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Phase II Study of Pemetrexed Plus Carboplatin in Malignant Pleural Mesothelioma

Giovanni L. Ceresoli, Paolo A. Zucali, Adolfo G. Favaretto, Francesco Grossi, Paolo Bidoli, Guido Del Conte, Anna Ceribelli, Alessandra Bearz, Emanuela Morenghi, Raffaele Cavina, Maurizio Marangolo, Hector J. Soto Parra, Armando Santoro

From the Department of Medical Oncology and Hematology and Medical Statistics Unit, Istituto Clinico Humanitas Istituto di Ricovero e Cura a Carattere Scientifico, Rozzano; Department of Medical Oncology, Unit 2, National Cancer Institute, Milan; Department of Medical Oncology, University Hospital, Padua; Department of Medical Oncology, National Institute for Cancer Research, Genoa; Department of Medical Oncology, Azienda Ospedaliera, Trieste; Department of Medical Oncology, Unit A, Regina Elena Cancer Institute, Rome; Department of Medical Oncology, Unit A, National Cancer Institute, Aviano; and Department of Oncology and Hematology, Istituto Oncologico Romagnolo, Ravenna, Italy

Address reprint requests to Giovanni Luca Ceresoli, MD, Department of Medical Oncology and Hematology, Istituto Clinico Humanitas Istituto di Ricovero e Cura a Carattere Scientifico, Rozzano, Milan, Italy; e-mail: giovanni_luca.ceresoli{at}humanitas.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: This multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM).

PATIENTS AND METHODS: Chemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m² and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B₁₂ supplementation. Pemetrexed was provided within the Expanded Access Program.

RESULTS: A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to progression was 6.5 months; median overall survival time was 12.7 months. Compliance to treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible.

CONCLUSION: Treatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM. Disease control rate, time to disease progression, and overall survival were similar to the results achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination could be an alternative option for these patients.

	INTRODUCTION

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Malignant pleural mesothelioma (MPM) is an aggressive tumor that usually has a poor prognosis. The incidence of MPM is increasing throughout most of the world, and it is predicted that it will increase in the next 10 to 20 years.¹ Only a minority of patients are eligible for radical surgery. Encouraging results have been reported with multimodality approaches, including extrapleural pneumonectomy, adjuvant chemotherapy, and hemithoracic radiotherapy,² but significant morbidity and mortality have been associated with these treatments³; furthermore, no randomized studies exist to support this approach. The efficacy of radiotherapy has not been proven.⁴ Most chemotherapy studies have used either single agents or combination regimens in the setting of small phase II trials; the rates of objective tumor regression have generally been less than 20%, with no significant impact on median survival.^5,6 In a meta-analysis of early trials, cisplatin was found to be the most active single drug.⁷ Carboplatin, a platinum analog that is better tolerated and easier to administer, produced similar response rates in a few phase II studies.^8-10 Pemetrexed, a novel multitargeted antifolate,¹¹ was shown to have activity as a single agent in a phase II trial in patients with MPM¹² and in phase I trials in combination with platinum analogs.^13,14 A large phase III trial testing pemetrexed and cisplatin versus cisplatin alone in 448 chemotherapy-naive patients with MPM showed a significant advantage with the combined regimen in terms of survival, time to progression (TTP), and response rate.¹⁵ Recently, the combination of raltitrexed and cisplatin as first-line treatment was reported to improve overall survival (OS) compared with cisplatin, providing further support for cisplatin with an antifolate as a reference regimen in patients with MPM.^16,17

Pemetrexed and carboplatin were found to be synergistic in preclinical models¹⁸ and active and well tolerated in a phase I trial in MPM patients,¹⁴ although no vitamin supplementation was administered. The recommended dose of the combination for phase II studies was pemetrexed 500 mg/m² and carboplatin area under the plasma concentration-time curve (AUC) 5 mg/mL/min. This study was designed to explore, in a large series of patients, the efficacy of the combination of pemetrexed and carboplatin as front-line therapy in patients with MPM. Pemetrexed was provided by Eli-Lilly (Indianapolis, IN) within the Expanded Access Program. The Expanded Access Program was a nonrandomized open-label safety study of pemetrexed as a single agent or in combination with cisplatin or carboplatin; patients were assigned to a treatment arm based on the investigator's clinical decision.

	PATIENTS AND METHODS

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Patient Selection
Patients were eligible if they had histologically proven MPM and were not candidates for curative surgery. The presence of unidimensionally and/or bidimensionally measurable disease was mandatory. Eligibility criteria included age older than 18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, and an estimated life expectancy of 12 weeks. An adequate bone marrow reserve was required, with absolute neutrophil count (ANC) 1.5 x 10⁹/L, platelets 100 x 10⁹/L, and hemoglobin 9 g/dL. Creatinine clearance, which was calculated by the Cockroft and Gault formula, had to be 45 mL/min; bilirubin had to be 1.5x the upper limit of normal (ULN); and ALT or AST had to be 3x ULN (AST could be elevated to 5x ULN in patients with known hepatic metastases). Prior systemic or intracavitary chemotherapy, documented brain metastases, serious comorbidities, or other malignancies were not allowed. Patients were also excluded if they were unable to discontinue administration of aspirin and/or other nonsteroidal anti-inflammatory agents for 2 days before (5 days for long-acting agents), the day of, and 2 days after the dose of pemetrexed.¹¹ Patients with a measurable recurrence after surgery were considered eligible; prior palliative radiotherapy was permitted.

Written informed consent was obtained from each patient before entering the study. The study was conducted after approval by the appropriate ethical review boards. Recommendations of the Declaration of Helsinki for biomedical research involving human patients were also followed.

Study Design
Our study was planned as a multicenter phase II trial of the combination of pemetrexed and carboplatin as front-line treatment in patients with MPM. Patients were enrolled prospectively from eight Italian institutions. The primary end point of the study was tumor response rate (RR). Secondary end points included toxicity, TTP, and OS.

Treatment
Pemetrexed and carboplatin were both administered on day 1, every 21 days. Pemetrexed was administered intravenously at a dose of 500 mg/m² over 10 minutes, followed 30 minutes later by carboplatin, which was administered as a 30-minute intravenous infusion at an AUC 5 mg/mL/min. All patients were supplemented with folic acid and vitamin B₁₂; folic acid was taken orally (350 to 600 µg daily) beginning at least 1 week before the first dose of chemotherapy and was continued throughout the duration of treatment for the study. Vitamin B₁₂ was administered intramuscularly at least 1 week before the first dose of chemotherapy and was administered approximately every 9 weeks throughout study. Dexamethasone, at a dose of 4 mg twice daily, was administered orally the day before, the day of, and the day after each chemotherapy treatment. Salicylates and nonsteroidal anti-inflammatory agents were not allowed during the 2 days before (5 days for long half-life agents), the day of, and the 2 days after treatment. Standard antiemetic prophylaxis with intravenous 5-hydroxytryptamine-3 antagonists was administered before chemotherapy.

Dose adjustments at the start of a subsequent cycle of therapy were based on hematologic and nonhematologic toxicity observed during the preceding course. Any patient requiring a dose reduction continued to receive a reduced dose for the remainder of the study. Dose delays of up to 42 days were permitted to allow recovery from toxicity. ANC had to be 1.5 x 10⁹/L and platelets had to be 100 x 10⁹/L before the start of any cycle. On recovery, patients with a nadir ANC less than 0.5 x 10⁹/L and platelets 50 x 10⁹/L received 75% of the previous pemetrexed dose or AUC 4 for carboplatin. Patients with a platelet nadir count less than 50 x 10⁹/L and any ANC received 50% of the previous pemetrexed dose or AUC 3 for carboplatin. If a recurrence of grade 3 or 4 thrombocytopenia or neutropenia was observed after two dose reductions, the patient was withdrawn from study. In the event of grade 3 or 4 nonhematologic toxicities, treatment was delayed until there was resolution to grade 1 or less before proceeding. Therapy was then resumed at 75% of the previous dose level (AUC 4 for carboplatin), if deemed appropriate by the treating physician. Creatinine clearance, which was calculated by the Cockroft and Gault formula, was evaluated before each dose. If a patient developed a value of less than 45 mL/min, then the next cycle was delayed until the creatinine clearance had returned to 45 mL/min.

Patient Assessment
Baseline assessment included a complete medical history and physical examination and CBC and chemistries. Creatinine clearance was calculated at baseline and also before each course of treatment. A CBC was taken weekly while patients were on treatment. A chest and abdomen computed tomography (CT) scan was performed at baseline. Patients were staged according to the TNM staging system proposed by the International Mesothelioma Interest Group.¹⁹

Best tumor response was evaluated for patients with bidimensionally measurable disease, unidimensionally measurable disease, or both according to the same criteria used by Vogelzang et al¹⁵ in the cisplatin/pemetrexed trial. No confirmatory scans were conducted on patients exhibiting partial response or stable disease (SD).

Treatment toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria version 2.0 grading system.²⁰ Dose-intensity (DI) was assessed separately for pemetrexed and carboplatin in patients receiving at least two cycles of chemotherapy. For pemetrexed, DI was calculated as median dose in milligrams per square meter per week. For carboplatin, DI was reported as the median AUC per week. The percentage of planned DI delivered for both drugs was also calculated and reported as relative DI (RDI).

After completion of the study treatment, patients were evaluated every 2 months with chest and abdomen CT scans until disease progression. Patients were also observed for survival until death or last contact if still alive. Second-line therapy was not planned in this trial. TTP was defined as time from study entry (first day of study treatment) until time of disease progression (as shown by radiologic or clinical examination) or death from any cause. Patients without any evidence of progressive disease were censored at the date of the last follow-up. OS was calculated as the time from study entry until death from any cause; patients who were alive on the date of last follow-up were censored on that date.

Statistical Analyses
The sample size of the trial was established according to the one-arm binomial sample model.²¹ The primary end point of the study was the response rate; response analysis was conducted on an intent-to-treat basis. A rate of 15% was considered to be ineffective, whereas a rate of 30% was considered to be of potential interest. This design yielded an = .05 with 95% power. According to this model, at least 98 patients had to be enrolled onto the study. The planned accrual period was 24 months. Ninety-five percent CIs for response rates were calculated.²² Actuarial survival curves were generated using the Kaplan-Meier method.²³ Median follow-up time was estimated with the use of the inverse Kaplan-Meier method.²⁴ Response and survival rates were analyzed according to the following variables: age (< 65 v 65 years, and as a continuous variable), sex, ECOG PS (0 v 1 to 2), histology (epithelial v nonepithelial), stage (II to III v > III), and European Organisation for Research and Treatment of Cancer (EORTC) prognostic model for MPM²⁵ (good v poor score). All parameters, except for age, were analyzed as categoric variables. The Fisher's exact test was used to compare percentages in subsets of patients through univariate analysis.²⁶ The impact of these variables on TTP and OS was evaluated by univariate analysis using the Cox proportional hazards regression model.²⁷ The independent value of variables was assessed in multivariate analysis using the Cox proportional hazards regression model, with an estimate of hazard ratios.²⁷ All probability values were two sided. Statistical analyses were performed using the software package Stata 9 (STATA Corp, College Station, TX).

	RESULTS

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Patient Characteristics
Between November 2002 and March 2005, a total of 102 patients were entered onto the study at the eight participating centers; their characteristics are listed in Table 1. There were 76 males and 26 females. The median age was 65 years, and 32 patients (31.4%) were older than 70 years. Most patients had a PS of 1 and epithelial histologic subtype (78%); 75.5% of patients had a poor EORTC prognostic score.

With a median follow-up time of 14.2 months (95% CI, 12.2 to 15.0 months), 47 patients were still alive, 26 of whom were alive without any evidence of disease progression. Figure 1 shows the actuarial TTP curve for the entire population; the median TTP was 6.5 months. The OS curve for all enrolled patients is shown in Figure 2. The median survival time was 12.7 months; the 6-month and 1-year survival estimates were 70.0% (95% CI, 60.0% to 78.0%) and 51.6% (95% CI, 40.7% to 61.5%), respectively. TTP was significantly related to good PS (P = .047) and epithelial histology (P = .02) in both univariate and multivariate analyses. No correlation was observed between TTP and age, sex, disease stage, or EORTC score. Patients' PS was the only factor significantly related to OS in univariate and multivariate analyses (P = .04); all of the other variables failed to show any correlation with survival. Response to treatment showed a trend that correlated with OS in univariate analysis (P = .069) and reached statistical significance in the multivariate model (P = .024). When SD patients were grouped with responders, the correlation with OS was much more significant (P < .001).

View larger version (8K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curve of time to disease progression for all patients (median time to progression, 6.5 months).

View larger version (7K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curve of overall survival time for all patients (median overall survival time, 12.7 months).

Hematologic toxicity was mild and consisted mostly of neutropenia (Tables 2 and 3). Febrile neutropenia was reported in two patients. Severe anemia was reported in 11.7% of patients (grade 4 in one patient only) and occurred as cumulative toxicity after the second cycle of treatment in most cases; overall, it was reported in 3.5% of total cycles. Grade 3 or 4 thrombocytopenia was even less frequent, occurring in 7.8% of patients and 2% of cycles. Nonhematologic toxicity was generally mild (Table 4). Acute rhabdomyolysis occurred in a 68-year-old male patient, who developed severe myalgias and weakness of the lower and upper limbs and abdominal tenderness. Laboratory studies revealed increased creatine kinase, myoglobin, AST, and ALT serum levels. The laboratory abnormalities and the weakness slowly improved with hydration, corticosteroids, and diuretics during the following weeks.²⁸ Nausea and vomiting, fatigue, conjunctivitis, and stomatitis were the most commonly reported nonlaboratory treatment adverse effects (Table 4). No treatment-related deaths were observed.

	DISCUSSION

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Our study, which included full vitamin supplementation, confirmed the acceptable activity and good toxicity profile of this regimen in a large cohort of patients. The radiologic regression rate of disease, which was evaluated according to the same criteria used by Vogelzang et al,¹⁵ was inferior to that reported with the cisplatin combination. However, response evaluation with CT measurements is particularly challenging in MPM because of its diffuse pattern of growth. Considerable discrepancy was reported among study investigators and independent reviewers in evaluation of patients treated with pemetrexed and cisplatin; tumor response could be confirmed in only half of patients.¹¹ Several response criteria have been proposed,^15,29 but the optimal evaluation method has yet to be defined.^30,31 Despite the apparently lower radiologic response rate, TTP and survival in our study were similar to the data reported with the standard cisplatin combination.¹⁵ In a recent overview of three prospective trials, the radiologic responses did not seem to be correlated with the survival improvement.³² Considering these data, the survival outcomes remain the best treatment end points in this disease. No second-line therapy was planned in our trial; this might have influenced OS data. However, the benefit of second-line chemotherapy in MPM is not proven. In a retrospective analysis of patients treated in the pemetrexed/cisplatin trial, Manegold et al³³ reported a significantly prolonged survival in the groups treated with poststudy chemotherapy (PSC); however, because assignment to PSC was not randomized, it was impossible to know whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC.

Therapy with carboplatin and pemetrexed was well tolerated; nonhematologic toxicity was negligible, except for a case of acute rhabdomyolysis, which was possibly related to the treatment. This compares favorably with the toxicity profile reported in the cisplatin/pemetrexed trial, in which a higher incidence of nausea and vomiting and fatigue was observed.¹⁵ The hematologic toxicity was fairly acceptable, with a short-lived neutropenia in approximately 20% of patients and a severe anemia (mainly grade 3) in 11.7% of patients; anemia was cumulative and occurred after the second cycle of treatment in the majority of patients. MPM is a life-threatening illness with a poor prognosis. Palliation is the main goal of treatment in nonsurgical patients. Therefore, disease control with a good PS and quality of life should be considered a valuable end point. Although the quality of life was not evaluated in our study, it is significant that ECOG PS improved or remained roughly stable in all patients achieving disease control.

In conclusion, our observations showed that the combination of pemetrexed and carboplatin was both active and well tolerated in patients with MPM. Disease control rate, TTP, and OS were similar to that achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination may be a viable option, especially for elderly or poor PS patients. Although the chemotherapy regimens of pemetrexed plus platinum derivatives clearly represent a step forward in the treatment of MPM, the prognosis for these patients remains poor, and new therapeutic strategies are eagerly awaited.

	Authors' Disclosures of Potential Conflicts of Interest and Author Contributions

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Giovanni L. Ceresoli, Paolo A. Zucali, Armando Santoro Provision of study materials or patients: Giovanni L. Ceresoli, Paolo A. Zucali, Adolfo G. Favaretto, Francesco Grossi, Paolo Bidoli, Guido Del Conte, Anna Ceribelli, Alessandra Bearz, Raffaele Cavina, Maurizio Marangolo, Hector J. Soto Parra, Armando Santoro Collection and assembly of data: Giovanni L. Ceresoli, Paolo A. Zucali, Adolfo G. Favaretto, Francesco Grossi, Paolo Bidoli, Guido Del Conte, Anna Ceribelli, Alessandra Bearz, Raffaele Cavina, Maurizio Marangolo, Hector J. Soto Parra Data analysis and interpretation: Giovanni L. Ceresoli, Paolo A. Zucali, Emanuela Morenghi, Armando Santoro Manuscript writing: Giovanni L. Ceresoli, Paolo A. Zucali, Armando Santoro Final approval of manuscript: Giovanni L. Ceresoli, Paolo A. Zucali, Adolfo G. Favaretto, Francesco Grossi, Paolo Bidoli, Guido Del Conte, Anna Ceribelli, Alessandra Bearz, Raffaele Cavina, Hector J. Soto Parra, Armando Santoro

 

	Acknowledgment

 
We thank Valter Torri, MD (Department of Oncology, Biometry Unit, Mario Negri Institute, Milan, Italy), for external review of the study database and design.

	NOTES

 
Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005; and the 11th World Conference on Lung Cancer, Barcelona, Spain, July 3-6, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted September 20, 2005; accepted January 12, 2006.

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