Colorectal

Question 1

What are the risk factors for CRC

Answer 1

Genetic risk factors
- Polyposis syndromes – including FAP, MYH polyposis syndrome, familial juvenile polyposis syndromes, Peutz-Jeghers syndrome, serrated syndrome.
- Non-polyposis syndromes – Lynch syndrome.

Modifiable risk factors
- Red meats, processed meats, ETOH, animal fats, sugar, smoking.

Unmodifiable risk factors
- UC and Crohns
- Male
Diabetes.

Question 2

What is the age for bowel screening in NZ?

Answer 2

Bowel screening NZ
- Faecal occult blood test between the ages of 60-74
In some parts of NZ, bowel screen begins at 50 for Maori.

Question 3

What are the WHO principles for a screening program?

Answer 3

10 WHO health principles for a screening program
1. Condition which is a recognized problem.
2. Recognizable latent period and symptomatic stage
3. Biology is well understood.
4. Accepted treatment for patients with diagnosed disease.
5. Effective screening test available.
6. Test is acceptable to the population.
7. Agreement on who should be screened.
8. Facilities for diagnosis and treatment and available.
9. That screening program is economically feasible.
10. Screening can be continually performed.

Only breast, cervical and colon cancer meet these criteria.

Question 4

What are the guidelines for surviellance for patients at increased risk of CRC?

Answer 4

Group 1
- Patients with first degree relative who had CRC > 55 years old.
- There is no specific surveillance recommendations for this group.

Group 2
- One first degree relative diagnosed with CRC < 55 years.
- Two first degree relatives on the same side of the family diagnosed with CRC at any age.
- Should have colonoscopy 5 yearly from aged 50 OR 10 years prior to earliest age at which CRC was diagnosed in family member. Once aged 60 – can join NBSB

Group 3
- Fhx of Lynch, FAP, or other CRC syndromes.
- 3 relatives on same side of family having CRC at any age with one being a first degree relative.
- There are quite a few other criteria but generally this looks Lynch syndrome risk factors and polyposis syndrome risk factors.
- These patients should be referred to the NZFGCS

Question 5

What are the common subtypes of CRC?

Answer 5

• Mucinous adenocarcinoma – 10% of all adenocarcinomas. >50% of the tumour volume is composed of extra-cellular mucin. Poorer prognosis
• Signet ring cell adenocarcinoma - < 1%. Requires >50% of tumour cells to show signet cell features. Often poorly differentiated high grade tumours. Associated with Lynch
  Medullary carcinoma – sheets of epithelioid neoplastic cells with a pushing border and tumour infiltrating lymphocytes. Associated with Lynch. Better prognosis.

Question 6

How is colon cancer graded?

Answer 6

Grading
- Is based on percentage of tumour which is glandular.
- >95% glandular – well differentiated – Grade 1
- 50-95% - moderately differentiated – Grade 2
- < 50% - poorly differentiated – Grade 3

Question 7

What is the staging of CRC

Answer 7

look up

Question 8

What are the risk factors for polyp developement?

Answer 8

Risk factors for polyp development
- Genetics – personal or FHx of polyps, genetic polyposis syndromes
- Environmental – low fibre diet, smoking, alcohol excess
Other – inflammatory bowel disease and age.

Question 9

What are the main pathological subtypes of polyps?

Answer 9

Pathological subtypes
- Tubular – most common. Network of branching epithelium. Often the pedunculated polyps.
- Villous – rare. Long glands, finger like projections. More likely to be sessile.
- Tubulovillous – component of both. Intermediate risk.

Question 10

What are the types of serrated polyps?

Answer 10

Serrated polyps
- Sore tooth appearance under the microscope.
- 3 types – hyperplastic polyps, traditional serrated adenomas, sessile serrated adenomas

Hyperplastic polyps
- No malignant potential – often found in the distal colon and rectum.

Traditional serrated adenomas
- Variable malignant potential
- More common the recto-sigmoid and distal colon.
- May behave like conventional adenoma and be pedunculated.

Sessile serrated polyps
- More concerning.
- More prominent in the right colon.
- Typical macroscopic appearance is a difficult to discern polyp with a cap of mucus
- Associated with high rates of synchronous or metachronous cancers.
- Up to 15% of these polyps will have high grade dysplasia.

Question 11

What are hamartomatous polyps? What syndromes are they associated with?

Answer 11

Hamartomata’s/Juvenile polyps
- Uncommon
- a/w familial polyposis syndromes, Peutz-Jehgers disease.
- Macroscopically rounded/spherical.
- Often pedunculated.
- Cherry red.
- Have mostly connective tissue – SM, lamina propria, inflammatory cells.
- Don’t have a malignant potentially.
In patients with a syndrome, the characteristic presentation is SB intussusception.

Question 12

What polyps are suitable for EMR? What polyps are not suitable for EMR?

Answer 12

Polyps suitable for endoscopic resection
- Small sessile polyps
- Good stalk

Polyps not suitable for endoscopic resection
- Sessile lesion which is >1/3 of the bowel circumference OR crossing 2 haustral folds.
- Polyps involving the appendiceal orifice.

Question 13

How is EMR performed?

Answer 13

Endoscopic mucosal resection
- Used for larger/more difficult polyps.
- Blue-dye is injected into the submucosal plane which allows the polyp to be lifted.
- Following that – specimen is removed in a piecemeal fashion.
- Can be very effective
- Requires further surveillance.
Because of the piecemeal resection, histological examination can be impacted as the depth of the polyp can be difficult to know.

Question 14

What is the definition of an in-situ carcinoma, intramucosa carcinoma, and invasive carcinoma?

Answer 14

In-situ cancer – confined to the mucosa
Intra-mucosal carcinoma – invasion into the lamina propria.
Invasive carcinoma – invasion of submucosa.

Question 15

Explain Haggit

Answer 15

• The level of invasion correlates to the likelihood of the polyp having lymph node metastasis
• Haggit 1-3 is associated with a very low risk of having lymph node metastasis.
• Haggit 4 (below the stalk) is associated with a risk of lymph node metastasis between 12-25%. You would suggest a resection.

Question 16

Explain Kikuchi

Answer 16

Kikuchi
- Sm1 – 0-3% risk of lymph node metastasis
- Sm2 – 8-10% risk. You would often offer resection but the risk of surgery needs to be balanced against this.
Sm3 – associated with a 25% risk of lymph node metastasis.

Question 17

What other features increase the risk of a polyp harbouring a malignancy

Answer 17

• Poorly differentiated tumour
• Margin or resection < 1mm. This margin can be difficult to determine if there has been a hot snare removal.
• LVI
• Tumour budding
  Piecemeal resection

Question 18

Explain the conventional pathway of CRC

Answer 18

Conventional pathway/Chromosomal instability pathway.
- Pathway which happens in most sporadic colorectal cancers and in FAP
- Step-wise cumulative genetic changes occur which progresses the adenoma into a carcinoma.
- APC – causes early adenoma
- KRAS – Involves in EFGR signaling. Causes intermediate adenoma. 50% of colorectal cancers have this mutation.
- SMAD4 mutation – intermediate to late adenoma
- Tp53 mutation – carcinoma

KRAS mutation is important to know. Cetuximab can be used for KRAS wild-type tumours (non-mutant) and this improves overall survival.

Question 19

Explain the microsatellite instability pathway

Answer 19

Microsatellite instability pathway
- Accumulation of short tandem repeat mistakes causing microsatellite instability.
- Pathway is associated with lynch syndrome.
- Begin with a germline mutation in the mismatch repair genes – MLH1, MSH2, MSH6, PMS2.
- These mismatch repair genes can be stained for on the tumour to see if normal expression is present.
- If there is loss of expression – the PCR testing can be done to determine if there is a mutation in those genes.
The microsatellite instability pathway should not have a mutation in BRAF.

Question 20

Explain the serrated/hypermethylation pathway

Answer 20

Serrated pathway/Hypermethylation pathway
- Key genetic mutation is a BRAF mutation
- BRAF is an oncogene and is similar to KRAS.
- Hypermethylation of an MLH1 promotor area leads to MLH1 protein inactivation – this changes a serrated adenoma into a dysplastic polyp or carcinoma.
- More common in woman and more common in the right colon.
- Slightly better prognosis than other pathway.
- Don’t respond as well to 5-FU therapy
- Usually has non-mutant KRAS.

*thus is you have a patient who has a loss of expression of MSH1, you should then test them for BRAF. If BRAF is positive/mutant, then this patient will not have Lynch syndrome

Question 21

What is the significance of BRAF in colorectal cancer

Answer 21

BRAF
- Determining BRAF status is important in colorectal cancer especially stage III and beyond.
- Mutant BRAF confers a poorer prognosis in microsatellite stablecancer but there is targeted therapy for this (BRAF inhibitors + MEK inhibitors)
Wild-type BRAF can be treated with EGFR inhibitors.

Question 22

Explain what molecular testing should occur in a patient diagnosed with CRC

Answer 22

1. All newly diagnosed cancers should be tested for MMR deficiency on initial biopsy.
   - This is MLH1. MSH2, MSH6, PMS2
   - If MSH2, MSH6 or PMS2 – need to test for Lynch.
   - If MLH1 is deficient – need to test BRAF which will help differentiate between a sporadic cancer and a Lynch syndrome associated cancer.
   - If BRAF is positive (mutant) in the context of a deficient MSH1 tumour, you can say this is a sporadic cancer.
2. Undertake BRAF mutation analysis or MLH1 Promotor methylation analysis for all cancers showing MLH1 deficiency.
   - If tumour demonstrates MLH1 protein loss then test for BRAF.
   - If BRAF is normal/preserved then test for MLH1 promotor hypermethylation.
   - If this is negative – refer for genetic testing.
3. Conduct BRAF mutation analysis in all newly diagnosed stage IV cancer
   - MMR proficient stage IV tumours which are BRAF mutant have a significantly poorer prognosis.
   - BRAF status will also determine what targeted therapy can be considered.
   Conduct extended RAS mutation testing before considering EGFR targeted monoclonal antibodies.

Question 23

Explain FAP

Answer 23

FAP
- Autosomally dominant inherited condition – mutation in the APC gene (tumour suppressor gene).
- 3 different phenotypic presentations depending on the location of the mutation within the APC gene.
- APC gene protein regulates B-catenin – leads to an accumulation of B-catenin within the cell nucleus which can cause the cell to become malignant.

Phenotypes
- Classical FAP – associated between 100-1000 adenomas (cumulative amount). 100% lifetime risk of colorectal cancer
- Attenuated phenotype – 10-100 adenoma’s – associated with right colon/proximal colonic cancers
- Profuse FAP – associated with >1000 adenomas. 100% life-time risk of CRC.

Other associations
- Fundic gland polyps of the stomach (same as the ones patients on PPI’s get) – don’t have a malignant potential
- Duodenal polyps – 5-10% lifetime risk of duodenal cancers. Occur later in life.
- Desmoid tumours (see below)
- Congenital hypertrophy of the retinal pigmented epithelium. If they have multiple and are bilateral this can be pathognomic of FAP.
- Multiple osteomas - often in mandible, skull or tibia.
- 4-5x risk of papillary thyroid cancers
- Hepatoblastomas
- Extra-hepatic biliary tree cancers
- Adrenal tumours.
Astrocytomas/glioblastomas.

Question 24

Explain desmoid tumours

Answer 24

Desmoid tumours
- 15-20% of FAP patients will develop a desmoid. Majority form in the abdomen, in particular the small bowel mesentery. Can also develop in the retroperitoneum and abdominal wall.
- Very rarely metastasize but can be locally invasive.
- Can regress with time – thus desmoids in the small bowel mesentery may initially be surveilled and only if progressing patient will proceed to a resection.
- Often occurs in areas where there has been trauma.
- Other treatments include tamoxifen, radiation, imatinib, and chemotherapy.

Question 25

Explain the Spegillman classification

Answer 25

Spigelman staging classification for duodenal polyps in FAP
- Looks at number of polyps, polyp size, histology, and degree of dysplasia.
- Dictates how aggressively patient should be surveilled and when patient should undergo duodenectomy.

Question 26

What is the management of a patient with FAP

Answer 26

Management of patients with known FAP
- Start screening at aged 10 – yearly flexi sig until polyps are found – at which point they should transfer to a yearly full colonoscopy.
- Colonoscopy should continue until they have a prophylactic colectomy.

Prophylactic surgery
- Recommended in all FAP patients
- Should occur between 15-25 years old.
- Options are total proctocolectomy with IPAA or colectomy + ileorectal anastomosis.
- Pros of leaving rectum – avoid pelvic dissection + associated effects on fertility. May also have a better functional outcome than an IPAA.
- Pros of IPAA – don’t need rectal surveillance.

Question 27

Explain MYH polyposis syndrome

Answer 27

MYH polyposis syndrome
- Autosomal recessive – this is the only autosomal recessive condition in colon cancer.
- Mutation in the MUTYH gene – a gene involved in DNA repair.
- Results in polyp formation.
- Typically polyps are small tubular or tubulovillous adenomas.
- Usually 10’s-100’s of polyps cumulatively.
- Increased risk of thyroid cancers and abdominal desmoid tumours.
- Cancer risk is 80% by 70 years old – occur later in life than FAP.
- Generally prophylactic colectomy isn’t recommended although sometimes patients will have so many polyps which cannot be managed endoscopically that you may want to consider one.
- Rectum can generally be left and surveilled.

Question 28

Explain Peutz-Jeghers syndrome

Answer 28

Peutz-Jeghers syndrome
- Autosomally dominant inherited mutation of the STK11 gene which encodes a tumour suppressor protein.
- Present with polyps in the SI, colon and rectum – non-neoplastic hamartomas.
- Polyps consist of non-neoplastic connective tissue covered by a hyperplastic epithelium.
- Typical presentation is small bowel intussusception in childhood or adolescents.
- Can also present with bleeding
- Other characteristic features are dark blueish buccal and mucosal pigmentation. Can also occur on hands, feet and anus.
- Also at risk of breast, ovary, cervical, fallopian tube, thyroid, lung, bile duct, pancreas, and testicular cancer.

even though the polyps are hamartoma’s, adenocarcinomas can arise from these hamartomas. The lifetime risk of developing colon cancer for these patients is 40-60%

Question 29

When should you test a patient for Peutz Jeghers and what testing should they have

Answer 29

When to do genetic testing? – requires 2 of 3
- GI hamartomata’s polyps.
- Cutaneous or mucosal pigmentation.
- Known family member with the syndrome

Surveillance
- Colonoscopy should start in childhood – three yearly.
- 3 yearly gastroscopies and MRI should start from aged 20.
Should also be periodically screened for breast, cervical and testicular cancers.

Question 30

Explain sessile serrated polyposis syndrome

Answer 30

Serrated polyposis syndrome
- Rare
- Molecular aetiology and pattern of inheritance is not known.
-
Diagnosis
- At least 5 histologically confirmed serrated polyps, proximal to the rectum, with at least 2 > 1cm.
- At least 20 serrated polyps anywhere in the colon. Need 5 proximal to the rectum

• No clear what the cancer risk is – could be up to 60%.
  Surveillance
• Should have a colonoscopy every 2 years (maximum interval).
• If this is not achievable – should consider colectomy – total colectomy with ileorectal anastomosis.

Serrated polyposis syndrome can be remembered as 5 with 2 biggies proximal to sigmoid, 20 anywhere, or one with Mum*

Question 31

Explain the presentation and treatment of juvenile polyposis syndrome

Answer 31

Familial juvenile polyposis
- Another autosomally dominant inherited condition.
- Mutation of the SMAD4 gene – which encodes a tumour suppressor gene.
- Present with multiple juvenile or hamartomata polyps – similar to the Peutz-Jeghers polyps.
- Often present with childhood with intussusception or bleeding.

Diagnosis
- Any number of juvenile polyps in a patient with a family history.
- Multiple juvenile polyps throughout the GI tract.
- At least 5 juvenile polyps of the colon.

unlike solitary juvenile polyps, patients with polyps who have familial juvenile polyposis syndrome, can develop adenocarcinoma from the polyps

Other associated cancers
- Gastric, pancreatic, duodenal.

Other conditions associated with familial juvenile polyposis.
- Hereditary haemorrhagic telangiectasia – can cause bleeding from vascular malformation in the GI tract and lung.
- 20% of patients will have other genetic abnormalities such as malrotation, cardiac anomalies etc.

Treatment
- Patients should be colonoscopically surveilled
Prophylactic surgery is only recommended if there are too many polyps to endoscopically resect.

Question 32

Explain Cowden syndrome

Answer 32

Cowden’s syndrome
- Autosomally dominantly inherited.
- Mutation in the PTEN gene which is a tumour suppressor gene.
- Multiple hamartomata’s polyps in the colon and stomach.
- Also associated with muco-cutaneous lesions on the mouth and lips.
- Associated with thyroid adenomas and goitre, fibrocystic disease of the breast, uterine leiomyomas.
- Associated with a lifetime risk of 15-25% of CRC.
- Often present with a heavy polyp burden.
- No clear guidelines about colonoscopic surveillance.
50% lifetime risk of breast cancer and 10% risk of thyroid cancer.

Question 33

What is Lynch syndrome

Answer 33

Lynch syndrome
- Autosomally dominantly inherited.
- Mutation in the MMR genes on chromosome 2 and 3.
- 4 MMR genes to know are MLH1, MSH2, MSH6, PSMS2.
- These genes encode mismatch repair proteins – if you have a mutation in this, your genes aren’t getting repair properly.

The terminology around HNPCC and Lynch syndrome has been confusing in the past.
According to the updated companion series – HNPCC is now an obsolete term. The two terms which should be used, are Lynch syndrome, and Lynch like syndrome.

Lynch syndrome – should be used where there is evidence of a germline MMR gene mutation.
Lynch like syndrome – should be used in patient with a family history suggestive of lynch with MMR deficient tumours, and no identifiable germline mutation.

Question 34

What is the Amsterdam criteria

Answer 34

Amsterdam criteria
- this is was used to identify patients who should be genetically tested for lynch.
- First written in 1991 then revised in 1999.
- It isn’t a great criteria because a lot of patients with proven lynch won’t meet the criteria and it will include a lot of people who do not have lynch.

Amsterdam II criteria.
- At least 3 relatives with a lynch syndrome associated cancer – colorectal, endometrial, small bowel, urothelial, one who should be a first degree relative.
- Two successive generations affected.
- One cancer diagnosed before the age of 50
- FAP exclude.
- Tumours are verified by pathological examination

can remember it as the 3,2,1 rule – 3 relatives across 2 generations with 1 being less than 50 and FAP excluded

Question 35

What is the Bethesda criteria for Lynch

Answer 35

Bethesda criteria.
- Can be used to determine when tumour tissue from an individual with colorectal cancer should be tested for microsatellite instability.
- I am not sure how relevant this is because according to the New Zealand MOH guidelines, all newly diagnosed colorectal cancer should be immunohistochemically tested for MLH1, MSH2, MSH6, and PMS2 and this will subsequently determine those who should be tested for Lynch.

The criteria is (any of)
- H – histopathological characteristics of a microsatellite unstable cancer – lymphoid aggregates, mucinous cancer, signet ring cancer, medullary growth pattern.
- E – extra HNPCC cancers which are synchronous or metachronous.
- A – age. Colorectal cancer diagnosed at age < 50 years.
- D – two or more second degree relatives with a lymph associated tumour at any age.
S – single person in the family with a lynch syndrome related tumour < 50 years old.

Question 36

What is the risk of CRC for Lynch. What are the risk of other cancers

Answer 36

Risk of cancer
- Can have up to an 80% lifetime risk of developing CRC
- Does depend on which MMR mutations there are
- MLH1 or MSH2 – very high up to 80% lifetime risk.
- MSH6 or PMS2 – up to 20% lifetime risk.

Other cancers
- 20% risk of gastric, ovarian, or urinary tract cancers.
- 50% risk of endometrial cancers depending on the genes effected.
- Lower rates of small bowel, pancreatic, hepatobiliary, breast and prostate cancers.

Question 37

What is the surveillance and treatment of Lynch syndrome

Answer 37

Screening
- Yearly colonoscopies from 25 years old or 5 years before the earliest relative developed CRC.
- Prophylactic colectomy is usually not recommended
- Young patients with cancers should be considered for an extended resection i.e. ileorectal anastomosis.

Aspirin/chemoprevention
- There is good studies that aspiring from 25 years old reduces the risk of CRC in patients with lynch.

Other
- TAH and bilateral saplingo-oophorectomy is recommended after child-bearing.
- Yearly urinalysis.
- Yearly gastroscopies from 30 years old.

Question 38

What agents are used for FOLFOX, FOLFIRI, and CAPOX

Answer 38

Chemotherapy used in colon cancer
- FOLFOX – 5-fluorouracil, leucovorin (folinic acid), and oxaliplatin.
- FOLFIRI – 5-FU, leucovorin (folinic acid), irinotecan
- XELOX – oxaliplatin and capecitabine.
If elderly may give 5-FU alone.

Question 39

What trials compared laparoscopic versus open surgery for Colon cancer surgery

Answer 39

Early large trials which compared laparoscopic colon surgery with open surgery
- CLASSIC trial (2005 Lancet) – UK trial with 4000 patients
- COLOR trial (2009 Lancet)
- ALCCaS trial – australisian trial published in Annals of Surgery 2008 – showed that lap surgery same post-operative complication rate but with quicker return of bowel function and length of stay.

All of these studies established equivalence for laparoscopic versus open for colon cancer. Lap surgery had less blood loss, quicker return of bowel function and shorter length of stay with equivalent oncological outcomes.

Question 40

How should splenic flexure tumours be managed

Answer 40

Splenic flexure tumours
- The surgical management of splenic flexure tumours is controversial.
- Options include an extended right, left hemicolectomy, or segmental resection of the splenic flexure.
- A 2020 meta-analysis published in Diseases of the Colon and rectum showed no difference in overall complication rate or overall survival.
- Extended right hemicolectomy is, however, associated with a higher risk of ileus.
- Of note – Siraj and MHM published a paper looking at splenic flexure drainage – vast majority of drainage was to the left colic.

NB
- A left hemicolectomy is defined as resection of the left colon including ligation of the IMA (thus including the left colic).
A segmental resection of the splenic flexure includes ligation of the left colic (thus preservation of the IMA) with ligation of the left branch of middle colic.

Question 41

Explain the factors of ERAS

Answer 41

ERAS
- Enhanced recovery after surgery program.
- Involves pre-operative education about what to expect, nutritional optimization, early feeding after surgery, early ambulation, early removal of drains.
- Clear fluids is often given up to 2 hours pre-operatively as well as a carbohydrate drink the night before.

Other pre-op considerations
- Fe infusion pre-op – reduces blood transfusion rate (which may implicate long term recurrence rate).
Stoma nurse review

Question 42

Explain the use of bowel prep in CRC surgery

Answer 42

Bowel prep
- There have been a raft of recent studies with meta-analysis looking at MBP and antibiotics – essentially when combined, they reduce the risk of SSI.
- MBP and antibiotics may reduce ileus and anastomotic leak rates – although the evidence is not as strong (retrospective studies).
Interestingly, WHO recommends its use but NICE does not.

Question 43

Explain the rationale behind adjuvant chemotherapy in resectable CRC

Answer 43

Chemotherapy for resectable non-metastatic bowel cancer
- Neoadjuvant chemotherapy is not being routinely used
- Is usually given adjuvant.

5-FU (Fluorouracil)
- Clinical trials in the 1980s showed that post-operative 5-FU for stage III colon cancer and above improved DFS and OS.
- Oral agents (capecitabine) has been shown to be as useful.
- 5-FU is in the anti-metabolite and pyrimidine analog family of medications.
- A small proportion of patients are deficient in the enzyme di-hydropyrimidine dehydrogenase (DPD) thus cannot be given 5-FU – if they are given it they can develop severe life-threatening toxicity.
- Side effects include inflammation of the mouth, loss of appetite, low blood cell counts, hair loss, and inflammation of the skin.

Oxaliplatin and 5-FU
MOSAIC trial (2004) showed that adding oxaliplatin to 5-FU for stage III CRC demonstrated an improved OS

Question 44

What are the indications for chemotherapy in resectable Colon cancer

Answer 44

Indication for adjuvant chemotherapy
- Stage III tumours – improves 5 year survival from 49-64%.
- FOLFOX and FOLFIRI are usually the treatment of choice.
- High risk stage II patients may be considered.

High risk stage II
- Poorly differentiated tumours
- Mucinous subtype
- LVI
- BD3 Tumour budding
- Bulking tumours – T3 or T4 or perforated cancer.
- <12 nodes in the specimen

High risk stage II disease with MSI
- A meta-analysis found that Stage II MSI tumours do not derive benefit from adjuvant 5-FU. Thus if you are going to consider chemotherapy for a patient with high risk stage II, you need to test for all the MMR mutations (although we do this for all cancers now anyway).

circulating tumour DNA is something that is being looked at. There are studies currently looking at measuring this and giving patients with circulating tumour DNA chemo and seeing if they do better

Question 45

What targetted therapies are used in colon cancer?

Answer 45

Targeted therapies
- Bevacizumab – inhibits VEG-F. Inhibits vascular growth appropriate with a tumour. Should be avoided in patients who have not had their primary resected because it is associated with high risks of bowel perforation.
- Cetuximab – EGFR inhibitor. Mutant-KRAS does not respond. In wild-type KRAS there is improved overall survival

*KRAS mutation in the conventional pathway but is usually not present in the serrated pathway. Is 50/50 in the microsatellite instability pathway

Question 46

What are the big trials which neoadjuvant treatment of rectal cancer is based on?

Answer 46

Intro
- Prior to the 1980s, local recurrence after rectal cancer surgery was as high as 40%.
- This is associated with intractable pain, severe urological dysfunction, and is difficult to treat.
- TME is arguably the most important technical advance in rectal cancer surgery.
- The initial TME series ad a local recurrence rate of just 3.7% and the first large series in TME showed a much higher 5 year survival.

Swedish Rectal Cancer trial (NEWJM 1997)
- The study showed that pre-operative radiotherapy led to reduced risk of local recurrence when compared with surgery alone.
- This study was done before TME was routine and thus it was difficult to know if radiotherapy actually had any benefit.

Dutch TME trial (NEJM 2001)
- This study aimed to answer the question if pre-operative radiotherapy reduces local recurrence in patients who undergo TME.
- This showed a significant reduction in local recurrence (2.4% versus 8.2%).

EORTC 22921 trial (NEJM 2016)
- This aimed to answer the question if adding chemotherapy to radiotherapy improved outcomes.
- Addition of 5-FU to radiotherapy didn’t improve survival, but it did improve local recurrence rates.

German Rectal cancer trial (NEJM 2004)
This aimed to evaluate if chemoradiotherapy should be given pre or post-surgery. IF found the pre-operative chemoradiotherapy was better tolerated, and had reduced rates of local recurrence (6 vs 13%).

Question 47

What are the indications for neoadjuvant treatment in Rectal cancer?

Answer 47

What are the current indications for neoadjuvant therapy?
- Neoadjuvant therapy should not be given universally to patients with rectal cancer as it is associated with increased rates of bowel and sexual dysfunction.
- Patients with an elevated of recurrence despite TME, should be identified, and offered neoadjuvant therapy.

These include
- Those with a threatened CRM,
- LVI
- T4 tumours
- Nodal involvement
- T3c + tumours
- In low rectal cancers to allow sphincter preservation

There are a lot of nuisances here i.e in a patient with a T1-2 N1 tumour, you could omit neoadjuvant treatment.

Question 48

What trials compared short course radiotherapy versus long course

Answer 48

Short course radiotherapy versus long course chemo-radiotherapy
- The Trans-Tasman Radiation oncology Group trial compared SCRT versus Long course CRT and found no difference in local recurrence rate at 3 years.
- The Polish Rectal Cancer trial compared SCRT and long course CRT for patients with cT3/4 tumours and found no difference in sphincter preservation.
- These above trial suggest that both treatments are as efficacious.

Where long course CRT is superior
- There is evidence that when the CRM is threatened, long course CRT is associated with a higher R0 resection rate.
Thus for bigger tumours, where downstaging is important prior to surgery – it is likely better to give long course CRT – this is what is used more often in Australasia.

Question 49

Explain RAPIDO, PRODIGE and STELLA

Answer 49

PRODIGE23 trial
- This compared induction chemotherapy with FOLFIRINOX followed by CRT versus CRT alone in patient with t3+ N0-2 tumours. Both groups received adjuvant chemotherapy.
- The intervention group had a reduced DFS, but there was no overall reduction in cancer-specific survival or overall survival.
- pCR rates were much higher in the intervention arm (28% versus 12%).
- There was no difference in local recurrence rates.

STELLAR trial
- Contrary to PRODGE23, this trial included SCRT in the TNT schedule.
- Patients with T3-4 and/or N+ were randomized to get either TNT with SCRT or CRT.
- Both arms got adjuvant CAPOX
- No difference in DFS was seen but there was an increased pCR (21 vs 12%).

RAPIDO trial
- This looked at patients with more advanced tumour – T4+, N2, threated CRM, EMVI, lateral lymph nodes.
- Received either SCRT + consolidation CAPOX or CRT.
- Only the CRT group received post-op chemotherapy.
- Disease related treatment failure was significant reduced in the TNT arm.
The issue with this trial is the CRT group had a lower rate of local recurrence at long term follow up

Question 50

When is long course neoadjvant radiotherapy used?

Answer 50

Long course radiotherapy
- Long course is given more commonly in Australasia
- Usually given as 50Gy – 1.8 Gy Fractions over 28 fractions
- Usually given with 5-FU or capecitabine
- Capecitabine is an oral 5-FU pro-drug.
- Longer course has higher rates of tumour downsizing and pCR.
Indicated over short course radiotherapy in patients with a larger tumour i.e T4 tumour, nodal disease in the mesorectum, if the tumour is close to the CRM.

Question 51

What are the downsides of neoadjuvant radiotherapy in rectal cancer?

Answer 51

Downsides of radiotherapy
- Potentially makes surgery more difficult due to scarring
- Increases risk of post-operative wound complications
Sexual dysfunction, proctitis, healing difficulties, endarteritis obliterans.

Question 52

What is the optimal time to wait after neoadjuvant radiotherapy?

Answer 52

Optimal timing of surgery after radiotherapy
- Historically was short – between 4-6 weeks.
- Optimal time has been stretched out to 8-12 weeks.
In patients with larger tumours and even longer wait may be indicated.

Question 53

What are the indications for adjuvant chemotherapy in rectal cancer?

Answer 53

Indications for adjuvant chemotherapy in rectal cancer.
- Usually patients with Stage II to IV will get it
- 6 months of adjuvant chemotherapy – 5-FU and oxaliplatin based. This is based on the MOSAIC trial 2004 showed that oxaliplatin added to 5-FU improves overall survival in CRC (not specifically rectal cancer).
There are also trials looking at patients with circulating tumour DNA and seeing if they would benefit from systemic treatment.

Question 54

When is local excision used in rectal cancer?

Answer 54

Local excision options
- Only indicated in setting of Tis or T1 which are accessible from the anal canal.
- Higher recurrence rates than resection
- Also does not allow for removal of the meso-rectal lymph nodes which means tumour is not fully staged.
Can possibly make further surgery more difficult.

Question 55

what is TME

Answer 55

TME
- Excision of the mesorectum en-bloc with dissection outside of the meso-rectal fascia which allows resection of the meso-rectal lymph nodes.
- TME hugely reduces local recurrence.
High ligation of IMA proximal to the origin of the left colic.

Question 56

What are the key principles of rectal cancer surgery?

Answer 56

Key surgical principles to remove a rectal cancer
- Abdominal exploration looking for metastatic disease
- Mobilization of the left colon and splenic flexure in order to obtain length on the conduit.
- High ligation of the IMA and IMV – divide IMV below the pancreas not on the pancreas
- The IMA should not be ligated flush with aorta as this risks damage to pelvic sympathetics (sympathetic trunk).
- Rectal dissection – TME principles – care taken to avoid damaging the seminal vesicles and prostate in men and vagina in woman.
- Nerve considerations – avoid injuring the superior hypogastric plexus (sympathetic) at the sacral promonentry . Avoid damaging the nervi erigentes (parasympathetic) which is located close to the prostate, seminal vesicles, and travel along the pelvic side wall.
- Mobilisation of the rectum should continue to 2cm below the tumour. 1cm margin may be acceptable if you want to perform a colo-anal anastomosis.
For all ULAR and most low anterior resections – you should perform a diverting loop ileostomy – has been shown to reduce the consequences of an anastomotic leak.

Question 57

What are the surgical options for an obstructing or near obstructing rectal cancer

Answer 57

Obstructing or near obstructing rectal cancer
- Options include upfront resection – you will lose the benefits of neoadjuvant chemoradiotherapy.
Can perform a loop colostomy – will decompress patient which will allow neoadjuvant chemoradiotherapy

Question 58

What is LARS

Answer 58

Low anterior resection syndrome
- The definition of LARS is “disordered bowel dysfunction following rectal resection, leading to a detriment in quality of life”.
- Symptoms of Lars include variable bowel function, altered stool consistency, repeated painful stills, emptying difficulties, urgency, and incontinence.
Treatment includes bulking agents, drugs to reduce intestinal motility, pelvic floor retraining, severe dysfunction sacral nerve stimulators.

Question 59

What does sexual and urinary dysfunction occur after rectal dissection

Answer 59

Sexual and urinary dysfunction after rectal surgery
- Damage to the superior hypogastric plexus at the level of the sacral promontory may lead to ejaculatory dysfunction in males (sympathetic)
- Damage to the nervi erigentes which lie between the seminal vesicles and prostate my cause erectile dysfunction (parasympathetic).
- Dissection posterior to Denonvillies fascia will reduce the risk of inadvertent damage to the nervi erigentes

*to recap – IMA origin and sacral promontory – superior leading to inferior hypogastric plexus. Damage to this damages pelvic sympathetic leading to ejaculatory dysfunction

low pelvic side wall and anterior to Denonvilliers fascia is where the nervi erigentes are, which are parasympathetics. Damage to this can lead to erectile dysfunction

damage to either of these nerves can result in urinary dysfunction

Question 60

What is HIPEC

Answer 60

HIPEC
- HIPEC is performed by administering mitomycin C in fluid at 42 degrees for 60-90 minutes.
Intravenous 5FU is given at the same time.