- Email: [email protected]
Phase II randomized study of weekly docetaxel alone or plus UFUR treatment in non-small cell lung cancer patients who failed previous chemotherapy
Lung Cancer (2008) 59, 64—68
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Phase II randomized study of weekly docetaxel alone or plus UFUR treatment in non-small cell lung cancer patients who failed previous chemotherapy Kun-ta Chou a, Yuh-Min Chen a,b,c,∗, Jen-Fu Shih a,b, Reury-Perng Perng a,b, Chun-Ming Tsai a,b, Jacqueline Whang-Peng c a
Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan School of Medicine, National Yang-Ming University, Taipei, Taiwan c Institute of Cancer Research, National Health Research Institutes, Taipei, Taiwan b
Received 18 January 2007; received in revised form 20 July 2007; accepted 23 July 2007
KEYWORDS Docetaxel; Non-small cell lung cancer; Salvage therapy; UFUR
Summary Purpose: This study aimed to assess the feasibility and efficacy of adding UFUR (UFT, tegafur/uracil) into weekly docetaxel treatment for non-small cell lung cancer (NSCLC) patients who failed previous platinum-based chemotherapy. Methods: Patients were randomized into two arms: docetaxel 40 mg/m2 intravenous infusion (IV) on days 1 and 8 of every 3 weeks (arm D), and docetaxel 35 mg/m2 IV on days 1 and 8 plus daily oral UFUR 150 mg/m2 of every 3 weeks (arm DU), with arm D as a control arm. Treatment was given to a maximum of 6 cycles and carried out in the outpatient clinic. Results: From January 2005 to March 2006, 48 patients were enrolled and randomized into the study, with 24 patients in each arm. The mean number of cycles of treatment was 4 in the D arm and 3.5 in the DU arm. Objective response rates were 29.2% in the D arm and 8.3% in the DU arm (p = 0.067). Toxicities were few and mild in degree in both arms. Median time to disease progression was 4.5 months in the D arm and 2.1 months in the DU arm (p = 0.4682). Median survival time was 10.9 months in the D arm and 15.2 months in the DU arm (p = 0.8442). Conclusions: The addition of UFUR to weekly docetaxel treatment did not improve response rate and time to disease progression in NSCLC patients who failed previous platinum-based chemotherapy. © 2007 Elsevier Ireland Ltd. All rights reserved.
∗
Corresponding author at: Chest Department, Taipei Veterans General Hospital, 201, Sec. 2, Shih-pai Road, Taipei 112, Taiwan. Tel.: +886 2 28757563; fax: +886 2 28763466. E-mail address: [email protected] (Y.-M. Chen). 0169-5002/$ — see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2007.07.016
Docetaxel alone or plus UFUR
1. Introduction Docetaxel was the first third-generation anti-cancer drug found to have activity in second-line chemotherapy for non-small cell lung cancer (NSCLC), with a prolongation of patient survival in phase III randomized trials comparing docetaxel with vinorelbine or ifosfamide, or with the best supportive care, for NSCLC patients who have failed previous chemotherapy [1,2]. Four years after these trials, pemetrexed showed similar activity with less toxicity, when compared with docetaxel treatment in a phase III randomized trial of NSCLC patients previously treated with chemotherapy [3,4]. In addition to these conventional chemotherapeutic agents, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), a new class of agent, has shown effectiveness in the salvage treatment of NSCLC patients who have failed previous chemotherapy, including erlotinib in second-line treatment and gefitinib for patients after failure with both platinum-based and docetaxel chemotherapies [3,5,6]. UFUR is composed of tegafur and uracil (UFT, tegafur/uracil), and is an orally active preparation of 5-fluorouracil (5-FU). Meta-analysis of adjuvant chemotherapy with single-agent UFUR therapy after surgery showed a significant survival benefit, with a hazard ratio of 0.799 (p = 0.015) [7]. In addition, UFUR was found to be effective against chemo-naive, advanced NSCLC when combined with cisplatin treatment [8—10]. UFUR is also a relatively safe chemotherapeutic drug; it is easy to combine with other chemotherapeutic agents and easy to administer in an outpatient setting [8,11]. Our previous randomized study showed weekly docetaxel chemotherapy produces less myelosuppression, and better compliance and response rates than the conventional every 3 weeks’ schedule [12]. In the present study, we investigated whether or not the addition of daily UFUR treatment into weekly docetaxel treatment could enhance the treatment effect without an obvious increase of toxicities.
2. Patients and methods The study was conducted according to existing rules for good clinical practice, and the study protocol was approved by the local ethics committee. Patients with NSCLC who had failed previous platinum-based chemotherapy were entered into the study after giving informed consent. Eligibility criteria were: a histological or cytological diagnosis of stage IIIb or IV NSCLC in patients who had failed previous platinumbased chemotherapy; a performance status of 0—2 on the Zubrod scale; clinically measurable disease, defined as bidimensionally measurable lesions; no previous radiotherapy on measurable lesion(s); adequate bone marrow reserve with a white blood cell (WBC) count ≥4000/mm3 , platelets ≥10,0000/mm3 , and hemoglobin ≥10 g/dL; and no previous history of docetaxel or UFUR treatment. Patients with inadequate liver function (total bilirubin > 1.5 times and ALT/AST > 3 times upper limit normal); or inadequate renal function with creatinine > 2.0 mg/dL, were excluded from the study. Baseline evaluations included a documentation of the patient’s history, a physical examination, and a performance
65 score. A complete blood cell count, urinalysis, serum biochemistry profile, ECG, chest roentgenography, whole body bone scan, brain CT scan, and chest (including the liver and adrenal glands) CT scan were also performed. Eligible patients were randomized into either: docetaxel 40 mg/m2 IV on days 1 and 8 of every 3 weeks (D arm), or docetaxel 35 mg/m2 IV on days 1 and 8 plus daily oral UFUR 150 mg/m2 every 3 weeks (DU arm). Dexamethasone 8 mg per oral 12 h before docetaxel treatment, 10 mg IV 30 min before docetaxel treatment, and 8 mg per oral 12 h after docetaxel injection were given as pre- and post-medications. A complete blood cell count was done within 24 h before every chemotherapy session, and on day 15 of cycles 1 and 2. Serum biochemistry studies were performed before every course of chemotherapy, and during the course, if clinically indicated. For dose adjustments, docetaxel was omitted if the absolute neutrophil count was less than 1.0 × 109 L−1 , and the platelet count was less than 75 × 109 L−1 on the day of docetaxel injection. For non-hematological toxicities, docetaxel doses were reduced to 80% if there were grade 3 toxicities, excluding nausea/vomiting and alopecia. No adjustment of the UFUR dose was made during the treatment course. Treatment was given until disease progression or after a maximum of 6 cycles. Drug-related adverse events and toxicities were recorded, according to the Common Toxicity Criteria of the National Cancer Institute (version 2.0). The Lung Cancer Symptom Scale was recorded before treatment, during every cycle thereafter, and when the patient completed or went off the study. Evaluation of response was performed after 3 and 6 cycles of treatment. Additional evaluation of response was also performed if needed. Types of response were assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST) [13]. This study was designed to enroll at least 28 qualified patients in each arm. This calculation assumes that the true response rate for the best treatment is 10% better than that for the others. Assume that the smaller response rate was 10% and the higher one was 20%, with a power of 0.85 and a p value of 0.05, and that each treatment group required 28 qualified patients [14]. A two-stage design with interim analysis of the response rate of both arms was done after enrollment of the initial 40 patients. Further enrollment or an early stopping of the trial was determined after this interim analysis. Survival was measured from administration of the first dose until the date of death or last follow-up. For statistical analysis, the Kaplan—Meier method with a logrank test was used for survival analysis. The Cox-regression test for multivariate survival analysis was utilized. For the statistical analysis of the Lung Cancer Symptom Scale, the Mann—Whitney test was used for a comparison of the two arms of treatment. The SPSS statistical program was used.
3. Results From January 2004 to March 2005, 48 patients were enrolled. Enrollment was stopped after 48 patients, because the interim analysis of the initial 40 patients showed a markedly inferior response rate in the test arm. Twenty-four patients were randomized into each arm.
66 Table 1
K.-t. Chou et al. Patient characteristics (n = 48)
Variable
p*
Patient number (%) Docetaxel (n = 24)
Docetaxel + UFUR (n = 24)
Sex Male Female
17 (70.8) 7 (29.2)
19 (79.2) 5 (20.8)
0.515
Age: mean (range)
67 (43—84)
64 (42—81)
0.398
WHO performance status 1 2
16 (66.7) 8 (33.3)
18 (75) 56 (25)
0.535
Staging IIIbw IV
2 (8.3) 22 (91.7)
5 (20.8) 19 (79.2)
0.229
Present treatment as Second line Third line Fourth line
22 (91.7) 1 (4.2) 1 (4.2)
23 (95.8) 1 (4.2) 0
0.412
Histology Adenocarcinoma Squamous cell NSCLC, type unspecified
17 (70.8) 5 (20.8) 2 (8.3)
17 (70.8) 3 (12.5) 4 (16.7)
0.689
Abbreviations: IIIbw, stage IIIb with malignant pleural effusion. * There was no statistical difference in patient clinical characteristics between the two treatment groups.
The mean age of the patients was 67 years in the D arm and 64 years in the DU arm. The clinical characteristics of these patients are listed in Table 1. There was no statistical difference in the clinical characteristics of the two arms of treatment in terms of sex, age, performance status, staging, histology, and present treatment as second-line or later treatment. All patients were assessable for toxicity profile and 46 patients were evaluable for treatment response. After 3 cycles of treatment, 7 patients achieved a partial response (PR) in the D arm (overall response rate of 29.2%), and 2 patients achieved a PR in the DU arm (overall response rate of 8.3%) (p = 0.067). Stable disease was found in 10 (41.7%) and 12 (50%) patients, respectively. After a median follow-up time of 16 months, the median time to disease progression was 4.5 months in the D arm and 2.1 months in the DU arm (p = 0.4682). Six-month progression-free survival was 28.4% in the D arm and 21.8% in the DU arm. The median survival time was 10.9 months in the D arm and 15.2 months in the DU arm (p = 0.8442). The 1-year survival rate was 49.2% and 56.4%, respectively. When considering all 48 patients together, survival was better in those who had a response to the treatment (n = 9, median 14.6 months vs. n = 39, median 10.9 months, p = 0.2202), stage IV (n = 41, median 13.5 months) rather than IIIbw (n = 7, median 9 months) (p = 0.7655), a better performance status (n = 34, median >16 months in PS 1 vs. n = 14, median 9.4 months in PS 2) (p = 0.0331), those who received tyrosine-kinase inhibitor (TKI) as salvage therapy (n = 29, median 15.2 months vs. n = 19, median 6.8 months) (p = 0.0847), those with adenocarci-
noma rather than other histologic types (n = 34, median 15.2 months vs. n = 14, median 8.6 months) (p = 0.1336), and females rather than males (n = 12, median >16 months vs. n = 36, median 9.8 months) (p = 0.133). Multivariate analysis, including sex, treatment arm, performance status, response to present treatment or not, stage, histology, and use of TKI as salvage therapy or not, showed that only performance status (p = 0.0226) had statistical significance, and use of TKI (p = 0.0689) had borderline significance. All patients enrolled into the study were eligible for toxicity evaluation. The toxicities were few and mild in severity in both arms. Major toxicities were either grade 3 or 4 neutropenia in both arms. There was no difference in myelotoxicity between the two treatment arms (Table 2). Regarding non-hematological toxicities, no patients suffered from grade 3 or 4 toxicities, except 1 patient with grade 3 asthenia, and 1 with grade 3 pneumonitis in the D arm. A total of 38 patients (20 in the D arm and 18 in the DU arm) completed the baseline Lung Cancer Symptom Scale questionnaire, after 2 months of treatment and after going off study. The results of the completed Lung Cancer Symptoms Scale showed that there was no statistically significant difference in the scales between the D and DU arms, either before or 2 months after treatment, or when the patient went off the study, and whether scored by the patients (nine items) or by the observers (six items), including the categories of loss of appetite, fatigue, cough, dyspnea, hemoptysis, pain, disease severity, daily activity, and quality of life (all items had a p value >0.05).
* ANOVA test with p = 0.367, 0.546, 0.34, and 0.179, for leukopenia, neutropenia, anemia, and thrombocytopenia, respectively. One patient in the D arm had uneventful febrile neutropenia.
0 6 (25) 0 0 5 (20.8) 1 (4.2) 0 0 3 (12.5) 2 (8.3) 8 (33.3) 1 (4.2) 2 (8.3) 2 (8.3) 16 (66.7) 1 (4.2) 14 (58.3) 13 (54.2) 0 22 (91.7) 1 (4.2) 5 (20.8) 0 0 4 (16.7) 2 (8.3) 0 0 5 (20.8) 6 (25) 5 (20.8) 0 5 (20.8) 2 (8.3) 19 (79.2) 0) 9 (37.5) 9 (37.5) 0 24 (100)
4 3 2 1
Number of patients (%) Toxicity\grade*
Hematological toxicity per patient (worst of any course) Table 2
67
Leukopenia Neutropenia Anemia Thrombocytopenia
0 0
1
Docetaxel + UFUR (n = 24) Docetaxel (n = 24)
2
3
4
Docetaxel alone or plus UFUR
4. Discussion Phase II randomized trials with an appropriate control arm are necessary and should be conducted before large phase III studies are initiated [15], since several randomized phase III studies have showed negative results by adding EGFR-TKI into doublet chemotherapy [16—18]. Phase III studies should be considered only if a positive signal is noted in phase II studies. The importance of this strategy is demonstrated in the combined usage of bevacizumab with paclitaxel plus carboplatin in the treatment of NSCLC [19]. When considering salvage chemotherapy, less treatmentrelated toxicity and more symptomatic relief are important issues. Our previous study showed that weekly docetaxel chemotherapy produced less myelosuppression, and better compliance and response rates than the conventional every 3 weeks’ schedule [12]. The present study was an attempt to find out whether or not the addition of UFUR can improve response or survival without increasing toxicities. Experimental studies have shown that UFUR and its metabolites inhibit tumor angiogenesis, especially in vascular endothelial growth factor (VEGF)-mediated angiogenesis. This inhibitory effect on tumor-associated angiogenesis was more marked when the drugs were administered continuously at low doses [20,21]. Thus, UFUR is suitable for metronomic chemotherapy via anti-angiogenesis mechanism [22]. In particular, the low toxicity profiles of UFUR may warrant the combination of this agent with other chemotherapeutic agents in the treatment of those who failed previous chemotherapy, and hope to undergo another salvage treatment. This hypothesis is supported by our previous study with gemcitabine plus UFUR against previously chemotherapy-treated NSCLC, showing a response rate of 15.6%, a median survival of 13.2 months, and toxicity that was minimal and mild in degree [11]. EGFR-TKI, such as gefitinib and erlotinib, is a new class of anti-cancer agents that has been found effective in the salvage treatment of NSCLC patients who have failed previous chemotherapy [5,6]. It was found that female gender, non-smoker, adenocarcinoma (especially those with bronchioloalveolar features), EGFR mutation, and East Asian ethnicity were known factors predicting a better response to EGFR-TKI treatment [5,23]. Although we did not randomize our patients to receive TKI after they had failed the present treatment, it is true that those who received EGFR-TKI in the present study had better survival than those who did not, and with borderline statistical significance. The median survival and 1-year survival rate was rather good in both arms of the present study. However, the response of the DU arm was relatively lower than that of the D arm. The causes of the low response rate in the DU arm may be inadequate docetaxel and/or UFUR dose-intensity. Other possibilities include the lack of an additive or synergistic effect, or even the counter-effect of both agents. The longer survival in DU group compared to D group was noted in this study. Since this trial is a randomized phase II trial, the number of patients is too small to achieve a statistical significant survival difference. It may have statistical significance between two groups if we gather the patients more. This kind of adding UFUR into docetaxel treatment is similar to so-called ‘‘tumor dormancy state’’ management [24].
68
K.-t. Chou et al.
5. Conclusion The addition of daily UFUR treatment into a weekly docetaxel schedule, as in the present study, showed no obvious effect, compared to weekly docetaxel treatment alone. A higher dose of docetaxel and/or UFUR is recommended if further phase II or III studies are planned.
Conflict of interest
[11]
[12]
[13]
The authors indicate no potential conflict of interest.
References
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[1] 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-smallcell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 2000;18:2354—62. [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. [3] Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker Jr S, et al. American society of clinical oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004;22:330—53. [4] 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. [5] Shepherd FA, Pereira JR, 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. [6] Kris MG, Natale RB, Herbst RS, Lynch Jr TJ, Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149—58. [7] Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M, et al. Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 2004;23:3860—7. [8] Langer CJ. The role of tegafur/uracil in pulmonary malignancy. Drugs 1999;58(Suppl. 3):71—5. [9] For the Japan UFT Lung Cancer Study Group. UFT plus cisplatin combination chemotherapy in the treatment of patients with advanced non-small cell lung carcinoma: a multi-institutional phase II trial. Cancer 2000;88:318—23. [10] Saito J, Nakai Y, Saijo Y, Nukiwa T, Koinumaru S, Matsuura Y, et al. A phase II trial of oral UFT plus cisplatin (CDDP) in
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patients with non-small cell lung cancer (NSCLC). Lung Cancer 2001;31:285—93. Chen YM, Perng RP, Tsai CM, Whang-Peng J. A phase II trial of gemcitabine plus UFUR combination chemotherapy in nonsmall-cell lung cancer patients failing previous chemotherapy. Lung Cancer 2006;52:333—8. Chen YM, Shih JF, Perng RP, Tsai CM, Whang-Peng J. A randomized trial of different docetaxel schedules in non-small cell lung cancer patients who failed previous platinum-based chemotherapy. Chest 2006;129:1031—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. J Natl Cancer Inst 2000;92: 205—16. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep 1985;69:1375—81. Buyse ME. Role of stratification and randomization in early trials of targeted agents. Edu Book Am Soc Clin Oncol 2006;24:119—21. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al. Gefitinib (ZD1839) in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial (INTACT 1). J Clin Oncol 2004;22:777—84. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib (ZD1839) in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial (INTACT 2). J Clin Oncol 2004;22:785—94. Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, et al. TRIBUTE: A phase III trial of erlotinib hydrochloride (osi-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892—9. Sandler AB, Gray R, Brahmer J, Dowlati A, Schiller JH, Perry MC, et al. Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial—–E4599. Pro Am Soc Clin Oncol 2005;23:a4. Yonekura K, Basaki Y, Chikahisa L, Okabe S, Hashimoto A, Miyadera K, et al. UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res 1999;5: 2185—91. Tanaka F, Yanagihara K, Otake Y, Miyahara R, Wada H. Angiogenesis and the efficacy of postoperative administration of UFT in pathologic stage I non-small cell lung cancer. Cancer Sci 2004;95:371—6. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004;4:423—36. Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23:2556—68. Indraccolo S, Favaro E, Amadori A. Dormant tumors awaken by a short-term angiogenic burst: the spike hypothesis. Cell Cycle 2006;5:1751—5.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/lungcan
Phase II randomized study of weekly docetaxel alone or plus UFUR treatment in non-small cell lung cancer patients who failed previous chemotherapy Kun-ta Chou a, Yuh-Min Chen a,b,c,∗, Jen-Fu Shih a,b, Reury-Perng Perng a,b, Chun-Ming Tsai a,b, Jacqueline Whang-Peng c a
Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan School of Medicine, National Yang-Ming University, Taipei, Taiwan c Institute of Cancer Research, National Health Research Institutes, Taipei, Taiwan b
Received 18 January 2007; received in revised form 20 July 2007; accepted 23 July 2007
KEYWORDS Docetaxel; Non-small cell lung cancer; Salvage therapy; UFUR
Summary Purpose: This study aimed to assess the feasibility and efficacy of adding UFUR (UFT, tegafur/uracil) into weekly docetaxel treatment for non-small cell lung cancer (NSCLC) patients who failed previous platinum-based chemotherapy. Methods: Patients were randomized into two arms: docetaxel 40 mg/m2 intravenous infusion (IV) on days 1 and 8 of every 3 weeks (arm D), and docetaxel 35 mg/m2 IV on days 1 and 8 plus daily oral UFUR 150 mg/m2 of every 3 weeks (arm DU), with arm D as a control arm. Treatment was given to a maximum of 6 cycles and carried out in the outpatient clinic. Results: From January 2005 to March 2006, 48 patients were enrolled and randomized into the study, with 24 patients in each arm. The mean number of cycles of treatment was 4 in the D arm and 3.5 in the DU arm. Objective response rates were 29.2% in the D arm and 8.3% in the DU arm (p = 0.067). Toxicities were few and mild in degree in both arms. Median time to disease progression was 4.5 months in the D arm and 2.1 months in the DU arm (p = 0.4682). Median survival time was 10.9 months in the D arm and 15.2 months in the DU arm (p = 0.8442). Conclusions: The addition of UFUR to weekly docetaxel treatment did not improve response rate and time to disease progression in NSCLC patients who failed previous platinum-based chemotherapy. © 2007 Elsevier Ireland Ltd. All rights reserved.
∗
Corresponding author at: Chest Department, Taipei Veterans General Hospital, 201, Sec. 2, Shih-pai Road, Taipei 112, Taiwan. Tel.: +886 2 28757563; fax: +886 2 28763466. E-mail address: [email protected] (Y.-M. Chen). 0169-5002/$ — see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2007.07.016
Docetaxel alone or plus UFUR
1. Introduction Docetaxel was the first third-generation anti-cancer drug found to have activity in second-line chemotherapy for non-small cell lung cancer (NSCLC), with a prolongation of patient survival in phase III randomized trials comparing docetaxel with vinorelbine or ifosfamide, or with the best supportive care, for NSCLC patients who have failed previous chemotherapy [1,2]. Four years after these trials, pemetrexed showed similar activity with less toxicity, when compared with docetaxel treatment in a phase III randomized trial of NSCLC patients previously treated with chemotherapy [3,4]. In addition to these conventional chemotherapeutic agents, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), a new class of agent, has shown effectiveness in the salvage treatment of NSCLC patients who have failed previous chemotherapy, including erlotinib in second-line treatment and gefitinib for patients after failure with both platinum-based and docetaxel chemotherapies [3,5,6]. UFUR is composed of tegafur and uracil (UFT, tegafur/uracil), and is an orally active preparation of 5-fluorouracil (5-FU). Meta-analysis of adjuvant chemotherapy with single-agent UFUR therapy after surgery showed a significant survival benefit, with a hazard ratio of 0.799 (p = 0.015) [7]. In addition, UFUR was found to be effective against chemo-naive, advanced NSCLC when combined with cisplatin treatment [8—10]. UFUR is also a relatively safe chemotherapeutic drug; it is easy to combine with other chemotherapeutic agents and easy to administer in an outpatient setting [8,11]. Our previous randomized study showed weekly docetaxel chemotherapy produces less myelosuppression, and better compliance and response rates than the conventional every 3 weeks’ schedule [12]. In the present study, we investigated whether or not the addition of daily UFUR treatment into weekly docetaxel treatment could enhance the treatment effect without an obvious increase of toxicities.
2. Patients and methods The study was conducted according to existing rules for good clinical practice, and the study protocol was approved by the local ethics committee. Patients with NSCLC who had failed previous platinum-based chemotherapy were entered into the study after giving informed consent. Eligibility criteria were: a histological or cytological diagnosis of stage IIIb or IV NSCLC in patients who had failed previous platinumbased chemotherapy; a performance status of 0—2 on the Zubrod scale; clinically measurable disease, defined as bidimensionally measurable lesions; no previous radiotherapy on measurable lesion(s); adequate bone marrow reserve with a white blood cell (WBC) count ≥4000/mm3 , platelets ≥10,0000/mm3 , and hemoglobin ≥10 g/dL; and no previous history of docetaxel or UFUR treatment. Patients with inadequate liver function (total bilirubin > 1.5 times and ALT/AST > 3 times upper limit normal); or inadequate renal function with creatinine > 2.0 mg/dL, were excluded from the study. Baseline evaluations included a documentation of the patient’s history, a physical examination, and a performance
65 score. A complete blood cell count, urinalysis, serum biochemistry profile, ECG, chest roentgenography, whole body bone scan, brain CT scan, and chest (including the liver and adrenal glands) CT scan were also performed. Eligible patients were randomized into either: docetaxel 40 mg/m2 IV on days 1 and 8 of every 3 weeks (D arm), or docetaxel 35 mg/m2 IV on days 1 and 8 plus daily oral UFUR 150 mg/m2 every 3 weeks (DU arm). Dexamethasone 8 mg per oral 12 h before docetaxel treatment, 10 mg IV 30 min before docetaxel treatment, and 8 mg per oral 12 h after docetaxel injection were given as pre- and post-medications. A complete blood cell count was done within 24 h before every chemotherapy session, and on day 15 of cycles 1 and 2. Serum biochemistry studies were performed before every course of chemotherapy, and during the course, if clinically indicated. For dose adjustments, docetaxel was omitted if the absolute neutrophil count was less than 1.0 × 109 L−1 , and the platelet count was less than 75 × 109 L−1 on the day of docetaxel injection. For non-hematological toxicities, docetaxel doses were reduced to 80% if there were grade 3 toxicities, excluding nausea/vomiting and alopecia. No adjustment of the UFUR dose was made during the treatment course. Treatment was given until disease progression or after a maximum of 6 cycles. Drug-related adverse events and toxicities were recorded, according to the Common Toxicity Criteria of the National Cancer Institute (version 2.0). The Lung Cancer Symptom Scale was recorded before treatment, during every cycle thereafter, and when the patient completed or went off the study. Evaluation of response was performed after 3 and 6 cycles of treatment. Additional evaluation of response was also performed if needed. Types of response were assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST) [13]. This study was designed to enroll at least 28 qualified patients in each arm. This calculation assumes that the true response rate for the best treatment is 10% better than that for the others. Assume that the smaller response rate was 10% and the higher one was 20%, with a power of 0.85 and a p value of 0.05, and that each treatment group required 28 qualified patients [14]. A two-stage design with interim analysis of the response rate of both arms was done after enrollment of the initial 40 patients. Further enrollment or an early stopping of the trial was determined after this interim analysis. Survival was measured from administration of the first dose until the date of death or last follow-up. For statistical analysis, the Kaplan—Meier method with a logrank test was used for survival analysis. The Cox-regression test for multivariate survival analysis was utilized. For the statistical analysis of the Lung Cancer Symptom Scale, the Mann—Whitney test was used for a comparison of the two arms of treatment. The SPSS statistical program was used.
3. Results From January 2004 to March 2005, 48 patients were enrolled. Enrollment was stopped after 48 patients, because the interim analysis of the initial 40 patients showed a markedly inferior response rate in the test arm. Twenty-four patients were randomized into each arm.
66 Table 1
K.-t. Chou et al. Patient characteristics (n = 48)
Variable
p*
Patient number (%) Docetaxel (n = 24)
Docetaxel + UFUR (n = 24)
Sex Male Female
17 (70.8) 7 (29.2)
19 (79.2) 5 (20.8)
0.515
Age: mean (range)
67 (43—84)
64 (42—81)
0.398
WHO performance status 1 2
16 (66.7) 8 (33.3)
18 (75) 56 (25)
0.535
Staging IIIbw IV
2 (8.3) 22 (91.7)
5 (20.8) 19 (79.2)
0.229
Present treatment as Second line Third line Fourth line
22 (91.7) 1 (4.2) 1 (4.2)
23 (95.8) 1 (4.2) 0
0.412
Histology Adenocarcinoma Squamous cell NSCLC, type unspecified
17 (70.8) 5 (20.8) 2 (8.3)
17 (70.8) 3 (12.5) 4 (16.7)
0.689
Abbreviations: IIIbw, stage IIIb with malignant pleural effusion. * There was no statistical difference in patient clinical characteristics between the two treatment groups.
The mean age of the patients was 67 years in the D arm and 64 years in the DU arm. The clinical characteristics of these patients are listed in Table 1. There was no statistical difference in the clinical characteristics of the two arms of treatment in terms of sex, age, performance status, staging, histology, and present treatment as second-line or later treatment. All patients were assessable for toxicity profile and 46 patients were evaluable for treatment response. After 3 cycles of treatment, 7 patients achieved a partial response (PR) in the D arm (overall response rate of 29.2%), and 2 patients achieved a PR in the DU arm (overall response rate of 8.3%) (p = 0.067). Stable disease was found in 10 (41.7%) and 12 (50%) patients, respectively. After a median follow-up time of 16 months, the median time to disease progression was 4.5 months in the D arm and 2.1 months in the DU arm (p = 0.4682). Six-month progression-free survival was 28.4% in the D arm and 21.8% in the DU arm. The median survival time was 10.9 months in the D arm and 15.2 months in the DU arm (p = 0.8442). The 1-year survival rate was 49.2% and 56.4%, respectively. When considering all 48 patients together, survival was better in those who had a response to the treatment (n = 9, median 14.6 months vs. n = 39, median 10.9 months, p = 0.2202), stage IV (n = 41, median 13.5 months) rather than IIIbw (n = 7, median 9 months) (p = 0.7655), a better performance status (n = 34, median >16 months in PS 1 vs. n = 14, median 9.4 months in PS 2) (p = 0.0331), those who received tyrosine-kinase inhibitor (TKI) as salvage therapy (n = 29, median 15.2 months vs. n = 19, median 6.8 months) (p = 0.0847), those with adenocarci-
noma rather than other histologic types (n = 34, median 15.2 months vs. n = 14, median 8.6 months) (p = 0.1336), and females rather than males (n = 12, median >16 months vs. n = 36, median 9.8 months) (p = 0.133). Multivariate analysis, including sex, treatment arm, performance status, response to present treatment or not, stage, histology, and use of TKI as salvage therapy or not, showed that only performance status (p = 0.0226) had statistical significance, and use of TKI (p = 0.0689) had borderline significance. All patients enrolled into the study were eligible for toxicity evaluation. The toxicities were few and mild in severity in both arms. Major toxicities were either grade 3 or 4 neutropenia in both arms. There was no difference in myelotoxicity between the two treatment arms (Table 2). Regarding non-hematological toxicities, no patients suffered from grade 3 or 4 toxicities, except 1 patient with grade 3 asthenia, and 1 with grade 3 pneumonitis in the D arm. A total of 38 patients (20 in the D arm and 18 in the DU arm) completed the baseline Lung Cancer Symptom Scale questionnaire, after 2 months of treatment and after going off study. The results of the completed Lung Cancer Symptoms Scale showed that there was no statistically significant difference in the scales between the D and DU arms, either before or 2 months after treatment, or when the patient went off the study, and whether scored by the patients (nine items) or by the observers (six items), including the categories of loss of appetite, fatigue, cough, dyspnea, hemoptysis, pain, disease severity, daily activity, and quality of life (all items had a p value >0.05).
* ANOVA test with p = 0.367, 0.546, 0.34, and 0.179, for leukopenia, neutropenia, anemia, and thrombocytopenia, respectively. One patient in the D arm had uneventful febrile neutropenia.
0 6 (25) 0 0 5 (20.8) 1 (4.2) 0 0 3 (12.5) 2 (8.3) 8 (33.3) 1 (4.2) 2 (8.3) 2 (8.3) 16 (66.7) 1 (4.2) 14 (58.3) 13 (54.2) 0 22 (91.7) 1 (4.2) 5 (20.8) 0 0 4 (16.7) 2 (8.3) 0 0 5 (20.8) 6 (25) 5 (20.8) 0 5 (20.8) 2 (8.3) 19 (79.2) 0) 9 (37.5) 9 (37.5) 0 24 (100)
4 3 2 1
Number of patients (%) Toxicity\grade*
Hematological toxicity per patient (worst of any course) Table 2
67
Leukopenia Neutropenia Anemia Thrombocytopenia
0 0
1
Docetaxel + UFUR (n = 24) Docetaxel (n = 24)
2
3
4
Docetaxel alone or plus UFUR
4. Discussion Phase II randomized trials with an appropriate control arm are necessary and should be conducted before large phase III studies are initiated [15], since several randomized phase III studies have showed negative results by adding EGFR-TKI into doublet chemotherapy [16—18]. Phase III studies should be considered only if a positive signal is noted in phase II studies. The importance of this strategy is demonstrated in the combined usage of bevacizumab with paclitaxel plus carboplatin in the treatment of NSCLC [19]. When considering salvage chemotherapy, less treatmentrelated toxicity and more symptomatic relief are important issues. Our previous study showed that weekly docetaxel chemotherapy produced less myelosuppression, and better compliance and response rates than the conventional every 3 weeks’ schedule [12]. The present study was an attempt to find out whether or not the addition of UFUR can improve response or survival without increasing toxicities. Experimental studies have shown that UFUR and its metabolites inhibit tumor angiogenesis, especially in vascular endothelial growth factor (VEGF)-mediated angiogenesis. This inhibitory effect on tumor-associated angiogenesis was more marked when the drugs were administered continuously at low doses [20,21]. Thus, UFUR is suitable for metronomic chemotherapy via anti-angiogenesis mechanism [22]. In particular, the low toxicity profiles of UFUR may warrant the combination of this agent with other chemotherapeutic agents in the treatment of those who failed previous chemotherapy, and hope to undergo another salvage treatment. This hypothesis is supported by our previous study with gemcitabine plus UFUR against previously chemotherapy-treated NSCLC, showing a response rate of 15.6%, a median survival of 13.2 months, and toxicity that was minimal and mild in degree [11]. EGFR-TKI, such as gefitinib and erlotinib, is a new class of anti-cancer agents that has been found effective in the salvage treatment of NSCLC patients who have failed previous chemotherapy [5,6]. It was found that female gender, non-smoker, adenocarcinoma (especially those with bronchioloalveolar features), EGFR mutation, and East Asian ethnicity were known factors predicting a better response to EGFR-TKI treatment [5,23]. Although we did not randomize our patients to receive TKI after they had failed the present treatment, it is true that those who received EGFR-TKI in the present study had better survival than those who did not, and with borderline statistical significance. The median survival and 1-year survival rate was rather good in both arms of the present study. However, the response of the DU arm was relatively lower than that of the D arm. The causes of the low response rate in the DU arm may be inadequate docetaxel and/or UFUR dose-intensity. Other possibilities include the lack of an additive or synergistic effect, or even the counter-effect of both agents. The longer survival in DU group compared to D group was noted in this study. Since this trial is a randomized phase II trial, the number of patients is too small to achieve a statistical significant survival difference. It may have statistical significance between two groups if we gather the patients more. This kind of adding UFUR into docetaxel treatment is similar to so-called ‘‘tumor dormancy state’’ management [24].
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5. Conclusion The addition of daily UFUR treatment into a weekly docetaxel schedule, as in the present study, showed no obvious effect, compared to weekly docetaxel treatment alone. A higher dose of docetaxel and/or UFUR is recommended if further phase II or III studies are planned.
Conflict of interest
[11]
[12]
[13]
The authors indicate no potential conflict of interest.
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