Archive for the ‘Gastric Cancer’ Category

Evolving Chemotherapy for Advanced and Metastatic Gastric Cancer

June 13, 2008

Gastric cancer is the fourth most common cancer worldwide, and the second leading cause of death worldwide.  The disease is often diagnosed at an advanced or metastatic stage, not curable by surgical means.  Therefore, palliative treatment to extend survival and to improve symptoms is important for patients.  Chemotherapy improves outcomes for advanced or metastatic gastric cancer patients, but standard cisplatin-5FU (flurouracil)-(CF) based regimens produce response in only 20-30% of patinets, and median overall survival (OS) remains poor at 7-8 months.   Median progression-free survival (PFS) for CF is 3-4 months. 

Recent studies have compared the addition of docetaxel (D) (Taxotere) to cisplatin-based regimens.  The final results of the TAX 325 Study comparing DCF to CF were reported in 2005 and published in 2007.  Response rate was 37% versus 25%, PFS was 5.6 months verus 3.7 months, and OS was 10.5 versus 9.6 months (all favoring DCF).  The 2-year survivals were 18 versus 9% (favoring DCF).  This was the highest reported 2-year OS in gastric cancer at the time.  Toxicities for both regimens were substantial, but manageable.  The problems of toxicity (febrile neutropenia, diarrhea, stomatitis, weight loss, nausea, vomiting) and poor QOL have made investigators and clinicians to question the risk/benefit ratio of  the regimen, at least in the schedule that was tested in TAX 325. 

The use of other regimens such as ECF (Epirubicin, Cisplatin, 5FU) has shown promise in advanced disease, but that regimen has potential cardiac risk, and reported OS is 8-9 months, not clearly advantageous when compared to CF. 

Therefore, recent efforts have focused on changes to schedule, infusion method, or the addition of new agents in an effort to reduce toxicity and to improve outcomes in gastric cancer.

At the ASCO Annual Meeting 2008, several abstracts were presented that employed such new schedules and/or agents in advanced or metastatic gastric cancer. 

2-day infusional 5FU, already commonly utilized in colon cancer therapy, is a less toxic method of 5FU delivery.  The abstract #4570 by Chiesa, et al. reported the outcome of DCF x 4 cycles every 2 weeks (with a modified dose and the 2-day infusion schedule of 5FU) followed by COFFI (oxaliplatin,irinotecan,5FU,Leucovorin, also with a 2-day infusional 5FU schedule) x 4 cycles every 2 weeks.  Treatment was every 2 weeks with peg-filgrastim support.  40 patients were enrolled.  28 were evaluable for response at the time of the report.  Dose reductions were required in 34% on DCF.  GI and hematologic toxicity were the main reasons.  After the DCF x 4, the overall response rate was 56% (2/28 CR + 16/28 PR).  21 patients proceeded to COFFI.  2 CRs after DCF maintained those durring COFFI.  Of the 16 PRs during DCF, 2 CRs were achieved, and 5 had further improvements in response).  2/7 patients with stable disease during DCF had PR with COFFI.  Two patients with liver metastases continue in CR at 33 and 16 months. The overall response rate to the entire program was 63%.  The 1 year survival was 31%.  The authors concluded that the program was feasible and highly effective.  

In abstract #4552, Enzinger et al. reported that bevacizumab (Avastin), cisplatin, docetaxel, and irinotecan in a three-week cycle produced a response rate of 63% in metastatic esophageal/gastric cancer.  UGT1A1 genotyping (*28 allele) predicted a high risk for occurrence of neutropenia and diarrhea from irinotecan in this regimen.

In abstract #4549, Han et al. reported the outcome of the the cetuximab (Erbitux) and FOLFOX6 regimen.  The response rate was 50%, with time-to-progression (TTP) 5.5 months, and OS 9.9 months.  The toxicity of this regimen appears to be more favorable than the other regimens noted above. 

These are good examples of the evolution of therapy options for gastric cancer.  Practicing physicians should not be limited in treatment choices for their gastric cancer patients because of rigid adherence to restricitve guidelines by payors or governmental agencies.  Such policies may function to limit cost of therapy (by restricting patients to CF or DCF approved therapy), with expected poor outcomes and higher than acceptable toxcities.  Newer treatments need to be promptly moved into clinical practice settintgs, potentially even when survival is not superior to existing standard therapy, if toxicity of the newer regimens are lower.  Such an approach will help better meet the goals of palliative therapy for patients.