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EDITORIAL |
From the Department of Surgery, Ioannina University Medical School, Ioannina, Greece.
Correspondence: Address correspondence to Dimitrios H. Roukos, MD, P.O. Box 105, Neochoropoulo, GR-43500 Ioannina, Greece; Fax: 30-651-48451; E-mail: droukos{at}cc.uoi.gr
Despite the declining incidence, the mortality of patients diagnosed with gastric cancer remains high. Surgery with curative potential is the treatment of choice. Although postsurgical risk (morbidity, mortality) has been reduced remarkably in recent years (mortality <5%), there has been moderate progress in the improvement of overall long-term survival rates. Estimates suggest that among all patients who have surgery for gastric cancer, about 10% to at best 30% in the West are still alive 5 years later.1–3 Undoubtedly a chance for long-term survival is provided only by complete tumor removal (R0 resection) by surgery, whereas, unfortunately for all other patients, i.e., with noncurative resection, unresected, or with distant metastatic disease, survival is extremely poor.1 But even after curative surgery, recurrence is often found in patients in the West1–4 and Japan5,6 and nearly always fatal.1–6 Because adjuvant chemotherapy or radiotherapy has been of little or no efficacy,1 the best way to improve outcome is to increase the rate of curative resection by detecting tumors early and to perform appropriate surgery to reduce the rate of recurrence. Indeed, using this strategy in Japan has increased the rates of R0 resection to about 80% and overall survival to between 50% and 60%.5 The rate of curative surgery in the West is still small ranging between 30% and 70%.1–4
Recurrence is the main cause of treatment failure after curative gastrectomy for patients with cancer. Frequency of recurrence, time to first recurrent event, and survival are strongly dependent on the stage of disease at the time of surgery and extent of surgical resection. The debate over the last two decades continues over the optimal extent of surgery between limited (D1) and extended (D2) lymph node dissection. Two European randomized trials2,3 failed to resolve this debate and was complicated by many variables. According to a recently described concept,7 it is estimated that approximately 30% of all patients who are suitable for potential curative surgery suffer from positive nodes around celiac axis (level II: stations 7 to 12).1–3,5 This fact clearly indicates both the necessity of D2 resection for an R0 resection and the insufficiency of D1 resection that results in residual disease and the fatal outcome in most, and perhaps all, patients with level II disease.7 This argument and the favorable studies on the outcomes of D2 resection from Japan5 and several specialized institutions in the West1 have convinced many investigators of the effectiveness of D2 resection for selected node-positive cancers. However, the adverse effect of D2 resection on postsurgical morbidity and mortality in the randomized trials suggest caution. The D2 technique should not be combined with pancreaticosplenectomy or performed by surgeons who are not familiar with the technique.
Classification according to the International Union against Cancer (UICC) accurately predicts overall survival but is unable to provide information in terms of overall recurrence, time-specific recurrence-appearance, and site-specific first recurrence. These valuable data are the basis for the development of causative recurrence-oriented and site-specific target therapies. The complexity of recurrence patterns involving locoregional, nodal, hematogenous, peritoneal, and combinations of these types of recurrence1,4,6 and a lack of prospective controlled studies suggest the need for well-documented recurrent data gathered prospectively for identification of site-specific risk factors.
Despite these limitations, recent reports from the West4 and Japan6 consistently indicate several critical key points in the mode of recurrence after curative resection. First, pathological serosa state is the determinant and independent factor for prediction of site-specific recurrence because patients with serosa-positive cancer are at high-risk for peritoneal spread, whereas patients with serosa-negative cancers are at risk for hematogenous recurrence. The presence of nodal metastasis markedly increases the risk of recurrence for both types of serosa status. Second, the risk for recurrence after standard gastrectomy with extended (D2) lymph node dissection is strongly determined by the tumor stage; it is low risk for both serosa and node-negative cancer (about 10%), but high risk in up to 85%4 for both serosa and node-positive cancer. Postoperative adjuvant chemotherapy or radiotherapy has been proven to be of little or no efficacy in reducing recurrence and improving survival.1 In a preliminary report of the Intergroup 116 US trial, it was suggested that some survival benefit may occur with the use of chemoradiotherapy after curative surgery. These findings should be approached with caution because many patients enrolled in the trial had an unacceptable limited (D0) surgery and survival rates in the treatment group were much lower or similar to that of surgery alone from Japan5 and Europe.1–3 The effectiveness of neo-adjuvant treatment with preoperative and/or intra-operative intra-peritoneal chemotherapy based on a numerous of theoretical advantages is now being tested in ongoing randomized trials.1 In general however, there is doubt over an overoptimism about cancer and expectations for large survival benefits from new agents-based combination regimens in the next few years is unrealistic.8
Why and how can it be explained that most (70%) patients develop a secondary tumor (recurrence) early (within 2 years)1,4,6 after complete tumor resection? Circulating tumor cells have been identified in peripheral blood even at earlier tumor stages by current molecular techniques (reverse transcriptase-polymerase chain reaction (RT-PCR)9 This fact strongly supports the theory that clinically occult tumor cells released from origin tumor before9 and during surgical maneuvers,10 enter the blood circulation, migrate, and form metastatic tumors to distant target organs. Previous experimental studies have shown that changes in tumor cell kinetics occur within 24 hours of the removal of the origin tumor and a week later a measurable tumor size can be observed.11 Therefore, these cells proliferate and invade surrounding tissues in the critical early postsurgical period. They form secondary tumors (recurrence) in the target organs (peritoneum, liver) and become clinically detectable early in the follow-up. The recent controversy over prognostic significance of circulating tumor cells9 underlines the complexity of the metastatic process. For example, most recent findings on molecular activity for breast cancer reveal that mediator molecules (ligand-receptor pair) regulate the metastatic process in the target organs.12,13 Because the significance of these molecules is probably not unique to breast cancer, one could speculate that similar or other molecules also regulate the metastatic process for gastric cancer.
These molecular-based findings explain and strongly indicate the limitations of surgery alone in reducing recurrence of advanced gastric cancer. Intense efforts and much work is needed toward the development of new agents that will be effective combinations for treatment and the identification of small molecule antagonists for a tailored causative site-specific preventive therapy. At present however, the appropriate extent of surgery, as determined by nodal status, with more or less extensive lymph node dissection for node-positive or node-negative cancers, respectively, should be performed with a standardized technique. This may reduce the risk for recurrence and improve outcome.
Received for publication May 22, 2001. Accepted for publication June 20, 2001.
REFERENCES
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  E. Briasoulis, M. Fatouros, and D. H. Roukos Level I Evidence in Support of Perioperative Chemotherapy for Operable Gastric Cancer: Sufficient for Wide Clinical Use? Ann. Surg. Oncol., October 1, 2007; 14(10): 2691 - 2695. [Full Text] [PDF]
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W.-J. Lee, A. M. Kappas, M. Fatouros, and D. H. Roukos It Is Still Not the Time to Change Surgical Strategy for Gastric Cancer Ann. Surg. Oncol., February 1, 2005; 12(2): 194 - 196. [Full Text] [PDF]
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