Colorectal, Anal, and Peritoneal Malignancy

Question 1

What is the benefit of adjuvant chemotherapy in Stage III colon cancer?

What about in stage II disease?

Answer 1

12 months of adjuvant 5-FU and LV confers a 30% absolute reduction in 5-year mortality. The addition of Oxaliplatin to either Capecitabine or 5-FU and LV increases this reduction in mortality by an additional 5%.

In patients with high-risk stage II disease, chemotherapy may confer an absolute 5-year survival advantage of 10%.

Question 2

What benefit does the addition of Oxaliplatin confer in “high-risk” stage II colon cancer?

Answer 2

None. Single agent therapy with 5-FU or Capecitabine should be used.

Question 3

What is the impact of adjuvant chemotherapy in rectal cancer?

Answer 3

Chemotherapy reduces local recurrence in patients with stage II/III rectal cancer but has not been shown to reduce subsequent metastatic disease or improve overall survival.

Question 4

What is Capecitabine?

Answer 4

Orally administered Capecitabine, is a fluoropyrimidine designed to mimic continuous infusion of 5-FU but with preferential action at the cancer site.

It has been shown to be as effective as 5-FU with LV but was associated with a lower incidence of neutropenia fever and sepsis.

Question 5

Which trial supports the use of Oxaliplatin in addition to 5-FU/LV or Capecitabine?

Answer 5

The MOSAIC trial (2004 NEJM): “Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.”

Ballpark 5-10% absolute reduction in 3-year mortality. Moreso for stage III.

Question 6

Which stage II colon cancer patients are considered “high-risk”?

What adjuvant therapy should they be offered and what survival advantage can they anticipate?

Answer 6

• T4 primary
• Obstruction or perforation
• Poorly differentiated histology
• LVI or PNI
• MSI

Single agent adjuvant chemotherapy; 5-FU or Capecitabine, NOT OXALIPLATIN! (no benefit). USA National Cancer Database studies suggest a 10% survival advantage.

Question 7

Summarise the evidence base around neoadjuvant chemotherapy in colon cancer.

Describe the two underlying seminal trials from the last 3 years.

Answer 7

• Neoadjuvant chemotherapy has no clear advantage over adjuvant chemotherapy and over-treatment is a barrier to large-scale adoption.

PRODIGE-22 (Ann. Surg. 2020): “Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of over-treating patients.”

FOXTROT (Ann. Onc. abstr 2019): “Six weeks NAC for operable primary colon cancer can be delivered safely, with improved perioperative morbidity and marked pathological downstaging including some pCRs. There is a trend toward better disease control at 2 years.”

Question 8

Why have the NCCN recommended that patients with stage II rectal cancer be treated in a similar fashion to those with stage III rectal cancer?

Answer 8

Unlike colon cancer, where patients are pre-operatively over-staged, retrospective studies out of MSKCC and MDACC have shown that 22% of patients with rectal cancer staged pre-operatively as stage II actually have positive nodes at time of TME.

Question 9

What did the 2012 Trans-Tasman Radiation Oncology Group trial show regarding Short versus Long Course?

Answer 9

Three-year local recurrence rates between short-course and long course were not statistically significantly different; the CI for the difference is consistent with either no clinically important difference or differences in favor of LC.

LC may be more effective in reducing LR for distal tumors. No differences in rates of distant recurrence, relapse-free survival, overall survival, or late toxicity were detected.

Question 10

Summarise the historical basis of TNT

(4 major points)

Answer 10

The historical bases of TNT lie on a number of factors:

1. Despite many advances over time, a substantial proportion of non-metastatic rectal cancer patients (especially among those with high-risk features) suffer tumour recurrence.
2. While adjuvant chemotherapy is still offered in many cases, this has never been shown to be beneficial if neoadjuvant radiotherapy and high-quality surgery are carried out; by contrast, it has long been hypothesised that moving systemic chemotherapy from the adjuvant to the neoadjuvant setting could ensure better compliance and an early and more efficient targeting of micrometastases, which now outperform local residual disease as the leading cause of recurrence
3. Emerging data suggesting a time-dependent radiotherapy effect on tumour regression have gradually led physicians to stretch the radiotherapy-to-surgery interval, thus opening an opportunity window for the delivery of sequential, preoperative chemotherapy.
4. Finally, intensification of neoadjuvant therapy has the potential to increase the proportion of patients who achieve clinical complete response (cCR), and could therefore become eligible for watch & wait, an approach that has gained more and more traction over the last few years given the excellent survival data and positive implications in terms of long-term functional outcome and quality of life.

Question 11

What are the risk factors for AIN and Anal SCC?

Answer 11

• HPV infection
• HIV infection
• High risk sexual behaviour:
• MSM
• Anoreceptive intercourse
• Multiple sexual partners
• Personal history of CIN, Gynaecological cancers
• Chronic immunosuppression
• Smoking

Question 12

Describe the classification of dysplastic lesions of the anal canal.

Answer 12

The initial Bethesda system consisting of AIN I, II, and III was modelled on cervical neoplasia. Further clarification of the relationship of AIN with HPV, and the discovery that the oncogenic pathways of anal and genital cancers are closely related, has recently led to a simpler system consisting of a two- tiered approach of “low grade” and “high grade squamous intraepithelial lesions” (LSIL and HSIL, respectively).

Under this system, AIN I corresponds to LSIL and AIN II/III to HSIL. HSIL lesions are considered premalignant, whereas LSIL lesions are not felt to be premalignant, but do have the potential to progress to HSIL.

The term ASCUS (atypical squamous cells of undetermined significance) will occasionally appear in pathology reports and can be generally included in the LSIL category.

Question 13

Describe the pathophysiology of HPV mediated anal SCC

Answer 13

Up to 95% of anal SCC is thought to be HPV-related.

HPV infects basal epithelial cells with a predilection for the transformation zone. The virus enters the cells and alters cellular function to produce viral proteins and replicate itself. High-risk HPV, (hrHPV) subtypes, specifically HPV 16 and HPV 18, produce viral proteins E6 and E7 which function like oncoproteins. In hrHPV subtypes, E6 and E7 viral proteins interact with cell cycle growth factors allowing for integration into the hosts DNA, leading to uncontrolled cellular reproduction and escape of programmed cell death.

With a persistent infection, there is potential for gene dysregulation resulting in increased cell growth and progression to a precancerous lesion and possibly invasive carcinoma.

Question 14

What is the estimated time course of HPV mediated anal SCC?

Answer 14

In the cervix, the development of cervical SCC via persistence of HPV may take approximately 10
years, with known cytological correlates for precancerous and malignant conditions.

HPV in anal SCC may progress through similar cycles of infection, clearance, persistence, and eventual progression leading to AIN and anal SCC.

Question 15

Describe the HPV Vaccine and its utility.

When should people get vaccinated?

What are the potential benefits?

Answer 15

In Australia, anyone over 9 years of age who wants to protect themselves against HPV are encouraged to talk to their primary care doctor about getting immunised.

The best time to get immunised is prior to becoming sexually active. The vaccine will not protect against HPV-related cancer from previous infections with any of the HPV types included in the HPV vaccine. 9 types of HPV are covered in the NIP vaccine, including the four strains (16, 18, 6, 11) most likely to cause severe disease.

It is important to appreciate that some studies demonstrate that HPV vaccine also appears to be effective in preventing recurrent high- grade AIN when administered after the diagnosis and treatment of high-grade AIN in HIV negative MSM. One study reported decreased rates of recurrent HSIL and anal cancer when vaccination was administered after diagnosis of HSIL.

Question 16

What is Fluorouracil?

How does it work?

Side effect profile?

What is Leucovorin?

Answer 16

Fluorouracil (FU) is a pyrimidine analog antimetabolite that interferes with DNA and RNA synthesis.

After activation, F-UMP (an active metabolite) is incorporated into RNA to replace uracil and inhibit cell growth. The active metabolite inhibits thymidylate synthetase, depleting thymidine triphosphate (required for DNA synthesis).

It undergoes hepatic metabolism and excreted in the urine.

Main adverse effects include bone marrow suppression, cardiotoxicity, GIT toxicity (diarrhoea, stomatitis, mucositis), and palmer-plantar erythrodysesthesia (hand-foot syndrome).

Leucovorin is a reduced form of folic acid and restores active folate stores required for DNA/RNA synthesis. It potentiates 5-FU.

Question 17

What is Oxaliplatin?

How does it work?

Side effect profile?

Answer 17

Oxaliplatin is a platinum derivative that is an alkylating agent type of chemotherapy.

The platinum compound binds to DNA, forming cross links, which in turn inhibits DNA replication and transcription, resulting in apoptosis.

Adverse reactions include bone marrow suppression, QT prolongation, GIT toxicity, haemorrhage, and neuropathy, both acute and persistent. Also hepatotoxic with sinusoidal injury (often used as NAC in liver mets).

Question 18

What is Bevacizumab?

How does it work?

What are the risks of Bev + FOLFOX/FOLFIRI?

Answer 18

Bevacizumab (Avastin) is a humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF).

The inhibition of tumour cell VEGF leads to a reduction in microvascular growth of tumor blood vessels and thus limits the blood supply to tumor tissues.

The addition of Bevacizumab to a regimen containing FU/LV plus Irinotecan or oxaliplatin (Bev + FOLFIRI or FOLFOX) showed benefit in improving survival for metastatic colorectal cancer, although was associated with additional adverse effect of bleeding, hypertension, bowel perforation, and thromboembolic events.

Question 19

What is Cetuximab?

How does it work?

Answer 19

Cetuximab is a mouse/human chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR); the benefit of this drug in metastatic colorectal cancer is limited to wild-type RAS/BRAF.

Its benefit is limited in stage III colon cancer, in the adjuvant setting post colectomy. This was even shown in wild-type RAS/BRAF stage III colon cancer as per two major trials – N0147 and PETACC8 trials (Andre et al. 2020, Kerr et al. 2016)

Question 20

What is meant by “Targeted Therapy” in colorectal cancer?

What are some common examples?

Answer 20

Targeted therapy refers to small molecules, such as monoclonal antibodies, that can augment molecular pathways critical to cancer-specific growth and maintenance.

Common examples of targeted therapy include antibodies against VEGF, the EGFR, B-type RAF (BRAF) V600E, and the human EGFR 2 (HER2).

Targeted therapy is now almost exclusively used in patients with metastatic disease.

Question 21

What are the main molecular sub-types of metastatic colorectal cancer (mCRC)?

Answer 21

The main molecular subtypes of mCRC are

1. KRAS/NRAS and BRAF wild type
2. KRAS/NRAS mutated
3. BRAF mutated
4. HER2 mutated
5. MSI high and MMR deficient

Question 22

What are the 3 main pathways of colorectal oncogenesis?

Answer 22

CRC evolves from 3 main pathways:

(1) Chromosomal instability (CIN) pathway
(2) MSI pathway
(3) CPG island mutator phenotype (CIMP) promotor pathway.

Aberrations within these molecular pathways are not mutually exclusive and occur in both sporadic and inherited CRCs. For example, CIN is present in 85%, CIMP in 20%, and MSI in 15% of tumors.

Question 23

Describe what is meant by the “Chromosomal Instability Pathway”

Answer 23

The CIN pathway was the first major genetic pathway identified in CRC and is the most common, with approximately 65-75% of sporadic cases CRC attributable to this pathway.

The traditional model of colorectal adenoma to carcinoma as decribed by Vogelstein typifies the CIN whereby multiple mutational events conspire to produce karyotypic variability and also oncogenicity.

The karyotypic variability reflects the high mutation phenotype, whereas the specific APC, KRAS, DCC, and p53 mutations represents specific oncogenic mutations.

Each of the key mutations represent important genes within recognised pathways that contribute to colorectal cancer:

• APC = wNT canonical pathway
• KRAS = MAPK/ERK pathway
• p53 = mTOR pathway and the p53 pathway
• SMAD4 = TGF-ß pathway
  *

Question 24

Describe the importance of the ERK-MAPK pathway.

Cite therapeutic targets within your answer.

Answer 24

The pathway most connected with the pathogenesis, progression, and oncogenic behavior of CRC is the ERK MAPK (extracellular-regulated-kinase mitogen-activated-pathway-kinase).

This pathway is one of the most important for cell proliferation and is frequently stimulated by binding of the growth factors to receptors in the cell membrane. One such receptor is epidermal growth factor receptor (EGFR). The EGF receptor is a therapeutic target for targeted antibody therapies such as Cetuximab and Panitumumab.

Mutations affecting the enzymes within this pathway have significant therapeutic implicaitons; KRAS mutations result in abnormally high activity through MAPK pathways, and signal transduction is no longer reliant on receptor stimulation. Therefore, targeted therapy with EGFR receptor blockers (Cetuiximab and Panitumumab) does not benefit patients with RAS mutations.

Question 25

Describe the incidence and key concepts regarding the treatment of KRAS/NRAS and BRAF wild-type tumours.

Answer 25

Incidence: Between 30% and 50% of patients with CRC are KRAS/BRAF wild-type; i.e. no mutation of KRAS/BRAF.

Key concepts: In combination with chemotherapy, EGFR inhibitors, such as cetuximab and panitumumab, have been shown to extend median survival compared with chemotherapy alone in mCRC patients.

Furthermore, 2 meta-analyses have demonstrated that left-sided colon and rectal cancers are strongly associated with response to EGFR inhibition. Therefore, current NCCN practice guidelines recommend that EGFR inhibitors be paired with chemotherapy as first-line treatment in KRAS/NRAS/BRAF wild-type tumors, particularly in left-sided mCRC.

As an alternative to EGFR inhibitors, the VEGF inhibitor bevacizumab may be administered alongside systemic chemotherapy as a first-line treatment of mCRC. However, a recent meta-analysis has demonstrated that VEGF inhibitors may be inferior to EGFR inhibitors. Therefore, bevacizumab may also be offered as a second-line treatment in cases that progress despite EGFR inhibition.

Question 26

Describe the incidence and key concepts in the treatment of KRAS/NRAS mutated tumours.

Answer 26

Incidence: Between 35% and 40% of patients are KRAS/NRAS mutated.

Key concepts: Targeted therapies are mainly ineffective and should not be offered to this group of patients, either alone or with other anticancer agents.

Question 27

Describe the incidence and key concepts in the treatment of BRAF mutated tumours.

What is Encorafenib and what role does it play?

Answer 27

Incidence: Between 5% and 15% of patients (90% of these patients have a V600E mutation)

Key concepts: First-line therapy usually consists of either oxaliplatin-based chemotherapy (FOLFOX or CAPOX) or irinotecan-based chemotherapy (FOLFIRI or CAPIRI).

In BRAF mutations, the mutated BRAF protein product is believed to be constitutively active and independent of EGFR inhibition by cetuximab or panitumumab. BRAF V600E mutations are, therefore, associated with inadequate response to the EGFR inhibitors cetuximab and panitumumab unless paired with a BRAF inhibitor. The combination of an EGFR inhibitor with a BRAF inhibitor (encorafenib) has been shown to extend overall survival.

Question 28

Provide an overview of the oncogenic pathways in colorectal cancer with respect to overlap with each other.

Answer 28

Question 29

What is meant by “the good, the bad, and the ugly” in rectal cancer?

How might this dictate treatment strategy?

How has this changed since Watch and Wait has been proposed?

Answer 29

Good - no risk factors for recurrence

• Absence of tumour penetration into the mesorectum (T1/2)
• Absence of nodal disease (N0)
• No CRM threat or EMVI
  
  • Up-front surgery

Bad - intermediate risk factors for recurrence

• cT3a/b
• cN1
  
  • Short course RT followed by surgery

Ugly - strong risk factors for recurrence

• EMVI
• Threatened CRM
• cN2
  
  • Chemoradioatherapy followed by surgery.

Updates since:

1. ​Since the MERCURY trial demonstrated that properly staged T3a/b or cN+ with surgery alone had recurrence rates <2%, one can argue that this group does not need radiotherapy and its s/e.
2. Neoadjuvant CRT (more frequently than short-course RT) could lead to complete tumor regression and, in select patients, to organ preservation, thus avoiding radical TME with its immediate morbidity, mortality and functional consequences. NACRT achieves cCR in lower stage tumours…

Question 30

Describe the MRI T-staging of rectal cancer.

Answer 30

Question 31

Contextualise the argument for organ preservation in rectal cancer surgery.

What are the rates of complications, overall morbidity, and mortality of rectal cancer surgery?

Answer 31

Overall morbidity from rectal cancer surgery approaches 26-45%, with anastomotic leakage occurring in up to 2.4-11% of cases and up to 65% of patients experience some degree of bowel dysfunction following surgery.

Major complications can occur in up to 35% (encompassing anastomotic leaks, sepsis, and respiratory failure)

Sexual or urinary dysfunction rates of 25% have been reported.

Overall mortality following rectal cancer surgery is 0.4-3.3% but can approach 12% in patient groups over the age of 85 years.

Question 32

What proportion of ypT0 rectal cancer patients who have undergone NACRT have nodal or mesorectal involvement?

What proportion of those with an incomplete clinical response are found to have a complete pathological repsonse?

Answer 32

15-20%

8-15%

i.e a complete clinical response is not completely predictive of a complete pathological response, and similarly, an incomplete clinical response may actually be a complete pathological response.

Question 33

How does Habr-Gama’s group define complete clinical response?

How has that changed over time?

What did Sammour’s group add?

Answer 33

i. The absence of ulcereration, stenosis, or mass on DRE and proctoscopy at 8 weeks
ii. No mesorectal or pelvic lymph node involvement on MRI
iii. Normal CEA
iv. whitening of the mucosa or telengectasia
v. Absence of FDG uptake on PET and absence of diffusion restriction on DWI MRI (added 2013)

Sammour and Chang added absence of residual tumour or replacement by fibrosis on T2 weighted MRI.

Question 34

What was the regimen used by Habr-Gama’s group in the original Watch and Wait paper?

What was the cCR rate?

How has their regimen changed and what rates of cCr are obtainable now?

Answer 34

The seminal paper by Habr-Gama in 2004 utilised a combination of 50.4Gy radiation over 28 fractions combined with 2 cycles of 5FU.

cCR were 26.8% in the inital series.

10 years later in 2014, Habr-Gama published cCR rates of 68% using an extended (6 cycle) 5FU-LV chemo regimen with 54Gy of rads.

In 2019 her team published cCR rates of 85.7% when cT2N0 cancer patients were given extended (6 cycles) chemo, though this time they called it consolidation chemotherapy and the paper focussed on organ preservation.

Question 35

Which rectal cancer patients should be offered neoadjuvant therapy?

(General principles and specific indications)

Answer 35

Neoadjuvant treatment has traditionally been indicated in patients at increased risk of locoregional recurrence as determined by clinical and radiological characteristics.

NCCN guidelines:

• Stage II-III disease (T3-4 any-N, or any-T with N1-2)

ESMO 2017 guidelines:

• Allow for the omission of chemoradiotherapy in patients with T3a/b and N1-2 tumours where other features place the patient at low risk of involved surgical resection margins/local recurrenc (i.e back high quality TME)

NZ and Australia:

• Australian guidelines allow for the omission of neoadjuvant treatment in T3a N0 rectal cancer.
• New Zealand guidelines are less prescriptive, recommending that neoadjuvant chemoradiation be given to patients “who are at risk of local recurrence”.

Question 36

Which patients should be offered TNT based on RAPIDO and PRODIGE-23?

(Underlying principle and specific selection criteria for the trials)

Answer 36

“Intensification of neoadjuvant treatment with pre-operative delivery of systemic dose chemotherapy could be a reasonable option for patients with most advanced tumours, who especially bear the risk of metastatic dissemination and distant recurrence”

The RAPIDO trial recruited only patients with at least one of the five following high-risk features as detected by baseline pelvic MRI:

• T4
• N2
• extramural venous invasion (EMVI)
• mesorectal fascia (MRF) involvement/threatening
• enlarged lateral pelvic lymph nodes.

The PRODIGE 23 trial recruited all stage II-III patients (as revealed by MRI +/- endorectal ultrasound) regardless of the presence of high-risk features!

Based on these data, it is reasonable to propose TNT to patients with stage III tumours and to those with stage II tumours bearing at least one of the aforementioned high-risk factors. Adopting such practice would mitigate concerns about the general risk of over-treatment, as patients who are considered here as suitable candidates for TNT are currently the most likely to be offered adjuvant chemotherapy following a non-TNT-based pre-operative strategy.

Question 37

Define acute ratiation toxicity

Answer 37

Acute radiation toxicity is defined as a side effect of radiation treatment that occurs during radiotherapy or within 3 months following its completion

Symptoms generally improve following cessation of treatment, however ~10% of patients will have persisting issues.

Question 38

Define chronic radiation toxicity

Answer 38

Onset of symptoms >3 months after finishing radiotherapy treatment.

Question 39

Provide an overview of the pathophysiology of radiotherapy-induced intestinal damage.

Answer 39

Radiotherapy induces pathological changes at a molecular and cellular level.

At the cellular level, the changes occur within the enterocytes as well as the vascular endothelium.

There are also radioation-associated changes to the microbiome that exacerbate the intestinal inflammation.

Question 40

Describe the pathophysiology of radiation-induced intestinal damage at a molecular level.

Answer 40

DNA is the principle target of ionizing radiation. At a molecular level, radiotherapy causes DNA damage via a direct and/or indirect action.

• Direct effect:
Molecular DNA bonds are directly ionized leading to double stranded DNA breaks.

• Indirect effect:
Ionizing radiation produces reactive oxygen and reactive nitrogen species (ROS/RNS). These diffuse and damage DNA bonds as well as the surrounding proteins and lipids.

DNA breaks result in activation of multiple transduction pathways such as p53 and nuclear factor kB. This leads to upregulation of target genes including proinflammatory cytokines (TNF-alpha, IL-1, IL-6), chemokines (IL-8), cell adhesion molecules (integrins, selectins) and cell surface receptors3. This incites an inflammatory reaction and ultimately ends in the accumulation of biologically active proteins that target the mucosa/submucosa inducing tissue injury.

Question 41

Describe the pathophysiology of radiation-induced intestinal damage at a cellular level with regard to the intestinal epithelium.

Which particular cells are most at risk?

What are the clinical consequences of radiation-induced intestinal damage?

Answer 41

The high proliferative rate of the gastrointestinal epithelium makes it particularly susceptible to injury from radiotherapy. The cells most at risk are the intestinal stem cells which reside within the crypts of Lieberkuhn.

Loss of the stem cells leads to crypt destruction/involution resulting in denudation of the mucosa. This exposes the lamina propria to luminal microbes, triggering an inflammatory response characterized by cellular infiltrates (T-lymphocytes, macrophages and neutrophils) that cause sustained tissue destruction.

Morphologically, this results in bowel wall inflammation/oedema, shortened villi and a reduced absorptive area. These changes lead to impaired absorption of fats, carbohydrates, bile salts and Vitamin B12 resulting in the loss of water, electrolytes and protein. This manifests clinically with weight loss, diarrhea and ultimately malnutrition.

Question 42

Describe the characteristic appearance of acute radiation-induced intestinal damage.

Answer 42

• Reduced crypt mitoses
• Inflammatory cell infiltrate
• Crypt abscess formation
• Epithelial denudation and ulceration

Question 43

Describe the characteristic histological changes associated with chronic radiation-induced intestinal damage.

Answer 43

• Lymphatic obstruction
• Obliterative endarteritis
• Submucosal fibrosis
• Tissue ischaemia

Question 44

Describe the pathophysiology of radiation-induced damage to the vascular endothelium.

Answer 44

After irradiation, the vascular endothelium acquires a pro-inflammatory, prothrombotic, and anti-fibrinolytic phenotype.

Increased expression of cell adhesion proteins leads to leukocyte recruitment and transmigration, as well as an increase in platelet aggregation.

Histologically, there is progressive occlusive vasculitis with foam cell invasion of the intima and hyaline thickening of the arteriolar wall. Reduced blood flow and ischaemia leads to collagen deposition and fibrosis in the submucosal layer.

If these changes become chronic, transmural fibrosis can occur leading to stricture formation.

Question 45

How is the microbiome affected by radiation therapy?

What effect does this have clinically?

Answer 45

Modification of the microbial profile can exacerbate intestinal inflammation.

Microbiota play an important in role in the development and homeostasis of the intestinal epithelium. Studies have shown that radiotherapy can lead to quantitative changes in specific gut microbiota, as well as reducing microbial heterogeneity.

The resulting dysbiosis can cause an alteration in the expression and distribution of intercellular tight junctions leading to penetration of antigens participating in the chronicity of intestinal inflammation.

Question 46

What are the risk factors associated with radiation-induced GI toxicity?

Answer 46

Therapy-related factors:

• Dose
• Mode of delivery (brachy better than external beam)
• Concurrent chemotherapy

Patient-related factors:

• Age
• Weight (slimmer worse!)
• Smoking
• Previous surgery (adhesions fix SB in place)
• Comorbidities (esp vascular RF, connective tissue d/o, HIV, IBD)

Question 47

Hydrogen breath testing and Selenium-75 homocholic acid conjugation with Taurine may be used in the work up for radiation induced enteropathy.

What do these tests assess for?

Answer 47

Hydrogen breath testing is a cheap, non-invasive tool that is diagnostic for bacterial overgrowth which can occur with radiation-induced strictures.

The SeCHAT (Selenium-75 homocholic acid conjugated with taurine) is a reliable test to confirm diagnosis of bile salt malabsorption.

Question 48

What are the endoscopic features of radiation proctitis?

Answer 48

Endoscopic:

• Friability of the mucosa with contact bleeding
• Pallor, telangectasia
• Loss of rectal distensibility

Question 49

What medical management options exist for radiation proctitis?

Answer 49

• Sucralfate enemas
• Topical formalin
• Hyperbaric oxygen

Question 50

What is Sucralfate? How is it used in radiation proctitis?

Answer 50

Sucralfate is a sulphonated polysaccharide which adheres and forms a protective layer over the rectal mucosa. It also stimulates prostaglandin synthesis, which increases local blood flow as well as the production of epidermal growth factor.

An effective treatment for 70 - 95% of patients.

Dose: 2mg of sucralfate in 20ml of water administered as enema twice daily for 4-6weeks

Question 51

How is topical formalin used in the treatment of radiation proctitis?

Answer 51

Formalin is known to sclerose fragile blood vessels in radiation-damaged tissues. Application directly to the mucosa produces local chemical cauterization, sealing the neovascularised telangiectatic spots and thus reduce bleeding. No standardised method of application.

Options (in the office or under sedation in endoscopy suite)

Typically direct application with formalin soaked gauze onto rectal mucosa, however others have described irrigation enema’s

At Charlie’s they place a sponge soaked with 4% formalin at each quadrant of the rectum via protoscopy for a contact time of 2mins/quadrant

Treatment can be repeated. It is important to avoid applying formalin to perianal skin because it is caustic. Can protect skin with jelonet dressing or flush out residual formalin with saline at the end of procedure

Single centre studies report symptom improvement in 25-90% of patients though high quality prospective controlled evidence is lacking.

Question 52

How is hyperbaric oxygen used to treat radiation procititis/enteritis?

Answer 52

Believed to promote wound healing by improving tissue oxygenation and angiogenesis. Shown to stimulate vascular endothelial cells and induce connective tissue elements to support regrowth of capillaries and epithelium

Has been shown to be effective in improving symptoms in 33-50% of patients. However its use is limited due to the fact that it requires several sessions over 6- 8 weeks, it is expensive and it is not widely available.

Question 53

Describe the endoscopic management options for radiation proctitis.

Answer 53

Argon plasma coagulation (APC) is the mainstay of endoscopic treatment:

• Uses inert argon gas as a conducting medium while a bipolar diathermy current is delivered.
• Limited depth of coagulation (0.5-3mm)
• Common setting: 1-2L/min argon flow, power of 40-60 watts with pulses of 1-2 seconds
• Uniform and predictable application can be performed under colonoscopic visualization
• Successful in 80-90% of patients
• More diffuse lesions may require repeated applications

Other methods include Laser therapy and RFA but these have largely been supplanted by APC which is less expensive, safer and more widely available.

1-3% risk of complications including perforation, bleeding and fistula formation.

Contact methods (bipolar, heater probe)

• Delivers therapy directly to the site of mucosal abnormality.
• Effective in 57% of patients.
• Disadvantages include transmural thermal injury as well as char formation on the tip of probe necessitating frequent cleaning.

Question 54

What is the role for surgery in the management of radiation proctitis?

Answer 54

Surgery is rarely required due to effectiveness of medical and endoscopic treatment.

It is largely reserved for patients with refractory symptoms and in patients with treatment related complications such as perforation, fistula or stricture formation.

If surgery is required, diversion is more commonly performed than a resection due to the hazardous nature of surgery in the irradiated pelvis. Diversion can resolve symptoms of pain, tenesmus, incontinence and obstruction. However in patients with severe bleeding proctectomy is best option as a defunctioning stoma rarely controls the bleeding.

Question 55

What is Small Intestinal Bowel Overgrowth?

What are the causes SIBO?

How can it be treated?

Answer 55

SIBO is a very heterogeneous syndrome characterised by an increased number and/or abnormal type of bacteria in the small bowel.

Quantitatively, this is defined as the finding of ≥ 10⁵ CFU/mL of jejunal aspirate (normal is < 10⁴ CFU/mL).

Clinical manifestations include bloating, increased flatulence, diarrhoea, and pain.

Small intestinal bacterial overgrowth (SIBO) can be caused:

1. Abnormal biomic activity
2. Altered anatomy
3. Motility disorders.

Treatment

• Antibiotics reduce bacterial overload and reverse the mucosal inflammation associated with overgrowth.
  
  • Amoxicillin/clavulanic acid or rifaximin are typically used
• Nutritional support
• Correct micronutrient deficiency
  
  • Vitamin B12, fat soluble vitamins, iron, thiamine
• Correct underlying cause if possible (eg. stricture)

Interventions (with unclear role)

• Prokinetics - anecdotal evidence of symptomatic improvement
• Probiotics – meta-analysis reported reduction in breath hydrogen concentration and abdominal pain but no improvement in diarrhoea.

Question 56

What are the indications for surgery with regard to the gastrointestinal complications of radiotherapy?

Answer 56

Indications for Surgery

• Obstruction

Typically secondary to stricture formation.

Surgery indicated when patients fail conservative management.

• Enteric fistula

1st line treatment would be non operative management following SNAP principles.

Surgery required if they fail conservative therapy.

• Perforation

Intestinal perforation can occur in the acute or chronic setting.

• Bleeding

Radiation induced damage to intestinal mucosa causes ulceration and bleeding.

Surgery is rarely required but may be needed in instances of catastrophic or refractory bleeding. Accurate localisation of bleeding source is important prior to surgery.

• Neoplasm

Radiotherapy can result in secondary malignancies within fields of irradiation 10-20yrs after treatment.

Question 57

Discuss preventative measures with regard to radiotherapy-associated toxicity.

Answer 57

The only proven measures are to alter the field of radiotherapy, i.e. make it more precise, and protect adjacent organs (belly-boards, bladder distension) and to alter the mechanism of delivery to make it more precise (multiple field arrangements, conformational delivery, intensity modulated therapy).

Dietary/nutritional and pharmacological measures do not exist outside animal models and research.

Question 58

Provide an overview of the complications of radiotherapy according to body system affected.

Answer 58

Question 59

Provide an overview of anal canal toxicity due to radiotherapy.

Answer 59

Acute

Acute anal toxicity is often self limiting and includes a mild perianal skin reaction, to desquamation and erythema. With worsening desquamation, pain can arise, and if the lower rectum is affected, tenesmus, bleeding and urgency can occur.

Management is supportive, and includes skin care, dietary modifications for incontinence, analgesia and corticosteroid suppositories.

Late

Late toxicity can appear months to years later. The most common complication is anorectal ulceration, however stricturing and fistulae can occur. Biopsy is often required to confirm the diagnosis and rule out other aetiology including SCC and Crohn’s disease.

There is little data to guide practice in severe or refractory anal ulceration, however hyperbaric oxygen and oral vitamin-A may play a role.

Sphincter dilation is standard treatment for anal stenosis. Colostomy is rarely required.

Question 60

Describe the Paris Classification of colonic polyps

Answer 60

The clinical implications of the classification mainly involve the assessment of endoscopic resectability. Lesions that clearly protrude into the lumen (type I) and those that grow predominantly at the level of the surrounding mucosa (type II) are usually amenable to endoscopic resection.

Question 61

Describe the macroscopic/endoscopic features of a polyp that confer risk of maligancy.

Answer 61

1. Polyp size
   
   • The bigger a polyp the higher the risk of invasive disease. A study by Nusko et al of nearly 12,000 polyps found that the risk of malignancy in polyps < 5mm was negligible but that risk rose to 42.7% for polyps greater than 25mm.
2. Polyp Site
   
   • Not consistently associated with malignancy but size for size, rectal polyps up to 36mm are higher risk, and above 36mm right sided polyps are worst.
3. Polyp Morphology
   
   • Irregularity, ulceration, depression, and hardness confer risk. Attempts have been made to categorise morphology using the Paris and Kudo Pit Classifications.

Question 62

Describe the Kudo-Pit Patterns and their importance.

Answer 62

Kudo, using chromoendoscopy and magnification, described the pit patterns of polyps to identify normal from neoplastic polyps.

The Kudo Classification identifies seven pit patterns which are predictive of the polyp containing invasive disease (increasing liklihood with increasing grade).

Question 63

Describe the NICE Narrow-Band-Imaging classification of polyps.

Answer 63

Type 1 - characteristic of hyperplastic polyps

• Colour - lighter or similar in colour to surroundings
• Vessels - small vessels or sparse network
• Surface - circular pattern with small dots

Type 2 - characteristic of adenomata

• Colour - darker (browner) than the surroundings
• Vessels - lighter centre surrounded by thicker brown vessels
• Surface - oval, tubular, gyrate

Type 3 - characteristic of malignancy

• Color: darker than surroundings, brownish, occ. lighter patches
• Vessels: areas with interrupted or absent vessels
• Surface: amorphous or no surface pattern

Question 64

What is the utility of MRI and USS in the assessment of rectal lesions?

Answer 64

With high resolution MRI, it is now possible to obtainimages that show the mucosa, submucosa, and muscularis propria. Recent studies have shown up to 89% concordance between hr-MRI and histopatholgical findings. MRI is also useful, but not definitive, in assessing nodal status and LVI/EMVI.

TRUS is less commonly used now that hr-MRI exists. TRUS has an accuracy of ~70% for T1-T4 lesions, with higher accuracy in T0 and T1 lesions.

Question 65

(Polyp Histopathology)

Provide detail on the degree of risk conferred by:

Depth of invasion

Resection margin

LVI

Tumour grade

Tumour budding

A combination of these things.

Answer 65

Depth of invasion

• Haggit_1-3 = <1%, Haggit₄ = 25%
• SM₁ and SM₂ = <10% nodal mets
• SM₃ = 25-30% nodal mets

Resection margin

• ~30% recurrence rate overall if margin positive

LVI

• Relative risk of 4.4 for nodal disease

Tumour grade

• Beaton’s meta-analysis found 46.8% of poorly-differentiated malignant polyps had positive lymph nodes.

Tumour budding

• Confers a 5-fold risk of nodal disease.

A combination of these things creates a compounding effect; i.e. 1 RF ~0.7% versus 3 RF 30%.

Question 66

What is the incidence of peritoneal metastases in CRC?

Synchronous and metachronous?

(CRPM)

Answer 66

Synchronous CRPM are seen in 3-14%.

Metachronous CRPM is seen in up to 19% of patient with CRC.

Question 67

What are the reasons why peritoneal metastases are thought to be more resistant to systemic chemotherapy?

Answer 67

1. Poor vascularisation of the peritoneal cavity
2. Altered tumour microenvironment in the peritoneal space
3. Poor penetration of drugs into the peritoneum

Question 68

What is the outlook for patients diagnosed with CRPM, who can undergo surgery, in terms of median survival and 5-year-survival?

Answer 68

In selected patients with isolated colorectal peritoneal metastases a favourable 30-58 months median survival, with a 27-46% five-year survival can be achieved with CRS and HIPEC.

i.e.

• 3-5 years median survival
• 25-50% chance of being alive at 5 years.

Local Australian series have also similarly demonstrated favorable median survival of 32-35 months in selected patients with CRPM undergoing CRS and HIPEC.

Narasimhan V, Britto M, Pham T, Warrier S, Naik A, Lynch AC, et al. Evolution of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: 8-Year Single-Institutional Experience. Dis Colon Rectum. 2019;62(10):1195-203.

Question 69

What is the rationale for HIPEC?

Answer 69

1. Intraperitoneal delivery increases local delivery of cytotoxic chemotherapy to the poorly vascularised peritoneum
2. The increased molecular size and limited absorption reduces systemic absorbtion and therefore systemic toxicity
3. Thirdly, the synergistic effect of heat is directly cytotoxic, and improves chemotherapy penetration into tissues.

Question 70

Provide an overview of HIPEC delivery.

Is there any evidence for method of delivery?

Answer 70

• Firstly, a recent systematic review reported that over 60 different HIPEC regimens around the world were used in the treatment of CRPM!
• There is no prospective evidence for open, closed, or lap.
• Oxaliplatin or Mitomycin-C HIPEC are delivered at 41-43°C usually after CRS but prior to formation of anastomoses.
• This can be in an open (coliseum) or closed (lap or temporised closure) fashion.
• Duration of Oxaliplatin is 30 minutes. Mitomycin-C in 90 minutes.
• Both HIPEC delivery techniques are generally performed in a ‘bidirectional’ manner. This involves combining HIPEC with intravenous chemotherapy (usually 5-FU).

Question 71

What are the advantages and disadvantages of open versus closed HIPEC delivery?

Answer 71

Open:

• Pros - The abdominal contents can be visualised and manually stirred to ensure homogenous distribution.
• Cons - Heat dissipation, spillage, splash of cytotoxic agents or aerosolisation of cytotoxic particles.

Closed:

• Pros - Prevents heat loss and minimises spillage of cytotoxic material in the operating theatre setting. The increased pressure within the closed compartment is thought to contribute to increased penetration of chemotherapy into tissues.
• Cons - Limits visualisation of the abdominal contents and can lead to pooling of chemotherapy agents in certain areas in the peritoneal cavity.

Question 72

What is the Peritoneal Carcinomatosis Index?

How is it calculated?

What is the utility?

Answer 72

In 1996, Sugarbaker and colleagues described the PCI to quantify peritoneal disease burden and determine patients who would benefit from CRS.

The PCI is the sum of scores from nine abdominopelvic regions and four small intestinal regions.

Each region is assigned a score between 0–3 based on the largest tumor size, with a maximum score of 39. Regions are assigned scores as follows:

• 0 = no tumor deposit
• 1 = largest tumor measures <0.5 cm
• 2 = largest tumor measures 0.5 to <5.0 cm
• 3 = largest tumor ≥ 5.0 cm or confluence of disease.

Although originally developed for intraoperative staging, with the drastic improvement and decreased costs of modern imaging techniques, PCI scores calculated with preoperative imaging have since been shown to be comparable to surgical PCI scores

The PCI score is now accepted as an independent risk factor for morbidity and mortality for patients undergoing CRS/HIPEC for appendiceal and colorectal malignancies. In general, lower PCI scores confer more favorable outcomes. For example, worse outcomes have been observed with CRS/HIPEC in patients with PCI >19 for appendiceal and CRC.

Question 73

How is completeness of cytoreductive surgery categorised?

What is the utility in this?

Answer 73

In 1994, Sugarbaker described the completeness of cytoreduction (CC) score to quantify residual disease after CRS:

• CC-0 = No residual disease
• CC-1 = <2.5mm of residual disease
• CC-2 = 2.5mm - 2.5cm of residual disease
• CC-3 = >2.5cm of disease left behind

Complete cytoreduction is associated with improved survival.

The American Joint Committee on Cancer staging manual provides an alternative cytoreduction completion scoring system to the CC score.

• R0 = Negative microscopic disease
• R1 = Positive microscopic disease
• R2a = Residual tumours <0.5cm
• R2b = Residual tumours 0.5cm to 2.0cm
• R2c = Residual tumours >2.0cm

Similar to the CC score, R0 and R1 resections are associated with improved survival in peritoneal carcinomatosis.

Question 74

What is the safety profile of HIPEC?

Who should be doing HIPEC?

Answer 74

Once considered a highly risky procedure with mortality ranging from 0–17% and morbidity up to 60%, CRS/HIPEC has been shown to be safe, with a similar or better risk profile compared to other major cancer operations when appropriate patients are selected.

In fact, over the last two decades, CRS/HIPEC-related mortality now averages 0–4%, with most high-volume centers reporting 0–1%.

As with other large oncologic surgeries, the quality of life for patients immediately following CRS/HIPEC decreases. However, 3–6 months after surgery, patients show improved quality of life and survival benefits.

In 2016, the NCCN modified its recommendations for CRC with peritoneal disease from HIPEC only in the setting of clinical trials to recommending HIPEC when performed at experienced centers.

The learning curve is between 90-220 cases.

Question 75

What is the role of HIPEC in the adjuvant setting?

Which trial assessed this?

Answer 75

There is no strong evidence that HIPEC for CRPM found after initial surgery provides any survival benefit.

The French ProphyloChip trial assessed this by randomising 150 patients with RF for CRPM (perforated primary, synchronous resected PM or ovarian mets) to surveillance or Dx Lap with CRS + HIPEC at 6 months.

There was no difference in DFS but a 41% rate of CD grade 3-4 complications!

Question 76

What are the current controversies/topical issues in the field of pelvic exenteration?

Answer 76

• The Limitations of Resectability
• The Use of Irradiation in the Pre-irradiated Pelvis
• Quality of Life following Exenteration
• Palliative Exenteration
• Exenteration in the Setting of Metastatic Disease

Question 77

Describe the relative contra-indications to curative exenteration surgery?

Answer 77

• Involvement of the sacrum above the level of S3
• Involvement of the lateral pelvic sidewall
• Extension through the greater sciatic notch
• Encasement of the iliac vessels

These “contra-indications” have been tested in high volume centres, with a number of these tumours resected with curative intent, with acceptable morbidity and mortality.

Question 78

In high-volume centres, what is the 5-year-survival offered by an R0 resection with pelvic exenteration?

Answer 78

50%

Question 79

Describe the risks and rationale associated with high sacrectomy in pelvic exenteration.

Answer 79

Despite higher rates of morbidity, particulalry with regard to blood loss and nerve damage, high sacral involvement should not be a contraindication to exenterative surgery.

Complete pathological excision at all margins leads to 55% disease-free survival (DFS) and 70% overall survival at ~3 years.

Without an attempt at surgical resection the average life expectancy for these patients is around seven months, with significant suffering.

Question 80

What are the main considerations in exenteration surgery when the lateral/vascular compartment is involved?

Answer 80

• Taking the internals is usually ok as the associated pelvic organ are also being excised
• Taking the common iliacs requires pre-operative vascular reconstruction, assuming there are no pre-existing collaterals
• Vascular reconstruction is made complex by the fact that native vessels are often unsuitable; the GSV is too small and using the superficial femoral leaves the leg reliant on venous drainage from profunda. Grafts are at risk of infection, and have higher thrombosis rates. This can be alleviated by instilling an arterial feeder to reduce the rate of venous thrombosis.
• Case-series publishing vascular reconstructions show an 82% complication rate, with 50% attributable to vascular issues. The rate of R0 resections is also lower than non-vascular cases (40% vs 80%).

Question 81

In patients with rectal cancer recurrence, what proportion recur with isolated local disease?

Is re-resection appropriate? What are the outcomes?

Compare this with primary exenteration surgery.

Answer 81

10%

In those who require exenteration for pelvic recurrence of rectal cancer, outcomes are generally poor compared to primary exenteration with R0 rates of 30-60% and 5-year-survival of ~30%.

cf index exenteration where R0 rates are generally 80-90% with 5-year-survival of ~50%

Question 82

Why is re-irradation feasible in exenteration surgery?

How can toxicity be reduced?

What are the suggested regimens with regard to dose and time since surgery?

Answer 82

• Toxicity from irradiation is calculated from continuous dosing, and studies suggest that significant healing can occur between treatments.
• Hyper-fractionated dosing (multiple fractions involving smaller doses) has been shown to reduce toxicity.
• Overall, re-irradiation has an acceptable toxicity profile and suggested regimes are 30-40Gy for tumours recurring in 12-24 months, 40-50Gy for recurrences between 24 and 36 months, and up to 55Gy for late recurrences, after 36 months.

Question 83

What are the side effects of re-irradiation and why might these be acceptable?

Answer 83

Re-irradiation may result in strictures, fistulas and haemorrhage and may occur in up to 30% of patients undergoing treatment. Obstruction and fistulas are the most common late toxicities (5-15% and 4-10% respectively).

However, local recurrences are also associated with both obstruction and fistulation (including through tumour destruction) which may balance out the risks associated with irradiation.

Question 84

Describe the effect of exenteration on quality of life.

What are the predictors of poor QoL after exenteration?

Answer 84

One of the largest prospective studies to report on QoL in exenteration found patients undergoing surgery had an initial decline in QoL in the first 3 months, returning to baseline at 3-6 months.

The QoL of those who did not undergo surgery gradually deteriorated as their disease progressed such that, at about 6-9 months, the QoL was less than those who underwent surgery, and this palliative group continued to have a sustained fall in QoL until death.

Predictors of poor postoperative QoL are:

• Poor preoperative QoL
• Female sex
• Need for a bony resection
• R1 or R2 resections.

Question 85

What is the role for exenteration in patients with metastases?

Answer 85

It seems reasonable for physically robust patients with limited disease that does not progress during treatment to consider staged resection.

Whether patients should receive chemotherapy first (as a ‘trial of biology’), pelvic resection then chemotherapy/metastectomy, or a liver first approach is unclear.

It must be understood that it is unlikely that patients will be fit to complete adjuvant chemotherapy following exenteration, and this could be an argument for upfront total neoadjuvant therapy.

Question 86

What is the role of exenteration is palliative pelvic cancers?

Answer 86

Because of high mortality and high morbidity, as well as cost, patient who have exensive metastatic disease or where an R0 resection is considered unlikely, alternatives for symptom control should be offered (such as chemoradiotherapy and gastrointestinal and/or urinary diversion).

Unfortunately, locally advanced pelvic malignancies have a propensity to progress and fistulate, with disabling symptoms of severe pain, bleeding, discharge and recurrent sepsis. As other treatment options are limited, palliative exenteration has been considered in select cases.

Question 87

Provide an overview of Pre-Sacral Tumour aetiology.

Provide examples of tumours from each category.

Answer 87

Tumours of the pre-sacral space may arise from any of the embryological constituents of this space, namely the hingut (endoderm), the neuroectoderm, and the bony margins and fibrofatty tissue (mesoderm).

• Hindgut / endoderm
  
  • Tailgut cyst (most common benign)
  • Rectal duplication cyst
• Mesoderm
  
  • Lipoma, angioma, leiomyoma etc.
  • Osseous tumours e.g. Ewing’s
• Ectoderm
  
  • Neurofibroma, ganglioneuroma, neuroblastoma

*Teratoma - all three germ layers.

Question 88

Discuss the consequences of pelvic nerve injury.

What is the consequence of unilateral nerve root injury during a Kraske procedure?

Answer 88

Iatrogenic injury to the nerves in the pre-sacral space, particularly the superior hypogastric plexus, can lead to a variety of pelvic organ dysfunctions including detrusor areflexia and urinary retention.

Severe injury, affecting the lumbar plexus and below, can result in loss of perineal sensation, loss of voluntary control of urethral and anal sphincter activity, and an acontractile detrusor muscle.

Anorectal function can be maintained if all unilateral nerve roots are sacrificed, or if the upper three sacral nerve roots are left intact bilaterally. However, if the S3 nerve roots are sacrificed bilaterally, the external sphincter will not contract during dilation of the rectum leading to various degrees of incontinence.

Question 89

Contextualise the argument for colonic stenting in terms of morbidity and mortality associated with emergency surgery in LBO.

Answer 89

Emergency surgery for LBO has a morbidity of ~40-50% and a mortality of 15-20%.

Question 90

What is the technical success rate in stent placement?

What is the clinical success rate?

Answer 90

Technical success in 90-98%

Clinical success in 85-90%

Question 91

What is the ESGE’s preference for palliative intervention in obstructing colon cancer?

Why? What specific parameters/outcomes are improved?

Answer 91

Five systematic reviews and/or meta-analyses have compared colonic stenting to palliative surgery, and based on their results the European Society of Gastrointestinal Endoscopy (ESGE) in their 2020 guidelines strongly recommend stenting as the preferred treatment for palliation of malignant large bowel obstruction.

Placement of a colonic stent has been shown to be significantly associated with:

• Shorter hospital admission
• Reduced ICU admission rate
• Shorter time to induction of chemotherapy

Conflicting results have been reported regarding short term mortality, with a reduced 30-day mortality in two meta-analyses and no significant difference observed in other studies.

Question 92

What is the median colonic stent patency in the palliative setting?

Answer 92

Median stent patency in the palliative setting ranges from 3 to 12 months, with a median of 106 days

Approximately 50% of stents remained patent at 12 months.

Question 93

What is the argument for colonic stenting as a bridge to surgery?

Answer 93

• Achieve decompression
• Correction of fluid and electrolyte disturbance
• Tumour staging
• Patient optimisation
• Elective versus emergency surgery
• Lower overall stoma formation rate

Question 94

What is the role of colonic stenting in extra-colonic malignancies?

Answer 94

Although technical and clincal success rates are lower in extra-colonic obstruction, particularly in peritoneal disease, compared with emergency surgery for the same cohort, colonic stenting has significantly lower short-term complications.

Question 95

What is the role of stenting in rectal tumours?

Answer 95

A tumour lower than 5cm is a relative contra-indication for stenting due to higher rates of stent migration and symptoms of tenesmus, pain, and incontinence.

Technical and clinical success rates are lower, but rectal stents may be used in patients unfit for surgery or who have a limited life-exepectancy.

Question 96

Describe the set-up and equipment for colonic stenting

Answer 96

Set-up:

• GA (long procedure, high risk of AP, minimises movement)
• Fluoro with water-soluble contrast eg Gastrograffin
• Colonoscopy with TTS stent

Equipment:

• Boston Scientific 450cm Jagwire
• Boston Scientific Wallflex Colonic Stent (6, 9, 12cm lengths)

Question 97

What do the markers on the Boston Scientific Wallflex colonic stent indicate?

How should these stent be placed?

Answer 97

This stent has 3 radio-opaque markers for reference:

• The first marker indicates the proximal extent of the stent
• The second, which is approximately 2/3 of the way along the stent, indicates the “point of no return” where the stent cannot be re-sheathed and adjusted
• The final marker indicates the distal end of the stent.

The stent should be deployed with at least 2cm exposed distal and proximal to the obstructing lesion. Ideal stent placement has a “waist” in the stent region traversing the tumour with a flare of the proximal and distal ends of the stent. Once the position is confirmed, the stent is deployed under continuous fluoroscopic guidance with endoscopic visualisation of the distal portion of the stent.

Question 98

What proportion of “pre-sacral masses” are congenital?

What proportion are benign?

What is the gender and age distribution?

Answer 98

A comprehensive literature review undertaken in 2016 identified 1708 patients from the literature.

• 60% of pre-sacral masses are congenital
• 70% pf pre-sacral masses are benign
• ~70% were female
• Mean age was 44.6

Question 99

Describe your work-up of a pre-sacral mass.

Answer 99

• MRI and PET scan and discussion at colorectal MDT:
  
  • If the lesion is cystic and asymptomatic and benign on MRI and PET scan then a surveillance strategy is offered to the patient.
  • If the PST is solid, then a biopsy is recommended.
    
    • For small lesions this may be an excisional biopsy.
    • For larger lesions a para-sacral or para-coccygeal biopsy is required.
  • MDT review of imaging and biopsy results

Question 100

Up to 50% of Pre-Sacral Tumours are asymptomatic.

What clinical features may be present and are there any features that help distinguish aetiology of a PST?

Answer 100

• Non-specific symptoms related to pre-sacral tumours
  
  • Pelvic pain (more common with malignancy)
  • Pressure
  • Change in bowel habit
  • Sexual dysfunction
• Hindgut derivatives
  
  • PR bleeding
  • Tenesmus
  • Pressure
• Osseous derivatives
  
  • Lower back pain
• Neuroectodermal derivatives
  
  • Pits or sinuses / post-anal dimple
  • Discharging sinus
  • Lower limb neurology

Question 101

What are the radiological signs of malignancy on MRI of pre-sacral tumours?

Answer 101

• Size (larger more likely malignant)
• Heterogeneous lesion
• Solid nature
• Irregular borders
• Located above the S3 vertebra
• T-1 hyposignal
• T-2 hypersignal
• Enhancement after gadolinium injection
• Invasion of neighbouring organs
• Destruction or remodelling of the sacrum

Question 102

Describe the role of biopsy in Pre-Sacral Tumours.

How can fistulae and malignant seeding be avoided?

Which lesions should not be biopsied?

Answer 102

Biopsy has become more useful in the evaluation of PSTs although there is a high diagnostic error rate of up to 44%/.

• Associated risk of fistula is avoided by excluding transanal, transvaginal, transperitoneal and transretroperitoneal routes.
• Minimise malignant seeding by using co-axial biopy, experienced radiogists, and a route that will be excised (para-coccygeal route).
• Pre-operative assessment with MRI can avoid fatal meningitis associated with biopsy of a meningiocoele.
• Pre-operative biopsy should be avoided in cystic lesions as infection and subsequent fibrosis can transform a relatively simple excision of a benign cyst into a difficult operation.

Question 103

What neoadjuvant strategies can be employed for Pre-Sacral Tumours?

Answer 103

• Neoadjuvant chemotherapy
  
  • Imatinib for advanced chordomas
  • Gefitinib and Cetuximab for metatstatic chordomas
  • NAC for Ewing’s sarcoma and osteogenic sarcoma
  • TACE for selected chordomas to reduce blood loss
• Neoadjuvant radiotherapy
  
  • Most PSTs are radio-resistant

Question 104

Describe your surveillance strategy for patients at risk of AIN/Anal SCC.

Answer 104

High risk populations for screening include:

• MSM
• HPV positive patients
• Previous vulval or cervical neoplasia
• Solid organ transplant recipients

Anal pap smear in these groups;

• If positive - HRA at expert centre
• If negative - repeat
  
  • In one year if HIV+
  • In two-three years if HIV-

Question 105

What should you do with HSIL?

Answer 105

Treat it, based on the ANCHOR trial of 2022.

Any form of treatment including surgical excision, ablation, or topical therapy with Imiquimod or topical 5-FU, results in a 60% risk reduction of progression to anal cancer.

Question 106

What should you do with LSIL?

Answer 106

Depends on HIV status:

• HIV positive - repeat HRA/EUA in one year
• HIV negative - return to GP for annual DRE or re-referral with new symptoms.

Question 107

Describe how High Resolution Anoscopy is performed.

Answer 107

1. An anoscope is placed into the anus with lidocaine lubrication
2. A swab soaked in 3-5% acetic acid solution is inserted into the anal canal while the anoscope is removed for several minutes.
3. After acetic acid application, which causes an “acetowhite change” in areas of abnormal transitional epithelium, the mucosa is carefully inspected for changes characteristic of AIN, including flat or slightly raised areas of thickened mucosa with or without vascular pattern abnormalities.
4. Lugol’s iodine is then applied in similar fashion, but in this case concerning lesions fail to stain with iodine (“Lugol’s negative”) because iodine is glycophillic and dysplastic tissues lack glycogen and appear a mustard colour.
5. Biopsies are taken of suspicious lesions, including condylomas, atypical surface configurations, punctuations, mosaicism, atypical vessels, or areas with colour changes seen on acetic acid staining that are subsequently found to be Lugol’s negative.

Question 108

What is the evidence for High Resolution Anoscopy?

How would you incorporate this into practice?

Answer 108

HRA is a user-dependant technique requiring significant time and effort, without high-quality evidence showing superiority to EUA and proctoscopy with regard to 5-year anal cancer progression rate.

Without formal training in HRA, it seems reasonable to screen high risk populations, and if cytology is positive, refer these patients to a centre with access to surgeons who perform this procedure.

If this is not availabe, then examination under anaesthesia with proctoscopy is a safe alternative as there is evidence showing a similar rate of progression to cancer with either technique.

*Note: HRA has superior sensitivity for detection of HSIL compared to Anal Pap Smear, but is much more expensive and resource-intense.

Question 109

Describe the types and efficacy of topical and ablative therapies for LSIL and HSIL

Answer 109

Topical:

1. Trichloroacetic acid - chemoablation
2. Imiquimod - topical TLR agonist/potentiator of cytokines
3. 5-FU - topical fluoropyrimidine

• Overall, topical therapies have a 40-70% response rate and are generally safe.

Ablative:

1. Electrocautery
   
   • highest resolution rate in HIV- patients (~80-100%)
2. Infra-red coagulation
3. Photodynamic therapy

• Ablative therapies are generally less well tolerated compared to topical therapies but appear to yield higher rates of response, though the literature is heterogenous; 10-70%!

Side effects include bleeding, pain, anal irritation

Question 110

Describe your work-up of anal SCC.

How does PET-CT affect management?

Answer 110

• EUA - particular attention to size and relationship to sphincter
• High quality pelvic MRI
• Endo-anal USS for small lesions (more sensitive than MRI)
• CT CAP for metastatic disease
• USS-guided FNA for clinically palpable lymph nodes
• PET-CT
  
  • Alters tumour volumes in ~40% of cases which changes radiation planning / radiation fields.
• Sentinel lymph node biopsy
  
  • Upstages 30% of patients with radiologically node negative disease but not routine.

Question 111

What factors are associated with a complete clinical repsonse in TNT?

Answer 111

• Younger age
• Normal CEA
• Clinical negative node status
• Smaller tumours
• p53 wild-type
• SMAD-4 tumours

i.e younger people with less aggressive tumours.

Question 112

In 2021, Kong et al (including Herriot) produced a meta-analysis of 15 comparative studies of ~5000 patients undergoing TNT or NACRT.

What were the findings?

Answer 112

• Better OS
• Better DFS
• Better pCR
• Fewer APRs
• Fewer R1 resections
• Less distant recurrence
• Better N-downstaging

Question 113

What is the rationale behind fractioned radiotherapy treatment?

Answer 113

Splitting the total radiation dose over multiple daily treatments (fractionation) is used because the DNA damage occuring in normal cells is repaired between treatments; meanwhile, the damage to cancer cells accumulates over time, causing preferential cancer cell death.

It is premised on the fact that cancer cells are more often in the midst of a reproductive cell cycle, and that their machinery for DNA repair is less robust than a normal cell.

Question 114

What is the estimated rate of secondary malignancy attributable to radiation therapy?

Answer 114

Studies suggest that 1 in 70 patients who survive 10 or more years following their primary malignancy will develop one of these secondary malignancies

Question 115

What is the frequency of ED in men treated with radiotherapy?

What is the mechanism?

What are the treatment options?

Answer 115

ED is predicted to affect one half of men treated with RadRx, though the true proportion is likely to be higher.

The mechanism is thought to be due to damage to the smooth muscles content, fibrotic changes to blood vessels, and neuronal damage.

Treatments include:

• PDE5-inhibitors (i.e. sildenafil)
• Vacuum devices
• Penile injections, penile prostheses
• Natural supplements

Question 116

What is the effect of radiotherapy on fertility and fecundity?

How can this be mitigated?

Answer 116

• The amount of radiation exposure to the ovaries determines whether infertility occurs as some or all of the eggs can be damaged.
• Severe damage may result in early menopause.
• Women who have radiotherapy to the uterus and conceive are higher risk of miscarriage, low birth weight infants and premature deliveries.
• Prevention of ovarian damage can be done using gonadal shielding, this method employs a lead shield to reduce the dose of radiation to the ovary
• Embryo cryopreservation or donor oocytes and gestational surrogacy are other methods of achieving fertility.

Question 117

What is the 5-year survival for patient with Colorectal Cancer and Liver Metastases (CRCLM)?

Overall versus resectable versus palliative?

What proportion of patients present with synchronous liver metastases?

Answer 117

• The 5 year OS of all patients with CRCLM is 25%
• This increases to 48.6% in patients who undergo resection of their disease
• But it drops to 2.2% in patients who receive palliative chemotherapy

Up to 15% of patients will present with liver mets.

Question 118

Describe the framework of management for patients diagnosed with colorectal cancer and potentially resectable metastatic disease.

Answer 118

After a clinical review of the patient, present at and MDT with a view to assess the following:

1. The patients fitness for treatment
2. The burden and resectability of liver disease:
   
   • Resectable
   • Borderline resectable
   • Unresectable
3. Sequence of events
   
   • Neoadjuvant treatment?
   • Colon first
   • Liver first
   • Synchronous resection

Question 119

What is the sensitivity and specificity of CEA in detecting recurrent colorectal cancer?

Answer 119

Sensitivity = 54%

Specificity = 66-75%

Question 120

What are the characteristics of colorectal hepatic metastases on MRI?

How does CT compare with MRI in terms of sensitivity with regard to CRCLM?

What hepatocyte-specific contrast agents can be used to improve assess lesions?

Answer 120

CRCLM are typically hypointense on T1 weighted pre-contrast images and hyperintense on T2.

Hepatocyte specific contrast agents, such as gadoxetate disodium (primovist), have become the contrast agent of choice. These agents are preferentially taken up by hepatocytes and excreted into the biliary tree. In the delayed HPB phase (10-20min after administration), metastatic lesions do not retain primovist and appear hypointense relative to the surrounding liver parenchyma.

Contrast enhanced MRI has become the gold standard radiological investigation for CRCLM. This is due to the fact that contrast enhanced MRI is more sensitive (95%) than conventional MRI or CT (87% and 85% respectively).

Question 121

What are the methods of assessing future liver remnant?

How much FLR is required?

Answer 121

Assessment of both the volumetric and dynamic future remant is important when planning liver resection for CRCLM.

• Volumetric:
  
  • CT with volumetric analysis software
• Dynamic:
  
  • Indocyanine Green
    
    • ICG is excreted in the bile without conjugation
    • Assumes homogenous liver function
  • HPB Scintigraphy
    
    • Qualitative hepatic processing of a RL nucleotide
    • More valuable in predicting failure of liver remnant.

It is generally recommended that you require:

• 20% FLR in a patient with normal hepatic parenchyma
• 30% FLR in those with chemotherapy induced liver injury
• 40% FLR in those with cirrhosis

Question 122

What techniques may be employed in patients with colorectal liver metastases to improve their chances of hepatic metastasectomy?

Answer 122

• Neoadjuvant chemotherapy to downsize tumours
• Portal vein embolization (PVE)
• Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)
• Use of locoregional ablation technology

*ALPPS is a two stage procedure; in stage one the liver is surgically divided to the level of the biliary plate, leaving about 10% of the bridging tissue intact. The contralteral PV branch is divided channeling the PV flow into the FLR. After ~9 days, in which the FLR can grow by ~30%, the second stage is performed removing the diseased liver with a FLR.

Question 123

What are the contra-indications for resection in patients with CRCLM?

Answer 123

The contraindications to surgery for CRCLM can be classified as either technical or oncological:

• Technical
  
  • Absolute
    
    • Unable to achieve an R0 resection with >20% FLR for normal liver
    • Presence of unresectable extrahepatic disease
  • Relative
    
    • R0 resection possible only with staged or adjunctive procedures
    • R1 resection
• Oncological
  
  • Concomitant extrahepatic disease that is unresectable
  • Tumour progression despite systemic therapy

Question 124

Describe your approach to sequencing of colorectal and hepatic surgery, and chemotherapy with regard to patients with colorectal cancer and liver metastases.

Answer 124

Patients with resectable CRCLM and asymptomatic CRC

• Chemotherapy should be given preoperatively, unless surgery of the primary and liver metastases is considered easy
• When both the primary tumour and CRLCM are resectable, simultaneous resection can be performed in selected patients undergoing limited hepatectomy.
• Synchronous resection should not be performed in high risk patients, when the hepatectomy would be major (involving 3 or more segments) or when complex rectal surgery is required.

Patients with non-resectable CLRCM and asymptomatic CRC

• Chemotherapy should be administered initially with the aim of achieving conversion to resectable disease
• If CRCLM become resectable, a liver first strategy should be advocated

Patients with resectable CRLCM and symptomatic CRC

• Resection of the primary should be performed first

Patients with non-resectable CRCLM and symptomatic CRC

• Resection of primary first followed by chemotherapy with aim of achieving resectability of CRCLM

Question 125

Describe the utility of Portal Vein Embolisation in the treatment of CRCLM.

What is the improvement in FLR?

What is the complication rate?

What proportion of patients undergoing PVE will be cancelled on the day of hepatic resection?

Answer 125

The aim of PVE is to induce ipsilateral atrophy and contralateral compensatory hypertrophy of the FLR, thereby reducing the risk of post-hepatectomy liver failure.

• PVE takes placed 4-6 weeks before resection
• 40-60% increase in FLR from baseline
• IR guided using coils, cyanoacrylate, gelatin etc
• Major complications in 2-3%
• In clinical practice, 20% will be cancelled on the day, usually due to disease progression.

Question 126

Both ESMO and the NCCN recommend upfront resection of synchronous colorectal liver metastases (instead of NAC) except for 3 scenarios.

What are the exceptions?

Answer 126

• 4 or more liver metastases
• Bilobar metastases
• Radiographic suspicion of portal node involvement.

These patients should undergo “neoadjuvant” chemotherapy to allow for a test of tumour biology.

Question 127

What is the rate of disappearance of a liver metastasis on systemic chemotherapy?

What increases the chances of this?

How should the disappearing liver met be managed?

Answer 127

• 5-38%
• Lesions at the greatest risk of disappearing are those <2cm in diameter and >1cm deep in the liver parenchyma
• Only 20% of radiologically disappearing lesions actually have a complete pathological repsonse so these areas need to be resected
  
  • i.e. up to 80% local recurrence
• Placement of a fiduciary marker by IR can aid with this. Intra-operative USS and complete mobilisation and inspection of the liver during metastasectomy is required.

Question 128

What is the rate of progression of LSIL to HSIL and HSIL to invasive cancer?

What factors contribute to this?

Answer 128

Depending on host and viral factors, LSILs regress, persist, or progress to high-grade squamous intraepithelial lesions (HSILs), the precursors of anal squamous cell carcinoma.

LSIL to HSIL:

• ~30% in HIV negative patients in two years
• ~60% in HIV positive patients in two years

HSIL / AIN3 (recent change in nomeclature) to invasive carcinoma:

• (Rate of diagnosis of anal SCC in HSIL/AIN3 patients)
• 1.2% at 12 months
• 2.6% at 24 months
• 3.7% at 36 months
• 5.7% at 60 months

i.e a little over a percentage point per year of diagnosis.

BUT the rate of progression is markedly higher in MSM and HIV+ patients, especially those with a low CD4 count.

Concordantly, it is lower in patients in stable sexual relationships and in those on highly active anti-retroviral therapy.

Question 129

How do you classify peritoneal malignancies.

Answer 129

1. Primary peritoneal
   
   • Peritoneal mesothelioma
   • Primary peritoneal cancer
2. Metastatic peritoneal:
   
   1. Intraperitoneal source
      
      • Gastric cancer (highest rates of metastatic PSM)
      • Ovarian cancer (highest rates of metastatic PSM)
      • Colorectal cancer
      • Appendiceal cancer
      • Small bowel tumours
      • Cholangiocarcinoma
      • Pancreatic cancer
      • Endometrial cancer
      • Sarcoma
   2. Extraperitoneal source
      
      • Lung cancer
      • Breast cancer (ILC)
      • Renal cancer
      • Melanoma

Question 130

What is the sensitivty of CT for peritoneal surface malignancy?

Explain this. How can it be improved?

Answer 130

A recent meta-analysis demonstrated a pooled sensitivity of 68% and a pooled specificity of 88% for CT imaging in the detection of PSM.

PSM tends to have the same attenuation characteristics as bowel and peritoneum. Motion artefact often causes difficults with interpretation.

PET-CT imaging has a reported sensitivity of 84% and specificity of 98% for PSM

Question 131

What are the absolute contra-indications to CRS in patients with poor-prognosis LAMN/HAMN, and appendiceal carcinoma?

What about high PCI scores?

What is the cut-off PCI for colorectal cancer?

Answer 131

• Extensive small bowel serosal involvement
• Mesenteric involvement causing retraction
• Distant metastatic disease
• PCI scores of up to 39 (max PCI) may be considered for LAMN/HAMN/appendiceal tumours, though a PCI >20 is a relative contra-indication.
• A PCI >20 is an absolute contra-indication for CRS in colorectal cancer.

Question 132

What is the impact of previous trans-anal excision on subsequent TME?

How does this affect counselling a patient?

Answer 132

Recently assessed in DCR May 2022:

• Longer operating time
• More blood loss
• Inferior TME
• Lower LN yield

Difficult to comment on oncological outcomes, unlikely to ever be an RCT on this.

The inherent risk must be balanced with potential benefits (such as organ preservation), factor- ing in patient age, comorbidity, preoperative best available staging, tumor height, preoperative rectal function, and patient choice.

Question 133

Compare the clinical and oncological outcomes between local excision versus TME for early rectal cancer.

Answer 133

While initial, retrospective, data suggested an inferior oncological outcome with LE manifest as higher local recurrence rates, subsequent meta-analyses including RCTs (2015 and 2019) have not borne this out. This may be due to the evolution of TAMIS and TEMS. The clinical outcomes (LOS, blood loss, complications etc.) favour LE.

Recently (DCR May 2022), evidence has emerged that TME following LE in cases, where LE histology mandated radical resection, is associated with inferior TME, longer operations, and higher blood loss.

In appropriately selected and consented patients, LE remains a viable option.

Question 134

What impact does lymphovascular invasion in colorectal cancer have on survival?

Answer 134

LVI is associated strongly with nodal mestases with an OR of between 5-7.

A direct impact on survival is hard to assess; there is evidence that, stage for stage, LVI predicts worse DFS and OS in stage II cancer with HRs of 1.7 and 2.5 respectively.

Question 135

What is Currarino syndrome and what is its relevance to the colorectal surgeon?

Answer 135

Currarino syndrome is an inherited congenital disorder where either the sacrum is not formed properly, or there is a mass in the presacral space in front of the sacrum, and there are malformations of the anus or rectum.

It should be excluded on discovery of a PST in the adult.

Anterior sacral meningocele is the most common presacral mass in patients with Currarino syndrome, occurring in 60% of cases. Inadvertent biopsy of a meningocoele can lead to fatal meningitis.

Question 136

What proportion of low rectal cancer have involved lateral pelvic lymph nodes?

Answer 136

15%

(Based on Japanese studies in patients without neoadjuvant treatment)

Question 137

What degree of local recurrence risk is conferred by positive lateral pelvic lymph nodes?

What is the effect of LPLND?

Answer 137

It depends on the size (short-axis-diameter / SAD) of the nodes on pre-treatment MRI:

• Nodes <5mm = 11%
• Nodes <7mm = 20%
• Nodes >10mm = 30-40%

Local recurrence drops to 3-5% with LPLND when indicated and LatLR drops to 0-6%.

Question 138

What is IMRT in the context of rectal cancer treatment?

Answer 138

Intensity Modulated Radiation Therapy.

IMRT uses advanced technology to manipulate photon beams of radiation to conform to the shape of a tumour.

It is accurate to within 2mm and minimises collateral tissue damage.

Question 139

Define perianal skin cancer.

Which perianal SCCs can be excised?

Answer 139

A perianal skin malignancy that can be completely visualised with distraction of the gluteal cheeks and is within 5cm from the anal orifice.

Perianal SCCs that are:

• well differentiated
• node negative
• T1 lesions
• not involving the sphincter complex

Can be treated with a 1cm excision margin.

Question 140

What are the criteria for resectability of CRCLM?

Answer 140

1. An R0 resection must be technically feasible
2. At least two adjacent segments need to be spared
3. Vascular and biliary outflow of the FLR must be preserved
4. The FLR must be functionally adequate

Question 141

Describe the pelvic lymph node stations.

Answer 141

As per the Japanese Society for Cancer of the Colon and Rectum

Question 142

What are the risk factors for lateral node involvement in rectal cancer?

Answer 142

• Low rectal tumour
• Advanced T stage (T3/4)
• Positive mesorectal nodes
• Poorly differentiated
• LVI
• Female gender
• Larger tumours

Question 143

How is the rectum described and divided by the Japanese with regard to stratification for lymph node drainage?

Answer 143

In Japan the rectum is divided into the upper rectum (Ra) and lower rectum (Rb), corresponding to the known anatomical drainage of the LPLNs .

The upper rectum is defined as the segment from the inferior border of the second sacral vertebrae to the peritoneal reflection, and the low rectum from the peritoneal reflection to the superior border of the puborectal sling.

Question 144

How are lateral pelvic lymph nodes assessed with regard to involvement on MRI?

Answer 144

Measurement of the Short Axis Diameter (SAD) of LPLNs has become the most utilised diagnostic criteria for suspicious LPLNs after several studies demonstrated a significant correlation with pathological LPLN metastases.

However, long axis size, combination of short and long axis and other morphological criteria (border irregularity, shape, mixed signal intensity and heterogeneity) have also been investigated. The MERCURY study used morphological criteria.

Question 145

What is the incidence of lateral pelvis lymph node involvement in rectal cancer?

Answer 145

The incidence of pathologically confirmed LPLN metastases for rectal cancer patients who undergo TME + LPLND without preoperative chemo or radiotherapy is around 14-17% in the largest studies.

The incidence increases to 20-40% in low rectal cancer within 2cm of the anal verge, sometimes in the absence of mesorectal LN involvement.

Question 146

Do lateral pelvic lymph nodes in rectal cancer represent systemic or locoregional disease?

Explain your answer.

Answer 146

The general consensus is that positive LPLN represent locoregional disease.

The seminal Japanese study (Akioyoshi 2012) of over 10,000 patients showed that in those that underwent prophylactic LPLND (n=5000):

• OS was better cf those undergoing curative surgery with stage IV disease
• OS and DF are no different between advanced mesorectal N2a disease and internal nodes, or between advanced mesorectal N2b disease and external nodes.

A subsequent multicentre international lateral node consortium study in 2019 consolidated this. A total of ~1200 patients with LARC within 8cm of the anal canal were treated as per local protocol.

• LPLN >7mm had a significant effect on LatLR
• There was no effect on distant recurrence/DFS.

Question 147

Is neoadjuvant radiotherapy sufficient treatment for positive lateral pelvic lymph nodes?

What is the latest consensus guidance on this?

Answer 147

Yes and no.

• LPLND + TME and SRT + TME are superior to TME alone, there is no evidence that prophylactic LPLND offers any advantage over SRT as long as good TME is performed.
• But overall, studies show that nCRT alone is not sufficient and LPLND is still indicated in select patients with enlarged (≥7mm) LPLNs.

Current evidence from the lateral node consortium indicates that LPLND should be performed for enlarged LPLNs (SAD >/= 7mm pre-treatment) that remain enlarged post nCRT (SAD >4mm internal iliac, and >6mm for obturator LNs) and that it is reasonable to observe enlarged LPLNs that adequately respond.

Question 148

What structures are at risk during LPLND?

Describe the morbidity of LPLND as described in meta-analyses.

Answer 148

• Ureters
• Hypogastric nerves
• Superior and inferior hypogastric plexi
• Common and external iliac vessels
• Internal iliac vessels and branches/tributaries thereof
• Obturator nerve and vessels

Meta-analyses have shown that LPLND confers:

• Greater blood loss
• Longer operative time
• Poorer autonomic function

In published series from high volume centres there is:

• No difference in sexual function
• No difference in urinary function

Question 149

Describe lymph node drainage of the rectum.

Answer 149

Lymphatic drainage / spread may occur through the upper lymphatic route (via superior rectal artery to the inferior mesenteric artery) or lateral lymphatic drainage (via middle rectal artery to the internal iliac and obturator basins).

Involvement of downward route occurs only when a distal rectal tumor invades the anal canal, leading to inguinal lymphnode metastasis.

Question 150

Outline the steps of LPLND.

Answer 150

1. Identify both ureters and retract (laterally open, medially lap)
2. Identify both hypogastric nerves at the aortic bifurcation but do not dissect or retract to avoid injury
   
   • Medial retraction of the ureter with its uretohypogastric fascia protects the nerves and forms the medial boundary of dissection.
3. Dissect the adipose + lymph node packet off the common iliac artery and vein, until obturator internus muscle is seen.
   
   • The obturator muscle is the lateral boundary of dissection
4. The obturator nerve is identified as it emerges from between the internal and external iliac veins.
5. The obturator vessels (artery arising from the IIA) are dissected and ligated, the packet is dissected with the obturator pedicle, until the obturator foramen.
6. Dissection is then performed along the vesicohypogastric plane, where branches of the internal iliac artery are dissected, divided, and the lymphoadipose tissue with them removed, down to the apex of the pelvic floor and adjacent to the bladder
   
   • The internal iliac vein forms the medial boundary of dissection
   • The distal aspect of the vesicular arteries and veins also need to be dissected and divided.

Question 151

Describe what is meant by the MSI pathway?

Answer 151

Microsatellite instability was the second major genetic pathway to be defined for CRC. It accounts for ~15% of CRC.

It is termed a hypermutable pathway due to the accumulation of multiple uncorrected DNA mutations. Microsatellite instability is almost always associated with a defect in one of the MMR proteins and so in practice MSI is identified by routine IHC screening of CRC for loss of expression of MLH₁, MSH₂, MSH₆, and PMS₁.

Question 152

What is Papillon therapy (aka CXB)?

Answer 152

Contact X-ray brachytherapy (CXB) is a novel treatment paradigm being explored for early rectal cancers.

This treatment modality has been in clinical use for 80 years but has only seen a revival in the UK with the availability of the new British Papillon machines. It is being assessed in the OPERA trial (Organ Preservation in Early Rectal Adenocarcinoma).

Question 153

Provide some general facts about Pre-Sacral tumours in terms of aetiology and surgical approach.

Answer 153

70% benign

70% congenital

70% female

70% accessible via Kratske

Question 154

Describe the approach to pre-sacral tumours by high-volume units.

Answer 154

Question 155

Describe the oncological outcomes in LE of pT1-2 rectal cancer when followed by no additional therapy (NAT), completion TME (cTME), and adjuvant chemoradiotherapy (aCRT).

Answer 155

(2020 meta-analysis in the BJS)

There is a substantial risk (~15%) of local recurrence in patients who receive NAT after LE, especially those with high-risk pT1 and pT2 rectal cancer (~30%).

The lowest recurrence risk is provided by cTME; aCRT has outcomes comparable to those of cTME for high-risk pT1 tumours, but shows a higher risk for pT2 tumours.

Question 156

What is the role of the p16 biomarker in anal lesions?

Answer 156

p16 serves as a surrogate biomarker of high-risk HPV and plays a critical role in the diagnosis of HPV-induced pre-cancer and cancer.

HSIL manifests as strong and diffuse positive p16 staining on IHC, whereas LSIL and normal squamous epithelia generally show no or limited p16 immunoreactivity.