respiratory investigation 52 (2014) 101–106
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients Takehito Shukuyaa,c,n, Toshiaki Takahashia, Hisao Imaia, Takaaki Tokitoa, Akira Onoa, Hiroaki Akamatsua, Tetsuhiko Tairaa, Hirotsugu Kenmotsua, Tateaki Naitoa, Haruyasu Murakamia, Masahiro Endob, Nobuyuki Yamamotoa a
Divisions of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan Divisions of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, Japan c Department of Respiratory Medicine, Juntendo University, Tokyo, Japan b
art i cle i nfo
ab st rac t
Article history:
Background: Cisplatin plus pemetrexed is a standard front-line chemotherapeutic regimen
Received 18 April 2013
for inoperable malignant pleural mesothelioma (MPM). However, no clinical trials have
Received in revised form
compared the efficacy of cisplatin plus pemetrexed and cisplatin plus gemcitabine, which
26 June 2013
may be comparable based on previous phase II study results. This study aimed at
Accepted 3 July 2013
evaluating the efficacy of cisplatin plus pemetrexed and comparing it with that of cisplatin
Available online 13 September 2013
plus gemcitabine in Japanese MPM patients.
Keywords:
Methods: From July 2002 to December 2011, 13 and 17 consecutive patients with inoperable
Malignant pleural mesothelioma
MPM were treated with cisplatin plus gemcitabine and cisplatin plus pemetrexed, respectively,
Cisplatin
at the Shizuoka Cancer Center. We reviewed the medical charts of these patients and evaluated
Gemcitabine
their characteristics as well as data regarding drug toxicity and antitumor efficacy.
Pemetrexed
Results: The response rates were 15% and 35% in the cisplatin plus gemcitabine and cisplatin
Chemotherapy
plus pemetrexed groups, respectively (P¼ 0.4069), while disease control rates were 77%, and 82%, respectively (P¼ 0.9999). Progression-free survival was significantly higher with cisplatin plus pemetrexed (median, 215.5 days) than with cisplatin plus gemcitabine (median, 142.5 days) (P¼0.0146; hazard ratio [HR], 0.3552). Overall survival showed a tendency towards being superior with cisplatin plus pemetrexed (median, 597.5 days) compared with cisplatin plus gemcitabine (median, 306.5 days) (P¼0.1725, HR, 0.5516). Hematological toxicities, especially thrombocytopenia and neutropenia, tended to be more frequent and severe in the cisplatin plus gemcitabine group. Conclusions: Cisplatin plus pemetrexed may be superior and should continue to be the standard front-line chemotherapeutic regimen for inoperable MPM. & 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
n
Corresponding author at: Juntendo University School of Medicine, Department of Respiratory Medicine, 2-1-1 Hongou, Bunkyou-ku, Tokyo, 113-8421 Japan. Tel.: +81 338133111; fax: +81 358021617. E-mail addresses: [email protected] (T. Shukuya), [email protected] (T. Takahashi), [email protected] (H. Imai), [email protected] (T. Tokito), [email protected] (A. Ono), [email protected] (H. Akamatsu), [email protected] (T. Taira), [email protected] (H. Kenmotsu), [email protected] (T. Naito), [email protected] (H. Murakami), [email protected] (M. Endo), [email protected] (N. Yamamoto). 2212-5345/$ - see front matter & 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resinv.2013.07.002
102
1.
respiratory investigation 52 (2014) 101 –106
Introduction
The combination of cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) given every 3 weeks was established as a standard-of-care front-line regimen after the largest phase III trial conducted in patients with chemotherapy-naïve malignant pleural mesothelioma (MPM) revealed an improvement in survival over cisplatin alone [1]. The combination regimen had a response rate of 41.3%, median time to progression of 5.7 months, and median overall survival (OS) of 12.1 months. However, the combination of cisplatin and gemcitabine has demonstrated comparable response and survival rates in several phase II trials [2–6], with response rates of 12–48% and median OS times of 9.4–13 months. However, no clinical trial has compared the efficacies of cisplatin plus pemetrexed and cisplatin plus gemcitabine; therefore, the question remains whether cisplatin plus gemcitabine is comparable to cisplatin plus pemetrexed in treating MPM patients. Pemetrexed alone or in combination with cisplatin is also used worldwide for the treatment of non-squamous nonsmall-cell lung cancer (NSCLC) [7]. Pemetrexed alone or in combination with cisplatin has shown increased efficacy in East Asian non-squamous NSCLC patients compared to Western populations [8,9]. However, there have been few reports examining the efficacy of cisplatin plus pemetrexed for MPM in East Asian patients including Japanese patients. Therefore, it is unclear whether the efficacy of pemetrexed in combination with cisplatin for the treatment of MPM is better in East Asian patients than in Western populations. The objective of our retrospective analysis was to evaluate the efficacy of cisplatin plus pemetrexed in the treatment of MPM in Japanese patients and to compare its efficacy with that of cisplatin plus gemcitabine.
gemcitabine were reduced in the event of grade 4 hematological toxicity or grade ≥3 severe non-hematological toxicity during the previous treatment cycle. The dose of cisplatin was also reduced in the event of a creatinine elevation generally equal to ≥1.5 mg/dL. When the white blood cell, neutrophil, or platelet counts were below 2000 mm3, 1000 mm3, or 75,000 mm3, respectively, or if an active infection was present, the administration of gemcitabine on day 8 was omitted.
2.2.2.
2.2.3.
Patients and methods
2.1.
Patient selection
We reviewed 13 and 17 consecutive patients with inoperable MPM who were treated with cisplatin plus gemcitabine and cisplatin plus pemetrexed, respectively, as first-line chemotherapy at the Shizuoka Cancer Center between July 2002 and December 2011. Tumor stage was determined according to the classification system of the International Mesothelioma Interest Group [10] This study was approved by institutional review board of Shizuoka Cancer Center (Approval date: November 26, 2012; Approved #: 24-J100-241-3). Written informed consent was not required, because this study is retrospective.
2.2.
Chemotherapy
2.2.1.
Cisplatin plus gemcitabine
Cisplatin (80 mg/m2) and gemcitabine (1000 mg/m2) were administered intravenously on day 1 and on days 1 and 8. The treatment cycles were repeated every 3 weeks for a maximum of 6 cycles. Generally, the doses of cisplatin and
Supportive care
All patients received prophylactic antiemetic therapy consisting of a 5-HT3 antagonist, aprepitant, metoclopramide, and dexamethasone according to the American Society of Clinical Oncology guidelines [11]. Aprepitant was approved for use in October 2009 in Japan. Granulocyte colonystimulating factor was used when patients with febrile neutropenia or grade 4 neutropenia required its administration depending on the judgment of the physician in charge.
2.3.
2.
Cisplatin plus pemetrexed
Cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) were administered intravenously on day 1. The treatment cycles were repeated every 3 weeks for a maximum of 6 cycles. Generally, the doses of cisplatin and pemetrexed were reduced in the event of grade 4 hematological toxicity or grade ≥3 severe non-hematological toxicity during the previous treatment cycle. The dose of cisplatin was also reduced in the event of creatinine elevation generally equal to ≥1.5 mg/dL. Patients were instructed to take a daily 1-g multivitamin supplement containing 500 mg of folate beginning 1 week prior to day 1 of cycle 1 until study discontinuation. Vitamin B12 (1000 mg) was intramuscularly injected starting 1 week prior to day 1 of cycle 1 and repeated every 9 weeks until the treatment ended.
Evaluation of efficacy and toxicity
Tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors, ver. 1.0 [12]. Acute adverse events were evaluated until 4 weeks after the last chemotherapy administration or until the patient's death in accordance with the Common Terminology Criteria for Adverse Events ver. 3.0 [13].
2.4.
Statistical analysis
To analyze progression-free survival (PFS) and OS, survival curves were drawn using the Kaplan–Meier method. The PFS was calculated from the date of initiation of the chemotherapy to the date of disease progression or death from any cause. The PFS was censored at the date of the last visit for those patients who were still alive without any documented disease progression. The OS was calculated from the date of initiation of the chemotherapy to the date of death and was censored at the date of the last visit for patients whose deaths could not be confirmed. The PFS and OS were compared using the log-rank test according to the chemotherapeutic regimens (cisplatin plus gemcitabine vs. cisplatin plus pemetrexed). Cox proportional hazards models were used to calculate the hazard ratio (HR). To evaluate
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respiratory investigation 52 (2014) 101 –106
differences in patient characteristics and the response to chemotherapy, the chi-square test or Fisher's exact test were used depending on the number of patients. P-values o0.05 were considered to be statistically significant. All statistical analyses were performed using JMP ver. 8.0 for Windows (SAS Institute Inc., Cary, NC, USA).
3.
Results
3.1.
Patient characteristics
From July 2002 to December 2011, 13 patients received cisplatin plus gemcitabine and 17 patients received cisplatin plus pemetrexed as first-line chemotherapy at the Shizuoka Cancer Center. Patient characteristics are shown in Table 1. There were no statistically significant differences between the 2 groups in terms of gender, age, tumor histology, performance status (PS), smoking history, asbestos exposure, or tumor stage. However, a trend was noted towards more men, older patients, smokers, and lower tumor stage in patients of the cisplatin plus pemetrexed group.
3.2.
Response to therapy and survival
Among the 13 patients in the cisplatin plus gemcitabine group, 2, 8, and 3 showed a complete response (CR)/partial response (PR), stable disease (SD), and progressive disease
(PD), respectively. The response rate was 15%, and the disease-control rate was 77%. In contrast, among the 17 patients in the cisplatin plus pemetrexed group, 6, 8, and 2 patients showed a CR/PR, SD, and PD, respectively. One patient in this group was not evaluable (NE). The response rate was 35%, and the disease-control rate was 82%. The differences in the response rate and disease-control rate between the 2 groups were not statistically significant (response rate, P¼ 0.4069; disease-control rate, P¼ 0.9999). In the cisplatin plus gemcitabine group, the median PFS and the median OS were 142.5 days and 306.5 days, respectively (Figs. 1 and 2). In the cisplatin plus pemetrexed group, the median PFS and the median OS were 215.5 days and 597.5 days, respectively (Figs. 1 and 2). There was a statistically significant difference in the PFS (log-rank P¼ 0.0146, HR, 0.3552, 95% confidence interval [CI]¼ 0.1461–0.8422), while OS only showed a non-significant tendency to be better in the cisplatin plus pemetrexed group (log-rank P ¼0.1725, HR, 0.5516, 95% CI¼ 0.2276–1.3211).
3.3.
Toxicity
A summary of the toxicities noted in both groups is shown in Table 2. Hematological toxicities, especially thrombocytopenia and neutropenia, tended to be more frequent and severe in the cisplatin plus gemcitabine group. However, there were no statistically significant differences in terms of grade 3 or
Table 1 – Patient characteristics. Gemcitabine plus cisplatin (N ¼13)
Pemetrexed plus cisplatin (N ¼ 17)
p-value
Gender (no./%) Male Female
9 4
16 1
0.1377
Age (years) Median Range
61 13–72
Histology (no./%) Epithelioid Sarcomatoid
10 2
77% 15%
11 4
65% 23%
1
8%
2
12%
PS (no./%) 0 1 2
1 11 1
8% 84% 8%
6 11 0
35% 65% 0%
0.1280
Smoking history (no./%) Never Smoker
5 8
38% 62%
3 14
18% 82%
0.2420
Asbestos exposure (no./%) Definite 4 Not definite 9
31% 69%
9 8
53% 47%
0.2828
IMIG Stage (no./%) I II III IV
0% 0% 15% 85%
1 2 5 9
6% 12% 29% 53%
0.2057
NOS
0 0 2 11
69% 31%
94% 6%
66 49–79
0.0539
Abbreviations: NOS, not otherwise specified; PS, performance status; IMIG, international mesothelioma interest group.
0.7696
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respiratory investigation 52 (2014) 101 –106
Cumulative survival (%)
100 cisplatin + gemcitabine cisplatin + pemetrexed
80 60 40 20 0 0
60
120
180
240
300
360
Dose reduction or omission of chemotherapy occurred in 2 patients in the cisplatin plus gemcitabine group (grade 3 febrile neutropenia and grade 4 thrombocytopenia in 1 patient and grade 4 thrombocytopenia in 1 patient) and in 3 patients in the cisplatin plus pemetrexed group (creatinine elevation in all 3 patients). Discontinuation of chemotherapy related to toxicity occurred in 1 patient in the cisplatin plus gemcitabine group (chemotherapy refusal due to prolonged fatigue) and in 1 patient in the cisplatin plus pemetrexed group (decreased PS due to prolonged infection). There were no treatment-related deaths in either group.
420
Duration (days)
Fig. 1 – Kaplan–Meier curves for progression-free survival (PFS) of patients treated with cisplatin plus gemcitabine and cisplatin plus pemetrexed (blue dashed line, cisplatin plus gemcitabine; red continuous line, cisplatin plus pemetrexed). The median PFS was 142.5 days in the cisplatin plus gemcitabine group and 215.5 days in the cisplatin plus pemetrexed group; there was a statistically significant difference in the median PFS between the 2 groups (log-rank P¼ 0.0146, hazard ratio [HR], 0.3552, 95% confidence interval [CI]¼0.1461–0.8422).
Cumulative survival (%)
100 cisplatin + gemcitabine cisplatin + pemetrexed
80 60 40 20 0 0
360
720
1080
1440
1800
Duration (days) Fig. 2 – Kaplan–Meier curves for the overall survival (OS) of patients treated with cisplatin plus gemcitabine and cisplatin plus pemetrexed (blue dashed line, cisplatin plus gemcitabine; red continuous line, cisplatin plus pemetrexed). The median OS was 306.5 days in the cisplatin plus gemcitabine group and 597.5 days in the cisplatin plus pemetrexed group; OS tended to be better in the cisplatin plus pemetrexed group (log-rank P¼ 0.1725, hazard ratio [HR], 0.5516, 95% confidence interval [CI]¼0.2276–1.3211).
more severe thrombocytopenia and neutropenia (grade 3 or more severe thrombocytopenia, P¼ 0.0606; grade 3 or more severe neutropenia, P¼ 0.1232). The incidences of other toxicities did not differ between the 2 groups. The median number of cycles of chemotherapy administered was 4 (range, 2–6) in the cisplatin plus gemcitabine group and 4 (range, 1–6) in the cisplatin plus pemetrexed group, with no significant difference between the 2 groups (Mann–Whitney test, P¼ 0.1341).
4.
Discussion
The combination of cisplatin and pemetrexed is a standard front-line chemotherapeutic regimen for inoperable MPM. However, there have been no clinical trials comparing the efficacies of cisplatin plus pemetrexed and cisplatin plus gemcitabine, which may be comparable on the basis of results obtained from previous phase II studies [2–6]. Based on differences between groups in the frequency of adverse events and efficacy in this study, cisplatin plus pemetrexed may be superior and should continue to be the standard front-line chemotherapeutic regimen for inoperable MPM. In a phase III study of NSCLC patients that compared firstline cisplatin plus pemetrexed to cisplatin plus gemcitabine, the frequency of grade ≥3 neutropenia, anemia, thrombocytopenia, and febrile neutropenia were significantly lower in patients in the cisplatin plus pemetrexed arm than in those in the other regimen. However, the frequency of grade ≥3 nausea was significantly higher in the cisplatin plus pemetrexed arm. In the present study, although hematological toxicities tended to be more frequent and severe in the cisplatin plus gemcitabine group, the differences were not statistically significant. However, the small number of patients in the present study may influence the detection of statistically significant differences. Because aprepitant was not used in Japan until October 2009, none of the patients treated with cisplatin plus gemcitabine received aprepitant, while 11 of the 17 patients treated with cisplatin plus pemetrexed received aprepitant. As a result, gastrointestinal toxicities were more frequent and severe in the cisplatin plus gemcitabine group, and the difference in gastrointestinal toxicities between the 2 groups was likely underestimated. Lee et al. presented a retrospective Canadian series comparing platinum plus gemcitabine (n¼ 38) with platinum plus pemetrexed (n¼ 34) and reported no difference in the OS [14]. However, because only the survival data of the patients referred to the British Columbia Cancer Agency were analyzed in their study, the tumor response, PFS, and toxicities were not analyzed; therefore differences between regimens in terms of these endpoints remain unknown. Kim et al. examined 14 patients with MPM who had been treated with frontline cisplatin-based combination chemotherapy [15]. The chemotherapeutic agent added to cisplatin was pemetrexed in 10 patients, cyclophosphamide-doxorubicin in 3 patients, and gemcitabine in 1 patient. PFS and OS were significantly
Table 2 – Toxicities experienced using the two combination therapies. Gemcitabine plus cisplatin (n ¼ 13)
Pemetrexed plus cisplatin (n ¼17)
Gr 2
Gr 3
Gr 4
≥Gr 3
All
Leukopenia Neutropenia Anemia Thrombocytopenia
2 3 4 5
7 4 6 2
3 5 3 2
0 1 0 3
23% 46% 23% 38%
92% 100% 100% 92%
Fatigue Anorexia Constipation Diarrhea Nausea Vomiting Infection Febrile neutropenia Bilirubin AST ALT Hyponatremia Creatinine elevation Pnemonitis Eruption
8 5 5 1 5 3 0 0 2 2 6 9 7 0 3
4 5 6 0 5 2 0 0 1 1 2 0 0 0 0
0 2 1 0 2 0 0 1 0 0 0 2 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0% 15% 8% 0% 15% 0% 0% 8% 0% 0% 0% 15% 0% 0% 0%
92% 92% 92% 8% 92% 38% 0% 8% 23% 23% 62% 85% 54% 0% 23%
AST, Aspartate aminotransferase; ALT, alanine aminotransferase.
Gr2
Gr 3
Gr 4
≥Gr 3
4 2 6 7
6 4 7 2
2 2 3 1
0 1 0 0
12% 18% 18% 6%
71% 53% 94% 59%
8 8 7 4 9 3 0 0 1 3 5 11 9 0 3
6 9 5 3 6 3 1 0 1 1 2 0 5 0 1
0 0 0 0 1 0 1 0 0 0 0 3 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0% 0% 0% 0% 6% 0% 6% 0% 0% 0% 0% 18% 0% 0% 0%
82% 100% 71% 41% 94% 35% 12% 0% 12% 24% 41% 82% 82% 0% 24%
Gr 1
All respiratory investigation 52 (2014) 101 –106
Gr 1
105
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respiratory investigation 52 (2014) 101 –106
higher in the cisplatin plus pemetrexed group than that in those in the non-pemetrexed groups. Furthermore, Nakagawa et al. reported a phase I/II study examining cisplatin plus pemetrexed in Japanese MPM patients in which the recommended doses were 75 mg/m2 cisplatin and 500 mg/ m2 pemetrexed every 3 weeks [16]. Of the 19 patients treated at the recommended dose, 7 patients achieved a PR, with a response rate in that study of 36.8%. The OS was 7.3 months, and 1 drug-related death occurred because of worsening of pre-existing pneumonia. Common grade ≥3 toxicities were neutropenia and decreased hemoglobin. The survival difference between the 2 groups in this study is inconsistent with the findings of Lee et al. but consistent with those of Kim et al. However, the non-pemetrexed group described in the study of Kim et al. consisted of only 4 patients, 3 of which were treated with cisplatin plus cyclophosphamide–doxorubicin. In contrast, the survival rates of the 2 groups in the present study were better than that of patients in the study undertaken by Nakagawa et al. [16]. Considering both the results of previous reports and the safety and efficacy described in this study, cisplatin plus pemetrexed should continue to be a standard chemotherapeutic regimen for the treatment of inoperable MPM. There are a few limitations in this study that should be considered. Because this study was retrospective and included a small number of patients, it is difficult to reach a definite conclusion. The severity of non-hematological toxicities may have been underestimated in the present study because of its retrospective nature. However, the toxicity data were recorded in detail in the patients' medical records, and the frequency and severity of both hematological and non-hematological toxicities in this study were consistent with those described in a previous phase III study examining and comparing cisplatin plus pemetrexed and cisplatin plus gemcitabine for NSCLC [7]. We examined all patients for evaluable lesions approximately every 2 months by computed tomography, magnetic resonance imaging, bone scintigraphy, or positron emission tomography during the treatment period and every 2–3 months after treatment. However, the intervals between evaluations in the present study were not as accurate as they would have been had this been a prospective study. Therefore, the comparison of PFS between the 2 groups is not completely reliable. Finally, because the use of cisplatin plus pemetrexed was initiated more recently than cisplatin plus gemcitabine, the outcome was usually better in the cisplatin plus pemetrexed group, as shown by the differences in the frequency of gastrointestinal toxicities.
5.
Conclusions
In conclusion, considering the differences in adverse events and efficacies observed in this study, cisplatin plus pemetrexed may be superior and should continue to be the standard front-line chemotherapeutic regimen for inoperable MPM. Because the number of patients with MPM is not high, further studies are necessary to determine the best agents for improving the outcomes of patients suffering from MPM.
Conflict of interest The authors have no conflicts of interest.
r e f e r e n c e s
[1] 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;21:2636–44. [2] Byrne MJ, Davidson JA, Musk AW, et al. Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 1999;17:25–30. [3] Castagneto B, Zai S, Dongiovanni D, et al. Cisplatin and gemcitabine in malignant pleural mesothelioma: a phase II study. Am J Clin Oncol 2005;28:223–6. [4] Kalmadi SR, Rankin C, Kraut MJ, et al. Gemcitabine and cisplatin in unresectable malignant mesothelioma of the pleura: a phase II study of the Southwest Oncology Group (SWOG 9810). Lung Cancer 2008;60:259–63. [5] Nowak AK, Byrne MJ, Williamson R, et al. A multicenter phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002;87:491–6. [6] van Haarst JM, Baas P, Manegold C, et al. Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma. Br J Cancer 2002;86:342–5. [7] Scagliotti GV, Parikh P, Pawel JV, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advancedstage non-small-cell lung cancer. J Clin Oncol 2008;26:3543–51. [8] Yang CH, Simms L, Park K, et al. Efficacy and safety of cisplatin/pemetrexed versus cisplatin/gemcitabine as first-line treatment in East Asian patients with advanced non-small cell lung cancer. Results of an exploratory subgroup analysis of a phase III trial. J Thorac Oncol 2010;5:688–95. [9] Ohe Y, Ichinose Y, Nakagawa K, et al. Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res 2008;14:4206–12. [10] Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. Chest 1995;108:1122–8. [11] Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011;29:4189–98. [12] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors (RECIST Guidelines). J Natl Cancer Inst 2000;92:205–16. [13] National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Bethesda, MD: Cancer Therapy Evaluation Program; August 9, 2006. 〈http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/ctc.htm〉. [14] Lee CW, Murray N, Anderson H, et al. Outcomes with firstline platinum-based combination chemotherapy for malignant pleural mesothelioma: a review of practice in British Columbia. Lung Cancer 2009;64:308–13. [15] Kim ST, Park JY, Lee J, et al. The efficacy of the frontline platinum-based combination chemotherapy in malignant peritoneal mesothelioma. Jpn J Clin Oncol 2010;40:1031–6. [16] Nakagawa K, Yamazaki K, Kunitoh H, et al. Efficacy and safety of pemetrexed in combination with cisplatin for malignant pleural mesothelioma: a phase I/II study in Japanese patients. Jpn J Clin Oncol 2008;38:339–46.
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients Takehito Shukuyaa,c,n, Toshiaki Takahashia, Hisao Imaia, Takaaki Tokitoa, Akira Onoa, Hiroaki Akamatsua, Tetsuhiko Tairaa, Hirotsugu Kenmotsua, Tateaki Naitoa, Haruyasu Murakamia, Masahiro Endob, Nobuyuki Yamamotoa a
Divisions of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan Divisions of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, Japan c Department of Respiratory Medicine, Juntendo University, Tokyo, Japan b
art i cle i nfo
ab st rac t
Article history:
Background: Cisplatin plus pemetrexed is a standard front-line chemotherapeutic regimen
Received 18 April 2013
for inoperable malignant pleural mesothelioma (MPM). However, no clinical trials have
Received in revised form
compared the efficacy of cisplatin plus pemetrexed and cisplatin plus gemcitabine, which
26 June 2013
may be comparable based on previous phase II study results. This study aimed at
Accepted 3 July 2013
evaluating the efficacy of cisplatin plus pemetrexed and comparing it with that of cisplatin
Available online 13 September 2013
plus gemcitabine in Japanese MPM patients.
Keywords:
Methods: From July 2002 to December 2011, 13 and 17 consecutive patients with inoperable
Malignant pleural mesothelioma
MPM were treated with cisplatin plus gemcitabine and cisplatin plus pemetrexed, respectively,
Cisplatin
at the Shizuoka Cancer Center. We reviewed the medical charts of these patients and evaluated
Gemcitabine
their characteristics as well as data regarding drug toxicity and antitumor efficacy.
Pemetrexed
Results: The response rates were 15% and 35% in the cisplatin plus gemcitabine and cisplatin
Chemotherapy
plus pemetrexed groups, respectively (P¼ 0.4069), while disease control rates were 77%, and 82%, respectively (P¼ 0.9999). Progression-free survival was significantly higher with cisplatin plus pemetrexed (median, 215.5 days) than with cisplatin plus gemcitabine (median, 142.5 days) (P¼0.0146; hazard ratio [HR], 0.3552). Overall survival showed a tendency towards being superior with cisplatin plus pemetrexed (median, 597.5 days) compared with cisplatin plus gemcitabine (median, 306.5 days) (P¼0.1725, HR, 0.5516). Hematological toxicities, especially thrombocytopenia and neutropenia, tended to be more frequent and severe in the cisplatin plus gemcitabine group. Conclusions: Cisplatin plus pemetrexed may be superior and should continue to be the standard front-line chemotherapeutic regimen for inoperable MPM. & 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
n
Corresponding author at: Juntendo University School of Medicine, Department of Respiratory Medicine, 2-1-1 Hongou, Bunkyou-ku, Tokyo, 113-8421 Japan. Tel.: +81 338133111; fax: +81 358021617. E-mail addresses: [email protected] (T. Shukuya), [email protected] (T. Takahashi), [email protected] (H. Imai), [email protected] (T. Tokito), [email protected] (A. Ono), [email protected] (H. Akamatsu), [email protected] (T. Taira), [email protected] (H. Kenmotsu), [email protected] (T. Naito), [email protected] (H. Murakami), [email protected] (M. Endo), [email protected] (N. Yamamoto). 2212-5345/$ - see front matter & 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resinv.2013.07.002
102
1.
respiratory investigation 52 (2014) 101 –106
Introduction
The combination of cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) given every 3 weeks was established as a standard-of-care front-line regimen after the largest phase III trial conducted in patients with chemotherapy-naïve malignant pleural mesothelioma (MPM) revealed an improvement in survival over cisplatin alone [1]. The combination regimen had a response rate of 41.3%, median time to progression of 5.7 months, and median overall survival (OS) of 12.1 months. However, the combination of cisplatin and gemcitabine has demonstrated comparable response and survival rates in several phase II trials [2–6], with response rates of 12–48% and median OS times of 9.4–13 months. However, no clinical trial has compared the efficacies of cisplatin plus pemetrexed and cisplatin plus gemcitabine; therefore, the question remains whether cisplatin plus gemcitabine is comparable to cisplatin plus pemetrexed in treating MPM patients. Pemetrexed alone or in combination with cisplatin is also used worldwide for the treatment of non-squamous nonsmall-cell lung cancer (NSCLC) [7]. Pemetrexed alone or in combination with cisplatin has shown increased efficacy in East Asian non-squamous NSCLC patients compared to Western populations [8,9]. However, there have been few reports examining the efficacy of cisplatin plus pemetrexed for MPM in East Asian patients including Japanese patients. Therefore, it is unclear whether the efficacy of pemetrexed in combination with cisplatin for the treatment of MPM is better in East Asian patients than in Western populations. The objective of our retrospective analysis was to evaluate the efficacy of cisplatin plus pemetrexed in the treatment of MPM in Japanese patients and to compare its efficacy with that of cisplatin plus gemcitabine.
gemcitabine were reduced in the event of grade 4 hematological toxicity or grade ≥3 severe non-hematological toxicity during the previous treatment cycle. The dose of cisplatin was also reduced in the event of a creatinine elevation generally equal to ≥1.5 mg/dL. When the white blood cell, neutrophil, or platelet counts were below 2000 mm3, 1000 mm3, or 75,000 mm3, respectively, or if an active infection was present, the administration of gemcitabine on day 8 was omitted.
2.2.2.
2.2.3.
Patients and methods
2.1.
Patient selection
We reviewed 13 and 17 consecutive patients with inoperable MPM who were treated with cisplatin plus gemcitabine and cisplatin plus pemetrexed, respectively, as first-line chemotherapy at the Shizuoka Cancer Center between July 2002 and December 2011. Tumor stage was determined according to the classification system of the International Mesothelioma Interest Group [10] This study was approved by institutional review board of Shizuoka Cancer Center (Approval date: November 26, 2012; Approved #: 24-J100-241-3). Written informed consent was not required, because this study is retrospective.
2.2.
Chemotherapy
2.2.1.
Cisplatin plus gemcitabine
Cisplatin (80 mg/m2) and gemcitabine (1000 mg/m2) were administered intravenously on day 1 and on days 1 and 8. The treatment cycles were repeated every 3 weeks for a maximum of 6 cycles. Generally, the doses of cisplatin and
Supportive care
All patients received prophylactic antiemetic therapy consisting of a 5-HT3 antagonist, aprepitant, metoclopramide, and dexamethasone according to the American Society of Clinical Oncology guidelines [11]. Aprepitant was approved for use in October 2009 in Japan. Granulocyte colonystimulating factor was used when patients with febrile neutropenia or grade 4 neutropenia required its administration depending on the judgment of the physician in charge.
2.3.
2.
Cisplatin plus pemetrexed
Cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) were administered intravenously on day 1. The treatment cycles were repeated every 3 weeks for a maximum of 6 cycles. Generally, the doses of cisplatin and pemetrexed were reduced in the event of grade 4 hematological toxicity or grade ≥3 severe non-hematological toxicity during the previous treatment cycle. The dose of cisplatin was also reduced in the event of creatinine elevation generally equal to ≥1.5 mg/dL. Patients were instructed to take a daily 1-g multivitamin supplement containing 500 mg of folate beginning 1 week prior to day 1 of cycle 1 until study discontinuation. Vitamin B12 (1000 mg) was intramuscularly injected starting 1 week prior to day 1 of cycle 1 and repeated every 9 weeks until the treatment ended.
Evaluation of efficacy and toxicity
Tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors, ver. 1.0 [12]. Acute adverse events were evaluated until 4 weeks after the last chemotherapy administration or until the patient's death in accordance with the Common Terminology Criteria for Adverse Events ver. 3.0 [13].
2.4.
Statistical analysis
To analyze progression-free survival (PFS) and OS, survival curves were drawn using the Kaplan–Meier method. The PFS was calculated from the date of initiation of the chemotherapy to the date of disease progression or death from any cause. The PFS was censored at the date of the last visit for those patients who were still alive without any documented disease progression. The OS was calculated from the date of initiation of the chemotherapy to the date of death and was censored at the date of the last visit for patients whose deaths could not be confirmed. The PFS and OS were compared using the log-rank test according to the chemotherapeutic regimens (cisplatin plus gemcitabine vs. cisplatin plus pemetrexed). Cox proportional hazards models were used to calculate the hazard ratio (HR). To evaluate
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differences in patient characteristics and the response to chemotherapy, the chi-square test or Fisher's exact test were used depending on the number of patients. P-values o0.05 were considered to be statistically significant. All statistical analyses were performed using JMP ver. 8.0 for Windows (SAS Institute Inc., Cary, NC, USA).
3.
Results
3.1.
Patient characteristics
From July 2002 to December 2011, 13 patients received cisplatin plus gemcitabine and 17 patients received cisplatin plus pemetrexed as first-line chemotherapy at the Shizuoka Cancer Center. Patient characteristics are shown in Table 1. There were no statistically significant differences between the 2 groups in terms of gender, age, tumor histology, performance status (PS), smoking history, asbestos exposure, or tumor stage. However, a trend was noted towards more men, older patients, smokers, and lower tumor stage in patients of the cisplatin plus pemetrexed group.
3.2.
Response to therapy and survival
Among the 13 patients in the cisplatin plus gemcitabine group, 2, 8, and 3 showed a complete response (CR)/partial response (PR), stable disease (SD), and progressive disease
(PD), respectively. The response rate was 15%, and the disease-control rate was 77%. In contrast, among the 17 patients in the cisplatin plus pemetrexed group, 6, 8, and 2 patients showed a CR/PR, SD, and PD, respectively. One patient in this group was not evaluable (NE). The response rate was 35%, and the disease-control rate was 82%. The differences in the response rate and disease-control rate between the 2 groups were not statistically significant (response rate, P¼ 0.4069; disease-control rate, P¼ 0.9999). In the cisplatin plus gemcitabine group, the median PFS and the median OS were 142.5 days and 306.5 days, respectively (Figs. 1 and 2). In the cisplatin plus pemetrexed group, the median PFS and the median OS were 215.5 days and 597.5 days, respectively (Figs. 1 and 2). There was a statistically significant difference in the PFS (log-rank P¼ 0.0146, HR, 0.3552, 95% confidence interval [CI]¼ 0.1461–0.8422), while OS only showed a non-significant tendency to be better in the cisplatin plus pemetrexed group (log-rank P ¼0.1725, HR, 0.5516, 95% CI¼ 0.2276–1.3211).
3.3.
Toxicity
A summary of the toxicities noted in both groups is shown in Table 2. Hematological toxicities, especially thrombocytopenia and neutropenia, tended to be more frequent and severe in the cisplatin plus gemcitabine group. However, there were no statistically significant differences in terms of grade 3 or
Table 1 – Patient characteristics. Gemcitabine plus cisplatin (N ¼13)
Pemetrexed plus cisplatin (N ¼ 17)
p-value
Gender (no./%) Male Female
9 4
16 1
0.1377
Age (years) Median Range
61 13–72
Histology (no./%) Epithelioid Sarcomatoid
10 2
77% 15%
11 4
65% 23%
1
8%
2
12%
PS (no./%) 0 1 2
1 11 1
8% 84% 8%
6 11 0
35% 65% 0%
0.1280
Smoking history (no./%) Never Smoker
5 8
38% 62%
3 14
18% 82%
0.2420
Asbestos exposure (no./%) Definite 4 Not definite 9
31% 69%
9 8
53% 47%
0.2828
IMIG Stage (no./%) I II III IV
0% 0% 15% 85%
1 2 5 9
6% 12% 29% 53%
0.2057
NOS
0 0 2 11
69% 31%
94% 6%
66 49–79
0.0539
Abbreviations: NOS, not otherwise specified; PS, performance status; IMIG, international mesothelioma interest group.
0.7696
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Cumulative survival (%)
100 cisplatin + gemcitabine cisplatin + pemetrexed
80 60 40 20 0 0
60
120
180
240
300
360
Dose reduction or omission of chemotherapy occurred in 2 patients in the cisplatin plus gemcitabine group (grade 3 febrile neutropenia and grade 4 thrombocytopenia in 1 patient and grade 4 thrombocytopenia in 1 patient) and in 3 patients in the cisplatin plus pemetrexed group (creatinine elevation in all 3 patients). Discontinuation of chemotherapy related to toxicity occurred in 1 patient in the cisplatin plus gemcitabine group (chemotherapy refusal due to prolonged fatigue) and in 1 patient in the cisplatin plus pemetrexed group (decreased PS due to prolonged infection). There were no treatment-related deaths in either group.
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Duration (days)
Fig. 1 – Kaplan–Meier curves for progression-free survival (PFS) of patients treated with cisplatin plus gemcitabine and cisplatin plus pemetrexed (blue dashed line, cisplatin plus gemcitabine; red continuous line, cisplatin plus pemetrexed). The median PFS was 142.5 days in the cisplatin plus gemcitabine group and 215.5 days in the cisplatin plus pemetrexed group; there was a statistically significant difference in the median PFS between the 2 groups (log-rank P¼ 0.0146, hazard ratio [HR], 0.3552, 95% confidence interval [CI]¼0.1461–0.8422).
Cumulative survival (%)
100 cisplatin + gemcitabine cisplatin + pemetrexed
80 60 40 20 0 0
360
720
1080
1440
1800
Duration (days) Fig. 2 – Kaplan–Meier curves for the overall survival (OS) of patients treated with cisplatin plus gemcitabine and cisplatin plus pemetrexed (blue dashed line, cisplatin plus gemcitabine; red continuous line, cisplatin plus pemetrexed). The median OS was 306.5 days in the cisplatin plus gemcitabine group and 597.5 days in the cisplatin plus pemetrexed group; OS tended to be better in the cisplatin plus pemetrexed group (log-rank P¼ 0.1725, hazard ratio [HR], 0.5516, 95% confidence interval [CI]¼0.2276–1.3211).
more severe thrombocytopenia and neutropenia (grade 3 or more severe thrombocytopenia, P¼ 0.0606; grade 3 or more severe neutropenia, P¼ 0.1232). The incidences of other toxicities did not differ between the 2 groups. The median number of cycles of chemotherapy administered was 4 (range, 2–6) in the cisplatin plus gemcitabine group and 4 (range, 1–6) in the cisplatin plus pemetrexed group, with no significant difference between the 2 groups (Mann–Whitney test, P¼ 0.1341).
4.
Discussion
The combination of cisplatin and pemetrexed is a standard front-line chemotherapeutic regimen for inoperable MPM. However, there have been no clinical trials comparing the efficacies of cisplatin plus pemetrexed and cisplatin plus gemcitabine, which may be comparable on the basis of results obtained from previous phase II studies [2–6]. Based on differences between groups in the frequency of adverse events and efficacy in this study, cisplatin plus pemetrexed may be superior and should continue to be the standard front-line chemotherapeutic regimen for inoperable MPM. In a phase III study of NSCLC patients that compared firstline cisplatin plus pemetrexed to cisplatin plus gemcitabine, the frequency of grade ≥3 neutropenia, anemia, thrombocytopenia, and febrile neutropenia were significantly lower in patients in the cisplatin plus pemetrexed arm than in those in the other regimen. However, the frequency of grade ≥3 nausea was significantly higher in the cisplatin plus pemetrexed arm. In the present study, although hematological toxicities tended to be more frequent and severe in the cisplatin plus gemcitabine group, the differences were not statistically significant. However, the small number of patients in the present study may influence the detection of statistically significant differences. Because aprepitant was not used in Japan until October 2009, none of the patients treated with cisplatin plus gemcitabine received aprepitant, while 11 of the 17 patients treated with cisplatin plus pemetrexed received aprepitant. As a result, gastrointestinal toxicities were more frequent and severe in the cisplatin plus gemcitabine group, and the difference in gastrointestinal toxicities between the 2 groups was likely underestimated. Lee et al. presented a retrospective Canadian series comparing platinum plus gemcitabine (n¼ 38) with platinum plus pemetrexed (n¼ 34) and reported no difference in the OS [14]. However, because only the survival data of the patients referred to the British Columbia Cancer Agency were analyzed in their study, the tumor response, PFS, and toxicities were not analyzed; therefore differences between regimens in terms of these endpoints remain unknown. Kim et al. examined 14 patients with MPM who had been treated with frontline cisplatin-based combination chemotherapy [15]. The chemotherapeutic agent added to cisplatin was pemetrexed in 10 patients, cyclophosphamide-doxorubicin in 3 patients, and gemcitabine in 1 patient. PFS and OS were significantly
Table 2 – Toxicities experienced using the two combination therapies. Gemcitabine plus cisplatin (n ¼ 13)
Pemetrexed plus cisplatin (n ¼17)
Gr 2
Gr 3
Gr 4
≥Gr 3
All
Leukopenia Neutropenia Anemia Thrombocytopenia
2 3 4 5
7 4 6 2
3 5 3 2
0 1 0 3
23% 46% 23% 38%
92% 100% 100% 92%
Fatigue Anorexia Constipation Diarrhea Nausea Vomiting Infection Febrile neutropenia Bilirubin AST ALT Hyponatremia Creatinine elevation Pnemonitis Eruption
8 5 5 1 5 3 0 0 2 2 6 9 7 0 3
4 5 6 0 5 2 0 0 1 1 2 0 0 0 0
0 2 1 0 2 0 0 1 0 0 0 2 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0% 15% 8% 0% 15% 0% 0% 8% 0% 0% 0% 15% 0% 0% 0%
92% 92% 92% 8% 92% 38% 0% 8% 23% 23% 62% 85% 54% 0% 23%
AST, Aspartate aminotransferase; ALT, alanine aminotransferase.
Gr2
Gr 3
Gr 4
≥Gr 3
4 2 6 7
6 4 7 2
2 2 3 1
0 1 0 0
12% 18% 18% 6%
71% 53% 94% 59%
8 8 7 4 9 3 0 0 1 3 5 11 9 0 3
6 9 5 3 6 3 1 0 1 1 2 0 5 0 1
0 0 0 0 1 0 1 0 0 0 0 3 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0% 0% 0% 0% 6% 0% 6% 0% 0% 0% 0% 18% 0% 0% 0%
82% 100% 71% 41% 94% 35% 12% 0% 12% 24% 41% 82% 82% 0% 24%
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Gr 1
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higher in the cisplatin plus pemetrexed group than that in those in the non-pemetrexed groups. Furthermore, Nakagawa et al. reported a phase I/II study examining cisplatin plus pemetrexed in Japanese MPM patients in which the recommended doses were 75 mg/m2 cisplatin and 500 mg/ m2 pemetrexed every 3 weeks [16]. Of the 19 patients treated at the recommended dose, 7 patients achieved a PR, with a response rate in that study of 36.8%. The OS was 7.3 months, and 1 drug-related death occurred because of worsening of pre-existing pneumonia. Common grade ≥3 toxicities were neutropenia and decreased hemoglobin. The survival difference between the 2 groups in this study is inconsistent with the findings of Lee et al. but consistent with those of Kim et al. However, the non-pemetrexed group described in the study of Kim et al. consisted of only 4 patients, 3 of which were treated with cisplatin plus cyclophosphamide–doxorubicin. In contrast, the survival rates of the 2 groups in the present study were better than that of patients in the study undertaken by Nakagawa et al. [16]. Considering both the results of previous reports and the safety and efficacy described in this study, cisplatin plus pemetrexed should continue to be a standard chemotherapeutic regimen for the treatment of inoperable MPM. There are a few limitations in this study that should be considered. Because this study was retrospective and included a small number of patients, it is difficult to reach a definite conclusion. The severity of non-hematological toxicities may have been underestimated in the present study because of its retrospective nature. However, the toxicity data were recorded in detail in the patients' medical records, and the frequency and severity of both hematological and non-hematological toxicities in this study were consistent with those described in a previous phase III study examining and comparing cisplatin plus pemetrexed and cisplatin plus gemcitabine for NSCLC [7]. We examined all patients for evaluable lesions approximately every 2 months by computed tomography, magnetic resonance imaging, bone scintigraphy, or positron emission tomography during the treatment period and every 2–3 months after treatment. However, the intervals between evaluations in the present study were not as accurate as they would have been had this been a prospective study. Therefore, the comparison of PFS between the 2 groups is not completely reliable. Finally, because the use of cisplatin plus pemetrexed was initiated more recently than cisplatin plus gemcitabine, the outcome was usually better in the cisplatin plus pemetrexed group, as shown by the differences in the frequency of gastrointestinal toxicities.
5.
Conclusions
In conclusion, considering the differences in adverse events and efficacies observed in this study, cisplatin plus pemetrexed may be superior and should continue to be the standard front-line chemotherapeutic regimen for inoperable MPM. Because the number of patients with MPM is not high, further studies are necessary to determine the best agents for improving the outcomes of patients suffering from MPM.
Conflict of interest The authors have no conflicts of interest.
r e f e r e n c e s
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