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Colorectal Cancer

Table of Contents
1 Disease Overview
        1.1 Screening, Risk Factors and Prevention
        1.2 History, Symptoms and Signs
        1.3 Diagnosis and Tumour Assessment
2 Staging
3 Stage Grouping
4 Treatment Modalities
        4.1 Surgery
        4.2 Chemotherapy
        4.3 Advanced Colorectal Cancer Stage IV
        4.4 Biologic agents
5 Follow-up
6 Pivotal Trials

Disease Overview

    Colorectal Cancer (CRC) is the second leading cause of cancer death in Canada and affects both men and women equally. It is estimated that in 2014, there will be an incidence of 24,400 cases, with 13,500 men and 10,800 women diagnosed with CRC. The estimated mortality rate in 2014 is 5,100 men and 4,200 women dying due to CRC (Canadian Cancer Society, 2014). It is both sporadic and familial.

Screening, Risk Factors and Prevention

    Screening colonoscopies have documented benefit on cancer-related mortality (Nishihara R, N Engl J Med 2013; Shaukat A, N Engl J Med 2013). The benefit of aspirin as secondary prophylaxis in patients with resected colorectal cancers appears to be linked to the presence of PIK3CA mutations (Liao X, N Engl J Med 2013; Domingo E, J Clin Oncol 2013).

Risk factors identified for colon cancer include the following:

  • Age
  • Race: Incidence is greater in individuals of African-American decent
  • Dietary factors: diet high in red meat and animal fat and low in fibre, fruits and vegetables
  • Lifestyle factors: alcohol use, smoking, obesity, sedentary lifestyle
  • Inflammatory bowel disease particularly ulcerative colitis increases the risk of colon cancer estimated to at 5-10% at 20 years after the diagnosis, synchronous cancers are common.
  • Genetic factors: There are two common inherited forms of colorectal cancer
      • Hereditary nonpolyposis colon cancer (HNPCC or Lynch I and II) is an inherited autosomal–dominant disease with high penetrance. Patients who inherit a mutant of this gene develop CRC at younger age. For patients with Lynch II Syndrome or HNPCC are at risk of developing other cancers such as; ovarian, pancreatic, breast, biliary, endometrial gastric, genitourinary and small bowel primaries. Approximately 5% of colorectal cancers associated with this syndrome. The genetic abnormality is Microsatellite Instability (MSI) is common in HNPCC cancers and is caused by mutations in a group of genes that code for DNA mismatch repair enzymes including MSH-2, MLH-1, PMS-I, PMS-2 and MSH-6 Genetic changes are frequently associated with tumourigenesis and progression.
      • HNPCC associated CRC is seen at younger age, proximal location, mucinous histology, and a higher grade at diagnosis. Prognosis is better in patients with MSI vs microsatelite stable tumours. These tumours are not sensitive to 5-Flourouracil based chemotherapy.
      • 10-15% of sporadic CRC have mismatch repair enzymes and thus have MSI.
      • Familial adenomatous polyposis (FAP) syndrome caused by APC gene mutation. Other Polyposis syndromes Peutz Jeghers and juvenile polyposis. Although classic FAP syndromes seen in only 0.5-1% of the overall number of CRC. Genetic changes are frequently associated with tumourigenesis and progression.
      • APC mutations activates the wnt signalling pathway are frequent in sporadic cancers and associated with familial adenomatous polyposis.

History, Symptoms and Signs

    Colon cancer may first be detected through screening. Early disease may be asymptomatic and/or complaints may be nonspecific, such as fatigue (due to iron-deficiency anemia) or weight loss. In more advanced disease, abdominal pain, diarrhea, bowel obstruction, rectal bleeding, a palpable abdominal mass, ascites, or hepatomegaly may be seen.

Diagnosis and Tumour Assessment

    Biopsy of suspicious lesions is required for Diagnosis. Staging is by pathologic assessment of the surgical specimen.

    Investigations include complete blood count, blood chemistry, liver function testing, and carcinoembryonic antigen (CEA) levels. Significantly elevated CEA may indicate advanced or disseminated disease. Imaging of the chest and abdomen are critical for staging. Thoracic, abdominal, and pelvic CT, MRI, and/or contrast ultrasound can provide adequate imaging. A barium study can define the primary lesion. Additional evaluation depends on the findings of these investigations and clinical presentation.


Staging

    Clinical presentation, laboratory studies, and imaging and definitive surgery with nodes assessment is required for staging ,which helps to determines the prognosis and plan for adjuvant treatments. Definitive staging is performed after surgical resection.

*Note: This includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.

^Note: Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retro-peritoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumour on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix or vagina).

**Tumour that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumour is present in the adhesion, microscopically, the classification should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN site-specific factor should be used for perineural invasion.

Note: A satellite peritumoural nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2) or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the Site-Specific Factor category Tumour Deposits (TD).


Stage Grouping

Note: cTMN is the clinical classification, pTNM is the pathologic classification.The y prefix is used for those cancers that are classified after neoadjuvant pre-treatment (e.g., ypTNM). Patients who have a complete pathologic response are ypT0N0cM0 that may be similar to Stage Group 0 or I. The r prefix is to be used for those cancers that have recurred after a disease-free interval (rTNM).

*Dukes B is a composite of better (T3 N0 M0) and worse (T4 N0 M0) prognostic groups, as is Dukes C (Any TN1 M0 and Any T N2 M0). MAC is the modified Astler-Coller classification.

Prognosis


Treatment Modalities

Surgery

    Surgery is curative for localized disease (stages I to III). Surgery may also be potentially curative in stage IV disease, if metastases are limited and located in the liver or lung. Resection of liver metastases with curative intent has improved long-term survival in some patients.

    The objective of surgery is to remove the primary tumour with an adequate negative margin, including lymphatic drainage areas. The section and extent of colon resected depends on the location and extent of the lesion. Open and laparoscopic procedures are equally effective and have similar rates of intra-operative and postoperative complications (e.g. re-resection, perioperative mortality, and surgical wound recurrence). Surgery may also be used in advanced disease to manage bleeding or intestinal obstruction.

Chemotherapy

    Studies have demonstrated significantly improved survival with postoperative adjuvant combination chemotherapy in colon cancer. In patients with stage III colon cancer, five year survival is 30-50% with surgery alone and adjuvant chemotherapy improves survival of 10-20% with 5FU and leucovorin for 6 months. Trials of adjuvant chemotherapy with FOLFOX vs. 5FU and leucovorin for 6 months, there was a 8-10% survival benefit of FOLFOX and thus, FOLFOX has been the standard adjuvant chemotherapy since 2004.

    Although the benefit of adjuvant chemotherapy is not as clear in stage II disease (85% survival with resection), a small but statistically significant survival benefit has been seen. High risk stage II patients with undifferentiated tumours, T4, obstruction, perforation, and less than 12 nodes resected in the specimen or a preoperative high CEA, should have a discussion of adjuvant chemotherapy. Patients with stage II CRC and mismatched repair deficiency (MMR-D/MSI-H) have an excellent prognosis and do not require adjuvant therapy.

    Efforts are underway to develop a molecular profile of prognostic variables that could potentially guide adjuvant treatment decisions in stage II colon cancer(Grayet al., J Clin Oncol 2011; Sargent et al., Ann Surg Oncol 2011; Salazar et al., J Clin Oncol 2011). These tests include gene expression signatures such as the Oncotype DX Colon and ColoPrint, as well as molecular detection assays. At this point, none of these assays is routinely recommended for use in clinical practice. It is used as a decision tool for adjuvant therapy in stage II colon cancer.

    Neoadjuvant chemotherapy may be used for cytoreduction in patients with isolated hepatic metastases, allowing surgical resection of previously unresectable liver lesions. The identification of prognostic factors might help distinguish patients at high risk for relapse and enrich the patient population with stage II disease, who will more likely benefit from adjuvant treatment, are being evaluated in prospective clinical trials.

Rectal Cancer

    Neoadjuvant chemoradiotherapy followed by total mesorectal excision is the standard treatment approach for stages T2-3 rectal cancer. Neoadjuvant chemotherapy with capecitabine (xeloda) and radiation followed by adjuvant Folfox, Xelox, or capecitabine for 6 months.

    Intravenous chemotherapy is generally administered using a central line such as porta cath. A central line reduces complications associated with administration of concentrated solutions.

Advanced Colorectal Cancer Stage IV

    Patients with stage IV disease have a curative chance if their metastases are amenable to complete surgical resection. The prognosis for patients with stage IV disease without specific therapy is poor, with a median survival of 5 to 6 months. The goal of systemic therapy is palliation to control symptoms and tends to improve survival. Overall survival of patients with metastatic colon cancer has improved with systemic therapy and biologic therapy as shown in the table below. For further information regarding toxicity and dosages, refer to: www.cancercare.on.ca

    The standard treatment for stage IV CRC with ECOG performance status of 1 to 2 is (FOLFIRI or FOLFOX or XELOX) + bevacizumab given every two weeks. Second line chemotherapy is given if there is any progression or toxicity with first line chemotherapy. Second line chemotherapy is any combination that the patient did not receive but bevacizumab is not approved if patients progress after first line.

    Third line chemotherapy on progression or toxicity could be irinotecan + cetuximab or panitumumab (only in patients with Kras wildtype).

    Capecitabine in combination with bevacizumab has emerged as one standard first-line treatment option in elderly patients with advanced colorectal cancer (Cunningham D, Lancet 2013).

Biologic agents

    Expanded RAS mutation testing for mutations in KRAS and NRAS exons 2, 3, and 4 is considered mandatory before use of EGFR monoclonal antibodies.

    Monoclonal antibodies, such as panitumumab and cetuximab, have been used to treat colorectal cancer, either alone or combined with chemotherapy in metastatic disease. These monoclonal antibodies are used if the tumour tissue is K-Ras wildtype only, and not in K-Ras mutated tumours. Agents used include antibodies to vascular endothelial growth factor such as bevacizumab and the chemotherapy regimen FOLFIRI in metastatic colorectal cancer. Most trials show improved progression-free and overall survival with these agents.

    VEGF-Trap (aflibercept) (approved by FDA in 2012) is a VEGF receptor decoy fusion protein that consists of extracellular domain components of VEGFR1 and VEGFR2 fused with the Fc region of IgG1. VEGF-Trap binds to the VEGF-A, VEGF-B, and PlGF ligands and prevents their interaction with VEGF receptors. Aflibercept was tested in a second-line trial with FOLFIRI, where 1,200 patients were randomly assigned to FOLFIRI with aflibercept or placebo. Overall survival was reached (13.5 vs. 12.1 months, HR 0.82, p = 0.0032)and was mirrored by improvements in progression-free survival (6.9 vs. 4.7 months, HR 0.758, p = 0.00007) and response rate (19.8% vs. 11.1%, p = 0.0001).

    Regorafenib was investigated in a placebo-controlled randomized phase III trial in a salvage therapy setting. Efficacy results of the trial demonstrated a benefit in overall survival for patients receiving regorafenib compared with placebo (6.4 vs. 5.0 months, HR 0.77, p = 0.0052, 291reference). The activity of regorafenib was also reflected in an improvement of progression-free survival (1.9 vs. 1.7 months, HR 0.49 , p < 0.000001).

    The most common severe toxicities observed with regorafenib were hand-foot skin reaction, fatigue, diarrhea, and hypertension. Patients should be encouraged to go on clinical trials to assess targetable mutation.

For further information regarding toxicity and dosages, refer to: www.cancercareontario.com

Immunotherapy

    Immunotherapy is evolving in colorectal cancer: A phase II study reports that a specific genomic abnormality called mismatch repair (MMR) deficiency predicts response to the anti-PD-1 antibody pembrolizumab. This marker predicted responses in patients with colorectal cancer.

Radiation

    Neoadjuvant chemoradiotherapy followed by total mesorectal excision has become the standard treatment approaches for Stage II and III rectal cancer. In colon cancer, radiation has no role in adjuvant therapy. In metastatic colon cancer, radiation is used for palliation at selected sites, such as brain, bone, single liver and lung.


Follow-up

    A healthy diet and lifestyle after treatment may be beneficial to patients with colorectal cancer. A prospective epidemiologic study has found an increased risk of recurrence and mortality among patients following a diet high in red meat, saturated fats, and refined carbohydrates, compared with a diet high in fish, poultry, fruits and vegetables.

    Vitamin D status and survival in metastatic CRC presented at ASCO 2015 (suppl 3; abstr 507) by Kimmie Ng et al showed that higher concentrations of plasma 25(OH)D are associated with significantly improved survival in metastatic CRC patients treated with chemotherapy + biologics. Randomized trials of vitamin D supplementation are warranted and patients should have the vitamin D levels done in the clinic.

    Approximately 85% of colon cancer recurrences occur within three years of resection. Regular surveillance is advised for patients with stage II and III resected colon cancer for at least five years. Recommended surveillance includes the following:

  • Physical examination: every 3 to 6 months for the first three years, every six months for the next two years and based on individualized risk assessment after that.
  • CEA levels: every 3 to 6 months for the first three years, and every six months for the next 2 years
  • Computed tomography of the chest and abdomen: annually for at least three years
  • Preoperative or postoperative colonoscopy to document absence of polyps or additional primary tumours, repeated at three years (if no high-risk pathology is present), and then every five years, if normal.

Pivotal Trials

Laurie JA, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol. 1989;7:1447-1456.pmid:2778478

Moertel CG, Fleming TR, MacDonald JS, et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med. 1995;122:321-326

Haller PJ, Catalano JS, Macdonald RJ and Mayer. Eastern cooperative Oncology Group (ECOG); Southwest Oncology Group (SWOG); Cancer and Leukemia Group B (CALGB) Fluorouracil (FU) leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: Five year final report of Int-0089 D.G. Proc Am Soc Clin Oncol. 1998;17:256

MOSAIC Trial. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-51.

X-ACT: Twelves, C. et al. Capecitabine as Adjuvant Treatment for Stage III Colon Cancer. N Eng J Med. 2005;352:2696-2704.