BOSTON—Debate continues about the role of preoperative chemoradiation added to chemotherapy in neoadjuvant treatment strategies for resectable gastric adenocarcinoma. At the Society of Surgical Oncology’s 2023 International Conference on Surgical Cancer Care, two surgical oncologists presented the relative merits of adding and not adding preoperative chemotherapy to the treatment regimen in this setting.
Pro: Pre-op Chemoradiation Should Be Added
On the pro side of the ledger, Brian Badgwell, MD, MS, a professor of surgery at The University of Texas MD Anderson Cancer Center, in Houston, began his presentation by wondering why clinicians even question the merits of adding chemoradiation for resectable gastric adenocarcinoma, particularly because the success of the approach in esophageal cancer has been well documented.
Longstanding Approach at MD Anderson
“MD Anderson has favored the chemoradiation approach for gastric adenocarcinoma since the 1990s, with good results,” Dr. Badgwell said. “With a few modifications, we’ve kept up with it since that time. But the long and the short of it is that there has never been a trial in the United States comparing chemoradiation with chemotherapy in gastric adenocarcinoma, and that lack of evidence has likely prevented many surgeons from adopting the technique.”
As Dr. Badgwell discussed, neoadjuvant preoperative chemoradiation is included in the latest version of the National Comprehensive Cancer Network (NCCN) treatment guidelines for gastric cancer, specifically for cT2 stage or higher (any N), where the approach garners a category 2B recommendation. (Preoperative chemotherapy carries a category 1 recommendation.) Chemoradiation is also an NCCN recommendation for medically fit, surgically unresectable gastric cancer patients.
Research has borne out the viability of the approach, Dr. Badgwell said, beginning with a 2001 trial of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction, who were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone (N Engl J Med 2001;345[10]:725-730). The trial found a median overall survival in the surgery-only group of 27 months, significantly less than the 36 months in the chemoradiotherapy group (hazard ratio for death, 1.35; P=0.005). Similarly, Smalley et al conducted a long-term follow-up (more than 10 years) of the same patient cohort and found strong, persistent benefit from adjuvant radiochemotherapy (J Clin Oncol 2012;30[19]:2327-2333).
More recent research has come to similar conclusions. In 2015, Dr. Badgwell and his co-investigators examined overall survival among patients with resectable gastric cancer who had been treated with preoperative chemoradiation therapy and gastrectomy (J Am Coll Surg 2015;221[1]:83-90). They found that among 192 patients who met inclusion criteria, 178 (93%) had an R0 resection. Furthermore, median overall survival for all patients was 5.8 years, while the five-year overall survival rate was 56%.
Yet for Dr. Badgwell, perhaps the most telling evidence has come from a multi-institutional analysis directly comparing the two approaches in resectable gastric adenocarcinoma (Ann Surg 2021;274[4]:544-548). Using data from MD Anderson and Moffitt Cancer Center, the researchers created propensity-matched cohorts of 231 patients who received chemoradiation and 174 who received chemotherapy alone.
That study found that chemoradiation and chemotherapy alone had similar rates of microscopically negative resections (93% vs. 91%; P=0.81), but chemoradiation had higher rates of complete pathologic response (15% vs. 4%; P=0.003) and lower pathologic stage (P=0.002). What’s more, median overall survival was found to be 53 months (95% CI, 30-77 months) in chemotherapy patients and 120 months in chemoradiation patients (95% CI, 101-138 months; P=0.015).
Despite the strength of these findings, Dr. Badgwell recognized they are not as strong as those from a randomized controlled study design. Results from two randomized controlled trials directly comparing the two approaches—TOPGEAR and CRITICS-II—are highly anticipated.
Better Margins and Pathologic Response
“It’s clear that using the preoperative chemoradiotherapy approach is associated with higher rates of a negative margin at surgery and higher rates of pathologic complete response,” Dr. Badgwell concluded. “But I think the big takeaway point for me is that we have not done a very good job of finding which patients should get the perioperative chemotherapy approach and which patients should get the radiation. At the end of the day, I’m hoping we’re able to do some genomic profiling or basic science work to help figure out which patients should get which treatment.”
Con: No Strong Evidence For Chemoradiation’s Benefit
The counterpoint to Dr. Badgwell’s argument was taken up by Vivian E. Strong, MD, the Iris Cantor Endowed Chair at Memorial Sloan Kettering Cancer Center, and a professor of surgery and an associate dean at Weill Cornell Medicine, both in New York City. Dr. Strong acknowledged that preoperative chemoradiation is included in the latest version of the NCCN guidelines for gastric cancer, but she was quick to point out that the strength of the recommendation calls into question its viability as a treatment strategy.
“It’s actually a grade 2B recommendation, which is considered a weak recommendation,” Dr. Strong said in an interview. “In fact, recommendations at that level will sometimes not be covered by insurance.
So, while there is good high-quality evidence that chemotherapy works—which is why it’s given the highest possible recommendation by the NCCN—that is not the case for chemoradiation.”
Equally important, Dr. Strong said, is the fact that chemoradiation has not been shown to prolong survival in gastric cancer patients. “Radiation does have an effect on local control by improving the R0 resection rate and the pathologic complete response. However, although multiple studies demonstrate how radiation exaggerates a local response, this effect does not translate into improved survival.”
The real issue, Dr. Strong said, is how effective a particular intervention is in terms of preventing progression to systemic disease, which is what ultimately proves fatal for gastric cancer patients.
“The goal is for patients to be cured, so it doesn’t matter if your local control looks better and then you develop systemic disease recurrence,” she said. “Systemic recurrence is what kills you. If you’re a patient with gastric cancer, you care about a cure. They understand that recurrence equates to incurable disease.”
There is a substantial body of evidence to demonstrate the efficacy of chemotherapy in patients with gastric adenocarcinoma, Dr. Strong said, dating back to the 2006 MAGIC trial, which showed a 13% five-year survival benefit with chemotherapy over surgery alone in 503 patients (N Engl J Med 2006;355[1]:11-20). This was followed in 2011 by a multicenter trial of 224 patients, which yielded comparable results (J Clin Oncol 2011;29[3]:1715-1721). Finally, 2019’s FLOT trial yielded an overall survival rate that was 9% better than that found in the MAGIC trial (Lancet 2019;393[10184]:1948-1957).
No Survival Benefit
What’s more, Dr. Strong continued, research has consistently demonstrated that adding postoperative chemoradiation to chemotherapy does not improve survival, including the ARTIST 1 and ARTIST 2 studies. In ARTIST 1, the researchers studied 458 patients with curatively resected gastric cancer with D2 lymph node dissection (J Clin Oncol 2012;30[3]:268-273). The investigation concluded that the addition of chemoradiation to chemotherapy did not significantly prolong disease-free survival (P=0.0862). In ARTIST 2, which comprised 546 patients with node-positive gastric cancer after D2 resection, the investigators came to a similar conclusion, finding that adding radiotherapy to chemotherapy did not significantly reduce the disease recurrence rate after D2 gastrectomy (Ann Oncol 2021;32[3]:368-374).
Studies comparing chemotherapy alone with preoperative chemoradiation have yielded similar results, Dr. Strong said. They include the 2012 CROss trial (N Engl J Med 2012;366[22]:2074-2084), the 2016 NeoRes-I study (Ann Oncol 2016;27[4]:660-667), and the 2023 Neo-AEGIS trial, which was presented in abstract form at the 2023 ASCO Gastrointestinal Cancers Symposium (abstract 295).
“The bottom line is that these studies show better R0 resection and better pathologic complete response with preoperative chemoradiation,” Dr. Strong said. “But there was absolutely no difference in recurrence and no difference in survival.”
Adverse Effects Are a Concern
On top of that, the addition of preoperative chemoradiation to chemotherapy carries potential side effects that clinicians need to consider before adopting the strategy.
“Radiation has detrimental long-term side effects,” Dr. Strong noted. “Long-term complications such as small bowel strictures, chronic bowel obstruction, renal failure, fistulas and radiation-induced angiosarcomas can all affect patients’ long-term quality of life and the need for additional tests, procedures and medical care. Truth be told, that’s my biggest issue with this. Radiation has the burden of showing definite improvement if I’m going to subject my patients to this.”
Immunotherapy Represents An Area of Agreement
If there was one area in which the researchers agreed, it was the potential for immunotherapy to make a tangible impact on the lives of gastric cancer patients. Both Drs. Badgwell and Strong cited the CheckMate-577 study, which evaluated a checkpoint inhibitor as adjuvant therapy in patients with esophageal or gastroesophageal junction cancer (N Engl J Med 2021;384[13]:1191-1203). The study found that for patients who received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among their counterparts given placebo.
“Other systemic therapies, such as immunotherapy, is really where the future lies in terms of helping a certain subset of patients with gastric cancer,” Dr. Strong said.
“At the end of the day,” Dr. Badgwell added, “we’re also going to start working on some of these newer treatments like immunotherapy, and I think that’s going to help quite a bit.”
—Michael Vlessides
Dr. Badgwell reported no relevant financial disclosures. Dr. Strong reported a financial relationship with Merck.
This article is from the September 2023 print issue.