5.1. Summary of Evidence
The mechanism underlying GC surgery as a metabolic surgery shares many similarities with bariatric Roux-en-Y Gastric Bypass. Both rely on reduction of gastric volume and anatomical reconstruction of the stomach [22].
BI reconstruction preserves gastric tract continuity. In contrast, in reconstruction techniques that involve duodenal bypass, BII, or RY, food bypasses the duodenum and proximal jejunum, reaching the distal ileum earlier. These two reconstruction techniques resemble bariatric surgery more than BI [14].
Bariatric and Oncometabolic Surgery share many concepts, but one major drawback is their substantially different target populations. Candidate patients for OS tend to be older, frailer, and lighter [9]. Consequently, in contrast to obese individuals receiving bariatric surgery, inferior outcomes are to be anticipated in oncological patients undergoing gastrectomy. Patients with GC are less likely to be obese. Therefore, the effect of weight loss is smaller than what is expected in bariatric patients. Another disparity is their age: oncological patients are generally older. Ageing exponentially increases surgical morbidity and mortality, leading to higher and more severe preoperative comorbidities and postoperative risks [44]. Lastly, in conventional GC surgery, the bypass length is usually shorter than in bariatric Roux-en-Y gastric bypass, leading to a weaker enteric effect [14].
Therefore, GC surgical techniques can be adjusted, thoroughly evaluated, and tailored to optimise therapeutic benefits without sacrificing oncological safety [45] for a particular and cautiously selected patient group. Oncometabolic Surgery involves adapting and choosing the best surgical method available for optimal oncologic and metabolic control.
To the best of our knowledge, this is the first meta-analysis exploring the impact of duodenal bypass (RY or BII), residual stomach, and the various GC reconstruction techniques on postoperative T2DM, HBP, and BMI reduction rate in patients with GC.
Diabetes Mellitus has been previously identified as a risk factor for GC due to insulin resistance, hyperinsulinemia, oxidative stress, and pro-inflammatory condition [46]. The improvement in T2DM following GC surgery is associated with a higher 5- year survival rate [29].
Duodenal Bypass demonstrated a significantly higher efficiency in the improvement of T2DM compared to BI reconstruction. For BII, the remission rate ranged from 13 to 83.5%, and for RY, it ranged from 30.7–90.5%. This wide variability may be attributed to distinct patient characteristics, different follow-up periods, lack of technical standardisation, different lengths of the biliopancreatic and alimentary limbs, or the fact that almost all included studies, the primary goal was the resection of the tumour rather than the improvement of glycaemic control.
The mechanism underlying T2DM remission after gastrectomy is similar to bariatric surgery. Two theories have been developed to explain this phenomenon: Foregut and Hindgut Hypotheses [47].
Lastly, we must highlight the essential role of gut hormones in remission, not only in T2DM, but also HBP, dyslipidaemia, and cardiovascular events. Studies have demonstrated that independently from weight loss, proximal intestinal bypass promotes T2DM improvement via incretins/anti-incretins, gut hormones or altered bile acid signalling [28, 48, 49].
According to several studies, the most significant independent predictors were the duration and severity of T2DM [8, 14, 15, 20–22, 25, 28, 34, 36, 40, 41] (preoperative diabetes duration, insulinogenic index, and HbA1c level) and weight loss [8, 17, 20, 22, 34, 36, 40] (preoperative BMI, and BMI reduction rate).
Several previous bariatric and gastrectomy studies have reported pancreatic β cell function as having an important role in T2DM remission. [50, 51] Patients with shorter T2DM duration have greater β cell activity. [15] Most studies state that glycaemic control would be more effective in GC patients with a shorter diabetes diagnosis time, not requiring insulin therapy, and with lower preoperative HbA1c levels [8, 20, 21, 25, 28, 36, 41]. Weight loss, higher preoperative BMI, and higher BMI
reduction rate, even in nonobese patients, were also important factors in the improvement of glucose metabolism [8, 17, 20, 22, 36, 38].
In 2021, a Korean Nationwide Population-Based Cohort Study stated that insulin use at baseline decreased the likelihood of postoperative T2DM remission and that conventional gastrectomy, especially total gastrectomy, is associated with T2DM remission, independent of postoperative weight loss [52].
Hypertension is a modifiable risk factor that is intimately linked to cardiovascular and cerebrovascular diseases and can affect the quality of life of cancer survivors [38]. Three articles [18, 31, 38] from this qualitative synthesis evaluated the influence of gastrectomy and its different reconstruction methods on blood pressure control in patients with a BMI < 30 kg/m2. Remission and improvement of HBP after gastrectomy ranged from 53.1 to 67.4%.
Two studies [18, 38] included in this quantitative synthesis showed significant superiority of duodenal bypass reconstruction over BI. However, no discernible difference was established between RY and BII. A statistically significant difference was observed in the extent of gastrectomy, demonstrating the superiority of RY Esophagojejunostomy. These findings were consistent with those in Dong Peng et al., that reported that total gastrectomy was associated with a greater remission rate of HBP and that no noticeable superiority was seen among the three reconstructive techniques for subtotal gastrectomy [18]. Both studies acknowledge that additional factors such as lifestyle modifications may play an important role.
Patients with GC and concurrent HBP after gastrectomy have rarely been reported. Further investigation is required on this subject as well as studies with larger sample sizes and longer follow-up times.
The effect of GC surgery on metabolic control has been evaluated in several studies involving oncologic patients with BMI < 30 kg/m2. In fact, most have shown that T2DM, HBP, and dyslipidaemia improve following gastrectomy in non-obese patients [23, 25, 28, 31, 38, 41]. However, it has also been proven that weight loss plays a crucial role in the metabolic status of patients with GC, suggesting that patients with lower BMI are less likely to benefit from metabolic surgery [20].
While weight loss resulting from decreased oral intake and reduced absorption after surgery can induce improvements in T2DM, duodenal bypass has been shown to improve glycaemic control in T2DM patients by itself. Weight loss and the effects of duodenal bypass act together to improve metabolic control after gastrectomy in non- obese patients [22].
Cerebrovascular, cardiac, and respiratory diseases are common causes of death in patients with early GC [53]. One of the main findings of Yong-ho Lee et al. was that patients who underwent gastrectomy for early GC had a similar overall
mortality as the general Korean population, but a significantly lower cardiovascular mortality [54].
Multiple studies included in this systematic review showed a significant lowering of TC, TG, and LDL levels and a rise of HDL after gastrectomy [25–28, 31, 34, 38].
Xi-Hsuan Lin et al. [26] states that GC patients who had undergone subtotal gastrectomy (BII and RY reconstruction) had significantly lower TC and TG levels, BMI, decreased waist circumferences, and occurrence of T2DM and Metabolic Syndrome. This finding was corroborated by You Na Kim et al. [27]. However, Kyu Chul Kang et al. reported that TC decreased independently of the reconstruction technique used [25].
Yong-ho Lee et al. reinforced the correlation between weight loss and patients' lipid profiles. After gastrectomy, a significant reduction in body weight and visceral fat might improve lipid metabolism and prevent atherosclerotic changes, leading to a reduction in cardiovascular mortality [54].
One retrospective study and one randomized controlled trial (373 patients) [30, 42] evaluated the influence of RY and BI on visceral fat reduction after gastrectomy. Visceral fat accumulation has been identified as an underlying cause of metabolic syndrome [55]. These two studies showed that both duodenal bypass and gastrectomy promoted significant visceral fat loss.
Even though the outcomes were better for obese patients, duodenal bypass was also helpful for patients with lower BMI and metabolic syndrome. Although the mechanisms underlying fat reduction or improvement in insulin resistance are not fully understood, fat malabsorption and gut hormones (GIP and GLP-1) are thought to play a crucial role in regulating fat metabolism [56, 57].
Long-limb bypass reconstruction has recently emerged as an option in GC surgery. Therefore, fewer data and research are available on this topic. Currently, no consensus on the optimal limb length has been established. However, some studies have suggested that increasing the length of biliopancreatic and alimentary limbs leads to better metabolic outcomes after gastrectomy [43].
Seven studies (433 patients) [14, 16, 19, 31, 33, 36, 40] investigated the effect of RY long-limb reconstruction on T2DM improvement, ranging from 50.8–85%. These studies showed that a longer modification of RY resulted in better outcomes for T2DM, HBP, and dyslipidaemia. Jong-Han Kim et al. reported a statistically significant superiority of RY long-limb over the conventional BII in a multicentre retrospective cohort of 226 patients for up to one year after surgery [16]. Yun Suk Choi et al. found that the results of LRYGJ in oncologic, diabetic, nonobese patients were similar to that of metabolic surgery in obese diabetic patients [14].
A prospective study of 40 patients compared long-limb RY with conventional RY for T2DM and HBP. It disclosed that the complication rate of OS group did not differ from the conventional group. Although no significant difference was observed between the two methods, the results showed higher remission rates for both T2DM (LRYGJ 77.8% and RYGJ 50%) and HBP (LRYGJ 68.8% and RYGJ 41.2%). Lastly,
it reported an improvement in dyslipidaemia in 61.5% of patients in the OS group. However, this study had a small sample size, and its primary endpoint was nutritional safety not OS efficacy [31].
Further research on the efficiency of long-limb RY reconstruction with larger sample sizes and long-term outcomes is needed to compare its results with those of traditional BII and RY gastrectomy. In addition, a standard biliopancreatic limb length should be established to obtain optimal results.
Who would benefit from Oncometabolic Surgery? Patients with longer life expectancies, with localised early-stage GC, who would require ongoing care for their metabolic comorbidities: younger oncologic patients with shorter duration of T2DM, HBP, and dyslipidaemia, especially those who cannot adequately control their comorbidities by optimal lifestyle modification or pharmacotherapy. Although numerous studies have shown excellent outcomes in individuals with normal BMI, this surgery would be particularly favourable for patients with obesity.
Figure 5 Potential treatment algorithm for early gastric cancer patients with metabolic diseases (Adapted from Won Jun Kim et al. [33] and ESMO Clinical Practice Guidelines [58]).