Does Docetaxel Add Benefit to the Oral Fluoropyrimidine S-1 in Gastric Cancer?

In Asian patients with previously untreated advanced or recurrent gastric cancer, overall survival (OS) and progression-free survival (PFS) were significantly improved when docetaxel was added to S-1, an oral fluoropyrimidine that is a standard treatment for this malignancy in East Asia and parts of Europe.

At the European Society for Medical Oncology (ESMO) 2012 Congress, investigators from the START trial (S-1 plus Docetaxel versus S-1 for advanced gastric cancer) presented an update to the survival analysis previously reported at the 2011 Gastrointestinal Cancers Symposium.  Kazuhiro Yoshida, MD, of Gifu University Hospital, Gifu, Japan, presented the findings at ESMO for the Japan Clinical Cancer Research Organization and the Korean Cancer Study Group Intergroup trial.

In the previous analysis, no statistically significant difference in overall survival was observed with the combination (HR 0.88; P = 0.1416).

“However, an independent biostatistician pointed out that there was a large number of censored cases, which led to an insufficient number of events for a proper [survival] analysis,” Yoshida said. “According to this recommendation, we performed further confirmation to resolve the censored cases to analyze the START trial properly.”

The current intention-to-treat analysis included 635 patients with advanced or relapsed gastric cancer randomly assigned to S-1 80 mg/m² on days 1-28 every 6 weeks or S-1 80 mg/m² on days 1-14 plus docetaxel 40 mg/m² on day 1 every 3 weeks. Patients received treatment until disease progression, for a median number of 5 cycles for the combination and 2 cycles for single-agent S-1. Patients were followed an average time of 11.4 months.

Median OS was 12.5 months in the docetaxel/S-1 group and 10.8 months in the S-1 group (HR = 0.837; P = 0.0319). PFS was 5.3 months versus 4.2 months, respectively (HR = 0.765; P = 0.001). The overall response rate in patients with measurable disease was 38.8% with the combination and 26.8% with S-1 alone (P = 0.005), Yoshida reported.

Several subsets derived a particular survival benefit from the combination: the Japanese cohort (versus Korean) (HR = 0.810), patients with non-measurable (versus measurable) disease (HR = 0.649), patients with ECOG performance status of 0 (HR = 0.780), and patients with no lymph node metastasis (HR = 0.688).

“Adding docetaxel to S-1 significantly improved OS, PFS and response rates, nevertheless it resulted in some increase proportion of hematological toxicities,” he said. Neutropenia grade 3 and higher was observed in 29% of patients, and febrile neutropenia in 3%, compared to 4.2% and 0%, respectively, with S-1 alone.

The findings point to docetaxel plus S-1 as a new treatment option for patients with untreated advanced gastric cancer, Yoshida concluded.

Gunnar Folprecht, MD, of the University Cancer Center in Dresden, Germany, discussed the findings. He said that the findings presented at ESMO “would be taken as positive.” Folprecht concluded that docetaxel plus S-1 is more effective than S-1 alone “if there had not been the analysis presented at the Gastrointestinal Cancers Symposium.”

Folprecht emphasized that the primary analysis was negative. That analysis showed 1-year survival to be 52.5% with the combination versus 46.0% with the single agent. Two-year survival showed 23.7% versus 20.6%, respectively; and 3-year survival was 13.0% versus 12.3% (HR 0.88; P = 0.1416).

S-1 is approved by the European Medicines Agency for advanced gastric cancer when given in combination with cisplatin, and the START trial suggests there may be a less toxic, platin-free way to give the drug, he added.

However, Folprecht stayed firm on his own views.

“My personal opinion is that docetaxel plus S-1 is not a new standard of care,” Folprecht said.

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