CRITICS Study: Equal Benefit From Adjuvant CT, CRT in Resectable Gastric Cancers

CRITICS Study: Equal Benefit From Adjuvant CT, CRT in Resectable Gastric Cancers

Dr. Marcel Verheij
The first results from the CRITICS study, presented during the “Gastrointestinal (Noncolorectal) Cancer” Oral Abstract Session on June 6, concluded that patients undergoing surgery with curative intent had similar overall survival (OS) and progression-free survival (PFS) regardless of whether they received chemotherapy (CT) or chemoradiotherapy (CRT) after surgery (Abstract 4000).

“The expected treatment difference in overall survival has not been observed, and the 5-year overall and median survival compare favorably with other studies in Western countries,” said Marcel Verheij, MD, PhD, of The Netherlands Cancer Institute, who presented the study.

“The study was clearly well conducted and was powered to answer the question that was posed. The design was rational, thoughtful, and the two arms were well balanced,” discussant Peter C. Enzinger, MD, of the Dana-Farber Cancer Institute, told the ASCO Daily News. “However, [this] is the third study that has failed to show the benefit of combining aggressive CT and CRT in resectable gastric cancer.”

The CRITICS Study

CRITICS was an international, multicenter, randomized, phase III study. Patients with stage Ib-IVa resectable gastric adenocarcinoma localized to the stomach or the gastroesophageal junction were enrolled on the study. All patients received preoperative CT with standard dosages of a combination of epirubicin, cisplatin, and capecitabine, or epirubicin, oxaliplatin, and capecitabine.

Following surgery, patients were randomly assigned to receive either CT (393 patients) with the same regimens used in the preoperative setting or CRT (395 patients). Radiation therapy was administered at 45 Gy in 25 fractions with a concurrent CT combination of cisplatin and capecitabine, both given at lower doses.

Study Results

Median follow-up was 4.2 years. For the primary endpoint, 5-year OS was similar for patients across the two arms: 40.8% for CT and 40.9% for CRT therapy, with corresponding median survival of 3.5 years and 3.3 years. Similar PFS was also reported across the two arms. 

However, only 47% and 52% of patients completed postoperative CT and CRT therapy, respectively. Patients did not receive postoperative treatment for several reasons, including personal preference, progressive disease, and toxicity in the preoperative setting. 

Dr. Verheij indicated that surgical quality was excellent, with 87% undergoing at least a D1+ dissection without splenectomy or pancreatectomy and removal of a median of 20 lymph nodes. “The surgical quality in this study addressed important shortcomings of previous studies, and adequate surgery remains the cornerstone of treatment in this setting,” he told the ASCO Daily News.

What’s Next?

According to Dr. Verheij, data from CRITICS suggest that preventing locoregional recurrence should be emphasized in the preoperative setting where patients can better tolerate therapy and where its effect may be more pronounced. That’s why the next randomized phase II study (CRITICS II) will evaluate three preoperative strategies: CT, CRT therapy, and combination CT and CRT therapy.

Dr. Peter C. Enzinger
Dr. Enzinger believes that combining aggressive CT and radiation therapy is not going to get us much further. Citing examples of CALGB 801010 and the ARTIS T studies, Dr. Enzinger argued that aggressive adjuvant trials have been disappointing and suggested that focus should remain on higher-risk lymph node–positive patients. In light of the failed GATSBY (ado-trastuzumab in advanced gastric cancer), NSABP C-08 (bevacizumab in adjuvant colon cancer), and AVANT (bevacizumab in adjuvant colon cancer) studies, he even questioned whether targeted therapies with trastuzumab (RTOG 1010) and bevacizumab (MAGIC-B) may work in this setting.

Dr. Enzinger expressed hopes for evaluating immunotherapies in the setting of early gastric cancer. In support of his argument, he pointed out that the PD-1 inhibitors pembrolizumab (KEYNOTE 012) and nivolumab (CheckMate 032) have both shown activity in advanced gastric cancers.

Indicating that gastric cancer has genotypic subtypes, Dr. Enzinger concluded, “We need to stop treating phenotypic gastric cancer. The cancer genome should drive future adjuvant trials of targeted therapies, particularly as we move into the immunotherapy era.”

---Alexander Castellino, PhD