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InternalMed_Harrison. Catheters are made of Silastic®, polyurethane, or polyvinyl chloride. Silastic catheters are less thrombogenic and are best for tunneled catheters. Polyurethane is best for temporary catheters. To avoid infection, dressing changes with dry gauze should be performed at regular intervals by nurses skilled in catheter care. Chlorhexidine solution is more effective than alcohol or iodine compounds. Appropriate monitoring for patients receiving PN is summarized in Table 98e-6. Even though premixed solutions of crystalline amino acids and dextrose are in common use, the future of evidence-based PN lies in computer-controlled sterile compounders that rapidly and inexpensively General sense of well-being


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InternalMed_Harrison. General sense of well-being Strength, as evidenced by getting out of bed, walking, and resistance exercise as appropriate Vital signs, including temperature, blood pressure, pulse, and respiratory rate Fluid balance: weight (recorded at least several times weekly); fluid intake (parenteral and enteral) vs. fluid output (urine, stool, gastric drainage, wound, ostomy) Parenteral nutrition delivery equipment: tubing, pump, filter, catheter, dressing Blood glucose, Na, K, Cl, HCO3, BUN Daily until stable and fully advanced; then twice weekly Serum creatinine, albumin, PO4, Ca, Baseline; then twice weekly Mg, Hb/Hct, WBC count aParameters are assessed daily unless otherwise specified. Abbreviations: BUN, blood urea nitrogen; Hb, hemoglobin; Hct, hematocrit; INR, international normalized ratio; WBC, white blood cell. Source: Adapted from the chapter on this topic in Harrison’s Principles of Internal Medicine, 16e, by Lyn Howard, MD.


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InternalMed_Harrison. generate personalized solutions that meet the specific protein and calorie goals for different patients in different clinical situations. For example, 1 L of a standard mixture of 5% amino acids/25% dextrose solution provides 50 g of amino acids (41.5 g of protein substrate) and 1000 kcal; the use of this solution to meet the 1.5–to 2.0-g/kg protein requirement of an acutely ill 70-kg patient requires the infusion of 2.5–3.4 L of fluid and a potentially excessively high energy dose of 2500-3300 kcal. When the body fat store is adequate, clinical evidence increasingly supports the greater safety and efficacy of high-protein, moderately hypocaloric SNS in such patients. A sterile compounder can accurately generate an appropriate recipe for such a patient. For example, 1 L of a solution including 600 mL of 15% amino acids, 300 mL of 50% dextrose, and 100 mL of electrolyte/micronutrient mix contains 75 g of protein substrate and 800 kcal; thus it is feasible to meet the patient’s protein


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InternalMed_Harrison. 600 mL of 15% amino acids, 300 mL of 50% dextrose, and 100 mL of electrolyte/micronutrient mix contains 75 g of protein substrate and 800 kcal; thus it is feasible to meet the patient’s protein requirement with only 1.4–1.9 L of solution and a more appropriate 1100–1520 kcal; any mild gap in energy provision is easily filled by use of intravenous lipid.


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InternalMed_Harrison. COMPLICATIONS Mechanical The insertion of a central venous catheter should be performed by trained and experienced personnel using aseptic techniques to limit the major common complications of pneumothorax and inadvertent arterial puncture or injury. The catheter’s position should be radiographically confirmed to be in the superior vena cava distal to the junction with the jugular or subclavian vein and not directly against the vessel wall. Thrombosis related to the catheter may occur at the site of entry into the vein and extend to encase the catheter. Catheter infection predisposes to thrombosis, as does the SRI. The addition of 6000 U of heparin to the daily parenteral formula for hospitalized patients with temporary catheters reduces the risk of fibrin sheath formation and catheter infection. Temporary catheters that develop a thrombus should be removed and, according to clinical findings, treated with anticoagulants. Thrombolytic therapy can be considered for patients with


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InternalMed_Harrison. infection. Temporary catheters that develop a thrombus should be removed and, according to clinical findings, treated with anticoagulants. Thrombolytic therapy can be considered for patients with permanent catheters, depending on the ease of replacement and the presence of alternative, reasonably acceptable venous access sites. Low-dose warfarin therapy (1 mg/d) reduces the risk of thrombosis in permanent catheters used for at-home parenteral SNS, but full anticoagulation may be required for patients who have recurrent thrombosis related to permanent catheters. A recent U.S. Food and Drug Administration mandate to reformulate parenteral multivitamins to include vitamin K at a dose of 150 μg/d may affect the efficacy of low-dose warfarin therapy. A “no vitamin K” version is available for patients receiving this therapy. Catheters can become occluded due to mechanical factors; by fibrin at the tip; or by fat, minerals, or drugs intraluminally. These occlusions can be managed with


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InternalMed_Harrison. for patients receiving this therapy. Catheters can become occluded due to mechanical factors; by fibrin at the tip; or by fat, minerals, or drugs intraluminally. These occlusions can be managed with low-dose alteplase for fibrin, with indwelling 70% alcohol for fat, with 0.1 N hydrochloric acid for mineral precipitates, and with either 0.1 N hydrochloric acid or 0.1 N sodium hydroxide for drugs, depending on the pH of the drug.


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InternalMed_Harrison. Metabolic The most common problems caused by parenteral SNS are fluid overload and hyperglycemia (Table 98e-7). Hypertonic dextrose stimulates a much higher insulin level than meal feeding. Because insulin is a potent antinatriuretic and antidiuretic hormone, Corrective Action Disturbance Cause with PN longed periods. Abbreviation: PN, parenteral nutrition.


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InternalMed_Harrison. hyperinsulinemia leads to sodium and fluid retention. Consequently, 98e-7 in the absence of gastrointestinal losses or renal dysfunction, net fluid retention is likely when total fluid intake exceeds 2000 mL/d. Close monitoring of body mass as well as of fluid intake and output is necessary to prevent this complication. In the absence of significant renal impairment, the sodium content of the urine is likely to be <10 meq/L. Provision of sodium in limited amounts (40 meq/d) and the use of both glucose and fat in the PN mixture will reduce serum glucose levels and help reduce fluid retention. The elevated insulin level also increases the intracellular transport of potassium, magnesium, and phosphorus, which can precipitate a dangerous re-feeding syndrome if the total glucose content of the PN solution is advanced too quickly in severely malnourished patients. To assess glucose tolerance, it is generally best to start PN with <200 g of glucose/d. Regular insulin can be added to the PN


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InternalMed_Harrison. PN solution is advanced too quickly in severely malnourished patients. To assess glucose tolerance, it is generally best to start PN with <200 g of glucose/d. Regular insulin can be added to the PN formula to establish glycemic control, and the insulin doses can be increased proportionately as the glucose content is advanced. As a general rule, patients with insulin-dependent diabetes require about twice their usual at-home insulin dose when receiving PN at 20–25 kcal/kg, largely as a consequence of parenteral glucose administration and some loss of insulin to the formula’s container. As a rough estimate, the amount of insulin provided can be proportionately similar to the number of calories provided as total parenteral nutrition (TPN) relative to full feeding, and the insulin can be placed in the TPN formula. Subcutaneous regular insulin can be provided to improve glucose control as assessed by measurements of blood glucose every 6 h. About two-thirds of the total 24-h amount can be


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InternalMed_Harrison. in the TPN formula. Subcutaneous regular insulin can be provided to improve glucose control as assessed by measurements of blood glucose every 6 h. About two-thirds of the total 24-h amount can be added to the next day’s order, with SC insulin supplements as needed. Advances in the TPN glucose concentration should be made when reasonable glucose control is established, and the insulin dose can be adjusted proportionately to the calories added as glucose and amino acids. These are general rules, and they are conservative. Given the adverse clinical impact of hyperglycemia, it may be necessary to use intensive insulin therapy as a separate infusion with a standard protocol to initially establish control. Once control is established, this insulin dose can be added to the PN formula. Acid-base imbalance is also common during parenteral SNS. Amino acid formulas are buffered, but critically ill patients are prone to metabolic acidosis, often due to renal tubular impairment. The use of


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InternalMed_Harrison. imbalance is also common during parenteral SNS. Amino acid formulas are buffered, but critically ill patients are prone to metabolic acidosis, often due to renal tubular impairment. The use of sodium and potassium acetate salts in the PN formula may address this problem. Bicarbonate salts should not be used because they are incompatible with TPN formulations. Nasogastric drainage produces hypochloremic alkalosis that can be managed by attention to chloride balance. Occasionally, hydrochloric acid may be required for a more rapid response or when diuretic therapy limits the ability to provide substantial sodium chloride. Up to 100 meq/L and up to 150 meq of hydrochloric acid per day may be placed in a fat-free TPN formula.


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InternalMed_Harrison. Infectious Infections of the central access catheter rarely occur in the first 72 h. Fever during this period is usually attributable to infection elsewhere or another cause. Fever that develops during parenteral SNS can be addressed by checking the catheter site and, if the site looks clean, exchanging the catheter over a wire, with cultures taken through the catheter and at the catheter tip. If these cultures are negative, as they usually are, the new catheter can continue to be used. If a culture is positive for a relatively nonpathogenic bacterium like Staphylococcus epidermidis, a second exchange over a wire with repeat cultures or replacement of the catheter can be considered in light of the clinical circumstances. If cultures are positive for more pathogenic bacteria or for fungi like Candida albicans, it is generally best to replace the catheter at a new site. Whether antibiotic treatment is required is a clinical decision, but C. albicans grown from the blood culture in a


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InternalMed_Harrison. like Candida albicans, it is generally best to replace the catheter at a new site. Whether antibiotic treatment is required is a clinical decision, but C. albicans grown from the blood culture in a patient receiving PN should always be treated with an antifungal drug because the consequences of failure to treat can be dire.


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InternalMed_Harrison. Catheter infections can be minimized by dedicating the feeding catheter to TPN, without blood sampling or medication administration. Central catheter infections are a serious complication, with an attributed mortality rate of 12–25%. Fewer than three infections per 1000 catheter-days should occur in central venous catheters dedicated to feeding. At-home TPN catheter infections may be treated through 98e-8 the catheter without its removal, particularly if the offending organism is S. epidermidis. Clearing of the biofilm and fibrin sheath by local treatment of the catheter with indwelling alteplase may increase the likelihood of eradication. Antibiotic lock therapy with high concentrations of antibiotic, with or without heparin in addition to systemic therapy, may improve efficacy. Sepsis with hypotension should precipitate catheter removal in either the temporary or the permanent TPN setting.


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InternalMed_Harrison. The types of enteral feeding tubes, methods of insertion, their clinical uses, and potential complications are outlined in Table 98e-8. The different types of enteral formulas are listed in Table 98e-9. Patients receiving EN are at risk for many of the same metabolic complications as those who receive PN and should be monitored in the same manner. EN can be a source of similar problems, but not to the same degree, because the insulin response to EN is about half of that to PN. Enteral feeding formulas have fixed electrolyte compositions that are generally modest in sodium and somewhat higher in potassium. Acid-base disturbances can be addressed to a more limited extent with EN.


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InternalMed_Harrison. External measurement: Short-term clinical situ-Aspiration; ulceration nostril, ear, xiphister-ation (weeks) or longer of nasal and esophanum; tube stiffened by periods with intermit-geal tissues, leading to ice water or stylet; posi-tent insertion; bolus stricture tion verified by air injec-feeding is simpler, but tion and auscultation or continuous drip with by x-ray pump is better tolerated External measurement: Short-term clinical Spontaneous pulling nostril, ear, anterior situations where gastric back into stomach superior iliac spine; tube emptying is impaired (position verified by stiffened by stylet and or proximal leak is aspirating content, pH passed through pylorus suspected; requires con->6); diarrhea common, under fluoroscopy or tinuous drip with pump fiber-containing formuwith endoscopic loop


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InternalMed_Harrison. Percutaneous place-Long-term clinical Aspiration; irritation ment endoscopically, situations, swallowing around tube exit site; radiologically, or surgi-disorders, or impaired peritoneal leak; balloon cally; after track is estab-small-bowel absorption migration and obstruclished, can be converted requiring continuous tion of pylorus to a gastric “button” drip Percutaneous place-Long-term clinical Clogging or displacement endoscopically or situations where gastric ment of tube; jejunal radiologically via pylorus emptying is impaired; fistula if large-bore tube or endoscopically or requires continuous drip is used; diarrhea from surgically directly into with pump; direct endo-dumping; irritation the jejunum scopic placement (PEJ) of surgical anchoring Abbreviation: PEJ, percutaneous endoscopic jejunostomy.


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InternalMed_Harrison. Abbreviation: PEJ, percutaneous endoscopic jejunostomy. Note: All small tubes are at risk for clogging, especially if used for crushed medications. In long-term enteral nutrition patients, gastrostomy and jejunostomy tubes can be exchanged for a low-profile “button” once the track is established. Source: Adapted from the chapter on this topic in Harrison’s Principles of Internal Medicine, 16e, by Lyn Howard, MD. 1. Caloric density: 1 kcal/mL 2. Protein: ~14% cals (caseinates, soy, lactalbumin) 3. Carbohydrate: ~60% cals (hydrolyzed corn starch, maltodextrin, sucrose) 4. Fat: ~30% cals (corn, soy, safflower oils) 5. Recommended daily intake of all minerals and vitamins in >1500 kcal/d 6. Osmolality: ~300 mosmol/kg 1. Caloric density: 1.5–2 kcal/mL (+) Fluid-restricted patients 2. a. b. Hydrolyzed protein to small Impaired absorption peptides (+) c. ↑ Arginine, glutamine, Immune-enhancing diets nucleotides, ω3 fat (+++) d.


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InternalMed_Harrison. a. b. Hydrolyzed protein to small Impaired absorption peptides (+) c. ↑ Arginine, glutamine, Immune-enhancing diets nucleotides, ω3 fat (+++) d. ↑ Branched-chain amino acids, Liver failure patients intolerant of aromatic amino acids (+++) 0.8 g of protein/kg e. Low protein of high biologic Renal failure patients for brief periods value if critically ill 3. Fat a. b. ↑ Fat (>40% cals) (++) Pulmonary failure with CO2 retention on standard formula, limited utility c. d. 4. Fiber: provided as soy Improved laxation polysaccharide (+) aCost: +, inexpensive; ++, moderately expensive; +++, very expensive. Note: ARDS, acute respiratory distress syndrome; MCT, medium-chain triglyceride; MUFA, monounsaturated fatty acids; ω3 or ω6, polyunsaturated fat with first double bond at carbon 3 (fish oils) or carbon 6 (vegetable oils). Source: Adapted from the chapter on this topic in Harrison’s Principles of Internal Medicine, 16e, by Lyn Howard, MD.


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InternalMed_Harrison. Source: Adapted from the chapter on this topic in Harrison’s Principles of Internal Medicine, 16e, by Lyn Howard, MD. Acetate salts can be added to the formula to treat chronic metabolic acidosis. Calcium chloride can be added to treat mild chronic metabolic alkalosis. Medications and other additives to enteral feeding formulas can clog the tubes (e.g., calcium chloride may interact with casein-based formulas to form insoluble calcium caseinate products) and may reduce the efficacy of some drugs (e.g., phenytoin). Since small-bore tubes are easily displaced, tube position should be checked at intervals by aspirating and measuring the pH of the gut fluid (normal: <4 in the stomach, >6 in the jejunum).


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InternalMed_Harrison. COMPLICATIONS Aspiration The debilitated patient with poor gastric emptying and impairment of swallowing and cough is at risk for aspiration; this complication is particularly common among patients who are mechanically ventilated. Tracheal suctioning induces coughing and gastric regurgitation, and cuffs on endotracheal or tracheostomy tubes seldom protect against aspiration. Preventive measures include elevating the head of the bed to 30°, using nurse-directed algorithms for formula advancement, combining enteral with parenteral feeding, and using post–ligament of Treitz feeding. Tube feeding should not be discontinued for gastric residuals of <300 mL unless there are other signs of gastrointestinal intolerance, such as nausea, vomiting, or abdominal distention. Continuous feeding using pumps is better tolerated intragastrically than bolus feeding and is essential for feeding into the jejunum. For small-bowel feeding, residuals are not assessed, but abdominal pain and distention


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InternalMed_Harrison. pumps is better tolerated intragastrically than bolus feeding and is essential for feeding into the jejunum. For small-bowel feeding, residuals are not assessed, but abdominal pain and distention should be monitored.


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InternalMed_Harrison. Diarrhea Enteral feeding often leads to diarrhea, especially if bowel function is compromised by disease or drugs (most often, broad-spectrum antibiotics). Sorbitol used to flavor some medications can also cause diarrhea. Diarrhea may be controlled by the use of a continuous drip, with a fiber-containing formula, or by the addition of an antidiarrheal agent to the formula. However, Clostridium difficile, which is a common cause of diarrhea in patients being tube-fed, should be ruled out as the etiology before antidiarrheal agents are used. H2 blockers may help reduce the net volume of fluid presented to the colon. Diarrhea associated with enteral feeding does not necessarily imply inadequate absorption of nutrients other than water and electrolytes. Amino acids and glucose are particularly well absorbed in the upper small bowel except in the most diseased or shortest bowel. Since luminal nutrients exert trophic effects on the gut mucosa, it is often appropriate to persist with tube


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InternalMed_Harrison. well absorbed in the upper small bowel except in the most diseased or shortest bowel. Since luminal nutrients exert trophic effects on the gut mucosa, it is often appropriate to persist with tube feeding despite diarrhea, even when this course necessitates supplemental parenteral fluid support.


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InternalMed_Harrison. Apart from conditions with drastically diminished small-intestinal 98e-9 absorptive function, there are no established indications for short peptide–based or elemental formulas.


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InternalMed_Harrison. In the United States, the only parenteral lipid emulsion avail able is made with soybean oil, whose constituent fatty acids have been suggested to be immunosuppressive under certain circumstances. In Europe and Japan, a number of other lipid emulsions are available, including those containing fish oil only; mixtures of fish oil, medium-chain triglycerides, and long-chain triglycerides as olive oil and/or soybean oil; mixtures of medium-chain triglycerides and long-chain triglycerides as soybean oil; and long-chain triglyceride mixtures as olive oil and soybean oil, which may be more beneficial in terms of metabolism and hepatic and immune function. Furthermore, a glutamine-containing dipeptide for inclusion in TPN formulas is available in Europe and may be helpful in terms of immune function and resistance to infection, although a recent study using a largerthan-recommended dose was associated with net harm.


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InternalMed_Harrison. The authors acknowledge the contributions of Lyn Howard, MD, the author in earlier editions of HPIM, to material in this chapter.


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InternalMed_Harrison. approach to the patient with Cancer Dan L. Longo The application of current treatment techniques (surgery, radiation therapy, chemotherapy, and biologic therapy) results in the cure of nearly two of three patients diagnosed with 99 seCtion 1 cancer. Nevertheless, patients experience the diagnosis of cancer as one of the most traumatic and revolutionary events that has ever happened to them. Independent of prognosis, the diagnosis brings with it a change in a person’s self-image and in his or her role in the home and workplace. The prognosis of a person who has just been found to have pancreatic cancer is the same as the prognosis of the person with aortic stenosis who develops the first symptoms of congestive heart failure (median survival, ~8 months). However, the patient with heart disease may remain functional and maintain a self-image as a fully intact person with just a malfunctioning part, a diseased organ (“a bum ticker”). By contrast, the patient with pancreatic cancer has a


InternalMed_Harrison

InternalMed_Harrison. may remain functional and maintain a self-image as a fully intact person with just a malfunctioning part, a diseased organ (“a bum ticker”). By contrast, the patient with pancreatic cancer has a completely altered self-image and is viewed differently by family and anyone who knows the diagnosis. He or she is being attacked and invaded by a disease that could be anywhere in the body. Every ache or pain takes on desperate significance. Cancer is an exception to the coordinated interaction among cells and organs. In general, the cells of a multicellular organism are programmed for collaboration. Many diseases occur because the specialized cells fail to perform their assigned task. Cancer takes this malfunction one step further. Not only is there a failure of the cancer cell to maintain its specialized function, but it also strikes out on its own; the cancer cell competes to survive using natural mutability and natural selection to seek advantage over normal cells in a recapitulation of


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InternalMed_Harrison. specialized function, but it also strikes out on its own; the cancer cell competes to survive using natural mutability and natural selection to seek advantage over normal cells in a recapitulation of evolution. One consequence of the traitorous behavior of cancer cells is that the patient feels betrayed by his or her body. The cancer patient feels that he or she, and not just a body part, is diseased.


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InternalMed_Harrison. No nationwide cancer registry exists; therefore, the incidence of cancer is estimated on the basis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, which tabulates cancer incidence and death figures from 13 sites, accounting for about 10% of the U.S. population, and from population data from the U.S. Census Bureau. In 2014, 1.665 million new cases of invasive cancer (855,220 men, 810,320 women) were diagnosed, and 585,720 persons (310,010 men, 275,710 women) died from cancer. The percent distribution of new cancer cases and cancer deaths by site for men and women is shown in Table 99-1. Cancer incidence has been declining by about 2% each year since 1992. Cancer is the cause of one in four deaths in the United States.


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InternalMed_Harrison. The most significant risk factor for cancer overall is age; two-thirds of all cases were in those older than age 65 years. Cancer incidence increases as the third, fourth, or fifth power of age in different sites. For the interval between birth and age 49 years, 1 in 29 men and 1 in 19 women will develop cancer; for the interval between ages 50 and 59 years, 1 in 15 men and 1 in 17 women will develop cancer; for the interval between ages 60 and 69 years, 1 in 6 men and 1 in 10 women will develop cancer; and for people age 70 and older, 1 in 3 men and 1 in 4 women will develop cancer. Overall, men have a 44% risk of developing cancer at some time during their lives; women have a 38% lifetime risk. Source: From R Siegel et al: Cancer statistics, 2014. CA Cancer J Clin 64:9, 2014.


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InternalMed_Harrison. Cancer is the second leading cause of death behind heart disease. Deaths from heart disease have declined 45% in the United States since 1950 and continue to decline. Cancer has overtaken heart disease as the number one cause of death in persons younger than age 85 years. Incidence trends over time are shown in Fig. 99-1. After a 70-year period of increase, cancer deaths began to decline in 1990–1991 (Fig. 99-2). Between 1990 and 2010, cancer deaths decreased by 21% among men and 12.3% among women. The magnitude of the decline is illustrated in Fig. 99-3. The five leading causes of cancer deaths are shown for various populations in Table 99-2. The 5-year survival for white patients was 39% in 1960–1963 and 69% in 2003–2009. Cancers are more often deadly in blacks; the 5-year survival was 61% for the 2003–2009 interval; however, the racial differences are narrowing over time. Incidence and mortality vary among racial and ethnic groups (Table 99-3). The basis for these differences is


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InternalMed_Harrison. 61% for the 2003–2009 interval; however, the racial differences are narrowing over time. Incidence and mortality vary among racial and ethnic groups (Table 99-3). The basis for these differences is unclear.


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InternalMed_Harrison. In 2008, 12.7 million new cancer cases and 7.6 million cancer deaths were estimated worldwide, according to estimates of GLOBOCAN 2008, developed by the International Agency for Research on Cancer (IARC). When broken down by region of the world, ~45% of cases were in Asia, 26% in Europe, 14.5% in North America, 7.1% in Central/South America, 6% in Africa, and 1% in Australia/New Zealand (Fig. 99-4). Lung cancer is the most common cancer and the most common cause of cancer death in the world. Its Approach to the Patient with Cancer Rate per 100,000 population Year of diagnosis Year of diagnosis


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InternalMed_Harrison. FIGURE 99-1 Incidence rates for particular types of cancer over the last 35 years in men (A) and women (B). (From R Siegel et al: CA Cancer J Clin 64:9, 2014.) incidence is highly variable, affecting only 2 per 100,000 African women but as many as 61 per 100,000 North American men. Breast cancer is the second most common cancer worldwide; however, it ranks fifth as a cause of death behind lung, stomach, liver, and colorectal cancer. Among the eight most common forms of cancer, lung (2-fold), breast (3-fold), prostate (2.5-fold), and colorectal (3-fold) cancers are more common in more developed countries than in less developed countries. By contrast, liver (2-fold), cervical (2-fold), and esophageal (2to 3-fold) cancers are more common in less developed countries. Stomach cancer incidence is similar in more and less developed countries but is much more common in Asia than North America or Africa. The most common cancers in Africa are cervical, breast, and liver cancers. It has been


InternalMed_Harrison

InternalMed_Harrison. is similar in more and less developed countries but is much more common in Asia than North America or Africa. The most common cancers in Africa are cervical, breast, and liver cancers. It has been estimated that nine modifiable risk factors are responsible for more than one-third of cancers worldwide. These include smoking, alcohol consumption, obesity, physical inactivity, low fruit and vegetable consumption, unsafe sex, air pollution, indoor smoke from household fuels, and contaminated injections.


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InternalMed_Harrison. Important information is obtained from every portion of the routine history and physical examination. The duration of symptoms may reveal the chronicity of disease. The past medical history may alert the physician to the presence of underlying diseases that may affect the choice of therapy or the side effects of treatment. The social history may reveal occupational exposure to carcinogens or habits, such as smoking or alcohol consumption, that may influence the course of disease and its treatment. The family history may suggest an underlying familial cancer predisposition and point out the need to begin surveillance or other preventive therapy for unaffected siblings of the patient. The review of systems may suggest early symptoms of metastatic disease or a paraneoplastic syndrome.


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InternalMed_Harrison. The diagnosis of cancer relies most heavily on invasive tissue biopsy and should never be made without obtaining tissue; no noninvasive diagnostic test is sufficient to define a disease process as cancer. Although in rare clinical settings (e.g., thyroid nodules), fine-needle aspiration is an acceptable diagnostic procedure, the diagnosis generally depends on obtaining adequate tissue to permit careful evaluation of the histology of the tumor, its grade, and its invasiveness and to yield further molecular diagnostic information, such as the expression of cell-surface markers or intracellular proteins that typify a particular cancer, or the presence of a molecular marker, such as the t(8;14) translocation of Burkitt’s lymphoma. Increasing evidence links the expression of certain genes with the prognosis and response to therapy (Chaps. 101e and 102e).


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InternalMed_Harrison. Occasionally a patient will present with a metastatic disease process that is defined as cancer on biopsy but has no apparent primary site of disease. Efforts should be made to define the primary site based on age, sex, sites of involvement, histology and tumor markers, and personal and family history. Particular attention should be focused on ruling out the most treatable causes (Chap. 120e). Once the diagnosis of cancer is made, the management of the patient is best undertaken as a multidisciplinary collaboration among the primary care physician, medical oncologists, surgical oncologists, radiation oncologists, oncology nurse specialists, pharmacists, social workers, rehabilitation medicine specialists, and a number of other consulting professionals working closely with each other and with the patient and family. Deaths per 100,000 women 0 20 40 60 C. Females, by site 80 100 Ovary Lung and bronchus Colorectum Uterus Breast Pancreas Stomach


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InternalMed_Harrison. Deaths per 100,000 women 0 20 40 60 C. Females, by site 80 100 Ovary Lung and bronchus Colorectum Uterus Breast Pancreas Stomach Deaths per 100,000 men Deaths per 100,000 people A. All sites combined B. Males, by site 1930 1940 1950 1960 1970 1980 1990 2000 2010 Year of death FIGURE 99-2 Eighty-year trend in cancer death rates for (A) women and (B) men by site in the United States, 1930–2010. Rates are per 100,000 age-adjusted to the 2000 U.S. standard population. All sites combined (A), individual sites in men (B) and individual sites in women (C) are shown. (From R Siegel et al: CA Cancer J Clin 64:9, 2014.)


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InternalMed_Harrison. Approach to the Patient with Cancer histologic examination of all tissues removed during the surgical procedure. Surgical procedures performed may include a simple lymph node biopsy or more extensive procedures such as thoracotomy, mediastinoscopy, or laparotomy. Surgical staging may occur in a separate procedure or may be done at the time of definitive surgical resection of the primary tumor. 60–69 Knowledge of the predilection of particular tumors for spreading to adjacent or distant organs helps direct the staging evaluation.


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InternalMed_Harrison. 60–69 Knowledge of the predilection of particular tumors for spreading to adjacent or distant organs helps direct the staging evaluation. 50–59 Information obtained from staging is used to define the extent of disease as localized, as exhibiting spread outside of the organ of origin to regional 40–49 but not distant sites, or as metastatic to distant sites. The most widely used system of staging is the TNM (tumor, node, metastasis) system codified by the International Union Against Cancer and the American Joint Committee on Cancer. The TNM classification is an anatomically based system that categorizes the tumor on the basis of the size of the primary tumor lesion (T1–4, where a higher number indicates a tumor of larger size), the presence of nodal involvement (usually N0 and N1 for the absence and presence, respectively, of involved nodes, although some tumors have more elaborate systems of nodal grading), and the presence of metastatic disease (M0


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InternalMed_Harrison. FIGURE 99-3 The decline in death rates from cancer is shown for different age ranges and M1 for the absence and presence, respectively, by sex and race for the 20-year period between 1991 and 2010 expressed as a percent-of metastases). The various permutations of T, N, age of the 1991 rate. (From R Siegel et al: CA Cancer J Clin 64:9, 2014.) The first priority in patient management after the diagnosis of cancer is established and shared with the patient is to determine the extent of disease. The curability of a tumor usually is inversely proportional to the tumor burden. Ideally, the tumor will be diagnosed before symptoms develop or as a consequence of screening efforts (Chap. 100). A very high proportion of such patients can be cured. However, most patients with cancer present with symptoms related to the cancer, caused either by mass effects of the tumor or by alterations associated with the production of cytokines or hormones by the tumor.


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InternalMed_Harrison. For most cancers, the extent of disease is evaluated by a variety of noninvasive and invasive diagnostic tests and procedures. This process is called staging. There are two types. Clinical staging is based on physical examination, radiographs, isotopic scans, computed tomography (CT) scans, and other imaging procedures; pathologic staging takes into account information obtained during a surgical procedure, which might include intraoperative palpation, resection of regional lymph nodes and/or tissue adjacent to the tumor, and inspection and biopsy of organs commonly involved in disease spread. Pathologic staging includes and M scores (sometimes including tumor histologic grade [G]) are then broken into stages, usually desig nated by the roman numerals I through IV. Tumor burden increases and curability decreases with increasing stage. Other anatomic staging systems are used for some tumors, e.g., the Dukes classification for colorectal cancers, the International Federation of


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InternalMed_Harrison. and curability decreases with increasing stage. Other anatomic staging systems are used for some tumors, e.g., the Dukes classification for colorectal cancers, the International Federation of Gynecologists and Obstetricians classification for gynecologic cancers, and the Ann Arbor classification for Hodgkin’s disease.


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InternalMed_Harrison. Certain tumors cannot be grouped on the basis of anatomic considerations. For example, hematopoietic tumors such as leukemia, myeloma, and lymphoma are often disseminated at presentation and do not spread like solid tumors. For these tumors, other prognostic factors have been identified (Chaps. 132-136).


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InternalMed_Harrison. In addition to tumor burden, a second major determinant of treatment outcome is the physiologic reserve of the patient. Patients who are bedridden before developing cancer are likely to fare worse, stage for stage, than fully active patients. Physiologic reserve is a determinant of how a patient is likely to cope with the physiologic stresses imposed by the cancer and its treatment. This factor is difficult to assess directly. Instead, surrogate markers for physiologic reserve are used, such as the patient’s age or Karnofsky performance status (Table 99-4) or Eastern Cooperative Oncology Group (ECOG) performance status the five LeaDing primary tumor sites for patients Dying of CanCer BaseD on age anD sex in 2010 Age, years 471taBLe 99-3 CanCer inCiDenCe anD mortaLity in raCiaL anD ethniC groups, uniteD states, 2006–2010 All M 217.3 276.6 132.4 191.0 152.2 F 153.6 171.2 92.1 139.0 101.3 Breast 22.7 30.8 11.5 15.5 14.8 Colorectal M 19.2 28.7 13.1 18.7 16.1


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InternalMed_Harrison. All M 217.3 276.6 132.4 191.0 152.2 F 153.6 171.2 92.1 139.0 101.3 Breast 22.7 30.8 11.5 15.5 14.8 Colorectal M 19.2 28.7 13.1 18.7 16.1 F 13.6 19.0 9.7 15.4 10.2 Kidney M 5.9 5.7 3.0 9.5 5.1 F 2.6 2.6 1.2 4.4 2.3 Liver M 7.1 11.8 14.4 13.2 12.3 F 2.9 4.1 6.0 6.1 5.4 Lung M 65.7 78.5 35.5 49.6 31.3 F 42.7 37.2 18.4 33.1 14.1 Prostate 21.3 50.9 10.1 20.7 19.2 Cervix 2.1 4.2 1.9 3.5 2.9 aBased on Indian Health Service delivery areas. Abbreviations: F, female; M, male. Source: From R Siegel R et al: Cancer statistics, 2014. CA Cancer J Clin 64:9, 2014. (Table 99-5). Older patients and those with a Karnofsky performance treatment is of the utmost importance in treatment planning. For some status <70 or ECOG performance status ≥3 have a poor prognosis cancers, chemotherapy or chemotherapy plus radiation therapy delivunless the poor performance is a reversible consequence of the tumor. ered before the use of definitive surgical treatment (so-called neoadju-


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InternalMed_Harrison. Increasingly, biologic features of the tumor are being related to prog-vant therapy) may improve the outcome, as seems to be the case for nosis. The expression of particular oncogenes, drug-resistance genes, locally advanced breast cancer and head and neck cancers. In certain apoptosis-related genes, and genes involved in metastasis is being settings in which combined-modality therapy is intended, coordinafound to influence response to therapy and prognosis. The presence tion among the medical oncologist, radiation oncologist, and surgeon of selected cytogenetic abnormalities may influence survival. Tumors is crucial to achieving optimal results. Sometimes the chemotherapy with higher growth fractions, as assessed by expression of proliferation-and radiation therapy need to be delivered sequentially, and other related markers such as proliferating cell nuclear antigen, behave more times concurrently. Surgical procedures may precede or follow other aggressively than tumors with lower


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InternalMed_Harrison. sequentially, and other related markers such as proliferating cell nuclear antigen, behave more times concurrently. Surgical procedures may precede or follow other aggressively than tumors with lower growth fractions. Information treatment approaches. It is best for the treatment plan either to follow obtained from studying the tumor itself will increasingly be used to a standard protocol precisely or else to be part of an ongoing clinical influence treatment decisions. Host genes involved in drug metabolism research protocol evaluating new treatments. Ad hoc modifications of can influence the safety and efficacy of particular treatments. standard protocols are likely to compromise treatment results.


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InternalMed_Harrison. Enormous heterogeneity has been noted by studying tumors; we The choice of treatment approaches was formerly dominated by the have learned that morphology is not capable of discerning certain local culture in both the university and the practice settings. However, distinct subsets of patients whose tumors have different sets of abnor-it is now possible to gain access electronically to standard treatment malities. Tumors that look the same by light microscopy can be very protocols and to every approved clinical research study in North different. Similarly, tumors that look quite different from one another America through a personal computer interface with the Internet.1 histologically can share genetic lesions that predict responses to treatments. Furthermore, tumor cells vary enormously within a single 1The National Cancer Institute maintains a database called PDQ (Physician patient even though the cells share a common origin. Data Query) that is accessible on the Internet under the


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InternalMed_Harrison. within a single 1The National Cancer Institute maintains a database called PDQ (Physician patient even though the cells share a common origin. Data Query) that is accessible on the Internet under the name CancerNet at www.cancer.gov/cancertopics/pdq/cancerdatabase. Information can be obtained MAKING A TREATMENT PLAN through a facsimile machine using CancerFax by dialing 301-402-5874. Patient From information on the extent of disease and the prognosis and information is also provided by the National Cancer Institute in at least in conjunction with the patient’s wishes, it is determined whether three formats: on the Internet via CancerNet at www.cancer.gov, through the the treatment approach should be curative or palliative in intent. CancerFax number listed above, or by calling 1-800-4-CANCER. The quality Cooperation among the various professionals involved in cancer control for the information provided through these services is rigorous.


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Approach to the Patient with Cancer

InternalMed_Harrison. Approach to the Patient with Cancer


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InternalMed_Harrison. Because cancer therapies are toxic (Chap. 103e), patient manage ment involves addressing complications of both the disease and its treatment as well as the complex psychosocial problems asso ciated with cancer. In the short term during a course of curative therapy, the patient’s functional status may decline. Treatment induced toxicity is less acceptable if the goal of therapy is palliation. The most common side effects of treatment are nausea 453.3 270.1385.3 246.3 378.1 302.3 358.2 285.2 354.0 273.5265.9 348.0 288.0 332.9 240.7 332.0 239.7 331.8 266.3 325.2 204.8 299.0 251.1 298.5 187.2 293.8 246.4 290.6 246.7 288.0 270.7 283.0 274.3 281.9 162.7 276.2 220.9 272.2 221.3 265.6 224.2 260.3 212.1 259.6 190.7 256.2 227.9 251.7 189.5 224.0 211.2 223.9 174.1 221.5 189.7 209.8 205.0 202.6 194.9 200.9 114.7 162.3 187.9 156.1 119.3 153.6 171.4155.4148.9 114.6105.386.3 80.3 Females Males and vomiting (see below), febrile neutropenia (Chap. 104), and myelosuppression (Chap. 103e). Tools are now


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InternalMed_Harrison. 200.9 114.7 162.3 187.9 156.1 119.3 153.6 171.4155.4148.9 114.6105.386.3 80.3 Females Males and vomiting (see below), febrile neutropenia (Chap. 104), and myelosuppression (Chap. 103e). Tools are now available to minimize the acute toxicity of cancer treatment.


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InternalMed_Harrison. New symptoms developing in the course of cancer treatment should always be assumed to be reversible until proven other wise. The fatalistic attribution of anorexia, weight loss, and jaun dice to recurrent or progressive tumor could result in a patient dying from a reversible intercurrent cholecystitis. Intestinal obstruction may be due to reversible adhesions rather than progressive tumor. Systemic infections, sometimes with unusual pathogens, may be a consequence of the immunosuppression associated with cancer therapy. Some drugs used to treat cancer or its complications (e.g., nausea) may produce central nervous Rate per 100,000 paraneoplastic syndromes such as the syndrome of inappropriate antidiuretic hormone. A definitive diagnosis should be pursued and may even require a repeat biopsy.


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InternalMed_Harrison. Rate per 100,000 paraneoplastic syndromes such as the syndrome of inappropriate antidiuretic hormone. A definitive diagnosis should be pursued and may even require a repeat biopsy. A critical component of cancer management is assessing the response to treatment. In addition to a careful physical examination in which all sites of disease are physically measured and recorded in a flow chart by date, response assessment usually requires periodic repeating of imaging tests that were abnormal


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InternalMed_Harrison. Algeria, SetifIndia, ChennaiEcuador, QuitoUganda, KyadondoEgypt, GharbiahPakistan, South KarachiTurkey, IzmirZimbabwe, Harare: AfricanPhilippines, ManilaSingaporeChina, ShanghaiColombia, CaliRussia, St PetersburgArgentina, Bahia BlancaChina, Hong KongBrazil, GoianiaPoland, CracowFinlandUSA, SEER 14 (Hispanic)KoreaDenmarkIsraelThe NetherlandsNorwayJapan, MiyagiUK, Merseyside and CheshireSpain, NavarraCanadaCzech RepublicGermany, SaarlandItaly, ParmaSwitzerland, GenevaAustralia, SouthNew ZealandUSA, SEER 14 (White)France, Bas-RhinUSA, SEER 14 (Black)


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InternalMed_Harrison. Incidence (n = 10,864,499) Mortality (n = 6,724,931) Prevalence (n = 24,576,453) at the time of staging. If imaging tests have become normal, repeat biopsy of previously involved tissue is performed to docu-FIGURE 99-4 Worldwide overall annual cancer incidence, mortality, and ment complete response by pathologic criteria. Biopsies are not5-year prevalence for the period of 1993–2001. (Adapted from A Jemal et al: usually required if there is macroscopic residual disease. A com- Cancer Epidemiol Biomarkers Prev 19:1893, 2010.)


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InternalMed_Harrison. Cancer Epidemiol Biomarkers Prev 19:1893, 2010.) The skilled physician also has much to offer the patient for whom curative therapy is no longer an option. Often a combination of guilt and frustration over the inability to cure the patient and the pressure of a busy schedule greatly limit the time a physician spends with a patient who is receiving only palliative care. Resist these forces. In addition to the medicines administered to alleviate symptoms (see below), it is important to remember the comfort that is provided by holding the patient’s hand, continuing regular examinations, and taking time to talk.


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InternalMed_Harrison. plete response is defined as disappearance of all evidence of disease, and a partial response as >50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions. The determination of partial response may also be based on a 30% decrease in the sums of the longest diameters of lesions (Response Evaluation Criteria in Solid Tumors [RECIST]). Progressive disease is defined as the appearance of any new lesion or an increase of >25% in the sum of the products of the perpendicular diameters of all measurable lesions (or an increase of 20% in the sums of the longest diameters by RECIST). Tumor shrinkage or growth that does not meet any of these criteria is considered stable disease. Some sites of involvement (e.g., bone) or patterns of involvement (e.g., lymphangitic lung or diffuse pulmonary infiltrates) are considered unmeasurable. No response is complete without biopsy documentation of their resolution, but partial responses may exclude their assessment


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InternalMed_Harrison. lung or diffuse pulmonary infiltrates) are considered unmeasurable. No response is complete without biopsy documentation of their resolution, but partial responses may exclude their assessment unless clear objective progression has occurred.


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InternalMed_Harrison. Status Functional Capability of the Patient 100 Normal; no complaints; no evidence of disease 90 Able to carry on normal activity; minor signs or symptoms of disease 80 Normal activity with effort; some signs or symptoms of Cares for self; unable to carry on normal activity or do the eastern Cooperative onCoLogy group (eCog) ECOG Grade 0: Fully active, able to carry on all predisease performance with out restriction ECOG Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work ECOG Grade 2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours


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InternalMed_Harrison. ECOG Grade 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours ECOG Grade 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair ECOG Grade 5: Dead Source: From MM Oken et al: Am J Clin Oncol 5:649, 1982. Human chorionic Gestational trophoblas-Pregnancy gonadotropin tic disease, gonadal Calcitonin Medullary cancer of the thyroid α Fetoprotein Hepatocellular carci-Cirrhosis, hepatitis noma, gonadal germ cell tumor Carcinoembryonic Adenocarcinomas of the Pancreatitis, hepatitis, antigen colon, pancreas, lung, inflammatory bowel breast, ovary disease, smoking Prostatic acid phos-Prostate cancer Prostatitis, prostatic phatase Neuron-specific enolase Small-cell cancer of the lung, neuroblastoma Lactate dehydrogenase Lymphoma, Ewing’s Hepatitis, hemolytic sarcoma anemia, many others Abbreviation: MGUS, monoclonal gammopathy of uncertain significance.


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InternalMed_Harrison. Lactate dehydrogenase Lymphoma, Ewing’s Hepatitis, hemolytic sarcoma anemia, many others Abbreviation: MGUS, monoclonal gammopathy of uncertain significance. Tumor markers may be useful in patient management in certain tumors. Response to therapy may be difficult to gauge with certainty. However, some tumors produce or elicit the production of markers that can be measured in the serum or urine, and in a particular patient, rising and falling levels of the marker are usually associated with increasing or decreasing tumor burden, respectively. Some clinically useful tumor markers are shown in Table 99-6. Tumor markers are not in themselves specific enough to permit a diagnosis of malignancy to be made, but once a malignancy has been diagnosed and shown to be associated with elevated levels of a tumor marker, the marker can be used to assess response to treatment.


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InternalMed_Harrison. The recognition and treatment of depression are important components of management. The incidence of depression in cancer patients is ~25% overall and may be greater in patients with greater debility. This diagnosis is likely in a patient with a depressed mood (dysphoria) and/or a loss of interest in pleasure (anhedonia) for at least 2 weeks. In addition, three or more of the following symptoms are usually present: appetite change, sleep problems, psychomotor retardation or agitation, fatigue, feelings of guilt or worthlessness, inability to concentrate, and suicidal ideation. Patients with these symptoms should receive therapy. Medical therapy with a serotonin reuptake inhibitor such as fluoxetine (10–20 mg/d), sertraline (50–150 mg/d), or paroxetine (10–20 mg/d) or a tricyclic antidepressant such as amitriptyline (50–100 mg/d) or desipramine (75–150 mg/d) should be tried, allowing 4–6 weeks for response. Effective therapy should be continued at least 6 months after resolution of


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InternalMed_Harrison. such as amitriptyline (50–100 mg/d) or desipramine (75–150 mg/d) should be tried, allowing 4–6 weeks for response. Effective therapy should be continued at least 6 months after resolution of symptoms. If therapy is unsuccessful, other classes of antidepressants may be used. In addition to medication, psychosocial interventions such as support groups, psychotherapy, and guided 473 imagery may be of benefit.


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InternalMed_Harrison. Many patients opt for unproven or unsound approaches to treatment when it appears that conventional medicine is unlikely to be curative. Those seeking such alternatives are often well educated and may be early in the course of their disease. Unsound approaches are usually hawked on the basis of unsubstantiated anecdotes and not only cannot help the patient but may be harmful. Physicians should strive to keep communications open and nonjudgmental, so that patients are more likely to discuss with the physician what they are actually doing. The appearance of unexpected toxicity may be an indication that a supplemental therapy is being taken.2


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InternalMed_Harrison. At the completion of treatment, sites originally involved with tumor are reassessed, usually by radiography or imaging techniques, and any persistent abnormality is biopsied. If disease persists, the multidisciplinary team discusses a new salvage treatment plan. If the patient has been rendered disease-free by the original treatment, the patient is followed regularly for disease recurrence. The optimal guidelines for follow-up care are not known. For many years, a routine practice has been to follow the patient monthly for 6–12 months, then every other month for a year, every 3 months for a year, every 4 months for a year, every 6 months for a year, and then annually. At each visit, a battery of laboratory and radiographic and imaging tests were obtained on the assumption that it is best to detect recurrent disease before it becomes symptomatic. However, where follow-up procedures have been examined, this assumption has been found to be untrue. Studies of breast cancer, melanoma, lung


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InternalMed_Harrison. detect recurrent disease before it becomes symptomatic. However, where follow-up procedures have been examined, this assumption has been found to be untrue. Studies of breast cancer, melanoma, lung cancer, colon cancer, and lymphoma have all failed to support the notion that asymptomatic relapses are more readily cured by salvage therapy than symptomatic relapses. In view of the enormous cost of a full battery of diagnostic tests and their manifest lack of impact on survival, new guidelines are emerging for less frequent follow-up visits, during which the history and physical examination are the major investigations performed.


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InternalMed_Harrison. As time passes, the likelihood of recurrence of the primary cancer diminishes. For many types of cancer, survival for 5 years without recurrence is tantamount to cure. However, important medical problems can occur in patients treated for cancer and must be examined (Chap. 125). Some problems emerge as a consequence of the disease and some as a consequence of the treatment. An understanding of these diseaseand treatment-related problems may help in their detection and management. Despite these concerns, most patients who are cured of cancer return to normal lives.


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InternalMed_Harrison. Despite these concerns, most patients who are cured of cancer return to normal lives. In many ways, the success of cancer therapy depends on the success of the supportive care. Failure to control the symptoms of cancer and its treatment may lead patients to abandon curative therapy. Of equal importance, supportive care is a major determinant of quality of life. Even when life cannot be prolonged, the physician must strive to preserve its quality. Quality-of-life measurements have become common endpoints of clinical research studies. Furthermore, palliative care has been shown to be cost-effective when approached in an organized fashion. A credo for oncology could be to cure sometimes, to extend life often, and to comfort always.


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InternalMed_Harrison. Pain Pain occurs with variable frequency in the cancer patient: 25–50% of patients present with pain at diagnosis, 33% have pain associated with treatment, and 75% have pain with progressive disease. The pain may have several causes. In ~70% of cases, pain is caused by the tumor itself—by invasion of bone, nerves, blood vessels, or mucous 2Information about unsound methods may be obtained from the National Council Against Health Fraud, Box 1276, Loma Linda, CA 92354, or from the Center for Medical Consumers and Health Care Information, 237 Thompson Street, New York, NY 10012.


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InternalMed_Harrison. Approach to the Patient with Cancer 474 membranes or obstruction of a hollow viscus or duct. In ~20% of cases, pain is related to a surgical or invasive medical procedure, to radiation injury (mucositis, enteritis, or plexus or spinal cord injury), or to chemotherapy injury (mucositis, peripheral neuropathy, phlebitis, steroid-induced aseptic necrosis of the femoral head). In 10% of cases, pain is unrelated to cancer or its treatment. Assessment of pain requires the methodical investigation of the history of the pain, its location, character, temporal features, provocative and palliative factors, and intensity (Chap. 18); a review of the oncologic history and past medical history as well as personal and social history; and a thorough physical examination. The patient should be given a 10-division visual analogue scale on which to indicate the severity of the pain. The clinical condition is often dynamic, making it necessary to reassess the patient frequently. Pain therapy should not


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InternalMed_Harrison. visual analogue scale on which to indicate the severity of the pain. The clinical condition is often dynamic, making it necessary to reassess the patient frequently. Pain therapy should not be withheld while the cause of pain is being sought. A variety of tools are available with which to address cancer pain. About 85% of patients will have pain relief from pharmacologic intervention. However, other modalities, including antitumor therapy (such as surgical relief of obstruction, radiation therapy, and strontium-89 or samarium-153 treatment for bone pain), neurostimulatory techniques, regional analgesia, or neuroablative procedures, are effective in an additional 12% or so. Thus, very few patients will have inadequate pain relief if appropriate measures are taken. A specific approach to pain relief is detailed in Chap. 10.


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InternalMed_Harrison. Nausea Emesis in the cancer patient is usually caused by chemotherapy (Chap. 103e). Its severity can be predicted from the drugs used to treat the cancer. Three forms of emesis are recognized on the basis of their timing with regard to the noxious insult. Acute emesis, the most common variety, occurs within 24 h of treatment. Delayed emesis occurs 1–7 days after treatment; it is rare, but, when present, usually follows cisplatin administration. Anticipatory emesis occurs before administration of chemotherapy and represents a conditioned response to visual and olfactory stimuli previously associated with chemotherapy delivery.


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InternalMed_Harrison. Acute emesis is the best understood form. Stimuli that activate signals in the chemoreceptor trigger zone in the medulla, the cerebral cortex, and peripherally in the intestinal tract lead to stimulation of the vomiting center in the medulla, the motor center responsible for coordinating the secretory and muscle contraction activity that leads to emesis. Diverse receptor types participate in the process, including dopamine, serotonin, histamine, opioid, and acetylcholine receptors. The serotonin receptor antagonists ondansetron and granisetron are the most effective drugs against highly emetogenic agents, but they are expensive.


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InternalMed_Harrison. As with the analgesia ladder, emesis therapy should be tailored to the situation. For mildly and moderately emetogenic agents, prochlorperazine, 5–10 mg PO or 25 mg PR, is effective. Its efficacy may be enhanced by administering the drug before the chemotherapy is delivered. Dexamethasone, 10–20 mg IV, is also effective and may enhance the efficacy of prochlorperazine. For highly emetogenic agents such as cisplatin, mechlorethamine, dacarbazine, and streptozocin, combinations of agents work best and administration should begin 6–24 h before treatment. Ondansetron, 8 mg PO every 6 h the day before therapy and IV on the day of therapy, plus dexamethasone, 20 mg IV before treatment, is an effective regimen. Addition of oral aprepitant (a substance P/neurokinin 1 receptor antagonist) to this regimen (125 mg on day 1, 80 mg on days 2 and 3) further decreases the risk of both acute and delayed vomiting. Like pain, emesis is easier to prevent than to alleviate.


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InternalMed_Harrison. Delayed emesis may be related to bowel inflammation from the therapy and can be controlled with oral dexamethasone and oral metoclopramide, a dopamine receptor antagonist that also blocks serotonin receptors at high dosages. The best strategy for preventing anticipatory emesis is to control emesis in the early cycles of therapy to prevent the conditioning from taking place. If this is unsuccessful, prophylactic antiemetics the day before treatment may help. Experimental studies are evaluating behavior modification.


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InternalMed_Harrison. Effusions Fluid may accumulate abnormally in the pleural cavity, pericardium, or peritoneum. Asymptomatic malignant effusions may not require treatment. Symptomatic effusions occurring in tumors responsive to systemic therapy usually do not require local treatment but respond to the treatment for the underlying tumor. Symptomatic effusions occurring in tumors unresponsive to systemic therapy may require local treatment in patients with a life expectancy of at least 6 months.


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InternalMed_Harrison. Pleural effusions due to tumors may or may not contain malignant cells. Lung cancer, breast cancer, and lymphomas account for ~75% of malignant pleural effusions. Their exudative nature is usually gauged by an effusion/serum protein ratio of ≥0.5 or an effusion/serum lactate dehydrogenase ratio of ≥0.6. When the condition is symptomatic, thoracentesis is usually performed first. In most cases, symptomatic improvement occurs for <1 month. Chest tube drainage is required if symptoms recur within 2 weeks. Fluid is aspirated until the flow rate is <100 mL in 24 h. Then either 60 units of bleomycin or 1 g of doxycycline is infused into the chest tube in 50 mL of 5% dextrose in water; the tube is clamped; the patient is rotated on four sides, spending 15 min in each position; and, after 1–2 h, the tube is again attached to suction for another 24 h. The tube is then disconnected from suction and allowed to drain by gravity. If <100 mL drains over the next 24 h, the chest tube is pulled, and


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InternalMed_Harrison. the tube is again attached to suction for another 24 h. The tube is then disconnected from suction and allowed to drain by gravity. If <100 mL drains over the next 24 h, the chest tube is pulled, and a radiograph is taken 24 h later. If the chest tube continues to drain fluid at an unacceptably high rate, sclerosis can be repeated. Bleomycin may be somewhat more effective than doxycycline but is very expensive. Doxycycline is usually the drug of first choice. If neither doxycycline nor bleomycin is effective, talc can be used.


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InternalMed_Harrison. Symptomatic pericardial effusions are usually treated by creating a pericardial window or by stripping the pericardium. If the patient’s condition does not permit a surgical procedure, sclerosis can be attempted with doxycycline and/or bleomycin. Malignant ascites is usually treated with repeated paracentesis of small volumes of fluid. If the underlying malignancy is unresponsive to systemic therapy, peritoneovenous shunts may be inserted. Despite the fear of disseminating tumor cells into the circulation, widespread metastases are an unusual complication. The major complications are occlusion, leakage, and fluid overload. Patients with severe liver disease may develop disseminated intravascular coagulation.


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InternalMed_Harrison. Nutrition Cancer and its treatment may lead to a decrease in nutrient intake of sufficient magnitude to cause weight loss and alteration of intermediary metabolism. The prevalence of this problem is difficult to estimate because of variations in the definition of cancer cachexia, but most patients with advanced cancer experience weight loss and decreased appetite. A variety of both tumor-derived factors (e.g., bombesin, adrenocorticotropic hormone) and host-derived factors (e.g., tumor necrosis factor, interleukins 1 and 6, growth hormone) contribute to the altered metabolism, and a vicious cycle is established in which protein catabolism, glucose intolerance, and lipolysis cannot be reversed by the provision of calories.


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InternalMed_Harrison. It remains controversial how to assess nutritional status and when and how to intervene. Efforts to make the assessment objective have included the use of a prognostic nutritional index based on albumin levels, triceps skinfold thickness, transferrin levels, and delayed-type hypersensitivity skin testing. However, a simpler approach has been to define the threshold for nutritional intervention as <10% unexplained body weight loss, serum transferrin level <1500 mg/L (150 mg/dL), and serum albumin <34 g/L (3.4 g/dL).


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InternalMed_Harrison. The decision is important, because it appears that cancer therapy is substantially more toxic and less effective in the face of malnutrition. Nevertheless, it remains unclear whether nutritional intervention can alter the natural history. Unless some pathology is affecting the absorptive function of the gastrointestinal tract, enteral nutrition provided orally or by tube feeding is preferred over parenteral supplementation. However, the risks associated with the tube may outweigh the benefits. Megestrol acetate, a progestational agent, has been advocated as a pharmacologic intervention to improve nutritional status. Research in this area may provide more tools in the future as cytokinemediated mechanisms are further elucidated.


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InternalMed_Harrison. Psychosocial Support The psychosocial needs of patients vary with their situation. Patients undergoing treatment experience fear, anxiety, and depression. Self-image is often seriously compromised by deforming surgery and loss of hair. Women who receive cosmetic advice that enables them to look better also feel better. Loss of control over how one spends time can contribute to the sense of vulnerability. Juggling the demands of work and family with the demands of treatment may create enormous stresses. Sexual dysfunction is highly prevalent and needs to be discussed openly with the patient. An empathetic health care team is sensitive to the individual patient’s needs and permits negotiation where such flexibility will not adversely affect the course of treatment.


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InternalMed_Harrison. Cancer survivors have other sets of difficulties. Patients may have fears associated with the termination of a treatment they associate with their continued survival. Adjustments are required to physical losses and handicaps, real and perceived. Patients may be preoccupied with minor physical problems. They perceive a decline in their job mobility and view themselves as less desirable workers. They may be victims of job and/or insurance discrimination. Patients may experience difficulty reentering their normal past life. They may feel guilty for having survived and may carry a sense of vulnerability to colds and other illnesses. Perhaps the most pervasive and threatening concern is the ever-present fear of relapse (the Damocles syndrome). Patients in whom therapy has been unsuccessful have other problems related to the end of life.


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InternalMed_Harrison. Death and Dying The most common causes of death in patients with cancer are infection (leading to circulatory failure), respiratory failure, hepatic failure, and renal failure. Intestinal blockage may lead to inanition and starvation. Central nervous system disease may lead to seizures, coma, and central hypoventilation. About 70% of patients develop dyspnea preterminally. However, many months usually pass between the diagnosis of cancer and the occurrence of these complications, and during this period, the patient is severely affected by the possibility of death. The path of unsuccessful cancer treatment usually occurs in three phases. First, there is optimism at the hope of cure; when the tumor recurs, there is the acknowledgment of an incurable disease, and the goal of palliative therapy is embraced in the hope of being able to live with disease; finally, at the disclosure of imminent death, another adjustment in outlook takes place. The patient imagines the worst in preparation


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InternalMed_Harrison. is embraced in the hope of being able to live with disease; finally, at the disclosure of imminent death, another adjustment in outlook takes place. The patient imagines the worst in preparation for the end of life and may go through stages of adjustment to the diagnosis. These stages include denial, isolation, anger, bargaining, depression, acceptance, and hope. Of course, patients do not all progress through all the stages or proceed through them in the same order or at the same rate. Nevertheless, developing an understanding of how the patient has been affected by the diagnosis and is coping with it is an important goal of patient management.


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InternalMed_Harrison. It is best to speak frankly with the patient and the family regarding the likely course of disease. These discussions can be difficult for the physician as well as for the patient and family. The critical features of the interaction are to reassure the patient and family that everything that can be done to provide comfort will be done. They will not be abandoned. Many patients prefer to be cared for in their homes or in a hospice setting rather than a hospital. The American College of Physicians has published a book called Home Care Guide for Cancer: How to Care for Family and Friends at Home that teaches an approach to successful problem-solving in home care. With appropriate planning, it should be possible to provide the patient with the necessary medical care as well as the psychological and spiritual support that will prevent the isolation and depersonalization that can attend in-hospital death.


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InternalMed_Harrison. The care of dying patients may take a toll on the physician. A “burnout” syndrome has been described that is characterized by fatigue, disengagement from patients and colleagues, and a loss of self-fulfillment. Efforts at stress reduction, maintenance of a balanced life, and setting realistic goals may combat this disorder.


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InternalMed_Harrison. End-of-Life Decisions Unfortunately, a smooth transition in treatment goals from curative to palliative may not be possible in all cases because of the occurrence of serious treatment-related complications or rapid disease progression. Vigorous and invasive medical support for a reversible disease or treatment complication is assumed to be justified. However, if the reversibility of the condition is in doubt, 475 the patient’s wishes determine the level of medical care. These wishes should be elicited before the terminal phase of illness and reviewed periodically. Information about advance directives can be obtained from the American Association of Retired Persons, 601 E Street, NW, Washington, DC 20049, 202-434-2277, or Choice in Dying, 250 West 57th Street, New York, NY 10107, 212-366-5540. Some states allow physicians to assist patients who choose to end their lives. This subject is challenging from an ethical and a medical point of view. Discussions of end-of-life decisions should


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InternalMed_Harrison. Some states allow physicians to assist patients who choose to end their lives. This subject is challenging from an ethical and a medical point of view. Discussions of end-of-life decisions should be candid and involve clear informed consent, waiting periods, second opinions, and documentation. A full discussion of end-of-life management is in Chap. 10.


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InternalMed_Harrison. Jennifer M. Croswell, Otis W. Brawley, Barnett S. Kramer Improved understanding of carcinogenesis has allowed cancer prevention and early detection (also known as cancer control) to expand beyond the identification and avoidance of carcinogens. Specific interventions to prevent cancer in those at risk, and effective screening for early detection of cancer, are the goals. Carcinogenesis is not an event but a process, a continuum of discrete tissue and cellular changes over time resulting in aberrant physiologic processes. Prevention concerns the identification and manipulation of the biologic, environmental, social, and genetic factors in the causal pathway of cancer.


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InternalMed_Harrison. Public education on the avoidance of identified risk factors for cancer and encouraging healthy habits contributes to cancer prevention and control. The clinician is a powerful messenger in this process. The patient-provider encounter provides an opportunity to teach patients about the hazards of smoking, the features of a healthy lifestyle, use of proven cancer screening methods, and avoidance of excessive sun exposure. Tobacco smoking is a strong, modifiable risk factor for cardiovascular disease, pulmonary disease, and cancer. Smokers have an approximately 1 in 3 lifetime risk of dying prematurely from a tobacco-related cancer, cardiovascular, or pulmonary disease. Tobacco use causes more deaths from cardiovascular disease than from cancer. Lung cancer and cancers of the larynx, oropharynx, esophagus, kidney, bladder, pancreas, and stomach are all tobacco-related.


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InternalMed_Harrison. The number of cigarettes smoked per day and the level of inhalation of cigarette smoke are correlated with risk of lung cancer mortality. Lightand low-tar cigarettes are not safer, because smokers tend to inhale them more frequently and deeply. Those who stop smoking have a 30–50% lower 10-year lung cancer mortality rate compared to those who continue smoking, despite the fact that some carcinogen-induced gene mutations persist for years after smoking cessation. Smoking cessation and avoidance would save more lives than any other public health activity. The risk of tobacco smoke is not limited to the smoker. Environmental tobacco smoke, known as secondhand or passive smoke, causes lung cancer and other cardiopulmonary diseases in nonsmokers.


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InternalMed_Harrison. The risk of tobacco smoke is not limited to the smoker. Environmental tobacco smoke, known as secondhand or passive smoke, causes lung cancer and other cardiopulmonary diseases in nonsmokers. Tobacco use prevention is a pediatric issue. More than 80% of adult American smokers began smoking before the age of 18 years. Approximately 20% of Americans in grades 9 through 12 have smoked a cigarette in the past month. Counseling of adolescents and young adults is critical to prevent smoking. A clinician’s simple advice can be of benefit. Providers should query patients on tobacco use and offer smokers assistance in quitting.


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InternalMed_Harrison. Prevention and Early Detection of Cancer 476 Current approaches to smoking cessation recognize smoking as an addiction (Chap. 470). The smoker who is quitting goes through identifiable stages that include contemplation of quitting, an action phase in which the smoker quits, and a maintenance phase. Smokers who quit completely are more likely to be successful than those who gradually reduce the number of cigarettes smoked or change to lower-tar or lower-nicotine cigarettes. More than 90% of the Americans who have successfully quit smoking did so on their own, without participation in an organized cessation program, but cessation programs are helpful for some smokers. The Community Intervention Trial for Smoking Cessation (COMMIT) was a 4-year program showing that light smokers (<25 cigarettes per day) were more likely to benefit from simple cessation messages and cessation programs than those who did not receive an intervention. Quit rates were 30.6% in the intervention group and 27.5%


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InternalMed_Harrison. per day) were more likely to benefit from simple cessation messages and cessation programs than those who did not receive an intervention. Quit rates were 30.6% in the intervention group and 27.5% in the control group. The COMMIT interventions were unsuccessful in heavy smokers (<25 cigarettes per day). Heavy smokers may need an intensive broad-based cessation program that includes counseling, behavioral strategies, and pharmacologic adjuncts, such as nicotine replacement (gum, patches, sprays, lozenges, and inhalers), bupropion, and/or varenicline. The health risks of cigars are similar to those of cigarettes. Smoking one or two cigars daily doubles the risk for oral and esophageal cancers; smoking three or four cigars daily increases the risk of oral cancers more than eightfold and esophageal cancer fourfold. The risks of occasional use are unknown. Smokeless tobacco also represents a substantial health risk. Chewing tobacco is a carcinogen linked to dental caries, gingivitis, oral


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InternalMed_Harrison. cancer fourfold. The risks of occasional use are unknown. Smokeless tobacco also represents a substantial health risk. Chewing tobacco is a carcinogen linked to dental caries, gingivitis, oral leukoplakia, and oral cancer. The systemic effects of smokeless tobacco (including snuff) may increase risks for other cancers. Esophageal cancer is linked to carcinogens in tobacco dissolved in saliva and swallowed. The net effects of e-cigarettes on health are poorly studied. Whether they aid in smoking cessation or serve as a “gateway” for nonsmoking children to acquire a smoking habit is debated.


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InternalMed_Harrison. Physical activity is associated with a decreased risk of colon and breast cancer. A variety of mechanisms have been proposed. However, such studies are prone to confounding factors such as recall bias, association of exercise with other health-related practices, and effects of preclinical cancers on exercise habits (reverse causality). International epidemiologic studies suggest that diets high in fat are associated with increased risk for cancers of the breast, colon, prostate, and endometrium. These cancers have their highest incidence and mortalities in Western cultures, where fat composes an average of one-third of the total calories consumed.


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InternalMed_Harrison. Despite correlations, dietary fat has not been proven to cause cancer. Case-control and cohort epidemiologic studies give conflicting results. In addition, diet is a highly complex exposure to many nutrients and chemicals. Low-fat diets are associated with many dietary changes beyond simple subtraction of fat. Other lifestyle changes are also associated with adherence to a low-fat diet.


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InternalMed_Harrison. In observational studies, dietary fiber is associated with a reduced risk of colonic polyps and invasive cancer of the colon. However, cancer-protective effects of increasing fiber and lowering dietary fat have not been proven in the context of a prospective clinical trial. The putative protective mechanisms are complex and speculative. Fiber binds oxidized bile acids and generates soluble fiber products, such as butyrate, that may have differentiating properties. Fiber does not increase bowel transit times. Two large prospective cohort studies of >100,000 health professionals showed no association between fruit and vegetable intake and risk of cancer. The Polyp Prevention Trial randomly assigned 2000 elderly persons, who had polyps removed, to a low-fat, high-fiber diet versus routine diet for 4 years. No differences were noted in polyp formation.


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InternalMed_Harrison. The U.S. National Institutes of Health Women’s Health Initiative, launched in 1994, was a long-term clinical trial enrolling >100,000 women age 45–69 years. It placed women in 22 intervention groups. Participants received calcium/vitamin D supplementation; hormone replacement therapy; and counseling to increase exercise, eat a low-fat diet with increased consumption of fruits, vegetables, and fiber, and cease smoking. The study showed that although dietary fat intake was lower in the diet intervention group, invasive breast cancers were not reduced over an 8-year follow-up period compared to the control group. No reduction was seen in the incidence of colorectal cancer in the dietary intervention arm. The difference in dietary fat averaged ∼10% between the two groups. Evidence does not currently establish the anticarcinogenic value of vitamin, mineral, or nutritional supplements in amounts greater than those provided by a balanced diet.


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InternalMed_Harrison. Risk of cancer appears to increase as body mass index increases beyond 25 kg/m2. Obesity is associated with increased risk for cancers of the colon, breast (female postmenopausal), endometrium, kidney (renal cell), and esophagus, although causality has not been established. In observational studies, relative risks of colon cancer are increased in obesity by 1.5–2 for men and 1.2–1.5 for women. Obese postmenopausal women have a 30–50% increased relative risk of breast cancer. An unproven hypothesis for the association is that adipose tissue serves as a depot for aromatase that facilitates estrogen production.


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InternalMed_Harrison. Nonmelanoma skin cancers (basal cell and squamous cell) are induced by cumulative exposure to ultraviolet (UV) radiation. Intermittent acute sun exposure and sun damage have been linked to melanoma, but the evidence is inconsistent. Sunburns, especially in childhood and adolescence, may be associated with an increased risk of melanoma in adulthood. Reduction of sun exposure through use of protective clothing and changing patterns of outdoor activities can reduce skin cancer risk. Sunscreens decrease the risk of actinic keratoses, the precursor to squamous cell skin cancer, but melanoma risk may not be reduced. Sunscreens prevent burning, but they may encourage more prolonged exposure to the sun and may not filter out wavelengths of energy that cause melanoma.


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InternalMed_Harrison. Educational interventions to help individuals assess their risk of developing skin cancer have some impact. In particular, appearance-focused behavioral interventions in young women can decrease indoor tanning use and other UV exposures. Self-examination for skin pigment characteristics associated with skin cancer, such as freckling, may be useful in identifying people at high risk. Those who recognize themselves as being at risk tend to be more compliant with sun-avoidance recommendations. Risk factors for melanoma include a propensity to sunburn, a large number of benign melanocytic nevi, and atypical nevi. Chemoprevention involves the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenesis before the development of invasive malignancy.


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InternalMed_Harrison. Cancer develops through an accumulation of tissue abnormalities associated with genetic and epigenetic changes, and growth regulatory pathways that are potential points of intervention to prevent cancer. The initial changes are termed initiation. The alteration can be inherited or acquired through the action of physical, infectious, or chemical carcinogens. Like most human diseases, cancer arises from an interaction between genetics and environmental exposures (Table 100-1). Influences that cause the initiated cell and its surrounding tissue microenvironment to progress through the carcinogenic process and change phenotypically are termed promoters. Promoters include hormones such as androgens, linked to prostate cancer, and estrogen, linked to breast and endometrial cancer. The distinction between an initiator and promoter is indistinct; some components of cigarette smoke are “complete carcinogens,” acting as both initiators and promoters. Cancer can be prevented or controlled


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InternalMed_Harrison. between an initiator and promoter is indistinct; some components of cigarette smoke are “complete carcinogens,” acting as both initiators and promoters. Cancer can be prevented or controlled through interference with the factors that cause cancer initiation, promotion, or progression. Compounds of interest in chemoprevention often have antimutagenic, hormone modulation, anti-inflammatory, antiproliferative, or proapoptotic activity (or a combination).


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InternalMed_Harrison. Alkylating agents Acute myeloid leukemia, bladder cancer Androgens Prostate cancer Aromatic amines (dyes) Bladder cancer Arsenic Cancer of the lung, skin Asbestos Cancer of the lung, pleura, peritoneum Benzene Acute myelocytic leukemia Chromium Lung cancer Diethylstilbestrol (prenatal) Vaginal cancer (clear cell) Epstein-Barr virus Burkitt’s lymphoma, nasal T cell lymphoma Estrogens Cancer of the endometrium, liver, breast Ethyl alcohol Cancer of the breast, liver, esophagus, head and neck Helicobacter pylori Gastric cancer, gastric MALT lymphoma Hepatitis B or C virus Liver cancer Human immunodeficiency Non-Hodgkin’s lymphoma, Kaposi’s sarcoma, virus squamous cell carcinomas (especially of the urogenital tract) Human papilloma virus Cancers of the cervix, anus, oropharynx Human T cell lymphotropic Adult T cell leukemia/lymphoma virus type 1 (HTLV-1) Immunosuppressive agents Non-Hodgkin’s lymphoma (azathioprine, cyclosporine, glucocorticoids)


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InternalMed_Harrison. Immunosuppressive agents Non-Hodgkin’s lymphoma (azathioprine, cyclosporine, glucocorticoids) Ionizing radiation (thera-Breast, bladder, thyroid, soft tissue, bone, peutic or diagnostic) hematopoietic, and many more Nitrogen mustard gas Cancer of the lung, head and neck, nasal sinuses Nickel dust Cancer of the lung, nasal sinuses Diesel exhaust Lung cancer (miners) Phenacetin Cancer of the renal pelvis and bladder Polycyclic hydrocarbons Cancer of the lung, skin (especially squamous cell carcinoma of scrotal skin) Radon gas Lung cancer Schistosomiasis Bladder cancer (squamous cell) Sunlight (ultraviolet) Skin cancer (squamous cell and melanoma) Tobacco (including Cancer of the upper aerodigestive tract, smokeless) bladder Vinyl chloride Liver cancer (angiosarcoma) aAgents that are thought to act as cancer initiators and/or promoters.


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InternalMed_Harrison. Vinyl chloride Liver cancer (angiosarcoma) aAgents that are thought to act as cancer initiators and/or promoters. Smoking causes diffuse epithelial injury in the oral cavity, neck, esophagus, and lung. Patients cured of squamous cell cancers of the lung, esophagus, oral cavity, and neck are at risk (as high as 5% per year) of developing second cancers of the upper aerodigestive tract. Cessation of cigarette smoking does not markedly decrease the cured cancer patient’s risk of second malignancy, even though it does lower the cancer risk in those who have never developed a malignancy. Smoking cessation may halt the early stages of the carcinogenic process (such as metaplasia), but it may have no effect on late stages of carcinogenesis. This “field carcinogenesis” hypothesis for upper aerodigestive tract cancer has made “cured” patients an important population for chemoprevention of second malignancies.


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InternalMed_Harrison. Oral human papilloma virus (HPV) infection, particularly HPV-16, increases the risk for cancers of the oropharynx. This association exists even in the absence of other risk factors such as smoking or alcohol use (although the magnitude of increased risk appears greater than additive when HPV infection and smoking are both present). Oral HPV infection is believed to be largely sexually acquired. Although no direct evidence currently exists to confirm the hypothesis, the introduction of the HPV vaccine may eventually reduce oropharyngeal cancer rates.


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InternalMed_Harrison. Oral leukoplakia, a premalignant lesion commonly found in smokers, has been used as an intermediate marker of chemopreventive activity in smaller shorter-duration, randomized, placebo-controlled 477 trials. Response was associated with upregulation of retinoic acid receptor-β (RAR-β). Therapy with high, relatively toxic doses of isotretinoin (13-cis-retinoic acid) causes regression of oral leukoplakia. However, the lesions recur when the therapy is withdrawn, suggesting the need for long-term administration. More tolerable doses of isotretinoin have not shown benefit in the prevention of head and neck cancer. Isotretinoin also failed to prevent second malignancies in patients cured of early-stage non-small cell lung cancer; mortality rates were actually increased in current smokers.


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InternalMed_Harrison. Several large-scale trials have assessed agents in the chemoprevention of lung cancer in patients at high risk. In the α-tocopherol/βcarotene (ATBC) Lung Cancer Prevention Trial, participants were male smokers, age 50–69 years at entry. Participants had smoked an average of one pack of cigarettes per day for 35.9 years. Participants received α-tocopherol, β-carotene, and/or placebo in a randomized, two-by-two factorial design. After median follow-up of 6.1 years, lung cancer incidence and mortality were statistically significantly increased in those receiving β-carotene. α-Tocopherol had no effect on lung cancer mortality, and no evidence suggested interaction between the two drugs. Patients receiving α-tocopherol had a higher incidence of hemorrhagic stroke.


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InternalMed_Harrison. The β-Carotene and Retinol Efficacy Trial (CARET) involved 17,000 American smokers and workers with asbestos exposure. Entrants were randomly assigned to one of four arms and received β-carotene, retinol, and/or placebo in a two-by-two factorial design. This trial also demonstrated harm from β-carotene: a lung cancer rate of 5 per 1000 subjects per year for those taking placebo and of 6 per 1000 subjects per year for those taking β-carotene. The ATBC and CARET results demonstrate the importance of testing chemoprevention hypotheses thoroughly before their widespread implementation because the results contradict a number of observational studies. The Physicians’ Health Trial showed no change in the risk of lung cancer for those taking β-carotene; however, fewer of its participants were smokers than those in the ATBC and CARET studies.


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InternalMed_Harrison. Many colon cancer prevention trials are based on the premise that most colorectal cancers develop from adenomatous polyps. These trials use adenoma recurrence or disappearance as a surrogate endpoint (not yet validated) for colon cancer prevention. Early clinical trial results suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), such as piroxicam, sulindac, and aspirin, may prevent adenoma formation or cause regression of adenomatous polyps. The mechanism of action of NSAIDs is unknown, but they are presumed to work through the cyclooxygenase pathway. Although two randomized controlled trials (the Physicians’ Health Study and the Women’s Health Study) did not show an effect of aspirin on colon cancer or adenoma incidence in persons with no previous history of colonic lesions after 10 years of therapy, these trials did show an approximately 18% relative risk reduction for colonic adenoma incidence in persons with a previous history of adenomas after 1 year. Pooled findings from


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InternalMed_Harrison. 10 years of therapy, these trials did show an approximately 18% relative risk reduction for colonic adenoma incidence in persons with a previous history of adenomas after 1 year. Pooled findings from observational cohort studies do demonstrate a 22% and 28% relative reduction in colorectal cancer and adenoma incidence, respectively, with regular aspirin use, and a well-conducted meta-analysis of four randomized controlled trials (albeit primarily designed to examine aspirin’s effects on cardiovascular events) found that aspirin at doses of at least 75 mg resulted in a 24% relative reduction in colorectal cancer incidence after 20 years, with no clear increase in efficacy at higher doses. Cyclooxygenase-2 (COX-2) inhibitors have also been considered for colorectal cancer and polyp prevention. Trials with COX-2 inhibitors were initiated, but an increased risk of cardiovascular events in those taking the COX-2 inhibitors was noted, suggesting that these agents are not suitable for


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InternalMed_Harrison. Trials with COX-2 inhibitors were initiated, but an increased risk of cardiovascular events in those taking the COX-2 inhibitors was noted, suggesting that these agents are not suitable for chemoprevention in the general population.


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InternalMed_Harrison. Epidemiologic studies suggest that diets high in calcium lower colon cancer risk. Calcium binds bile and fatty acids, which cause proliferation of colonic epithelium. It is hypothesized that calcium reduces intraluminal exposure to these compounds. The randomized controlled Calcium Polyp Prevention Study found that calcium supplementation


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InternalMed_Harrison. Prevention and Early Detection of Cancer 478 decreased the absolute risk of adenomatous polyp recurrence by 7% at 4 years; extended observational follow-up demonstrated a 12% absolute risk reduction 5 years after cessation of treatment. However, in the Women’s Health Initiative, combined use of calcium carbonate and vitamin D twice daily did not reduce the incidence of invasive colorectal cancer compared with placebo after 7 years. The Women’s Health Initiative demonstrated that postmenopausal women taking estrogen plus progestin have a 44% lower relative risk of colorectal cancer compared to women taking placebo. Of >16,600 women randomized and followed for a median of 5.6 years, 43 invasive colorectal cancers occurred in the hormone group and 72 in the placebo group. The positive effect on colon cancer is mitigated by the modest increase in cardiovascular and breast cancer risks associated with combined estrogen plus progestin therapy. A case-control study suggested that statins


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InternalMed_Harrison. on colon cancer is mitigated by the modest increase in cardiovascular and breast cancer risks associated with combined estrogen plus progestin therapy. A case-control study suggested that statins decrease the incidence of colorectal cancer; however, several subsequent case-control and cohort studies have not demonstrated an association between regular statin use and a reduced risk of colorectal cancer. No randomized controlled trials have addressed this hypothesis. A meta-analysis of statin use showed no protective effect of statins on overall cancer incidence or death.


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InternalMed_Harrison. Tamoxifen is an antiestrogen with partial estrogen agonistic activity in some tissues, such as endometrium and bone. One of its actions is to upregulate transforming growth factor β, which decreases breast cell proliferation. In randomized placebo-controlled trials to assess tamoxifen as adjuvant therapy for breast cancer, tamoxifen reduced the number of new breast cancers in the opposite breast by more than a third. In a randomized placebo-controlled prevention trial involving >13,000 preand postmenopausal women at high risk, tamoxifen decreased the risk of developing breast cancer by 49% (from 43.4 to 22 per 1000 women) after a median follow-up of nearly 6 years. Tamoxifen also reduced bone fractures; a small increase in risk of endometrial cancer, stroke, pulmonary emboli, and deep vein thrombosis was noted. The International Breast Cancer Intervention Study (IBIS-I) and the Italian Randomized Tamoxifen Prevention Trial also demonstrated a reduction in breast cancer incidence with


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InternalMed_Harrison. thrombosis was noted. The International Breast Cancer Intervention Study (IBIS-I) and the Italian Randomized Tamoxifen Prevention Trial also demonstrated a reduction in breast cancer incidence with tamoxifen use. A trial comparing tamoxifen with another selective estrogen receptor modulator, raloxifene, in postmenopausal women showed that raloxifene is comparable to tamoxifen in cancer prevention. This trial only included postmenopausal women. Raloxifene was associated with more invasive breast cancers and a trend toward more noninvasive breast cancers, but fewer thromboembolic events than tamoxifen; the drugs are similar in risks of other cancers, fractures, ischemic heart disease, and stroke. Both tamoxifen and raloxifene (the latter for post-menopausal women only) have been approved by the U.S. Food and Drug Administration (FDA) for reduction of breast cancer in women at high risk for the disease (1.66% risk at 5 years based on the Gail risk model:


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InternalMed_Harrison. women only) have been approved by the U.S. Food and Drug Administration (FDA) for reduction of breast cancer in women at high risk for the disease (1.66% risk at 5 years based on the Gail risk model: http://www.cancer.gov/bcrisktool/).