© The Author (2008). Published by Oxford University Press. All rights reserved
Docetaxel Monotherapy as a Second-line Treatment after Failure of Fluoropyrimidine and Platinum in Advanced Gastric Cancer: Experience of 154 Patients with Prognostic Factor Analysis
Division of Oncology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
For reprints and all correspondence: Yoon-Koo Kang, Division of Oncology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-2dong, Songpa-gu, Seoul 138-736, South Korea. E-mail: ykkang{at}amc.seoul.kr
Received June 7, 2007; accepted August 4, 2007
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Abstract |
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Objective: To investigate the efficacy and safety of docetaxel monotherapy as salvage chemotherapy for advanced gastric cancer (AGC) in clinical practice and to determine the prognostic factors in these patients.
Methods: We retrospectively reviewed the medical records of patients with AGC for whom fluoropyrimidine and platinum had previously failed and who had received docetaxel salvage monotherapy between December 2000 and March 2006. Docetaxel was administered at a dose of 75 mg/m2 intravenously every 3 weeks with dexamethasone prophylaxis.
Results: A total of 154 patients received 583 cycles of docetaxel with a median of three cycles per patient (range 1–10). The median age was 54 years (range 27–75 years). The objective response rate of 86 patients with measurable lesions was 14%, with 1 complete response and 11 partial responses, with a median response duration of 5.6 months. An additional 25 patients achieved stable disease. The median time to progression (TTP) for all patients was 2.6 months [95% confidence interval (CI), 2.2–2.9] and the median overall survival (OS) from the start of docetaxel chemotherapy was 7.2 months (95% CI, 5.9–8.5). The chemotherapy was generally well tolerated. Multivariate analysis showed that the Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 versus 2) was an independent prognostic factor for both TTP and OS. Disease status indicative of a relatively small tumor burden (resected metastatic or recurrent tumor) was a predictor for better TTP and good differentiation of the tumor was a predictor for better OS.
Conclusion: Docetaxel 75 mg/m2 is relatively active and tolerable as a second-line salvage treatment after failure of fluoropyrimidine and platinum in general clinical practice for AGC.
Key Words: docetaxel • advanced gastric cancer • salvage chemotherapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingReferences |
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According to a report by the Korean Cancer Registry, gastric cancer is not only the most common cancer (24%) but is also the second-leading cause of cancer deaths in Korea (1). More than half of all patients diagnosed with gastric cancer will have unresectable disease. Even patients with an operable tumor have high rates of both local and distant recurrence. In unresectable or recurrent cases where no curative treatment is possible, systemic chemotherapy has been used in an attempt to control cancer-related symptoms and improve survival. Previous randomized studies have shown that cytotoxic chemotherapy can prolong overall survival (OS) and improve the quality of life of these patients (2–4).
Various chemotherapeutic agents, such as 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin-C, doxorubicin, cisplatin, etoposide, and epirubicin, have been shown to be effective in advanced gastric cancer (AGC). Among them, 5-FU and cisplatin have been widely used as combination therapies; for example, FP (5-FU and cisplatin) and ECF (epirubicin, cisplatin, and 5-FU). ECF is associated with significant benefits in terms of response rate (RR) and survival in patients with AGC compared with FAMTX (5-FU, adriamycin, and high-dose MTX) chemotherapy in randomized Phase III studies (5,6). In addition, FP is associated with improved RR and time to progression (TTP) compared with FAM (5-FU, doxorubicin, and mitomycin) or 5-FU monotherapy in a randomized Phase III trial. Therefore, fluoropyrimidine and platinum-based combination chemotherapy is now widely accepted as a standard regimen for first-line therapy for AGC. Recently, oral 5-FU prodrugs, such as capecitabine (7–9) and S-1 (TS-1; tegafur, gimeracil, oteracil potassium) (10–12), have been actively investigated in clinical trials and are increasingly used in clinical practice, where they have replaced intravenous infusion of 5-FU, which required hospital admission or placement of intravenous infusion pumps. However, unfortunately, about half of all patients do not respond to current first-line chemotherapy; furthermore, most patients who achieve response to the first-line chemotherapy eventually experience disease progression. Therefore, there is a need for effective salvage treatment after failure of first-line chemotherapy, but there are limited data on the safety and efficacy of second-line treatment in AGC, and few reports on the outcomes and prognostic factors in this setting.
Docetaxel is a semi-synthetic taxoid with a unique mechanism of action different from that of fluoropyrimidine and platinum. It has been reported to have cytotoxic activity against a broad spectrum of human solid tumors, and there is little cross resistance and toxicity overlap between docetaxel and 5-FU/cisplatin (13,14). So, docetaxel is a reasonable chemotherapeutic agent for salvage treatment of patients for whom 5-FU and platinum therapy has failed. Docetaxel has shown good single agent activity in previously treated patients as well as in chemotherapy-naïve patients with AGC (15–17). Recently, we also reported a reasonable activity (16% RR and 2.5 months of TTP) of docetaxel as a salvage chemotherapy in a prospective Phase II trial (18). However, it is unknown whether docetaxel is active and tolerable in the clinical-practice setting as well as in the clinical-trial setting. Therefore, we conducted a retrospective study to evaluate the efficacy and tolerability of docetaxel salvage chemotherapy in clinical practice and to analyse prognostic factors in these patients.
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PATIENTS AND METHODS |
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PATIENTS
Between December 2000 and March 2006, 186 patients with AGC were treated with docetaxel alone as second-line chemotherapy at the Asan Medical Center, South Korea. Subjects were included in the present study if they fulfilled the following eligibility criteria: (i) histologically confirmed gastric adenocarcinoma; (ii) prior exposure and failure to a combination of fluoropyrimidine (5-FU, capecitabine, doxifluridine, S-1, or UFT) and platinum (cisplatin, heptaplatin, or oxaliplatin) chemotherapy; (iii) aged more than 18 years; (iv) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or better; (v) no evidence of central nervous system metastases; (vi) adequate bone marrow and renal/hepatic organ functions.
Of the 186 patients, 32 were excluded from this study because they had received fluoropyrimidine alone or other regimens as first-line chemotherapy. To estimate the patients' tumor burden, they were classified into three groups according to their disease status at the time of first-line chemotherapy: those with initially metastatic disease (initially presenting with metastatic disease), those with recurrent disease (tumor recurrence after previous curative gastrectomy), and those with resected metastatic disease (those with residual disease after gastrectomy).
DRUG ADMINISTRATION AND TOXICITY ASSESSMENT
Docetaxel 75 mg/m2 was given as a 1-h intravenous infusion in 200 ml of water with 5% dextrose every 3 weeks. Dexamethasone 8 mg p.o. bid was given for the prophylaxis of potential hypersensitivity for 3 days prior to starting docetaxel administration. Treatment was continued until disease progression or unacceptable toxicity occurred or the patient chose to discontinue treatment. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3. The chemotherapy cycle was delayed when patients had neutropenia (<1500/mm3) or thrombocytopenia (<100 000/mm3) on the day of infusion. The dose of docetaxel was reduced by 25% in patients who experienced any of the following serious toxicities in the previous cycles: Grade 4 neutropenia lasting for more than 7 days, febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding, and any Grade 3 non-hematologic toxicity other than nausea, vomiting, anorexia, and alopecia.
FOLLOW-UP EXAMINATION AND RESPONSE EVALUATION
Physical examination, chest X-rays, complete blood counts (CBCs), and biochemical tests were performed before each chemotherapy cycle. Computed tomography (CT) scans were performed every 2–3 cycles until the tumor progressed. Tumor response was classified according to the response evaluation criteria defined by the Response Evaluation Criteria in Solid Tumors (RECIST) (19). Confirmation of the response was not required for this study because repeating CT scans 4 weeks afterward is not practical in clinical practice.
STATISTICS
All patients who received at least cycle of docetaxel treatment were included in the intention-to-treat analysis of efficacy. The RR was calculated only in patients with measurable disease. The TTP was determined by the interval between initiation of therapy to the time of first disease progression or death, and OS was measured from the first day of docetaxel treatment until death or the last day of the follow-up period. TTP and OS were estimated using the Kaplan–Meier method. SPSS for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analyses.
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RESULTS |
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PATIENT CHARACTERISTICS
The pretreatment characteristics of the patients are listed in Table 1. The median age was 54 years. The most common front-line chemotherapy regimen was capecitabine/cisplatin combination chemotherapy (50%). The main metastatic sites were the peritoneum (48.7% of cases), abdominal lymph nodes (45.5%), and the liver (37.7%); other sites of disease included lung, cervical lymph node, and bone. After failure of docetaxel salvage chemotherapy, 47 patients (30.5%) received a third-line treatment: irinotecan and 5-FU/leucovorin FOLFIRI, 59.5%), oxaliplatin and 5-FU/leucovorin (FOLFOX, 12.8%), irinotecan monotherapy (12.8%), and others (14.9%).
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DRUG DeLIVERY
A total of 154 patients received 583 cycles of docetaxel with a median of three cycles per patient (range 1–10). The actual median dose intensity per patient was 24.3 mg/m2/week with a relative dose intensity of 97.4%. The dose reduction from the initial dose occurred in 11%. The major reason for dose reduction was neutropenia.
EFFICACY
Of the 86 measurable patients, there was one complete response and 11 partial responses, with a RR of 14%. Twenty-five patients showed stable disease, 44 patients progressed, and the tumor growth control rate was 43%. Two patients chose to discontinue treatment before evaluation, and three patients were lost to follow-up. The median duration of response was 5.6 months (range 3.5–16.2 months). At a median follow-up duration of 13.3 months for the surviving patients (range 8.5–26.9 months), the median TTP and OS for all patients in this study were 2.6 months [95% confidence interval (CI), 2.2–2.9] and 7.2 months (95% CI, 5.9–8.5), respectively (Fig. 1).
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TOXICITY
A total of 507 cycles of chemotherapy were administered, with a median of 3 cycles (range 1–10 cycles) per patient. The frequencies of treatment-related hematologic and non-hematologic adverse events are shown in Table 2. Events of hematologic Grade 3–4 toxicity included anemia (10.5%), neutropenia (12.5%), and febrile neutropenia (9.9%). Asthenia (13.6%) was the most common non-hematologic Grade 3–4 adverse event.
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PROGNOSTIC FACTORS
The results of a univariate analysis of various patient and tumor variables are shown in Table 3. PS of the patient significantly affected TTP and OS. Patients with ECOG PS 0 or 1 had improved TTP and OS compared with those patients with ECOG PS 2 (P = 0.033 and P = 0.002, respectively). TTP for the resected metastatic and recurrent groups was longer than those of the initially metastatic group (P = 0.016).
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Multivariate analyses showed that PS of the patients was the only independent prognostic factor affecting both TTP [hazard ratio (HR), 1.753; 95% CI, 1.081–2.844; P = 0.023] and OS (HR, 1.974; 95% CI, 1.217–3.200; P = 0.006) (Table 4). In addition, disease status and histologic differentiation were significant independent prognostic factors for TTP (HR, 1.423; 95% CI, 1.006–2.013; P = 0.046) and OS (HR, 1.530; 95% CI, 1.058–2.214; P = 0.024), respectively.
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DISCUSSION |
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Several studies have shown that chemotherapy is associated with a significant survival advantage and an improved quality of life compared with the best supportive care (2–4). However, most patients receiving first-line chemotherapy eventually develop progressive disease, whereas there is no established second-line regimen. In this study, we found that docetaxel monotherapy was an active and safe salvage chemotherapy when used in routine clinical practice for patients with AGC for whom fluoropyrimidine and platinum-based first-line chemotherapy had previously failed.
In the current study, the efficacy of docetaxel given at 3-week intervals, at a dose of 75 mg/m2, was similar to the published data from most second-line chemotherapy trials for gastric cancer patients refractory to fluoropyrimidine and/or platinum. Giuliani et al. (20) reported a 17% RR with a median OS of 6 months in 30 patients who were refractory to ECF or PELF (cisplatin, epirubicin, leucovorin, and 5-FU). Taguchi et al. (21) and Vanhoefer et al. (22), respectively, reported a 24% RR with docetaxel 60 mg/m2 in 59 patients and a 20% RR with docetaxel 100 mg/m2 in 25 patients who had already been exposed to first-line 5-FU and cisplatin. Our results are also similar to those reported for other monotherapies involving paclitaxel 225 mg/m2 (23) or mitomycin C 20 mg/m2 (24). In a study of 1080 patients enrolled in Phase III trials of 5-FU-based first-line therapy, Chau et al. (25) reported that approximately 20% of patients received second-line chemotherapy, with a RR of 13.3% (95% CI, 6.8–22.5%), and a median survival of 5.6 months. The RR (14%) and median OS (7.2 months) in our study seem to be at least equivalent to those reported in previous studies.
Docetaxel has been shown to lack cross-resistance with other drugs commonly used in AGC and to have an additive effect when combined with fluoropyrimidine and platinum (26). Our results showed that the toxicity was manageable in clinical practice, with asthenia being the most common non-hematologic toxicity of Grade 2 or higher, and there was no discontinuation of treatment due to non-hematologic toxicities. The most-frequent and often dose-limiting toxicity was neutropenia, which is easily manageable (26). The incidence of Grade 3 or 4 neutropenia was 12.5%, which is less than that reported by Giuliani (20) and Vanhoefer (22). The toxicity profile seems to be more favorable than those reported in studies using irinotecan-based chemotherapy (27). However, we should be cautious when comparing the hematologic toxicities between studies because the hematologic monitoring strategies could be different. In the current study, CBC tests were repeated just before each chemotherapy cycle, whereas they were repeated every week in other studies.
The role of second-line chemotherapy in AGC has not been demonstrated in randomized Phase III trials. Furthermore, it is unlikely that this type of randomized Phase III trial can be performed in AGC because second-line chemotherapy is commonly used. In non-small-cell lung cancer, the role of docetaxel salvage chemotherapy in survival prolongation has been established through randomized Phase III trials (28), even though the salvage chemotherapy showed limited activity in terms of RR and progression-free survival. So, it is possible that docetaxel salvage chemotherapy could be beneficial for AGC where it shows at least similar or better activity than in non-small-cell lung cancer.
As in other prognostic-factor studies, PS was found to be an independent prognostic factor for both TTP (HR, 1.753; 95% CI, 1.081–2.844; P = 0.023) and OS (HR, 1.974; 95% CI, 1.217–3.200; P = 0.006) in this study. This means that a patient with a good PS is a particularly good candidate for salvage docetaxel chemotherapy. In our previous study with capecitabine and cisplatin first-line chemotherapy, disease status was also an independent prognostic factor for both TTP and OS (29) because the disease status reflects the tumor burden at the start of chemotherapy. However, in this study, the disease status at the start of first-line chemotherapy was a prognostic factor for TTP (HR, 1.423; 95% CI, 1.006–2.013; P = 0.046) but not for OS. This may be because the tumor burden could have changed during the first-line chemotherapy; hence, the disease status at the start of first-line chemotherapy may not reflect the tumor burden at the start of salvage chemotherapy. On the other hand, the TTP of first-line chemotherapy may reflect not only the sensitivity of the tumor to first-line fluoropyrimidine and platinum combination chemotherapy but also the general chemosensitivity or the biologic aggressiveness of the tumor. Therefore, the TTP and/or OS of second-line therapy may be dependent on the TTP of first-line chemotherapy.
In conclusion, we have shown that docetaxel monotherapy at a dose of 75 mg/m2 is safe and effective in clinical practice as a second-line treatment of AGC after failure of fluoropyrimidine and platinum-based first-line chemotherapy.
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Funding |
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This study was supported in part by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A060775).
Conflict of interest statement
None declared.
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References |
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