Docetaxel, cisplatin, and fluorouracil in gastric cancer: does the punishment fit the crime?

As medical oncologists, we face making decisions every day about the choice of palliative chemotherapy for our patients with advanced malignancies. We are fortunate in esophagogastric cancer to have an increasing armamentarium of chemotherapy agents, including fluoropyrimidines, platinates, taxanes, anthracyclines, and topoisomerase I inhibitors. Targeted therapies affecting the vascular endothelial and the epidermal growth factor receptor pathways are now being screened in phase II and III trials. Despite a myriad of twoand three-drug chemotherapy regimens in the oncology literature, there is no consensus about the optimal chemotherapy for advanced gastric cancer. In deciding which therapy to administer, we must carefully weigh cost, toxicity, and complexity of administration of therapy with the relative efficacy, quality of life (QOL), and tolerance in patients. This includes a careful assessment of the individual patient’s performance status, burden of comorbid conditions, and age. When addressing these questions, I take inspiration from The Mikado by Gilbert and Sullivan, whose main character is given the task of doling out the appropriate punishment for particular crimes, including either beheading or boiling in oil for the crime of flirtation. Fortunately for the protagonists and the audience, these punishments are never meted out during the course of the opera. With oncologic therapy having the significant potential to expose patients to toxic complications, what magnitude of benefit from treatment justifies what level of toxicity for patients to endure? Modest advances have clearly been made in the development of chemotherapy for advanced gastric cancer. Single agents achieve responses in 10% to 20% of patients with a median survival time of 6 to 7 months, and the index regimen of cisplatin in combination with continuous-infusion fluorouracil (CF) increases response rates to 20% to 30% and median survival time to 7 to 8 months. Phase III trials that add a third agent to CF, including epirubicin plus CF (ECF) and docetaxel plus CF (DCF), report a 10% increase in response rate to 35% to 40% and a 1-month improvement in median survival time to 9 months but at the cost of increasing toxicity. How can we best evaluate and compare twoand three-drug regimens in gastric cancer to select the best therapy? In this issue, Roth et al report a randomized phase II trial comparing ECF, DCF, and the two-drug regimen of docetaxel and cisplatin (DC), with the end point of selecting the superior docetaxel regimen for further phase III evaluation. Also in this issue, Ajani et al present QOL and clinical benefit data from the pivotal V325 trial comparing DCF with CF. The V325 phase III trial of DCF in gastric cancer, which was recently reported by Van Cutsem et al, treated 445 patients with metastatic gastric cancer with either standard CF or DCF. This large and well-conducted trial represents a landmark accomplishment in this disease. Although described as a poor prognosis population, patients treated on V325 had a good performance status (99% had a Karnofsky performance status of 80% to 100%) and were relatively young (median age, 55 years). A significant response rate advantage was seen for DCF compared with CF (37% v 25%, respectively), as well as an improved time to tumor progression (5.6 v 3.7 months, respectively). Although only a modest 0.6month increase in median survival time was observed for DCF, both 1and 2-year survival rates were improved by 8% to 9%, with one of the highest 2-year survival rates (18%) ever reported for a chemotherapy trial in gastric cancer. However, the modest gains in this trial occurred at the cost of substantial toxicity. Rates of grade 3 to 4 stomatitis ranged from 21% to 27%, diarrhea ranged from 8% to 18%, neutropenia ranged from 57% to 82%, and febrile neutropenia ranged from 27% to 29%. Rates of hospitalization for these daunting toxicities were not reported by the authors, although deaths from therapy occurred in only 3% to 5% of patients treated. Fifty percent of patients receiving DCF were taken off therapy either because of adverse events from treatment or because of patient withdrawal of consent. With the advent of regulatory approval of docetaxel for the treatment of gastric cancer based on the V325 data, should we routinely use DCF as first-line treatment of patients? Will older patients with poorer performance status be able to tolerate the rigors of such therapy, and are the benefits worth the toxicity? Two studies reported by Ajani et al in this issue present QOL and clinical benefit data for patients treated on the V325 study and place the toxicity data in another context. DCF resulted in a longer time to 5% deterioration in global QOL measures compared with CF (6.5 v 4.2 months, respectively). Looking at individual QOL measures, time to deterioration was also significantly slower for DCF, with the exception of physical functioning. Although QOL assessment favored DCF over CF, neither regimen led to improvement in QOL, and the title of the paper, “Better Quality of Life. . .” for DCF should be restated as “Better Preservation of Quality of Life. . .” for DCF. In a second related article, Ajani et al evaluated the clinical benefit of DCF compared with CF in V325. The analyses JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 22 AUGUST 1 2007