1 1555 Gemcitabine and Vinorelbine in Pemetrexed-Pretreated Patients With Malignant Pleural Mesothelioma Paolo A. Zucali, MD 1 Giovanni L. Ceresoli, MD 1 Isabella Garassino, MD 1 Fabio De Vincenzo, MD 1 Raffaele Cavina, MD 1 Elisabetta Campagnoli, MD 1 Federico Cappuzzo, MD 1 Silvia Salamina, MD 1 Hector J. Soto Parra, MD 2 Armando Santoro, MD 1 1 Department of Medical Oncology and Hematology, Humanitas Clinical Institute of Rozzano, Milan, Italy. 2 Department of Medical Oncology, Garibaldi- Nesima Hospital, Catania, Italy. BACKGROUND. Pemetrexed-cisplatin chemotherapy is the standard of care in the first-line treatment of unresectable malignant pleural mesothelioma (MPM). Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first-line setting. The objective of this study was to evaluate the activity and toxicity of the gemcitabine-vinorelbine combination in pemetrexed-pretreated patients with MPM. METHODS. From January 2004 to September 2006, 30 consecutive patients who were pretreated with pemetrexed with or without a platinum-derivative were enrolled. Gemcitabine 1000 mg/m 2 and vinorelbine 25 mg/m 2 were administered intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles or until progression or unacceptable toxicity. RESULTS. A partial response was observed in 3 patients (10%; 95% confidence interval [CI], %), and 10 patients (33.3%; 95% CI, %) had stable disease after treatment. Overall, 13 patients (43.3%; 95% CI, %) achieved disease control. The median time to progression was 2.8 months (range, months), and the median survival was 10.9 months (range, months). Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in 11% of patients and thrombocytopenia occurring in 4% of patients; no case of febrile neutropenia was observed. Nonhematologic toxicity generally was mild. CONCLUSIONS. The gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM. The role of second-line treatment in MPM needs to be evaluated in prospective trials in large series of patients who are stratified according to previous treatment and prognostic factors. Cancer 2008;112: Ó 2008 American Cancer Society. Address for reprints: Polo A. Zucali, MD, Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Via Manzoni 56, Rozzano (Milan), Italy; Fax: (011) ; Received July 9, 2007; revision received September 20, 2007; accepted October 24, KEYWORDS: malignant pleural mesothelioma, second-line chemotherapy, pemetrexed-pretreated patients, gemcitabine-vinorelbine combination. Malignant pleural mesothelioma (MPM) is an aggressive tumor that usually has a poor prognosis. Its incidence is increasing throughout most of the world, and it is predicted that it will rise in the next 10 to 20 years. 1 Most patients with MPM are not amenable to radical surgery, and systemic therapy is the only potential treatment option for the majority of patients. The combination of cisplatin (Platinol; Bristol-Myers Squibb, New York, NY) and pemetrexed (Alimta; Eli-Lilly and Company, Indianapolis, Ind) has recently become the standard of care in the first-line treatment of MPM. In fact, this combination significantly improved the response rate (RR), time to progression (TTP), overall survival (OS), and quality of life compared with cisplatin alone. 2 For patients who are unfit to receive a cisplatin-based chemotherapy, pemetrexed alone 3 or ª 2008 American Cancer Society DOI /cncr Published online 19 February 2008 in Wiley InterScience (www.interscience.wiley.com).
2 1556 CANCER April 1, 2008 / Volume 112 / Number 7 combined with carboplatin (Paraplatin; Bristol-Myers Squibb 4 ) has been proposed as an alternative treatment choice. The role of second-line chemotherapy in MPM is not yet established. Two small trials dedicated to second-line chemotherapy with the cisplatin analog ZD0473 (cis-amminedichloro [2 methylpyridine] platinum [II]; AstraZeneca Pharmaceuticals, Cheshire, United Kingdom) and with the combination of raltitrexed (Tomudex; AstraZeneca Pharmaceuticals) and oxaliplatin (Eloxatin; Sanofi-Aventis, Paris, France) did not report efficacy but demonstrated the possibility of recruiting patients with good performance status to second-line studies. 5,6 In addition, case study reports and Phase II studies that included some pretreated patients have provided evidence that additional response is possible after second-line chemotherapy. 7 9 Recently, a noteworthy activity of pemetrexed, both alone and combined with carboplatin, as second-line treatment after prior platinumbased chemotherapy was reported. 10 In a randomized, multicenter Phase III study examining pemetrexed as second-line chemotherapy versus best supportive care (BSC), treatment with pemetrexed provided clinical benefit with a statistically significant improvement in TTP, whereas improvement in OS was not reported, possibly because of the influence of poststudy chemotherapy (PSC) on the BSC arm. 11 However, because pemetrexed-based regimens are being used increasingly in the first-line setting, 2,12 second-line chemotherapy should focus on other compounds in the future. Gemcitabine (Gemzar; Eli-Lilly and Company, Indianapolis, Ind) and vinorelbine (Navelbine; Pierre Fabre, Castres, France) have shown some activity as single agents or in combination in first-line treatment of MPM. Gemcitabine showed an activity as a single agent ranging from 0% to 31%, 13,20 and it is not known to be cross-resistant with pemetrexed. Moreover, as a single agent or in combination, gemcitabine was the most commonly used agent in PSC patients who were treated in the Phase III pemetrexed trial 21 and is considered 1 of most interesting drugs to explore in the second-line setting after pemetrexed-based chemotherapy. However, the cumulative cisplatin neurotoxicity and ototoxicity limit the enthusiasm for a cisplatin/gemcitabine combination approach in a second-line setting. 16,17 Alternatively, carboplatin and oxaliplatin 7,25,26 could be combined with gemcitabine. Vinorelbine is the only vinca alkaloid with proven single-agent activity in MPM. Treatment of 29 assessable MPM patients with weekly vinorelbine 30 mg/m 2 produced a partial response (PR) rate of 24% and an improvement in general physical symptoms in 41% of patients. 15 In a dose-finding study, Delord and colleagues observed that the coadministration of gemcitabine and vinorelbine did not enhance the toxicity profile of either drug in patients with advanced, previously treated malignancies. Moreover, this regimen demonstrated activity in a pretreated patient with MPM. 27 On the basis of this background, the objective of the current study was to assess the antitumor activity and toxicity of the combination of gemcitabine and vinorelbine in a population of pemetrexed-pretreated patients with MPM. MATERIALS AND METHODS Patient Selection Patients were eligible for this trial if they had histologically confirmed MPM that was not amenable to curative surgery and that was relapsing or progressing after 1 prior pemetrexed-based chemotherapy regimen. Eligibility criteria included age >18 years, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, and an estimated life expectancy 12 weeks. Adequate organ function was required along with an absolute neutrophil count /L, platelets /L, hemoglobin 9 g/dl, bilirubin 1.5 times the upper limit of normal, aspartate and alanine transferase levels 3 times the upper limit of normal, and creatinine <2.0 mg/dl. Patients who were receiving palliative radiation therapy for painful lesions were allowed to enter the trial provided the patient had measurable disease outside the irradiated site. Previous treatment without pemetrexed-based chemotherapy, documented brain metastases, serious comorbidities, or other malignancies were not allowed. Written, informed consent was obtained from each patient before beginning treatment. Treatment Patients received gemcitabine at the dose of 1000 mg/m 2 intravenously as a 30-minute infusion followed by vinorelbine administered as a bolus infusion at the dose of 25 mg/m 2. Both drugs were given on Days 1 and 8 every 3 weeks. Standard antiemetic prophylaxis with intravenous metoclopramide was used before chemotherapy. Treatment was administered on an outpatient basis. Patients who demonstrated no disease progression continued treatment for a maximum of 6 cycles or until the withdrawal criteria were met. Dose adjustments at the start of a subsequent cycle of therapy were based on hematologic and nonhematologic toxicity observed during the preced-
3 Gemcitabine-Vinorelbine in MPM Patients/Zucali et al ing course. Any patient who required a dose reduction continued to receive a reduced dose for the remainder of the study. The administration of the next cycle was delayed in the case of: 1) an absolute neutrophil count of < /L and/or a platelet count of < /L; 2) any grade 3 or 4 nonhematologic toxicity (except for nausea/vomiting) that did not resolve to grade 1 or less; or 3) an ECOG PS >2. If these toxicities had not resolved by Day 28, then the dose was reduced for the next cycle at 75% of the previous dose level. No other systemic anticancer therapies were permitted. Patients were allowed supportive care measures and symptomatic treatment for any drug-related toxicity. Patient Assessment Baseline assessment included a complete medical history, physical examination, and complete blood count and chemistries. A chest and abdomen computed tomography (CT) scan was obtained at baseline. Patients were staged according to the International Mesothelioma Interest Group Tumor, Lymph Node, Metastasis (TNM) staging system. 28 Best tumor response was evaluated according to validated hybrid unidimensional and bidimensional criteria. 2 No confirmatory scans were conducted on patients who exhibited a PR or stable disease (SD). Treatment toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria version 3.0 grading system. 29 Dose intensity (DI) was assessed separately for gemcitabine and vinorelbine in patients who received at least 2 cycles of chemotherapy as the median dose in milligrams per square meter per week. The percentage of planned DI delivered for both drugs also was calculated and reported as the 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 also were followed for survival until death or last contact if they remained alive. Study Design and Statistical Analysis This study was planned as a single-institution Phase II trial. Patients were enrolled prospectively. The sample size of the trial was calculated according to the Simon 2-stage design, 30 with a type I and II error of <10% each, to differentiate between an RR of 10% and a response of 30%. According to this model, initial analysis was planned after 14 patients had been treated, and there was further accrual to a total of 25 patients if at least 1 objective response was observed in the first 14 patients. The planned accrual period was 24 months. The primary endpoints of the study were tumor RR and tolerability; secondary endpoints included TTP and OS. TTP was defined as time from study entry (first day of study treatment) until the time of patient progression (as demonstrated on 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 at the date of last follow-up were censored at that date. The Kaplan-Meier method was used to calculate actuarial survival and follow-up. 31,32 Survival rates were analyzed according to the following variables: age (<70 years vs 70 years), ECOG PS (0 vs 1 vs 2), histology (epithelial vs nonepithelial), European Organization for Research and Treatment of Cancer (EORTC) prognostic score (good score vs poor score), 33 response to previous pemetrexed-based chemotherapy (PR or SD vs progressive disease), and TTP on previous pemetrexed-based chemotherapy (<6 months vs 6 months). The impact of these variables on TTP and OS was evaluated by using the Gehan Wilcoxon test. 34 Statistical analyses were performed by using the software package Stata 10 (STATA Corp, College Station, Tex). RESULTS Patients Characteristics Between January 2004 and September 2006, 30 consecutive patients who progressed after pemetrexedbased chemotherapy were enrolled. Their characteristics are listed in Table 1. There were 22 men and 8 women. The median age was 66 years (range, years). Most patients had a PS 1 (83%), an epithelial histologic subtype (70%), and a poor EORTC prognostic score (73%). Twenty-five patients (84%) had chest involvement only, whereas the remaining patients also had extrathoracic tumor sites. All patients had previously received a pemetrexed-based chemotherapy, and a PR and SD were reported in 6 patients (20%) and 15 patients (50%), respectively. Four patients (13%) had previously received pemetrexed as single agent, and 26 patients (87%) had received it in combination with a platinum agent, including cisplatin in 1 patient and carboplatin in 25 patients. Efficacy Twenty-nine of the 30 patients were evaluated for response, and 1 refused further treatment after 1
4 1558 CANCER April 1, 2008 / Volume 112 / Number 7 TABLE 1 Patient Characteristics Characteristics No. of patients (N 5 30) % Age, y Median 66 Range Sex Men Women 8 27 ECOG performance status EORTC prognostic score Good 8 27 Poor Histologic subtype Epithelial Sarcomatoid 2 7 Mixed cell 5 16 Unspecified 2 7 Previous treatment Pemetrexed 4 13 Pemetrexed/carboplatin Pemetrexed/cisplatin 1 3 Response to prior P-ChT CR 0 0 PR 6 20 SD PD 9 30 Median time of previous P-ChT response (range), mo PR 8.7 (7 10.7) SD 9 (4 19.8) ECOG indicates Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; P-ChT, pemetrexed-based chemotherapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. cycle and was not reassessed. According to an intention-to-treat analysis, 3 patients had a PR (10%; 95% confidence interval [CI], %), 10 patients had SD (33.3%; 95% CI, %) and 17 patients had progressive disease (56.7%; 95% CI, %). No complete responses were observed. The disease control rate (PR and SD for at least 6 weeks) was 43.3% (95% CI, %). Table 2 summarizes the outcome of the study population according to clinical characteristics. With a median follow-up of 10.8 months (95% CI, months) for all patients and 14.2 months (95% CI, months) for the patients who remained alive, 21 patients died and 9 were still alive. The median TTP was 2.8 months (range, months), and the median OS was 10.9 months (range months) (Fig. 1). Progression-free survival (PFS) rates at 3 months, 4 TABLE 2 Outcome of the Study Population According to Clinical Characteristics Characteristic No. of patients (%) TTP, mo OS, mo Median P Median P Histology Epithelial 21 (70) Nonepithelial 9 (30) ECOG performance status 0 9 (30) (53) (17) EORTC score Good 8 (27) Poor 22 (73) Age, y <70 21 (70) (30) TTP of previous treatment, mo 6 19 (63) <6 11 (37) Response to previous treatment PR and SD 21 (70) PD 9 (30) TTP indicates time to progression; OS, overall survival; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. months, and 6 months were 44.8% (95% CI, %), 44.8% (95% CI, %), and 31% (95% CI, %), respectively. Treatment Delivery and Toxicity In total, 111 cycles of chemotherapy were delivered, and dose reductions occurred in 19 cycles (17% of all cycles). Patients received a median of 3 cycles of treatment (range, 1 6 cycles). Twenty-five patients (83%) received 2 or more cycles; in these patients, the median delivered DI was mg/m 2 per week for vinorelbine (RDI, 82.4%) and mg/m 2 per week for gemcitabine (RDI, 87.5%). Treatment generally was tolerated well. Hematologic toxicity was the most frequently reported side effect (Table 3), with grade 3 or 4 neutropenia observed in 3 patients (10%). No episodes of febrile neutropenia were reported. Nonhematologic toxicity generally was mild (Table 3). One death occurred during the treatment because of pneumonitis (without neutropenia) in a patient with SD who previously underwent extrapleural pneumonectomy. At the end of chemotherapy, among 13 patients achieving disease control, ECOG PS was stable in 9 patients, improved in 2 and worsened in 2.
5 Gemcitabine-Vinorelbine in MPM Patients/Zucali et al TABLE 3 Hematologic and Nonhematologic Toxicity by Patient (N 5 30)* No. of patients Toxicity Grade 1 Grade 2 Grade 3 Grade 4 Grade 3 4, % Neutropenia Anemia Thrombocytopenia Fatigue Nausea/vomiting Constipation Diarrhea Stomatitis Conjunctivitis Fever * Other toxicities that were reported as rare events included grade 2 hepatotoxicity (1 patient) and grade 2 peripheral neurotoxicity (1 patient). FIGURE 1. Survival curves. TTP indicates time to progression; OS, overall survival. DISCUSSION Second-line chemotherapy is being used increasingly in MPM, because patients who achieve a clinical benefit from first-line chemotherapy frequently still are healthy at the time of disease progression. However, to date, the role of second-line chemotherapy in MPM has not been proven, and few data are available to select effective drugs. In particular, prospective trials of second-line chemotherapy in pemetrexedpretreated patients with MPM are lacking (Table 4). In a retrospective analysis of patients who were treated in the Phase III pemetrexed trial, approximately 42% of all patients received some form of PSC. This group of patients had a significantly prolonged survival. However, because PSC was not randomized, it is impossible to know whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival were able to receive more PSC. 21 In fact, the crucial point is to distinguish between the clinical/radiologic stability caused by treatment effect and the natural history of disease. To our knowledge, only 2 randomized studies have demonstrated that chemotherapy may be better than BSC in patients with MPM. 11,35 In particular, vinorelbine plus BSC in the first-line setting produced an improvement in terms of OS compared with BSC alone, although the difference was not statistically significant, 35 whereas pemetrexed in the second-line setting provided clinical benefit with a statistically significant improvement in terms of TTP, but not in terms of OS. 11 In the current study, we tested vinorelbine combined with gemcitabine in a population of patients who progressed after receiving pemetrexed-based chemotherapy. Hematologic and nonhematologic toxicities were mild. Grade 3 and 4 neutropenia was observed as the main toxicity in 3 patients (12.5%). One death occurred during the treatment because of pneumonitis (without neutropenia) in a patient with SD who previously underwent extrapleural pneumonectomy. The low rate of reduced cycles and the high median delivered DI of both study drugs provided evidence of good tolerability of this regimen in this group of patients. Although quality of life was not evaluated in our study, we observed that ECOG PS remained roughly stable in most patients who achieved disease control. Overall, the RR (10%), disease control rate (43.3%), TTP (2.8 months), and OS (10.9 months) were in line with data reported in the literature (Table 5). It is noteworthy that the proportion of patients who had SD was considerable. Emerging data suggest that the survival outcomes faithfully reflect the drugs activity and should represent the best treatment endpoints in patients with MPM in view of the marked difficulty in assessing radiologic response. 36,37 Fennell et al. demonstrated that the radiologic response did not appear to be
6 1560 CANCER April 1, 2008 / Volume 112 / Number 7 TABLE 4 Studies of Second-line Chemotherapy in Patients With Malignant Pleural Mesothelioma Reference Regimen No. RR, % DCR, % mttp, mo msv, mo Pemetrexed-naive patients Giaccone ZD0437 (platinum analog) 47 12* Porta Raltitrexed 1 oxaliplatin Fizazi Raltitrexed 1 oxaliplatin wks 44 wks Sorensen Pemetrexed NR 147 d 294 d Sorensen Pemetrexed 1 carboplatin NR 222 d 258 d Jassem y Pemetrexed NR Fennell Irinotecan 1 cisplatin 1 mitomycin Pemetrexed-pretreated patients Serke Oxaliplatin1/2gemcitabine 18 22* 50 NR NR RR indicates response rate; DCR, disease control rate; mttp, median time to progression; msv, median survival; NR, not reported; 1/2, with or without, d, day. * Responses were reported as minor responses. y Randomized trial of pemetrexed versus best supportive care (data reported for pemetrexed arm only); irinotecan (Campto; Pfizer, Capelle aan den IJssel, the Netherlands). correlated with survival improvement. 38 A recent overview of the EORTC Lung Cancer Group pointed out that replacement of the RR by TTP as the primary endpoint would allow a better selection of clinically active drugs. 39 In our study, PFS was not designed as the primary endpoint. However, considering the 3 EORTC categories (although they were not derived from second-line studies), our regimen demonstrated an activity between insufficient and moderate. Accordingly, the PFS rate at 6 months was 31%, which is in the range of regimens with poor activity in the first-line setting, but it could be revalued in view of the second-line setting of our combination and the characteristics of our population. The majority of our population (73%) had a poor EORTC prognostic score, which is expected to be associated with a shorter survival. 33 Indeed, stratifying our data for EORTC score, patients who had good scores had a significantly improved OS compared with patients who had poor scores (Table 2). Similarly, OS was significantly longer in patients who had a good ECOG PS. In addition, as reported in randomized trials of second-line therapy in patients with small cell and nonsmall cell lung cancer, in our MPM population, disease progression during firstline therapy and a shorter interval from completion of first-line therapy were correlated with shorter TTP and OS after second-line treatment (Table 2). In conclusion, the results from this study suggest the feasibility of giving second-line chemotherapy to patients with MPM. Unfortunately, the results remain modest, although chemotherapy could be offered to these patients for palliation. However, MPM should be considered an ideal field in which to test new chemotherapy agents as well as new therapeutic strategies, including antiangiogenic compounds, small molecules or monoclonal antibodies that target different molecular pathways, and gene therapy. 40 Although it has been demonstrated that targeted therapy with epidermal growth factor receptor and platelet-derived growth factor receptor inhibitors and antiangiogenic drugs is ineffective in unselected patients, an improvement in our knowledge of the major molecular pathways involved in MPM should define proper targets for the systemic treatment of this disease. Reinduction of apoptosis by manipulating its critical control points (tumor necrosis factor 10 receptor, histone deacetylases, and the proteasome), the inhibition of hepatocyte growth factor and its receptor c-met, the inhibition of angiogenesis, and evaluating the synergism between chemotherapy and targeted therapy all are interesting fields in which to develop new, effective treatments. The role of second-line treatment in MPM needs to be evaluated in prospective trials on large series of patients stratified according to previous treatment, prognostic factors, and biologic features. REFERENCES 1. Peto J, Decarli A, La Vecchia C, La Vecchia C, Levi F, Negri E. The European mesothelioma epidemic. Br J Cancer. 1999;79: Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21: Scagliotti GV, Shin DM, Kindler HL, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol. 2003;21: Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006;24:
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