Neoadjuvant Therapy for Gastric Cancer

Drs. Chadha, Kuvshinoff, and Javle have provided a wellwritten review of the rationale and literature supporting neoadjuvant therapy and gastric cancer. Although the incidence of gastric cancer is declining in the United States, approximately 1 million new cases will be diagnosed worldwide this year with over 700,000 deaths, resulting in a disease-related mortality of nearly 75%.[1] These figures emphasize the need for new and improved treatment strategies in this disease. In contrast to other gastrointestinal malignancies, there has been little systematic evaluation of neoadjuvant multimodality approaches for patients with gastric cancer. Given its natural history and biology, this approach is logical and may yield therapeutic benefit. Rationale
The rationale behind neoadjuvant therapy is as follows: (1) Patients with rapidly progressive disease are spared the morbidity of laparotomy (eg, 12% in the series by Ajani et al)[2]; (2) the tumor is treated with an intact blood supply, facilitating improved delivery of chemotherapy as well as oxygen, promoting chemoand radiosensitization; (3) there is a theoretical decreased risk of seeding at the time of resection; (4) potential "downstaging" of the tumor may be achieved, facilitating margin-negative (R0) resection and greater margin clearance; (5) in the postoperative setting, many patients experience prolonged recovery, delaying or preventing delivery of potentially beneficial adjuvant therapy; (6) radiation treatment planning is facilitated with an "intact" normal stomach and tumor. Staging
Because peritoneal dissemination is a common mode of spread of gastric cancer, staging laparoscopy should be considered in patients undergoing neoadjuvant therapy. Laparoscopy may visualize peritoneal metastases undetectable by computed tomography (CT) or positron-emission tomography (PET). Recent studies have reported that laparoscopy may identify small peritoneal deposits in approximately 25% to 35% of patients without evidence of metastasis on CT.[3] These data have prompted inclusion of laparoscopy in the staging evaluation of patients with locoregional gastric cancers in the most recent National Comprehensive Cancer Network guidelines. Additionally, peritoneal washings with cytologic analysis can be obtained at laparoscopy. If positive for malignancy, prognosis is similar to patients with macroscopic metastases.[4,5] These patients may be spared the morbidity of laparotomy and chemoradiation treatment strategies. Evaluation of the role of PET scanning in gastric cancer is under active investigation. Fluorodeoxyglucose uptake of gastric cancer has been found to be variable. For patients with tumor exhibiting signet ring histology or extensive mucin production, a high incidence of false negative results has been reported with PET.[6] Recent data suggest that treatment response to chemoradiation in esophageal cancer by PET scan predicts for pathologic response and long-term outcome following neoadjuvant therapy.[ 7] Similarly, emerging data have suggested that patients with gastric cancer responding to neoadjuvant therapy by PET criteria demonstrate improved histologic response and survival, with responses apparent within 2 weeks of treatment initiation.[8] Such information may be useful in optimizing preoperative regimens on a case-by-case basis and enhancing treatment selection. Overall staging accuracy in gastric cancer with endoscopic ultrasonography (EUS) is approximately 75%; accuracy of lymph node staging is 50% to 65%. In staging of primary disease, accurate characterization of earlystage lesions by EUS may be problematic.[ 3] These factors should be considered in radiation planning for patients undergoing neoadjuvant treatment (discussed below). Radiation Planning
From a radiation oncologist's perspective, treatment of gastric cancer patients in the neoadjuvant setting may enhance the accurate identification of the stomach and primary tumor, as well as perigastric and regional nodal basins. In the adjuvant setting, the radiation oncologist "reconstructs" the tumor bed and gastric volumes based on preoperative studies and operative findings, or may utilize "standardized" fields encompassing all nodal basins, potentially leading to toxicity and poor tolerance. In some situations, postoperative radiation fields may be larger than those treated neoadjuvantly, with increased early and late morbidity (eg, proximal tumors requiring esophagectomy with thoracic or cervical anastomosis). There are potential disadvantages with neoadjuvant strategies. Gastric cancer radiation fields are designed based on tumor location (ie, gastroesophageal junction, fundus, body, antrum), depth of invasion, and extent of nodal involvement. Pooled pathologic data predicting the likelihood of varying nodal station involvement by tumor location and pathologic features (eg, Maruyama index) aids the radiation oncologist in defining nodal basins at risk. Preoperative imaging with EUS, PET, and CT may result in staging inaccuracies, leading to larger or smaller radiation fields than would be used in the adjuvant setting when pathologic staging is available. For example, in patients with resected T2, N0 disease of the gastric cardia with subserosal invasion, postoperative nodal irradiation is often limited to the perigastric region; however, in patients with T2, N+ disease, larger fields are often designed to encompass perigastric, celiac, splenic, and suprapancreatic regions, as well as other potential sites depending on the number of nodes examined/involved. If staging for patients treated neoadjuvantly erroneously suggests no evidence of nodal involvement, smaller fields may be treated vs those treated in the adjuvant setting. Similarly, the risk of "overstaging" exists, where neoadjuvant strategies may not be indicated (eg, T1, N0 disease). Trials
Adjuvant chemoradiation in resected gastric cancer patients has become a standard practice in the United States based on the results of the Intergroup 0116 trial. This study evaluated stage IB-IV gastric cancer patients undergoing margin-negative resection. Patients were randomized to (1) no further treatment or (2) adjuvant chemoradiation with fluorouracil(Drug information on fluorouracil) (5-FU)-based chemotherapy. Median survival in patients receiving surgery only was 27 months vs 36 months in patients receiving chemoradiation, with 3-year survival rates of 41% and 50%, respectively. As noted by the authors, approximately one-third of proposed radiation fields required modification following central review, indicating that the design of "standard" radiation fields requires experience and care to ensure accurate and safe delivery of treatment.[9] A study from Beijing randomized 370 patients with gastric cardia adenocarcinoma to either neoadjuvant irradiation (40 Gy in 4 weeks) or surgery only. Five-year survival in patients receiving preoperative irradiation was 30% vs 20% in the surgery-alone group (P = .009). Additionally, local regional recurrence rates were significantly decreased in patients receiving preoperative irradiation. This suggests that preoperative therapy is feasible and may afford a survival benefit in gastric cancer patients.[10] Preliminary evidence from phase II studies suggests that neoadjuvant combined- modality therapy in the treatment of gastric cancer is feasible and potentially beneficial. As discussed, Ajani et al treated 34 patients with localized gastric cancer with neoadjuvant 5-FU, cisplatin(Drug information on cisplatin), and radiation therapy. In patients undergoing resection a pathologic complete response rate of 30% and a median survival of 64 months in completely responding patients were reported. These results should stimulate further investigation of neoadjuvant strategies. Future Directions
Despite the controversies that exist in the treatment of gastric cancer (limited vs extended lymph node dissection, sequencing of chemoradiation, optimal chemotherapy agents), the reality is that the majority of patients diagnosed with gastric cancer will succumb to this malignancy with contemporary treatment methods. Current therapies have only a modest impact on survival. Further investigation into early prediction of treatment response with individualization of therapy remains an area of promise. Given the high rate of development of distant metastases, significant advances in the treatment of gastric cancer are likely to come from novel treatment agents. These advances include the implementation of newer systemic therapies with conventional treatments, such as vascular endothelial growth factor inhibitors and epidermal growth factor receptor antagonists, along with the development of newer "targeted" therapies