The current standard of care for the treatment of locally advanced gastric cancer includes surgical resection in combination with either adjuvant chemoradiotherapy, perioperative chemotherapy, or adjuvant chemotherapy.1-4 To reconcile the contribution of chemotherapy, the recent Cancer and Leukemia Group B (CALGB) 80101 (Intergroup) trial compared the addition of epirubicin and cisplatin—known as the medical research council adjuvant gastric infusional chemotherapy or MAGIC trial—with fluorouracil (5-FU)-based chemoradiotherapy in the adjuvant setting and showed no difference in survival with the additional agents.5 Given the perceived lack of progress in the adjuvant setting, attention has turned to improving neoadjuvant strategies for gastric cancer.
Findings to date
Lowy and colleagues showed that among 83 gastric cancer patients treated with neoadjuvant chemotherapy in three separate phase II trials, those patients who had a clinical and/or pathologic response had an 83 percent five-year survival rate in contrast to 31 percent for those patients who were nonresponsive to neoadjuvant chemotherapy. In fact, response to chemotherapy was the single positive prognostic factor on multivariate analysis.6 However, clinical response could only be measured following completion of treatment, and therefore non-responders (n=37) completed all neoadjuvant chemotherapy even though they may not have benefitted from this therapy.
Weber and colleagues investigated the use of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to predict patient response to therapy before resection. They examined 40 consecutive patients with gastroesophageal junction (GEJ) adenocarcinoma who underwent a FDG-PET scan 14 days after initiation of cisplatin and 5-FU/leucovorin (given as a 36-day cycle for three months). Using response by FDG-PET, with a decrease of standard uptake value maximum (SUVmax) of at least 35 percent, the researchers found a 93 percent sensitivity and 95 percent specificity correlation of FDG-PET response to clinical response.7 This study was followed by a prospective trial that confirmed that patients with a drop in SUVmax of 35 percent had a 90 percent two-year survival rate in contrast to a 25 percent two-year survival rate for those patients who did not achieve a metabolic response (see Figures 1 and 2).8
To further expand knowledge regarding the effect of metabolic response, the Metabolic response evalUatioN for Individualization of neoadjuvant Chemotherapy in Esophageal and esophagogastric adeNocarcinoma, or MUNICON, phase II trial accrued 114 patients with Siewert I and II GEJ tumors who underwent early FDG-PET during neoadjuvant chemotherapy. Those patients who did not meet the pre-specified decrease of 35 percent SUVmax proceeded to surgical resection without completing neoadjuvant chemotherapy, whereas those who responded by FDG-PET finished chemotherapy prior to surgery. FDG-PET responders (n=50) were more likely to have an R0 resection, earlier T stage tumors, and less lymph node involvement in comparison with non-responders (n=54).
In addition, event-free and overall survival was improved in responders versus non-responders.9 Interestingly, patients who had a metabolic response on FDG-PET but did not experience a histologic response (48 percent of responders, n=24) had the same survival rate as those without a metabolic response (none of whom had a histologic response). This observation implies that stopping ineffective chemotherapy early to proceed to surgery does not affect the outcomes for these patients.
The follow-up MUNICON II trial examined the role of salvage neoadjuvant chemoradiation for FDG-PET non-responders. Although a better histopathologic response was achieved with chemoradiotherapy, the primary endpoint of increased R0 resection with this approach was not reached and survival remained dismal in this group of patients.10
The Alliance 021302 trial will attempt to answer some of the remaining questions surrounding PET-directed oncologic therapy for gastric cancer, including whether an early switch to salvage chemotherapy in non-responders, as determined by FDG-PET, offers a survival benefit for patients with gastric cancer undergoing neoadjuvant therapy. The rationale for this approach lies in the chemosensitivity of gastric cancer to several active agents that have demonstrated response in the second- and third-line settings for advanced disease.
Patients with FDG-PET evaluable locally advanced Siewert type II and III gastric adenocarcinoma will be eligible for one cycle of epirubicin, cisplatin or oxaliplatin, and fluorouracil or capecitabine followed by restaging FDG-PET. Those patients with a maximum standardized uptake value response of greater than 35 percent on central imaging review will continue oncologic treatment at their physicians’ discretion. The non-responders will be randomized to either (1) surgical resection at approved centers with quality control followed by adjuvant 5-FU or capecitabine chemoradiotherapy, or (2) switch to chemotherapy (with docetaxel and irinotecan) for two cycles. Following restaging FDG-PET and surgery, patients in this arm will receive an additional three cycles of salvage chemotherapy in the adjuvant setting (see Figure 3).
Figure 3. Study schema for Alliance Trial 021302
Early intervention to identify and adjust treatment for non-responders to a therapeutic strategy will only translate to improved survival if the test of response is noninvasive and easily reproducible, and if an alternative regimen can provide the desired response.
If FDG-PET can guide direction of oncologic therapy in gastric cancer, can it be applied to other gastrointestinal cancer systems that rely on neoadjuvant therapy, such as locally advanced rectal and pancreatic cancer? We anticipate that the Alliance 021302 trial will provide some insight into this critical question. For questions regarding Alliance A021302, contact Manish Shah, MD, at email@example.com.
- MacDonald J, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared to 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.
- Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357(18):1810-1820.
- Bang YJ, Kim YW, Yong HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 lymphadenectomy (CLASSIC): A phase III open-label, randomized controlled trial. Lancet. 2012;379(9813):315-321.
- Fuchs C, Tepper JE, Niedzwiecki D, et al. Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin and infusional CI 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALBG 80101. J Clin Oncol. 2011;29:abs4003.
- Lowy A, Mansfeld PF, Loach SD, Pazdur R, Dumas P, Ajani JA. Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer. Ann Surg. 1999;229(3):303-308.
- Weber W, Ott K, Becker K, et al. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol. 2001;19(12):3058-3065.
- Ott K, Fink U, Becker K, et al. Prediction of response to preoperative chemotherapy in gastric cancer by metabolic imaging: Results of a prospective trial. J Clin Oncol. 2003;21(24):4604-4610.
- 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.
- Buschenfelde C, Hermann K, Schuster T, et al. (18)F-FDG PET-guided salvage neoadjuvant radiochemotherapy of adenocarcinoma of the esophagogastric junction: The MUNICON II trial. J Nucl Med. 2011;52(18):1189-1196.