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Future Possibilities/Clinical Trials/Treatment Algorithm
Completely Resected Lesions
Many patients with gross complete resection of their gastric cancer are not cured with surgery alone. The final results of the British and Dutch multicenter trials evaluating the value of extended lymphadenectomy demonstrated that the procedure produced greater morbidity with no impact on survival. Because experienced surgeons have performed extended node dissection without significant increases in surgical morbidity or mortality rates, 75,78 use of the procedure is still reasonable in node-positive patients. Such patients will still be at high risk for local-regional and systemic relapse, however, and should receive postoperative CRT (Table 75-13). This philosophy is supported by the nonrandomized South Korea analysis by Kim and associates, which appeared to demonstrate an advantage in disease control and survival in 544 patients who received postoperative CRT following D2 resection versus the 446 surgery-alone patients (5-year OS: 57% vs. 51%, P = 0.02; 5-year RFS: 54.5% vs. 47.9%, P = 0.016). 192 Early results from the South Korea phase III trial suggest that postoperative chemoradiation improved 3-year DFS in node-positive patients who had a D2 node dissection. 193
The U.S. GI Intergroup replacement phase III randomized trial was designed to build on the positive results of INT 0116 120,187,188 by testing 5-FU infusion versus bolus 5-FU + leucovorin as the concurrent chemotherapy during EBRT, and ECF chemotherapy versus 5-FU + leucovorin as the maintenance component of chemotherapy. Preliminary analyses did not demonstrate improvements in survival with the more aggressive experimental arm when compared with the chemoradiation control arm from INT 0116. 190
On the basis of encouraging results with preoperative chemoradiation (CRT) 193-197 for patients with locally advanced adenocarcinoma of the esophagus and/or GEJ (i.e. POET trial) and the survival advantage for perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancers in the British and French phase III trials, 61,163 future phase III studies should evaluate preoperative chemotherapy (alone or followed by preoperative or postoperative CRT) and preoperative CRT in combination with resection for patients with potentially resectable gastric cancers. Although some investigators and institutions may prefer to simply replace postoperative adjuvant CRT with perioperative ECF chemotherapy, it would seem advantageous to attempt to combine the advances in disease control and survival found with both approaches, in that neither approach by itself resulted in optimal relapse or survival outcomes.
Locally Advanced Disease (Unresectable for Cure)
For patients with locally advanced disease that appears unresectable for cure, it seems reasonable to build on existing positive segments of treatment data (EBRT plus chemotherapy, IORT, preoperative chemotherapy, preoperative chemoradiation) plus patterns of relapse information. External irradiation plus chemotherapy or IORT alone or added to EBRT has controlled disease and produced long-term survival in 10% to 20% of patients in most single-institution analyses and randomized trials in patients with residual disease after resection. Neoadjuvant chemotherapy for unresectable disease has resulted in subsequent total resection of disease in 20% to 73% of patients in several European trials with EAP, FAMTX, or other regimens. However, the incidence of subsequent local-regional relapse is significant, even after total resection. It would be of interest to merge these components of treatment.
Following preoperative chemotherapy, patients with marginal gross total or subtotal resection with residual disease or resection but high-risk factors for relapse (beyond the gastric wall, nodes positive, or both) should be placed on studies that evaluate IORT, postoperative EBRT, or both in conjunction with concurrent and maintenance chemotherapy. For patients who are unresectable after preoperative (neoadjuvant) chemotherapy but still have localized tumor on the basis of preoperative staging (including laparoscopy) or exploratory laparotomy, EBRT plus concurrent chemotherapy should be given. Decisions regarding attempts at later resection alone or plus IORT could be individualized by institution.
An alternate approach is to initiate treatment with preoperative CRT followed by restaging, resection (alone or plus IORT), and postoperative maintenance chemotherapy. Questions to be addressed with this approach include whether to give several cycles of multiagent chemotherapy before initiating concomitant CRT or whether to start with concomitant CRT, how many cycles of chemotherapy to deliver, and which agents to give both with irradiation and as the systemic component of treatment.
It is unlikely that significant advances will be made through the addition of other new chemotherapy drugs to those already available. Molecular profiling of tumors may allow more individualized approaches to patient care. With this type of approach advances will more likely occur through the use of targeted therapies, as demonstrated with trastuzumab. A variety of trials with targeted therapy used alone or in combination with chemotherapy are under way. Ultimately, the goal must focus on improvements in both OS and response rate, while continually focusing on quality of life. Adequately powered trials in both the phase II and phase III settings will be important in providing meaningful answers.
Treatment Algorithm by Tumor, Lymph Node, and Metastasis Disease Extent
The contents of this section are supported by Table 75-13 and Figures 75-8 and 75-9.
Total surgical resection of the adenocarcinoma with a radical subtotal gastrectomy and reconstruction with gastrojejunostomy is recommended as standard treatment. Patients with posterior-wall T2N0M0 lesions should be evaluated for postoperative adjuvant CRT (see next discussion).
Postoperative CRT is the preferred standard of treatment in the United States based on demonstrated improvement in survival (disease-free and overall) when compared with a surgery-alone control arm in the phase III U.S. GI trial (INT 0116). 129,187,188
Our institutions prefer the use of preoperative CRT for patients who have T1–2N1–3M0 or T3N0–3M0 GEJ cancers at the time of EUS, because we can usually design safer EBRT fields for preoperative CRT rather than postoperative CRT. If transhiatal resection is performed, keeping the reconstructed stomach in the mediastinal midline, postoperative CRT can be given more safely than if Ivor-Lewis resection is performed. For patients who are at high risk for surgical resection following preoperative CRT (medical comorbidities), if there is a clinical complete response based on endoscopy and PET/CT, surgery may reasonably be kept in reserve for local relapse. 344
Preoperative CRT followed by restaging, gross total resection (may include en bloc resection of adjacent organs), and IOERT is recommended for potentially resectable T4N0–3 lesions in institutions with IOERT capability. Postoperative CRT has also been used for completely resected lesions.
For patients with locally unresectable T4N0–3M0 gastric or GEJ cancers, preoperative or primary CRT or multiple-drug chemotherapy can be used, preferably in the setting of controlled prospective clinical trials. For patients with good performance status, the treatment approach would preferably involve preoperative CRT, restaging, and surgical resection with an attempt at marginal gross total resection and IOERT.
Multidrug chemotherapy combinations are the preferred treatment for patients with metastatic cancers. Patients should be placed on controlled trials if available. Palliative irradiation can be used for painful metastatic lesions but is otherwise not indicated. Palliative resection may be indicated for patients with obstruction or bleeding, if total gastrectomy can be avoided.
Nutritional Support during Chemoradiation
Many patients who receive preoperative CRT (with plans to proceed to surgical resection) or primary CRT may require parenteral or enteral hyperalimentation during treatment. This support may also be necessary in subsets of patients with borderline performance status who are candidates for postoperative CRT. Improvement in nutritional status may require stent placement during endoscopy, feeding jejunostomy, or percutaneous endoscopic gastrostomy tube placement. Feeding jejunostomy may be preferable to percutaneous endoscopic gastrostomy tube placement for patients receiving preoperative CRT, so as to preserve later use of the stomach for reconstruction.