CHAPTER      32

Nutrition Support of Patients with Gynecologic Cancer

MARK SCHATTNER MOSHE SHIKE

INTRODUCTION

Cachexia and weight loss are common manifestations of cancer and exert major impacts on quality of life and survival. Malnutrition is a complex, multifactorial phenomenon that leads to progressive weight loss and deficiency of specific nutrients. Both cancer and its various therapeutic modalities contribute to cachexia. Advances in understanding nutritional requirements and intermediary metabolism, and major technologic progress in the ability to provide nutritional support, have made it possible to feed almost any patient with cancer. Nevertheless, the indications for and the appropriate use of the various modalities of nutritional support are still evolving, and many questions remain unanswered.

Malnutrition in most patients with cancer is usually a manifestation of general calorie-protein deficits that result in progressive weight loss and weakness; however, it is important to recognize that in some patients, specific nutrient deficiencies, such as magnesium deficiency or vitamin B12 deficiency, can be present even in the absence of weight loss and can contribute significantly to morbidity and even mortality.

Gynecological malignancies and their multimodal therapies may be associated with severe malnutrition. Although some nutritional problems occur in patients with cervical and endometrial cancer, they are most commonly seen in those with ovarian cancer, particularly in advanced stages when intra-abdominal metastasis severely impairs gastrointestinal function. Because of the high incidence of malnutrition and its impact on the patient with cancer, nutritional assessment and appropriate therapy should be integral parts of the overall treatment plan.

NUTRITIONAL ASSESSMENT

Nutritional assessment in cancer patients is an ongoing process. It should be a part of the patient’s initial evaluation and should be updated periodically. It is especially important to determine the nutritional state prior to therapeutic interventions as well as during and after an acute illness, with the goal of identifying those patients who could benefit from a specific form of nutritional support. The nutritional assessment method used must be simple, accurate, and inexpensive. Anthropometric parameters, serum protein measurements, and immunologic tests have classically formed the basis of the nutritional evaluation; however, they all have significant deficiencies.

Anthropometric and Biochemical Markers

Anthropometric measurements such as weight, skin fold thickness, mid-arm muscle circumference, and creatinine/height index can all provide useful information but have major limitations. Change in weight is the single most useful measurement of the nutritional status when the change does not reflect changes in total body water. The often-present edema, effusions, ascites, or intravenous hydration limit the use of weight as a nutritional parameter. In addition, inaccuracies in scales and different clothing in hospitals and at home can often be sources of misleading information on changes in weight. Measurements of skin folds and mid-arm muscle circumference (1) are useful tools in studies but have very limited use in clinical practice. A creatinine/height index derived by dividing the patient’s 24-hour creatinine excretion by that of a healthy person of the same height offers a sensitive measure of early protein calorie malnutrition (2) but requires collection of a 24-hour urine specimen and is affected by alterations in renal function, which may not be indicative of the nutritional state.

Low levels of serum proteins such as albumin, prealbumin, transferrin, and retinol-binding protein were classically thought to represent malnutrition. However, in the malnourished sick patient, low levels of these proteins can be nonspecific. They are dependent on intact hepatic synthetic function as well as hydration status. At times, they can be low as a manifestation of severe illness (infection, metastatic cancer, multisystem organ failure) without being a reflection of the nutritional state. In addition, they can function as acute phase reactants and therefore be in the normal or elevated range in a clinically malnourished patient. The role of serum protein measurements in the nutritional assessment of an ill patient with cancer is therefore very limited. Similar limitations apply to the role of immunologic parameters such as total lymphocyte count and delayed cutaneous hypersensitivity. In simple starvation, both of these measures may be decreased and can return to normal with initiation of nutritional support. However, in the cancer patient undergoing chemotherapy, surgery, or radiotherapy or in the midst of an acute illness, these parameters have little determinative value in the assessment of the nutritional state (3, 4).

The above parameters have been combined to create numerous nutritional assessment indices. The most extensively studied is the Prognostic Nutritional Index (PNI), which factors measurements of serum albumin, serum transferrin, triceps skin fold, and delayed cutaneous hypersensitivity (5). Buzbey et al. prospectively studied the PNI in patients undergoing gastrointestinal surgery and found that it could accurately stratify patients into high, intermediate, or low risk of developing postoperative complications (6). It must be understood, however, that the index is only as good as the parameters from which it is calculated, and the same limitations outlined above are present in any of these indices.

Subjective Global Assessment

The clinical assessment of the nutritional status has always been used to some extent as part of the general medical history and physical examination. The validity of a formal clinical assessment of the nutritional status was demonstrated in a landmark study by Baker et al., who developed the Subjective Global Assessment (SGA) (7). The SGA is based on a complete history and physical examination, with special emphasis on six areas: change in weight, dietary intake, gastrointestinal symptoms, functional capacity, physiologic stress, and physical signs of nutritional deficiencies. These data are used to place the patient into one of three groups. Group “A” (normal nutritional status) is made up of those patients without restriction of food intake or absorption, no change in functional status, and stable or increasing weight. Group “B” (mild malnutrition) consists of patients with evidence of decreased food intake and functional status but little or no change in body weight, while those with severe reduction in food intake, functional status, and loss of weight comprise group “C” (severe malnutrition).

The SGA has consistently been shown to be reproducible and reliable in identifying patients at risk for developing complications associated with malnutrition. In the initial study of 59 patients electively admitted to a general surgical ward interobserver reproducibility in classification of the nutritional status was 81%, and in a later study of 202 patients, it was found to be 91% (7,8). Group assignment based on the SGA had prognostic significance on the ensuing clinical course. The initial study by Baker and colleagues showed a significant increase in incidence of infection, use of antibiotics, and length of hospitalization in Group “C” when compared to Group “A” (7). In the followup study of 202 patients undergoing gastrointestinal surgery, the rate of septic and nonseptic complications in Group “C” was 7 times greater than in Group “A” (8). However, it must be recognized that although nutritional parameters are used to determine the SGA, the classification may still represent severity of illness rather than specific nutritionally related complications. Only a determination that the classification predicts which patients will respond favorably to nutritional support (with a decrease in complications) can validate the specificity of this technique. Nevertheless, the SGA provides a simple, reproducible, and accurate method to identify patients who are malnourished who could possibly benefit from nutritional support. Clinical assessments similar to the SGA have been shown to be superior to immunologic testing, plasma protein measurements, and bioelectrical impedance in providing a useful evaluation of nutritional status (7–12).

More recently, the SGA has been shown to predict survival and tolerance to chemotherapy among women with ovarian cancer (13,14). It is now considered the preferred method of nutritional assessment for patients with gynecological cancers (15).

PREVALENCE OF MALNUTRITION

The prevalence of malnutrition depends on the tumor type and stage, the organs involved, and the anticancer therapy. Concurrent nonmalignant conditions such as diabetes and intestinal diseases can be important contributing factors.

The prevalence of weight loss during the 6 months preceding diagnosis of cancer was reported from a multicenter cooperative study of patients with 12 types of cancer (16). The lowest frequency (31% to 40%) and severity of weight loss were found in patients with breast cancer, hematologic cancers, and sarcomas. Intermediate frequency of weight loss was found in patients with colon, prostate, and lung cancer (54% to 64%). Patients with cancer of the pancreas and stomach had the highest frequency (over 80%) and severity of weight loss. Approximately 35% of the patients with lung cancer lost more than 5% of their body weight. This underscores the fact that even if the tumor does not involve the gastrointestinal tract directly, there can be significant weight loss because of systemic and metabolic derangements and loss of appetite. The study did not report on patients with gynecologic malignancies, in whom weight loss can also be very frequent and severe. Other studies revealed that over 40% of patients receiving medical treatment for a variety of cancers were malnourished (17,18). Among surgical patients in a Veterans Administration hospital, 39% of those undergoing a major operation for cancer were malnourished, as judged by either a nutrition risk index or a combination of weight loss and low serum proteins (19). Data on the prevalence and impact of malnutrition in patients with gynecologic tumors mirror the observations in patients with other cancers. In a study of 67 consecutive patients hospitalized with gynecologic cancers at the University of Texas, it was found that 54% of the women were malnourished as determined by the PNI (20). In 1983, Tunca (21) examined the nutritional state of gynecologic oncology patients at time of diagnosis using serum albumin, serum transferrin, immune response, and weight loss. Patients with advanced (stage III or IV) ovarian carcinoma had the highest incidence of severe malnutrition, while those with cancer of the cervix, endometrium, or vulva reported weight loss with no indication of malnutrition from serum markers or immune response testing. Twenty of the 21 patients with advanced ovarian carcinoma were anergic to recall antigens, and the mean levels of all serum markers examined were significantly lower than those found in patients with early (stage I or II) ovarian carcinoma or cancer of the cervix, vulva, or endometrium. Orr et al. (22,23) assessed the degree of protein-calorie malnutrition and evidence of vitamin deficiency in 78 patients with untreated cervical cancer. The incidence of protein-calorie malnutrition as assessed by anthropometrics, serum markers, and immune testing was directly related to tumor stage: 4% in stage I, 20% in stage II and III, and 60% in stage IV disease (22). Two-thirds of patients with untreated cervical cancer were found to have reduced blood levels of at least one vitamin. Mean serum levels of folate, b-carotene, and vitamin C at the time of admission were all significantly below control values (23). Similar observations of significant protein-calorie malnutrition were seen in 25 patients with endometrial cancer (24). Using the SGA to study 194 patients with gynecologic cancers, Laky showed that 24% of all patients were malnourished. The prevalence of malnutrition was highest in ovarian cancer (67%) and lowest in endometrial cancer (6%) (15).

SIGNIFICANCE OF MALNUTRITION

The impact of malnutrition on the cancer patient was demonstrated in a report by Warren in 1932 (25). Based on data from autopsies, the conclusion was that cachexia was the leading cause of death in a group of 400 patients with various cancers. More recent studies have confirmed the significant impact of malnutrition on the quality of life and prognosis of the cancer patient. In the aforementioned multicenter, cooperative study of patients receiving chemotherapy (16), those who presented with weight loss at the time of diagnosis had decreased performance status and survival compared with those without weight loss. In a study of patients with limited, inoperable lung cancer, weight loss was a major predictive factor for survival (17). The negative impact of malnutrition was also demonstrated in surgical patients with malignant and benign diseases. Malnourished patients undergoing a major operation were at greater risk for postoperative morbidity and mortality than were well-nourished patients (19,26).

The impact of malnutrition on patients with a primary gynecologic malignancy is striking. While examining the role of total parenteral nutrition (TPN) in their patients, Terada and colleagues noted that those patients who developed major complications such as a fistula, wound infection, pneumonia, renal failure, respiratory failure, or those who died had significantly more weight loss and lower serum transferrin levels at the time of presentation (27). They concluded that these parameters might be of value in predicting clinical outcome in patients requiring nutritional support. This was confirmed in a study by Geisler, who found that in patients with ovarian cancer, those patients who were malnourished had increased postoperative complications. This difference could be mitigated if preoperative nutritional support could reverse the malnutrition (28). Several other studies have confirmed the relationship of malnutrition to poor surgical outcome in patients with primary gynecologic malignancies. Burnett et al. (29) reported that in 92 gynecologic oncology patients requiring colonic surgery, those who were classified as malnourished on the basis of serum markers were significantly more likely to develop major perioperative complications or die. Donato et al. (30) reported that of the 104 patients with ovarian carcinoma undergoing intestinal surgery, those considered to be malnourished on the basis of serum protein measurements and weight loss preoperatively had significantly more infectious complications, while other variables including preoperative bowel obstruction, extent of debulking, number of intestinal procedures, or hand versus stapled anastomosis failed to correlate with the rate of infectious complications (30). Poor nutritional status has been shown to be an independent predictor of prolonged postoperative ICU stay in patients with ovarian cancer (31).

In addition to predicting surgical outcome and perioperative complications, malnutrition is associated with increased neutropenic fever following chemotherapy, prolonged hospital stay, decreased quality of life, and reduced overall survival among women with gynecologic cancers (13,14,15,20,32).

ETIOLOGY OF MALNUTRITION

Cancer can induce a wide variety of derangements in the nutritional status, ranging from generalized malnutrition with severe weight loss and muscle wasting to a single nutrient deficiency. The etiology of malnutrition in the cancer patient is multifactorial. Nutritionally relevant derangements can be induced by the tumor locally (i.e., gastrointestinal obstruction), by malabsorption, or by humoral factors produced by the tumor itself or by reaction of the immune system to the tumor. All modalities of cancer therapy, surgery, radiation, chemotherapy, immunotherapy, and palliative treatments, may be associated with side effects and complications that can impair the nutritional status.

The etiologic factors of malnutrition in the cancer patient, whether caused by tumor or antitumor therapies, can be classified into three major categories: decreased food intake, malabsorption, and metabolic derangements that result in inefficient, wasteful metabolism.

Impaired Food Intake and Absorption

Both tumor and cancer treatment modalities can lead to decreased food intake through direct effects on the gastrointestinal tract or systemic effects leading to anorexia. Obstruction of the gastrointestinal tract can be caused by any gynecologic malignancy through external compression, or more rarely, by direct invasion. Although at times localized obstructions can be relieved surgically or endoscopically, the obstruction due to peritoneal carcinomatosis often seen in advanced ovarian cancer is particularly difficult to manage surgically. Often, draining gastrostomy with parenteral nutrition (when appropriate) is the only option for providing nutrition and symptomatic relief (33–35).

Tumors can induce anorexia without local involvement of the gastrointestinal tract. The pathophysiology of this phenomenon is not well understood. Norton et al. (36) utilized a model of surgically coupled tumor-bearing and normal rats with parabiotic cross-circulation to show that tumor-induced anorexia is mediated by circulating substances. Tumor-induced impairment of smell and taste has been well described (26,37–40), but the mechanism has not been defined. There is growing evidence that glycoproteins, cytokines, and neuropeptides play an important role in the pathogenesis of cancer cachexia. Bernstein et al. (41,42) demonstrated in a rat model that infusion of tumor necrosis factor (TNF) mimics tumor induced anorexia and these effects are mediated via the area postrema and the caudal medial nucleus of the solitary tract in the central nervous system.

Therapies used for gynecologic malignancies often result in complications that impair nutrient intake and absorption. Surgical interventions can lead to fistulae, short bowel syndrome, infections, and ileus, all of which impair oral intake significantly. In a review of 12 years of colonic surgery in gynecologic oncology patients, the rate for major systemic complications (myocardial infarction, pulmonary embolism, renal failure, sepsis) was 13.7%, and the rate of major bowel complications (abscess, fistulae, hemorrhage, obstruction) was 12.1% (29). Adjuvant radiation and chemotherapy have been shown to increase the incidence of major complications after pelvic exenteration (43).

Radiotherapy can lead to various derangements in the structure and function of the gastrointestinal tract. Damage to the gastrointestinal tract following radiation to the abdomen and pelvis most commonly affects the small bowel, followed by the transverse colon, sigmoid, and rectum. Predisposing risk factors include pervious abdominal surgery, pelvic inflammatory disease, thin body habitus, hypertension, and diabetes mellitus (44). In general, a dose of 5,000 rads is the threshold for significant injury. In the acute phase of radiation enteritis, virtually all patients experience anorexia, nausea, and vomiting, which are thought to be mediated by effects of serotonin on the gut (45) and the central nervous system (46). This is followed 2 to 3 weeks later by direct injury to the intestinal mucosa, resulting in diarrhea and mild to moderate malabsorption. Most patients will have complete resolution of these acute symptoms. However, a significant minority of patients who received radiotherapy will experience chronic dysfunction of the gastrointestinal tract (47). There is often a latent period of 1 to 2 years, and possibly as long as 20 years, before the symptoms of chronic radiation enteropathy surface (48,49). In a review of 102 patients with radiation enteritis after treatment for cervical or endometrial cancer, the median time to development of severe symptoms such as obstruction or perforation was 18 months (50).

Chronic radiation enteropathy is characterized pathologically by transmural injury leading to submucosal fibrosis, edema, lymphatic ectasia, and obliterative endarteritis, which can induce colicky abdominal pain, diarrhea, steatorrhea, ulceration, perforation, stricture, and fistula formation (44). Yeoh et al. (51) retrospectively studied the effects of pelvic irradiation given for the treatment of cervical cancer in 30 randomly selected women who had undergone radiotherapy 1 to 6 years earlier. Significant dysfunction of the gastrointestinal tract was detected. Nineteen of the patients had frequency of bowel movements, bile acid absorption, and vitamin B₁₂ absorption outside of the control range. The authors concluded that abnormal gastrointestinal function is essentially an inevitable long-term complication of pelvic irradiation (51). Huaebye and colleagues (52) prospectively studied the gastrointestinal motility patterns in 41 patients with chronic abdominal complaints after radiotherapy for gynecologic cancer. Impaired fasting motility was found in 29% of patients, and motor response after a meal was attenuated in 24%. Postprandial delay of the migrating motor complex was found to be an independent predictor of malnutrition as assessed by weight loss and serum albumin. Impaired motility of the small bowel, therefore, is a key factor in the symptoms experienced by patients with chronic radiation enteropathy (52). Chronic radiation enteritis predisposes to numerous secondary complications. Danielsson et al. (53) studied 20 patients with chronic or intermittent diarrhea occurring in women 2 or more years after receiving radiotherapy for gynecologic tumors. Bile acid malabsorption was detected in 65% of patients, while evidence of bacterial overgrowth on D-xylose or cholyl-glycine breath tests was found in 45%. Treatment with bile acid binders or antibiotics resulted in a significant decline in the number of daily bowel movements. The authors concluded that treatment of these secondary complications of radiation-induced enter-opathy can offer significant symptomatic relief. In 47 patients with gynecologic malignancies who had gastrointestinal complaints lasting more than 4 months after radiotherapy, Kwitko et al. (54) found 19 partial small bowel obstructions, 11 cases of malabsorption, and 5 fistulae. The mortality from radiation damage to the small bowel in this report was 32%. More recently, Boland reported on a 25-year experience with postresection short bowel syndrome secondary to radiation therapy. The majority of the cases were in women who received pelvic radiation for gynecologic cancers (55). Improved fractionation of radiotherapy and protective shielding of the intestine where possible have reduced these complication rates (56). More recent studies of patients who received radiation therapy for uterine cancer found the prevalence of significant chronic radiation enteritis to be approximately 4% (57).

Chemotherapy is often associated with decreased food intake. Mucositis and diarrhea are commonly seen during therapy with cytotoxic agents that affect the replicating cells of the intestinal mucosa, such as 5-flourouracil, methotrexate, and bleomycin. The vinca alkaloids can cause ileus and constipation mediated by toxic effects on gastrointestinal neural pathways, while cisplatin and nitrosoureas are highly emetic (58,59). Significant nausea, vomiting, stomatitis, and diarrhea occur in 15% of patients receiving intravenous taxol and 55% in those receiving the drug orally (60). In addition to direct effects on the GI tract, chemotherapy in women with gynecologic cancers has significant effects on olfactory and gustatory function, leading to reduced appetite and weight loss (61).

The psychological impact of a malignancy and its associated therapies can also lead to decreased nutrient intake. Depression is a frequent cause of anorexia in this population, with up to 58% of cancer patients having depressive symptoms and 38% meeting criteria for major depression (62).

Metabolic Derangements

Even with normal nutrient intake patients with cancer are at risk for malnutrition due to inefficient nutrient utilization and wasteful metabolic pathways. Compared to simple starvation, cancer cachexia is associated with altered metabolism of carbohydrates, fat, protein, vitamins, and minerals. Therefore, in order to optimize nutritional support in the cancer patient, it is imperative to consider metabolic derangements along with problems of ingestion, digestion, and absorption.

Increase in basal energy expenditure has been reported in many but not all studies of patients with malignancy (63–69). In patients with newly diagnosed small cell lung cancer, Russel et al. (67) showed a mean increase of 37% in basal energy expenditure, which fell substantially in those who responded to chemotherapy. Similar findings have been reported for gastric cancer (64) and sarcoma (70). Elevated basal energy expenditure will drop after tumor resection (71). There are limited data on the metabolic rate in patients with gynecologic cancers (69). Dickerson et al. (72) used indirect calorimetry to determine the resting energy expenditure in 31 patients with ovarian cancer and 30 patients with cervical cancer. Fifty-five percent of those with ovarian cancer were found to be hypermetabolic (BEE >110% predicted by the Harris-Benedict equation), while only 13% of patients with cervical cancer were hypermetabolic. These differences could not be explained by differences in the extent of disease, nutritional status, body temperature, or nutrient intake.

Abnormalities in carbohydrate metabolism in cancer patients include glucose intolerance and peripheral insulin resistance (73–76). These most often become apparent in the patient with advanced metastatic cancer found to have hyperglycemia, which is refractory to high-dose insulin infusion (76,77). In comparison, in simple starvation, patients are most often euglycemic or hypoglycemic. The hyperglycemia seen in cancer patients is exacerbated by increased hepatic gluconeogenesis. Shaw et al. (78) showed that this increase in glucose production is correlated with tumor burden and decreases after tumor resection. An increase in wasteful metabolic cycles such as the Cori cycle likely also contributes to altered glucose metabolism in cancer patients. Tumor cells produce lactate, which is used as substrate for gluconeogenesis in the Cori cycle and reconverted to glucose. For each cycle, there is a net loss of four high-energy phosphate bonds, leading to a large amount of energy wasted in this futile cycle. Though initial studies showed that the increase in the Cori cycle had a large contribution to increased energy expenditure in patients with metastatic disease and weight loss, subsequent studies show that an increase in the Cori cycle has only a minor role in alterations of glucose metabolism. There is ongoing research identifying other futile cycles (79).

Lipid metabolism may also be abnormal in patients with a malignancy. There is often increased lipolysis with weight loss, and this leads to a decrease in fat mass, which can be out of proportion to the loss of lean body mass (75,80). In addition, patients with cancer are often hyperlipidemic, and this may be mediated by TNF-α (81). In contrast to normal homeostasis, cancer patients fail to suppress lipolysis with glucose infusion (78). Several causes of increased lipolysis have been proposed, including decreased food intake, stress response to illness with adrenal medullary stimulation and increased circulating catecholamine levels, insulin resistance, and release of lipolytic factors produced by the tumor itself or by myeloid tissue cells (82). One such factor has been well characterized (83). Lipid mobilizing factor (LMF), a 24-kDa glycoprotein produced by tumors has been shown to stimulate increased lipid mobilization from adipocytes (84). LMF is thought to act through binding of β-adrenergic receptors and subsequent upregulation of mitochondrial uncoupling proteins (85,86). Animal studies have shown that LMF causes loss of body weight (specifically a loss of body fat), which is independent of caloric food intake (87). The activity of LMF in the urine and serum of cancer patients has been shown to correlate with the degree of weight loss (88) and tumor burden (89). In addition to its effect on lipid metabolism, there is preliminary evidence that LMF may protect tumor cells from free radical toxicity and may therefore make tumors less responsive to certain chemotherapeutic agents that induce oxidative damage (90).

High total body protein turnover, with increased synthesis and catabolism, characterizes the alterations of protein metabolism seen in cancer patients (91,92). This results in depletion of muscle mass and loss of nitrogen, and contrasts with the adaptive decrease in protein turnover seen in patients with uncomplicated starvation (93). Total parenteral nutrition given to patients with cancer will result in gains of weight and body fat, net gains of total body nitrogen, but no suppression of the high protein flux (92,93). The predominant mechanism of muscle protein loss in cancer patients is an ubiquitin-associated pathway (94). In this pathway polyubiquitin chains are attached to proteins, which are then recognized and degraded by a proteasome complex. This pathway is regulated, in part, by proteolysis-inducing factor (PIF). PIF is a 24-kDa glycoprotein produced by human tumors and was found in the urine of cancer patients who were losing weight, but not in the urine of cancer patients who were maintaining their weight. In fact, PIF expression directly correlates with the severity of weight loss. There are multiple mechanisms by which PIF induces weight loss. PIF has a direct effect on skeletal muscle by decreasing protein synthesis and increasing protein degradation by upregulating the ubiquitin-proteasome dependent pathway. PIF also increases the expression of proinflammatory cytokines (i.e., interleukin-6 and -8), which independently cause weight loss, and induces the shedding of syndecans (transmembrane proteoglycans), which has been shown to be related to increased metastases and mortality (79,95). Effective treatment of the underlying cancer has been shown to reverse ubiquitin-dependent proteolysis of skeletal muscle (96). Better understanding of this process holds the promise of improving therapy to attenuate the loss of protein seen in patients with cancer (97).

Cytokines play an important role in inducing the metabolic derangements seen in the cancer patient (69). They mediate increased energy expenditure, whole body protein turnover, rise in serum triglyceride levels, and high glycerol turnover (25,98). TNF can be detected in the serum of cancer patients (99), and in animal models, it causes protein wasting, depletion of body fat, and anorexia (100,101). High serum levels of interleukin-1 and interleukin-6 are also present in patients with advanced cancer and cachexia. Interventions to downregulate these cytokines result in improved appetite, body weight, and quality of life (102).

The combined effects of these wasteful and inefficient alterations in metabolism make it difficult to restore nutritional status in the patient with cancer and cachexia despite the use of specialized nutritional support. This is in contrast with what is seen in patients with uncomplicated starvation who exhibit changes in metabolism, which act to conserve energy and body tissues, and in whom nutritional support is highly efficacious in reversing the effects of malnutrition.

NUTRITIONAL THERAPIES

There are four types of nutritional therapies: parenteral nutrition, enteral nutrition, oral dietary therapy, and drug therapy aimed at improving appetite and food intake. Depending on the patient’s condition, nutritional support in the cancer patient has two distinct objectives: (a) provision of nutrition during anticancer therapies to counteract their nutritionally related side effects and improve outcome following these therapies and (b) support in patients with long-term or permanent severe impairment of the gastrointestinal tract. In these patients, nutritional support may be required for indefinite periods of time. Results of numerous clinical trials support the use of nutritional support only in limited situations during anticancer therapies. In the group with prolonged gastrointestinal failure, nutritional support may be a lifesaving therapy because patients could die of starvation without TPN or enteral feeding.

Total Parenteral Nutrition

TPN is an effective method for delivery of nutrients directly into the blood, and thus overcomes the major causes of cancer-induced weight loss, including decreased food intake and dysfunction of the gastrointestinal tract. Survival for more than 20 years in patients nourished exclusively by TPN clearly demonstrates the life-saving role of this method of nutritional support. Initially, it seemed logical that TPN would be an effective adjuvant therapy for most cancer patients undergoing radiation therapy, surgery, or chemotherapy because of the accompanying cachexia and inability to eat adequately. Randomized studies, however, have shown that TPN only benefits a select subgroup of cancer patients during anticancer therapy.

Efficacy

In patients receiving chemotherapy with or without radiation therapy, TPN can lead to improvements of several nutritional parameters. Both body weight and body fat increase (93). Deficits of specific vitamins, minerals, and trace elements can be corrected, and hydration status can be improved (93,103). TPN, however, does not alter many of the metabolic derangements encountered in the cancer patient. Increased glucose oxidation and turnover persist (78,104), as does muscle proteolysis (105,106) and increased lipolysis (107). Finally, TPN does not stop the overall losses of body nitrogen (108). The relevant issue for the clinician is the effect of TPN on the morbidity and mortality associated with cancer therapy and whether TPN can allow more intense therapy as was initially hoped. Numerous randomized trials have examined this issue. Studies of patients undergoing chemotherapy for carcinoma of the ovary (33), lung (109,110), colon (108), testes (111), lymphoma (112), and other tumors (113) have been conducted. However, the patients in these studies were largely unselected. Many were not malnourished and others had adequate oral intake with intact gastrointestinal function, making intravenous nutrition unnecessary, futile, and potentially harmful. Numerous meta-analyses concluded that nondiscriminatory use of TPN in patients undergoing chemotherapy offers no improvement in mortality, response to chemotherapy, or reduction in treatment associated complications (114–116). This conclusion was echoed in a consensus statement from the National Institutes of Health, the American Society for Parenteral and Enteral Nutrition, and the American Society for Clinical Nutrition (117). The improvement in nutritional parameters afforded by TPN in patients receiving chemotherapy is not necessarily translated into improved clinical outcome. Thus, the routine use of TPN in these patients is not indicated.

There are circumstances, however, in which nutritional support with parenteral nutrition should be considered. These include prevention of the effects of starvation in a patient unable to tolerate oral or enteral feedings for a prolonged period of time (usually more than 7 to 10 days), maximization of performance status in a malnourished patient prior to chemotherapy or surgery, and in patients undergoing bone marrow transplantation (118). TPN may have a stimulatory effect on tumor cell cycle kinetics (119). It was hoped that this effect would induce improved tumor response to cell cycle-specific chemotherapy. Conclusive proof of such a response remains elusive.

A few randomized studies have examined the use of TPN in patients receiving radiotherapy to the abdomen and pelvis (120–123). These studies did not show any clear benefit from the routine administration of TPN.

The role of TPN in the perioperative period has been extensively studied (19,124–128). In an early study by Mueller et al. (128), 10 days of preoperative TPN was associated with nutritional improvement and significant reduction in major postoperative complications and mortality. These impressive results have not been confirmed in subsequent studies. At Memorial Sloan-Ketttering Cancer Center, a prospective study of 117 patients undergoing curative resection for pancreatic cancer randomized to receive TPN or intravenous fluids in the postoperative period showed no benefit from routine use of postoperative TPN (129). The group receiving TPN had a significant increase in postoperative infectious complications. The largest prospective randomized trial investigating the role of TPN in the perioperative setting was the Veterans Administration Cooperative Study (19). In this study, 395 patients were randomized to receive 7 to 15 days of preoperative and 3 days of postoperative TPN, or oral feeding plus intravenous fluids. TPN did not improve morbidity or 90-day mortality. However, subgroup analysis showed that patients considered to be severely malnourished had fewer infectious complications if they received TPN. The authors concluded that the routine administration of preoperative TPN should be limited to patients who are severely malnourished, unless there are other specific indications.

Randomized studies specifically examining the role of perioperative TPN in patients with gynecologic malignancies are lacking. In a report by Terada (27), perioperative parenteral nutritional support was given to 84 of 99 patients. There were no major complications attributed to TPN, but 27% of the patients experienced minor complications: 11% due to central line placement or catheter sepsis, 2% due to fluid overload, and 13% had metabolic complications. There was no report on overall perioperative morbidity or mortality in comparison to patients who did not receive perioperative TPN.

These data and others provided the basis for a consensus statement from the National Institutes of Health, the American Society for Parenteral and Enteral Nutrition, and the American Society for Clinical Nutrition regarding the use of perioperative TPN, which states the following: (a) 7 to 10 days of preoperative TPN in a malnourished patient with gastrointestinal cancer results in a 10% reduction in postoperative complications; (b) routine use of postoperative TPN in malnourished surgical patients who did not receive preoperative TPN results in a 10% increase in complications; (c) if by postoperative day 5 to 10 a patient is unable to tolerate oral or enteral feedings, then TPN is indicated to prevent the adverse effects of starvation. This panel, however, cautioned that in the majority of studies looking at perioperative TPN, the amount and type of parenteral nutrition given was not optimal, and often patients were given excess calories. Therefore, the results may differ with the provision of relatively hypocaloric formulas (117). It is reasonable to extend these recommendations to the gynecologic oncology patient undergoing surgery (Table 32.1).

Composition of TPN Solution

Once the decision to proceed with parenteral nutritional support is made, access to a large bore central vein should be obtained. This allows the use of calorically dense, hypertonic solutions, which are often necessary in severely ill patients who may have restriction on the amount of intravenous fluids they can receive. The solution must provide the protein and caloric needs, fluid, minerals, trace elements, and vitamins. Although indirect calorimetry and nitrogen balance can be used to determine energy and protein requirements, they are too costly and cumbersome for routine use. There are numerous formulas, charts, and tables that can provide estimates of protein and calorie requirements. Estimates of nutrition requirements are based on weight and adjusted for the degree of physiologic stress encountered by the patient. Generally, patients require approximately 30 Kcal/kg nonprotein calories, 1 g/kg amino acids, and about 2,000 mL of fluid. As illness severity increases and organs’ functions change, adjustments may be required. Nonprotein calories can be provided as dextrose or lipid, and the relative amounts of these should also be individualized. Lipids provide 9 Kcal/g compared to 3.4 for dextrose (in dextrose solutions, glucose is present as glucose-monohydrate; hence, a gram contains less than 4 Kcal). Lipid calories are particularly useful in patients who have high caloric requirements but cannot tolerate a large fluid load. In addition, lipids are useful in patients with severe pulmonary or hepatic dysfunction as glucose metabolism produces more carbon dioxide, which can add to the burden of the ailing lung and can lead to fatty infiltration of the liver. Up to 60% of caloric requirements can be provided as lipid, but serum triglyceride levels must be monitored closely. Appropriate electrolyte content of TPN solutions is of critical importance. The amounts have to be tailored to the patient’s requirements and organ’s function. Care must be taken to prevent potentially fatal hypokalemia or hypophosphatemia (particularly in the patient with severe weight loss), which can be precipitated by insulin induced transport of the minerals to the intracellular space when inadequate amounts are given. Other electrolyte disorders, such as cisplatin-induced hypomagnesemia and SIADH, are common in the patient with gynecologic malignancy and must be addressed when ordering TPN. The TPN solution must also contain vitamins, minerals, and trace elements. Typically, these are available as standard commercial combination products. However, certain patients require specific modifications. For example, a patient with persistent diarrhea requires zinc supplementation in excess of the amounts present in standard trace element solutions.

Complications

Complications associated with TPN can be classified as catheter related, metabolic, or infections. Catheter complications most often occur during placement of a central venous catheter and include pneumothorax, hemothorax, arterial injury, and hematoma. These can all be minimized when the procedure is performed by an experienced physician (130). Cobb et al. (131) reported a 3% incidence of pneumothorax, arrhythmia, thrombus, or bleeding during 523 intravenous catheter placements. A more recent study of subcutaneous peripheral infusion ports in women with gynecologic malignancies demonstrated a thrombosis rate of 26% during a mean follow-up of 105 days. The authors concluded that other types of vascular access devices may be preferable in this patient population (132).

Metabolic derangements are frequently encountered during support with TPN, and the prescribing physician must be well versed in the pathophysiology of these disorders. Hyperglycemia is the most common abnormality (130), and if not corrected, can lead to an osmotic diuresis, dehydration, acidosis, and hyperosmolar coma. One metabolic complication that deserves special mention is the “refeeding syndrome.” In chronically ill patients with severe malnutrition, there is often a depletion of total body phosphorus and potassium. The phosphorous deficits may be masked by increased renal phosphorous absorption designed to maintain normal serum levels. When nutritional support is initiated, the infusion of a large glucose load with subsequent surge in insulin leads to increased cellular uptake of phosphorous and potassium, which may induce severe life-threatening hypokalemia and hypophosphatemia (133,134). These disorders cause widespread tissue and organ dysfunction, including muscle weakness, rhabdomyolysis, heart failure, cardiac arrhythmias, and respiratory failure, and may result in death in extreme cases (134). Therefore, in patients with evidence of severe undernutrition, nutrition support should be initiated with small amounts of dextrose calories, supplemental phosphorous and potassium, and careful monitoring of serum phosphorous and electrolytes.

TPN has been associated with cholestatic liver disease, as well as fatty infiltration of the liver and glycogen deposition. These abnormalities have been attributed to infusion of excessive glucose calories, imbalance of amino acids, and rarely, fatty acid deficiency (135). Elevation of serum transaminases may occur, but it is generally mild (135,136). Severe liver dysfunction in adult TPN recipients is rare and requires a search for causes other than TPN.

Infections are particularly serious complications in patients with malignancy receiving TPN. In an evaluation of seven studies comparing TPN plus chemotherapy to chemotherapy alone, Klein and Koretz found four studies that showed an increase in infectious complications in patients receiving TPN (122). A meta-analysis by the American College of Nutrition showed a fourfold increase in infections when patients receiving chemotherapy were given TPN (114). In a prospective, randomized study of TPN following pancreatic resection, recipients of TPN had significantly more infectious complications (129). Data from a VA randomized cooperative study showed that patients with mild to moderate malnutrition given perioperative TPN had increased rates of infections, while those with severe malnutrition developed significantly fewer infections when supported with TPN (19). Infectious complications are related to both central venous catheters and a variety of sites (wound infection, abscess, and pneumonia).

Home TPN

Long-term TPN in the home can be a lifesaving treatment in an appropriately selected group of patients. It is clear that cancer patients who have had severe gastrointestinal injury, such as massive intestinal resection or severe radiation enteritis, and in whom the cancer has been cured or is well controlled, benefit from long-term TPN at home (137). Survival rates and TPN-related complications in such patients are comparable to those seen in patients with benign diseases (Crohn’s disease, intestinal necrosis) who require home TPN. Among patients with widely metastatic disease and poor prognosis, home TPN offers very limited benefit (106). Only 15% of such patients survive longer than 1 year on home TPN (52). Recently developed techniques for placing feeding tubes make it possible to hydrate and feed patients enterally, even in the presence of gastrointestinal obstruction (118), and thus obviate the need for home TPN in patients with upper gastrointestinal tract dysfunction. In terminally ill patients, TPN should be avoided. The concern that such patients should not be “starved to death” is not a justification for TPN. A recent uncontrolled study of terminally ill cancer patients hospitalized at a long-term care facility suggested that these patients did not experience hunger or thirst, and that in those who experienced such symptoms, small amounts of food alleviated the symptoms (138). In such patients, the utilization of TPN either in the home or at health care facilities cannot be justified.

For patients with inoperable bowel obstruction due to metastatic ovarian cancer, predicting which patients will benefit from home TPN can be difficult (139). In a review of 9,897 days of home TPN administered to 75 patients with various cancers and intestinal obstruction, it was shown that a Karnofsky performance status greater than 50 at the initiation of TPN could accurately predict which patients would have improved quality of life while on home TPN. The authors concluded that home TPN should be avoided if the performance status is below this level (140). In addition, patients with a life expectancy of less than 2 to 3 months will not benefit from home TPN (106,140). In a study from Yale-New Haven Hospital of 17 patients with inoperable bowel obstruction due to malignancy, patients with ovarian cancer had the shortest survival (39 days) compared to patients with colon cancer (90 days) and appendiceal cancer (184 days) (141). Therefore, only a highly selected minority of patients with inoperable bowel obstruction can potentially benefit from home TPN. A recent study from Brown University evaluated 55 patients with terminal ovarian cancer and found the use of TPN conferred a median survival benefit of 4 weeks (142). Currently, the best selection criteria for such patients are a fair or better performance status and the potential for further antitumor therapy (Table 32.2).

Enteral Nutrition

Enteral feeding delivers a liquid-nutrient formula into the gastrointestinal tract through tubes placed into the stomach or small intestine. As in oral feeding, an adequately functioning small intestinal mucosa is required for absorption of nutrients. Enteral feeding can overcome many difficulties encountered in patients with a wide variety of gastrointestinal tract dysfunction. A proximal gastrointestinal obstruction can be bypassed; tubes can be placed distal to obstructions as far as the jejunum, and thus circumvent obstructing lesions of the oral cavity, esophagus, stomach, duodenum, or proximal jejunum (143,144). The liquid-nutrient formula can be delivered as a slow, continuous infusion, thus maximizing absorption by a limited intestinal surface, which can be overwhelmed by the higher volume delivered during oral feeding. Such an approach may be useful in patients with radiation enteritis, short bowel syndrome (with adequate remaining short bowel, usually 3 to 4 ft), or partial obstruction of the bowel.

Route of Administration and Nutrient Formula

Short-term (<2 weeks) access to the gastrointestinal tract can be obtained through nasogastric or nasoenteric tubes. Patients requiring longer nutritional support should have a gastrostomy or jejunostomy tube placed endoscopically, radiologically, or surgically. In comparison to nasal tubes, gastrostomy or jejunostomy tubes are wider (15 to 24 Fr) and therefore less likely to be obstructed by medications or nutrient solutions. In addition, they are fixed in the stomach or the upper intestine and do not migrate into the esophagus. Thus, the risk of aspiration is considerably decreased (143). These tubes are more comfortable and aesthetically pleasing (145). These benefits were demonstrated in a randomized study of patients after an acute dysphagic stroke, which showed patients fed with a gastrostomy tube had more optimal provision of nutrients, achieved a better nutritional state, and had less mortality than those fed with nasogastric tubes (146). Patients with gastrostomy tubes have been shown in prospective studies to receive over 90% of prescribed feedings compared to only 55% in patients fed through nasal tubes. These differences are largely attributed to nasogastric tube dislodgment (147). In a randomized study of 33 women with gynecologic malignancies, enteral feedings through a needle catheter jejunostomy maintained postoperative nutrition as measured by serum transferrin levels and was associated with few complications (148). The authors concluded that women with gynecologic cancers should have a jejunostomy placed at the time of operation if it is anticipated that long-term nutritional support will be required.

Stay updated, free articles. Join our Telegram channel

Join