Dr. Jackson and colleagues have provided a concise and cogent review of the state of the art of therapies adjunctive to surgery in patients with resectable gastric and gastroesophageal adenocarcinomas. It is essential for clinicians to be aware of the applicable therapeutic strategies that may increase survival in patients with gastric and gastroesophageal cancers, since these tumors occur in over 900,000 people throughout the world each year.
As with most gastrointestinal cancers, the cornerstone of successful therapy for stomach cancer is complete surgical resection of the primary tumor. A core question that must be addressed is whether there are proven techniques in addition to surgery that will improve cure rates in patients with resectable gastroesophageal cancers? The nuances surrounding the answer to this question are discussed by Jackson et al.
In many neoplasms such as breast cancer, lung cancer, and colon cancer, cytotoxic chemotherapy given as adjuvant therapy after resection of the primary tumor has been shown to improve disease-free and overall survival. It is reasonable to ask whether this strategy has proven effective in gastric cancer. As described by Jackson et al, postoperative cytotoxic chemotherapy may result in small improvements[3,4] in patient outcome, but the level of benefit—typically, far less than a 10% increase in survival—is not considered to be clinically significant. As a result, clinicians have not adopted adjuvant chemotherapy as a standard of care. I do not doubt that at some point in the future, improved cytotoxic and/or targeted therapies will prove beneficial in cases of resected gastroesophageal cancers, but we are not there yet.
If postoperative chemotherapy is not helpful, what are the acceptable strategies to improving outcome in cases with adenocarcinoma of the stomach/distal esophagus? Jackson and colleagues discuss the two therapeutic strategies supported by data from well powered phase III clinical trials that show improvement of outcome in surgically resected patients with gastroesophageal cancer.
In 2006, Cunningham and colleagues presented the results of a well designed and executed phase III trial evaluating the role of perioperative chemotherapy in the management of resectable gastric cancer. Patients with resectable gastric cancer were randomly allocated to a combination of chemotherapy and gastric resection or to gastric resection alone. The cases allocated to the chemotherapy-and-surgery treatment arm were to receive both pre- and postoperative therapy with ECF (epirubicin [Ellence], cisplatin, fluorouracil [5-FU]). The surgery-alone cases underwent curative-intent gastectomy and received no adjuvant therapy. The major outcomes evaluated by Cunningham and colleagues were progression-free and overall survival. The study enrolled 503 patients, with 250 receiving perioperative chemotherapy and 253 being treated with surgical resection alone.
Analysis of the trial, as noted by Jackson et al, showed convincing benefit from the use of ECF chemotherapy. The 5-year overall survival rate was 36% for the chemotherapy-treated patients and 23% for those receiving surgical resection alone (log rank P = .008). This 13% improvement in survival corresponds with a 25% reduction in risk of death. Progression-free survival was also improved by chemotherapy (log rank P = .001). In the chemotherapy/surgery/chemotherapy cases, there were also encouraging trends in other outcomes such as decreased tumor size and reduction in the extent of nodal metastases. Toxicity of perioperative chemotherapy was manageable.
If perioperative chemotherapy with ECF improves survival, downstages tumors, and is reasonably safe, should it be considered a standard of care in the management of resectable gastric cancer? There are several aspects to this question. First, is ECF the "best" chemotherapy? Cunningham and colleagues note that ECF is a chemotherapy program developed in the early 1990s and that there are newer, less complex chemotherapy programs now available that are active in advanced gastric cancer.[7,8] Are these more recently developed treatment programs better than ECF? The answer to this question is becoming available. As Jackson et al point out, the oral fluorinated pyrimidine capecitabine (Xeloda) may be substituted for 5-FU in ECF-like regimens, and it is highly likely that oxaliplatin (Eloxatin) will replace cisplatin in these regimens.
Timing of Treatment
1. Parkin D, Bray F, Ferlay J, et al: Global cancer statistics, 2002. CA Cancer J Clin 55:74-108, 2005.
2. André T, Boni C, Mounedji-Boudiaf L, et al, for the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004.
3. Hermans J, Bonenkamp JJ, Boon MC, et al: Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol 11:1441-1447, 1993.
4. Earle CC, Maroun JA: Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: Revisiting a meta-analysis of randomized trials. Eur J Cancer 35:1059-1064, 1999.
5. Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastro-esophageal cancer. N Engl J Med 355:11-20, 2006.
6. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261-267, 1997.
7. Sumpter K, Harper-Wynne C, Cunningham D, et al: Report of two protocol planned interim analyses in a randomized multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced esophagogastric cancer receiving ECF. Br J Cancer 92:1976-1983, 2005.
8. Cunningham D, Rao S, Starling N, et al: Randomised multicentre phase III studsy comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer: The REAL 2 trial (abstract LBA4017). J Clin Oncol 24(18S):182s, 2006.
9. Macdonald JS, Smalley SR, Benedetti J, et al: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345:725-730, 2001.