Despite recent advances in the management of gastric cancer, most patients diagnosed with this disease will live less than one year once the disease has metastasized. Few countries have screening programs for gastric cancer in place, and most patients with gastric cancer will be diagnosed with locally advanced or metastatic disease—generally micrometastatic disease that results in recurrence, usually within two years following resection of the primary cancer.
In the U.S., the fatality-to-case ratio for gastroesophageal cancers is 0.66, suggesting that approximately two-thirds of newly diagnosed patients will have metastatic disease at some point in the course of their illness and will require systemic therapy.1 Many drugs are considered active in these diseases, including platinums (cisplatin and oxaliplatin), fluoropyrimidines, irinotecan, taxanes, and targeted therapies (for example, trastuzumab and ramucirumab).2 Despite the many treatment options available, median survival for advanced gastric cancer remains dismal at eight to 10 months.3,4 Hence, the question remains, how can we use new technology and the drugs available to improve patient outcomes?
Oncologists suggest that therapies that effectively treat micrometastatic disease will have the greatest potential impact on patient outcomes. In Europe and the U.S., a common approach is to administer perioperative chemotherapy for resectable gastroesophageal cancer, a strategy based on the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) Trial.5 The MAGIC study was the first trial to show an improvement in survival with use of perioperative chemotherapy in patients with gastric, gastroesophageal junction (GEJ), and lower esophageal cancers. In this trial, the chemotherapy arm showed a statistically significant improvement in overall survival (OS) (five-year OS rates 36 percent versus 23 percent; hazard ratio (HR) 0.75, 95 percent confidence interval (CI) [0.60-0.93]; p=0.009) compared with surgery alone.
A similar degree of benefit was noted in the second landmark trial of perioperative chemotherapy, the French Fédération Nationale des Centres de Lutte contre le Cancer (FNCLCC)/Fédération Francophone de Cancérologie Digestive (FFCD) 9703 study.6 Treatment with perioperative chemotherapy resulted in significantly improved OS (five-year OS rate 38 percent versus 24 percent; HR 0.69, 95 percent CI [0.50-0.95]; p=0.02). Similar to the MAGIC Trial, the subgroup of GEJ tumors derived the highest benefit from perioperative chemotherapy (HR 0.57, 95 percent CI [0.39-0.83]).
Human Epidermal Growth Factor Receptor (HER) 2-directed therapy improved survival in patients with metastatic HER2-positive gastric and GEJ adenocarcinoma,7 and represents a promising predictive marker for HER2-positive, early-stage disease. However, the addition of HER2-targeted therapy to chemotherapy in the neoadjuvant or adjuvant setting remains unproven and is being examined in Europe (NCT02581462, NCT02205047).
PET scans as a biomarker for treatment planning
Serial fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography scanning can identify response to preoperative chemotherapy by evaluating the change in the standardized uptake value (SUV) of the administered FDG as compared with the baseline. This response may be identified early in the preoperative treatment plan, before completion of the first cycle.8-12 FDG-PET non-responders, which comprise approximately 50 percent of patients who initiate preoperative therapy, have significantly worse outcomes.
However, what are the options when we identify early in treatment that a patient has a poor response to chemotherapy and is destined for a worse outcome? Would early assessment of response afford the opportunity to modify therapy in those patients who are not responding and potentially improve patient outcomes? This strategy is being tested in a prospective clinical trial: Alliance A021302: Impact of Early FDG-PET Directed Intervention on Preoperative Therapy for Locally Advanced Gastric Cancer: A Randomized Phase 2 Study (NCT02485834). In this study, patients with FDG-avid locally advanced gastric cancer receive standard preoperative chemotherapy in cycle 1. A PET scan is performed on-study at the end of cycle 1 (paid for by the study), followed by a central review to determine if the patient is classified as a PET responder or PET non-responder. A PET responder is defined as having at least a 35 percent reduction in SUV compared with the baseline PET scan. PET non-responders—patients with tumors that had less than 35 percent reduction in SUV (about 50 percent of all patients)—will then go on to enroll in the study (see Figure 1) if they remain surgical candidates (that is, no distant disease identified on PET). Patients are randomized to either salvage perioperative chemotherapy with docetaxel/irinotecan for two cycles, followed by surgery and additional chemotherapy in the adjuvant setting, or to surgical resection as the next step, followed by chemoradiation. This study is actively recruiting.
Figure 1. A021302: Impact of early FDG-PET directed intervention in locally advanced gastric cancer
This is an important national study that seeks to answer these questions: Does it matter if we identify poorly responding patients early in the treatment plan? And can altering therapy affect their outcomes? The findings of this study could substantially improve the outcomes in those gastric cancer patients who have the worst prognosis. Any interest or support is appreciated.
- Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
- Shah MA. Gastrointestinal cancer: Targeted therapies in gastric cancer—the dawn of a new era. Nat Rev Clin Oncol. 2014;11(1):10-11.
- Power DG, Kelsen DP, Shah MA. Advanced gastric cancer—slow but steady progress. Cancer Treat Rev. 2010;36(5):384-392.
- Shah MA, Kelsen DP. Gastric cancer: A primer on the epidemiology and biology of the disease and an overview of the medical management of advanced disease. J Natl Compr Canc Netw. 2010;8(4):437-447.
- Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. New Engl J Med. 2006;355(1):11-20.
- Ychou M, Boige V, Pignon J, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: An FNCLCC and FFCD Multicenter phase III trial. J Clin Oncol. 2011;29(13)1715-1721.
- 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.
- Wieder HA, Brücher BL, Zimmermann F, et al. Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol. 2004;22(5):900-908.
- Ott K, Weber WA, Lordick F, et al. Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction. J Clin Oncol. 2006;24(29):4692-4698.
- Lordick F, Ott K, Krause BJ, et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: The MUNICON phase II trial. Lancet Oncol. 2007;8(9):797-805.
- Ott K, Herrmann K, Lordick F, et al. Early metabolic response evaluation by fluorine-18 fluorodeoxyglucose positron emission tomography allows in vivo testing of chemosensitivity in gastric cancer: Long-term results of a prospective study. Clin Cancer Res. 2008;14(7):2012-2018.
- Shah MA, Yeung H, Coit D, et al. A phase II study of preoperative chemotherapy with irinotecan (CPT) and cisplatin (CIS) for gastric cancer (NCI 5917): FDG-PET/CT predicts patient outcome. American Society of Clinical Oncology, Annual Proceedings, Orlando, FL, 2007.