Annals of Oncology 17 (Supplement 5): v103–v105, 2006
symposium article doi:10.1093/annonc/mdj962
Pemetrexed and malignant pleural mesothelioma
M. Marangolo & B. Vertogen
Dipartimento di Oncologia ed Ematologia – Unita Operativa di Oncologia Medica, Azienda USl – Ravenna, Italy
Malignant Pleural Mesothelioma (MPM) continues to be a challenging problem; because few patients may be
treated with radical surgery and conventional chemotherapy have achieved very dismal results. Pemetrexed is
a new drug with multitarget antifolate activity which seems to be particularly active in many solid tumors and also
in MPM. The principal clinical experiences of pemetrexed alone or in combination with other compounds, chieﬂy
platinum and its derivative, are reported. The Italian study on 1114 cases of MPM treated over 30 months is
discussed and the deﬁnitive results will be available after a complete external review of all responsive patients.
Key words: pemetrexed, malignant pleural mesothelioma, chemotherapy
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introduction these biological aspects could be a good target for novel
therapeutic approaches [6, 7].
Malignant Pleural Mesothelioma (MPM) is an aggressive tumor Pemetrexed (AlimtaÒ) is a novel antimetabolite that inhibits
that arises from the surface serosal cells of pleural cavities, and it the folate-dependent enzymes thymidylate synthase,
is primarily associated with the exposure to Chrysolite, dihydrofolate reductase, and glycinamide ribonucleotide
a particular asbestos ﬁber. Individuals who have been exposed formyltransferase. Pemetrexed has demonstrated activity in
for long periods of time during their work the highest risk;
clinical trials in a large variety of tumor types, including lung,
the projected lifetime risk among these workers, when exposed breast, colon, pleura, pancreas, stomach, bladder, head and
from early adulthood, is as high as 20%. neck, and cervix. Pemetrexed is rapidly metabolized into active
It has been estimated that in UK the annual deaths for MPM polyglutamate forms which are potent inhibitors of several
will raise until approximately 2010 ; in Italy the incidence tetrahydrofolate cofactor-requiring enzymes critical for the
and mortality for MPM are dramatically increased from the synthesis of purines and thymidine. Functionally, pemetrexed
period between 1978–1982 and 1993–1998: in fact, the acts as a prodrug for its polyglutamate forms. Two different
respective ﬁgures for male and female population describing transporters are known to take extracellular folates, and some
epidemiological data raised from 0.9 and 0.4 to 2 and antifolates, into the cell: these are the reduced folate carrier and
0.9 · 100 000 of incidence, and from 0.89 and 0.39 to 1.89 the folate receptor. One of the characteristics that make
and 0.85 · 100 000 of the mortality . pemetrexed unique is that a focused approach has been
MPM commonly develops in the ﬁfth to seventh decade of age, developed to eliminate and control some clinical toxicities.
typically 20 to 50 years after the ﬁrst documented asbestos Multivariate analyses demonstrated that pre-treatment total
exposure. Prognosis is poor with a median survival of 10 to plasma homocysteine levels signiﬁcantly predicted severe
17 months from symptoms onset and 9 to 13 months from thrombocytopenia and neutropenia, with or without associated
diagnosis. Until recently, chemotherapy has not changed the grade 3/4 diarrhea, mucositis, or infection. Routine vitamin
natural history of the disease, and radiotherapy has a minimal B12 and folic acid supplementation have resulted in decreased
impact on survival and in symptom palliation . The role of frequency/severity of toxicities associated with pemetrexed
surgery is uncertain for the most part of patients, chieﬂy as without affecting efﬁcacy, making this novel antifolate a safe and
consequence of the delayed diagnosis, although a small number of efﬁcacious anticancer agent .
cases have shown a long-term survival after radical surgery . The ‘social’ characteristic of the disease and the expected
In recent years, a large body of knowledge has been acquired increasing incidence in the next few years, together with the
from basic research on MPM; in more than 70% of availability of more effective therapies make the MPM one
mesotheliomas a hyper-expression of EGFR, independently of the most interesting ﬁelds of basic and clinical research in
from histotype, has been demonstrated; moreover, the presence oncology today.
of SV40, a monkey oncogenic virus, in the non-epithelial
mesothelioma seems to correlate with increased production of
Vascular Endothelial Growth Factor and poor prognosis .
Further data are available about the Cyclo-Oxigenase 2 hyper-
expression as a result of the chronic inﬂammatory process due Pemetrexed, as single agent, has been used in a multicenter
to the exposure to asbestos, and the peculiar characteristic of the cooperative phase II study carried out in 64 patients
presence, in the MPM cells, of Reduced Folate Carrier; both ¨
chemotherapy-naıve with measurable disease at the dose of
ª 2006 European Society for Medical Oncology
symposium article Annals of Oncology
500 mg/m2 every 3 weeks; the most part of patients (43) received previous treatments, or combination of pemetrexed plus
vitamin supplementation to control the hematological severe ¨
cisplatin to 80 naıve patients. Response rates were 5.5% for
toxicity. Nine (14.1%) of the patients achieved a partial pemetrexed alone and 32.5% for the combination treatment; in
remission, and the median estimated overall survival was 10.7 41.1% and 36.3% respectively patients were in stable disease,
months. The addiction of folinic acid and vitamin B12 and the median survivals were 4.1 and 7.6 months . The
represented a great progress, because the dramatic reduction of Italian study, by Ceresoli et al., used pemetrexed and carboplatin
hematological toxicity was reinforced by an increased efﬁcacy: AUC 5 given both on day 1 every 3 weeks to 78 consecutive
7 of the nine partial responders received vitamin ¨
naıve patients. The response rate was 20% and stable disease was
supplementation, and the median overall survival was 13 achieved in 44% of patients; the median time to progression was
months for supplemented versus 8 months for patients not 6 months . In each study the toxicity was limited because all
given vitamins. The authors concluded that pemetrexed as of the patients being treated with vitamin supplementation. The
single agent, and with vitamin supplementation, is a safe and combination of pemetrexed and gemcitabine is of particular
potentially useful therapeutic option for MPM . interest chieﬂy for unﬁt patients with severe co-morbidities
The most important study on pemetrexed and MPM is the unable to receive platinum compounds. Two schedules have
prospective, randomized, phase III trial published by Vogelzang been investigated: in each group of patients pemetrexed was
 in which 226 patients were randomized to receive given at 500 mg/m2 on day 1 every 21 days; in the ﬁrst group,
pemetrexed and cisplatin on a three week schedule and 222 56 patients received pemetrexed on day 8 and gemcitabine
patients as a control group received cisplatin as single agent. 1250 mg/m2 on days 1 and 8; in the second group, 52 patients
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Median survival time in the pemetrexed/cisplatin arm was 12.1 received the same drugs, same doses, but pemetrexed was
months versus 9.3 months in the control arm (P = 0.020, 2-sided given on day 1. The authors concluded that pemetrexed plus
log-rank test). The hazard ratio for death of patients in the gemcitabine is active in MPM and has an acceptable toxicity
pemetrexed/cisplatin arm versus those in the control arm was proﬁle. Administering pemetrexed on D8 is associated with
0.77. Median time to progression was signiﬁcantly longer in the a higher response rate although the median TTP is similar in
pemetrexed/cisplatin arm: 5.7 months versus 3.9 months both cohorts .
(P = 0.001). Response rates were 41.3% in the pemetrexed/ In conclusion, it seems currently reasonable to consider
cisplatin arm versus 16.7% in the control arm (P <0.0001). pemetrexed a real progress in the treatment of MPM, especially
After the ﬁrst 117 patients vitamin supplementation was given in combination with cisplatin or carboplatin.
to the patients and a dramatic fall in the incidence of severe
haematological and gastrointestinal side effects were observed.
Although the design and conduction of the study deserve the Italian experience of expanded
some critical aspects, however the authors conclude that, despite access program: the JMFL study
some limitation in the design and conduction of the study, The primary objective of this study is to provide the drug for the
pemetrexed in combination with cisplatin should be a safe treatment of patients with MPM. Patient access to pemetrexed
and effective treatment for patients with MPM. This study has been given to this protocol prior to and during its review by
represents a further step in the therapy of mesothelioma and Regulatory Agencies for commercial release. The secondary
currently the combination of pemetrexed and cisplatin is objectives include: (i) improving safety knowledge, (ii)
considered, the standard treatment for MPM . determining the time to progressive on, and (iii) determining
After this experience further studies have been presented, the best overall tumour response. No restrictive criteria have
chieﬂy in abstract form, employing the combinations of ¨
been stated for the patients’ accrual: in particular naıve and
cisplatin/carboplatin or gemcitabile and pemetrexed. A non- previously treated patients have been registered. Each
randomized, open-label study was designed to gather additional investigator had three therapeutic options: (A) pemetrexed
efﬁcacy and safety data of pemetrexed alone or in combination 500 mg/m2 i.v. over 10 min followed 30 min later by cisplatin
with cisplatin. Treatment in chemo-naivepatients consisted of 75 mg/m2 i.v. over 2 h on day 1 of each 21-day cycle, (B)
pemetrexed 500 mg/m2 in combination with cisplatin 75 mg/m2
given once every 21 days for a maximum of 6 cycles. All patients
Table 1. Patients’ characteristics
received folic acid, vitamin B12, and steroid prophylaxis.
Antitumor response from 295 patients shows 10 patients (3.4%)
with CR, 42 (14.2%) with PR, 129 (43.7%) with SD and 114 Characteristics Number %
(38.6%) with PD. The number and severity of serious adverse Evaluable patients 322
events were acceptable and predominantly related to cisplatin Male 233 72.5
toxicities. On the basis of the favourable toxicity proﬁle and the Female 89 27.5
promising response rate, the combination of pemetrexed and Mean age 62
cisplatin should be a new standard treatment for MPM . Previous radical surgery 61 18.9
Three phase II studies have been presented at the ASCO Time to relapse from surgery 16.5 months
Pretreated patients 145 45
meeting in 2005; two with the combination of pemetrexed and
Patients responsive (CR+PR) 41 28.5
platinum compounds and the last with the combination of
On study treatment
pemetrexed and gemcitabine. In the Orlando’s study, 73 all
Pemetrexed alone 90 27.9
patients were accrued in an expanded access program designed
Pemetrexed + Cisplatin or Carboplatin 232 72.1
to give pemetrexed as single agent to patients relapsed after
v104 | Marangolo & Vertogen Volume 17 | Supplement 5 | May 2006
Annals of Oncology symposium article
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