Lung cancer is one of the malignant tumors with the highest incidence in the world. Early diagnosis of lung cancer is difficult due to the insidious symptoms. Therefore, most patients have progressed to an advanced stage at diagnosis. Chemotherapy as the main treatment approach for advanced lung cancer can improve patient survival and their quality of life.1 Pemetrexed is a novel folic acid antagonist with multiple targets (i.e., multitarget antifolate). Since its approval by the Food and Drug Administration (FDA) in 2004 as standard treatment of non-small cell lung cancer (NSCLC), pemetrexed has been widely used in clinical practice.2 In this report, we compare the effects and toxicities in advanced NSCLC patients treated with pemetrexed monotherapy versus pemetrexed plus platinum combination agent so as to provide a basis for standard second-line chemotherapy.
The clinical data from 52 patients with advanced NSCLC who were admitted to the Shanghai Chest Hospital between August 2006 and October 2008 for second-line treatment were retrospectively reviewed (Table 1). Ten patients received pemetrexed monotherapy and 42 were treated with pemetrexed-platinum combination therapy. The dose, schedule and mode of administration of pemetrexed and platinum were in accordance with the approved Chinese regulatory authority instructions. The inclusion criteria are as follows: (1) patients ≥18 years old with cytology/histology confirmed NSCLC of clinical stages IIIb/IV; (2) patients failed to first-line chemotherapy; (3) adequate hematologic function and adequate hepatic/renal function were required; (4) the performance status (PS) score was 0-2 at baseline.
All the patients were followed up, with a median duration of 12.93 months. The last visit was conducted on November 30, 2008 by telephone interview.
The primary end point of this study was overall survival (OS), defined as the time between date of diagnosis and date of death, or last date of follow-up. Secondary end points were disease control rate (DCR), progression-free survival (PFS), 1-year survival rate, and toxicities. The efficacy was evaluated consistently according to RECIST response evaluation criteria, including complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). DCR was defined as the number of patients rated as PR or CR or SD divided by the total number of patients evaluated (×100%). The treatment response was evaluated after the end of second-line therapy. PFS was defined as the time between date of first-time second-line therapy and date of death for patients dead without progression, or the last date of follow-up. Safety was evaluated according to National Cancer Institute (NCI) common toxicity criteria (version 3.0) as grade 0-IV.
Chi-square was used to compare data between groups. Kaplan-Meier method and life-table were used for survival analysis. Single factor analysis and the COX regression model were done to analyze the relationship between the influential factors and the prognosis of disease. A P value less than 0.05 was considered statistically significant. All statistical analysis was conducted using the SPSS 10.0 software package.
Primary end point
Of the 52 patients, 3 patients (3/52, 5.77%) were lost to follow up, all in the pemetrexed+platinum combination group. A total of 19 (19/49, 38.78%) patients died at the time of this study, including 3 patients in pemetrexed monotherapy group and 16 in pemetrexed combination therapy group. The median OS was 16.00 months and 17.12 months respectively (χ2=0.09, P=0.76) (Figure 1).
Secondary end points
All the 52 patients were evaluated for efficacy after second-line therapy. In the pemetrexed monotherapy group, DCR was 70%, including 0 CR, 2 PR, 5 SD and 3 PD. In the pemetrexed + platinum combination therapy group, DCR was 73.81%, including 0 CR, 8 PR, 23 SD and 11 PD. No statistically significant difference was found for DCR between the two groups (χ2=0.06, P=0.81).
The median PFS was 2.87 months in pemetrexed monotherapy group and 6.43 months in pemetrexed combination group (χ2=0.15, P=0.70) (Figure 2). The 1-year survival rate for these two groups were 56.17% and 55.64% respectively (χ2=0.33, P=0.57).
All the 52 patients were evaluated for toxicities after second-line therapy. One patient (10%) in pemetrexed monotherapy group had grade III leucopenia and 7 (16.67%) patients in the combination group had grade III/IV leucopenia. No grade III/IV gastrointestinal toxicity was found in pemetrexed monotherapy group and 5 (11.90%) patients had grade III/IV gastrointestinal toxicity in the combination group. No significant difference was found in either leucopenia (χ2=1.19, P=0.96) or gastrointestinal toxicity (χ2=2.31, P=0.77) between the two groups (Table 2). In addition, some patients in both groups had tolerable fatigue after their second-line therapy. No significant liver or renal impairment or other decreased blood cell count was identified.
Single factor analysis
Single factor analysis showed that factors including surgery history, PS score before treatment, clinical stage, and response to second-line treatment influenced the prognosis of NSCLC (all P <0.05) (Table 3).
COX regression analysis demonstrated surgery history (P=0.041, 95% CI: 1.053-12.915), and PS score before treatment (P=0.043, 95% CI: 1.059-42.496) had effects on survival (Table 4).
There were 18 elderly patients (≥60, 60-80 years) in this study, including 7 in the pemetrexed monotherapy group and 11 in the combination therapy group. All of them were included in the final survival analysis. No significant difference of OS was found between the two subgroups of elderly patients (χ2=0.01, P=094) (Figure 3). The DCR of elderly patients in monotherapy group was 71.43%, including 0 CR, 2 PR, 3 SD and. The DCR of elderly patients in the combination therapy group was 72.73%, including 0 CR, 2 PR, 6 SD and 3 PD. No significant difference was found for the DCR between groups (χ2=0.004, P=0.95). The PFS did not show significant difference between the two subgroups of elderly patients (χ2=0.14, P=0.70) (Figure 4). No significant difference was found in the 1-year survival rate (χ2=0.03, P=0.87) between the two subgroups of elderly patients.
No elderly patient in pemetrexed monotherapy group had grade III/IV leucopenia or gastrointestinal toxicity. In the pemetrexed+platinum combination group there were three incidences of grade III/IV leucopenia and gastrointestinal toxicity (7.14%) respectively. The difference of leucopenia (χ2=9.95, P=0.01) and gastrointestinal reaction (χ2=7.66, P=0.03) was statistically significant between these two subgroups. This indicates that pemetrexed + platinum combination agent may have higher toxicity for the elderly patients (Table 5). In addition, no other adverse events were found in the two subgroups of elderly patients.
Pemetrexed is a pyrrolo and pyrimidine-based multitarget folic acid antagonist, which interferes with cell replication by inhibiting folate-dependent enzymes such as thymidylate synthetase, dihydrofolate reductase and glycinamide riboneucleotide transformylase so as to produce antineoplastic effect.2 In 2004, Hanna et al3 studied the efficacy and safety of pemetrexed 500 mg/m2 versus docetaxel 75 mg/m2 every 3 weeks as second-line therapy for the treatment of NSCLC in a large scale (n=571) randomized Phase III clinical trial. The results showed that the efficacy was similar between these two drugs. However, pemetrexed was safer with significantly lower toxicity than docetaxel in terms of hematological adverse events and alopecia.
The FDA now has approved pemetrexed as standard treatment for NSCLC. National Comprehensive Cancer Network (NCCN) Clinical Guidelines also list pemetrexed monotherapy as one of the standard second-line regimens for the treatment of NSCLC.1 However, platinum-based chemotherapy is still dominating at the present time.4 In practice, clinicians usually would like to use a pemetrexed plus platinum combination as an option for second-line treatment in order to improve the treatment efficacy. However, a number of clinical trials and clinical experience remind us that pemetrexed+platinum combination agent may lead to more prominent hematological toxicity and gastrointestinal reactions in some patients, which may affect patients' quality of life to varying degrees.5
This study retrospectively reviewed the clinical data of second-line treatment of 52 patients with advanced NSCLC. Of these patients, 46 (88.46%) had received their first-line chemotherapy regimens containing a new third generation antitumor agent combined with platinum. ECOG1594 data suggested that a chemotherapy regimen containing a new third generation antitumor agent and platinum did not show significant improvement in OS, median survival time and overall response rate.6 After second-line therapy, the DCR was similar between the two treatment groups. PFS, OS and the 1-year survival rate did not show a significant difference between groups. We have noticed that the OS time of the two groups in this study was 16.00 months and 17.12 months and 1-year survival rate was 56.17% and 55.64% respectively, which are higher than those reported by Hanna et al.3 But a Phase III Japanese clinical study7 in 2008 reported the efficacy and toxicity of pemetrexed 500 mg/m2 versus 1000 mg/m2 for retreatment of Japanese patients with advanced NSCLC. In their report, the median survival time of pemetrexed 500 mg/m2 every 3 weeks was 16 months, and the 1-year survival rate was 59.2%, which is comparable to our results. We think this result may be associated with the higher sensitivity to chemotherapy in Asian patients, the high proportion of patients with a good PS score and the presence of non-squamous tissue type (which is more sensitive to pemetrexed) in this study. Also, nearly 40% of the patients in our study had target drugs in their previous treatments, which may also contribute to survival.
The main toxic effects of pemetrexed are myelosuppression, fatigue, and fever. Some patients may have ecdysis, rash, and hypersensitivity.8 Appropriate supplementation of folic acid and vitamin B12 can reduce the toxicity of pemetrexed treatment. Shepherd et al9 showed that pemetrexed combined with platinum can induce dose-limiting toxicities such as myelosuppression and fatigue. In our study, the incidence of grade III/IV toxicities were higher in the combination therapy group than in the monotherapy group, especially in leucopenia and gastrointestinal toxicity. However, the difference did not reach statistical significance. No treatment-related-death was found in this study. All the toxicities were tolerable.
Currently, as the population is aging and the incidence of lung cancer is getting higher, the treatment of lung cancer in elderly patients has become a focus of concern. Elderly patients usually have poorer liver, renal, and bone marrow reserve, with more comorbidity. This usually makes them less tolerable to chemotherapy, therefore susceptible to more chemotherapy-induced toxicities. For this reason, American Society of Clinical Oncology (ASCO) clinical guidelines recommend third generation cytotoxic agent monotherapy in elderly patients with advanced NSCLC. Such drugs have the advantage of high efficacy but low toxicity. Pemetrexed plays a very important role in the treatment of lung cancer in elderly patients. Weiss et al10 analyzed the efficacy and toxicity of pemetrexed monotherapy versus docetaxel monotherapy as second-line treatment in NSCLC patients of 70 years or older. Their results suggested that patients with a good PS score (0-2 points) can still benefit from chemotherapy similarly to younger patients. As for safety profile, the incidence of myelosuppression was higher in elderly patients than in non-elderly patients but the difference did not reach statistical significance. Kudoh et al11 considered that pemetrexed monotherapy can be beneficial and safe to those elderly patients with an otherwise good health status. The results of this study showed that for old (≥60 years) NSCLC patients, pemetrexed monotherapy has an efficacy similar to pemetrexed + platinum combination therapy. The survival did not show a significant difference between the two regimens. As for safety profile, pemetrexed + platinum combination regimen induced higher hematological and gastrointestinal toxicities in elderly patients. Therefore, we suggest that for old patents with a good PS score, pemetrexed monotherapy should be used as a second-line regimen to ensure both efficacy and safety, so as to improve their quality of life.
In conclusion, the results of this study showed that no significant difference was found between pemetrexed monotherapy and pemetrexed + platinum combination regimen in terms of survival. Meanwhile, a combination regimen may significantly increase the toxicity in elderly patients and affect their quality of life. For this reason, our conclusion still supports NCCN clinical guidelines, namely, pemetrexed monotherapy should be used as the standard second-line regimen for NSCLC patients. Considering the retrospective nature of this study, more extensive clinical practice should be required to further confirm this conclusion.
1. Stinchcombe TE, Socinski MA. Considerations for second-line therapy of non-small cell lung cancer. Oncologist 2008; 13: 28-36.
2. Cohen MH, Johnson JR, Wang YC, Sridhara R, Pazdur R. FDA drug approval summary: Pemetrexed
for injection (Alimta) for the treatment of non-small cell lung cancer. Oncologist 2005; 10: 363-368.
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: 1589-1597.
4. Kim YH, Kim JS, Choi YH, In KH, Park HS, Hong DS, et al. Phase II study of docetaxel and cisplatin combination chemotherapy in metastatic or unresectable localized non-small-cell lung cancer. Int J Clin Oncol 2002; 7: 114-119.
5. D'Addario G, Pintilie M, Leighl NB, Feld R, Cerny T, Shepherd FA. Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 2005; 23: 2926-2936.
6. Wakelee H, Belani CP. Optimizing first-line treatment options for patients with advanced NSCLC. Oncologist 2005; 10 Suppl 3: 1-10.
7. 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: 4206-4212.
8. Molina JR, Adjei AA. The role of Pemetrexed
(Alimta®, LY231514) in lung cancer therapy. Clin Lung Cancer 2003; 5: 21-27.
9. Shepherd FA, Dancey J, Arnold A, Neville A, Rusthoven J, Johnson RD, et al. Phase II study of pemetrexed
disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced nonsmall cell lung carcinoma. Cancer 2001; 92: 595-600.
10. 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: 4405-4411.
11. Kudoh S, Takeda K, Nakagawa K, Takada M, Katakami N, Matsui K, et al. Phase III study of compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol 2006; 24: 3657-3663.
Keywords:© 2009 Chinese Medical Association
carcinoma, non-small-cell lung; antineoplastic agents; pemetrexed