Pretreated Advanced Gastric Cancer Research Articles

Multicenter randomized phase II study of weekly docetaxel alone versus weekly docetaxel plus oxaliplatin as a second-line chemotherapy in patients with advanced gastric cancer: Preliminary response and safety results.

e14570 Background: Gastric cancer is a frequent malignancy with worldwide estimated incidence of 990,000 cases, representing 7.8% of all cancers in 2008. There are limited data suggesting a benefit for doublet second-line chemotherapy in advanced gastric cancer. Methods: The eligibility criteria were patients 1) with prior exposure to cisplatin based chemotherapy and advanced or recurrent stomach cancer 2) with pathologically proven gastric adenocarcinoma, 3) with an ECOG performance status 0 to 2, 4) with measurable lesions. Each treatment cycle was consisted of docetaxel 36 mg/m2 in docetaxel mono therapy group and docetaxel 36 mg/m2, oxaliplatin 80 mg/m2 in docetaxel/oxaliplatin doublet therapy group on days 1, 8. The primary end point of this study was response rate, and secondary end points included toxicity, progression free and overall survival. Results: Fifty two patients were enrolled; median age was 63 years; male (n=42) and female (n=10); docetaxel mono therapy (n=27) and docetaxel/oxalliplatin doublet therapy (n=25). The median number of cycles administered was 2.5 (range,1-9). Fourty eight patients were assessable for efficacy. Four partial responses, 7 stable diseases in mono therapy group (RR; 4/27, 14.8%) and 1 complete remission, 4 partial responses, 13 stable diseases in double therapy group (RR; 5/25, 20.0%) were confirmed (p=0.198). Median progression free survival was 1.97 months in the mono therapy group and 4.93 months in doublet therapy group (p=0.007). Median overall survival was 11.57 months in the mono therapy group and 8.13 months in doublet therapy group (p=0.650). Grade 3 or 4 adverse events were reported in 11 of 52 patients; G3 pain were in 2 patients and G3 pneumonia was in 1 patient in mono group, G3/4 neutropenia were 5 patients in the combination group, G3 nausea, vomiting, general weakness was 1 patient each group in combination group. Conclusions: Weekly docetaxel/oxaliplatin doublet therapy showed superior progression free survival to monotherapy group as second line therapy in cisplatin pretreated advanced gastric cancer patients.

A multicenter, randomized phase III trial comparing second-line chemotherapy (SLC) plus best supportive care (BSC) with BSC alone for pretreated advanced gastric cancer (AGC).

4004 Background: Currently no evidence that SLC in AGC patients will result in substantial prolongation of survival when compared to BSC exists, and there is potential for toxicity from the treatment. The efficacy and safety of SLC using either single-agent docetaxel or irinotecan was evaluated in a randomized phase III trial. Methods: Two-hundreds two patients with AGC, one or two prior chemotherapy regimen(s) involving both fluoropyrimidines and platinum, and an Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomly assigned 2:1 to SLC or BSC. Choice of SLC, either docetaxel 60 mg/m2 every 3 weeks or irinotecan 150 mg/m2 every 2 weeks, was left to the discretion of investigators. Randomization was stratified by PS and the number of prior chemotherapy. All patients received standard BSC regimen a priori defined in the study protocol. Primary endpoint was the overall survival (OS). Results: Between Sep 2008 and Sep 2010, 193 eligible patients, 74% with one prior chemotherapy and 54% with PS 0, were enrolled: SLC (n=128) or BSC (n=65). SLC was generally well tolerated, with all-cause deaths within 30 days of random assignment of 3% and 4%, respectively, on SLC and BSC arm. As of current analysis, 128 (66%) patients died. In the intent-to-treat population, a significant difference in OS (5.1 months for SLC v 3.8 months for BSC) was observed (hazard ratio, 0.63; 95% confidence interval, 0.47-0.86; P=0.004). The OS benefit for SLC was relevant in most of the prospectively defined subgroups including age, gender, PS, number of prior treatments, number of metastatic sites, hemoglobin levels, and response to prior chemotherapy. Significantly more patients on SLC arm received further salvage chemotherapy than those on BSC arm (40% v 22%, respectively; P=0.011). Conclusions: This is the largest phase III trial comparing SLC plus BSC with BSC alone in AGC. In pretreated patients, SLC is tolerated and significantly improves OS when added to BSC.

A feasibility analysis from the patient preference randomized phase III clinical trial of second-line chemotherapy (SLC) in advanced gastric cancer (AGC) patients pretreated with both fluoropyrimidines and platinum.

4147 Background: There is no evidence that SLC in AGC patients will result in substantial prolongation of survival when compared to best supportive care (BSC), and there is potential for toxicity from the treatment. However, SLC is often offered to pretreated AGC patients for anecdotal reasons. Methods: The study comprises two parts: patient preference trial (PPT) and randomized controlled trial (RCT). In a prospective, multicenter trial, pretreated AGC patients with a performance status (PS) ≤ 1 were first offered randomization. If willing to participate RCT, the patient was randomly assigned 2:1 to SLC or BSC. If the patient refused randomization, but nevertheless agreed to receive treatment of their preferences, the patient received their treatment of choice (SLC or BSC). In the SLC regimen, single-agent docetaxel or irinotecan was selected at the discretion of investigator. Primary endpoint is the overall survival in the RCT patients, and the target sample size is 200 RCT patients. The main outcome measure in this feasibility analysis is the proportion of patients enrolled onto RCT compared with the proportion of those enrolled onto PPT. Results: As of Dec 2009, a total of 182 eligible patients were entered onto this study. Eighty-one patients entered RCT (SLC, n = 55; BSC, n = 28), and 101 patients received treatment of their preferences (SLC, n = 70; BSC, n = 29). The degree of RCT refusal was more pronounced in patients with a PS of 0 (vs. 1; p = 0.04). In the PPT patients, those without measurable disease (p < 0.01) and aged > 55 years (p < 0.01) declined SLC. Conclusions: This analysis suggests that pretreated AGC patients clearly prefer SLC. The high degree of RCT refusal is, at least in part, due to concern about random assignment or difficulty with accepting BSC without the possibility of anticancer effects. No significant financial relationships to disclose.

Oxaliplatin, 5-fluorouracil and Leucovorin (FOLFOX-4) Combination Chemotherapy as a Salvage Treatment in Advanced Gastric Cancer

This study was designed to determine the efficacy and safety of FOLFOX-4 chemotherapy as a salvage treatment for patients with advanced gastric cancer (AGC). The AGC patients with an ECOG performance status of 0~1 and progressive disease after prior treatments were registered onto this phase II trial. The patients received oxaliplatin (85 mg/m² on day 1), leucovorin (200 mg/m² on days 1 and 2) and 5-fluorouracil (400 mg/m² as a bolus and 600 mg/m² as a 22-hour infusion on days 1 and 2) every 2 weeks. For the 42 treated patients, a total of 228 chemotherapy cycles (median: 5, range: 1~12) were administered. Twenty-nine patients (69%) received FOLFOX-4 chemotherapy as a third-(50%) or fourth-line (19%) treatment. On the intent-to-treat analysis, 9 patients (21%) achieved a partial response, which was maintained for 4.6 months. The median progression-free survival and overall survival were 3.0 months and 6.2 months, respectively. The frequently encountered toxicities were neutropenia and gastrointestinal side effects, including anorexia. Although there was one possible treatment-related death, the toxicity profiles were generally predictable and manageable. Salvage chemotherapy with FOLFOX-4 is an effective and tolerable regimen for those heavily pretreated AGC patients who have a good performance status.

A Phase II Feasibility Study of Weekly Paclitaxel in Heavily Pretreated Advanced Gastric Cancer Patients with Poor Performance Status

Purpose: We investigated the efficacy and safety of weekly paclitaxel monotherapy in previously treated patients with advanced gastric cancer (AGC) and poor performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG). Patients and Methods: Patients with evaluable disease who failed at least one previous chemotherapy and had a PS of 2–3, received paclitaxel 70 mg/m² on days 1, 8 and 15 every 4 weeks. Results: The median overall survival (OS) was 5.5 months (95% confidence interval, CI, 3.3–7.8) and progression-free survival was 2.1 months (95% CI, 1.2–3.0). The overall response rate was 3.8% and the disease control rate was 25.0%. Treatment-related toxicities were tolerable. OS was 7.1 (95% CI, 5.4–9.5) and 3.7 months (95% CI, 2.1–5.3) for patients with PS-ECOG 2 and 3, respectively (p < 0.001). When evaluated according to the previous treatment, OS was 5.1 (95% CI, 3.3–7.0) and 6.5 months (95% CI, 3.8–9.3) for patients receiving two and three or more lines of treatment, respectively (p = 0.815). With multivariate analysis, PS was a significant factor for OS. Conclusion: Survival in patients treated with weekly paclitaxel monotherapy was comparable to other second- or third-line chemotherapies for AGC, with acceptable toxicities in previously treated patients with poor PS.

Phase II study of combination chemotherapy of 5-fluorouracil, low-dose leucovorin, and oxaliplatin (FLOX regimen) in pretreated advanced gastric cancer

BackgroundThis phase II study describes the efficacy and safety of combination chemotherapy of 5-fluorouracil (5-FU), low-dose leucovorin, and oxaliplatin (FLOX regimen) for pretreated advanced gastric cancer. Patients and methodsPatients who had been previously treated with greater than or equal to one regimen were enrolled. Patients received an oxaliplatin 75 mg/m2 on day 1, 5-FU 1000 mg/m2 on days 1–3, and leucovorin 20 mg/m2 on days 1–3, every 3 weeks. The primary end point was overall survival (OS). ResultsAmong the 52 patients enrolled, 26 patients were treated as second line, and the remaining 26 patients were enrolled as third- or fourth line. A total of 203 cycles of chemotherapy were administered with the median being three cycles (range 1–15) per patient. The median OS was 6.6 months [95% confidence interval (CI) 4.5–8.8] and the median progression-free survival was 2.5 months (95% CI 1.9–3.0). The response rate was 4% (95% CI 0–9%), and the disease control rate was 48% (95% CI 34–62%). The most common toxic effects of grade 3/4 were neutropenia (16%) and vomiting (6%). ConclusionsThe FLOX regimen showed modest activity as a salvage treatment in pretreated advanced gastric cancer with a favorable compliance.

A Phase II Study of Sequential Methotrexate and 5-fluorouracil Chemotherapy in Previously Treated Gastric Cancer: A Report from the Gastrointestinal Oncology Group of the Japan Clinical Oncology Group, JCOG 9207 Trial

As prognosis of advanced gastric cancer is still poor, a standard regimen after first-line fluorouracil (FU)-based chemotherapy has not yet been established. Therefore, we conducted a phase II study to evaluate the efficacy and toxicity of sequential treatment with methotrexate (MTX) and also 5-FU as second-line chemotherapy in patients with advanced gastric cancer. Treatment consisted of weekly doses of MTX (100 mg/m(2), i.v. bolus), followed by 5-FU (600 mg/m(2), i.v. bolus) 3 h after MTX administration. Leucovorin rescue therapy (six doses of 10 mg/m(2), given at 6-h intervals) was commenced 24 h after a treatment with MTX. The primary endpoint was the response rate. Between December 1992 and June 1995, 56 patients were registered in this study and one was ineligible. All registered patients were included in all analyses. The median age of the patients was 60 years (20-75 years). Most patients (75%) had a performance status of 0 or 1, and 51 (90%) received 5-FU-based chemotherapy as first-line treatment. The major adverse events were myelosuppression and gastrointestinal toxicity. Grade 4 neutropenia occurred in 6.3% of the patients. The overall objective response rate was 9.0% [five partial responses among 56 patients, 95% confidence interval (CI): 3.0-20%]. The median overall survival time was 237 days, and the 1-year survival proportion was 21.4%. Sequential MTX/5-FU therapy provides good survival outcomes with tolerable toxicity despite a limited response in patients with previously treated advanced gastric cancer. This regimen is now being evaluated in a randomized study in patients with pretreated advanced gastric cancer, by the Japan Clinical Oncology Group.

Capecitabine and doxorubicin combination chemotherapy as salvage therapy in pretreated advanced gastric cancer

The aim of this study was to evaluate the activity and the safety of a combination regimen of capecitabine and doxorubicin as salvage chemotherapy in advanced gastric cancer patients who had undergone one or two prior chemotherapy regimens. Patients received capecitabine, 2,500 mg/m(2)/day PO for 14 days (D1-14) and doxorubicin, 30 mg/m(2) IV on day 1 every 3 weeks until disease progression. The response was evaluated according to RECIST criteria, and the toxicity was evaluated by NCI-CTC (version 2.0). Forty-five patients were enrolled. Twenty-six patients were treated as second-line chemotherapy and the remaining patients as third-line chemotherapy. A total of 152 cycles of chemotherapy (median 2, range 1-12) were administered. Median dose intensities of capecitabine and doxorubicin were 11,326 and 9.6 mg/m(2)/week, respectively. The overall response rate was 6.7% (95% CI, 4.1-12.5%) and the disease control rate was 46.7% (95% CI, 28.6-87.1%) according to an intent-to-treat analysis. The median progression-free survival was 11.3 weeks (95% CI, 5.6-16.7 weeks). The median overall survival was 29.1 weeks (95% CI, 18.3-39.9 weeks) with one-year survival rate of 24%. Severe (grade III/IV) hematologic and non-hematologic toxicity was uncommon and included nausea/vomiting in five (11.1%), neutropenia in two (4.4%), anemia in one (2.2%), and hand-foot syndrome in one patient (2.2%). The combination of capecitabine and doxorubicin is a feasible salvage regimen in advanced pre-treated gastric cancer.

MIX (mitomycin C, irinotecan, capecitabine) regimen in the treatment of advanced gastric cancer (AGC). A phase I study of the Gruppo Oncologico dell’Italia Meridionale (GOIM)

4195 Background: In our previous experience the combination of MMC (M) and Irinotecan (I) demonstrated to be active in pretreated advanced gastric cancer pts. Capecitabine (X) more active than fluorouracil plus folinic acid and is synergic when combined with CPT-11 in patients with colorectal cancer. Taking into account these data the GOIM started a phase I study to determine the dose-limiting toxicities (DTLs) and the maximum tolerated dose (MTD) of the MIX triple drugs combination in AGC pts. Methods: M and I were administered at fixed doses, according to our previous experience, and as follow: M 8 mg/mq on day 8, I 150 mg/mq on day 1 and 15; X was administered at escalated doses starting from 1250 mg/mq p.o. in two divided doses, from 2 to 15 day, and increasing of 250 mg/mq at each dose level. The cycles were administered every 4 weeks. DLTs were evaluated in the first cycle and defined as: NCI grade 3–4 febrile neutropenia, grade 4 thrombocytopenia, and any ≥ grade 3 non haematologic toxicity. The MTD was defined as the dose level immediately below that at which the DLTs were observed in 2/3 patients. Results: Nine patients (male/female: 5/4) with median ECOG PS 1, were treated on 3 dose-levels. Dose escalation and DLTs are listed in the following table. A median of 3 cycles for patient was administered. On first and second dose level no grade 3–4 haematological toxicity was observed. At the third dose level, one pt had grade 3 febrile neutropenia that required hospitalizaton and one pt had grade 4 neutropenia without fever. Conclusions: In our study the DLT of the MIX combination therapy was neutropenia reached at the third dose level. The recommended dose for phase II-III studies is 8, 150, and 1500 mg/mq for the three drugs, respectively. A phase II study with this combination in previously untreated pts is started. No significant financial relationships to disclose.

Phase II study of irinotecan + 5FU/FA for patients with previously treated advanced gastric cancer

4076 Background: Pozzo et al. (ASCO 2001) reported substantial activity of irinotecan combined with 5-fluoro-uracil + folinic acid (5FU/FA) in chemonaive patients with locally advanced (LA) or metastatic gastric cancer. An ongoing Belgian multicentre phase II study was set up to evaluate the safety and efficacy of irinotecan + 5-FU/FA in patients with pretreated advanced gastric cancer. Methods: Patients with confirmed LA or metastatic gastric adenocarcinoma, including oesophagogastric junction, written consent obtained, adequate performance status, intact organ function. Failure of prior ciplatin-5FU based chemotherapy. Patients were treated with a regimen of irinotecan 180 mg/m2 i.v. infusion followed by LV5FU2 every 2 weeks. Results: Up to date 38 patients are evaluable for safety and 33 for efficacy. Median age: 62 years. A total of 283 cycles (median 6, range 1–31) were administered with an overall relative dose intensity of 95%. Severe (grade 3/4) drug-related adverse events were rare (% of cycles):...

Phase II study of irinotecan + 5FU/FA for patients with previously treated advanced gastric cancer

4076 Background: Pozzo et al. (ASCO 2001) reported substantial activity of irinotecan combined with 5-fluoro-uracil + folinic acid (5FU/FA) in chemonaive patients with locally advanced (LA) or metastatic gastric cancer. An ongoing Belgian multicentre phase II study was set up to evaluate the safety and efficacy of irinotecan + 5-FU/FA in patients with pretreated advanced gastric cancer. Methods: Patients with confirmed LA or metastatic gastric adenocarcinoma, including oesophagogastric junction, written consent obtained, adequate performance status, intact organ function. Failure of prior ciplatin-5FU based chemotherapy. Patients were treated with a regimen of irinotecan 180 mg/m2 i.v. infusion followed by LV5FU2 every 2 weeks. Results: Up to date 38 patients are evaluable for safety and 33 for efficacy. Median age: 62 years. A total of 283 cycles (median 6, range 1–31) were administered with an overall relative dose intensity of 95%. Severe (grade 3/4) drug-related adverse events were rare (% of cycles): neutropenia (<1%) and fatigue (<1%). In general, these events didn't jeopardise further treatment. Efficacy: Three PR and 15 SD were seen with a tumour growth control rate (PR + SD>6 months) of 30.3% and median time of tumour growth control in these patients of 8.3 months (range 5.8–13.4). These patients received a median of 14.0 cycles (range 7–31). Overall median TTP was 3,7 months (range 0.5–13.4). Conclusions: These preliminary data indicate that irinotecan + 5FU/FA is active in patients previously treated for advanced gastric cancer with tumour growth control (PR + SD>6 months) achieved in 30.3 % patients during 8.3 months and with a very acceptable toxicity profile. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharma Aventis; Amgen

Irinotecan (CPT-11) and Mitomycin-C (MMC) as second-line treatment in advanced gastric cancer patients. A phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM)

4235 Background: Irinotecan (CPT-11) is active in the treatment of advanced gastric cancer (AGC) (Futatsuki K: JPN Cancer Chem. 1994, 21 (7) 1033–1038; Khone CH: Proc. Asco 1999, 18: 258). Mitomycin-c is traditionally considered active in AGC. CPT-11 and MMC demonstrated to be synergic in colture (Kano Y: Int. J. Cancer 1992, 50: 604–610). Taking in account these data the GOIM started a phase II study to evaluate the activity and toxicity of this combination in pretreated AGC patients. Methods: Pretreated AGC patients with PS ≥ 70- ≤ 100 (Karnofsky scale), age between 18–75 years, bidimensionally measurable disease, life expectancy more than 3 months, adequate bone-marrow, renal and hepatic function, written informed consent, entered into the trial. The two drugs were administered as follow: CPT-11 at the dosage of 150 mg/mq (120 mg/mq if age >70 years) as 90' iv infusion on days 1–8 and MMC at 8 mg/mq as short infusion immediately after CPT-11 on day 1. The cycles were repeated every 4 weeks. Up to now, 29 patients were enrolled. Their main characteristics were: sex (M/F) 18/11, median age 66 (range 42–75), median PS 80. The main sites of disease: liver 13, lymph nodes 10, local relapse 5, lung 3, peritoneum 5. Eleven patients had multiple sites of disease. Results: Twenty-four patients are evaluable for activity and toxicity; two are too early and three patients are not evaluable (two refused). One CR (4%) and 9 PR (37%), 4 SD (17%) and 10 PD (42%) were observed, for an overall objective response rate of 41% and a tumor growth control rate of 58%. The median time to disease progression was 5 months and the median overall survival was 10+ months. The main observed percent toxicity rate (G1–2 vs 3–4, NCI criteria) were: leukopenia 54/4, neutropenia 42/17, anemia 54/4, nausea/vomiting 42/4, diarrhea 33/0, mucositis 4/0, cholinergic syndrome 17/0. In 9 pts (37.5%) G-CSF was employed. Conclusions: The combination of CPT-11 and MMC is active and well tolerated in pretreated AGC patients; further studies will clarify its role also in untreated patients. No significant financial relationships to disclose.

Irinotecan (CPT-11) and Mitomycin-C (MMC) as second-line treatment in advanced gastric cancer patients. A phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM)

4235 Background: Irinotecan (CPT-11) is active in the treatment of advanced gastric cancer (AGC) (Futatsuki K: JPN Cancer Chem. 1994, 21 (7) 1033–1038; Khone CH: Proc. Asco 1999, 18: 258). Mitomycin-c is traditionally considered active in AGC. CPT-11 and MMC demonstrated to be synergic in colture (Kano Y: Int. J. Cancer 1992, 50: 604–610). Taking in account these data the GOIM started a phase II study to evaluate the activity and toxicity of this combination in pretreated AGC patients. Methods: Pretreated AGC patients with PS ≥ 70- ≤ 100 (Karnofsky scale), age between 18–75 years, bidimensionally measurable disease, life expectancy more than 3 months, adequate bone-marrow, renal and hepatic function, written informed consent, entered into the trial. The two drugs were administered as follow: CPT-11 at the dosage of 150 mg/mq (120 mg/mq if age >70 years) as 90' iv infusion on days 1–8 and MMC at 8 mg/mq as short infusion immediately after CPT-11 on day 1. The cycles were repeated every 4 weeks. Up to now, 29 patients were enrolled. Their main characteristics were: sex (M/F) 18/11, median age 66 (range 42–75), median PS 80. The main sites of disease: liver 13, lymph nodes 10, local relapse 5, lung 3, peritoneum 5. Eleven patients had multiple sites of disease. Results: Twenty-four patients are evaluable for activity and toxicity; two are too early and three patients are not evaluable (two refused). One CR (4%) and 9 PR (37%), 4 SD (17%) and 10 PD (42%) were observed, for an overall objective response rate of 41% and a tumor growth control rate of 58%. The median time to disease progression was 5 months and the median overall survival was 10+ months. The main observed percent toxicity rate (G1–2 vs 3–4, NCI criteria) were: leukopenia 54/4, neutropenia 42/17, anemia 54/4, nausea/vomiting 42/4, diarrhea 33/0, mucositis 4/0, cholinergic syndrome 17/0. In 9 pts (37.5%) G-CSF was employed. Conclusions: The combination of CPT-11 and MMC is active and well tolerated in pretreated AGC patients; further studies will clarify its role also in untreated patients. No significant financial relationships to disclose.

Paclitaxel and carboplatin in pretreated advanced gastric cancer: A phase II study

In the present study, the combination of paclitaxel and carboplatin was applied in the treatment of gastric carcinoma. This cytotoxic combination has been an effective regimen with acceptable toxicity in ovarian, lung and head and neck cancers. We evaluated 47 patients (37 male, 10 female), all with advanced disease and all having undergone prior chemotherapy treatment. All patients had disease progression or no response to the prior treatment. Forty-four patients had undergone a previous gastrectomy for gastric adenocarcinoma and 3 patients were inoperable at diagnosis. Paclitaxel 175 mg/m2 was administered as a three-hour infusion, followed by carboplatin 5 AUC infused for 90 min. Thirteen (27.66%) patients showed partial response with a median survival of 10 months; 3 (6.38%) patients showed minor response and 13 patients, stable disease with clinical benefit. The median survival of patients with minor response and disease stability was 6 months. Eighteen (38.29%) patients had disease progression with a median survival of 3 months. It appears that in advanced cancer patients, the paclitaxel-carboplatin combination is an effective second-line treatment, resulting in partial response and disease stability in 61% of patients as well as in a prolongation of median survival.