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The Clinical Respiratory Journal
Current concepts in chemotherapy for malignant pleural
mesothelioma
Department of Oncology, Finsen Centre, National University Hospital, Copenhagen, Denmark Abstract
Key words
Objectives: The aim of this study was to provide an overview of the most active chemotherapy – malignant pleural single agents and combination regimens in malignant pleural mesothelioma mesothelioma – review – treatment Correspondence
Data Source: Literature on English-language trials in humans was searched on Jens Benn Sørensen, MD, DMSc, MPA, Chief Medline until October 2007. Indexing terms were malignant pleural mesothelioma Study Selections: Trials with Ն15 patients and with data on activity were included.
Results: Detorubicin and pirarubicin have response rates (RRs) of 22%–26%, epi- rubicin of 5%–15%, docetaxel of 5%–23% and vinorelbine of 24%. Other active agents were ifosfamide (3%–24%) and mitomycin C (21%). Carboplatin and cis- platin have an overall RR of 11% in three studies and 17% in four studies, respec- tively. Antimetabolites were active, including methotrexate (37%), raltitrexed (21%),edatrexate (16%–25%) and pemetrexed (15%). With respect to combination che- motherapy regimens, only cisplatin with either pemetrexed or raltitrexed has been compared with other substances, in both cases to cisplatin monotherapy. Both showed a survival advantage, which was statistically significant in the trial including pemetrexed, suggesting that chemotherapy improved survival in MPM. No studieshave compared chemotherapy with the best supportive care alone, and none hascompared different combination chemotherapy regimens with each other.
Conclusions: A number of single-agent cytotoxics posess moderate activity againstMPM. A number of platinum-based combination chemotherapy regimens showsimilar activities, but none has been compared with another combination. Cisplatinwith either raltitrexed or pemetrexed has improved survival compared with cis-platin alone, and may be used as a reference treatment in randomized trials.
Targeted agents should be explored in order to further improve the outcome.
Please cite this paper as: Sørensen JB. Current concepts in chemotherapy for malig-nant pleural mesothelioma. The Clinical Respiratory Journal 2008; DOI:10.1111/j.1752-699X.2008.00046.x.
Introduction
tors of prognosis are stage, gender, weight loss, regionalsymptoms and histologic subtype, with the epithelial Malignant mesothelioma is a rare disease with an esti- mated incidence of about 1 per 100 000 annually in The treatment of malignant pleural mesothelioma North America and Europe. The neoplasm may origi- (MPM) has, so far, not been very successful, and cure is nate from the pleura, pericardium, peritoneum or the rare. Surgery is rarely possible, but extrapleural pneu- tunica vaginalis testis, among which the pleural origin monectomy may be possible in selected patients (3, 4).
is most common, accounting for about three out of The use of radiotherapy is limited by the vast surface four cases. A CT scan, PET-CT or MRI is necessary for area of tumor involvement, the proximity of radio- the staging and evaluation of the response to therapy.
sensitive organs and the limited sensitivity of mesothe- Prognosis is generally poor, with median survival times lioma to radiotherapy. Radiotherapy has, accordingly, from 4–12 months in inoperable cases (1). The predic- mostly been used for palliative purposes (1).
The Clinical Respiratory Journal (2008) • ISSN 1752-6981 2008 The Author. Journal compilation 2008 Blackwell Publishing Ltd Chemotherapy has been evaluated mostly in phase II was 41%, which ranks vinorelbine among the most trials, and most single agents have revealed low activity, with response rates (RRs) below 20%. More recently, With respect to alkylating agents, cyclophosphamide a limited number of active single agents have been appears to be without activity (1), while varying results reported on (1, 5). In addition, combination chemo- have been obtained with ifosfamide, with RRs ranging therapy regimens have revealed significant activity in from 3% to 24% (19–21). Also, mitomycin C may MPM, and randomized trials have suggested improve- possess activity (22). With respect to platinum com- ment in survival and in the quality of life. This has led pounds, only moderate activity has been obtained with to expanded indications for chemotherapy in MPM carboplatin (overall RR of 11% among 88 patients) outside of clinical trials. The current review thus aimed (23–25), while cisplatin has been of somewhat higher to provide the background for the use of chemo- efficacy (overall RR of 17% among 94 patients) One of the most interesting classes of agents is the antimetabolites, among which methotrexate has Response evaluation
revealed a 37% RR (30), and edatrexate has inducedresponses in 18%–25% of the patients (31). Pemetr- The measurement of tumor response to antineoplastic exed is a multitargeted antifolate with a 14% RR as a chemotherapy in MPM is notoriously difficult, both single agent in chemotherapy-naïve MPM patients when using the World Health Organization and the (32). Also, raltitrexed has been confined with activity in RECIST criteria, because of the parietal growth pat- terns of these tumors (6, 7). Recently, the modified Moderate activity has been observed with the intra- RECIST criteria for use in MPM have been suggested, pleural administration of gamma interferon (34) or measuring tumor thickness perpendicular to the chest with interleukin-2 in early-stage disease with 23% and wall or mediastinum in two positions at three separate 8%–24% responses, respectively (35, 36).
levels on thoracic CT scans (8). The use of differentsystems in various reports may contribute to variationsin the RRs observed, in addition to the variationscaused by the different distributions of known and Combination chemotherapy
unknown prognostic variables and possible differences There has been considerable interest in combination in activity between the treatment regimens under chemotherapy in MPM and based on uncontrolled studies, combination chemotherapy appears to havehigher RRs than single-agent chemotherapy. Non- Single-agent chemotherapy
platinum-based combinations have generally shownvery modest activity, and a recent review discovered an Generally, single-agent treatments for MPM have overall RR of 10% among 247 patients in 12 trials (37).
revealed low activity, usually with RRs below 20%, and RRs higher than 30% are very rare (1, 9). Selected platinum-based combinations because of their note- studies evaluating single-drug chemotherapy in MPM worthy activity, especially for cisplatin, but also to are shown in Table 1. Anthracyclines, such as doxoru- some extent for carboplatin, and possibly also in the bicin (10, 11) and epirubicin (12, 13), have revealed light of the activity of combination chemotherapy, only moderate activity. However, detorubicin (14) and including cisplatin or carboplatin, in various other pirarubicin (15) may be confined with RRs of about solid tumors. Some of the most used regimens in MPM 20%, though having been evaluated in only one study are shown in Table 2 (38–48). There is a paucity of each. The taxane docetaxel has revealed RRs varying randomized trials, and no trials have compared any chemotherapy regimen with the best supportive care.
Among the vinca alkaloids, vinorelbine has attracted Only two recent phase III trials have been adequately interest in a phase II trial using vinorelbine 30 mg/m2 powered to discover the differences between the differ- IV weekly (18). A cycle consisted of six weekly injec- ent treatments under investigation (38, 39). Both trials tions and the median number of injections was 12.
compared an antimetabolite plus cisplatin with cispl- Toxicity was modest. The intention to treat RR among atin alone. Pemetrexed is a multitargeted antifolate 29 chemotherapy-naïve MPM patients was 24% (95% with a 14% RR as a single agent in chemotherapy-naïve confidence level, 10%–44%), and the fraction of MPM patients (32), and a randomized trial showed patients alive 1 year from the time of the first treatment that the combination chemotherapy with pemetrexed The Clinical Respiratory Journal (2008) • ISSN 1752-6981 2008 The Author. Journal compilation 2008 Blackwell Publishing Ltd Table 1. Selected single-agent chemotherapy in series of at least 15 patients
*Agent was administrered as intrapleural therapy for early-stage disease.
and cisplatin was significantly superior to cisplatin The initial high RR of 48% observed with cisplatin single-agent treatment with respect to both time to and gemcitabine (44) was not confirmed in a subse- progression, overall survival and quality of life (39).
quent trial using the same regimen (45). The combi- Likewise, raltitrexed is another antimetabolite that nations of cisplatin with either mitomycin C and revealed a 21% RR in a phase II study (33), and a vinblastine (47) or with epirubicin (48) showed RRs comparison of raltitrexed and cisplatin with cisplatin below 20%, though the median survival was 13.3 alone showed an improved survival with the combina- months in the latter trial (Table 2). RRs above 20% tion, though not significant (38). These two studies have been seen with cisplatin or carboplatin together point toward a survival advantage with the use of che- with antimetabolites such as pemetrexed and raltitr- motherapy in MPM, and this concept has subsequently exed (38, 39, 41, 42) or together with the vinka alka- gained widespread acceptance and use, both employ- loid, vinorelbine (40). Thus, a number of regimens ing these two regimens and by use of other active seem to possess similar activity, without any regimen being clearly superior. No combination chemotherapy The Clinical Respiratory Journal (2008) • ISSN 1752-6981 2008 The Author. Journal compilation 2008 Blackwell Publishing Ltd regimens have been compared with each other in ran- The activity of chemotherapy in MPM is thus still modest; hence, novel agents need to be evaluated foruse in combination chemotherapy regimens for theimprovement of the outcome. The addition of inter-feron or interleukine has not added activity to combi-nation chemotherapy regimens (1, 48).
The improvement of antineoplastic treatment is mandatory in order to further improve prognosis butmay be difficult to achieve with the older antineoplas- tic agents. The incorporation of new targeted agentsmay thus be necessary in order to achieve higher anti-neoplastic activity in the future and improve prognosisfor this dismal disease.
The role of the trimodal treatment (i.e. neo-adjuvant chemotherapy followed by extrapleural pneumonec-tomy and irradiation) is being explored in several trials in order to improve prognosis in selected subgroups of MPM. The Nordic Mesothelioma Group has, as yet, treated 44 out of 50 planned patients in a Pan-Scandinavian trimodal trial. Hopefully, this and othertrials may prove to improve survival and cure rate inthis disease.
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