Finding Optimal Therapy for Gastric Cancer
Abstract & Commentary
By William B. Ershler, MD
Synopsis: A trial undertaken by EORTC was designed to determine if neoadjuvant chemotherapy would be successful in the absence of post-surgical chemotherapy in enhancing overall survival in patients with locally advanced gastric cancer. The trial did not accrue sufficient numbers of patients to demonstrate a survival benefit. However, presurgical chemotherapy was associated with a higher rate of complete resection and fewer positive lymph nodes, features that suggest progression-free and overall survival might be favorably affected.
Source: Schumacher C, et al. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organization for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol. 2010;28:5210-5218.
It is now apparent that patients with locally advanced gastric cancer benefit from chemotherapy administered both before and after resection.1,2 However, inasmuch as a large percentage of those completing surgical excision are incapable of completing post-surgical chemotherapy, the question remains whether neoadjuvant therapy alone would result in comparable benefits in terms of overall survival. To test this, investigators within the European Organization for Research and Treatment of Cancer (EORTC) conducted a phase III trial in which they employed strict preoperative staging and surgical resection guidelines, and a standard preoperative chemotherapy regimen for those assigned to the neoadjuvant treatment arm.
Patients with locally advanced adenocarcinoma of the stomach or esophagogastric junction were randomly assigned to preoperative chemotherapy followed by surgery, or to surgery alone. For those receiving chemotherapy, treatment consisted of two 6-week cycles of cisplatin (50 mg/m2) intravenous (IV) over 1 hour on days 1, 15, and 29, followed by d-L-folinic acid 500 mg/m2 IV over 2 hours and fluorouracil 2,000 mg/m2 continuous infusion over 24 hours on days 1, 8, 15, 22, and 36. Surgery was undertaken shortly after randomization for those not receiving chemotherapy and within four weeks of completing treatment for those randomized to neoadjuvant treatment. The surgical resection consisted of a subtotal or total gastrectomy, with extension depending on the location of the primary tumor and either a D1, or preferably, a D2 lymphadenectomy.
It was estimated that approximately 180 patients would be needed, in each of the two arms, to detect a statistically significant improvement in median survival from the estimated 17 months with surgery alone to 24 months for those receiving neoadjuvant chemotherapy. The trial was initiated in July of 1999 and closed in June of 2007, having enrolled only 144 patients (72 in each arm). Furthermore, the death rate for those receiving surgery alone was less than was anticipated, and this, combined with the smaller number of subjects, resulted in insufficient power to detect a difference in overall survival. Yet, responses in terms of successful resection and rate of lymph-node positivity was determined.
Of those entered on trial, over 50% had tumors located in the proximal third of the stomach. Of the 72 patients randomized to neoadjuvant therapy, 69 were evaluable. Of these, 14 discontinued protocol treatment either in the first or second cycle, primarily because of toxicity, and 45 received the three months of treatment, although some with dose reductions. The neoadjuvant therapy resulted in complete or partial response in 36.2% (25 of 69), as determined by pre-surgical imaging and endoscopy.
The International Union Against Cancer R0 resection rate was 81.9% after neoadjuvant chemotherapy, as compared with 66.7% with surgery alone (p = .036). The surgery-only group had more lymph-node metastases than the neoadjuvant group (76.5% vs. 61.4%; p = .018). Postoperative complications were more frequent in the neoadjuvant arm (27.1% vs. 16.2%; p = .09).
This trial showed a significantly increased resection rate and fewer lymph-node metastases in patients with locally advanced gastric cancer receiving three months of preoperative aggressive chemotherapy. It is disappointing that accrual wasn't better, as it would have been very helpful to show an improvement in overall survival in light of the significant toxicity associated with treatment and the increase in surgical complications among those who had received chemotherapy. That stated, it is unlikely that the current trial would have demonstrated improved survival even with a full 360 enrolled patients because the surgery-alone arm fared better than expected. The authors speculate that this might have been the result of a more careful pre-surgical staging coupled with the practice of undertaking a more extensive lymph-node dissection (D2) in 92% of those enrolled.
The take-home message is that neoadjuvant chemotherapy is likely to be an important approach for patients with locally advanced gastric cancer. The question of whether post-surgical treatment adds more remains unresolved. Furthermore, whether a less-toxic regimen, perhaps with oxaliplatin, would result in comparable or better responses needs to be the subject of future clinical trials.
The failure of a high-quality organization like EORTC to recruit sufficiently for this study is of considerable concern. Gastric cancer, like so many of the malignancies we treat, remains a disease for which optimal therapy needs to be established. Community physicians need to partner with their academic colleagues to assure the success of the much-needed clinical trials.
1. Bioige V, et al. Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD-FCD 9703 trial. J Clin Oncol. 2007;25 Supplement):4510a.
2. Cunningham D, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11-20.