Treatment
Primary Treatment of Localized Disease
Management of gastric cancer relies primarily on surgical resection of the involved stomach, with reconstruction to preserve intestinal continuity, as resection provides the only chance for cure. Radiotherapy and chemotherapy now have better-defined roles as adjuncts to surgery and in patients with unresectable tumors. Perioperative chemotherapy and chemoradiation therapy remain active areas of current investigation.
Surgery
The objectives of operative treatment for potentially curable gastric cancers are confirmation of resectability, performance of a complete resection, facilitation of appropriate pathologic staging, and reestablishment of GI continuity and function.
Confirmation of resectability. Laparoscopy has emerged as an excellent tool to assess the extent of disease and resectability before the surgeon performs an open laparotomy. Laparoscopy adds to the accuracy of preoperative imaging, primarily in cases of peritoneal spread or small liver metastases. As a result, morbidity, hospital stay, and costs have been reduced significantly in patients with unresectable lesions. In addition, peritoneal washings can be obtained, although use of the findings to guide further treatment remains uncertain.
Extent of resection. The extent of gastric resection depends on the site and extent of the primary cancer. Subtotal gastrectomy is preferred over total gastrectomy, because it leads to comparable survival but lower morbidity. A 5-cm margin of normal stomach appears to be sufficient in proximal and distal resections. For lesions of the gastroesophageal junction or the proximal third of the stomach, proximal subtotal gastrectomy can be performed. If total gastrectomy is necessary, transection of the distal esophagus and proximal duodenum is required, and omentectomy is performed. In Japan, there is a growing experience with more limited resections of early-stage gastric cancer. This trend includes endoscopic mucosal resection of nonulcerated T1 N0 lesions and pylorus-preserving gastrectomy. Laparoscopic resections are also being performed more frequently, with preliminary data from randomized trials showing no significant differences regarding morbidity and mortality between open and laparoscopic procedures to date.
Extent of lymphadenectomy. The extent of lymph node resection, including the number of nodes removed at the time of gastrectomy, continues to be controversial. Preferably, lymphadenectomy includes the lymphatic chains along the celiac, left gastric, splenic, and hepatic arteries, which allows for more precise lymph node staging. The exact level designation of lymph nodes varies with the site and intragastric location of the primary tumor. To support current TNM staging criteria, 16 or more lymph nodes should be obtained at minimum and examined for an accurate N classification. Removal of lymph nodes immediately adjacent to the stomach (paracardial, paragastric at the lesser or greater curvature, parapyloric) has been termed D1 dissection. A more extensive D2 dissection would also remove retroperitoneal "second echelon" lymph nodes along the celiac trunk, left gastric artery, hepatic artery, splenic artery, and splenic hilus.
Improved long-term survival rates for Japanese patients had been attributed to the extended lymphadenectomies routinely performed in this country. Because the improvement in survival after gastrectomy during recent decades was usually associated with the performance of extended lymph node dissections (D2 dissections or greater), this practice appeared to be sensible if performed with acceptable complication rates. Retrospective data had shown that D2 lymphadenectomy is safe and does not increase morbidity. Recent population data reviews have linked higher total lymph node numbers (up to 40) to superior survival.
Initial data in two European randomized trials showed no significant differences in overall long-term survival between D1 and D2 dissection groups. Both studies found higher postoperative morbidity and mortality in the D2 (extended) group, largely due to a higher rate of splenectomy and/or partial pancreatectomy performed with those dissections. An update of the randomized Dutch D1D2 trial has demonstrated a significant advantage to D2 dissection at 15 years in terms of deaths from gastric cancer (37% after D2, 48% after D1 dissection, P = .01). In addition, a significant long-term survival advantage was conferred by D2 dissection in female patients who underwent curative resection (35% vs 21%, P = .03) and in patients with stage II (33% vs 15%, P = .03) or N2 diseases (19% vs 0%, P = .07). Interestingly, the beneficial D2 dissection impact on local recurrence and survival does not seem to be enhanced by postoperative chemoradiotherapy, whereas chemoradiotherapy appears to improve both categories after mere D1 dissections. Gastrectomy with extended lymphadenectomy should primarily be performed in specialized centers by experienced surgeons, and splenectomy and pancreatectomy should be avoided; for adequate staging, at least 16 lymph nodes should be removed and analyzed.
Reconstruction methods. After distal gastrectomy, Billroth I gastroduodenostomy or, more commonly, Billroth II gastrojejunostomy methods are acceptable for reconstruction. Reflux esophagitis is a common problem when the gastric reservoir is too small. After total or subtotal gastrectomy, a Roux-en-Y esophagojejunostomy is usually performed.
Resection of extragastric organs. Resection of extragastric organs may be required to control T4 disease. Such a resection can be associated with long-term survival. Splenectomy should be avoided unless it is indicated by direct tumor extension, because it significantly increases the rate of complications.
Neoadjuvant Therapy
Prompted by the promising results and acceptable toxicity of preoperative (neoadjuvant) chemoradiation therapy in other parts of the GI tract (eg, esophagus, rectum), there is growing interest in neoadjuvant therapy for gastric cancer. Neoadjuvant treatment may be performed in an attempt to convert an initially unresectable cancer to resectable status (so-called conversion therapy), or it may be used in advanced but resectable disease felt to be at high risk for recurrence following surgery alone.
The MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial investigated perioperative treatment with epirubicin(Drug information on epirubicin), cisplatin(Drug information on cisplatin), and continuous 5-fluorouracil (5-FU) infusion (ECF) vs surgery alone, demonstrating improvements in progression-free and overall survival rates with the addition of chemotherapy. These results have been nonconsistently confirmed in other large randomized trials; EORTC (European Organisation for Research and Treatment of Cancer) 40954, which closed early due to poor accrual, did not demonstrate a survival advantage for those getting purely neoadjuvant chemotherapy. Nonetheless, in resectable patients, perioperative chemotherapy added to surgery is now a standard of care in many parts of the world.
Adjuvant Therapy
Treatment and survival by stage in patients with gastric carcinomaThe 5-year survival rate after "curative resection" for gastric cancer is only between 30% and 40% (Table 2). Treatment failure stems from a combination of local or regional recurrence and distant metastases. Investigators have studied adjuvant therapy in the hope of improving treatment results. A North American Intergroup trial randomizing resected patients (stages IB-IV[M0]) to receive chemoradiation therapy or observation showed significant improvement in median disease-free survival (median 19 vs 30 months) and overall survival (26 vs 35 months) with adjuvant therapy, and the use of postoperative chemoradiation therapy, usually with continuous infusion of 5-FU, is the standard of care in the United States. Population studies have suggested that adjuvant therapy is underutilized in the United States.
Radiotherapy
Locoregional recurrence as a component of failure is common in patients undergoing curative resection for gastric cancer. Radiotherapy can decrease the rate of locoregional failure but has not been shown to improve survival as a single postoperative modality. Postoperative radiotherapy may be appropriate in patients who are not candidates for chemotherapy.
Chemotherapy
Chemotherapy alone as a surgical postoperative adjunct does not have a defined role in the United States. Individual randomized trials of chemotherapy plus surgery vs resection alone have mostly not demonstrated a definite survival advantage, with the possible exception of patients with widespread nodal involvement and older patients, who may do better with chemotherapy. Meta-analyses of postoperative chemotherapy plus surgery vs resection alone have shown minor reductions in death rates, but no specific regimen can be recommended. Alternative chemotherapy delivery methods such as intraperitoneal chemotherapy have been evaluated in phase III trials with promising results, and are an area of future study.
Neoadjuvant chemoradiation has also been explored as a way to improve tolerability of chemoradiation and to improve resectability and pathologic response rates compared with chemotherapy. A phase III randomized trial suggested that neoadjuvant treatment with chemotherapy and radiation provides superior pathologic outcomes compared with neoadjuvant chemotherapy. A trend toward improved survival with chemotherapy and radiation was seen. An ongoing phase III international trial (TOPGEAR) will evaluate the use of ECF preoperatively compared with 2 cycles of ECF followed by chemoradiotherapy with 5-FU and radiotherapy to 45 Gy. Both groups will receive 3 cycles of ECF postoperatively.
Sidebar: Intensifying chemotherapy has not been effective at improving disease-free or overall survival in patients with resected gastric cancer. The Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S trial) was presented at the 2012 meeting of the American Society of Clinical Oncology (ASCO). A total of 1,106 patients with resected pT2b-T4 gastric or gastroesophageal junction adenocarcinoma (D1 or greater resection) were randomized to FOLFIRI (fluorouracil [5-FU], leucovorin, irinotecan(Drug information on irinotecan)) for 4 cycles followed by docetaxel(Drug information on docetaxel) and cisplatin for 3 cycles vs 5-FU and leucovorin for 9 cycles. At a median follow-up of 49 months, there was no evidence of significant difference in disease-free or overall survival, with increased toxicity in the intensified-chemotherapy arm (Bajetta E et al: J Clin Oncol 30[suppl]: abstract LBA4001, 2012).
Chemoradiation therapy
Patients with T3-T4 any N M0 tumors are at highest risk of locoregional recurrence after potentially curative surgery (surgery in which all macroscopic tumor has been resected with no evidence of metastatic disease) for gastric cancer. Even patients with node-negative disease (T3 N0) have a gastric cancer-related mortality of about 50% within 5 years. Mortality is significantly worse in patients with node-positive disease or in those with incomplete (R1, R2) resection.
In the North American Intergroup trial (INT-0116) previously mentioned in the section on "Adjuvant therapy," patients were randomized to receive chemoradiation therapy or observation following resection of stages IB-IV (M0) adenocarcinoma of the stomach. Chemoradiation therapy following resection of these high-risk patients significantly improved both disease-free and overall survival rates. Because of the apparent benefit of reducing locoregional recurrences, but not distant recurrences, it is possible that more routine use of D2 lymphadenectomy may modify this recommendation in the future. D2 lymphadenectomy was performed in only 10% of the patients in this trial. Subgroup analysis revealed that the outcome did not differ based upon the type of lymphadenectomy (P = .80). Still, since only a small percentage of patients underwent the recommended D2 dissection, further research is necessary before firm conclusions can be made in this area. A 10-year update of this trial was published in 2012; Smalley et al reported that patients who were offered chemoradiation continued to enjoy improved survival (hazard ratio [HR] = 1.32) and disease-free survival (HR = 1.51).
Despite this trial, significant controversy regarding the need for adjuvant treatment persists and is perhaps growing. Many studies support the contention that aggressive, formal D2 resection may obviate the need for adjuvant treatment in many cases. Other studies and subgroup analyses support the recommendations for adjuvant treatment as concluded in the North American trial. These conflicting results, as well as distinct differences in results between Eastern and Western nations, suggest that this issue may take many years to resolve. In the interim, it is appropriate to recommend adjuvant chemoradiotherapy to patients in North America who undergo initial gastrectomy. Studies by the Cancer and Leukemia Group B (CALGB) and other groups do not support that intensification of therapy above that delivered on INT0116 will improve disease-free or overall survival.
Newer radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT) and advanced image guidance, have been explored as a way to reduce the toxicity and improve accuracy of radiation treatments. These techniques may be especially helpful in reducing small bowel and kidney damage during chemoradiation, although data from large series are not yet available to confirm these results from small series.
A recent retrospective study from Korea evaluated chemoradiation compared with observation in patients who underwent a D2 dissection. Overall survival in this series was higher for patients who received adjuvant therapy, suggesting that a D2 dissection does not preclude the need for adjuvant therapy. This benefit, however, could be predominantly derived from the systemic treatment component. The role of radiation therapy in addition to capecitabine(Drug information on capecitabine) (Xeloda) and cisplatin was evaluated in a large Korean phase III trial of patients undergoing D2 gastrectomy (ARTIST [Adjuvant Chemoradiation Therapy in Stomach Cancer Trial]); there was no disease-free survival benefit from the radiation overall, but some benefit in the node-positive patient subset (HR = 0.69; P = .047). Another Asian trial (CLASSIC [Capecitabine and Oxaliplatin(Drug information on oxaliplatin) Adjuvant Study in Stomach Cancer]) has shown a disease-free survival benefit to postoperative chemotherapy alone with capecitabine and oxaliplatin (Eloxatin) after D2 gastrectomy (3-year disease-free survival 74% vs 59%; HR = 0.56; P < .001).
Studies by the CALGB and other groups do not support that intensification of therapy with ECF above that delivered with 5-FU alone in INT0116 will improve disease-free or overall survival.
Imatinib mesylate (Gleevec) given for 3 years or longer now represents standard of care in the postoperative setting, for selected GIST patients. The American College of Surgeons Oncology Group (ACOSOG) Z9001 randomized trial found that 1 year of imatinib(Drug information on imatinib) mesylate extends recurrence-free survival but not overall survival, compared with placebo following resection of intermediate- or high-risk GIST. On the placebo arm, KIT mutation in exon 11 was prognostic for worse recurrence-free survival; patients with rectal primaries receiving imatinib also had poorer outcomes. Interestingly, only one event occurred among patients harboring the PDGFR D842V mutation, believed to be imatinib-resistant. Thus, tumor pathology and mutational status were both prognostic and predictive of recurrence-free survival after surgical resection of GIST (Lancet 373: 1097-1104, 2009). The recently presented SSGXVIII/AIO trial showed a better recurrence-free survival and overall survival in patients with high-risk, resected GIST receiving 36 months of adjuvant imatinib, compared with 12 months of treatment (see sidebar).
Sidebar: In the Scandinavian Sarcoma Group Trial XVIII, patients with resected GISTs deemed to be at high risk of recurrence were randomized to imatinib mesylate, at 400 mg per day, for 1 vs 3 years. Those receiving the drug for a longer period had better 5-year relapse-free (66% vs 48%) and overall (92% vs 82%) survival. More patients getting longer therapy had high-grade adverse events, questionably due simply to the prolonged therapy. A high fraction of those on the 3-year arm dropped out (26%), other than for reasons of recurrence, raising the question of how to improve compliance when administering postoperative targeted therapies (Joensuu H et al:JAMA 307:1265–1272, 2012).
