1 Heidelberg University Medical Center, Mannheim, Germany; 2 Eli Lilly and Company, Indianapolis, IN, USA; 3 Hospital Grosshansdorf, Grosshansdorf, Germany; 4 Asklepios-Fachklinik, Munchen-Gauting, Germany; 5 St Hildegardis-Krankenhaus, Mainz, Germany; 6 University Hospital Gasthuisberg, Leuven, Belgium; 7 Hospital de Mataro, Barcelona, Spain; 8 Nevada Cancer Institute, Las Vegas, NV, USA
* Correspondence to: Professor Dr C. Manegold, Heidelberg University Medical Center, Department of Surgery, Theodor-Kutzer-Ufer 13, 68167 Mannheim, Germany. Tel: +49-8-621-383-2199; Fax: +49-621-383-1430; Email: prof.manegold{at}t-online.de
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and methods:: Eighty-four patients from the pemetrexed plus cisplatin arm and 105 patients from the single-agent cisplatin arm received PSC. KaplanMeier survival estimates were compared by treatment groups, and by PSC and non-PSC subgroups.
Results:: The percentage of patients receiving PSC was imbalanced between the treatment arms. Fewer pemetrexed plus cisplatin treated patients received PSC (37.2% versus 47.3%). A multiple regression analysis performed in this trial showed that PSC had a statistically significant correlation with prolonged survival (P <0.01), adjusting for baseline prognostic factors and treatment intervention. The adjusted hazard ratio for PSC over non-PSC subgroups was 0.56 (confidence interval 0.440.72).
Conclusions:: PSC in malignant pleural mesothelioma was significantly associated with prolonged survival. It is not known whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC. The pemetrexed plus cisplatin treatment group had a statistically significant survival advantage even though fewer patients from that arm of the trial received PSC. The potentially beneficial role of PSC should be assessed in prospective trials.
Key words: malignant pleural mesothelioma, pemetrexed, second-line chemotherapy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Chemotherapy has not been commonly accepted as standard treatment for MPM [9], until recently, perhaps, when the results of the largest trial in patients with unresectable MPM were reported [10
]. This trial demonstrated that combination chemotherapy (pemetrexed plus cisplatin) was well tolerated and survival time was significantly increased (median survival time 12.1 versus 9.3 months; log-rank P=0.020; hazard ratio 0.77). Time to disease progression was significantly longer in the pemetrexed plus cisplatin arm (median time to progression 5.7 versus 3.9 months; log-rank P=0.001) as opposed to the cisplatin arm, and the response rates were significantly higher (41.3% versus 16.7%; P <0.001). Pemetrexed plus cisplatin treated patients also demonstrated improvement in pulmonary function [11
] and reported improvement in dyspnea and pain [12
]. The addition of folic acid and vitamin B12 supplementation resulted in a significant reduction in pemetrexed-related toxicity, without adversely affecting survival time. Thus pemetrexed plus cisplatin is likely to be used widely as first-line chemotherapy for MPM.
Patients who experience clinical benefit from such first-line chemotherapy are frequently still healthy when radiological progression of MPM is documented, and commonly inquire about second-line therapy. Few data are available to guide the oncologist in selecting second-line chemotherapy, because the vast majority of MPM chemotherapy trials have included only chemotherapy-naïve patients. However, several recent phase II trials have evaluated the effectiveness of chemotherapy in previously treated patients. Giaccone et al. [13] examined the efficacy and safety of ZD0473, a cisplatin analog, in the second-line setting in MPM. This study substantiated the ability to accrue healthy patients to second-line chemotherapy trials, but no major responses were seen with this agent. A slightly more promising second-line chemotherapy trial was reported by Fizazi et al. [1
]. Their study enrolled both chemotherapy-naïve and previously treated patients to receive combination therapy of the thymidylate synthase inhibitor, raltitrexed, and oxaliplatin. The study showed activity, acceptable tolerability and an overall response rate of 20% for both patient groups. Other smaller studies have suggested benefit of second-line chemotherapy as well. For example, Vogelzang [14
] observed a favorable response to cisplatin plus gemcitabine in two of three patients who failed prior treatment with single-agent doxorubicin.
The retrospective analysis presented in our trial was performed to characterize patients with advanced MPM who received post-study chemotherapy (PSC) treatment, the type of chemotherapy received and the potential impact further treatment may have on survival time. Since an unknown number of patients received additional therapy beyond second-line chemotherapy, we use the term post-study chemotherapy in this report rather than the term second-line chemotherapy.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
On subsequent post-study visits, data regarding PSC were collected only if it was the first time the patient received PSC. Investigators were not instructed to collect data on PSC if it was third-line (or greater).
Inclusion criteria
All 448 randomized and treated patients of the phase III trial were included in the current analysis. Patients were classified into two groups, PSC or no PSC. Patients were assigned to the PSC group if they received PSC either as a single agent or as combination therapy.
Data collection
Baseline demographics included age, gender, performance status, disease stage, histology and geographic region (Table 1). The PSC agent administered was recorded, but dose, schedule, duration of therapy, response to PSC and time to progression related to PSC were not recorded, since these data were not a primary or secondary end point of the study. Survival time was recorded from randomization to death or date of last contact.
|
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
An alternative explanation is that the chemotherapy agents used in PSC may have altered the natural history of MPM. Gemcitabine, as a single agent and in combination, was the most commonly used agent in PSC. Single-agent gemcitabine has had a variable rate of activity reported in the treatment of MPM (0% to 31%) [15]. It is not known to be cross-resistant with pemetrexed and gemcitabine/cisplatin is an active combination in MPM in the first-line setting, producing objective response rates of 20% to 30%, and symptomatic relief in patients who have stable or responding disease [16
, 17
].
KaplanMeier estimates of survival showed that PSC is associated with significantly prolonged survival (Figure 3). Interestingly, in our study, in spite of the larger number of patients in the cisplatin arm receiving PSC, the pemetrexed plus cisplatin arm experienced a significantly longer survival time (log-rank P=0.02). Moreover, the longer median time from completion of first-line therapy to the start of second-line therapy observed in the pemetrexed plus cisplatin treated patients exemplifies the effectiveness of the pemetrexed plus cisplatin combination. Because receipt of PSC was not randomized, it is impossible to conclude that receipt of PSC was responsible for any prolonged survival. Patients who had prolonged survival may simply have received more PSC.
The observed differences in median time from completion of first-line therapy to the initiation of second-line therapy suggest that a randomized trial in the second-line setting may need to be stratified by this interval. The interval may be prognostic for benefit and a randomized second-line trial is needed to make this determination.
A literature survey recently identified 16 published phase II mesothelioma chemotherapy trials that included second-line patient populations [18]. Remarkably, only one was a dedicated phase II trial [13
]. In spite of that deficiency, partial responses to a variety of agents and combinations were observed in 5% to 10% of patients in many of these studies. Furthermore, according to this survey, the number of patients demonstrating benefit in the second-line setting seems to be steadily increasing. This survey, and our phase III study, suggest that chemotherapy drug sensitivity and potentially non-cross resistance among chemotherapy drugs exists in MPM as it does in other diseases, and could be explored for patient benefit.
Our findings, in conjunction with the previously mentioned studies in the second-line setting, suggest the feasibility of conducting second-line phase II chemotherapy trials perhaps with gemcitabine as a single agent, or in combination, after pemetrexed/cisplatin therapy. However, cumulative cisplatin neuro- and ototoxicity limit the enthusiasm for a cisplatin combination approach. Alternatively, carboplatin could be combined with gemcitabine, as it shows lesser neuro- and ototoxicity [1921
]. The oxaliplatin/gemcitabine combination is also an attractive candidate for further study owing to favorable tumor responses for oxaliplatin in cisplatin-pretreated patients [1
] and because this combination has activity in MPM [22
]. Fizazi et al.'s data [1
] suggest a lack of resistance or non-cross-resistance with oxaliplatin plus raltitrexed in cisplatin-pretreated MPM patients.
Recently, Van Meerbeeck et al. [23] presented the results of a 250-patient randomized study of cisplatin with or without raltitrexed as first-line treatment of MPM. Treatment with raltitrexed and cisplatin produced superior response rate and survival time compared with cisplatin, and was well tolerated. These results further demonstrate the utility of anti-folates in MPM. It will be interesting to know how many patients from this trial received PSC, the patient characteristics agents used and the impact PSC may have had on the survival results.
A number of questions should be addressed prior to initiating phase II and particularly phase III trials for second-line chemotherapy in MPM. For instance, assignment of risk/prognostic groups, prior response duration, optimal duration of treatment and consequences of long-term therapy for patients. To determine the extent of benefit from PSC, or from non-cytotoxic treatment, randomized controlled trials would need to be performed against the current standard, namely best supportive care. As demonstrated in randomized trials of second-line therapy in non-small-cell lung cancer, the interval from completion of first-line therapy to the beginning of second-line therapy is prognostic for survival. In our trial, the high variability in time from completion of first-line therapy to the initiation of second-line therapy suggests that a second-line MPM trial may need to be stratified by this interval.
This retrospective analysis of patients receiving PSC from our phase III trial of pemetrexed plus cisplatin in MPM suggests that PSC has a positive impact on survival. In view of this observation, the role of PSC should be prospectively assessed.
![]() |
Acknowledgements |
---|
Received for publication May 21, 2004. Revision received January 10, 2005. Accepted for publication January 14, 2005.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. 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 2003; 39: 353357.[CrossRef][ISI][Medline]
3. Sorensen PG, Bach F, Bork E, Hansen HH. Randomised trial of doxorubicin versus cyclophosphamide in diffuse malignant pleural mesothelioma. Cancer Treat Rep 1985; 69: 14311432.[ISI][Medline]
4. Samson MK, Wasser LP, Borden EC et al. Randomized comparison of cyclophosphamide, imidazole carboxamide, and adriamycin versus cyclophosphamide and adriamycin in patients with advanced stage malignant mesothelioma: a Sarcoma Intergroup Study. J Clin Oncol 1987; 5: 8691.
5. Chahinian AP, Antman K, Goutsou M et al. Randomised phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B. J Clin Oncol 1993; 11: 15591565.
6. Vogelzang NJ, Taub RN, Shin D et al. Phase III randomized trial of onconase vs doxorubicin in patients with unresectable malignant mesothelioma. Proc Am Soc Clin Oncol 2000; 19: 577a (Abstr 2274).
7. Tomek S, Emri S, Krejcy K, Manegold C. Chemotherapy for malignant pleural mesothelioma: past results and recent developments. Br J Cancer 2003; 88: 167174.[CrossRef][ISI][Medline]
8. Herndon JE, Green MR, Chahinian AP et al. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 1998; 113: 723731.
9. Sterman DH, Larry R, Kaiser LR, Albelda SM. Advances in the treatment of malignant pleural mesothelioma. Chest 1999; 116: 50420.
10. 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 2003; 21: 26362644.
11. 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. Proc Am Soc Clin Oncol 2003; 22: 659 (Abstr 2651).
12. 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. Proc Am Soc Clin Oncol 2003; 22: 621 (Abstr 2496).
13. Giaccone G, O'Brien ME, Byrne MJ et al. Phase II trial of ZD0473 as second-line therapy in mesothelioma. Eur J Cancer 2002; 38 (Suppl 8): S19S24.
14. Vogelzang NJ. Gemcitabine and cisplatin: Second-line chemotherapy for malignant mesothelioma? J Clin Oncol 1999; 17: 26262627.[Medline]
15. Kindler HL, van Meerbeeck JP. The role of gemcitabine in the treatment of malignant mesothelioma. Semin Oncol 2002; 29: 7076.
16. Byrne MJ, Davidson JA, Musk AW et al. Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 1999; 17: 2530.
17. Nowak A, Byrne M, Williamson R. Multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002; 87: 491496.[CrossRef][ISI][Medline]
18. Pavlakis N, Vogelzang NJ. Second-line chemotherapy. In Pass H, Carbone M, Vogelzang N (eds): Malignant Mesothelioma. New York, NY: Springer Verlag. In press 2005.
19. Mbidde EK, Harland SJ, Calvert AH, Smith IE. Phase II trial of carboplatin (JM8) in treatment of patients with malignant mesothelioma. Cancer Chemother Pharmacol 1986; 18: 284285.[ISI][Medline]
20. Raghavan D, Gianoutsos P, Bishop J et al. Phase II trial of carboplatin in the management of malignant mesothelioma. Clin Oncol 1990; 8: 151154.
21. Vogelzang NJ, Goutsou M, Corson JM et al. Carboplatin in malignant mesothelioma: A phase II study of the Cancer and Leukemia Group B. Cancer Chemother Pharmacol 1990; 27: 239242.[CrossRef][ISI][Medline]
22. Schutte W, Blankenburg T, Lauerwald K et al. A multicenter phase II study of gemcitabine and oxaliplatin for malignant pleural mesothelioma. Clin Lung Cancer 2003; 4: 294297.[Medline]
23. Van Meerbeeck JP, Manegold C, Gaafar R et al. A randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: An intergroup study of the EORTC Lung Cancer Group and NCIC. Proc Am Soc Clin Oncol 2004; 22: 6222 (Abstr 7021).