Pemetrexed in Malignant Pleural Mesothelioma
Pemetrexed in Malignant Pleural Mesothelioma
Malignant pleural mesothelioma
(MPM) is a rare, aggressive
malignancy that has been
linked with exposure to one or more
types of asbestos fibers. Asbestos exposure
is associated with 70% to 80%
of all cases of mesothelioma; 60% of
these cases are directly related to occupation
and 20% are paraoccupational.[
1] Because of the relationship to
occupational exposure, mesothelioma
is seen predominately in males (5:1),
as they are more likely to be employed
in occupations that have an increased
exposure to asbestos.
Asbestos fibers all have unique
physical, chemical, and biological
properties and are divided into two
major groups. The serpentine group
of asbestos fibers includes the crysotile
fibers, and the amphibole group
of fibers includes crocidolite, amosite,
anthophyllite, and tremolite fibers.
The carcinogenic effects of asbestos
appear to be related to its physical
properties, and crocidolite is the
most oncogenic type of asbestos fiber.[
2] The long needlelike amphibole
fibers appear to lodge in the distal
respiratory system more readily than
short fibers; after inhalation, fibers
that remain tend to accumulate in the
lower third of the lungs adjacent to
the visceral pleura.
The latency period from time of
asbestos exposure to onset of malignant
mesothelioma is long, and may
be 30 to 40 years. In the United
States, the first ban on the use of asbestos
was in 1971. Because of the
long latency period, incidence was
expected to peak at 2,300 cases per
year around 2000. In Europe, where
the elimination of the use of asbestos
did not occur as quickly as in the
United States, there will be an estimated
250,000 deaths from mesothelioma
in the next 30 to 35 years,
and the peak incidence is expected to
occur in 2020. There is some evidence
that suggests that genetics, radiation,
and viruses may interact with
environmental carcinogens, such as
asbestos, causing malignancy.
Malignant mesothelioma arises
from the surface serosal cells of the
pleural, peritoneal, and pericardial
cavities. Of the three morphologic
types of pleural mesothelioma, epithelial
is the most common morphologic
type and is seen in 60% of cases,
mixed or biphasic types occurs in 30%
of cases and the sarcomatoid type occurs
in 10% of cases. Sarcomatoid
tumors have a poorer differentiation
phenotype and are associated with a
poorer prognosis than epithelial or
The most common symptoms at
presentation are dyspnea and/or chest
pain. Patients commonly have large
unilateral pleural effusions on chest
x-ray, and over 50% of patients have
pleural calcifications on computerized
tomography (CT) scan and often coalescing
nodules and plaques on visceral
and parietal pleura are seen.
Mesothelioma can involve the chest
wall, pericardium, interlobar fissures
and diaphragm, as well as the pleura.
The prognosis for patients with
mesothelioma is dismal due to limited
therapeutic options; few drugs have
demonstrated activity in this tumor.
Numerous agents, as monotherapy and
combination therapy, have been studied
in patients with malignant pleural
mesothelioma, with no drug or regimen
emerging as the clear standard of
care. In these studies, anthracyclines,
platinum compounds, alkylating
agents, topoisomerase agents, antimicrotubule
agents, platinum agents, and
antimetabolites have demonstrated
activity in this tumor. Response rates
in these studies were generally below
15%, with a few exceptions.
The antimetabolites, as single
agents, consistently produced response
rates of 15% to 20%. Of all
the antimetabolites, the antifolates
have produced the highest response
rates as single agents in the treatment
of malignant mesothelioma. Numerous
combination regimens have also
been investigated. Combinations with
a platinum agent and an antimetabolite
have produced response rates of
16% to 45%.[9-15] The antifolates
appear to be the most active class of
agents investigated in the treatment
of MPM to date. Trials investigating
the efficacy of trimetrexate, edatrexate,
raltitrexed (Tomudex) and methotrexate
have demonstrated activity,
with response rates up to 40%. Table
1 shows studies of antifolates in mesothelioma.[16-19]
Several ongoing clinical trials are
evaluating the activity of newer agents
including gemcitabine (Gemzar),
pemetrexed (Alimta), ranpirnase, raltitrexed/
oxaliplatin (Eloxatin) combination,
and anti-EGFR agents such as
gefitinib (Iressa) and erlotinib (OSI-
774, Tarceva). Of these, pemetrexed
seems to be the most promising drug.
In addition, data suggest that gemcitabine
is active in patients with MPM.
Pemetrexed has been studied in three
trials in patients with MPM, and two
phase I trials included patients with
MPM. In a phase II trial, pemetrexed
was studied as a single agent in patients
with MPM. This study included
more than 60 MPM patients; nearly
60% of patients in this trial received
full vitamin supplementation and 30%
of patients received partial or no vitamin
Phase II Single-Agent
Pemetrexed Trial in MPM
Distribution of patient characteristics
was well balanced between the
two groups (supplemented and nonsupplemented
patients); most patients
had advanced disease, good performance
status (Karnofsky performance
status of 80 to 100), and an epithelial
histologic subtype of MPM. The
response and survival data are shown
in Table 2. Because it can be difficult
to obtain objective tumor measurements
in MPM, two determinations
of best response were performed on
each patient: one by the investigator
and one by an external expert panel.
The investigator-assessed response
rate was as 14.1% in all patients. Supplemented
patients had higher response
rates than nonsupplemented
patients-16.3% compared with
9.5%, respectively. Survival was longer
in supplemented patients than nonsupplemented
survival was 13 and 8 months, median time to disease progression was
4.8 and 3 months, and 1-year survival
was 54.2% and 34.2% in supplemented
and nonsupplemented patients, respectively.
For the entire patient
population, the 1-year survival of
47.8% and median survival of 10.7
months seems promising, despite the
fact that this was a phase II study.
Randomized Phase III Study of
A randomized phase III study of
pemetrexed/cisplatin vs cisplatin was
conducted in patients with MPM. Patients
were randomly assigned to receive
pemetrexed at 500 mg/m2 followed
by cisplatin at 75 mg/m2 on day
1, every 21 days, or cisplatin at 75 mg/
m2 on day 1, every 21 days. Patients
were stratified according to pain level,
analgesic consumption, and dyspnea at
study entry, treatment center and country,
degree of disease measurability,
performance status, gender, histologic
subtype, baseline white blood cell count,
and baseline homocysteine levels. During
the course of the study, three treatment-
related deaths were noted in the
first 43 patients.
Other studies of pemetrexed demonstrated
that severe toxicities may
be linked to high levels of homocysteine
and methymalonic acid. A large
multivariate analysis suggested that
such toxicity and possibly some deaths
may be related to reduced folic acid
and vitamin B12 pools. The protocol
was amended in December 1999, requiring
folic acid and vitamin B12 supplementation
for all patients receiving
As a result of this change, this study
had three patient populations: patients
who were enrolled in the study prior
to the protocol amendment and never
received vitamin supplementation;
partially supplemented patients who
were enrolled at the time this change
was made and received vitamin supplementation
after the protocol was
amended; and fully supplemented patients
who received vitamin supplementation
from the time of study
enrollment. The sample size of the
study was increased to ensure adequate
statistical power of the fully
supplemented group of patients. Of
the patients enrolled, 70 patients never
received vitamin supplementation,
47 patients were partially supplemented,
and 331 patients were fully supplemented.
The primary objective of
this trial was survival; secondary objectives included time to progressive
disease, time to treatment failure, tumor
response rate, duration of response,
pulmonary function testing,
lung density analysis, and quality-oflife
Patient characteristics were well balanced between the two arms: pemetrexed/ cisplatin (n = 226) vs singleagent cisplatin (n = 222). Nearly 70% of patients had an epithelial tumor type, approximately 10% had the sarcomatoid type, and 16% of patients had a mixed type in both groups. In each arm the majority of patients, almost 80%, had stage III or IV disease. Over 80% of patients enrolled had a Karnofsky performance status of at least 80. The median number of cycles of therapy received depended on whether or not patients received vitamin supplementation. In patients who were never supplemented, a median of only two cycles of therapy could be administered. In fully supplemented patients, the median number of cycles of therapy increased to six in the combination arm and four in the cisplatin arm. Supplemented patient were well balanced between the arms: pemetrexed/cisplatin (n = 168) vs single- agent cisplatin (n = 163). Toxicity
Differences in hematologic toxicity were significant between the two arms of the study. Patients who received pemetrexed/cisplatin experienced more anemia, leukopenia, neutropenia, and thrombocytopenia than did patients who received single- agent cisplatin. The incidence of febrile neutropenia was l.8% in the pemetrexed/cisplatin arm, and no febrile neutropenia was reported in the single-agent cisplatin arm. Among nonhematologic toxicities, nausea, vomiting, fatigue, diarrhea, dehydration, and stomatitis were significantly higher in the pemetrexed/cisplatin arm than in the single-agent cisplatin arm. Comparing the toxicities seen in patients who received pemetrexed/cisplatin with and without vitamin supplementation revealed that patients who received vitamin supplementation from the start of the study experienced less toxicity than those who received partial or no vitamin supplementation. The incidence of grades 3/4 neutropenia decreased from 38% to 23%, anemia 9% to 4%, and thrombocytopenia 9% to 5%, respectively, in nonsupplemented and fully supplemented patients. Efficacy
Figure 1 illustrates a CT scan of a study patient prior to treatment with pemetrexed/cisplatin and at visit 4. These graphically illustrate a clear response associated with pemetrexed/ cisplatin. Overall, the tumor response rate was significantly higher on the pemetrexed/cisplatin arm (41.3%) than in the patients who received cisplatin (16.7%). Differences in response rates were also significant between fully supplemented patients who received pemetrexed/cisplatin compared with those who received cisplatin (45.5% vs 19.6%, respectively). Table 3 contains efficacy data for all patients and for fully supplemented patients. Survival between the pemetrexed/ cisplatin and cisplatin arms was also statistically significant, 12.1 vs 9.3 months, respectively. Time to disease progression was 5.7 months in patients who received pemetrexed/ cisplatin vs 3.9 months in patients who received cisplatin monotherapy. This difference was also statistically significant.[ 22] An analysis of this phase III study was conducted by Symanowsi et al, on prognostic variables affecting survival. Vitamin supplementation, good Karnofsky performance ptatus, early-stage disease, and epithelial subtype were associated with improved survival. This analysis demonstrated that Karnofsky status, disease stage, and histology were powerful predictors of survival in patients with MPM. Another analysis of this trial included evaluation of lung function and its correlation to tumor response. Patients who experienced a tumor response had consistently better pulmonary function tests than did patients with stable disease; patients with stable disease had better pulmonary function tests than those with progressive disease. Figure 2 shows changes in forced vital capacity of patients on the pemetrexed/cisplatin and cisplatin single-agent arms of the study over six cycles of therapy. Quality-of-life data in this study demonstrated an advantage for the combination of pemetrexed/cisplatin over single-agent cisplatin. Using the LCSS-Meso instrument, global quality of life, pain, dyspnea, fatigue, anorexia, and cough were compared between the two arms. The majority of these parameters reached statistical significance between the two arms by week 15, in favor of the pemetrexed/cisplatin arm (Figure 3). Manegold and colleagues identified the incidence of post study chemotherapy among patients in this trial and determined that 38% of patients who received pemetrexed/cisplatin received post study chemotherapy compared with 48% of patients who received cisplatin monotherapy. The most commonly identified second-line therapy was gemcitabine followed by vinorelbine and doxorubicin. A phase III trial of pemetrexed plus best supportive care (BSC) vs BSC as second- line therapy in patients with MPM is ongoing. Discussion Many agents have been investigated in the treatment of MPM with no clear standard of care emerging. The antifolate class of agents shows the most promise of the agents investigated in the treatment of this aggressive disease. Recent data have demonstrated that pemetrexed, as a single agent and in combination with cisplatin, is an active agent with manageable toxicity when folic acid and vitamin B12 supplementation is administered concurrently. Pemetrexed has demonstrated efficacy with toxicity that is manageable with the addition of vitamin supplementation. The combination of pemetrexed/cisplatin significantly improved the survival in comparison to cisplatin alone. Other analyses demonstrated significantly improved lung function and quality of life in patients who received pemetrexed/cisplatin compared with patients who received cisplatin monotherapy. Supplementation with vitamins demonstrated an improvement in toxicity and efficacy.
2. Carbone M, Kratzke RA, Testa JR: The pathogenesis of mesothelioma. Semin Oncol 29(1):2-17, 2002.
3. Miller BG, Searl A, Davis JM, et al: Influence of fibre length, dissolution and biopersistence on the production of mesothelioma in the rate peritoneal cavity. Ann Occup Hyg 43:155-166, 1999.
4. Stanton MF, Layard M, Tegeris A, et al: Carcinogenicity of fibrous glass: Pleural response in relation for fiber dimension. J Natl Cancer Inst 58:589, 1977.
5. Vogelzang NJ: Emerging insights into the biology and therapy of malignant mesothelioma. Semin Oncol 29(suppl 18):35-42, 2002.
6. Price J: Analysis of current trends in United States mesothelioma incidence. Am J Epidemiol 145:211-218, 1997.
7. Peto J, Decarli A, La Vecchia C, et al: The European mesothelioma epidemic. Br J Cancer 79(3-4):666-672, 1999.
8. Testa JR, Pass HI, Carbone M: Benign and malignant mesothelioma, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 6th ed, pp 1937-1943. Philadelphia, Lippincott Williams & Wilkins, 2001.
9. Maisano R, Caristi N, Toscano G, et al: Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: Results of a pilot study. Tumori 87(6):391-393, 2001.
10. Fizazi K, Doubre H, Le Chevalier T, et al: Combination of raltitrexed and oxaliplatin is an active regimen in malignant mesothelioma: Results of a phase II study. J Clin Oncol 21(2):349-354, 2003.
11. Favaretto AG, Aversa SM, Paccagnella A, et al: Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: A multicentric phase II study. Cancer 97(11):2791-2797, 2003.
12. Hughes A, Calvert P, Azzabi A, et al: Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma. J Clin Oncol 20(16):3533-3544, 2002.
13. Thodtmann R, Depenbrock H, Dumez H, et al: Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin. J Clin Oncol 17(10):3009-3016, 1999.
14. Nowak AK, Byrne MJ, Williamson R, et al: A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 87(5):491-496, 2002.
15. Byrne MJ, Davidson JA, Musk AW, et al: Cisplatin and gemcitabine treatment for malignant mesothelioma: A phase II study. J Clin Oncol 17(8):2626-2627, 1999.
16. Vogelzang NJ, Weissman LB, Herndon JE 2nd, et al: Timetrexate in malignant mesothelioma: A Cancer and Leukemia Group B phase II study. J Clin Oncol 12(7):1436-1442, 1994.
17. Kindler HL, Belani CP, Herndon JE 2nd, et al: Edatrexate (10-ethyl-deaza-aminopterin) (NSC #626715) with or without leukovorin rescue for malignant mesothelioma. Sequential phase II trials by the Cancer and Leukemia Group B. Cancer 86(10):1985-1991, 1999.
18. Solheim OP, Saeter G, Finnanger AM, et al: High-dose methotrexate in the treatment of malignant mesothelioma of the pleura. A phase II study. Br J Cancer 65(6):956-960, 1992.
19. Baas P, Ardizzoni A, Grossi F, et al: The activity of raltitrexed (Tomudex) in malignant pleural mesothelioma: An EORTC phase II study (08992). Eur J Cancer 39(3):353-357, 2003.
20. Scagliotti GV, Shin DM, Kindler HL: Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 21(8):1556-1561, 2003.
21. Shin DM, Scagliotti G, Kindler H, et al: A phase III trial of pemetrexed in malignant pleural mesothelioma (MPM) patients: Clinical outcome, role of vitamin supplementation, respiratory symptoms, and lung function (abstract 1175). Proc Am Soc Clin Oncol 22:294a, 2002.
22. 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 21(14):2636-2644, 2003.
23. Symanowski JT, Rusthoven J, Nguyen B, et al: Multiple regression analysis of prognostic variables for survival from phase III study of pemetrexed + cisplatin vs. cisplatin in malignant pleural mesothelioma (abstract 2602). Proc Am Soc Clin Oncol 22:647, 2003.
24. Paoletti P, Pistolesi M, Rusthoven JJ, et al: Correlation of pulmonary function tests with best tumor response status: Results from the phase III study of pemetrexed+ cisplatin vs. cisplatin in malignant pleural mesothelioma (abstract 2651). Proc Am Soc Clin Oncol 22:659, 2003.
25. Gralla RJ, Hollen PJ, Liepa AM, et al: Improving quality of life in patients with malignant pleural mesothelioma: Results of the randomized pemetrexed + cisplatin vs. cisplatin trial using the LCSS-meso instrument (abstract 2496). Proc Am Soc Clin Oncol 22:621, 2003.
26. Manegold C, Symanowski J, Gatzemeier U, et al: Secondary (post-study) chemotherapy in the phase III study of pemetrexed + cisplatin vs. cisplatin in malignant pleural mesothelioma is associated with longer survival (abstract 2684). Proc Am Soc Clin Oncol 22:667, 2003.