Research Note
Comparison of pemetrexed and docetaxel as salvage chemotherapy for the treatment for nonsmall-cell lung cancer after the failure of epidermal growth factor receptor-tyrosine kinase inhibitors
Journal of International Medical Research 2014, Vol. 42(1) 191–197 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060513505808 imr.sagepub.com
Lei Dong1, Zhao-feng Han2, Zi-hui Feng3 and Zhi-yang Jia4
Abstract Objective: To compare the therapeutic effects and adverse reactions of pemetrexed and docetaxel as salvage chemotherapy in patients with nonsmall-cell lung cancer (NSCLC) after the failure of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI). Methods: In this randomized Phase 2 trial, patients with NSCLC who had previously failed EGFRTKI therapy were randomized to receive intravenous pemetrexed (500 mg/m2 for 21 days [one cycle]) or docetaxel (75 mg/m2 for 21 days [one cycle]). Therapeutic effects were evaluated according to Response Evaluation Criteria in Solid Tumours standards and adverse effects were evaluated according to the US National Cancer Institute Common Terminology Criteria for Adverse Events. Results: There was no statistically significant difference in disease control rate, response rate, median survival and 1-year survival between treatment groups. Rates of nausea, myelosuppression, renal damage and hair loss were significantly higher in the docetaxel group than the pemetrexed group. Conclusion: Pemetrexed is effective and well tolerated as salvage chemotherapy in patients with NSCLC after EGFR-TKI failure and may be a suitable therapeutic option in these patients. 4
Department of Nuclear Medicine and Iconography, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
1
Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 2 Department of Burns, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 3 Department of Gerontology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Corresponding author: Master Lei Dong, Oncology Department, The First Affiliated Hospital of Zhengzhou University, Number one, Constructive East Road, Zhengzhou 450052, Henan, China. Email: [email protected]
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Keywords Pemetrexed, docetaxel, epidermal growth factor receptor-tyrosine kinase inhibitor, nonsmall-cell lung cancer Date received: 15 July 2013; accepted: 3 August 2013
Introduction Nonsmall-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers.1 Platinum-based dual-drug chemotherapy is widely used in clinical practice to treat NSCLC but rates of tumour resistance and recurrence are high, the response rate is only 20–40% and the median survival time is 8–10 months.2–4 The use of conventional drugs as second- or third-line chemotherapy can improve survival quality and extend progression-free survival (PFS) in advanced NSCLC.5,6 Drug resistance has been observed in patients with NSCLC treated with epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs),7 and the optimum chemotherapeutic regimen in these patients is unclear. Docetaxel and pemetrexed are currently used in clinical practice as second-line chemotherapy in patients with NSCLC.4 In order to provide a basis for their use in clinical practice, the aim of the present study was to compare the therapeutic effects and adverse reactions associated with pemetrexed and docetaxel as salvage chemotherapy in patients with NSCLC in whom EGFR-TKIs had failed to work.
Patients and methods Study population Patients with NSCLC treated at The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China between January 2008 and January 2012 were randomized to receive pemetrexed or docetaxel according to a computergenerated randomization schedule. The study was a randomized Phase 2 trial.
The primary endpoint was survival and the secondary endpoint was response rate. Inclusion criteria were: (i) a diagnosis of NSCLC, as determined by exfoliative cytology, percutaneous lung biopsy or bronchofiberscope biopsy, consistent with the World Health Organization 2011 histological classification;8 (ii) EGFR-TKI failure (defined as evidence of disease progression while on continuous EGFR-TKI therapy); (iii) age 18 years; (iv) Eastern Co-operative Oncology Group score 0.05) as determined by 2-test for categorical data and Student’s t-test for continuous data. a Immunohostochemistry and pathology indicated adenoasquamous carcinoma.
Table 2. Comparison of response rates after treatment with pemetrexed or docetaxel in patients with nonsmall-cell lung cancer who had failed previous treatment with epidermal growth factor receptor-tyrosine kinase inhibitors. Response
Pemetrexed, n ¼ 54
Docetaxel, n ¼ 55
Complete response Partial response Stable disease Progressive disease Response rate Disease control rate
2 (3.7) 10 (18.5) 16 (29.6) 26 (48.2) 12 (22.2) 28 (51.9)
3 (5.5) 11 (20.0) 15 (27.3) 26 (47.3) 14 (25.5) 29 (52.7)
Data are expressed as n (%) of patients. There was no statistically significant difference between treatment groups with regard to any response parameter (P > 0.05) as determined by Student’s t-test.
The median survival time was 8.5 1.1 months and 8.4 1.1 months in the pemetrexed and docetaxel groups, respectively, and the corresponding 1-year survival rates were 25.9% (14/54) and 25.5% (14/55). There was no statistically significant difference between treatment groups with regard to median survival time or 1-year survival rate. Compared with the pemetrexed group, patients receiving docetaxel experienced significantly higher rates of nausea, myelosuppression, renal damage and hair loss (all P < 0.05, Table 3).
Discussion The pathogenesis of NSCLC, a common glandular epithelial cancer, is unclear, although it appears to be strongly associated with long-term smoking, air pollution, vocational factors, chronic lung diseases, familial inheritance and endocrine disorders.12 Early symptoms of NSCLC include mainly extrapulmonary manifestations involving the joints, such as clubbed finger or hypertrophic pulmonary osteoarthropathy; later symptoms include cough, dyspnoea, weight loss and chest pain.13 It has been shown that conventional second- or third-line chemotherapy can improve survival quality and extend PFS in patients with NSCLC,5,6 but elderly patients in particular have a low tolerance for the adverse effects associated with treatment as their organ reserve capacity is low.14 Selection of an efficacious and well tolerated chemotherapy regimen is, therefore, especially challenging in elderly patients with NSCLC.15 Advanced NSCLC is commonly treated with pemetrexed and docetaxel. Docetaxel is unique among the taxane anticancer drugs in that it is administered intravenously. It promotes tubulin polymerization and inhibits microtubule depolymerization such that nonfunctional microtubules are formed, which subsequently restrict tumour cell
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Table 3. Adverse events graded by severity following treatment with pemetrexed or docetaxel in patients with nonsmall-cell lung cancer who had failed previous treatment with epidermal growth factor receptortyrosine kinase inhibitors. Pemetrexed, n ¼ 54
Docetaxel, n ¼ 55
Adverse event
I
II
III
IV
Total
I
II
III
IV
Total
Neutropenia Thrombocytopenia Anaemia Nausea Diarrhoea Neurotoxicity Renal damage Hepatic injury Hair loss Erythema
8 4 2 4 2 15 5 2 2 2
5 1 1 2 1 7 0 1 1 1
2 0 1 0 1 2 0 0 0 0
0 0 0 0 0 0 0 0 0 0
15a 5a 4 6a 4 24 5a 3 3a 3
19 11 4 16 3 15 11 2 15 3
12 14 2 5 1 8 3 1 3 1
5 4 0 4 1 3 1 0 1 0
2 1 0 0 0 0 0 0 0 0
38 30 6 25 5 26 15 3 19 4
Data are presented as n of patients. Adverse event were graded according to the US National Cancer Institute Common Terminology Criteria for Adverse Events.11 a Statistically significant difference between treatment groups (P < 0.05) as determined by Student’s t-test.
mitosis.16–18 Research has suggested that docetaxel is more effective in the treatment of cancer than paclitaxel: the concentration of docetaxel has been shown to be four times higher than that of paclitaxel in somatocytes and its affinity for microtubules is twice that of paclitaxel.19,20 In addition, docetaxel has been found to persist in tumour cells longer than paclitaxel.21 Docetaxel is used as second-line therapy in anthracyclineresistant breast cancer22 and has been used alone or in combination with other drugs in chemotherapeutic regimens for NSCLC, prolonging patient survival.23 The pharmacokinetic profile of docetaxel is consistent with a three-compartment model and faecal excretion is the main route of elimination.24 Docetaxel exhibits a plasma protein binding ratio of more than 95% and cytochrome P540 3A4 (CYP3A4) is involved in its metabolism, meaning that docetaxel is suitable as salvage treatment after failure of cisplatin chemotherapy.25 Pemetrexed is a multi-target antifolic acid preparation containing pyrrole pyrimidine that can inhibit key enzymes in the folate-
dependent metabolic pathways thereby affecting tumour growth.26,27 It inhibits the activities of dihydrofolate synthetase, thymidylate synthetase and glycinamide ribonucleotide formyltransferase. In addition, it transports folate carrier and the cell membrane-folate binding protein transport system into cells to synthesize glutamic acid, which inhibits enzyme activity to prevent tumour growth.28 Pemetrexed is eliminated from the body via the urine with a creatinine clearance rate of 90 ml/min.29 The plasma protein binding ratio of pemetrexed is approximately 81%, which is independent of renal function.30 After achieving effective maintenance therapy, pemetrexed has been shown to extend overall survival, especially in NSCLC.31 The present study indicated that there was no statistically significant difference in DCR, RR, median survival time and 1-year survival rate between pemetrexed and docetaxel in patients with NSCLC who had previously failed EGFR-TKIs. Rates of nausea, myelosuppression, renal damage and hair loss were, however, significantly
Downloaded from imr.sagepub.com at EXETER UNIV LIBRARY on March 18, 2015
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higher in patients treated with docetaxel compared with pemetrexed. These findings suggest that the therapeutic effect of pemetrexed is similar to that of docetaxel in patients with NSCLC after EGFR-TKI failure, but that pemetrexed may be better tolerated than docetaxel. This study has several limitations. The number of participants was small, the median follow-up time was only 1 year, and there was no analysis of subgroups according to EGFR or ALK markers. These factors should addressed in further studies. The optimum salvage chemotherapy regimen for NCLC after TKI failure remains to be further investigated. In conclusion, the present study demonstrated the pemetrexed was effective as salvage chemotherapy in patients with NSCLC after EGFR-TKI failure and that it was associated with a lower incidence of adverse reactions than docetaxel. These data indicate that pemetrexed may be a suitable chemotherapeutic option for patients with NSCLC after EGFR-TKI failure. Declaration of conflicting interest The authors declare that there are no conflicts of interest.
Funding This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors.
References 1. Li Y, Jiang Q, Nia N, et al. Decreased expression of microRNA-375 in nonsmall cell lung cancer and its clinical significance. J Int Med Res 2012; 40: 1662–1669. 2. Scagliotti GV, De Marinis F, Rinaldi M, et al. Phase III randomized trial comparing three platinum-based doublets in advanced nonsmall-cell lung cancer. J Clin Oncol 2002; 20: 4285–4291.
3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 4. Cheng G. Progress of clinical research in ‘‘tailor’’ chemotherapy for non-small-cell lung cancer. Zhongguo Fei Ai Za Zhi 2008; 11: 10–13. [in Chinese, English abstract]. 5. Weiss JM and Stinchcombe TE. Second-line therapy for advanced NSCLC. Oncologist 2013; 18: 947–953. 6. Shepard FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated nonsmall-cell lung cancer. N Engl J Med 2005; 353: 123–132. 7. Lee JC, Jang SH, Lee KY, et al. Treatment of non-small cell lung carcinoma after failure of epidermal growth factor receptor tyrosine kinase inhibitor. Cancer Res Treat 2013; 45: 79–85. 8. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/ European Respiratory Society: international multidisciplinary classiEcation of lung adenocarcinoma: executive summary. Proc Am Thorac Soc 2011; 8: 381–385. 9. Fromme EK, Eilers KM, Mori M, Hsieh YC, et al. How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30. J Clin Oncol 2004; 22: 3485–3490. 10. Gerber DE, Dahlberg SE, Sandler AB, et al. Baseline tumour measurements predict survival in advanced non-small cell lung cancer. Br J Cancer 2013; 109: 1476–1481. 11. Basch E, Iasonos A, McDonough T, et al. Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study. Lancet Oncol 2006; 7: 903–909. 12. Colditz GA. Cancer and the environment: the American Cancer Society prevention priorities. CA Cancer J Clin 2009; 59: 341–342. 13. Hamilton W, Peters TJ, Round A, et al. What are the clinical features of lung cancer before the diagnosis is made?
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A population-based case–control study. Thorax 2005; 60: 1059–1065. Sequist LV and Fidias P. Treatment of advanced non-small cell lung cancer in the elderly. Semin Respir Crit Care Med 2005; 26: 289–297. Fan Y, Huang ZY, Yu HF, et al. Efficacy of salvage chemotherapy in the advanced nonsmall cell lung cancer patients who failed the treatment of chemotherapy and EGFR-TKI. Zhonghua Zhong Liu Za Zhi 2010; 32: 859–863. [in Chinese, English abstract]. Davies AM, Lara PN Jr, Mack PC, et al. Docetaxel in non-small cell lung cancer: a review. Expert Opin Pharmacother 2003; 4: 553–565. Saloustros E and Georgoulias V. Docetaxel in the treatment of advanced non-small-cell lung cancer. Expert Rev Anticancer Ther 2008; 8: 1207–1222. Horn L, Visbal A, Leighl NB, et al. Docetaxel in non-small cell lung cancer: impact on quality of life and pharmacoeconomics. Drugs Aging 2007; 24: 411–428. Anderson A, Warren DJ, Brunsvig PF, et al. High sensitivity assays for docetaxel and paclitaxel in plasma using solid-phase extraction and high-performance liquid chromatography with UV detection. BMC Clin Pharmacol 2006; 6: 2. Winefield RD, Entwistle RA, Foland TB, et al. Differences in paclitaxel and docetaxel interactions with tubulin detected by mutagenesis of yeast tubulin. ChemMedChem 2008; 3: 1844–1847. Verschraegen CF, Sittisomwong T, Kudelka AP, et al. Docetaxel for patients with paclitaxel-resistant Mu¨llerian carcinoma. J Clin Oncol 2000; 18: 2733–2739. Baur M, van Oosterom AT, Die´ras V, et al. A phase II trial of docetaxel (Taxotere) as
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second-line chemotherapy in patients with metastatic breast cancer. J Cancer Res Clin Oncol 2008; 134: 125–135. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. Baker SD, Sparreboom A and Verweij J. Clinical pharmacokinetics of docetaxel: recent developments. Clin Pharmacokinet 2006; 45: 235–252. Lee JL, Ryu MH, Chang HM, et al. A phase II study of docetaxel as salvage chemotherapy in advanced gastric cancer after failure of fluropyrimidine and platinum combination chemotherapy. Cancer Chemother Pharmacol 2008; 61: 631–637. Rollins KD and Lindley C. Pemetrexed: a multitargeted antifolate. Clin Ther 2005; 27: 1343–1382. Socinski MA, Stinchcombe TE, Hayes DN, et al. The evolving role of pemetrexed (Alimta) in lung cancer. Semin Oncol 2005; 32(2 suppl. 2): S16–S22. Goldman ID and Zhao R. Molecular, biochemical, and cellular pharmacology of pemetrexed. Semin Oncol 2002; 29(6 suppl 18): 3–17. Calvert AH. Biochemical pharmacology of pemetrexed. Oncology (Williston Park) 2004; 18: 13–17. Latz JE, Chaudhary A, Ghosh A, et al. Population pharmacokinetic analysis of ten phase II clinical trials of pemetrexed in cancer patients. Cancer Chemother Pharmacol 2006; 57: 401–411. Jiang Y, Owonikoko TK, Ramalingam SS, et al. What is the role of maintenance therapy in the treatment of non-small cell lung cancer? Ther Adv Med Oncol 2010; 2: 229–235.
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Comparison of pemetrexed and docetaxel as salvage chemotherapy for the treatment for nonsmall-cell lung cancer after the failure of epidermal growth factor receptor-tyrosine kinase inhibitors
Journal of International Medical Research 2014, Vol. 42(1) 191–197 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060513505808 imr.sagepub.com
Lei Dong1, Zhao-feng Han2, Zi-hui Feng3 and Zhi-yang Jia4
Abstract Objective: To compare the therapeutic effects and adverse reactions of pemetrexed and docetaxel as salvage chemotherapy in patients with nonsmall-cell lung cancer (NSCLC) after the failure of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI). Methods: In this randomized Phase 2 trial, patients with NSCLC who had previously failed EGFRTKI therapy were randomized to receive intravenous pemetrexed (500 mg/m2 for 21 days [one cycle]) or docetaxel (75 mg/m2 for 21 days [one cycle]). Therapeutic effects were evaluated according to Response Evaluation Criteria in Solid Tumours standards and adverse effects were evaluated according to the US National Cancer Institute Common Terminology Criteria for Adverse Events. Results: There was no statistically significant difference in disease control rate, response rate, median survival and 1-year survival between treatment groups. Rates of nausea, myelosuppression, renal damage and hair loss were significantly higher in the docetaxel group than the pemetrexed group. Conclusion: Pemetrexed is effective and well tolerated as salvage chemotherapy in patients with NSCLC after EGFR-TKI failure and may be a suitable therapeutic option in these patients. 4
Department of Nuclear Medicine and Iconography, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
1
Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 2 Department of Burns, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China 3 Department of Gerontology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Corresponding author: Master Lei Dong, Oncology Department, The First Affiliated Hospital of Zhengzhou University, Number one, Constructive East Road, Zhengzhou 450052, Henan, China. Email: [email protected]
Downloaded from imr.sagepub.com at EXETER UNIV LIBRARY on March 18, 2015
192
Journal of International Medical Research 42(1)
Keywords Pemetrexed, docetaxel, epidermal growth factor receptor-tyrosine kinase inhibitor, nonsmall-cell lung cancer Date received: 15 July 2013; accepted: 3 August 2013
Introduction Nonsmall-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers.1 Platinum-based dual-drug chemotherapy is widely used in clinical practice to treat NSCLC but rates of tumour resistance and recurrence are high, the response rate is only 20–40% and the median survival time is 8–10 months.2–4 The use of conventional drugs as second- or third-line chemotherapy can improve survival quality and extend progression-free survival (PFS) in advanced NSCLC.5,6 Drug resistance has been observed in patients with NSCLC treated with epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs),7 and the optimum chemotherapeutic regimen in these patients is unclear. Docetaxel and pemetrexed are currently used in clinical practice as second-line chemotherapy in patients with NSCLC.4 In order to provide a basis for their use in clinical practice, the aim of the present study was to compare the therapeutic effects and adverse reactions associated with pemetrexed and docetaxel as salvage chemotherapy in patients with NSCLC in whom EGFR-TKIs had failed to work.
Patients and methods Study population Patients with NSCLC treated at The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China between January 2008 and January 2012 were randomized to receive pemetrexed or docetaxel according to a computergenerated randomization schedule. The study was a randomized Phase 2 trial.
The primary endpoint was survival and the secondary endpoint was response rate. Inclusion criteria were: (i) a diagnosis of NSCLC, as determined by exfoliative cytology, percutaneous lung biopsy or bronchofiberscope biopsy, consistent with the World Health Organization 2011 histological classification;8 (ii) EGFR-TKI failure (defined as evidence of disease progression while on continuous EGFR-TKI therapy); (iii) age 18 years; (iv) Eastern Co-operative Oncology Group score 0.05) as determined by 2-test for categorical data and Student’s t-test for continuous data. a Immunohostochemistry and pathology indicated adenoasquamous carcinoma.
Table 2. Comparison of response rates after treatment with pemetrexed or docetaxel in patients with nonsmall-cell lung cancer who had failed previous treatment with epidermal growth factor receptor-tyrosine kinase inhibitors. Response
Pemetrexed, n ¼ 54
Docetaxel, n ¼ 55
Complete response Partial response Stable disease Progressive disease Response rate Disease control rate
2 (3.7) 10 (18.5) 16 (29.6) 26 (48.2) 12 (22.2) 28 (51.9)
3 (5.5) 11 (20.0) 15 (27.3) 26 (47.3) 14 (25.5) 29 (52.7)
Data are expressed as n (%) of patients. There was no statistically significant difference between treatment groups with regard to any response parameter (P > 0.05) as determined by Student’s t-test.
The median survival time was 8.5 1.1 months and 8.4 1.1 months in the pemetrexed and docetaxel groups, respectively, and the corresponding 1-year survival rates were 25.9% (14/54) and 25.5% (14/55). There was no statistically significant difference between treatment groups with regard to median survival time or 1-year survival rate. Compared with the pemetrexed group, patients receiving docetaxel experienced significantly higher rates of nausea, myelosuppression, renal damage and hair loss (all P < 0.05, Table 3).
Discussion The pathogenesis of NSCLC, a common glandular epithelial cancer, is unclear, although it appears to be strongly associated with long-term smoking, air pollution, vocational factors, chronic lung diseases, familial inheritance and endocrine disorders.12 Early symptoms of NSCLC include mainly extrapulmonary manifestations involving the joints, such as clubbed finger or hypertrophic pulmonary osteoarthropathy; later symptoms include cough, dyspnoea, weight loss and chest pain.13 It has been shown that conventional second- or third-line chemotherapy can improve survival quality and extend PFS in patients with NSCLC,5,6 but elderly patients in particular have a low tolerance for the adverse effects associated with treatment as their organ reserve capacity is low.14 Selection of an efficacious and well tolerated chemotherapy regimen is, therefore, especially challenging in elderly patients with NSCLC.15 Advanced NSCLC is commonly treated with pemetrexed and docetaxel. Docetaxel is unique among the taxane anticancer drugs in that it is administered intravenously. It promotes tubulin polymerization and inhibits microtubule depolymerization such that nonfunctional microtubules are formed, which subsequently restrict tumour cell
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Table 3. Adverse events graded by severity following treatment with pemetrexed or docetaxel in patients with nonsmall-cell lung cancer who had failed previous treatment with epidermal growth factor receptortyrosine kinase inhibitors. Pemetrexed, n ¼ 54
Docetaxel, n ¼ 55
Adverse event
I
II
III
IV
Total
I
II
III
IV
Total
Neutropenia Thrombocytopenia Anaemia Nausea Diarrhoea Neurotoxicity Renal damage Hepatic injury Hair loss Erythema
8 4 2 4 2 15 5 2 2 2
5 1 1 2 1 7 0 1 1 1
2 0 1 0 1 2 0 0 0 0
0 0 0 0 0 0 0 0 0 0
15a 5a 4 6a 4 24 5a 3 3a 3
19 11 4 16 3 15 11 2 15 3
12 14 2 5 1 8 3 1 3 1
5 4 0 4 1 3 1 0 1 0
2 1 0 0 0 0 0 0 0 0
38 30 6 25 5 26 15 3 19 4
Data are presented as n of patients. Adverse event were graded according to the US National Cancer Institute Common Terminology Criteria for Adverse Events.11 a Statistically significant difference between treatment groups (P < 0.05) as determined by Student’s t-test.
mitosis.16–18 Research has suggested that docetaxel is more effective in the treatment of cancer than paclitaxel: the concentration of docetaxel has been shown to be four times higher than that of paclitaxel in somatocytes and its affinity for microtubules is twice that of paclitaxel.19,20 In addition, docetaxel has been found to persist in tumour cells longer than paclitaxel.21 Docetaxel is used as second-line therapy in anthracyclineresistant breast cancer22 and has been used alone or in combination with other drugs in chemotherapeutic regimens for NSCLC, prolonging patient survival.23 The pharmacokinetic profile of docetaxel is consistent with a three-compartment model and faecal excretion is the main route of elimination.24 Docetaxel exhibits a plasma protein binding ratio of more than 95% and cytochrome P540 3A4 (CYP3A4) is involved in its metabolism, meaning that docetaxel is suitable as salvage treatment after failure of cisplatin chemotherapy.25 Pemetrexed is a multi-target antifolic acid preparation containing pyrrole pyrimidine that can inhibit key enzymes in the folate-
dependent metabolic pathways thereby affecting tumour growth.26,27 It inhibits the activities of dihydrofolate synthetase, thymidylate synthetase and glycinamide ribonucleotide formyltransferase. In addition, it transports folate carrier and the cell membrane-folate binding protein transport system into cells to synthesize glutamic acid, which inhibits enzyme activity to prevent tumour growth.28 Pemetrexed is eliminated from the body via the urine with a creatinine clearance rate of 90 ml/min.29 The plasma protein binding ratio of pemetrexed is approximately 81%, which is independent of renal function.30 After achieving effective maintenance therapy, pemetrexed has been shown to extend overall survival, especially in NSCLC.31 The present study indicated that there was no statistically significant difference in DCR, RR, median survival time and 1-year survival rate between pemetrexed and docetaxel in patients with NSCLC who had previously failed EGFR-TKIs. Rates of nausea, myelosuppression, renal damage and hair loss were, however, significantly
Downloaded from imr.sagepub.com at EXETER UNIV LIBRARY on March 18, 2015
196
Journal of International Medical Research 42(1)
higher in patients treated with docetaxel compared with pemetrexed. These findings suggest that the therapeutic effect of pemetrexed is similar to that of docetaxel in patients with NSCLC after EGFR-TKI failure, but that pemetrexed may be better tolerated than docetaxel. This study has several limitations. The number of participants was small, the median follow-up time was only 1 year, and there was no analysis of subgroups according to EGFR or ALK markers. These factors should addressed in further studies. The optimum salvage chemotherapy regimen for NCLC after TKI failure remains to be further investigated. In conclusion, the present study demonstrated the pemetrexed was effective as salvage chemotherapy in patients with NSCLC after EGFR-TKI failure and that it was associated with a lower incidence of adverse reactions than docetaxel. These data indicate that pemetrexed may be a suitable chemotherapeutic option for patients with NSCLC after EGFR-TKI failure. Declaration of conflicting interest The authors declare that there are no conflicts of interest.
Funding This research received no specific grant from any funding agency in the public, commercial or notfor-profit sectors.
References 1. Li Y, Jiang Q, Nia N, et al. Decreased expression of microRNA-375 in nonsmall cell lung cancer and its clinical significance. J Int Med Res 2012; 40: 1662–1669. 2. Scagliotti GV, De Marinis F, Rinaldi M, et al. Phase III randomized trial comparing three platinum-based doublets in advanced nonsmall-cell lung cancer. J Clin Oncol 2002; 20: 4285–4291.
3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 4. Cheng G. Progress of clinical research in ‘‘tailor’’ chemotherapy for non-small-cell lung cancer. Zhongguo Fei Ai Za Zhi 2008; 11: 10–13. [in Chinese, English abstract]. 5. Weiss JM and Stinchcombe TE. Second-line therapy for advanced NSCLC. Oncologist 2013; 18: 947–953. 6. Shepard FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated nonsmall-cell lung cancer. N Engl J Med 2005; 353: 123–132. 7. Lee JC, Jang SH, Lee KY, et al. Treatment of non-small cell lung carcinoma after failure of epidermal growth factor receptor tyrosine kinase inhibitor. Cancer Res Treat 2013; 45: 79–85. 8. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/ European Respiratory Society: international multidisciplinary classiEcation of lung adenocarcinoma: executive summary. Proc Am Thorac Soc 2011; 8: 381–385. 9. Fromme EK, Eilers KM, Mori M, Hsieh YC, et al. How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30. J Clin Oncol 2004; 22: 3485–3490. 10. Gerber DE, Dahlberg SE, Sandler AB, et al. Baseline tumour measurements predict survival in advanced non-small cell lung cancer. Br J Cancer 2013; 109: 1476–1481. 11. Basch E, Iasonos A, McDonough T, et al. Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study. Lancet Oncol 2006; 7: 903–909. 12. Colditz GA. Cancer and the environment: the American Cancer Society prevention priorities. CA Cancer J Clin 2009; 59: 341–342. 13. Hamilton W, Peters TJ, Round A, et al. What are the clinical features of lung cancer before the diagnosis is made?
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