Randomized Phase III Study of Cisplatin With or Without Raltitrexed in Patients With Malignant Pleural Mesothelioma: An Intergroup Study of
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《临床肿瘤学》
the University Hospital, Ghent, Belgium
National Cancer Center, Cairo, Egypt
UMC Mannheim, Germany
Erasmus MC, Rotterdam, the Netherlands
University Hospital, Antwerp, Edegem, Belgium
NCIC DC, Ontario, Canada
EORTC DC, Brussels, Belgium
Free University Medical Center, Amsterdam, the Netherlands
ABSTRACT
PURPOSE: We conducted a phase III trial to determine whether first-line treatment with raltitrexed, a thymidine synthase inhibitor, and cisplatin results in superior outcome compared with cisplatin alone in patients with malignant pleural mesothelioma (MPM).
PATIENTS AND METHODS: Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B). In patients with measurable disease, response was monitored using the Response Evaluation Criteria in Solid Tumors criteria. Health related quality of life (HRQOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Lung Module (QLQ-LC13).
RESULTS: Two hundred fifty patients were randomized: 80% male; median age, 58 years; and WHO PS, 0, 1, 2 in 25, 62, and 13% of cases, respectively. There were no toxic deaths. The main grade 3 or 4 toxicities observed were neutropenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, response rate was 13.6% (arm A) versus 23.6% (arm B; P = .056). No difference in HRQOL was observed on any of the scales. Median overall and 1-year survival in arms A and B were 8.8 (95% CI, 7.8 to 10.8) v 11.4 months (95% CI, 10.1 to 15), respectively, and 40% v 46%, respectively (P = .048).
CONCLUSION: A combination of raltitrexed and cisplatin improves overall survival compared with cisplatin alone. This study confirms that a combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM, without harmful effect on HRQOL.
INTRODUCTION
Mortality of malignant pleural mesothelioma (MPM) in men has been increasing in most Western European countries, and the annual number of deaths among males is expected to increase from 5000 in 1998 to 9000 by 2018.1 The crude incidence of the disease varies between 21 and 30 per million inhabitants in the United Kingdom, Belgium, and the Netherlands and between 11 and 20 per million in other Western European countries, with an expected peak around 2020 before declining.2,3 Median survival of patients with MPM is less than 1 year, and most patients are not amenable to radical surgery. Performance status, histological subtype, and stage are the independent prognostic factors.4 Of all novel agents tested by the European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Group, none achieved single-agent activity of more than 20%.5-11 In a literature-based qualitative and quantitative overview of chemotherapy, cisplatin was found to be the most active single-agent regimen.12 The observed response rate reported with high-dose methotrexate lent support to further research concerning use of antifolates in the treatment of this disease.13
A critical step in the de novo pathway of DNA synthesis is the production of thymidine monophosphate from deoxyuridine monophosphate. This reaction is catalyzed by the enzyme thymidylate synthase (TS), which uses 5,10-methylene tetrahydrofolic acid as a cofactor. Raltitrexed (Tomudex) is a quinazoline folate analog that acts as a pure and specific TS inhibitor. The preclinical in vitro studies demonstrated that raltitrexed selectively inhibits TS.14 It is also a good substrate for the enzyme folylpolyglutamate synthetase, which converts raltitrexed into its polyglutamate forms. These polyglutamates are retained within the cells for long periods of time and are up to 100-fold more potent inhibitors of TS than the parent compound. Raltitrexed is registered in Europe for the treatment of advanced colorectal cancer.
A phase II study of the EORTC with single-agent raltitrexed in unpretreated patients showed a response rate of 21%.15 Further studies consisting of raltitrexed combined with oxaliplatin have demonstrated response rates varying from 20 to 35% in patients with MPM.16,17 This promising activity led the EORTC Lung Cancer Group to investigate whether the addition of raltitrexed to cisplatin, compared with cisplatin alone, would improve the outcome and health-related quality of life (HRQOL) of patients with MPM.
PATIENTS AND METHODS
Patients
To be eligible, patients had to have histologically proven diagnosis of MPM, not amenable for radical resection, WHO performance status 0 to 2, age of at least 18 years, and adequate hepatic and renal function and bone marrow reserve. Baseline values had to be at least: hemoglobin, 10 g/dL; white blood cell count, 4 x 109/L; absolute neutrophil count, 2 x 109/L; thrombocyte count, 100 x 109/L; albumin, 3 g/dL; and creatinine clearance (measured or calculated), 65 mL/min. Bilirubin had to be lower than 1.46 mg/dL and serum creatinine lower than 1.69 mg/dL. Alanine aminotransferase and aspartate aminotransferase had to be lower than 2.5x the upper normal limit, except in the case of liver involvement, where it had to be less than 5x the upper normal limit. Prior systemic or intracavitary cytotoxic drugs, symptomatic CNS metastases, uncontrolled infections, or other malignancies were not allowed. Palliative radiotherapy to painful lesions or to prevent the development of metastases along biopsy tracks was allowed. Patients had to provide written informed consent before randomization.
Study Design
This study was a multicenter, randomized study comparing treatment with raltitrexed and cisplatin with cisplatin alone in patients with MPM. The primary outcome was overall survival. Secondary outcomes included progression-free survival, safety, tumor response rate, and HRQOL. Patients were randomly assigned to raltitrexed combined with cisplatin or cisplatin alone. Patient randomization was stratified for the following baseline stratification factors: institution, performance status (0 v 1 to 2) and white blood cell count (less than 8.3 x 109/L v at least 8.3 x 109/L). The study protocol was approved by the EORTC Protocol Review Committee and by each participating center’s institutional review board.
Treatment
Cisplatin was given intravenously (IV) at 80 mg/m2 in 1 to 2 hours in both arms of the study; raltitrexed (Tomudex; AstraZeneca, Alderley Park, UK) was administered IV at 3 mg/m2 in 15 minutes, preceding cisplatin. Both drugs were given on day 1 of each cycle and repeated every 3 weeks until progression, severe toxicity, or patient refusal. Standard intravenous hydration and antiemetic regimens were given according to institutional practice. Prophylactic administration of any vitamin or colony-stimulating factor was not recommended. Dose adjustments of raltitrexed in the next treatment cycles were recommended for any combination of diarrhea and hematological toxicity according to the following schedule: raltitrexed 2.25 mg/m2 for any grade 2 diarrhea and for any grade 3 hematological toxicity; raltitrexed 1.5 mg/m2 for any grade 3 diarrhea and/or grade 4 hematological toxicity. Raltitrexed was withdrawn in case of any grade 4 diarrhea and if a grade 3 diarrhea coincided with a grade 3 hematological toxicity. A patient discontinued protocol treatment if grade 3 or 4 toxicity occurred after a dose reduction or if three dose reductions were required. Dose delays up to 14 days were permitted for recovery from study drug toxicity. Dose escalations were not allowed.
Assessments During and After Treatment
Baseline and retreatment assessment included a complete history and physical examination, complete blood cell count, creatinine clearance, liver enzymes, total bilirubin, and serum electrolytes, total protein, albumin, and calcium.
Independent pathology review was required, either by the national mesothelioma board or by the EORTC reference pathologist (E.V.M.); however, inclusion was based on local pathologist’s original diagnosis. Central pathology review of tissue blocks consisted of light microscopy and the additional use of a standard panel of immunohistochemical markers for cytokeratins, mesothelial cells, and adenocarcinoma.18
Chest imaging by computed tomography was performed at baseline and before every other cycle of treatment while a patient was enrolled onto the study and every 6 weeks after completion of study therapy. Objective response was evaluated and calculated only in patients presenting with measurable disease, using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.19 Selection of possible target lesions had to be performed before randomization. HRQOL assessment was mandatory for all centers by using the EORTC QLQ-C30 (version 3) and the EORTC lung cancer specific questionnaire.20-22 Assessments were conducted at baseline and before every new cycle of treatment. HRQOL data collection was an integral part of the clinical trial. The items on the measures were scaled and scored using the recommended EORTC procedures.23 Differences of at least 10 points (on a 0 to 100 scale) were classified as the minimum "clinically meaningful" change in a HRQOL parameter.24
Statistical Analyses
The primary end point of this trial was overall survival. Secondary end points were toxicity (graded according to the Common Toxicity Criteria25), progression-free survival, and quality of life. Survival was computed from randomization to the time of death from any cause. Patients who were alive on the date of last follow-up were censored on that date. Progression-free survival was defined as the time elapsed from randomization to progression or death from any cause. Patients alive and without progressive disease at the time of analysis were censored at the date of last follow-up.
Among the eligible patients with measurable disease, objective response to treatment was assessed as secondary end point and compared using a 2 test. Overall survival and progression-free survival were estimated on all patients using the Kaplan-Meier method and compared using the two-sided log-rank test, based on an intention-to-treat analysis. Among the patient population with measurable disease, objective response to treatment and duration of response were assessed as secondary end points.
Considering a two-sided type I error of 0.05 and two interim analyses, using an alpha-spending function with an O’Brien-Fleming boundary,26 to have 80% power to detect a 50% increase in the median duration of survival in the combination arm, a total of 195 deaths had to be reported before performing the final analysis. Assuming a median duration of survival in the cisplatin-alone arm of 8 months, a recruitment period of 24 months, and a further follow-up of approximately 9 months, the protocol had foreseen the inclusion of 240 patients to observe the required number of deaths. Planned interim analyses were performed after 36 and 84 deaths occurred. The results of these interim analyses were not declared to the investigators but were submitted to an Independent Data Monitoring Committee (IDMC). The first and second interim analyses were performed at the .00000258 and .00178731 a level, respectively. Therefore, the P value of this final analysis should be less than 0.04926583 to statistically conclude a difference between the treatment arms. After the review of the first interim analysis (April 2002), the IDMC recommended to the LCG to continue trial accrual. Recommendation of the IDMC after the second interim analysis (November 2002) was that the trial should increase its accrual to observe 278 deaths of a total of 340 patients, to be able to detect a 40% increase in the median overall survival with the same power. However, because of a lack of funding for extension of patient accrual, the trial was stopped after inclusion of 250 patients, as initially planned.
Univariate and multivariate analyses were performed on overall survival to repeat the prognostic factors analysis performed in the same patient population by Curran et al.4 For the multivariate analysis, a Cox multivariate proportional hazards model, stratified for treatment was used with a step-down (backward) variable selection procedure (at the .05 level). Both univariate and multivariate analyses were stratified by treatment arm.
A linear mixed-model approach was used for the HRQOL analysis, with differences estimated with a one-step, autoregressive covariance structure. The overall health status/quality of life (QOL) scale was used as the primary HRQOL end point, and our hypothesis was that there would be no significant difference between treatment arms. The remaining of the scales was explored as a secondary end point. Sensitivity analysis was performed to investigate reasons for missing values; a general linear regression model was used to test the dependence of this probability on several baseline clinical variables: age, T-stage, N-stage, M-stage, type of prior surgery, histology, and institution. In addition, analysis of complete cases, last observation carried forward, was provided to check the robustness of the main results along with a pattern mixture model being used to check the stability of findings. Reporting of the HRQOL aspect of this trial was performed according to recent guidelines.27
AstraZeneca provided the raltitrexed and an educational grant for data management and study conduct. The study was designed and conducted by L.C.G. and National Cancer Institute of Canada investigators in accordance with the Helsinki declaration. The data were collected, managed, and analyzed by the EORTC Data Center.
RESULTS
Characteristics of Patients and Treatment
March 2000 to January 2003, 250 patients were randomly assigned; 126 received raltitrexed/cisplatin, and 124 received cisplatin only. Of these, four were considered ineligible because of either inadequate baseline laboratory values, prior pleurodesis with bleomycin, absence of tissue diagnosis or prior non–small-cell lung cancer (one patient each). Patients were accrued from 24 institutions; three of the institutions accounted for more than half of the enrolled patients (see Appendix). These 250 patients are the basis for the analysis of both overall and progression-free survival end points; one patient who switched arms and two patients who died before first toxicity assessment are excluded from toxicity reporting (Fig 1). As shown in Table 1, treatment arms were well balanced with regard to patient and tumor characteristics as well as to the EORTC prognostic score. Patients were predominantly male with a median age of 58 years (range, 19 to 80 years). Median interval between first diagnosis and randomization was 52 days. Most tumors had an epithelial component, whereas 79% presented with stage III or IV disease. No patient had prior systemic chemotherapy, but 13% of patients had prior local radiotherapy. The local pathologist’s diagnosis of mesothelioma was reviewed in 202 cases, and the central pathologist concurred in 92% of the cases.
One patient was allocated to the combination arm but treated with cisplatin only in error. Raltitrexed/cisplatin patients received slightly more treatment cycles than those receiving cisplatin alone (Table 2). The delivered dose-intensity of all study drugs was highly efficient, with a median relative dose-intensity exceeding 95% in each arm. Follow-up was reported till August 2004 and exceeded a median of 2 years at the time of analysis. Second-line chemotherapy was reported in 32% of patients, without difference between arms.
Toxicities and QOL
Hematological toxicity was mild and consisted mostly of neutropenia, with doubled frequency in the combined arm (Table 3). The frequency of febrile neutropenia and infection without neutropenia was low in both arms. Nonhematological toxicity was variable and mild, and no unexpected toxicities occurred. More fatigue, nausea, and vomiting were observed with the combined therapy. Toxicity was the reason for stopping treatment in 23% of patients in the cisplatin-only arm and in 30% of patients in the combined arm. No toxic deaths were reported. There were four early deaths during treatment, three in the cisplatin-alone arm (two of progressive disease and one patient died at home of unknown cause) and one in the cisplatin/raltitrexed arm (sudden death, probably because of disease progression). Two patients died at home of unknown causes; two patients progressed. Five patients died within 1 month of stopping treatment, one in the cisplatin alone arm and three in the raltitrexed/cisplatin arm. One died as a result of pulmonary embolism, and four died as a result of disease progression.
Compliance with HRQOL questionnaire—expressed as percentage of forms received over expected—exceeded 85% throughout the treatment. The estimated mean scores per time point and per treatment arm for overall health status/QOL scale, calculated from 1013 on-treatment QOL forms, showed no time trend or treatment-over-time interaction (Fig 2). Both arms demonstrated impairment in baseline scores for all the scales compared with a normative population, and this level of impairment remained consistent over the treatment period (data not shown). One exception was nausea and vomiting, which did increase equally from baseline levels in both arms to clinically significant meaningful levels during treatment. However, none of the scales of the QLQ-C30 or LC 13 showed any statically and clinically significant differences over time. The additional sensitivity analyses supported the results of the main findings.
Efficacy
Among 213 eligible patients with measurable disease, two complete responses in the combined treatment arm were observed. The objective response rate was 14% in the cisplatin-only arm and 24% in the combined arm (P = .06) (Table 4). Stable disease was the best response in 54% and 53% of patients in the cisplatin-only arm and the combined arm, respectively. Early discontinuation and symptomatic deterioration occurred in 7% and 4% of patients in the cisplatin-only arm and the combined arm, respectively.
The vast majority of patients died because of progression of disease, 92% in the cisplatin arm and 90% in the combination arm. The median and the 1-year survival were 8.8 months and 39.6%, respectively, in the cisplatin arm and 11.4 months and 46.2%, respectively, in the combination arm (Fig 3; hazard ratio 0.76; 95% CI, 0.58 to 1.00; P = .048). The difference in progression free survival was also almost significant (P = .058), with a median of 4.0 months in the cisplatin and 5.3 months in the combined arm (Fig 4).
By univariate analysis, poor performance status, high white blood cell count, high platelet count, low hemoglobin level, nonepithelial histological subtype, abnormal alkaline phosphatase, and a shorter interval since diagnosis were all associated with poor prognosis.
Overall survival was significantly different between the poor and the good prognosis group of patients as defined by Curran et al (P = .0141). Median and 1-year survival were 12.4 months (95% CI, 10.6 to 15.6) and 51.1% (95% CI, 41.5 to 60.7), respectively, in the good prognosis group and 8.1 months (95% CI, 7.3 to 10.1) and 35.3% (95% CI, 26.6 to 43.9), respectively, in the poor prognosis group. Considering the variables included in the univariate analysis, the multivariate model retained the following factors: interval since diagnosis, platelet count, hemoglobin difference, stage, and histological subtype (Table 5).
DISCUSSION
This is the second reported randomized controlled trial in patients with advanced MPM wherein single-agent cisplatin is compared with its combination with an antifolate.28 Pemetrexed in combination with cisplatin is currently approved by the US Food and Drug Administration for the treatment of patients with MPM whose disease is unresectable or who are otherwise not candidates for curative surgery.29 As is the case with pemetrexed, raltitrexed combined with cisplatin shows an improvement of both survival end points. Keeping in mind that two interim analyses were performed, the observed difference in overall survival in the present study can be interpreted as significant. Furthermore, the magnitude of the clinical effect on survival is similar in both studies: a 2.6-month increase in median survival in the present study (from 8.8 to 11.4 months) and a 2.8-month increase in the pemetrexed study (from 9.3 to 12.1 months). It is likely that an increase in sample size, as was advocated by the IDMC, would have resulted in a more significant result of both survival end points in favor of the combination treatment.
In the United Kingdom, a randomized trial is currently evaluating the efficacy of either a mitomycin/vindesine/cisplatin or a single-agent vinorelbine regimen versus a control arm consisting of active supportive care.30 Although the choice of the present control arm is debatable, we chose cisplatin for its documented single-agent activity in mesothelioma. A similar design has been used in advanced non–small-cell lung cancer to determine the activity of novel agents and allow their registration.31
Distribution of baseline and prognostic factors is similar to the ones based on data from patients included in previous EORTC phase II trials.4 The median overall survival in the cisplatin-only arm is also similar with the same arm of the pemetrexed study,28 and with the previous EORTC phase II experience (8.4 months).4 The response rate of 14% in the control arm is similar to the 16.7% that was observed in the cisplatin-only arm of the pemetrexed study, as well as with the average response observed on cisplatin in historical phase II studies.12 Because response evaluation is notoriously difficult in MPM, several different response criteria have been proposed.32 Modified RECIST criteria were used in the pemetrexed study.33 It has been argued that the difference in response observed among phase II studies with gemcitabine and cisplatin can be traced back to the use of these different response criteria in MPM.34,35 This is also the most reasonable explanation for the difference in response rate observed with the combination therapies in both studies. Inconsistencies in response assessments among investigators, independent reviewers, and the United States Food and Drug Administration in the cisplatin-pemetrexed study reflect the difficulty of radiographic assessments in malignant mesothelioma.29
Pemetrexed and raltitrexed are both antifolates targeting TS, an enzyme involved in pyrimidine metabolism. Like other antimetabolites, raltitrexed and pemetrexed have both been associated with dose-dependent severe myelosuppression and mucositis, resulting in unpredictable mortality. This toxicity was circumvented by the prophylactic supplementation of folic acid and vitamin B12 in a cohort of the pemetrexed study patients. We observed neither major hematological toxicity nor toxic death in the present study, despite the absence of routine prophylactic use of vitamins or colony-stimulating factors. This observed difference in toxicity between the two studies is probably due to the additional blocking of other enzymes of the folate metabolism by pemetrexed.
We observed no change or deterioration of overall health status/QOL scale by adding raltitrexed to cisplatin. Furthermore, none of the scales and items showed any significant and clinically meaningful difference at any time point during treatment. In the pemetrexed study, both arms reported similar progressive interference with overall health status/QOL scale through cycle 3. Overall health status/QOL scale stabilized for pemetrexed/cisplatin in later cycles.36 Improvements in dyspnea and pain were observed with pemetrexed/cisplatin. None of the observed changes, however, was deemed clinically important.29 We did notice a clinically meaningful increase over time in nausea and vomiting (from baseline) at cycle two over the subsequent treatment. However, this increase was similar in both arms.
It is highly unlikely that an imbalance in second-line treatment is responsible for the observed outcome, because pemetrexed was not yet available in Europe at the time of the study, and all other cytostatic drugs are of unproven value in the second-line treatment of mesothelioma.
Performance status, stage, and histological subtype are known prognostic factors in surgical series of MPM. Their value in advanced cases is more controversial, in view of the inaccuracy of clinical staging and the sampling bias of small biopsies. Nevertheless, we were able to confirm the value of the prognostic index developed earlier. Low hemoglobin, increased thrombocyte count, and shorter interval between diagnosis and randomization probably all reflect a more biologic aggressive behavior. Their value in the prognostic model needs to be explored further.
In conclusion, the present study brings the necessary confirmation that selected patients with advanced MPM should be treated with cisplatin and an antifolate instead of cisplatin only. The combination of cisplatin and raltitrexed used in the present study was furthermore well tolerated and did not have a harmful effect on HRQOL.
Appendix
The following institutions with their respective investigators and accrual have contributed to this study:
The Netherlands: Erasmus MC Rotterdam (J.P. van Meerbeeck, R.J. van Klaveren, S. Burgers, M. de Jonge): 52; UMC, Utrecht (N. Schl?sser): 7; Egypt: National Cancer Institute Cairo (R. Gaafar): 43; Germany: Thoraxklinik Rorhbach, Heidelberg (C. Manegold): 33; United Kingdom: Weston PK, Sheffield (M. Hatton, P. Lorigan): 10; City Hospital, Nottingham (P. Woll): 10; Western General Hospital, Edinburgh (A. Price): 7; Royal Marsden Hospital, London, UK (M. O’Brien): 3; Poland: Gdansk Medical University (J. Jassem): 11; Regional Lung Center, Poznan (R. Ramlau): 10; Canada: Cancer Center, London (M. Vincent): 6; McGill University, Montreal (V. Hirsch): 6; Princess Margaret Hospital, Toronto (F. Shepherd): 4; Regional Cancer Center, Hamilton (A. Neville): 2; Trillium Health Center (C. Gapski): 2; France: Centre Hospitalier Universitaire de Marseille (P. Astoul): 13; Hopital C Nicolle, Rouen (L. Thiberville): 1; Belgium: UZ Gasthuisberg Leuven (K. Nackaerts, J. Vansteenkiste): 10; Peru: Institut Enferm Neoplast, Lima (H. Gomez): 10; Italy: Universita di Genova (A. Ardizzoni): 6; Switzerland: Kantonspital St Gallen (O. D’Addario): 2; Inselspital, Bern (D. Betticher): 1; Kantonspital Basel (B. Pless): 1.
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We acknowledge the efforts of Annelore Dehoorne and Sonia Dussenne in data management, the collaboration of all investigators mentioned in the Appendix, and all patients for their precious confidence.
NOTES
Supported by an educational grant by AstraZeneca and by Grants No. 5U10-CA11488-30 through 5U10-CA11488-34 from the National Cancer Institute.
Presented as a late breaking abstract at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, June 7, 2004.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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National Cancer Center, Cairo, Egypt
UMC Mannheim, Germany
Erasmus MC, Rotterdam, the Netherlands
University Hospital, Antwerp, Edegem, Belgium
NCIC DC, Ontario, Canada
EORTC DC, Brussels, Belgium
Free University Medical Center, Amsterdam, the Netherlands
ABSTRACT
PURPOSE: We conducted a phase III trial to determine whether first-line treatment with raltitrexed, a thymidine synthase inhibitor, and cisplatin results in superior outcome compared with cisplatin alone in patients with malignant pleural mesothelioma (MPM).
PATIENTS AND METHODS: Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B). In patients with measurable disease, response was monitored using the Response Evaluation Criteria in Solid Tumors criteria. Health related quality of life (HRQOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Lung Module (QLQ-LC13).
RESULTS: Two hundred fifty patients were randomized: 80% male; median age, 58 years; and WHO PS, 0, 1, 2 in 25, 62, and 13% of cases, respectively. There were no toxic deaths. The main grade 3 or 4 toxicities observed were neutropenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, response rate was 13.6% (arm A) versus 23.6% (arm B; P = .056). No difference in HRQOL was observed on any of the scales. Median overall and 1-year survival in arms A and B were 8.8 (95% CI, 7.8 to 10.8) v 11.4 months (95% CI, 10.1 to 15), respectively, and 40% v 46%, respectively (P = .048).
CONCLUSION: A combination of raltitrexed and cisplatin improves overall survival compared with cisplatin alone. This study confirms that a combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM, without harmful effect on HRQOL.
INTRODUCTION
Mortality of malignant pleural mesothelioma (MPM) in men has been increasing in most Western European countries, and the annual number of deaths among males is expected to increase from 5000 in 1998 to 9000 by 2018.1 The crude incidence of the disease varies between 21 and 30 per million inhabitants in the United Kingdom, Belgium, and the Netherlands and between 11 and 20 per million in other Western European countries, with an expected peak around 2020 before declining.2,3 Median survival of patients with MPM is less than 1 year, and most patients are not amenable to radical surgery. Performance status, histological subtype, and stage are the independent prognostic factors.4 Of all novel agents tested by the European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Group, none achieved single-agent activity of more than 20%.5-11 In a literature-based qualitative and quantitative overview of chemotherapy, cisplatin was found to be the most active single-agent regimen.12 The observed response rate reported with high-dose methotrexate lent support to further research concerning use of antifolates in the treatment of this disease.13
A critical step in the de novo pathway of DNA synthesis is the production of thymidine monophosphate from deoxyuridine monophosphate. This reaction is catalyzed by the enzyme thymidylate synthase (TS), which uses 5,10-methylene tetrahydrofolic acid as a cofactor. Raltitrexed (Tomudex) is a quinazoline folate analog that acts as a pure and specific TS inhibitor. The preclinical in vitro studies demonstrated that raltitrexed selectively inhibits TS.14 It is also a good substrate for the enzyme folylpolyglutamate synthetase, which converts raltitrexed into its polyglutamate forms. These polyglutamates are retained within the cells for long periods of time and are up to 100-fold more potent inhibitors of TS than the parent compound. Raltitrexed is registered in Europe for the treatment of advanced colorectal cancer.
A phase II study of the EORTC with single-agent raltitrexed in unpretreated patients showed a response rate of 21%.15 Further studies consisting of raltitrexed combined with oxaliplatin have demonstrated response rates varying from 20 to 35% in patients with MPM.16,17 This promising activity led the EORTC Lung Cancer Group to investigate whether the addition of raltitrexed to cisplatin, compared with cisplatin alone, would improve the outcome and health-related quality of life (HRQOL) of patients with MPM.
PATIENTS AND METHODS
Patients
To be eligible, patients had to have histologically proven diagnosis of MPM, not amenable for radical resection, WHO performance status 0 to 2, age of at least 18 years, and adequate hepatic and renal function and bone marrow reserve. Baseline values had to be at least: hemoglobin, 10 g/dL; white blood cell count, 4 x 109/L; absolute neutrophil count, 2 x 109/L; thrombocyte count, 100 x 109/L; albumin, 3 g/dL; and creatinine clearance (measured or calculated), 65 mL/min. Bilirubin had to be lower than 1.46 mg/dL and serum creatinine lower than 1.69 mg/dL. Alanine aminotransferase and aspartate aminotransferase had to be lower than 2.5x the upper normal limit, except in the case of liver involvement, where it had to be less than 5x the upper normal limit. Prior systemic or intracavitary cytotoxic drugs, symptomatic CNS metastases, uncontrolled infections, or other malignancies were not allowed. Palliative radiotherapy to painful lesions or to prevent the development of metastases along biopsy tracks was allowed. Patients had to provide written informed consent before randomization.
Study Design
This study was a multicenter, randomized study comparing treatment with raltitrexed and cisplatin with cisplatin alone in patients with MPM. The primary outcome was overall survival. Secondary outcomes included progression-free survival, safety, tumor response rate, and HRQOL. Patients were randomly assigned to raltitrexed combined with cisplatin or cisplatin alone. Patient randomization was stratified for the following baseline stratification factors: institution, performance status (0 v 1 to 2) and white blood cell count (less than 8.3 x 109/L v at least 8.3 x 109/L). The study protocol was approved by the EORTC Protocol Review Committee and by each participating center’s institutional review board.
Treatment
Cisplatin was given intravenously (IV) at 80 mg/m2 in 1 to 2 hours in both arms of the study; raltitrexed (Tomudex; AstraZeneca, Alderley Park, UK) was administered IV at 3 mg/m2 in 15 minutes, preceding cisplatin. Both drugs were given on day 1 of each cycle and repeated every 3 weeks until progression, severe toxicity, or patient refusal. Standard intravenous hydration and antiemetic regimens were given according to institutional practice. Prophylactic administration of any vitamin or colony-stimulating factor was not recommended. Dose adjustments of raltitrexed in the next treatment cycles were recommended for any combination of diarrhea and hematological toxicity according to the following schedule: raltitrexed 2.25 mg/m2 for any grade 2 diarrhea and for any grade 3 hematological toxicity; raltitrexed 1.5 mg/m2 for any grade 3 diarrhea and/or grade 4 hematological toxicity. Raltitrexed was withdrawn in case of any grade 4 diarrhea and if a grade 3 diarrhea coincided with a grade 3 hematological toxicity. A patient discontinued protocol treatment if grade 3 or 4 toxicity occurred after a dose reduction or if three dose reductions were required. Dose delays up to 14 days were permitted for recovery from study drug toxicity. Dose escalations were not allowed.
Assessments During and After Treatment
Baseline and retreatment assessment included a complete history and physical examination, complete blood cell count, creatinine clearance, liver enzymes, total bilirubin, and serum electrolytes, total protein, albumin, and calcium.
Independent pathology review was required, either by the national mesothelioma board or by the EORTC reference pathologist (E.V.M.); however, inclusion was based on local pathologist’s original diagnosis. Central pathology review of tissue blocks consisted of light microscopy and the additional use of a standard panel of immunohistochemical markers for cytokeratins, mesothelial cells, and adenocarcinoma.18
Chest imaging by computed tomography was performed at baseline and before every other cycle of treatment while a patient was enrolled onto the study and every 6 weeks after completion of study therapy. Objective response was evaluated and calculated only in patients presenting with measurable disease, using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.19 Selection of possible target lesions had to be performed before randomization. HRQOL assessment was mandatory for all centers by using the EORTC QLQ-C30 (version 3) and the EORTC lung cancer specific questionnaire.20-22 Assessments were conducted at baseline and before every new cycle of treatment. HRQOL data collection was an integral part of the clinical trial. The items on the measures were scaled and scored using the recommended EORTC procedures.23 Differences of at least 10 points (on a 0 to 100 scale) were classified as the minimum "clinically meaningful" change in a HRQOL parameter.24
Statistical Analyses
The primary end point of this trial was overall survival. Secondary end points were toxicity (graded according to the Common Toxicity Criteria25), progression-free survival, and quality of life. Survival was computed from randomization to the time of death from any cause. Patients who were alive on the date of last follow-up were censored on that date. Progression-free survival was defined as the time elapsed from randomization to progression or death from any cause. Patients alive and without progressive disease at the time of analysis were censored at the date of last follow-up.
Among the eligible patients with measurable disease, objective response to treatment was assessed as secondary end point and compared using a 2 test. Overall survival and progression-free survival were estimated on all patients using the Kaplan-Meier method and compared using the two-sided log-rank test, based on an intention-to-treat analysis. Among the patient population with measurable disease, objective response to treatment and duration of response were assessed as secondary end points.
Considering a two-sided type I error of 0.05 and two interim analyses, using an alpha-spending function with an O’Brien-Fleming boundary,26 to have 80% power to detect a 50% increase in the median duration of survival in the combination arm, a total of 195 deaths had to be reported before performing the final analysis. Assuming a median duration of survival in the cisplatin-alone arm of 8 months, a recruitment period of 24 months, and a further follow-up of approximately 9 months, the protocol had foreseen the inclusion of 240 patients to observe the required number of deaths. Planned interim analyses were performed after 36 and 84 deaths occurred. The results of these interim analyses were not declared to the investigators but were submitted to an Independent Data Monitoring Committee (IDMC). The first and second interim analyses were performed at the .00000258 and .00178731 a level, respectively. Therefore, the P value of this final analysis should be less than 0.04926583 to statistically conclude a difference between the treatment arms. After the review of the first interim analysis (April 2002), the IDMC recommended to the LCG to continue trial accrual. Recommendation of the IDMC after the second interim analysis (November 2002) was that the trial should increase its accrual to observe 278 deaths of a total of 340 patients, to be able to detect a 40% increase in the median overall survival with the same power. However, because of a lack of funding for extension of patient accrual, the trial was stopped after inclusion of 250 patients, as initially planned.
Univariate and multivariate analyses were performed on overall survival to repeat the prognostic factors analysis performed in the same patient population by Curran et al.4 For the multivariate analysis, a Cox multivariate proportional hazards model, stratified for treatment was used with a step-down (backward) variable selection procedure (at the .05 level). Both univariate and multivariate analyses were stratified by treatment arm.
A linear mixed-model approach was used for the HRQOL analysis, with differences estimated with a one-step, autoregressive covariance structure. The overall health status/quality of life (QOL) scale was used as the primary HRQOL end point, and our hypothesis was that there would be no significant difference between treatment arms. The remaining of the scales was explored as a secondary end point. Sensitivity analysis was performed to investigate reasons for missing values; a general linear regression model was used to test the dependence of this probability on several baseline clinical variables: age, T-stage, N-stage, M-stage, type of prior surgery, histology, and institution. In addition, analysis of complete cases, last observation carried forward, was provided to check the robustness of the main results along with a pattern mixture model being used to check the stability of findings. Reporting of the HRQOL aspect of this trial was performed according to recent guidelines.27
AstraZeneca provided the raltitrexed and an educational grant for data management and study conduct. The study was designed and conducted by L.C.G. and National Cancer Institute of Canada investigators in accordance with the Helsinki declaration. The data were collected, managed, and analyzed by the EORTC Data Center.
RESULTS
Characteristics of Patients and Treatment
March 2000 to January 2003, 250 patients were randomly assigned; 126 received raltitrexed/cisplatin, and 124 received cisplatin only. Of these, four were considered ineligible because of either inadequate baseline laboratory values, prior pleurodesis with bleomycin, absence of tissue diagnosis or prior non–small-cell lung cancer (one patient each). Patients were accrued from 24 institutions; three of the institutions accounted for more than half of the enrolled patients (see Appendix). These 250 patients are the basis for the analysis of both overall and progression-free survival end points; one patient who switched arms and two patients who died before first toxicity assessment are excluded from toxicity reporting (Fig 1). As shown in Table 1, treatment arms were well balanced with regard to patient and tumor characteristics as well as to the EORTC prognostic score. Patients were predominantly male with a median age of 58 years (range, 19 to 80 years). Median interval between first diagnosis and randomization was 52 days. Most tumors had an epithelial component, whereas 79% presented with stage III or IV disease. No patient had prior systemic chemotherapy, but 13% of patients had prior local radiotherapy. The local pathologist’s diagnosis of mesothelioma was reviewed in 202 cases, and the central pathologist concurred in 92% of the cases.
One patient was allocated to the combination arm but treated with cisplatin only in error. Raltitrexed/cisplatin patients received slightly more treatment cycles than those receiving cisplatin alone (Table 2). The delivered dose-intensity of all study drugs was highly efficient, with a median relative dose-intensity exceeding 95% in each arm. Follow-up was reported till August 2004 and exceeded a median of 2 years at the time of analysis. Second-line chemotherapy was reported in 32% of patients, without difference between arms.
Toxicities and QOL
Hematological toxicity was mild and consisted mostly of neutropenia, with doubled frequency in the combined arm (Table 3). The frequency of febrile neutropenia and infection without neutropenia was low in both arms. Nonhematological toxicity was variable and mild, and no unexpected toxicities occurred. More fatigue, nausea, and vomiting were observed with the combined therapy. Toxicity was the reason for stopping treatment in 23% of patients in the cisplatin-only arm and in 30% of patients in the combined arm. No toxic deaths were reported. There were four early deaths during treatment, three in the cisplatin-alone arm (two of progressive disease and one patient died at home of unknown cause) and one in the cisplatin/raltitrexed arm (sudden death, probably because of disease progression). Two patients died at home of unknown causes; two patients progressed. Five patients died within 1 month of stopping treatment, one in the cisplatin alone arm and three in the raltitrexed/cisplatin arm. One died as a result of pulmonary embolism, and four died as a result of disease progression.
Compliance with HRQOL questionnaire—expressed as percentage of forms received over expected—exceeded 85% throughout the treatment. The estimated mean scores per time point and per treatment arm for overall health status/QOL scale, calculated from 1013 on-treatment QOL forms, showed no time trend or treatment-over-time interaction (Fig 2). Both arms demonstrated impairment in baseline scores for all the scales compared with a normative population, and this level of impairment remained consistent over the treatment period (data not shown). One exception was nausea and vomiting, which did increase equally from baseline levels in both arms to clinically significant meaningful levels during treatment. However, none of the scales of the QLQ-C30 or LC 13 showed any statically and clinically significant differences over time. The additional sensitivity analyses supported the results of the main findings.
Efficacy
Among 213 eligible patients with measurable disease, two complete responses in the combined treatment arm were observed. The objective response rate was 14% in the cisplatin-only arm and 24% in the combined arm (P = .06) (Table 4). Stable disease was the best response in 54% and 53% of patients in the cisplatin-only arm and the combined arm, respectively. Early discontinuation and symptomatic deterioration occurred in 7% and 4% of patients in the cisplatin-only arm and the combined arm, respectively.
The vast majority of patients died because of progression of disease, 92% in the cisplatin arm and 90% in the combination arm. The median and the 1-year survival were 8.8 months and 39.6%, respectively, in the cisplatin arm and 11.4 months and 46.2%, respectively, in the combination arm (Fig 3; hazard ratio 0.76; 95% CI, 0.58 to 1.00; P = .048). The difference in progression free survival was also almost significant (P = .058), with a median of 4.0 months in the cisplatin and 5.3 months in the combined arm (Fig 4).
By univariate analysis, poor performance status, high white blood cell count, high platelet count, low hemoglobin level, nonepithelial histological subtype, abnormal alkaline phosphatase, and a shorter interval since diagnosis were all associated with poor prognosis.
Overall survival was significantly different between the poor and the good prognosis group of patients as defined by Curran et al (P = .0141). Median and 1-year survival were 12.4 months (95% CI, 10.6 to 15.6) and 51.1% (95% CI, 41.5 to 60.7), respectively, in the good prognosis group and 8.1 months (95% CI, 7.3 to 10.1) and 35.3% (95% CI, 26.6 to 43.9), respectively, in the poor prognosis group. Considering the variables included in the univariate analysis, the multivariate model retained the following factors: interval since diagnosis, platelet count, hemoglobin difference, stage, and histological subtype (Table 5).
DISCUSSION
This is the second reported randomized controlled trial in patients with advanced MPM wherein single-agent cisplatin is compared with its combination with an antifolate.28 Pemetrexed in combination with cisplatin is currently approved by the US Food and Drug Administration for the treatment of patients with MPM whose disease is unresectable or who are otherwise not candidates for curative surgery.29 As is the case with pemetrexed, raltitrexed combined with cisplatin shows an improvement of both survival end points. Keeping in mind that two interim analyses were performed, the observed difference in overall survival in the present study can be interpreted as significant. Furthermore, the magnitude of the clinical effect on survival is similar in both studies: a 2.6-month increase in median survival in the present study (from 8.8 to 11.4 months) and a 2.8-month increase in the pemetrexed study (from 9.3 to 12.1 months). It is likely that an increase in sample size, as was advocated by the IDMC, would have resulted in a more significant result of both survival end points in favor of the combination treatment.
In the United Kingdom, a randomized trial is currently evaluating the efficacy of either a mitomycin/vindesine/cisplatin or a single-agent vinorelbine regimen versus a control arm consisting of active supportive care.30 Although the choice of the present control arm is debatable, we chose cisplatin for its documented single-agent activity in mesothelioma. A similar design has been used in advanced non–small-cell lung cancer to determine the activity of novel agents and allow their registration.31
Distribution of baseline and prognostic factors is similar to the ones based on data from patients included in previous EORTC phase II trials.4 The median overall survival in the cisplatin-only arm is also similar with the same arm of the pemetrexed study,28 and with the previous EORTC phase II experience (8.4 months).4 The response rate of 14% in the control arm is similar to the 16.7% that was observed in the cisplatin-only arm of the pemetrexed study, as well as with the average response observed on cisplatin in historical phase II studies.12 Because response evaluation is notoriously difficult in MPM, several different response criteria have been proposed.32 Modified RECIST criteria were used in the pemetrexed study.33 It has been argued that the difference in response observed among phase II studies with gemcitabine and cisplatin can be traced back to the use of these different response criteria in MPM.34,35 This is also the most reasonable explanation for the difference in response rate observed with the combination therapies in both studies. Inconsistencies in response assessments among investigators, independent reviewers, and the United States Food and Drug Administration in the cisplatin-pemetrexed study reflect the difficulty of radiographic assessments in malignant mesothelioma.29
Pemetrexed and raltitrexed are both antifolates targeting TS, an enzyme involved in pyrimidine metabolism. Like other antimetabolites, raltitrexed and pemetrexed have both been associated with dose-dependent severe myelosuppression and mucositis, resulting in unpredictable mortality. This toxicity was circumvented by the prophylactic supplementation of folic acid and vitamin B12 in a cohort of the pemetrexed study patients. We observed neither major hematological toxicity nor toxic death in the present study, despite the absence of routine prophylactic use of vitamins or colony-stimulating factors. This observed difference in toxicity between the two studies is probably due to the additional blocking of other enzymes of the folate metabolism by pemetrexed.
We observed no change or deterioration of overall health status/QOL scale by adding raltitrexed to cisplatin. Furthermore, none of the scales and items showed any significant and clinically meaningful difference at any time point during treatment. In the pemetrexed study, both arms reported similar progressive interference with overall health status/QOL scale through cycle 3. Overall health status/QOL scale stabilized for pemetrexed/cisplatin in later cycles.36 Improvements in dyspnea and pain were observed with pemetrexed/cisplatin. None of the observed changes, however, was deemed clinically important.29 We did notice a clinically meaningful increase over time in nausea and vomiting (from baseline) at cycle two over the subsequent treatment. However, this increase was similar in both arms.
It is highly unlikely that an imbalance in second-line treatment is responsible for the observed outcome, because pemetrexed was not yet available in Europe at the time of the study, and all other cytostatic drugs are of unproven value in the second-line treatment of mesothelioma.
Performance status, stage, and histological subtype are known prognostic factors in surgical series of MPM. Their value in advanced cases is more controversial, in view of the inaccuracy of clinical staging and the sampling bias of small biopsies. Nevertheless, we were able to confirm the value of the prognostic index developed earlier. Low hemoglobin, increased thrombocyte count, and shorter interval between diagnosis and randomization probably all reflect a more biologic aggressive behavior. Their value in the prognostic model needs to be explored further.
In conclusion, the present study brings the necessary confirmation that selected patients with advanced MPM should be treated with cisplatin and an antifolate instead of cisplatin only. The combination of cisplatin and raltitrexed used in the present study was furthermore well tolerated and did not have a harmful effect on HRQOL.
Appendix
The following institutions with their respective investigators and accrual have contributed to this study:
The Netherlands: Erasmus MC Rotterdam (J.P. van Meerbeeck, R.J. van Klaveren, S. Burgers, M. de Jonge): 52; UMC, Utrecht (N. Schl?sser): 7; Egypt: National Cancer Institute Cairo (R. Gaafar): 43; Germany: Thoraxklinik Rorhbach, Heidelberg (C. Manegold): 33; United Kingdom: Weston PK, Sheffield (M. Hatton, P. Lorigan): 10; City Hospital, Nottingham (P. Woll): 10; Western General Hospital, Edinburgh (A. Price): 7; Royal Marsden Hospital, London, UK (M. O’Brien): 3; Poland: Gdansk Medical University (J. Jassem): 11; Regional Lung Center, Poznan (R. Ramlau): 10; Canada: Cancer Center, London (M. Vincent): 6; McGill University, Montreal (V. Hirsch): 6; Princess Margaret Hospital, Toronto (F. Shepherd): 4; Regional Cancer Center, Hamilton (A. Neville): 2; Trillium Health Center (C. Gapski): 2; France: Centre Hospitalier Universitaire de Marseille (P. Astoul): 13; Hopital C Nicolle, Rouen (L. Thiberville): 1; Belgium: UZ Gasthuisberg Leuven (K. Nackaerts, J. Vansteenkiste): 10; Peru: Institut Enferm Neoplast, Lima (H. Gomez): 10; Italy: Universita di Genova (A. Ardizzoni): 6; Switzerland: Kantonspital St Gallen (O. D’Addario): 2; Inselspital, Bern (D. Betticher): 1; Kantonspital Basel (B. Pless): 1.
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We acknowledge the efforts of Annelore Dehoorne and Sonia Dussenne in data management, the collaboration of all investigators mentioned in the Appendix, and all patients for their precious confidence.
NOTES
Supported by an educational grant by AstraZeneca and by Grants No. 5U10-CA11488-30 through 5U10-CA11488-34 from the National Cancer Institute.
Presented as a late breaking abstract at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, June 7, 2004.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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