Gastric Cancer Trial Asks 'Globally Significant Question'

Zosia Chustecka

October 07, 2015

VIENNA ― The ongoing TOPGEAR trial in gastric cancer is addressing a "globally significant question," says principal investigator Trevor Leong, MD, from the Division of Radiation Oncology at the Peter MacCallum Cancer Centre, Melbourne, Australia.

The trial is investigating the novel use of preoperative chemoradiation, and the results from part 1 of the study (n = 120) show that it is safe and feasible, Dr Leong told delegates here at European Cancer Congress (ECC) 2015.

The second part of the trial, which addresses efficacy with the end point of overall survival, is now under way, with the aim of recruiting a further 625 patients, for a total sample size of 752.

Current accrual is 202 patients recruited from 68 active sites, Dr Leong told the meeting attendees. In total, 80 centers are involved in 15 countries in Asia-Pacific, Europe, and North America.

The TOPGEAR trial is important, because at present, the treatment of gastric cancer varies widely around the world, said Josep Tabernero, MD, PhD, head of medical oncology at Vall d'Hebron University Hospital, Barcelona, Spain, in a commentary prepared by the European Society for Medical Oncology (ESMO). Surgery offers a curative option, and both chemotherapy and radiotherapy are added to prevent relapse. However, the best way to sequence these modalities remains unclear, he noted.

Currently, perioperative chemoradiotherapy is the standard of care in Europe, whereas postoperative chemoradiotherapy is the standard of care in North America, and postoperative chemotherapy is the preferred option in Asia, he explained.

The perioperative choice, favored in Europe, is based on robust data from two phase 3 clinical trials, Dr Tabernero commented. In the MAGIC study ( N Engl J Med . 2006 Jul 6;355:11-20), patients who received perioperative chemotherapy with epirubicin, cisplatin, and 5-fluorouracil (5-FU) showed a significantly improved 5-year overall survival of 36%, compared with 23% in the control group, who were treated with surgery alone. A second study, FFCD 9703 (J Clin Oncol. 2007;25;18 suppl 4510) showed a similar gain with perioperative use of cisplatin and 5-FU.

However, a third phase 3 trial of perioperative chemotherapy, the EORTC 40954 (J Clin Oncol. 2010;28:5210-5218), which ran in parallel, could not demonstrate a statistically significant benefit in terms of survival, probably because of poor recruitment. "However, it did show more small tumors and R0 resection in the patients within the perioperative chemotherapy arm," Dr Tabernero noted.

Other recent studies support the use of postoperative chemoradiotherapy as a standard of care, as favored in North America. The INT 0116 study ( N Engl J Med . 2001;345:725-730) showed that treatment with 5-FU and radiotherapy after surgery improved median overall survival to 35 months, compared with 27 months in the control group, which was treated with surgery alone. Two other trials also demonstrated a clear benefit of adding postoperative chemoradiation, the ACTS-GT study, using chemotherapy with S-1, and the CLASSIC trial, using the combination of capecitabine and oxaliplatin.

The TOPGEAR trial examines a new approach, that of using preoperative chemoradiation, and addresses the issue of "whether giving the most complete strategy up front will translate into a survival benefit," Dr Tabernero commented.

Giving chemoradiation before surgery has the advantage of downstaging as well as potential micrometastasis eradication, Dr Tabernero commented. In addition, chemoradiation is better tolerated when given before surgery than afterward.

TOPGEAR Introduces Preoperative CRT

Patients in the control arm of the trial receive perioperative chemotherapy with epirubicin, cisplatin, and 5-FU (perioperative ECF), which was established as a standard of care by the MAGIC trial. This consists of three preoperative and three postoperative cycles of ECF.

Patients in the experimental arm receive a similar treatment, but they also receive additional preoperative chemoradiation (45 Gy with concurrent 5-FU) as well as two cycles of ECF prior to surgery. They then receive three further cycles of ECF following gastric resection.

Results from part 1 of the trial, conducted in 120 patients, show that the experimental arm is safe and feasible and has an acceptable toxicity profile, Dr Leong told the meeting. Preoperative chemoradiation does not affect surgical compliance, he said, and does not increase surgical morbidity ― there was a similar rate of surgical complications in both treatment arms.

The results showed no significant differences between the two groups. The proportion of patients receiving preoperative chemotherapy was 93.3% in the control group and 98.3% in the experimental arm, and 92% of these patients also received preoperative chemoradiation.

The proportion of patients proceeding to surgery was 90% in the control group and 85% in the experimental group. Among the patients who underwent surgery, 64% of the control group and 50% of the experimental group received postoperative chemotherapy.

Table. Adverse Events (Grade ≥3)

  Control Group Experimental Group
Vomiting 6.7% 8.3%
Diarrhea 11.7% 16.7%
Neutropenia 40% 45%
Febrile neutropenia 8.3% 10%
Anastomotic leak 5.6% 7.8%
Intra-abdominal sepsis 7.40% 5.90%

 

"The safety profile shows very similar toxicity between the two arms," Dr Tabernero commented. "Therefore, the experimental approach is completely feasible. Now we will have to wait for the efficacy in order to know the benefit of this more intense perioperative strategy."

"By answering the question of the multimodality sequence, the results of this trial will help to unify the treatment of local and locally advanced gastric cancer around the world," Dr Tabernero commented. "The challenge then would be where to incorporate targeted strategies, considering the heterogeneity of these tumors."

The trial is funded by the National Health and Medical Research Council (Australia), the Canadian Institute of Health Research, the EORTC Academic Fund, Cancer Australia, and HRC New Zealand. The TOPGEAR investigators report no relevant financial relationships.

European Cancer Congress (ECC) 2015: Abstract 2200. Presented September 29, 2015.

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