NATIONAL HARBOR, MD. – There are no hard and fast rules when it comes to selecting neoadjuvant or adjuvant therapy for patients with gastric cancer, according to Dr. Daniel G. Coit.
"Clinical trials of adjuvant therapy describe the impact of treatment on one group relative to another group. They do not predict the impact of treatment on an individual patient," said Dr. Coit, a surgical oncologist at Memorial Sloan-Kettering Cancer Center, New York.
Dr. Daniel G. Coit
Patient selection is a multi-step process that must incorporate an understanding of the risk of recurrence, the absolute benefit of treatment, strategies to improve the odds for achieving a benefit, and individual patient comorbidities and preferences, Dr. Coit said at the annual Society of Surgical Oncology Cancer Symposium.
Where oncologists often run into trouble is in the interpretation of data on benefits from clinical trials, and on the question of neoadjuvant vs. adjuvant therapy, both, or neither, he said.
Therapy delivered prior to surgery is likely to be better tolerated and improve the chance of R0 or "clean" resections. Neoadjuvant therapy can also help to identify, before surgery, those patients unlikely to respond metabolically or histologically to therapy, which can serve as both a prognostic factor for poor outcomes, and as a guide for additional pre- or postoperative therapy, Dr. Coit said.
Adjuvant therapy, on the other hand, allows treatment decisions to be based on an accurate estimate of recurrence risk using postoperative pathologic staging, he added.
"If we’re going to even consider preoperative therapy, neoadjuvant chemotherapy, we need to have some sense for how good our preoperative or pretreatment risk-assessment tools are. They’re not all that good," he said.
He noted that in a 2001 study (J. Clin. Gastroenterol. 2001;32:41-4) of 549 patients who were tested for carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA-19-9) before gastrectomy for gastric cancer, elevated levels of both markers were associated with "increased depth of invasion, more extensive nodal metastases, liver metastases, and less ‘curability.’ "
However, the authors found on multivariate analysis that a doubling of the normal threshold CEA was the only preoperative factor predictive of prognosis.
Endoscopic ultrasound (EUS), which is about 75% accurate at identifying node-positive vs. node-negative disease and at distinguishing early- from late-stage disease, is "very poorly predictive of outcome."
"The same thing happens with N stage: the endoscopic observation of node positivity is a terrible predictor of outcome," Dr. Coit said.
There are a few published nomograms that are fairly good at predicting disease-specific survival after R0 resections for gastric cancer, he noted, but these are all based on postoperative pathology findings, and "as yet we do not have a good nomogram for preoperative risk assessment."
Preventing recurrence
The goal of current therapy is to prevent recurrence at all costs, because few patients who experience recurrence will be salvageable, Dr. Coit said.
Studies of adjuvant therapy for gastric cancer with either postoperative 5-fluorauracil (5FU) and radiation (N. Engl. J. Med. 2001;345:725-30), postoperative epirubicin, cisplatin, and continuous 5FU infusion (ECF) (N. Engl. J. Med. 2006;355:11-20), or the oral fluoropyrimidine agent S-1, which is not available in the United States (N. Engl. J. Med. 2007:357:1810-20) all show about a 10% benefit, meaning that 10 patients would need to be treated for 1 to benefit.
More recently, in the CLASSIC trial (Lancet 2012;379:315-21) 1,035 patients with stage II-III gastric cancer who underwent curative resections with D2 extended lymph node dissection who were randomized to adjuvant capecitabine (Xeloda) and oxaliplatin had a 74% 3-year disease-free survival rate, compared with 59% for patients managed with postoperative observation only (hazard ratio 0.56, P less than .0001).
This trial showed that if patients are determined to have high-risk disease on postoperative pathology, "you have a very legitimate option available to you for postoperative treatment," Dr. Coit said.
In the ARTIST trial (J. Clin. Oncol. 2011;30:268-73), 458 patients underwent curative surgery with D2 lymph node dissection and were randomized to postoperative Xeloda/cisplatin (XP) or XP plus concurrent capecitabine radio therapy. The researchers found no statistically significant difference in 3-year disease-free survival among all patients, although there was some evidence of a benefit for XP plus radiation in patients with node-positive disease (P = .04).
Enriching the population
"It’s very clear that clinical trials do show a modest improvement in survival among the group of patients receiving adjuvant chemotherapy. The adjuvant therapy has no impact whatsoever in virtually 90% of the patients who are being treated, and we need to enrich this population that’s likely to benefit," he stated.