Untreated Advanced Gastric Cancer Research Articles

Phase II trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) as first-line treatment for advanced gastric cancer

The efficacy of chemotherapy for advanced gastric cancer with palliative intent compared with supportive care alone is now widely accepted. However, the best choice of chemotherapy regimen for patients with advanced gastric cancer is still a matter of controversy and requires further investigation. This study is performed to evaluate the efficacy and safety of the FOLFOXIRI regimen (oxaliplatin 85 mg/m as a 2-h intravenous infusion, irinotecan 165 mg/m as a 90-min infusion, leucovorin 200 mg/m as a 2-h infusion, 5-fluorouracil 3200 mg/m as a 48-h continuous infusion on day 1, every 2 weeks) as first-line treatment for advanced gastric cancer. Forty-seven (95.9%) of the 49 patients were assessable for response. Two cases of complete response and 29 cases of partial response were confirmed, giving an overall response rate of 63.3% [95% confidence interval (CI): 49.8-76.8%]. The median time to progression and overall survival for all patients were 7.3 months (95% CI: 6.0-8.6 months) and 11.9 months (95% CI: 9.4-14.4 months), respectively. The estimate of overall survival at 12 months was 42.9% (95% CI: 29.0-56.7%). Most patients experienced neutropenia during their course of therapy with 49% of patients (n=23) for grade 3/4 neutropenia. Grade 3 nausea/vomiting, stomatitis, and diarrhea were observed in 20 (42.6%), two (4.3%), and five (10.6%) patients, respectively. Yet, no grade 4 nonhematologic toxicity was observed. The FOLFOXIRI combination is a tolerated treatment modality with promising activity in previously untreated advanced gastric cancer patients.

A phase II study of modified FOLFOX as first-line chemotherapy in elderly patients with advanced gastric cancer

The aim of this study was to evaluate the efficacy and safety of biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX regimen) in elderly patients with advanced gastric cancer (AGC). Forty-six eligible patients older than 65 years with previously untreated AGC received oxaliplatin 85 mg/m intravenously over a 2-h period on day 1, together with leucovorin 400 mg/m over 2 h, followed by a 46-h infusion of 5-fluorouracil 2600 mg/m every 2 weeks. All patients were evaluable for efficacy and toxicity. A median of seven cycles (range 1-12) was administered. The overall response rate was 45.6% [95% confidence interval (CI): 31-61%] with two complete responses, 19 partial responses, 15 stable diseases, and 10 progressions. Median time to progression was 6.2 months (95% CI: 4.6-7.8) and median overall survival was 9.8 months (95% CI: 8.2-11.4). Toxicity was fairly mild. Grade 3 toxicities included neutropenia (8.7%), nausea (4.3%), vomiting (4.3%), diarrhea (2.2%); and grade 4 toxicities occurred in none of the patients. Grades 1-2 peripheral neuropathy was reported in 43.5% of patients. The modified FOLFOX regimen is active, well tolerated as first-line chemotherapy for elderly patients aged above 65 years with AGC.

Feasibility Study of Biweekly Capecitabine, Oxaliplatin, and Irinotecan in Patients with Untreated Advanced Gastric Cancer

Capecitabine in combination with oxaliplatin and irinotecan (COI regimen) is active and well tolerated in metastatic colorectal cancer. Since there is no internationally adopted standard regimen, we have conducted a pilot study of COI in untreated advanced gastric cancer. Patients received irinotecan, 180 mg/m2 infused over 90 min on day 1, followed by oxaliplatin, 85 mg/m2 in a 3-hr infusion on day 2, and capecitabine, 1000 mg/m2/day orally twice daily from days 2 to 6 of a biweekly schedule. Treatment was continued up to 8 cycles or until progression of disease occurred. Response (RECIST criteria) was assessed after the first three cycles and was to be confirmed at least 4 weeks following the first response. A total of 12 patients (5 men and 7 women) with a median age of 54 years (range, 42-65) was prospectively enrolled. Most of the patients (83%) had metastatic disease. Three complete responses, four partial responses and two disease stabilizations occurred in the intention-to-treat cohort, with an overall response rate of 58% (95% confidence interval, 28-85%). Median time to progressive disease and overall survival were 6.4 and 12 months, respectively. A total of 68 cycles was administered, with a median of 6 cycles per patient (range, 1-8). Grade 3 neutropenia occurred in two patients. The most common non-hematologic grade 3 toxicities were nausea (3 patients) and diarrhea 12 patients). These preliminary findings suggest that biweekly COI is a feasible and promising triplet for the first-line treatment of advanced gastric cancer. A large multi-institutional phase II study of the combination has already been planned in this setting.

Oral Fluoropyrimidines (Capecitabine or S-1) and Cisplatin as First Line Treatment in Elderly Patients with Advanced Gastric Cancer: A Retrospective Study

This study aimed to evaluate the safety and efficacy of oral fluoropyrimidines and cisplatin therapy in elderly patients with untreated advanced gastric cancer (AGC) retrospectively. In addition, we evaluated the relative activity and toxicity of these agents in this patient population. Clinical data from 72 patients with previously untreated AGC, who were treated with capecitabine/cisplatin and S-1/cisplatin, were reviewed. Oral fluoropyrimidines were administered orally twice a day on Days 1-14. The dose of capecitabine was 1250 mg/m(2) and that of S-1 was 50 mg [body surface area (BSA) < 1.5 m(3)] or 60 mg (BSA > 1.5 m(3)) twice a day. Cisplatin was administered intravenously on Day 1 (before the first dose of capecitabine or S-1) at a dose of 70 mg/m(2) over a 2 h period. The chemotherapy cycle was of 3 weeks (with oral capecitabine or S-1). Thirty-two and 40 patients received the S-1 and capecitabine regimens, respectively, and were included in the analysis. The S-1 protocol had a response rate of 40.6%, a median time-to-progression (TTP) of 5.4 months and a median survival of 9.6 months. The capecitabine had a response rate of 55%, a median TTP of 5.9 months and a median survival of 10.2 months. Each protocol had a similar incidence of Grade 3 or 4 adverse events. However, there was a higher rate of the hand-foot syndrome (6 versus 37%) and diarrhea (25 versus 32%) in the capecitabine group. Oral fluoropyrimidines and cisplatin in elderly patients with untreated AGC showed encouraging results. The treatment was well tolerated with a manageable toxicity profile. The comparison of S-1 with capecitabine showed that capecitabine had a slightly higher response rate (statistically not significant) in addition to a higher rate of adverse events such as the hand-foot syndrome and diarrhea. These data should be warranted with further prospective studies.

A multi-center phase II study of S-1 plus paclitaxel as first-line therapy for patients with advanced or recurrent unresectable gastric cancer

This study was conducted to evaluate the safety and efficacy of S-1 and paclitaxel combination therapy for patients with advanced gastric cancer. Eligible patients had previously untreated advanced or relapsed gastric cancer with measurable lesion(s) and an ECOG PS of 0-2. Treatment consisted of S-1 35 mg/m(2) p.o. b.i.d. on days 1-14 followed by a 7-day off plus paclitaxel 70 mg/m(2) i.v. on days 1 and 8 of a 21-day cycle. Fifty-six patients (M/F = 37/19) were enrolled. The median age was 59 years. The median number of cycles administered was six (range 1-18). Out of the 53 patients evaluated, there was 1 (1.9%) CR, 20 (37.7%) confirmed PRs, 5 (9.4%) unconfirmed PRs, 21 (39.6%) SDs, and 6 (11.3%) PDs. The objective tumor response was 39.6%. The median time to progression was 29 weeks. The median survival was 51 weeks. All 56 patients were assessed for treatment safety. The treatment was well tolerated with grade 3/4 neutropenia in 20%/13%, grade 3 febrile neutropenia in 7%, grade 2/3 diarrhea in 9%/4%, vomiting in 11%/0%, stomatitis in 4%/4%, and neuropathy in 4%/0% of patients. S-1 and paclitaxel combination treatment is an effective regimen with a favorable toxicity profile in patients with advanced gastric cancer.

Multicenter phase II study of capecitabine plus oxaliplatin as a first-line therapy in Chinese patients with advanced gastric cancer

The efficacy of chemotherapy for advanced gastric cancer with palliative intent compared with supportive care alone is now widely accepted. However, the survival advantage is small, and no internationally accepted standard regimen has emerged. This study is performed to evaluate the response rate, time to progression, and safety of the combination of capecitabine (1000 mg/m twice daily, days 1-14) plus oxaliplatin (130 mg/m as a 2-h intravenous infusion on day 1) every 3 weeks, in previously untreated Chinese patients with advanced gastric cancer. Sixty-five (95.6%) of the 68 patients were assessable for response. Three cases of complete response and 34 cases of partial response were confirmed, giving an overall response rate of 54.4% [95% confidence interval (CI), 42.6-66.2%]. The median time to progression and overall survival for all patients were 5.7 months (95% CI, 2.0-8.8 months) and 10.5 months (95% CI, 5.0-15.1 months). The most severe hematologic adverse event was neutropenia, which occurred with grade 3 intensity in three (4.6%) patients and grade 4 in one (1.5%) patient. Thrombocytopenia and leukopenia occurred with grade 3 intensity in five (7.7%) and three (4.6%) patients, respectively. However, no grade 4 thrombocytopenia and leukopenia were observed. Grade 1/2 nausea/vomiting and diarrhea were observed in 33 (50.8%), 17 (26.2%), 26 (40%), 44 (67.7%), and 13 (20%) patients, respectively, and grade 3 nausea/vomiting and diarrhea were observed in one (1.5%) and four (6.2%) patients. Yet, no grade 4 nonhematologic toxicity was observed. Capecitabine/oxaliplatin combination chemotherapy is active in Chinese patients with previously untreated advanced gastric cancer.

A Pilot Study of Oxaliplatin, Fluorouracil and Folinic Acid (FOLFOX-6) as First-Line Chemotherapy in Advanced or Recurrent Gastric Cancer

Background: To evaluate the efficacy and toxicity of an oxaliplatin, fluorouracil (5-FU), and folinic acid (FOLFOX-6) combination therapy in patients with advanced or recurrent gastric cancer. Methods: Patients with previously untreated advanced or recurrent gastric cancer received oxaliplatin 100 mg/m² and leucovorin 400 mg/m² (2-hour intravenous infusion) followed by a 5-FU bolus of 400 mg/m² (10-min infusion) and then 5-FU 2,600–3,000 mg/m² (46-hour continuous infusion). The chemotherapy was repeated every 14 days. Results: Fifty-one patients were enrolled in this study. Of these, 46 were assessable for efficacy, and all patients were assessable for toxicity. Three of 51 patients achieved a complete response, and 18 had partial responses, giving an overall response rate of 41.2%. Stable disease was observed in 11 (21.6%) patients and progressive disease in 14 (27.5%). The median time to progression was 5.4 months, and the median overall survival was 12.1 months. NCI-CTC grade 3/4 hematological toxicities were neutropenia and anemia in 9.8 and 7.8% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in 3 (5.9%) patients. Other NCI-CTC grade 3 or 4 toxicities included diarrhea in 3 patients (5.9%) and vomiting in 5 (9.8%). There were no treatment-related deaths. Conclusions: This oxaliplatin/5-FU/folinic acid regimen shows good efficacy and an acceptable toxicity profile in advanced or recurrent gastric cancer patients; further clinical trials are warranted.

Biweekly Oxaliplatin in Combination With Continuous Infusional 5-Fluorouracil and Leucovorin (Modified FOLFOX-4 Regimen) as First-Line Chemotherapy for Elderly Patients With Advanced Gastric Cancer

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin (OXA) in combination with continuous infusional 5-fluorouracil (5-FU) and leucovorin (LV) administered every 2 weeks (modified FOLFOX-4 regimen) in elderly patients with advanced gastric cancer (AGC). A total of 44 previously untreated AGC patients aged 65 or older were treated with OXA 85 mg m-2 on day 1, LV 200 mg m-2 as a 2-hour infusion followed by a 22-hour infusion of 5-FU 1000 mg m using a multichannel programmable pump, repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and 40 patients for response. Median age was 69 years (65-83). The response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 52.5% (95% confidence interval: 44.6%-68.0%) with 3 complete responses, 18 partial responses, 11 stable diseases, and 8 progressions. Median time to progression was 6.5 months and median overall survival was 10.0 months. Toxicity was generally mild. Grade 3 hematologic toxicities of neutropenia, anemia, and thrombocytopenia were in 6.8%, 2.3%, and 4.5% of the patients, respectively. No grade 4 hematologic toxicities occurred. Grade 1 peripheral neuropathy was a common event (34.1%), whereas grade 3 peripheral neuropathy was recorded in only 1 (2.3%) patient. An acute hypersensitivity reaction was observed in 1 patient during administration. The modified FOLFOX-4 regimen is an active and well-tolerated chemotherapy for elderly patients aged > or =65 years with AGC. OXA may occasionally cause mild hypersensitivity.

Phase II Trial of a Biweekly Regimen of Fluorouracil and Leucovorin Plus Irinotecan in Patients with Previously Untreated Advanced Gastric Cancer

To investigate the therapeutic value and safety of the biweekly regimen of 5-fluorouracil (5-FU) and leucovorin (LV) plus irinotecan (CPT-11) in patients with previously untreated advanced gastric cancer (AGC). A total of 50 patients (M/F 35/15; median age = 65) with AGC, none of whom had received chemotherapy for advanced disease, were accrued in this trial. Fifteen patients (30%) were 70 years old or older. At the time of their accrual, cytotoxic chemotherapy, consisting of LV 100 mg/m2 (2-hour i.v. infusion) followed by 5-FU 400 mg/m2 (bolus) and 5-FU 600 mg/m2 (22-hour continuous infusion) on therapeutic days 1 and 2 plus CPT-11 180 mg/m2 (1-hour infusion) on day 1, was initiated. Treatment courses were repeated every 2 weeks until evidence of progressive disease, unacceptable toxicity or withdrawal of consent. All patients were assessable for toxicity and 48 of 50 for response evaluation, having completed at least four courses of chemotherapy. Complete response was achieved in 2 patients (4%, intent to treat) and partial response in 16 (32%) (overall response rate, 36%; 95% confidence interval [CI]: 22%-50%). Twenty-four patients (48%) had stable disease and 6 patients (16%) progressed. The median time to progression was 8 months (95% CI: 6-10 months) and median overall survival 14 months (95% CI: 6-22 months). Between the subgroups of patients <70 years old and 70 or older, there were no significant differences in efficacy. One toxic death occurred. Treatment tolerance was generally mild to moderate and easy to treat. The main grade 3/4 toxicities were neutropenia (32%), diarrhea (16%), and anemia (8%). Grade 3-4 neutropenia was the only treatment-related serious adverse event significantly more common in patients older than those aged ≤70 (53.3% vs 22.8%, respectively; P = 0.03). Our data suggest that the biweekly regimen of LV and 5-FU plus CPT-11 in untreated patients with AGC is active and has an acceptable safety profile. Further evaluation of this regimen seems to be warranted in a phase III trial.

A multi-center phase II study of S-1 plus paclitaxel as first-line therapy in patients with advanced or relapsed gastric cancer

4634 Background: S-1 is an oral prodrug of 5-fluorouracil (5-FU) including two modulators to enhance the antitumor effect and to decrease gastrointestinal toxicity. Paclitaxel has the synergistic antitumor effect with 5-FU. This study were planned to evaluate the efficacy and safety of S-1 and paclitaxel combination therapy in advanced gastric cancer. Methods: Eligible patients had untreated advanced or relapsed gastric cancer with measurable lesion(s), histologic proof, ECOG PS 0–2, adequate organ function, and signed informed consent. Treatment consisted of S-1 35mg/m2 p.o. b.i.d. on days 1–14 plus paclitaxel 70mg/m2 i.v. on days 1&amp; 8 of a 21-day cycle. Measurable and/or unmeasurable lesion was assessed after every 2 courses with RECIST criteria. Results: A total of 56 patients (M/F=37/19) were enrolled. The median age was 59 years with advanced (n=43) and relapsed (n=13) gastric cancer. The common metastatic lesions were abdominal lymph nodes (71%), liver (39%), and peritoneum (21%). Out of 53 evaluable patients, there was 1 (2%) CR, 25 (47%) PRs, 21 (40%) SDs, and 6 (11%) PDs. Objective tumor response was 49%. Median duration of response was 5.4+months after the confirmation of response. Median follow-up was 9.6 month. Median PFS was 7.7 months and median survival was 14.6 months. Median number of cycle was 6 (range, 1–14). The relative dose intensity of S-1 and paclitaxel was 93%, both. The most common causes of delayed cycle and dose reduction were neutropenia and diarrhea, respectively. All 56 patients were assessed for safety. This treatment was well tolerated with grade 3/4 neutropenia in 14%/5%, grade 3 febrile neutropenia in 5%, grade 2/3 N/V in 21%/0%, anorexia in 18%/2%, diarrhea in 9%/4%, stomatitis in 7%/4%, and neuropathy 7%/0% of patients. Conclusions: S-1 and paclitaxel combination chemotherapy showed significant antitumor effect with manageable and tolerable toxicities in patients with advanced gastric cancer. (This study was partially supported by a grant of the Korea Health 21 R&amp;D Project, Ministry of Health &amp; Welfare, Republic of Korea (0412-CR01–0704–0001)) No significant financial relationships to disclose.

Randomised prospective phase II study of combination chemotherapy epidoxorubicin, cisplatin, 5-FU (ECF) versus epidoxorubicin, cisplatin, capecitabin (ECX) in patients with advanced or metastatic gastric cancer

4571 Background: In phase II studies ECF with 5- FU inf. resulted in response rates (RR) &gt; 50 %. Despite high responses the potential drawback of ECF may be the poor patient’s (pts) acceptability of the indwelling catheter and external infusion pump and related complications: sepsis, catheter-related infections, shoulder pain, thrombosis and pneumothorax. Capecitabin can maintain a constant level of 5- FU without complications and inconvenience associated with central venous access. The aim was to compare the efficacy and safety ECF versus ECX. Secondary endpoint was overall survival. Methods: Pts with histological proven, previously untreated advanced or metastatic gastric cancer, &gt;18 years, ECOG performance status 0- 2 and adequate organ and hematological function were randomized to ECF or ECX. In ECF epidoxorubicin 50 mg/m2 and cisplatin 60 mg/m2 were administrated on day 1 by i.v., 5- FU 200 mg/m2/day was administrated by cont. inf. day 1- 14 of each cycle. Cycle was repeated every 3 weeks. In ECX epidoxorubicin 50 mg/m2 and cisplatin 60 mg/m2 were administrated on day 1 by i.v., capecitabin 825 mg/m2 twd was administrated orally day 1- 14. Cycle was repeated every 3 weeks. Results: Seventy- one pts were enrolled in this study between Jan 03 to Dec 05. Male 80 %, median age 56 yrs (40- 77). Thirty pts received ECF and 41 pts received ECX . All pts were assessable for responses and toxicity. The overall clinical RR were 45 % including 12.9 % partial responses (PR) and 6.4 % complete responses (CR) in ECF group and 69 % including 21.4 % PR and 4.7 % CR in ECX group. Median OS and TTP were 8.8 months (mos) ± 7.8 and 6.0 mos ± 4.4 in ECF group and 10.5 mos ± 7.2 and 7.0 mos ± 4.6 in ECX group respectively. The most frequent grade ¾ side effects graded according to CTCAE - 3 were fatigue - 20 % in ECF group and 19.5 % in ECX group, hematological (neutropenia) - 16 % in ECF group and 4.8 % in ECX group, nausea - 10 % in ECF group and 7.3 % in ECX group, diarrhea - 2.4 % in ECX group, hand- foot syndrome - 2.4 % in ECX group. Conclusions: ECX is at least effective as ECF with less toxic pattern and more convenient for pts and could replace ECF in first- line therapy in pts with advanced or metastatic gastric cancer. No significant financial relationships to disclose.

Randomized phase II trial of irinotecan, leucovorin and 5-fluorouracil (ILF) versus cisplatin plus ILF (PILF) for advanced gastric cancer

4580 Background: Irinotecan, in combination with 5-fluorouracil (FU) or cisplatin, clearly demonstrated efficacy against gastric cancer. We compared the combination of irinotecan, leucovorin and FU (ILF) with cisplatin plus ILF (PILF) as first-line chemotherapy in patients with advanced gastric cancer (AGC). Methods: Patients with chemotherapy-naïve, histologically-confirmed, metastatic gastric adenocarcinoma were randomized to receive irinotecan 150 mg/m2 on day 1, leucovorin 20 mg/m2 and a 22-h infusion of FU 1,000 mg/m2 on days 1 and 2 (ILF), or ILF plus cisplatin 30 mg/m2 on day 2 (PILF). Treatment was repeated every 2 weeks until disease progression, unacceptable toxicity, or patients’ refusal. Primary endpoint was response rate which assessed every 4 cycles of chemotherapy. With a single-stage phase II design, the required number of patients was at least 35 per each arm. Results: Of 91 patients registered, 46 patients were treated with ILF and 44 with PILF. For both arms, 635 chemotherapy cycles were delivered (median, 6 for ILF and 8 for PILF; p=0.46). Both ILF and PILF were generally well tolerated. However, PILF was associated with, although statistically insignificant, substantially more grade 3 or 4 toxicities than ILF (46% and 38%, respectively). In the ILF and PILF arm, 11% and 25% of patients, respectively, discontinued treatment because of toxicity. Treatment duration was similar for both arms (4.3 for ILF v 5.6 months for PILF; p=0.13). Four patients died during treatment: one in the ILF arm and 3 in the PILF arm. The objective response rate was 37% for both arms. Disease control (response plus stable disease) was achieved in 59% and 73% (p=0.02) of patients treated with ILF and PILF. There were no significant differences in therapeutic efficacy between ILF and PILF with respect to progression-free (4.8 v 6.2 months; p=0.60) and overall (10.9 v 10.4 months; p=0.93) survival. Conclusions: Both ILF and PILF appear to be active as first-line chemotherapy for AGC, with acceptable safety profiles. Given the comparable efficacy results, ILF could be a reasonable standard chemotherapy for untreated AGC patients. No significant financial relationships to disclose.

Phase II study of epirubicin plus oxaliplatin and infusional 5-fluorouracil as first-line combination therapy in patients with metastatic or advanced gastric cancer

The purpose of this study was to evaluate the efficacy and safety of an epirubicin, oxaliplatin and infusional 5-fluorouracil combination in patients with advanced gastric cancer. Patients with previously untreated advanced measurable gastric cancer received epirubicin (50 mg/m2, day 1), oxaliplatin (130 mg/m2 2-h infusion, day 1) and 5-fluorouracil (750 mg/m2, 24-h infusion, day 1-3) every 3 weeks. The primary endpoint of this phase II study was the response rate according to Response Evaluation Criteria in Solid Tumors. Out of 48 patients, 46 were evaluable for efficacy and 48 for toxicity. A median of five cycles (range 1-6) was administered. The overall best response rate was 47.8% (95% confidence interval 33-63%) including 2.2% complete responses and 45.6% partial responses. The median time for progression and median overall survival was 5 (95% confidence interval 4.1-5.9) and 11 months (95% confidence interval 8.1-13.9), respectively. Grade 3/4 neutropenia and leukocytopenia were observed in 25 and 12.5% of patients, respectively. Grade 3/4 nonhematological toxicities included nausea (6.3%), vomiting (14.6%), neurological toxicity (10.4%) and mucositis (2.1%). The epirubicin, oxaliplatin and infusional 5-fluorouracil regimen was effective and well tolerated as a front-line chemotherapy for patients with metastatic or advanced gastric cancer, and should be evaluated further.

Phase III Study of Docetaxel and Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for Advanced Gastric Cancer: A Report of the V325 Study Group

In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric cancer patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over docetaxel and cisplatin for comparison against cisplatin and fluorouracil (CF; reference regimen) in the phase III part. Advanced gastric cancer patients were randomly assigned to docetaxel 75 mg/m2 and cisplatin 75 mg/m2 (day 1) plus fluorouracil 750 mg/m2/d (days 1 to 5) every 3 weeks or cisplatin 100 mg/m2 (day 1) plus fluorouracil 1,000 mg/m2/d (days 1 to 5) every 4 weeks. The primary end point was time-to-progression (TTP). In 445 randomly assigned and treated patients (DCF = 221; CF = 224), TTP was longer with DCF versus CF (32% risk reduction; log-rank P < .001). Overall survival was longer with DCF versus CF (23% risk reduction; log-rank P = .02). Two-year survival rate was 18% with DCF and 9% with CF. Overall response rate was higher with DCF (chi2 P = .01). Grade 3 to 4 treatment-related adverse events occurred in 69% (DCF) v 59% (CF) of patients. Frequent grade 3 to 4 toxicities for DCF v CF were: neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy (19% v 14%). Complicated neutropenia was more frequent with DCF than CF (29% v 12%). Adding docetaxel to CF significantly improved TTP, survival, and response rate in gastric cancer patients, but resulted in some increase in toxicity. Incorporation of docetaxel, as in DCF or with other active drug(s), is a new therapy option for patients with untreated advanced gastric cancer.

Extended safety and efficacy data on S-1 plus cisplatin in patients with advanced gastric carcinoma in a multi-center phase II study

4083 Background: We obtained additional phase II safety and efficacy data in a multi-center setting on an active regimen of S-1 plus cisplatin; the experimental arm of the global phase III First-Line Advanced Gastric cancer Study (FLAGS). Methods: Eligible patients had untreated advanced gastric cancer (AGC), histologic proof, KPS ≥70%, adequate organ function, and gave written consent. Patients received S-1 (25mg/m2 p.o. bid on days 1–21) plus cisplatin (75mg/m2 i.v. on day 1) every 28 days. All reported confirmed overall response rate (C-ORR), response durations, and time-to-progression (TTP) are externally reviewed. Results: All 72 patients were assessed for safety and 64 for efficacy. The median age was 56 years and median KPS was 90%. Median no. of cycles was 4. C-ORR was 50% (95% CI, 37%-63%). Median duration of response is &gt;6 months. At 6 months, only 35% of patients have had cancer progression. Median survival (n=72) is 10.5 months (95% CI, 9.3 to NR). At least one SAE occurred in 43% of patients. The frequent grade 3 or 4 adverse events (occurring in &gt;10% of patients) included: fatigue/asthenia (26%), vomiting (21%), nausea (18%), diarrhea (17%), neutropenia (18%), anorexia (11%), and dehydration (11%). Febrile neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. Conclusions: These extended data confirm that S-1 plus cisplatin has a very desirable safety profile and impressive efficacy data in AGC. FLAGS will complete accrual of &gt;700 patients by March of 2007. (Supported by Taiho Pharma-USA). [Table: see text]

Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients (pts) with advanced gastric cancer (AGC): Efficacy and safety results

LBA4018 Background: The oral fluoropyrimidine capecitabine has proven efficacy and safety in colorectal and breast cancer. Phase II data in AGC suggested that XP would show comparable efficacy to a standard FP regimen, with potential safety and convenience advantages. This phase III study evaluated XP vs. FP in first-line AGC. Methods: Pts with previously untreated measurable AGC received either oral capecitabine (1000mg/m2 bid d1–14) + cisplatin (80mg/m2 i.v. d1) q3w (XP arm) or 5-FU (800mg/m2/d continuous infusion, d1–5) + cisplatin (80mg/m2 i.v. d1) q3w (FP arm). XP requires 1 day per 3 weeks in hospital; FP requires 5 days. Pts were treated until disease progression or unacceptable toxicity. Primary endpoint: non-inferiority (NI) in progression-free survival (PFS), defined as upper limit of 95% CI of hazard ratio (HR) &lt;1.4 (first test) and &lt;1.25 (second test). Results: From Apr 03 to Jan 05, 316 pts were enrolled in 46 centers/13 countries. Arms were well balanced: median age (years, range) XP (56, 26–74), FP (56, 22–73); median Karnofsky PS 80 (range 70–100) in both arms; male/female (%): XP (64/36) FP (69/31). Median no. of cycles was 5 (XP and FP). Median follow-up is 22.1 months. Primary endpoint was met: HR 0.81 (95% CI 0.63–1.04). XP was superior to FP in terms of overall response rate (ORR, RECIST). Efficacy is presented in the table. Most common treatment-related grade 3/4 adverse events (XP vs. FP) were: neutropenia (16 vs. 19%), vomiting (7 vs. 9%), stomatitis (2 vs. 7%), diarrhea (5 vs. 5%), and anemia (5 vs. 3%). Other grade 3/4 events occurred in &lt;5% of pts. The rate of all-grade hand-foot syndrome was low (22 vs. 4%). Conclusions: XP showed highly significant non-inferiority for PFS and significant superiority for ORR vs. FP with similar safety. These findings suggest that capecitabine should become the fluoropyrimidine of choice for AGC, given the efficacy, reduced hospitalization time and simplified regimen. No significant financial relationships to disclose. [Table: see text]

A Phase II Study of Docetaxel and Cisplatin in Patients with Gastric Cancer Recurring After or Progressing During 5-FU/Platinum Treatment

Docetaxel plus cisplatin (DP) is a combination chemotherapy regimen that is active against untreated advanced gastric cancer. We evaluated the feasibility of DP treatment in patients with recurring or metastatic gastric cancer who had been previously treated with other chemotherapy regimens. The DP regimen consisted of docetaxel (75 mg/m(2) i.v.) and cisplatin (60 mg/m(2) i.v.) over 1 h on Day 1 every 4 weeks for a maximum of nine cycles. Thirty-seven patients (28 men, 9 women; median age, 53 years; range 28-71 years) received a total of 128 cycles of therapy (median, 3; range 1-9). Twenty-six patients had recurrent disease and 11 had metastatic tumors. The objective response rate was 32.4% (95% confidence interval = 16.6-48.3%), including 1 complete response and 11 partial responses. Eleven had stable disease, whereas 12 had progressive disease. The median duration of response was 70.5 days (range 30-392 days). Grade 3/4 toxicities included anemia (10.8%), leukopenia (27.0%), neutropenia (51.4%), thrombocytopenia (2.7%), nausea/vomiting (5.4%) and oral mucositis (13.5%). Median time to progression was 136 days and median overall survival was 235 days. The DP combination was well tolerated and effective for patients with metastatic gastric cancer treated previously with 5-fluorouracil/platinum chemotherapy.

721 ORAL Similar safety results of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) from a phase III trial in patients (pts) with previously untreated advanced gastric cancer (AGC)

721 ORAL Similar safety results of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) from a phase III trial in patients (pts) with previously untreated advanced gastric cancer (AGC)

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m−2 on day 1, FA 200 mg m−2 as a 2 h infusion followed by bolus 5-FU 400 mg m−2 and a 22 h infusion of 5-FU 600 mg m−2, repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer.

Can cisplatin and infused 5-fluorouracil be replaced by oxaliplatin and capecitabine in the treatment of advanced oesophagogastric cancer? The REAL 2 trial

The therapeutic options available for the treatment of advanced oesophagogastric cancer are numerous. However, relatively few randomised trials can provide evidence-based recommendations for first-line chemotherapy combinations. A series of multi-centre trials has established epirubicin, cisplatin and infused 5-fluorouracil (5-FU) (ECF) as the standard first-line regimen in the UK [1–3]. With the availability of newer cytotoxic agents, the challenge has been to show improved efficacy compared with the recognised standard. Oxaliplatin is a third-generation platinum compound that contains a 1,2-diaminocyclohexane (DACH) carrier ligand [4]. This bulky DACH ligand is thought to account for a broad spectrum of anti-tumour activity, including gastric cancer. As with other platinum agents, oxaliplatin forms platinum-DNA adducts, which cause intraand inter-strand crosslinking of DNA molecules, thus inhibiting DNA replication. Widely used for patients with colorectal cancer, oxaliplatin has a unique toxicity profile consisting of cold-induced peripheral neuropathy and laryngodysesthesia; however, otoand nephro-toxicity ismuch reduced compared with cisplatin. Several phase II clinical trials have shown efficacy of oxaliplatin combined with 5-FU for patients with previously untreated advanced gastric cancer [5–7]. Oral fluoropyrimidines, such as capecitabine, offer an alternative to intravenously administered 5-FU; they are convenient for the patient, and offer an improved toxicity profile. Capecitabine is a fluoropyrimidine prodrug that is metabolised to 5-FU in a three-step process [8]. The last step requires thymidine phosphorylase, which is significantly more active in tumours compared with