Neoadjuvant and Adjuvant Therapy for Gastric Cancer

SELECTION OF TREATMENT APPROACH

Since data exists for all 3 approaches (perioperative chemotherapy, adjuvant chemoradiotherapy, and adjuvant chemotherapy), various meta-analyses have been done to clarify which approach is the best. In a recent meta-analysis of 6 randomized controlled trials reported between 2010 and 2012, which involved 1171 patients with resected gastric cancer, adjuvant chemotherapy was compared to adjuvant chemoradiotherapy.⁵⁵ Five of the studies were from East Asia, while one was from a Western country. Adjuvant chemoradiation was associated with a lower local-regional recurrence rate (OR 0.46 [95% CI 0.32 to 0.67]) and better 5-year DFS rate (OR 1.56 [95% CI 1.09 to 2.24]). However, there was no statistical difference in 5-year overall survival rate (OR 1.32 [95% CI 0.92 to 1.88]). Similar results were reported by Zhou et al in 2016.⁵⁶ This meta-analysis included 4 randomized controlled trials reported between 2010 and 2015, with a total of 960 patients who had undergone a D2 resection for gastric cancer. Compared to adjuvant chemotherapy, adjuvant chemoradiotherapy significantly reduced the loco-regional recurrence rate (LRRR; relative risk [RR] 0.50 [95% CI 0.34 to 0.74], P = 0.0005) and improved DFS (HR 0.73 [95% CI 0.60 to 0.89], P = 0.002). Again, no difference in overall survival was seen (HR 0.91 [95% CI 0.74 to 1.11], P = 0.34).

Adjuvant chemotherapy and perioperative chemotherapy have also been compared. In a recent meta-analysis of 14 randomized controlled trials (8 Asian, 6 European) involving 2093 patients with resected gastric or GEJ cancer, perioperative chemotherapy was associated with improved overall survival when compared to adjuvant chemotherapy (HR 0.48 [95% CI 0.35 to 0.67], P < 0.001).⁵⁷ The benefit of perioperative chemotherapy over adjuvant chemotherapy has also been reported in a 2016 meta-analysis by Zhao et al.⁵⁸ A total of 1240 patients were included from 5 randomized controlled trials and 6 clinical controlled trials, all from Asian countries. The 5-year overall survival rate was significantly better in the perioperative chemotherapy group compared to the adjuvant chemotherapy group (RR 0.77 [95% CI 0.64 to 0.92], P < 0.01). Furthermore, the 2 groups showed no significant differences in the postoperative complication rates (RR 0.98 [95% CI 0.63 to 1.51], P = 0.91) or adverse effects of chemotherapy (P > 0.05 for all adverse effects).

While these meta-analyses may offer some insight on the best treatment approach, they should be interpreted with caution. Most studies included in these meta-analyses were from Asian countries, and their findings may not be applicable to Western countries. Furthermore, the heterogeneity of trials and inclusion of nonrandomized trials make it difficult to draw conclusions. There are several ongoing trials that will help to define the optimal treatment approach.

CASE CONTINUED

The patient is presented at tumor board and the consensus is to proceed with the perioperative chemotherapy approach. The patient undergoes echocardiography, which reveals a normal ejection fraction. He receives 3 cycles of neoadjuvant EOX (epirubicin, oxaliplatin, and capecitabine). After 3 cycles of neoadjuvant EOX, the patient has a repeat CT that shows marked interval reduction in the size of the primary gastric neoplasm and interval decrease in the size of the small perigastric lymph nodes. He subsequently undergoes a total gastrectomy with J-tube placement. Pathology shows ypT3N0 disease with 0 out of 47 lymph nodes involved and negative margins. He then receives 3 cycles of adjuvant EOX.

• What are the recommendations for surveillance?

According to the current NCCN guidelines, a history and physical exam should be performed every 3 to 6 months for 1 to 2 years, then every 6 to 12 months for 3 to 5 years, and then annually.²³ Labs, CT chest/abdomen, and EGD should be done as clinically indicated. Patients who have undergone surgical resection should be monitored for nutritional deficiencies (vitamin B12 and iron).

GASTROESOPHAGEAL JUNCTION TUMORS

Tumors arising in the GEJ or gastric cardia within 5 cm of the GEJ that extend into the GEJ or distal esophagus are staged and treated as esophageal cancers.²¹ The primary treatment for T1/T2N0 tumors is surgical resection. In patients with T3 or higher or node-positive adenocarcinoma of the GEJ, a combined modality approach is preferred, with preoperative chemoradiotherapy followed by surgical resection.⁵⁹ The CROSS trial demonstrated a significant survival benefit with preoperative chemoradiation using carboplatin/paclitaxel compared to surgery alone in patients with esophageal or GEJ cancer (49 months versus 24 months, HR 0.66, P = 0.003).⁶⁰

ONGOING TRIALS

As mentioned previously, several randomized clinical trials are in progress to clarify the optimal treatment approach. The MAGIC-B/MRC-ST03 is a randomized phase 2/3 trial looking at perioperative epirubicin, cisplatin, and capecitabine (ECX) with or without bevacizumab in patients with resectable lower esophageal, GEJ, or gastric cancer.⁶¹ The TOPGEAR trial, a randomized phase 2/3 study being conducted in Canada and Europe, is comparing perioperative ECF chemotherapy with preoperative chemoradiation plus perioperative ECF chemotherapy.⁶² In Asia, the PRODIGY trial is a phase 3, open-label, randomized study comparing neoadjuvant docetaxel, oxaliplatin, and S-1 followed by surgery and adjuvant S-1 versus surgery plus adjuvant S-1 in patients with locally advanced gastric cancer (T2-T4 or node positive).⁶³ Primary endpoint is PFS and secondary endpoints are overall survival, R0 resection rate, and safety.

Trials comparing adjuvant chemotherapy to adjuvant chemoradiotherapy are also being conducted. In the Dutch CRITICS study, a randomized phase 3 trial, patients with stage Ib-Iva resectable gastric cancer were given 3 cycles of epirubicin, cisplatin/oxaliplatin, and capecitabine (ECC/EOC), followed by D2 resection and either 3 cycles of ECC/EOC or chemoradiation with weekly cisplatin and daily capecitabine.⁶⁴ Between January 2007 and April 2015, a total of 788 patients were enrolled. In a preliminary report presented at ASCO in 2016, the 5-year survival rate was similar between the 2 arms (41.3% for chemotherapy arm and 40.9% for chemoradiotherapy arm, P = 0.99). The Korean ARTIST II trial is comparing adjuvant S-1 and S-1/oxaliplatin with or without radiotherapy in patients with D2-resected gastric cancer.⁶⁵ Similarly, the NCT01711242 trial is comparing adjuvant XELOX alone versus XELOX with concurrent capecitabine/radiotherapy in patients with resected D2 gastric cancer.⁶⁶

The ToGA trial established a survival benefit of trastuzumab in combination with chemotherapy in HER2-positive metastatic gastric cancer.⁶⁷ Consequently, there are ongoing clinical trials to assess the role of trastuzumab in nonmetastatic gastric cancer. The TOXAG study is a phase 2 trial looking at the safety and tolerability of adjuvant oxaliplatin, capecitabine, and trastuzumab with radiation in patients with resected HER2-positive gastric or GEJ adenocarcinoma.⁶⁸ The NCT01130337 clinical trial is evaluating perioperative XELOX/trastuzumab in patients with resectable gastric or GEJ adeno-carcinoma.⁶⁹