therapy'.)

INVESTIGATIONAL THERAPIES — A range of other approaches have been or are being studied in an effort to improve upon the systemic therapy for MPM. None of these has an established role in the treatment of mesothelioma and is not indicated outside the context of a formal clinical trial.

Although addition of nintedanib (a vascular endothelial growth factor [VEGFR], platelet-derived growth factor receptor [PDGFR], and fibroblast growth factor receptor [FGFR] tyrosine kinase inhibitor) to chemotherapy showed progression-free survival (PFS) benefit in a phase II trial [72], there was no observed benefit in the phase III trial (6.8 versus 7 months among those receiving chemotherapy with or without nintedanib) [73].

Vorinostat, an oral histone deacetylase inhibitor, showed some evidence of activity in an initial phase I study [74]. However, more extensive evaluation did not confirm a clinically meaningful benefit from this approach. In a phase III trial, 661 previously treated patients were randomly assigned to either vorinostat or placebo [75]. PFS was prolonged with vorinostat (median, 6.3 versus 6.1 weeks; hazard ratio [HR] 0.75, 95% CI 0.63-0.88). However, this increase was not clinically significant. Also, the difference in overall survival was not significant (median, 30.7 versus 27.1 weeks; HR 0.98, 95% CI 0.83-1.17).

Agents targeting mesothelin, such as MORAb-009, SS1P, BAY 9409343, and CRS-207, have showed preliminary efficacy against mesothelioma in clinical trials. Several randomized trials are ongoing.

Other experimental agents that have been studied include angiogenesis inhibitors (thalidomide [76]), lurbinectedin [77], and tyrosine kinase inhibitors (sorafenib [78], sunitinib [78], imatinib [79-81], vatalanib [82], and cediranib [83]).

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer" and "Society guideline links: Pleural mesothelioma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Pleural mesothelioma (The Basics)")

SUMMARY AND RECOMMENDATIONS

Treatment algorithm – Our treatment approach is summarized in the algorithm (algorithm 1) and in the points below.

Initial treatment

For patients with advanced malignant pleural mesotheliomas (MPM) who are not candidates for surgery, our approach to initial therapy depends on histology:

-For those with nonepithelioid histologies, we suggest initial treatment with nivolumab plus ipilimumab rather than chemotherapy (Grade 2B), although the opposite sequence is also acceptable.

-For those with epithelioid histologies, we suggest combination chemotherapy using a platinum-based doublet, with or without bevacizumab, rather than nivolumab plus ipilimumab (Grade 2C), although nivolumab plus ipilimumab is a reasonable alternative, particularly for those who are unlikely to tolerate chemotherapy. (See 'First-line treatment' above.)

When using chemotherapy, our general approach is to utilize a platinum agent with pemetrexed, also including prophylactic folic acid and vitamin B12.

-The addition of bevacizumab to cisplatin and pemetrexed has been shown to increase progression-free and overall survival. At this time, regulatory approval is pending for bevacizumab with cisplatin and pemetrexed, and UpToDate contributors are divided in regards to whether or not they incorporate it. If bevacizumab is considered, patients should be typically <75 years of age, with a good performance status, and without contraindications. (See 'Addition of bevacizumab' above.)

-Some UpToDate contributors use maintenance pemetrexed after four to six cycles of the platinum-pemetrexed doublet, rather than discontinuation of treatment, extrapolating from data in the non-small cell lung cancer setting. However, other UpToDate contributors do not use maintenance pemetrexed. (See 'Pemetrexed plus cisplatin' above and "Systemic chemotherapy for advanced non-small cell lung cancer", section on 'Cytotoxic chemotherapy'.)

-We suggest against the routine addition of tumor-treated fields to chemotherapy for advanced MPM, given associated toxicities and the availability of only limited, nonrandomized data (Grade 2C). Alternatively, however, it is acceptable to use it in select patients who accept the risks of toxicities and limitations in available data. (See 'Role for tumor-treating fields?' above.)

Subsequent-line treatment

For those who experience progression on initial treatment with immunotherapy, next-line treatment is with chemotherapy, with a choice between single and combination therapy dependent on the patient's performance status and preferences. (See 'For those initially treated with immunotherapy' above.)

For patients initially treated with chemotherapy who progress at least six months after completion, we suggest rechallenge with the initial chemotherapy regimen (Grade 2C). (See 'Progression >6 months after completion of platinum-based therapy' above.)

For patients initially treated with chemotherapy who progress on or within six months of their initial regimen, we suggest either immunotherapy or a single-agent chemotherapy agent to which they have not yet been exposed, rather than further treatment with combination chemotherapy (Grade 2C).

Combined-modality treatment – The chemotherapy approaches used in the treatment of advanced MPM have been integrated into combined-modality approaches along with pleurodesis and radiation therapy. These approaches are discussed separately. (See 'Other aspects of management' above and "Initial management of malignant pleural mesothelioma".)

ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate acknowledges Dr. Vogelzang's past work as an author for this topic.

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