Comprehensive overview of management guideline in colorectal cancer

1. Management Guideline in
Colorectal Cancer
Dr Atul Gupta
DM Resident
Radiotherapy & Oncology
AIIMS Jodhpur

2. • Epidemiology
• Screening Principles
• Diagnostic Work-up
• Treatment Guidelines (NCCN & ESMO)
• Follow-up Principles
Topics to be discussed -

4. Etiological Factors -
Source- Devita(12th edition)

5. Screening Principles -
Who are at high risk?
1. Medical H/O adenoma, colon cancer, IBD
2. Significant family h/o CRC or adenoma
3. An Inherited cancer syndrome (as FAP, HNPCC, Turcot,
Peutz-Jeghers)
For average risk population-
(Age>45yrs, No H/o Adenoma/CRC, No H/O IBD, Negative
family history)
1. Colonoscopy-
• Optimal age range- 50-74 yrs, with an optimal repetition
interval for a negative test of 10yrs
• Flexible sigmoidoscopy every 5-10yrs , should be
combined with fecal occult blood test
2. Non-invasive test-
• Recommended from age of 50yrs in average risk
population who are not taking part in colonoscopic
screening programmes (annually or no later than 3 yrs)
• High Resolution fecal occult blood test
• Fecal immunochemical testing
• Novel test- DNA based tests
Source- NCCN Guideline Version 3.2022, ESMO Guideline

6. Screening Principles in high risk population-
1. If personal h/o IBD present----------> either colonoscopy or chromoendoscopy to be
done------> IBD to be managed-------> colonoscopic follow-up every 2-3 yrs
2. If Positive family history present-
• >= 1 first degree relative with CRC at any age----> colonoscopy beginning at age 40yrs
or 10yrs before earliest diagnosis of CRC------->repeat every 5 yearly
• Second or third degree relative at any age-------> colonoscopy beginning at 45yrs age--
----->repeat every 10yearly
3. FAP- Flexible sigmoidoscopy to start at ages 10 to 12 y. Genetic testing (for FAP,
upper endoscopy with side-viewing scope) should be done every 1 to 3 yearly
4. HNPCC- Colonoscopy every 1 to 2 y starting at ages 20 to 25 y or 10 y younger than
the earliest case in the family, whichever comes first
Source- NCCN Guideline Version 3.2022, ESMO Guideline

7. Diagnosis of Colo-rectal Cancer-
Symptoms Signs
Lower GI Bleeding Palpable Mass
Alteration in bowel habits Adenopathy
Abdominal Pain Hepatomegaly
Change in Appetite, Weakness Jaundice
Obstructive symptoms Pulmonary Signs (s/o metastasis)
Bright Bleeding PR ( Left sided CRC)
Malena (Right sided CRC)
Source- Devita(12th edition)

8. Source- ESMO Guideline 2022

9. AJCC 8th Edition Staging-
T staging-
• T1- tumor invading submucosa
• T2- tumor invading the muscularis propria
• T3- tumor invades through muscularis propria
into peri-colorectal tissues
• T4a- Tumor invades through visceral peritoneum
• T4b- Tumor directly invades or adheres to
adjacent organs or structures
N Staging-
• N1a- one regional LN positive
• N1b- 2 or 3 LN positive
• N1c- tumor deposits in subserosa, mesentry or
perirectal tissues
• N2a- 4 to 6 LN positive
• N2b- >=7 LN positive
M Staging-
• M1a- Metastasis to one site/organ without peritoneal metastasis
• M1b- Metastasis to two or more sites without peritoneal metastasis
• M1c- Metastasis to peritoneal surface with/without other
site/organ metastasis

10. Management of Localized Colon Cancer

11. Source- ESMO Guideline 2022
• For hyperplastic/adenomatous polyps/non-invasive
adenocarcinoma(Tis)- Endoscopic resection is sufficient
• For Invasive Carcinoma(pT1)- management determined by
polyp morphology and presence of histological features associated
with adverse outcome-
 Lymphatic or venous invasion
 Grade 3 differentiation
 Significant (Grade >1) tumor budding
 <2mm negative margin
• For a pedunculated polyp with a pT1 carcinoma confined to the head,
neck and stalk (Haggitt 1-3), endoscopic resection with proper follow-
​up is sufficient, even with the presence of submucosal invasion, pro-
vided there are no other unfavorable factors
• The presence of any un-favorable factor in a sessile or flat polyp
(Paris classification) with a pT1 carcinoma mandates surgical resec-
tion in patients with average operative risk. The goal is complete le-
sion resection, including lymph node removal for optimal risk assess-
ment.

12.  Management of locally infiltrative colon cancers -
• Infiltrative colon cancers require surgery, with the goal of wide resection of the involved bowel segment and its lymphatic
drainage
• Resection should include a segment of colon of at least 5 cm on either side of the tumor
• En bloc colonic and mesentery resection is recommended to clearly define stage II versus stage III disease and to identify
and eradicate potential lymph node metastases; ≥ 12 lymph nodes should be resected, when feasible
• En bloc resection of adjacent organ-​invaded portions must be carried out in case of pT4b disease
• During the procedure, a complete assessment of the peritoneal cavity and ovaries should be carried out to investigate for
possible metastases
• Laparoscopic colectomy can be safely carried out for colon cancer when technical expertise is available in the absence of
contraindications
Source- ESMO Guideline 2022

13. CRC Pathogenesis
MSI
Chromosome
Instability Pathway
MSI-H
 15% of CRC
 Associated with defective DNA mismatch repair function
 Mutation in DNA mismatch repair gene as
MLH1,MSH,MSH6,PMS2
 Mostly right sided, high grade
 More likely to be node negative
 Better long term prognosis
 Responds better to immunotherapy with PD-1 blockers
Chromosome instability
pathway(MSS)
 85% of CRC
 Genetic alteration involving LOH,
chromosome amplification and
translocations
• Universal MMR or MSI testing is recommended in all newly diagnosed patients with colorectal cancer.
• Testing for MSI may be accomplished by polymerase chain reaction (PCR) or a validated NGS panel, the
latter especially in patients with metastatic disease who require genotyping of RAS and BRAF.

15. Adjuvant treatment in locally infiltrative colon cancer-
Prognostic factors for risk assessment-
• Lymph-node sampling <12
• pT4 stage including perforation
• High grade tumor
• LVSI/PNI
• Tumor presenting with obstruction
• High pre-op CEA Level
MSI/MMR status – most validated prognostic
molecular marker in deciding adjuvant therapy
• Adjuvant single-​agent
5-​fluorouracil (5-​FU)
decreases the risk of
death by 3-5% in
high-​risk stage II
colon cancer
• Adjuvant fluoropyrim-
idines (FPs) alone de-
crease the risk by 10-
15% in stage III dis-
ease, with a further 4-
5% improvement us-
ing oxaliplatin-​contain-
ing combinations
Source- ESMO Guideline 2022
Relative C/I for adj CT-
1. ECOG >2
2. Uncontrolled infection
3. Severe liver/renal dysfunction
4. HF (NYHA III or IV)
5. Other Co-morbidities

16. Adjuvant Treatment in Stage II Colon Cancer
Timing of Adjuvant Chemotherapy-
• Adjuvant ChT should be commenced as
soon as possible after surgery and ideally
not later than 8 weeks
• Population-​based studies have shown that
some benefit may be derived from adjuvant
ChT with delays up to 5-6 months but that
benefit is minimal or absent if adjuvant ther-
apy is started > 6 months after surgery
Source- ESMO Guideline 2022

17. Adjuvant Treatment in Stage III Colon Cancer
Source- ESMO Guideline 2022, NCCN Guideline 2.2023
1. (Andre T, et al. Lancet Oncol 2020;21:1620-1629).
2. Grothey A, et al. N Engl J Med 2018;378:1177-1188
 While non-inferiority of 3 mo vs. 6 mo of CAPEOX has not
been proven, 3 mo of CAPEOX numerically appeared similar
to 6 mo of CAPEOX for 5-year overall survival (82.1% vs.
81.2%; hazard ratio [HR], 0.96), with considerably less
toxicity .¹
These results support the use of 3 mo of adjuvant CAPEOX
over 6 mo in the vast majority of patients with stage III colon
cancer.
 In patients with colon cancer, staged as T1–3, N1 (low-risk
stage III), 3 mo of CAPEOX is non-inferior to 6 mo for
disease-free survival (DFS); non-inferiority of 3 mo vs. 6 mo
of FOLFOX has not been proven.
 In patients with colon cancer staged as T4, N1–2 or T any,
N2 (high-risk stage III), 3 mo of FOLFOX is inferior to 6 mo
for DFS, whereas non-inferiority of 3 mo vs. 6 mo of
CAPEOX has not been proven. Grade 3+ neurotoxicity rates
are lower for patients who receive 3 mo vs. 6 mo of
treatment (3% vs. 16% for FOLFOX; 3% vs. 9% for CAPEOX).²

18. High-risk factors for recurrence (exclusive of
those cancers that are MSI-H):
 poorly differentiated/undifferentiated
histology
 lymphatic/vascular invasion
 bowel obstruction
 <12LN examined
 PNI positive
 Close/positive margins
 Localized perforation

19. Management of Metastatic Colon Cancer

23. Follow-up Recommendations for Patients with Colon Cancer

24. • Detection of recurrences may be improved with intensive follow-​up, although precise algorithms for op-
timal surveillance have not been defined
• CT scanning, including optimal liver assessment, is more sensitive than ultrasonography for liver re-
lapse follow-​up and can detect chest recurrences
• Liver MRI may be an alternative when a CT scan shows confusing liver lesions
• History, physical examination and CEA determination are advised every 3-6 months for 3 years and ev-
ery 6-12 months at years 4 and 5 after surgery
• Colonoscopy must be carried out at year 1 and every 3-5 years thereafter, looking for metachronous
adenomas and cancers.
• CT scans of the chest and abdomen every 6-12 months for the first 3 years can be considered in pa-
tients who are at higher risk of recurrence according to the TNM classification
• Other laboratory and radiological examinations are of unproven benefit and must be restricted to pa-
tients with suspicious symptom
Source- ESMO Guideline 2022

25. Management of Rectal Cancer

26. Risk Factors Protective factors
High BMI , T2DM Healthy lifestyle
Long standing IBD Consumption of garlic, milk, high calcium diet,
high fiber diet
Excessive consumption of red meat/processed
meat, Tobacco
NSAID & Vit D consumption
Hereditary Association
(Colon>Rectum)
Etiological Factors -

27. Location Rigid proctoscopy Flexible Endoscopy MRI
Low Upto 5cm Upto 5cm Upto 4cm
Middle 5-10cm 5-10cm 4-8cm
High 10-15cm 10-15cm 8-12cm
Reference Level Anal Verge Anal Verge Anorectal Junction

29. Changing Paradigm in management of Rectal Cancer-

31.  High-risk features include positive margins, lympho-vascular invasion, poorly differentiated tumors, or
sm3 invasion (submucosal invasion to the lower third of the submucosal level)

32.  A benefit for the addition of oxaliplatin to 5-FU/leucovorin in patients aged ≥70 years has not been proven.
 Observation following transabdominal resection can be considered in patients with pT3N0 rectal cancer if the tumor was well-
differentiated or moderately well differentiated carcinoma invading less than 2 mm into the mesorectum, without lymphatic or venous
vessel involvement and was located in the upper rectum. ¹
1. Willett CG, et al. Dis Colon Rectum 1999;42:167-173.

35. Response Assessment post NACTRT-
• The standard methods of clinically re-assessing patients following preoperative therapy are DRE, proctoscopy
and MRI re-imaging
• Routine chest and abdomen restaging after neoadjuvant CRT is not recommended, but patients with more ad-
vanced cT4 cancers, threatened CRM and the presence of EMVI, should be re-staged within 3 months of origi-
nal staging to exclude metastatic disease prior to surgery
• This is not recommended for earlier stage tumors unless clinical progression, including new symptoms or dra-
matically increased serum CEA, is observed

36. Post NACTRT response Assessment-
cCR & Wait & Watch Approach¹
• Following CRT or SCPRT, 10-40% of patients achieve a clinical
complete response (cCR) at 12 weeks from the start of treat-
ment, depending on initial stage and currently unknown molecu-
lar factors
• A cCR is the absence of any palpable tumour or irregularity at
DRE, no visible lesion at rectoscopy except a flat scar, telang-
iectasia or whitening of the mucosa and can also include ab-
sence of any residual tumour in the primary site and draining
lymph nodes on imaging with MRI or ERUS, and negative biop-
sies from the scar
• An initially raised CEA level which returns to normal (< 5 ng/mL)
after CRT is associated with an increased likelihood of cCR and
pCR
• Dedicated centres have reported encouraging oncological and
functional outcome results for selected patients treated with
standardised CRT and a non-operative strategy
• Longer follow-up and more patients treated in controlled
prospective studies are needed to validate the watch-and-wait
approach and large databases, such as the European Registry
of Cancer Care (EURECCA) database, will provide more guid-
ance
Patients Planned for Surgery-
• In LARC, the primary tumour/​CRM should be re-evaluated with MRI after CRT prior to resection, although
this may both underestimate (poor discrimination between residual tumour and radiation-induced fibrosis)
and overestimate pathological response and T downstaging (tumour fragmentation)
• MRI tumour regression grading can discriminate/determine good and poor responders and predict survival
outcomes, but does not correlate well with histopathological tumour regression grade (TRG)
• For SCPRT in resectable cancers not requiring downstaging, immediate surgery [within 7 days from the end
of neoadjuvant treatment, and within 0-3 days if the patient is ≥ 75 years (< 10 days from the first RT frac-
tion)] is recommended
• In practice, the timing of surgery varies widely (4-12 weeks) due to patient/​surgeon choice, recovery from
treatment and/​or waiting list issues 1. Pozo ME, Fang SH. Watch and wait approach to rectal cancer: A review. World J
Gastrointest Surg. 2015 Nov 27;7(11):306-12. doi: 10.4240/wjgs.v7.i11.306. PMID:
26649153; PMCID: PMC4663384.

37.  Prospective, randomized phase II trial
 324 patients with stage II or III rectal adenocarcinoma treated
with induction chemotherapy followed by chemoradiotherapy
(INCT-CRT) or chemoradiotherapy followed by consolidation
chemotherapy (CRT-CNCT) and either total meso-rectal
excision (TME) or watch-and-wait on the basis of tumor
response.

38. Management of Metastatic Rectal Cancer

39. OVERVIEW-
• Metastatic rectal cancer management should reflect tumour- and disease-related characteristics, pa-
tient-related factors (comorbidity, socioeconomic factors and expectations of the patient) and treat-
ment-related factors, such as toxicity
• ChT alone may be insufficient where the primary tumour remains in situ and untreated, and local RT
palliation of rectal symptoms may be required
• SCPRT is preferable to CRT, allowing systemic ChT to start within 2 weeks from treatment initiation,
palliating symptoms in most patients and avoiding salvage stoma for some
• If the patient has a chance for cure (oligometastatic disease), rapid local control with effective sys-
temic ChT and appropriate sequence/​timing of metastasectomy is the aim
• SCPRT with triplet ChT (capecitabine–oxaliplatin–bevacizumab) facilitates resection of borderline re-
sectable liver metastasis and the primary tumour, but in the absence of randomised studies, the MDT
should be responsible for critical treatment decisions in patients with potentially curable metastatic dis-
ease.

42.  A positive CRM was defined as involvement of mesorectal fascia or tumour within 1 mm of the
mesorectal fascia for upper and mid-rectal tumours.
 Disease involving or within 1 mm of inter-sphincteric plane or levator ani muscle was considered
as involved CRM for low rectal tumours.

44. Recommendation 1.1. Doublet (folinic acid, fluorouracil [FU], and oxaliplatin [FOLFOX], or folinic acid, FU, and irinotecan
[FOLFIRI]) backbone chemotherapy should be offered as first-line therapy to patients with initially unresectable
microsatellite stable (MSS) or proficient mismatch repair (pMMR) mCRC (Type: Evidence-based, benefits outweigh harms;
Evidence quality: Moderate; Strength of recommendation: Strong)
Recommendation 1.2. Triplet (folinic acid, FU, oxaliplatin, and irinotecan [FOLFOXIRI]) backbone chemotherapy may be
offered as first-line therapy to selected patients with initially unresectable MSS or pMMR mCRC (Type: Evidence-based,
benefits outweigh harms; Evidence quality: Moderate; Strength of recommendation: Weak).
Recommendation 2.1 Pembrolizumab should be offered as first-line therapy to patients with microsatellite instability-high or
deficient mismatch repair mCRC (Type: Evidence-based, benefits outweigh harms; Evidence quality: Moderate; Strength of
recommendation: Strong

45. Recommendation 3.1 Anti–epidermal growth factor receptor (EGFR) therapy plus doublet chemotherapy should be
offered as first-line therapy to patients with MSS or p-MMR left-sided RAS wild-type mCRC (Type: Evidence-based, benefits
outweigh harms; Evidence quality: Moderate; Strength of recommendation: Strong)
Recommendation 4.1. Cytoreductive surgery (CRS) plus systemic chemotherapy may be recommended for selected
patients with colorectal peritoneal metastases (Type: Evidence-based, benefits outweigh harms; Evidence quality:
Moderate; Strength of recommendation: Weak).
Recommendation 4.2. Oxaliplatin-based hyperthermic intraperitoneal chemotherapy is not recommended as an addition
to CRS for treatment of patients with colorectal peritoneal metastases (Type: Evidence-based, harms outweigh benefits;
Evidence quality: Moderate; Strength of recommendation: Strong).
Recommendation 5.1. Stereotactic body radiation therapy may be recommended following systemic therapy for patients
with oligo-metastases of the liver who are not considered candidates for resection (Type: Evidence-based, benefits
outweigh harms; Evidence quality: Low; Strength of recommendation: Weak)
Recommendation 6.1. Surgery with or without perioperative chemotherapy should be offered to patients with mCRC who
are candidates for potentially curative resection of liver metastases (Type: Evidence-based, benefits outweigh harms;
Evidence quality: Moderate; Strength of recommendation: Weak).

47. Thanks