Colorectal Cancer

Wim Ceelen GI Heelkunde UZ Gent

wim.ceelen@ugent.be

www.kankerregister.org

The burden of cancer in Belgium

Causes of colorectal cancer

Johnson CM Meta-analyses of colorectal

cancer risk factors. Cancer Causes Control. 2013

Jun;24(6):1207-22.

The gut and colorectal cancer

Wang X Microbiome-driven carcinogenesis in colorectal cancer: Models and mechanisms. Free Radic Biol Med. 2016 Oct 31

The gut microbioma and CRC: potential mechanisms

• Production of toxins that damage tight junctions, activate cellular signaling cascades, and produce inflammation that results in genetic damage (e.g., enterotoxigenic B. fragilis)

• Sulfate-reducing bacteria can produce HS that diffuses into epithelial cells to damage DNA (e.g., Fusobacterium spp. or B. wadsworthia

• Loss of mucus can allow bacteria and viruses to adhere and invade epithelial cells, activate signaling cascades, and produce DNA damage (e.g., toxin-producing E. coli or human papillomaviruses)

• Bacteria can translocate intact epithelium via M cells to polarize ordinarily quiescent mucosal macrophages and generate inflammation, bystander effects, DNA damage, and chromosomal instability

Dienstmann Nature Reviews Cancer 17, 79–92 (2017)

Guinney Nat Med 2015

Molecular subtypes of CRC

Colon cancer screening

• Methods– Left colonoscopy

– Total colonoscopy

– Imaging: CT or MR colonography

– Stool occult blood (iFOB), stool DNA

• Flanders: population screening age 55-75 (preventive medicine = Flemish community competence)

• https://www.dikkedarmkanker.bevolkingsonderzoek.be/

Other screening programs in Flanders

• Breast cancer:

https://borstkanker.bevolkingsonderzoek.be

• Cervix cancer:

https://baarmoederhalskanker.bevolkingso

nderzoek.be/

Colorectal cancer: workup

• Family history

• Endoscopy– Total colonoscopy + biopsies

– Obstructing tumor: total colonoscopy postop

– Low rectal cancer: EUS

• Imaging– CT scan chest and abdomen

– Low rectal cancer: MRI

– PET-CT: no role in staging

• CEA

TNM: other components

• G (1–4): the grade of the cancer S (0-3): elevation of serum tumor markers

• R (0-2): the completeness of resection: no –microscopic (histology margins) – macroscopic residual disease

• L (0-1): invasion into lymphatic vessels

• V (0-2): invasion into vein (no, microscopic, macroscopic)

• C (1–5): a modifier of the certainty (quality) of the last mentioned parameter

TNM: prefix parameters

• c: stage given by clinical and/or imaging examination

• p: stage given by pathologic examination of a surgical specimen

• y: stage assessed after neoadjuvant (preoperative) chemotherapy and/or radiation therapy

• r: stage for a recurrent tumor

• a: stage determined at autopsy.

• u: stage determined by ultrasonography or endosonography

https://cancerstaging.org/references-tools/quickreferences/pages/default.aspx

Example: staging of rectal cancer

• Clinical examination: fixed? Mobile?

• Colonoscopy + biopsies

• CT scan chest and abdomen

• Endoscopic ultrasound: T stage

• MRI of the pelvis: involved nodes? CRM?

• Serum CEA

Colorectal cancer TNM 7

Example: ypT4aN2bM0 L0V1 R0

Peritoneal Cancer Index (Sugarbaker)

Principles of surgical resection of a

primary colon cancer

• Aim: resection specimen with free microscopic margins (R0)

• Should include draining nodal basin to allow accurate N staging– Most guidelines: at least 12 LN’s should be

examined

– Colon cancer: mesocolon, rectal cancer: mesorectum

– Exceptions: most soft tissue sarcomas (GIST, liposarcoma)

Complete mesocolic excision (CME)

Hohenberger Colorectal Dis 2008

West NP. Understanding optimal colonic cancer surgery: comparison of Japanese D3 resection and European complete mesocolic excision

with central vascular ligation. J Clin Oncol. 2012 May 20;30(15):1763-9

West J Clin Oncol 2009

The case for CME

• In favour

– Highlights importance of sound surgical technique

– Increases LN count

– Improves DFS in retrospective studies

• Against

– Local, nodal recurrence of CC is rare

– Therapeutic effect probably nihil

– Increased complication rate

CME standard

Organ injury 9.1 % 3.6 % <0.001

Splenic

injury

3.2 % 1.2 % 0.004

SMV injury 1.7 % 0.2 % <0.001

Sepsis 6.6 % 3.2 % 0.001

Br J Surg 2016

Märkl World J Gastroenterol 2015

Confounding variables

Lymphocytic reaction to CRC is associated with

longer survival, and related to LN count

Overall lymphocytic reaction score: Crohn's-like reaction (0-3), peritumoral reaction (0-3),

intratumoral periglandular reaction (0-3), and TIL (0-3).

Ogino Clin Cancer Res 2009

High tie Low tie

Cirocchi Surg Oncol 2012

High tie versus Low tie: 5 year overall survival

Anastomotic leak

Kuhry Cancer Treat Rev 2008

Laparoscopic surgery for CRC: meta-analysis

Ann Surg 2011

SLN mapping using ICG and optical imaging (near infrared)

Watanabe DCR 2016

Adjuvant chemotherapy

• Stage III– 15-20% absolute decrease in risk of death

– Standard: FP with oxaliplatin

– Addition of bevacizumab without added value

• Stage II– 5% absolute decrease

– Tailored approach: high risk patients

Surgery for rectal cancer

• Anatomy and biology different from colon cancer– Largely extraperitoneal (2/3)

– More extensive systemic (not portal) venous drainage more often pulmonary metastasis

• Main challenges:– avoidance of local recurrence in the pelvis

• Standardized technique: total mesorectal excision (TME)

• Neoadjuvant treatment: radiotherapy or chemoradiation

– Avoidance of permanent colostomy (rectal amputation)

– Preservation of urogenital function

Carl Toldt (1840-1920)

Neoadjuvant therapy: for whom?

• All locally advanced rectal cancers (T3,T4)

• All node positive cancers

• Cancers close to the anal verge, when

aiming at SSS

• Cancers with a CRM margin < 5 mm

Preop RT: how?

Short course (5x5

Gy)

Long term CRT (25

fractions)

Interval with surgery 3-5 days At least 6 weeks

Allows downsizing no yes

Enhances pathol response no yes

May be combined with

chemotherapy/biologicals

no yes

Preoperative chemoradiation

• Sound rationale (radiosensitization; systemic

effect)

• Promising results in irresectable disease

(downstaging; enhance resectability)

• Resectable disease: numerous phase II trials– pCR rate:18.5% (95% CI:15.6–21.4)

– sphincter preservation rate: 58.7% (95% CI: 51.7–65.7)

– Acceptable treatment related toxicity (grade 3 or 4 toxicity: 2.8–

28%)

– post-operative morbidity (including anastomotic leaks) not

different from surgery alone series

Condiderations for adjuvant therapy

• Stage III– No trial data in rectal cancer only

– Reasonable to treat as stage III colon cancer

• Stage II or less– EORTC 22921 showed benefit of adj 5FU in ypT1-2, but not in yp T3-4

• Not shown in other trials

• Methodological flaws

– ypCR: significantly better survival (pooled analysis: HR 0.44, 95%CI 0.34-0.57; p<0.0001)

– Confounding yp stage versus c stage

– Reasonable to omit adj therapy in ypCR, and treat according to pretherapy N stage

Total Mesorectal Excision

• Based on:– pathological-clinical studies from the 1980s (Heald and

Quirke) showing distal spread in the mesorectum AND a significant relation between involvement of the circumferential resection margin (CRM) and local recurrence

• Encompasses:– Excision of (nearly) complete mesorectum in mid and

lower third cancers – down to the pelvic floor

– Preservation of CRM by sharp dissection

Heald RJ, Husband EM, Ryall RDH. The mesorectum in rectal cancer surgery:

the clue to pelvic recurrence? Br J Surg. 1982;69:613-616.

Miles E. A method of performing abdominoperineal excision for carcinoma of the rectum

and of the terminal portion of the pelvic colon. Lancet, 1908

A distal margin of < 10 mm is safe

Tumor

Rectum

Mesorectum

Effect of a surgical training programme on outcome of rectal cancer

in the County of Stockholm. Martling et al. Lancet 2000

Br J Surg 2002

16%

9%

Abdominoperineal resection (APR) – rectal amputation

The problem with rectal amputation in distal rectal cancer

Nagtegaal J Clin Oncol 2005

Evidence of the Oncologic Superiority of Cylindrical Abdominoperineal Excision for

Low Rectal Cancer. West et al. J Clin Oncol 2008

ELAPE: Cylindrical or

extralevator

resection In APR

Bianco F. Extralevator with vs nonextralevator abdominoperineal excision for rectal cancer: the RELAPe

randomized controlled trial. Colorectal Dis. 2017 Feb;19(2):148-157

Negoi Am J Surg 2016

Meta-analysis: ELAPE versus APR

Minimally invasive surgery for colon cancer

• Endoscopic: ESD (endoscopic submucosal

dissection)

• Hybrid techniques: NOTES

• Transanal surgery

• Laparoscopic surgery

– Standard: HD, 3D,...

– Robotic

ESD

• For early stage cancer (maximal pT1 with

superficial mucosal invasion: sm1)

• For malignant polyps

https://www.youtube.com/watch?v=kngn2NY6gC8

Transanale resectie

Transcoccygeale resectie (Kraske)

Transanale minimaal invasieve chirurgie (TAMIS)

Operatie-rectoscoop (Buess)

Transanal TME (TaTME)

NOTES (Natural orifice translumenal

endoscopic surgery)

https://www.intuitivesurgical.com/

Considerations for organ preservation

• Current CRT regimens: ypCR 15-20% max

• Smaller tumours higher response rate

• cCR difficult to ascertain

• Risk of LR prohibitive after local excision,

unless neoadjuvant CRT

LR

Kidane DCR 2014 (T1N0M0 rectal cancer)

DSS

Intra-operative radiotherapy

• Main indication: locally recurrent disease

• External photon radiotherapy

• External electron radiotherapy

• High dose rate brachytherapy

Mobile, self-shielded electron linear accelerator (LINAC) designed to deliver Intraoperative

Radiation Therapy (IORT) to cancer patients during surgery

Afterloading unit

Intraoperative HDR Brachytherapy

γ

Surgery for peritoneal metastases

Michielsen Eur Radiol 2014

Whole body DWI-MRI as imaging standard

Peritoneal – plasma barrier

Flessner M. In: Intraperitoneal Cancer Therapy: Principles and Practice, T&F 2016

Ceelen Nat Rev Clin Oncol 2010

How to enhance the efficacy of IPDD?

• Increased exposure time

• Novel drug formulations: thermosensitive gels; nanocarriers

• Addition of hyperthermia

• Manipulation of tumor stroma– IFP reduction: antifibroblast therapy, antiangiogenic

therapy

– Hyaluronidase

– ‘Priming’ with paclitaxel

• Vasoconstriction (epinephrin)

• Increased IP pressure (e.g. PIPAC)

Pressurized Intraperitoneal Aerosol Therapy

(PIPAC)