First-line Treatment For Advanced Gastric Cancer Research Articles

A phase II study of intra-arterial chemotherapy of 5-fluorouracil, cisplatin, and mitomycin C for advanced nonresectable gastric cancer

The best choice of chemotherapy regimen for patients with advanced gastric cancer (AGC) is still a matter of controversy and requires further investigation. This study was performed to evaluate the efficacy and safety of intra-arterial infusion chemotherapy of 5-fluorouracil 1000 mg/m, cisplatin 50 mg/m, and mitomycin C 10 mg/m (FCM) repeated every 6 weeks, as first-line treatment for AGC. Forty-seven (95.9%) of the 49 patients were assessable for response. Four cases of complete response and 28 cases of partial response were confirmed, giving an overall response rate of 65.3% [95% confidence interval (CI): 52.0-78.6%]. The median time to progression and overall survival for all patients was 8.3 months (95% CI: 6.8-9.8 months) and 14.5 months (95% CI: 12.0-17.0 months). The estimate of overall survival at 12 and 24 months was 55.1% (95% CI: 41.2-69.0%) and 18.4% (95% CI: 7.5-29.2%), respectively. Most patients experienced neutropenia during their course of therapy with 21.3% of patients (n = 10) for grade 3/4 neutropenia. Grade 3 stomatitis, lethargy, and palmar-plantar erythema were observed in two (4.3%), eight (17.0%), and one (2.1%) patients, respectively. Yet, no grade 4 nonhematological toxicity was observed. Intra-arterial infusion chemotherapy of 5-fluorouracil 1000 mg/m, cisplatin 50 mg/m, and mitomycin C 10 mg/m is a tolerated treatment modality with promising activity in patients with previously untreated AGC.

PP113 Cetuximab with irinotecan/folinic acid/5-FU as first-line treatment inadvanced gastric cancer: A prospective multi-center phase II study and its molecular markers of the Arbeitsgemeinschaft Internistische Onkologie

PP113 Cetuximab with irinotecan/folinic acid/5-FU as first-line treatment inadvanced gastric cancer: A prospective multi-center phase II study and its molecular markers of the Arbeitsgemeinschaft Internistische Onkologie

Phase IIb trial of fluorouracil, leucovorin, oxaliplatin, and paclitaxel (POF) compared with fluorouracil, feucovorin, and irinotecan (IF) as first-line treatment for advanced gastric cancer (AGC)

e15642 Background: Primary results of POF as 1st and 2nd line treatment for AGC have been presented at ASCO 2007 and 2008. We report here data on the feasibility and the toxicity of POF versus IF(Dank, et al, ASCO 2005) in 1st line treatment of AGC. Methods: Patients with previously untreated, advanced, unresectable, and histologically confirmed adenocarcinoma of the gastric or gastroesophageal junction were randomly assigned to POF or IF regiment. Treatment was continued until disease progressed, unacceptable toxicity, or patient choice. Results: 25 patients were entered in this study between March 2007 and July 2007: 13 in the POF group and 12 in the IF group. The median patient age was 55 years (range, 36 to 67 years), 18 were males and 7 were females. No complete response was observed. The response rate was 62.5% (POF) and 33.3% (IF) respectively. At a median follow-up of 285 days, 7(POF) versus 6(IF) patients were still alive. Hematological toxicity was the most frequent toxicity in both groups. Grade 3 to 4 neutropenia were 38.5% (POF) versus 8.3% (IF). Diarrhea was found 0% and 8.3% in POF and IF group respectively. No grade 3 peripheral neurotoxicity was observed. Conclusions: Compared with IF regiment, POF could also be used as first-line treatment for AGC with acceptable safety profile, good efficacy, and more encouraging results. No significant financial relationships to disclose.

Phase II study of cetuximab plus weekly cisplatin and 24-hour infusion of high-dose 5-fluorouracil and leucovorin for the first-line treatment of advanced gastric cancer

4567 Background: Cisplatin-HDFL regimen, using weekly 24-hour infusions of cisplatin and high-dose 5-fluorouracil (5-FU) and leucovorin, is commonly used in Taiwan for patients with advanced gastric cancer (GC), showing an overall response rate of approximately 60% (95% CI: 45%-76%) [J Clin Oncol (Suppl) 2006; 24(18S): A14063 ]. We have demonstrated that cetuximab is cytotoxic to human GC cells, and has a chemosensitizing effect for cisplatin and 5-FU in GC cells [Proc AACR 2006; 47: A1233]. Methods: All patients had pathologically confirmed metastatic/ recurrent chemonaive GC, at least 1 measurable lesion, a fasting serum triglyceride level > 70 mg/dl, WHO PS 0/1/2, adequate hepatic, renal, and bone marrow functions. Cetuximab 400 mg/m2 was given as 2h infusion, initially (i.e., D1 of cycle 1); and followed by weekly 1h infusion of 250 mg/m2 (i.e., D8, D15, D22 of cycle 1, and D1, D8, D15, D22 of cycle 2). Cisplatin 35 mg/m2 was given as a 24h infusion, admixing with 5-FU 2,000 mg/m2 and leucovorin 300 mg/m2 (HDFL), D1, D8. A 24h infusion of HDFL was given on D15. Cycles were repeated every 28 days, and response evaluation was performed every 2 cycles & at the end of protocol treatment. The primary end-point was confirmed objective response rate (RR) by RECIST. Results: Between Dec. 2005 and Nov. 2008, 35 patients (M:19, F:16) with a median age of 56 (40–74) were enrolled and evaluable for response assessment. The overall RR was 68.6% (51–83%, 95% C.I.) with 1 CR and 23 PRs. Among a total of 269 cycles (median: 7, range: 2 to 22+ cycles) given, Gr3/4 neutropenia, infection, and hepatic toxicity developed in 6.0%, 4.8%, and 0.74% of 269 cycles, respectively. Two patients have developed acute hepatitis B flare-up among seven HBsAg (+) carriers, and were well controlled by lamivudine. Gr1, Gr2, and Gr3 acne- like rashes have developed in 57.1%, 31.4%, 5.7%; and Gr1, Gr2, Gr3 paronychia have developed in 40.0%, 8.6%, and 2.9% of 35 patients, respectively. Median PFS (range: 3 to 22+ months) and median OS (range: 3 to 35+ months) was11.0 and 14.5 months, respectively. Conclusions: Cetuximab plus infusional cisplatin-HDFL is a highly effective regimen with low toxicity and favourable survival in the first-line treatment of advanced GC. No significant financial relationships to disclose.

Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial

BackgroundTo compare capecitabine/cisplatin with 5-fluorouracil/cisplatin as first-line treatment for advanced gastric cancer (AGC). Patients and methodsIn this randomised, open-label, phase III study, patients received cisplatin (80 mg/m2 i.v. day 1) plus oral capecitabine (1000 mg/m2 b.i.d., days 1–14) (XP) or 5-FU (800 mg/m2/day by continuous infusion, days 1–5) (FP) every 3 weeks. The primary end point was to confirm noninferiority of XP versus FP for progression-free survival (PFS). ResultsA total of 316 patients were randomised to XP (n = 160) or FP (n = 156). In the per-protocol population, median PFS for XP (n = 139) versus FP (n = 137) was 5.6 versus 5.0 months. The primary end point was met with an unadjusted hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.63–1.04, P < 0.001 versus noninferiority margin of 1.25]. Median overall survival was 10.5 versus 9.3 months for XP versus FP (unadjusted HR = 0.85, 95% CI 0.64–1.13, P = 0.008 versus noninferiority margin of 1.25). The most common treatment-related grade 3/4 adverse events in XP versus FP patients were as follows: neutropenia (16% versus 19%), vomiting (7% versus 8%), and stomatitis (2% versus 6%). ConclusionsXP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.

Phase I/II and pharmacokinetic study of combination chemotherapy with S-1 and oxaliplatin in patients with previously untreated metastatic or recurrent gastric cancer

4557 Background: A novel oral fluoropyrimidine, S-1, and oxaliplatin (OX) have been reported to be highly active in advanced gastric cancer (AGC). The objectives of this study were to define the maximal-tolerated dose (MTD) of S-1 in combination with a fixed dose of OX, and to determine the activity and safety of this combination regimen at the recommended dose (RD) when used as the first line treatment of AGC. Methods: Treatment consisted of intravenous OX at a fixed dose of 130 mg/m2 on D1 followed by twice a day oral S-1 [35 mg/m2; level 1(n=3), 40 mg/m2; level 2(n=6), 45 mg/m2; level 3(n=3), or 50 mg/m2; level 4(n=6)] from D1-D14 of a 21-day cycle. At each level, a cohort of 3 patients (pts), which could be expanded to 6 pts, was studied. Dose-limiting toxicities (DLT) were determined during the first treatment cycle. Pharmacokinetic analysis of tegafur, 5-FU, CDHP, and oxonate was performed in 6 pts treated with RD using an optimized HPLC and UV absorption spectrophotometry. Results: In phase I part of the study(n=18), DLT occurred only one pt at level 2 who experienced unconscioussness due to hyponatremia. DLT was not observed in any other pts even though the level 4 dose cohort was expanded to 6 pts. The RD was determined to be level IV and 47 eligible pts, including 2 pts with measurable disease allocated to dose level 4 in the phase I portion, were enrolled in phase II portion. A total of 250 cycles of chemotherapy were administered. The median age was 55 years (31–70) and ECOG PS was 0/1 in 89% of pts. The objective response was observed in 26 (61%; 95% CI, 53–73%) of 43 evaluable pts. SD was achieved in 13 (30%) pts. With a median FU of 19.1 months (m) (95% CI, 18.5–19.7m), median PFS was 6.6 m (95% CI, 4.0–9.2m) with a median OS of 12.5 m (95% CI, 9.2–15.8m). G3–4 toxicities included thrombocytopenia (39%), neutropenia (28%), anemia (17%), febrile neutropenia (FN, 8%), asthenia (8%), and anorexia (8%). There was one G5 FN during the 1st cycle which appeared to be related with DPD deficiency. The pharmacokinetic profiles of S-1 components or its active metabolite did not differ whether S-1 was administered singly or combined with OX. Conclusions: OX plus S-1 regimen is highly active against AGC with favorable toxicity profiles in patients with AGC. No significant financial relationships to disclose.

Phase I/II study of combination chemotherapy with S-1 and cisplatin every 3 week schedule in patients with metastatic or recurrent gastric cancer

15066 Background: S-1 plus cisplatin has been reported to be highly active in advanced gastric cancer (AGC). The objectives of this study were to define the maximal-tolerated dose (MTD) of S-1, given for 2 weeks separated by 1 week rest, with a fixed dose of cisplatin, and to determine the activity and safety of this combination regimen at the recommended dose (RD) when used as the first line treatment of AGC. Methods: Cisplatin was fixed at a dose of 60 mg/m2 on D1 and the starting dose of S-1 was 30 mg/m2 bid (level I) on D1 to D14 every 3 weeks. The dose of S-1 was increased by 5 mg/m2 bid up to 50 mg/m2 bid (level V) unless MTD was achieved. At every level, a cohort of 3 patients (pts), which could be expanded to 6 pts, was studied. Dose-limiting toxicities (DLTs) were assessed for the first 2 cycles. Results: From February 2004 to January 2006, 62 eligible pts were enrolled. In phase I (N=21), DLTs occurred at level V (S-1 50 mg/m2 bid), with 2 of 3 pts developing G3 diarrhea or febrile neutropenia. The RD was determined at level IV (45 mg/m2 bid) because only 1 DLT occurred out of 6 pts at this level. After the first 20 pts (series I) were enrolled in phase II, the protocol was amended; the S-1 dose was reduced down to 40 mg/m2 bid (level III, series II, N=23) because of poor bone marrow recovery and resultant treatment delay. At the time of analysis, a total of 272 cycles of chemotherapy were administered. The median age was 52 years (28–70) and ECOG PS was 0/1 in 98% of pts. The objective response was observed in 20(47%; 95% CI, 36–66%) of 43 pts. SD was achieved in 15 (35%) pts. With a median FU of 12.1 months (range 9.8–23.3) for all survivors, median PFS was 5.3 months (95% CI, 4.6–6.0 months) with a median OS of 10.0 months (95% CI, 5.1–14.8 months). G3–4 toxicities included neutropenia (33%), anemia (31%), anorexia (24%), and asthenia (14%); however severe febrile neutropenia, abdominal pain, and stomatitis were never observed. Conclusions: The cisplatin plus S-1 regimen incorporating 2-weeks on and 1-week off is highly active against gastric adenocarcinoma with favorable toxicitiy profiles in Korean patients. No significant financial relationships to disclose.

Combination Chemotherapy with Capecitabine (X) and Cisplatin (P) as First Line Treatment in Advanced Gastric Cancer: Experience of 223 Patients with Prognostic Factor Analysis

The efficacy and safety of the combination of capecitabine (X) and cisplatin (P) in the treatment of advanced gastric cancer (AGC) have already been shown in several prospective clinical trials. In this study, we sought to evaluate the efficacy and feasibility of the XP combination for the treatment of AGC in clinical practice and to determine the prognostic factors affecting treatment outcomes. Clinical data from 223 patients with previously untreated metastatic, unresectable, or recurrent gastric carcinoma who were treated with XP between March 2000 and December 2004 at a single center were reviewed. Each 3-week chemotherapy cycle consisted of oral capecitabine (1000-1250 mg/m2 twice a day on days 1-14) and i.v. cisplatin (60-80 mg/m2 on day 1). Of the 223 patients, 32 had distant metastases but palliative gastrectomy (resected metastatic), 82 had recurrent disease after previous curative gastrectomy (recurrent), and 109 had distant metastases without gastrectomy (initially metastatic). Patients received a median of five cycles of chemotherapy (range, 1-12 cycles). Among the 123 patients with measurable disease, seven achieved complete responses and 49 had partial responses, giving an overall response rate (RR) of 45.5% in the intention-to-treat population (95% CI, 32.9-50.2%). There were no differences in RR among the groups of resected metastatic, recurrent and initially metastatic patients (66.7 versus 36.5 versus 50.8%, P = 0.35). After a median follow-up of 11.9 months (range, 2.1-51.9 months), the median time to progression (TTP) was 6.3 months (95% CI, 5.2-7.4 months) and the median overall survival (OS) was 11.1 months (95% CI, 9.4-12.9 months). In the resected metastatic, recurrent and initially metastatic groups, TTP was 8.7, 6.8 and 5.8 months (P = 0.02) and median OS was 14.7, 12.4 and 9.6 months (P = 0.03), respectively. Multivariate analysis showed that relatively small tumor burden (resected metastatic or recurrent versus initially metastatic groups) (OR = 1.418, 95% CI, 1.021-1.967, P = 0.037) and good performance status (ECOG 0-1 versus 2) (OR = 3.800, 95% CI, 2.417-5.974, P < 0.001) were independent prognostic factors affecting overall survival. The combination of capecitabine and cisplatin was active and well tolerated as a first line treatment of AGC in general clinical practice. Disease status and performance status of the patients were the most important factors in treatment outcomes.

A pilot study of cisplatin, irinotecan, leucovorin and 5-fluorouracil (PILF) combination chemotherapy for advanced gastric cancer.

Irinotecan, in combination with leucovorin/5-fluorouracil (FU) or with cisplatin, is known to be active for treating advanced gastric cancer (AGC). This pilot study evaluated a novel three-drug combination of irinotecan, leucovorin/FU and cisplatin as a first-line treatment of AGC. The primary endpoint was to assess the feasibility in anticipation of conducting a larger phase II study. Chemotherapy-naive AGC patients received irinotecan 150 mg/m(2) on day 1, and leucovorin 200 mg/m(2) and a 22-h infusion of FU 1000 mg/m(2) on days 1 and 2. Cisplatin 30 mg/m(2) was administered on day 2. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity. Of the 17 eligible patients, two patients had an ECOG performance status of 2 and their median age was 48 years (range: 31 to 69). A total of 117 chemotherapy cycles were delivered (median: 6, range: 1 to 12). The causes of treatment discontinuation were disease progression in 9 patients (53%), refusal (35%) and toxicity (12%). Although grade 3 or 4 neutropenia (41% of patients) was the major toxicity that required dose adjustments, only one episode of febrile neutropenia occurred. Grade 3 or 4 nausea and vomiting, diarrhea and fatigue were observed in 35%, 35% and 29% of patients, respectively. None of the patients died of toxicity during treatment. Of the 16 patients who were evaluable for response, 7 (44%) experienced a partial response. This novel multi-drug combination was tolerated well in patients with AGC. Based on the encouraging efficacy and tolerability, a randomized phase II study is ongoing in this disease setting.

Capecitabine (X) combined with cisplatin (P) as 1st-line therapy in Chinese patients (pts) with advanced gastric cancer (AGC)

4047 Background: Despite a recent fall in incidence, gastric cancer remains common in China. 5-FU plus P is a standard treatment for AGC, producing response rates of 27–51% in randomized trials, although few Chinese data are available. We evaluated the efficacy and safety of replacing the 5-FU component with X (Xeloda) as 1st-line therapy in Chinese AGC pts. Methods: We enrolled 145 pts between Jun 2002 and May 2003. All had measurable AGC (WHO), and adequate Karnofsky PS, bone marrow, renal and hepatic functions. Prior radiotherapy or adjuvant chemotherapy was permitted. Patients received capecitabine 1000 mg/m2 orally twice daily on days 1–14 plus fractionated cisplatin 20 mg/m2 i.v. on days 1–5, every 3 weeks. Results: Baseline characteristics of the 130 pts evaluable to date: 98 men, 32 women; median age 53.7 years (range 23–80); median Karnofsky PS 80 (60–100); 82% of pts had 1 metastatic site, and 18% had ≥2, the most common being the lymph nodes (44%), liver (42%), and stomach (17%). The median treatment duration is currently 6 cycles (range 2–6). Efficacy findings are shown in the table: response rate 45% (95% CI, 36–53%). Median progression-free and overall survival have not yet been reached. There were no grade 4 and very few grade 3 adverse events (all <5%): SGPT and SGOT, hand-foot syndrome, nausea, vomiting, anemia, diarrhea, anorexia, anaphylaxis. Most events were easily managed with dose adjustment and/or suitable treatments, except 1 pt with anemia who withdrew after 2 cycles. Conclusions: X combined with fractionated P is highly active and very well tolerated as first-line treatment for AGC, with comparable results to 5-FU/P. These results provide the rationale for randomized testing of the combination, although standard single infusion of P would enhance convenience. No significant financial relationships to disclose.

Capecitabine (X) combined with cisplatin (P) as 1st-line therapy in Chinese patients (pts) with advanced gastric cancer (AGC)

4047 Background: Despite a recent fall in incidence, gastric cancer remains common in China. 5-FU plus P is a standard treatment for AGC, producing response rates of 27–51% in randomized trials, although few Chinese data are available. We evaluated the efficacy and safety of replacing the 5-FU component with X (Xeloda) as 1st-line therapy in Chinese AGC pts. Methods: We enrolled 145 pts between Jun 2002 and May 2003. All had measurable AGC (WHO), and adequate Karnofsky PS, bone marrow, renal and hepatic functions. Prior radiotherapy or adjuvant chemotherapy was permitted. Patients received capecitabine 1000 mg/m2 orally twice daily on days 1–14 plus fractionated cisplatin 20 mg/m2 i.v. on days 1–5, every 3 weeks. Results: Baseline characteristics of the 130 pts evaluable to date: 98 men, 32 women; median age 53.7 years (range 23–80); median Karnofsky PS 80 (60–100); 82% of pts had 1 metastatic site, and 18% had ≥2, the most common being the lymph nodes (44%), liver (42%), and stomach (17%). The median treatment duration is currently 6 cycles (range 2–6). Efficacy findings are shown in the table: response rate 45% (95% CI, 36–53%). Median progression-free and overall survival have not yet been reached. There were no grade 4 and very few grade 3 adverse events (all <5%): SGPT and SGOT, hand-foot syndrome, nausea, vomiting, anemia, diarrhea, anorexia, anaphylaxis. Most events were easily managed with dose adjustment and/or suitable treatments, except 1 pt with anemia who withdrew after 2 cycles. Conclusions: X combined with fractionated P is highly active and very well tolerated as first-line treatment for AGC, with comparable results to 5-FU/P. These results provide the rationale for randomized testing of the combination, although standard single infusion of P would enhance convenience. No significant financial relationships to disclose.