Colorectal cancer

Abstract

Colorectal cancer had a low incidence several decades ago. However, it has become a predominant cancer and now accounts for approximately 10% of cancer-related mortality in western countries. The 'rise' of colorectal cancer in developed countries can be attributed to the increasingly ageing population, unfavourable modern dietary habits and an increase in risk factors, such as smoking, low physical exercise and obesity. New treatments for primary and metastatic colorectal cancer have emerged, providing additional options for patients; these treatments include laparoscopic surgery for primary disease, more-aggressive resection of metastatic disease (such as liver and pulmonary metastases), radiotherapy for rectal cancer, and neoadjuvant and palliative chemotherapies. However, these new treatment options have had limited impact on cure rates and long-term survival. For these reasons, and the recognition that colorectal cancer is long preceded by a polypoid precursor, screening programmes have gained momentum. This Primer provides an overview of the current state of the art of knowledge on the epidemiology and mechanisms of colorectal cancer, as well as on diagnosis and treatment.

Figure 1. Colorectal neoplasia at different stages

(a) A small sessile adenoma. (b) An advanced, larger sessile adenoma. (c) A large, dish-shaped, ulcerating sigmoid carcinoma. The tumour covers most of the circumference, but has not yet led to substantial obstruction of the lumen.

Figure 2. The age-standardized incidence and mortality rates in men (m) and women (f) (per 100.000 people) across geographic zones

Rates are consistently higher in men than in women, and vary considerably between regions. Highest rates occur in Australia and New Zealand, Europe and North America.

Figure 3. The polyp to colorectal cancer sequences

Currently, two discrete normal colon to colorectal cancer sequences have been identified. Both sequences involve the progression of normal colon epithelial cells to aberrant crypt foci, followed by early and advanced polyps with subsequent progression to early cancer and then advanced cancer. The ‘classic’ or traditional pathway (top) involves the development of tubular adenomas that can progress to adenocarcinomas. An alternate pathway (bottom) involves serrated polyps and their progression to serrated colorectal cancer has been described in the last 5–10 years. The genes mutated or epigenetically altered are indicated in each sequence; some genes are shared between the two pathways whereas others are unique (for example, BRAF mutations and CpG Island Methylator Phenotype (CIMP) only occur in the serrated pathway). The signalling pathways deregulated during the progression sequence are also shown, with the width of the arrow reflecting the significance of the signalling pathway in tumour formation. APC, adenomatous polyposis coli; CIN, chromosomal instability; CTNNB1, catenin-β1; FAM123B, family with sequence similarity 123B (also known as AMER1); FZD10, frizzled class receptor 10; LRP5, low-density lipoprotein receptor-related protein 5; MAPK, mitogen-activated protein kinase; MSI, microsatellite instability; PI3K, phosphatidylinositol 3-kinase; PI3KCA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-α; PTEN, phosphatase and tensin homologue; SFRP, secreted frizzled-related protein; SMAD4, SMAD family member 4; TGFβ, transforming growth factor-β; TGFBR2, TGFβ _receptor 2. Figure adapted from , Nature Publishing Group.

Figure 4. Surgical planes for right colon surgery

The mesocolon harbours the major blood vessels and draining lymph nodes; surgical planning involves considering the large blood vessels and the resection lines. For the caecum and the ascending colon (before the hepatic flexure), the main vessels are the ileocolic and right colic artery. The transverse colon begins at the hepatic flexure and ends at the splenic flexure; important vessels to consider in this region are the middle colic artery (via the superior mesenteric artery) arcading on the left side, with branches of the left colic artery (inferior mesenteric artery). The descending colon ‘bends’ at the sigmoid colon (at the left iliac crest) before continuing to the rectum. In the paracolic grooves, the parietal peritoneum is attached to the lateral border of the visceral peritoneum that overlies the colon and forms the surgical planes referred to as White Line of Toldt, which gives access to the avascular plane above Gerota’s fascia — the fascia on top of the retroperitoneum covering the kidney and ureter — without interfering with peri-renal space or ureters.

Figure 5. Laparoscopic surgery for colorectal cancer

(a) A sigmoidectomy can be performed using three to six trocars. The laparoscopic exploration via the supraumbilical trocar (position 2) is a guide for the location of the other operating trocars. (X) The tumour location. (1) A 5 mm trocar in the left hypochondrium, for retracting the descending colon. (2) The first trocar to be introduced is a 12 mm trocar through the umbilical port. (3) A 12 mm trocar is used as an optical and operating port. (4) A 5 mm trocar is used for retracting tissue. (5) Carbon dioxide insufflation: pneumoperitoneum. (b) The number of trocar ports for right colectomy varies from depending on the surgeon and operative difficulties. Trocar positioning is also variable, but our standard for a tumour in the caecum (shown in insert, position X) approach is to place (1) a 12 mm trocar in left hypochondrium as an optical or operating port. (2) The umbilical port side can be extended to a small laparotomy to extract the dissected colon and perform the extracorporeal anastomosis. (3) A 5 mm trocar is placed for operating and retracting the tissue (ascending colon or caecum). (4) A 5 mm trocar is used to retract the hepatic flexure, to expose ileocolic and right colic vessels, and perform the division. In both images, the patient’s head is at the top, their feet at the bottom.

Figure 6. Stoma surgery for colorectal cancer

A colostomy is a surgical procedure in which a stoma (from the Greek for ‘mouth’ or ’opening’) is formed by drawing the healthy end of the large intestine (colon) through an incision in the anterior abdominal wall and suturing it into place. (a) For stoma positioning (sites 1–4), the subcostal line, lateral border of the rectal abdominus muscle, anterosuperior spine of the ilium, shape of the abdomen and abdominal creases (for example, when trousers and belt are worn, and while sitting) are considered. Ill-placed ostomies result in invalidating leakage and dermatitis. The position of an end ileostomy or a loop ileostomy is preferable in the right hypochondria (position 1); a loop transversostomy is preferred in the right upper quadrant (position 2) to preserve the left side upper and lower quadrants (positions 3 and 4, respectively) for a definitive end colostomy if necessary. (b) In end stoma formation, the inside of the intestinal loop with the mucosa is placed at the abdominal wall. End stomas provide only one lumen, commonly formed to stay. A well-placed ostomy is about 2–3 cm above the skin, which ensures that the faeces are not in contact with the skin. (c) In loop stoma formation, two openings are sewn into the skin: efferent and afferent. The afferent (in) limb produces the stool and the efferent (out) limb allows passage of flatus from the distal portion of the bowel.

Figure 7. Surgical planes for rectal surgery

The plane between the urogenitoury structures (prostate, urethra and seminal vesicle in men, and the vagina, uterus and ovaries in women) and the rectum is called Denonvilliers’ fascia. The dissection plane of the total mesorectal excision is sharp around the mesorectal fascia and surrounds the mesorectal fat, in which the draining lymph nodes and the rectum are located. The plane is avascular, and avoids the parasympatethic and sympathetic nerves in the pelvic lateral space, which coordinate sexual and urinary function. The superior hypogastric plexus is formed at the level of the sacral promontory, distally dividing in the hypogastric nerves. Together with the parasympathetic erigentes nerves, these form the inferior hypogastric (pelvic) plexus, which should not to be clamped during surgery to avoid damage. The pudendal nerve innervates the external sphincter, puborectalis muscle and external genitalia, among other structures.

Figure 8. Emerging drug targets and drug candidates in colorectal cancer

The Cancer Genome Atlas and various other genomics projects have identified several novel potential molecular targets and markers in colorectal cancer that might be used to guide specific treatments for subgroups of patients. These targets include the Wnt, transforming growth factor (TGF)-β and epidermal growth factor (EGF) receptor signaling pathways. Experimental agents targeting these molecules are included in grey boxes. APC, adenomatosis polyposis coli; BMP, Bone morphogenetic protein; BMPR, BMP receptor; CK1, casein kinase 1; Dsh, Dishevelled; GSK3, glycogen synthase kinase 3; LRP, low-density lipoprotein receptor-related protein; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; P (in a red circle), phosphate; PDK, 3-phosphoinositide-dependent protein kinase; PI3K, phosphatidylinositol 3-kinase; PIP₂, phosphatidylinositol-(4,5)-bisphosphate; PIP₃, phosphatidylinositol-(3,4,5)-trisphosphate; PTEN, phosphatase and tensin homologue; SFRP, Secreted frizzled-related protein 1; SMAD, SMAD family member; TGFβR, TGF)-β receptor.