Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

107. Colorectal Cancer

Lisa E. Davis, Weijing Sun, and Patrick J. Medina


KEY CONCEPTS

 Images Advancing age, inherited and acquired genetic susceptibilities, lifestyle choices, inflammatory bowel disease, type 2 diabetes mellitus, and environmental factors are associated with colorectal cancer risk.

 Images Regular use of aspirin and other nonsteroidal antiinflammatory drugs, calcium intake, and higher blood vitamin D levels may reduce risk of colorectal cancer, but they are not currently recommended for routine cancer prevention.

 Images Effective colorectal cancer screening programs incorporate regular examination of the entire colon starting at age 50 years for average-risk individuals. Colorectal adenomas can progress to cancer and should be removed.

 Images The histologic stage of colorectal cancer upon diagnosis—determined by depth of bowel invasion, lymph node involvement, and presence of metastases—is the most important prognostic factor for disease recurrence and survival.

 Images The treatment goal for stages I, II, and III colon cancer is cure; surgery should be offered to all eligible patients for this purpose. Six months of fluoropyrimidine-based adjuvant systemic therapy reduces the risk of cancer recurrence and overall mortality in patients with stage III and select populations with stage II colon cancer. An oxaliplatin-containing regimen further reduces risk as compared with fluoropyrimidine alone.

 Images Combined modality neoadjuvant therapy consists of fluoropyrimidine-based chemosensitized radiation therapy and surgery for patients with stage II or III cancer of the rectum and is considered standard of care to decrease risk of local and distant disease recurrence.

 Images Preoperative chemotherapy may reduce tumor size and convert unresectable disease to resectable disease in selected patients with metastatic colorectal cancer. This strategy offers the potential for prolonging overall survival and cure for metastatic disease.

 Images Chemotherapy is palliative for metastatic disease. A fluoropyrimidine with oxaliplatin or irinotecan improves survival compared to fluoropyrimidine monotherapy and should be offered to patients who are candidates for aggressive treatment. The ability for patients to receive all active cytotoxic agents (e.g., fluoropyrimidine, oxaliplatin, irinotecan) during the course of their disease improves their overall survival.

 Images Bevacizumab plus fluoropyrimidine-based chemotherapy as initial therapy for metastatic disease is considered standard of care and provides a survival benefit as compared with combination chemotherapy alone.

 Images The addition of cetuximab or panitumumab to initial treatment for KRAS wild-type advanced or metastatic disease may improve tumor response rates and survival. Individuals who have disease progression after initial therapy not containing an epidermal growth factor receptor (EGFR) inhibitor may benefit from cetuximab or panitumumab, either alone as a single agent or combined with other drugs. However, patients with codon 12 or 13 KRAS gene mutations should not receive cetuximab or panitumumab as these tumor mutations predict lack of treatment response.


Colorectal cancer involves the colon, rectum, and anal canal. It is one of the three most common cancers occurring in adult men and women in the United States and accounts for about one in nine cancer diagnoses. In 2013, an estimated 142,820 new cases will be diagnosed, of which 102,480 will involve the colon and 40,340 the rectum.1 An additional 7,060 new cases of cancer involve the anus, anal canal, or anorectum.1

For both adult men and women, colorectal cancer is the third leading cause of cancer-related deaths in the United States. An estimated 50,830 deaths will occur during 2013.1

Mortality and incidence rates associated with colorectal cancer in the United States have decreased steadily over the past two decades. Incidence rates vary worldwide, with the highest incidence rates in economically developed countries in North America, Europe, New Zealand, and Australia, whereas lowest rates are found in Central America, Africa, and South-Central Asia.2 Colorectal cancer mortality rates have been decreasing in and are comparable between the United States and several Western countries; mortality rates continue to increase in less developed countries in eastern Europe and Central and South America.2

Multiple factors are associated with the development of colorectal cancer, including inherited susceptibility, environmental and lifestyle factors, and certain disease states. Overall, about 39% of affected individuals undergo a surgical procedure alone intended for cure. An additional 37% of individuals can potentially be cured with surgery followed by adjuvant radiation therapy (XRT), chemotherapy, or both. Curability is influenced primarily by the depth of tumor penetration, involvement of lymph nodes, and presence of metastatic disease. Five-year survival rates are about 91% and 88% for persons with early stages of colon and rectal cancer, respectively.3 After the tumor has spread regionally to adjacent lymph nodes or tissues, 5-year survival rates drop to about 70% for both colon and rectal cancer; 5-year survival for individuals with metastatic disease is about 12%.

Treatment modalities for colorectal cancer include surgery, XRT, chemotherapy, and targeted molecular therapies (e.g., angiogenesis inhibitors, epidermal growth factor receptor inhibitors). Surgery is the important and definitive procedure associated with cure. XRT can improve curability following surgical resection in rectal cancer and may reduce symptoms and complications associated with advanced disease. Chemotherapy is used in the adjuvant setting to increase cure rates and in treatment for advanced stages of disease to prolong survival. Selected patients with advanced disease who receive aggressive preoperative chemotherapy and targeted therapies experience higher resection rates and can be potentially cured. Much progress has been made in the treatment of advanced disease, the ability to identify candidates for potentially curative surgical procedures, and the availability of active drug regimens that improve patients’ survival.

EPIDEMIOLOGY

Colorectal cancer is the third most common malignancy worldwide, accounting for more than 1.2 million new cases annually.2 The variation in colorectal cancer occurrence worldwide is at least 20-fold.2 The highest incidence rates are found in Australia and New Zealand, Europe, and North America. The lowest incidence rates are seen in less-developed areas such as Africa, South Central Asia, and Central America. Most recently, incidence rates have rapidly increased in newer economically developed countries in eastern Europe and in Japan, Korea, and China.2 The influence of environmental factors (e.g., increased intake of caloric-dense foods and physical inactivity) on colorectal cancer risk has become evident through studies of migrants, where the incidence of colorectal cancer increases rapidly within first-generation immigrants who migrate from low- to high-risk areas.2 However, colorectal cancers are known to develop more frequently in certain families, and genetic predisposition to this disease is also well recognized.

The incidence of invasive colon cancer is greatest among males, who have an age-adjusted incidence rate of 37.4 per 100,000, as compared with females for whom the rate is 29.9 per 100,000.3 Invasive cancer of the rectum occurs less frequently; the incidence rate is 16.5 and 10.3 per 100,000 for males and females, respectively. Differences in colorectal cancer incidence exist among ethnic groups in the United States, where incidence is highest among African Americans compared to white, American Indian/Alaska Native, Hispanic/Latino, and Asian American/Pacific Islander males and females.1 Cultural and genetic factors, as well as disparities in access to healthcare services, may influence risk among population groups.1

The overall incidence of colon and rectal cancers in the United States continues to decline, with an annual percent decrease of 2.5% from 1975 to 2009.3 Cancer incidence rates have declined in every major ethnic group since 1975, although less among American Indian/Alaska Natives. Most recent rapid declines in incidence rates are attributed to screening and polyp removal.1 Figure 107-1 displays trends for incidence and mortality rates among white and African American males and females in the United States.

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FIGURE 107-1 National Cancer Institute, Surveillance Epidemiology and End Results (SEER) incidence and mortality rates for invasive colon and rectum cancer, 1975–2009. SEER 9 areas and US Mortality Files (National Center for Health Statistics, CDC). Rates are age-adjusted to the 2000 U.S. standard population (19 age groups—Census P25-1103). (From reference 3.)

Cancer of the colon and rectum accounts for about 9% of all cancer deaths in the United States. The median age for death from cancer of the colon or rectum is 74 years.3 It is estimated that 50,830 individuals will die of colorectal cancer in the United States in 2013, which represents a continued decline in overall combined mortality for both colon and rectal cancer by more than 30% observed during the last 20 years.1 Overall mortality rates are highest among African American males and females, although a steep rate of decline began in the late 1990s.3 Colorectal cancer death rates are decreasing among all ethnic groups; however, mortality rates are not statistically lower in American Indian/Alaska Natives.3 Factors contributing to the overall decline in colorectal cancer mortality include decreasing incidence rates, screening programs with early polyp removal, and more effective and better tolerated treatments. Differences among different world geographic regions, and in population groups in the United States, may also reflect variations in underlying tumor biology, stage at diagnosis, access to screening programs, and availability of effective treatments.13

ETIOLOGY AND RISK FACTORS

Numerous studies suggest that the development of colorectal cancer is related to both uncontrollable and modifiable risk factors. Age, family history, clinical and genetic susceptibilities cannot be controlled by individuals. However, lifestyle choices, dietary and environmental factors that affect the bowel may influence an individual’s risk of developing colorectal cancer.

Personal Medical History

Age

An individual’s risk of developing cancer of the colon or rectum increases with advancing age, with the likelihood of cancer diagnosis increasing after 40 years of age and rising progressively after age 50.3The median age at diagnosis is 69 years.3 Although fewer than 20% of patients are less than 50 years of age at the time of diagnosis, the incidence of colorectal cancer is increasing in this age group, in contrast to overall rates of decline among adults age 50 years and older. The reasons for this pattern are unclear, but may reflect increasing trends in obesity and detrimental dietary factors among younger people.4

Adenomatous Polyps or Colorectal Cancer

A prior history of high-risk adenomatous polyps, particularly multiple adenomas or size ≥10 mm, is associated with increased risk of colorectal cancer.5 Individuals with a prior diagnosis of colon or rectal cancer have a greater risk of developing a new malignancy at another area in their colon or rectum as compared to individuals without a prior history of colorectal cancer.

Inflammatory Bowel Disease

Images Chronic ulcerative colitis, particularly when it involves the entire large intestine, predisposes individuals to colorectal cancer at a rate that is 5- to 10-fold greater than average.6 The risk is even greater for young individuals and increases for all affected individuals with increasing extent of bowel involvement and disease duration. The cumulative risk of colorectal cancer is low early in life, but increases from 2% at 10 years after diagnosis to 8% and 18% at 20 and 30 years, respectively.6 Chronic underlying inflammation, oxidative stress, and release of various cytokines, including nuclear factor-kappa B (NF-κB) and tumor necrosis factor-alpha (TNF-α), appear to promote tumorigenesis.7 The progressive dysplastic changes that bowel mucosa undergo are similar to those observed in adenomatous polyps. Similarly, patients with Crohn’s disease are also at increased risk, and the risk is believed to be about that of patients with ulcerative colitis.6 As compared with sporadic colon cancer or cancer associated with ulcerative colitis, colon cancer in patients with Crohn’s disease tends to arise in the proximal colon.6 This is most likely related to the area of bowel affected by the chronic inflammatory process in individuals with Crohn’s disease. Overall, persons diagnosed with either disease constitute about 1% to 2% of all new cases of colorectal cancer each year.

Type 2 Diabetes Mellitus

Images Type 2 diabetes mellitus, independent of body mass size and physical activity level, is associated with increased colorectal cancer risk, although glycosylated hemoglobin (HbA1c) alone as an indicator of hyperglycemia and association with colorectal cancer is inconsistent.8 Metabolic syndrome is associated with an elevated risk of colorectal cancer.8 In a meta-analysis of 15 studies, diabetes was associated with a 30% increase in risk of colorectal cancer and increased risk of colorectal cancer mortality.9 Features associated with type 2 diabetes, such as hyperinsulinemia and elevated levels of free insulin-like growth factor-1 (IGF-1), promote tumor cell proliferation.8,10Individuals diagnosed with colorectal cancer and type 2 diabetes have a higher risk of all-cause mortality compared to individuals without diabetes.10 Risk of death from cardiovascular disease was higher among patients receiving insulin whereas colorectal cancer related mortality was lower with insulin use. Individuals with type 2 diabetes mellitus treated for colorectal cancer also have decreased disease-free survival and overall survival and experience a higher incidence of treatment-related diarrhea and risk of death.

Family History and Inherited Genetic Risk

Colorectal Cancer or Adenomatous Polyps

Images Three specific patterns of colon cancer occurrence are generally observed: sporadic, familial, and recognized hereditary syndromes. Although most cases of colon cancer are sporadic in nature, about 20% of patients who develop colorectal cancer will have a family history of colorectal cancer.11,12 In these families, the frequency of colorectal cancer is too high to be considered sporadic, but the pattern is not consistent with an inherited syndrome. First-degree relatives of patients diagnosed with colorectal cancer have an increased risk of the disease, particularly if the relative was diagnosed at age 60 or younger.12Similarly, parents and siblings of relatives diagnosed with adenomatous polyps are at increased risk for developing colorectal cancer. The reasons for these associations are not established, but may be related to a combination of inherited genes and environmental factors.12

Hereditary Syndromes

Images Colorectal cancer is a consequence of several well-defined genetic syndromes.1115 The two most common forms of hereditary colon cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Both forms result from a specific germline mutation. FAP is a rare autosomal dominant trait caused by inactivating mutations of the adenomatous polyposis coli (APC) gene and accounts for 0.2% to 1% of all colorectal cancers. The disease is manifested by hundreds to thousands of tiny sessile adenomatous polyps that carpet the colon and rectum, typically arising during adolescence.13 The polyps continue to proliferate throughout the colon, with eventual transformation to malignancy. The risk of developing colorectal cancer for individuals with untreated FAP is virtually 100%; most will develop colorectal cancer by the fourth and fifth decades of life.12,13Several variants of FAP exist and are associated with different extracolonic manifestations.13

HNPCC, also referred to as Lynch syndrome, is an autosomal dominant inherited syndrome and is the most common hereditary predisposition for colorectal cancer.11 Germline mutations in one of the DNA mismatch-repair (MMR) genes, most commonly MLH1MSH2MSH6, or PMS2, are responsible for HNPCC, which accounts for 2% to 4% of overall colorectal cancer cases.11 The estimated lifetime risk of developing colorectal cancer by age 70 years is about 66% and 43% for male and female carriers of germline MMR mutations, respectively.14 Multiple generations within a family are affected, and colorectal cancer develops early in life, with a mean age at time of diagnosis of about 45 years of age.1315 About one-third of individuals with HNPCC develop another HNPCC-related extracolonic malignancy within the following 10 years.15 In contrast to FAP, adenomatous polyps are not a primary manifestation of the HNPCC. Polyps that do form tend to be located primarily in the right-sided, or proximal colon. If HNPCC is suspected in a patient diagnosed with colorectal cancer, typically due to early age at diagnosis or family cancer history, the tumor is examined for evidence of deficient MMR to distinguish between sporadic or germline genetic mutations. Criteria for diagnosis of HNPCC have been established, and it is important to identify carriers of these MMR mutations so that they can be counseled and followed appropriately.1315

Enzyme Polymorphisms

ImagesIncreasing evidence suggests that genetic polymorphisms in drug-metabolizing enzymes, such as N-acetyltransferases (NAT1 and NAT2), cytochrome P450 (CYP) isoenzymes, glutathione-S-transferase (GST) enzymes, methylenetetrahydrofolate reductase (MTHFR), and hemochromatosis gene mutations, may confer genetic susceptibility to colorectal cancer.16 Individuals with certain variations in NAT1, NAT2, CYP1A2, CYP1A1, and CYP2E1 enzyme genotypes may be particularly susceptible to carcinogenic effects of a high dietary intake of meat, tobacco smoke, or other environmental factors.16,17

Lifestyle Factors

Nonsteroidal Antiinflammatory Drug and Aspirin Use

Images Several lifestyle factors are known to affect colorectal cancer risk (Table 107-1). Observational studies have reported that regular (at least two doses per week) nonsteroidal antiinflammatory drug (NSAID) and aspirin use is associated with a reduced risk of colorectal cancer. In an average-risk individual, regular aspirin use is associated with a 13% to 28% reduction in the risk of colorectal adenoma, and the risk of colorectal cancer and mortality is reduced by 30% to 40%.18,19 Regular daily aspirin use reduces colorectal adenoma recurrence, and colorectal cancer incidence and mortality in patients with prior adenomas or diagnosis of colorectal cancer.8,18,19

TABLE 107-1 Lifestyle Factors Associated with Colorectal Cancer Risk

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Benefit has also been seen with NSAID and cyclooxygenase-2 inhibitor (COX-2) use. NSAID use over a 10- to 15-year period is associated with protection against adenomas and colorectal cancer, with a 30% to 50% reduction in the risk of colorectal cancer.19,20 The protective effects of these agents appear to be related to their inhibition of COX-2 and free radical formation. COX-2 overexpression is seen in precancerous and cancerous lesions in the colon and is associated with decreased colon cancer cell apoptosis and increased production of angiogenesis-promoting factors.18,19 Up to 50% of colorectal adenomas and 85% of sporadic colon carcinomas have elevated levels of COX-2 and COX-2 overexpression in colorectal cancer is associated with a worse survival. COX-2 appears to play a role in polyp formation, and COX-2 inhibition suppresses polyp growth, restores apoptosis, and decreases expression of proangiogenic factors. Inhibition of COX-2 also downregulates the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which plays an important role in carcinogenesis and cancer cell resistance to apoptosis.21

Postmenopausal Hormone Replacement Therapy

Exogenous postmenopausal oral hormone replacement therapy is associated with a significant reduction in colorectal cancer risk.22 Risk reduction is seen in postmenopausal women receiving both estrogen only and combined estrogen and progestin therapy, and persists for about 10 years after therapy is discontinued.

Several mechanisms for a protective effect of estrogens on the bowel have been identified.8 Age-related declines in estrogen levels are associated with estrogen receptor hypermethylation, which is associated with reduced expression of the estrogen receptor gene and dysregulated colonic mucosal cell growth. Estrogen may also interact with bile acids, or alter levels of insulin and IGF-1, an important mitogen that influences cell-cycle progression in certain cells. However, because postmenopausal hormone replacement therapy increases breast cancer risk and harmful cardiovascular effects, its use is not recommended to prevent colorectal cancer.

Obesity and Physical Inactivity

Images Physical inactivity and elevated body mass index (BMI), independent of level of physical activity, are associated with an elevated risk of colon adenoma, colon cancer, and rectal cancer.8,12,23,24Individuals with a higher level of activity throughout life have the lowest risk, which may be up to 50% lower than that of physically inactive individuals. Possible hypotheses are that physical activity stimulates bowel peristalsis, resulting in decreased bowel transit time; or that exercise-induced alterations in body glucose, insulin resistance, hyperinsulinemia, and possibly other hormones reduce tumor cell growth.23

In most studies, a 5-unit increase above a healthy BMI was associated with increased risk of colorectal cancer in men, but the relationship is weaker and less consistent for women, possibly because of interactions with age or hormone replacement therapy.23,24 Differences in body composition and distribution of fat weight among men and women could contribute to this discrepancy.8,22 Several mechanisms have been proposed to explain the association between body size and colorectal cancer risk, including insulin resistance, chronic inflammation, and alterations in growth factors or steroid hormones.8

Alcohol and Tobacco Use

Images Alcohol consumption increases the risk of colorectal cancer, but stronger associations have been observed for men than for women, possibly because alcohol consumption is generally greater in men than in women.8 Lifetime and baseline alcohol consumption increase risk of cancer of the colon and rectum, and an alcohol intake greater than 30 g/day (about two drinks/day) affects risk.8,12 Proposed mechanisms include impaired folate metabolism, abnormal DNA methylation, suppressed tumor immune surveillance, and other procarcinogenic effects related to alcohol intake.8

Cigarette smoking is associated with an increased risk of colorectal cancer and mortality, with a stronger association for cancer of the rectum than for cancer of the colon.8,12,25 A dose relationship with increasing number of pack-years and cigarettes smoked per day was also statistically significant but only among patients who had smoked for at least 30 years. As compared to never-smokers, the risks of colorectal cancer and mortality in smokers were 18% and 25% higher, respectively.25 Early tobacco use may also influence risk of cancer recurrence and mortality among colon cancer survivors, possibly due to an increase in genetic alterations that influence tumor behavior.26

Dietary Intake and Nutrients

Images Epidemiologic studies of worldwide incidence of colorectal cancer suggest that economic development and dietary habits strongly influence its development. However, findings based on epidemiologic data are subject to potential biases and inconsistencies in how dietary factors are categorized and measured, and numerous studies have been able to clearly establish only a few specific dietary habits as independent risk factors for colorectal cancer development.

Fiber, Fruit, and Vegetables

Images Worldwide, high-fiber dietary patterns have been associated with a low incidence of colorectal cancer.8,27,28 Dietary fiber is composed of both water-soluble and insoluble remnants of plant cells that are not processed by normal human digestive enzymes. Foods that are high in fiber include vegetables, fruits, grains, and cereals. Dietary fiber is postulated to reduce colonic mucosal cell exposure to carcinogens through the dilution or reduced absorption of carcinogens in the bowel, reduced fecal pH, reduced bowel transit time, alterations in bile acid metabolism, or increased production of short-chain fatty acids.8 At present, the role of dietary fiber with regard to amount, source, and type and colorectal cancer risk requires further study.

Red Meat, Processed Meat, and Fat

Images Studies suggest that dietary fat intake may be associated with colorectal cancer risk.8,27 This may have resulted from the use of dietary evaluations that focused on the quantity, origin, or type (saturated, monounsaturated, and polyunsaturated) of fat rather than on the source of dietary fat ingested. Dietary fat may promote cancer development as a result of its effect on fecal bile acid concentrations. Dietary fat ingestion stimulates the release of bile acids that are converted by colonic flora to secondary bile acids, which are associated with bowel mucosal irritation and cell proliferation responses and may promote tumor growth.27

The association between red, but not white, meat consumption and colorectal cancer is strongest, which may be related to the heterocyclic amines and polycyclic aromatic hydrocarbons formed during the cooking process, or the presence of specific fatty acids in red meat such as arachidonic acid.8,27 Processed meat products containing certain preservatives may increase exogenous exposure to carcinogenic N-nitroso compounds.27 Although red and processed meat and high saturated fat intake has been associated with increased risk of colorectal cancer, the exact nature and magnitude of these risks have not been determined.

Calcium and Vitamin D

Images Inverse associations between dietary calcium, vitamin D intake, and serum 25-hydroxyvitamin D3 levels, and colorectal cancer risk have been reported in several observational studies.8,27,29 Calcium may exert antiproliferative effects by binding to bile and fatty acids in the small intestine, thereby reducing colonic epithelial cell exposure to mutagens.8 In addition, calcium induces differentiating, pro-apoptotic, and direct growth-restraining activities on both normal and tumor cells in the gastrointestinal tract.8,27 Vitamin D has antiproliferative and differentiation and pro-apoptotic effects on colonic epithelial cells and on a variety of tumor cells.8,29,30 Most of its actions are mediated through a high-affinity nuclear vitamin D receptor (VDR), and the expression of this receptor is altered during different phases of colon cancer development.30 Other genes involved in key signaling pathways that influence colorectal cancer development, such as Wnt/β-catenin, are also regulated by the VDR transcription factor.30 Thus, cellular responsiveness to vitamin D and associated cancer risk is unlikely limited to dietary intake alone. Vitamin D and calcium appear to interact synergistically to protect against adenoma recurrence and colorectal cancer.8

Folate and Other Micronutrients

Folate intake has been linked to colorectal cancer risk through epidemiologic and experimental studies in cell lines, animals, and humans.8,31 However, the underlying basis for this is complex, particularly because alcohol use, smoking, genetic variants of the MTHFR gene, and other factors can interfere with folate metabolism.8,31 Cellular folates act to accept and donate methyl groups in cellular processes that influence DNA synthesis and methylation of DNA, RNA, and proteins.31 Variations in DNA methylation of gene promoter regions influence gene expression and DNA stability. Inappropriate hypermethylation leads to inactivation of tumor suppressor gene function and hypomethylation can result in oncogene activation.31

The relationship between the timing of folate exposure to the development of neoplastic foci may influence what appears to be a bimodal impact of folate on tumorigenesis.8,31 Moderate folate supplementation, if initiated prior to the establishment of neoplastic foci, may be protective, whereas excessive or increased intake might enhance growth of established early neoplastic lesions.8,31 Thus, an adequate dietary folate intake may be enough to lower the risk of colorectal cancer, and exceeding normal intake may not be beneficial.

Epidemiologic and animal model data suggest that deficiencies in other dietary micronutrients, including vitamin B6, selenium, vitamin C, vitamin E, and carotenoids, may increase colorectal cancer risk, but there is no convincing evidence that the incidence of colorectal cancer is greater in patients with low serum levels than in patients with adequate levels.8

PATHOPHYSIOLOGY

Anatomy and Bowel Function

The large intestine consists of the cecum; the ascending, transverse, descending, and sigmoid colon; and the rectum (Fig. 107-2). In adults, it extends about 1.5 m and has a diameter ranging from 8 cm in the cecum to 2 cm in the sigmoid colon. The function of the large intestine is to receive 500 to 2,000 mL of ileal contents per day. Absorption of fluid and solutes occurs in the right colon or the segments 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. Mucus secretion from goblet cells into the intestinal lumen lubricates the mucosal surface and facilitates movement of the dehydrated feces. It also serves to protect the luminal wall from bacteria and colonic irritants such as bile acids.

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FIGURE 107-2 Colon and rectum anatomy.

Four major tissue layers, from the lumen outward, form the large intestine: the mucosa, submucosa, muscularis propria, and serosa (Fig. 107-3). Embedded in the submucosa and muscularis propria is a rich lymphatic capillary system. Lymphatic channels do not extend into the mucosa. The muscularis propria consists of circular smooth muscle and outer longitudinal smooth muscle bands. Contraction of these muscle groups moves colonic material toward the anal canal. The outermost layer of the colon, the serosa, secretes a fluid that allows the colon to slide easily over nearby structures within the peritoneum. The serosa covers only the anterior and lateral aspects of the upper third of the rectum. The lower third lies completely extraperitoneal and is surrounded by fibrofatty tissue as well as adjacent organs and structures.

Images

FIGURE 107-3 Cross-section of bowel wall.

The surface epithelium of the colonic mucosa undergoes continual renewal, and complete replacement of epithelial cells occurs every 4 to 8 days. Cell replication normally takes place within the lower third of the crypts, the tubular glands located within the intestinal mucosa. The cells then mature and differentiate to either goblet or absorptive cells as they migrate toward the bowel lumen. The total number of epithelial cells remains relatively constant as the number of cells migrating from the crypts is balanced by the rate of exfoliation of cells from the mucosal surface. This two-phase process is critical to the malignant transformation of the epithelial cells. The number of dysplastic and hyperplastic aberrant crypt foci increases with increasing age; as the mass of abnormal cells accumulates at the top of the crypt and starts to protrude into the stream of fecal matter, their contact with fecal mutagens can lead to further cell mutations and eventual adenoma formation.

Colorectal Tumorigenesis

The development of a colorectal neoplasm is a multistep process involving several genetic and phenotypic alterations of normal bowel epithelium structure and function, leading to dysregulated cell growth, proliferation, and tumor development. Because most colorectal cancers develop sporadically, with no inherited or familial disposition, efforts have been directed toward identifying these alterations and learning whether detection of such changes may lead to improved cancer detection or treatment outcomes.

Features of colorectal tumorigenesis include genomic instability, activation of oncogene pathways, mutational inactivation or silencing of tumor-suppressor genes, and activation of growth factor pathways.32,33 A genetic model has been proposed for colorectal tumorigenesis that describes a process of transformation from adenoma to carcinoma (Fig. 107-4). The adenoma to carcinoma sequence of tumor development reflects an accumulation of mutations within colonic epithelium that confers a selective growth advantage to the affected cells. Key elements of this process include hyperproliferation of epithelial cells to form a small benign neoplasm or adenoma in conjunction with acquisition of various genetic mutations.32 These mutations occur early and frequently in sporadic cases of both adenomas and colorectal cancer. Somatic mutations must occur in multiple genes to produce the malignant transformation. Table 107-2 lists important genetic mutations that are associated with colorectal cancers.

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FIGURE 107-4 Genetic changes associated with the adenoma–carcinoma sequence in colorectal cancer. The accumulation of genetic changes in the pathogenesis of colorectal cancer includes microsatellite instability (MSI) initiated by aberrant DNA methylation or mismatch repair (MMR) gene mutation with subsequent disruption in transforming growth factor-β receptor type II (TGF- β2R) and BAX signaling; mutation in the adenomatous polyposis coli (APC) gene or abnormalities in β-catenin leading to inappropriate activation of the Wnt signaling pathway; mutational activation of cyclooxygenase-2 (COX-2) and impaired prostaglandin degradation from loss of 15-prostaglandin dehydrogenase (15-PGDH); KRAS, PIK3CA, or BRAF oncogene activation; increased epidermal growth factor receptor (EGFR) signaling; and deletions or mutations of tumor suppressor genes SMAD4, PTEN, P53. Chromosomal instability (CIN) is a common feature of sporadic disease, but causative factors are not defined. The sequence of molecular events may differ between somatic and inherited genetic alterations. (Data from references 13, 32, 33, and 34.)

TABLE 107-2 Genetic Mutations Associated with Colorectal Cancer

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Genomic Instability

Genomic instability plays an integral role in normal colonic or rectal mucosal transformation to carcinoma.34 Three molecular pathways that lead to genomic instability are the microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN) pathways. The most common type is CIN, which leads to alterations in chromosomal structure and copy number.32,34 Important consequences of CIN include imbalanced chromosome number (aneuploidy), chromosomal gene amplifications, and loss of a wild-type allele of a tumor-suppressor gene, also referred to as loss of heterozygosity (LOH). Up to 85% of sporadic colorectal cancers exhibit CIN and the tumor suppressor genes APCP53, and SMAD4 are commonly affected.3234

Microsatellites are series of repeat nucleotide sequences that are spread out across the entire genome. Microsatellite replication errors within tumor DNA occur frequently, and mutations of the MMR genes that recognize and regulate DNA mismatch-repair errors contribute to MSI and colorectal tumorigenesis.32,34 Germline mutation of MMR genes is an important characteristic of HNPCC but somatic mutations are also present in about 15% of sporadic colorectal cancers.34

Alterations in gene expression or function in the absence of DNA sequence alterations are referred to as epigenetic changes, and these are usually due to methylation of DNA gene promotor regions or histone modifications.34CIMP is characterized by hypermethylation of a panel of multiple genes that are associated with gene silencing and subsequent loss of tumor suppressor gene function.34 About 15% of sporadic colorectal cancers arise as a consequence of CIMP.

Oncogene and Tumor Suppressor Gene Alterations

Mutation or loss of the APC tumor suppressor gene is a key factor involved in tumor formation through activation of the Wnt signaling pathway, a mediator of cell cycle progression, cell proliferation, differentiation, and apoptosis.10,32,34 The APC gene encodes for APC protein that binds to and degrades cytoplasmic β-catenin, a downstream component of the Wnt signaling pathway. In the absence of functional APC, β-catenin accumulates in the cytoplasm, then enters the nucleus and activates transcription of various genes, leading to constitutive activation of the Wnt signaling pathway. Inactivation of the APC gene is the single gene defect responsible for FAP, and is frequently an initiating event in sporadic colorectal cancer.32

Mutational inactivation of P53 represents a frequent and second key step in colorectal tumorigenesis.32 Normal P53 gene expression is important for G1 cell-cycle arrest to facilitate DNA repair during replication and to induce apoptosis. A third step in tumor progression is the mutational inactivation of the transforming growth factor-β (TGF-β) signaling pathway, which facilitates adenoma transition to high-grade dysplasia or carcinoma and also inactivates SMAD4.32 In normal epithelium, TGF-β has an antiproliferative role and induces growth arrest and apoptosis. Alterations in SMAD4 or TGF-β receptors lead to a loss of the normal growth inhibitory response to TGF-β.

Several oncogene activating mutations play an important role in promoting colorectal cancer.32 Mutations in members of the Ras gene family—KRASHRAS, and NRAS—in addition to BRAF, activate the mitogen-activated protein kinase (MAPK) signaling pathway, which stimulates cell proliferation and other activities that promote carcinogenesis. Mutations of PIK3CA, which encodes the catalytic subunit of a PI3K survival pathway, increase production of phosphatidylinositol-3,4,5-triphosphate (PIP3), which influences cell growth, proliferation, and survival.34 Mutation or loss of PTEN, a tumor suppressor gene that antagonizes PI3K signaling, produces similar effects.32,34 Multiple additional genetic alterations contribute to carcinoma formation and metastases by altering cellular growth, metabolism, migration and invasive capabilities, and angiogenesis.34

Growth Factor Signaling Pathways

Aberrant signaling of growth factor pathways plays an important role in colorectal tumorigenesis. Activation of prostaglandin signaling is an early step in the adenoma to carcinoma transformation process and is induced by upregulated expression of COX-2 and inflammation.32 COX-2 mediates the synthesis of prostaglandin E2, which stimulates cancer growth.32 Furthermore, 80% of colorectal cancers have loss of 15-prostaglandin dehydrogenase (15-PGDH), the rate-limiting enzyme responsible for prostaglandin degradation. Gene amplification of the epidermal growth factor receptor (EGFR) gene that encodes for a transmembrane glycoprotein involved in signaling pathways that affect cell growth, differentiation, proliferation, and angiogenesis, is present in 5% to 15% of colorectal cancers.33 EGFR activation enables downstream signaling of the MAPK, PI3K, and Akt pathways that influence colorectal tumorigenesis. EGFR is over-expressed in up to 75% of colorectal cancers and high tumor EGFR overexpression is associated with worse prognosis.35 These mechanisms are relevant because of the availability of pharmacologic agents that can influence these signaling pathways and affect cell growth.

Histology

Adenocarcinomas account for about 94% of tumors of the large intestine.3 Other histologic types such as mucinous adenocarcinoma, mucin-producing adenocarcinoma, signet-ring adenocarcinoma, and neuroendocrine carcinomas occur less frequently. Adenocarcinomas are assigned one of three tumor grade designations based on the degree of cellular differentiation, the degree to which the tumor resembles the structure, and function of its cell of origin. The most differentiated adenocarcinomas are grade I tumors, whereas grade III tumors are considered “high grade,” the most undifferentiated, and have frequently lost the characteristics of mature normal cells. Poorly differentiated tumors are associated with a worse prognosis than those that are relatively better differentiated.36

Mucinous adenocarcinomas possess the same basic structure as adenocarcinomas but differ in that they secrete an abundant quantity of extracellular mucus. They account for only about 10% of colorectal carcinomas but tend to be frequent in patients with MMR mutations.36 Signet-ring adenocarcinomas also have a characteristic appearance but are uncommon. Signet-ring histology occurs more frequently in individuals younger than 50 years of age, patients with ulcerative colitis, and tends to present at a more advanced stage of disease at diagnosis.36 Both mucinous and signet-ring adenocarcinoma histologies confer a poor prognosis.36

PREVENTION AND SCREENING

Cancer prevention efforts can be considered as either primary or secondary. Primary prevention strategies aim to prevent the development of colorectal cancer in a population at risk. Secondary prevention approaches are undertaken to prevent malignancy in a population that has already manifested an initial disease process. Several promising primary and secondary prevention strategies are currently undergoing study (Table 107-3).8,18,20,28,3743

TABLE 107-3 Prevention Strategies for Colorectal Cancer

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Diet

Images Although early studies suggest that a substantial increase in daily dietary fiber or decrease in dietary fat intake might significantly reduce colorectal cancer risk, results from prospective, controlled trials show no protective effects of fiber intake on colorectal adenoma or carcinoma risk. However, a recent meta-analysis suggests a 10% reduction in colorectal cancer risk with 10 g daily intake of total dietary and cereal fiber and up to a 20% risk reduction with three servings of whole grains daily.27,28 There is insufficient evidence to support the use of fiber supplementation as a colorectal cancer prevention strategy at this time.

Chemoprevention

Images The most widely studied agents for the chemoprevention of colorectal cancer are aspirin, nonaspirin NSAIDs, and COX-2 selective inhibitors, but current guidelines do not recommend their use as chemopreventive agents.8,18,20,40 The effectiveness of these agents has been studied in high-risk individuals and within the general population.

In individuals with FAP, celecoxib, NSAIDs, and aspirin have been studied to delay development of adenomatous polyps and to reduce polyp recurrence following colectomy with a retained rectum, but they are not viewed as alternatives to surgery.20 In randomized, controlled trials, celecoxib 400 mg orally twice daily as an adjunct to usual care significantly reduced the mean size and number of colorectal polyps after 6 to 9 months of treatment. However, FDA approval for celecoxib was withdrawn because of lack of data showing long-term benefit. Sulindac has been shown to induce adenoma regression, but does not appear to delay or prevent malignancy. The benefits of these agents are transient, because patients experience an increase in size and number of polyps within a few months after discontinuing treatment. Sulindac is not recommended as chemoprevention for individuals with FAP. These agents may be useful to reduce adenoma recurrence following surgery, but additional data with long-term use are needed.

Nonaspirin NSAIDs and COX-2 inhibitors were associated with reduced risk of sporadic and recurrent colorectal adenomas in cohort and case-control studies, and COX-2 inhibitors were also effective in controlled trials.8Celecoxib was associated with a 34% relative risk reduction in adenoma recurrence and 55% risk reduction in the incidence of advanced adenomas.20 Optimal dosing, agents, and duration of treatment remain to be determined, and potential cardiovascular events in addition to risk of gastric ulceration and bleeding with these agents are of concern. Although NSAIDs may be appropriate for selected individuals at high risk for colorectal cancer but low risk for cardiovascular disorders, the United States Preventive Services Task Force has concluded that potential harms associated with their use outweigh benefits for prevention of colorectal cancer in the general population.41


Clinical Controversy…

Emerging data support the use of aspirin as colorectal cancer chemoprevention for patients with Lynch syndrome and regular long-term aspirin use modestly reduces colorectal cancer risk in individuals without Lynch syndrome. However, because of the small risk of serious bleeding associated with even low-doses, aspirin use is not recommended for cancer prevention in the general population. The role of aspirin chemoprevention in patients with Lynch syndrome and family history of colorectal cancer is undecided.

The use of aspirin as both a primary and a secondary chemopreventive agent remains controversial. Aspirin reduces of risk of sporadic and recurrent adenomas by about 17% and advanced adenomas by 28%.20,42 Higher aspirin doses reduced the incidence of colorectal cancer over a 23-year follow-up period by 26% among the general population, but lower doses (75 to 300 mg) of daily aspirin for 5 years was also associated with a risk reduction in colorectal cancer incidence and in 20-year mortality from colorectal cancer by 34%.20,40,42 Individuals with Lynch syndrome who received aspirin 600 mg daily for at least 2 years experienced a 59% reduction in colorectal cancer risk that became evident 5 years after the aspirin was first started and had been discontinued.42 Although the optimal aspirin dose and treatment durations are unknown, increasing evidence supports a chemoprotective effect of aspirin in select high-risk individuals and in the general population. The extent of risk reduction appears to be inversely related to duration of therapy and the chemopreventive effects of aspirin may be delayed by several years. However, the balance of risks and benefits with long-term aspirin use is currently unclear, and aspirin is not recommended for colorectal cancer chemoprevention. PIK3CA mutations, which are present in up to 20% of colorectal cancers, may serve as a biomarker to identify patients diagnosed with colorectal cancer who may benefit from adjuvant aspirin therapy.21

Randomized controlled trials of calcium, vitamin D, and folate supplementation as chemoprevention have also been conducted, but findings do not support their use at this time.8,20,43 Individuals at high risk of colorectal cancer may experience a moderate reduction in risk of recurrent colorectal adenomas with 5 years of calcium supplementation.20 However, individuals with adequate vitamin D levels and no known increased risk of colorectal cancer do not appear to benefit from calcium or vitamin D supplementation. In two trials, folate supplementation was associated with a nonsignificant increase in adenoma recurrence. Based on these results, the use of folate supplementation to reduce colorectal cancer risk is not recommended at this time.8 Several trials of difluoromethylornithine (DFMO), an irreversible inhibitor of the polyamine synthetic pathway, show promising activity as a chemopreventive agent, particular in combinations.8 Additional intervention trials of various micronutrients, epigenetic modulators, and other chemopreventive agents have been completed or are ongoing.8,18,20,28,29,31,3739

Surgical Resection

Surgical resection remains an option to prevent colon cancer in individuals at extremely high risk for its development. Despite the effects of NSAIDs and COX-2 selective inhibitors on adenoma development and recurrence in individuals with FAP, their effects are incomplete and surgical resection is necessary for cancer prevention for these high-risk individuals. Individuals with FAP who are found to have polyposis on lower endoscopy screening examinations should undergo total proctocolectomy and ileal pouch–anal anastomosis or subtotal colectomy with an ileorectal anastomosis, typically starting around age 20 years.13 Because of the high incidence of metachronous cancers (45%) in patients with HNPCC, prophylactic subtotal colectomy with an ileorectal anastomosis is recommended for those individuals.13Colonoscopic polypectomy, removal of polyps detected during screening colonoscopy, is considered the standard of care for all individuals to prevent the progression of premalignant adenomatous polyps to adenocarcinomas.

Screening

Images Colorectal cancer screening decreases mortality by detecting cancers at an early, curable stage, and by detecting and removing adenomatous polyps. Multiple screening recommendations for early detection of colorectal cancer have been established; differences exist in specific screening guidelines published by various organizations.5,4449 Structural tests detect colorectal polyps and cancer whereas fecal-based tests detect early cancer. This section reviews available screening techniques for colon and rectal cancer.

Colonoscopy

Images Colonoscopy facilitates examination of the entire large bowel to the cecum in most patients, and allows for simultaneous removal of premalignant lesions. Although no randomized trials show that colonoscopy decreases colorectal cancer mortality, cohort and case control trials demonstrate a 56% to 77% decrease in the incidence in colorectal cancer with colonoscopy and polyp removal and about a 50% reduction in colorectal mortality.46 Although it allows for greater visualization of the colon, colonoscopy involves sedation, complete bowel preparation, and is associated with greater risk and inconvenience to patients. However, it is the preferred screening method based on its superior ability to detect and remove lesions in the proximal as well as distal colon and colonoscopy is therefore considered the gold standard for colorectal screening.45,46

Flexible Sigmoidoscopy

Images Flexible sigmoidoscopy (FSIG) uses a 40 to 60 cm flexible sigmoidoscope to examine the lower half of the bowel to the splenic flexure for most patients, and is thus capable of detecting 50% to 60% of cancers.4446Randomized trials show that FSIG decreases colorectal cancer incidence and mortality by 31% and 38%, respectively.4446 The combination of FSIG and a fecal-based test appears to improve sensitivity for lesions that will be missed by sigmoidoscopy alone, but the true benefit of this approach to general practice has not been established.45 FSIG offers the advantage of not requiring sedation or extensive bowel preparation, but the entire colon cannot be examined with FSIG and suspicious lesions must be evaluated by colonoscopy.

Computed Tomography Colonography

Images Computed tomography colonography (CTC), also referred to as virtual colonoscopy, is an imaging procedure that creates two- or three-dimensional images of the colon by combining multiple helical computed tomography (CT) scans. Initial tests show high sensitivity and specificity for detecting adenomas at least 6 mm in size and sedation is not required.46 However, the procedure requires complete bowel preparation, is associated with radiation exposure, and many individuals will still be referred for colonoscopy to remove detected lesions. Individuals who refuse to undergo invasive colonoscopy or FSIG may find this screening method more acceptable.

Double-Contrast Barium Enema

Images A double-contrast barium enema (DCBE) involves coating the interior bowel with barium and distending it with air to produce an image of the entire colon in most examinations, and the retained barium outlines small polyps and mucosal lesions. This approach is the least expensive method of examining the entire colon, but is considered inferior to colonoscopy for detecting polyps and colorectal cancer.44,46In addition, DCBE requires bowel preparation cleaning, is associated with radiation exposure, and a supplemental colonoscopy is required if suspicious lesions are identified. However, DCBE is considered an alternative for individuals who do not wish to undergo or are not suitable for colonoscopy.

Fecal Occult Blood Tests

Images Fecal occult blood tests (FOBTs) are used to detect occult blood in the stool that may be associated with bleeding adenomas or cancer. Results from randomized, controlled trials of annual FOBT screening show a reduction in colorectal cancer mortality by 33%.4446 Unlike structural tests, FOBTs are noninvasive and do not require bowel preparation. Two main methods are available to detect occult blood in the feces: guaiac-based FOBT (gFOBT) and fecal immunochemical tests (FITs), that is, the immunochemical fecal occult blood test (iFOBT). Several guaiac-based tests are available that detect peroxidase activity of heme when hemoglobin comes in contact with a guaiac-impregnated paper. When a solution containing hydrogen peroxide is poured over the paper, a blue color appears if the test is positive. The testing process is complex and requires specific patient counseling to avoid inaccurate results (Table 107-4).

TABLE 107-4 Patient Counseling Points Prior to Guaiac-Based Stool Tests

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Clinical guidelines have been developed for performing and interpreting results of gFOBT.45 Several limitations associated with FOBT screening are of concern. Many early-stage tumors do not bleed, and therefore the false-negative rates are about 70% for cancer and 90% for polyps. In addition, the test results may not be valid because the test is often poorly performed both in the home and in physician office settings.45,46 However, these concerns are addressed by testing three successive stool samples. False-positive results can prove to be very expensive and inconvenient for a patient because of the follow-up tests required to confirm a positive result. Annual screening, preferably using a high-sensitivity gFOBT (e.g., Hemoccult SENSA), is an acceptable option for individuals at average risk for colorectal cancer. It should be noted that FOBT conducted in conjunction with a digital rectal exam during an office visit is not considered adequate colorectal screening.

FITs (iFOBTs) were developed to reduce false-positive and false-negative test results associated with the gFOBT. FIT uses antibodies to detect the globin protein portion of human hemoglobin. Globin is degraded by enzymes in the upper gastrointestinal tract; therefore, FIT is more specific for lower gastrointestinal bleeding. Also, immunochemical tests do not produce false-negative results in the presence of vitamin C.45 Moreover, testing involves a single stool sample collection annually. Comparative studies report that FIT is more accurate than gFOBT for detecting cancer and advanced adenomas, although colonoscopy identifies more adenomas.50

Stool DNA Screening Tests

Molecular screening strategies analyze stool samples for presence of potential markers of malignancy in cells that are shed from pre-malignant polyps or adenocarcinomas in the bowel.4446 Adenoma and carcinomas can contain certain DNA mutations and markers of MSI that can be detected using a multiple marker panel for stool DNA (sDNA) testing. However, no FDA-approved sDNA tests are currently commercially available.46

Screening Summary

Images Table 107-5 outlines current U.S. screening guidelines for early detection of colorectal cancer with the goal of cancer prevention. Men and women who are at average risk for colorectal cancer (their only risk factor is age ≥50 years) should begin regular screening starting at age 50 years with a colonoscopy every 10 years, annually using a sensitive gFOBT or FIT, or undergo FSIG every 5 years, alone or in conjunction with annual FOBT. Several screening methods are available, and because each method is associated with different benefits and potential harms, patient preferences and available resources should be considered for individual patients.45 More rigorous (usually starting at an earlier age) screening recommendations are given for moderate- to high-risk individuals and colonoscopy is generally preferred for initial screening and surveillance following polyp removal in this population.5,45,46,49Most organizations recommend discontinuing screening and surveillance in populations when risk may outweigh benefit.5The United States Preventive Services Task Force (USPSTF) recommends routine colorectal cancer screening for individuals age 50 to 75 years with different consideration given to adults 76 to 85 years and recommends against screening for adults older than 85 years.5 The American College of Physicians recommends against screening adults older than age 75 years or with a life expectancy of less than 10 years.44

TABLE 107-5 Guidelines for Colorectal Cancer Screening in the United States for Individuals at Average Risk, 50 Years of Age and Older

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DIAGNOSIS

Signs and Symptoms

The signs and symptoms associated with colorectal cancer can be extremely varied and nonspecific. Patients with early-stage colorectal cancer are often asymptomatic, and lesions are usually found as a result of screening studies. Any change in bowel habits (e.g., constipation, diarrhea, or alteration in size or shape of stool), abdominal pain, or distension may all be warning signs of a malignant process. Obstructive symptoms and changes in bowel habits frequently develop with tumors located in the transverse and descending colon. Bleeding is the most common symptom of rectal cancer. Bleeding may be acute or chronic and can appear as bright red blood mixed with stool or melena. Iron-deficiency anemia, presenting as weakness and fatigue, frequently develops as a result of chronic occult blood loss.

About 20% of patients with colorectal cancer present with metastatic disease.3 Metastatic spread occurs as a result of direct tumor invasion of adjacent tissues or by lymphatic or hematogenous spread. The venous drainage of the colon and rectum influences the pattern of metastases most commonly seen. The most common site of metastasis is the liver, often the only site of metastatic disease in 40% of patients, followed by the lungs and then bones, specifically the sacrum, coccyx, pelvis, and lumbar vertebrae. Liver metastases are present in 5% to 10% of patients at presentation.

Workup

When a patient is suspected of having colorectal carcinoma, a complete history and physical examination should be performed. The patient history should include a past medical history and family history, especially noting the presence of inflammatory bowel disease, colorectal cancer, polyps, and familial clustering of cancers to assess risk for an inherited colorectal cancer syndrome. A complete physical examination includes careful abdominal examination for the presence of masses or ascites, a rectal examination, and an assessment for possible hepatomegaly and lymphadenopathy. A breast and pelvic examination is recommended in all women.

An evaluation of the entire large bowel requires a total colonoscopy and allows for tissue collection for a histologic evaluation to provide a preliminary diagnosis following the procedure. Patients with invasive cancer of the colon or rectum require a complete staging workup with laboratory testing and CT scans of the abdomen, pelvis, and chest. Baseline laboratory tests should be obtained and include a complete blood cell count, platelet count, international normalized ratio (INR), prothrombin time, activated partial thromboplastin time, liver chemistries, renal function tests, and carcinoembryonic antigen (CEA) level. Abnormal liver chemistry test results may suggest liver involvement with tumor. However, patients with metastatic disease to the liver may have normal liver chemistries, and abnormal liver test results are not always indicative of metastatic disease. Iron studies (e.g., serum ferritin, serum iron, and total iron-binding capacity) may be useful to identify iron-deficiency in patients with anemia.

CEA belongs to a group of cell-surface glycoproteins termed oncofetal proteins, which are expressed during embryonic development and reexpressed on the cell surfaces of many carcinomas, particularly those originating from the gastrointestinal tract. CEA concentrations can be measured in the blood and can therefore potentially serve as a marker for colorectal cancer. Elevated CEA levels are more frequent in patients with metastatic disease but not all colorectal cancers produce CEA. It is important to recognize, however, that several concomitant disease states are associated with an elevated CEA: liver diseases, gastritis, peptic ulcer disease, diverticulitis, chronic obstructive pulmonary disease, chronic or acute inflammatory conditions, and diabetes.51 Most commercially available assays list a value of less than 5 ng/mL as the upper limit of normal. Although CEA measurement is too insensitive and nonspecific to be used as a screening test for early-stage colorectal cancer, it is the surrogate marker of choice for monitoring colorectal cancer response to treatment, particularly if the pretreatment concentration is elevated.51 The CEA test may have preoperative prognostic implications because it has been shown to correlate with the size and degree of differentiation of the carcinoma. Elevated preoperative CEA levels correlate with a poor survival and may predict likelihood of recurrence, regardless of tumor stage at diagnosis. However, it should not be used as an indication for adjuvant therapy. After a potentially curative resection, CEA levels should return to normal within 4 to 6 weeks. Persistently elevated CEA levels may indicate residual disease, while elevations after normalization may indicate relapsed disease.


CLINICAL PRESENTATION

General

    • Patient symptoms are usually nonspecific and can vary drastically among patients.

Symptoms

    • Change in bowel habits (generally an increase in frequency) or rectal bleeding.

    • Constipation, depending on the location of the tumor.

    • Nausea, vomiting, and abdominal discomfort.

    • Fatigue may be present if anemia is severe.

Signs

    • Blood in the stool is the most common sign.

    • Hepatomegaly and jaundice in advanced disease.

    • Leg edema as a consequence of lymph node involvement, thrombophlebitis, fistula formation, weight loss, and pain in the lower back or radiating down the legs may be indicative of widespread disease.

Laboratory Tests

    • Positive guaiac stool test and anemia (iron deficiency) from blood loss.

    • Elevated carcinoembryonic antigen (most patients).

    • Elevated liver enzymes may be present with metastatic disease.

Radiographic imaging studies evaluate the extent of disease involvement. Contrast dye-enhanced CT scans of the chest, abdomen, and pelvis are performed to evaluate pulmonary, hepatic and retroperitoneal involvement and occult abdominal and pelvic disease, and to determine the depth of tumor penetration into the bowel wall and/or invasion to adjacent organs. In certain cases magnetic resonance imaging (MRI) of the abdomen and pelvis may be performed. If findings from CT or MRI scans are not sufficient to detect metastases, a glucose analog [18F]-fluorodeoxyglucose-positron emission tomography (PET) scan may be performed to confirm metastatic disease. PET imaging can provide functional information to discriminate between benign and malignant disease by detecting tumor-related metabolic alterations in affected tissues. PET scans are commonly used for the detection of recurrent colorectal cancer in patients with rising CEA levels and inconclusive findings on standard imaging studies. A PET scan is often combined with or followed by a CT scan because anatomical localization of a lesion using PET alone can be difficult. For rectal cancer, assessment of the extent of tumor spread into the surrounding mesorectum and depth of invasion within the bowel wall may be performed using MRI or endorectal ultrasound (EUS), respectively.

Because of the increased likelihood of HNPCC in patients diagnosed with colorectal cancer younger than the age of 50 years, MMR protein testing on the cancer specimen is recommended.49 The level of MMR protein expression can be determined by immunohistochemistry, which is decreased with MMR gene mutations. Gene sequencing can also be performed to detect MSI. If immunohistochemical analysis of the tumor reveals absence of MLHI protein expression, BRAF gene mutation testing is recommended to distinguish between somatic and germline MLH1 gene mutation.49 Individuals with abnormal MMR protein expression or MSI should be referred for genetic counseling as additional testing and cancer susceptibility risk assessment may be appropriate for themselves and family members.

STAGING

Images The purpose of the staging examinations is to determine the extent of disease, which allows the oncologist to develop treatment options and estimate overall prognosis. The same TNM classification system is used for cancers of the colon and rectum since the categories reflect similar survival outcomes.52,53 This classification takes three aspects of cancer growth: T (tumor penetration), N (lymph node involvement), and M (presence or absence of metastases) into account. The TNM classification also allows for various subdivisions within each of the three categories, which is then used for determining the disease stage. Table 107-6 summarizes the staging definitions used in the TNM system and corresponding 5-year survival rates.52,54 Figure 107-5 shows the various stages of cancer based on cancer penetration through the bowel wall and extension to regional lymph nodes.

TABLE 107-6 Colon Cancer by TNM Classification and Associated 5-Year Relative Survival

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Images

FIGURE 107-5 TNM staging for colorectal cancer. (From Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J: Harrison’s Principles of Internal Medicine, 18th ed. http://www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All right reserved.)

PROGNOSIS

Images The stage of colorectal cancer upon diagnosis is the most important independent prognostic factor for survival and disease recurrence. Five-year relative survival is about 91% for individuals who present with a localized tumor stage at diagnosis as compared with about 12% for individuals with metastatic disease at diagnosis.3

Clinical factors present at the time of diagnosis that are associated with a poor prognosis and decreased survival include bowel obstruction or perforation, high preoperative CEA level, distant metastases, and location of the primary tumor in the rectum or rectosigmoid area.55 Along with resection of the primary tumor, a minimum of 12 lymph nodes must be examined to accurately determine regional lymph node involvement and predict lymph node-negative disease.55 The pathologic assessment also includes determination of TNM stage, tumor type, and histologic grade, presence of venous and lymphatic invasion, and whether the resected margins are free of tumor.56Consideration of these factors plays an important role in determining optimal strategies for treatment and appropriate follow-up.

Additional morphologic tumor features that have negative prognostic value with regard to clinical outcome include infiltrative tumor border configuration, evidence of perineural invasion, extranodal tumor deposits, and presence of tumor budding, characterized by clusters of cells that possess properties of malignant stem cells and are associated with increased risk of local and distant spread.56 A high density of tumor-infiltrating lymphocytes (TILs) in the tissue specimen is associated with a favorable outcome.55,56

Certain molecular markers, particularly MSI, 18q/DCC mutation or LOH, BRAF V600E mutation, and KRAS mutations, are also associated with colorectal cancer prognosis, although the pathologic stage of disease remains the primary prognostic assessment.57

Colorectal cancers with allelic LOH on chromosome 18q or absent DCC protein are associated with a worse prognosis within stages II and III disease, but data are insufficient to warrant use of this test in practice at this time.56,57MSI can be determined through DNA sequencing or by immunohistochemistry staining for protein products of the MMR genes. Colorectal cancers that demonstrate high MSI (MSI-H) appear to be associated with a more favorable outcome and appear to predict the benefit of adjuvant fluoropyrimidines for early-stage disease.5557 Tumor DNA BRAF and KRAS mutation status appear to be linked to overall survival but are not used to determine prognosis.

Although multiple prognostic biomarkers for colorectal cancer have been identified, single molecular tests other than MSI are not used routinely in clinical practice. However, several multigene assays have been developed that provide prognostic information to assist in identifying individuals at high risk for cancer recurrence from early-stage disease.57,58 The Oncotype DX colon cancer assay is commercially available and has been validated in several trials as a prognostic test for stage II and III colon cancer.5759 Gene expression profiles classify risk of recurrence of low, intermediate, or high, and these scores are prognostic for recurrence, disease-free survival (DFS), and overall survival (OS). The ColoPrint gene expression assay characterizes risk of recurrence as low or high, and is undergoing further validation in clinical trials.58 The ability for these and other gene signature assays in development to predict which patients may benefit from adjuvant chemotherapy has not been well established.

TREATMENT

Colorectal Cancer

Desired Outcomes

Treatment goals for cancer of the colon or rectum are based on the stage of disease at presentation. Stages I, II, and III disease are considered potentially curable and are managed with the goal of eradicating potential micrometastases after surgical resection. Based on the numbers and site(s) of metastases, about 20% to 30% of patients with metastatic colorectal cancer may be cured, if their metastases are considered resectable. Most patients with stage IV disease are not curable, and treatments for metastatic disease are considered palliative to reduce symptoms, avoid disease-related complications, and prolong survival. However, special attention should be given to those with oligo-lesions in the liver or lung since potential cure is still possible for some of these patients.

General Approach to Treatment

Performance status, concomitant disease states, lifestyle factors, patient preferences, and patient age (although advanced age is not an absolute contraindication for aggressive therapies) must be considered in the treatment planning process. Special or emergent conditions, such as bowel obstruction or perforation, severe pain, anemia, or other symptomatic problems, need to be addressed acutely, after which time a more long-term disease-specific plan can be developed. The treatment approaches for cancer of the colon or rectum reflect two primary treatment goals: curative therapy for localized disease and palliative therapy for metastatic cancer.

For patients for whom treatment intent is curative, surgical resection of the primary tumor is the most important component of therapy. Depending on the extent of disease and whether the tumor originated in the colon or rectum, further adjuvant chemotherapy or chemotherapy plus XRT (chemoradiation) may be appropriate. For selected patients with resectable metastases, surgical resection may be an option. However, for most patients with metastases, systemic chemotherapy is the mainstay of treatment; XRT may also be useful for disease palliation of localized symptoms. Patients with metastatic disease who are asymptomatic may benefit from initiation of therapy, and continuous treatment should be considered.

Operable Disease

Surgery

Images Individuals with operable—stages I, II, and III—cancer of the colon or rectum should undergo complete surgical resection of the primary tumor mass with regional lymphadenectomy as a curative approach for their disease.60The surgical approach for colon cancer generally involves complete resection of the tumor with at least a 5 cm margin of tumor-free bowel and a regional lymphadenectomy.

The preferred surgical procedure for rectal cancer is a total excision of the mesorectum (TME), the surrounding tissue containing perirectal fat and draining lymph nodes.60,61 If the distal margin clear of tumor is at least 1 cm, sphincter-preserving surgery may be possible for patients with cancers in the middle and lower portion of the rectum. Individuals who are not candidates for sphincter-sparing resections or have extensive local spread of tumor will require an abdominoperineal resection (APR). This involves removal of the distal sigmoid, rectosigmoid, rectum, and anus with the establishment of a permanent sigmoid colostomy.

Colectomies for colon cancer can be performed as open procedures or laparoscopically. Laparoscopic colectomy has become an accepted procedure for colon and rectal cancer.60 This technique appears to produce similar results to conventional surgery, with the benefits of a smaller surgical incision, shorter hospital stay, shorter duration of ileus, and reduced pain. Complications associated with colorectal surgery include infection, anastomotic leakage, obstruction, adhesion formation, sexual dysfunction, and malabsorption syndromes, depending on the site and extent of resection. Complications affecting bowel function associated with surgery for rectal cancer increase as the level of anastomosis approaches the anus.

Adjuvant Therapy for Colon Cancer

Adjuvant therapy in colorectal cancer is administered to selected individuals after complete tumor resection in an attempt to eliminate residual micrometastatic disease, thereby decreasing tumor recurrence and improving survival rates. Because more than 90% of patients with stage I colon or rectal cancer are cured by surgical resection alone, adjuvant therapy is not indicated.58,60,61

Adjuvant chemotherapy is standard therapy for patients with stage III colon cancer. The presence of lymph node involvement with tumor places patients with stage III colon cancer at high risk for recurrence, and the risk of death within 5 years of surgical resection alone is as high as 70%, depending on the number of lymph nodes involved.60 In this population of patients, adjuvant chemotherapy significantly decreases risk of cancer recurrence and death and is standard of care.

The role of adjuvant chemotherapy for all patients without lymph node involvement (stage II) colon cancer is controversial because early studies that showed improvements in survival included patients with both stage II and III colon cancer. However, the QUASAR trial, which included patients with mostly stage II disease, showed a significant improvement in OS with adjuvant fluorouracil and leucovorin as compared to observation alone.60

Patients with stage II disease who are at higher risk for relapse include those with inadequate lymph node sampling, perforation of the bowel at presentation, poorly differentiated tumors, perineural invasion, and T4 lesions (stage IIB/IIC), and many practitioners offer this therapy to selected patients, with a detailed discussion with patients regarding the potential benefits versus treatment-related toxicities.56,59Individuals with MSI-H tumors have a better prognosis compared to those with MSI-L and may not benefit or even be harmed from adjuvant fluoropyrimidine chemotherapy.59 In addition, subgroup analysis from the QUASAR trial indicated that individuals greater than 70 years of age did not appear to benefit from adjuvant chemotherapy.60 Optimal dosing, administration schedule, and duration of therapy have yet to be determined, but most practitioners use the same treatment approach as that used for patients with stage III colon cancer.

Adjuvant Radiation Therapy Adjuvant XRT has a limited role in colon cancer because most recurrences are extrapelvic and occur in the abdomen. A subset of patients with recurrent disease or with T4tumors that have penetrated fixed structures may benefit from adjuvant fluorouracil-based chemoradiation, with consideration of intraoperative radiation.58 Selected candidates may also be considered for preoperative fluorouracil-based chemoradiation to improve resectability. Adverse effects associated with XRT in colorectal cancer can be acute or chronic. Acute effects primarily include hematologic depression, dysuria, diarrhea, abdominal cramping, and proctitis. Chronic symptoms that sometimes persist for months following discontinuation of XRT include persistent diarrhea, proctitis or enteritis, small bowel obstruction, perineal tenderness, sexual dysfunction, and impaired wound healing.

Adjuvant Systemic Chemotherapy Images Standard adjuvant chemotherapy regimens include a fluoropyrimidine (fluorouracil [with leucovorin] or capecitabine) as a single agent and in combination with oxaliplatin.6269 The addition of leucovorin increases the binding affinity of the active fluorouracil metabolite to thymidylate synthase (TS), thus enhancing its cytotoxic activity. Combinations of fluorouracil plus leucovorin have been studied extensively in the adjuvant setting, based on the observation that fluorouracil plus leucovorin substantially improves response rates as compared with fluorouracil alone for metastatic disease.58,60 When leucovorin is unavailable, levoleucovorin, the active isomer of racemic leucovorin, can be substituted as an alternative. The recommended levoleucovorin dose is 50% of the leucovorin dose.70

Schedules of fluorouracil and leucovorin administration vary among the different regimens. Historically in the United States, the Roswell Park regimen and the Mayo Clinic regimen were once commonly used, while in Europe, treatments such as the de Gramont regimen favored a continuous IV schedule of fluorouracil (Table 107-7).

TABLE 107-7 Chemotherapy Regimens for the Adjuvant Treatment of Colorectal Cancer

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Clinical studies comparing the efficacy of bolus and continuous infusion schedules generally favor continuous infusion of fluorouracil, which is probably related to its short plasma half-life and S-phase specificity for optimal TS inhibition. Continuous IV infusions also permit increased fluorouracil dose intensity, which may account for the higher response rates observed with prolonged infusions of fluorouracil. In most common combination regimens, fluorouracil is administered by both IV bolus injection and continuous IV infusion. This method of administration is now the most common method of administration in the United States and has replaced the Roswell Park and Mayo Clinic regimens.

Clinically significant differences in toxicity occur based on the dose, route, and schedule of fluorouracil administration. Leukopenia is the primary dose-limiting toxicity of IV bolus fluorouracil, although diarrhea, stomatitis, and nausea and vomiting can also occur.71 The incidence and severity of stomatitis can be significantly reduced with the use of oral cryotherapy. In this approach, the patient is instructed to chew and hold ice chips in the mouth during the period between 5 minutes prior to and 30 minutes following the bolus injection of fluorouracil. The protective effects of this procedure are probably related to the local vasoconstriction caused by the ice chips, which temporarily reduces blood flow to the oral mucosa, thereby reducing drug exposure to the oral mucosa.

Although continuous IV infusion fluorouracil is generally well tolerated, dose-limiting toxicities can be substantial. A distinct toxicity, palmar–plantar erythrodysesthesia (“hand–foot syndrome” or PPE), and stomatitis occur most frequently with this route of administration.71 Hand–foot syndrome occurs in 24% to 40% of patients receiving extended continuous IV infusions and is characterized by painful swelling and erythroderma of the soles of the feet, palms of the hands, and distal fingers. The skin toxicity is fully reversible on interruption of therapy or dose reduction and is not life threatening, but it can be significant and acutely disabling. The incidence of stomatitis, diarrhea, and hematologic toxicity is not substantial at standard doses, but it increases with increasing fluorouracil doses. No significant difference is noted in the incidence of mucositis, diarrhea, nausea and vomiting, or alopecia between continuous and bolus IV fluorouracil administration.71

An additional determinant of 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 fluorouracil to inactive metabolites. A rare pharmacogenetic disorder characterized by complete or near-complete deficiency of this enzyme has been identified in patients with cancer. Patients with this enzyme deficiency develop severe toxicity, including death, after fluorouracil administration. Molecular studies have identified a relationship between allelic variants in the DPYD gene (the gene that encodes DPD) and a deficiency in DPD activity.57

In summary, fluorouracil and leucovorin can be administered in a variety of treatment schedules, but none has proven superior with regard to overall patient survival. Table 107-7 lists examples of some of these regimens.

Fluorouracil Plus Oxaliplatin Images Current National Comprehensive Cancer Network (NCCN) guidelines recommend oxaliplatin-containing regimens as the preferred treatment for patients with stage III colon cancer who can tolerate combination therapy, and most practitioners incorporate oxaliplatin into adjuvant treatment regimens.58 These recommendations are based on results from the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial, where the addition of oxaliplatin resulted in a 20% risk reduction in disease recurrence and increased 5-year DFS (73% vs. 67%) as compared with fluorouracil plus leucovorin alone. With a median follow-up of 82 months, the addition of oxaliplatin resulted in a statistically significant absolute 6-year OS difference of 2.5%.63 Oxaliplatin was associated with increased risk of paresthesia, neutropenia, and gastrointestinal toxicity (nausea, vomiting, diarrhea) that were manageable with supportive care. Further supporting the role of oxaliplatin in the adjuvant setting are the results of the National Surgical Adjuvant Breast and Bowel Project C-07 trial, which compared bolus fluorouracil and leucovorin, with or without oxaliplatin.64 A significant risk reduction in disease recurrence by 20% was seen with oxaliplatin added to the fluorouracil backbone. As expected, neurotoxicity was increased with oxaliplatin. This method of administration, called the FLOX regimen (fluorouracil, leucovorin, oxaliplatin), is associated with increased diarrhea and neuropathies as compared with the aforementioned regimen used in the MOSAIC trial. Though listed as an option according to current NCCN guidelines, its use is limited by its toxicity.58

Further modifications of the FOLFOX4 (infusional fluorouracil and leucovorin, oxaliplatin) regimen may also improve tolerability. Capecitabine has been evaluated in adjuvant studies as a replacement for fluorouracil in an attempt to improve the safety and ease of administration of the chemotherapy regimen. The use of CapOx (capecitabine plus oxaliplatin) has been demonstrated to be superior to bolus fluorouracil alone in patients with stage III disease with regard to 3-year DFS (71% vs. 67%), but no difference in OS was observed. The toxicities differed for the two regimens, with increased risks of neuropathies and hand–foot syndrome with CapOx and increased risk of neutropenia/neutropenic fever with fluorouracil.66

Capecitabine Images Capecitabine is FDA approved as a single agent in the adjuvant setting and has been shown to be noninferior to bolus fluorouracil and leucovorin in patients with stage III colon cancer.65Both regimens were given for 6 months. DFS between the groups was found to be equivalent. Secondary end points of relapse-free survival (hazard ratio [HR] 0.86; P = 0.04) and safety were improved with capecitabine. In particular, the incidence of diarrhea, stomatitis, and neutropenia was decreased with capecitabine, but the incidence of hand–foot syndrome was increased with capecitabine. This regimen is recommended when patients are considered unable to tolerate combination therapy.58

Investigational Approaches Despite its proven benefit in the metastatic setting, irinotecan has not shown a benefit in the adjuvant setting and should not be used outside of clinical trials. Three trials have evaluated the addition of irinotecan to bolus or continuous infusion fluorouracil and leucovorin, and all failed to demonstrate a DFS benefit. Cancer and Leukemia Group B (CALGB) 89803 compared the irinotecan, fluorouracil, and leucovorin (IFL) regimen to bolus fluorouracil and leucovorin; not only was there no DFS benefit, but the IFL regimen was associated with significant toxicity.72 The Third Pan-European Trial in Adjuvant Colon Cancer (PETACC-3) and ACCORD studies, which used infusional regimens similar to fluorouracil, leucovorin, and irinotecan (FOLFIRI), also found no difference in DFS as compared with infusional fluorouracil and leucovorin.69,73

With the success of cetuximab and bevacizumab in the metastatic setting, adjuvant trials evaluating monoclonal antibodies in combination with the previously mentioned regimens were conducted. The final results of the NSABP-C08 trial that compared FOLFOX with or without bevacizumab did not meet its primary end point of DFS.74 Also, results showed no benefit in 3-year DFS from the addition of cetuximab to the combination of infusional fluorouracil plus oxaliplatin (mFOLFOX6) as adjuvant therapy for patients with KRAS wild-type stage III colon cancer.75 Therefore, there is no role for these agents in the adjuvant treatment setting at this time.

Selection of an Adjuvant Regimen Selecting a specific regimen from those listed in Table 107-7 requires an assessment of several patient-specific factors, including the performance status of the patient, comorbid conditions that may exist, and patient preferences for treatment based on lifestyle factors that are important to the patient. If a clinical trial is not an option, most patients with a good performance status will receive oxaliplatin in combination with fluorouracil and leucovorin. Single-agent capecitabine may be the preferred option for patients with preexisting neuropathies, such as diabetic patients, or those patients wishing not to receive IV chemotherapy for any other reason. Fluorouracil and leucovorin has limited use at this time but is an acceptable option for patients who cannot receive oxaliplatin and are unable to tolerate or take oral capecitabine. For example, patients who develop severe hand–foot syndrome may tolerate bolus fluorouracil/leucovorin because this toxicity is minimal with this administration method.

Patient age should also be considered when selecting an appropriate regimen. Subset analysis of the MOSAIC and NSABP-C07 trials have demonstrated no OS benefit from adding oxaliplatin to patients older than the age of 70 years and these patients may be appropriate for fluoropyrimidine-based therapy.60,64


Clinical Controversy…

Current guidelines discourage the use of age as a sole determining factor in choosing an adjuvant chemotherapy regimen. However, subset analysis of large clinical trials has shown that patients older than the age of 70 years may not benefit from adjuvant oxaliplatin and may need to be treated differently.

Adjuvant and Neoadjuvant Therapy for Rectal Cancer

Images Rectal cancer involves those tumors found below the peritoneal reflection in the most distal 15 cm of the large bowel, and as such is distinct from colon cancer in that it has a propensity for both local and distant recurrence. The higher incidence of local failure and overall poorer prognosis associated with rectal cancer is a result of anatomic limitations in excising adequate radial margins around the rectal tumor. Most patients with stage II or stage III rectal cancer should receive combined-modality therapy consisting of XRT and fluoropyrimidine-based chemotherapy perioperatively.60

Neoadjuvant Therapy Images Neoadjuvant (preoperative) chemoradiation is considered standard of care for most patients with stage II or II rectal cancer because of significant reduction in local recurrence, fewer toxicities, and improved sphincter-preserving surgeries as compared to postoperative chemoradiation.61 However, some patients are unable to tolerate a typical 5- to 6-week chemoradiation regimen and may be more appropriate candidates for a short course of preoperative radiation therapy alone. Chemotherapy combined with XRT typically involves continuous infusion fluorouracil, oral capecitabine, or bolus fluorouracil and leucovorin; the addition of oxaliplatin to either fluoropyrimidine was associated with increased toxicities without clear improvements in complete remission rates or survival benefit.60Although oxaliplatin and other agents continue to be evaluated in this setting, the addition of oxaliplatin or biologic agents (e.g., cetuximab, panitumumab, bevacizumab) is currently not recommended.76

Adjuvant Therapy Images Current NCCN guidelines for rectal cancer indicate that preoperative fluoropyrimidine-based chemotherapy plus XRT is the preferred initial treatment for resectable T3 N0, any T, N1–2, or T4/locally unresectable lesions.76 This should be followed by additional adjuvant chemotherapy after surgery to total 6 months of chemotherapy (combined total from preoperative and postoperative regimens). Postoperative treatment regimens include bolus fluorouracil and leucovorin, infusional fluorouracil, capecitabine, CapOx, or FOLFOX. Combined chemoradiation is preferred for patients that do not receive preoperative radiation therapy.60,61,76

Metastatic Disease: Initial Therapy

Multiple efficacious treatment options for metastatic colorectal cancer are available. Patients are generally considered as having resectable, potentially resectable, or unresectable metastatic disease. Surgery and XRT are used to manage isolated sites of tumor. Chemotherapy is for disseminated disease and the primary treatment modality for unresectable metastatic colorectal cancer. Patients with resectable or potentially resectable metastases are candidates for multimodality therapy.77 Tumor KRAS genotyping for mutation status is recommended for patients at the time when metastatic disease is diagnosed to identify appropriate treatment options.58 Testing can also be performed on archived tissue samples obtained when the cancer was initially diagnosed.

Resectable or Potentially Resectable Metastatic Colorectal Cancer

Surgery Images Up to 25% of patients will present with hepatic metastases at the time of diagnosis, and 60% of patients with colorectal cancer will develop hepatic metastases sometime during the course of their disease.78 The lung is the second most common site of cancer recurrence. Resection of colorectal cancer metastases (metastasectomy) can achieve 5-year OS rates between 20% and 50%, whereas 5-year OS in patients with unresectable metastatic disease is uncommon. Therefore, a primary goal is surgical resection of metastases with curative intent in those individuals for whom complete surgical resection is realistically possible. Patients with no significant general medical risk factors, fewer than four hepatic lesions, CEA levels less than 200 ng/mL, small tumor size, lack of extrahepatic tumor, and adequate surgical margins have the best opportunity for an improved long-term outcome.78 The primary site of tumor should also be completely resected. Complete surgical resection of discrete metastases in extrahepatic sites, such as the lung, peritoneum, abdomen, and brain, has been less studied but appears to benefit patients with small numbers of metastases who are appropriate candidates for surgery. Adjuvant systemic chemotherapy is recommended to reduce the risk of recurrence following resection.58

Neoadjuvant (Conversional) and Adjuvant Chemotherapy

Images Patients that present with metastatic disease isolated to the liver or lung and who undergo resection of all metastatic and primary lesions have an increased probability of survival compared with those whose metastatic lesions remain unresected.77 Therefore, strategies to increase the success rate of these resections (or convert unresectable lesions to resectable) is the primary goal in these patients. Neoadjuvant chemotherapy, also referred to as conversional chemotherapy, is the primary method to increase complete resection rates in both patients with resectable or potentially resectable liver or lung lesions. In some cases, individuals with metastatic disease initially deemed unresectable may achieve significant tumor regression following neoadjuvant chemotherapy to then be considered for surgery.77

The optimal sequencing of chemotherapy for patients with initially resectable metastatic disease is controversial, as treatment options include surgery followed by chemotherapy or perioperative (pre- and postoperative) chemotherapy with surgery.58,78 Because of the high risk of recurrence following resection of metastases, postoperative chemotherapy is always recommended. Administration of both pre- and postoperative chemotherapy is common practice, but hepatotoxicity associated with preoperative chemotherapy should be considered. Steatohepatitis occurs in 4% to 8% of patients who receive irinotecan-containing regimens and vascular sinusoidal obstructive liver injury develops in 20% to 52% of patients receiving oxaliplatin.78 Therefore, surgery is performed as soon as possible after the disease becomes resectable. Preoperative chemotherapy is limited to a 2-to-3-month time period and patients undergo close monitoring.

The choice of agents depends on patient-specific factors but may include regimens such as FOLFOX, FOLFIRI, FOLFOXIRI (infusional fluorouracil and leucovorin, oxaliplatin, irinotecan), CapOx, and FOLFOX alternating with FOLFIRI. Biologic agents have been added to the foregoing regimens.79 If patients receive bevacizumab, surgery should not occur within 6 weeks of the last dose of therapy, and bevacizumab should not be restarted until 6 to 8 weeks after surgery. EGFR inhibitors should be considered only in patients that have tumors with wild-type KRAS. Postoperative chemotherapy should be administered to patients to complete a total of 6 months of chemotherapy (pre- and postoperative).58

Patients with unresectable lesions are eligible for the same chemotherapy regimens (Table 107-7). However, because the primary goal is surgical resection whenever possible, patients should be evaluated for possible resection after every 2 months of therapy. If resection occurs, adjuvant chemotherapy should be administered to complete a total of 6 months of chemotherapy.

Hepatic-Directed Therapies Images Individuals with liver-only or liver-predominant metastatic disease may be considered for hepatic-directed therapy in addition to or as an alternative to surgical resection. Hepatic artery infusion (HAI) involves the placement of a permanent access catheter to the hepatic artery through which chemotherapy can be infused directly into the liver.80 This approach offers the advantage of delivering high drug concentrations to tumors locally, thereby limiting systemic toxicities. Floxuridine and fluorouracil have undergone the most study for hepatic artery infusion, but other active agents such as irinotecan, oxaliplatin, and cetuximab have also been studied. Trials involving HAI have been conducted in patients with unresectable liver metastases to render the disease resectable and as adjuvant therapy following curative resection of isolated metastases. Overall objective tumor response rates range between 40% and 100%, but HAI is associated with potential biliary toxicity and the technical expertise required warrants use in selected patients by experienced practitioners.58,80 XRT can be directed to sites of hepatic tumor using external beam radiation therapy (EBRT) or percutaneous arterial injection of micron-sized embolic particles loaded with a radioisotope (radioembolization). Tumor ablation procedures use radiofrequency ablation (RFA) or microwave energy to generate heat that destroys localized tumor cells. Cryoablation placement of a cryoprobe into the tumor, either percutaneously or intraoperatively, and then lowering the probe temperature to –20 to –40°C and rewarming it in cycles, resulting in formation of an ice ball that causes tumor destruction. These strategies may be useful for patients who have very small hepatic lesions and are unable to undergo liver resection surgery but they are less successful than surgical interventions.80

Unresectable Metastatic Colorectal Cancer

Unless the primary tumor is causing an obstruction, surgery in patients with established unresectable disease is rarely indicated. XRT may be useful to control localized symptoms in patients with metastatic colorectal cancer. Systemic chemotherapy palliates symptoms and improves survival in patients with unresectable disease. Common treatment regimens include combinations of cytotoxic and biologic agents.

Chemotherapy Images Accepted initial chemotherapy regimens for metastatic colorectal cancer consist of oxaliplatin-containing regimens (FOLFOX, CapOx), irinotecan-containing regimens (FOLFIRI), oxaliplatin plus irinotecan plus fluorouracil plus leucovorin (FOLFOXIRI), infusional fluorouracil plus leucovorin alone, and capecitabine alone.8185 Current guidelines recommend the addition of bevacizumab to FOLFOX, CapOx, FOLFIRI, infusional fluorouracil plus leucovorin, and capecitabine alone, or an EGFR inhibitor added to FOLFOX or FOLFIRI, as appropriate.58 Multiple treatment regimens are effective for metastatic disease.62,67,81113 The goals of therapy, history of prior chemotherapy, tumor KRAS mutation status, and risk of drug-related toxicities should be considered when an appropriate management strategy is defined for each individual. Treatment regimens are the same for metastatic cancer of the colon and rectum. Table 107-8 lists common chemotherapeutic regimens for metastatic disease.

TABLE 107-8 Chemotherapeutic Regimens for Metastatic Colorectal Cancer

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Currently, most metastatic colorectal cancers are incurable, and treatment goals are to control cancer growth, reduce patient symptoms, improve quality of life, and extend survival. The benefit of palliative chemotherapy for metastatic colorectal cancer as compared to observation or supportive care alone with regard to these treatment goals has been established. Results from multiple randomized trials and meta-analyses demonstrate that chemotherapy prolongs life and improves quality of life of patients with metastatic colorectal cancer.60,114

Most first-line chemotherapy regimens used for metastatic colorectal cancer incorporate a fluoropyrimidine. Irinotecan or oxaliplatin added to a fluoropyrimidine-based regimen significantly improves response rates, progression-free survival (PFS), and median survival.60 Biologic agents further improve response rates and survival when combined with chemotherapy as compared to chemotherapy alone. Patients considered appropriate for initial intensive chemotherapy typically receive an oxaliplatin or irinotecan-containing regimen with infusional fluorouracil plus leucovorin and a biologic agent. Capecitabine can be substituted for fluorouracil and leucovorin. Patients that are not considered appropriate candidates for initial intensive therapy may be considered for fluoropyrimidine monotherapy, a fluoropyrimidine regimen combined with a biologic agent, or EGFR inhibitor monotherapy, as appropriate.58Patients may receive multiple different regimens, and the sequence of drugs used appears less important than exposure to all active agents during the course of cancer treatments.60 Table 107-9 summarizes comparative outcome data from potentially useful chemotherapeutic treatments for metastatic colorectal cancer.

TABLE 107-9 Comparative Outcomes from Selected Trials in Metastatic Colorectal Cancer

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Fluorouracil-Based Regimens Images Fluorouracil administered as a single agent by IV bolus induces response rates of only 10% to 20% and is therefore considered ineffective for metastatic colorectal cancer. Several continuous IV infusion fluorouracil regimens have been developed to increase the duration of drug exposure during the S-phase of the cell cycle and increase cytotoxicity. No clear survival advantages are observed for any particular regimen, but continuous infusion schedules of fluorouracil when combined with irinotecan or oxaliplatin are better tolerated and commonly used in clinical practice.

Leucovorin is frequently added to fluorouracil in an attempt to improve treatment outcomes. Response rates of 14% to 58% have been observed with a variety of fluorouracil doses in combination with leucovorin at doses ranging from 20 to 500 mg/m2.55 Leucovorin administration sequence and timing may be important factors in the efficacy of biochemical modulation of fluorouracil. Leucovorin administration prior to fluorouracil is the most effective approach to enable intracellular-reduced folates to accumulate prior to fluorouracil administration. Despite significantly higher response rates and improved PFS achieved with leucovorin-modulated fluorouracil regimens, their effect on OS is modest.

Bimonthly and weekly regimens of infusional fluorouracil plus leucovorin are the most common treatment schedules for metastatic disease. Increased response rates are noted in bimonthly regimens of fluorouracil administered first as an IV bolus infusion followed by a 22-hour continuous infusion in combination with high-dose leucovorin administered over 2 hours (de Gramont regimen).69 A similar but simplified “high-dose infused regimen” includes IV bolus fluorouracil with leucovorin followed by 46-hour continuous infusion fluorouracil.84 These regimens are considered superior to IV bolus regimens due to higher tumor response rates, lower toxicity, and improved PFS.114

In summary, a weekly or bimonthly schedule of leucovorin plus fluorouracil (either bolus or continuous infusion) may be more convenient for the patient in terms of fewer scheduled clinic appointments, less interference with work schedules, and ease of dose adjustments based on toxicity. However, the incorporation of newer agents into treatment regimens rather than continual adjustments of fluorouracil and leucovorin doses and administration schedules have led to the greatest advances in drug therapy for metastatic colorectal cancer and will be discussed in the following sections.

Fluorouracil and Leucovorin Plus Irinotecan Images Irinotecan added to fluorouracil plus leucovorin as initial therapy for metastatic disease improves tumor response rates, time to progression, and OS. In a randomized trial of 387 previously untreated patients with advanced colorectal cancer, irinotecan plus fluorouracil and leucovorin was compared to fluorouracil plus leucovorin with regard to tumor response, survival, and quality of life (Table 107-9).102Patients randomized to fluorouracil plus leucovorin could receive weekly fluorouracil (2,600 mg/m2) as a 24-hour IV infusion plus leucovorin (500 mg/m2), or the de Gramont regimen of IV bolus and infusional fluorouracil. For the three-drug treatment, a weekly regimen of irinotecan (80 mg/m2) with a 24-hour infusion of fluorouracil (2,300 mg/m2) plus leucovorin 500 mg/m2, or an every-2-week regimen consisting of irinotecan (180 mg/m2) on day 1 with IV bolus fluorouracil (400 mg/m2) followed by a 22-hour IV infusion (600 mg/m2) plus leucovorin (200 mg/m2given on days 1 and 2) can be used. Tumor response, median time-to-disease progression, and OS were all greater in the irinotecan group. Diarrhea and neutropenia were the most common toxicities and were worse in the irinotecan-containing groups. Diarrhea was the most common reason for dose reduction or treatment discontinuation with the weekly regimens and led to hospital admission for 32% of patients receiving irinotecan as compared with 12% of patients who received only fluorouracil plus leucovorin. Neutropenia was the most common cause of dose reductions with the every-2-week regimens. Results from questionnaires indicated that quality of life consistently declined later in the irinotecan group.

A second randomized trial compared the addition of irinotecan to weekly IV bolus fluorouracil plus leucovorin (IFL regimen) to the Mayo Clinic regimen and to irinotecan alone as first-line therapy in 683 patients with metastatic colorectal cancer.114 Although the combination of irinotecan, fluorouracil, and leucovorin resulted in significantly increased tumor response rates and improved PFS and OS as compared with fluorouracil plus leucovorin and irinotecan alone, respectively, the IFL regimen was associated with unacceptable toxicity. Modifications of the original IFL regimen have been made to give irinotecan on an every-2-weeks schedule with fluorouracil as a continuous infusion (FOLFIRI regimen). The median OS is improved by about 6 months with decreased toxicity by this method of administration, and irinotecan administered as IFL is not recommended.58,105

The most common adverse effects of irinotecan in these regimens are diarrhea, neutropenia, nausea and vomiting, dehydration, asthenia, abdominal pain, and alopecia; diarrhea and neutropenia are dose limiting.102 Two distinct patterns of diarrhea have been described. Early-onset diarrhea occurs during or within 2 to 6 hours after irinotecan administration and is characterized by lacrimation, diaphoresis, abdominal cramping, flushing, and/or diarrhea. These cholinergic symptoms, thought to be caused by inhibition of acetylcholinesterase, respond to atropine 0.25 to 1 mg given IV or subcutaneously. About 10% of patients experience the acute symptoms during or shortly following the irinotecan. More commonly, late-onset diarrhea occurs 1 to 12 days after irinotecan administration and may last for 3 to 5 days. Late-onset diarrhea may require hospitalization or discontinuation of therapy, and fatalities have been reported. The incidence of late-onset diarrhea can be decreased with aggressive antidiarrheal intervention. Aggressive intervention with high-dose loperamide therapy should consist of 4 mg taken at the first sign of soft or watery stools, followed by 2 mg orally every 2 hours until symptom-free for 12 hours; this regimen can be modified to 4 mg taken orally every 4 hours during the night.

The severity of delayed diarrhea has been correlated with the systemic exposure (i.e., area under the concentration-versus-time curve) of irinotecan and SN-38 (irinotecan’s active metabolite) and with genetic polymorphisms in the enzyme uridine diphosphate-glucuronosyltransferase (UGT1A1), which is responsible for the glucuronidation of SN-38 to inactive metabolites. Reduced or deficient levels of the UGT1A1 enzyme are observed in Gilbert syndrome, a familial hyperbilirubinemia disorder, and correlate with irinotecan-induced diarrhea and neutropenia.115 An FDA-approved test for deficiency in this enzyme is available, and clinicians can consider obtaining these results for individual patients prior to initiating irinotecan-based therapy to see if a dose reduction is warranted.

Based on these studies, the addition of irinotecan to fluorouracil plus leucovorin (FOLFIRI) increases survival when compared to fluorouracil plus leucovorin in the first-line treatment of metastatic colorectal cancer. These data support the current consensus that the three-drug treatment regimen be considered a first-line option for metastatic colorectal cancer. Accordingly, irinotecan is FDA-approved as first-line therapy for metastatic colorectal cancer in combination with fluorouracil and leucovorin.

Fluorouracil and Leucovorin Plus Oxaliplatin Images Oxaliplatin, in combination with infusional fluorouracil plus leucovorin, is FDA-approved for use in first-line and salvage regimens for metastatic colorectal cancer (Table 107-8). Oxaliplatin incorporation into fluorouracil-based regimens as first-line therapy for metastatic colorectal cancer is associated with higher response rates and improved PFS, with variable effects on OS.101 Oxaliplatin is not effective as a single agent in colorectal cancer and is therefore only used in combination regimens.

Intergroup Trial N9741, a comparison of oxaliplatin plus fluorouracil and leucovorin (FOLFOX4) to weekly irinotecan plus IV bolus fluorouracil and leucovorin (IFL), and a combination of irinotecan plus oxaliplatin (IROX) in 795 patients with previously untreated metastatic colorectal cancer showed superior efficacy with FOLFOX4.100 The IROX arm showed no advantage over either of the other two arms. Significant improvements in response rates, PFS, and median survival were seen with FOLFOX4 as compared with IFL (Table 107-9). However, because of the crossover study design and different methods of fluorouracil administration among treatment arms, it is not possible to evaluate the true contributions of oxaliplatin and irinotecan combined with fluorouracil plus leucovorin in this study.

In a phase III cooperative group study, a simplified combined bolus and infusional fluorouracil regimen with irinotecan (FOLFIRI) was compared with oxaliplatin combined with the same fluorouracil plus leucovorin schedule (FOLFOX6) in previously untreated patients with advanced colorectal cancer to determine whether the sequence of administration of both regimens differed with regard to efficacy and toxicities.82 Patients were randomized to receive initial treatment with FOLFIRI or FOLFOX6, and at disease progression the patients then received the alternate regimen. Both sequences resulted in similar response rates, PFS, and median survival, but the grade 3 or 4 toxicity profiles were different. Neurotoxicity, neutropenia, and thrombocytopenia were more common with FOLFOX6, while febrile neutropenia, nausea/vomiting, mucositis, and fatigue were significantly more frequent with FOLFIRI. Therefore, based on this trial either FOLFOX or FOLFIRI are acceptable chemotherapy backbones for the first-line treatment of metastatic colorectal cancer.

Oxaliplatin has minimal renal toxicity, myelosuppression, and nausea and vomiting when compared with other platinum-based drugs. Oxaliplatin is associated with both acute and persistent neuropathies.116The acute neuropathies occur within 1 to 2 days of dosing and resolve within 2 weeks. The neuropathies usually occur peripherally, but may also occur in the jaw and tongue. A rare acute syndrome of pharyngolaryngeal dysesthesia (1% to 2% of patients) is characterized by subjective sensations of difficulty in swallowing and shortness of breath. Overall, acute neuropathies occur in about 90% of patients, and are precipitated or exacerbated by exposure to cold temperatures or cold objects. Thus, patients should be instructed to avoid cold drinks and use of ice, and to cover skin before exposure to cold or cold objects. Several prophylactic and treatment strategies have been studied with varying degrees of success. Carbamazepine, gabapentin, amifostine, and calcium and magnesium infusions have been used to both prevent and treat oxaliplatin-induced neuropathies.116 Persistent neuropathy is typically a cumulative adverse effect, occurring after 8 to 10 cycles, and is seen mostly in patients who are responding to therapy.100 The neuropathy is characterized by paresthesia, dysesthesia, and hypoesthesia, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking as a result of impaired proprioception). Persistent neuropathy occurs in about one-half of patients receiving oxaliplatin but usually resolves with dosage reductions or cessation of oxaliplatin therapy.114,116 Prophylaxis with calcium and magnesium infusions has not been proven effective. A “stop-and-go” approach where oxaliplatin is temporarily discontinued after 3 months of therapy (or sooner with significant neuropathic symptoms) with the other drugs continued, reduces neurotoxicity without compromising OS and has been advocated.58,114,116 Oxaliplatin can be reinitiated at disease progression in those patients that experience near complete resolution of neurotoxicity. Anticonvulsant and antidepressant agents are potentially useful to treat symptoms.

Fluorouracil and Leucovorin plus Oxaliplatin plus Irinotecan Images To further improve survival rates achieved with FOLFOX and FOLFIRI regimens, a four-drug regimen (FOLFOXIRI) was developed and has been compared with FOLFIRI.83 FOLFOXIRI improved PFS and OS compared to FOLFIRI and a higher proportion of patients receiving FOLFOXIRI were able to undergo radical resection of metastases. As expected, FOLFOXIRI causes more neutropenia, neurotoxicity, diarrhea, and alopecia, but may be appropriate for medically fit individuals with diffuse aggressive disease to palliate symptoms and as potential conversion therapy.58,83,114

Capecitabine Images Capecitabine is an oral, tumor-activated, and tumor-selective fluoropyrimidine carbamate. Capecitabine is converted to fluorouracil through a three-step activation process, the final step being activation by thymidine phosphorylase, which is present in greatest concentrations at the tumor site. These activation steps lead to about a threefold increase in tumor fluorouracil levels. Capecitabine was compared to fluorouracil plus leucovorin as first-line therapy for metastatic colorectal cancer in two randomized phase III trials. In a pooled analysis of 1,207 patients randomized to capecitabine (1,250 mg/m2 orally twice daily for 14 days, repeated every 3 weeks) or the Mayo Clinic regimen, tumor response to capecitabine was superior to that of fluorouracil plus leucovorin (26% vs. 17%).85 Time-to-tumor-progression and median survival, however, were no different. Hand–foot syndrome was more common with capecitabine, whereas grades 3 or 4 neutropenia and stomatitis were more common with fluorouracil plus leucovorin. The convenience of oral administration and different toxicity profile make capecitabine a useful substitution for infusional fluorouracil in regimens for metastatic disease.

Both irinotecan and oxaliplatin have been combined with capecitabine. In a study of more than 2,000 patients with metastatic colon cancer, FOLFOX was compared with the combination of capecitabine, fluorouracil, and leucovorin (CapOx) and found to have equivalent OS and PFS. Toxicity was as expected with increased grades 3 or 4 neutropenia (including neutropenic fever) and increased diarrhea and hand–foot syndrome seen with oxaliplatin and capecitabine-based regimens, respectively.60,114 Based on these results, CapOx is an acceptable first-line option for the treatment of metastatic colorectal cancer.58

The combination of capecitabine with irinotecan resulted in no survival benefit compared with IFL and showed inferior results when compared with FOLFIRI in a randomized trial of 430 patients. Additionally, the combination of capecitabine with irinotecan had higher rates of nausea, vomiting, and dehydration and is not recommended for use outside of clinical trials.105,114

The current FDA-approved indication for capecitabine in metastatic colorectal cancer is when therapy with a fluoropyrimidine alone is desired. Replacement of fluorouracil-leucovorin with capecitabine in other regimens is not currently approved, although completed trials demonstrate that capecitabine is a suitable replacement for infusional fluorouracil in combination with oxaliplatin but not irinotecan.

Biologic Therapy Images Current guidelines and clinical practice recommend the addition of biologic therapy to one of the chemotherapy backbones mentioned above.58

Bevacizumab Images Bevacizumab is a recombinant, humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). Bevacizumab, in combination with IV fluorouracil-based chemotherapy, was FDA approved in 2004 for initial treatment of patients with metastatic colorectal cancer. Results from randomized trials show increased PFS and OS benefit as compared with chemotherapy alone.114

A phase III trial of bevacizumab in combination with IFL as first-line therapy in patients with metastatic colorectal cancer has also been completed. Patients were randomized to receive IFL and either placebo or bevacizumab 5 mg/kg every 2 weeks.103 The addition of bevacizumab to IFL therapy resulted in an increase in response rate (35% vs. 45%) and median survival (15.6 vs. 20.3 months) and PFS (6.24 vs. 10.6 months) as compared with IFL alone. The frequency of typical adverse effects associated with IFL chemotherapy was not increased with the addition of bevacizumab. The risk of grade 3 hypertension was significantly increased in the bevacizumab group, but the risk of bleeding, thromboembolism, and proteinuria was similar in the bevacizumab and placebo groups. The hypertension is easily managed with oral antihypertensive agents. The risk of gastrointestinal perforation was increased by the addition of bevacizumab to IFL, and patients complaining of abdominal pain associated with vomiting or constipation should be considered for this rare but potentially fatal complication. Bevacizumab is also associated with a twofold increased risk of arterial thrombotic events, with patients who are older than age 65 or who have a prior history of arterial thrombotic events at greatest risk. Nevertheless, because these individuals derive the same survival benefits with bevacizumab as do other patients, they may be appropriate candidates to receive bevacizumab.

An infusional fluorouracil regimen should be used with the combination of bevacizumab and irinotecan. A randomized phase III trial demonstrated a median OS of 28 months compared with 19.2 months with FOLFIRI and IFL, respectively (HR 1.79; P = 0.037) when given in combination with bevacizumab.105 A third arm of this trial replaced fluorouracil and leucovorin with capecitabine and was found to be inferior to FOLFIRI; during accrual the trial was amended to add bevacizumab to all treatment arms. The capecitabine arm remained inferior to FOLFIRI. Based on these results, capecitabine should not be administered with irinotecan, with or without bevacizumab.

Bevacizumab has also been combined with oxaliplatin in a variety of chemotherapy regimens for the initial treatment of metastatic colon cancer. In contrast to irinotecan-containing regimens, the method of fluorouracil administration (or substitution with capecitabine) does not appear to significantly affect outcomes. One trial, randomized one cohort of patients to one of three oxaliplatin-based regimens (TREE-1 [arm 1: oxaliplatin plus infusional fluorouracil {5-FU}; arm 2: oxaliplatin plus bolus 5-FU; arm 3: oxaliplatin plus oral capecitabine]) while the second cohort of patients (TREE-2) received the same chemotherapy regimens plus bevacizumab as their first-line treatment for metastatic colon cancer.81 The addition of bevacizumab was associated with increased overall response rate and longer time-to-progression and median survival, although these differences were not significant as a consequence of the small sample size. Overall median survival was 18.2 months in the TREE-1 cohort and 23.7 months in the TREE-2 cohort with the addition of bevacizumab. In a separate phase III trial, the addition of bevacizumab to oxaliplatin-based chemotherapy (capecitabine and oxaliplatin [CapOx] or FOLFOX) significantly improved PFS but not OS.104 Studies that compare the addition of bevacizumab to oxaliplatin- and irinotecan-containing combinations with bevacizumab are ongoing.

EGFR Inhibitors Images EGFR inhibitors may also be used in combination with first-line chemotherapy. Results with cetuximab in the first-line metastatic setting combined with FOLFIRI suggest that the combination improves response rates and PFS to either chemotherapy regimen without adding substantial toxicity.107

The benefit of EGFR inhibitors is limited to patients with wild-type KRAS tumors and they should not be used in patients with tumor KRAS mutations.114 Cetuximab combined with FOLFIRI demonstrated an increase in PFS of 1.2 months and improved median OS from 21 to 24.9 months (HR 0.84, P = NS) compared with FOLFIRI alone in the subset of patients with wild-type KRAS.107 No benefit is seen in patients with mutant KRAS. Cetuximab is FDA-approved for administration in a weekly schedule, but bimonthly infusions have been used and may be more convenient.89

Conflicting results have been seen with the use of cetuximab in combination with FOLFOX. Initial reports demonstrated an increased response rate and a decreased PFS (HR 0.57; P =.0163) with the combination as compared with FOLFOX4 alone in patients with wild-type KRAS.108 However, a large phase III trial failed to confirm the benefit of this regimen and demonstrated no difference in PFS or OS with the combination of FOLFOX and cetuximab and current NCCN guidelines do not recommend this combination.58 This lack of benefit was seen in patients with both KRAS wild-type and mutant tumor types.

Panitumumab can be combined with either FOLFOX or FOLFIRI in patients with KRAS wild-type tumors. PFS was increased with the combination of FOLFOX plus panitumumab compared to FOLFOX alone in a randomized phase III trial (9.6 vs. 8 months; P = 0.02) in patients demonstrated to have KRAS wild-type tumors.86 No benefit was seen, and a possible harmful effect was seen in patients with mutant KRAS tumors.

Panitumumab was also combined with FOLFIRI in a phase II trial and demonstrated activity without substantially increasing the toxicity of FOLFIRI.90 In this trial, PFS was improved by 1.7 months with the combination of panitumumab and FOLFIRI in patients with KRAS wild-type tumors (8.9 vs. 7.2 months, respectively).

For reasons that are not well understood, the addition of panitumumab or cetuximab to bevacizumab plus irinotecan- or oxaliplatin-containing chemotherapy reduces PFS and is currently not recommended. The Panitumumab Advanced Colorectal Cancer Evaluation Study (PACCE) trial and the CAIRO2 demonstrated a decrease in PFS of 1.4 months when panitumumab and 1.3 months when cetuximab was added to bevacizumab-containing chemotherapy, respectively.117,118 Both of these differences were clinically and statistically significant. The results from these trials demonstrate the potential pitfalls of treating patients with multiple biologic agents outside of the setting of a clinical trial and why this practice should be avoided.

Selection of an Initial Metastatic Regimen

Several factors should be considered when selecting first-line therapy for metastatic colorectal cancer when disease palliation is the primary treatment goal. Based on the comparable results of FOLFIRI versus mFOLFOX6, either of these regimens (FOLFOX or FOLFIRI) are considered the reference standard in metastatic colorectal cancer. Most patients will receive first- and second-line regimens and patient preference for either sequence of treatments based on their different toxicity profiles is important. Preexisting neuropathies may lead to FOLFIRI being chosen initially, whereas increased bilirubin or known UGT1A1 deficiency (known risk factors for delayed diarrhea) may lead to FOLFOX as the initial choice. Alopecia occurs much more frequently with irinotecan compared to oxaliplatin combinations. Because FOLFOX can cause persistent neuropathy, a rationale for starting with FOLFIRI is based on the observation that time to progression is longer with first-line treatment than in second line; therefore, the time to death during which some patients will have to live with neuropathy may be shorter.114 Capecitabine is an appropriate substitute for IV fluorouracil in oxaliplatin combination regimens. Because of higher response rates and modest survival benefit with FOLFOXIRI, this four-drug combination may be useful for patients with initially aggressive and symptomatic disease. Although efficacy with IROX is inferior to FOLFOX or FOLFIRI, this regimen might be considered for patients that are not candidates for a fluoropyrimidine.

The 2013 NCCN guidelines recommend the addition of bevacizumab to any initial fluoropyrimidine-based regimen unless its use is contraindicated in an individual patient.58 EGFR inhibitors are an alternative first-line option in patients with wild-type KRAS tumors only. Fluorouracil plus leucovorin alone or capecitabine monotherapy is also appropriate first-line treatment for those individuals who cannot tolerate three-drug combination regimens.

Metastatic Disease: Second-Line and Subsequent Therapy

Systemic chemotherapy represents the mainstay of therapy for patients whose disease progresses following initial treatment for metastatic disease. Table 107-10 lists treatment options for refractory metastatic disease. Treatment options are based on the type of and response to prior treatments, the site and extent of disease, and patient factors and treatment preferences.

TABLE 107-10 Second-line and Salvage Chemotherapy Regimens for Metastatic Colorectal Cancera

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Systemic Chemotherapy

On disease progression following standard initial therapy, appropriate treatment options depend primarily on the type of prior therapy received. Because most patients will have received a combination of a fluoropyrimidine with either irinotecan or oxaliplatin, second-line therapy with the alternate regimen should be considered. Patient survival can exceed 2 years with this approach and it is important for patients to receive all traditional chemotherapy options if possible. Targeted agents can either be added to the above regimens or used as single agents.

Irinotecan Irinotecan was initially FDA approved as a second-line treatment for recurrent or progressive disease following fluorouracil. Two phase III trials compared irinotecan to either best supportive care or continuous-infusion fluorouracil in patients who had progressed within 6 months of treatment with fluorouracil.109,110 Both trials demonstrated an improvement in OS with irinotecan as compared to the control arms. However, this approach is rarely used since single agent fluorouracil is rarely given as first-line therapy.

The use of the FOLFIRI regimen after progression with first-line FOLFOX demonstrated an objective response rate of 4% with a median PFS of 2.5 months.82 These results are consistent with observations that demonstrate improved outcomes in those patients who are able to receive all active cytotoxic agents during the course of their disease.114

Based on these results, irinotecan should be considered standard second-line therapy for patients with disease progression with first-line treatment with oxaliplatin-containing regimens. Continuous-infusion fluorouracil (FOLFIRI), with or without biologic therapy, is most commonly given.

Oxaliplatin Oxaliplatin plus fluorouracil and leucovorin should be considered for patients who received primary treatment with irinotecan plus fluorouracil. Despite the low activity of single-agent oxaliplatin against fluorouracil-refractory disease, when oxaliplatin has been administered in a bimonthly regimen with high-dose leucovorin and continuous fluorouracil infusion, a 21% response rate with a median survival in excess of 10 months has been reported.114 The combination of oxaliplatin plus fluorouracil and leucovorin is also effective as salvage therapy after initial treatment with irinotecan plus fluorouracil and leucovorin, with a similar response rate.114 Although irinotecan can be used effectively as a single agent in colorectal cancer, it should be noted that oxaliplatin does not have substantial activity alone, and should only be given in combination with a fluoropyrimidine.

Targeted Therapy

Images EGFR inhibitors may be administered in combination with irinotecan but can be used as single agents in patients who cannot tolerate irinotecan-based chemotherapy. Angiogenesis inhibitors are also used in second-line and subsequent therapy. However, the monoclonal antibodies bevacizumab and ziv-aflibercept are not given as single agents.

EGFR Inhibitors Images Cetuximab is active in chemotherapy-refractory disease as a single agent and in combination with continued irinotecan.60 The combination of cetuximab plus irinotecan was compared with cetuximab monotherapy in 329 patients with colorectal cancer who had progressed on irinotecan.97 Cetuximab was given 400 mg/m2 IV as a loading dose, followed by weekly infusions of 250 mg/m2 IV plus irinotecan or cetuximab alone until disease progression. The objective response rates, 23% and 11% with cetuximab plus irinotecan and cetuximab alone, respectively, were very encouraging, and resulted in the endorsement of cetuximab by the FDA via accelerated approval. Median survival was 8.6 months for the combination and 6.9 months with monotherapy (P = 0.48). Time-to-disease-progression was significantly longer with cetuximab plus irinotecan than with cetuximab alone (4.1 vs. 1.5 months; HR 0.54), even among patients who also had oxaliplatin-refractory disease. The incidence of grade 3 or 4 adverse effects was as anticipated based on previous trials; asthenia (14%) and a follicular rash (9%) occurred most commonly with cetuximab alone, and in addition to typical irinotecan-related side effects (e.g., nausea, vomiting, diarrhea, and neutropenia). Another phase III trial that compared single agent cetuximab to best supportive care in patients refractory to oxaliplatin or irinotecan-based regimens confirmed these results.110 Cetuximab demonstrated a 23% improvement in OS compared with best supportive care (HR, 0.77; 95%; P =.0046).

The combination of cetuximab and irinotecan has also been evaluated in the second-line setting in patients’ naïve to irinotecan after oxaliplatin-based failures. The trial referred to as the EPIC trial, randomized patients to cetuximab plus irinotecan (N = 648) or irinotecan alone (N = 650).93 The trial failed to meet its primary end point of an improvement of OS (HR = 0.98; P =.71) but did demonstrate significant improvements in PFS and relative risk (RR) with cetuximab. An important caveat for most initial trials with cetuximab is that KRAS testing was not initially performed. Retrospective analyses of these studies show that antitumor effects are limited to patients with wild-type KRAS.114

Panitumumab is a fully human monoclonal antibody targeted to the EGFR that was FDA approved for use in patients with metastatic colorectal cancer that no longer responds to previous therapy. The approval was based on a comparison of panitumumab to best supportive care in patients who had experienced disease progression after standard chemotherapy, including a fluoropyrimidine, irinotecan, and oxaliplatin. Patients received best supportive care or panitumumab (6 mg/kg IV every 2 weeks) until tumor progression.98 Those patients who received panitumumab showed a 46% decrease in the rate of tumor progression compared with those who only received best supportive care (HR 0.54, 95% confidence interval [CI] 0.44 to 0.66). Retrospective analysis of KRAS testing demonstrated that the benefit was limited to patients with wild-type KRAS in that no responses and a decreased PFS was reported in patients with KRAS mutations treated with panitumumab.114 As expected, dermatologic toxicities were observed in patients receiving panitumumab, as well as fatigue, abdominal pain, nausea, and diarrhea. Only one hypersensitivity reaction was reported.

Panitumumab has also been studied in combination with FOLFIRI in the second-line setting. In one of the first trials to prospectively evaluate end points by KRAS status, a phase III trial randomized patients to FOLFIRI with or without panitumumab.112 In the KRAS wild-type group, a 2-month improvement in PFS was demonstrated; OS was not statistically different, although there was a trend to improvement with the panitumumab. Both monotherapy with panitumumab or combination with chemotherapy regiments such as FOLFIRI are recommended by current NCCN guidelines as second-line options (Table 107-10).58

Current evidence does not support restricting the use of EGFR inhibitors to patients with immunohistochemical evidence of EGFR-positive staining but rather results stress the influence of KRAS mutations on the efficacy of EGFR inhibitors in treating colorectal cancer.58 KRAS is located downstream from the EGFR receptor and is involved in the EGFR signaling cascade by activating the MAPK pathway that influences cellular proliferation. Activating mutations in exon 2 are able to activate KRAS independent of EGFR receptor activation.57 Therefore, EGFR receptor inhibition strategies are not effective in controlling cancer proliferation and growth. Several studies have demonstrated that KRAS mutational status predicts response to EGFR inhibitors used in colorectal cancer and its status should be determined prior to starting therapy directed at the EGFR receptor. Therapy with an EGFR inhibitor is not recommended in patients with mutant KRAS.58

Tumors harboring BRAF mutations are also associated with a poor prognosis and a poor response to EGFR inhibitors in patients with wild-type KRAS.57 Although BRAF mutation testing is not routinely recommended at this time, BRAF mutation status may be considered in patients with wild-type KRAS.58 Individuals with BRAF mutations should not receive EGFR inhibitors.

Neither of the EGFR inhibitors should be used in the second-line setting if they were part of a patient’s initial treatment regimen. Therefore, the initial first-line regimen determines whether cetuximab should be used as monotherapy or combined with irinotecan in the second-line setting (Table 107-10).

Angiogenesis Inhibitors Angiogenesis inhibitors are also used in the second-line setting. In patients who did not receive bevacizumab in their initial treatment, FOLFOX plus bevacizumab is recommended based on phase III data. Results from Eastern Cooperative Group 3200 demonstrated that bevacizumab, in combination with FOLFOX4, improved survival in patients with previously treated advanced colorectal cancer.111 It should be noted that patients were excluded if they received prior oxaliplatin or bevacizumab and the dose of bevacizumab was 10 mg/kg instead of 5 mg/kg. Median survival was improved from 10.7 to 12.5 months (P = 0.0018). The FDA has also approved the use of bevacizumab after progression on first-line bevacizumab. In the Phase III registry trial, patients were randomized at progression to second-line treatment with chemotherapy plus bevacizumab or chemotherapy alone.113 The chemotherapy regimen was switched in the second-line setting based on what they received in the first-line setting (e.g., if FOLFOX was given in the first-line setting, therapy was changed to FOLFIRI). The primary end point of OS was 1.4 months longer with bevacizumab and reached statistical significance.


Clinical Controversy…

Continuation of bevacizumab after disease progression has recently been FDA approved. Originally justified based on retrospective data that demonstrate improved survival, a confirmatory phase III trial demonstrated a small improvement in OS. Benefit of this strategy versus changing the antiangiogenic therapy to a new agent that targets the same pathway will need to be determined.

Ziv-aflibercept, a soluble recombinant fusion protein that was designed to block the angiogenic process, is also approved in the second-line setting. The agent was developed by fusing sections of the VEGFR-1 and VEGFR-2 immunoglobulin domains to the Fc portion of human immunoglobulin G1 (IgG1) and blocks VEGF-A, VEGF-B, and placental growth factor (PIGF) by “trapping” the ligands before they get to the native transmembrane receptors. In a phase III randomized trial, FOLFIRI plus ziv-aflibercept was compared to FOLFIRI after progression on an oxaliplatin-based regimen.88 The trial met its primary end point with an improvement in OS (13.5 months for FOLFIRI/ziv-aflibercept vs. 12.1 months for FOLFIRI/placebo; HR, 0.82; P = 0.003). It is dosed at 4 mg/kg as an IV infusion over 1 hour every 2 weeks and is associated with similar adverse effects as bevacizumab.

Regorafenib, a small-molecule inhibitor of tumor angiogenesis (VEGFR-1, VEGFR-2, and VEGFR-3) and other downstream targets (C-KIT, RET, RAF1, and BRAF), is approved for the third- or fourth-line treatment of metastatic colorectal cancer. This oral agent is dosed 160 mg once daily for the first 21 days of each 28-day cycle. In a phase III trial of patients with metastatic colorectal cancer and progression during or within 3 months of last chemotherapy, regorafenib demonstrated a 1.4-month improvement in OS when compared to placebo.99 Because this is an oral-only regimen, patients must be counseled on its use and potential toxicity. Regorafenib should be taken with a low-fat breakfast and may interact with CYP P4503A4 inducers and inhibitors. Toxicities include hypertension, hand–foot syndrome, and hepatotoxicity.

Hepatic-Directed Therapies

Patients with unresectable or nonablatable hepatic-predominant metastases or who are unable to undergo surgery may be candidates for chemoembolization, radioembolization, or HAI chemotherapy, as discussed previously.80Hepatic arterial chemoembolization delivers high concentrations of cytotoxic agents directly to the tumor and results in the embolization or devascularization of the liver, which blocks perfusion of the tumor and eliminates its blood supply. This procedure involves the instillation of a mixture that incorporates chemotherapeutic agents, radioactive contrast dye, and/or an embolic agent directly into the hepatic artery. Agents most commonly used include doxorubicin, mitomycin, and cisplatin, which are usually dissolved in about 10 to 15 mL of a radiographic contrast dye. Addition of an embolic agent to the mixture results in either a temporary or permanent occlusion of the hepatic artery. Local tumor response rates with these strategies are high and most patients will experience partial or complete relief of symptoms. Toxicities include postembolization syndrome characterized by nausea, fatigue, and transient elevations in hepatic enzymes and bilirubin, gastrointestinal ulcerations, and biliary toxicity. Although various hepatic-directed therapies offer potential disease palliation in select patients with unresectable, yet limited hepatic metastases, no conclusive survival advantage has been demonstrated.

New Strategies and Agents in Development

The number of active cytotoxic agents against cancers of the colon and rectum is limited. These traditional chemotherapy agents, which target rapidly dividing cells, kill both malignant and nonmalignant cells, and new cancer therapies are needed to improve therapeutic outcomes. In particular, targeted therapies aimed at the underlying cancer pathology are increasingly being developed and used in colorectal cancer treatment. A variety of agents targeted toward augmenting the host immune system response have undergone, or are currently undergoing, study for colorectal cancer, including monoclonal antibodies and tumor vaccines. Additional strategies include regulating tumor growth through the inhibition of various cell proliferation, survival, and death pathways, angiogenesis, and cancer stem cells. Agents that can alter microenvironmental factors that support angiogenesis and tumor metastases may also be of benefit.

PERSONALIZED PHARMACOTHERAPY

Drug therapy for patients diagnosed with colorectal cancers should be individualized based on several established tumor and patient pharmacogenetic factors that influence treatment response. In addition, various tumor characteristics, patient genetics, and molecular markers may predict prognosis and/or response to certain therapies and provide the rationale for pharmacogenomic strategies to select appropriate therapies for individual patients. Table 107-11 summarizes potential predictive markers for individualizing colorectal cancer treatment.

TABLE 107-11 Potential Predictive Markers for Personalized Pharmacotherapy for Colorectal Cancer

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The most important development in biomarkers for colorectal cancer treatment has been validation of KRAS mutation status as a predictive marker for lack of tumor response to EGFR inhibitors.60,119 Tumors should be tested for KRAS mutations at diagnosis of stage IV disease; patients with KRAS mutations on codons 12 and 13 on chromosome 12 are not candidates for EGFR inhibitors. However, not all KRASmutations confer similar biology. In contrast to codon 2 mutations, KRAS G13D mutations may be associated with improved outcomes to cetuximab in first-line therapy, but additional studies are needed.120Because only about 60% of patients with KRAS wild-type tumors respond to treatment, additional factors have been explored for their ability to predict response to EGFR inhibitors, including BRAF V600E mutation, and mutation or loss of PTEN or PIK3CA.33,60 Although the predictive value of BRAFmutation status has not been established, the presence of this mutation appears to be associated with lack of response to EGFR monoclonal antibody inhibitors.119

About 12% to 22% of stage II and III colorectal cancers show high-frequency microsatellite instability (MSI-H), which is associated with an improved prognosis.60 Findings from pooled analyses of patients with MSI-H tumors who received adjuvant fluorouracil indicate a lack of response to treatment, perhaps due to an improved overall prognosis and/or additional factors. Nevertheless, some practitioners use MSI status to determine which patients with low-risk stage II colorectal cancer should not receive adjuvant fluorouracil. Current NCCN guidelines recommend MSI testing for stage II colon cancers because MSI-H status confers a good prognosis and those patients do not benefit from adjuvant fluorouracil.58

Of factors predictive for tumor sensitivity to fluorouracil, TS expression has been most studied. Tumors that overexpress TS, an enzyme that converts deoxyuridine monophosphate to deoxythymidine monophosphate, an essential step for DNA synthesis, are less sensitive to fluorouracil chemotherapy.57 Patients whose cancers have higher levels of TS appear to have a significantly worse overall 5-year survival than patients whose cancers have a low level of TS.55 However, no large cooperative group trial has identified a subgroup of patients who failed to benefit from fluorouracil plus leucovorin therapy based on tumor TS levels. Therefore, tumor testing for TS overexpression is not routinely used to select fluorouracil treatments.57

TFAP2E, a gene that encodes transcription factor AP-2 epsilon, is frequently hypermethylated in colorectal cancer.121 TFAP2E hypermethylation and decreased expression is associated with nonresponse to fluorouracil chemotherapy, independent of MSI, mutations of key regulatory cancer genes, or genes known to affect fluorouracil metabolism. Additional studies are needed to confirm the role of TFAP2Emutation testing for optimal drug selection.

Tumors with P53 mutations demonstrate a high degree of resistance to radiation, fluorouracil, and certain other chemotherapeutic agents and are associated with a less-favorable prognosis. However, because of difficulties with adequately sensitive and specific immunohistochemical analysis to identify P53 mutations, widespread testing and application of this as a marker is unlikely.57

Patients that are homozygous for a UGT1A1 7-repeat allele (UGT1A1*28) are at increased risk for severe diarrhea with irinotecan. A FDA-approved test to determine UGT1A1 genotype is commercially available. Although some individuals advocate testing UGT1A1 genotype prior to starting irinotecan, widespread testing has not been adopted.57 The package insert recommends an initial reduced dose in patients with UGT1A1*28 genotype.

Although patients who are deficient in DPD experience severe and potentially life-threatening toxicities with conventional doses of fluorouracil, determination of DPD activity is relatively time consuming and the techniques are not amenable to routine clinical practice. However, genetic testing for DPYD polymorphisms can identify patients who would require lower fluorouracil doses to avoid severe toxicity. As an alternative, plasma ratio determinations of uracil and dihydrouracil, which are more easily obtainable, can identify individuals with DPD deficiency that are at risk of developing significant toxicities.122

Excision repair cross-complementing C1 (ERCC1) is a DNA excision repair protein that has been evaluated as a predictive test for response to platinum chemotherapy.57 Certain ERCC1 polymorphisms are associated with decreased ERCC1 protein expression, which may predict for response to and improved survival with FOLFOX chemotherapy.57 Presently, there is a lack of consensus as to the preferred test for tumor ERCC1 expression, immunohistochemistry analysis or mRNA expression using reverse-transcription polymerase chain reaction (RT-PCR). However, testing approaches to aid in optimal drug selection may become available in the future.

Tests for other polymorphisms that may be useful to predict treatment toxicity have been established but are not routinely used. Germline polymorphisms that result in decreased TS expression are associated with an increased frequency of fluorouracil toxicities, including myelosuppression, diarrhea, and mucositis.57 MTHFR polymorphisms that are linked to reductions in intracellular folate pools have been associated with increased capecitabine toxicity.57

Because of the wide inter- and intrapatient variability in fluorouracil pharmacokinetics and a narrow therapeutic range, pharmacokinetic optimization of fluorouracil represents a potential strategy to individualize dosing and optimize efficacy and minimize adverse effects.123 Published data suggest that only 20% to 30% of patients treated with fluorouracil achieve therapeutic concentrations.124 A prospective study that compared pharmacokinetically guided fluorouracil dosing with conventional dosing in patients with metastatic colorectal cancer demonstrated that pharmacokinetically guided dose adjustments reduced grade 3/4 toxicities, increased the objective tumor response rate, and provided a higher yet not significantly increased survival rate.125 Valid assay methods that facilitate therapeutic drug monitoring are now available and are being used in some centers. Algorithms are available for specific treatment protocols that enable practitioners to determine doses based on patient physiological and pathophysiological characteristics.123 Whether clinicians adopt this strategy and if it will indeed advance therapeutic outcomes have yet to be established.

EVALUATION OF THERAPEUTIC OUTCOMES

The goal of monitoring is to evaluate whether the patient is receiving any benefit from the management of the disease or to detect recurrence. Similarly, examinations help to determine whether preventive interventions or screening studies effectively reduce an individual’s risk for developing colorectal cancer or presenting with an advanced stage of disease. 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 radiographs, abdominal or pelvic CT scans or radiographs, depending on the site of disease being evaluated for response, and CEA measurements every 3 months if the CEA is or was previously elevated. In addition, a complete blood cell count should be obtained prior to each course of chemotherapy administration to ensure that hematologic indices are adequate. Baseline liver function tests and an assessment of renal function should be evaluated prior to and periodically during therapy. These tests and other selected serum chemistries should also be evaluated with the development of any new symptoms or significant change in disease status. Patients should be evaluated during every treatment visit for the presence of anticipated side effects, which generally include loose stools or diarrhea, nausea or vomiting, mouth sores, fatigue, and fever, as well as other side effects such as neuropathy, skin rash, and hepatotoxicity that are typically associated with oxaliplatin, EGFR inhibitors, and regorafenib, respectively. Serum electrolytes, including magnesium, should be monitored for during treatment with EGFR inhibitors. Patients receiving bevacizumab, ziv aflibercept, or regorafenib should be evaluated for hypertension and proteinuria.

Symptoms of recurrence such as pain syndromes, changes in bowel habits, rectal or vaginal bleeding, pelvic masses, anorexia, and weight loss develop in less than 50% of patients. A greater percentage of recurrences are detected in asymptomatic patients because of increased serum CEA levels that lead to further examination. Although the value of CEA monitoring for asymptomatic disease recurrence is questioned by some because of the related expense and emotional stress associated with false-positive elevations, CEA monitoring plays an important role in postoperative follow-up studies for most individuals. A PET scan can be considered to identify localized sites of metastatic disease when a rising CEA level suggests metastatic disease but CT scans and other imaging studies are negative.

Patients who undergo curative surgical resection, with or without adjuvant therapy, require close follow-up based on the premise that early detection and treatment of recurrence could still render them cured. In addition, early treatment for asymptomatic metastatic colorectal cancer appears superior to delayed therapy. Specific practice guidelines for postoperative surveillance examinations following successful treatment for stage II or III disease were developed by NCCN and include: history, physical examination, and CEA test every 3 to 6 months for the first 2 years, then every 6 months for a total of 5 years; annual chest and abdominal and pelvic CT scans for up to 5 years following primary therapy; and colonoscopy at about 1 year after surgery. Repeat colonoscopies are recommended at 3 years, unless findings of polyps warrant closer follow-up. Less intensive surveillance is recommended for patients treated for stage I disease because of low risk of recurrence.58

Posttreatment surveillance should also include a survivorship care plan with immunizations for vaccine-preventable diseases, early detection of second primary cancers, and support systems that encourage smoking cessation, establish regular exercise and maintain a healthy BMI, and encourage healthy lifestyle and dietary choices.58

Recent advances in the treatment for cancer of the colon and rectum now offer the potential to improve patient survival, but for many patients, improved DFS and PFS represent equally important therapeutic outcomes. Although treatment approaches for metastatic colorectal cancer have been historically assessed by their ability to produce a measurable objective tumor response, which is generally believed necessary for any treatment to improve survival, the effects of therapies on survival are clinically more meaningful than their ability to induce a tumor response. However, with the availability of multiple active treatments for metastatic disease, and the likelihood that patients will receive more than one during the course of their treatment, improvements in OS with new therapies will be increasingly difficult to determine.

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 and performance status, and other quality-of-life indicators, as well as PFS and time-to-treatment failure. Because most metastatic colorectal cancers are incurable, a specific decision regarding an individual patient’s care will ultimately be required. This decision should be based on a careful assessment of the balance between risks associated with treatment (or lack thereof) and benefits of treatment. Effort should also be made to ensure that the costs of screening, diagnostic tests, treatments, and procedures for colorectal cancer are consistent with their value in improving patient outcomes.

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