BOWEL CANCER AND SCREENING IN LYNCH SYNDROME Nick Beck Colorectal surgery, Southampton

BOWEL CANCER AND SCREENING IN LYNCH SYNDROME How common is bowel cancer? (How common is Lynch syndrome?) Screening guidelines for colonoscopy in Lynch syndrome Colonoscopy & Other methods of screening (again) Treatment of bowel cancer

Bowel cancer is a common cancer About 1 in 20 (5%) of the population will develop colorectal cancer

How common is bowel cancer in Lynch Syndrome/HNPCC? There is a wide variation in cancer risk between families. The risk is influenced by environmental and genetic factors Carriers of a MMR gene mutation have a 25-70% risk of developing CRC

Lynch syndrome is probably underdiagnosed Identification is important as individuals can benefit from lifesaving cancer surveillance

Improving the identification of Lynch Syndrome Increasing awareness (in population) Promoting the taking of a family history by doctors Via patients diagnosed with bowel cancer or endometrial cancer Young age onset Multiple tumours Affected family members Molecular analysis of the tumour (Bethesda criteria – complex) Systematic testing of all pts with CRC for loss of MMR – Identified about 3% of pts had LS.

Why do we screen the bowel of Lynch Syndrome patients ?

Because the risk of bowel cancer is high in HNPCC patients Because we can detect polyps before they become cancers Because we can detect bowel cancer at an earlier stage Because bowel cancer can be completely cured if detected early enough.

Screening for bowel cancer in Lynch Syndrome Is it effective? YES Colorectal surveillance is the only surveillance protocol in LS proved to be effective Regular colonoscopy – leads to a reduction in CRC related mortality Regular colonoscopy – significant reduction in overall mortality

What is the optimal interval between examinations? Ongoing discussion 3-year interval proved to be effective (Jarvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995;108:1405–11).

But probably colonoscopy should be more frequent: it is known that cancer can be found/develop after a ‘negative’ screening examination – ‘interval cancer’. Although most of these cancers are early (stage I and II) some are more advanced (5-20%).

Number of studies looking at effectiveness of screening with different intervals (1, 1-2, 2 yearly) but they have not compared the intervals. Most interval cancers were right sided (57-62%) Most int cancers were in individuals over 40 (but not all) Mortality is associated with a lack of participation in a screening programme. Perhaps the risk is less for pts with an MSH6 mutation (but not significant)

so Colonoscopy screening in LS patients reduces the chance of dying from CRC Screening should be at least 3 yearly but probably 1-2 yearly. It’s very important that the colonoscopy is complete (to the caecum) It’s very important that people turn up for their screening

The British Society of Gastroenterologists recommends colonoscopy at least every 2 years from the age of 25. Recommendations for screening in HNPCC (USA) © 2014 by American Society of Clinical Oncology - Colonoscopy every 1 to 2 years, starting at age 20 to 25 or 5 years before the youngest case in the family. No upper limit is established.

Dedicated family history screening lists Team familiar with Lynch syndrome One colonoscopist, one colorectal nurse specialist (Sue), Genetics input Consultant delivered High completion rate Aim for high level of participation (try to contact non-attenders) and re- arrange date. (high participation, high completion rate, comfortable examination, ‘One stop’ service)

colonoscope Insert scope view Identify polyps Remove polyps

Are there any alternatives to screening with colonoscopy? CT colonography (‘virtual colonoscopy’) possible (Radiation dose) MRI colon perhaps ‘CT colon’ or ‘CT abdo/Pelvis’ not sensitive enough Capsule endoscopy better for small bowel USS not good enough Faecal Occult Blood (FOB) BCSP but not for HNPCC Molecular markers / stool testing possible in the future

CT colonography / CT colonoscopy / Virtual colonoscopy. Well tolerated Good at picking up cancer and large polyps Not as sensitive for smaller polyps Not therapeutic Radiation dose

Denver residents get: 6 mSv per year Cross country flight: 0.02 mSv Friday August 15 2014 BBC News reports on a sharp rise in the number of CT scans being performed, exposing people to the potential health risks of radiation. Patients receive a dose of radiation during a CT scan CT scans can be vital for helping make decisions about treatment However, it is not possible to calculate the cancer risk due to exposure to CT scans because there is a lack of data. Radiation is meaured a variety of ways. One of the units of measurement is Sieverts (Sv). This meaures the effect of radiation on the body. We are naturally exposed to radiation from many different sources such as the earth, atmosphere and space. Background radiation at sea level: 3 mSv per year Denver residents get: 6 mSv per year Cross country flight: 0.02 mSv X ray Chest: 0.06 mSv CT Head: 3 mSv CT Chest: 5 mSv (equivalent to 100 chest xrays) CT Abdomen: 5-10 mSv (Some experts believe that above 50 mSv there is a slight increase in risk of cancer).

MRI colonography No radiation But not therapeutic And not better tolerated than colonoscopy Beth Israel Deaconess Medical Center, compared the efficacy of MRC using air as an intraluminal contrast agent with optical colonoscopy in 46 patients. MRC identified lesions greater than 10 mm with 100% sensitivity and specificity. For intermediate and small lesions, sensitivity dropped to 50% and 15%, respectively, while specificity remained high. While these results indicate that the technology is effective, other results revealed that patients are just as resistant to MRC as they are to optical colonoscopy. Keeling found that 35% preferred MRC over optical colonoscopy, 33% preferred colonoscopy to MRC, and 32% had no preference. Patients reported slightly more discomfort with MRC but more embarrassment with optical colonoscopy

Treatment of colorectal cancer Surgery is the primary treatment. Debate about the extent of surgery required Radiotherapy (?) Chemotherapy (?) Bowel cancer is often curable

Surgery

Surgery for HNPCC patients In general outcomes for surgery for colorectal cancer patients are very good Many patients are cured Many cases can be performed with laparoscopic surgery (keyhole) Mortality rates are low But it’s not clear how (or if) surgery should change if the CRC develops in a HNPCC patient.

How much of the colon should be removed?

Segmental resections

Segmental vs radical resections

Surgical treatment for colorectal cancer After standard treatment of a CRC -The risk of developing a second cancer is 16% at 10 years (despite close surveillance)

Reduction of risk with further resection vs Risk of further resection Reduction of quality of life with further resection Functional outcome worse after extensive surgery but the quality of life was similar!

Choice of operation? Balance of risks Not clear if there is a need to be more radical. Sometimes there are multiple cancers – more radical Sometimes large polyps / more polyps than usual – more radical Discuss with Genetics team Discuss with your surgeon Surgical outcomes are very good After surgery - Continue colonoscopy screening

Other additional treatments? Radiotherapy (for rectal cancer) Chemotherapy (difficult) colorectal cancers characterised by deficient MMR are distinct from tumours that arise from chromosomal instability MSI – H have a better prognosis but MSI – H don’t seem to benefit from Adjuvant flurouracil (FU) based chemotherapy Discuss with oncology

Any questions? Or during tea/coffee break?

Risk of cancer according to carrier: MLH1-mutation carriers tend to develop CRC at younger ages MSH2 carriers seem to be at higher risk for extracolonic cancers Women with MSH6 mutations may have a greater lifetime risk of endometrial cancer than CRC. PMS2 carriers have a lower risk for CRC and endometrial cancer (15% to 20%) compared with carriers of other MMR gene © 2014 by American Society of Clinical Oncology Hereditary Colorectal Cancer Syndromes: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the Familial Risk–Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guidelines Elena M. Stoffel, Pamela B. Mangu, Stephen B. Gruber, Stanley R. Hamilton, Matthew F. Kalady, Michelle Wan Yee Lau, Karen H. Lu, Nancy Roach and Paul J. Limburg

Lifetime risks of other cancers in HNPCC: Endometrial cancer (lifetime risk, 30% to 60%) - surgical removal of the uterus and ovaries has been shown to reduce incidence of endometrial and ovarian Ca. tumours of the urinary tract (lifetime risk, 5% to 12%) small intestine ovary (lifetime risk, 4% to 12%) stomach (lifetime risk, 8% to 10%) pancreas (lifetime risk, 4%) biliary tract brain skin