Lower GI Flashcards
Describe the epidemiology and risk factors for rectal cancer
Incidence (Australian statistics - colorectal cancer)
- 15540 cases annually
- 4th most common malignancy
Slight male predominance (1.2:1)
Disease of the developed world (esp Australia, NZ, USA, Europe)
- Uncommon in South Asia and Africa
Median age is approximately 60 years
- Incidence in younger people is rising
Aetiology
Risk Factors
1) Diet-related (disease of affluence) a. Likely due to high-meat/high-fat diets with low-fibre b. Migrants adopt risk of new country within 1 generation 2) Sedentary lifestyle & obesity 3) Smoking 4) Alcohol consumption 5) Benign bowel disease (e.g. inflammatory bowel disease) 6) Familial/genetic a. HNPCC (hereditary non-polyposis colorectal cancer) --> Lynch syndrome (MMRd) --> 5% b. FAP (familial adenomatous polyposis) --> APC --> 1% c. Li-Fraumeni --> p53 d. Other polyposis syndromes: i. Gardner syndrome -5q deletion (APC) –FAP with retinal hypertrophy and osteomas ii. Turcot syndrome = brain tumour with HNPCC or FAP (eg. Medulloblastoma iii. Peutz-Jeghers syndrome (STK11) iv. MUTYH-associated polyposis (MUTH autosomal recessive) v. NAP (NTHL-1 assoc polyposis) vi. Juvenile polyposis syndrome (SMAD4) vii. Cowden syndrome (PTEN) viii. Polymerase proofreading-associated polyposis (PPAP). (POL-E, POL-D) ix. Serrated polyposis syndrome (RNF43) 7) Previous pelvic radiotherapy 8) History of cystic fibrosis
Protective Factors
1) High-fibre diet 2) NSAID/Aspirin use 3) Physical activity
Describe the lymphatic drainage of the rectum and colon
○ Rectal LN drainage:
§ Upper/middle third: Superior rectal vein→ Inferior mesenteric vein (Liver mets).
§ Distal third: dual drainage. Above + Middle/Inferior Rectal vein→ IVC (Lung mets).
§ Extension to anus/below pectinate→ inguinal nodes.
○ Colon LN drainage
* Left colon→ IMA.
* Right colon→ SMA.
* pAO at risk if cancer invades retroperitoneum and external iliac if cancer invades adjacent organs.
Describe the surgical options for rectal cancer.
LAR Low anterior resection (Sphincter preservation)
LAR involves resection of the rectum followed by a colorectal or coloanal anastomosis
Also involves TME
Aim for sphincter preservation
For mid-upper lesions and selected lower lesions
Criteria
* Invasive rectal cancer
* A negative distal margin
* Adequate presurgical anorectal sphincter function
APR resection for low level tumours (Permanent colostomy)
APR treats low-lying rectal carcinomas: Removes the sigmoid colon, rectum and anus, leaving behind a permanent colostomy.
Total mesorectal excision (TME): Removing the mesorectal lymphovascular tissue
Abdominal operation: Distal sigmoid colon is mobilised, superior rectal artery is ties. TME performed. The colon is transected at least 5cm proximal to rectal tumor. Stoma is made.
Perineal operation: Anterior dissection made and the disconnected sigmoid/rectum are bought through the perineal excisison
Criteria
* Locally advanced low-lying rectal cancer * A negative distal margin of 1cm cannot be achieved with sphincter preservation Poor pre-surgical anorectal function
Describe the pathology for colorectal neoplastic polyps
Macroscopic:
Neoplastic polyps could be pedunculated polyps or sessile polyps
- If pendunculated polyps
o Exophytic mucosal growth with a stalk protruding into the lumen
o May be single or multiple polyps throughout the colon depending on the natural history and aetiology
o It may ulcerate, bleed or obstruct the lumen of the bowel
- If sessile, flat broad mucosal growth withlittle or no stalk, and may cover the mucosa of the bowel
o They may ulcerate and erode the mucosa lining cauding bleeding
Microscopic
- Tubular adenoma 45%
o >75% Tubular or glandular with crypt architexture
- Tubulovillous 6%
o Mixed of tubular and villous architecture, villous composed of 25-50%
- Villous 1%
o >50% Villous architecture, forming frond like projections
- Serrate sessile <5%
o Flat adenoma with serration of the epithelium with dilated crypts base and mucin retention, and lateral growth
Describe the risk factors for progression for colonic polyps to malignancy.
> 3 polyps
* Polyps larger than 10mm
* Right sided colonic polyps
* Serrated polyps
* Villous or tubulovillous adenoma =up to 30% risk of progression
Hereditary polyposis syndrome
Polypectomy reduces risk by 80%
Describe familial adenomatous polyposis coli
~100% cancer by age 50. APC genetic testing, early screening, colectomy, or proctocolectomy after onset of polyposis. Desmoids in 10-20%.
Autosomal dominant,
Mutation in APC gene (tumour suppressor), multiple possible mutations with varying penetrance
Clinical:
* Hundreds of colonic polyps, colorectal cancer at a young age (or family history). Nonspecific abdominal symptoms (diarrhoea, abdo discomfort, rectal bleeding)
* 100% lifetime risk of colon cancer
* CHRPE: Hypertrophy of retinal epithelium –flat pigmented lesions
* Osteomas of mandible
* Impacted teeth, supernumery teeth
* Epidermoid cysts of face
* Fibromas of back, trunk
Extracolic manifestations (list at least 4 conditions; 2 of which have malignant potential).
* Desmoid tumour 10-15%, especially abdomen, increased after surgical trauma
* Duodenum and papilla of Vater adenocarcinoma 10%, and adenomas 100%
* Gastric polyps 50%(1% progress to gastric cancer)
* Thyroid cancer -2% -annual US screening
* Hepatoblastoma (rare childhood cancer)
* WNT medulloblastoma (paediatric)
Risk reduction:
* Flexible sigmoidoscopy or colonoscopy annually starting at 10 to 12 years of age.[6] Surveillance should continue until the polyp load is unable to be controlled with endoscopic removal.
* Definitive surgical management involves colectomy with or without proctectomy.
○ If rectum left then proctoscopy 6monthly
* NSAIDS don’t reduce risk
Gastroscopy/duodenoscope from age
Describe lynch syndrome.
Mutation of genes that affect DNA mismatch repair (MLH1, MSH2, MSH6, PMS2, EPCAM). Autosomal dominant
Mismatch repair genes are necessary for repairing incorrect pairing of nucleotide bases during DNA replication. If these “mismatches” are not corrected, then the resulting copy may not function properly leading to an increased risk for cancer.
Rate 1/280 but many undiagnosed, fairly uniform geographic/ethnic distribution
2-4% of colorectal cancers
2% of endometrial cacners
Testing methodology:
Tumour: IHC (loss of MLH1, MSH2, MSH6,
PMS2),
MLH1 can be hypermethylated by BRAF 600E
MSI = high or low (PCR or NGS)
Germline testing
Amsterdam 1,2 criteria for family history
Colorectal 20-50%
Esp R sided, Adenomas transform quicker to cancer (particularly poorly diff medullary, mucinous, signet, increased infiltrating lymphocytes)
Endometrial 40%
Ovarian 10-20%
Gastric 5%, pancreatic, biliary cholangiocarinoma
Upper urinary tract TCC
Prostate
Brain (GBM)
Sebacious gland tumour, Keratoacanthoma
Noncancers:
Risk management:
* Colonoscopy from age 25-35, every 1-2 years * Aspirin low dose 100-300mg * Hysterectomy from age 40-50 * Ovary: BSO @ hysterectomy, hormone replacement therapy ○ No evidence for Ca125 or pelvic US surveillance * Gastric -scope from age 30, and asians ○ Screen and treat H pylori * Urothelial, prostate –no evidence.
Discuss the screening for colorectal cancer.
AJGP- CRC Screening
FOBT done every 2 yr from 50-74 in low risk patient
Consider Aspirin (100-300mg daily) for everyone 50-70yo, regardless of risk; to prevent CRC (level 1 evidence shows reduction of CRC occurrence by 24% and CRC associated mortality by 35% at 10 years. Mechanism unknown)
If macroscopic melaena, refer for colonoscopy without FOBT
Evidence for FOBT:
- NEJM- use of FOBT screening reduce CRC by 33%
- MA and systematic review showed that screening through gFOBT, iFOBT, Flexi sigmoidoscope and colonoscopy – no diff in all-cause mortality between the diff methods. There is a 18% reduction in disease specific mortality
FOBT- occult blood tests for presence of blood in the stool, start from 50 years of age
* simple, safe, cheap, accessible tests for the general population, if positive, then patient needs to have further investigations to confirm the presence of CRC/ polyps
* Limitation: relatively low sensitivity and specificity for CRC, result can be falsely pos by diet, haemorrhoids or other causes of bleeding, can create unnecessary worry in false positivie result
Sigmoidoscopy: inspection +/- bx of the colon up to the sigmoid using a flexible sigmoidoscopy
* Less invasive than colonoscopy, simpler to perform, high specificity and sensitivity than FOBT, can provide tissue bx for diagnosis
* Limitation: only inspect up tot eh sigmoid, cannot inspect the remaining fo the colon, need adequate bowel prep, need to be suitable/ light for light sedation, limited availability only performed by specialist, procedural risk and complications
Colonoscopy: Full inspection for he large bowel using a flexible colonoscopy
* Good inspection of the large colon and provide biopsy, high specificity and sensitivity
* Limitation: risk of perforation, need to be fit for light sedation, need adequate bowel prep for accurate assessment of mucosa, invasive and operator dependent, limited availability only performed by specialist, procedural risk and complications, cannot examine the remaining of the bowel is cannot transverse an obstruction point
Virtual colonoscopy/ CT colonography: using high resolution CT to examine for bowel abnormality, need adequate bowel prep, bowel dilatation with CO2, IV contrast, oral contrast, and buscopan as part of the prep for the CT
* Non invasive, no procedural risk and complications, can examine the proximal aspect of the bowel past the obstruction point, quicker than a colonoscopy, can detect extracolonic pathology, suitable for pt unfit/higih risk for colonoscopy
* Limitation: limited specificity and sensitivity, cannot provide tissue biopsy, residual faeces can interfere interpretation, exposure to radiation
Describe the classical pathogenesis pathway for colorectal cancer
Classical step-wise carcinogenesis model (85%)
1) Inactivation of APC (somatic/germline mutation or epigenetic change) a. APC usually promotes degradation of β-catenin b. When APC is inactivated --> β-catenin accumulates --> activation of Wnt signalling pathway c. Acts as a transcription factor (e.g. MYC and cyclin D) 2) Allows early adenoma formation 3) Activating mutations in KRAS develop --> allow progression in adenoma a. If <1cm, then <10% chance of KRAS mutation b. If >1cm, then >50% chance of KRAS mutation 4) Additional mutations (or epigenetic silencing) may complete carcinogenesis a. SMAD2 & SMAD4 --> TGF-β pathway inactivation b. P53 mutation
Describe the mismatch repair deficient pathogenesis pathway for colorectal cancer
Mismatch Repair Deficiency (MMRd) pathway (10-15%)
1) Germline or somatic inactivation of MMR proteins a. MLH1, MSH2, MSH6, PMS2 2) Microsatellite instability ensues a. Hypermutability that occurs during mitosis b. Accumulation of DNA damage --> microsatellite regions (repeated sequences of DNA) 3) Inactivation of important genes a. TGF-β (receptor type 2) --> responsible for inhibition of colonic epithelial cell proliferation b. BAX --> pro-apoptotic molecule 4) Uncontrolled cellular growth --> proliferation of abnormal clones
Describe the differences between left and right sided colorectal cancers
Adenocarcinomas are distributed equally throughout the colon
Biological differences exist
Left-sided (distal incl rectum)
- More likely to be annular constricting growths
- More likely associated with traditional carcinogenesis pathway (APC)
○ p53 mutation
○ APC mutation
○ KRAS mutation
Right-sided (proximal)
- More likely to be polypoid exophytic masses
- More likely to be a mucinous tumour
- More likely to be associated with MMRd/hypermutated pathway (Lynch Syndrome)
○ BRAF mutation
○ TGF-β mutation
Describe the pathology for colorectal adenocarcinoma
- Most common subtype
- Macroscopic
○ Left-side/rectum = annular constricting masses with narrowed lumen
○ Right-sided/proximal = polypoid, exophytic and fungating masses - Microscopic
○ Multiple subtypes
§ Micropapillary –> small clusters of malignant cells with eosinophilic cytoplasm
□ Poor prognosis with early nodal metastasis
§ Mucinous –> extra-cellular mucin comprising >50% of the tumour mass
□ Respond poorly to upfront chemotherapy
§ Signet-ring cell –> intra-cellular mucin in >50% of all cells (displaces nucleus to side of cell)
□ Associated with MSI-H and Lynch syndrome (HNPCC)
□ May form a diffuse infiltration rather than discrete mass
□ Aggressive phenotype, tendency for early metastasis
§ Medullary –> non-gland forming cancer with large eosinophilic cells which grow in sheets
□ Associated with MMRd –> MSI-H and Lynch syndrome (HNPCC)
□ Favourable prognosis
§ Serrated
§ Sarcomatoid
○ Histologic grading (based on gland formation)
§ Low-grade
□ Grade 1 = >95% has gland formation
□ Grade 2 = 50-95% has gland formation
§ High-grade
□ Grade 3 = <50% has gland formation
□ Grade 4 = undifferentiated (no gland formation or other differentiation) - Immunohistochemistry
○ POS = CK20, CDX2, MUC2 (mucin)
○ NEG = CK7 (positive in 15% of rectal cancers) - Cytogenetics
○ APC, TP53, KRAS
○ MSI instability via IHC for MLH1, MSH2, MSH6 and PMS2
- Macroscopic
List the primary tumour and subtypes that can occur in the rectum/colon.
1) Adenocarcinoma (>90%)
a. Mucinous
b. Signet-ring cell
c. Micropapillary
d. Medullary
e. Serrated
f. Sarcomatoid
2) Neuroendocrine Tumour (carcinoid)
3) Neuroendocrine Carcinoma
4)Leiomyosarcoma
Discuss the immune system as a prognostic marker for colorectal cancer
Tumour infiltrating lymphocytes
- A marker of immune activation by tumour - Increased TILs good prognostic factor - Lymphocytes= T cells, B cells, NK cells, macrophages, dendritic cells and neutrophils - High mutation load and frequent frame shift mutations e.g. MSI instability lead to production of neoantigens that trigger lymphocytic infiltration - T cell infiltration associated with good outcomes --> immunotherapy aim to upregulate and precent its exhaustion and apoptosis in tumours e.g. by immune checkpoint inhibitors
Describe the features of a colorectal cancer pathological synoptic report
· Photographic record of surgical specimen and assessment of TME quality
· Specimen type
· Number of Tumours (for multiple primary Tumours, each Tumour requires a complete report)
· Tumour location relative to anterior peritoneal reflection for rectal Tumours: entirely above, below or straddling
· Tumour size, site, extension
· Macroscopic Tumour perforation
· Macroscopic intactness of mesorectum (required only for rectal Tumours)
· Histologic type, grade
· Margins
· Lymphovascular invasion: present or not identified
o Small vessel
o Large vessel: intramural or extramural
· Perineural invasion
· Treatment effect
o No known presurgical therapy
o Present
§ Complete response: no viable cancer cells (can have acellular mucin present)
§ Near complete response: single cells or rare small groups of cancer cells
§ Partial response: more than single cells or rare small groups of residual cancer with Tumour regression
§ Poor or no response: extensive cancer with no evident Tumour regression
· Tumour deposits
· Regional lymph node: number of examined and number of involved
· Ancillary studies performed (depending on local protocols)
o Microsatellite instability
What are the prognostic features for colorectal cancer?
Patient Factors
- Age
- Performance status
- Participation in screening
- High pre-treatment CEA
Tumour Factors
- TNM staging
- Histological subtype (e.g. signet cell poorer prognosis)
- Positive histological
○ MMRd and MSI-H (predicts response to ICI)
○ High TILs (lower risk of metastasis –> presume immune response systemically)
§ Activated (CD45RO pos) –> CD4 and CD8 T-lymphocytes
§ NOTE: FoxP3+ Treg subset imparts worse prognosis
- Negative histological
○ High-grade/poor differentiation
○ High-grade tumour budding (small cluster of cells separate to tumour at the invasive front)
○ EMVI
○ LVI
○ PNI
○ Desmoplastic stroma
○ KRAS mutation (no response to EGFR TKI)
○ BRAF mutation (only if MSI-L)(BRAFV600E)
- R colon cancer worse than L/rectal -different embryological origin
Treatment Factors
- High-volume centre
- R0 resection (including preservation of CRM)
- TME quality
○ Impacted by: advanced T stage, Low rectal tumours (<8cm from anal verge), advanced age and low surgical case volume
- Sufficient LN removed (at least 12)
- Response to neoadjuvant therapy
Discuss the history and examination for colorectal cancer
History
- Presenting Illness ○ Now often present asymptomatic § Screening FOBT +/- colonoscopy § Incidental FDG-PET avidity (study for alternate reason) ○ Early symptoms § Haematochezia (bright red) +/- anaemia (microcytic & appears like iron deficiency) § Pain/discomfort on defecation § Change in bowel habits (fluctuating constipation/diarrhoea) § Tenesmus § Constitutional Symptoms (weight loss, fevers, night sweats) ○ Late symptoms § PR haemorrhage § Pain outside of defecation (e.g. perineal/pelvic/sciatic/sacral – local invasion) § Fistula (e.g. rectovaginal or rectovesical fistula) § Obstruction § Symptoms of metastases (e.g. liver failure, bony pain, etc.) - Past Medical History ○ Other cancers or polyposis (Lynch syndrome, FAP) § Previous radiotherapy § Primary sclerosing cholangitis ○ Inflammatory Bowel Disease § x20 increased risk § Chron's and UC has similar risk for length of bowel involved ○ Radiosensitising conditions - Medications ○ Radiosensitisers - Family History ○ Previous malignancies (genetic predisposition) - Social ○ Smoking and alcohol
Examination
- General appearance ○ Cachexia ○ Anaemia - Abdominal palpation ○ Hepatomegaly - PR examination ○ Sphincter preservation
Describe the work up for colorectal cancer.
- Faecal Occult Blood (screening)
- Colonoscopy + biopsy
○ Full colonoscopy required (not just flexi sigmoidoscopy)
§ 2-5% risk of synchronous primary & increasing incidence in right-sided lesions
○ Consider EUS (MR is preferred alternative) - CT Colonography is an alternative
○ High sensitivity and specificity (>95%)
○ NEG = requires colonoscopy for biopsy anyway
○ Can use in case of obstruction - Bloods
○ FBC +/- cross match (anaemia)
○ EUC and CMP
○ LFT and coags
○ CEA
○ DYPD (capecitabine safety) - Imaging
○ CT CAP staging
○ MR Rectum (required for T-staging)
§ Need EUS if MR contraindicated (e.g. PPM)
§ Can identify EMVI, T-stage (inc subclassification of cT3), distance to CRM, pelvic LNs
○ FDG-PET is not funded in initial staging
§ Only funded following initial therapy for re-staging if suspected residual/metastatic disease
- Colonoscopy + biopsy
Describe the management of cT1N0 rectal cancer
- Transanal Endoscopic Microsurgery (TEM) can be considered
○ Criteria
§ Superficial T1 disease
§ <3cm diameter and involving <30% of lumen circumference
§ Mobile lesion
§ No nodal or distant metastases on imaging
§ Willing to comply with frequent surveillance
§ Grade 1/2
○ Acceptable surgery
§ En-bloc excision (piecemeal is inadequate)
§ Well-differentiated pathology
§ No PNI or LVI
§ Margin of at least 3mm- If not suitable upfront, or adverse factors on pathology
○ Proceed as per T2 or T3 protocol as appropriate (e.g. surgery or neoadjuvant)
○ Positive margins or piecemeal resections should be offered immediate radical surgery
- If not suitable upfront, or adverse factors on pathology
Describe the staging for colorectal cancer
T1
Invades the submucosa
T2
Invades the muscularis propia
T3
Invades into peri-rectal tissue (outside of muscularis)
- T3a = <1mm
- T3b = 1-5mm
- T3c = 6-15mm
- T3d = >15mm
T4
Invades visceral peritoneum
N1
1-3 regional LN
N2
4 or more regional LN
Describe the management of cT2N0 rectal cancer
- Should be offered a total mesorectal excision (low-anterior or abdomino-perineal resection)
○ Risk of nodal metastases is sufficiently high to justify (>10%)- No role for routine neoadjuvant therapy
- Adjuvant therapy is risk adapted
○ No adjuvant therapy = if pT1-3, pN0-1, CRM >2mm and mesorectum intact
○ Adjuvant therapy mandated = pT4, bulky pN2 disease, disturbed mesorectum, extensive EMVI - Low-rectal tumours (controversial)
○ Can consider neoadjuvant therapy to downstage and aim for sphincter preservation
○ Highly controversial approach - If upfront TME is performed and incidental pT3+ or N+ disease is found
○ Management options
§ Long course chemoRT (Capecitabine or 5FU) -> FOLFOX or CAPEOX
§ FOLFOX or CAPEOX -> Long course chemoRT (Capecitabine or 5FU)
§ FOLFOX or CAPEOX alone (only suitable for pT3N0 or pT1-3N1)
Observation (only suitable for pT3N0)
Describe the management of cT3 or N+ rectal cancer
- All patients require good TME surgery
○ Improved local control when compared with a local excision only
§ Evidence from the UK CR07 trial suggests that, without RT, a local recurrence rate of 5% can be achieved if a complete mesorectal excision is carried out with a negative CRM
○ Distal coning is common as the pelvis becomes narrowed the lower down one gets in the pelvic girdle. Distal coning is why low rectal cancer is associated with poor quality TME.- Neoadjuvant therapy is superior to adjuvant therapy
○ Reasons for superiority
§ Improved locoregional control
§ Improved sphincter preservation rate
§ Reduced rate of anastomotic stenosis
○ Neoadjuvant options include
§ Short-course RT (25Gy/5F) with surgery to follow within OTT of 10 days (or at 8 weeks)
□ Trials show that short course not effective in patients with close/involved CRM
§ Long-course chemoRT (50.4Gy/28F with capecitabine) with surgery to follow at 8 weeks
○ Default is short-course RT, select long-course if:
§ cT4 or cN2 disease (especially if extramesorectal LN)
§ Close CRM (<2mm)
§ Low-rectal tumour (view to sphincter preservation)
§ Bulky or borderline un-resectable tumour
§ Uncertain if patient will proceed to surgery (i.e. possible definitive RT)
§ Young age (easily tolerate treatment and typically have worse disease) - Will require adjuvant chemotherapy
○ Typically 4 months of FOLFOX or deGramont 5-FU - Neoadjuvant therapy may be excluded if (ESMO guideline)
○ T3a or T3b; mid-to-high rectal cancer; clear MRF
○ Node positivity does not exclude this approach - Very controversial approach (would advocate for neoadjuvant short-course RT in these patients)
- Neoadjuvant therapy is superior to adjuvant therapy
Short course RT- only for mid rectal T3
-don’t use for low rectal tumour due to strictures
Long course RT is otherwise standard
TNT used for younger, fit patients with advanced disease
Otherwise as there is only 3yr data, everyone else gets neoadjuvant treatment over TNT
Discuss the non-operative management of rectal cancer
- Complete clinical response:
○ no evidence of residual disease on DRE, rectal MRI and direct endoscopic evaluation
○ Watch and wait approach (non operative) can be considered in experienced MDT centres- Not standard of care
○ Data limited
○ No randomised evidence of AS/WW vs. Surgery
○ Existing TNT trials incorporate TME as part of treatment regimen
○ Increasingly used in the US (and now a treatment option in NCCN 2024 guidelines)
○ degree to which risk of local and/or distant failure maybe increased relative to surgery is not established
○ Lacks long term follow up, larger sample size and careful observational studies before can be routinely managed
○ Recent studies have found that neither PET/MRI/CT can accurately determine pathological complete response, complicating appropriate selection; and LN mets are still seen in a subset of pt with pathological complete response - Rationale:
○ consideration for clinical complete responders with improvement in preoperative treatment and imaging
○ Some suggestion patients can be spared surgery (and associated morbidities) with a clinical complete response to chemoRT
○ Although data limited, likely safe with the use of surgery in patients with tumour regrowth
○ Functional outcomes better in watch and wait group: better bowel function scores, less incontinence and proportion of pt avoiding permanent colostomy - Notes:
○ Disease recurrence occurs most frequently in the first 2-3 years warrants more intense surveillance in this period
○ 30% will develop distant mets
○ 30% LR recurrence
○ OPRA (phase II) - stage II/III - TNT, CRT >chemo or chemo>CRT ; then AS
§ 3 yr TME 10% better with CRT first (41 vs 53%)
§ DFS the same in both groups - OPRA trial included (NCCN similar)
○ DRE, flexible sig and CEA every 4 months for first 2 years, then every 6 months for yr 3-5,
○ MRI every 6 months for first 2 years, then every 12 months for 3-5 years (NCCN recommend every 6 months for 3 years)
○ CT CAP once a year for 5 years
○ Colonoscopy once at year 1 and year 5
- Not standard of care
Discuss management of bulky, locally advanced rectal cancer.
- Exclude bowel obstruction (or impending obstruction)
○ May need urgent defunctioning stoma prior to standard therapy- Aim for total neoadjuvant therapy approach
○ Indications
§ Threatened CRM
§ T4 disease
§ Borderline or unresectable
§ Bulky N2 disease (subjective)
§ Low-rectal tumours with aim of sphincter preservation (controversial)
○ Regimens
§ PRODIGE-23
□ Induction chemotherapy (3 months of FOLFIRINOX)
□ Neoadjuvant long-course chemoradiotherapy (50.4Gy/28F with concurrent capecitabine)
□ TME
□ Adjuvant chemotherapy (3 months of FOLFOX)
§ RAPIDO
□ Neoadjuvant short-course radiotherapy (25Gy/5F)
□ Neoadjuvant consolidation chemotherapy for 4 months (6x CAPOX or 9x FOLFOX)
□ TME
□ Adjuvant chemotherapy not mandated
§ OPRA trial - Patients should be re-assessed after neoadjuvant treatment to direct surgical strategy and type of operation (ESMO)
○ DRE, Proctoscopy, MRI
○ Currently not enough evidence to support ‘watch and wait’ approach if cCR
○ Routine re-staging of chest/abdomen not recommended
§ Unless cT4, threatened CRM or presence of EMVI on initial staging, to exclude metastatic disease prior to surgery
- Aim for total neoadjuvant therapy approach
Discuss the evidence for total neoadjuvant treatment in rectal cancer.
Combination of induction chemotherapy with the standard treatment paradigm
- Rationale is to improve the risk of distant metastasis (and thus survival), improve chemotherapy tolerance and downstage tumour
PRODIGE-23 trial (Conroy, 2021) ○ 461 patients with cT3-4 rectal cancer were randomised to § 3 months of FOLFIRINOX, long course chemoRT (50Gy/25#), TME and 3 months of adjuvant FOLFOX § Long-course chemoRT, TME and six months of adjuvant FOLFOX ○ Improved pCR rate with TNT (28% vs 12%) ○ Improved 3-year DFS with TNT (76% vs 69%) ○ No difference in OS (91% vs 88%) RAPIDO trial (Bahadoer, 2021) ○ 920 patients with cT4 or cN2 rectal cancer were randomised to: § SCRT followed by 6 cycles of neoadjuvant CAPOX (or x9 cycles FOLFOX) before proceeding to TME § Long-course chemoradiotherapy followed by TME -> optional x8 CAPOX or x12 FOLFOX (59% of patients received) ○ 3-year DFS was improved in the RAPIDO group (76.3% vs 69.6%) ○ 3-year DMFS was improved in the RAPIDO group (80% vs 73.2%) ○ Improved pCR in the RAPIDO group ○ 5yr Locoregional recurrence 10% worse with short course compared to long course when: § cT4, EMVI, cN2, involved MRF, enlarged lateral lymph nodes
Discuss the prognosis of rectal cancer and a suitable follow up schedule
Prognosis
Likelihood of local control following neoadjuvant RT and TME
- Approximately 80+%
Follow-Up
Locally Advanced Rectal Cancer
- Clinical review every three months for the first two years ○ Examination including PR each visit ○ Bloods prior to each visit (FBC, EUC, LFT and CEA) ○ CT CAP every six months - Clinical review every six months thereafter ○ Examination including PR each visit ○ Bloods prior to each visit (FBC, EUC, LFT and CEA) ○ CT CAP annually - Discharge after five years - Colonoscopy schedule: ○ 1 year after surgery ○ Every 3 years thereafter (if normal)
Describe the anatomy of the anus in relation to anal cancer.
Histological segments of anal canal
- Proximal third = columnar rectal epithelium
- Middle third = transition zone
- Distal third = squamous epithelium (non-hair bearing)
External perianal skin = hair-bearing squamous epithelium
Dentate line broadly divides the upper third of the anal canal from the lower two thirds
Histology of cancers is broadly split along this line (but not absolute)
- Proximal third = adenocarcinoma (need to exclude true rectal aetiology)
- Distal two-thirds = squamous cell carcinoma
HPV can be implicated regardless of location
Distinguishing anal canal cancers and perianal skin cancer
- Anal canal –> if gentle traction of buttocks is applied and the bulk/entirety of the tumour is not visible
- Perianal skin –> if lesion is easily visible in entirety (and within 5 cm of verge)
If there is doubt, manage as anal canal
Discuss the pathology for anal SCC, adenocarcinoma and small cell carcinoma.
Squamous cell carcinoma
- Most common variant by far
- Need to distinguish from perianal SCC of skin
- Macroscopic ○ Nodular and ulcerating tumours ○ Invade deeply and often spread proximally/distally - Microscopic ○ Appears consistent with SCC as seen elsewhere § May be keratinising (below dentate line) or non-keratinising (above dentate line) § Most mixed ○ Subtypes § Basaloid --> peripherally palisading pattern, central necrosis, desmoplastic stroma § Mucoepidermoid --> mucinous microcysts § Small cell --> anaplastic small cell appearance, no NE differentiation ○ Often associated with Intra-epithelial neoplasia
Adenocarcinoma
- Very rare malignancy (5% of anal malignancies)
- Need to distinguish from rectal adenocarcinoma with involvement of anus
- Associated with chronic inflammation (rather than HPV)
- Macroscopic ○ As per SCC - Microscopic ○ Haphazard distribution of small glands with scant mucin ○ Cells may be mucinous ○ Granulomatous reaction may be present - Immunohistochemistry ○ POS = CK7, MUC5AC ○ NEG = CK20, CDX2
Describe the staging for anal cancer
T1: <2cm
T2:2-5cm
T3:>5cm
T4: Local invasion of vagina/urethra/bladder
N1:
Regional LN metastases
M1
Distant metastases
AJCC8:
- Tumours arisiing within the skin at or distal to the squamous mucocutaenous junction that can be seen in their entirety with gentle traction placed on the buttocks and are within 5cm of the anus are “perianal cancers”
- Local treatment (surgery or RT alone) is only used when the lesion is VERY separate from the anal verge and is a discrete skin lesion
Discuss the evidence for the dose used in anal cancer.
Poor quality data currently directs optimal radiation dose
RTOG cross-trial comparison (John, 1996) ○ RTOG 9208 trial --> patients received 59.4Gy with concurrent 5-FU + MMC (with a scheduled 2-week break) ○ RTOG 8704 trial --> patients received 45Gy with concurrent 5-FU and MMC (no break) ○ The toxicity profiles were comparable, but the higher dose lead to higher colostomy rate (30% vs 9%) § Limitation is that dose boost was given as a split course
Further data is expected from the multi-arm PLATO trial (UK ACT group)
- ACT 3
○ Non-randomised trial investigating surgery alone for early stage small anal-cancers
- ACT 4
○ Randomised phase II trial for patients with intermediate risk disease
○ Randomise to standard dose chemoRT (50.4Gy/28F) vs low-dose (41.1Gy/23F)
- ACT 5
○ Randomised phase II/III trial for locally advanced anal cancers
○ Randomise to standard dose chemoRT (53.2Gy/28F) or dose-escalation (58.8Gy/28F or 61.6Gy/28F)
Describe radiotherapy toxicity in anal cancer and incidence.
Discuss prognosis in anal cancer and a suitable follow up schedule.
CRT = 70% complete response.
?15% persistent, 15% local recurrence
Colostomy free survival
- 70-80% at 5 years
○ ?10% for treatment toxicity
Most anal cancers recurrences occur within 2 years (80%)
Several studies suggest salvage APR has 30-77% LC after CCRT.
Follow-Up
- Takes 6 months for clinical response. No biopsy unless enlarging mass or ulcerated mucosa - - Clinical review every three months for two years ○ PR examination and inguinal nodal palpation at each visit - Clinical review every six months for years 3-5 ○ PR examination and inguinal nodal palpation at each visit - Annual CT CAP ○ MR pelvis is a reasonable alternative - Proctoscopy & EUA schedule (if tolerated) ○ 6 months post completion of chemoRT ○ Annually thereafter for 3 years (if normal) - No biopsy unless enlarging mass or ulcerated mucosa - ACT-II showed that optimal time for evaluation of disease response is 26 weeks, due to slow regression post treatment
Os
T1 90%
T3-4 70%
Node pos 50%
