Systemic treatment for unresectable malignant pleural mesothelioma | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Systemic treatment for unresectable malignant pleural mesothelioma

UpToDate, 2015


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 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 [2,3].

Initial evaluation and clinical approach

Most patients with malignant pleural mesothelioma (MPM) present with the gradual onset of pulmonary symptoms (dyspnea, cough, chest pain). Symptoms generally lead to a diagnosis when extensive intrathoracic disease is present.

Diagnosis

Typical findings on chest imaging combined with a history of asbestos exposure may raise the suspicion of a MPM. The diagnosis of MPM requires an adequate tissue sample from the tumor.

The most widely used staging system is the tumor (T), node (N), metastasis (M) staging system that is used by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) (table 1) [4].

Clinical approach

A multidisciplinary treatment plan is based upon the assessment of the extent of disease, the patient’s overall condition including cardiopulmonary function and other comorbidity, and their desire for aggressive treatment.

  • Surgical candidates: For patients who have surgically resectable disease limited to one hemithorax and have no medical contraindication to surgery, we use a combined modality approach that incorporates surgery aimed at a maximal complete resection (MCR) with chemotherapy and radiation therapy (RT).
  • Non surgical candidates: For patients who have disease in which an MCR is not feasible and for those who are not candidates for definitive surgery because of age, inadequate cardiopulmonary reserve, or other comorbidity, systemic chemotherapy and symptom directed treatment may be beneficial.

After the initial evaluation for possible resection, approximately 80% of patients with pleural MPM will not be candidates for combined modality approach that includes definitive surgery.

Prognostic factors

Various studies have looked at different clinical and pathologic parameters in order to identify patients with particularly good or poor prognoses.

The Cancer and Leukemia Group B (CALGB) and the European Organization for Research and Treatment of Cancer (EORTC) have identified key clinical prognostic factors (table 2 and table 3) [5-7]. In all the large surgical trials done to date, histology has had a significant impact on prognosis, with sarcomatoid and biphasic subtypes having worse outcomes compared to epithelioid mesothelioma.

The small number of mesothelioma patients enrolled in clinical trials and the heterogeneity of study populations has limited the identification of molecular biomarkers for prognosis. New molecular technologies, such as gene expression profiling, may eventually classify patients into distinct prognostic subgroups [8,9].

Response assessment

There are several ways to assess clinical benefit: response rate, disease control rate, progression-free survival, and overall survival. Overall survival has been the primary endpoint in contemporary randomized trials [10].

Both the objective response rate and progression-free survival have been used as surrogates for efficacy in older studies [11]. In malignant pleural mesothelioma studies, there are two radiographic measurement systems that are employed using thoracic CT scans: RECIST and modified RECIST (table 4) [12,13]. Modified RECIST measures the pleural rind or tumor thickness in a perpendicular manner to the chest wall in two positions at three separate levels on a chest CT scan [14]. The sum of these six measurements is used to define response using RECIST criteria.

Other imaging modalities are under investigation for use in mesothelioma tumor measurements. Positron emission tomography combined with CT scanning (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 computed tomography alone [15]. However the PET/CT endpoint has not been validated in phase III trials.

Measurement of serum levels of soluble mesothelin-related peptide (SMRP) may be useful in detecting recurrence of disease after surgical resection. It is less clear whether it can assess response to systemic therapy [16]. This approach has been shown to correlate with the radiologic assessment.

Combination chemotherapy

Combination chemotherapy using the regimen of cisplatin plus pemetrexed became the most widely used regimen, based upon a phase III trial that demonstrated a prolongation of overall survival compared to treatment with cisplatin alone.

The only randomized trial that directly compared chemotherapy (single agent vinorelbine or a combination of mitomycin, vinblastine, and low-dose cisplatin) to active supportive was terminated prematurely due to poor accrual [17]. That trial failed to demonstrate a statistically significant improvement in overall survival. However, subsequent trials using contemporary cisplatin-based doublets have demonstrated a significant prolongation in overall survival compared with single agent cisplatin.

Pemetrexed plus cisplatin

The combination of pemetrexed and cisplatin, incorporating prophylactic folic acid and vitamin B12, increased overall survival compared with single agent chemotherapy in patients with malignant pleural mesothelioma whose disease was either unresectable or who are not otherwise candidates for potentially curative surgery. The role of maintenance pemetrexed after completion of four to six cycles of the platinum-based doublet remains uncertain.

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 [18]. The median survival was significantly longer 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%).

Differences in survival were most striking in patients who received supplementation with folic acid and vitamin B12 during therapy [18]. 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 to nonsupplemented patients [18,19].

In a multivariate regression analysis of prognostic factors derived from this trial, factors predictive of longer overall survival were therapy group, vitamin supplementation group, Karnofsky performance status (90-100 versus 70-80, (table 5)), disease stage, histologic subtype, and white blood cell count (≥8200/microL versus lower values) [20].

There are no standard assays for predictive biomarkers that are currently recommended. However, a retrospective study of 60 malignant pleural mesothelioma patients correlated low thymidylate synthase levels with improved time to progression and overall survival [21]. Prospective trials to evaluate thymidylate synthase as a predictive biomarker for pemetrexed therapy are ongoing.

Pemetrexed cisplatin plus bevacizumab

The addition of bevacizumab to the pemetrexed cisplatin regimen improved both progression-free and overall survival compared with pemetrexed plus cisplatin without bevacizumab in a large phase III trial.

In the MAPS trial, 448 patients were randomly assigned to pemetrexed cisplatin plus bevacizumab or to pemetrexed cisplatin alone [22]. The trial was limited to patients with pleural mesothelioma, and only patients who were not eligible for radical surgery were included. Cisplatin (75 mg/m2) and pemetrexed (500 mg/kg) 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 presented at the 2015 American Society of Clinical Oncology (ASCO) meeting:

  • With a median follow-up of 39 months, progression-free survival was significantly increased with the bevacizumab combination compared with cisplatin pemetrexed alone (median 9.6 versus 7.5 months, hazard ratio [HR] 0.61, 95% CI 0.50-0.75).
  • Overall survival was significantly increased with the combination as well (median 18.9 versus 16.1 months, HR 0.76, 95% CI 0.61-0.94).

The improvement in overall survival was in contrast to three prior phase II trials. This may have been partially attributable to limiting the pemetrexed cisplatin to six cycles, rather than continuing with maintenance. The addition of bevacizumab to pemetrexed plus cisplatin has not received regulatory approval in the United States or Europe.

Pemetrexed plus carboplatin

Carboplatin has been substituted for cisplatin in conjunction with pemetrexed in an effort to decrease toxicity [23-25].

In the larger of two nonrandomized phase II studies, 102 patients were treated every 21 days with carboplatin (AUC 5) plus pemetrexed (500 mg/m2), with folic acid and vitamin B12 supplementation [23]. Objective responses were observed in 19%, 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, compared to those who were younger [26].

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.

Raltitrexed plus cisplatin

The combination of raltitrexed plus cisplatin prolongs survival compared to cisplatin alone in patients with previously untreated advanced mesothelioma.

This was illustrated in a phase III trial in which 250 patients were randomly assigned to raltitrexed (3 mg/m2) plus cisplatin (80 mg/m2, both in 21 day cycles) or the same dose of cisplatin alone [27,28]. The following findings were noted:

  • Overall survival in all randomized patients was significantly increased with the combination regimen: the median survival was 11.4 versus 8.8 months with single agent cisplatin and the one-year survival was 46 versus 40% [27].
  • In the 213 patients with measurable disease, the combined therapy group had a higher objective response rate (24 versus 14%, p = 0.06) [27].
  • A separate analysis of health-related quality of life (QOL) showed that overall QOL was impaired at baseline but was stable for those remaining on treatment with both regimens [28]. Dyspnea improved with treatment, an effect that was statistically significant for the two-drug regimen.

Raltitrexed is not commercially available in the United States.

Gemcitabine plus cisplatin

Gemcitabine has been combined with platinum compounds, including cisplatin [29-33], carboplatin [34], and oxaliplatin [35]. Response rates for these combinations have ranged from 15 to 48%, with acceptable levels of toxicity.

The potential value of the gemcitabine plus cisplatin regimen was illustrated by 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 [33]. The median survival was approximately 15 months on both treatment arms, consistent with the results seen with cisplatin plus pemetrexed [10]. No overall survival 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 regimens

Cisplatin has also been combined with a number of older chemotherapy agents in phase II studies. These include anthracyclines (doxorubicin, epirubicin) [36-39], the combination of fluorouracil, mitomycin, plus etoposide [36-38], and the combination of methotrexate plus vinblastine [40,41].

The results from these studies do not suggest any advantage compared to combinations of cisplatin plus either pemetrexed or gemcitabine and in fact may be somewhat inferior [17,41].

Single agent chemotherapy

Phase II studies have found clinical activity, as evidenced by response rates, for a number of agents. Although single agent chemotherapy has not been shown to prolong survival in previously untreated patients [10], these agents have a role as second-line therapy in some patients.

Agents that have shown substantial activity in phase II include the following:

Platinum compounds — In a meta-analysis of virtually all phase II trials published through 2001, cisplatin was the most active single agent [42]. Cisplatin has thus become the backbone for combination chemotherapy regimens.

Carboplatin may also have activity although the data are much less extensive [43,44].

Pemetrexed — The most extensive data in the second-line setting are for pemetrexed, either alone or in combination with cisplatin [45-50]. Other drugs that have been used include gemcitabine, vinorelbine, and anthracyclines.

An analysis of the phase III EMPHACIS trial of pemetrexed plus cisplatin versus cisplatin [18] identified second-line (post-study) chemotherapy as a significant predictor of extended survival [50]. A survival benefit from chemotherapy was suggested by a retrospective multiple regression analysis of patient risk factors.

Additional information about the role of second-line chemotherapy comes from a multicenter trial, in which 243 previously treated patients were randomly assigned to pemetrexed or best supportive care [49]. Pemetrexed significantly increased the median progression-free survival, 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).

However, pemetrexed did not improve median survival (8.4 versus 9.7 months with best supportive care). An overall survival benefit may have been obscured, since 52% of those assigned to best supportive care received systemic chemotherapy once disease progression was evident. Other antifolates with single agent activity include methotrexate [51], edatrexate [52], and raltitrexed [53].

Other agents — Several other agents have also demonstrated activity in phase II studies, based upon rates of objective tumor regression. These may be useful as second line therapy when they were not part of the original chemotherapy regimen. Such agents include gemcitabine [54-56], anthracyclines [57-59], and vinca alkaloids [56,60,61].

Experimental approaches

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

As an example, vorinostat, an oral histone deacetylase inhibitor showed some evidence of activity in an initial phase I study [62]. 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 [63]. Progression-free survival was significantly prolonged with vorinostat (median 6.3 versus 6.1 weeks, hazard ratio [HR] 0.75, 95% CI 0.63-0.88). However, the difference in overall survival was not significant (median 30.7 versus 27.1 weeks, HR 0.98, 95% CI 0.83-1.17).

Other experimental agents that have been studied include angiogenesis inhibitors (thalidomide [64]), tyrosine kinase inhibitors (sorafenib [65], sunitinib [65], imatinib [66-68], vatalanib [69], and cediranib [70]).

Immunotherapy using checkpoint inhibitors may offer a more promising direction for disease control. In a preliminary report, treatment of 25 mesothelioma patients (88% with previous systemic therapy) with the anti-PD1 antibody pembrolizumab resulted in 6 partial responses and 13 patients with stable disease, for an overall disease control rate of 76% [71]. All responding patients remained on therapy at the time of analysis. Additional clinical studies with pembrolizumab are being initiated.

Older immunotherapeutic approaches using interferons or interleukin-2, either alone or in combination with chemotherapy, did not offer substantive advantage [72-75].

Summary and recommendations

  • For patients with advanced pleural mesotheliomas (MPM) who are not candidates for a combined modality approach that incorporates definitive surgery, we recommend treatment with combination chemotherapy using a platinum based doublet rather than single agent chemotherapy (Grade 1B). This approach has been shown to significantly prolong overall survival compared with single agent chemotherapy using cisplatin.
    • The addition of bevacizumab to the pemetrexed cisplatin regimen increased progression-free and overall survival compared with pemetrexed plus cisplatin, but publication of this trial and further analysis will be needed before this regimen can be widely recommended.
    • Our preferred regimen is pemetrexed plus cisplatin, including prophylactic folic acid and vitamin B12, based upon the more extensive clinical experience with this regimen. Other platinum-based doublet regimens that may be as effective but that have been studied less extensively include pemetrexed plus carboplatin, gemcitabine plus cisplatin, and raltitrexed plus cisplatin.
  • For patients who progress on their initial platinum-based regimen, we suggest single agent chemotherapy with an active agent such as gemcitabine or pemetrexed that was not included in the original chemotherapy regimen (Grade 2C). Other older agents that also have some activity in MPM include anthracyclines and vinca alkaloids.
  • The chemotherapy approaches used in the treatment of advanced MPM have been integrated into combined modality approaches along with definitive surgery and radiation therapy. These approaches are discussed separately.
  • Patients should be included in formal clinical trials whenever possible.

Prognostic indices of survival for advanced mesothelioma in CALGB* studies

CALGB studies

Study Dates Response, % MST, months
#8435 (Mitomycin/cisplatin) 6/84-10/86 26 8.1
14 8.8
#8638 (Carboplatin) 2/87-2/88 7 7.1
#8833 (DHAC) 6/88-6/89 17 6.7
#8933 (Trimetrexate) 7/89-8/91 12 3.9
12 9.8
#9031 (DHAC/cisplatin) 7/90-7/93 14 6.4
#9131 (Edatrexate) 5/92-9/94 25 9.6
18 6.9
#9234 (Paclitaxel) 3/93-9/94 9 5

Poor prognostic factors in multivariate analysis

  Variable Relative risk
Pleural disease Present 2.64
Lactic dehydrogenase (LDH) >500 IU/L 1.91
Poor performance status (PS) PS1 1.65
PS2 2.71
Platelet count >400,000/microL 1.57
Epithelial histology Absent 1.33
Age Each year over 75 yo 1.34

CALGB prognostic groups

Group Characteristics MST, months
Group I PS, 0; age <49 years 12.5
PS, 0; age ≥49 years; HGB* ≥14.6 14.5
Group II PS, 1 or 2; WBC* < 8.7; no chest pain 9.5
Group III PS, 0; age >49 years; HGB <14.6 9.3
PS, 1 or 2; WBC < 15.6; chest pain; weight loss; HGB ≥ 12.3 9.3
PS, 1 or 2; 9.8 ≤ WBC < 15.6; chest pain; weight loss; HGB ≥ 11.2 9.6
Group IV PS, 1 or 2; 8.7 ≤ WBC <15.6; no chest pain 6.6
Group V PS, 1 or 2; WBC <15.6; chest pain; no weight loss; HGB <12.3 3.9
PS, 1 or 2; 9.8 ≤ WBC <15.6; chest pain; weight loss; HGB <11.2 4.9
PS, 1 or 2; WBC < 9.8; chest pain; weight loss

3.9

Group VI

PS, 1 or 2; WBC  ≥ 15.6

1.4

CALGB: cancer and leukemia Group B; MST: median survival time; Mos: months; DHAC: dihydro-5-azacytidine; WBC: white blood cell count, X 1000/microL; HGB: hemoglobin (HGB is given in g/%; WBC, x 1000/microL).

Prognostic indices of survival for advanced mesothelioma in EORTC studies

EORTC studies
Study Response (%) MST (months)
Mitoxantrone 2.4 7.5
Epidoxorubicin 13.5 8.9
Etoposide (IV) 4.2 6.7
Etoposide (PO) 7.3 8.7
Paclitaxel 0 9.3
Poor prognostic factors in multivariate analysis
  Variable MST (months)
Performance status (PS) Good (0) 10.7
Poor (1-2) 7.2
WBC count High (>8.3) 6
Low (<8.3) 10.4
Hemoglobin difference* High (>1 g/dL) 7.3
Low (<1 g/dL) 9.6
Histologic diagnosis Definite 9.8
Possible 6
Sarcomatous subtype Present 5
Other subtype 8.4-9.1
EORTC prognostic groups
Group characteristics MST (months) 1 yr OS 2 yr OS
Low risk (prognostic score <1.27) 10.8 40% 14%
Equivalent to having 0-2 poor prognostic factors
High risk (prognostic score >1.27) 5.5 12% 0%
Equivalent to having three or more poor prognostic factors

EORTC: European Organization for Research and Treatment of Cancer; MST: median survival time; WBC: white blood cell count, X 1000/microL.
* The difference relative to 16 g/dL in males and 14 g/dL in females.

Response Evaluation Criteria in Solid Tumors (RECIST)

Response assessment RECIST guideline, version 1.0[1] RECIST guideline, version 1.1[2]
Target lesions
CR Disappearance of all target lesions Disappearance of all target lesions and reduction in the short axis measurement of all pathologic lymph nodes to ≤10 mm
PR ≥30% decrease in the sum of the longest diameter of the target lesions compared with baseline ≥30% decrease in the sum of the longest diameter of the target lesions compared with baseline
PD

≥20% increase in the sum of the longest diameter of the target lesions compared to the smallest sum of the longest diameter recorded since treatment started

OR

The appearance of one of more new lesions

≥20% increase of at least 5 mm in the sum of the longest diameters of the target lesions compared with the smallest sum of the longest diameter recorded

OR

The appearance of new lesions including those detected by FDG-PET

SD Neither PR nor PD Neither PR nor PD
Non-target lesions
CR Disappearance of all non-target lesions and normalization of tumor marker levels Disappearance of all non-target lesions and normalization of tumor marker levels
IR, SD Persistence of one or more non-target lesions and/or the maintenance of tumor marker levels above normal limits Persistence of one or more non-target lesions and/or the maintenance of tumor marker levels above normal limits
PD Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions

The appearance of one of more new lesions or unequivocal progression

If patient has measurable disease, an increase in the overall level, or substantial worsening in non-target lesions, such that tumor burden has increased, even if there is a SD or PR in target lesions

If no measurable disease, an increase in the overall tumor burden comparable in magnitude to the increase that would be required to declare PD in measurable disease (eg, an increase in pleural effusions from trace to large, or an increase in lymphangitic disease from localized to widespread)

CR: complete response; IR: incomplete response; PD: progressive disease; SD: stable disease; FDG-PET: fludeoxyglucose-positron emission tomography.

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