Esophagogastric Junction and Gastric Adenocarcinoma: Neoadjuvant and Adjuvant Therapy, and Future Directions

Figure 1: Kaplan-Meier Plot of Estimated Overall 5-Year Survival in Patients With Esophageal or Esophagogastric-Junction Cancer Who Underwent Neoadjuvant Chemoradiotherapy Followed by Surgery vs Surgery Alone, According to an Intention-to-Treat Analysis

Figure 2: Overall Survival Data From the SWOG-Directed Intergroup Study 0116 After 10+ Years of Follow-Up

In North America, gastric cancer is the third most common gastrointestinal malignancy and the third most lethal neoplasm overall. In Asia, gastric cancer represents an even more serious problem: in Japan, it is the most common cancer in men. The standard primary therapy for gastric cancer is surgical resection; in esophagogastric-junction (EGJ) adenocarcinoma, which is often included in studies of gastric cancer, surgery is also typically the initial management strategy. However, the rates of locoregional and distant recurrence following surgery with curative intent have remained high. Investigators have explored a variety of ways of reducing these rates and improving survival in patients with gastric and EGJ cancers. These strategies have included explorations of the optimal extent of regional lymphadenectomy at the time of gastric resection; investigation of different neoadjuvant, perioperative, and adjuvant chemotherapy regimens; use of preoperative and postoperative radiation therapy; and the use of pre- and postoperative chemoradiotherapy (CRT). To date, benefit has been seen in gastric cancer patients with the use of what is called a “D2 resection” (which includes lymph nodes of stations 7 through 12) and with adjuvant CRT (in the West) or adjuvant chemotherapy with S-1 (in Japan); and neoadjuvant CRT has been shown to have a survival benefit in patients with EGJ cancers.

Overview

There were an estimated 29,590 new cases of carcinoma of the esophagus and stomach in 2013 and approximately 26,100 deaths,[1] and gastric cancer is the second most common cancer worldwide.[2] The purpose of this review is to update, present some of the new data on, and outline the controversies regarding neoadjuvant and adjuvant therapy of esophagogastric junction (EGJ) and gastric adenocarcinoma. It should be noted that many studies include squamous cell carcinomas of the esophagus with adenocarcinomas of the EGJ region, while other studies combine gastric cancers with adenocarcinomas of the EGJ region. This review will be confined to EGJ and gastric adenocarcinomas.

Gastric cancer epidemiology

Although gastric cancer has declined globally since World War II, it is still common, especially in some parts of the world. China accounts for more new cases than any other country.[3-5] In Japan, gastric cancer is the most common cancer in men.[6] In North America, gastric cancer is the third most common gastrointestinal malignancy behind colorectal and pancreas carcinoma and the third most lethal neoplasm overall.[7]

Prognosis

The prognosis for Japanese patients is estimated to be 40% to 60% survival at 5 years-far better than the 20% 5-year survival rate seen in similar cohorts in developed Western countries.[8,9] This difference reflects the facts that in the United States, more than 65% of gastric cancers are diagnosed as stage T3/T4, and that nearly 80% of gastric cancers have lymph node involvement at diagnosis.[10] Even in US patients whose cancer is resected with curative intent, the recurrence rate is 40% to 65%.[11]

The stage of the resected gastric cancer is the most important predictor of both 5-year survival and recurrence.[12,13] The 5-year survival rate for stage I gastric cancer is 57% to 71%. The 5-year survival declines to 33% to 47% for stage II, 9% to 20% for stage III, and 4% for stage IV.[14] In completely resected tumors, nodal status is a more important predictor of survival than T category.[15] In resected patients with involved lymph nodes, the ratio of the involved lymph nodes to the uninvolved nodes is the single most important prognostic factor for survival.[16]

Differences between East and West

In the West, gastric cancer typically develops along the proximal lesser curvature, in the cardia and in the junction.[17] In the Western Hemisphere, there has been a proximal migration of gastric malignancies, and the incidence of adenocarcinoma of the esophagus, EGJ, and cardia is increasing.[18] On the other hand, in Japan and other Eastern countries, nonproximal tumors are in the majority.[19]

In the East, intestinal histology is more common than the diffuse histology that is seen in the West.[20] Meanwhile, in the West, the incidence of diffuse gastric cancer has remained stable or is increasing, while the incidence of intestinal-type gastric cancer is declining.[21] Patients from the East tend to be about 5 years younger than in the West, but comorbidities are higher in the West.[22] Screening for gastric cancer is much more commonly performed in Japan, and as a result, cancers are detected earlier there.[23] The habitus of the typical Japanese patient allows for a more complete lymph node dissection, and Japanese surgeons may be more experienced since the incidence is so much greater.[24] These factors are believed to contribute to the better prognosis enjoyed by patients in countries in the East.

Pathogenesis

Gastric adenocarcinoma is associated with Helicobactor pylori infection, chronic gastritis, smoking, high salt intake, and pernicious anemia.[25-29] True adenocarcinomas of the esophagus are uncommon and most are located just above the EJC, with a clear distal margin of squamous epithelium. Because the natural history, staging, prognosis, and treatment are virtually identical for adenocarcinoma of the esophagus, EGJ, and cardia, there is also speculation about a common pathogenesis. This hypothesis is further bolstered by the association of both adenocarcinoma of the esophagus and EGJ carcinomas with Barrett esophagus, gastroesophageal reflux disease (GERD), and obesity, and the inverse relationship between H pylori infection of the stomach and adenocarcinomas of both the esophagus and EGJ junction. H pylori infection reduces gastric acidity, and combined with GERD, there is less toxic exposure to the gastric contents. (Carcinoma of the cardia does not have a similar relationship with H pylori.)[30-33]

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited form of an aggressive linitis plastica type of gastric cancer.[34] The disease is attributable to mutations in the type I E-cadherin gene referred to as CDHI.[35] There is also an excess of lobular carcinoma of the breast in women from HDGC families with the CDHI mutations.[36] A treatment option in identified probands is a prophylactic gastrectomy, a measure that is worth considering because the penetrance is in the range of 70%.[37] However, the protective value of the procedure has to be weighed against the associated morbidity.

Surgical Management

Management of carcinomas of the EGJ has been controversial. Stein, Feith, and Siewert define adenocarcinomas of the EGJ (AEGs) as tumors that have their center within 5 cm proximal or distal to the anatomical cardia; they have differentiated three distinct tumor types within this area:

• AEG type I: adenocarcinoma of the distal esophagus, which usually arises from an area with specialized intestinal metaplasia of the esophagus (such as is seen in Barrett esophagus) and which may infiltrate the EGJ from above.

• AEG type II: true carcinoma of the cardia, which arises from the cardiac epithelium or short segments with intestinal metaplasia at the EGJ.

• AEG type III: subcardial gastric carcinoma, which infiltrates the EGJ and distal esophagus from below.

These tumors have been classified as esophageal cancer. Lesions that arise beyond 5 cm of the EGJ or are within the 5 cm of the EGJ but do not extend to the esophagus are classified as gastric cancers.[38] Adenocarcinomas of the esophagus, the EGJ, or the gastric cardia are generally managed as esophageal cancers and are treated with a transhiatal or thoracoabdominal esophagectomy.[39]

The standard primary therapy for gastric cancer remains surgical resection.[40] The 5-year survival declines dramatically when lymph nodes are involved.[41] Metastatic disease is not considered curable. For years, the standard surgery for all gastric cancer patients was a total gastrectomy. It was shown in the 1980s and early 1990s that a subtotal gastrectomy for distal gastric adenocarcinoma led to similar outcomes with a significantly better quality of life.[42] This approach has also become the standard of care for lesions in the gastric body. A total gastrectomy is still indicated for gastric carcinomas that arise in the fundus.[43]

There continued to be a high rate of locoregional and distant recurrence after surgery for curative intent. This led to an ongoing debate about the optimal extent of the regional lymphadenectomy at the time of the gastric resection. The Japanese Gastric Cancer Association has identified three lymph node levels: D1, D2, and D3. The first level, D1, includes the perigastric nodes, which are called D1. The second-level lymph nodes are referred to as D2 and include stations 7 through 12. The third level of lymph nodes are called D3 and include stations 13 through 16.[44] The Japanese consider a D2 lymphadenectomy to be a standard surgical operation that leads to superior survival.[45] Three major trials have compared a D1 lymphadenectomy with a D2 lymphadenectomy. The British Surgical Cooperative Group found no difference in resected gastric cancer patients randomized to a D1 or D2 lymphadenectomy.[46] The 5-year survival was 35% in both the D1 group and the D2 group. Patients in the D2 group who had a splenectomy and pancreatectomy performed as part of their lymphadenectomy had a poorer survival. A similar finding was found in the Dutch D1 vs D2 lymphadenectomy trial.[47] There was increased morbidity and mortality in the D2 cohort. There was a higher incidence of splenectomy and distal pancreatectomy in the D2 group. At 15 years of follow-up, there was no difference in survival, although a subset analysis of patients with nodal involvement suggested a benefit for the D2 resection.[48] The third study was titled the German Gastric Cancer Study.[49] Again, a D1 lymphadenectomy was compared with a D2 lymphadenectomy. A D1 lymphadenectomy was defined as removal of ≤ 25 lymph nodes and a D2 resection was removal of > 25 lymph nodes. Survival was statistically superior in patients with stage II (T2N1) disease who underwent the more extensive lymphadenectomy. Although still controversial, the Dutch D1 vs D2 lymphadenectomy study and the German Gastric Cancer study both demonstrated an improvement in survival in patients with nodal disease who underwent a D2 lymphadenectomy. The debate about the extent of the lymphadenectomy may become moot, however, since an adequate cancer operation requires removal of at least 15 lymph nodes, and this usually can only be accomplished with a D2 resection.[50] Although the initial trials of a D2 vs D1 lymphadenectomy showed that the D2 resection was associated with greater morbidity and mortality, with better training, surgeons in the West no longer see excess complications with the D2 lymphadenectomy.[51]

Neoadjuvant and Perioperative Chemotherapy

Many strategies have been employed to improve the survival rate of surgery alone in gastric cancer, leading to the establishment of standards of treatment for these patients. The potential advantage of a neoadjuvant approach includes the potential to downstage a patient’s cancer, thus allowing more patients to have their tumors resected and to receive chemotherapy sooner, potentially resulting in the eradication of metastatic disease.

Clinical trials have evaluated the perioperative and neoadjuvant paradigm in gastric cancer. Two of the trials have shown a survival advantage and have guided the direction in which gastric cancer is treated in Western Europe. The French FNLCC/FFCD trial randomly assigned 224 patients with stage II or greater gastric cancer, EGJ cancer, or distal esophageal cancer to either surgery alone or surgery with perioperative chemotherapy with infusional fluorouracil (5-FU) and cisplatin for 2 or 3 courses and 3 to 4 courses postoperatively for a total of 6 cycles.[52] There was significant improvement in the 5-year survival in the chemotherapy group: 38%, compared with 24% in the surgery-only group. Some of the general criticisms of the study include the discovery that endoscopic ultrasound was not yet available at all centers at the time of the trial, and the fact that the planned sample size was never reached. Also, grade 3/4 neutropenia was seen in about 20% of patients in the chemotherapy arm, and 50% of the patients randomized to chemotherapy never received postoperative chemotherapy.

The other positive and widely cited trial is the MAGIC trial.[53] This trial consisted of 503 patients with stage T2 or higher cancers who were randomly assigned to surgery alone or to a regimen of 3 cycles of preoperative chemotherapy and 3 cycles of postoperative chemotherapy with epirubicin, cisplatin, and 5-FU infusion. Of the patients in the study, 26% had EGJ or distal esophageal lesions. There was a significant improvement in the 5-year survival in the chemotherapy group: 36%, compared with 23% in the surgery-only group. However, only 42% of the patients assigned to the chemotherapy arm were able to complete the entire regimen.

The European Organisation for the Research and Treatment of Cancer (EORTC) 40954 trial was a neoadjuvant trial that randomly assigned 144 patients either to preoperative chemotherapy with 2 cycles of cisplatin, 5-FU infusion, and leucovorin, or to surgery alone.[54] No postoperative chemotherapy was planned. The study was stopped due to poor accrual; however, a statistically significant advantage was seen in the neoadjuvant chemotherapy cohort: an 81.9% R0 resection rate, compared with a rate of 66.7% in the surgery-alone group. The postoperative complication rate was higher in the chemotherapy group (27.1% vs 16.7% ). The trial did not demonstrate a survival benefit for neoadjuvant chemotherapy.[54]

Adjuvant Chemotherapy

There are multiple studies in the literature comparing surgery alone for gastric cancer vs surgery with adjuvant chemotherapy. Most have not shown a benefit for adjuvant chemotherapy. These results led to several meta-analyses, which have shown a significant survival benefit for adjuvant chemotherapy.

In Japan, it is common to give the oral drug S-1 as an adjuvant chemotherapeutic agent.[55] S-1 is an oral fluoropyrimidine that consists of three agents: ftorafur, 5-chloro-2, 4-dihydroxypyrimidine (a dihydropyrimidine dehydrogenase inhibitor), and oxonic acid (an inhibitor of the phosphorylation of intestinal 5-FU, which is responsible for 5-FU–related diarrhea). A total of 1,059 patients were enrolled in the Japanese ACTS-GC trial, which included patients with stage II or III resected gastric cancer.[56] All patients had undergone a D2 lymphadenectomy, which is the standard in Japan. The 5-year overall survival was statistically better in the patients who received adjuvant S-1 than the 5-year survival in those who received placebo (72% vs 61%). The results in the treated and even the placebo group were better than what has been reported in Western studies of similarly staged gastric cancer patients. Again, this lends support to the hypothesis that gastric cancer in the East is different from gastric cancer in Western countries. S-1 was tested and submitted for approval in the United States, but the US Food and Drug Administration declined to approve it because the agent was not believed to add any benefit to currently available therapies.

The CLASSIC trial evaluated the benefit of adding therapy with capecitabine and oxaliplatin vs surgery alone in 1,035 stage II/III patients from China, Taiwan, and South Korea who had undergone a gastric resection with a D2 lymphadenectomy.[57] The primary endpoint was disease-free survival. At a median follow-up of 34.2 months, the disease-free survival in the chemotherapy-plus-surgery arm was 74%, compared with 59% in the surgery-only cohort. There was significant chemotherapy-related toxicity, which led to a dose reduction in 90% of the patients in the chemotherapy arm. Grade 3 or 4 adverse events were reported in 56% of the patients who received chemotherapy but in just 6% of the patients who only had surgery.[57]

Radiation Therapy

Radiation therapy as a sole therapy has been evaluated in the preoperative and postoperative settings. A study by Zhang and colleagues enrolled 370 patients with adenocarcinoma of the gastric cardia and randomly assigned them either to preoperative radiation therapy or to surgery alone.[58] The number of patients in the preoperative radiation therapy group whose cancers were resected was higher, and overall survival in this group was also superior (30% vs 20%). The British Stomach Cancer Group randomly assigned 432 patients to surgery alone or to surgery with postoperative radiation therapy or chemotherapy.[59] There was no benefit for the addition of postoperative radiation or chemotherapy; however, there was a statistically significant decrease in the rate of locoregional recurrence in the radiation therapy arm (27% with surgery alone vs 10% with postoperative radiation therapy).

Neoadjuvant Chemoradiotherapy

There are no large phase III randomized trials that address the value of neoadjuvant chemoradiotherapy (CRT) for patients with noncardia gastric cancers. Several phase II trials have shown a complete pathologic response in 11% to 25% of patients treated with neoadjuvant chemotherapy and radiation therapy.[60-62] The German POET trial (Preoperative Chemotherapy or Radiochemotherapy in Esophagogastric Adenocarcinoma Trial) was limited to patients with locally advanced T3/4NXMO adenocarcinomas of the EGJ.[63] In this trial, patients were randomly assigned to receive either chemotherapy followed by surgery or chemotherapy followed by CRT followed by surgery. The patients in the CRT arm had a significantly higher rate of complete response (15.6% vs 2.0%) and a higher rate of tumor-free lymph nodes (64.4% vs 37.7%). Preoperative CRT improved the 3-year survival from 27.7% to 47.4%. The trial was closed early due to poor accrual. However, there was a nonsignificant trend toward a survival advantage for the preoperative CRT group (P = .07).

Preoperative CRT for esophageal or EGJ cancer was studied in a recently published trial referred to as the CROSS trial (Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study).[64] The control arm was treated with surgery only and the other arm received 5 weekly doses of paclitaxel and carboplatin with simultaneous radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery. Overall survival was statistically significantly better in the CRT group, with a median overall survival of 49.4 months, compared with 24.0 months in the surgery-alone arm. The CRT regimen was well tolerated, and the in-hospital mortality was 4.0% in each group (Figure 1).

Postoperative Chemoradiotherapy

The Intergroup trial (INT) 0116/Southwest Oncology Group (SWOG) trial 9008, conducted in the 1990s, was a randomized phase III trial that was paradigm-shifting.[65] Prior to this study, there had been no significant change in survival following curative gastric surgery in 30 years. A total of 559 patients with primary T3 or T4 tumors and/or positive lymph nodes were randomly assigned either to adjuvant CRT with bolus 5-FU and radiation therapy or to observation, after curative gastric resection. After a median of 10 years of follow-up, the overall survival continued to demonstrate a strong survival advantage for adjuvant CRT, with a hazard ratio for overall survival of 1.32 (P = .0046) (Figure 2). Second malignancies were numerically more common in the adjuvant group, but not statistically significant. One of the criticisms of the trial was that only 10% of the patients underwent a D2 lymph node dissection, and 54% did not even have a D1 lymph node dissection.

The Cancer and Leukemia Group B (CALGB) 80101 trial compared the protocol used in INT-0116 (postoperative bolus leucovorin and 5-FU for cycles 1, 2, and 4, with infusional 5-FU and concurrent radiation therapy given during cycle 2) with a regimen of postoperative epirubicin, cisplatin, and infusional 5-FU for cycles 1, 2, and 4, and infusional 5-FU with concurrent radiation therapy for cycle 2.[66] At 3 years, there was no difference in overall survival.

Chemotherapy vs Chemoradiotherapy

The ARTIST trial involved 458 patients with completely resected gastric cancer who all had had a D2 lymphadenectomy.[67] The adjuvant chemotherapy arm received 6 courses of capecitacine and cisplatin, and the combined-modality arm received 2 courses of capecitabine and cisplatin followed by capecitabine and radiation therapy followed by an additional 2 courses of capecitabine and cisplatin. The study was not designed to evaluate overall survival. There was no difference in disease-free survival between the two arms, although in an unplanned analysis, node-positive patients in the chemotherapy arm had a better disease-free survival.[67]

Future Directions

Although diagnostic techniques (eg, endoscopic ultrasound) and surgical skills (eg, laparoscopic procedures) have improved, the survival of patients with gastric cancer still remains low. Also, incremental improvements seen with current chemotherapy regimens, while real, have been small. Recent research has focused on the fundamental cause of gastric cancer. It is hoped that this research will lead to a better understanding of the molecular pathogenesis of gastric cancer and thus to more targeted therapies. A brief review of the common known genetic pathways in gastric cancer will provide some indication of the directions that future therapies are likely to take.

The genetic pathogenesis of gastric cancer is multifaceted and involves multiple pathways. Proto-oncogenes such as Src, Ras, myc, Sis, and Myk belong to the family of housekeeping genes that encode for proteins that regulate growth factors, growth factor receptors, intracellular informational molecules, and transcriptional regulators. Overactivation or abnormal expression of these proto-oncogenes leads to abnormal cellular proliferation and differentiation. Conversely, deletion or inactivation of tumor suppressor genes, such as p53 and Rb, will lead to carcinogenesis by via aberrant expression of their encoding proteins, which inhibit cell growth and lead to programmed cell death.[68,69]

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein. Overexpression of EGFR in gastric tumor cells can lead to increased tumor invasiveness, angiogenesis, and inhibition of tumor cell apoptosis. Human epidermal growth factor receptor 2 (HER2) is a member of the EGFR family.[70] Twenty-one percent of gastric adenocarcinomas are HER2-positive; HER2 is associated with large tumors, lymphatic invasion, a more distal location, the intestinal type of histology, and serosal invasion.[71] The 5-year survival is markedly lower for patients with HER2-positive tumors than for those whose tumors do not have HER2 expression.[72] The phase III ToGA (Trastuzumab for Gastric Cancer) trial was a landmark study that demonstrated the benefit of adding trastuzumab to chemotherapy in patients with HER2-positive metastatic gastric cancer.[73] Median overall survival was statistically better in those assigned to the chemotherapy-plus-trastuzumab arm compared with those in the chemotherapy-alone arm (13.8 months vs 11.1 months, respectively). A possible role for trastuzumab in HER2-overexpressing locally advanced adenocarcinoma of the esophagus will be explored in a planned National Cancer Institute–sponsored trial (ClinicalTrials.gov identifier NCI-2011-02601) that will evaluate paclitaxel, carboplatin, and radiation therapy with or without trastuzumab in this population.[74]

The development of neovascularization is essential for tumor metastasis. A higher tumor vessel density correlates with greater opportunity for tumor metastasis.[75] Disruption of the vascular endothelial growth factor (VEGF) pathway is believed to inhibit tumor growth by reducing the blood supply to the tumor. It is also hypothesized that targeting the VEGF pathway leads to improvement in the delivery of chemotherapy to the tumor by promoting more permeability of the surrounding tumor blood vessels. Unfortunately, the recent Avastin in Gastric Cancer (AVAGAST) study in patients with metastatic gastric cancer failed to show a benefit when bevacizumab, an inhibitor of VEGF-A, was added to chemotherapy.[76]

Several additional areas of future research in the treatment of gastric cancers appear promising. Disorders of cell-cycle regulation can lead to cell carcinogenesis. Cyclins and cyclin-dependent kinases are important in gastric carcinogenesis. Increased expression of cyclin E is associated with poor prognosis in gastric cancer.[77] Flavopiridol is a cyclin-dependent kinase inhibitor. While inactive alone, it has shown activity in chemotherapy-treated gastric cell lines. This agent is being studied in combination with irinotecan.[78]

Single-nucleotide polymorphisms of HER2, E-cadherin, and matrix metalloproteinase 9 (MMP-9) are being evaluated for their ability to predict the risk of a malignant phenotype in gastric cancer.[79] (The lower survival seen in gastric cancer patients who are HER2-positive has already been mentioned. High levels of the degradation product of E-cadherin in plasma are associated with gastric cancer metastasis,[80] and MMPs are another class of molecules that facilitate angiogenesis.) DNA microarray analysis is a powerful method of identifying new genes that may have a role in gastric cancer pathogenesis, and also could be used to identify biomarkers for diagnosis or treatment.[81]

Conclusion

There has been incremental progress in the treatment of gastric cancer. The CROSS study has resulted in greater use of neoadjuvant CRT in patients with EGJ and esophageal carcinomas, with significant benefit. In the United States, the D2 lymphadenectomy is becoming a more standard procedure with less morbidity. The standard therapy after a complete gastric resection is modeled after the INT-0116/SWOG 9008 study: more clinicians are using continuous 5-FU with concurrent radiation therapy. In Europe, the perioperative regimen tested in the MAGIC study has gained wide acceptance. In Japan, where the survival rate exceeds rates reported in the West, adjuvant chemotherapy with S-1 remains the standard.

It is hoped that earlier detection, a better understanding of the molecular pathogenesis of gastric cancer, and incorporation of new therapies at an earlier stage, such as trastuzumab in select patients, will lead to better survival rates.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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