Cancer of the Stomach and Gastroesophageal Junction
Leonard L. Gunderson, John H. Donohue, Steven R. Alberts, Jonathan B. Ashman and Dawn E. Jaroszewski
Summary of Key Points
Staging Evaluation
• Staging should always include history and physical examination, complete blood cell count, liver chemistries, chest x-ray film, endoscopy with biopsy, ultrasound (determine degree of direct tumor extensions), and computed tomography (CT) of the abdomen (define extragastric disease).
• Additional studies that may help define extent of disease include upper gastrointestinal imaging, CT of the chest (for gastroesophageal junction [GEJ] lesions), laparoscopy (to rule out peritoneal seeding or early liver metastases), and positron emission tomography.
Primary Therapy
• Surgical resection is the primary therapy of resectable gastric and GEJ cancers.
• Cure rates of 80% or higher are achieved only with early lesions (patients with nodes negative, confined to mucosa or submucosa), which are uncommon in the United States.
• Role for extended node dissection has not been found in randomized trials.
Adjuvant Therapy
• Adjuvant therapy (chemotherapy, irradiation) is indicated on the basis of patterns of relapse and survival results with surgery alone (high rates of local-regional relapse and distant metastases).
• Adjuvant chemotherapy has a modest, significant benefit and has become the standard in Asia.
• Irradiation alone reduced local-regional relapse and improved overall survival (OS) in a Beijing trial of 370 patients testing preoperative irradiation versus surgery alone (5-year OS 30% vs. 20%, P = 0.009).
• The U.S. intergroup phase III trial of 556 patients found a survival benefit for combined-modality postoperative irradiation plus chemotherapy versus surgery alone (3-year relapse-free survival 48% vs. 31%, P = 0.001; 3-year OS 50% vs. 41%, P = 0.005).
• A British phase III trial of 503 patients demonstrated a survival advantage for perioperative ECF chemotherapy (epirubicin, cisplatin, 5-fluorouracil [5-FU]) when compared with surgery alone (5-year OS 36% vs. 23%, P = 0.009).
• A French phase III trial of 224 patients demonstrated a survival advantage for perioperative cisplatin and 5-FU compared with surgery alone (5-year OS 38% vs. 24%, P = 0.02).
• The POET trial of 120 patients with GEJ lesions tested preoperative chemotherapy versus chemoradiotherapy (CRT); outcomes trends favored preoperative CRT over chemotherapy alone for both OS (P = 0.07) and local control (P = 0.06).
Locally Advanced Disease (Borderline Resectable/Unresectable)
• Combined external beam radiation therapy (EBRT) plus chemotherapy or intraoperative radiation therapy (IORT) produced long-term survival in 10% to 20% of patients in most randomized and nonrandomized trials.
• Neoadjuvant chemotherapy studies reveal possible increase in resection rates but high incidence of local-regional relapse (consider addition of IORT alone or with EBRT and concurrent chemotherapy to neoadjuvant chemotherapy regimens).
Treatment of Metastatic Disease
• Multiple-drug chemotherapy regimens have response rates of 30% to 50%, and provide some improvement in OS, including the two- and three-drug regimens ECF, EOX (epirubicin, oxaliplatin, capecitabine), and DCF (docetaxel, cisplatin, 5-FU).
• A phase III trial of 594 patients showed a significant improvement in OS with the addition of trastuzumab to chemotherapy in patients with HER-2-positive tumors (median OS 13.8 vs. 11.1 months, P = 0.0046)
1. A patient with linitis plastica should be considered for:
2. A patient with a clinical T4, N1, M0 carcinoma of the GEJ (staging with endoscopic ultrasound and imaging studies) should be managed with (more than one answer is acceptable)
A Esophagogastrectomy, then adjuvant postoperative chemoradiation
B Total gastrectomy, then adjuvant therapy
C Preoperative chemoradiation, then esophagogastrectomy
3. A patient with a clinical T3, N0, M0 carcinoma of the distal stomach (EUS, other staging) should be managed with (up to two answers are acceptable)
A Total gastrectomy, then adjuvant therapy
B Neoadjuvant therapy, then total gastrectomy
C Subtotal gastrectomy plus >D1 node dissection, then adjuvant postoperative chemoradiation
D Neoadjuvant therapy, then subtotal gastrectomy plus >D1 node dissection
4. A 64-year-old man of European descent is seen in regard to a new diagnosis of metastatic adenocarcinoma arising from the cardia of the stomach. During his workup, evidence of lung, liver, and peritoneal metastases are seen by a computed tomography scan. A biopsy of the primary tumor shows signet ring cells and evidence of 2+ HER-2 staining by immunohistochemistry, but no amplification by fluorescence in situ hybridization (FISH). The patient has moderate abdominal discomfort, but a good performance status. He has no other significant health problems. Which of the following is true?
A Trastuzumab is a potential option in patients with HER-2 overexpression as defined by either 2-3+ immunohistochemical staining or FISH amplification.
B Cisplatin with 5-fluorouracil, capecitabine, or S-1 are all potential chemotherapy options for this patient.
C A three-drug regimen of cisplatin, 5-fluorouracil, and epirubicin provides a significant overall survival advantage compared to cisplatin and 5-fluorouracil, and methotrexate.
D A phase III trial demonstrated an overall survival advantage to the use of irinotecan, 5-fluorouracil, and leucovorin, compared to cisplatin and 5-fluorouracil.
5. A 55-year-old woman presents with epigastric discomfort and chronic dyspepsia. During the evaluation of her symptoms, she is found to have a moderately differentiated adenocarcinoma of the gastric cardia. Endoscopic ultrasound shows penetration of the tumor through the muscularis propria and one enlarged node adjacent to the tumor. A positron emission tomography/computed tomography scan shows no evidence of metastatic disease and strong enhancement of the primary tumor and adjacent lymph node. What would be the most appropriate approach to the treatment of her cancer?
A Surgery plus either perioperative chemotherapy or preoperative or postoperative chemoradiation are appropriate options based on randomized phase III trials.
B Given the apparent early stage of the cancer, surgery alone is an appropriate option.
C Primary chemoradiation without surgery provides the same outcome as preoperative chemoradiation followed by surgery for early-stage adenocarcinomas of the cardia.
1. Answer: D. In view of the propensity for submucosal and subserosal spread of gastric/gastroesophageal junction (GEJ) cancer, resection margins of at least 5 cm are preferred, and total gastrectomy is usually necessary for patients with linitis plastica.
2. Answer: A and C. For patients with high-risk gastric or GEJ cancer, surgery plus postoperative chemoradiation has been shown to have improved overall survival and disease-free survival (OS and DFS) versus surgery alone in the U.S. GI Intergroup phase III trial. Randomized phase III trials demonstrate survival advantages (DFS, OS) for preoperative chemoradiation plus surgery versus surgery alone for high-risk patients with esophageal or GEJ cancers. Preoperative chemoradiation is usually preferred over postoperative chemoradiation in this setting, because preoperative irradiation fields can be more conservative and preoperative irradiation or chemoradiation can alter the implantability of cells that may be spread as a result of marginal surgical resection for a T4 lesion.
3. Answer: C and D. For most cancers arising in the antrum or body of the stomach, subtotal gastrectomy provides adequate resection margins. Routine total gastrectomy does not provide better outcomes than subtotal gastrectomy in randomized phase III trials and large institutional experiences, provided a 5-cm margin of resection beyond the visible tumor can be achieved with subtotal gastrectomy. With regard to optimal extent of lymph node dissection, phase III trials have not demonstrated a survival advantage for D2 versus D1 node dissections.
4. Answer: C. The three-drug regimens of epirubicin, cisplatin, and 5-fluorouracil (ECF) and docetaxel, cisplatin, and 5-fluorouracil (DCF) have shown the ability to create a significantly improved overall survival. However, these regimens may have significant toxicity. In patients with a poor performance status or elderly patients, consideration of a two-drug regimen may be more appropriate. Based on a phase III trial, the combination of irinotecan, 5-fluorouracil, and leucovorin is less active than cisplatin and 5-FU. The use of trastuzumab is indicated only in patients with tumors that either have an HER-2 immunohistochemical score of 3+ or amplification by FISH. The scoring of HER-2 in gastric cancer is somewhat different than in breast cancer. It is important to make this distinction in the evaluation of gastric cancers. When evaluating HER-2 status, a biopsy of either the primary tumor or a metastasis can be used. A high degree of homology exists between the primary tumor and metastases in regard to the HER-2 status.
5. Answer: A. On the basis of the patient’s current workup, she has a clinical stage IIB (cT3N1M0) cancer of the cardia. Based on this staging, appropriate treatment options based on positive phase III trials include surgery preceded or followed by chemoradiation or the use of perioperative chemotherapy. Both of these approaches have shown significant survival advantages over surgery alone. Although European phase III trials do not demonstrate a survival advantage for preoperative chemoradiation plus surgery (trimodality) versus chemoradiation alone for patients with esophageal cancer, because of increased morbidity with the trimodality treatment approach, this option has not been evaluated in phase III trials for patients with gastric cancer.
