Annals of Oncology Advance Access originally published online on December 20, 2007
Annals of Oncology 2008 19(2):370-373; doi:10.1093/annonc/mdm501
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lung cancer |
Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM)
1 Department of Oncology, Novi Ligure Hospital, viale Giolitti, Novi Ligure (AL)
2 Department of Oncology, Ospedale ‘C. Poma’, viale Albertoni, Mantova
3 Department of Oncology, Ospedale ‘Villa Scassi’, Corso Onofrio Scassi, Genova
4 Department of Oncology, Ospedale Maggiore della Carità, Corso Mazzini, Novara
5 Department of Pneumology, Ospedale Regionale di Aosta, viale Ginevra, Aosta
6 Department of Pneumology, Ospedale ‘S. Spirito’, viale Giolitti, Casale Monferrato (AL)
7 Occupational Medicine Unit, University of Genoa, Largo Rosanna Benzi, Genova, Italy
* Correspondence to: Dr M. Mencoboni, via Giovanni Torti 6/13, 16143 Genoa, Italy. Tel: +39-010-4102639; Fax: +39-010-8630625; E-mail: manlio.mencoboni{at}fastwebnet.it
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussion and conclusionsReferences |
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Background: The aim of this study was to evaluate the activity and toxicity of pemetrexed and carboplatin combination as first-line chemotherapy in malignant pleural mesothelioma (MPM).
Patients and methods: Patients with measurable advanced MPM and a zero to two Eastern Cooperative Oncology Group (ECOG) performance status (PS) were enrolled. The schedule was pemetrexed 500 mg/m2 in combination with carboplatin area under the curve 5, every 21 days. In all, 76 patients were treated. Median age was 65 years; median ECOG PS was zero.
Results: Grade 3 hematological toxicity according to World Health Organization criteria was seen in 36 (47.3%) patients; grade 4 hematological toxicity in 5 (6.5%) patients. There were 16 (21%) partial responses and 3 (4%) complete responses, for an overall response rate of 19 (25%) [95% confidence interval (CI) 15.3–34.7]. In all, 29 (39%) (95% CI 28–48) patients reported stable disease. The median survival was estimated at 14 months.
Conclusion: This combination of carboplatin and pemetrexed is moderately active and the toxicity is acceptable.
Key words: chemotherapy, mesothelioma, pemetrexed
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussion and conclusionsReferences |
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Malignant pleural mesothelioma (MPM) is a locally invasive malignancy, but only a minority of patients can benefit from surgical resection. Most patients with MPM, treated or untreated, die of complications from local disease due to increasing tumor bulk. There are no published standards of care for the treatment of resectable MPM, and treatment decisions are influenced not only by the functional evaluation of these often elderly individuals but also by the philosophy of the treating physician.
The evolution of the use of surgery in MPM with or without intraoperative or postoperative innovative adjuvant therapies is subject to continuous modifications; multimodality protocols that incorporate surgery as part of the package are being explored in larger numbers of patients. The vast majority of MPM, however, is unresectable. Chemotherapy is the treatment of choice in these cases. Among recently introduced chemotherapeutic agents only vinorelbine, edatrexate, gemcitabine and raltitrexed have demonstrated response rates (RRs) >20% [1]. Platinum compounds and doxorubicin are also effective and have been considered standard treatment for many years [2] even if they have not had a significant impact on overall survival (OS) rates [3]. Binary combinations with cisplatin, carboplatin and gemcitabine have proven feasible and show encouraging activity in lung cancer and MPM [4, 5]. Three-agent combinations (with vinorelbine) have also been attempted [6] but have always yielded poor results. The median survival of 337 patients treated in 10 clinical trials by the Cancer and Leukemia Group B [all of whom were required to have a performance status (PS) 0 to 2] was 7 months [7, 8]. In recent years, one phase II trial demonstrated a 14.5% RR for single-agent pemetrexed disodium in patients with previously untreated MPM [1]. In another phase II study [9] which evaluated the efficacy of pemetrexed with and without folic acid and vitamin B12 supplementation for the treatment of MPM, the RR was 14.1% in patients without vitamin supplementation and 16% in patients with vitamin supplementation; OS was 8 months for nonsupplemented patients and 13 months for supplemented patients.
Pemetrexed is a multifolate antagonist that blocks three metabolic pathways of folate metabolism (glycinamide ribonucleotide formyltransferase, thymidylate sinthase and dihydrofolate reductase). Problems of sporadic life-threatening toxicity identified in early studies of this and other antifolates were resolved by the discovery that they were caused by functional folate deficiency and could be avoided by a low-dose nutritional supplement of folic acid and vitamin B12 [10]. Pemetrexed has demonstrated clinical activity in non-small-cell lung cancer, as well as in a wide array of other solid tumors, including mesothelioma, breast, colorectal, bladder, cervical, gastric and pancreatic cancer. In non-small-cell lung cancer, single-agent activity has been documented in the first- and second-line settings in phase II and phase III trials.
The largest randomized trial on MPM showed an improved median survival from 9.3 to 12.1 months with cisplatin and pemetrexed versus cisplatin alone [11].
Cisplatin, however, produces often notable toxic effects and may be dangerous for unfit patients such as those who have mesothelioma. Its derivative, carboplatin, is often better tolerated.
Building on these results, we designed a phase II study to evaluate the activity and toxicity of the combination of pemetrexed and carboplatin as first-line chemotherapy to treat patients affected by advanced MPM, including patients with bad PS.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussion and conclusionsReferences |
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patient eligibility
Patients were considered eligible if they had histologically proven MPM not amenable to curative surgery, younger than 75 years of age, measurable disease on thoracic computed tomography (CT) scan and an Eastern Cooperative Oncology Group (ECOG) PS of zero to two. Other eligibility criteria were a life expectancy of >3 months, adequate bone marrow (leukocyte count >3000/mm3, platelet count >100 000/mm3 and hemoglobin >10 g/dl), hepatic [total bilirubin level <1.5 times the upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase levels <2.0 times the ULN] and renal functions (serum creatinine clearance <1.5 mg/dl or a calculated serum creatinine clearance >60 ml/min).
Patients were excluded if they had systemic chemotherapy and/or radiotherapy, previous or concurrent malignancies except for nonmelanoma skin cancer or cervical carcinoma in situ, psychiatric disorders, documented brain metastases, clinical evidence of heart failure or evidence of infections. The study was carried out according to the ethical principles of the Helsinki Declaration, with local Institutional Review Board approval and signed informed consent from all patients.
treatment plan
This study was a multicenter phase II trial using a combination of carboplatin and pemetrexed chemotherapy in patients with advanced MPM. The primary end point was the evaluation of activity in terms of tumor RR. Secondary end points were OS, time to progression (TtP) and toxicity related to the treatment.
Carboplatin was delivered to an area under the curve (AUC) of 5 over 30 min on day 1 and pemetrexed was diluted in 100 ml of normal saline and administered at a dose of 500 mg/m2 i.v. >10 min on day 1. Cycles were repeated every 21 days. All patients received folic acid supplementation at a dose of 400 µg daily, beginning at least 7 days before the first dose of pemetrexed and one injection of vitamin B12 intramuscularly 7–14 days before beginning the treatment. Folic acid was continued and vitamin B12 was repeated every 8 weeks throughout study until 21 days after the last dose of pemetrexed. Desamethasone 8 mg was given intramuscularly on the day before, the day of and the day after therapy. Antiemetic regimen with a 5-hydroxytryptamine antagonist was administered before therapy. Chemotherapy was discontinued in the event of disease progression or unacceptable toxicity or after a maximum of nine cycles.
Cycles were repeated at 100% of the programmed doses if neutrophil and platelet counts were 
1.5 x 109/l and 100 x 109/l, respectively. In case of a neutrophil nadir >0.5 x 109/l and a platelet count 50 x 109/l, patients received 75% of the previous doses; administered programmed doses were reduced to 50% if platelet nadir count was <50 x 109/l with any neutrophil count. In the event of more than or equal to grade 3 diarrhea, mucositis and other non-hematologic toxic effects, treatment was delayed until resolution and then was resumed at 75% of the previous dose level. If any dose reduction occurred, patients continued to receive the same dose throughout the study. Treatment was discontinued if delayed for up to 42 days from the last administration of combination chemotherapy.
baseline and treatment evaluations
All patients underwent a comprehensive medical history review, a physical examination, a complete blood count and biochemistry profile. The baseline staging evaluation included chest–abdominal scan and direct thoracoscopy. Patients were staged according to the tumor–node–metastasis international staging system [12]. For the pretreatment tumor evaluation, the most evident tumor thickening was measured in two positions on transverse sections of CT scans taken at three separate levels; the sum of these six segments was calculated at baseline.
CT scans were repeated after the third cycle of chemotherapy and at the end of treatment. Thereafter, tumor reassessment was carried out at 2-month intervals. Patient response was measured according to mesothelioma-modified Response Evaluation Criteria in Solid Tumors [13].
Complete response (CR) was defined as the disappearance of all known disease on two consecutive occasions 4 weeks apart; partial response (PR) as at least a 30% decrease of the above-mentioned baseline measure; stable disease (SD) as a decrease of <30% or an increase of <25% and progressive disease (PD) as at least a 25% increase above baseline or as the appearance of new lesions. Common toxicity criteria according to the National Cancer Institute Grading System (version 2.0) were used in the evaluation of treatment toxicity [14].
statistical methods
OS time and time to disease progression were defined as the time from the date of first dose administration to the date of death from any cause or to the date of disease progression, respectively. Because the response of an intent-to-treat protocol is presumed to be 
20%, and taking into account an alfa error of 0.05% and a 95% confidence interval (CI), 76 enrolled patients were deemed to be necessary. The end point of efficacy of this chemotherapy regimen is reached in the event of response in at least 16 patients. The Kaplan–Meier method was used to generate survival and average follow-up curves [15].
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussion and conclusionsReferences |
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patients characteristics
From July 2003 to March 2005, 76 chemo-naive patients were treated with this combination chemotherapy. Baseline characteristics of patients are reported in Table 1.
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There were 54 males and 22 females. The median age was 65 years (range 40–75). The ECOG median PS was zero (range 0–3). Histologic findings were as follows: epithelial in 57 (75%) patients, mixed in 13 (17.1%) patients, sarcomatous in 3 (3.9%) patients and unspecified in 3 (3.9%) patients. Most patients were stage III or IV according to the International Mesothelioma Interest Group classification.
dose administration and efficacy
A total of 537 cycles were administered for a median number of eight cycles per patient. As for dose intensity analysis, the median delivered dose intensity for pemetrexed was 160.1 mg/m2/week with a relative dose intensity (RDI) of 96%. For carboplatin RDI was 97%.
Apart from two patients who were considered lost at follow-up, all patients were evaluated for response according to an intent-to-treat-analysis.
There were 3 (4%) CR and 16 (21%) PR for an overall response rate (ORR) of 19 patients (25%) (95% CI 15.3–34.7); 29 (38%) (95% CI 28–48) and 28 (37%) patients were considered to have SD and PD, respectively.
The median OS was estimated at 14 months (range 1.8 to 33+) and the median TtP was 8 months (range 1–23.5). The median duration of response was calculated at 6 months (range 3–26).
OS survival curve for the whole group are presented in Figure 1.
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toxicity
The treatment was generally well tolerated; toxicity consisted mainly of neutropenia and thrombocytopenia. In particular, 36 (47%) patients reported grade 3, and 5 (6.5%) patients grade 4 hematological toxicity. Grade 3 gastrointestinal toxicity, specifically vomiting, was seen in nine (11.8%) patients. No events of neutropenic fever or grade 4 gastrointestinal toxicity were documented. Other toxic effects included grade 3 astenia in four (5.2%) cases and grade 3 fever in four (5.2%). Other toxic effects were mild to moderate. The aforementioned toxic effects are reported in Table 2.
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discussion and conclusions |
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TopAbstractintroductionpatients and methodsresultsdiscussion and conclusionsReferences |
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The clinical characteristics of patients with MPM are usually very discouraging and, unfortunately, the disease is often at an advanced stage at presentation. Under these conditions, the standard treatment option is systemic chemotherapy and, recently, pemetrexed plus cisplatin has exhibited an interesting activity [11], as well as the association of cisplatin and raltitrexed [16].
Due to the poor clinical conditions of these patients, and taking into consideration the potential toxicity of cisplatin, its analogue carboplatin could provide an interesting alternative, particularly in elderly or poor PS patients.
An ORR of 32% was reported with a carboplatin and pemetrexed combination in a phase I dose-escalating study [17]. The treatment, at the recommended dose of AUC 5 and 500 mg/m2 for carboplatin and pemetrexed, respectively, was well tolerated and 70% of the patients showed a clinical improvement after just two courses, 3 weeks apart. More recently, Ceresoli et al. [18] demonstrated an 18.6% activity in terms of ORR with this regimen. At the same dose and schedule of administration, the efficacy seems to be slightly lower compared with that observed in our study. Nevertheless, it is well known that response evaluation is a critical problem for MPM patients, owing in large part to the fact that an optimal and universally accepted assessment system does not exist at present [19].
Noteworthy in terms of toxicity is that this regimen was generally well tolerated. Moreover, we have to bear in mind that the standard cisplatin–pemetrexed combination is considered to be more toxic, and that its superior activity, demonstrated over single drugs (see cisplatin) or probably compared with other regimens (see carboplatin plus pemetrexed), does not translate into such a tangible improvement in OS. In fact, in a pemetrexed plus cisplatin versus cisplatin alone phase III randomized trial, Vogelzang demonstrated that the median survival time was statistically better for patients treated with the combination regimen. The magnitude of this benefit, however, was not so evident (a difference of 12.1 versus 9.3 months in terms of OS) [11].
We can conclude that, at this schedule of administration, the carboplatin–pemetrexed chemotherapy combination could become an interesting treatment option for MPM, particularly in elderly or poor PS patients.
Received for publication June 2, 2007. Revision received September 12, 2007. Accepted for publication September 14, 2007.
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