The Impact of Antitumor Therapy on Nutrition

WILLIAM A. KOKAL, MD

The treatment of the cancer patient by surgery, chemotherapy or radiation therapy can impose significant nutritional disabilities on the host. The nutritional disabilities seen in the tumor-bearing host from antitumor therapy are produced by factors which either limit oral intake or cause malabsorption of nutrients. The host malnutrition caused as a consequence of surgery, chemotherapy or radiation therapy assumes even more importance when one realizes that many cancer patients are already debilitated from their disease.
Cancer 55273 - 278,1985.

well documented that cancer can produce malnutrition in the tumor-bearing host. The various therapeutic modalities used to treat cancer, such as surgery, chemotherapy, and radiation therapy, may also have a dramatic impact on the nutritional status of the host. Antitumor therapies may produce only transient mild nutritional disturbances in the cancer patient, such as mucositis from chemotherapy, or may lead to severe permanent nutritional problems, as in the case of massive small bowel resection. This report provides an overview of the nutritional consequences of surgery, chemotherapy and radiation therapy seen in the treatment of the cancer patient.
T HAS BEEN

Surgery

Surgery is the primary mode oftreatment ofalmost all cancers arising in the alimentary tract. Thus, it is not unexpected that surgical resection of alimentary tract tumors can have a major nutritional impact on the host. The nutritional disability imposed on the host depends on many factors, including the site of the tumor, the extent of resection of the alimentary canal, and whether vagotomy was performed. The nutritional consequences of radical cancer surgery are listed in Table 1. Radical resection of cancers arising in the oropharynx may lead to prolonged nutritional sequela. Resection of segments of the mandible, tongue, or pharynx can lead to significant difficulties in mastication as well as deglutition. The difficulties in mastication and deglutition in the postsurgical patient are greatly compounded when radiation therapy has been given either preoperatively or

From the Department of Surgery, City of Hope National Medical Center, Duane, California. Address for reprints: William A. Kokal, MD, City of Hope National Medical Center. I500 East Duarte Road, Duane, CA 9 10 10.

postoperatively. The xerostomia and fibrosis secondary to radiation therapy adds to the difficulty in swallowing in this group of patients. Although the malnutrition produced by radical resection of head and neck cancers can be alleviated by tube feedings, enteral alimentation may be needed for extended periods of time. Pittman and associates noted that 43% of the patients undergoing radical head and neck surgery needed nutritional support via tube feeding for more than 15 days.' Resection of thoracic esophagus has been associated with steatorrhea and diarrhea.2 Various authors have noted that the fat malabsorption and diarrhea demonstrated in the esophagectomized patient is similar to that noted in patients who have truncal vagotomy and gastric drainage procedure^.^-^ This suggests that the vagotomy done as part of the en bloc resection of the esophageal cancer, plays the major role in causing steatorrhea and diarrhea in esophagectomized patient^.^ The nutritional disability imposed by esophagectomy with the associated vagotomy is relatively minor and can be easily corrected with increased caloric intake or subsitution of medium-chain triglycerides in the diet.5 The surgical resection of gastric cancer can cause host malnutrition due to malabsorption, as well as other factors which may limit the host's caloric intake. Malnutrition, as defined by patients who were less than 85% of their ideal body weight, occurred in 30%of the patients who had total gastrectomies in the series by Schrock and Way.6 Lawrence and co-workers have demonstrated malabsorption of fat and protein in the total gastrectomy ~ a t i e n tThe mean values for fat absorption in the total .~ gastrectomy patient were approximately 80%of that of control^.^ The fat malabsorption seen, however, does not correlate with weight loss experienced by the ~ a t i e n t . ~ Furthermore, the nutritional disability from steatorrhea is minor. A similar observation is made on protein malabsorption in the gastrectomized patient. Although mal-

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TABLE. Nutritional Consequences of Radical Resection* I

Organs resected Oral cavity and pharynx Thoracic esophagus Nutritional sequelae Dependency on tube feedings Gastric stasis (secondary to vagotomy) Fat malabsorption Gastrostomy feedings in patients without reconstruction Dumping syndrome Fat absorption Anemia Pancreatobiliary deficiency with fat malabsorption Decrease in efficiency of absorption (general) Vitamin BIZ and bile salt absorption Fat malabsorption and diarrhea; vitamin B I2 malabsorption; gastric hypersecretion Water and electrolyte loss

Stomach Small intestine Duodenum Jejunum Ileum Massive (>75%) Colon (total or subtotal)

* Reprinted with permission from Lawrence W Jr. Nutritional consequences of surgical resection of the gastrointestinal tract for cancer. Cancer Res 1977; 3712379-2386. absorption of protein does occur after total gastrectomy, it is of little clinical impact and can be easily overcome by a minor increase in protein intake. The major nutritional disability after total gastrectomy appears to be a limitation of caloric intake by the patient. This limited caloric intake is due to several factors as loss of food reservoir, esophagitis and the dumping syndrome. The dumping syndrome consists of a myriad of gastrointestinal symptoms such as diarrhea, nausea, abdominal cramps, as well as sympathetic autonomic discharge. Lawrence has noted that significant dumping symptoms occur in 10%to 25% of those patients who underwent subtotal gastrectomy, and noted a higher percentage in patients who had total gastric resect i o n ~The gastrointestinal symptoms and sympathetic .~ discharge can be so unpleasant for the patient that an aversion to eating develops. The correction of the nutritional disabilities in the gastrectomy patient is primarily through prevention of the dumping syndrome. This prevention has classically been done by frequent small feedings of a low carbohydrate, high protein and fat diet. Occasionally, the dumping symptoms are not alleviated by dietary measures. Various surgical procedures have been devised in this small group of patients refractory to dietary control. The operations proposed to correct dumping symptoms include such procedures as a reverse peristaltic loop of small bowel or creation ofan intestinal reservoir.a Other nutritional deficiencies which may occur in the patient following gastrectomy are decreased absorption of calcium, iron, and vitamin B12. Massive small bowel resection is infrequently performed in surgery for abdominal cancers. However, significant metabolic disturbances can arise when such ex-

tensive intestinal resection is necessary. The extent ofthe nutritional deficienciesseen after intestinal resection are dependent on several factors such as the amount of the small bowel resected, the extent to which ileum or jejunum is resected, and whether the ileocecal valve and right colon are removed in conjunction with the small bowel. Significant malabsorption usually does not occur until over 75Yo of the entire small bowel is resected. The malabsorption seen in these patients after extensive surgical resection can be compounded by postoperative gastric hypersecreti~n.~~~ gastric hypersecretion This can further intensify the diarrhea seen in the patients with short-gut syndrome. The increase in intraluminal intestinal acid concentration after massive small bowel resection can also inhibit enzyme digestion of nutrients. I Nutritional deficits caused by the extensive intestinal resection consist of fluid and electrolyte losses, steatorrhea, as well as deficiences in iron, calcium and vitamin D. When more than 100 cm of the ileum is removed, marked increases in steatorrhea occur. The diarrhea noted in the patients with extensive ileal resections can further be intensified by malabsorption of bile salts5Vitamin B 12 deficienciescan occur in this setting. Although extensive small bowel resection may have a tremendous initial metabolic impact on the patient, the small bowel has a great capacity for adaptation. The remaining small bowel has been shown to significantly increase its absorptive capacity following extensive resections.I2-I4The phenomena ofadaption by the small bowel may lessen the long term nutritional impact of massive intestinal resection. Colectomy performed for colon carcinoma has a limited effect on the nutritional status ofthe host. In patients who have had a total colectomy or ileoanal anastomosis, profuse diarrhea may occur, producing large fluid and electrolyte losses. The remaining bowel rapidly adapts after colon resection, so that these fluid losses quickly diminish. Therefore, the long-term nutritional disabilities in patients who have had a total colectomy or ileoanal anastomosis are of minor clinical importance. Cancer of the pancreas is one of the leading causes of death from cancer in the United States. Although only about 10% of the patients with carcinoma of the pancreas will be resectable for cure, pancreatectomy may have a significant impact on the nutritional status of the host.Is Pancreatic exocrine insufficiency has been reported in 22% to 28% of the patients undergoing a pancreaticoduodenectomy for carcinoma of the head of the pancreas or periampullary region.I6-I8Pancreatic exocrine deficiency can lead to malabsorption of fat, fat soluble vitamins (vitamins A, D, E, and K), amino acids, and various minerals such as calcium and magne~ium.~ The pancreatic exocrine insufficiency which occurs following surgical resection can be reasonably managed by

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with Severe Nausea and Vomiting
Drug

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use of a commercial pancreatic enzyme preparation. Various authors have proposed that total pancreatectomy is the preferred treatment for all operable carcinomas of the p a n ~ r e a s . Total~pancreatectomy can ~,~ impose an even greater metabolic disturbance on the host beyond that of pancreatic exocrine insufficiency. All such patients have diabetes. A severely labile diabetes can occur in 20% of the patients.2 Furthermore, the usual diabetic type diet with its increased percentage of protein and fat can further exacerbate the pre-existing steatorrhea. l 9 Chemotherapy Chemotherapy may have important nutritional consequences in the tumor bearing host. Chemotherapeutic agents may contribute to host malnutrition through a variety of direct and indirect mechanisms, including nausea and vomiting, mucositis, organ injury, and learned food aversions. The adverse nutritional effects of chemotherapy can be compounded in the host who is already cachectic from his tumor, or who has received prior or concurrent radiation therapy. Nausea and vomiting frequently accompany administration of most antitumor drugs. The nausea and vomiting induced by chemotherapy is mediated through the vomiting center in the medullary reticular formation. The severity and duration of the nausea and vomiting seen from chemotherapeutic agents is dependent on the agent used, its dose and route of administration, and whether the patient has developed anticipatory vomiting or a conditioned aversion to the chemotherapy. Chemotherapeutic agents most commonly associated with severe nausea and vomiting are nitrogen mustard, chloroethyl nitrosoureas, streptozotocin, cisplatin, and imidazole carboxamide ( DTIC)22 (Table 2). Virtually all of the patients who receive these agents will experience significant nausea and vomiting. Other common antitumor agents can show a high incidence of vomiting during their administration. Adriamycin (doxorubicin) has been reported to induce vomiting in about 60% of the patients.23Vomiting seen in 5-fluorouracil(5-FU) therapy has been reported from only occasional, to an incidence of 50Yo to 65% depending on the dose and frequency of drug admini~tration.~*-~ nausea and The vomiting that occurs during chemotherapy can have a marked nutritional impact on the host who may already be debilitated from cancer or complications of treatment of the tumor by either surgery or radiation therapy.22 Chemotherapeutic agents are most active on rapidly proliferating cells. Since the mucosa of alimentary tract has cells with a very rapid growth fraction, it is not surprising that many chemotherapeutic drugs could have significant gastrointestinal toxicity. Mucositis is the

TABLE Chemotherapeutic Agents Commonly Associated 2.

Severity and duration Occurs in virtually all patients May be severe but usually subsides within 24 hours Variable but may be severe Occurs in nearly all patients Tolerance improves with each succeeding dose on a 5day schedule May be very severe Tolerance improved with intravenous hydration and continues 5day infusions. Nausea may persist for several days. Occurs in virtually all patients Tolerance improves with each succeeding dose on a 5day schedule

Nitrogen mustard

Chloroethyl nitrosoureas Streptozotwin

Cisplatinum

lmidazole carboxamide (DTIC)

* Reprinted with permission from Mitchell EP, Schein PS.Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol 1982; 95264.

major gastrointestinal toxicity of chemotherapeutic agents. Significant mucositis can be produced by various agents including methotrexate, 5-W, actinomycin D, Adriamycin, bleomycin, and vinblastine22 (Table 3). The mucositis produced by these agents may be greatly enhanced when concurrent radiation therapy is given.23-28,29 Mucositis from methotrexate infusion can present as severe painful ulcerations in the oral cavity.30 Mucositis from such agents as 5-FU can present as bloody diarrhea. As mentioned, the renewal rate of the alimentary tract mucosa is rapid, so that the mucositis following chemotherapy is usually short lived. The vinca alkaloid, vincristine, can cause abdominal
TABLE Chemotherapeutic Agents Commonly 3. Associated with Mucositis*
Drug
~~

Related factors May be quite severe with prolonged infusions or compromised renal function. Severity is enhanced by irradiation. May be prevented with adequate citrovorum rescue factor. More severe with higher doses, frequent schedule, and arterial infusions. Very common and may prevent oral alimentation. Severity enhanced by irradiation. May be severe and ulcerative. Increased with liver disease. Severity enhanced by irradiation. May be severe and ulcerative. Frequently ulcerative.

Methotrexate

5-Fluorouracil Actinomycin D Adriamycin Bleomycin Vinblastine

* Reprinted with permission from Mitchell EP,Schein PS.Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol 1982; 95264.

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TABLE Effects of Radiotherapy Creating Nutritional Sequelae. 4.

Region Head and Neck Early Odynophagia Xerostomia Mucositis Anorexia Dysosmia Hypogeusia Dysphagia Anorexia Nausea Vomiting Diarrhea Acute enteritis Acute colitis Late Ulcer Xerostomia Dental caries Osteoradionecrosis Trismus Hypogeusia Fibrosis Stenosis Fistula Ulcer Malabsorption Diarrhea Chronic enteritis Chronic colitis

can persist long after all gastrointestinal symptoms have subsided.

Radiation Therapy

Thorax Abdomen and

pelvis

Adapted with permission from Donaldson SS,h n o n RA.Alterations of nutritional status: Impact of chemotherapy and radiation therapy. Cancer 1979; 43:2036-2052.

pain, constipation and adynamic i l e ~ s . ~This autol-~~ nomic nervous system dysfunction appears to be more severe in the elderly patient, as well as in the dose-dependent patient.33The ileus produced by vincristine may last up to two weeks. Thus, vincristine administration may lead to major metabolic disturbances in the host. Indirect effects of chemotherapy in the tumor-bearing host may also play a role in host malnutrition. Candidiasis or moniliasis of the gastrointestinal tract is a not uncommon occurrence during chemotherapy, especially in patients with leukemias and l y m p h o r n a ~Gas.~~ trointestinal candidiasis can occur in oral cavity, pharynx, or esophagus. Candidiasis in these areas can produce symptoms of a painful mouth, odynophagia, and dysphagia. All of these symptoms can lead to a dramatic reduction of oral intake in the cancer patient. Learned food aversions, the intense dislikes that develop as a result of the association of various foods with unpleasant gastrointestinal symptoms,35are another indirect mechanism through which chemotherapy can adversely affect the nutritional status of the host. Symptoms such as nausea and vomiting are frequently from antitumor therapy. Although any antitumor therapy may cause learned food aversions, chemotherapy is the most common clinical cause. The severe nausea and vomiting that occurs during chemotherapy can cause aversions to food consumed prior to chemotherapy administration. The aversion developed to food is most likely to be against foods which are new or novel to the patient.36 Repeated association of gastrointestinal discomfort with a specific food can produce learned food aversions even to familiar items.37Berstein has shown that 48% of the patients who received gastrointestinal toxic chemotherapy developed learned food aversion^.'^ Learned food aversions occurring during chemotherapy

Radiation therapy can cause a variety of effects on the host which may have a significant metabolic impact. Early radiation effects such as mucositis, diarrhea, xerostomia, alterations in taste and learned food aversions can contribute to host malnutrition. Problems seen long after the completion of radiotherapy, such as mucosal ulceration, alimentary tract strictures or obstruction, osteoradionecrosis of the mandible, trismus, intestinal fistulas, malabsorption and enteritis, may also contribute to prolonged nutritional impairment of the host38s39 (Table 4). Radiation effects in the alimentary tract are dependent on numerous factors such as the site, the total dose, fractionation and field size of the radiation administered. Furthermore, the radiation complications may be significantly affected by associated antitumor therapy such as surgery or ~hemotherapy.~~ Radiotherapy is an important therapeutic modality in the treatment of head and neck cancers. Such therapy can dramatically decrease food intake on the tumorbearing host through several mechanisms. One of the most important mechanisms that occur in the patient during head and neck irradiation is mouth blindness or alterations in taste.40As early as 2 weeks following the initiation of therapy, changes in taste acuity may occur, consisting of a decreased ability to recognize certain tastes, especially bitter and salty.41 the study by ChenIn charick and Mossman over 85% ofthe patients undergoing head and neck irradiaton developed subjective changes in their taste perception. These changes in taste perception were manifested as either a loss of taste or an unpleasant taste during eating.42 note, over 50%of the Of patients in the latter study complained that high protein foods, i.e., meat, eggs, etc., were associated with an abnormal It is easily appreciated that as food loses its taste or actually becomes unpleasant tasting, oral intake will quickly diminish. Xerostomia is a common problem during radiotherapy in the head and neck cancer patient. When the major salivary glands are in the field of ionizing radiation, the amount of salivary production decreases in conjunction with an increase in the viscosity of the saliva. The changes in salivary secretion can lead to a thick tenacious saliva, which in itself can greatly impair swallowing.43Furthermore, xerostomia can also lead to accelerated dental caries.* The combined factors of dysphagia and accelerated dental caries can both contribute to reduction in oral intake of the patient. The mucosa of the alimentary tract is sensitiveto radiation exposure. The degree to which mucositis occurs is

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A major cause of steaand electrolyte dependent on such factors as dose fractionation and size torrhea and diarrhea in the patients undergoing such of the treatment field. Stomatitis during the course of therapy is choleretic e n t e r ~ p a t h yCholeretic en.~~~~~ head and neck radiation may produce such problems as teropathy represents malabsorption of bile salts by the painful mucosal ulcerations and intraoral bleeding, conirradiated small bowel, which will cause fat malabsorptributing to host hypophagia. tion in the host. In addition, bile salts entering the colon Other acute radiation effects that could impair host in sufficient quantity will inhibit water absorption and nutrition have been described in the head and neck pastimulate colonic peristalsis, causing further fluid and tient, including loss of smell and learned food averelectrolyte deficiencies. Deficiencies in both disaccharis i o n ~ . ~With~all the oral intake-suppressive mecha-~ dase and peptidase enzymes have also been noted in the nisms operative in the irradiated head and neck cancer irradiate small bowel.57 patient, it is not surprising that malnutrition can occur The late radiation effects of abdominopelvic irradiaduring the cancer therapy. Donaldson has shown that tion occur in 0.5% to 15% of the patientss8 These effects 93%of the patients lost weight while undergoing curative can radiation therapy to the oropharynx and h y p o p h a r y n ~ . ~ ~ be noticed months to years after completion of radiotherapy, and can be manifested as intestinal obstrucWhen one appreciates that a large number of head and tion, enteritis, or colitis or fistula formation. All these neck cancer patients are already malnourished prior to late complications of radiation therapy can have an adantitumor therapy, the nutritional deficits imposed on verse effect on the hosts nutritional status. these patients during radiotherapy could be devastati r ~ g Aggressive nutritional support in the head and .~~ Summary neck cancer patient undergoing radiation therapy is frequently needed in the form of tube feeding. It has been well documented that surgery, chemotherLate effects of head and neck radiotherapy can proapy, and radiation therapy used in the treatment of duce such problems as mucosal ulceration and osteoracancer may produce significant nutritional disabilities in dionecrosis of the mandible or trismus. Larson and assothe host. The nutritional disabilities imposed by antituciates have examined patients with oropharyngeal mor therapy have even greater importance when one carcinomas who were treated solely by radiation therrealizes that the cancer patient may already be malnourapy. He noted that 56% of those patients developed muished from his disease prior to treatment. The clinician cosal ulcerations, osteoradionecrosis of the mandible, or responsible for the care of the cancer patient must be both complications following therapy.47 Of those paaware of nutritional deficits imposed by the various motients who developed the latter, 41% required a partial dalities of antitumor therapy. In this manner, the detrimandi bulectomy. mental effects of host malnutrition may be prevented. Radiation therapy, a common modality of treatment of patients with thoracic malignancies, may produce REFERENCES esophagitis during the course of treatment. Esophageal stricture, ulceration, or even perforation may be late I . 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