Defining the optimal treatment of locally advanced gastric cancer

Gastric cancer (GC) is a major cause of cancer-related morbidity and mortality worldwide. The relatively low incidence of GC in the U.S. and controversy surrounding the applicability of evidence from Asia to U.S. patients have confounded efforts to establish a consensus approach for locally advanced disease. For the last decade, alternative approaches, including adjuvant chemoradiotherapy and perioperative chemotherapy supported by level I evidence, have vied for primacy. Meanwhile, some centers have advocated for the use of neoadjuvant chemoradiotherapy and adjuvant chemotherapy without radiation in selected patient cohorts. Outcomes of a recent clinical trial, however, have compelled a reassessment of older trial data and provided momentum for a more uniform application of systemic therapy before surgery.

Trials of multimodality therapy

One of the first trials to affirm the advantage of multimodality therapy for resectable GC in the U.S. was the SWOG (formerly the Southwestern Oncology Group)/Intergroup-0116 trial¹—the results of which were published in 2001. This study randomized 556 patients with resected ≥T3 or node-positive adenocarcinoma of the stomach or gastroesophageal junction (GEJ) to observation versus adjuvant fluorouracil and leucovorin plus 4500cGy of radiation. Three-year survival rates were 50 percent in the adjuvant therapy group versus 41 percent in the surgery-only group. Despite criticisms regarding the extent and standardization of surgery in this trial, it provided an evidence base for adjuvant chemoradiotherapy and continues to influence practice.

In 2006, outcomes from the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial supported an alternative approach of perioperative (both pre- and postoperative) chemotherapy.² This study randomized 503 patients with clinical stage II adenocarcinoma of the stomach, GEJ or distal esophagus to perioperative ECF (epirubicin, cisplatin, and fluorouracil) chemotherapy, or surgery alone. Five-year survival rates were 36.3 percent in the perioperative chemotherapy group and 23 percent in the surgery group. Concerns regarding the tolerability of ECF and evidence suggesting similar efficacy of alternative regimens with reduced toxicity in the metastatic setting have led to the adoption of perioperative systemic therapy approaches with other drug combinations in clinical practice.

Despite largely philosophical arguments in favor of one approach over the other, the impression of equipoise and the absence of high-level comparative data have justified a range of strategies. Uncertainty regarding the role of radiotherapy in patients undergoing more extensive locoregional surgery (that is, D2 lymphadenectomy) has further obfuscated identification of a consensus approach. Nonetheless, data from national registries indicate increasing use of neoadjuvant therapy in practice, perhaps reflecting dissemination of the results of the MAGIC trial and wider acceptance of neoadjuvant therapy approaches for high-risk malignancies in general.³

Recently, data from the docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) 4 study were reported and provide further support for the perioperative chemotherapy approach. This study compared the FLOT regimen with ECF/ECX (epirubicin, cisplatin, and fluorouracil or capecitabine) in patients with resectable gastric or GEJ adenocarcinoma.⁴ Compliance with the adjuvant component of therapy was better in the FLOT arm than in the ECF/ECX arm (50 percent versus 37 percent). With a median follow-up of 43 months, median overall survival in the FLOT group was 50 months versus 35 months with ECF/ECX. These early outcomes and the improved tolerability of the FLOT regimen are leading to a rapid shift in clinical practice.

Unanswered questions

Emerging evidence suggests that molecularly defined subgroups of locally advanced GCs are less likely to respond to perioperative chemotherapy (or chemotherapy in general). For example, perioperative ECF or adjuvant capecitabine/oxaliplatin appear to be less effective in patients with mismatch repair-deficient or MSI-high tumors.^5,6 Exploratory subgroup analysis of the FLOT4 data suggests that GEJ tumors—disproportionately enriched for the chromosomal instability consensus molecular subtype—are most likely to respond to FLOT. These data compel consideration of tailored perioperative strategies (for example, immune checkpoint blockade, targeted therapies) for molecularly selected tumors. Additionally, the availability of more active and better-tolerated systemic regimens with higher response rates compels a reassessment of the role for radiotherapy in resected patients. Future trials may provide answers to these questions and further improve outcomes for patients with gastric cancer.

References

1. 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.
2. 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.
3. Sherman KL, Merkow RP, Bilimoria KY, et al. Treatment trends and predictors of adjuvant and neoadjuvant therapy for gastric adenocarcinoma in the United States. Ann Surg Oncol. 2013;20(2):362-370.
4. Al-Batran SE, Hofheinz RD, Pauligk C, et al. LBA-008Docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) as perioperative treatment of resectable gastric or gastro-esophageal junction adenocarcinoma: The multicenter, randomized phase 3 FLOT4 trial (German Gastric Group at AIO). Ann Oncol. 2017;28(Suppl_3).
5. Smyth EC, Wotherspoon A, Peckitt C, et al. Mismatch repair deficiency, microsatellite instability, and survival: An exploratory analysis of the Medical Research Council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3(9):1197-1203.
6. Choi YY, Kim H, Shin SJ, et al. Microsatellite instability and programmed cell death-ligand 1 expression in stage II/III gastric cancer: Post hoc analysis of the CLASSIC randomized controlled study. Ann Surg. May 1, 2019 [Epub ahead of print].