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Japanese Journal of Clinical Oncology Advance Access published online on October 24, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn118
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© The Author (2008). Published by Oxford University Press. All rights reserved

Efficacy and Toxicity of Pemetrexed as a Third-line Treatment for Non-small Cell Lung Cancer

Jong-Mu Sun1,2, Keun-Wook Lee1,2, Jee Hyun Kim1,2, Yu Jung Kim1,2, Ho Il Yoon1,2, Jae-Ho Lee1,2, Choon-Taek Lee1,2 and Jong Seok Lee1,2

1 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam
2 Department of Internal Medicine, Seoul National University, College of Medicine, Seoul, Republic of Korea

For reprints and all correspondence: Jong Seok Lee, Department of Internal Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeongi-do, 463-707, Republic of Korea. E-mail: jslee{at}snubh.org

Received August 14, 2008; accepted September 24, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
Objective: Pemetrexed has been approved for second-line treatment in non-small cell lung cancer (NSCLC). However, the role of third-line pemetrexed therapy in NSCLC has not yet been generally accepted. We attempted to validate third-line pemetrexed therapy and evaluate predictive factors for pemetrexed therapy for NSCLC.

Methods: Medical records of NSCLC patients who received pemetrexed therapy that progressed after systemic therapy were reviewed retrospectively. We stratified patients according to clinicopathologic characteristics to find predictive factors for pemetrexed therapy.

Results: A total of 100 patients were eligible for analysis, and overall progression-free survival (PFS) was 3.03 months. The objective response rate was 12%, and the toxicity profile was favorable. Pemetrexed was used as a second-line treatment in 30% of patients, and as third- or further-line treatment in 70%. Comparing the efficacy of pemetrexed in these two settings (second-line versus third- or further-line), there was no significant difference in terms of PFS (3.07 versus 2.83 months, P = 0.86). When we evaluated predictive factors by multivariate analysis, performance status significantly influenced PFS.

Conclusions: Pemetrexed is a suitable third-line treatment option with good efficacy and tolerable toxicity profile for NSCLC.

Key Words: non-small cell lung cancer • second-line • third-line • pemetrexed


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
Current first-line treatment for advanced non-small cell lung cancer (NSCLC) is generally platinum-based combination chemotherapy, which prolongs median survival time (1). Despite these favorable results with first-line treatment, most patients experience disease progression and need second-line treatment.

Docetaxel is the first agent to have been studied in a randomized Phase III trial, which showed that median survival was significantly longer with docetaxel treatment than with the best supportive care (BSC) in second-line treatment (7.0 versus 4.6 months, P = 0.047) (2). Pemetrexed is a multi-target antifolate agent, and the Phase III JMEI trial demonstrated that pemetrexed (500 mg/m2) had similar efficacy with a better safety profile when compared with standard 3-weekly docetaxel (75 mg/m2) as a second-line treatment (3). The BR.21 trial, which compared erlotinib (epidermal growth factor receptor, tyrosine kinase inhibitor; EGFR TKI) and BSC in patients with previously treated advanced NSCLC showed a survival benefit with erlotinib therapy (6.7 versus 4.7 months, P < 0.001) (4). In that study, 49.4% of patients received erlotinib as third- or further-line treatment. Based on the large proportion of third-line treatment, erlotinib was approved not only for second-line, but also for third-line treatment.

There is no guideline for chemotherapy (except erlotinib) in NSCLC patients who failed two systemic therapy regimens. However, many patients have actually received third-line chemotherapy in the community oncology setting (5). Pemetrexed is considered to be less toxic than other chemotherapy regimens, with excellent efficacy and safety in elderly cancer patients (6,7). Therefore, pemetrexed could be a good candidate for third-line treatment. However, there has been no study about the validity of third-line pemetrexed therapy.

We evaluated retrospectively the efficacy and toxicity of pemetrexed in advanced NSCLC patients, especially as a third-line treatment, and performed subgroup analyses to determine the clinicopathologic characteristics that correlated to clinical benefit.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
The study population consisted of 100 patients who received pemetrexed because of progression after the platinum doublet treatment regimen at Seoul National University Bundang Hospital between April 2007 and June 2008. Clinicopathologic data and follow-up information until 10 September 2008 were retrieved from medical records. All patients had histological or cytological confirmation of locally advanced or metastatic NSCLC, stage IIIB or IV, and were not suitable for loco-regional treatment. We accepted patient characteristics (PS, stage, smoking habit, age) that were checked within a month before the first cycle date of pemetrexed therapy. A never smoker was defined as one who either has never smoked at all or has smoked ≤100 cigarettes.

Treatment
The patients were given pemetrexed 500 mg/m2 as a 10-min intravenous infusion on Day 1 every 21 days. Dexamethasone (4 mg) was taken twice daily on the day before, the day of, and the day after each dose of pemetrexed. Folic acid supplementation (1000 µg) was taken orally daily beginning approximately 1–2 weeks prior to the first dose of pemetrexed and continued until 3 weeks after treatment discontinuation. A 1000 µg vitamin B12 injection was administered intramuscularly approximately 1–2 weeks before the first dose of pemetrexed and was repeated approximately every 9 weeks until 3 weeks after therapy discontinuation. Baseline assessment, such as a history, physical examination, complete blood count, comprehensive blood chemistries, chest X-ray, was measured every cycle. Treatment was continued until disease progression, unacceptable toxicity, or the patient or physician decided to discontinue therapy. Dose reductions or delays were decided by the physician, based on nadir counts or clinically significant non-hematologic toxicities.

Response and Toxicity
Tumor responses were assessed with computed tomography every two cycles, but were evaluated early when significant progression signs appeared. Objective tumor responses were based on the Response Evaluation Criteria in Solid Tumors (RECIST) (8). The duration of response was measured from the time that the measurement criteria were met for complete response (CR) or partial response (PR) until the first date that recurrent or progressive disease (PD) was objectively documented. Toxicities were checked every cycle throughout the pemetrexed therapy. All such toxicities were evaluated according to the National Cancer Institute Common Toxicity Criteria version 3.0 (9).

Statistical Analysis
The progression-free survival (PFS) encompassed the time from the first cycle of pemetrexed therapy to documented progression or death from any cause until the date of the last follow-up visit for patients who were still alive and who had not progressed. Clinicopathologic characteristics as predictive indicators for the efficacy of pemetrexed were investigated in terms of PFS. Survival curves were estimated by the Kaplan–Meier method, and the log-rank test was used to compare PFS time between clinicopathologic characteristics. Objective tumor response rates and disease control rates in each patient's data were calculated and the chi-square test was used to evaluate differences in response rates. Statistical analysis was performed using SPSS 13.0 (SPP Inc., Chicago, IL, USA), and statistical significance was considered to be P ≤ 0.05.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Conflict of interest statement
 References
 
Patients Characteristics and Distribution
All pemetrexed-treated patients were observed regardless of available tumor response or toxicity data (N = 100). The median follow-up period was 5.3 months. The baseline patient and disease characteristics according to the line of pemetrexed therapy are listed in Table 1. A large proportion (70%) of our patients received pemetrexed as third- or further-line treatment. About half of the patients were females (N = 49). Performance status (PS) 0–1 was present in 79 patients, and PS ≥2 in 21 patients. The overall median age of the patients was 64.5 years (range, 27–82 years), where 28 patients out of 100 were elderly (≥70 years). Fifty-three percent of patients were never smokers, which included 20% of males and 88% of females. Forty-seven patients were ever smokers (18 were current smokers). Eighty-eight patients had non-squamous cell carcinoma (adenocarcinoma: N = 65, indeterminate non-small cell carcinoma: N = 23), and 12 patients had squamous cell carcinoma. Seventy patients were Stage IV and 30 were Stage IIIB. All patients had been treated with a platinum-based chemotherapy as first-line treatment: 56 underwent the gemcitabine-platinum regimen, 43 received the taxane-platinum regimen, and one was treated with the irinotecan-platinum regimen. Best response to first-line therapy was as follows: PR in 27 patients (28.7% of evaluable patients), SD in 43 patients (45.7%) and PD in 24 patients (25.5%).


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  		Table 1. Patient characteristics

 
Response Data
The median cycle of pemetrexed administration was three cycles (range, 1–13): in particular, 20 patients (20%) completed at least six cycles of pemetrexed, 13 received more than six cycles: two, six, two, two and one patients had 7, 8, 10, 11 and 13 cycles, respectively.

Concerning response, 12 patients reported PR, and 43 patients had SD, accounting for a disease control rate of 55% with pemetrexed therapy. Thirty-eight patients experienced PD as a best response; for seven patients, the response could not be checked due to death or follow-up loss before response evaluation. Median response duration (in responding patients) was 5.32 months (range, 0.13–9.07 months). Six out of the 12 patients who achieved PR were receiving pemetrexed therapy as of the day follow-up ended: five out of those six patients received more than six cycles of pemetrexed.

Survival Data and Subgroup Analyses
The overall survival (OS) and PFS for all patients were 12.8 and 3.03 months, respectively. Table 2 shows subgroup analyses for PFS. Of the stratification factors entered into the univariate analysis, there were no significant differences according to factors such as age (≥70 versus <70 years), smoking (never-smoker versus ever-smoker), stage (IIIB versus IV), number of prior systemic therapy (1 versus ≥2), and best response to first-line systemic therapy. Statistical significance was observed for PS (P = 0.006), gender (P = 0.016) and histology (P = 0.015). By multivariate analysis, only PS showed persistent predictive relevance.


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  		Table 2. Univariate and multivariate analyses for progression-free survival

 
Efficacy of Third- or Further-Line Pemetrexed Therapy
All patients received platinum-based chemotherapy as first-line treatment. The number of patients who had been treated with docetaxel and EGFR TKI (erlotinib/gefitinib) were 58 and 54 (36/18), respectively. Forty-four patients received both docetaxel and EGFR TKI before pemetrexed therapy. The PFS of 58 patients who had previously received docetaxel was 2.83 months and was not different from that (3.27 months) of those who had not been treated with docetaxel (P = 0.26).

Pemetrexed was used in second- (30%), third- (23%), fourth- (31%), fifth- (11%) and sixth-line (5%) settings. Seventy patients (70%) received pemetrexed as third- or further-line treatment. Comparing the efficacy of second-line and third- or further-line pemetrexed therapy, there was no significant difference in terms of PFS (3.07 versus 2.83 months, P = 0.86) (Table 2, Fig. 1). Response data for each line of pemetrexed therapy are shown in Table 3. Objective response rates for the second-line group and the third- or further-line group were 7.0 and 14.2%, respectively. Disease control rates in second-line, third-line, fourth-line and fifth/sixth-line were 54, 65, 48 and 56%, respectively. In addition, disease control rates in second-line and third- or further-line are not significantly different (54 versus 56%, P = 0.96).


Figure 1
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  		Figure 1. Progression-free survival (PFS) curves of patients with second-line versus third- or further-line pemetrexed therapy.

 

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  		Table 3. Best response data for each line of pemetrexed therapy

 
If we count the line of treatment after ruling out EGFR TKI from prior systemic therapy, pemetrexed was used as second- (37%), third- (45%), fourth- (13%) and fifth-line (5%). There was also no difference in PFS between second-line and third- or further-line pemetrexed therapy (3.26 and 2.80 months) (P = 0.45).

Toxicity
All patients were assessed for toxicity. Treatment-related death occurred in one patient, and the cause of death was pneumonia. Six patients refused further pemetrexed therapy due to toxicities (four, fatigue; two, sensory neuropathy), and four of those six patients were on second-line pemetrexed therapy. A delay in chemo-administration occurred in four patients (two, infection; one, skin rash; one, diarrhea). One patient required dose modification due to previous neutropenic fever.

Toxicity profiles are summarized in Table 4. Fatigue was the most frequent adverse event (8%), and other adverse events were less frequent (≤4%).


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  		Table 4. Toxicity profiles

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Conflict of interest statement
 References
 
We attempted to evaluate predictive factors for a better outcome with pemetrexed therapy, analyzing subgroup analyses for PFS. By univariate analyses, good predictive factors were female, non-squamous cell carcinoma, PS 0–1. However, only PS maintained significance by multivariate analyses. The median follow-up period of our study was short (5.3 months). For this reason, we could not evaluate OS for all subgroups. Therefore, we analyzed the efficacy of pemetrexed according to PFS. However, several pemetrexed studies have showed some correlation between OS and PFS in determining the efficacy of pemetrexed (3,10,11), and that female, good PS, non-squamous cell carcinoma were predictive factors for a better outcome with pemetrexed therapy (10–14). PFS in our study (3.03 months) was similar to that in the JMEI trial, where the median PFS was 2.9 months, and to those in other studies (3,10,11).

Until 2005, when erlotinib showed a survival advantage over BSC in second- or third-line settings (4), there was no evidence supporting the efficacy of third-line treatment in NSCLC. Among chemotherapeutic drugs, pemetrexed and docetaxel were approved as second-line treatment based on positive results in prospective studies (2,3,15). Docetaxel studies enrolled patients who received not only one prior chemotherapy, but two or more prior chemotherapy regimens, encompassing as many as 20–35% of all patients (2,15). However, there were no comparative analyses between these subgroups (second-line versus third- or further-line). Furthermore, the JMEI trial (Pemetrexed versus Docetaxel trial) evaluated second-line treatment exclusively (3). In our study, 70% of patients received pemetrexed therapy in third- or further-line settings. As Table 1 shows, patient characteristics of third- or further-line group were not so different from those of the second-line group. The median PFS of third- or further-line groups was similar to that of patients who received pemetrexed in the second-line setting (2.83 versus 3.07 months, P = 0.86). Disease control rates of second-line and third- or further-line also were not different (P = 0.96).

The long-standing efficacy of pemetrexed in third-line treatment might be partially due to the favorable toxicity profile of pemetrexed (7,16). The median age of our population was 64.5 years, and 28% of the patients were elderly (≥70 years). Furthermore, pemetrexed was used in a relatively poorer PS population (21% in PS ≥ 2) than in the JMEI trial, where 11.4% were in PS 2. Although with a large proportion of elderly and poor PS patients, the toxicity profile was mild and acceptable. One treatment-related mortality (TRM) among 100 patients was not unusual, in accordance with the data in the JMEI trial (three TRM of 265 patients) (3). In addition, as Table 4 shows, toxicity profiles between second-line group versus third- or further-line group were not very different.

In conclusion, there is controversy about the role for further administration of chemotherapy in patients failing second-line treatment (17,18), and no randomized prospective study is ongoing about this issue. However, a number of patients who failed second-line treatment are in good enough PS to receive further chemotherapy, or strongly want to receive further treatment even in rather poor PS. In these situations, we should weigh the benefit and toxicity of further chemotherapy. The results of our study suggest that pemetrexed could give more benefit than harm to patients, especially to women or to those with non-squamous cell carcinoma or in good PS.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
References
 
None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Conflict of interest statement
 References
 
1 Breathnach OS, Freidlin B, Conley B, Green MR, Johnson DH, Gandara DR, et al. Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: sobering results. J Clin Oncol (2001) 19:1734–42.[Abstract/Free Full Text]

2 Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol (2000) 18:2095–103.[Abstract/Free Full Text]

3 Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol (2004) 22:1589–97.[Abstract/Free Full Text]

4 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med (2005) 353:123–32.[Abstract/Free Full Text]

5 Murillo JR, Koeller J. Chemotherapy given near the end of life by community oncologists for advanced non-small cell lung cancer. Oncologist (2006) 11:1095–9.[Abstract/Free Full Text]

6 Kulkarni PM, Chen R, Anand T, Monberg MJ, Obasaju CK. Efficacy and safety of pemetrexed in elderly cancer patients: results of an integrated analysis. Crit Rev Oncol Hematol (2008) 67:64–70.[CrossRef][Web of Science][Medline]

7 Weiss GJ, Langer C, Rosell R, Hanna N, Shepherd F, Einhorn LH, et al. Elderly patients benefit from second-line cytotoxic chemotherapy: a subset analysis of a randomized phase III trial of pemetrexed compared with docetaxel in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol (2006) 24:4405–11.[Abstract/Free Full Text]

8 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst (2000) 92:205–16.[Abstract/Free Full Text]

9 Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol (2003) 13:176–81.[CrossRef][Web of Science][Medline]

10 Bearz A, Garassino I, Cavina R, Favaretto A, Boccalon M, Talamini R, et al. Pemetrexed single agent in previously treated non-small cell lung cancer: a multi-institutional observational study. Lung Cancer (2008) 60:240–5.[CrossRef][Web of Science][Medline]

11 Ohe Y, Ichinose Y, Nakagawa K, Tamura T, Kubota K, Yamamoto N, 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.[Abstract/Free Full Text]

12 Weiss GJ, Rosell R, Fossella F, Perry M, Stahel R, Barata F, et al. The impact of induction chemotherapy on the outcome of second-line therapy with pemetrexed or docetaxel in patients with advanced non-small-cell lung cancer. Ann Oncol (2007) 18:453–60.[Abstract/Free Full Text]

13 Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol (2008) 26:3543–51.[Abstract/Free Full Text]

14 Ciuleanu TE, Brodowicz T, Belani CP, Kim J, Krzakowski M, Laack E, et al. Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: a phase III study [Abstract]. Proc Am Soc Clin Oncol (2008) 26.

15 Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol (2000) 18:2354–62.[Abstract/Free Full Text]

16 Pujol JL, Paul S, Chouaki N, Peterson P, Moore P, Berry DA, et al. Survival without common toxicity criteria grade 3/4 toxicity for pemetrexed compared with docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): a risk-benefit analysis. J Thorac Oncol (2007) 2:397–401.[CrossRef][Medline]

17 de Marinis F, Grossi F. Clinical evidence for second- and third-line treatment options in advanced non-small cell lung cancer. Oncologist (2008) 13(Suppl. 1):14–20.[Abstract/Free Full Text]

18 Massarelli E, Andre F, Liu DD, Lee JJ, Wolf M, Fandi A, et al. A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small-cell lung cancer. Lung Cancer (2003) 39:55–61.[CrossRef][Web of Science][Medline]


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