Cancers of the stomach and esophagus are a substantial cause of morbidity and mortality worldwide. In the last 15 years, randomized data from the U.S. and Europe have emerged in support of multimodality treatment strategies for the management of resectable cases—specifically, preoperative chemoradiotherapy for tumors of the esophagus and perioperative chemotherapy or adjuvant chemoradiotherapy for gastric cancers. Also during this time, a growing array of novel targeted agents have been introduced and applied to the management of a variety of tumor types. More recently, studies have sought to improve the efficacy of existing approaches with more active therapeutic combinations.
Treatment paradigms
The two randomized trials upon which contemporary treatment paradigms for gastric cancer in the U.S. are based are Intergroup 0116 and the MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) trial.1,2 The former established the efficacy of chemoradiotherapy and 5-Fluorouracil (5-FU)/Leucovorin (LV) after surgical resection. The latter established epirubicin, cisplatin, and 5-FU (ECF) administered perioperatively as a first-line chemotherapy regimen. These two studies demonstrated similar survival advantages with disparate approaches. The apparent equipoise between these strategies has undercut efforts to establish a consensus approach.
A number of ongoing and recently completed clinical trials have been designed to reconcile different elements of these competing approaches. One such study is Cancer and Leukemia Group B (CALGB) 80401, a randomized phase III multicenter trial designed to determine whether a postoperative chemoradiotherapy regimen including ECF improves overall survival in patients with completely resected gastroesophageal (GE) junction or gastric adenocarcinoma compared to 5-FU/LV (as in the Intergroup 0116 regimen). Secondary endpoints examined were disease-free survival and adverse events. Between 2003 and 2009, 546 patients (5-FU/LV: 280; ECF: 266)—most of whom had locally advanced (T3/T4 or node-positive) disease—were randomized to adjuvant 5-FU/LV or ECF followed by 5-FU-based chemoradiotherapy. A similar proportion of patients in each arm completed therapy, although Grade 4 toxicities were higher in the 5-FU/LV arm. Three-year disease-free (46 percent versus 47 percent) and overall (50 percent versus 52 percent) survival were not significantly different between the 5-FU/LV and ECF arms. Treatment with either 5-FU/LV or ECF achieved a near-identical median survival (37 and 38 months, respectively) to that achieved with chemo-radiotherapy (36 months) in the Intergroup 0116 trial.
Metastatic adenocarcinoma or squamous cell carcinoma
of esophagus or GE junction (Siewert I/II)
Combining treatment options
Therapeutic options for the management of metastatic GE cancer remain limited. A growing understanding of the molecular pathways underlying tumorigenesis has prompted efforts to combine targeted herapies with conventional cytotoxic chemotherapy. Targets of interest include the human epidermal growth factor (HER) family receptors (for example, epidermal growth factor receptor [EGFR], HER2 and HER3), among others. ToGA (trastuzumab for gastric cancer), a large phase III trial in metastatic gastric cancer examining the role of HER2-targeted therapy using trastuzumab in addition to cisplatin plus capecitabine/5-FU, showed significantly improved objective response rates (35 percent to 47 percent, p=0.0017), progression-free survival (5.5 to 6.7 months, p=0.0002), and overall survival (11.1 to 13.8 months, p=0.0046) in the trastuzumab arm.3
While early studies indicated efficacy of agents targeting EGFR in proximal gastric and esophageal cancers, more recent randomized phase III trials (panitumumab in REAL-3 and cetuximab in EXPAND) have not reproduced this success.4,5 In parallel with these observations, CALGB 80403/Eastern Cooperative Oncology Group 1206 was conducted as a phase II multicenter trial designed to determine objective response rates in patients with chemotherapy-naïve and metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or GE junction (Siewert I/II) randomized to combinations of anti-EGFR monoclonal antibody cetuximab (C) with three disparate regimens: (a) ECF, (b) IC (irinotecan/cisplatin), or (c) FOLFOX (5-FU/LV/oxaliplatin) (see figure, this page). Between 2006 and 2009, 245 patients (ECF-C: 82, IC-C: 83, FOLFOX-C: 80 patients) were enrolled. Although all three regimens achieved response rates greater than 40 percent, IC-C was the least efficacious and most toxic; although ECF-C demonstrated slightly greater tumor response compared with FOLFOX-C (57.8 percent versus 53.6 percent), FOLFOX-C was the least toxic. An added benefit of cetuximab was suggested by improvements in response rate (by 15 percent) and overall survival (by 2.5 months) in both ECF-C and FOLFOX-C arms compared with historical phase III results in similar patient populations.
Unanswered questions
These studies, and others that have yet to mature, add to our growing understanding of these diseases, but they also underscore the significant gaps in our knowledge. It remains difficult to reconcile elements of existing randomized studies on resectable gastric cancer (for example, the efficacy of perioperative but not adjuvant chemotherapy alone in the U.S., and the apparent need for adjuvant radiotherapy in the U.S. but not in Asia).
It also remains clear that the promise of targeted therapies has not been fulfilled for many of the more aggressive malignancies. Further studies are needed to address these challenges and provide a basis for more effective treatments.
References
- 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. 2001;345(10):725-730.
- Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11-20.
- Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697.
- Waddell T, Chau I, Cunningham D, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):481-489.
- Lordick F, Kang YK, Chung HC, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):490-499.
