The Oncologist, Vol. 9, Suppl 2, 9–15,
June 2, 2004
© 2004 AlphaMed Press
The Treatment of Advanced Gastric Cancer: New Findings on the Activity of the Taxanes
Eric Van Cutsem
University Hospital Gasthuisberg, Leuven, Belgium
Correspondence:
Eric Van Cutsem, M.D., Ph.D., University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Telephone: 32-16-344-225; Fax: 32-16-344-419; e-mail: eric.vancutsem{at}uz.kuleuven.ac.be
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Explain the role and evolution of chemotherapy for advanced gastric cancer.
- Discuss results of phase II trials evaluating taxanes in advanced gastric cancer.
- Describe the results and clinical implications of a phase III trial of docetaxel, cisplatin, and fluorouracil in advanced gastric cancer.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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Globally, gastric cancer is one of the most common types of cancer and one of the most frequent causes of cancer-related death. Despite many advances in the diagnosis and treatment of this disease, the prognosis for gastric cancer remains poor, especially in more advanced stages. In metastatic disease, benefits in survival and quality of life have been demonstrated in patients with unresectable or metastatic gastric cancer receiving chemotherapy plus best supportive care versus best supportive care alone. The taxanes, which are among the most promising cytotoxic agents in clinical use, have shown encouraging activity in early-phase studies as single agents and in combination regimens in the treatment of advanced gastric cancer. Recently, interim results of a randomized phase III trial comparing the triplet of docetaxel, cisplatin, and 5-fluorouracil with a standard reference regimen of cisplatin and 5-fluorouracil were reported. Patients treated with the docetaxel-containing regimen had a statistically superior response rate and time to disease progression as well as a clinically significant prolongation of survival. This study underscores the importance of developing new therapeutic options for patients with advanced gastric cancer.
Key Words. Taxanes • Docetaxel • Paclitaxel • Gastric cancer • Advanced gastric cancer
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INTRODUCTION
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Worldwide, gastric cancer is estimated to be the fourth most common type of cancer and the second most frequent cause of cancer-related mortality [1]. The incidence of gastric cancer is particularly high in Asia, South America, and Eastern Europe. In Japan, gastric cancer is the most common cause of cancer death [2]. Despite an overall decline in the incidence of gastric cancer over the past few decades, the site of origin within the stomach has changed, with a rising incidence of cancer of the cardia and gastroesophageal junction [3].
The past decade has brought forth many advances in the field of gastric cancer. These include a better understanding of tumor biology and the role of infectious and environmental etiologies; improvements in surgical techniques, radiation, and chemotherapy; and more accurate staging approaches. In spite of these advances, prognosis still remains poor, with the majority of patients presenting with advanced disease [4].
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THE ROLE OF CHEMOTHERAPY IN ADVANCED GASTRIC CANCER
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A number of randomized clinical trials have established the role of chemotherapy in the treatment of patients with advanced gastric cancer. In the four trials that compared chemotherapy plus best supportive care with best supportive care alone, patients who received chemotherapy had longer survival times [5–8]. Median survival was approximately 7.5–12 months in the chemotherapy-treated groups versus 3–5 months for patients receiving best supportive care alone. The improvement in median survival was significant in three of the four studies. In two studies measuring quality of life, this too was superior in the chemotherapy-treated groups over best supportive care alone [7–8].
For many years, 5-fluorouracil (5-FU)- and cisplatin-based regimens have been considered the reference treatment. Commonly used regimens have included epirubicin, cisplatin, and continuous-infusion 5-FU (ECF); 5 days infusion of 5-FU plus cisplatin every 4 weeks; a weekly infused regimen of 5-FU/leucovorin (LV) over 24 hours plus cisplatin (50 mg/m2) every 2 weeks, as studied by the European Organization for Research and Treatment of Cancer; and LV (200 mg/m2), 5-FU bolus (400 mg/m2), plus a 22-hour infusion of 5-FU (600 mg/m2) on days 1 and 2 in combination with cisplatin (50 mg/m2) every 2 weeks. Although gastric cancer is a relatively chemosensitive disease with response rates of 30%-40%, chemotherapy in the advanced setting is limited by a low complete response rate, response durations that are short-lived, and considerable toxicities.
Several new drugs have emerged, including the taxanes, the topoisomerase-I inhibitor irinotecan, and the third-generation platinum derivative oxaliplatin, which provide more effective and better tolerated regimens for the treatment of advanced gastric cancer. Response rates up to 65% have been demonstrated in phase II trials evaluating combination regimens of these new agents [9–12]. Other drugs, such as the fluoropyrimidines S-1 and capecitabine, may provide an attractive alternative to standard infusional 5-FU [13–14]. Research efforts have also centered on novel targeted therapies, such as epidermal growth factor receptor inhibitors, alone or in combination with chemotherapy [15]. The focus of this review is on the promising role of the taxanes in the treatment of advanced gastric cancer.
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TAXANES IN ADVANCED GASTRIC CANCER
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Although the taxanes share a number of pharmacologic characteristics and similar mechanisms of action (tubulin stabilization and cell cycle arrest), they are distinctly different. In preclinical studies, docetaxel has demonstrated a greater affinity for tubulin, a longer plasma half-life, and longer intracellular retention time than paclitaxel [16]. In addition, the taxanes exhibit different profiles of drug resistance [17–18]. Despite these differences, both docetaxel and paclitaxel have shown encouraging activity in the treatment of patients with advanced gastric cancer. Monotherapy with either drug in the front-line treatment of advanced disease, as well as in the second-line setting, has produced response rates of approximately 15%-24% [19–23]. It is the appreciable activity seen in these early phase II studies along with the lack of cross-resistance to other drugs and the nonoverlapping toxicities that led researchers to consider further development of the taxanes in combination with existing fluoropyrimidine-platinum regimens in advanced gastric cancer.
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PACLITAXEL-BASED COMBINATIONS: PHASE II STUDIES
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Paclitaxel appears to have a schedule-dependent synergy with platinum compounds, as documented in established human gastric cancer cell lines [24]. This synergy has led to the development of paclitaxel-platinum combination regimens in a number of solid tumors, including gastric cancer. Phase II studies of paclitaxel-containing combinations in the treatment of patients with advanced gastric cancer are listed in Table 1
[9, 25–29]. Combination regimens of paclitaxel plus platinum or paclitaxel plus 5-FU yielded response rates of 22%-65% and median survival times of approximately 10 months (range 6–14 months). Although the studies differed with respect to drug regimen and population treated, the regimens were generally well tolerated, with myelosuppression as the most common toxicity. Other toxicities associated with these combinations included alopecia, myalgia, mucositis, and neurotoxicity.
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DOCETAXEL-BASED COMBINATIONS: PHASE II STUDIES
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Docetaxel, as a single agent, has demonstrated activity in patients with advanced gastric cancer who have been previously treated with chemotherapy, as well as in patients who have failed to respond to chemotherapy [20–21, 23]. Encouraged by these findings, a number of studies assessed docetaxel-based combination regimens in the advanced disease setting (Table 2) [10, 30–36]. The Swiss Group for Clinical Cancer Research and the European Institute for Oncology in Milan collaboratively studied the combination of docetaxel and cisplatin in a phase II trial of 48 patients with advanced gastric cancer [30]. Docetaxel (85 mg/m2) was administered with cisplatin (75 mg/m2) every 3 weeks for up to 8 cycles. In the intent-to-treat analysis, 56% of the patients achieved a response, and two of those patients achieved a complete response. The median time to progression (TTP) was 6.6 months and the median overall survival (OS) time was 9 months. Other more recently reported studies of docetaxel in combination with cisplatin compare favorably with the European study. Kettner et al. [31] and Ridwelski et al. [10] reported response rates of approximately 40% in patients with advanced gastric cancer who received the two-drug combination. The median survival times in both studies were comparable.
Docetaxel has also been studied in combination with 5-FU. In a phase II trial, locally advanced or metastatic gastric cancer patients received docetaxel (75 mg/m2 or 100 mg/m2) in combination with 24-hour continuous-infusion 5-FU (1,800 mg/m2) plus LV on days 1, 8, and 15 of a 28-day cycle [32]. A 28% overall response rate was reported. The median survival time of 7.7 months was comparable with those found in phase II studies of other combinations in the advanced disease setting. In another phase II trial, 85 patients with untreated recurrent or metastatic gastric cancer were randomized to treatment with docetaxel plus 5-FU or docetaxel plus irinotecan [33]. With a median follow-up of 14 months, both combinations demonstrated activity (37.5% and 33.3% overall response rates, respectively), with no significant differences noted in therapeutic efficacy. Findings of these studies are important and offer new alternatives to cisplatin-containing regimens in the treatment of advanced gastric cancer.
The efficacy and tolerability of docetaxel-containing two-drug regimens have provided a basis for combinations of three or more drugs. In a multinational randomized phase II study, the two-drug combination of docetaxel and cisplatin (TC) was directly compared with the combination of docetaxel, cisplatin, and 5-FU (TCF) [34–36]. The aim of that study was to determine the best docetaxel-containing regimen, as determined by an Independent Data Monitoring Committee (IDMC), for comparison in a phase III trial against an acceptable standard of cisplatin and 5-FU. In that study, 158 patients, all but 2% with metastatic disease, were randomized to receive either docetaxel (85 mg/m2) plus cisplatin (75 mg/m2) every 3 weeks or docetaxel (75 mg/m2) plus cisplatin (75 mg/m2) on day 1 plus continuous-infusion 5-FU (750 mg/m2) on days 1–5 every 3 weeks. In the intent-to-treat analysis, both the overall response rate (43% versus 28%) and the TTP (5.9 months versus 5.0 months) favored the TCF arm over the TC arm. Patients who received the TCF combination experienced more gastrointestinal toxicity. Hematologic toxicities, on the other hand, were comparable between the two arms. Based on the efficacy and safety data, the IDMC designated the TCF combination as the experimental arm of the phase III portion of the trial.
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RANDOMIZED PHASE III TRIAL OF DOCETAXEL, CISPLATIN, AND 5-FU IN ADVANCED GASTRIC CANCER: INTERIM RESULTS OF V325
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In the largest international phase III trial reported to date in advanced gastric cancer, chemotherapy-naïve patients with metastatic or locally advanced unresectable gastric cancer were randomized to receive either the investigational arm of the triplet combination of docetaxel, cisplatin, and 5-FU (DCF) or the reference standard regimen of cisplatin and 5-FU (CF) (Fig. 1) [37, 38]. The treatment dosages (mg/m2/week) for cisplatin and 5-FU were identical in both arms of the study, thereby allowing a true assessment of the benefit of adding docetaxel to the standard reference regimen.
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Figure 1. V325 phase III study design. Adequate hydration and antiemetics as required. Response assessment every 8 weeks independent of treatment schedule.
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The primary end point of the study was TTP. OS, response rate, duration of response, safety, and quality of life were secondary end points. The study was designed to detect, with 95% accuracy, an increase in median TTP from 4 to 6 months and an increase in median OS time from 8 to 12 months. Target accrual has been met, with 460 patients enrolled in the study, 230 patients per arm. Demographic and tumor characteristics were well balanced between the two arms. Among the treated patients, the median age was 54 years, 68% of primary tumors were located in the gastric body, and 98% of patients had metastatic disease. Table 3 shows the recently reported results of the planned interim analysis. DCF was associated with a significantly superior response rate and TTP versus CF (Table 3). The p value for TTP of 0.0008 and risk ratio of 1.704 exceeded the prespecified values needed to confer superiority. Patients treated with DCF had a 70% higher chance of remaining disease free at any point after 2 months. Overall survival, although longer in the DCF-treated group compared with the CF group (10.2 months versus 8.5 months; p = 0.0064), did not reach statistical significance, as the prespecified p value of 0.0053 was not reached. The conditional probability of a statistically significant survival outcome favoring DCF at study maturity, however, is 99.4%.
DCF, not surprisingly, was associated with a greater incidence of grade 3/4 hematologic toxicities, specifically neutropenia, febrile neutropenia, and neutropenic infection (84%, 16%, and 14%, respectively), compared with CF (60%, 6%, and 7%, respectively). Hematopoietic growth factors were not mandated in this study, despite the known myelosuppressive potential of the docetaxel-containing regimen. Grade 3/4 nonhematologic toxicities were comparable between the two arms (Table 4). The most notable differences were in the incidence of diarrhea (20% with DCF versus 8% with CF) and stomatitis (23% with DCF versus 30% with CF).
This landmark phase III study, which demonstrated clear superiority with the incorporation of docetaxel in the advanced setting, has underscored the importance of researching new treatment options in this challenging disease. The findings of this trial are placed in perspective with other landmark studies in advanced gastric cancer in Table 5 [37–41]. There are also several other combination studies ongoing. In the phase III part of study V306, the investigational regimen of irinotecan, 5-FU, and LV is being tested against the standard reference regimen of cisplatin and 5-FU. The activity of 5-FU, LV, and irinotecan has been proven in a randomized phase II study versus the doublet of irinotecan and cisplatin [42]. The V306 trial has completed accrual, with efficacy data forthcoming. In the United Kingdom, a phase II/III trial (REAL-2) with an interesting study design is ongoing to compare the UK reference regimen of ECF with three new and potentially promising chemotherapy regimens (Fig. 2). As noted by the trial design, the currently regarded standards, cisplatin and 5-FU, are being replaced by oxaliplatin and capecitabine, respectively. In the phase II portion of that trial, which was recently reported, comparable activity was demonstrated in all arms of the study, thus warranting continued randomization to the target patient accrual [43].
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Figure 2. Randomized phase III trial comparing capecitabine with 5-FU and oxaliplatin with cisplatin: REAL-2 trial design. Stratification factors: extent of disease; performance status; center.
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CONCLUSIONS
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The treatment of gastric cancer remains a great challenge to oncologists. Despite advances in diagnosis and treatment, the prognosis for patients with advanced disease still remains poor. As such, there is considerable interest in the research and development of newer cytotoxic regimens and novel targeted therapies. The taxanes represent a class of drugs with considerable activity in a number of tumor types. Early-phase trials of paclitaxel and docetaxel, alone or in combination, have shown encouraging results in the treatment of patients with advanced gastric cancer. In the recently reported interim analysis of the phase III V325 trial, docetaxel, when combined with cisplatin and 5-FU, proved to be superior to the standard cisplatin plus 5-FU regimen in terms of response rate, time to tumor progression, and overall survival. These findings represent an important milestone in the treatment of patients with advanced gastric cancer. Ongoing phase III trials will provide promising new information, which may redefine the role of chemotherapy in the treatment of advanced gastric cancer.
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ACKNOWLEDGMENT
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E.V.C. has received research grants for clinical studies from Aventis.
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Received February 27, 2004;
accepted for publication April 5, 2004.
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Learning Objectives
Abstract
