Gastric Cancer Follow-up

A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.

Direct mortality rate within 30 days after a surgical procedure for gastric cancer has been reduced substantially over the last 40 years. Most major centers report a direct mortality rate of 1-2%.

Early postoperative complications include anastomotic failure, bleeding, ileus, transit failure at the anastomosis, cholecystitis (often occult sepsis without localizing signs), pancreatitis, pulmonary infections, and thromboembolism. Further surgery may be required for anastomotic leaks.

Late mechanicophysiologic complications include dumping syndrome, vitamin B-12 deficiency, reflux esophagitis, and bone disorders, especially osteoporosis.

Postgastrectomy patients often are immunologically deficient, as measured by blastogenic and delayed cutaneous hypersensitivity responses.

Unfortunately, only a minority of patients with gastric cancer who undergo a surgical resection will be cured of their disease. Most patients have a recurrence.

Patterns of failure

Several studies have investigated the patterns of failure after surgical resection alone. Studies that depend solely on the physical examination, laboratory studies, and imaging studies may overestimate the percentage of patients with distant failure and underestimate the incidence of local failure, which is more difficult to detect.

A reoperation series from the University of Minnesota may offer a more accurate understanding of the biology of the disease. In this series of patients, researchers surgically reexplored patients 6 months after the initial surgery and meticulously recorded the patterns of disease spread. The total local-regional failure rate approached 67%. The gastric bed was the site of failure in 54% of these cases, and the regional lymph nodes were the site of failure in 42%. Approximately 26% of patients had evidence of distant failure. The patterns of failure included local tumor regrowth, tumor bed recurrences, regional lymph node failures, and distant failures (ie, hematogenous failures and peritoneal spread). Primary tumors involving the gastroesophageal junction tended to fail in the liver and the lungs. Lesions involving the esophagus failed in the liver.^[26]

Adjuvant therapy

The pattern of failure prompted a number of investigations into adjuvant therapy. The rationale behind radiotherapy is to provide additional local-regional tumor control. Adjuvant chemotherapy is used either as a radiosensitizer or as definitive treatment for presumed systemic metastases.

Adjuvant radiotherapy

Moertel and colleagues randomized postoperative patients with advanced gastric cancer to receive 40 Grays (Gy) of radiotherapy or 40 Gy of radiotherapy with 5-FU as a radiosensitizer and demonstrated improved survival associated with the combined-modality therapy.^[27]

The British Stomach Cancer Group reported lower rates of local recurrence in patients who received postoperative radiotherapy than in those who underwent surgery alone.^[28]

The update of the initial Gastrointestinal Tumor Study Group series revealed higher 4-year survival rates in patients with unresectable gastric cancer who received combined-modality therapy than in those who received chemotherapy alone (18% vs 6%).^[29]

In a series from the Mayo Clinic, patients were randomized to receive postoperative radiotherapy with 5-FU or surgery alone, and improved survival was demonstrated in patients receiving adjuvant therapy (23% vs 4%).^[30]

Intraoperative radiotherapy

Some authors suggest that intraoperative radiotherapy (IORT) shows promising results.

This alternative method of delivering radiotherapy allows for a high dose to be given in a single fraction while in the operating room so that other critical structures can be avoided.

The National Cancer Institute randomized patients with grossly resected stage III/IV gastric cancer to receive either 20 Gy of IORT or 50 Gy of postoperative external beam radiation. Local failure was delayed in the patients treated with IORT (21 mo vs 8 mo). Although the median survival duration also was higher (21 mo vs 10 mo), this figure did not reach statistical significance.^[31]

Adjuvant chemotherapy

Numerous randomized clinical trials comparing combination chemotherapy in the postoperative setting to surgery alone did not demonstrate a consistent survival benefit.

Recent meta-analyses have shown a hint of statistical benefit. In one meta-analysis of 13 randomized trials, adjuvant systemic chemotherapy was associated with a significant survival benefit (odds ratio for death, 0.80; 95% CI, 0.66-0.97). In subgroup analysis, there was a trend toward a larger magnitude of effect for trials in which at least two thirds of the patients had node-positive disease.^[32]

A postoperative chemoradiation study was prompted in part by the patterns of local failure often preceding systemic spread.

Adjuvant chemoradiotherapy

A randomized phase III study performed in the United States, Intergroup 0116, demonstrated a survival benefit associated with postoperative chemoradiotherapy compared with surgery alone.^[2]

In this study, patients underwent an en bloc resection.

Patients with T3 and/or N+ adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive a bolus of 5-fluorouracil (5-FU) and leucovorin (LV) and radiotherapy or observation.

Patients who received the adjuvant chemoradiotherapy demonstrated improved disease-free survival (from 32% to 49%) and improved overall survival rates (from 41% to 52%) compared to those who were merely observed.

This regimen is considered the standard of care in the United States.

Neoadjuvant chemotherapy

Neoadjuvant chemotherapy may allow downstaging of disease to increase resectability, decrease micrometastatic disease burden prior to surgery, allow patient tolerability prior to surgery, determine chemotherapy sensitivity, reduce the rate of local and distant recurrences, and ultimately improve survival.

A European randomized trial also demonstrated survival benefit when patients were treated with 3 cycles of preoperative chemotherapy (epirubicin, cisplatin, and 5-fluorouracil) followed by surgery and then 3 cycles of postoperative chemotherapy compared with surgery alone. The benefit was comparable to that obtained with postoperative chemoradiation in the US trial.^[3] However, the Gastric Chemotherapy Group for Japan did not demonstrate a significant survival benefit with neoadjuvant chemotherapy.

Choice of preoperative and postoperative chemotherapy versus postoperative chemotherapy and radiation remains controversial, and an ongoing United States Intergroup study, CALGB 80101, will look more closely at that question.

Advanced unresectable disease

Many patients present with distant metastases, carcinomatosis, unresectable hepatic metastases, pulmonary metastases, or direct infiltration into organs that cannot be resected completely.

In the palliative setting, radiotherapy provides relief from bleeding, obstruction, and pain in 50-75% of patients. The median duration of palliation is 4-18 months.

Surgical procedures such as wide local excision, partial gastrectomy, total gastrectomy, simple laparotomy, gastrointestinal anastomosis, and bypass also are performed with palliative intent, with a goal of allowing oral intake of food and alleviating pain.

Platinum-based chemotherapy, in combinations such as epirubicin/cisplatin/5-FU or docetaxel/cisplatin/5-FU, represents the current first-line regimen. Other active regimens include irinotecan and cisplatin and other combinations with oxaliplatin and irinotecan.

Results of cisplatin-based chemotherapy have been largely discouraging, with median time to progression of 3-4 months and overall survival of approximately 6-9 months despite reported response rates of up to 45%. Early results reported in 2007 by Japanese clinicians suggest some improvement in both response rates and survival with the oral fluoropyrimidine S-1 used alone or in combination with cisplatin.^[33] (S-1 combines 3 investigational drugs: tegafur, a prodrug of 5-FU; gimeracil, an inhibitor of fluorouracil degradation; and oteracil or potassium oxanate, a GI tract adverse-effect modulator.) These results remain to be confirmed by ongoing studies in Europe and North America.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF) is currently being evaluated for use in advanced gastric cancer.^[34]

Novel treatment strategies may be guided by the use of gene signatures.^[35] Kim et al reported that combined overexpression of MYC, EGFR, and FGFR2 predicts a poor response of metastatic gastric cancer to treatment with cisplatin and fluorouracil.^[36]

Ishido et al reported that in patients receiving S-1 chemotherapy after gastrectomy for advanced gastric cancer, intratumoral mRNA expression of thymidylate synthase (TS) is an independent prognostic factor for response to chemotherapy. In 39 patients who received postoperative S-1, recurrence-free survival and overall survival were significantly longer in patients with low TS expression than in those with high TS expression (P=0.021 and 0.016, respectively), whereas in 40 patients treated with surgery only, TS expression did not correlate with survival.^[37]

Overexpression of human epidermal growth factor receptor 2 (HER2) is a significant negative prognostic factor for gastric cancer. In the international ToGA trial (trastuzumab with chemotherapy in HER2-positive advanced gastric cancer), about 22% of patients with advanced gastric cancer were found to have tumors that overexpressed HER2. In this phase III trial, 594 patients with HER2-positive advanced gastric cancer were randomized to receive standard chemotherapy alone or chemotherapy plus trastuzumab (Herceptin). Overall survival with trastuzumab was 13.8 months, compared with 11.1 months in the chemotherapy group (hazard ratio, 0.74, P = .0046).^[38]

Although modest, this 2.7-month improvement in overall survival is clinically meaningful in this group of patients, who have a poor prognosis. In addition to the impact on overall survival, trastuzumab improved all of the secondary end points, including progression-free survival (increased from 5.2 mo to 6.7 mo; P = .002) and overall response rate (increased from 34.5% to 47%; P =.0017).

Trastuzumab was approved in October of 2010 for the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. It is administered in combination with cisplatin and capecitabine or 5-fluorouracil in patients who have not received prior treatment for metastatic disease. The trastuzumab dose consists of an initial cycle of 8 mg/kg intravenously (IV) infused over 90 minutes, followed by subsequent cycles of 6 mg/kg IV infused over 30-90 minutes every 3 weeks. Treatment is continued until the disease progresses.

For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education article, Stomach Cancer.