Regimen For Gastric Cancer Research Articles

Abstract C204: Inhibition of c-Met signaling in combination with cisplatin and 5-fluorouracil significantly enhances antitumor effects in gastric cancer models

Abstract Gastric cancer is currently the second most frequent cancer-related cause of death with an incidence rate of approximately one million cases annually. The present worldwide standard of care treatment regimen for gastric cancer is the combination of 5-fluorouracil (5-FU) and platinum analog (cisplatin). Many receptor tyrosine kinases are deregulated in gastric cancer including erbB2, c-Met, and EGFR. The purpose of our study was to dissect the role of c-Met signaling in gastric cancer and test the effects of our c-Met inhibitor (MK-8033) alone and in combination with the standard of care agents 5-FU and cisplatin. As a monotherapy, MK-8033 potently inhibited proliferation in a panel of gastric cancer cell lines in vitro. When administered simultaneously with cisplatin and 5-FU, the effects of the combination were diverse, ranging from additive to antagonistic. Altering the treatment schedule by the addition of 5-FU and cisplatin prior to MK-8033 resulted in an overall combination benefit across the panel. In a gastric cancer xenograft model, while MK-8033 alone significantly inhibited tumor growth progression, the co-administration of 5-FU and cisplatin with MK-8033 showed greater benefit than either the monotherapy or the standard regimen. In vitro cell cycle and survival analysis support the observed in vivo data, and provides a mechanistic rationale for the observed combination benefit. Our data suggest the combination of c-Met inhibitors with standard of care agents 5-FU and cisplatin may be beneficial in gastric cancer patients with activated c-Met signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C204.

Challenge for a better combination with basic evidence

5-Fluorouracil (5-FU) has been the most widely accepted and studied chemotherapeutic agent, and many combination chemotherapeutic regimens have been reported. However, until recently, a standard regimen for metastatic gastric cancer had not been established. The combination of S-1 and cisplatin is a good candidate as a standard first-line regimen for metastatic gastric cancer. On the other hand, interest in biochemical modulation has become wide spread recently. The low level of dihydropyrimidine denhydrogenase (DPD), thymidylate synthase (TS) activities, and a high level of orotate phosphoribosyl-transferase (OPRT) activity enhance the antitumor effect of 5-FU and S-1. Docetaxel is one of the agents that modulate these enzyme expressions and activities. Moreover, the response rate of combination therapy of docetaxel and S-1 for metastatic gastric cancer was 56.3% and median survival time was 14.3 months in a phase II study, showing it to be a good candidate for a new standard regimen for gastric cancer. A phase III collaborative study, START (S-1 and Taxotere for advanced gastric cancer randomized phase III trial), is now under way in Japan and Korea.

Docetaxel, Cisplatin, and Fluorouracil in Gastric Cancer: Does the Punishment Fit the Crime?

Docetaxel, Cisplatin, and Fluorouracil in Gastric Cancer: Does the Punishment Fit the Crime?

Phase II clinical trial of XELOX as first line treatment for patients with unresectable or metastatic gastric cancer

15062 Background: The survival of advanced gastric cancer remains poor, while no chemotherapy regimen was recognized standard. Oxaliplatin and Capecitabine (Xeloda) have demonstrated promising antitumor efficacy in advanced colorectal cancer. The present study was conducted to further evaluate the efficacy and safety of XELOX (Oxaliplatin and Xeloda) regimen in gastric cancer. Methods: Patients with unresectable or metastatic gastric cancer were enrolled into this study. They all receive the XELOX regimens (Oxaliplatin 130mg/ m2 intravenously in 2 hours on day 1 followed by oral capecitabine 1000mg/ m2 twice daily for 14 days every 3 weeks).We evaluated the response every 2 cycles. Results: The median age of the total enrolled 45 patients was 55 years (range, 22–82 years), including 32 male and 13 female. They received a median of 5 cycles (range, 2–8 cycles) of XELOX. 21 of 45 patients (46.7%) achieved an objective response, 1 patient (2.2%) had completed response. 17 patients (37.8%) experienced stable disease. Median time to tumor progression (TTP) and median overall survival were not available yet due to the further follow-up needed. Most toxicity events were mild to moderate in XELOX regimen, with grade 3/4 neutropenia of 8.9 %, thrombocytopenia of 6.7%, anemia of 11.1%, hand-foot syndrome of 6.7 % and diarrhea of 6.7 %. Grade 3 neuropathy was 4.4%. The patients with advanced gastric cancer had a good tolerance to this chemotherapy. Conclusions: XELOX is a highly effective first-line treatment for unrsectable and metastatic gastric cancer. The response rates in this trial seems to be similar to those observed with FU/leucovorin/oxaliplatin combinations. XELOX is tolerable well in the treatment of advanced gastric cancer. No significant financial relationships to disclose.

Novel cytotoxic regimens in gastric cancer

The docetaxel-cisplatin-5-fluorouracil (TCF) triplet has demonstrated superiority over cisplatin-5-fluorouracil (CF) and subsequently gained approval in the USA and Europe for the treatment of advanced gastric cancer. While this is a major advancementin gastric cancer therapy, there is potential to further improve outcomes by optimizing and building of the TCF regimen. The availability of ‘new’ cytotoxic agents such as oxaliplatin, irinotecan, capecitabine and S-1, as well as the biological agents, provides many options for modifying the standard TCF regimen, as used in the TAX 325 study. Potential strategies to improve efficacy, tolerability and/or convenience include variations in the dosing schedule, the substitution of cisplatin with oxaliplatin, the substitution of 5-fluorouracil with oral fluoropyrimidines, and the addition of biological agents. Emerging data support the feasibility of these strategies and will be reviewed in this article.

Does endoscopic ultrasound staging already allow individual treatment regimens in gastric cancer

The aim of our study was to evaluate the accuracy of preoperative TNM staging with endoscopic ultrasound (EUS) in gastric cancer patients in comparison with the pathohistological stage of the resected specimen, and to determine the possible implications of EUS for individualized treatment of gastric cancer patients at our institution. The study included 82 patients operated for resectable gastric cancer between January 1(st) 2001 and July 1(st) 2003 at the Maribor Teaching Hospital Department of Abdominal and General Surgery. The EUS stage was assessed preoperatively at the Endoscopical Unit, and the pathohistological stage in the resected specimen was determined postoperatively at the Department of Pathologic Morphology according to recommended standards. Comparison of EUS and pathohistological assessments revealed accuracy of EUS staging for locoregional tumor infiltration (category T) in 68% of patients. The accuracy of EUS staging was 68% for T1, 69% for T2, 69% for T3 and 60% for T4. Lymph nodes (category N) were correctly staged with EUS in 57% of cases. The EUS stage was correct for lymph nodes with no metastases (N-) in 40% of cases, and for lymph nodes with metastases (N+) in 90%. There was no significant difference in accuracy of EUS staging with regard to tumor site (P = 0.768) or tumor size (P = 0.766). According to our results the accuracy of EUS staging matched pathohistological staging with regard to tumor infiltration and lymph node stage in 68% and 57% of cases respectively. Underestimation of the final T2 and T3 stages as T1 stage by EUS presents a problem regarding the consistency of EUS examination at our institution, particularly with respect to individual treatment for early gastric cancer. The present uncertainty in EUS stage reliability makes it necessary to have a strategy of radical resection with D2 lymphadenectomy in patients within EUS stages T1-T3, with additional CT examinations in more advanced EUS stages in order to visualize the circumstances of tumor growth. Nevertheless, EUS provides an opportunity for the surgeon to gain more insight into the loco-regional circumstances of the gastric tumor process. For development of individual modes of treatment based on EUS staging, a more reliable assessment of EUS stage is mandatory.

A Phase II Study of Infusional 5-Fluorouracil and Low-Dose Leucovorin with Docetaxel for Advanced Gastric Cancer

Background: The standard chemotherapy regimen for advanced gastric cancer has not yet been established. We investigated the efficacy and the safety of the combination of docetaxel with infusional 5-fluorouracil (5-FU) and leucovorin (FLT) in advanced gastric cancer. Methods: Patients received docetaxel 75 mg/m² (1-hour infusion) followed by a leucovorin bolus 20 mg/m² and a 24-hour infusion of 5-FU 1,000 mg/m² (day 1–3) every 3 weeks. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the toxicity was evaluated by National Cancer Institute common toxicity criteria (NCI-CTC). Results: Sixty-six patients were enrolled. Median relative dose intensity was 86%. Of 57 evaluable patients, the overall response rate was 25.7%. The response rate was 34.2% in chemonaïve patients and 14.2% in the patients who had previously received treatment. Median time to progression and overall survival duration were 5.2 and 9.7 months, respectively. The most frequent grade 3–4 toxicity was neutropenia, which was the major cause of treatment delay. Other hematological and nonhematological toxicities were rare. Conclusions: The FLT regimen showed a comparable efficacy with other second-generation regimens. Because of the low nonhematological toxicity, this could be a potential alternative to the cisplatin-containing regimens in gastric cancer.

5-FU plus leucovorin (Mayo Regimen) for concurrent chemoradiotherapy after surgery in patients with resectable locally advanced gastric carcinoma: Preliminary results of a phase II study

4196 Background: Patients with locoregionally advanced carcinoma of the stomach have a grim outcome due to frequent local and systemic recurrences after surgery. To potentially increase the local control or survival rate and decrease relapses, we investigated a strategy of concurrent chemoradiotherapy and followed by consolidation chemotherapy after surgery. Methods: Operable 71 patients (Stage IB-IV, M0) underwent total or subtotal gastrectomy. Adjuvant chemotherapy (250 mg/m2 5-FU) was administered concurrently on the first day of every radiotherapy weeks [which was totally standart field radiotherapy (RT), or total abdominal field RT up to 20 Gy first, then returned to standart field RT], . After chemoradiotherapy regimen, consolidation chemotherapy consisted of 450 mg/mg 5-FU plus 20 mg/m2 Leucovorin was applied up to four cycles, q28 d. Results: Of 71 patients have been enrolled, 67 (94%) of 37 (55%) were randomized to standart field RT arm, and 30 (45%) were randomized to total abdominal irradiation arm. There were not significant difference between two arms according to the age, sex, surgical approach, tumor localization, and stages. Six patients in both arms did not get consolidation chemotherapy. The median follow-up was 7.5 months (range: 6–29 m). One-year progression-free survival was 53% and 65% on the first and second arm, respectively. The overall survival was 63% and 70% on the first and second arm, respectively. Nine patients (24%) on the first, and 12 (40%), and on the second arm were died. There was not a significant difference between the two groups. Commonest side effects during chemoradiotherapy were grade 3–4 neutropenia on the first arm (14%), diarrhea on the second arm (17%). There were no deaths related to chemotherapy, chemoradiotherapy, or surgery. Conclusions: Preliminary results suggest the feasibility of postoperative adjuvant chemoradiotherapy with 5-FU followed by consolidation chomotherapy with MAYO regimen in gastric cancer with acceptable toxicities. No significant financial relationships to disclose.

5-FU plus leucovorin (Mayo Regimen) for concurrent chemoradiotherapy after surgery in patients with resectable locally advanced gastric carcinoma: Preliminary results of a phase II study

4196 Background: Patients with locoregionally advanced carcinoma of the stomach have a grim outcome due to frequent local and systemic recurrences after surgery. To potentially increase the local control or survival rate and decrease relapses, we investigated a strategy of concurrent chemoradiotherapy and followed by consolidation chemotherapy after surgery. Methods: Operable 71 patients (Stage IB-IV, M0) underwent total or subtotal gastrectomy. Adjuvant chemotherapy (250 mg/m2 5-FU) was administered concurrently on the first day of every radiotherapy weeks [which was totally standart field radiotherapy (RT), or total abdominal field RT up to 20 Gy first, then returned to standart field RT], . After chemoradiotherapy regimen, consolidation chemotherapy consisted of 450 mg/mg 5-FU plus 20 mg/m2 Leucovorin was applied up to four cycles, q28 d. Results: Of 71 patients have been enrolled, 67 (94%) of 37 (55%) were randomized to standart field RT arm, and 30 (45%) were randomized to total abdominal irradiation arm. There were not significant difference between two arms according to the age, sex, surgical approach, tumor localization, and stages. Six patients in both arms did not get consolidation chemotherapy. The median follow-up was 7.5 months (range: 6–29 m). One-year progression-free survival was 53% and 65% on the first and second arm, respectively. The overall survival was 63% and 70% on the first and second arm, respectively. Nine patients (24%) on the first, and 12 (40%), and on the second arm were died. There was not a significant difference between the two groups. Commonest side effects during chemoradiotherapy were grade 3–4 neutropenia on the first arm (14%), diarrhea on the second arm (17%). There were no deaths related to chemotherapy, chemoradiotherapy, or surgery. Conclusions: Preliminary results suggest the feasibility of postoperative adjuvant chemoradiotherapy with 5-FU followed by consolidation chomotherapy with MAYO regimen in gastric cancer with acceptable toxicities. No significant financial relationships to disclose.

Biweekly fluorouracil-based regimen in gastric cancer

Biweekly fluorouracil-based regimen in gastric cancer

Ist neoadjuvante Therapie für lokal fortgeschrittene Magenkarzinome Standard?

Despite surgical efforts and encouraging data of a few postoperative therapy trials, locally advanced gastric cancer is in need of the development of effective multimodal therapeutic concepts. Regarding preoperative therapy the goal is to raise the number of complete tumor resections (R0-resections) leading to an improved prognosis of the disease. Neoadjuvant therapy has the theoretical advantage of early destruction of distant micrometastasis with a consecutive reduction of tumor relapse outside the resection margins. The likelihood of R0-resections should be increased with the response of the primary tumor to neoadjuvant therapy. Neoadjuvant chemotherapy using platinum based regimens in gastric cancer has shown its activity in a number of phase II studies. Especially after response to chemotherapy the survival was significantly better after complete surgical tumor resection. The neoadjuvant use of a sequence of chemotherapy followed by radiotherapy before gastrectomy did result in a complete histopathological response in 20-25% of gastric cancer patients. This regimen seems to be promising, but there are still no long term results available. Parallel to the expected data from the first phase III studies the main impact of research in this field has to be focused on to the development of new and effective therapeutic agents and with accompanying identification of factors which are able to predict the response to neoadjuvant treatment.

Which chemotherapy regimen for gastric cancer?

Which chemotherapy regimen for gastric cancer?

Phase II Study with Folinic Acid, Etoposide, 5-Fluorouracil and Cisplatin (FLEP) for Advanced Gastric Cancer

Background: Cisplatin is an active drug in advanced gastric cancer and acts synergis-tically with etoposide and 5-fluorouracil (5-FU). These were the reasons for adding cisplatin (P) to the combination of folinic acid, etoposide, and 5-FU (ELF), which is one of the newer and active regimens for the treatment of advanced gastric cancer. Patients and Methods: 29 patients with advanced gastric cancer were treated with folinic acid (300 mg/m2), etoposide (100 mg/m2), 5-FU (500 mg/m2), and cisplatin (30 mg/m2) intravenously on days 1, 2, and 3. Cycles were repeated on days 22-28. Results: 2 (7%) complete and 9 (31%) partial remissions were achieved. The medium remission duration was 6 months and the median survival time was 7 months. The main toxicity of FLEP was severe myelosuppression of WHO grades 3 and 4 leucocytopenia in 38 and 21 % of the patients. Conclusions: FLEP is an active regimen for gastric cancer with respect to remission induction. However, because of the marked objective and subjective side effects, and a response rate which was not different from ELF alone, the further evaluation of this combination is not meaningful in this tumor.