9 Mar 2018

Surgery for oesophagogastric cancer is a double-edged sword

Prof Wendy Brown (centre) and Dr Paul Burton (to Wendy's left) are co-authors on a paper investigating how surgery, while effective for removing tumours, can spread cancer cells.
by Anne Crawford

Radical surgery is the principal treatment to cure oesophagogastric cancer, one of the most rapidly increasing and deadliest cancers. But it has long been suspected that in some cases the surgical incisions involved can cause unseen microscopic deposits of cancer to disseminate and spread throughout the body.

Researchers in The Alfred’s Hospital’s Upper Gastrointestinal (GI) Surgical Unit investigated what was behind the surgery-induced spread in the cancer with findings that have important implications for further research aimed at identifying potential therapeutic solutions. Two more studies are currently underway.

Oesophagogastric (gullet/stomach) cancer rates have risen 400% in the past 30 years, spurred on by a rise in obesity rates. Survival rates are poor.

The researchers – a collaboration of upper GI surgeons, scientists and with final year honours student Andrew Long as first author – were led by Professor of Surgery at Monash University, Professor Wendy Brown.

Surgeon Dr Paul Burton, one of the senior authors, said they decided to investigate after randomised studies elsewhere failed to show conclusively that wholesale removal of tissue in addition to the tumour was the best option.

“Logically, everyone thinks that the more tissue around the tumour that gets removed, the more likely you are to cure the cancer, but data don’t support that,” Dr Burton said. “This study was really about dealing with this dreadful disease by better understanding it,” he said.

“We’ve seen it in unfortunate patients where you do your best surgery, but unfortunately microscopic cells spread throughout the body and take root, sometimes it is almost as though the surgery has resulted in progression of the disease rather than controlling it,” Dr Burton said.

Dr Burton said there was an old wives’ tale describing this – “letting the air at it” – likening the spread of cancer to the spread of a smouldering fire that explodes and takes off once it’s exposed to oxygen. 

Spread occurs in around 50% of cases, with the other 50% of patients being cured of the cancer, he said.

However, without radical surgery, which removes the whole tumour, surrounding tissue, glands and lymph glands, the mortality rate is 95%.

“There’s been a lot of work done on how much inflammation you cause with the trauma you create by making a cut and dissecting the organ. It is also thought that inflammation is a key driver of cancer progression,” Dr Burton said.

“Our research sought to identify inflammatory pathways that can be blocked by drugs thereby slowing down the progression of the cancer and enhancing the effects of surgery. This hasn’t been looked at a lot.”

Patients from the Alfred and Cabrini hospitals who had radical surgery in a 12-month period participated in the study. Blood samples were taken and adipose (fat) tissue was collected from a range of different areas where cancers are known to take root after surgery.

Surprisingly, it was found that inflammation, and particularly molecules known to promote the implantation of tumour cells, were found not just at the site of surgery but throughout the whole body.

“That’s something that had been suspected but had never been measured in such detail,” Dr Burton said.

Wide variation was also observed between individuals.

The findings, whilst early, are important. Published late last year in the ‘ANZ Journal of Surgery’, they previously attracted positive feedback when presented at forums both nationally and internationally.

The researchers are now identifying more specific signalling pathways that promote the development of the oesophageal and gastric cancers that may be implicated in the rapid spread of the cancers after surgery, and have identified specific molecules involved. That work, yet to be published, is expected to be presented at conferences in the next six months.

“We’ve taken big steps towards getting the key suspects that are actively promoting drivers of that spread particularly associates with surgery. Then there is the prospect of developing new therapies able to block those pathways,” Dr Burton said.

The research may also apply to other cancers more broadly.

Key contributors to the study are Dr Geraldine Ooi, Associate Professor Peter Nottle and Professor Matthew Watt. The Alfred Hospital is the principal centre in Victoria conducting surgery on the oesophagus and stomach.

The researchers hope findings will eventually help tailor individualised operating plans so that patients more likely experience the spread of cancer after surgery could be spared the operation and offered other treatment.

Long AJ, Burton PR, De Veer MJ, Ooi GJ, Laurie CP, Nottle PD, Watt MJ, Brown WA. Radical gastric cancer surgery results in widespread upregulation of pro-tumourigenic intraperitoneal cytokines. ANZ J Surg. 2017 Nov 30. doi: 10.1111/ans.14267. [Epub ahead of print]

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