Gastric cancer: Recent updates in surgical and multimodality therapy

Although the incidence of gastric cancer in the U.S. is slowly declining, it still is a deadly diagnosis for many patients. In 2018, an estimated 26,240 people in the U.S. were diagnosed with gastric cancer, and 10,800 died of the disease. The five-year overall survival (OS) is 68.1 percent for patients with localized disease but is much lower for patients with regional lymph node (LN) involvement (30.6 percent) or distant disease (5.2 percent).¹

Two classic randomized control trials in gastric cancer, the Intergroup (INT-0116) trial and the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, have formed the basis of multimodality therapy for gastric cancer for nearly two decades. INT-0116, published in 2001, demonstrated an improvement in OS among patients with resected stage IB-IV(M0) gastric cancer treated with adjuvant fluorouracil (5-FU)-based chemoradiation versus surgery alone (36 versus 27 months).² Five years later, the British MAGIC trial found an improved five-year OS in stage II–IV(M0) in patients randomized to receive perioperative chemotherapy with three cycles of epirubicin, cisplatin, and 5-FU (ECF) preoperatively and three cycles postoperatively, compared with patients treated with surgery and observation (36.3 percent versus 23 percent).³

However, both of these studies had major limitations, which has led to controversy regarding the optimal management of resectable gastric adenocarcinoma. In contrast to current operative practice, most of the patients in INT-0116 (54 percent) underwent a D0 dissection, which is a less than complete resection of N1 nodes, and only 10 percent of the study cohort underwent a D2 LN dissection (that is, lymphadenectomy of the perigastric, celiac, splenic, hepatic artery, and cardiac LNs). Many critics have suggested that the survival benefit of chemoradiation was only observed due to inadequate surgical therapy. In contrast, a major criticism of the MAGIC trial was the poor compliance with chemotherapy. A high proportion of patients (58.4 percent) assigned to the perioperative chemotherapy arm were unable to complete all six cycles because of progression of disease or cancer-related death (15.6 percent), postoperative complications (4 percent), or treatment toxicity (6 percent), leading to concerns about the generalizability of this treatment regimen to clinical practice.

Recent evidence

Despite the benefit of both adjuvant chemoradiation and perioperative chemotherapy based on the best available evidence, the optimal treatment for gastric cancer has remained controversial in the absence of a direct comparative trial. The recently published CRITICS (Chemotherapy Versus Chemoradiotherapy After Surgery and Preoperative Chemotherapy for Resectable Gastric Cancer) trial from the Netherlands (2007–2015) sought to address this issue by randomizing nearly 800 patients with resectable gastric cancer to either perioperative (pre- and postoperative) chemotherapy (epirubicin, cisplatin or oxaliplatin, and capecitabine) or perioperative chemotherapy combined with postoperative chemoradiation (45 Gray [Gy] in 25 fractions with capecitabine and cisplatin).⁴ Median survival was 43 months in the chemotherapy arm and 37 months in the chemotherapy plus postoperative chemoradiation arm (p = 0.90), failing to demonstrate an added survival benefit of postoperative chemoradiation following perioperative chemotherapy and resection. Notably, only 59 percent of patients in the perioperative chemotherapy-only arm and 62 percent of patients in the chemotherapy plus chemoradiation arm initiated the protocol-specified adjuvant therapy after gastrectomy. The persistently observed poor compliance with postoperative therapy has encouraged the development of studies that focus on the optimization of preoperative treatment strategies.

Perhaps one of the most notable studies in gastric cancer is the recently presented Perioperative Chemotherapy with Docetaxel, Oxaliplatin, and Fluorouracil/Leucovorin (FLOT) Versus Epirubicin, Cisplatin, and Fluorouracil or Capecitabine (ECF/ECX) for Resectable Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (FLOT4-AIO) trial, which was a multicenter, randomized phase III trial from Germany.⁵ Given the high toxicity of the MAGIC regimen (ECF), this study compared an alternative perioperative chemotherapy regimen, involving 716 patients with at least a T2 tumor and/or clinically node positive disease. Only 37 percent of patients in the ECF/ECX study arm completed therapy, versus 50 percent in the FLOT arm. In addition to the reduced toxicity, FLOT improved both progression-free and OS, with a median survival of 50 months in the FLOT arm compared with 35 months in the ECF/ECX arm. Based on these findings, docetaxel, oxaliplatin, and FLOT has become the preferred perioperative (pre- and postoperative) chemotherapy regimen at most high-volume centers in the U.S.

Updates in surgical approach

In addition to the emerging evidence focused on systemic therapy in gastric cancer, new evidence regarding surgical management of this disease is emerging. Based on the results of the randomized Dutch D1D2 Trial (Dutch Gastric Cancer Group Trial) showing a survival benefit of D2 LN dissection after 15-year follow-up,⁶ National Comprehensive Cancer Network guidelines recommend D2 LN dissection for gastric cancer.⁷ According to Japanese guidelines, the extent of D1 and D2 LN dissection may vary depending on tumor location.⁸ If distal gastrectomy is performed, neither D1 nor D2 include station #10 (splenic hilar LNs); therefore, splenectomy should not be performed. In the setting of a total gastrectomy, D2 LN dissection, including station #10, is recommended; however, the role of routine splenectomy for proximal gastric cancer remains controversial.

The Japanese Clinical Oncology Group conducted a multicenter randomized control trial investigating the survival impact of prophylactic splenectomy in patients with proximal cT2–4, nonlinitis gastric cancer without greater curvature involvement.⁹ From 2002 to 2009, the study enrolled 505 patients who underwent total gastrectomy with D2 lymphadenectomy, either with or without splenectomy, at one of 36 specialized institutions, defined as gastric cancer surgical units with perioperative mortality of less than 2 percent. An R0 resection was achieved in nearly all patients (only four R1 resections). Among patients who underwent splenectomy, the postoperative complication rate doubled (30 percent versus 16 percent; p <0.001) because of an increased incidence of pancreatic fistula (13 percent versus 2 percent) and abdominal abscess (8 percent versus 4 percent). Postoperative mortality was similar (0.4 percent versus 0.8 percent; p = 0.62). At a median follow-up of 72 months, no difference in five-year OS was detected (75.1 percent in splenectomy and 76.4 percent in spleen-preserving arm). Based on these data, the authors concluded that prophylactic splenectomy should be avoided in total gastrectomy for proximal gastric cancer that does not invade the greater curvature.

Ongoing trials in resectable gastric cancer

Although the use of preoperative chemotherapy has sharply increased over the past 10 years in the U.S.,¹⁰ the role of preoperative radiation remains unknown. The ongoing TOPGEAR (A Randomized, Phase III Trial of Perioperative ECF Chemotherapy with or Without Preoperative Chemoradiation for Resectable Gastric Cancer) phase III international trial is investigating the benefit of preoperative chemoradiation in addition to perioperative chemotherapy.¹¹ In this trial, the chemotherapy-only group receives pre- and postoperative ECF (three cycles for each), and the chemoradiation group receives chemoradiation (45Gy in 25 fractions with concurrent 5-FU) in place of the third cycle of ECF. A planned interim safety analysis of 120 patients (planned accrual 752) reported high compliance rates with preoperative therapy (>90 percent) and expected low compliance rates with postoperative therapy (53 percent in chemoradiation group and 65 percent in chemotherapy-only group), as well as an equivalent toxicity profile. The final results from this ongoing trial are highly anticipated.

Similarly, the Dutch CRITICS-II (A Multicenter Randomized Phase II Trial Of Neo-Adjuvant Chemotherapy Followed by Surgery Versus Neo-Adjuvant Chemotherapy and Subsequent Chemoradiotherapy Followed by Surgery Versus Neo-Adjuvant Chemoradiotherapy Followed by Surgery in Resectable Gastric Cancer) phase II trial is investigating the optimal preoperative treatment regimen by comparing preoperative chemotherapy (docetaxel, oxaliplatin, and capecitabine), preoperative chemotherapy followed by preoperative chemoradiation (45Gy with paclitaxel and carboplatin), and preoperative chemoradiation alone. The primary endpoint of this trial is event-free survival, with the intention that these results will inform a follow-up phase III trial comparing the identified optimal regimen with standard therapy.¹² See Table 1, for a summary of the trials.

Table 1. Recently completed and ongoing trials in resectable gastric cancer

Conclusions and future directions

Treatment of localized gastric cancer remains a significant problem; however, recent advances in the optimization of perioperative chemotherapy and surgical safety have led to significant improvements in short- and long-term outcomes, with low perioperative mortality and median survival of 50 months in Western patients. Current best practice is for perioperative chemotherapy with docetaxel, oxaliplatin, and FLOT with gastrectomy and D2 lymphadenectomy without splenectomy. Further improvements in perioperative multimodality completion, perhaps with total neoadjuvant approaches, and treatment of patients with microscopic peritoneal involvement are needed, including better defining the role of heated intraperitoneal chemotherapy.

Furthermore, the role of targeted therapy (for example, anti-HER2) and immunotherapy in the multimodality treatment of patients with nonmetastatic gastric cancer remain undefined. Novel clinical trial designs, such as presurgical or window trials, are needed to address these important questions.

References

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