Is there any hope for patients with advanced gastric cancer after failure of fluoropyrimidine and platinum?

By Dr Daoyuan Wang, MD; AmMed Cancer Center

Although the incidence of gastric carcinoma has fallen in most Western countries, it remains a significant problem in terms of global health and is the second most common cause of cancer mortality worldwide. Gastric cancer is often diagnosed at an advanced stage, with approximately half of all patients presenting with unresectable, locally advanced, or metastatic disease. Combination chemotherapy remains the standard of care for advanced gastric cancer and four randomized studies comparing best supportive care and chemotherapy versus best supportive care alone have shown that chemotherapy improves survival and quality of life. 

Numerous classical chemotherapy agents including 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin-C, doxorubicin, cisplatinum, etoposide, and epirubicin, have all shown clinical activity in advanced gastric cancer (AGC). Among them, 5-FU and cisplatinum have been widely used as a component of combination therapy such as in the widely used ECF regimen (epirubicin, cisplatinum, and 5-FU). In addition, randomized trials have shown that the combination of 5-FU and cisplatinum is associated with improved RR and time to progression (TTP) compared with FAM (5-FU, doxorubicin, and mitomycin) or 5-FU monotherapy. Unfortunately, nearly half of all AGC patients will not respond to cisplatinum-based first-line chemotherapy. Furthermore, most patients who achieve response to the first-line chemotherapy will ultimately experience clinical disease progression and require second-line treatment. There is a pressing need for effective salvage treatment after the failure of first-line chemotherapy in AGC. In addition, there are few data on the safety and efficacy of second-line treatments in Chinese patients with AGC. 

It has recently been shown that the combination of taxanes and oxaliplatin (OXA) may be synergistic in vitro, when docetaxel (DOC) is administered before OXA; the same conclusion was reached in a phase I study. Several potential advantages support the rationale for testing the combination of DOC and OXA (DOCOX) in the treatment of AGC. Both agents have a significant activity in AGC. Furthermore, OXA has similar efficacy to cisplatinum with less hematological toxicity and OXA is less emetogenic than cisplatinum eliminating the need for intravenous hydration. 

Currently, Dr Haijun Zhong and his colleagues finished a phase II clinical trial of docetaxel plus oxaliplatin (DOCOX) as a second-line treatment after failure of fluoropyrimidine and platinum in Chinese patients with advanced gastric cancer, and published it in Anti-cancer Drugs 2008; 19:1013-1018. They evaluated an experimental combination regimen of docetaxel (60mg/m²) as an intravenous infusion of less than 1 h, followed by oxaliplatin (130mg/m²) intravenously for less than 2 h. Both drugs were administered on day 1 of a 21-day cycle, in in Chinese patients with AGC who had received a cisplatinum-based first-line therapy earlier.. The trial enrolled 48 patients of whom 46 (95.8%) were assessable for response. The median time to progression was 4.4 months (95% confidence interval (CI): 3.4-5.4 months) and the median overall survival was 7.2 months (95% CI: 6.6-12.1 months). Partial response was confirmed in 11 of 48 cases (22.9%; 95% CI: 10.9-34.9%) and no complete responses were seen. Significant hematologic toxicity was noted with grade 3 and grade 4 neutropenia occurring in 21.7% and 4.3% of patients, respectively, as well as grade 3 thrombocytopenia occurring in 4.3% of patients. Grade 3 febrile neutropenia occurred in 6.5% of the patients. There were no treatment-related deaths during on the study.  

"Docetaxel and oxaliplatin have modest activity with predictable hematologic toxicity when given as salvage therapy for Chinese patients treated earlier for AGC." Dr Daoyuan Wang said, who was the corresponding author of this study, from AmMed Cancer Center, Shanghai Ruijin Hospital, Medical School of Shanghai Jiaotong University, "Given the short duration of response more focus should be given to newer biologic agents and triplet regimens."

By Dr Daoyuan Wang, MD
AmMed Cancer Center
Shanghai Ruijin Hospital
Medical School of Shanghai Jiaotong University
Email: ghealth2008@gmail.com
Tel: +86-1360 1628 114

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