Patrick J. Medina
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Identify the risk factors for colon cancer.
2. Recognize the signs and symptoms of colorectal cancer.
3. Describe the treatment options for colorectal cancer based on patient-specific factors, such as stage of disease, age of patient, genetic mutations, and previous treatment received.
4. Outline the pharmacologic principles for agents used to treat colorectal cancer.
5. Develop a monitoring plan to assess the efficacy and toxicity of agents used in colorectal cancer.
6. Educate patients about the adverse effects of chemotherapy that require specific patient counseling.
7. Outline preventive and screening strategies for individuals at average and high-risk for colorectal cancer.
KEY CONCEPTS
Although there are numerous risk factors for developing colorectal cancer, age is the biggest risk factor for sporadic colorectal cancer.
Diets high in fat and low in fiber are associated with increased colorectal cancer risk, whereas the regular use of aspirin (and nonsteroidal anti-inflammatory drugs [NSAIDs]) and calcium supplementation may decrease the risk of colorectal cancer.
Effective colorectal cancer screening programs incorporate annual fecal occult blood testing in combination with regular examination of the entire colon starting at age 50 for average-risk individuals and should be recommended by all health care providers.
Most patients with colorectal cancer are asymptomatic early but may develop changes in bowel or eating habits, fatigue, abdominal pain, and blood in stool.
The stage of colorectal cancer is determined by the tumor-node-metastasis (TNM) staging system and is the most important prognostic factor for patient survival. Disease stages I to III are curable, whereas patients with stage IV disease are treated with the goal of palliation.
Adjuvant chemotherapy is not needed in patients with stage I colon cancer, may be beneficial in selective high-risk patients with stage II colon cancer, and is standard of care in patients with stage III colon cancer.
5-Fluorouracil, leucovorin and oxaliplatin chemotherapy (FOLFOX) is the standard regimen used in adjuvant colon cancer. It is usually given for 6 months.
Triple-drug therapy consisting of 5-fluorouracil and leucovorin with oxaliplatin or irinotecan improves survival compared to 5-fluorouracil plus leucovorin alone, and is considered as standard first-line therapy for metastatic disease. The addition of bevacizumab is recommended to be added to 5-fluorouracil-based regimens based on improvements in overall survival.
Treatment of relapsed or refractory metastatic disease uses agents not given in the first-line setting.
Adjuvant therapy consisting of 5-fluorouracil-based chemotherapy in combination with radiation therapy should be offered to patients with stage II or III cancer of the rectum.
INTRODUCTION
Colorectal cancer is one of the three most common cancers diagnosed in the United States and includes cancers of the colon and rectum. In 2008, an estimated 148,810 new cases will be diagnosed and an estimated 49,960 deaths will occur making colorectal cancer the second leading cause of cancer-related deaths in the United States.1 Prognosis is primarily determined by the stage of disease with the majority of patients with early stage (I or II) disease cured. Treatment options for colorectal cancer include surgery, radiation, chemotherapy, and new targeted molecular therapies.
EPIDEMIOLOGY AND ETIOLOGY
Colorectal cancer occurs at a much higher rate in industrialized parts of the world such as North America and Europe, while the lowest rates are seen in less-developed areas suggesting that environmental and dietary factors influence the development of colorectal cancer.2 In addition to these environmental factors, colorectal cancers are known to develop more frequently in certain families, and genetic predisposition to this cancer is well known.
The incidence of colorectal cancer is greatest among males, who have an approximately 1.5 times greater risk for developing colorectal cancer than women. Overall, colon and rectal cancers make up approximately 10% of all cancer diagnoses in men and women in the United States.1 The median age at diagnosis is 72 years with very few cases occurring in individuals less than 45 years of age.3 Age appears to be the biggest risk factor for the development of colorectal cancer with 70% of cases diagnosed in adults older than 65 years of age.
Though still the third leading cause of cancer death, mortality rates for colorectal cancer have declined over the last 30 years as a result of better and increasingly used screening modalities and more effective treatments.
RISK FACTORS
Besides age, the development of colorectal cancer appears to be caused by variety of dietary or environmental factors, inflammatory bowel disease, and genetic susceptibility to the disease. Table 91–1 lists well-known risk factors for developing colorectal cancer. Epidemiologic studies of worldwide incidence of colorectal cancer suggest that dietary habits strongly influence its development.
High-fat, low-fiber diets, which usually occur in tandem, have been associated with an increased risk of colorectal cancer. The association between red meat consumption and colorectal cancer is strongest, possibly a result of the heterocyclic amines formed during cooking or the presence of specific fatty acids in red meat such as arachidonic acid. While data indicate that animal meat and saturated fat intake are associated with an increased risk of colorectal cancer, the exact increase in risk is unknown. The evidence for low-fiber diets as a risk factor is based on the ingestion of large amounts of dietary fiber being associated with a small, inconsistent, reduced colorectal cancer risk. Foods that are high in fiber include vegetables, fruit, grains, and cereals. The protective effects of fiber may be a result of reduced absorption of carcinogens in the bowel, reduced bowel transit time, or a reduction in dietary fat intake associated with high fiber diets.4,5
The degree of colorectal cancer risk-reduction associated with increased consumption of vegetables and fruit is variable but generally modest and has ranged from no difference to a 25% decrease in cancer risk in prospective studies.4–6 A large pooled analysis of 13 prospective cohort studies found dietary fiber intake to be inversely associated with the risk of colorectal cancer; however, upon multivariate analysis for other dietary risk factors, the benefit was no longer seen.6 This analysis does not account for the known benefits of a fiber-rich diet for noncancerous conditions like diabetes and coronary artery disease.
Table 91–1 Risk Factors for Colorectal Cancer
General
Age is the primary risk factor
Dietary
High-fat, low-fiber diets
Lifestyle
Alcohol
Smoking
Obesity/physical inactivity
Comorbid conditions
Inflammatory bowel disease (ulcerative colitis and Crohn’s disease)
Hereditary/genetic
FAP and HNPCC
Family history
The risk of colorectal cancer appears to be inversely related to calcium and folate intake. Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, daily supplementation of calcium (1,000 mg) with vitamin D3 (400 IU) for 7 years had no effect on the incidence of colorectal cancer among postmenopausal women when compared to a placebo group in the randomized trial involving 18,106 females The benefit of calcium and vitamin D on preventing colon cancer may require longer follow-up.7
Calcium’s protective effect may be related to a reduction in mucosal cell proliferation rates or through its binding to bile salts in the intestine while dietary folate helps maintain normal bowel mucosa. Based on its role in DNA methylation, folate intake has been associated with modifying the risk of colorectal cancer. Epidemilogic evidence suggests that higher intake of folate will decrease the risk for the development of colorectal cancer. However, studies are inconsistent and whether benefit is limited to certain patient populations requires further study. In addition, the timing of folate intake may be important with early intake preventing colorectal cancer and later intake promoting the progression of disease.8,9 Additional micronutrient deficiencies have been demonstrated through several studies to increase colorectal cancer risk and include selenium, vitamin C, vitamin D, vitamin E, and β-carotene; however, the benefit of dietary supplementation does not appear to be substantial.10
Chronic use of several medications has been shown to influence the risk of developing colorectal cancer. Studies have consistently demonstrated that regular (at least two doses per week) nonsteroidal anti-inflammatory drug (NSAID) and aspirin use is associated with a reduced risk of colorectal cancer.10–12 Additional studies support these findings that regular aspirin or NSAID use may decrease the risk of colorectal cancer by as much as 50%.11,12 The potential mechanisms by which these agents exert their protective effects appear to be linked primarily to their inhibition of cyclooxygenase-2 (COX-2), and protective effects may be limited to those precancerous lesions that overexpress COX-2.13 Colorectal cancers with weak or absent expression of COX-2 may not derive the same benefit from long-term COX-2 inhibition.13 Exogenous hormone use, particularly postmenopausal hormone replacement therapy, is associated with a significant reduction in colorectal cancer risk in most studies with the greatest benefit in women who are on current hormone replacement therapy.14 Unfortunately, the known risks of hormone replacement therapy outweigh this benefit and routine use of hormone replacement therapy to prevent colorectal cancer is not recommended.
Personal attributes such as physical inactivity and elevated body mass index (BMI) are associated with up to a twofold increase in the risk of colorectal cancer. Decreased bowel transit time and exercise-induced alterations in body glucose, insulin levels, and perhaps other hormones may reduce tumor cell growth.10,15 Type 2 diabetes mellitus, independent of body mass size and physical activity level, is also associated with an increased risk of colorectal cancer in women and supports a role for hyperinsulinemia as a possible link between obesity, sedentary lifestyle, diabetes mellitus, and colorectal cancer.15Additional lifestyle choices that increase the risk of colorectal cancer include alcohol consumption and smoking that may increase the risk of colorectal cancer by generating carcinogens or their direct toxic effects on bowel tissue.10
Inflammatory bowel diseases, such as chronic ulcerative colitis, particularly when it involves the entire large intestine, and to lesser extent Crohn’s disease, confer increased risk for colorectal cancer. Overall, persons diagnosed with either disease constitute about 1% to 2% of all new cases of colorectal cancer each year.
Finally, as many as 10% of cases are thought to be hereditary, resulting from genetic mutations. The two most common forms of hereditary colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC).4 FAP is a rare autosomal dominant trait that is caused by mutations of the adenomatous polyposis coli (APC) gene and accounts for 1% of all colorectal cancers. The disease is manifested by hundreds to thousands of polyps arising during adolescence.16 The risk of developing colorectal cancer for individuals with untreated FAP is virtually 100% and patients will require early screening for the disease, and likely prophylactic total colectomy. HNPCC, also an autosomal dominant syndrome, accounts for up to 5% of colorectal cancer cases.16 In contrast to FAP, juvenile polyps occur rarely and the average age of colorectal cancer in these patients is closer to that of average risk patients, with most patients diagnosed in their forties. Testing for HNPCC mutations is available but reserved for those individuals who meet strict diagnostic criteria.
Up to 25% of patients who develop colorectal cancer will have a family history of colorectal cancer unrelated to a mutation described above. First-degree relatives of patients diagnosed with colorectal cancer have an increased risk of the disease that is at least two to four times that of persons in the general population without a family history.17
Summary of Risk Factors
In summary, the true association between most dietary factors and risk of colorectal cancer is unclear. The protective effects of fiber, calcium, and a diet low in fat are not completely known at this time. NSAID use and hormonal use appear to decrease the risk of colorectal cancer while physical inactivity, alcohol use, and smoking appear to increase the risk of colorectal cancer. Clinical risk factors and genetic mutations are well-known risks for colorectal cancer.
SCREENING
Health care professionals must be aware of and promote appropriate screening recommendations for colorectal cancer in their patients. Effective screening programs incorporate fecal occult blood tests (FOBTs) and regular examinations. Appropriate screening of patients at normal and high risk for colorectal cancer leads to the detection of smaller, localized lesions and higher cure rates.18 Screening techniques include a digital rectal exam, FOBTs, and imaging of the colon. The use of FOBTs annually in combination with digital rectal exams has led to earlier diagnosis of early stages of disease and may reduce colorectal cancer mortality by up to one-third.18 Two main methods are available to detect occult blood in the feces: guaiac dye and immunochemical methods. The Hemoccult II is the most commonly used FOBT in the United States and is a guaiac-based test. Proper counseling by health care providers is required to receive accurate test results. Table 91–2 lists common reasons for inaccurate results with the guaiac tests and requires appropriate counseling on the use of these tests. Fecal immunochemical tests (FIT) (InSure, and others), which use antibodies to detect hemoglobin, are also available for use. One advantage of immunochemical tests is that they do not react with dietary factors or medications. Both FOBTs can be recommended in screening protocols for patients.
Patient Encounter, Part 1
GW is a 61-year-old man who presents to your clinic with a chief complaint of abdominal discomfort and cramping for the last 3 weeks not relieved with over-the-counter medications. While obtaining your medical history, he states that he also has seen small amounts of blood in his stool on and off for 4 months. He has a medical history positive for hypertension and obesity. He states that he has smoked a pack of cigarettes per day for the last 40 years and drinks 4 to 6 beers every couple of days.
What risk factors does GW have for colon cancer?
Does he have clinical symptoms suggestive of colon cancer?
What additional tests need to be ordered to diagnosis colon cancer?
Table 91–2 Common Reasons for Inaccurate Results from Guaiac Stool Tests
In addition, imaging of the colon with a sigmoidoscopy, colonoscopy, or double-contrast barium enema is required every 5 to 10 years in most individuals. Colonoscopy is the preferred procedure as it allows for greater visualization of the entire colon and simultaneous removal of lesions found during screening.18 A sigmoidscopy only examines the lower half of the colon, and a double-contrast barium enema requires a supplemental colonoscopy to remove any lesions found during the screening process. Several revisions to the colorectal cancer screening guidelines have been made in an attempt to increase the compliance to screening guidelines. These include the use of computed tomographic colonography (CTC) and stool DNA testing as acceptable screening methods. CTC, also known as “virtual colonoscopy,” uses integrated 3D and 2D images to detect and characterize polyps. Although noninvasive compared to colonoscopy, adequate bowel preparation, which is often cited as the reason for noncompliance, is still required. In addition, any lesions found on examination require a follow-up colonoscopy.
Stool DNA testing detects molecular markers associated with advanced colorectal cancer. Because this test is not dependent on the detection of bleeding, which can be sporadic, it requires only a single stool collection. How often and what molecular markers to test for are undergoing further evaluation. Table 91–3 is a summary of the current American Cancer Society guidelines for screening and surveillance for early detection of colorectal polyps and cancer.18
COLORECTAL CANCER PREVENTION
Strategies to prevent colorectal cancer can be done with pharmacologic or surgical interventions and involve either preventing the initial development of colorectal cancer (primary prevention) or preventing cancer in patients that demonstrate early signs of colorectal cancer (secondary prevention).
The most widely studied agents for the chemoprevention of colorectal cancer are agents that inhibit COX-2 (aspirin, NSAIDs, and selective COX-2 inhibitors) and calcium supplementation.19 COX-2 appears to play a role in polyp formation and COX-2 inhibition suppresses polyp growth. In 1999, the FDA approved the use of celecoxib to reduce the number of colorectal polyps in patients with FAP, as an adjunct to usual care. This may delay the need for surgical intervention in these patients but the results cannot be extrapolated to the general population. The dose of celecoxib for this indication is 400 mg orally twice daily and the risk of cardiovascular damage from COX-2 inhibition needs to be assessed carefully in these patients. The use of aspirin as both a primary and secondary chemoprevention agent has also been studied. In a prospective, randomized trial, low-dose (81 mg/day) aspirin was shown to decrease the incidence of additional polyps by 19% in patients with a previous history of at least one polyp.20
Table 91–3 Colon Cancer Screening Guidelines
Calcium supplementation appears to be associated with a moderate reduction in risk of recurrent colorectal adenomas with prospective studies demonstrating a nonstatistical decrease in adenoma recurrence and its role as a chemoprevention agent remains under investigation.19
Additional agents including selenium, folic acid, and HMG-CoA reductase inhibitors (statins) show promise as chemopreventive agents in colorectal cancer and preliminary and confirmatory studies evaluating their effectiveness have been completed or are ongoing.19
Surgical resection remains an option to prevent colorectal cancer in individuals at extremely high risk for its development such as patients diagnosed with FAP. Individuals with FAP who are found to have polyps on screening examinations require total abdominal colectomy. In addition, removal of noncancerous polyps detected during screening colonoscopy is considered standard of care to prevent the progression of premalignant polyps to cancer.
PATHOPHYSIOLOGY
Anatomy and Bowel Function
The large intestine consists of the cecum; ascending, trans-verse, descending, and sigmoid colon; and the rectum (Fig. 91–1). The function of the large intestine is to receive contents from the ileum, absorb water, and package solid waste for excretion. Absorption of materials occurs in segments of the colon proximal to the middle of the transverse colon, with movement and storage of fecal material in the left colon and distal segments of the colon.
FIGURE 91–1. Colon and rectum anatomy. (From DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Patholphysiologic Approach, 6th ed. New York: McGraw-Hill, 2005; Fig. 127–2.)
Four major tissue layers, from the lumen outward, form the large intestine: the mucosa, submucosa, muscularis externa, and serosa (Fig. 91–2). Complete replacement of surface epithelial cells occurs every 7 to 10 days with the total number of epithelial cells remaining constant in normal colonic tissue. As patients age, abnormal cells accumulate on the surface epithelium and protrude into the stream of fecal matter, their contact with fecal mutagens can lead to further cell mutations and eventual adenoma formation.16
Colorectal Tumorigenesis
The development of a colorectal neoplasm is a multistep process of several genetic and phenotypic alterations of normal bowel epithelium leading to unregulated cell growth, proliferation, and tumor development. A genetic model has been proposed for colorectal tumorigenesis that describes a process of transformation from adenoma to carcinoma. This model of tumor development reflects an accumulation of mutations within colonic epithelium that give a selective growth advantage to the cancer cells.16 Genetic changes include activating mutations of oncogenes, mutations of tumor suppressor genes, and defects in DNA mismatch repair genes.
Additional genes and protein receptors are believed important in colorectal tumorigenesis. COX-2, which is induced in colorectal cancer cells, influences apoptosis and other cellular functions in colon cells, and overexpression of the epidermal growth factor receptor (EGFR), a transmembrane glycoprotein involved in signaling pathways that affect cell growth, differentiation, proliferation, and angiogenesis, occurs in the majority of colon cancers.11,21 These mechanisms are potentially important because of the availability of pharmacologic agents targeted to inhibit these processes.
FIGURE 91–2. Cross-section of bowel wall. (From DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Patholphysiologic Approach, 6th ed. New York: McGraw-Hill, 2005; Fig. 127–3.)
Over 90% of colorectal cancers that develop are adenocarcinomas and are assigned a grade of I to III based on how similar they are compared to normal colorectal cells. Grade I tumors most closely resemble normal cellular structure, whereas grade III tumors have frequently lost the characteristics of mature normal cells. Grade III tumors are associated with a worse prognosis than grade I turmors.22
CLINICAL PRESENTATION AND DIAGNOSIS
The signs and symptoms associated with colorectal cancer can be extremely varied, subtle, and nonspecific. Most patients are asymptomatic but may develop changes in bowel or eating habits, fatigue, abdominal pain, and blood in the stool.
TREATMENT
Desired Outcome
Staging is required to determine the extent of disease and is necessary in developing patient treatment options and determining patient prognosis. The tumor-node-metastasis (TNM) classification system that takes into account T (tumor size and depth of tumor invasion), N (lymph node involvement), M (presence or absence of metastases) is used to stage patients from stage I to stage IV. CT scans and appropriate assessment of lymph node involvment during surgical resection are essential in determining the stage of disease and subsequent treatment options. At this time, routine MRI and PET scans for initial staging are not recommended. Figure 91–3 depicts how the three categories are used in combination to determine the stage of disease. The stage of colorectal cancer upon diagnosis is the most important prognostic factor for survival and disease recurrence. Stages I, II, and III disease are considered potentially curable and are aggressively treated in an attempt to cure these patients. Patients who develop stage IV disease are treated to reduce symptoms, avoid disease-related complications, and prolong survival.
Clinical Presentation and Diagnosis of Colorectal Cancer
General
Patients are often asymptomatic in early stages of disease
Symptoms
Changes in bowel habits, abdominal pain, anorexia, nausea and vomiting, weakness (if anemia is severe), and tenesmus
Signs
Blood in stool and weight loss
Laboratory Tests
• Patients may have a low hemoglobin level from blood loss
• Positive FOBT
• Liver function tests (International Normalization Ratio, activated partial thromboplastin time, and bilirubin) may be abnormal if disease has metastasized to the liver.
• Carcinoembryonic antigen (CEA) level may be high. Normal level is less than 2.5 ng/mL (2.5 mcg/L) in nonsmokers and less than 5 ng/mL (5 mcg/L) in smokers
Imaging Tests
Chest x-ray, CT scan, or position-emission tomography (PET) scan may be positive if cancer has spread to the lungs, liver, or peritoneal cavity
Patient Encounter, Part 2: Medical History, Physical Examination, and Diagnostic Tests
PMH: Hypertension since age 47, which is not well controlled; obesity; the patient is 65% over his ideal body weight
FH: Mother and father both dead. Father died of a myocardial infarction at age 62; mother died of colon cancer at age 64. Patient states that “many” relatives have cancer in his family
SH: Works as an auto mechanic. Drinks alcohol frequently, and smokes a pack of cigarettes daily. Patient also does no exercise and states that he eats fast food daily. He is married with twin boys aged 29
Meds: Atenolol 50 mg orally once daily
ROS: (+) Abdominal cramping, mild nausea and loss of appetite, blood in stool, and fatigue
PE:
VS: 153/90 mm Hg, P 78, RR 16, T 37.2°C (99°F), ht 183 cm (72 in.), wt 128 kg (282 lb)
Abd: Distended and tender to touch, (+) bowel sounds, and heme (+) stools
Labs: Positive hemoglobin 11.3 g/dL (113 g/L or 7 mmol/L) (decreased from 14.8 g/dL [148 g/L or 9.2 mmol/L] last year)
Imaging and Diagnostic Studies
• Colonoscopy revealed multiple polyps in his transverse colon.
• Biopsy revealed three polyps positive for adenocarcinoma of the colon.
• Staging CT scan revealed metastatic disease in the liver, lung, and bone.
• All other findings negative.
Because GW has stage IV colon cancer, how does this affect your treatment plan compared with stage I–III disease?
What is your treatment goal for him?
What nonpharmacologic and pharmacologic options are available to GW?
General Approach to Treatment
The treatment approaches for colorectal cancer reflect two primary treatment goals: curative therapy for localized disease (stages I to III) and palliative therapy for metastatic cancer (stage IV). Surgical resection of the primary tumor is the most important part of therapy for patients in whom cure is possible.23 Depending on the stage of disease and whether the tumor originated in the colon or rectum, further adjuvant chemotherapy or chemotherapy plus radiation may be needed after surgery to cure these patients. In the metastatic setting, pharmacologic intervention is the main treatment option.
FIGURE 91–3. Stage I: Cancer is confined to the lining of the colon. Stage II: Cancer may penetrate the wall of the colon into the abdominal cavity but does not invade any local lymph nodes. Stage III: Cancer invades one or more lymph nodes but has not spread to distant organs. Stage IV: Cancer has spread to distant locations in the body, which may include the liver, lungs, or other sites. (From http://www.cancer.gov/cancertopics/pdq/treatment/colon/Patient/page2.)
Nonpharmacologic Therapy
Operable Disease (Stages I–III)
Surgery Individuals with stage I to III colorectal cancer should undergo a complete surgical resection of the tumor mass with removal of regional lymph nodes as a curative approach for their disease.23Surgery for rectal cancer depends on the region of tumor involvement with attempts to retain rectal function as a goal of the surgical procedure. Overall, surgery for colorectal cancer is associated with a low morbidity and mortality rate. Common complications associated with colorectal surgery include infection, anastomotic leakage, obstruction, adhesion formation, and malabsorption syndromes.
Radiation Therapy There is currently no role for adjuvant radiation in colon cancer. However, patients who receive surgery for rectal cancer receive radiation therapy to reduce local tumor recurrence. Adjuvant radiation plus chemo-therapy is considered standard treatment for patients with stage II or III rectal cancer after the surgical procedure is complete.24 Preoperative radiation may be used to reduce the initial size of rectal cancers in order to make the surgical procedure easier.
Metastatic Disease (Stage IV)
Surgery Unlike stages I to III disease, the benefit of surgical resection in most patients with metastatic disease is limited to symptomatic improvement. Select patients who have from one to three small nodules isolated to the liver, lungs, or abdomen may have a prolongation of survival, though cure is rare. Five-year survival for patients who undergo surgical resection of metastases isolated to the liver is approximately double that of patients who are not surgical candidates with approximately 33% of patients alive at 5 years.25 Alternatives to surgery include destroying the tumor through freezing and thawing (cryoablation), heat (radiofrequency), or alcohol injection though these appear to be less successful than surgical resection.23,25 Because the majority of these patients will relapse, many practitioners offer adjuvant chemotherapy to select patients following potentially curative resection, but further studies are needed to determine an optimal treatment regimen.25 Additionally, neoadjuvant approaches to patients with isolated hepatic lesions will be discussed later in the chapter.
Radiation Symptom reduction is the primary goal of radiation for patients with advanced or metastatic colorectal cancer.
Pharmacologic Therapy
Table 91–4 lists common chemotherapy regimens used in colorectal cancer, and the abbreviations used in the literature to describe them.
Operable Disease (Stage I–III)
Adjuvant chemotherapy is administered after tumor resection to decrease relapse rates and improve survival in patients with colon cancer by eliminating micrometastatic disease that is undetected on imaging studies. Patients diagnosed with stage I colon or rectal cancer are usually cured by surgical resection, and adjuvant chemotherapy is not indicated in these patients.23 The role of adjuvant chemotherapy for stage II colon cancer is controversial but may benefit certain high-risk groups. Table 91–5 lists adjuvant treatment regimens based on stage and performance status. Adjuvant chemotherapy for patients with stage II disease has not been shown to be superior to surgery alone with the exception of high-risk patients. High-risk patients that may benefit include those with inadequate nodes sampled for staging, bowel perforation upon diagnosis, T4 lesions, and those with unfavorable histology. The use of tumor gene profiling may predict patients with stage II disease that would benefit from adjuvant chemo-therapy but requires further validation in prospective trials.26 Consequently, the American Society of Clinical Oncology does not recommend the routine use of adjuvant chemo-therapy in the general patient population unless part of a clinical trial.27 Patients with stage II colon cancer should be enrolled into carefully controlled clinical trials to assess the impact of new agents and prognostic models. Adjuvant chemotherapy is standard therapy for patients with stage III colon cancer. The presence of lymph node involvement in the resected specimen places patients with stage III colon cancer at high risk for relapse; the risk of death within 5 years of surgical resection alone is as high as 70%.23 In this population of patients, adjuvant chemotherapy significantly decreases risk of cancer recurrence and death and is considered standard of care.
Table 91–4 Dosing Schedules of Chemotherapy Regimens for Colon Cancera
5-Fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy is the standard regimen used in adjuvant colon cancer. It is usually given for 6 months. 5-Fluorouracil alone results in a small improvement in survival that can vary based on the method of 5-fluorouracil administration. Studies suggest that continuous IV 5-fluorouracil infusion treatment schedules are more effective as adjuvant therapy.28
Table 91–5 Treatment Regimens for Adjuvant Colon Cancer
More often, 5-fluorouracil is administered as part of a combination regimen. The most frequently used combination is that of 5-fluorouracil, oxaliplatin, and leucovorin. The combination of 5-fluorouracil plus leucovorin has undergone extensive study in the adjuvant setting with decreased rates of recurrence and improved survival seen in patients receiving 5-fluorouracil plus leucovorin compared to surgery alone. A pooled analysis demonstrated that 5-year disease-free survival and overall survival were increased by 12% and 7% with adjuvant 5-fluorouracil-based chemotherapy, respectively.29 5-Fluorouracil and leucovorin can be administered in a variety of treatment schedules, but none has proven superior with regard to overall patient survival. In the past, the United States has favored bolus regimens based on patient convenience. However, improved availability and comfort in use of portable infusion pumps has led to an increase in use of the continuous IV schedule of 5-fluorouracil commonly advocated in Europe. Patients are treated with 6 months of adjuvant therapy. Longer regimens do not improve patient outcomes. No standard exists for the best schedule of 5-fluorouracil and leucovorin administration, though continuous infusions may be less toxic and have improved response rates (though no survival advantage) when compared to bolus regimens.
Oxaliplatin added to the combination of 5-fluorouracil and leucovorin has further improved response rates in the adjuvant setting. The MOSAIC trial, conducted in over 2,200 patients, demonstrated that the addition of oxaliplatin to 5-fluorouracil and leucovorin decreases disease recurrence and improves disease-free and overall survival in patients with stage III disease.30 These results led to the approval of the FOLFOX4 regimen, given for 6 months, for the adjuvant treatment of colon cancer. This regimen is considered standard of care for patients with stage III disease unless their performance status is so poor that clinicians do not feel they could tolerate intensive combination therapy. Age alone should not determine whether patients receive combination adjuvant therapy or not as elderly patients have been found to equally benefit from this approach with minimal addition of adverse effects.31 Every effort should be made to minimize adverse treatment effects and utilize this regimen in patients with stage III colon cancer as this is the only regimen demonstrated to improve overall survival in these patients.30,31
Capecitabine is an oral prodrug of 5-fluorouracil that is also effective in the adjuvant setting and is being evaluated as a replacement for 5-fluorouracil for patient convenience and possible economic and safety reasons. Data suggest that capecitabine is at least equivalent to bolus 5-fluorouracil and leucovorin in efficacy and is better tolerated by patients.32 An increase in hand-foot syndrome and decreased mucositis and neutropenia are seen with capecitabine when compared to bolus 5-fluorouracil. Consequently, most practitioners feel that capecitabine is an acceptable alternative to IV 5-fluorouracil plus leucovorin. However, the role of capecitabine with additional chemo-therapy agents such as oxaliplatin or compared to the more common infusional 5-fluorouracil requires further study in the adjuvant setting.
Metastatic Disease (Stage IV)
Traditional chemotherapy and targeted biological therapies are the mainstay of treatment for metastatic colon or rectal cancer and have improved the median survival of these patients to over 20 months.33Most often, a combination of chemotherapy agents with biological therapies is administered to these patients. Currently, metastatic colorectal cancer is incurable and treatment goals are to reduce patients’ symptoms, improve quality of life, and extend survival. Combination chemotherapy regimens have been demonstrated to result in prolongation of survival with tolerable adverse effects. Similar to the adjuvant setting, 5-fluorouracil plus leucovorin continues to be in most first-line chemotherapy regimens used for metastatic colorectal cancer. A variety of continuous IV infusion 5-fluorouracil and bolus regimens can be used; however, in comparison to IV bolus 5-fluorouracil, response rates with continuous infusion 5-fluorouracil are approximately doubled. In a meta-analysis of six randomized trials evaluating over 1,200 patients with advanced colorectal cancer, continuous infusions of 5-fluorouracil had a significantly higher tumor response rate, a small increase in survival, and lower incidence of myelosuppression, diarrhea, and mucositis when compared to bolus regimens.33,34
Additional agents have been added to the 5-fluorouracil and leucovorin regimen with superior response and survival rates compared to the two drugs used alone. The addition of irinotecan to 5-fluorouracil plus leucovorin (IFL) significantly improves response rates and survival, without adversely affecting quality of life. In a landmark trial, this regimen was superior to 5-fluorouracil plus leucovorin with regard to tumor response, survival, and quality of life.35 As a result, irinotecan received approval from the FDA in 2000 as first-line therapy for metastatic colorectal cancer in combination with 5-fluorouracil and leucovorin. Soon thereafter, oxaliplatin in combination with 5-fluorouracil and leucovorin (FOLFOX4) demonstrated improvement in median survival when compared to the IFL regimen described above. A comparison of oxaliplatin plus 5-fluorouracil and leucovorin (FOLFOX4) to weekly IFL showed superior efficacy with FOLFOX4 compared to IFL with regard to response rates and survival.36 Several study design questions including the crossover design and differing methods of 5-fluorouracil administration led several practitioners to debate the significance of these results. Patients on the IFL arm received weekly IV bolus 5-fluorouracil, while FOLFOX4 patients received 5-fluorouracil as IV bolus followed by continuous infusion IV, which is thought to increase response rates. A larger European study validated these concerns when it compared a combined bolus and infusional 5-fluorouracil regimen plus irinotecan (FOLFIRI) to the FOLFOX regimen (using a slightly different schedule) with crossover to the opposite arm upon relapse.37 No difference in patient survival was seen with either regimen and toxicity was as expected. Neuropathy and neutropenia were more common with FOLFOX and diarrhea, nausea, vomiting, dehydration, and febrile neutropenia were more common with FOLFIRI. Based on improved survival data with the FOLFOX and FOLFIRI regimens, irinotecan administered in a bolus fashion, as described in the IFL regimens, is no longer recommended for routine use. When irinotecan-based combination chemotherapy is to be given for the metastatic treatment of colon cancer, it should be as FOLFIRI described in Table 91–4.
Targeted or biologic agents have been approved for use in metastatic colorectal cancer. Bevacizumab, in combination with IV 5-fluorouracil-based chemotherapy, is approved by the FDA for initial treatment of patients with metastatic colorectal cancer. Results from randomized trials show increased benefit compared to chemotherapy alone. One phase III trial of bevacizumab in combination with IFL as first-line therapy in patients with metastatic colorectal cancer has also been completed with a 5-month increase in median survival seen with the addition of bevacizumab with manageable adverse effects.38 The results of this study show the relevance of angiogenesis as an important target for the treatment of metastatic colorectal cancer. Similar to when used without bevacizumab, FOLFIRI is superior to IFL in combination with bevacizumab. Survival was improved by approximately 9 months with FOLFIRI plus bevacizumab compared to IFL plus bevacizumab.39
The addition of bevacizumab when added to first-line oxaliplatin-based chemotherapy has also been demonstrated to improve progression-free survival but did not positively impact response rates or overall survival.40 Based on these results, bevacizumab is recommended as part of all 5-fluorouracil-based chemotherapy regimens used for the first-line treatment of metastatic colorectal cancer unless contraindicated. Bevacizumab should not be used in patients who present with or develop the following conditions until they are stabilized or treated, including patients with GI perforation or fistulas involving a major organ, recent (within 28 days) major surgeries or open wounds, wound dehiscence requiring medical intervention, hypertensive crisis or uncontrolled severe hypertension, hypertensive encephalopathy—serious bleeding, a severe arterial thromboembolic event, moderate or severe proteinuria (2 g or higher of proteinuria/24 hours); nephrotic syndrome, and reversible posterior leukoencephalopathy syndrome.
In summary, most practitioners select first-line treatment for metastatic colorectal cancer from among these currently approved, triple-drug treatments: oxaliplatin plus 5-fluorouracil plus leucovorin (FOLFOX); irinotecan plus 5-fluorouracil plus leucovorin (FOLFIRI); bevacizumab plus 5-fluorouracil-based chemotherapy (FOLFIRI or FOLFOX).41
The routine replacement of 5-fluorouracil with capecitabine in biologic combination regimens should not be recommended outside of controlled clinical trials. In one phase III trial, capecitabine in combination with irinotecan and bevacizumab was inferior to FOLFIRI plus bevacizumab with no improvement in safety.39 This inferiority with capecitabine may be specific to its use with irinotecan. When given in combination with oxaliplatin and bevacizumab as the (CAPOX) regimen, improvements in disease control were demonstrated. Based on these results, CAPOX is an acceptable alternative to FOLFOX in most instances; both regimens can be given with or without bevacizumab.41
5-Fluorouracil plus leucovorin or capecitabine alone is appropriate first-line treatment only for those individuals for whom three-drug combination regimens are believed too toxic. The site(s) of tumor involvement, history of prior chemotherapy, and patient-specific factors help define the appropriate management strategy. The most important factor in patient survival is not the initial regimen but whether or not patients receive all three active chemotherapy drugs (5-fluorouracil, irinotecan, and oxaliplatin) at some point in their treatment course.42
Second-Line Therapy
Treatment of relapsed or refractory metastatic disease uses agents not given in the first-line setting. Because most patients will have received a combination of 5-fluorouracil with either irinotecan or oxaliplatin, second-line therapy with the alternate regimen should be considered.41 If targeted agents such as bevacizumab were not part of the initial regimen, addition to the second-line regimen should be strongly considered.
An additional option includes the use of cetuximab either alone or in combination with irinotecan-based chemotherapy.41,43 Cetuximab is FDA approved for use in EGFR expressing metastatic colorectal cancer in combination with irinotecan but can be used as a single agent in patients who cannot tolerate irinotecan-based chemotherapy. The results appear to be best when irinotecan is continued due to synergy demonstrated between the two agents.41,43
Recent evidence suggests that cetaximab is only effective in KRAS wild-type colon tumors. All patients who are candidates for cetuximab should have their tumor tested for KRAS mutations, and cetuximab should only be used in those without mutations.
Cetuximab is given as at loading dose of 400 mg/m2 IV followed by weekly infusions of 250 mg/m2 IV until disease progression. The incidence of grade 3 or 4 adverse effects was as anticipated based on previous trials; asthenia and rash occurred most commonly with cetuximab alone. The benefit of adding cetuximab to oxaliplatin-based regimens or as part of initial therapy for metastatic colorectal cancer is an area of active investigation. Initial data suggest that cetuximab adds to the response rates in both of these settings and supports its use as initial therapy of metastatic colorectal cancer.41 However, no direct comparison can be made to bevacizumab-based regimens, and cetuximab should be reserved for relapsed patients or in those for whom bevacizumab is contraindicated.41 Immunohistochemical (IHC) evidence of EGFR-positive staining in tumors is recommended in the product labeling, though the clinical activity has been seen in EGFR-negative tumors and EGFR status as determined by IHC should not limit its use.41
Salvage Therapy
Third-line options for patients with metastatic colorectal cancer are limited. Panitumumab, another EGFR inhibitor, is approved for patients who have progressed after 5-fluorouracil, oxaliplatin, and irinotecan. Compared to best supportive care, it was demonstrated to improved disease progression.41,44 Like cetuximab, panitumomab should only be used in patients without a KRAS mutation. Use in combination with chemotherapy or other biologics is not currently recommended.
Patients who fail standard treatment for metastatic colorectal cancer should be encouraged to participate in a clinical trial evaluating new treatment approaches for this incurable disease. Table 91–6 lists treatment options for first- and second-line treatment of metastatic colorectal cancer. Patients with good performance status are treated more aggressively than those with poor performance status because of their ability to better tolerate chemotherapy.
Metastatic Patients With Isolated Hepatic Metastasis
Patients with metastatic lesions in the liver that remain unresectable have a poor outcome with limited chance for long-term survival. One approach to treating these patients is to resect the lesion and then give adjuvant chemotherapy. Unfortunately, the majority of patients with hepatic lesions are unresectable at diagnosis. For these patients, neoadjuvant chemotherapy should be considered in attempt to convert their tumors unresectable to resectable.41
Patient Encounter, Part 3: Creating a Care Plan
Based on the information presented, create a care plan for this patient’s colon cancer. Your plan should include:
(a) the patient’s drug-and nondrug-related needs and problems,
(b) the goals of therapy,
(c) a treatment plan specific to GW that includes strategies to prevent adverse effects of chemotherapy,
(d) a follow-up plan to determine whether the goals have been achieved and the adverse effects of chemotherapy have been minimized, and
(e) a plan for treatment options when the initial therapy is no longer achieving the goals of therapy.
Table 91–6 Treatment Options for Metastatic Colon Cancera
FOLFOX and FOLFIRI have both been demonstrated to allow for an increase in surgical resection and increase the potential for long-term survival.41 Recent studies have added bevacizumab to combination chemotherapy regimens with success. No more than 8 to 10 weeks of chemotherapy should be given to avoid liver complications associated with it, and health care practitioners should take precautions to ensure that bevacizumab is not given within 6 weeks of surgery in this setting.41,45
Hepatic arterial infusion pumps have been used in the setting of isolated liver metastases, but this practice has fallen out of favor given improvements in local therapy such as radiofrequency ablation, cryoablation, and chemoembolization.
SPECIFIC AGENTS USED IN COLORECTAL CANCER
Table 91–7 lists all FDA-approved drugs used in colorectal cancer along with their mechanism of action and common toxicities.
5-Fluorouracil
5-Fluorouracil acts as a “false” pyrimidine inhibiting the formation of the DNA base thymidine.23,44 The main mechanism by which it accomplishes this is by inhibiting the enzyme thymidylate synthase, the rate-limiting step in thymidine formation. 5-Fluorouracil must first be metabolized to its active metabolite (F-dUMP). Additionally, metabolites of 5-fluorouracil may incorporate into RNA inhibiting its synthesis.
5-Fluorouracil is commonly used in the adjuvant and metastatic treatment of colon and rectal cancers. Various dosing administration techniques and schedules have been developed with 5-fluorouracil including IV bolus every 3 to 4 weeks, IV continuous infusion, weekly IV boluses and IV boluses, followed by continuous infusions of 5-fluorouracil. Clinical studies comparing efficacy of bolus and continuous infusion schedules generally favor continuous infusion of 5-fluorouracil. This is consistent with evidence that suggests that the duration of infusion may be an important determinant of the biologic activity of 5-fluorouracil, particularly because of its short plasma half-life, S-phase specificity, and relatively slow growth of colon tumors.23,33,44
Clinical significant differences in toxicity also differ based on the dose, route, and schedule of 5-fluorouracil administration. Leukopenia and mucositis are the primary dose-limiting toxicities of bolus 5-fluorouracil, whereas palmar-plantar erythrodysesthesia (“hand-foot syndrome”) and diarrhea occur most frequently with continuous infusions of 5-fluorouracil.23,33,34 Health care practitioners can offer valuable patient advice to decrease the impact of these adverse effects. Patients can be informed to suck on ice chips prior to and for up to 30 minutes after 5-fluorouracil boluses to decrease the incidence of mucositis. Hand-foot syndrome, characterized by painful swelling and redness of the soles of the feet and palms of the hand, can be minimized with loose fitting clothing and keeping skin moist. Additional toxicities include moderate nausea and vomiting, skin discoloration, nail changes, photosensitivity, and neurologic toxicity.
Table 91–7 FDA-Approved Drugs Used in Colon Cancer
An additional determinate of 5-fluorouracil toxicity, regardless of the method of administration, is related to its catabolism and pharmacogenomic factors. Dihydropyrimidine dehydrogenase (DPD) is the main enzyme responsible for the catabolism of 5-fluorouracil to inactive metabolites.46 A number of polymorphisms in DPD have been identified, in which patients have a complete or near-complete deficiency of this enzyme. This results in unusually severe toxicity, including death, after the administration of 5-fluorouracil. Approximately 3% of patients have a complete lack of DPD activity with other patients demonstrating a partial deficiency in enzyme activity. Although patients may be tested for level of DPD activity, it is not routinely done, but may be considered in patients who develop severe toxicity after 5-fluorouracil administration.
Leucovorin is commonly given with 5-fluorouracil. Leucovorin acts to increase the affinity of 5-fluorouracil to thymidine synthase, thus increasing the pharmacologic activity of 5-fluorouracil.23 Leucovorin is most effective when administered prior to 5-fluorouracil and can be given by IV bolus or as a continuous infusion. Health care practitioners can also expect an increase in 5-fluorouracil toxicities (leukopenia, mucositis, and diarrhea) when leucovorin is given in combination with 5-fluorouracil.
Capecitabine
Capecitabine (Xeloda) is an oral prodrug of 5-fluorouracil that is designed to be selectively activated by tumor cells. Capecitabine undergoes a three-step conversion to 5-fluorouracil, the last step being phosphorylation by thymidine phosphorylase (TP). TP levels are reported to be higher in tumor cells than normal tissues; therefore, the systemic exposure of active drug is minimized and tumor concentrations of the active drugs are optimized.32,33 Once the drug is converted to 5-fluorouracil, it has the same mechanism of action. The current FDA-approved indication for capecitabine is for use in metastatic and adjuvant colorectal cancer when monotherapy is desired, though it is actively being investigated as a replacement for 5-fluorouracil in most combinations of colon and rectal cancer regimens. Capecitabine has been demonstrated to be at least equivalent to bolus IV 5-fluorouracil in the metastatic and adjuvant setting with improved patient tolerability.32,47 Hand-foot syndrome and diarrhea are common with capecitabine as its toxicities (and pharmacologic activity) appear to mimic those of continuous infusions of 5-fluorouracil. Both irinotecan and oxaliplatin have been combined with capecitabine. Capecitabine in combination with oxaliplatin appears to be as safe and effective as IV-based 5-fluorouracil in the treatment of colorectal cancer.41,44 Combinations with irinotecan have had mixed results and are not routinely recommended.39,41
The dose of capecitabine ranges from 1,000 to 1,250 mg/m2 twice a day when used by itself; lower doses are often used when it is given in combination with irinotecan or oxaliplatin or in patients with renal insufficiency. The dose should be taken on a full stomach with breakfast and dinner. Capecitabine administered with warfarin can result in significant increases in patients’ International Normalized Ratio (INR) and requires close monitoring. The convenience of oral administration potentially requiring less clinic visits and an improvement in toxicity makes capecitabine a useful alternative to IV 5-fluorouracil both by itself and incorporated into other regimens used in colorectal cancer.
Irinotecan
Irinotecan (Camptosar) is a topoisomerase-I inhibitor that forms a complex with the covalently bound DNA topoisomerase I enzyme and interferes with the DNA breakage-resealing process.33,44 Binding permits uncoiling of the double-stranded DNA, but it prevents subsequent resealing of the DNA, resulting in double-stranded DNA breaks. Irinotecan is a prodrug that is converted by carboxlyesterases to its active form SN-38. Irinotecan is indicated for the first-line treatment of metastatic colorectal cancer in combination with 5-fluorouracil and leucovorin or as a single agent in patients who fail first-line therapies. Irinotecan is not recommended as part of the adjuvant treatment of colorectal cancer at this time.
The major toxicity of irinotecan is diarrhea, which can occur both early and late in therapy.41,44 The early diarrhea is a cholinergic reaction that occurs in the first 24 hours (often during the infusion) in up to 10% of patients and responds to atropine 0.25 to 1 mg IV. The late diarrhea seen in a larger percent of patients occurs 7 to 14 days after the irinotecan infusion. Health care practitioners have to be diligent in counseling patients on this adverse reaction and counseling them on the proper use of antidiarrheals. At the first change in bowel habits, an intensive loperamide regimen should be started by patients (4 mg initially, followed by 2 mg every 2 hours until diarrhea-free for 12 hours). If diarrhea does not stop, or worsens, patients should be instructed to call their health care provider immediately. Late-onset diarrhea may require hospitalization or discontinuation of therapy, and fatalities have been reported. Additional toxicities with irinotecan include leukopenia (including neutropenic fever) and moderate nausea and vomiting. Toxicities of irinotecan appear to be greater when the drug is given weekly when compared to other administration schedules.
Similar to 5-fluorouracil, there is a pharmacogenomic abnormality associated with irinotecan toxicity. UDP-glucuronosyltransferase (UGT1A1) is an enzyme that is responsible for the glucuronidation of SN-38 to inactive metabolites, and reduced or deficient levels of this enzyme correlate with irinotecan-induced diarrhea and neutropenia.41,44,48 Recently, the FDA approved a blood test that detects variations in this gene. This test may assist health care providers in predicting which patients may develop severe toxicities from “normal” doses of irinotecan and can be ordered prior to patients receiving irinotecan.41 The package insert recommends dose reductions of one levels in patients who are UGT1A1 homozygous variants. Irinotecan is administered as an IV bolus over 60 to 90 minutes in a variety of dosing schedules.
Oxaliplatin
Oxaliplatin (Eloxatin) is similar to other platinum analogs (cisplatin) in that it binds to the N-7 position of guanine that results in cross-linking of DNA and double-stranded DNA breaks.23,33,44 Oxaliplatin differs from cisplatin in that the DNA damage induced by oxaliplatin may not be as easily recognized by DNA repair genes, often seen in colorectal cancer. Oxaliplatin, in combination with 5-fluorouracil-based regimens, is indicated for the first- and second-line treatment of metastatic colorectal cancer as well as the adjuvant treatment of colorectal cancer.
The dose-limiting toxicity of oxaliplatin is acute and chronic neuropathy.49 Acute neuropathies occur within 1 to 2 days of dosing, resolve within 2 weeks, and usually occur peripherally. These acute neuropathies occur in almost all patients to some degree and are exacerbated by exposure to cold temperature or cold objects. Health care providers should instruct patients to avoid cold drinks, use of ice, and to cover skin before exposure to cold or cold objects. In addition, carbamazepine, gabapentin, amifostine, and calcium and magnesium infusions have been used to both prevent and treat oxaliplatin-induced neuropathies, although use of these agents is not widely accepted.43 Persistent neuropathies generally occur after eight cycles of oxaliplatin and are characterized by defects that can interfere with daily activities (e.g., writing, buttoning, swallowing, and walking). Patients may receive predefined breaks from oxaliplatin to decrease the onset of these toxicities with reinitiation of therapy.36 This strategy varies among protocols, but involves administering a certain number of predefined oxaliplatin cycles and then stopping. Maintenance therapy with another agent is usually administered and then the oxaliplatin-based regimen is restarted based on the protocol. These neuropathies occur in up to half of patients receiving oxaliplatin but usually resolve with dosage reductions or after oxaliplatin is stopped.33,49 Oxaliplatin has minimal renal, myelosuppressive effects, and nausea/vomiting when compared to other platinum drugs. Oxaliplatin is given IV in a variety of dosing schedules with a typical dose of 85 mg/m2 IV every 2 weeks.
Bevacizumab
Bevacizumab (Avastin) is a recombinant, humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). VEGF is a proangiogenic growth factor found in many cancers including colorectal and is thought to promote blood vessel formation and metastasis of the tumor by binding to VEGF receptors on tumors. Bevacizumab inhibits circulating VEGF, preventing it from binding to receptors and decreasing the formation of new blood vessels.33 Additionally, bevacizumab may allow for increased concentrations of traditional chemotherapy such as irinotecan to reach the tumor to exert its pharmacologic effect. Bevacizumab is not effective alone and must be used in combination with other agents effective in colorectal cancer. It is indicated for first-line treatment of patients with metastatic colorectal cancer in combination with IV 5-fluorouracil-based regimens. Bevacizumab has also been shown to increase survival in the second-line setting when used in combination with the FOLFOX regimen in patients who have not yet received bevacizumab.41
Adverse effects associated with bevacizumab include hypertension which is common but easily managed with oral antihypertensive agents.38,50 Thrombotic events (including myocardial infarctions, pulmonary embolisms, and deep vein thrombosis) occur more frequently in the elderly patients with cardiovascular risk factors and need to be monitored routinely. Because bevacizumab interferes with normal wound healing, it should not be given shortly before or after surgical procedures.50 Initiation within 28 days of surgery is not recommended to allow for proper wound healing and decrease the risk of bleeding. The amount of time needed after bevacizumab discontinuation to perform elective surgical procedures is less clear but health care providers should take into consideration bevacizumab’s half-life of approximately 20 days when making clinical decisions.50 Patients should have their urine checked for protein prior to each dose of bevacizumab to check for potential kidney damage. Patients who have developed 2+ protein on the urinalysis require additional testing prior to receiving therapy. These patients will have their 24-hour urine collected and assessed for protein. Therapy is interrupted for 2 g or more of proteinuria/24 hours and resumed when proteinuria was less than 2 g/24 hours. Finally, there is a risk of GI perforation that is rare but potentially fatal. Patients complaining of abdominal pain associated with vomiting or constipation should be counseled to call their physician immediately. Bevacizumab is commonly given at a dose of 5 mg/kg IV every 14 days until disease progression. Once disease progresses and salvage chemotherapy is initiated, the benefit of continuing bevacizumab is unclear.
Cetuximab and Panitumumab
Cetuximab (Erbitux) and panitumumab (Vectibix) are monoclonal antibodies directed against the EGFR. Cetuximab is a chimeric antibody, whereas panitumumab is a fully human monoclonal antibody. The EGFR receptor is overexpressed in colorectal cancers and leads to an increase in tumor proliferation and growth.23,33,44 Cetuximab received FDA approval for use in EGFR-expressing meta-static colorectal cancer in irinotecan relapsed or refractory patients. Cetuximab should be administered in combination with irinotecan, but can be used as a single agent in patients who cannot tolerate irinotecan-based chemo-therapy. Panitumumab is approved as monotherapy agent and should not be used in combination with other agents outside of clinical trials.
Both agents are well tolerated with infusion-related reactions being cetuximab’s dose-limiting toxicity and rash most commonly seen with panitumumab. Patients receiving cetuximab require premedication with acetaminophen and diphenhydramine and may require modifications to their adminstration schedule or permanent discontinuation if they develop severe allergic toxicity. A skin rash and diarrhea are also commonly seen with both agents, and health care practitioners should provide counseling to patients about these adverse effects. Treatment options include common medications used to treat acne (doxycycline), topical and systemic steroids, and general skin care. Development of rash may be a surrogate marker of response and clinicians should attempt to minimize the complications of the rash prior to discontinuing therapy.41 Other toxicities common to both agents include low magnesium, calcium, and potassium levels that require checking levels and replacement therapy as clinically indicated. A rare (less than 1%) interstitial lung disease is seen with all agents that inhibit EGFR and patients should be instructed to report any new onset shortness of breath. Cetuximab has an initial loading dose of 400 mg/m2 IV infusion. Weekly doses of 250 mg/m2 are then administered starting the following week. Panitumumab is given 6 mg/kg every 2 weeks.
Patient Encounter, Part 4: Screening and Preventing Colon Cancer
GW is concerned about his twin boys developing colon cancer given his disease and his family history of cancer. He asks for advice on preventing colon cancer and ways to detect the disease earlier in his children.
What is the role for chemoprevention for GW’s children?
What are the screening recommendations for colon cancer?
Do these change for GW’s children?
Recent data have demonstrated specific tumor characteristics that may assist clinicians in predicting who may respond to these agents. Early IHC staining for EGFR status is not useful in predicting response as both EGFR-positive and -negative patients response at the same rate. Fluorescence in situ hybridization (FISH) of EGFR copy number and KRAS gene mutation status have recently demonstrated predictive value. Patients with high EGFR gene copy number and wild-type (nonmutated) KRAS are more likely to benefit from cetuximab or panitumumab therapy.41,44 In particular, testing for KRAS mutational status is now part of the disease workup to define patients who may derive benefit from cetuximab or panitumumab. Most clinical trials currently underway are now stratifying patients based on KRAS status to further assist clinicians in defining appropriate therapy for this subset of patients.
RECTAL CANCER
Although often treated similarly to colon cancer, there are some important differences in the treatment of rectal cancer, especially in the adjuvant setting. Rectal cancer involves those tumors found in distal 15 cm of the large bowel and, as such, is very distinct from colon cancer in that it has a propensity for both local and distant recurrence. The higher incidence of local failure and poorer overall prognosis associated with rectal cancer is due to limitations in surgical techniques. Therefore, multimodality therapies with a combination of chemotherapy, radiation, and surgery are at the forefront in the treatment of rectal cancer with the main goal of survival and quality of life by preserving the function of the anal sphincter. In addition, because treatment with surgery, radiation, or systemic chemotherapy at the time of the recurrence is often suboptimal, adjuvant therapy after tumor resection is an important aspect of treatment of the primary tumor. Similar to adjuvant therapy for colon cancer, 5-fluorouracil provides the basis for chemotherapy regimens for rectal cancer.
Adjuvant therapy consisting of 5-fluorouracil-based chemotherapy in combination with radiation therapy should be offered to patients with stage II or III cancer of the rectum.51 Radiation therapy decreases the rate of local recurrences whereas the 5-fluorouracil decreases the risk of distant tumor recurrence as well as acting as a radiosensitizer. Toxicities from combined modality therapy include severe hematologic toxicity, enteritis, and diarrhea. Additional trials have sought to determine optimal combinations of concurrent radiation and 5-fluorouracil. Similar to tumors in the colon, continuous infusions of 5-fluorouracil appear to be superior to bolus doses. However, leucovorin does not appear to improve efficacy of adjuvant treatment for rectal cancer. Use of oral alternatives to 5-fluorouracil that are also known to enhance radiation effects, such as capecitabine, are under investigation with preliminary data suggesting the combination of capecitabine and radiation will be safe and effective. In addition, based on the efficacy in colon cancer, FOLFOX regimens have moved into clinical trials in the adjuvant setting.
Another unique aspect of rectal cancer is the use of neoadjuvant therapy. Preoperative radiation (with or without chemotherapy) is given to downstage the tumor prior to surgical resection to improve sphincter preservation.51 The issue of pre-versus postoperative radiation is a subject of debate and investigation in the United States and will require further data to determine the superiority of a specific neoadjuvant protocol.
Finally, once rectal cancer is metastatic, similar regimens as outlined in the colon cancer section are used for palliation of symptoms.51
OUTCOME EVALUATION
The goal of monitoring is to evaluate whether the patient is receiving any benefit from the management of the disease, to detect recurrence, and to minimize the adverse effects of treatment. During treatment for active disease, patients should undergo monitoring for measurable tumor response, progression, or new metastases; these tests may include chest CT scans or x-rays, abdominal or pelvic CT scans or x-rays, depending on the site of disease being evaluated for response, and carcinoembryonic antigen (CEA) measurements every 3 months if the CEA is or was previously elevated.52 A PET scan can be considered to identify localized sites of meta-static disease in situations where a rising CEA level suggests metastatic disease but CT scans and other imaging studies are negative. Symptoms of recurrence such as pain, changes in bowel habits, rectal bleeding, pelvic masses, anorexia, and weight loss develop in fewer than 50% of patients. Patients who undergo curative surgical resection, with or without adjuvant therapy, require close follow-up because early detection and treatment of recurrence could still result in patient cures. In addition, early treatment for asymptomatic metastatic colorectal cancer appears superior to delayed therapy. Colorectal cancer surveillance guidelines published by the American Society of Clinical Oncology recommend against routinely monitoring liver function tests, CBC, FOBT, CT scans, annual chest x-rays, or pelvic imaging in asymptomatic patients.52
In addition, a complete blood count should be obtained prior to each course of chemotherapy administration to ensure that hematologic values are adequate. In particular, white blood counts and absolute neutrophil counts can be decreased in patients receiving chemotherapy such as irinotecan and 5-fluorouracil. Baseline liver function tests and an assessment of renal function should be evaluated prior to and periodically during therapy. Other selected laboratory tests include checking for the presence of protein in the urine in patients receiving bevacizumab and monitoring of magnesium, calcium, and potassium in patients receiving cetuximab or panitumumab.
Patients should be evaluated during every treatment visit for the presence of anticipated side effects from their treatment, and health care practitioners should anticipate these adverse reactions and aggressively treat and prevent them from occurring. These generally include loose stools or diarrhea from irinotecan, 5-fluorouracil, and capecitabine; hand-foot syndrome from 5-fluorouracil and capecitabine; nausea or vomiting from irinotecan, 5-fluorouracil, and oxaliplatin; mouth sores from 5-fluorouracil; neuropathies from oxaliplatin; bleeding and hypertension from bevacizumab; and skin rash associated cetuximab and panitumumab.
SUMMARY
Recent advances in the treatment of cancer of the colon and rectum now offer the potential to improve patient survival but for many patients, improved disease-and progression-free survival represent equally important therapeutic outcomes. In the absence of the ability of a specific treatment to demonstrate improved survival, important outcome measures should include the effects of the treatment on patient symptoms, daily activities, performance status, and other quality-of-life indicators. Individualized patient care to balance the risks associated with treatment and benefits of a specific treatment regimen is necessary to optimize patient outcomes.
Abbreviations Introduced in This Chapter
Patient Care and Monitoring
1. Review any available diagnostic data to determine the status of the colon cancer.
2. Obtain a thorough history of prescription, nonprescription, and natural drug product use.
3. Evaluate patient-specific factors that may dictate treatment regimen. Does the patient have a known pharmacogenomic deficiency? What lifestyle issues are important to the patient?
4. Determine if any dose modifications are required in the chemotherapy regimen prescribed. Does the patient have adequate blood counts to receive chemotherapy?
5. Educate the patient on drug therapy and possible treatment-related adverse effects, and counsel the patient on appropriate recommendations to prevent or minimize these adverse effects. What medications are for the treatment of cancer and what medications are to prevent the adverse effects of chemotherapy?
6. Develop a plan to prevent treatment-related adverse effects. Are the antiemetics appropriate? Does the patient understand the possible adverse effects and when to call the physician versus when patient-directed care is appropriate?
7. Warning signs to report to the physician (depends on regimen used) include fever, diarrhea, mucositis, and hand-foot syndrome.
8. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions.
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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