Japanese Journal of Clinical Oncology Advance Access originally published online on October 16, 2006
Japanese Journal of Clinical Oncology 2006 36(12):761-767; doi:10.1093/jjco/hyl106
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© 2006 Foundation for Promotion of Cancer Research
A Phase II Trial of Docetaxel Plus Capecitabine in Patients with Previously Treated Non-Small Cell Lung Cancer
Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea
For reprints and all correspondence: Jin Soo Lee, Center for Lung Cancer, National Cancer Center Hospital, 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do, 411-764, Republic of Korea. E-mail: jslee{at}ncc.re.kr
Received April 17, 2006; accepted July 27, 2006
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Abstract |
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BACKGROUND: A combination of docetaxel (T) and capecitabine (X) showed synergistic effects in preclinical studies and phase III randomized trials of metastatic breast cancer. We conducted this phase II study to examine its efficacy in previously treated non-small cell lung cancer (NSCLC) patients.
METHODS: Patient eligibility required advanced NSCLC with measurable lesion(s), at least one prior regimen failure and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Treatment consisted of T 36 mg/m2 i.v. on days 1 and 8 plus X 1000 mg/m2 p.o. b.i.d. on days 1–14 of a 21-day cycle (level I) or T 30 mg/m2 i.v. on days 1 and 8 plus X 625 mg/m2 p.o. b.i.d. on days 1–14 of a 21-day cycle (level II).
RESULTS: A total of 35 patients (M/F=24/11) were enrolled; 29 had received one prior regimen and 19 had received platinum-based regimens. Significant non-hematologic toxicities were observed after the treatment given at level I, including one treatment-related death. Subsequently 29 patients were treated at level II. The treatment at level II was well tolerated with grade 3 or 4 neutropenia only in 10%, grade 3 asthenia in 21% and stomatitis in 14% of patients. Four (15%) of 27 evaluable patients had partial response (PR) at level II and eight (30%) had stable disease (SD).
CONCLUSIONS: The TX regimen showed modest antitumor effects in patients with previously treated NSCLC. For further studies, we recommend T 30 mg/m2 i.v. on days 1 and 8 plus X 625 mg/m2 p.o. b.i.d. on days 1–14 of a 21-day cycle.
Key Words: docetaxel • capecitabine • non-small cell lung cancer • second-line treatment
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Two phase III randomized docetaxel trials (TAX 317 and TAX 320) demonstrated therapeutic benefits of the second-line therapy over the best supportive care in non-small cell lung cancer (NSCLC) patients (1, 2). However, the response rates were less than 10%, while 50–60% of the patients had grade 3/4 neutropenia and grade 3/4 asthenia was reported in 12–18% of the patients (1, 2). More active but less toxic chemotherapy regimens are urgently needed for the second-line treatment and also for the front-line treatment of NSCLC.
Recently, synergistic antitumor activity of docetaxel (T) plus capecitabine (X) combination was reported in preclinical and clinical studies (3–7). In a phase III randomized trial of TX combination in advanced breast cancer, O'Shaughnessy et al. reported a therapeutic advantage of the TX combination over docetaxel monotherapy (5). The TX combination was superior to docetaxel monotherapy in time to progression (6.1 versus 4.2 months), overall survival (14.5 versus 11.5 months), and tumor response rate (42% versus 30%). The putative mechanism for the observed synergism of the TX combination was T-induced up-regulation of thymidine phosphorylase expression. Expression of thymidine phosphorylase was also reported in 30% or more NSCLC samples examined (8).
Since there is no report on the activity of single-agent capecitabine in previously treated NSCLC patients, however, it is quite speculative to assess whether or not, and how much, if any, capecitabine would contribute to the outcome of docetaxel therapy in this clinical trial setting. Thus, we conducted this phase II study of TX combination in patients with previously treated NSCLC. The primary objective of this study was to evaluate its efficacy and toxicity in previously treated NSCLC patients.
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PATIENTS AND METHODS |
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Eligibility
Eligible patients were required to have locally advanced or metastatic NSCLC that had progressed during or after at least one or more chemotherapy regimens. Before the study entry, a minimum of 21 days must have elapsed after any prior chemotherapy. At least one bi-dimensionally measurable lesion, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2 was required, as was adequate bone marrow (leukocyte count
4.0x109 cells/l and platelet count of 150x109 cells/l), hepatic (total bilirubin level 
1.5 mg/dl), and renal function (serum creatinine level 1.5 mg/dl). No restriction was placed on the number of prior chemotherapy regimens or the amount of prior chemotherapy. Patients who had received prior radiation therapy were eligible if at least 3 weeks had elapsed from completion of radiation and there were other evaluable lesion(s). Patients with brain metastases were eligible if they were neurologically stable. Exclusion criteria included prior history of malignancies except basal cell carcinoma of the skin or carcinoma in situ of the cervix, active infection or other serious underlying medical conditions. All patients signed written informed consent approved by the institutional review board (IRB) of the National Cancer Center Korea.
Baseline and Treatment Evaluation
All patients underwent a medical history and physical examination. Assessment including complete blood cell count, renal and liver function tests, urinalysis, performance status evaluation, height and weight determination (including weight loss) were conducted within 2 weeks before the study entry. Chest X-rays, chest and abdominal computed tomography (CT) scans, brain MRI or CT, and radionuclide bone scan were conducted within 4 weeks before enrollment. Complete blood cell count and chemistry were repeated on days 8 and 15. Before each course, routine examination and toxicity evaluation were repeated. Toxicity was graded according to National Cancer Institute common toxicity criteria (NCI-CTC). Hand–foot syndrome (HFS) was graded 1 to 3, as defined in previous capecitabine clinical studies (9).
Treatment
Chemotherapy was given on the outpatient basis. Docetaxel 36 mg/m2 was administered as a 1-h intravenous infusion on days 1 and 8 of each 3-week cycle along with capecitabine 1000 mg/m2 p.o. b.i.d. on days 1–14 (dose level I). Docetaxel was prepared according to the manufacturer's directions in 200 ml 5% dextrose in water. Oral dexamethasone, 8 mg, was administered after 12 h and immediately before docetaxel and 12 h after docetaxel and ondansetron 8 mg IV for emesis. At dose level I, grade 3 asthenia and HFS were noted in two of six patients respectively, and one patient had treatment-related death. Thereafter, the docetaxel dose level was reduced to 30 mg/m2 on days 1 and 8, and capecitabine to 625 mg/m2 p.o. b.i.d. on days 1–14 of a 21-day cycle (dose level II). This reduced dose level (dose level II) was re-approved by the IRB. A maximum of six cycles was given or until disease progression as toxicity permitted.
Dose Modification
The next course of treatment was to begin only when the leukocyte count recovered above 3000/mm3 and the platelet count above 100 000/mm3 and any treatment-related toxicity resolved to grade 1 or lower; otherwise, treatment was withheld for up to 1 week. If the toxicity had not resolved to grade 0 to 1 at the end of this period, treatment was delayed for one additional week.
Docetaxel treatment on day 8 was withheld for grade 2 or higher hyperbilirubinemia or any other grade 3 or higher toxicity during the scheduled day of docetaxel administration and the patient was re-evaluated weekly until symptoms regressed to grade 2 or lower. Missed doses of docetaxel were not made up. The next cycle of treatment was restarted at the same dose for grade 3 toxicity and was reduced by 25% for grade 4 toxicity during the preceding cycle.
Capecitabine was withheld within a cycle for grade 2 non-hematologic (except isolated hyperbilirubinemia or alopecia) or grade 3 or higher hematologic toxicity. Capecitabine was resumed at the original dose level for grade 2 non-hematologic or grade 3 hematologic toxicity, or with 25% dose reduction for grade 3 or higher non-hematologic or grade 4 hematologic toxicity. For grade 2 to 3 HFS, capecitabine treatment was withheld until resolution to grade 1 or lower and then restarted at the same dose (for grade 2 HFS) or at 75% of the preceding dose level (for grade 3 HFS). Capecitabine treatment was not interrupted for isolated hyperbilirubinemia.
Response Evaluation
Responses were evaluated every three cycles using the same evaluation method. Objective tumor responses were evaluated according to the World Health Organization criteria (10). Objective responses (complete response or partial response) were independently confirmed by an external referee. Post treatment evaluation was performed every 2–3 months until death or progressive disease (PD). Treatment after PD was left to the discretion of the treating physician.
Statistics
For this trial, the sample size was calculated according to Simon's two-stage minimax design (11). According to the two-stage design, this trial was planned to stop if no response was observed in the first 18 patients. Otherwise, 32 patients were planned to be enrolled. With a target objective response rate of 20% versus response rate of no interest of 5% and a power of 0.90 at a one-side significance level of 0.05, accrual of 32 evaluable patients was projected. The treatment is considered effective if four or more responses are observed in 32 evaluable patients.
All patients who received at least one course of therapy were considered assessable for toxicity and all eligible patients who completed at least one cycle of therapy were included for response evaluation.
Survival was estimated using the Kaplan–Meier method (12). CI (confidence interval) was constructed around the Kaplan–Meier estimates using Greenwood's variance formula. 95% CI for response rate were calculated using methods for exact binomial confidence intervals (SPSS software, version 9.0; SPSS Inc, Chicago, IL). Dose intensity was calculated by using the method of Hryniuk and Bush (13).
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RESULTS |
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Patients' Characteristics
Thirty-five patients were enrolled, whose characteristics are listed in Table 1. The median age was 60 years (range, 28–79 years). Males and adenocarcinomas were predominant. Twenty-nine (83%) patients had received one prior regimen (14-cisplatin-containing regimen, 14-gemcitabine plus vinorelbine, 1-etoposide plus vincristine plus cyclophosphamide) while six (17%) had received two or more regimens (5-cisplatin-containing regimen, 1-gemcitabine plus vinorelbine and iressa). Best responses to prior treatment regimens were assessable in 34 patients and 14 (40%) patients had achieved objective responses to prior treatment. Most of the patients had progressive disease during or shortly after prior therapy; 28 (80%) patients had treatment-free interval of less than 3 months since the last administration of prior chemotherapy (Table 1).
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Efficacy
All patients were eligible for toxicity evaluation, but three patients were not evaluable for response evaluation, two as a result of the patient's refusal after the first dose of treatment and one because of death with brain infarction on day 28 of the first cycle. Overall, out of 32 evaluable patients, there were no complete responses (CR), four (12%) partial responses (PR), 11 (35%) stable disease (SD), and 17 (53%) progressive disease (PD) (Table 2). All four partial responders were treated at dose level II. The objective response rate for dose level II was 15.4% (95% CI, 1.5% to 29.3%). The durations of response were 123 days, 36 days, 61 days, 70 days and the median time to progression for all evaluable patients was 2.1 months (95% CI, 0.7–17.0). After a median follow-up of 19.6 months, the median survival was 8.7 months with a 1-year survival rate of 34.3% (Fig. 1).
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Treatment Cycle Administered
A total of 114 cycles were administered, 18 cycles at dose level I with a median of three (range, 1–6 cycles) and 96 cycles at dose level II with a median of three (range, 1–6 cycles).
At dose level I, treatment was delayed for a median of 7 days in four (22%) of 18 cycles and dose reduction was necessary in six (33%) cycles. The main causes for the delay and dose reduction were HFS and neutropenia. The reasons for discontinuation of treatment were disease progression in three, and one each was treatment-related adverse effect and patient's refusal owing to toxicity. The mean dose intensity (DI) was 20.8 mg/m2/week (86.6% of planned dose) for docetaxel and 8195 mg/m2/week (87.8% of planned dose) for capecitabine at the dose level I.
Dose level II was not as toxic as dose level I. At dose level II, treatment was delayed in three patients for a median of 10 days in only nine (9%) of 96 cycles and dose reduction was necessary for only seven patients in 14 (13%) cycles. The causes for the delay and dose reduction were asthenia, stomatitis and hepatic dysfunction. The most common reason for discontinuation of treatment was disease progression. The mean DI was 18.6 mg/m2/wk (93.2% of planned dose) for docetaxel and 5139 mg/m2/wk (88.1% of planned dose) for capecitabine.
Hematologic Toxicity
At dose level I, grade 3 or 4 neutropenia occurred in two (34%) of six patients and grade 2 anemia in three (50%). There was one treatment-related death as a result of sepsis associated with subungal abscess. At dose level II, grade 3 or 4 neutropenia occurred only in three (10%) of 29 patients with one febrile neutropenia, grade 2 or 3 anemia in 17 (58%) and grade 3 thrombocytopenia in two (7%) patients (Table 3).
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Non-hematologic Toxicity
At dose level I, grade 3 asthenia occurred in two patients, grade 3 HFS in two patients. At dose level II, the most common grade 3 non-hematologic toxicity was asthenia (21%) and stomatitis (14%) (Table 3). At this dose level, no grade 3 HFS occurred and grade 2 HFS was noted in only one (3%) patient and grade 2 nail change occurred in eight (27%) patients. Fluid retention occurred in nine (31%) patients and only one patient needed diuretics. Pneumonitis, presumed to be drug related, occurred in two patients and one patient had received oxygen and steroid therapy.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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While docetaxel monotherapy is firmly established as a second-line therapy for advanced NSCLC (1, 2), there are continuing efforts to discover more effective second-line regimen(s), including the docetaxel-containing combination regimens (14–16). Two phase II studies of docetaxel plus gemcitabine combination, for example, reported 28–36% response rates with 7–11 months of median survival. Although its efficacy was not yet confirmed by phase III trials, promising results seen in those phase II studies lead us to further explore other possibilities, such as TX combination as in our study.
Capecitabine is an oral 5-fluorouracil (5-FU) prodrug, which is converted to 5-FU by the angiogenic enzyme thymidine phosphorylase as the final step in a three-step enzymatic process (17). At preclinical and clinical levels, docetaxel has been shown to enhance the antitumor activity of capecitabine via up-regulation of thymidine phosphorylase expression (3–7), which was reported in NSCLC (8) and was higher in malignant tissues than normal tissue (18, 19).
In a phase III randomized trial of TX combination in advanced breast cancer, the TX combination showed therapeutic advantage over docetaxel monotherapy in terms of overall survival and response rate (5) (Table 4). In a separate study of TX combination as a first-line treatment of chemo-naïve NSCLC patients (20), we administered 36 mg/m2 of docetaxel on days 1 and 8 with concurrent administration of capecitabine 1000 mg/m2 p.o. b.i.d. on days 1–14 of a 21-day cycle to exploit the time dependency of the thymidine phosphorylase up-regulation, which was well demonstrated in the preclinical and phase I studies of TX combination (3, 7).
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In the current study, which re-confirmed the time-old notion that previously treated patients do not tolerate the same chemotherapy DI as the chemo-naïve patients, we found that the toxicity profile became much more manageable at dose level II. The non-hematologic toxicities, such as stomatitis, diarrhea, nausea/vomiting, and HFS and nail change were noted, but the incidences of grade 3 or 4 were less than 10% except asthenia and stomatitis. This toxicity profile was very favorably comparable with other studies, even with the phase III study of TX combination reported by O'Shaughnessy et al. (5) (Table 4).
Unlike the once-every-3 weeks schedule of docetaxel administration, which was associated with dose-limiting myelosuppression and asthenia (6), the most common toxicity of weekly docetaxel was fatigue, asthenia and HFS (7) (Table 4). In the present study, we found that docetaxel 30 mg/m2 can be given safely without undue toxicities on days 1 and 8 together with capecitabine 625 mg/m2 orally twice a day on days 1–14 of a 21-day cycle. Weekly docetaxel administration on days 1 and 8 of a 21-day cycle was well tolerated by most patients with reasonable toxicity profiles (21, 22). In the phase I study of weekly TX regimen reported by Nadella et al. (7), for example, the recommended dose schedule was docetaxel 36 mg/m2 on days 1, 8 and 15 days plus capecitabine 625 mg/m2 p.o. b.i.d. for 14 days of a 28-day cycle (Table 4). In a recent phase I study of weekly TX regimen, Ramanathan et al. recommended docetaxel 30 mg/m2 given i.v. on days 1 and 8 plus capecitabine 825 mg/m2 p.o. b.i.d. for 14 days of a 21-day cycle (23). In this phase I study, the major reasons for dose modification were HFS and mucositis with capecitabine and fatigue and neutropenia with docetaxel. Based on the results of our phase II study and other phase I and II studies, our recommended TX dose schedule is docetaxel 30 mg/m2 i.v. on days 1 and 8 plus capecitabine 625 mg/m2 p.o. b.i.d. for 14 days, to be repeated every 21 days as toxicity permits.
In the current study, TX regimen at dose level II showed the modest antitumor effect, i.e. the response rate was 15.4%, but the overall survival was pretty much prolonged, as shown by a median survival of 8.7 months. After TX regimen, 19 patients (54%) received further chemotherapy and four or more cycles of chemotherapy were administered in 10 patients (29%) as a third- or fourth-line therapy. Those treatments could have contributed to some extent to the prolongation of survival time. Nevertheless, given the promising survival outcome of patients treated with TX combination as the first-line therapy, further studies are warranted to re-evaluate the efficacy of this regimen using a new dose schedule that was safe and had manageable toxicity profiles. In conclusion, TX combination chemotherapy showed modest antitumor effects in patients with previously treated NSCLC. For further studies, we recommend T 30 mg/m2 i.v. on days 1 and 8 plus X 625 mg/m2 p.o. b.i.d. on days 1–14 of a 21-day cycle.
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Acknowledgments |
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This work was supported in part by the grant from National Cancer Center Korea (NCC 0210240).
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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