Seminars in Oncology
Volume 32, Issue 3 , Pages 336-350, June 2005

New Agents in the Management of Advanced Mesothelioma

  • Nicholas J. Vogelzang

      Affiliations

    • Nevada Cancer Institute, Las Vegas, NV
    • Corresponding Author InformationAddress reprint requests to Nicholas J. Vogelzang, MD, Nevada Cancer Institute 10000 W Charleston Blvd, Las Vegas, NV 89135
    • ,
  • Camillo Porta

      Affiliations

    • Medical Oncology, IRCCS San Matteo University Hospital, Pavia, Italy
    • Salvatore Maugeri Foundation, Pavia, Italy; Italian Mesothelioma Group (GIMe)
    • ,
  • Luciano Mutti

      Affiliations

    • Local Health Authority 11-Piedmont, Vercelli, Italy
    • Salvatore Maugeri Foundation, Pavia, Italy; Italian Mesothelioma Group (GIMe)

Article Outline

Malignant pleural mesothelioma (MPM) is a seemingly uncommon tumor whose incidence has in fact increased steadily and progressively over the last 30 years. Indeed, an actual “epidemic” is expected in Europe over the next 20 years. Despite unquestionable improvement in the diagnostic methods at our disposal and the availability of new treatment strategies, the prognosis of MPM patients remains dramatically poor (12 to 18 months’ median survival from diagnosis), although exceptional cases of long-survivors are reported in all literature series. The current review will cover the dramatic improvements in the treatment of this rare disease that have been recently achieved, as well as the promise that new, molecular-targeted therapies, such as bortezomid, mTOR (mammalian target of rapamycin) inhibitors, and Met inhibitors, seem to offer for the next few years. With pemetrexed we now have a drug that is able to impact patient survival. Together with the newer drugs, rapidly emerging from the laboratory to be applied in the clinic, we have the hope of making further advances in the struggle against this disease.

 

Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura. According to the Surveillance, Epidemiology and End Results (SEER) database, approximately 2,200 new cases were diagnosed in the United States in 2000.1 At least 80% of these patients were diagnosed in stage III/IV and were not candidates for surgical cure. With a median survival of less than 12 months,2 advanced-stage mesothelioma is the prototype of an aggressive solid tumor. Aside from supportive care or hospice care, chemotherapy remains the only option of therapy available for most patients; to date, literally hundreds of phase II trials have been conducted in this population in an attempt to discover active agents. In fact, most agents have some ability to cause regression of disease in a small percentage (usually 10% to 15%) of treated patients.3 Rather than review agents, classes, and combinations of agents that are active or inactive, it is most instructive to first consider the definition of “active.” At least three factors (and probably more) influence the response of mesothelioma to chemotherapy. These are: (1) host and tumor prognostic factors for response; (2) type and quality of the imaging modalities used to define response; and (3) nonradiologic definitions of response.

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Factors Influencing Response to Chemotherapy 

Host and Tumor Prognostic Factors for Response 

Pathologic stage (tumor size, nodal status, etc, determined at the time of surgery) and performance status of the patient usually define prognosis. The limitations of pathologic staging are well known, but a pathologic/surgical staging system for MPM has been proposed and validated4 and the poor prognosis of cancer-containing lymph nodes has been confirmed.5 However, pathologic staging is rarely performed in patients receiving only chemotherapy, and thus two cancer cooperative groups that have conducted many chemotherapy trials in MPM devised clinical prognostic systems to define prognosis. Based on multicenter data from patients treated with protocol-based chemotherapy, the systems of the European Organization for the Research and Treatment of Cancer (EORTC) and the Cancer and Leukemia Group B (CALGB, Table 1) both highlight the vital importance of performance status in predicting outcome.6, 7 Patients who spent 50% or more of waking hours bedridden (performance status 3 or 4) were excluded from the trials as being a priori unfit for any anticancer therapy. Even with this key exclusion, the median survival in the EORTC patients was only 12.6 months from diagnosis and 8.4 months from trial entry,6 while in the case of the CALGB patients, the median survival from trial entry was 7.0 months.7 Further clinical criteria were used by the CALGB to distinguish six groups of patients with predicted survivals ranging from 1.4 to 13.6 months (Table 1). The CALGB concluded that groups five and six (with predicted survivals of <5 months and including all but not only performance status 2 patients) were probably unfit for chemotherapy trials. Prospective validation of these prognostic groupings and, in particular the poor prognosis of CALGB categories 5 and 6, has been reported by two independent groups.8, 9 Furthermore, Vogelzang et al10 conducted a phase III randomized trial of ranpirnase versus doxorubicin without stratifying by CALGB categories. After randomizing more than 150 patients, these investigators found a statistically significant imbalance in the study, with a larger number of poor prognosis group 5 and 6 patients randomized to the experimental arm, ie, ranpirnase.

Table I. Prognostic Groups in Malignant Mesothelioma as Defined by the CALGB
Prognostic GroupDefining VariablesMedian Survival (mo)
1PS = 0, age < 49 yr13.9
PS = 0, age > 49 yr, Hgb ≥ 14.6 g/dL
2PS = 1 or 2, WBC < 8.7 × 103/μL, no chest pain9.5
3PS = 0, age ≥ 49 yr, Hgb < 14.6 g/dL9.2
PS = 1 or 2, WBC < 15.6 × 103/μL, chest pain, no weight loss, Hgb ≥ 12.3 g/dL
PS = 1 or 2, 9.8 × 103/μL ≤ WBC < 15.6 × 103/μL, chest pain, weight loss, Hgb ≥ 11.2 g/dL
4PS = 1 or 2, 8.7 × 103/μL ≤ WBC < 15.6 × 103/μL, no chest pain6.5
5PS = 1 or 2, WBC < 15.6 × 103/μL, chest pain, no weight loss, Hgb < 12.3 g/dL4.4
PS = 1 or 2, 9.8 × 103/μL ≤ WBC < 15.6 × 103/μL, chest pain, weight loss, Hgb < 11.2 g/dL
PS = 1 or 2, WBC < 9.8 × 103/μL, chest pain, weight loss
6PS = 1 or 2, WBC ≥ 15.6 × 103/μL1.4

Abbreviations: PS, performance status; Hgb, hemoglobin; WBC, white blood cell count.

Modified from Herndon et al.7

This necessity of taking prognostic factors into account in MPM trials was underscored in the EMPHACIS trial (for Evaluation of Mesothelioma in a PHase III Study of Alimta with CISplatin), which included 456 patients (448 patients evaluable as intent to treat) entered on a single-blind trial conducted from 1998 to 2001 at 99 medical institutions worldwide.11 Patients were stratified according to nine prognostic factors and randomly assigned to cisplatin (75 mg/m2) with either pemetrexed (500 mg/m2) or saline placebo, once every 3 weeks. The results are discussed below. However, one of the major benefits of the trial, other than demonstrating a survival advantage for the two-drug regimen, was the identification and validation of prognostic factors for patients treated with chemotherapy. Symanowski et al reported in abstract form the results of a multivariate analysis of the prognosis of patients stratified and treated in the EMPHACIS trial.12 The analyses, shown in Table 2, Table 3, demonstrate that the combination of low-stage disease and good performance status was as predictive of prolonged survival (17.3 months’ median survival time), as was the combination of a high (good) performance status, stage III/IV disease, a low white blood cell count, and epithelial histology (20 months’ median median survival time). Gene expression patterns in mesothelioma samples may soon lead to improved prognostic systems.13, 14, 15

Table 2. Regression Analysis of EMPHACIS Trial: Identification of Significant Factors Predicting Survival in 434 Patients Randomized and Treated With Complete Baseline Data
ParameterWald χ2P Value
UnivariateMultivariate
Age.054—
Gender.347—
Race.500—
Geography.836—
Time from Dx.234—
Prior RT.392—
KPS<.001<.001
Histology<.001<.001
Stage<.001<.001
WBC<.001<.001
TG.020.003
Vitamin supplementation<.001<.001

Abbreviations: Dx, diagnosis; RT, radiotherapy; KPS, Karrofsky performance status; WBC, White blood cell count; TG, triglycerides.

Modified from Symanowski et al.12

Table 3. Prognostic Groups Defined by Symanowski et al in the EMPHACIS Trial
GroupDescriptionnMS95% CI
1High KPS, late stage, epithelial, low WBC5420.014.8–22.5
2High KPS, late stage, epithelial, high WBC7312.610.3–14.9
3High KPS, early stage6117.314.4–NC
4High KPS, late stage, other histology497.56.3–11.6
5Low KPS, epithelial1298.46.6–9.9
6Low KPS, other histology685.74.2–7.1

Abbreviations: MS, median survival; CI, confidence interval; KPS, karnofsky performance status; WBC, white blood cell count; NC, not computable due to high censoring.

Type and Quality of the Imaging Modalities Used to Define Response to Chemotherapy 

Most (but not all) trials conducted since 1980 have used computed topography (CT) scans to define as active an agent that causes regression of the disease. Regression has been defined as a greater than 50% decrease of bi-dimensionally measured cancer. However, the response of mesothelioma to therapy (either progression or regression) has been difficult for clinicians to evaluate consistently and reproducibly, mostly because of the circumferential morphology, the lack of bi-dimensionally tumor masses in many patients, and the axial extent of the disease. In studies unrelated to mesothelioma, substantial inter- and intra-observer variability in the selection and measurement of indicator metastatic lesions in CT scans has been reported,16, 17 and it is likely that such variability is further magnified by the difficulties encountered in measuring MPM (although few studies have been reported). Furthermore, MPM is commonly accompanied by pleural effusions, which may obscure the accurate interpretation of tumor dimensions. The recent development of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria18 for defining radiologic response of solid tumors (>30% regression of disease in one dimension) may improve the accurate assessment of MPM clinical trial results. However, at least one study reported that the RECIST criteria needed extensive modification in order to apply to MPM.19, 20 Clearly, CT scans have improved the management of the disease, but more reproducible CT-based two-dimensional tumor measurement methods are still needed and are being developed.21 This situation may begin to improve with the widespread utilization of the new modified RECIST criteria for assessment of response in MPM, first promulgated by Byrne et al22, 23 and applied in the EMPHACIS trial.

Briefly, according to these criteria, change in disease is assessed by measuring the tumor thickness perpendicular to the chest wall or mediastinum of up to three involved areas of pleural rind. Each of the three measured rinds should be separated from the next rind by at least 2 cm on transverse cuts of CT scan. Each rind can be measured at up to three separate points provided that at least one measurement is greater than 1.5 cm. The sum of the nine or fewer measurements defines a pleural unidimensional measure; at reassessment, pleural thickness should be measured at the same position, at the same level, and by the same observer. Nodal, subcutaneous, and other bi-dimensionally measurable lesions should be measured uni-dimensionally as per the RECIST criteria.

Therefore, complete response (CR) was defined as complete absence of measurable, nonmeasurable but assessable, and unassessable disease with no new lesions and no disease-related symptoms. Partial response (PR) was defined as a ≥50% reduction from baseline of the sum of the products of perpendicular diameters of bi-dimensionally measurable disease when only such disease was present, a ≥30% decrease in the sum of the greatest diameters of uni-dimensionally measurable lesions when only such disease was present, or a reduction of either type of disease as defined above and the other type at least stable when both types were present, with nonmeasurable lesions being at least stable, with no new lesions. Any CR or PR in the EMPHACIS trial required confirmation 4 weeks later. Tumor response rate was defined as the proportion of patients who experienced either a CR or a PR × 100. Tumor progression was defined as the appearance of a new or relapsed lesion/site, a 50% increase in the sum of products of all bi-dimensionally measurable lesions over the smallest sum observed when only such disease was present, a 25% increase in the sum of the longest dimension of uni-dimensionally measurable lesions over smallest sum observed when only such disease was present (in the presence of both disease types, progression of either type as defined above and at least stable disease for the other), worsening of assessable disease, or death from disease. Stable disease was disease that did not qualify as CR, PR, or progression.

Clearly, these criteria are complex and difficult to use in real-time clinical practice. Thus the need for automated techniques to perform these cumbersome and repetitive tasks is obvious. Alternatively, other response criteria need to be developed.

Magnetic resonance imaging (MRI) is a useful technique in preoperative staging.23, 24 Fluid can be delineated from tumor, because liquids have high signal intensity on the T2-weighted images. Gadolinium contrast-enhanced T1-weighted fat-suppressed two-dimensionsal FLASH sequence (Fast Low Angle SHot) in three planes gives more information than enhanced CT.25 Stewart et al reported that contrast-enhanced MRI successfully predicted resectability in 97% of 51 MPM patients.26 As far as the characteristics of MRI following chemotherapy or other systemic agents,27 few studies are available in the literature.28, 29

Positron emission tomography (PET) with the radionuclide imaging agent 18fluoro-deoxyglucose (FDP) has gained increasing acceptance as a sensitive and accurate imaging technique for several neoplasms, including MPM24, 30, 31, 32, 33, 34; in particular, PET may be superior to CT for defining mediastinal lymph node involvement by MPM 24, 33 and may also help to detect occult extrathoracic disease in both newly diagnosed and previously imaged patients.24, 35 Flores at al reported on the prognostic ability of the standardized uptake value (SUV) of the PET scan.36, 37 Patients with higher SUVs (tumors that were more metabolically active) had a shortened median survival compared to those with a lower SUV. Those with low SUV and epithelial histology had the best prognosis, while those with high SUV and nonepithelial histology fared worst. However, these data were not integrated into a multivariate analysis nor has the technique been applied to patients treated with chemotherapy.

Nonradiologic Definitions of Response 

Another definition of an “active” agent or combination is that the agent or combination improves the quality of life or reverses the symptoms of mesothelioma. In the EMPHACIS trial, 206 of the 448 patients (45%) had a Karnofsky performance status of 70 or 80, meaning that they had significant symptoms attributed to MPM, including chest pain, dyspnea, and weight loss. Among the 337 MPM patients treated on phase II trials by the CALGB, a similar rate of performance status 2 (Karnofsky performance status 70 to 80) was found. In fact, the potential beneficial results of the paclitaxel, gemcitabine, and irinotecan phase II trials of the CALGB were compromised by large numbers of patients with a performance status of 2.38, 39, 40 Thus, the CALGB leadership of the mesothelioma subcommittee decided to restrict entry to future mesothelioma trials to only performance status 90 and 100 patients. The CALGB also decided against studying the quality of life due to cost and manpower restraints and the concern that uncontrolled phase II trials could not give definitive answers. This type of decision has been made by other centers and groups as well, and thus there have been few studies of quality-of-life improvements following chemotherapy. Those that have been performed demonstrated the ability of chemotherapy to improve quality of life. Indeed, a clinical benefit (as measured by reduction in pain and dyspnea) occurred in up to 40% to 50% of patients treated with a three-agent regimen41; in another encouraging report from Byrne et al, 47% of patients treated with cisplatin and gemcitabine had a 30% or greater reduction in the thickness of the pleural rind and improvement in symptoms.42 A follow-up multicenter trial of the same regimen in 53 patients reported only a 17% rate of activity43; quality of life was assessed by the EORTC QLQ-C30 questionnaire and pulmonary function was also evaluated. Only responders to chemotherapy had a significant improvement in pulmonary function, whereas quality of life improved in patients with both PR and stable disease. Steele et al reported a radiographic PR rate of 24% using the single-agent vinorelbine,44 but using the Rotterdam Symptom Checklist, they found that 48% and 76% of patients, respectively, had improvements in respiratory symptoms and in psychosocial functioning.

Reporting for the EMPHACIS trial investigators, Gralla et al found that 93% of patients had three or more of the following symptoms: pain, dyspnea, fatigue, cough, anorexia, and decreased activity.45 Using the Lung Cancer Symptom Scale (LCSS), modified for patients with mesothelioma to include patient reported outcomes (PROs), the authors reported that the two-drug combination was associated with significant and sustained improvement in quality of life and symptom relief (including pain, dyspnea, fatigue, anorexia, and cough). The EMPHACIS investigators also demonstrated that the LCSS-Meso instrument had a very high patient and staff acceptance and recommended its use in future MPM studies. Paoletti et al also reported for the EMPHACIS investigators on the changes in vital capacity (VC), slow vital capacity (SVC), forced vital capacity (FVC), and forced expiratory volume in 1 second (FEV1) as a function of radiographic response.46 Responders in both groups had a significant improvement in pulmonary function tests when compared to those with disease progression. Interestingly, patients with stable disease as their best radiographic response also had a statistically significant improvement in VC, SVC, FVC, and FEV1 compared to patients with disease progression. The Medical Research Council and British Thoracic Society are following up the EMPHACIS trial with a study that will randomize more than 800 patients with malignant mesothelioma to either single-agent vinorelbine, a mitomycin/vinblastine/cisplatin combination, or active supportive care to confirm whether chemotherapy improves either quality or length of life in this disease.47 Unfortunately, this trial is threatened by low accrual.

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Status of Medical Treatment of Mesothelioma Before Pemetrexed 

In the last two decades of the previous century, a multitude of cytotoxic drugs were tested in MPM, both as single agents and within combination regimens; from these earlier studies, mainly small phase II trials enrolling a limited number of poorly staged (due to inadequate imaging procedures) patients, it had become clear that there was a limited, if any, advantage of using a combination of chemotherapy compared to single agents.48

More recently, however, the combination of two drugs, usually an antimetabolite and a platinum derivative, emerged as a de facto standard of treatment for MPM patients,11 even though, once again, the use of doublets of cytotoxic drugs was mainly supported by the results of phase II studies.49 Among the most commonly used doublets, cisplatin (or carboplatin) and gemcitabine,39, 42, 43, 50, 51 as well as raltitrexed and oxaliplatin,52, 53 were the most promising, at least in a first-line setting.54

In a recent review of first line chemotherapy for MPM, Baas clearly showed that, similarly to what has been observed in non-small cell lung cancer,55 all doublets of older agents are probably equivalent,56 with few, unconfirmed, exceptions (Table 4).

Table 4. Representative Older “Doublet” Chemotherapy Regimens Used for MPM
No. of PatientsObjective Response RateMedian Survival Time (mo)
Methotrexate-based combinations
High-dose methotrexate + interferon2429%17
High-dose methotrexate + interferon3921%13
Anthracyclin-based combinations
Doxorubicin + cyclophosphamide3611%8
Doxorubicin + ifosfamide4023%7–8.5
Doxorubicin + cisplatin5919%8.8–10
Doxorubicin + 5-azacytidine3622%13
Doxorubicin + interferon α2416%11
Cisplatin-based combinations
Cisplatin + pirarubicin3915%NA
Cisplatin + DHAC2917%6.4
Cisplatin + irinotecan1527%7
Cisplatin + vinblastine2025%5–19*
Cisplatin + mitomycin C3526%7.7
Cisplatin + interferon4922%6–12
Cisplatin (weekly) + etoposide2524%∼9.5
Cisplatin (weekly) + interferon3027%15
Cisplatin + gemcitabine (q4)2148%10
Cisplatin + gemcitabine (q3)3215%10
Oxaliplatin + vinorelbine2113%NA

Abbreviations: DHAC, dihydroazacytidine; q4, every 4 weeks; q3, every 3 weeks; NA, not available.

Note the small sample sizes and the consistent response rates and survival times.

As far as adding a third (and sometimes a fourth) cytotoxic agent, isolated studies suggested the possibility of improving antitumor activity; indeed, at least four studies41, 57, 58, 59 reported percentages of objective response of at least 20% (32% in the Italian study) using different combination regimens. Although interesting, these latter results should be confirmed in larger phase II and III studies. Furthermore, pemetrexed, a newer drug that has changed the natural history of MPM, has not been investigated in any three- or four-drug regimens.

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New Agents for Therapy of Mesothelioma: Pemetrexed 

Pemetrexed is a new agent whose novel mechanism of action (Fig 1) is the inhibition of glycinamide ribonucleotide formyl transferase (GARFT), which, in turn, leads to purine depletion.60 Although developed as an inhibitor of dihydrofolate reductase (DHFR) (similar to methotrexate) it also inhibits thymidylate synthase (TS) (similar to 5-fluorouracil and the antifolate raltitrexed).61 These other effects of pemetrexed lead to pyrimidine depletion. The combination of purine and pyrimidine depletion by a single drug is unique among antineoplastic agents.62 Pemetrexed enters the cell primarily through the reduced folate carrier, but Wang et al63 demonstrated the presence of a unique high-affinity folate transport mechanism in mesothelioma cells that selectively transports pemetrexed compared to other antifolates and TS inhibitors. This finding also may explain some of the treatment efficacy of pemetrexed in MPM. Once intracellular, pemetrexed undergoes irreversible polyglutamation (mostly to the pentaglutamated form) by folypoly-gamma-glutamate synthase. The polyglutamated pemetrexed is retained within the cell and inhibits GARFT at concentrations of 65 ± 16 nmol/L, whereas nonpolyglutamated pemetrexed inhibits GARFT at 9,300 ± 690 nmol/L. Polyglutamated methotrexate and raltitrexed only inhibit GARFT at 80,000 nmol/L and 132,000 nmol/L, respectively.64 The polyglutamated drug is nearly 100-fold more potent at inhibiting TS than the parent compound, but polyglutamated pemetrexed and the parent compound are equipotent inhibitors of DHFR (Table 5).

Table 5. Effects of Pemetrexed, Raltitrexed, and Methotrexate (polyglutamated or not) on TS, DHFR, and GARFT
CompoundTS (nmol/L)DHFR (nmol/L)GARFT (nmol/L)
Pemetrexed109±9.07.0±1.99,300±690
Pemetrexed Glu51.3±0.37.2±0.465±16
Raltitrexed6.0±0.945±3424,000
Raltitrexed Glu51.4±0.130±3132,000
Methotrexate13,0000.00480,000
MTX Glu5470.0042,500

Abbreviations: TS, thymidylate synthase; DHFR, dihydrofolate reductase; GARFT, glycinamide ribonucleotide formyl transferase; MTX, methotrexate.

Phase I studies exploring three treatment schedules were conducted by Lilly Oncology: daily × 5 every 21 days, weekly × 4 every 42 days, and once every 21 days. The 10-minute infusion once every 21 days was found to be the schedule that allowed the delivery of the highest dose intensity65 and has been recommended for most phase II and III trials. The current recommended dose is 500 mg/m2 as a 10-minute intravenous (IV) bolus every 21 days. The dose-limiting toxicities (DLTs) on this schedule were neutropenia, thrombocytopenia, and fatigue. In a review of 880 patients treated at or above the 500-mg/m2 dose level, myelosuppression was the principal drug-related toxicity, with a frequency of grade 3/4 neutropenia of 40% to 50%, and grade 3/4 thrombocytopenia of 15%. Acneiform rashes were seen in about 20% of patients and were prevented with dexamethasone 4 mg twice daily for 3 days, starting 1 day prior to treatment. Pemetrexed has demonstrated activity in multiple tumor types,66 including MPM,67 non-small cell lung cancer,68 and breast,69 colorectal,70, 71 pancreas, gastric,71 bladder, head and neck, and cervical cancers.72

In a phase I and pharmacokinetic trial of pemetrexed with cisplatin, patients with solid tumors were enrolled into one of two cohorts73; the first cohort received both pemetrexed and cisplatin on day 1 of a 21-day cycle, and the second cohort received pemetrexed on day 1 and cisplatin on day 2 of a 21-day cycle. Forty patients were enrolled into the day 1 cohort; the maximum tolerated dose was reached at 600 mg/m2 pemetrexed and 100 mg/m2 cisplatin, with DLTs of thrombocytopenia and febrile neutropenia. Eleven patients were enrolled into the day 1/2 cohort (pemetrexed day 2). The toxicity of the day 1/2 schedule, including two therapy-related deaths, led to the adoption of the day 1 schedule. Partial responses were seen in both cohorts in a variety of cancers, including five of 13 patients with MPM. Patients with pleural effusions were not excluded from this study and the toxicity and pharmacokinetics of these patients did not differ from that of other patients. Based on these phase I results, a randomized phase III trial of cisplatin plus pemetrexed versus cisplatin in MPM patients was initiated in late 1998.

While these trials were being conducted, it became clear that severe gastrointestinal toxicity and severe neutropenia combined in the occasional patient to cause drug-related death (DRD). Studies with other agents inhibiting DHFR and TS suggested that poor nutritional status contributed to the likelihood of similar types of severe toxicity.73, 74, 75, 76, 77

Investigating the relationship between folic acid supplementation and toxicity led the authors to conclude that the addition of folic acid probably reduced toxicity while preserving antitumor activity. These clues led Lilly biostatisticians and clinicians to conduct an analysis of the entire pemetrexed database of 880 patients in mid 1999. The analysis suggested an increased risk of DRD in patients who had the combination of severe gastrointestinal toxicity and severe neutropenia. A multivariate analysis based on 880 patients, none of whom had received folic acid and vitamin B12 supplementation, was performed to determine which clinical and laboratory factors might correlate with DRD; Bunn et al concluded that grade 4 neutropenia accompanied by grade 3/4 infection, grade 3/4 diarrhea, and tumor type were all significantly associated with DRD.77 A second multivariate analysis was performed by Niyikiza et al on 305 patients who had baseline levels of homocysteine (HCY), methylmalonic acid (MMA), and cystathionine (CTH) measured and recorded. These levels reflect deficiency states of folic acid, and vitamins B12 and B6, respectively. Multiple factors potentially affecting the risk of severe toxicity were included in the analysis. Patients who received folic acid supplementation at any point during therapy or who received any dosing regimen other than pemetrexed 500 to 600 mg/m2 were removed from the analysis, leaving a final sample size of 246 patients. Results showed that an elevated HCY level at baseline was highly correlated with severe toxicity (either grade 3/4 neutropenia, neutropenia accompanied by infection, or grade 3/4 diarrhea). When MMA levels were also raised, the risk of the toxicities substantially increased.78 However, some patients with severe toxicity had HCY and MMA levels at the upper end of the normal range, suggesting that they could be relatively folic acid- and/or vitamin B12-deficient and, thus, also at increased risk for severe toxicity. Therefore, a decision was made in December 1999 to require supplementation with dietary folic acid (350 to 1,000 μg) and vitamin B12 (1,000 μg intramuscular injection) for all patients receiving pemetrexed. Vitamin B12 was included in the supplementation because approximately 15% of patients were vitamin B12-deficient and were not expected to achieve lower HCY levels with the supplementation of daily folic acid only. A recent safety assessment of the impact of folic acid and vitamin B12 supplementation on the severe toxicities related to pemetrexed therapy confirmed the hypothesis that the administration of daily folic acid and vitamin B12 reduces HCY levels and results in a significant reduction of death and toxicity associated with pemetrexed.79

The phase III EMPHACIS trial was reported in abstract form in 2002 and in final form in 2003.11 The trial exceeded accrual expectations and randomized 456 eligible patients to pemetrexed 500 mg/m2 IV bolus over 10 minutes plus cisplatin 75 mg/m2 administered every 3 weeks (n = 226) or to single-agent cisplatin 75 mg/m2 plus saline (to preserve blinding) administered every 3 weeks (n = 222); eight patients never received therapy. As noted earlier, the trial was modified in December 1999 to require supplementation with 350 to 1,000 mg folic acid orally per day and 1000 mg vitamin B12 intramuscularly every 9 weeks in both arms of the study.

As shown in Fig 2, a statistically significant longer median survival time was observed in all patients receiving the combination therapy versus those receiving cisplatin alone (12.1 months v 9.3 months, respectively; hazard ratio [HR] = 0.77; P = .020). One-year survival rates were also higher in the pemetrexed/cisplatin group (50.3% v 38.0%). Median time to progressive disease was significantly longer for patients in the pemetrexed/cisplatin arm compared with those in the cisplatin-only arm (5.7 months v 3.9 months; HR = 0.68, P = .001). Tumor response rates (as measured by an average 30% reduction in the thickness of the pleural rind measured at up to nine points on the CT scan) were 41.3% in the combination arm versus 16.7% in the cisplatin-alone arm (Fisher’s exact P <.001). Time to disease progression, pulmonary function,46 and quality of life45 also improved in a statistically significant manner in pemetrexed/cisplatin-treated patients.

  • View full-size image.
  • Figure 2. 

    Survival curve relative to the EMPHACIS trial, showing a statistically significant longer median survival time for the patients who received the Pemetrexed/cisplatin combination versus cisplatin alone: 12.1 months versus 9.3 months, respectively (hazard ratio [HR] = 0.77; P = .020).

Serious adverse events, including DRD, World Health Organization (WHO) grade 3/4 neutropenia, thrombocytopenia, nausea, and vomiting were more common with pemetrexed/cisplatin than with cisplatin alone (22.5% v 7.2%, respectively). Supplementation with folic acid and vitamin B12 resulted in consistent declines in toxicity. The relative risk of select toxicities were calculated for both the intent-to-treat population and for the fully supplemented subgroup are shown in Fig 3. These results indicate that pemetrexed plus cisplatin treatment that includes supplementation with folic acid and vitamin B12 provides a superior risk-benefit ratio for MPM patients. Moreover, the improvements in tolerability did not come at the expense of decreased efficacy. Median survival times for patients who received supplementation at any time throughout the median of six cycles of treatment were 13.2 months for patients treated with pemetrexed/cisplatin and 9.4 months for patients treated with cisplatin alone (HR = 0.71, log-rank P = .022).

  • View full-size image.
  • Figure 3. 

    Relative risk of select toxicities calculated for both the intent-to-treat population (randomized and treated, n = 448) and for the fully folate- and vitamin B12-supplemented subgroup (patients supplemented with FA/B12; n = 331) within the EMPHACIS trial. SAE, serious adverse effects; FA, folic acid.

This trial had several important features that support the credibility of the results and the relevance to general oncology. The MPM patient population was typical in terms of age, performance status, and histology. The median survival for cisplatin-treated patients was consistent with (if not slightly better than) previous reports. The methods of response assessment by serial CT scan, modified from the method used by Byrne et al,22 provide a good and reproducible model for future trials, and the serial assessment of health-related quality of life and pulmonary function provided important supplemental information about the clinical benefits of pemetrexed/cisplatin therapy. These trial results not only establish pemetrexed/cisplatin therapy as the new standard of care for patients with advanced mesothelioma,80 but also provide an important foundation for exploring the use of this combination for induction chemotherapy with MPM patients who are candidates for curative surgery.

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New Agents for Therapy of Mesothelioma: Ranpirnase 

Ranpirnase (Onconase; Alfacell, Bloomfield, NJ) is an antineoplastic ribonuclease derived from frog eggs,81 which has antitumor activity in mesothelioma. Indeed, in a multicenter trial of ranpirnase (480 μg/m2 IV weekly) in 105 patients, four of 81 patients with evaluable disease had a PR, two had a minor response, and 35 had stabilization of previously progressive disease.8 For the entire group, the median survival duration was 6 months, and the 1- and 2-year survival rates were 34% and 22%, respectively. When the 81 patients who fell within groups 1 to 4 of the CALGB prognostic categories were analyzed separately, the median, and 1- and 2-year survival rates were 8.3 months, and 42% and 27%, respectively. The CALGB data for the 1- and 2-year survival rates in groups 1 to 4 were 27% and 12%, respectively.

In a phase III trial 157 patients with advanced disease were randomly assigned to receive ranpirnase (480 μg/m2 IV weekly) or doxorubicin (60 mg/m2 IV every 3 weeks). In a preliminary report, the median survival time (∼8 months) and the 1- and 2-year survival rates were not significantly different between the two groups. However, the two arms were imbalanced, with twice as many patients with poor prognosis (CALGB groups 5 and 6) in the ranpirnase group than in the doxorubicin group. Subgroup analysis excluding these poor-prognosis patients revealed a trend in the median survival (P = .1) favoring ranpirnase over doxorubicin (11.6 v 9.6 months).82 Ranpirnase continues to be tested in a phase III trial in MPM; the new study design compares doxorubicin plus ranpirnase versus doxorubicin alone and the study accrual goal is 240 patients.

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Newer Agents: From the Bench to the Bedside 

Epidermal Growth Factor Receptor Pathway Inhibitors 

The epidermal growth factor receptor (EGF-R) is a transmembrane glycoprotein belonging to the ErbB family of tyrosine kinase proteins.83, 84 This family includes four members: the EGFR (also known as ErbB1/HER1), ErbB2/neu/HER2, ErbB3/HER3, and ErbB4/HER4. Each of these proteins possesses three different domains: the extracellular domain, which is involved in recognizing and binding the ligands (epidermal growth factor [EGF), the transforming growth factor-alpha [TGF-α] for ErbB1) that are able to activate the receptor; the membrane spanning sequence, which is involved in the interaction between receptors; and the intracellular domain, in which resides the enzymatic activity of the tyrosine kinase that is able to phosphorylate tyrosine residues on different intracellular adaptor proteins and the receptor itself.85, 86

Upon binding with a variety of ligands, receptor dimerization, which is essential for the subsequent generation of intracellular signal, is rapidly induced; receptor pairings can consist of two molecules of the same type (homodimers) or two molecules of different types (heterodimers); receptor dimerization is followed by activation of intrinsic protein tyrosine kinase activity, tyrosine phosphorylation, and activation of intracellular signal transduction pathways, such as the PI3K/AKT and the ras/raf/MEK/MAPK pathways. Ultimately, the activation of the EGFR mediates several tumor cell functions, including proliferation, survival, induction of angiogenesis, invasion, and metastasis.83, 84 The EGFR is broadly overexpressed on many human tumors, especially of epithelial origin. It is of considerable debate as to whether such overexpression per se affects survival (negatively or positively).

Several different anti-EGFR therapies have been developed in the past two decades, including murine or humanized anti-EGFR antibodies87, 88 and, more recently, EGFR-tyrosine kinase inhibitors (EGFR-TKIs).89, 90 EGFR-TKIs apparently act by directly binding to either the adenosine triphosphate (ATP) and/or the enzyme-substrate binding site and inhibiting tyrosine kinase phosphorylation; however, since regression in response to anti-EGFR-TKIs can be observed also in tumors with very low levels of expression of EGFR, inhibition of other TKIs downstream of the EGFR may also be responsible. One orally active quinazoline derivative, gefitinib (Iressa, AstraZeneca, Macclesfield, England) has recently been approved in the United States for use as third-line therapy in non-small cell lung cancer, and a second agent, OSI 774/erlotinib (Tarceva, OSI Pharmaceuticals/Genentech/Roche, South San Franscisco, CA) was approved in November 2004.91, 92

Since the early 1990s, MPM tissue and cell lines have been known to overexpress EGFR; Govindan et al showed by immunohistochemistry that 11 of 13 epithelioid, two of four biphasic, and one of seven sarcomatoid MPM overexpressed EGFR.93 Jånne et al demonstrated activity of both agents against MPM cell lines.94 The CALGB has completed a phase II trial of gefitinib in MPM patients but reported only one or two responses in 44 patients.95 Likewise, the Southwest Oncology Group has completed a phase II study of erlotinib in MPM.96 Although both studies are pending final publication, the low level of single-agent activity demonstrated to date makes it unlikely that EGFR inhibition will play a major role in the therapy of MPM.

Platelet-Derived Growth Factor Receptor Pathway Inhibitors 

Platelet-derived growth factor (PDGF) and PDGF-receptors (PDGF-R) are a family of ligands and receptors. The PDGF-Rs occur as α and β homodimers or α/β heterodimers and, again, belong to the protein tyrosine kinase family of receptors.97 Like the EGFRs, these proteins have a variable extracellular domain while the intracellular portion of each receptor contains a conserved tyrosine kinase domain. A similar domain is found in the colony-stimulating factor-1 (CSF-1) and c-kit receptors, which are closely related to PDGF-R.97

Overactivity of the PDGF/PDGF-R axis has been implicated in certain malignancies,98 including MPM.99 Moreover, normal mesothelial cells predominantly express PDGF α-receptor mRNA and protein, whereas most malignant mesothelioma cell lines produce PDGF β-receptor mRNA and protein and are not only capable of PDGF β-receptor transcription but of α-receptor transcription as well.99 The clinical effects of these differences are at present still unknown.

Several inhibitors of the PDGF/PDGF-R pathway are under clinical development, including SU101, GFB-111, imatinib, and PTK 787. SU101 (leflunomide, formerly developed by Sugen Inc [Pfizer, La Jolla, CA]) inhibits a variety of different tyrosine kinases, including PDGF-R.100 Several phase I-II studies in solid tumors were performed before drug development was discontinued. GFB-111101 is another drug that selectively binds PDGF (and, at a lesser extent, vascular endothelial growth factor [VEGF]). It will be an interesting drug to test since both pathways appear to be activated in MPM.

Imatinib mesylate (Gleevec, Novartis Pharma, Parsippany, NJ) is a highly selective inhibitor of the bcr/abl-mutated tyrosine kinase, but it also inhibits certain activating mutations of the c-kit receptor and of PDGF-R. With its remarkable activity against chronic myeloid leukemia and gastrointestinal stromal tumors,102, it was the first TKI approved by the US Food and Drug Administration (FDA). In vitro experiments demonstrated that imatinib can cause apoptosis and death via inhibition of the AKT/PIK3 pathway in MPM cell lines, enhance sensitivity of MPM cell lines to chemotherapy (L. Mutti, personal communication), and synergize with gemcitabine.103 However, the University of Chicago Cancer Research Center has completed a phase II study of imatinib in 17 MPM patients, mostly with chemotherapy refractory disease. No PRs or CRs were seen and at least one patient seemed to experience explosive tumor growth while on the drug104; similar, negative, results have been observed in Italy.105 PTK 787 has completed phase II testing in metastatic renal cancer106 and has demonstrated definite antitumor activity. In late 2003, the CALGB opened a phase II trial of this agent in MPM in chemotherapy-naive patients.

Vascular Endothelial Growth Factor Signaling Pathway Inhibition 

The rationale for inhibition of VEGF signaling in cancer therapy has been extensively and recently reviewed.107, 108, 109, 110, 111 In the case of MPM, the rationale is quite strong for inhibiting this pathway. VEGF, VEGF-C, and their receptors are overexpressed in MPM tissue, cell lines, and pleural effusions, as well as in some nonmalignant mesothelial specimens and effusions112, 113, 114, 115, 116; furthermore, it has been recently demonstrated that simian virus 40 (SV40) can cause VEGF release in SV40-positive MPM cells, and that the entire viral genome is required for this effect.117

Neutralizing antibodies against VEGF receptors significantly reduced MPM cell growth in vitro.116 In a nude mouse model, pretreatment with an anti-VEGF receptor antibody was able to reduce malignant pleural effusion in vivo.118 Circulating VEGF levels and tissue microvascular density, which significantly correlated with VEGF and VEGF-C levels, are negative prognostic factors in MPM patients.113, 114 Since VEGF receptors are found on megakaryocytes,119 there is some speculation that elevated circulating VEGF levels are the cause for the common thrombocytosis seen in MPM.

At least three angiogenesis inhibitors, SU5416, bevacizumab, and thalidomide, have been or are in clinical trials of MPM. SU5416 (formerly developed by Sugen) inhibits the tyrosine kinase activity of the VEGF receptor flk-1.120 The University of Chicago Cancer Research Center studied SU5416 (145 mg/m2 IV over 1 hour with high-dose dexamethasone pre-medication, twice weekly, every 4 weeks for a minimum of two courses) in 22 minimally pretreated patients and observed PRs in three patients and disease stabilizations in five others.121 A review of SU5416-induced adverse events within phase II studies showed an excessive risk of thrombosis,122 and when a phase III trial of SU5416 added to standard therapy for metastatic colon cancer did not show a survival advantage, development of the drug was halted.123

Bevacizumab (Avastin, Genentech, South San Francisco, CA) is a recombinant human anti-VEGF monoclonal antibody that blocks the binding of VEGF to its receptors. Although prior phase III trials in breast and lung cancer were negative, a phase III trial of irinotecan/5-fluorouracil/leucovorin ± bevacizumab in 815 metastatic colorectal cancer patients showed a striking inhibitory survival advantage of nearly 5 months in favor of the bevacizumab arm.124 Ten investigative sites in the United States, sponsored by the National Cancer Institute and led by the University of Chicago Cancer Research Center, are evaluating cisplatin/gemcitabine with or without bevacizumab chemotherapy in a double-blind, placebo-controlled, randomized phase II trial in patients with both pleural and peritoneal mesothelioma. Of the planned accrual of 106 patients, 103 have entered the trial.

Thalidomide, a derivative of glutamic acid, was marketed in Europe as a sedative hypnotic in the early 1960s. It was withdrawn when phaecomyelia (congenital developmental abnormalities of the limb buds) occurred in infants whose mothers used the drug during pregnancy. In retrospect, that abnormality was due to lack of development of the angiogenic system of the extremities. Following recognition of its beneficial effects in treating graft-versus-host disease, erythema nodosum leprosum and human immunodeficiency wasting syndrome, it was FDA-approved, albeit under strict regulation. Recognition of its anti-angiogenetic properties125 led to its evaluation in the treatment of multiple myeloma,126 as well in other solid malignancies,127 such as renal cell carcinoma.128 A number of other biologic actions have been documented for thalidomide, including the suppression of basic fibroblast growth factor and VEGF-driven angiogenesis, and the inhibition of the production of tumor necrosis factor-α. Thalidomide is being studied in MPM at the University of Maryland, in Australia,129 and at the Netherlands Cancer Institute. Although no published results are yet available, preliminary communications suggest a lack of activity.

Targeting the Hepatocyte Growth Factor and Downstream Signaling Pathways 

Discovered in 1990 by the Vande Woude laboratory at the National Cancer Institute,130 hepatocyte growth factor/scatter factor (HGF/SF) is now recognized as a multifunctional growth factor that can induce many biologic functions that are critical to the malignant phenotype, including cell scattering, invasion, proliferation, and morphogenesis. The c-Met receptor is a tyrosine kinase; it is the only known receptor for HGF/SF and it mediates all HGF/SF-induced biologic activities. Upon HGF/SF stimulation, the c-Met receptor is tyrosine-phosphorylated, which is followed by the recruitment of multiple signaling molecules to its multiple cytoplasmic domains. This phosphorylation, in turn, leads to the activation of a complex network of intra- and extracellular responses.131, 132

c-Met gene amplification can be found in only a few primary carcinomas such as papillary renal cancer and thyroid cancer, but it is present in a significant proportion of metastasis from lung, breast, and prostate cancers. Plasma HGF levels are elevated in many malignancies and an HGF/Met autocrine loop has been reported in a number of cancers, including MPM; both HGF plasma levels and tissue expression have been found to be negative prognostic factors in a variety of human cancers.133

An HGF/SF/c-Met autocrine loop has been demonstrated both in MPM cell lines and in MPM tissue samples,134, 135, 136 and their overexpression has been associated with an increased microvessel density, as well as with increased matrix metalloproteinases expression.137, 138, 139

Cacciotti et al140 demonstrated that SV40 infection of human mesothelial cells induces Met receptor activation via an autocrine loop. When SV40 replicates in vitro and infects adjacent human mesothelial cells, it induces an HGF-dependent Met activation and cell-cycle progression into S-phase. Cacciotti et al hypothesized that a limited number of SV40-positive cells may be sufficient to direct normal human mesothelial cells toward malignant transformation.140

The only specific Met inhibitor identified to date is a TKI, SU11274 (Sugen Inc),141 but solubility problems preclude clinical development. An antibody to the c-Met receptor is under development.142 However, the signaling pathway of HGF/SF/c-Met and other tyrosine kinases may be also inhibit the downstream pathway by interfering with the PI3K/AKT pathway. The PI3K/AKT pathway is downstream of many of the above receptor activation-mediated signaling pathways in MPM and thus is another potential target for cancer treatment (D. Barbone, manuscript submitted).

Targeting the mTOR 

In a report on the gene expression profile of 16 MPM specimens, Singhal et al15 found that eLF-4A1, eLF-4E, and eLF-4G (all components of the eLF-4 complex, which is involved in the translation of mRNA) are upregulated 1.7- to 3.8-fold in MPM tissues. The PI3K-AKT pathway is activated by many growth factors and interacts with mTOR (mammalian target of rapamycin) a 289,000-kd protein. mTOR, in turn, phosphorylates p70s6 kinase and releases the eLF-4 complex to allow efficient protein translation and subsequent cell growth.143 Rapamycin, a natural macrolide approved for human use to prevent allograft rejection, is a potent inhibitor of mTOR. CCI779 (Wyeth Laboratories, Philadelphia, PA)144 and RAD 001 (Novartis Pharmaceuticals, Parsippany, NJ)145 are non-immunosuppressive analogues of rapamycin under study as anticancer agents.146 CCI 779 was studied in 111 patients with metastatic renal cancer and caused a 7% PR rate and a 26% minor response rate.147 Given the upregulation of the eLF-4 in MPM tissues and the activity of CCI-779, a phase II study in MPM seems logical and worthwhile.

Targeting the Proteasome/Ubiquitin Pathway 

The rapid, efficient, and irreversible elimination of damaged or obsolete proteins is a key mechanism for controlling the activation or repression of a number of key cellular processes. Obsolete or damaged proteins are ubiquinated and then processed by the proteasome complex. The primary protein degradation pathway of the cell (accounting for ∼80% of all proteins) is via this structure.

The proteasome is a large, multi-protein particle, present in both the cytoplasm and the nucleus of all eukaryotic cells, composed of two functional components: a 20S core catalytic complex and a 19S regulatory subunit. Proteins to be degraded are marked with five or more ubiquitin chains, which bind to a receptor on the 19S complex; once recognized by the regulatory complex, ubiquitin chains are removed and the protein is denatured. The protease activity resides in a channel at the center of the 20S complex, which is formed from four stacked, multi-protein rings. The outer α subunit rings form a narrow channel that allows only denatured proteins to enter the catalytic chamber formed by the central β subunit rings. Inside the catalytic chamber, proteins are surrounded by six protease-active sites (three on each β subunit ring) that complete the degradation process.148 Proteolysis by the proteasome/ubiquitin pathway is a key metabolic process, and elimination of proteasome activity results in cell death. Cyclins, cyclin-dependent kinase inhibitors, and tumor-suppressor genes (eg, cyclin B1, p21Waf1/Cip1, p27, p53, and IκB) are all processed through this pathway, and the inhibition of their degradation sensitizes cells to apoptosis.149

By inhibiting the proteasome, the nuclear factor κB (NF-κB) signaling pathway is also inhibited. NF-κB is a cellular survival factor whose transcription is prevented in quiescent cells through binding by a specific inhibitor, IκB, which sequesters the NF-κB p50/p65 heterodimer in the cytoplasm; in response to cellular stresses, IκB releases NF-κB and itself undergoes proteasome-mediated degradation.150 Free NF-κB then translocates to the nucleus to activate genes that protect the cell from apoptosis and promote cell growth and differentiation, as well as the synthesis of growth factors and angiogenesis factors.148 Dysregulation of the NF-κB signaling is an important feature of some hematologic malignancies,151, 152 and activation of this pathway can stimulate proliferation and/or reduce the effectiveness of chemotherapy and/or radiation.149 Targeting the NF-κB signaling is an attractive approach in MPM since asbestos fibers are able to cause the translocation of NF-κB p65 subunit into the nucleus, and they can increase NF-κB DNA binding activity in rat lung epithelial and pleural mesothelial cells.153 In addition, the cyclin-dependant kinase inhibitor p27 is degraded by the proteasome, and decreased p27 levels are observed in MPM. Inhibition of the proteasome raises p27 levels leading to apoptosis. For example, when fibroblasts transformed by the oncogenic virus SV40 are treated with a proteasome inhibitor, p27 levels increase and apoptosis ensues.154 Finally, recent data suggest that PS-341 could potentiate the antitumor activity of the new topoisomerase-I inhibitor gimatecan in an in vitro MPM model system.155

Bortezomib (PS-341, Velcade, Millennium Pharmaceuticals, New York, NY) is a potent and selective inhibitor of the proteasome. Preclinical and phase I and II studies have been completed and the drug has recently been approved by the FDA for the treatment of chemotherapy-refractory multiple myeloma.156 The current recommended schedule of 1.5 mg/m2 IV twice per week for 2 weeks every 21 days may induce cumulative neuropathy.157 Phase II studies of bortuzimib in MPM either as a single agent or combined with chemotherapy are indicated. The starting dose should be 1.3 mg/m2 twice daily for 2 of every 3 weeks, with cautious dose escalation in the absence of neuropathy.

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Conclusions 

In concluding a review on new approaches for MPM treatment in 2002,158 Nowak et al complained of “the lack of effective conventional modalities,” that, however, “has permitted enrollment of patients in clinical trials of novel therapies”; today, only 3 years later, the situation has changed radically.

We now have a new, active, standard of treatment—pemetrexed plus cisplatin—which improves MPM patients’ survival. Furthermore, although in its infancy, molecular-based targeted therapy holds promise, with a number of new agents reaching the clinic in the near term.

Of course, the whole picture is still unsatisfactory. Globally, no patient with unresectable disease appears to be cured, overall median survival time is still poor, and some of the promising newer agents seem to have failed (ie, Gleevec as a single agent).

Despite this, the therapeutic nihilism that surrounded MPM is no longer justified; we can now rely on several active drugs, and the scenario of a molecular-tailored therapy is within our reach. For the first time, we have the realistic hope of making another set of steps forward in the struggle against this disease.

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PII: S0093-7754(05)00080-1

doi:10.1053/j.seminoncol.2005.02.010

Seminars in Oncology
Volume 32, Issue 3 , Pages 336-350, June 2005

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