Pemetrexed and malignant pleural mesothelioma by alicejenny


									                                                                                                        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 [1]; 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 [2].                                          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 [3]. 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 [8].
cases have shown a long-term survival after radical surgery [4].                     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 [5].
Further data are available about the Cyclo-Oxigenase 2 hyper-
                                                                                  clinical experiences
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 [13]. 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 [14]. 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 [9].                   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
[10] 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 [15].
(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 [11].                     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 [12].           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
pemetrexed 500 mg/m2 i.v. over 10 min on day 1 of each 21-day                     2. International Agency for Research on Cancer. Cancer Epidemiologic Database.
cycle, or (C) pemetrexed 500 mg/m2 i.v. over 10 min followed               
30 min later by carboplatin AUC 5 i.v. over 30 min on day 1                       3. Ball Dl, Cruickshank DG. The treatment of malignant Mesothelioma of the pleura:
                                                                                     review of a 5-yr experience with special reference to radiotherapy. Am J Clin
of each 21-day cycle. Vitamin supplementation was
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                                                                                  4. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in
defined doses and schedules.                                                          malignant pleural Mesothelioma: A Lung Cancer Study Group trial. J Thorac
   All patients were required to have the following characteristics                  Cardiovasc. Surg 1991; 102: 1–9.
to be enrolled in the study: histologically proven diagnosis of                   5. Janne PA, Taffaro ML, Sanglia R, Johnsosn BE. Inhibition of Epidermal
mesothelioma in patients not candidates for curative surgery;                        Growth Factor Receptor signalling in malignant pleural mesothelioma. Cancer
measurable or evaluable lesions; a minimum of 2 weeks from                           Res 2002; 62: 5242–47.
pleurodesis, PS Karnofsky ‡70; adequate organ function;                           6. Marrogi A, Pass HI, Khan M et al. Human mesothelioma samples overexpress
personal compliance and geographic proximity, signed                                 both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS2):
                                                                                     in vitro antiproliferative effect of a COX-2 inhibitor. Cancer Res 2000; 60:
informed consent.
   During a period of 30 months, from 12/02 to 05/05, 1114                        7. Wang Y, Zhao R, Chattopadhyay S, Goldman ID. A novel folate transport activity
patients have been enrolled in this study, from 84 Italian                           in human mesothelioma cell lines with high affinity and specificity for the new
Oncology and Pneumology Clinical Centres. A preliminary                              generation antifolate, Pemetrexed. Cancer Res 2002; 62: 5434–37.
analysis has been made on 322 evaluable patients whose                            8. Niyikyza C, Baker SD, Seitz DE et al. Homocysteine and methylmalonic acid :
principal characteristics are reported in Table 1.                                   markers to predict and avoid toxicity from Pemetrexed therapy. Mol Cancer Ther

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   No conclusive results are available and an independent review                     2002; 1: 545–52.
board will evaluate all patients who achieved CR, PR or stable                    9. Scagliotti MV, Shin DM, Kindler Hl et al. Phase II study of Pemetrexed with or
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                                                                                 10. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of Pemetrexed
the characteristics of patients daily admitted to the oncology and                   in combination with cisplatin versus cisplatin alone in patients with malignant
pneumology units. The preliminary feeling is that in terms of                        pleural mesothelioma. J Clin Oncol 2003; 21: 2636–2644.
response rate, including stable disease, and in terms of toxicity,               11. Hazarika M, White RM, Booth BP et al. Report from the Food and Drug
the use of pemetrexed, alone or in combination with platinum                         Administration. Pemetrexed in malignant pleural mesothelioma. Clin Cancer Res
compounds, provides to the patients a good chance of therapy                         2005; 11: 982–992.
with a low profile of hematological and gastrointestinal                          12. Wozniak AJ, Janne P, Belani CP et al. Pemetrexed in combination with cisplatin
toxicities. Definitive results of this large study will be                            in the treatment of chemonaive patients with Malignant Pleural Mesothelioma
                                                                                     (MPM): Outcomes on Expanded Access Program (EAP). Proc ASCO 2004; Abstr
available at the end of external review.
                                                                                 13. Orlando M, Wozniak AJ, Janne P et al. Survival update of a subset of previously
disclosures                                                                          treated patients with Malignant Pleural Mesothelioma (MPM) in an expanded
                                                                                     access program (eap) of Pemetrexed (P) alone or in combination with cisplatin
Dr Marangolo has indicated that he is a member of the                                (cis). Proc ASCO 2005; Abstr #7173.
speakers’ bureau of Eli Lily Italia.                                             14. Ceresoli GL, Zucali PA, Favaretto A et al. A phase II study of pemetrexed and
                                                                                     carboplatin as front-line chemotherapy in patients with malignant pleural
                                                                                     mesothelioma. Proc ASCO 2005; Abstr #7172.
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Volume 17 | Supplement 5 | May 2006                                                                                   doi:10.1093/annonc/mdj962 | v105

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