the Medizinische Klinik mit Schwerpunkt Hmatologie und Onkologie, Charite, Universittsmedizin Berlin, Campus Virchow-Klinkum
    HELIOS-Klinikum Berlin, Robert-Rssle-Klink, Charite Campus Buch
    Onkologische Schwerpunktpraxis Tiergarten, Berlin
    Stdtisches Klinikum St. Georg, Leipzig
    Vinzenz-Pallotti-Krankenhaus, Hmato-onkologische Ambulanz, Bergisch-Gladbach, Germany

    ABSTRACT

    PATIENTS AND METHODS: Patients with metastatic or locally advanced gastric adenocarcinoma without prior chemotherapy were randomly assigned to receive either ECF (epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 day 1, and fluorouracil 200 mg/m2 days 1 through 21, every 3 weeks) or DF (docetaxel 75 mg/m2 day 1, and fluorouracil 200 mg/m2 days 1 through 21, every 3 weeks).

    RESULTS: Ninety patients were randomly assigned. Toxicity was rarely severe. Major toxic effects included diarrhea, stomatitis, and leukopenia in the DF arm and nausea, vomiting, and leukopenia in the ECF arm. Forty-three of 45 patients in each arm were assessable. In the DF arm, two patients (4.4%, intent to treat) experienced a confirmed complete tumor remission as best response, and 15 patients (33.3%) experienced a confirmed partial remission (overall response rate [ORR], 37.8%; 95% CI, 25.9% to 51.9%). Two patients (4.4%) in the ECF arm showed confirmed complete remission, and 14 (31.1%) showed confirmed partial remission (ORR, 35.6%; 95% CI, 24.8% to 48.7%). For the DF and ECF arms, the median survival was 9.5 and 9.7 months, and the median time to tumor progression 5.5 and 5.3 months, respectively.

    CONCLUSION: DF can be safely given in an ambulant setting. Compared with ECF, the dual combination of DF shows promising efficacy and may be an alternative treatment option that avoids cisplatin.

    INTRODUCTION

    With the hope of improving efficacy and tolerability, there is considerable interest in the potential of relatively new cytotoxic agents, such as irinotecan,5,6 oxaliplatin,7,8 and docetaxel. These drugs are investigated in phase II and phase III studies for gastric cancer.

    Docetaxel as a single agent showed promising activity in previously untreated patients with gastric cancer. Response rates of 18% to 24% have been described.9-12 In the second-line setting, response rates of 20% were reported.13 The combination of docetaxel and cisplatin or docetaxel, cisplatin, and FU (DCF) has been investigated by two multinational study groups.14,15 Both groups considered FU to contribute significantly to the activity of the regimen,15,16 so both groups have chosen the triple combination of DCF to compare with cisplatin-FU (CF) combinations in ongoing phase III trials.17,18 Interim results of the American-led trial, which have been recently presented, show a superior response rate of the triple combination DCF compared with CF.18

    Although cisplatin is often used in combination protocols, its contribution to the regimen's activity is still open for debate. Because cisplatin adds significantly to the toxicity and usually requires intense intravenous (IV) hydration, we initiated our study avoiding cisplatin to develop a modern well-tolerated combination chemotherapy ideal for an outpatient setting and to expand the choice of regimens with differing toxicity profiles to better tailor treatments to patients.

    A combination of docetaxel with FU (DF) seemed theoretically promising. FU is one of the most efficacious single agents for gastric cancer19,20 and, therefore, part of most of the potent chemotherapy combinations for this disease.3,18,21 In tumor models, FU and docetaxel are highly synergistic.22 Clinical evidence suggests lack of cross-resistance.13 The dual combination of DF has been explored in phase I and II studies23 and showed activity in gastric cancer.24,25 A continuous infusion of FU was chosen (200 mg/m2 days 1 to 21) because it seems more effective than FU bolus but results in less myelotoxicity,26 reducing myelotoxicity avoids overlapping toxicity to docetaxel, and it is a proven efficacious way of FU administration in the reference regimen ECF.3

    We initiated this trial as a randomized phase II study comparing DF with ECF, one of the best investigated reference regimens.3,4 ECF served as an internal control arm to avoid selection bias.

    PATIENTS AND METHODS

    Eligibility

    After they signed informed consent, patients were included if they met the following eligibility criteria: histologically proven gastric adenocarcinoma, which was locally advanced and not curable by operation, or metastatic disease; measurable or assessable lesions; age 75 years or younger; Eastern Cooperative Oncology Group performance status of 2 or less; no prior chemotherapy; adequate function of bone marrow (leukocytes ≥ 3,000/μL and thrombocytes ≥ 100,000/μL), heart (cardiac ejection fraction within normal limits), kidneys (creatinine clearance ≥ 60 mL/min), and liver (bilirubin ≤ 1.5 mg/dL); and contraception if with reproductive potential. None of the following criteria were permitted: previous chemotherapy, second malignancy, uncontrolled infection, symptomatic CNS metastases, parallel radiation therapy, other parallel therapy aiming at tumor reduction, and life expectancy of less than 3 months.

    Pretreatment Evaluation

    History was taken, a full-body examination was performed, and tumor-related symptoms were recorded. A blood sample was collected for CBC, multichannel chemical surveys, and electrolyte measurements. The following investigations were performed obligatorily at study entry: bone scintigraphy, ECG, echocardiogram with evaluation of ventricular function, measurement of the creatinine clearance, audiogram, chest x-ray, abdominal ultrasound, computed tomography (CT) of the abdomen, and, only if indicated, CT scan of the thorax, and gastroscopy (if indicated).

    Treatment

    Patients were randomly assigned to receive DF (docetaxel 75 mg/m2 day 1, and FU 200 mg/m2 days 1 through 21 continuous infusion, every 3 weeks) or ECF (epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 day 1, and FU 200 mg/m2 days 1 through 21 continuous infusion, every 3 weeks). Docetaxel was delivered in 500 mL of normal saline over 1 hour. The FU continuous infusion was administered with a portable infusion pump (7-day pump) through an IV port and changed weekly. ECF was delivered as published.3 In the DF arm, concomitant dexamethasone from the day before until the day after docetaxel application was administered to prevent fluid retention, and metoclopramide, alizaprid, or 5-hydroxytryptamine-3 antagonists were used as antiemetics. Supportive medication in the cisplatin arm consisted of 5-hydroxytryptamine-3 antagonists and corticosteroids for antiemesis and intensive IV fluid management concomitant to cisplatin medication as published.3

    Chemotherapy was administered until tumor progression, side effects, or a maximum of 10 cycles. Assessment of tumor-related symptoms was performed every 3 weeks. Evaluation of side effects took place on a weekly basis.

    Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0. Depending on the severity of side effects observed, the chemotherapy was paused, or the dose was reduced. FU infusion was paused and omitted in case of diarrhea or mucositis of CTC grade 1 or greater or hand and foot syndrome of CTC grade 2 or greater. FU was reduced by 25% if, at any time, diarrhea, mucositis, or hand and foot syndrome of CTC grade 3 or greater occurred. Application of cisplatin and epirubicin or docetaxel was delayed as long as there was diarrhea or mucositis of CTC grade 1 or greater, hand and foot syndrome of CTC grade 2 or greater, neutropenia less than 1,500/μL, or thrombocytopenia less than 100,000/μL. Cisplatin was reduced if the glomerular filtration rate was between 60 and 40 mL/min. Epirubicin was reduced in case of CTC grade 4 neutropenia persisting longer than 7 days or accompanied by fever, thrombocytopenia of CTC grade 3 or greater, or elevated bilirubin levels. The dose of docetaxel was reduced in case of CTC grade 4 neutropenia persisting longer than 7 days or accompanied by fever, thrombocytopenia of CTC grade 3 or greater, elevated bilirubin levels, or peripheral neuropathy of CTC grade 2 or greater. Chemotherapy was terminated when one of the following criteria was met: peripheral neuropathy of CTC grade 3 or greater, bilirubin level more than 3.5 x the upper normal limit, creatinine clearance less than 40 mL/min, cardiac ejection fraction less than 50%, or other severe toxicity.

    For evaluation of tumor response, the best objective imaging technique for the particular patient was selected from the pretreatment evaluation (either CT scan, ultrasound, or conventional x-ray imaging). The same technique was then performed every 6 weeks by the same investigator, and tumor response was assessed together with an independent radiologist. Response was graded according to WHO criteria.27 All evaluations had to be confirmed by a second assessment not less than 4 weeks apart.

    Patients who received at least one cycle of treatment were considered assessable for response and toxicity. Patients who developed rapid tumor progression after any amount of therapy also were evaluated. Data for tumor response are based on an intent-to-treat analysis. The duration of patient survival was calculated from the time of initial treatment until death or last observation. The time to disease progression was calculated from the time of initial treatment until documented progression.

    Statistical Considerations

    An optimal, two-stage Simon design28 was used to determine the number of patients needed to be accrued in the experimental arm (DF). The control arm (ECF) did not influence this calculation. It was believed that a response rate of greater than 25% would justify continuing the trial (H0). The response rate was expected to be 45% (H1). The probability of accepting the treatment combination with response probability H0 (25%) is {alpha} = 0.10. The probability of rejecting the combination with response probability of H1 = 45% is  = 0.10. If at least three of the first 14 patients showed an objective response, the study could be continued to a total of 44 patients (second stage). If a response of at least 14 patients could be documented, the hypothesis H0 could be rejected. Survival duration and time to tumor progression were calculated by using the Kaplan-Meier method.

    As a randomized phase II study, the trial was not intended and not statistically powered to perform a head-to-head comparison of response rate and toxicity of the two treatment arms. ECF serves as an internal control arm to avoid selection bias.

    RESULTS

    Patient Characteristics

    Patient characteristics are listed in Table 1. Because of randomization, patient characteristics are well balanced between the treatment groups. All patients had a histologically proven adenocarcinoma originating from the stomach. Lower esophageal or gastroesophageal junction carcinomas were not included.

    Treatment Characteristics

    Two hundred thirty-two cycles of DF and 218 cycles of ECF were administered. The median number of 3-week cycles administered in the DF and ECF arms was four and four, respectively. In 27 patients (60.0%) treated with DF and in 24 patients (53.3%) treated with ECF, chemotherapy application had to be delayed at some point during their therapy because of toxicity. Dose reductions had to be performed in 10 patients (22.2%) in the DF arm and in eight patients (17.8%) in the ECF arm because of toxicity as well.

    Response

    Eighty-six (95.5%) of 90 patients were assessable for response. Four patients, two in each treatment arm, were not assessable but were included in the intent-to-treat analysis and kept in the denominator of the response rate. Two patients in the ECF arm stopped their therapy (one patient after one cycle and one patient after two cycles) because of toxicity and the patient's refusal of further therapy. A tumor evaluation could not be performed. One patient treated with DF refused further therapy after one cycle, and after the first cycle of DF, one patient died of pneumonia that was neither tumor nor chemotherapy related.

    Thirty-six of the 43 assessable patients in the DF arm and 39 of the 43 assessable patients in the ECF arm had bidimensionally measurable disease. The imaging technique used consistently for all response evaluations was CT scan, ultrasonography, nuclear magnetic resonance, or endosonography in 20, 19, one, and three patients in the DF arm and 25, 15, zero, and three patients in the ECF arm, respectively.

    Data from the initial best response and from those responses that could be confirmed at least 4 weeks later are listed in Table 2. The overall response rate (ORR) for the patients treated with DF (complete response [CR] + partial response [PR]) was 40.0% (95% CI, 27.3% to 45.6%) including best initial responses and 37.8% (95% CI, 25.9% to 51.9%) considering only confirmed responses. The ORR for ECF patients was 44.4% (95% CI, 31.9% to 57.9%) including all responses and 35.6% (95% CI, 24.8% to 48.7%) including only confirmed responses. All six patients who achieved a CR (three patients in each arm) had bidimensionally measurable disease. Tumor manifestations of the three patients in the experimental DF arm were liver metastases (patient 1), liver and peritoneal metastases (patient 2), and lymph node metastases (patient 3). The median duration of response for patients treated with DF was 28 weeks for CR, 24 weeks for PR, 28 weeks for minor response, and 14 weeks for stable disease. The median duration of response in the ECF arm was 29 weeks for CR, 29 weeks for PR, 4 weeks for minor response, and 23 weeks for stable disease.

    The median time to tumor progression in the DF arm was 5.5 months (95% CI, 2.8 to 8.3 months), and in the ECF arm, it was 5.3 months (95% CI, 3.0 to 7.6 months; Fig 1). The median survival time for patients treated with DF and ECF was 9.5 months (95% CI, 6.7 to 12.0 months) and 9.7 months (95% CI, 8.1 to 11.5 months; Fig 2), respectively.

    Forty-three of 45 patients in the DF arm and 38 of 45 patients in the ECF arm had tumor-related symptoms before therapy. Twenty-nine patients (67.4%; 95% CI, 53% to 79%) treated with DF and 22 patients (57.9%; 95% CI, 42% to 72%) treated with ECF showed an improvement in at least one of their symptoms without worsening of any other symptom.

    Toxicity

    All 90 patients were assessable for toxicity (Table 3). Asthenia, diarrhea, stomatitis, and hematotoxicity were the most frequent side effects of DF. Nausea, vomiting, asthenia, and hematotoxicity were the major toxic effects of ECF. There was one treatment-related death in a patient treated with ECF. The patient showed malignant ascites and a pretherapeutic creatinine clearance of 78 mL/min. He was treated with ECF and developed acute renal failure as part of a hepatorenal syndrome. Dialysis was performed, but the patient died.

    DISCUSSION

    The predominant toxicities of DF were diarrhea, stomatitis, and leukopenia. The major toxicities of ECF were nausea, vomiting, and leukopenia. Although diarrhea was rarely severe under either regimen, 13% of patients had grade 3 to 4 stomatitis in the DF arm compared with only 2% of patients in the ECF arm. Grade 3 to 4 leukopenia was common and occurred in 42% of the DF-treated patients, a percentage slightly lower than the 53% observed under ECF. Complications caused by hematotoxicity were rare, with only 4.4% of patients experiencing neutropenic fever under either regimen. Nausea and vomiting were more frequent under ECF than under DF (all grades, 73% v 62%, respectively) but rarely severe. There was one toxic death in the ECF arm as a result of renal failure.

    Toxicity rates reported for ECF in the original work of Webb et al3 are similar to the data reported here. Grade 3 to 4 leukopenia-neutropenia was more frequently documented in the current study (53% v 36% reported by Webb et al), possibly because of the weekly full CBCs performed in the current study. Treatment delays and dose reductions are similar between the ECF and DF arms in the current study (ECF, 53.3% and 17.8%; DF, 60% and 22.2%, respectively) and are comparable to the published data for ECF (32% and 41%, respectively).3 The predominance of treatment delays compared with dose reductions in the current study might be a result of the early detection of side effects because of weekly assessment. The similarity of the toxicity profile of ECF used in the current study compared with the published data validates the internal control arm of ECF and confirms the validity of the documented toxicities in the experimental arm of DF.

    It can be concluded that DF shows manageable toxicities. The profile of DF seems different from ECF. There were no unexpected toxicities. Thus, DF can safely be given in an ambulant setting. The different toxicity profile may help to individualize the treatment for patients.

    DF shows promising response rates of 40% and 37.8% (all responses and confirmed responses). With 17 patients showing a confirmed response, the criteria set by the statistical model to reject the hypothesis H0 were met. The response rate is similar to ECF response rates observed in the current study (44.4% for all responses and 35.6% for confirmed responses). Time to tumor progression and median survival time were similar for patients treated with DF and ECF. Two thirds of the symptomatic patients in the DF arm experienced amelioration of their symptoms (subjective symptomatic improvement rate, 67.4%), a rate that is at least as good as that seen with ECF (57.9%).

    The ORR of 44.4% for ECF documented in the current study is equal to that reported for ECF by Webb et al3 (45%). The median survival time and time to tumor progression seen for ECF (9.7 and 5.3 months, respectively) were also similar to the published data (8.9 and 7.4 months, respectively).3 The fact that the response and survival data for ECF could be reproduced with the patients treated in the current trial shows that there was no unexpected selection bias. Therefore, it seems feasible to use the ECF arm in the current trial as a control arm to evaluate the efficacy of DF. Although the data do not suggest any obvious difference in the efficacy of DF and ECF, it is of note that this trial was not designed as a phase III study to compare the two regimens statistically.

    DF has been found to be efficacious against gastric cancer in other studies. Using a combination of docetaxel (75 to 100 mg/m2 day 1) together with FU (1,800 mg/m2/24 h days 1, 8, and 15) in a 4-week cycle, Constenla et al24 documented a response rate of 28% in 25 assessable patients. In a pilot trial, docetaxel was used on a weekly basis (25 mg/m2) together with continuous-infusion FU (150 mg/m2/d for 14 days, every 3 weeks), leading to responses in 12 of 14 patients.25 In a British, randomized, phase II study, docetaxel (85 mg/m2 day 1) and FU (750 mg/m2 days 1 to 5 continuous infusion, every 3 weeks) was compared with docetaxel (60 mg/m2 day 1) plus irinotecan (250 mg/m2 day 1, every 3 weeks); response rates of 33.3% and 37.5%, respectively, were observed, with a higher rate of grade 3 to 4 toxicities in the irinotecan-containing combination.29 Our current study and the studies cited earlier confirm the tolerability and efficacy of the DF combination. To our knowledge, the current trial is the largest study using the dual combination of DF, the only one with an internal control arm of an established chemotherapy, and the only one using FU as a continuous infusion on days 1 through 21, which was established by the ECF regimen.

    Other investigators studied the dual combination of docetaxel-cisplatin, omitting FU, in phase II trials. Response rates of 56% and 37.2% were reported.14,30

    Because FU probably plays a significant part in the activity of ECF, attempts were made to include FU into the combination of cisplatin and docetaxel.16,17 A randomized phase II study compared the dual combination of cisplatin and docetaxel (cisplatin 75 mg/m2 and docetaxel 85 mg/m2 day 1, every 3 weeks) with the FU-containing DCF regimen (docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, and FU 750 mg/m2 days 1 through 5, every 3 weeks).15 The response rates were 28% (in 76 patients) for docetaxel-cisplatin and 43% (in 79 patients) for DCF. It was judged that FU plays a significant role in this combination, so this triple combination (DCF) was taken forward into a randomized phase III study to be compared with CF (cisplatin 100 mg/m2 day 1 and FU 1,000 mg/m2 days 1 through 5, every 4 weeks). Interim results, which have recently been presented, showed statistical superiority in the response rate of 38.7% and a median survival of 10.2 months for DCF (n = 111) versus a response rate of 23.2% and a median survival of 8.5 months for CF (n = 112).18 This study confirms the significant contribution of docetaxel to the effectiveness of chemotherapy. The combination CF used in this trial18 as a control arm to DCF had been tested by a European Organization for Research and Treatment of Cancer (EORTC) trial21 and did not show superiority to FAMTX in contrast to ECF.3 The response rate achieved with CF in the EORTC trial of 20% is similar to the response rate reported by Ajani et al.18 In the EORTC trial, it was concluded that CF could not serve as a reference chemotherapy in the future. It would therefore be interesting to see DCF be compared with ECF. The response rate reported for the triple combination of DCF (38.7%; median survival, 10.2 months) is similar to the response rates for the dual combination of DF (37.8% for confirmed responses; median survival, 9.5 months) documented in the current trial. These results underline that it is worth asking the question whether a cisplatin-containing triple combination is necessary to achieve tumor remission and prolongation of survival. Cisplatin certainly adds toxicity.

    The current study suggests that DF has efficacy similar to ECF and DCF.3,18 Compared with ECF or DCF, the DF regimen has the advantage of being more easily administered in an outpatient setting, avoiding the time-consuming intensive hydration necessary for cisplatin administration.3 By avoiding cisplatin-associated toxicities, DF may enlarge the spectrum of chemotherapeutically treatable patients and may help tailor active treatments to individual patients.

    A randomized phase III study comparing the regimens DF, ECF, and DCF would be interesting. DF might be a new active alternative to cisplatin-containing regimens. Future replacements of continuous-infusion FU by capecitabine might make this combination even more attractive.

    Authors' Disclosures of Potential Conflicts of Interest

    NOTES

    Supported by a research grant from Aventis Pharma Deutschland GmbH, Bad Soden, Germany.

    Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

    REFERENCES

    1. Wilke H, Korn M, Khne C, et al: Phase II results of weekly infusional high-dose FU (HD-FU) plus folinic acid (FA) and biweekly cisplatin (C) for advanced gastric cancer. Ann Oncol 7:46, 1996 (suppl 5)

    2. Rougier P, Ducreux M, Mahjoubi M, et al: Efficacy of combined 5-fluorouracil and cisplatinum in advanced gastric carcinoma: A phase II trial with prognostic factor analysis. Eur J Cancer 30A:1263-1269, 1994

    3. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261-267, 1997

    4. Ross P, Cunningham D, Scarffe H, et al: Results of a randomised trial comparing ECF with MCF in advanced oesophago-gastric cancer. Proc Am Soc Clin Oncol 18:272a, 1999 (abstr 1042)

    5. Ajani JA, Baker J, Pisters PW, et al: CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma: Results of a phase II study. Cancer 94:641-646, 2002

    6. Pozzo C, Bugat R, Peschel C, et al: Irinotecan in combination with CDDP or 5-FU and folinic acid is active in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma: Final results of a randomised phase II study. Proc Am Soc Clin Oncol 20:134a, 2001 (abstr 531)

    7. Al-Batran SE, Atmaca A, Hegewisch-Becker S, et al: Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol 22:658-663, 2004

    8. Artru P, Andre T, Tigaud JM, et al: Oxaliplatin (OXA), 5-fluoro-uracil (FU) and folinic acid (FA) (FOLFOX 6) in advanced/metastatic gastric carcinoma (A/MGC) patients (Pts): Final results of a multicenter phase II study. Proc Am Soc Clin Oncol 20:164a, 2001 (abstr 654)

    9. Taguchi T, Sakata Y, Kanamaru R, et al: Late phase II clinical study of RP56976 (docetaxel) in patients with advanced/recurrent gastric cancer: A Japanese Cooperative Study Group trial (group A). Gan To Kagaku Ryoho 25:1915-1924, 1998

    10. Mavroudis D, Kouroussis CH, Androulakis N, et al: Frontline treatment of advanced gastric cancer with docetaxel and granulocyte colony-stimulating factor (G-CSF). Am J Clin Oncol 23:341-344, 2000

    11. Sulkes A, Smyth J, Sessa C, et al: Docetaxel (Taxotere) in advanced gastric cancer: Results of a phase II clinical trial—EORTC Early Clinical Trials Group. Br J Cancer 70:380-383, 1994

    12. Einzig AI, Neuberg D, Remick SC, et al: Phase II trial of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy: The Eastern Cooperative Oncology Group (ECOG) results of protocol E1293. Med Oncol 13:87-93, 1996

    13. Vanhoefer U, Wilke H, Harstrick A, et al: Phase II study of docetaxel as second line chemotherapy (CT) in metastatic gastric cancer. Proc Am Soc Clin Oncol 18:303a, 1999 (abstr 1163)

    14. Roth AD, Maibach R, Martinelli G, et al: Docetaxel (Taxotere)-cisplatin (TC): An effective drug combination in gastric carcinoma—Swiss Group for Clinical Cancer Research (SAKK), and the European Institute of Oncology (EIO). Ann Oncol 11:301-306, 2000

    15. Ajani JA, Fodor M, Van Cutsem E, et al: Multinational randomized phase II trial of docetaxel (T) and cisplatin (C) with or without 5-fluorouracil (FU) in patients (Pts) with advanced gastric or GE junction adenocarcinoma (AGC-AGEJC). Proc Am Soc Clin Oncol 19:247a, 2000 (abstr 957)

    16. Roth AD, Maibach R, Morant R, et al: 5-FU in protracted continuous IV infusion (5-FUpiv) can be added to Taxotere-cisplatin (TC) without dose-reduction of TC in advanced gastric carcinoma (AGC). Proc Am Soc Clin Oncol 18:245a, 1999 (abstr 943)

    17. Roth AD, Ajani J: Docetaxel-based chemotherapy in the treatment of gastric cancer. Ann Oncol 14:41-44, 2003 (suppl 2)

    18. Ajani JA, Van Cutsem E, Moiseyenko V, et al: Docetaxel (D), cisplatin, 5-fluorouracil compare to cisplatin (C) and 5-fluorouracil (F) for chemotherapy-nave patients with metastatic or locally recurrent, unresectable gastric carcinoma (MGC): Interim results of a randomized phase III trial (V325). Proc Am Soc Clin Oncol 22:249a, 2003 (abstr 999)

    19. Moynihan T, Hansen R, Anderson T, et al: Continuous 5-fluorouracil infusion in advanced gastric carcinoma. Am J Clin Oncol 11:461-464, 1988

    20. Cocconi G, DeLisi V, Di Blasio B: Randomized comparison of 5-FU alone or in combination with mitomycin and cytarabine (MCF) in the treatment of advanced gastric cancer. Cancer Treat Rep 66:1263-1266, 1982

    21. Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:2648-2657, 2000

    22. Burris HA: Docetaxel in combination with fluorouracil for advanced solid tumors. Oncology (Huntingt) 11:50-52, 1997 (suppl 8)

    23. Tubiana-Mathieu N, Merrouche Y, Cupissol D, et al: A phase II study of docetaxel (Taxotere) (TXT) in metastatic or recurrent squamous cell carcinoma (SCC) of the head and neck. Proc Am Soc Clin Oncol 17:412a, 1998 (abstr 1587)

    24. Constenla M, Garcia-Arroyo R, Lorenzo I, et al: Docetaxel, 5-fluorouracil, and leucovorin as treatment for advanced gastric cancer: Results of a phase II study. Gastric Cancer 5:142-147, 2002

    25. Chun HG, Puccio CA, Mittelman A: Weekly docetaxel and continuous infusion (CI) 5-fluorouracil (5-FU) in elderly patients (pts) with cancer of the stomach and distal esophagus. Proc Am Soc Clin Oncol 20:162a, 2001 (abstr 645)

    26. Meta-Analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301-308, 1998

    27. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, WHO Offset Publication No. 48, 1979

    28. Simon R: Optimal two-stage design for phase II clinical trials. Control Clin Trials 10:1-10, 1989

    29. Hawkins R, Cunningham D, Soerbye H, et al: Randomized phase II trial of docetaxel plus irinotecan versus docetaxel plus 5-fluorouracil (5FU) in patients with untreated advanced gastric adenocarcinoma (AGAC). Proc Am Soc Clin Oncol 22:257a, 2003 (abstr 1032)

    30. Ridwelski K, Gebauer T, Fahlke J, et al: Combination chemotherapy with docetaxel and cisplatin for locally advanced and metastatic gastric cancer. Ann Oncol 12:47-51, 2001

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