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Impact of Antitumor Therapy on Nutrition
Nutrition and Cancer II
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Impact of Antitumor Therapy on Nutrition
Oliver]. McAnena, M.B., F.R.C.S.(I),* and]ohn M. Daly, M.D., F.A.C.S.t
Malnutrition with tissue wasting frequently accompanies malignancy and is one of the major causes of morbidity in patients with cancer. Up to 66 per cent of patients with cancer develop inanition during the course of their disease. 29, 93 Cancer cachexia may be related to reduced caloric intake due to tumor-related mechanical obstruction of the gastrointestinal tract or to distant effects of the tumor on host-substrate metabolism. Multimodal antineoplastic therapy invariably affects the host, by mechanical and physiologic alterations due to operation or at a cellular level using chemotherapy or radiation therapy. These treatment modalities exert a varying impact on the nutritional status of the host, which adds to the cachexia resulting from the tumor itself and leaves the patient with a severe nutritional deficiency. The purpose of this article is to outline the various means by which surgery, radiation treatment, and chemotherapy influence the nutritional status of the cancer-bearing host.
SURGERY Operative therapy is the primary treatment modality for many cancers, particularly those of the gastrointestinal tract. The immediate metabolic response to uncomplicated operations in patients *Fellow in Surgical Oncology, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York t Jonathan E. Rhoads Professor of Surgery and Chief, Division of Surgical Oncology, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Surgical Clinics of North America-Vol. 66, No.6, December 1986
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Table 1. Nutritional Consequences of Radical Operative Resection ORGANS RESECTED
Oral cavity and pharynx Thoracic esophagus
Stomach
Small intestine Duodenum Jejunum Ileum Massive (> 75%)
Colon (total or subtotal)
NUTRITIONAL SEQUELAE
Dependency on tube feedings Gastric stasis (secondary to vagotomy) Fat malabsorption Gastrostomy feedings in patients without reconstruction Dumping syndrome Fat malabsorption Anemia Pancreatobiliary deficiency with fat malabsorption Decrease in efficiency of absorption (general) Vitamin B12 and bile salt absorption Fat malabsorption and diarrhea Vitamin B12 malabsorption Gastric hypersecretion Water and electrolyte loss
From Lawrence, W., Jr.: Nutritional consequences of surgical resection of the gastrointestinal tract for cancer. Cancer Res., 37:2379-2386, 1977, with permission.
with cancer is similar to the response to operations of similar magnitude for benign disease. As a result of surgical trauma, energy requirements are increased. A net catabolic state results from mobilization of fat stores, skeletal muscle protein, and visceral protein to meet the increased demand for glucose. A positive nitrogen balance is achieved within a few days in the patient who undergoes an uncomplicated operation as the primary therapy for malignancy. However, the nutritionally debilitated patient may undergo operation with multiple deficiencies, depleted in all components of body composition except total body water. 14, 137 Longer-term effects of operation are dependent on the site of the tumor, the extent of resection, and whether or not a vagotomy was performed. The potential nutritional consequences of radical cancer surgery are listed in Table 1. Protein-calorie malnutrition is a major problem in patients with head and neck malignancies, because these patients frequently have a prior history of alcoholism and poor dietary habits, which in turn result in multiple protein and mineral deficiencies at the time their head and neck cancers are diagnosed;" Like many other patients with cancer, these patients are frequently anorectic and have abnormalities of taste and smell. 27, 28, 42 Starting with an already deficient nutrient base, the patient with head and neck cancer must frequently undergo treatment that further compromises the ability to ingest nutrient substances. These patients often require ablative procedures that cause mechanical and physiologic alterations that make adequate dietary intake difficult. 2, 31
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Resection of segments of the tongue or mandible hampers deglutition. The complex physiologic sequence of swallowing is frequently altered by operations on the tongue, palate, and pharynx. Although some of these changes may be temporary, many patients will have permanent difficulty with either chewing or swallowing. Greater emphasis on reconstruction with wiring of the jaws and use of myocutaneous flaps lengthen the duration of surgically induced nutritional disability. When complications such as pharyngocutaneous fistulas occur, the time during which patients are unable to eat increases further. The nutritional problems in the patient with head and neck cancer are further compounded by the frequent use of adjuvant radiation treatment and chemotherapy. Diminished salivary secretions from radiation-induced fibrosis of the salivary glands add to problems with mastication.P 89 Stomatitis and mucositis from radiation treatment and chemotherapy also result in diminished oral intake. For all of these reasons patients with head and neck cancer frequently require perioperative nutritional support. A patient who cannot ingest adequate quantities of nutrients orally, but who has a functional gastrointestinal tract, can usually be maintained or replenished by tube feeding. Pittman and associates noted that 43 per cent of their patients who underwent radical head and neck surgery required nutritional support via tube feeding for more than 15 days.101 When the gastrointestinal tract is not available because of persistent nausea, vomiting, mechanical obstruction, or malabsorption, the application of total parenteral nutrition (TPN) is indicated. Daly and colleagues found that patients with head and neck cancer treated with TPN perioperatively had minimum morbidity, gained weight, and experienced an increase in the feeling of general wellbeing. 121 Although thoracic esophagectomy has been associated with steatorrhea and diarrhea;'!" most patients remain well nourished by simply increasing caloric intake or supplementing their diets with medium-chain triglycerides." The development of steatorrhea and diarrhea has been attributed to the vagotomy performed as part of the en bloc esophageal resection. 98, 119 Despite impairment of fat and protein absorption following gastrectomy, there is a poor correlation between the ability of the patient to maintain body weight and the degree of observed steatorrhea;" which is mild compared with that noted after massive small bowel resection. Following gastrectomy, a modest weight loss of less than 10 per cent of preoperative weight is common, even in patients with benign disease. This is a result of rapid gastric emptying" and altered intestinal transit. 70 Kotler and colleagues identified a distinct
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subgroup of postgastrectomy patients in whom persistent undernutrition is associated with rapid intestinal transit and elevated postprandial plasma concentrations of enteroglucagon and neurotensin."" These hormones are secreted from the distal intestine in response to luminal stimulation. 7, 45 Food intake may be impaired after gastric surgery by a decrease in the size of the gastric pouch, leading to early satiety. 126 However, the limitation of food intake following gastrectomy is due mainly to postgastrectomy symptoms (that is, dumping syndrome). 76, 82, 88, 105 Vitamin and mineral deficiencies may also occur following radical gastrectomy for cancer. Iron deficiency anemia may occur and may be exacerbated by a decreased intake of dietary iron. 13, 129 Megaloblastic anemia and neurologic sequelae may result from deficiency of vitamin B12 from 6 months to 4 years following gastric resection. 79 This responds readily to parenteral administration ofB12. Inadequate absorption of vitamin D as a result of steatorrhea associated with gastrectomy may occasionally contribute to osteomalacia. 26, 37 The B group of vitamins and vitamin A may also be less efficiently absorbed, but a deficiency is readily preventable by oral supplementation. Malfunction of the small intestine can occur if sufficient bowel is resected. In operations for gastrointestinal cancer, extensive small bowel resection is not usually necessary. Nutritional sequelae in patients undergoing small bowel surgery are a relative rarity. Unless patients have undergone resection of greater than 75 per cent of their small bowel, the ability of the remaining small bowel to increase its absorptive capacity prevents major clinical problems after resection. This adaptive capability of the small bowel mucosa increases for a variable amount of time following resection. 34, 139 In particular, the reserve capacity of the ileum can compensate for functional changes produced by loss of more proximal small bowel. 11, 144 Some patients may develop persistent gastric hypersecretion following extensive small bowel resection, 15, 53 which may add to the degree of diarrhea present from the primary resection. The resultant alteration of pH in the small bowel lumen from gastric acid hypersecretion and alteration in gastrointestinal flora can inhibit intestinal digestion of nutrients. 140 Although cancers of the colon and rectum account for over 65 per cent of all gastrointestinal tumors in the United States.!" the long-term nutritional disabilities in patients who have had a total colectomy are not usually of major significance. Following ileoanal anastomosis, large Huid and electrolyte losses may develop as a result of profuse diarrhea. This usually resolves as the remaining small bowel adapts, and adverse nutritional sequelae are not usually observed in these patients. Surgery of accessory digestive organs can have significant nutri-
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tional consequences. Pancreatic resection, in particular, can result in severe nutritional deficiency. This occurs as a result of malabsorption of fat, protein, and long-chain carbohydrates. 18, 43, 120, 143 While the loss of pancreatic enzymes is difficult to replace adequately by oral means, the metabolic effects of the decrease or loss of endogenous insulin further compounds the effect on nutritional status.:" Up to 28 per cent of patients who undergo pancreaticoduodenectomy for periampullary carcinoma or carcinoma of the head of the pancreas have significant pancreatic exocrine insufficiency. 4, 86 Following total pancreatectomy, all patients will have diabetes, in 20 per cent of whom it will be extremely difficult to control. 84, 100 Therefore, malnutrition is a major complication of pancreatic surgery, and its management requires a careful and vigorous clinical approach. The regenerative capacity of the liver following resection frequently prevents adverse long-term nutritional sequelae after the initial postoperative period. 120 During this regeneration period, however, there is frequently a significant reduction in serum albumin, fibrinogen, and other anticoagulant factors produced by the liver. There may also be a transient fall in serum calcium, sodium, potassium, and triglycerides.?"
CHEMOTHERAPY Therapeutic approaches with cancer chemotherapeutic agents may profoundly affect the nutritional status of the host. These effects may be direct, by altering intracellular protein or DNA synthesis of host cells, or indirect, by producing nausea," vomiting;':" anorexia and learned food aversions. Alterations in taste may result from a direct or indirect action of plasma or salivary drug secretion on taste buds.62, 127 Nausea and vomiting are the most common immediate manifestations of administration of many chemotherapeutic or immunotherapeutic agents. 95 These symptoms are often severe and prolonged in patients receiving cancer chemotherapy and result in decreased oral intake, fluid and electrolyte imbalance, general weakness, and weight loss. Patients with cancer acquire learned aversions to foods consumed before chemotherapy treatments that induce nausea and vomiting," and these aversions contribute to cancer-associated anorexia. Cancer chemotherapeutic agents almost invariably are associated with nausea and vomiting to some degree. Among those less likely to cause vomiting are vincristine and certain alkylating agents (chlorambucil, busulfan, l-phenylalanine mustard). Nausea and vomiting
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Table 2. Emetic Potential of Commonly Used Cancer Chemotherapeutic Agents* Imidazole carboxamide (DTIC)87, III
Cisplatin"' 57, 59, 69, 109, 142, 146 Actinomycin':" 113, 115 Streptozotocin'
Vinblastine" Vincristine'< " Bleomycin" Chlorambucil'? 81,142
Melphalan" Busulfan"
*Agents are listed in
order from highest to lowest emetic potential.
occur with almost every major class of compound, including most of the alkylating agents (Table 2). Certain immunotherapeutic compounds (levamisole and Corynebacterium parvum) can also cause nausea and vomiting. Differences in the frequency and sensitivity of emesis occur among patients and even among treatment courses in the same patient. The types of emesis may be caused by different mechanisms. Chemotherapy-induced vomiting is mediated by the chemoreceptor trigger zone located in the area postrema of the fourth ventricle. 12, 19 Other distinct types of emesis seen in patients receiving chemotherapy for cancer include anticipatory emesis and delayed emesis. There are many effective antiemetics available that can be used either alone or in combination. Administration of these agents is usually tailored to the individual. The most effective agents are metoclopramide, butyrophenones, and corticosteroids. 54 Recently, adjunctive anxiolytic agents have also been used effectively, and cannabinoids have been proposed as an effective method of antiemetic therapy. 49, 136 Many cancer chemotherapeutic agents are toxic to the rapidly dividing cells of the gastrointestinal tract. Their administration in high doses is frequently limited by this side effect. 61 The squamous mucosa of the oral, pharyngeal, and esophageal surfaces has a more rapid turnover than skin. Cells in the depths of the mucosal crypts undergo rapid cell division and are a logical target for cancer chemotherapeutic agents. The toxic effects of these agents are clinically apparent as stomatitis, cheilosis, glossitis, and pharyngitis, or as diarrhea from the toxic effect on the cells of the small intestinal
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Table 3. Chemotherapeutic Agents Associated with Gastrointestinal Side Effects Oral Mucosal Toxicity
Actinomycin D 60 , 116 High-dose methotrexate" Methylglyoxal bisguanyl-hydrazone'?' 5-Fluorouracil 114 Adriamycin 96 Daunorubicin Cyclophosphamide"
Diarrhea
Actinomycin D Methylglyoxal bisguanyl-hydrazone 5-Fluorouracil Methotrexate BCNU,CCNU Streptozotocin Cyclophosphamide (uncommon)
Alternating Diarrhea and Constipation
Vincristine'"
and colonic mucosa. These toxicities are accompanied by an inability to continue adequate oral intake and result in dehydration, electrolyte imbalance, and inanition, which further compromise the nutritional status of the host. Table 3 outlines the drugs in which gastrointestinal toxicity is most commonly observed. Constipation and adynamic ileus, alternating with diarrhea, are frequently observed and troublesome complications associated with administration of vincristine. The frequency and severity appear to be dose related, 46, 58 and these symptoms may result in diminished oral intake and enhanced cancer cachexia. Although morphologic alterations of small intestinal mucosa have been reported": 91,106, 115, 124, 135, 145 with decreased mucosal cell dissacharidase activity;" the effects of cancer chemotherapeutic agents on absorptive function do not appear to be significant. However, in some patients with pre-existing small intestinal malabsorption and villus atrophy with malignant disease remote from the gastrointestinal tract, treatment may worsen malabsorption and further contribute to weight loss and anorexia. 35, 83 Oral candidiasis and moniliasis of the gastrointestinal tract can lead to a marked reduction of oral intake. Mycotic superinfection may be related to administration of cancer chemotherapy either alone or in combination with antibiotics and corticosteroids. Whereas many patients are asymptomatic, dysphagia, odynophagia, painful mouth, and retrosternal pain are not infrequent distressing symptoms." Overall, the gastrointestinal side effects of cancer chemotherapy agents are transient and may not significantly alter the nutritional status of the host who has a good performance status. However, in a patient who is already debilitated from disease, or in the individual receiving concomitant radiation therapy, the side effects of chemo-
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therapy and malnutrition may substantially increase morbidity unless adequate nutritional support is provided.
RADIATION TREATMENT Radiation therapy can have a significant impact on the nutritional status of the host by its effect on the rapidly dividing mucosal crypt cells of the gastrointestinal tract. The severity of the injury is related to the dose of radiation administered and the volume of tissue treated.F Radiation effects on the gastrointestinal tract may appear early or late. The early effects are generally transient, and symptoms subside within a few weeks after completion of treatment. Early symptoms are manifested by diarrhea, with or without gastrointestinal bleeding, nausea, vomiting, weight loss, mucositis, xerostomia, alterations in taste, and food aversion. Patients receiving whole body irradiation develop emesis almost immeditely. Seven to 15 days later an intestinal syndrome develops, which is characterized by diarrhea, often accompanied by intestinal bleeding." Late gastrointestinal complications include stricture, fistula, bowel perforation, and malabsorption.!" Biopsies of the small bowel mucosa obtained from cancer patients undergoing abdominal irradiation have demonstrated shortening and irregularities of the microvilli of the absorptive cells with dilatation of the endoplasmic reticulum after 3300 rads and often in the absence of gastrointestinal symptoms. 104 Oral complications of radiation treatment can result in a significant reduction in caloric intake. These problems are for the most part the result of local tissue changes from irradiation. Implants, therefore, tend to result in more problems than external beam irradiation. Mucosal atrophy, fibrosis of salivary glands, and damage to taste buds frequently occur" Mucositis is usually observed at a dose level of about 2000 rads when therapy is administered at a rate of 200 rads per day. It is self-limiting, however, and usually resolves in 2 to 3 weeks after termination of treatment. During this time, however, oral intake may be severely limited. 63 Xerostomia is frequently experienced by patients receiving radiation therapy for head and neck cancer. Salivary secretions decrease and become thick and tenacious. The number of oral bacteria increases, and dental caries characteristically appears a few months after the start of radiotherapy from an alteration in oral pH, elimination of mechanical flushing, and decreased salivary IgA. 77 Loss of taste is a troublesome consequence of radiation treatment of patients with head and neck cancer. It is usually noted during a cumulative dose of 1000 to 2000 rads.?" The loss of the ability to
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differentiate between bitter and salty tastes is particularly distressing and leads to an aversion to foods with such tastes. Taste sensation, however, usually returns within 12 months of completion of therapy.17,92 The development of mandibular osteoradionecrosis is the most serious long-term complication of radiation treatment of head and neck cancer. The reported incidence of osteoradionecrosis ranges from 4 to 35 per cent; 90 per cent of cases occur in the mandible. 92 Of patients who developed this condition, Larson and colleagues observed that 41 per cent required a partial mandibulectomy.P which leads to obvious difficulties in glutition. Radiation therapy is frequently utilized in the treatment of thoracic malignancies, either alone or in combination with sensitizing or adjuvant chemotherapy. Esophagitis without esophageal stricture was reported as common in a series of 300 patients undergoing mediastinal irradiation.?" The incidence varies from 3 to 100 per cent in the literature. 1,3,26,38,56,68,97,117,122,138 The occurrence of esophagitis and the degree of severity appear to increase with increasing doses of radiation;" The true incidence of long-term esophageal complications resulting from mediastinal irradiation is not known, however. It appears that whereas radiation esophagitis is common, severe esophagitis and esophageal stricture rarely occur. In patients receiving mediastinal irradiation, these short- and long-term complications result in dysphagia, which adversely affects caloric intake. The most common complication observed in patients receiving radiation therapy for pelvic cancer is radiation-induced enteritis. 41, 48 Previous abdominal surgery, hypertension, and diabetes mellitus may predispose to these effects. 24, 80, 108, 134 This can result in malabsorption of fat, protein, and carbohydrate and in fluid and electrolyte abnormalities. 6, 131 Such patients may require later operative resection or bypass for stricture, perforation, or hemorrhage. Galland and Spencer recently reviewed 70 patients who presented to a surgical unit with radiation enteritis. 50 The average interval between radiotherapy and radiation-induced problems was 2 years, but in seven the interval was more than 15 years. This demonstrated that when chronic radiation enteritis does develop, it is associated with considerable morbidity associated with malabsorption or requirement for further small bowel resection for perforation or stricture, all of which have adverse effects on the nutritional status of the patient. Combination chemotherapy and radiotherapy are believed to have a cumulative adverse effect on the cells of the gastrointestial tract. A recent review from M. D. Anderson Hospital demonstrated esophagitis in 80 per cent of all patients receiving combination therapy for non-small cell lung cancer. Patients receiving simultaneous chemotherapy and radiation treatment were at greater risk of
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developing an esophageal stricture and/or perforaton compared with patients receiving split courses of chemotherapy and radiotherapy. 133 Similarly, synchronous chemotherapy and radiotherapy for head and neck cancer have been associated with increased host toxicity, 16, 112 but other studies have suggested improved response without increased toxicity. 102
SUMMARY Surgery, radiation, and chemotherapy can result in further deterioration in nutritional status in patients who are frequently malnourished as a consequence of their underlying malignancy. Many of the effects are transient, and patients who have a good performance status may exhibit minimal alterations in nutritional parameters during the course of treatment. However, antitumor treatment may enhance morbidity, and in some, it leads to mortality if patients are in poor nutritional status ab initio. Such malnourished patients must be recognized prior to initiation of treatment, and steps must be taken to maintain adequate nutrition. The known toxic effects of many cancer therapeutic regimens must be weighed against their potential benefits.
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68. Krauss, S., Perez, C., Lowenbraun, S., et aI.: Combined modality treatment of localized small cell carcinoma of the bronchus. Lancet, 1:129-132, 1975. 69. Kris, M. G., Garalla, R. J., Clarke, R. A., et aI.: Incidence, course and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J. Clin. OncoI., 3:1379-1384, 1985. 70. Ladas, S. D., Isaacs, P. E. T., Quereshi, Y., et aI.: Role of the small intestine in postvagotomy diarrhea. Gastroenterology, 85:1088-1093, 1983. 71. Lambert, H. E., and Berry, R. J.: High dose cisplatin compared with high dose cyclophosphamide in the management of advanced epithelial ovarian cancer (FIGO stages III and IV): Report from the North Thames Cooperative Group. Br. Med. J., 2290:889-893, 1985. 72. Larson, D. L., Lindberg, R. D., Lane, E., et aI.: Major complications of radiotherapy in cancer of the oral cavity and oropharynx: A 10-year retrospective study. Am. J. Surg., 146:531-536, 1983. 73. Lawrence, W., Jr.: Nutritional consequences of surgical resection of the gastrointestinal tract for cancer. Cancer Res., 37:2379-2386, 1977. 74. Lawrence, W., Jr., Vanamee, P., Peterson, A. S., et al.: Alterations in fat and nitrogen metabolism after total and subtotal gastrectomy. Surg. Gynecol. Obstet., 110:601616, 1960. 75. Love, R. R., Nerenz, D. R., and Leventhal, H.: Anticipatory nausea with cancer chemotherapy: Development through two mechanisms. Proc. Am. Soc. Clin. Oncol., 2:62, 1983. 76. Machella, T. E.: The mechanism of postgastrectomy "dumping syndrome." Ann. Surg., 130:145-159, 1949. 77. MacCarthy-Leventhal, E. M.: Post radiation mouth blindness. Lancet, 2:1138-1139, 1959. 78. Mcfrertnott, W. V., Jr., and Ackroyd, F. W.: Nutrient demands imposed by surgery of the liver. Am. J. Clin. Nutr., 23:652-656, 1970. 79. MacLean, L. D.: Megaloblastic anemia following total and subtotal gastrectomy: Collective review. Intern. Abstr. Surg., 106:415-423, 1958. 80. Maruyama, Y., VanN agell, J. R., UtIey, J., et aI.: Radiation and small bowel complications in cervical carcinoma therapy. Radiology, 112:699-703, 1974. 81. Masterson, J. C;., Calame, R. J., and Nelson, J.: A clinical study on the use of chlorambucil in the treatment of carcinoma of the ovary. Am. J. Obstet. Gynecol., 79:1002-1007, 1960. 82. Matthews, D. H., Lawrence, W., Jr., Poppell, J. W., et al.: Change in effective circulating volume during experimental dumping syndrome. Surgery, 48:185-194, 1960. 83. Mitchell, E. P., and Schein, P. S.: Gastrointestinal toxicity of cancer chemotherapeutic agents. Semin. Oncol., 1982. 84. Miyata, M., Takao, T., Uozumi, T., et al.: Insulin secretion after pancreatoduodenectomy. Ann. Surg., 179:494-498, 1974. 85. Moertel, C. G., Reitemeir, R. J., and Huhn, R. G.: Fluorinated pyrimidine therapy of gastrointestinal cancer. Gastroenterology, 46:371-378, 1964. 86. Monge, J. J., Judd, E. S., and Gage, R. P.: Radical pancreatoduodenectomy: A 22 year experience with complications, mortality rate and survival rates. Ann. Surg., 160:711719, 1964. 87. Moore, G. E., and Mieselbaugh, D.: DTIC (NSC-45388) toxicity. Cancer Treat. Rep., 60:219, 1976. 88. Morris, G. C., Greenfield, L. J., Jordan, G. L., et aI.: Physiologic considerations in the dumping syndrome. Ann. Surg., 150:90-98, 1959. 89. Mossman, K., and Scheer, A.: Complications of radiotherapy of head and neck cancer. Ear Nose Throat J., 56:90-95, 1977. 90. Mossman, K. L., and Henkin, R. I.: Radiation induced changes in taste acuity in cancer patients. Int. J. Radiat. Oncol. BioI. Phys., 4:663-670, 1978. 91. Muggia, A, L., Wagman, E., Mills, S. S., et al.: Response of the gastrointestinal tract of the mouse to 5-fluorouracil. Am. J. Pathol., 420:407-4145, 1963. 92. Murray, C. G., Herson, J., Daly, T. E., et al.: Radiation necrosis of the mandible: A 10 year study. Part 1. Factors influencing the onset of necrosis. Int. J. Radiat. Oncol. BioI. Phys., 6:543-548, 1980.
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93. Nixon, D., Heymsfield, S., Cohen, A., et al.: Protein-calorie undernutrition in hospitalized cancer patients. Am. J. Med., 68:683-690, 1980. 94. Ochoa, M., Jr.: Alkylating agents in clinical cancer chemotherapy, Ann. N. Y. Acad. Sci., 163:921-930, 1969. 95. Ohnuma, T., and Holland, J. F.: Nutritional consequences of cancer chemotherapy and immunotherapy. Cancer Res., 37:2395-2406, 1977. 96. Omura, G. A., Blessing, J. A., Major, F., et al.: A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: A gynecologic oncology group study. J. Clin. Oncol., 3:1240-1245, 1985. 97. Perez, C. A., Stanley, K., Rubin, P., et al.: A prospective randomized study of various irradiation doses of fractionation schedules in the treatment of inoperable non-oat cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer, 45:2744-2753, 1980. 98. Phillips, D. F., Wollaeger, E. E., Ellis, F. H., Jr., et al.: Fecal excretion of fat and nitrogen after esophageal gastrectomy in man. Surgery, 49:433-439, 1961. 99. Phillips, T. L., and Margolis, L.: Radiation pathology and the clinical response of lung and esophagus. Front. Radiat. Ther. Oncol., 6:254-273, 1972. 100. Pilam, M. B., and Re Mine, W. H.: Further evaluation oftotal pancreatectomy. Arch. Surg., 110:506-511, 1975. 101. Pittman, M. R., Janes, E., and Palmer, B. V.: Postoperative enteral tube feeding in patients with squamous carcinoma of the head and neck. Nutr. Support Serv., 2:610, 1982. 102. Posner, M. R., Weichselbaum, R. R., Fitzgerald, T. J., et al.: Treatment complications after sequential combination chemotherapy and radiotherapy with or without surgery in previously untreated squamous cell carcinoma of the head and neck. Int. J. Radiat. Oncol. BioI. Ppys., 11:1887-1893, 1985. 103. Regelson, W., and Holland, J. F.: Clinical experience with methyl-glyoxal-bis-guanylhydrazone dichloride. A new agent with clinical activity in acute myelocytic leukemia and the lymphomas. Cancer Chemother. Rep., 27: 15-26, 1973. 104. Reynolds, W. R., Hickey, A. J., and Feldman, M. I.: Dental management of the cancer patient receiving radiation therapy. Clin. Prevent. Dent., 2:5-9, 1980. 105. Roberts, K. E., Randall, H. T., Fart, H. W., et al.: Cardiovascular and blood volume alterations resulting from intrajejunal administration or' hypertonic solutions to gastrectomized patients: The relationship of these changes to the dumping syndrome. Ann. Surg., 140:631-640, 1954. 106. Roche, A. C.~ Bognel, J. C., Bognel, C., et a1.: Correlation between the histological changes and glucose intestine absorption following a single dose of 5-fluorouracil. Digestion, 3:195-212, 1970. 107. Rochlin, D. B., Shiner, J., Langdon, E., et al.: Use of 5-fluorouracil in disseminated solid neoplasms. Ann. Surg., 156:105-113, 1962. 108. Roswit, B., Malsky, S. J., and Reid, C. B.: Severe radiation injuries of the stomach, small intestine, colon and rectum. A.J.R., 114:460-475, 1972. 109. Saller, R., and Hellenbrecht, D.: Comparison of the antiemetic efficacy of the two highdose benzamides, metoclopramide and alizapride, against cisplatin-induced emesis. Cancer Treat. Rep., 69:1301-1303, 1985. 110. Schein, P. S., O'Connell, M. J., Bloom, J., et al.: Clinical antitumor activity and toxicity of streptozotocin (NSC-85998). Cancer, 34:993-1000, 1974. Ill. Schepatz, S.: History and development of DTIC. Cancer Treat. Rep., 60:123-124, 1976. 112. Seagren, S. L., Byfield, J. E., Davidson, T. M., et al.: Bleomycin, cyclophosphamide and radiotherapy in regionally advanced epidermoid carcinoma of the head and neck. Int. J. Rad. Oncol. BioI. Phys., 8:127-132, 1982. 113. Seibert, K., Golub, G., Smiledge, P., et al.: Continuous streptozotocin infusion. A phase 1 study. Cancer Treat. Rep., 63:2035-2037, 1979. 114. Seifert, P., Baker, L. M., Reed, M. L., et al.: Comparison of continuously infused 5fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma. Cancer, 36:123-129, 1975. 115. Shaw, M. T., Spector, M. H., and Ladman, A. J.: Effects of cancer, radiotherapy and cytotoxic drugs on intestinal structure and function. Cancer Treat. Rev., 6:141-151, 1979.
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116. Shaw, R. K., Moore, E. W., Mueller, P. S., et al.: The effect of actinomycin D on childhood neoplasms. Am. J. Dis. Child., 99:628-635, 1960. 117. Shehata, W. M.: Role of radiation therapy in bronchogenic carcinoma. Ohio State Med. J., 73:605-611, 1977. 118. Shils, M. E., and Gilat, T.: The effect of esophagogastrectomy on absorption in man: Clinical and "metabolic" observations. Gastroenterology, 50:347-357, 1966. 119. Shils, M. E.: The esophagus, the vagi and fat absorption: Collective review. Surg. Gynecol. Obstet., 132:709-715, 1971. 120. Shils, M. E.: Nutritional problems associated with gastrointestinal and genitourinary cancer. Cancer Res., 37:2366-2372, 1977. 121. Silverberg, E., Seidman, H., Mushinski, M. A., et al.: Cancer Statistics 1985. American Cancer Society, 1985, p. 12. 122. Slawson, R. G., and Scott, R. M.: Radiation therapy for patients with asymptomatic lung cancer. Radiology, 135:481-484, 1980. 123. Small, M. D., Cavanaugh, R. L., Gottlieb, L., et al.: The effect of aminopterin on the absorption of xylose from the rat small intestine. Am. J. Dig. Dis., 4:700-705, 1959. 124. Sobhon, R., Wanichanon, C., and Stretarugsa, P.: Morphological changes induced by cyclophosphamide in crypt epithelium of the small intestine in mice. Am. J. Anat., 149:563-584, 1977. 125. Solomon, J., Alexander, M. J., and Steinfeld, J. L.: Cyclophosphamide: A clinical study. J.A.M.A., 183:165-170, 1963. 126. Stammers, F. A. R.: A clinical approach to an analysis and treatment of postgastrectomy syndromes. Br. J. Surg., 49:28-36, 1961. 127. Steele, W. H., Stuart, J. F. B., Whiting, B., et al.: Serum, tear and salivary concentrations of methotrexate in man. Br. J. Clin. Pharmacol., 7:207-211, 1979. 129. Stevens, A. R., Jr., Pirzio-Biroli, G., Harkins, H. N., et al.: Iron metabolism in patients after partial gastrectomy. Ann. Surg., 149:534-538, 1959. 130. Stolinsky, D. C., Solomon, J., Pugh, R. P., et al.: Clinical experience with procarbazine in Hodgkin's disease, reticulum cell sarcoma, and lymphosarcoma. Cancer, 26:984990, 1979. 131. Stryker, J. A., Mortel, R., and Hepner, G. W.: The effect of pelvic irradiation on lactose absorption. Int. J. Radiat. Oncol. BioI. Phys., 4:859-863, 1978. 132. Trier, J S., and! Browning, T. H.: Morphologic response of the mucosa of human small intestine to x-ray exposure. J. Clin. Invest., 45:194-204, 1966. 133. Umsawasdi, T., Valdivieso, M., Barkley, H. T., et al.: Esophageal complications from combined chemoradiotherapy (cyclophosphamide + Adriamycin + cisplatin + XRT) in the treatment of non-small cell lung cancer. Int. J. Radiat. Oncol. BioI. Phys., 11:511-519, 1985. 134. VanNagell, J. R., Maruyama, Y., Parker, J. C., et al.: Small bowel injury following radiation therapy for cervical cancer. Am. J. Obstet. Gynecol., 118:163-167, 1974. 135. Venho, V. M. K.: Effect of methotrexate on drug absorption from rat small intestine in situ and in vitro. Acta Pharmacol. Toxicol., 38:450-464, 1966. 136. Vincent, B. J., McQuiston, D. J., Einhorn, L. H., et al.: Review of cannabinoids and their antiemetic effectiveness. Drugs, 25(Suppl. 1):52-62, 1983. 137. Warnold, I., Lundholm, K., and Shersten, T.: Energy balance and body composition in cancer patients. Cancer Res., 38:1801-1807, 1978. 138. Watson, T. A.: Supervoltage roentgen therapy in cancer of the lung. Am. J. Roentgenol., 75:525-529, 1956. 139. Weinstein, L. D., Shoemaker, C. P., Hersh, T., et al.: Enhanced intestinal absorption after small bowel resection in man. Arch. Surg., 99:560-566, 1969. 140. Weser, E., Fletcher, J. T, and Urban, E.: Short bowel syndrome. Gastroenterology, 77:572-579, 1979. 141. Wilcox, P. rv1., Fetting, F. H., Nettesheim, K. M., et al.: Anticipatory vomiting in women receiving cyclophosphamide, methotrexate and 5-FU (CMF) adjuvant chemotherapy for breast carcinoma. Cancer Treat. Rep., 66:1601-1604, 1982. 142. Williams, C. J., Mead, G. M., Macbeth, F. R., et al.: Cisplatin combination chemotherapy versus chlorambucil in advanced ovarian carcinoma: Mature results of a randomized trial. J. Clin. Oncol., 3:1455-1462, 1985. 143. Wollaeger, E. E., Comfort, M. W., Clagett, O. T., et al.: Efficiency of gastrointestinal tract after resection of head of pancreas. J.A.M.A., 137:838-848, 1948.
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144. Wright, H. K., and Tilson, M. D.: The short gut syndrome: Pathophysiology and treatment. Curr. Probl. Surg., 3, 1971. 145. Wurth, M. A., and Musacchia, X. J.: Mechlorethamine effects on intestinal absorption in vitro and on cell proliferation. Am. J. Physiol., 225:73-80, 1973. 146. Yagoda, A., Watson, R. C., Gonzalez-Vitale, J. C., et al.: Cis-dichlorodiamine-platinum in advanced bladder cancer. Cancer Treat. Rep., 60:917-923, 1976. John M. Daly, M D. Hospital of the University of Pennsylvania 4 Silverstein Pavilion 3400 Spruce Street Philadelphia, PA 19104
0039-6109/86 $0.00
+ .20
Impact of Antitumor Therapy on Nutrition
Oliver]. McAnena, M.B., F.R.C.S.(I),* and]ohn M. Daly, M.D., F.A.C.S.t
Malnutrition with tissue wasting frequently accompanies malignancy and is one of the major causes of morbidity in patients with cancer. Up to 66 per cent of patients with cancer develop inanition during the course of their disease. 29, 93 Cancer cachexia may be related to reduced caloric intake due to tumor-related mechanical obstruction of the gastrointestinal tract or to distant effects of the tumor on host-substrate metabolism. Multimodal antineoplastic therapy invariably affects the host, by mechanical and physiologic alterations due to operation or at a cellular level using chemotherapy or radiation therapy. These treatment modalities exert a varying impact on the nutritional status of the host, which adds to the cachexia resulting from the tumor itself and leaves the patient with a severe nutritional deficiency. The purpose of this article is to outline the various means by which surgery, radiation treatment, and chemotherapy influence the nutritional status of the cancer-bearing host.
SURGERY Operative therapy is the primary treatment modality for many cancers, particularly those of the gastrointestinal tract. The immediate metabolic response to uncomplicated operations in patients *Fellow in Surgical Oncology, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York t Jonathan E. Rhoads Professor of Surgery and Chief, Division of Surgical Oncology, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Surgical Clinics of North America-Vol. 66, No.6, December 1986
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Table 1. Nutritional Consequences of Radical Operative Resection ORGANS RESECTED
Oral cavity and pharynx Thoracic esophagus
Stomach
Small intestine Duodenum Jejunum Ileum Massive (> 75%)
Colon (total or subtotal)
NUTRITIONAL SEQUELAE
Dependency on tube feedings Gastric stasis (secondary to vagotomy) Fat malabsorption Gastrostomy feedings in patients without reconstruction Dumping syndrome Fat malabsorption Anemia Pancreatobiliary deficiency with fat malabsorption Decrease in efficiency of absorption (general) Vitamin B12 and bile salt absorption Fat malabsorption and diarrhea Vitamin B12 malabsorption Gastric hypersecretion Water and electrolyte loss
From Lawrence, W., Jr.: Nutritional consequences of surgical resection of the gastrointestinal tract for cancer. Cancer Res., 37:2379-2386, 1977, with permission.
with cancer is similar to the response to operations of similar magnitude for benign disease. As a result of surgical trauma, energy requirements are increased. A net catabolic state results from mobilization of fat stores, skeletal muscle protein, and visceral protein to meet the increased demand for glucose. A positive nitrogen balance is achieved within a few days in the patient who undergoes an uncomplicated operation as the primary therapy for malignancy. However, the nutritionally debilitated patient may undergo operation with multiple deficiencies, depleted in all components of body composition except total body water. 14, 137 Longer-term effects of operation are dependent on the site of the tumor, the extent of resection, and whether or not a vagotomy was performed. The potential nutritional consequences of radical cancer surgery are listed in Table 1. Protein-calorie malnutrition is a major problem in patients with head and neck malignancies, because these patients frequently have a prior history of alcoholism and poor dietary habits, which in turn result in multiple protein and mineral deficiencies at the time their head and neck cancers are diagnosed;" Like many other patients with cancer, these patients are frequently anorectic and have abnormalities of taste and smell. 27, 28, 42 Starting with an already deficient nutrient base, the patient with head and neck cancer must frequently undergo treatment that further compromises the ability to ingest nutrient substances. These patients often require ablative procedures that cause mechanical and physiologic alterations that make adequate dietary intake difficult. 2, 31
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Resection of segments of the tongue or mandible hampers deglutition. The complex physiologic sequence of swallowing is frequently altered by operations on the tongue, palate, and pharynx. Although some of these changes may be temporary, many patients will have permanent difficulty with either chewing or swallowing. Greater emphasis on reconstruction with wiring of the jaws and use of myocutaneous flaps lengthen the duration of surgically induced nutritional disability. When complications such as pharyngocutaneous fistulas occur, the time during which patients are unable to eat increases further. The nutritional problems in the patient with head and neck cancer are further compounded by the frequent use of adjuvant radiation treatment and chemotherapy. Diminished salivary secretions from radiation-induced fibrosis of the salivary glands add to problems with mastication.P 89 Stomatitis and mucositis from radiation treatment and chemotherapy also result in diminished oral intake. For all of these reasons patients with head and neck cancer frequently require perioperative nutritional support. A patient who cannot ingest adequate quantities of nutrients orally, but who has a functional gastrointestinal tract, can usually be maintained or replenished by tube feeding. Pittman and associates noted that 43 per cent of their patients who underwent radical head and neck surgery required nutritional support via tube feeding for more than 15 days.101 When the gastrointestinal tract is not available because of persistent nausea, vomiting, mechanical obstruction, or malabsorption, the application of total parenteral nutrition (TPN) is indicated. Daly and colleagues found that patients with head and neck cancer treated with TPN perioperatively had minimum morbidity, gained weight, and experienced an increase in the feeling of general wellbeing. 121 Although thoracic esophagectomy has been associated with steatorrhea and diarrhea;'!" most patients remain well nourished by simply increasing caloric intake or supplementing their diets with medium-chain triglycerides." The development of steatorrhea and diarrhea has been attributed to the vagotomy performed as part of the en bloc esophageal resection. 98, 119 Despite impairment of fat and protein absorption following gastrectomy, there is a poor correlation between the ability of the patient to maintain body weight and the degree of observed steatorrhea;" which is mild compared with that noted after massive small bowel resection. Following gastrectomy, a modest weight loss of less than 10 per cent of preoperative weight is common, even in patients with benign disease. This is a result of rapid gastric emptying" and altered intestinal transit. 70 Kotler and colleagues identified a distinct
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subgroup of postgastrectomy patients in whom persistent undernutrition is associated with rapid intestinal transit and elevated postprandial plasma concentrations of enteroglucagon and neurotensin."" These hormones are secreted from the distal intestine in response to luminal stimulation. 7, 45 Food intake may be impaired after gastric surgery by a decrease in the size of the gastric pouch, leading to early satiety. 126 However, the limitation of food intake following gastrectomy is due mainly to postgastrectomy symptoms (that is, dumping syndrome). 76, 82, 88, 105 Vitamin and mineral deficiencies may also occur following radical gastrectomy for cancer. Iron deficiency anemia may occur and may be exacerbated by a decreased intake of dietary iron. 13, 129 Megaloblastic anemia and neurologic sequelae may result from deficiency of vitamin B12 from 6 months to 4 years following gastric resection. 79 This responds readily to parenteral administration ofB12. Inadequate absorption of vitamin D as a result of steatorrhea associated with gastrectomy may occasionally contribute to osteomalacia. 26, 37 The B group of vitamins and vitamin A may also be less efficiently absorbed, but a deficiency is readily preventable by oral supplementation. Malfunction of the small intestine can occur if sufficient bowel is resected. In operations for gastrointestinal cancer, extensive small bowel resection is not usually necessary. Nutritional sequelae in patients undergoing small bowel surgery are a relative rarity. Unless patients have undergone resection of greater than 75 per cent of their small bowel, the ability of the remaining small bowel to increase its absorptive capacity prevents major clinical problems after resection. This adaptive capability of the small bowel mucosa increases for a variable amount of time following resection. 34, 139 In particular, the reserve capacity of the ileum can compensate for functional changes produced by loss of more proximal small bowel. 11, 144 Some patients may develop persistent gastric hypersecretion following extensive small bowel resection, 15, 53 which may add to the degree of diarrhea present from the primary resection. The resultant alteration of pH in the small bowel lumen from gastric acid hypersecretion and alteration in gastrointestinal flora can inhibit intestinal digestion of nutrients. 140 Although cancers of the colon and rectum account for over 65 per cent of all gastrointestinal tumors in the United States.!" the long-term nutritional disabilities in patients who have had a total colectomy are not usually of major significance. Following ileoanal anastomosis, large Huid and electrolyte losses may develop as a result of profuse diarrhea. This usually resolves as the remaining small bowel adapts, and adverse nutritional sequelae are not usually observed in these patients. Surgery of accessory digestive organs can have significant nutri-
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tional consequences. Pancreatic resection, in particular, can result in severe nutritional deficiency. This occurs as a result of malabsorption of fat, protein, and long-chain carbohydrates. 18, 43, 120, 143 While the loss of pancreatic enzymes is difficult to replace adequately by oral means, the metabolic effects of the decrease or loss of endogenous insulin further compounds the effect on nutritional status.:" Up to 28 per cent of patients who undergo pancreaticoduodenectomy for periampullary carcinoma or carcinoma of the head of the pancreas have significant pancreatic exocrine insufficiency. 4, 86 Following total pancreatectomy, all patients will have diabetes, in 20 per cent of whom it will be extremely difficult to control. 84, 100 Therefore, malnutrition is a major complication of pancreatic surgery, and its management requires a careful and vigorous clinical approach. The regenerative capacity of the liver following resection frequently prevents adverse long-term nutritional sequelae after the initial postoperative period. 120 During this regeneration period, however, there is frequently a significant reduction in serum albumin, fibrinogen, and other anticoagulant factors produced by the liver. There may also be a transient fall in serum calcium, sodium, potassium, and triglycerides.?"
CHEMOTHERAPY Therapeutic approaches with cancer chemotherapeutic agents may profoundly affect the nutritional status of the host. These effects may be direct, by altering intracellular protein or DNA synthesis of host cells, or indirect, by producing nausea," vomiting;':" anorexia and learned food aversions. Alterations in taste may result from a direct or indirect action of plasma or salivary drug secretion on taste buds.62, 127 Nausea and vomiting are the most common immediate manifestations of administration of many chemotherapeutic or immunotherapeutic agents. 95 These symptoms are often severe and prolonged in patients receiving cancer chemotherapy and result in decreased oral intake, fluid and electrolyte imbalance, general weakness, and weight loss. Patients with cancer acquire learned aversions to foods consumed before chemotherapy treatments that induce nausea and vomiting," and these aversions contribute to cancer-associated anorexia. Cancer chemotherapeutic agents almost invariably are associated with nausea and vomiting to some degree. Among those less likely to cause vomiting are vincristine and certain alkylating agents (chlorambucil, busulfan, l-phenylalanine mustard). Nausea and vomiting
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Table 2. Emetic Potential of Commonly Used Cancer Chemotherapeutic Agents* Imidazole carboxamide (DTIC)87, III
Cisplatin"' 57, 59, 69, 109, 142, 146 Actinomycin':" 113, 115 Streptozotocin'
Vinblastine" Vincristine'< " Bleomycin" Chlorambucil'? 81,142
Melphalan" Busulfan"
*Agents are listed in
order from highest to lowest emetic potential.
occur with almost every major class of compound, including most of the alkylating agents (Table 2). Certain immunotherapeutic compounds (levamisole and Corynebacterium parvum) can also cause nausea and vomiting. Differences in the frequency and sensitivity of emesis occur among patients and even among treatment courses in the same patient. The types of emesis may be caused by different mechanisms. Chemotherapy-induced vomiting is mediated by the chemoreceptor trigger zone located in the area postrema of the fourth ventricle. 12, 19 Other distinct types of emesis seen in patients receiving chemotherapy for cancer include anticipatory emesis and delayed emesis. There are many effective antiemetics available that can be used either alone or in combination. Administration of these agents is usually tailored to the individual. The most effective agents are metoclopramide, butyrophenones, and corticosteroids. 54 Recently, adjunctive anxiolytic agents have also been used effectively, and cannabinoids have been proposed as an effective method of antiemetic therapy. 49, 136 Many cancer chemotherapeutic agents are toxic to the rapidly dividing cells of the gastrointestinal tract. Their administration in high doses is frequently limited by this side effect. 61 The squamous mucosa of the oral, pharyngeal, and esophageal surfaces has a more rapid turnover than skin. Cells in the depths of the mucosal crypts undergo rapid cell division and are a logical target for cancer chemotherapeutic agents. The toxic effects of these agents are clinically apparent as stomatitis, cheilosis, glossitis, and pharyngitis, or as diarrhea from the toxic effect on the cells of the small intestinal
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Table 3. Chemotherapeutic Agents Associated with Gastrointestinal Side Effects Oral Mucosal Toxicity
Actinomycin D 60 , 116 High-dose methotrexate" Methylglyoxal bisguanyl-hydrazone'?' 5-Fluorouracil 114 Adriamycin 96 Daunorubicin Cyclophosphamide"
Diarrhea
Actinomycin D Methylglyoxal bisguanyl-hydrazone 5-Fluorouracil Methotrexate BCNU,CCNU Streptozotocin Cyclophosphamide (uncommon)
Alternating Diarrhea and Constipation
Vincristine'"
and colonic mucosa. These toxicities are accompanied by an inability to continue adequate oral intake and result in dehydration, electrolyte imbalance, and inanition, which further compromise the nutritional status of the host. Table 3 outlines the drugs in which gastrointestinal toxicity is most commonly observed. Constipation and adynamic ileus, alternating with diarrhea, are frequently observed and troublesome complications associated with administration of vincristine. The frequency and severity appear to be dose related, 46, 58 and these symptoms may result in diminished oral intake and enhanced cancer cachexia. Although morphologic alterations of small intestinal mucosa have been reported": 91,106, 115, 124, 135, 145 with decreased mucosal cell dissacharidase activity;" the effects of cancer chemotherapeutic agents on absorptive function do not appear to be significant. However, in some patients with pre-existing small intestinal malabsorption and villus atrophy with malignant disease remote from the gastrointestinal tract, treatment may worsen malabsorption and further contribute to weight loss and anorexia. 35, 83 Oral candidiasis and moniliasis of the gastrointestinal tract can lead to a marked reduction of oral intake. Mycotic superinfection may be related to administration of cancer chemotherapy either alone or in combination with antibiotics and corticosteroids. Whereas many patients are asymptomatic, dysphagia, odynophagia, painful mouth, and retrosternal pain are not infrequent distressing symptoms." Overall, the gastrointestinal side effects of cancer chemotherapy agents are transient and may not significantly alter the nutritional status of the host who has a good performance status. However, in a patient who is already debilitated from disease, or in the individual receiving concomitant radiation therapy, the side effects of chemo-
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therapy and malnutrition may substantially increase morbidity unless adequate nutritional support is provided.
RADIATION TREATMENT Radiation therapy can have a significant impact on the nutritional status of the host by its effect on the rapidly dividing mucosal crypt cells of the gastrointestinal tract. The severity of the injury is related to the dose of radiation administered and the volume of tissue treated.F Radiation effects on the gastrointestinal tract may appear early or late. The early effects are generally transient, and symptoms subside within a few weeks after completion of treatment. Early symptoms are manifested by diarrhea, with or without gastrointestinal bleeding, nausea, vomiting, weight loss, mucositis, xerostomia, alterations in taste, and food aversion. Patients receiving whole body irradiation develop emesis almost immeditely. Seven to 15 days later an intestinal syndrome develops, which is characterized by diarrhea, often accompanied by intestinal bleeding." Late gastrointestinal complications include stricture, fistula, bowel perforation, and malabsorption.!" Biopsies of the small bowel mucosa obtained from cancer patients undergoing abdominal irradiation have demonstrated shortening and irregularities of the microvilli of the absorptive cells with dilatation of the endoplasmic reticulum after 3300 rads and often in the absence of gastrointestinal symptoms. 104 Oral complications of radiation treatment can result in a significant reduction in caloric intake. These problems are for the most part the result of local tissue changes from irradiation. Implants, therefore, tend to result in more problems than external beam irradiation. Mucosal atrophy, fibrosis of salivary glands, and damage to taste buds frequently occur" Mucositis is usually observed at a dose level of about 2000 rads when therapy is administered at a rate of 200 rads per day. It is self-limiting, however, and usually resolves in 2 to 3 weeks after termination of treatment. During this time, however, oral intake may be severely limited. 63 Xerostomia is frequently experienced by patients receiving radiation therapy for head and neck cancer. Salivary secretions decrease and become thick and tenacious. The number of oral bacteria increases, and dental caries characteristically appears a few months after the start of radiotherapy from an alteration in oral pH, elimination of mechanical flushing, and decreased salivary IgA. 77 Loss of taste is a troublesome consequence of radiation treatment of patients with head and neck cancer. It is usually noted during a cumulative dose of 1000 to 2000 rads.?" The loss of the ability to
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differentiate between bitter and salty tastes is particularly distressing and leads to an aversion to foods with such tastes. Taste sensation, however, usually returns within 12 months of completion of therapy.17,92 The development of mandibular osteoradionecrosis is the most serious long-term complication of radiation treatment of head and neck cancer. The reported incidence of osteoradionecrosis ranges from 4 to 35 per cent; 90 per cent of cases occur in the mandible. 92 Of patients who developed this condition, Larson and colleagues observed that 41 per cent required a partial mandibulectomy.P which leads to obvious difficulties in glutition. Radiation therapy is frequently utilized in the treatment of thoracic malignancies, either alone or in combination with sensitizing or adjuvant chemotherapy. Esophagitis without esophageal stricture was reported as common in a series of 300 patients undergoing mediastinal irradiation.?" The incidence varies from 3 to 100 per cent in the literature. 1,3,26,38,56,68,97,117,122,138 The occurrence of esophagitis and the degree of severity appear to increase with increasing doses of radiation;" The true incidence of long-term esophageal complications resulting from mediastinal irradiation is not known, however. It appears that whereas radiation esophagitis is common, severe esophagitis and esophageal stricture rarely occur. In patients receiving mediastinal irradiation, these short- and long-term complications result in dysphagia, which adversely affects caloric intake. The most common complication observed in patients receiving radiation therapy for pelvic cancer is radiation-induced enteritis. 41, 48 Previous abdominal surgery, hypertension, and diabetes mellitus may predispose to these effects. 24, 80, 108, 134 This can result in malabsorption of fat, protein, and carbohydrate and in fluid and electrolyte abnormalities. 6, 131 Such patients may require later operative resection or bypass for stricture, perforation, or hemorrhage. Galland and Spencer recently reviewed 70 patients who presented to a surgical unit with radiation enteritis. 50 The average interval between radiotherapy and radiation-induced problems was 2 years, but in seven the interval was more than 15 years. This demonstrated that when chronic radiation enteritis does develop, it is associated with considerable morbidity associated with malabsorption or requirement for further small bowel resection for perforation or stricture, all of which have adverse effects on the nutritional status of the patient. Combination chemotherapy and radiotherapy are believed to have a cumulative adverse effect on the cells of the gastrointestial tract. A recent review from M. D. Anderson Hospital demonstrated esophagitis in 80 per cent of all patients receiving combination therapy for non-small cell lung cancer. Patients receiving simultaneous chemotherapy and radiation treatment were at greater risk of
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developing an esophageal stricture and/or perforaton compared with patients receiving split courses of chemotherapy and radiotherapy. 133 Similarly, synchronous chemotherapy and radiotherapy for head and neck cancer have been associated with increased host toxicity, 16, 112 but other studies have suggested improved response without increased toxicity. 102
SUMMARY Surgery, radiation, and chemotherapy can result in further deterioration in nutritional status in patients who are frequently malnourished as a consequence of their underlying malignancy. Many of the effects are transient, and patients who have a good performance status may exhibit minimal alterations in nutritional parameters during the course of treatment. However, antitumor treatment may enhance morbidity, and in some, it leads to mortality if patients are in poor nutritional status ab initio. Such malnourished patients must be recognized prior to initiation of treatment, and steps must be taken to maintain adequate nutrition. The known toxic effects of many cancer therapeutic regimens must be weighed against their potential benefits.
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