Colorectal, Anal, and Peritoneal Malignancy Flashcards

Question

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

Answer 1

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.

Answer 2

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.

Answer 3

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.

Answer 4

**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...

Answer 5

**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.

Answer 6

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.

Answer 7

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.

Answer 8

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.

Answer 9

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”.

Answer 10

*"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.

Answer 11

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.

Answer 12

Onset of symptoms **\>3 months** after finishing radiotherapy treatment.

Answer 13

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.

Answer 14

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.**

Answer 15

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.

Answer 16

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

Answer 17

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

Answer 18

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.

Answer 19

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.**

Answer 20

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)

Answer 21

**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**.

Answer 22

Endoscopic: * Friability of the mucosa with contact bleeding * Pallor, telangectasia * Loss of rectal distensibility

Answer 23

* Sucralfate enemas * Topical formalin * Hyperbaric oxygen

Answer 24

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**

Answer 25

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.

Answer 26

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.**

Answer 27

**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.

Answer 28

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.

Answer 29

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.

Answer 30

_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.

Answer 31

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.

Answer 32

**_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.

Answer 33

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.

Answer 34

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.

Answer 35

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).

Answer 36

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

Answer 37

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.

Answer 38

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%.

Answer 39

Synchronous CRPM are seen in 3-14%. Metachronous CRPM is seen in up to 19% of patient with CRC.

Answer 40

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

Answer 41

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.*

Answer 42

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.**

Answer 43

* 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).

Answer 44

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.

Answer 45

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.**

Answer 46

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.

Answer 47

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.

Answer 48

**_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!**

Answer 49

* 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

Answer 50

* 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.

Answer 51

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**.

Answer 52

* 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%).

Answer 53

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%

Answer 54

* 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.

Answer 55

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.

Answer 56

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.**

Answer 57

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.

Answer 58

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, l**ocally 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.

Answer 59

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.

Answer 60

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.

Answer 61

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

Answer 62

Technical success in 90-98% Clinical success in 85-90%

Answer 63

**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.

Answer 64

Median stent patency in the palliative setting ranges from 3 to 12 months, with a **median of 106 days** **A**pproximately 50% of stents remained patent at 12 months.

Answer 65

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

Answer 66

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.**

Answer 67

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.

Answer 68

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)

Answer 69

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.

Answer 70

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**

Answer 71

* **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

Answer 72

* 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

Answer 73

* 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

Answer 74

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.

Answer 75

* 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

Answer 76

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-

Answer 77

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.

Answer 78

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.

Answer 79

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.

Answer 80

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.**

Answer 81

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

Answer 82

* 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.

Answer 83

* Younger age * Normal CEA * Clinical negative node status * Smaller tumours * p53 wild-type * SMAD-4 tumours i.e younger people with less aggressive tumours.

Answer 84

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

Answer 85

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.

Answer 86

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

Answer 87

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

Answer 88

* 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.

Answer 89

* 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.

Answer 90

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

Answer 91

Sensitivity = 54% Specificity = 66-75%

Answer 92

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)**.

Answer 93

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

Answer 94

* 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 ## Footnote *\*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.*

Answer 95

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

Answer 96

**_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

Answer 97

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.**

Answer 98

* 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.

Answer 99

* 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.

Answer 100

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._**

Answer 101

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

Answer 102

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**

Answer 103

* 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.

Answer 104

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.

Answer 105

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.

Answer 106

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.

Answer 107

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._**

Answer 108

15% (Based on Japanese studies in patients without neoadjuvant treatment)

Answer 109

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%.

Answer 110

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.

Answer 111

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.

Answer 112

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

Answer 113

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

Answer 114

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

Answer 115

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.

Answer 116

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.**

Answer 117

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.

Answer 118

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.**

Answer 119

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.**

Answer 120

* 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

Answer 121

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.

Answer 122

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.

Answer 123

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.

Answer 124

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).

Answer 125

70% benign 70% congenital 70% female 70% accessible via Kratske

Answer 126

*(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.

Answer 127

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.