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Phase II Study of Pemetrexed Plus Carboplatin in Malignant
Pleural Mesothelioma
Giovanni L. Ceresoli, Paolo A. Zucali, Adolfo G. Favaretto, Francesco Grossi, Paolo Bidoli, Guido Del Conte,
Anna Ceribelli, Alessandra Bearz, Emanuela Morenghi, Raffaele Cavina, Maurizio Marangolo,
Hector J. Soto Parra, and Armando Santoro
ABSTRACT
Purpose
This multicenter, phase II clinical study was conducted to evaluate the activity of the combination
of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM).
Patients and Methods
Chemotherapy-naive patients with measurable disease and adequate organ function, who were
not eligible for curative surgery, received pemetrexed 500 mg/m
2
and carboplatin area under the
plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All
patients received folic acid and vitamin B
12
supplementation. Pemetrexed was provided within the
Expanded Access Program.
Results
A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two
complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%).
Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall,
67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to
progression was 6.5 months; median overall survival time was 12.7 months. Compliance to
treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for
carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and
grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible.
Conclusion
Treatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM.
Disease control rate, time to disease progression, and overall survival were similar to the results
achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin
combination could be an alternative option for these patients.
J Clin Oncol 24:1443-1448. © 2006 by American Society of Clinical Oncology
INTRODUCTION
Malignant pleural mesothelioma (MPM) is an ag-
gressive tumor that usually has a poor prognosis.
The incidence of MPM is increasing throughout
most of the world, and it is predicted that it will
increase in the next 10 to 20 years.
1
Only a minority
of patients are eligible for radical surgery. Encourag-
ing results have been reported with multimodality
approaches, including extrapleural pneumonec-
tomy, adjuvant chemotherapy, and hemithoracic
radiotherapy,
2
but significant morbidity and mor-
tality have been associated with these treatments
3
;
furthermore, no randomized studies exist to sup-
port this approach. The efficacy of radiotherapy has
not been proven.
4
Most chemotherapy studies have
used either single agents or combination regimens
in the setting of small phase II trials; the rates of
objective tumor regression have generally been less
than 20%, with no significant impact on median
survival.
5,6
In a meta-analysis of early trials, cisplatin
was found to be the most active single drug.
7
Carbo-
platin, a platinum analog that is better tolerated and
easier to administer,produced similar response rates
in a few phase II studies.
8-10
Pemetrexed, a novel
multitargeted antifolate,
11
was shown to have activ-
ity as a single agent in a phase II trial in patients with
MPM
12
and in phase I trials in combination with
platinum analogs.
13,14
A large phase III trial testing
pemetrexed and cisplatin versus cisplatin alone in
448 chemotherapy-naive patients with MPM
showed a significant advantage with the combined
regimen in terms of survival, time to progression
(TTP), and response rate.
15
Recently, the combina-
tion of raltitrexed and cisplatin as first-line treat-
ment was reported to improve overall survival (OS)
From the Department of Medical
Oncology and Hematology and Medical
Statistics Unit, Istituto Clinico Humani-
tas Istituto di Ricovero e Cura a Carat-
tere Scientifico, Rozzano; Department
of Medical Oncology, Unit 2, National
Cancer Institute, Milan; Department of
Medical Oncology, University Hospital,
Padua; Department of Medical Oncol-
ogy, National Institute for Cancer
Research, Genoa; Department of Medi-
cal Oncology, Azienda Ospedaliera,
Trieste; Department of Medical Oncol-
ogy, Unit A, Regina Elena Cancer Insti-
tute, Rome; Department of Medical
Oncology, Unit A, National Cancer Insti-
tute, Aviano; and Department of Oncol-
ogy and Hematology, Istituto
Oncologico Romagnolo, Ravenna, Italy.
Submitted September 20, 2005;
accepted January 12, 2006.
Presented in part at the 41st Annual
Meeting of the American Society of Clini-
cal Oncology, Orlando, FL, May 13-17,
2005; and the 11th World Conference on
Lung Cancer, Barcelona, Spain, July 3-6,
2005.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Address reprint requests to Giovanni
Luca Ceresoli, MD, Department of
Medical Oncology and Hematology, Isti-
tuto Clinico Humanitas Istituto di Ricov-
ero e Cura a Carattere Scientifico,
Rozzano, Milan, Italy; e-mail:
giovanni_luca.ceresoli@humanitas.it.
© 2006 by American Society of Clinical
Oncology
0732-183X/06/2409-1443/$20.00
DOI: 10.1200/JCO.2005.04.3190
JOURNAL OF CLINICAL ONCOLOGY
ORIGINAL REPORT
VOLUME 24 䡠 NUMBER 9 䡠 MARCH 20 2006
1443
Copyright © 2006 by the American Society of Clinical Oncology. All rights reserved.
Downloaded from www.jco.org by ADOLFO FAVARETTO on March 23, 2006 from 217.148.121.8.
compared with cisplatin, providing further support for cisplatin with
an antifolate as a reference regimen in patients with MPM.
16,17
Pemetrexed and carboplatin were found to be synergistic in pre-
clinical models
18
and active and well tolerated in a phase I trial in
MPM patients,
14
although no vitamin supplementation was adminis-
tered. The recommended dose of the combination for phase II studies
was pemetrexed 500 mg/m
2
and carboplatin area under the plasma
concentration-time curve (AUC) 5 mg/mL/min. This study was de-
signed to explore, in a large series of patients, the efficacy of the
combination of pemetrexed and carboplatin as front-line therapy in
patients with MPM. Pemetrexed was provided by Eli-Lilly (Indianap-
olis, IN) within the Expanded Access Program. The Expanded Access
Program was a nonrandomized open-label safety study of pemetrexed
as a single agent or in combination with cisplatin or carboplatin;
patients were assigned to a treatment arm based on the investigator’s
clinical decision.
PATIENTS AND METHODS
Patient Selection
Patients were eligible if they had histologically proven MPM and were
not candidates for curative surgery. The presence of unidimensionally and/or
bidimensionally measurable disease was mandatory. Eligibility criteria in-
cluded age older than 18 years, Eastern Cooperative Oncology Group (ECOG)
performance status (PS) of ⱕ 2, and an estimated life expectancy of ⱖ 12
weeks. An adequate bone marrow reserve was required, with absolute neutro-
phil count (ANC) ⱖ 1.5 ⫻ 10
9
/L, platelets ⱖ 100 ⫻ 10
9
/L, and hemoglobin
ⱖ 9 g/dL. Creatinine clearance, which was calculated by the Cockroft and
Gault formula, had to be ⱖ 45 mL/min; bilirubin had to be ⱕ 1.5⫻ the upper
limit of normal (ULN); and ALT or AST had to be ⱕ 3⫻ ULN (AST could be
elevated to 5⫻ ULN in patients with known hepatic metastases). Prior sys-
temic or intracavitary chemotherapy, documented brain metastases, serious
comorbidities, or other malignancies were not allowed. Patients were also
excluded if they were unable to discontinue administration of aspirin and/or
other nonsteroidal anti-inflammatory agents for 2 days before (5 days for
long-acting agents), the day of, and 2 days after the dose of pemetrexed.
11
Patients with a measurable recurrence after surgery were considered eligible;
prior palliative radiotherapy was permitted.
Written informed consent was obtained from each patient before enter-
ing the study. The study was conducted after approval by the appropriate
ethical review boards. Recommendations of the Declaration of Helsinki for
biomedical research involving human patients were also followed.
Study Design
Our study was planned as a multicenter phase II trial of the combination
of pemetrexed and carboplatin as front-line treatment in patients with MPM.
Patients were enrolled prospectively from eight Italian institutions. The pri-
mary end point of the study was tumor response rate (RR). Secondary end
points included toxicity, TTP, and OS.
Treatment
Pemetrexed and carboplatin were both administered on day 1, every
21 days. Pemetrexed was administered intravenously at a dose of 500
mg/m
2
over 10 minutes, followed 30 minutes later by carboplatin, which
was administered as a 30-minute intravenous infusion at an AUC 5 mg/
mL/min. All patients were supplemented with folic acid and vitamin B
12
;
folic acid was taken orally (350 to 600
g daily) beginning at least 1 week
before the first dose of chemotherapy and was continued throughout the
duration of treatment for the study. Vitamin B
12
was administered intra-
muscularly at least 1 week before the first dose of chemotherapy and was
administered approximately every 9 weeks throughout study. Dexametha-
sone, at a dose of 4 mg twice daily, was administered orally the day before, the
day of, and the day after each chemotherapy treatment. Salicylates and non-
steroidal anti-inflammatory agents were not allowed during the 2 days before
(5 days for long half-life agents), the day of, and the 2 days after treatment.
Standard antiemetic prophylaxis with intravenous 5-hydroxytryptamine-3
antagonists was administered before chemotherapy.
Dose adjustments at the start of a subsequent cycle of therapy were based
on hematologic and nonhematologic toxicity observed during the preceding
course. Any patient requiring a dose reduction continued to receive a reduced
dose for the remainder of the study. Dose delays of up to 42 days were
permitted to allow recovery from toxicity. ANC had to be ⱖ 1.5 ⫻ 10
9
/L and
platelets had to be ⱖ 100 ⫻ 10
9
/L before the start of any cycle. On recovery,
patients with a nadir ANC less than 0.5 ⫻ 10
9
/L and platelets ⱖ 50 ⫻ 10
9
/L
received 75% of the previous pemetrexed dose or AUC 4 for carboplatin.
Patients with a platelet nadir count less than 50 ⫻ 10
9
/L and any ANC received
50% of the previous pemetrexed dose or AUC 3 for carboplatin. If a recurrence
of grade 3 or 4 thrombocytopenia or neutropenia was observed after two dose
reductions, the patient was withdrawn from study. In the event of grade 3 or 4
nonhematologic toxicities, treatment was delayed until there was resolution to
grade 1 or less before proceeding. Therapy was then resumed at 75% of the
previous dose level (AUC 4 for carboplatin), if deemed appropriate by the
treating physician. Creatinine clearance, which was calculated by the Cockroft
and Gault formula, was evaluated before each dose. If a patient developed a
value of less than 45 mL/min, then the next cycle was delayed until the
creatinine clearance had returned to ⱖ 45 mL/min.
Patient Assessment
Baseline assessment included a complete medical history and physical
examination and CBC and chemistries. Creatinine clearance was calculated at
baseline and also before each course of treatment. A CBC was taken weekly
while patients were on treatment. A chest and abdomen computed tomog-
raphy (CT) scan was performed at baseline. Patients were staged according
to the TNM staging system proposed by the International Mesothelioma
Interest Group.
19
Best tumor response was evaluated for patients with bidimensionally
measurable disease, unidimensionally measurable disease, or both according
to the same criteria used by Vogelzang et al
15
in the cisplatin/pemetrexed trial.
No confirmatory scans were conducted on patients exhibiting partial response
or stable disease (SD).
Treatment toxicity was evaluated according to the National Cancer In-
stitute Common Toxicity Criteria version 2.0 grading system.
20
Dose-intensity
(DI) was assessed separately for pemetrexed and carboplatin in patients receiv-
ing at least two cycles of chemotherapy. For pemetrexed, DI was calculated as
median dose in milligrams per square meter per week. For carboplatin, DI was
reported as the median AUC per week. The percentage of planned DI delivered
for both drugs was also calculated and reported as relative DI (RDI).
After completion of the study treatment, patients were evaluated every 2
months with chest and abdomen CT scans until disease progression. Patients
were also observed for survival until death or last contact if still alive. Second-
line therapy was not planned in this trial. TTP was defined as time from study
entry (first day of study treatment) until time of disease progression (as shown
by radiologic or clinical examination) or death from any cause. Patients with-
out any evidence of progressive disease were censored at the date of the last
follow-up. OS was calculated as the time from study entry until death from any
cause; patients who were alive on the date of last follow-up were censored on
that date.
Statistical Analyses
The sample size of the trial was established according to the one-arm
binomial sample model.
21
The primary end point of the study was the re-
sponse rate; response analysis was conducted on an intent-to-treat basis. A rate
of 15% was considered to be ineffective, whereas a rate of 30% was considered
to be of potential interest. This design yielded an
␣
⫽ .05 with 95% power.
According to this model, at least 98 patients had to be enrolled onto the study.
The planned accrual period was 24 months. Ninety-five percent CIs for re-
sponse rates were calculated.
22
Actuarial survival curves were generated using
the Kaplan-Meier method.
23
Median follow-up time was estimated with the
use of the inverse Kaplan-Meier method.
24
Response and survival rates were
analyzed according to the following variables: age (⬍ 65 v ⱖ 65 years, and as a
Ceresoli et al
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continuous variable), sex, ECOG PS (0 v 1 to 2), histology (epithelial v non-
epithelial), stage (II to III v ⬎ III), and European Organisation for Research
and Treatment of Cancer (EORTC) prognostic model for MPM
25
(good v
poor score). All parameters, except for age, were analyzed as categoric vari-
ables. The Fisher’s exact test was used to compare percentages in subsets of
patients through univariate analysis.
26
The impact of these variables on TTP
and OS was evaluated by univariate analysis using the Cox proportional
hazards regression model.
27
The independent value of variables was assessed in
multivariate analysis using the Cox proportional hazards regression model,
with an estimate of hazard ratios.
27
All probability values were two sided.
Statistical analyses were performed using the software package Stata 9 (STATA
Corp, College Station, TX).
RESULTS
Patient Characteristics
Between November 2002 and March 2005, a total of 102 patients
were entered onto the study at the eight participating centers; their
characteristics are listed in Table 1. There were 76 males and 26
females. The median age was 65 years, and 32 patients (31.4%) were
older than 70 years. Most patients had a PS of ⱕ 1 and epithelial
histologic subtype (78%); 75.5% of patients had a poor EORTC prog-
nostic score.
Efficacy
All 102 patients were evaluated for best tumor response, which
was assessed according to an intent-to-treat analysis. Two patients
experienced a complete response (lasting 10⫹ and 11 months),
whereas a partial response was achieved in 17 patients, for an objective
response rate of 18.6% (95% CI, 11.6% to 27.5%). Response was
observed in patients with epithelial (15 patients) or mixed histotype;
no response was registered in patients with sarcomatoid MPM. The
median duration of partial responses was 8 months (range, 3 to 15⫹
months). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) were
considered to have SD, and 35 (34.3%) had progressive disease. Over-
all, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to
74.8%). No patient or treatment-related variable was significantly
related to response in univariate analysis. Sixty-nine patients (68%)
were symptomatic at the time of study enrollment. ECOG PS im-
proved or was stable in the majority of patients who achieved response
or SD. In responders, baseline PS was 0 in three patients and 1 in 16
patients; post-treatment PS values were 0 in 10 patients and 1 in nine
patients. Patients with SD had a baseline PS of 0, 1, and 2 in 21, 25, and
two patients, respectively; the corresponding post-treatment numbers
were 23, 22, and three patients, respectively.
With a median follow-up time of 14.2 months (95% CI, 12.2 to
15.0 months), 47 patients were still alive, 26 of whom were alive
without any evidence of disease progression. Figure 1 shows the actu-
arial TTP curve for the entire population; the median TTP was 6.5
months. The OS curve for all enrolled patients is shown in Figure 2.
The median survival time was 12.7 months; the 6-month and 1-year
survival estimates were 70.0% (95% CI, 60.0% to 78.0%) and 51.6%
(95% CI, 40.7% to 61.5%), respectively. TTP was significantly related
to good PS (P ⫽ .047) and epithelial histology (P ⫽ .02) in both
univariate and multivariate analyses. No correlation was observed
between TTP and age, sex, disease stage, or EORTC score. Patients’ PS
was the only factor significantly related to OS in univariate and mul-
tivariate analyses (P ⫽ .04); all of the other variables failed to show any
correlation with survival. Response to treatment showed a trend that
correlated with OS in univariate analysis (P ⫽ .069) and reached
statistical significance in the multivariate model (P ⫽ .024). When SD
patients were grouped with responders, the correlation with OS was
much more significant (P ⬍ .001).
Study Drug Administration and Toxicity
Patients received a median of six cycles of treatment; 79 patients
(77%) completed at least four cycles. Overall, 482 cycles of chemother-
apy were delivered. Dose reductions were uncommon and were nec-
essary in only 29 cycles (6% of total cycles). The median delivered DI
of both study drugs, which was calculated for 96 patients receiving ⱖ
two cycles, was high, with an RDI of 97% for pemetrexed and an RDI
of 98% for carboplatin.
Table 1. Patient Characteristics
Characteristic
No. of
Patients
(N ⫽ 102) %
Sex
Male 76 74.5
Female 26 25.5
Age, years
Median 65
Range 38-79
ECOG performance status
03332
16160
288
Histologic subtype
Epithelial 80 78
Sarcomatoid 7 7
Mixed cell 8 8
Unspecified 7 7
EORTC prognostic score
Good 25 24.5
Poor 77 75.5
IMIG stage
II 11 11
III 34 33
IV 49 48
Relapse after EPP 8 8
Abbreviations: ECOG, Eastern Cooperative Oncology Group; EORTC, Euro-
pean Organisation for Research and Treatment of Cancer; IMIG, International
Mesothelioma Interest Group; EPP, extrapleural pneumonectomy.
Fig 1. Kaplan-Meier curve of time to disease progression for all patients (median
time to progression, 6.5 months).
Pemetrexed/Carboplatin in Pleural Mesothelioma
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Hematologic toxicity was mild and consisted mostly of neutro-
penia (Tables 2 and 3). Febrile neutropenia was reported in two
patients. Severe anemia was reported in 11.7% of patients (grade 4 in
one patient only) and occurred as cumulative toxicity after the second
cycle of treatment in most cases; overall, it was reported in 3.5% of
total cycles. Grade 3 or 4 thrombocytopenia was even less frequent,
occurring in 7.8% of patients and 2% of cycles. Nonhematologic
toxicity was generally mild (Table 4). Acute rhabdomyolysis occurred
in a 68-year-old male patient, who developed severe myalgias and
weakness of the lower and upper limbs and abdominal tenderness.
Laboratory studies revealed increased creatine kinase, myoglobin,
AST, and ALT serum levels. The laboratory abnormalities and the
weakness slowly improved with hydration, corticosteroids, and di-
uretics during the following weeks.
28
Nausea and vomiting, fatigue,
conjunctivitis, and stomatitis were the most commonly reported non-
laboratory treatment adverse effects (Table 4). No treatment-related
deaths were observed.
DISCUSSION
The combination of pemetrexed and cisplatin has recently been estab-
lished as the standard of care in systemic therapy for MPM.
16
The
addition of folic acid and vitamin B
12
significantly reduced the toxicity
of this combination, especially hematologic toxicity.
11
The typical
nonhematologic toxicity profile of cisplatin (GI, neurologic, and re-
nal) is questionable in the context of a palliative treatment, especially
for poor performance and elderly patients. Carboplatin has the poten-
tial advantages of having a better adverse effect profile and better ease
of administration. In a phase I study in 25 patients with MPM, the
combination of pemetrexed and carboplatin was active and well tol-
erated, with a reported response rate of 32%.
14
Our study, which included full vitamin supplementation, con-
firmed the acceptable activity and good toxicity profile of this regimen
in a large cohort of patients. The radiologic regression rate of disease,
which was evaluated according to the same criteria used by Vogelzang
et al,
15
was inferior to that reported with the cisplatin combination.
However, response evaluation with CT measurements is particularly
challenging in MPM because of its diffuse pattern of growth. Consid-
erable discrepancy was reported among study investigators and inde-
pendent reviewers in evaluation of patients treated with pemetrexed
and cisplatin; tumor response could be confirmed in only half of
patients.
11
Several response criteria have been proposed,
15,29
but the
optimal evaluation method has yet to be defined.
30,31
Despite the
apparently lower radiologic response rate, TTP and survival in our
study were similar to the data reported with the standard cisplatin
combination.
15
In a recent overview of three prospective trials, the
radiologic responses did not seem to be correlated with the survival
improvement.
32
Considering these data, the survival outcomes re-
main the best treatment end points in this disease. No second-line
therapy was planned in our trial; this might have influenced OS data.
However, the benefit of second-line chemotherapy in MPM is not
proven. In a retrospective analysis of patients treated in the pem-
etrexed/cisplatin trial, Manegold et al
33
reported a significantly pro-
longed survival in the groups treated with poststudy chemotherapy
(PSC); however, because assignment to PSC was not randomized, it
Fig 2. Kaplan-Meier curve of overall survival time for all patients (median overall
survival time, 12.7 months).
Table 2. Hematologic Toxicity by Patient (N ⫽ 102)
Toxicity
Toxicity Grade
1
(No.)
2
(No.)
3
(No.)
4
(No.) 3-4 (%)
Neutropenia 17 25 9 11
ⴱ
19.6
Thrombocytopenia 17 3 6 2 7.8
Anemia 33 30 11 1 11.7
ⴱ
Febrile neutropenia was reported in two patients.
Table 3. Hematologic Toxicity by Cycle (N ⫽ 482)
Toxicity
Toxicity Grade
1
(No.)
2
(No.)
3
(No.)
4
(No.) 3-4 (%)
Neutropenia 60 59 36 11 9.7
Thrombocytopenia 51 12 7
ⴱ
3
ⴱ
2
Anemia 166 79 16† 1† 3.5
ⴱ
Grade 3 or 4 thrombocytopenia occurred after the second cycle in seven
(70%) of 10 patients.
†Grade 3 or 4 anemia occurred after the second cycle in 15 (88%) of 17 patients.
Table 4. Nonhematologic Toxicity by Patient (N ⫽ 102)
Toxicity
ⴱ
Toxicity Grade
1
(No.)
2
(No.)
3
(No.)
4
(No.) 3-4 (%)
Nausea/vomiting 47 17 1 0 1
Fatigue 31 13 1 0 1
Stomatitis 3 7 0 0 0
Conjunctivitis 20 3 0 0 0
Diarrhea 2 0 3 0 3
Constipation 5 1 0 0 0
ⴱ
Other toxicities reported as rare events included the following: grade 4
rhabdomyolysis (one patient), grade 2 hepatotoxicity (one patient), grade 2
arthralgia-myalgia (two patients), grade 2 genitourinary mucositis (two pa-
tients), and grade 1 skin rash (two patients).
Ceresoli et al
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was impossible to know whether the reduced risk of death was associ-
ated with PSC or whether patients who had prolonged survival tended
to receive more PSC.
Therapy with carboplatin and pemetrexed was well tolerated; non-
hematologic toxicity was negligible, except for a case of acute rhabdomy-
olysis, which was possibly related to the treatment. This compares
favorably with the toxicity profile reported in the cisplatin/pemetrexed
trial, in which a higher incidence of nausea and vomiting and fatigue
was observed.
15
The hematologic toxicity was fairly acceptable, with a
short-lived neutropenia in approximately 20% of patients and a severe
anemia (mainly grade 3) in 11.7% of patients; anemia was cumulative
and occurred after the second cycle of treatment in the majority of
patients. MPM is a life-threatening illness with a poor prognosis.
Palliation is the main goal of treatment in nonsurgical patients.
Therefore, disease control with a good PS and quality of life should
be considered a valuable end point. Although the quality of life was
not evaluated in our study, it is significant that ECOG PS improved
or remained roughly stable in all patients achieving disease control.
In conclusion, our observations showed that the combination of
pemetrexed and carboplatin was both active and well tolerated in
patients with MPM. Disease control rate, TTP, and OS were similar to
that achieved with the standard regimen of pemetrexed and cispla-
tin, suggesting that the carboplatin combination may be a viable
option, especially for elderly or poor PS patients. Although the
chemotherapy regimens of pemetrexed plus platinum derivatives
clearly represent a step forward in the treatment of MPM, the
prognosis for these patients remains poor, and new therapeutic
strategies are eagerly awaited.
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■■■
Acknowledgment
We thank Valter Torri, MD (Department of Oncology, Biometry Unit, Mario Negri Institute, Milan, Italy), for external review of the study
database and design.
Pemetrexed/Carboplatin in Pleural Mesothelioma
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Authors’ Disclosures of Potential Conflicts of Interest and Author Contributions
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Giovanni L. Ceresoli, Paolo A. Zucali, Armando Santoro
Provision of study materials or patients: Giovanni L. Ceresoli, Paolo A. Zucali, Adolfo G. Favaretto, Francesco Grossi, Paolo Bidoli, Guido Del Conte,
Anna Ceribelli, Alessandra Bearz, Raffaele Cavina, Maurizio Marangolo, Hector J. Soto Parra, Armando Santoro
Collection and assembly of data: Giovanni L. Ceresoli, Paolo A. Zucali, Adolfo G. Favaretto, Francesco Grossi, Paolo Bidoli, Guido Del Conte,
Anna Ceribelli, Alessandra Bearz, Raffaele Cavina, Maurizio Marangolo, Hector J. Soto Parra
Data analysis and interpretation: Giovanni L. Ceresoli, Paolo A. Zucali, Emanuela Morenghi, Armando Santoro
Manuscript writing: Giovanni L. Ceresoli, Paolo A. Zucali, Armando Santoro
Final approval of manuscript: Giovanni L. Ceresoli, Paolo A. Zucali, Adolfo G. Favaretto, Francesco Grossi, Paolo Bidoli, Guido Del Conte, Anna Ceribelli,
Alessandra Bearz, Raffaele Cavina, Hector J. Soto Parra, Armando Santoro
Ceresoli et al
1448
JOURNAL OF CLINICAL ONCOLOGY
Copyright © 2006 by the American Society of Clinical Oncology. All rights reserved.
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