Colorectal Cancer

Introduction

Colorectal cancer is a major public health problem in western countries, with the highest incidence rates in North America, Western Europe, Australia, and New Zealand. Excluding skin cancers, it is the third most common cancer in both men and women, and the third most common cause of cancer death in men and fourth in women [1]. Colon cancer is 2.5 times more common than rectal cancer, and both have different natural histories and thus separate treatment strategies. About 90-95% of all colorectal cancers are adenocarcinomas, with the remainder comprised of squamous cell, neuroendocrine or undifferentiated carcinomas.

Epidemiology and Etiology

• Incidence of over 100,000 new cases of colon cancer and 45,000 new cases of rectal cancer in the United States, both being more common in men than women. Incidence rates are higher amongst African Americans than Caucasians [1,2]. 
• Incidence of colorectal cancer decreased 35% between the 1990s and 2016 due to screening, but the overall incidence in younger patients has doubled, driven mostly by rectal cancer. The underlying etiology is a subject of debtate, but hypotheses include increased childhood consumption of processed foods and obesity.
• Mortality rate as high as 55,000/year, with age-adjusted mortality rate highest in African American males. Colon cancer is now the leading cause of cancer death in males under fifty and second for females under fifty, after breast cancer [3].
• Etiology is highly associated with lifestyle-associated risk factors and has been linked to germline or somatic genetic mutations in colonic epithelium, leading to a neoplastic phenotype.
  • High yield: Colorectal cancer typically requires multiple germline and somatic mutations. In a commonly tested pathway, first an APC mutation (either acquired or inherited) places the epithelium at risk, a subsequent KRAS mutation cause a benign polyp. Finally, loss of p53 triggers malignant transformation. There are many pathways, but medical students should be aware of this example.
• Hereditary autosomal dominant syndromes associated with increased risk include familial adenomatous polyposis (FAP) and Lynch syndrome, formerly known as hereditary non-polyposis colon cancer (HNPCC) [4,5].

Table 1: Comparison of Hereditary Syndromes in Colorectal Cancer

• Modifiable risk factors include obesity; diabetes; smoking, alcohol consumption, red meat consumption, high-fat, low-fiber diets; deficiencies of vitamins D and E, calcium, and selenium; and low levels of physical activity.
• Additional risk factors include adenomatous polyps, which are believed to be precursors to malignancy, inflammatory bowel disease and family history.
• Regular aspirin intake has been associated with lower incidence and mortality associated with colorectal cancer [5].

Screening

• For average risk adults, the American Cancer Society (ACS) recommends:
  • Flexible sigmoidoscopy every 5 years after age 45, or alternatively, colonoscopy every 10 years.
  • Fecal occult blood test (guaiac test) yearly after age 45.
• Clinical Presentation
• History: Variable, nonspecific presentation including rectal bleeding (hematochezia), change in bowel habits and stool caliber, especially pencil thin stools, and abdominal pain, especially with left-sided tumors; rectal cancers often present with tenesmus (urgency) and rectal bleeding; metastatic disease presents with systemic symptoms of weight loss, anorexia, jaundice if liver involved.
• Physical exam: Hemoccult positive stool, hepatomegaly, abdominal mass.
• Lab studies: CBC with differential, showing anemia in right-sided tumors due to chronic blood loss; chemistry panel including liver and renal functions; serum CEA; CA 19-9.
• Diagnostic studies: Colonoscopy with biopsies is best; proctosigmoidoscopy gives limited data due to shorter scope length but may be used if rectal cancer is suspected. Air contrast barium enema is useful but requires colonoscopy if lesions are visualized.
  • Molecular studies to detect BRAF V600E, KRAS, or NRAS mutations. Biopsy specimens may also be evaluated for the presence of microsatellite instability or mutations in mismatch repair genes.

Imaging

• Abdominal, chest pelvis CT + MRI for all patients.

Natural Course and Pathology

• Staging: Pathologic stage following tumor resection is single most important prognostic factor and is based on the depth of tumor invasion into and through the intestinal wall, the number of regional lymph nodes involved, and the presence or absence of distant metastasis [6]. American Joint Committee on Cancer (AJCC) system is most widely used clinical and pathologic staging system. T and N classifications are considered to be important prognostic factors.
• Most common sites of metastases are liver, lung, and bone, but peritoneal metastases may also occur. Local pelvic recurrence is a common problem in rectal cancer.
• Poor prognostic factors include elevated preoperative CEA level; poor health status at diagnosis; mucinous and signet-ring patterns on histology; bowel wall/regional lymph node/perineural invasion; evidence of bowel obstruction or perforation, advanced stage at diagnosis (especially T and N). Associated but not fully established prognostic markers include low DNA ploidy, high S-phase fraction, DCC gene deletion, p53 and KRAS mutations [7].

Treatment

Early-stage disease of colon

• Surgery is initial therapy of choice for localized, potentially curable cases. Postoperative treatment and survival depend on pathologic stage of tumor.
• Radiation therapy preoperatively has not improved overall rates of survival, distant recurrence, or cure in colon cancer [8]. Radiation may be considered postoperatively for larger, fixed tumors or for close/positive margins.
• Adjuvant chemotherapy: Standard of care includes capecitabine or 5-FU. Adjuvant therapy typically consists of combination chemotherapy such as FOLFOX (folinic acid, oxaliplatin, 5-FU) or CAPOX (capecitabine + oxaliplatin) or standalone capecitabine. Immunotherapy can be used in patients who have tested positive for hereditary colorectal cancer syndromes and remain under investigation for other patient cohorts.  
  • Autologous tumor vaccines have been under investigation for decades with little success. Recently, however, the ability to quickly identify and sequence tumor antigens has accelerated tumor vaccine research with some success. In 2012, a Phase III trial in the Netherlands showed significant benefit and minimal side effects for stage II colon cancer patients [9].
• Perioperative infusion of chemotherapy into portal vein may play role in reducing risk of developing hepatic metastases, but data is inconclusive at present. Bevacizumab in combination with FOLFOX has been shown to prolong progression free survival in metastatic colorectal cancer patients when used as a first line treatment, though data has been mixed [10, 11].

Early-stage disease of rectum

• Upfront surgery is the preferred approach for early stage, node negative tumors. Additional therapy is generally recommended for patients with larger tumors and positive lymph nodes found on pathologic examination. One such approach is postoperative chemoradiation followed by chemotherapy alone [12, 13].
• Chemotherapy agent of choice is 5-FU and oxaliplatin-based therapies. Infusional 5-FU and mitomycin with radiation has achieved 5-year survival rates of about 70% [14, 15].

Metastatic colorectal cancer

• Surgical resection of metastases associated with long-term disease-free survival in 25-40% of patients able to undergo resection [15, 16]. All operative candidates require extensive pre-operative evaluation to determine appropriateness of surgery.
• Radiation for palliative treatment and control of symptoms (pain, bleeding)
• Systemic chemotherapy with various 5-FU based regimens. Regional therapy includes delivery of chemotherapy into the hepatic artery thorough implantable infusion pumps, with fluorodeoxyuridine (FUDR) being the most commonly used agent.