CONTINUING EDUCATION

Wyeth
TRENDS IN PHARMACY AND PHARMACEUTICAL CARE

An ongoing CE program of The University of Florida College of Pharmacy and DRUG TOPICS

The University of Florida College of Pharmacy is accredited by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education. Accredited in every state requiring CE.® ACPE # 012-999-04-228-H01

This lesson is no longer valid for CE credit after 5/31/06.

CREDIT:

This lesson provides two hours of CE credit and requires a passing grade of 70%.*

OBJECTIVES:

Upon completion of this article, the pharmacist should be able to:

• Provide a comprehensive overview of colorectal cancer pathophysiology, screening, diagnosis, and prevention
• Explain the mechanisms of action, side effects, and place in therapy for treatment modalities used in the management of colorectal cancer
• Outline practice guidelines for the management of local, regional, and metastatic colorectal cancer
• Define the role of the pharmacist in the management of colorectal cancer

*To receive credit you must complete the evaluation. Upon successful completion, the University of Florida College of Pharmacy will mail Statements of Credit for written quizzes within 10 working days. Participants completing the program on-line may print a Statement of Credit after successfully completing the program.

GOAL:

To provide an understanding of colorectal cancer, its management, and how pharmacists may play an important role

Colorectal cancer: Screening, treatment, and prevention

By Tina B. Stacy, Pharm.D., BCOP Adjunct Assistant Professor

While colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, it is the second-leading cause of cancer-related mortality. An estimated 600,000 new cases of CRC were diagnosed worldwide in 2003, accounting for 9% of human cancers. In the United States, 105,500 new cases of colon cancer and 42,000 new cases of rectal cancer were diagnosed, while 57,100 deaths occurred. Interestingly, over the past 30 years, the population-adjusted incidence for CRC has remained constant while mortality has decreased. This decrease in mortality is likely due to more extensive screening techniques, diet improvements, and improved treatment modalities.

Click here to view full-size graphic

Anatomy

The large bowel includes the cecum; appendix; ascending, transverse, descending, and sigmoid colons; rectum; and anus. The mucosa, submucosa, muscularis externa, and serosa comprise the four tissue layers. The colon and anterior third of the rectum are contained within the peritoneum, thereby hematogenous drainage is primarily into portal circulation. Drainage into portal circulation and the inferior vena cava occur from the distal two-thirds of the rectum, which lies outside the peritoneal cavity.

Pathophysiology

CRC is believed to be a product of many interactions, including genetic and environmental factors, but its etiology has not been fully identified. Microbiologic examination reveals adenocarcinoma to be the most common histology (>90%), while mucinous adenocarcinoma, signet-ring cell carcinoma, and carcinoma simplex comprise less than 10%.

From small beginnings, CRC can proliferate to involve one or more tissue layers anywhere within the large bowel. For reasons yet to be determined, epithelial cells lining the large bowel hyperproliferate to form small benign neoplasms or adenomas. Next, numerous genetic mutations must occur to transform the normal epithelial cells into malignant cells. Significant laboratory investigation has been conducted to elucidate these genetic mutations. To date, chromosomal abnormalities associated with CRC include the following: mutations of tumor suppressor genes, adenomatous polyposis coli (APC), p53, and DCC ("deleted in colorectal cancer" gene); as well as the development of oncogenes k-ras and N-ras. DCC gene loss has been identified in 70% of CRC cases while k-ras oncogene mutations occur in 50%.

Following local invasion of bowel wall, CRC metastasizes via lymphatic and hematogenous routes to regional lymph nodes, liver, lungs, peritoneal cavity, adrenals, ovaries, and bone. Metastasis to the brain is rare. Recalling the hematogenous drainage discussed previously, the liver is the primary site of metastatic invasion from primary lesions located in the colon and anterior third of the rectum. The lungs are the primary site of metastatic invasion for CRC lesions located in the distal two-thirds of the rectum. At the time of initial resection, 40% to 70% of CRCs have metastasized to regional lymph nodes and up to 60% have venous invasion.

Epidemiology

The incidence of CRC development is 19 in 100,000 for individuals less than 65 years of age and 337 in 100,000 for individuals greater than 65. The overall lifetime risk is 5%. Although the risk for development of CRC increases with increasing age, an estimated 3% of diagnosed cases are in individuals less than 40 years of age. The median age of diagnosis of CRC is 69 years. Of note, individuals of Hispanic and African-American descent are typically diagnosed at a younger age.

Risk factors

Although several risk factors have been identified in the development of CRC, an estimated 75% of cases have no identifiable risk factor except advanced age. Known risk factors include diet, genetics, and environmental factors.

Studies indicate a diet classified as high fiber/low fat results in significantly lower incidence of CRC development. Increased fecal bile acid concentrations are believed to induce bowel lumen proliferation. Consumed fiber has the potential to bind these bile acids and decrease the concentration of unbound bile acid in the gut. In addition, the fermentation of fiber may alter the intestinal pH, thereby decreasing neoplastic transformation of epithelial cells. Conversely, diets high in fat result in a slow gastrointestinal transit time allowing potential carcinogens prolonged contact time with luminal surfaces.

A positive family history is present in 10% to 15% of individuals with CRC. Studies indicate that individuals with a first-degree relative with CRC face a three-fold greater risk of developing CRC than the general population.

Two distinct hereditary CRC syndromes have been identified: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Familial polyposis syndrome is an autosomal dominant mutation in the APC gene, which results in the development of hundreds or thousands of intestinal adenomatous polyps. If left untreated, 70% to 100% of individuals diagnosed with FAP will develop CRC by the fourth decade of life. FAP accounts for 1% of all CRC cases diagnosed in the United States. Upon diagnosis, total colectomy is the recommended intervention. Due to the significant risk for CRC development, the offspring of patients with APC are recommended to undergo annual flexible sigmoidoscopy starting at 10 to 12 years of age and continuing until age 40.

Hereditary nonpolyposis CRC accounts for 5% of CRC cases. Also known as Lynch syndrome, HNPCC results in an increased incidence of predominantly right-sided colon cancer. Derived from an autosomal dominant mutation, HNPCC pathogenesis is linked to mutations in mismatch repair genes including hMSH2, hMLH1, hPMS1, and hPMS2. Two distinct syndromes exist. Lynch I is characterized by the absence of extracolonic neoplasms, while Lynch II is typified by extracolonic neoplasms involving the ovary, breast, endometrium, gastrointestinal tract, and bile ducts. The median age of diagnosis is 46 years, while 50% of cases are diagnosed by age 80. Offspring of individuals diagnosed with HNPCC should begin biennial colonoscopy at age 25 as well as screening for extracolonic malignancies.

Inflammatory bowel disease (IBD) accounts for approximately 1% to 2% of CRC cases. The risk associated with ulcerative colitis and Crohn's disease depends on the length of bowel involved and the duration of active disease. Overall, individuals with IBD have three times the risk compared with the general population.

Environmental factors play a role in the development of CRC. Studies of migrant populations have shown that the incidence of CRC is a product of an individual's current geographic location and not country of origin. Individuals who reside in rural locales have a decreased incidence of CRC compared with those residing in urban areas. Interestingly, in the United States, CRC is more common in the East and North than in the West and South.

Additional factors associated with an increased risk for CRC include previous CRC diagnosis or pelvic irradiation, obesity, alcohol use, tobacco smoking, previous noncancer surgery, and elevated serum lipids. Table 1 provides guidelines from the American Cancer Society (ACS) to reduce the risk of CRC development.

Presentation

Histologic examination at time of initial resection indicates that an estimated 40% of individuals have localized disease limited to the intestinal tract at the time of diagnosis, while 40% present with regional disease that includes regional lymph nodes. CRC predominantly affects the sigmoid and ascending colon (26%) and the rectum (29%). Unfortunately, 20% of individuals are diagnosed with metastatic disease involving the liver or lung.

The most common presenting symptoms associated with CRC are rectal bleeding and abdominal pain. Additionally, individuals may complain of a change in bowel habits, abdominal mass, and lethargy. Symptoms are typically associated with the location of the primary tumor. In the right side of the bowel, the intestinal contents are comprised mostly of liquids. Therefore, bowel habits may have little to no noticeable change. Lethargy commonly results from right-sided lesion ulceration and subsequent blood loss. Left-sided lesions result in obstructive symptoms due to the solid nature of the bowel contents. Obstructive symptoms such as cramping, constipation, or diarrhea may appear. Rectal lesions may cause an irregular blood spotting of stools, a sense of incomplete emptying, and painful evacuation. Advanced and metastatic disease are associated with lower-extremity edema, jaundice, and weight loss.

Diagnosis, staging, and prognostic factors

Since early stage CRC may be asymptomatic, laboratory tests and imaging techniques may be required to ascertain an accurate diagnosis. A digital rectal examination (DRE), sigmoidoscopy, and barium enema may be used to determine the presence of CRC. A DRE detects tumors in the anus and within seven to 10 centimeters of the anal verge. Sensitivity of DRE decreases with proximal shift in location of the CRC to the right colon.

Endoscopy, including flexible sigmoidoscopy and colonoscopy, is considered the cornerstone of CRC diagnosis. Flexible sigmoidoscopy instruments are available in 35- and 65-centimeter lengths. Sixty-five centimeters allows for visualization of the splenic flexure, thereby detecting two-thirds of all CRC cases.

Additionally, a thorough history and physical exam are needed. Physicians may order the following laboratory tests to diagnose CRC: complete blood count, international normalized ratio (INR), activated partial thromboplastin time (aPTT), liver function tests (LFT), and plasma carcinoembryonic antigen (CEA). CEA, a cell surface glycoprotein, may be used at diagnosis to classify an individual's prognosis. Studies indicate the presence of CEA is neither a useful screening nor a diagnosis of CRC due to its poor sensitivity (40%) and specificity (90%). Appropriate uses include preoperative staging, postoperative use after hepatic resection, and monitoring response in individuals with metastatic disease.

Colorectal cancer staging is based upon the American Joint Committee on Cancer (AJCC) classification system, also known as the TNM system. Classification of CRC depends on the depth of tumor invasion into and through the bowel wall as well as lymph node involvement and the presence of distant metastatic sites. Pathologic examination of a completely resected colon for rectal cancer and the surrounding mesenteric tissue is necessary. Generally, stage I disease is localized, stage II is locally advanced involving adjacent structures, stage III involves lymh nodes, and stage IV is metastatic disease.

Currently, four independent prognostic factors have been identified in an effort to estimate the risk of CRC recurrence. Stage is considered the most important prognostic factor. The five-year survival rates are 90% for individuals diagnosed with localized disease, 65% for regional disease, and 8% with metastatic disease. The histologic grade influences survival independent of stage. Individuals with well-differentiated carcinomas (grades 1 and 2) have better five-year survival than those with poorly differentiated carcinomas (grades 3 and 4).

The anatomic location of the primary tumor is another independent prognostic factor. For equal stages, individuals diagnosed with rectal lesions have poorer prognosis while those diagnosed with ascending colon lesions have the best prognosis. Lastly, clinical presentation with bowel obstruction or perforation confers a worsened prognosis. Additionally, CEA results may reflect the extent of disease spread and prognosis, as larger tumors tend to produce significantly higher levels of CEA.

Treatment overview

Following the diagnosis of CRC, the first goal is to determine the extent of disease involvement. Surgical resection is the primary method utilized to determine the extent of tumor invasion. Following surgical resection, adequate staging may be accomplished. At the time of primary resection, if adjacent organs, such as the small bowel or bladder, are involved, they may be resected as well.

• Colorectal cancer stage I. The primary treatment modality for individuals diagnosed with stage I CRC remains wide surgical excision plus lymphadenectomy. The five-year survival rate associated with surgical intervention alone for stage I is greater than 90%. Therefore, adjuvant therapy is not advocated at this time.

• Colorectal cancer stages II-III. With surgery alone, the five-year survival rates for colon cancer stages II and III are 60% to 80%, and less than 50%, respectively. Conflicting data regarding the utility of adjuvant chemotherapy in the setting of stage II colon cancer has led to significant disparity in its management. Several studies indicate that the benefit of adjuvant chemotherapy has not been shown. Although not fully understood, a possible explanation for this lack of benefit may be the poor participation in clinical trials to date. A meta-analysis of 1,000 individuals with stage II colon cancer showed a statistically insignificant difference in five-year survival rates (82% adjuvant chemotherapy, 80% surgical excision alone). Alternatively, the National Surgical Adjuvant Breast and Bowel Project (NSABP) advocates the use of adjuvant chemotherapy in stage II colon cancer due to a small but consistent benefit noted in serial NSABP trials. Due to this disparity, scientific efforts are focused on determining individuals at high risk for relapse based upon prognostic factors and genetic characteristics of individual tumor lines. Factors being evaluated include the following: S-phase, tumor ploidy, p53 status, levels of thymidylate synthesis, and the presence or absence of chromosomal mutations. As a result, following surgical resection, individuals diagnosed with stage II colon cancer should be considered for participation in clinical trials involving adjuvant treatment regimens such as chemotherapy, radiation therapy, or immunotherapy.

Conversely, the clinical benefit of adjuvant chemotherapy has been shown in individuals diagnosed with stage III colon cancer. Results indicate adjuvant chemotherapy provides a 25% relative increase in overall survival when combined with primary surgical excision. Adjuvant chemotherapy is administered after surgical excision with the intent to improve outcomes.

Debate continues regarding the most appropriate adjuvant chemotherapy regimen. Extensive clinical trials have evaluated the benefit of 5-fluorouracil-containing regimens. Early clinical trials evaluated the effectiveness of 5-fluorouracil plus levamisole. This combination reduced the risk for CRC recurrence by 41% if administered for a total of one year after initial resection. Additionally, the five-year survival rate was improved from 50% to 62% when compared with surgical resection alone, and the cancer-related mortality was decreased by 33%. Later trials evaluated the use of 5-fluorouracil plus leucovorin. Comparative analysis indicated a similar reduction in the rate of recurrence, five-year survival, and overall mortality when administered for six months following initial surgical resection. As a consequence, the standard treatment regimen for stage III colon cancer is now 5-fluorouracil plus leucovorin. Table 1 provides various adjuvant chemotherapy regimens.

• Rectal cancer stages I-III. Rectal cancer is three times more likely to recur locally compared with proximal colonic tumors in part because the anatomic confines of the rectum preclude wide resection margins and much of the rectum lacks an outer serosal layer. Surgical excision and lymphadenectomy are considered the treatment of choice for stage I disease. Due to the potential for relapse noted with stages II and III, adjuvant therapy with 5- fluorouracil-based chemotherapy plus radiation therapy is recommended to reduce pelvic relapse. Treatment is initiated 22 to 70 days following surgical resection with 5-fluorouracil given as a radiosensitizer. A significant reduction in rates of local recurrence, distant metastases, and colon-related deaths were noted among stages II and III individuals who are given 5-fluorouracil.

• Colorectal cancer stage IV. The five-year survival rate following surgical resection of metastatic CRC is 8%. In an effort to extend survival and improve symptoms, surgery for metastatic lesions, radiation therapy, and/or chemotherapy should be initiated as adjuvant or neoadjuvant therapy.

The most common sites for CRC metastases are the liver and lung. Solitary or limited (<3 lesions) hepatic metastasis should be resected. Five-year survival associated with hepatic metastasis resection is 20% to 40%, while no survival advantage has been documented following pulmonary metastasis resection.

If hepatic lesions are too large or too numerous for initial resection, neoadjuvant chemotherapy or chemo-embolization may be utilized. Hepatic artery infusion using 5-fluorouracil or floxuridine may be used to decrease hepatic metastasis size and number while mitomycin C, doxorubicin, and cisplatin alone or in combination are used for chemoembolization purposes.

Additionally, surgery and radiation therapy may be used for symptom management. Although not considered curative, surgery may be used to manage obstruction or perforation. Radiation therapy is used to manage symptoms associated with localized disease.

For many years, chemotherapy regimens containing 5-fluorouracil have been the treatment of choice for individuals with metastatic CRC. Unfortunately, these regimens do not produce the significant improvement in five-year survival and decrease in mortality observed in individuals with stage III CRC. As a result, various clinical trials were conducted to evaluate the effectiveness of 5-fluorouracil plus leucovorin in combination with newer chemotherapy modalities, including irinotecan and oxaliplatin.

Saltz and colleagues developed the first of the aggressive regimens containing 5-fluorouracil, leucovorin, and irinotecan (Table 1). Use of this combination results in an improvement in quality of life and survival when compared with 5-fluorouracil plus leucovorin alone. The response rate improved from 15% to 36% with a median duration of six to 8.1 months. In addition, there was an improvement in progression-free and overall survival when compared with continuous infusion 5-fluorouracil alone. A decrease in tumor symptoms and improvement in quality of life was noted compared with the best supportive care. Similar data were observed in oxaliplatin studies.

Due to the increased toxicity associated with these regimens, a thorough patient evaluation must be completed to determine the most appropriate candidates. Individuals with poor performance status, advanced age (greater than 65 years), or considered at high risk for development of significant side effects should not receive these aggressive regimens. Appropriate regimen options include a 5-fluorouracil plus leucovorin regimen, irinotecan single agent, oxaliplatin single agent, or capecitabine alone. For progressive or recurrent lesions, salvage chemotherapy is indicated. Salvage regimens include continuous infusion 5-fluorouracil (if not previously given), capecitabine, or radiation therapy for painful or obstructive lesions.

Follow-up

Studies indicate that 85% of CRC recurrences are evident within three years of initial surgical resection. Therefore, close follow-up is imperative. Clinical evaluation should be completed frequently during the first two years following diagnosis. A thorough history and physical examination is recommended every three months for two years, then semiannually thereafter for an additional five years. Clinical evaluations have determined chest radiographs to be as good as computed tomography scans in detecting disease recurrence and metastasis. Individuals should have a chest radiograph completed every one to two years. Repeat colonoscopy studies should be performed annually for the first one to three years. If all studies are negative, colonoscopy may be repeated every two to three years. CEA levels should be determined at the initial diagnosis. After completion of therapy, CEA should be evaluated every three months for two years and then semiannually for two to five years. Lastly, in the presence of rising CEA values, further studies, including magnetic resonance imaging, computed tomography, or ultrasound, may be indicated.

Approved agents: Chemotherapy and biologics

• Fluorouracil. The cornerstone of colorectal cancer chemotherapy regimens is 5-fluorouracil. Dose, route, and scheduling variations exist between numerous regimens, which have been developed over the years. To date, the optimal dose and schedule have not been determined. Clinical trials indicate that the use of continuous infusion 5-fluorouracil results in improved disease-free survival and overall survival rates when compared with short infusions.

In 2000, the Food & Drug Administration and Oncologic Drugs Action Committee reviewed data provided by physicians regarding their 5-fluorouracil practices. Interestingly, 90% of physician practices utilize short-infusion 5-fluorouracil as the administration of choice. Compliance and quality of life associated with short 5-fluorouracil infusions were the most commonly provided reasons for their use. Additionally, in order to provide continuous infusions, physician practices must have access to ambulatory infusion pumps, or patients must have home health benefits. The use of short-infusion 5-fluorouracil bypasses these requirements.

Toxicities most commonly associated with 5-fluorouracil include stomatitis, diarrhea, and mild-to-moderate nausea and vomiting. Neutropenia is most commonly associated with short infusions, while palmar-plantar erythrodysthesia is observed with protracted continuous infusions. In an effort to decrease the incidence of stomatitis, individuals should be encouraged to have a dental examination before initiation of chemotherapy to treat any dental or periodontal disease. Additionally, if stomatitis is experienced, pharmacists are key to providing management recommendations. The discontinuation of alcohol-containing mouth rinses, such as chlorhexidine, is imperative. Coating agents, oral lubricants, topical anesthetics, and opioid analgesics may be used for pain management.

Leucovorin is administered with 5-fluorouracil to stabilize binding to thymidylate synthase resulting in a reduction in the rate of DNA replication and repair. Drug interactions noted with this combination include increases in phenytoin and warfarin levels following the initiation of 5-fluorouracil and leucovorin therapy. Although the mechanism is currently unknown, pharmacists should carefully follow phenytoin levels and INRs after 5- fluorouracil and leucovorin therapy is started.

• Irinotecan. Irinotecan, a camptothecin analog, was approved for use in the United States in 1996 for the management of metastatic CRC. Irinotecan is metabolized by carboxylesterases to form the active agent SN-38. After conversion, SN-38 undergoes significant enterohepatic recycling that contributes to its prolonged elimination half-life. As a result, individuals with impaired hepatic function (total bilirubin > 1 mg/dL) are at increased risk for development of toxicities.

The most common toxicity associated with irinotecan administration is diarrhea. Diarrhea is characterized by early or delayed onset. Early diarrhea develops within 24 hours following the administration of irinotecan. Cholinergic in nature, early diarrhea is associated with diaphoresis, flushing, and abdominal cramps. The treatment of choice is atropine 0.25 mg to 1 mg given by rapid intravenous infusion. Delayed, or secretory, diarrhea is associated with prolonged systemic exposure to SN-38. Beginning one to two days following irinotecan administration, delayed diarrhea is characterized by continuous watery bowel movements. If not appropriately and quickly managed, patients may develop electrolyte imbalances and dehydration requiring hospitalization. High-dose loperamide is the treatment of choice. At the first episode of watery diarrhea, patients should be instructed to take loperamide 2 mg by mouth every two hours or 4 mg by mouth every four hours. All patients who receive irinotecan therapy should be discharged from the hospital or clinic with a prescription for high-dose loperamide as a precaution.

• Capecitabine. Metabolized to form 5-fluorouracil, capecitabine is an oral equivalent of its intravenous predecessor. The use of capecitabine has resulted in similar results noted with 5-fluorouracil and leucovorin regimens. As a result, capecitabine was approved in 2001 for use in metastatic CRC in individuals requiring single-agent 5-fluorouracil. Additionally, capecitabine therapy should be considered in individuals with contraindications to combination regimens with irinotecan, 5- fluorouracil, and leucovorin. The side effect most commonly associated with capecitabine therapy is palmar-plantar erythrodysthesia (68.3% patients). Various prevention strategies have been employed in an effort to reduce this bothersome side effect. Many clinicians advocate the use of pyridoxine (vitamin B6) 200 mg by mouth once daily. Studies proving the usefulness of pyridoxine are limited. Keeping hands and feet well moisturized is another management strategy. The use of occlusive balms such as "bag balm" has been reported to provide subjective improvement in symptoms. As noted with 5- fluorouracil, capecitabine interacts with phenytoin and warfarin by unknown mechanisms. Consequently, pharmacists should closely monitor phenytoin levels and INRs during capecitabine therapy.

• Oxaliplatin. Oxaliplatin is a third-generation platinum drug approved for the management of advanced CRC. Therapy with oxaliplatin should be considered in individuals who are appropriate candidates for aggressive chemotherapy regimens. Additionally, oxaliplatin- containing regimens should be considered for individuals who are showing disease progression or recurrence within six months of receiving combination 5-fluorouracil, leucovorin, and irinotecan. Side effects most commonly experienced include neutropenia, nausea and vomiting, and neuropathy. Patients should be premedicated with a 5-HT₃ antagonist with or without dexamethasone for the prevention of nausea and vomiting. Acute and delayed syndromes characterize oxaliplatin-neuropathy. Acute neuropathy is transient and experienced immediately following treatment. Commonly cold-induced, acute neuropathy is experienced by 70% to 80% of individuals receiving oxaliplatin. Peripheral sensory, or delayed, neuropathy is a cumulative dose-limiting toxicity noted in 10% to 40% of patients receiving cumulative doses greater than 680 mg/m². Dose reduction or discontinuation of therapy should be considered in individuals experiencing significant gastrointestinal, hematologic, or neurotoxicity.

• Cetuximab (Erbitux, IMC-C225). Cetuximab was approved in February 2004 for use in combination with irinotecan for the treatment of epidermal growth factor receptor-(EGFR) expressing metastatic CRC or as a single agent for EGFR-expressing metastatic CRC in patients intolerant to irinotecan-based chemotherapy. Cetuximab is a murine monoclonal antibody that targets epidermal growth factor. As a result, signal transduction, which generally leads to cell proliferation, and survival are inhibited. Histologic studies indicate that 72% of colorectal tumors overexpress epidermal growth factor. To determine EGFR overexpression, the FDA has approved a test kit that may be used by pathologists to analyze a colon tissue sample.

When the drug was administered in combination with irinotecan, 22% of patients responded with a delay in tumor growth by 4.1 months. Used as a single agent, 10.8% of patients responded with a delay in tumor growth of 1.5 months. Although no survival benefit has been documented, cetuximab is associated with a decreased incidence of side effects when compared with traditional chemotherapy regimens, which led to its approval.

Severe infusion-related reactions, characterized by bronchospasm, stridor, hoarseness, urticaria, and hypotension, may occur due to the murine moiety. Ninety percent of these reactions occur with first-dose administration. Such reactions require immediate interruption of cetuximab infusion and permanent discontinuation from further treatment. Interventions, which must be readily available, include epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen. Mild-to-moderate infusion-related reactions may be managed by slowing the infusion rate and administering antihistamines prior to subsequent doses. Additional side effects include the development of an acneform rash (88%), dry skin, tiredness or weakness (73%), constipation (28%), diarrhea (28%), nausea (29%), and fever (33%).

• Bevacizumab (Avastin). Approved in February 2004 as first-line therapy in the management of metastatic CRC, bevacizumab is a murine monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). VEGF is specific for the abnormal vasculature that develops as part of tumor growth and metastasis. When blocked by bevacizumab, tumors cannot stimulate new blood vessel formation, resulting in blood and nutrient depletion for tumor cells. In a phase III study evaluating 925 individuals with metastatic CRC, a 4.7-month survival advantage was noted in individuals who received bevacizumab in combination with the Saltz regimen as compared with those who received chemotherapy alone. Overall response rates for the Saltz regimen plus bevacizumab versus the Saltz regimen alone were 45% and 35%, respectively. Currently, no data justify the use of bevacizumab as a single agent.

Side effects commonly associated with bevacizumab administration include hypertension, tiredness, thromboembolism (19.3%), diarrhea, neutropenia, headache, appetite loss, and stomatitis. Less common, but severe, side effects include gastrointestinal perforation requiring surgery, impaired wound healing, and bleeding (3.1%).

Investigational agents

• Edrecolomab (EpCAM, Panorex). Edrecolomab is a murine monoclonal antibody that targets the surface of the glycoprotein 17-1A antigen. Clinical trials evaluating the use of edrecolomab have shown a decreased death rate (32%) and reduction in relapse (23%) with seven years' follow-up in stage III CRC when compared with observation alone. No clinical benefit, as defined by response or survival, has been noted in individuals with metastatic disease.

Chemoprevention

The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) results in a decrease in colonic polyp formation and regression of existing polyps. The specific mechanism is poorly understood. The inhibition of prostaglandin synthesis by aspirin and NSAIDs may play a role in inhibition of cell proliferation, inhibition of cyclooxygenase, prevention of free radical formation, and inhibition of epidermal growth factor. This protective effect has been well documented in randomized, double-blind, placebo-controlled trials evaluating the use of NSAIDs in patients with familial polyposis. Sulindac 150 mg by mouth twice daily significantly reduced the mean number and diameter of polyps compared with placebo. Three months following the discontinuation of sulindac therapy, the size and number of polyps increased but remained significantly lower than at baseline.

Celecoxib therapy results in a selective inhibition of COX-2. Histologic studies indicate a significant upregulation of COX-2 in human epithelial cancers such as colon, esophageal, lung, breast, and prostate. In an effort to evaluate the effectiveness of celecoxib in the prevention of colonic polyps in patients diagnosed with FAP, a randomized, placebo-controlled trial was completed. Individuals were assigned to receive either placebo, celecoxib 100 mg by mouth twice daily, or celecoxib 400 mg by mouth twice daily. The resulting decrease in polyps for placebo, 100 mg celecoxib, and 400 mg celecoxib was 4.5%, 14.5%, and 28%, respectively. As a result, the FDA approved celecoxib for use in FAP to reduce the number of adenomatous polyps.

Diets characterized as high in fiber and low in fat are associated with a decreased incidence of CRC. Recalling the previous discussion, consumed fiber has the potential to bind bile acids, which have been implicated in the induction of bowel lumen proliferation. Diets high in fat result in a slow gastrointestinal transit time allowing potential carcinogens prolonged contact time with luminal surfaces. Additional measures, which require further evaluation regarding their ability to decrease the incidence of colorectal cancer, include physical activity, calcium and Vitamin D supplementation, and selenium.

Screening recommendations

Currently, flexible sigmoidoscopy in combination with fecal occult blood test (FOBT) is the screening technique of choice. Flexible sigmoidoscopy should be completed every five years with an annual FOBT. Although colonoscopy allows for visualization of the entire length of the colon, no study completed to date has shown a difference in mortality when compared with flexible sigmoidoscopy. While flexible sigmoidoscopy requires minimal preparation for the procedure, colonoscopy requires preparation and full bowel evacuation to be performed. If performed, colonoscopy should be repeated every 10 years.

FOBT results in an increased diagnosis of early-stage CRC and is associated with a 30% decrease in mortality. When completed, 2% of individuals greater than 50 years of age will have a positive FOBT result. Of these, 10% will have CRC, 30% polyps, and 60% false positives. The limitations of FOBT are numerous. Twenty percent to 25% of CRC lesions do not bleed enough for detection, diet and medications may affect results, and red meats and fresh vegetables with peroxidase activity, such as radishes, cauliflower, cantaloupe, and horseradish, may yield false positive results. Additionally medications such as aspirin and NSAIDs may increase fecal blood loss, resulting in false positive results. Vitamin C inhibits Hemoccult II test, resulting in false negatives.

Double-contrast barium enema allows for the examination of the entire length of the colon. While considered virtually as good as colonoscopy, barium enema is considered better than either flexible sigmoidoscopy or FOBT alone. Limitations to the use of double-contrast barium enema include the fact that lesions cannot be immediately removed or biopsied and small polyps may be missed. Consensus has not been reached regarding the optimal frequency for double-contrast barium enema. Currently, every five to 10 years is recommended.

Conclusion

Colorectal cancer and its treatment result in significant morbidity and mortality. This year, an estimated 600,000 individuals will be diagnosed worldwide; more than 57,100 patients will die. In 2003, in the United States alone, 147,500 new cases of CRC were diagnosed. These statistics alone provide adequate rationale for the continued investigation into newer, more effective treatment modalities. Pharmacists possess the ability to prevent and manage treatment-related toxicities by providing pertinent drug information and clinical trial interpretation. Pharmacists are at the bedside and pharmacy counter with the patients. As the most accessible healthcare provider, pharmacists must be armed with up-to-date information regarding toxicity prevention and management techniques, quality-of-life improvement strategies, and medical information.

References are available upon request.

TEST QUESTIONS

Write your answers on the answer form below (photocopies of the answer form are acceptable) or on a separate sheet of paper. Mark the most appropriate answer.

1. Which of the following is not associated with the decreased mortality associated with colorectal cancer?

a. More extensive screening techniques
b. Improved treatment modalities
c. Decreased incidence of inflammatory bowel disease
d. Diet improvements

2. The most common site for colorectal cancer is the:
a. Rectum
b. Ascending colon
c. Transverse colon
d. Sigmoid colon

3. The primary site of metastasis from the colon and anterior third of the rectum is the:

a. Liver
b. Bone
c. Lung
d. Brain

4. Which of the following incurs the greatest risk for colorectal cancer development?

a. Crohn's disease
b. High-fat diet
c. HNPCC
d. FAP

5. Screening recommendations for HNPCC are as follows:

a. Flexible sigmoidoscopy beginning at age 10-12 and continuing until age 40
b. Beginning at age 50, flexible sigmoidoscopy plus FOBT
c. Beginning at age 40, flexible sigmoidoscopy plus FOBT
d. Biennial colonoscopy at age 25 and extracolonic malignancy work-up

6. DR is a 52-year-old Caucasian male. He is an avid runner and consumes no alcohol or tobacco products. DR presents to his primary care physician complaining of abdominal cramping and constipation. Following flexible sigmoidoscopy, it is confirmed that DR has colorectal cancer. Based upon the presentation, where is the likely location of the tumor?

a. Right-side colon
b. Left-side colon
c. Appendix
d. Rectum

7. Surgical resection reveals a well-differentiated adenocarcinoma involving the submucosa and several regional lymph nodes. DR has which stage of colorectal cancer?

a. Stage IIb
b. Stage IIIa
c. Stage IIIb
d. Stage IV

8. Based on DR's diagnosis and prognostic factors, which of the following is the most appropriate management?

a. Radiation therapy
b. Careful observation
c. 5-fluorouracil plus leucovorin
d. Saltz regimen

9. DR calls to report significant stomatitis five days after chemotherapy completion. All of the following are appropriate treatments except:

a. Chlorhexidine mouth rinse
b. Oral lubricants
c. Topical anesthetics
d. Opioid analgesics

10. Due to DR's increased risk for relapse, which one of the following monitoring plans should be recommended?

a. Colonoscopy every 10 years with annual FOBT
b. Computed tomography of chest and abdomen every three months
c. CEA every three months
d. Flexible sigmoidoscopy every five years with annual FOBC

11. Two years after initial surgical resection, laboratory evaluation reveals an increase in CEA. DR also reports feeling increased nonspecific discomfort on his right side. Following computed tomography of the chest and abdomen, five hepatic metastases are found. What is the most appropriate management?

a. Surgical resection
b. Saltz regimen
c. Radiation therapy to liver
d. Hepatic artery infusion

12. Thirty-six hours after treatment, DR calls to report significant diarrhea. What is the most appropriate treatment?

a. Loperamide
b. Hospitalization for IV fluids
c. Atropine
d. Watching and waiting

13. What is the recommended treatment for an individual diagnosed with stage II rectal cancer?

a. Surgery then 5-FU plus radiation therapy
b. Surgery then 5-FU plus leucovorin
c. Surgery then clinical trial participation
d. Surgery then radiation therapy

14. Side effects associated with short intravenous infusion of 5-fluorouracil include all of the following except:

a. Neutropenia
b. Stomatitis
c. Diarrhea
d. Palmar-Plantar erythrodysthesia

15. Which of the following is an appropriate premedication for oxaliplatin?

a. Filgrastim 300 mcg SC
b. Gabapentin 600 mg PO
c. Ondansetron 24 mg IV
d. Normal Saline 1 liter IV

16. Which of the following is the dose-limiting toxicity of oxaliplatin?

a. Neutropenia
b. Neuropathy
c. Nephrotoxicity
d. Cardiotoxicity

17. Cetuximab works by inhibition of:

a. Thymidylate synthase
b. Epidermal growth factor receptor
c. Microtubule formation
d. Vascular endothelial growth factor

18. Bevacizumab dosing recommendations are as follows:

a. 10 mg/kg QO week single agent
b. 3 mg/kg QO week single agent
c. 10 mg/kg QO week with Saltz regimen
d. 3 mg/kg QO week with Saltz regimen

19. CZ is a 40-year-old female who comes into the pharmacy concerned about her colorectal cancer risk. She has just learned that her 78-year-old uncle has been diagnosed with stage I disease. What is the most appropriate chemoprevention regimen for CZ?

a. Genetic counseling
b. Colonoscopy Q 10 years beginning now
c. Celecoxib 400 mg PO BID
d. Five servings of fruits and vegetables per day

20. Which of the following is the appropriate screening recommendation for individuals with normal colorectal cancer risk?

a. Colonoscopy every 10 years plus annual FOBT
b. Computed tomography of chest and abdomen every five years
c. Double-contrast barium enema every five years
d. Flexible sigmoidoscopy every five years plus annual FOBT

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Tina Stacy. CE: Colorectal cancer: Screening, treatment, and prevention. Drug Topics May 17, 2004;148:60.