Systemic Therapy for Colon Cancer




Colorectal cancer (CRC) is a common and frequently fatal disease in North America. A multidisciplinary approach to the prevention, diagnosis, and treatment of this disease is essential. There have been many advances in the surgical and medical treatment of CRC over the last 10 years. This article reviews the indications, efficacy, and toxicity of chemotherapy and targeted therapy for patients who have CRC.


Colorectal cancer (CRC) is a common and frequently fatal disease in North America. In the United States, 106,680 new cases of colon cancer and 41,930 new cases of rectal cancer were reported in 2006, with an estimated 55,170 deaths attributed to CRC . In Canada, there were approximately 20,000 new cases of CRC, with an estimated 8500 deaths in 2006 .


Risk Factors


Many environmental and hereditary factors are associated with an increased risk for developing CRC. There are multiple genetic predispositions to CRC. The genetic condition associated with the highest risk for developing CRC is familial adenomatous polyposis (FAP) caused by germline mutation of the tumor-suppressor adenomatous polyposis coli (APC) gene. FAP is transmitted in an autosomal dominant fashion. Individuals who have FAP virtually always develop CRC by the age of 40 years if not treated by prophylactic removal of the colon and rectum .


A more common genetic disorder that increases the risk for CRC is hereditary non-polyposis colorectal cancer (HNPCC), characterized by dysfunction in DNA mismatch repair genes. HNPCC is inherited in an autosomal dominant manner . It is associated with an early age of colon cancer diagnosis and right-sided colon cancer. The diagnosis of HNPCC is suspected by either the Amsterdam or the more recent and more liberal Bethesda Criteria, which identify individuals who have a strong likelihood of mismatch repair gene mutation. Such individuals should be referred for genetic counseling and evaluation.


Other individual risk factors for CRC include a personal history of adenomatous polyps, a personal or family history of colon cancer, and a personal history of ulcerative colitis, especially pancolitis for more than 10 years. Protective factors that may reduce the risk include a diet high in fruits and vegetables and low in animal fat and red meat . Other suggested protective factors include dietary calcium, nonsteroidal antiinflammatory drugs, and frequent physical activity. Postmenopausal women administered hormone replacement therapy have a decreased incidence of CRC .


Screening the general population for CRC reduces disease morbidity and mortality . Various screening tools have been recommended, including colonoscopy, double contrast barium enemas, sigmoidoscopy, annual fecal occult blood test (FOBT), and CT virtual colonoscopy. Of these screening tests, colonoscopy is considered the gold standard because it directly visualizes the entire colon, provides biopsy capability, and is therapeutic in the removal of precancerous polyps. The American Cancer Society (ACS) recommends that all asymptomatic individuals undergo initial screening colonoscopy at age 50. Individuals at a higher-than-average risk, on the basis of family history, genetic screening, or other risk factors, should begin screening before age 50. Routine screening colonoscopies should be repeated every 10 years in asymptomatic individuals who have a negative index colonoscopy.


Patients who have first-degree relatives who had CRC should undergo CRC screening beginning at age 40, or 10 years earlier than the age of onset of the CRC in their first-degree relative . Our practice is to initiate colonoscopic screening at either age 40, or 20 years younger than the index case, whichever occurs sooner.


Despite the established benefit and clear guidelines for screening, the North American population is underscreened. More than 70 million people in the United States are 50 years of age or older and thus eligible for screening. Yet as of 2004, only 28.3 million (40.4%) have been screened for CRC, including 21.6 million by colonoscopy and 6.7 million by FOBT . In Canada, only about 20% of individuals aged 50 to 59 years have been screened for CRC by any screening method, with a mere 4% of the screen-eligible population aged 50 to 74 years undergoing screening colonoscopy in 2001 .




Presentation and Evaluation


Patients typically present with nonspecific symptoms, including abdominal pain, change in bowel habits, melena, hematochezia, or fatigue. Patients frequently are anemic. Approximately 20% of patients initially present with metastatic disease. Preoperative staging routinely includes an abdominal and pelvic CT scan. The role of preoperative chest roentgenogram versus chest CT is controversial. The current American Society of Clinical Oncology (ASCO) surveillance guidelines, however, recommend chest CT . Because of the emerging role of metastasectomy for liver metastasis and the increasing role of neoadjuvant systemic therapy, a baseline chest CT is reasonable. Measurement of a carcinoembryonic antigen (CEA) level is recommended preoperatively.




Presentation and Evaluation


Patients typically present with nonspecific symptoms, including abdominal pain, change in bowel habits, melena, hematochezia, or fatigue. Patients frequently are anemic. Approximately 20% of patients initially present with metastatic disease. Preoperative staging routinely includes an abdominal and pelvic CT scan. The role of preoperative chest roentgenogram versus chest CT is controversial. The current American Society of Clinical Oncology (ASCO) surveillance guidelines, however, recommend chest CT . Because of the emerging role of metastasectomy for liver metastasis and the increasing role of neoadjuvant systemic therapy, a baseline chest CT is reasonable. Measurement of a carcinoembryonic antigen (CEA) level is recommended preoperatively.




Nutritional Status


Optimizing the nutritional status of the patient who has CRC is an important concern of the surgeon, gastroenterologist, and medical and radiation oncologist. Many solid tumors, including CRC, are associated with obesity and the metabolic syndrome of hyperglycemia and insulin resistance . Paradoxically, malignancy and its various treatment modalities induce a catabolic state and impair the function of the GI tract, resulting in weight loss. These metabolic abnormalities increase surgical complication rates, including impaired wound healing and thromboembolism. An increased body mass index (BMI) also presents challenges to the medical and radiation oncologist when calculating the ideal dose of therapy. Patients who have CRC should work with their physicians and dietitians to develop a customized dietary plan to maintain an ideal BMI. Patients who have CRC who consume a diet high in fruits, vegetables, and non-red meats have an improved outcome when compared with those who consume a traditional Western diet high in red meat and refined grains .




Surgery


The primary curative therapy is surgery, either by traditional open colectomy or, most recently, laparoscopically assisted colonic resection. These two techniques were reported as equivalent in efficacy in a large randomized trial performed by experienced surgeons . Surgical resection optimally includes complete resection of the primary tumor and sampling of at least 12 regional lymph nodes. The surgeon should also inspect the entire abdominal cavity, palpate for evidence of metastatic disease, and obtain biopsies should a questionable metastatic lesion be encountered.


The optimal locoregional management of rectal cancer is more complex and anatomically more difficult than that for colon cancer because of its location within the bony pelvis, as opposed to the abdomen, and its location below the peritoneal reflection. Endorectal ultrasound or pelvic MRI should be standardly performed preoperatively. Tumors that are imaged as non–full thickness (T1–2, N0) should undergo initial surgical resection. If the final pathology remains non–full thickness and node-negative, no further therapy is routinely indicated. If the final pathology demonstrates full thickness, or if lymph nodes contain cancer, then postoperative chemoradiotherapy is indicated. If the initial endorectal evaluation indicates a full-thickness tumor (T3–4), preoperative chemoradiotherapy should be administered. Appropriate surgical treatment includes total mesorectal excision.


Metastasectomy is well established. Single or few metastatic lesions confined to either lung, liver, or ovary are potentially curable and should be considered for resection. A dedicated hepatic surgeon can aggressively resect liver metastases. Patients who have liver-only metastases deserve evaluation by a hepatic surgeon unless there is multifocal spread to all hepatic lobes. In patients who have surgically resectable hepatic metastases, 5-year survival approaches 40% .


Postoperative Management of Stage II and III Disease


Postoperative, or adjuvant, systemic therapy has become routine and standard for stage III colon cancer. Adjuvant therapy should also be strongly considered in stage II patients. It is generally recommended for any medically fit patient who has stage II cancer with unfavorable factors, including colonic perforation, unfavorable histology, colonic obstruction, or lymphovascular invasion. The optimal choice of adjuvant chemotherapy has recently changed from a 6-month course of 5-fluorouracil (5FU)-based chemotherapy alone to a 6-month course of infusional 5FU plus leucovorin (LV) and oxaliplatin (FOLFOX) based on a large trial of adjuvant systemic therapy for resected stage II or III colon cancer ( Table 1 ) . This trial demonstrated an increase in disease-free survival at 3 years from 72.9% to 78.2% ( P = .002) with addition of oxaliplatin to FU/LV. Toxicities were comparable between the two groups, with the exception that oxaliplatin is associated with a much higher rate of paresthesia: 12.4% versus 0.2% grade 3 (serious) toxicity. This neurotoxicity persisted at a grade 3 level in 1.1% of treated patients at 1 year of follow-up.



Table 1

Systemic therapy for colorectal cancer






















































































Therapy Mechanism of action Indications Potential common toxicities
5- Fluorouracil (5-FU) Blocks the enzyme thymidylate synthase, which is essential for DNA synthesis Multiple uses in combination with other agents in the adjuvant (postoperative) and palliative settings Nausea, diarrhea
Myelosuppression
Fatigue
Capecitabine Blocks thymidylate synthase (orally administered prodrug converted to 5-FU) Multiple uses in combination with other agents in the adjuvant (postoperative) and metastatic setting Nausea, diarrhea
Myelosuppression
Fatigue
Palmar-plantar syndrome (hand-foot syndrome)
Oxaliplatin Inhibits DNA replication and transcription by forming inter- and intra-strand DNA adducts/cross-links Used in combination with 5FU, LV (FOLFOX) in the adjuvant (postoperative) and metastatic setting Peripheral neuropathy
Nausea, diarrhea
Fatigue
Myelosuppression
Hypersensitivity
Irinotecan Inhibits topoisomerase I, an enzyme that facilitates the uncoiling and recoiling of DNA during replication Used alone or in combination with 5FU, LV (FOLFIRI) in the metastatic setting Cholinergic (acute diarrhea)
Nausea, late diarrhea
Fatigue
Myelosuppression
Alopecia
Bevacizumab Monoclonal antibody that binds to VEGF ligand Used in combination with either FOLFOX or FOLFIRI in the metastatic setting Hypertension
Arterial thrombotic events
Impaired wound healing
Gastrointestinal perforation
Cetuximab Monoclonal antibody to EGFR (chimeric) that blocks the ligand-binding site Used with irinotecan or as a single agent in the metastatic setting Acneform rash
Hypersensitivity
Hypomagnesemia
Fatigue
Panitumumab Monoclonal antibody to EGFR (fully humanized) that blocks the ligand-binding site Used as a single agent in the metastatic setting Acneform rash
Hypomagnesemia
Fatigue

Only gold members can continue reading. Log In or Register to continue

Feb 26, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Systemic Therapy for Colon Cancer
Premium Wordpress Themes by UFO Themes