This blog provides free general information for anyone who is seeking information on bariatric and metabolic surgery and its effect on cancer risk reduction, mostly focus on gastric and oesophageal cancers.

This is not intended as a medical consult. Please seek proper medical advice for individual assessment and management.

Introduction

Obesity has been associated with an increased risk for oesophageal, colon, pancreatic, breast, endometrial and renal cancer.

There may be an increased risk for leukemia, gall bladder, liver, ovarian and prostate cancer.

It is well known that obesity has been linked to decreased life expectancy from weight related metabolic complications (ischaemic heart disease, cardio-vascular disease, T2DM related complications, etc). Less is known about obesity and cancers.

There are unequivocal evidence that bariatric surgery is recommended for morbidly obese patients to:

• Lose weight which is the primary end point
• Improve medical co-morbidities and metabolic parameters, the secondary end point
• Prevent premature cardiovascular mortality
• Improve health related quality of life
• Reduce the risk of developing obesity related cancers in the long term

Background information

Cancer and metabolic mechanisms   Obesity may promote carcinogenesis due to the chronic low grade inflammation and release of pro-inflammatory cytokine/adipokine and inflammatory factors (TNFa, IL2, IL6) from the visceral adipose tissue.   Adipokines are altered in the obese. A reduction in adiponectin and increase in leptin may result in changes in glucose homeostasis, lipid metabolism, immunity, cell proliferation, insulin resistance and T2 diabetes mellitus.   Various mechanisms such as dysregulation in lipid metabolism, adipokine mediated inflammation, gut dysbiosis, immunosuppressive microenvironment (impaired gut barrier function, metabolic endotoxaemia) and hormonal imbalance may play an important role in the cancer pathway.   Obesity related chronic inflammation is an important mediator of tumour initiation, progression of the cancerous phenotype.   Obesity and insulin resistance/dyslipidaemia can lead to occurrence, progression, proliferation and metastasis of pancreatic cancer cells as well.   In other words central/visceral obesity affect metabolic, anti apoptotic, mitogenic and pr-angiogenesis pathways thus promoting carcinogenesis.

Benefits of bariatric and metabolic surgery Bariatric and metabolic surgery has been reported to result in reduced chronic low grade inflammation up to 4 years after surgery. Weight loss after bariatric and metabolic surgery is associated with significant improvements in metabolic parameters, liver enzymes and favourable changes adipokine levels.   Bariatric surgery reduces inflammatory markers (CRP, IL6, TNFa, IL1B), reduce ghrelin and leptin. There is an increase in adiponectin, GLP-1 and polypeptide PYY.   Bariatric surgery was associated with lower risk of obesity associated cancer and cancer related mortality. Bariatric surgery has been linked to reduce overall cancer risk in obese population, which include: *Colorectal cancer (hazard ratio 0.64) *Liver cancer (odds ratio 0.4) *Breast cancer (risk ratio 0.5) *Ovarian cancer (risk ratio 0.47) *Endometrial cancer (risk ratio 0.33)

Introduction

To start with, there are a few important points to note:

• Gastro-oesophageal reflux (GOR) incidence and severity is associated with obesity. The prevalence of GOR is about 50% in obese patients.

• The incidence of oesopahgeal, junctional or gastric adenocarcinoma in Western countries is much less common compared to some Asian countries (such as South Korea or Japan).
• The incidence of these cancers after a sleeve gastrectomy, one anastomosis or Roux Y gastric bypass is extremely uncommon.
• The pathogenesis of oesophageal or gastric adenocarcinoma is not completely understood. It is hypothesized that the gastric acid plus bile reflux (from the small intestine back into the sleeve or remnant excluded stomach of the gastric bypass) and oesophagus having a role in the cancer progression.
• At the present time there are no consensus on routine pre-op or post op gastroscopy screening.

A recent meta-analysis showed that de novo GOR occurs in 1/4 of obese patients but the figure may be up to 83% (when they are assessed by objective measures such as pH monitoring). There is poor symptom correlation with GOR.

The Barrett’s oesophagus incidence is about 6%, which is similar to the general population and the non operated morbidly obese population.

Screening gastroscopy and/or colonoscopy

This will be difficult to perform for every patient before elective bariatric surgery.

It may be prudent to recommend a screening gastroscopy and/or colonoscopy for patients at risk:

• Chronic or severe symptomatic gastro-oesophageal reflux
• Before converting the gastric band to another bariatric procedure
• Food intolerance, iron deficiencies
• High risks groups such as certain ethnic groups (Asia, Latin America) or those at higher risk (family history of gastric cancer, HNPCC, Li-Fraumeni syndrome, gastric dysplasia/metaplasia, Menetrier’s disease).
• ? For the older population group before having a primary one anastomosis or Roux Y gastric bypass

Types of bariatric surgery

Sleeve gastrectomy, reflux oesophagitis, Barrett’s and oesophageal adenocarcinoma

Oesophageal adenocarcinoma after a sleeve gastrectomy is a rare event.

Another study reported that there is an increase in de novo reflux from 2 to 35% after a sleeve gastrectomy. The refluxate could be mixed acid and biliary alkaline reflux.

Barrett’s oesophagus (BE) is estimated to be present in 1-2% of the general population.

BE is diagnosed in 7-10% of patients with chronic GOR.

After sleeve gastrectomy, the incidence of BE is reported to be 1 – 27%, average of 9%. The IFSO study found an incidence of BE in the pre-op patients to be 2% and is the same incidence of 2% after a sleeve gastrectomy.

BE is a risk factor for oesophageal adenocarcinoma but only a minority of patients will develop cancer.

• The annual risk is about 0.1 to 0.5%.
• The incidence of oesophageal adenocarcinoma in general population is about 0.06% and double for the obese.
• One study reported the incidence of cancer after sleeve gastrectomy in 0.08%.

Reflux mechanisms

The sleeve gastrectomy may result in:

• Decreased lower oeosphageal sphincter pressure
• Alter the angle of His
• Interruption of the sling fibers during stapling
• Removal of the gastric fundus
• Twisting of the pouch
• Loss of compliance and increased intra gastric pressure

The acid reflux causes metaplastic changes to the columnar epithelium of the lower oesophagus resulting in BE.

The bile reflux causes an inflammatory response, leading to oxidative DNA damage and cell death leading to the dysplasia – carcinoma sequence.

Some studies after a sleeve gastrectomy reported bile reflux into the gastric tube but minimal amount into the distal oeosphagus.

Ongoing studies and more research are needed in this area of gastro-oesophageal acid + duodeno-gastric-oesooahgeal bile reflux in the pathogenesis of gastric and oesophageal adenocarcinoma.

Common statements about laparoscopic sleeve gastrectomy and reflux

Sleeve gastrectomy is deemed to be a refluxogenic operation, it increases the risk for GOR maybe up to 5 fold compared to the Roux Y gastric bypass.

There may be more reflux oesophagitis on gastroscopy after a sleeve.

However the higher incidence of gastro-oesophageal reflux (GOR) after a sleeve is not necesarily followed by an increased rate of Barrett’s oesophagus or oesophageal adenocarcinoma.

The explanation may be due to the low level of bile reflux, a decrease in inflammation due to weight loss and hormonal changes, as well as improved dietary habits after bariatric surgery.

Also in the surgical literature so far, the oesophageal or junctional adenocarcinoma following bariatric surgery has been mostly reported for patients who had a RYGBP not a sleeve gastrectomy.

• This could be selection bias with the RYGBP surgery recommended for chronic reflux patients who may have a pre-malignant condition.
• With longer period of follow up more reliable long term data will be available.

Roux Y gastric bypass and gastric/oesophageal cancer

After a primary non-resectional one anastomosis or Roux Y gastric bypass, two unique gastric cancer may occur in the gastric pouch or remnant excluded stomach. However these are relatively very rare cancers.

First of all, as a background information, we need to mention that gastric adenocarcinoma is relatively rare in Western countries compare to Asian countries such as Japan and South Korea.

RYGBP is still commonly performed in Western countries with little concerns about the long term consequence of remnant gastric cancers.

Once again, to re-iterate that the pathogenesis of oesophageal or gastric adenocarcinoma is not completely understood.

The risk factor may include Helicobacter pylori, inherited condition (such as hereditary diffuse gastric cancer and linnitus plastica), bile reflux back into the remnant stomach, changes in gastric and intestinal microbiota.

Some researchers suggest that changes in pepsinogen 1 and 2, gastric anti Helicobacter pylori antibodies may be associated with atrophic gastritis and possibly metaplasia and cancer.

Obviously a gastroscopy can not be performed to check the remnant stomach after a bypass procedure. A double balloon enteroscopy or diagnostic laparoscopy is not easy to do after a gastric bypass.

• It may be prudent to recommend patients to have a screening gastroscopy and colonoscopy before performing a gastric bypass, especially for the older patient cohort with a history of acid reflux, gastritis and iron deficiency.
• Some surgeons suggest a resectional RYGBP (removing the remnant stomach) for high risk populations (Asia, Latin America) or those at higher risk (family history of gastric cancer, HNPCC, Li-Fraumeni syndrome, gastric dysplasia/metaplasia, Menetrier’s disease).

One anastomosis gastric bypass and gastric/oesophageal cancer

Similar to the sleeve after an OAGB there is a reported increase in reflux, either de novo symptoms or worsening of pre-existing reflux symptoms. Not only that there may be an increased in non-acid/bile reflux with exposure of the distal stomach and oesophagus to bile acids.

This is a much debated topic at this stage especially amongst bariatric surgeons in the USA. Hopefully more information will be available in future studies and research with regards to bile reflux and gastric/oesophageal adenocarcinoma.

Bariatric surgery and pancreatic cancer

Pancreatic cancer is relatively less common than other cancers.

But pancreatic cancer is the 7^th leading cause of cancer globally and the incidence has been increasing in recent years. Pancreatic adenocarcinomas are often unresectable and even then it has a low survival rate.

Obesity has been reported to increase the risk of pancreatic cancer by 1.6 fold.

With the pancreas there may be other factors in play, such as:

• Insulin resistance causes pancreatic B cells to secrete more insulin (hyperinsulinaemia)
• Insulin activates stellate cells, which causes pancreatic fibrosis and connective tissue formation which promote pancreatic cancer
• Insulin and Insulin like growth factor signalling drives cell carcinogenesis (eg. T2DM patients treated with insulin have a higher risk for developing pancreatic cancer)

Bariatric surgery and moderate weight loss has been shown to improve insulin sensitivity and overall inflammatory status to help reduce obesity related cancer risk.

Bariatric surgery may be associated with a reduced risk of pancreatic cancer but these effects may disappear with time.

Bibliography

Ann Surg 2020 ; 271 (2): 257 – 65. Yeung K, Penney N, Ashrafian L, et al. Does sleeve gastrectomy expose the distal oesophagus to severe reflux ? A systematic review and meta-analysis.

Obes Surg 2019; 29 (3): 1031-9. Wiggins T, Antonowicz S, Markar S. Cancer risk following bariatric surgery-systematic review and meta-analysis of national population based cohort studies.

Jama 2022; 327 (24): 2423 – 33. Aminian A, Wilson R, Al-Kurd A, et al. Association of bariatric surgery with cancer risk and mortality in adults with obesity.

Br J Surg 2020; 107 (4): 348 – 54. Almazeedi S, El-Abd R, Al-Khamis A, et al. Role of bariatric surgery in reducing the risk of colorectal cancer: a meta-analysis.

Surg Obese Relat Dis 2020; 16: 1596 – 602. Ishihara B, Farah D, Fonseca, et al. The risk of developing breast, ovarian and endometrial cancer in obese women submitted to bariatric surgery: a meta-analysis.

Obes Surg 2023. Fan H, Mao Q, Zhang W, et al. The impact of Bariatric Surgery on Pancreatic Cancer Risk: a Systematic Review and Meta-Analysis.