Treating Colorectal Cancer in the Elderly Population

Supported by an educational grant from
sanofi aventis 

Author:
Eric M. Chevlen, MD
Assistant Professor, Internal Medicine
Northeastern Ohio Universities College of Medicine
St. Elizabeth Health Center
Youngstown, OH

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The goal of this continuing education activity is to provide healthcare professionals with the information necessary to treat elderly patients with colorectal cancer.

LEARNING OBJECTIVES

Although the age-adjusted incidence of new cases has declined slightly since 1998, colon cancer remains the third most common malignancy to strike Americans, and the third most common cause of cancer death in both men and women. Over 100,000 new cases will be diagnosed in 2007. About half that number are expected to die of the disease.¹

Like most cancers, colon cancer is more common in the elderly. While the age-adjusted incidence, as noted, has declined, that fact is counterbalanced by the increasing longevity of the population. In other words, slightly fewer cases may be occurring per age cohort, but the increasing number of elderly persons implies that colon cancer will remain a significant and increasing public health problem into the foreseeable future. Because the elderly are prone to numerous co-morbidities, their treatments must be guided by both reliable evidence from large clinical trials and attention to individual and even idiosyncratic needs.

This review is intended to provide an overview of colon cancer, with special attention to the disease in elderly patients when the patient’s age may have an impact in decision-making. Except where noted, this review excludes consideration of rectal cancer.

NATURAL HISTORY OF COLON CANCER

The etiology of colon cancer involves a complex interaction of environmental and hereditary factors. Known environmental risk factors include high-calorie diet, high red-meat consumption, overcooked red-meat consumption, high saturated fat consumption, excess alcohol consumption, cigarette smoking, sedentary lifestyle, and obesity.² There is some evidence that non-steroidal anti-inflammatory drug (NSAID) use actually decreases the risk of colon cancer.³

Some people have a hereditary predisposition toward colorectal cancer. Increased risk is found in people who have familial polyposis. There is also a hereditary increased risk of colon cancer in some families who do not have polyposis. This hereditary nonpolyposis colorectal cancer (HNPCC) is also called Lynch syndrome.⁴ A personal history of ulcerative colitis or Crohn's colitis also increases the risk of colorectal cancer.⁵

Colon cancer arises from the mucosa, the inner lining of the bowel wall. This is ordinarily an area of rapid cell turnover. The cell population is renewed every 5 to 6 days. Most colon cancers arise in an orderly progression from normal to malignancy. The first step probably involves activation of a gene called APC, so named because it is usually seen in adenomatous polyps of the colon. The majority of colon cancers arise from benign polyps,⁶ and may take as long as 10 years to evolve into frank malignancy. Most colon cancers are characterized by abnormalities of other genes in addition to APC, such as p53, Ras, and SMAD4.⁷ As the tumor slowly grows, the epithelial cells that form its surface gradually become less differentiated. The polyp exhibits hyperplasia and then dysplasia before frank neoplasia is manifest. The cancer arises in the lumen of the bowel, but as it progresses, it invades the bowel wall. An invasive colon cancer has access to the lymphatics within the bowel wall. It is no wonder, then, that regional lymph nodes are commonly the first site of spread of colon cancer. Since much of the venous drainage of the colon goes through the portal venous system to the liver, that organ is a common site of distant metastases. Lung metastases may also occur. Although not unheard of, bone and brain metastases are less common with colon cancer than they are with lung or breast cancer.

MICROSCOPIC STRUCTURE OF THE COLON

Since the prognosis of colon cancer depends upon the stage of the disease, and because the stage of the disease depends upon the depth of invasion of the tumor, a brief review of the microscopic structure of the colon is appropriate.

The bowel wall has an orderly arrangement of four layers. From lumenal border to external wall, they are the mucosa, the submucosa, the muscularis (or muscularis propria), and the serosa (or adventitia). The mucosa is the innermost layer of the large bowel. The cells which line the lumen of the gut are epithelial cells, similar to those that line the rest of the gastrointestinal tract. The epithelium is supported by a thin layer of border cells called the lamina propria, and deep to that is the muscularis mucosae. The muscularis mucosae is also a thin layer of cells, and forms the deep border of the mucosa. It is important not to confuse the muscularis mucosae with the deeper and much thicker layer of muscle cells called the muscularis propria. The tissue between the muscularis mucosae and the muscularis propria is called the submucosa. It consists of fibrous connective tissue, fibroblasts, mast cells, blood and lymphatic vessels, and nerve fibers. The muscularis propria is the layer of the bowel that gives it its motility. The muscles of the bowel wall contract in orderly fashion to allow the normal propulsion of the bowel contents. The serosa is the outermost layer of the colon; it is smooth, slick, and shiny. It allows the bowel to slide freely within the abdominal cavity. The loose connective tissue between the muscularis propria and the serosa is called the subserosa.

STAGING OF COLON CANCER

It seems to be common sense that the bigger a cancer is, the more it has invaded into normal tissue, the more widely it has spread outside of the primary site, and the worse is the prognosis. Colon cancer represents a case in which common sense is correct. To provide a uniform standard of describing cases of colon cancer, the American Joint Committee on Cancer (AJCC) has established a staging system based on the features of the primary tumor, the number and extent of regional lymph node metastases, and the presence or absence of distant metastases. This is known as the TNM system, which stands for Tumor, lymph Node, and Metastasis. Although this system has its imperfections, it is a standard which has been used worldwide for over fifty years.⁸

The primary tumor is scored according to how deeply into the bowel wall it has invaded. A T1 tumor invades into the submucosa or less, but not into the muscularis propria. A T2 tumor invades into the muscularis propria, but not into the serosa. A T3 tumor invades through the muscularis propria into the subserosa. A T4 tumor penetrates through the bowel wall to invade other organs or to perforate the serosa itself.

The N staging describes the lymph nodes removed with the cancer at the time of surgery or visible radiographically. A stage N0 disease has no lymph node involvement. Stage N1 has 1 to 3 regional lymph nodes involved with cancer. An N2 disease has more than 3 positive lymph nodes.

The staging of metastases is straightforward. If distant metastases are present, the disease is called M1. If not, it is M0.

The staging of the disease depends upon the various T, N, and M combinations. Stage I disease has T1 or T2, but no lymph node involvement or distant metastases. Stage II disease is T3 or T4, again with no other sites of involvement. Stage III disease is any T stage, so long as the N stage is N1 or N2, and the M stage is 0. Stage IV disease means metastatic disease—M1—no matter what the T and N stages are.

Figure 1. Staging of colon cancer.
Source: http://health.yahoo.com/topic/coloncancer/treatment/article/healthwise/ncicdr0000062954

PRINCIPLES OF PATHOLOGY OF COLON CANCER

As will be discussed in detail in the section on adjuvant chemotherapy, proper staging of the disease is essential for proper treatment. If patients are understaged, they will get inadequate therapy. If they are overstaged, they will receive unnecessary and, perhaps, dangerous therapy. The need for proper coordination between surgeon and pathologist is apparent. The AJCC has recommend evaluation of a minimum of 12 lymph nodes to accurately identify Stage II colon cancers.⁹ Evaluation of fewer lymph nodes increases the risk that a positive one will elude detection, and that the patient will falsely be labeled as having stage II disease rather than stage III disease. Most patients with stage III disease need adjuvant chemotherapy. There is little evidence that chemotherapy is beneficial in most patients with stage II disease. In addition to providing this vital information concerning lymph node status, the pathologist should report on the grade of the tumor (how close to or far from normal it looks under the microscope), the size and penetration of the primary tumor, and whether the margins of resection are free of cancer.

SCREENING FOR COLON CANCER

In considering screening for colon cancer, it must be kept in mind that not all populations are at equal risk. Patients with a particular risk factor for colon cancer may need more frequent screening than does the standard risk population. Similarly, patients who have already been diagnosed as having a premalignant lesion or cancer do not fall into the category of “screening.” They are better considered as patients under surveillance—a completely different concept.

Like most other medical interventions, screening for disease carries both risks and benefits. Screening procedures may be uncomfortable and expensive. While the serious complication rate of colonoscopy is quite low, it is still not zero. False positive findings may lead to unnecessary procedures; false negative findings may give spurious reassurance while allowing a potentially fatal disease to progress unchecked. Ideally, screening procedures, like therapeutic interventions, should demonstrate their value in prospectively randomized clinical trials.¹⁰

There is good evidence that fecal occult blood testing (FOBT) reduces the risk of death due to colon cancer. Unfortunately, the absolute amount of that reduction is not great. Another troubling finding of studies of FOBT is that, while the death rate due to colon cancer is reduced, there is no evidence that the overall death rate is reduced.¹¹ More sensitive and specific procedures, such as colonoscopy, will likely prove to be more useful than FOBT in screening for colon cancer, but evidence to support that claim awaits the results of ongoing clinical trials. The American Cancer Society has recommended that people over age 50 years be screened for colorectal cancer with one of the following:¹²

     • Annual FOBT with either a guaiac-based (gFOBT) or immunochemical-based test (iFOBT) following
       manufacturer's recommendations for specimen collection;
     • Flexible sigmoidoscopy every 5 years;
     • Annual gFOBT or iFOBT, plus flexible sigmoidoscopy every 5 years;
     • Double contrast barium enema (DCBE) every 5 years;
     • Colonoscopy every 10 years.

Several fine points about these recommendations should be noted. First, single panel FOBT in the medical office using a stool sample collected during a digital rectal exam (DRE) is not a recommended option, owing to its very low sensitivity for advanced adenomas and cancer. Moreover, patients should be informed that unless the FOBT is performed with strict adherence to the manufacturer’s instructions, the poor sensitivity of the test makes it a poor choice for colorectal cancer screening.

As noted, patients who are at above average risk for colorectal cancer require surveillance rather than screening. These high-risk patients include individuals with:⁵

     • A history of adenomatous polyps;
     • A personal history of curative-intent resection of colorectal cancer;
     • A family history of either colorectal cancer or colorectal adenomas diagnosed in a
       first-degree relative before age 60 years;
     • A significantly higher risk due to a history of inflammatory bowel disease of significant duration; and
     • A significantly higher risk due to a known or suspected presence of one of two hereditary syndromes, 
       specifically, HNPCC or familial adenomatous polyposis (FAP).

Ironically, while the screening of the general population is often inadequate, many patients under surveillance for these conditions are actually receiving far more intervention than may be necessary.¹³

SURGERY OF COLON CANCER

Almost all patients with colon cancer require surgical excision of the tumor. The goals of the surgery are twoold: First, the surgery is curative in most cases of early stage disease. Even when the patient presents with metastatic disease, excision of the tumor may reduce the likelihood of his having pain, bleeding, and bowel obstruction.¹⁴ Patients with metastatic disease but without symptoms from the primary tumor may nonetheless benefit from palliative bowel resection.¹⁵

Open surgical resection of the primary tumor and regional lymph nodes is the standard surgical treatment for patients with colon cancer. Laparoscopic-assisted colectomy (LAC) has been examined as an alternative approach in a multicenter prospectively randomized noninferiority trial. When compared to open laparotomy, LAC was associated with slightly shorter hospital stays and decreased use of analgesics.¹⁶ The recurrence rate and overall survival were not significantly different between the two approaches. It must be noted, however, that one-fifth of the patients randomized to LAC ended up having an open procedure. Also, patients with transverse colon cancer were excluded from the study, and the investigators were all quite experienced in the procedure.¹⁶

It may be that thorough surgical removal of regional lymph nodes does more than improve the staging of patients; it may have some therapeutic value in reducing total body tumor burden and thereby improve the prognosis independent of its effect on accurate staging of the patient.¹⁷ Indirect evidence for this comes from the fact that post-operative prognosis varies with the number of lymph nodes removed by the surgeon. This is true for both stage II and stage III disease.¹⁸ In light of this, it is disheartening that elderly patients are more likely than their younger cohorts to have inadequate lymphadenectomies with their cancer resection.¹⁹

Not surprisingly, the post-operative complication rate is higher in older patients than in younger ones. However, age per se may not be the key factor for that difference. Elderly patients are more likely to present with proximal tumors, bowel obstruction, or need for emergency surgery—all factors known to worsen the prognosis. A multivariate analysis suggested that age was not an independent risk factor for postoperative mortality.²⁰ Patients undergoing surgery for cancer are at risk of post-operative deep vein thrombosis. This risk can be reduced by routine prophylactic use of unfractionated heparin or low-molecular-weight heparin.²¹

ADJUVANT CHEMOTHERAPY

Most patients who present with stage I or II colon cancer have success with surgery alone. Stage I patients are clearly not candidates for adjuvant chemotherapy, and its use in stage II patients is controversial because the data supporting such use is weak.²² However, stage III colon cancer carries a much worse prognosis. Without adjuvant therapy, about half of these patients will die within 5 years of diagnosis.²² There is by now compelling evidence that adjuvant chemotherapy can reduce the risk of recurrence and risk of death for stage III colon cancer patients. Although elderly patients are less likely than younger ones to receive adjuvant therapy, the benefit for them is no less than it is for the younger patients.²³

There has been rapid improvement in the therapy of recurrent colon cancer in the last few years. New regimens shown to be of greater efficacy in this setting have also been applied as adjuvant therapies. Unlike the case for recurrent disease, it takes large trials and many years to measure the impact of adjuvant therapy.

For close to 50 years, the foundation of chemotherapy of colon cancer has been 5-fluorouracil (5-FU). This drug is administered intravenously, and is thought to exert its antitumor effect, at least in part, by disrupting the cancer cell’s ability to replicate its DNA.²⁴ Nowadays, the drug is almost always administered concurrently with leucovorin (or folinic acid), a form of the vitamin folic acid which increases the efficacy of the 5-FU. One short-coming of 5-FU is that the drug is cleared from the blood stream within minutes of its being injected as a bolus.²⁵ Administering 5-FU as a continuous intravenous infusion for a number of hours increases the exposure of the cancer cells to its toxic effect. Unfortunately, that also increases the toxicity of the drug.

Oxaliplatin is another drug proven to be useful when used with 5-FU in the adjuvant treatment of stage III colon cancer. Adding it to the combination of 5-FU and leucovorin significantly increases the benefit of the treatment.²⁶ The combination of these three drugs is usually known by the acronym FOLFOX. There are by now several variations of the FOLFOX regimens—though not all of them have been tested in the adjuvant setting—each one bearing a different numerical suffix. The most recent is FOLFOX-7. Like many platinum-based drugs, oxaliplatin can cause a peripheral neuropathy. Uniquely, however, it can cause an acute cold allodynia, beginning within minutes of the treatment. This can even affect the pharynx, so that patients receiving oxaliplatin may be unable to tolerate cold fluids for several days after the infusion.²⁷ Several interventions have been tried to prevent the neurotoxicity associated with oxaliplatin. One of these is concurrent infusion of calcium and magnesium along with the oxaliplatin. A retrospective comparison of patients so treated showed that they experienced less neurotoxicity than did patients who did not receive the infusions.²⁸ On the basis of this study, the intervention was widely adopted. Recently, a prospectively randomized trial has investigated this practice and called it into question. The CONCEPT trial (Combined Oxaliplatin Neurotoxicity Prevention Trial) randomized patients with relapsed colon cancer to different oxaliplatin-containing chemotherapy regimens, with or without calcium and magnesium infusions to reduce neurotoxicity. On June 15, 2007, the CONCEPT trial was closed based upon a recommendation from the Data Monitoring Committee (DMC). An unplanned, interim analysis performed by the DMC indicated that Ca/Mg infusions administered in this study may be associated with a reduced response rate to FOLFOX treatment. The data are in the process of being verified and final analysis is pending.²⁹

Another agent of proven benefit for the adjuvant therapy of colon cancer is capecitabine. This is an oral agent, usually taken twice a day for 14 days, with a 1-week break between cycles, for a total of 6 cycles. The drug may be considered a pro-drug, since it is converted to 5-FU intracellularly. The half-life of oral capecitabine is much longer than that of bolus 5-FU; this has the theoretical advantage of ensuring that adequate serum levels of the drug are present to impair DNA replication of cancer cells as they enter the S-phase of their growth cycle.³⁰ When used as a single agent in the adjuvant setting, capecitabine is at least as good as 5 daily intravenous boli of 5-FU and leucovorin repeated every 28 days.³¹ The dose in this non-inferiority study was eight cycles of oral capecitabine, at a dose of 1250 mg per square meter of body-surface area, twice daily on days 1 through 14 every 21 days. The FDA has approved capecitabine for this use. Capecitabine has a somewhat different side-effect profile from 5-FU. The oral agent is less likely to cause stomatitis and neutropenia, but it is more likely to cause hand-foot syndrome. This is a painful and sometimes disabling dermatologic reaction characterized by pain, swelling, erythema, and blistering of the palms and soles.

Elderly Patients and Adjunct Chemotherapy
Unfortunately, elderly patients with stage III colon cancer have not been offered the benefit of adjuvant chemotherapy as much as their younger cohorts. A national survey showed that 87% of patients under age 55 were offered adjuvant therapy. Among patients aged 55 to 74, only 65% were offered the therapy; patients age 75 or older were offered adjuvant therapy only 43% of the time.³²

It might be argued that older patients are less likely to need adjuvant chemotherapy of colon cancer because they are not likely to live long enough to experience recurrent disease, but this argument is contradicted by the data. Even at age 70, the average, otherwise-healthy person has a life expectancy of an additional 15 years.³³ Similarly, it is not legitimate to argue that elderly patients are less likely to benefit from adjuvant chemotherapy because of intolerance of the treatment. A meta-analysis of clinical trials involving over 85,000 patients with stage III colon cancer showed that the elderly have the same benefit of adjuvant therapy as do younger patients.²³ This was true even in the group of patients over 80 years old. Another meta-analysis of adjuvant chemotherapy, specifically assessing its impact on the elderly, found a higher risk of serious leukopenia, but equal benefit of adjuvant chemotherapy in elderly as compared with younger patients.³⁴

Oxaliplatin therapy in the elderly was the focus of a pooled analysis of four studies of its use with other agents both in the adjuvant setting and that of recurrent disease. These trials enrolled close to 4,000 patients. In this comparison, the elderly experienced slightly more neutropenia and thrombocytopenia, but there was no statistically significant difference in their rate of other adverse effects. Importantly, the elderly did not receive dose reductions more often than the younger patients did. Age was not significantly associated with survival in the treatment of recurrent colon cancer with oxaliplatin-based regimens. There are some limitations of this study, however. Only 16% of the patients in these pooled trials were over 70, and the patients enrolled in these studies probably represent a select group (that is, with fewer co-morbidities than average), about whom generalizations may be applied only with great caution.³⁵

TREATMENT OF RECURRENT COLON CANCER

Typical sites of recurrence of colon cancer are the liver, lungs, and (less often) bones. Brain metastases are less commonly seen with colon cancer than with lung or breast cancer. Although metastatic colon cancer is not curable with currently available treatments, nonetheless such treatment can prolong survival and improve quality of life.

There are several treatment options for the chemotherapy of recurrent colon cancer. The most commonly used regimens are combinations of prolonged infusions of 5-FU and leucovorin with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). FOLFOX is discussed in the section “Adjunct Chemotherapy.”

Irinotecan has a mechanism of action different from that of the other drugs used to treat colon cancer, justifying its use in combination with other agents. The drug is activated in vivo to the metabolite SN-38. SN-38 inhibits the enzyme topoisomerase, thereby causing lethal damage to cancer cells. SN-38 is inactivated by the hepatic enzyme uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). It follows, therefore, that patients who are deficient in UGT1A1 activity will have higher and more prolonged serum levels of SN-38 after irinotecan therapy than patients with normal enzymatic activity.³⁶ This increased exposure to SN-38 is associated with a greater risk of adverse effects.³⁷ The most severe toxicity of irinotecan is diarrhea, although neutropenia may occur from this drug as it does with so many other chemotherapy agents. Patients with Gilbert’s disease, a hereditary deficiency in UGT1A1 function characterized by mild hyperbilirubinemia, should not receive full doses of irinotecan. Irinotecan has been studied as a single agent for the treatment of recurrent colorectal cancer. It has modest activity, about a 10% partial response rate, and about 35% stable disease rate. A prospective, randomized, multicenter phase III study found that patients older than age 70 tolerated the drug as well as did those under age 70. The benefit of this monotherapy was the same in both age cohorts.³⁸

Bevacizumab is now part of the standard therapy of recurrent colon cancer. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF). As metastatic deposits of cancer grow, they require new blood vessels to supply the enlarging mass of neoplasm. This process of new blood vessel growth is called angiogenesis. VEGF, secreted by cancer cells, promotes angiogenesis, so it follows that an inhibitor of VEGF would reduce angiogenesis and reduce tumor growth. Prospectively randomized trials have shown that adding bevacizumab to irinotecan-based chemotherapy improves the survival in patients with recurrent colon cancer.³⁹ Similarly, adding bevacizumab to oxaliplatin-based chemotherapy improves survival.⁴⁰ The toxicity profile of bevacizumab is different from that of cytotoxic chemotherapy. Because it inhibits angiogenesis, an important aspect of vascular homeostasis, use of bevacizumab has been associated with gastrointestinal perforations, wound healing complications, hemorrhage, and arterial vascular thromboses. The drug should not be administered within 28 days of major surgery. Epistaxis and hypertension are probably more common but less serious side effects. As is true of other monoclonal antibodies, the infusion of bevacizumab may rarely elicit a hypersensitivity reaction.⁴¹

There are two other monoclonal antibodies approved by the FDA for treatment of colon cancer, both targeting the receptor for epidermal growth factor (EGFR). Activation of EGFR by various ligands leads to a cascade of intracellular events, culminating in DNA synthesis and cell proliferation. Cetuximab is a chimeric monoclonal antibody directed against EGFR. It is FDA-approved for use in the treatment of patients who have metastatic colorectal cancer and whose tumor expresses EGFR. It may be used with continuing irinotecan treatment for patients whose disease has progressed after irinotecan without cetuximab. It may also be used as a single agent for patients who are unable to tolerate irinotecan.⁴² Panitumumab is a very similar agent to cetuximab. They target the same EGFR, but vary slightly in chemical structure, with panitumumab being a fully humanized monoclonal antibody. Panitumumab is indicated for treatment of patients whose tumor expresses EGFR and who have had progressive cancer after previous chemotherapy. Use of these monoclonal antibodies may be associated with infusion reactions. Also, most of the patients receiving either of these agents develop a skin reaction. The severity may vary from mild dermatitis to severe reactions complicated by sepsis and death. It is likely that the skin toxicity is intrinsic to the drug mechanism of activity, since EGFR is expressed in skin, and other agents that disrupt that receptor or its intracellular effector pathway cause similar skin toxicity.

Elderly Patients and Chemotherapy to Treat Recurrent Disease
Unfortunately, as is the case with adjuvant chemotherapy, the elderly are less likely than younger patients to be offered chemotherapy to treat recurrent disease. This practice is not supported by data from clinical trials. Quite the contrary, a clinical trial which randomized patients with recurrent colon cancer to receive either FOLFOX or FOLFIRI as initial chemotherapy, with rotation to the other regimen upon progression, assessed the impact of age on clinical outcome. In both first-line and second-line settings, the elderly (age > 65) experienced toxicity no different from that of younger patients, and they enjoyed the same benefit of the therapy.⁴³

Similarly, a phase III clinical trial of 5-FU/leucovorin with or without oxaliplatin to treat metastatic colon cancer found that, with the exception of grade 3 diarrhea, the elderly patients tolerated the therapy as well as did younger patients. Unfortunately, the study analysis does not compare the benefit of treatment by age group.⁴⁴ A meta-analysis of the FOLFIRI study was presented at the 2006 meeting of the American Society of Clinical Oncology, but final results have not yet been reported in publication. That study showed no difference in response for older versus younger patients. It did show that severe stomatitis and neutropenia were more common in the elderly patients.⁴⁵

Unfortunately, the aforementioned studies on bevacizumab combination therapies did not report toxicity and response by age group, so it is not known if the elderly respond differently to these agents than younger patients do.

Age-specific effects of cetuximab have not been reported. The pivotal trial on panitumumab did not stratify patients by age, but reported no difference in outcome for patients age 65 years and older compared with those under age 65.⁴⁶

SUMMARY

Colon cancer remains a major health problem in the elderly. Realistically, we have little power to influence the risk of the disease. However, we should offer the elderly the benefit of screening for early diagnosis. Like younger patients, they should have thorough surgical therapy and pathological assessment of their tumors. Also like younger patients, those with high-risk or recurrent disease may benefit from chemotherapy. The available science gives no support to therapeutic nihilism in this cohort of patients.

1. Colon cancer in the elderly:
a. affects about 50,000 Americans a year
b. affects about 100,000 Americans a year
c. is an indolent disease with a low case fatality rate
d. is the number one cause of cancer death in America

2. Known risk factors for colon cancer include:
a. high saturated fat consumption
b. cigarette smoking
c. obesity
d. all of the above

3. From lumenal border to external wall, the order of the layers of the bowel are:
a. the mucosa, the submucosa, the muscularis (or muscularis propria), and the serosa (or adventitia).
b. the mucosa, the muscularis (or muscularis propria), the submucosa, and the serosa (or adventitia).
c. the submucosa, the mucosa, the muscularis (or muscularis propria), and the serosa (or adventitia).
d. the serosa (or adventitia), the submucosa, the mucosa, the muscularis (or muscularis propria)

4. A colon cancer which has invaded into the muscularis propria, spread to 2 regional lymph nodes, but has not metastasized is staged as:
a. T1N2M1
b. T2N1M0
c. T1N1M0
d. T2N2M0

5. The cancer described in question four would be staged as:
a. Stage I
b. Stage II
c. Stage III
d. Stage IV

6. The American Joint Committee on Cancer (AJCC) has recommended that the number of lymph nodes examined with resected colon cancer specimens be at least:
a. 3
b. 5
c. 12
d. 20

7. The American Cancer Society has recommended which of the following as screening tests for colon cancer:
a. annual fecal occult blood test
b. flexible sigmoidoscopy every 5 years
c. double contrast barium enema (DCBE) every 5 years
d. all of the above

8. When compared to standard open laparotomy, laparoscopic-assisted colectomy has the following advantages:
a. 5
b. 10
c. both a and b
d. neither a nor b

9. In colon cancer surgery, thorough removal of regional lymph nodes:
a. makes staging more accurate, but does not affect prognosis
b. has no impact on staging, but improves prognosis
c. makes staging more accurate, and improves prognosis
d. has no impact on staging or prognosis

10. Adjuvant chemotherapy is of proven benefit in which stage(s) of colon cancer?
a. stage II
b. stage III
c. both a and b
d. neither a nor b

11. The acronym FOLFOX stands for the combination of:
a. fluorouracil, levamisole, and oxaliplatin
b. fluorouracil, leucovorin, and oxandrolone
c. fluorouracil, leucovorin, and oxaliplatin
d. fluconazole, leucovorin, and oxaliplatin

12. Capecitabine use is associated with which side effect?
a. peripheral neuropathy
b. hand-foot syndrome
c. dose-related myocardial damage
d. pulmonary fibrosis

13. Compared to younger patients, elderly patients receiving adjuvant chemotherapy for stage III colon cancer:
a. benefit more
b. benefit less
c. benefit the same
d. have not been compared

14. Typical sites of metastases in colon cancer include:
a. lung, brain, and bones
b. brain, bones, and spleen
c. lung, skin, and bones
d. lung and liver

15. Irinotecan’s mechanism of action is:
a. alkylation of DNA
b. disruption of spindle formation during metaphase
c. inhibition of thymidylate synthase
d. inhibition of topoisomerase

16. A phase III clinical trail of 5-FU/leucovorin with or without oxaliplatin to treat metastatic colon cancer found that the elderly patients tolerated the therapy as well as did younger patients, except that the elderly had more:
a. grade 3 diarrhea
b. neutropenia
c. thrombocytopenia
d. peripheral neuropathy

17. Bevacizumab is a monoclonal antibody directed against:
a. HER-2 ((human epidermal growth factor receptor 2)
b. epidermal growth factor (EGFR)
c. vascular endothelial growth factor (VEGF)
d. CEA (carcinoembryonic antigen)

18. Patients who have had major surgery should:
a. receive bevacizumab within 2 weeks for maximum benefit
b. receive reduced dose bevacizumab
c. not receive bevacizumab if they are receiving heparin or enoxaparin
d. not receive bevacizumab for at least 4 weeks

19. A patient receiving combined agent chemotherapy for recurrent colon cancer develops epistaxis and hypertension. The most likely drug causing these side effects is:
a. bevacizumab
b. 5-fluorouracil
c. capecitabine
d. irinotecan

20. Patients receiving panitumumab or cetuximab are likely to develop
a. alopecia
b. neutropenia
c. delayed nausea and vomiting
d. dermatitis