ANCONA, Italy -- A five-drug postoperative chemotherapy regimen for gastric cancer that appeared promising in preliminary studies did not improve survival, researchers here reported.
ANCONA, Italy, April 20 -- An intensive, five-drug postoperative chemotherapy regimen that appeared promising in preliminary studies did not improve survival for gastric cancer patients, researchers here report.
The five-year survival rate was about 50% for patients on the five-drug weekly regimen as well as for those on a standard two-drug monthly regimen, said Stefano Cascinu, M.D., of the Universita Politecnica delle Marche here, and colleagues.
The five-year disease-free survival rate was about 40% in both patient groups, the Italian research team reported in the April 18 issue of the Journal of the National Cancer Institute.
Neither drug regimen was well-tolerated, which suggests that post-gastrectomy patients may not be able to handle any postoperative chemotherapy regimen well, even one with relatively low toxicity, the study authors said. Researchers should begin exploring neoadjuvant chemotherapy and other preoperative adjuvant therapies, they concluded.
The multicenter, randomized, prospective study included 400 patients who had undergone surgery for gastric cancer from 1998 to 2003. All patients were at high-risk for cancer recurrence, including patients with serosal invasion and lymph node metastasis.
About half the patients received eight weekly administrations of cisplatin (40 mg/m2 ), leucovorin (250 mg/m2), epidoxoorubicin (35 mg/m2), 5-fluorouracil (500 mg/m2), and glutathione (1.5 g/m2) with the support of filgrastim. This intensive, five-drug regimen is called the PELFw regimen.
The other half received a standard regimen consisting of six monthly administrations of a five-day course of 5-fluorouracil (375 mg/m 2 daily) and leucovorin (20 mg/m 2 daily). Median follow up was 54 months.
The overall five-year survival rate was 52% with the PELFw regimen and 50% with the standard regimen. The PELFw regimen did not reduce the risk of death (hazard ratio=0.95; 95% confidence interval=0.70 to 1.29).
Five-year disease free survival was 41% with the PELFw treatment and 40% with the standard treatment. The more-intensive regimen did not reduce the risk of cancer recurring (HR=0.98; 95% CI=0.75 to 1.29).
Poor tolerance and compliance were common in both patient groups. Only 19 patients (9.4%) were able to complete the PELFw regimen without dose or timing changes. Only 85 (43%) of patients were able to finish the standard regimen without such changes.
Neutropenia grade 3 or 4 was more common with the PELFw regimen (27 versus 17 patients). Grade 3 or 4 anemia was also more common with PELFw (13 versus 1 patient). Diarrhea was more common in the standard regimen (15 versus five patients), as was mucositis (16 versus 0 patients).
Previous studies have shown the five-year survival rate after surgery for gastric cancer ranges from 15% to 35%. "The unexpectedly long survival time in our trial may be due to several factors, among them, the high quality of surgery (number of D1 and D2 resections) observed in our trial," the authors said.
"In conclusion, our study did not show any benefit of an intensive adjuvant chemotherapy for curatively resected gastric cancer patients compared with a standard regimen," the authors said.
"Furthermore, toxicity associated with postoperative chemotherapy?suggests that it may be preferable to move toward preoperative approaches," they said.
The study serves as a reminder "that many new regimens, despite initial enthusiasm based on preliminary studies, are ultimately shown to be ineffective or at least no more effective than other available treatments," said Susan Ellenberg, Ph.D., and Weijing Sun, M.D., of the University of Pennsylvania, in an accompanying editorial.
In addition, the study's unexpectedly low mortality rate "unquestionably depleted the power of the study to identify any but very large improvements," Dr. Ellenberg and Dr. Sun said.
Nevertheless, the data don't even hint at a beneficial trend, and "the authors, while pointing out the reduced power, appropriately draw the straightforward conclusion that this intensive regimen is no better than the more 'standard' regimen against which it was tested," they said.
The editorialists also pointed out that studies such as this one underscore the need to evaluate new regimens in well-designed and conducted randomized trials rather than using historical controls.
Thus, "the observation of a survival rate vastly higher than had been anticipated could easily have led to the conclusion that this regimen was a huge advance over previous approaches to adjuvant therapy for gastric cancer; such a conclusion would likely today be leading many patients and their physicians to choose what is clearly a suboptimal and perhaps completely ineffective therapy instead of other regimens for which there is more definitive evidence of efficacy," they wrote.