Impact of Surgical Expertise on Outcomes of Patients with Gastric Cancer
Dimitrios H. Roukos, MD, Michael Fatouros, MD and Angelos M Kappas, MD
From the Department of Surgery, Ioannina University School of Medicine, 45110 Ioannina, Greece,
Curative surgery - the complete removal of the tumor (R0 resection) - has long been considered the treatment of choice and the only treatment modality able to provide cure in localized gastric cancer. But until now, the optimal extent of this surgical resection still remains highly debated. Several factors including tumor stage and difficulties in accurate pre-, or intra-operative staging-prediction, surgical complications, risks of residual disease and recurrence, as well as quality of life (QOL) differentially influence and complicate the selection of appropriate extent of surgery. How important may be the role of surgical quality in the clinical outcomes of patients with gastric cancer?
Surgery, a treatment-related factor, may significantly affects both survival and QOL of patient with gastric cancer. Here we highlight the role of surgical quality in the clinical outcomes of gastric cancer patient. The term quality of surgery under a wide description should involve both decision-making about the optimal extent of surgery and the safe performance of the selected less or more extensive surgery. But until now the interest cto nearly exclusively been focused on the discussion as whether limited (D1) or extended (D2) node dissection should be performed in all stages -early or late- cancer and not to a tumor stage-oriented approach. Here we discuss the risks and benefits of such a tumor stage-tailored surgical strategy that is increasingly receiving attention.
Approximately 40% of patients in the USA to 70% of the patients in the Western world1 and in up to 85% in Japan, are presented with a potentially completely resectable tumor. Formation of secondary tumor(s) -recurrence- in these patients after surgical removal of the primary tumor is the cause of treatment failure and death. Recurrence occurs in the gastric bed and perigastric lymph nodes (locoregional), in peritoneal surface (peritoneal carcinomatosis) and at distant sites via circulating cancer cells in blood vessels (haematogenous spread) and lymphatic vessels (lymphogenous spread).
Principal goal of surgery therefore is to reduce risk of recurrence. How and why extent surgery may influence recurrence risk and clinical outcomes? Appropriate surgery with sufficient resection margins from the primary tumor and complete dissection of positive nodes can primarily reduce the risk of local and nodal failure as well as distant recurrence via lymphatic spread. Less favorable seems to be the role of surgery, in reducing peritoneal and hematogenous dissemination through less extensive surgical maneuvers. Locoregional recurrence rates of 40% after limited "curative' D1 surgery and 12%-20% after extended (D2) lymph node dissection[4,5](see and site-specific risk of recurrence) reveal the importance of radical surgery in reducing recurrence-risk.
Although randomized trials[6,7] with limitations in design and conduction(see optimal lymph node dissection) failed to confirm these difference in recurrence and survival between D1 and D2 groups, current relevant research confirms the importance of aggressive resection of tumor margins to combat lymphatic dissemination.
Lymphogenic metastasis is an important predictor of survival in gastric cancer. Recent experimental and clinical evidence supports that both vascular endothelial growth factor VEGF-C and VEGF-D induce lymphangiogenesis in tumor[9-11] and are associated with lymph node metastasis in a variety of human tumors including gastric cancer.[12,13] These VEGFC-overexpressing tumors all had functional lymphatic vessels in the tumor margin of a current study. The researchers conclude that functional lymphatics in the tumor margin are responsible for lymphatic metastasis and therefore tumor margins should be treated aggressively by surgery. However, at clinical detection of most tumors, cancer cells have already spread via the lymphatic system to the nearby lymph nodes or distant organs.
Approximately 30% of the patients with a curable tumor8 have positive the level II nodes (N2 disease in the Japanese anatomical classification14), and thus an in fact R0 resection can be achieved only by a D2 and not a D1 node dissection. But D2 dissection is associated with longer time consumed and increased morbidity and mortality risk than D1 dissection[6,7] by lack of surgical experience. For this reason as well as whether the advantage of D2 dissection in the reduction of residual nodal disease and recurrence rate may also be translated into an evidence-based survival benefit, the extent of lymph node dissection is highly debated.[6-8] Surgical decision on extent of node dissection should consider several parameters and balance risk and benefits.
The most realistic way today to combat metastatic nodal disease and to prevent further lymphatic spread at distant organs is provided by appropriate surgical lymphadenectomy. The future of prevention and treatment of lymphatic metastasis may involve a combination of both optimal surgery and antilymphangiogenic therapy with the use of agents such anti-VEGF-C, anti-VEGF-D, and other molecules that block different steps in lymphatic metastasis.[10,15,16]
The extent of stomach resection -distal subtotal, proximal or total gastrectomy- has long been established. Tumor site and histology according to Lauren-classification -more extensive surgical margins for diffuse type rather than intestinal type of cancer- are the criteria for decision-making.[1,17] However, there is now a trend toward less extensive gastric resection in early-stage tumors for the improvement of QOL. The effectiveness of endoscopic mucosal resection (EMR), pylorus-preserving surgery and laparoscopic wedge resection is now investigating. EMR provides excellent QOL and probably does not increase risks of recurrence and death when the selection criteria of size (< 2 cm), depth of invasion (mucosal cancer) and histology (intestinal type) are met. Although there is still lack of evidence supported from randomized controlled trial, EMR is advocated as the primary treatment of choice in Japan. The very small proportion of early-detected mucosal cancers, is the major limitation of such strategy in the western World.
Another important matter of discussion in the surgical treatment of gastric cancer is whether and when gastrectomy combined with an additional organ resection might be beneficial. Over the past two decades splenectomy or pancreaticosplenectomy was often performed in all stages-cancer and was involved in the design of two recent randomized trials.[6,7] However, this aggressive surgery increases operative morbidity and mortality without survival improvement.[1,5-7] Interestingly, this additional organ resection was pathologically confirmed as T4 disease in only 14%20 suggesting that in most cases additional organ resection is in fact unnecessary for an R0 resection. Accumulating evidence supports that prophylactic resection of the spleen, pancreas or other organ does more harm than benefit and should not be performed. The resection of the spleen particularly suggests caution because of a possible immunologic role of the spleen against postoperative infections and tumor recurrence(see spleen preservation vs resection)
However, in advanced T4 cancers extensive radical surgery including additional organ resection is needed to accomplish an R0 resection. This aggressive surgical approach can be performed safely and can improve overall survival according to a current report from specialized institution, but usually increases risks of operative morbidity and mortality. Whether this primary surgery or neo-adjuvant treatment for tumor reduction and subsequent surgical resection for localized advanced disease is more beneficial remains unclear and is investigating in randomized trials.
Accumulating evidence indicates that extent of surgical procedure strongly influences recurrence rate and survival on one side and complications and quality of life on the other. The more extensive the surgery the lower the risk of residual disease, recurrence and death but the higher the rates of operative morbidity and the adverse effects on QOL. Thus, decision about extent of surgery is a balance of risks and benefits. Because less extensive surgery is not associated with increased risk of recurrence in earlier-stages cancer, preoperative accurate prediction of tumor spread (staging) is determinant for decision-making. However, despite advances in imaging technology -endoscopic ultrasonography, computer tomography, magnetic resonance imaging and positron emission tomography-, which have increased substantially the accuracy of tumor depth (T-stage) and distant metastasis (M-stage), prediction of nodal status is not just high as to allow with safety decision about lymphadenectomy.
Ideally, if the tumor-stage could be accurately predicted, optimal surgery might be focused on the minimum extent of surgery needed to accomplish an R0 resection with sufficient resection of tumor margins. This tumor stage-oriented procedure then involves a wide spectrum of treatments from minimally invasive approaches (EMR, laparoscopic approach, function-preserving gastrectomy) to aggressively extensive resections. But such strategy prerequisites a numerous of conditions including the availability of expertise teams of surgeons, oncologists and endoscopists as well as of modern diagnostic and therapeutic technology. In many regional hospitals in the western World a change of standard D1 resection to less or more extensive resections is and will be remain challenging.
A new era towards a tumor stage-based less or more extensive surgery in the management of gastric cancer has already been started. However, caution suggests the lack of evidence from randomized trials that this strategy, compared with the standard surgical procedure, offers better survival and QOL. At present, this surgical approach is used in a few specialized institutions, particularly in Japan, but with increased experience and improvements in accurate tumor staging-prediction and therapeutic technology is expected to be used wider in the future. Given that, any adjuvant treatment is of little effectiveness in improving survival, the quality of surgery provided by surgical team in both decision-making and performance of optimal extent of ts surgery with minimal morbidity strongly affects both survival and quality of life.
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