Robert M. Russell, M.D., and Joel Mason, M.D.

In the last three years, Dr. Russell has received grant/research support from BASF and Roche Vitamins. Dr. Russell has also served as a consultant for Whitehall Robbins-Quaker; Dr. Mason has received grant/research support from Mead-Johnson Nutritional and also served as a consultant for Mead-Johnson Nutritional.

Release Date: 04/11/2002
Termination Date: 04/11/2005

Estimated time to complete: 1 hour(s).

Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Upon completion of this Cyberounds^®, the participant should be able to:

• Discuss the variety of factors that conspire to create malnutrition in the cancer patient
• Discuss the basic alterations in macronutrient metabolism that is involved in the process
• List and identify which subsets of cancer patients benefit from intensive nutritional support.

Russell

Malnutrition is commonly found in adult, hospitalized patients with a variety of conditions but malnutrition is most prevalent among patients who have been sick for a long time with a chronic disease such as cancer. Joel, can you tell us how common malnutrition is in the various types of cancers that are commonly encountered in American hospitalized patients?

Mason

Rob, certainly, malnutrition among cancer patients is common, although a precise answer to your question is somewhat difficult because it depends upon how you define malnutrition. I can tell you, for instance, that in one very large survey of several thousand patients who were about to embark on chemotherapy, about one-sixth of those patients had sustained an unintentional weight loss exceeding 10% of their usual body weight.(1)

I focus on this particular statistic because exceeding this threshold (i.e., greater than 10% loss of usual body weight) has been shown in numerous settings to be that threshold beyond which the physiology of the body, as well as clinical outcomes, start to decline as a result of the underlying malnutrition.

Obviously, there are a lot of factors that determine which particular cancer patients might sustain weight loss. The type of cancer is one such determinant. For instance, in the same survey I mentioned above, only about 6% of patients with leukemia, sarcomas and breast cancer presented with more than 10% weight loss, whereas patients with gastrointestinal cancers had a prevalence of significant malnutrition amounting to 15-40%. Head and neck cancers are most frequently associated with malnutrition and in several surveys more than 40% of head and neck cancer patients present with a similar degree of malnutrition.(2)

Russell

Is there any evidence that the type of malnutrition you are talking about has a genuine impact on morbidity and mortality outcomes?

Mason

That's an excellent question, and frequently asked, given the very significant morbidity and mortality that's associated with cancer itself. There is a plethora of case control and prospective cohort studies that strongly suggest that a substantial degree of malnutrition (such as the 10% value indicated above) does lead to adverse consequences for these patients. Data indicate that this degree of malnutrition reduces responsiveness to chemotherapy and radiotherapy, increases perioperative morbidity in cancer patients, worsens their quality of life and indeed diminishes the likelihood of survival.(3),(4)

However, there are no definitive data that prove that the malnutrition causes these adverse consequences in these patients, and it is likely that we will never have that data. But the implication from the observational studies is certainly very strong. Perhaps the strongest evidence is that, in certain settings, we can positively impact on patient outcomes by feeding the malnourished cancer patient.

Pathophysiology of Malnutrition

Russell

There are many mechanisms whereby cancer patients can become malnourished -- for example, pain, depression and effects of chemotherapeutic drugs or radiotherapy. Can you give us a better feel for the underlying pathophysiology of malnutrition in the cancer patient? What are the most important elements that bring about malnutrition -- or that can be predictive of malnutrition?

Mason

That's a rather complex issue because. in most cancer patients, the loss of weight is multi-factorial. The first point I'd like to make is that if the physician is going to adequately address the issue of malnutrition in the cancer patient, it's often helpful to identify the various factors that created the malnutrition in the first place. Certainly, there are many alterations in protein and energy metabolism that occur and I'll discuss those in further detail later in this Cyberounds^®.

Very simple and mundane factors are frequently involved in the genesis of malnutriton such as insufficient dietary intake. The suppression of appetite is very common among cancer patients secondary to emotional depression, which you mentioned, or from the loss of taste sensation as a result of chemotherapy. Sometimes, anorexia evolves as a learned aversion to eating because of symptoms such as nausea and vomiting. In addition, other mechanisms that are sometimes overlooked are those involved in the physical impairment of the swallowing mechanism. This is extremely common in the head and neck cancer patient, where there may be physical impingement of the swallowing mechanism either from the tumor itself or the surgery or radiotherapy that's used to treat the tumor.(5)

Altered Metabolism

Russell

Could you give us more details about the altered metabolism in the cancer patient?

Mason

There is much heterogeneity among studies of this nature but, certainly, in many instances, there have been gross alterations in protein metabolism, carbohydrate metabolism and fat metabolism that might explain weight loss and contraction of the lean body mass. Many studies have shown that there is both a decrease in protein synthesis in the lean mass as well as an increase in degradation of existing protein, particularly in the skeletal muscle of the cancer patient.(6)

The mediators of this increased protein catabolism seem to be cytokines, which are produced either by the tumor itself or by surrounding macrophages and lymphocytes that are involved in the body's reaction to the tumor. A detailed discussion of the pathophysiology is beyond the scope of this Cyberounds^® but cytokines such as TNFα, IL1, IL6 and gamma-interferon all seem to play a very important role.

Interestingly, a factor has been identified from the urine of patients with cancer cachexia, but not in normal people or cancer patients without cachexia, called protein-mobilizing factor. This proteoglycan has been reported to induce prompt proteolysis in isolated muscle preparations and a reduction in lean mass in intact animals. Upon first review, this protein-mobilizing factor would certainly seem to be the holy grail of agents that might be responsible for wasting in cancer, although there has been some difficulty in reproducing some of these observations, so the status of protein mobilizing factor continues to be one of investigation.

Similarly, there are changes in carbohydrate metabolism. For instance, the Cori Cycle, which is the process in the body whereby lactate that is produced by the tumor or some other source is recycled in the liver into glucose, appears, in certain cancer patients, to be operating at quite high levels. This is significant because the Cori Cycle is a so-called "futile" cycle, consuming more ATP than it ultimately produces. Although increased levels of the Cori Cycle are evident in some cancer patients, it remains unclear how large a role this plays in the weight loss that cancer patients sustain. Glucose intolerance and hyperglycemia is seen and appears to be largely a result of insulin insensitivity, and again, appears to be a result, at least in part, of increased local or systemic levels of cytokines.

Lastly, there are remarkable changes in lipid metabolism. Probably the largest single effect is a decreased activity of lipoprotein lipase, which is responsible for the lipolysis of triglycerides into the component fatty acids. The decreased lipolysis tends to cause the frequently observed hypertriglyceridemia in cancer patients and impairs the body's ability to tap fat stores because the component fatty acids are not available. This process happens in concert with increased lipolysis in the peripheral adipose stores, contributing to the hypertriglyceridemia.

In brief, these major alterations in metabolism seem to conspire to induce disproportionately large contractions of the lean body mass with relatively modest decreases in fat mass. This is similar to what we see in acutely ill, hospitalized patients and is probably mediated by many of the same factors such as the cytokines. A reminder: more than 95% of the metabolic activity in the body is contained in the lean body mass that accounts for all the metabolic machinery that maintains homeostasis. Therefore, we are particularly concerned about the contraction of lean body mass and its impact on both physiology and clinic outcomes.

Nutritional Assessment Tools

Russell

In the chronically ill cancer patients, there are many possibilities for using nutritional status assessment tools such as Body Mass Index (BMI) and triceps skin fold. In cancer patients, is there a role for categorizing patients using these various measurements? Also, in the literature, there are various 'prognostic indices.' Is there a role for calculating these prognostic indices in order to decide whether or not to provide aggressive nutritional support?

Mason

I would argue that it is extremely important to keep in mind the various means to assess nutritional status in cancer patients. As we'll discuss, there are only a few situations where the provision of aggressive nutritional support has been shown to be beneficial to cancer patients. The physician needs to be able to make an appropriate decision about those instances when it's important. To do so, the physician must have an awareness of the patient's nutritional status.

There are many high technology ways to do nutritional assessment, but I think it's worth emphasizing that some of the very simple approaches to determine protein/calorie status are just as effective on a practical level. For instance, an unintentional loss of greater than 10 percent of the usual body weight has not only been shown to be that threshold beyond which the physiology of the body becomes adversely affected by malnutrition, but is also that threshold beyond which patients start to have increasingly poor clinical outcomes, such as infections, other causes of morbidity as well as mortality. This also applies to the cancer patient.

Nutritional status assessment by body weight is not applicable for some patients. In the patient with cirrhosis and ascites, body weight is not a good indicator. In these patients, we frequently rely on an index that indirectly measures skeletal muscle mass called the "creatinine-height index" -- collect a 24-hour urine, measure the sample's creatinine and then compare the measured creatinine to the height of the individual. Since a fixed percentage of skeletal muscle creatine is converted into creatinine each day, this is an indirect measure of skeletal muscle mass. The figure is then compared to a standardized table and one exists for each gender.(7)

There are several nutritional indices, usually logistic regression models of several measures of nutritional status, that are used to predict the outcome of hospitalized patients. The "prognostic nutritional index" was developed in cancer patients about to undergo major surgery approximately 20 years ago. This is a reasonably accurate predictor of the likelihood of morbid and mortal events in the hospital in these pre-op patients. The formula appears as follows:

PNI %= 158-[1.66 X albumin (g/L)]-[0.78 X triceps skin fold (mm)]-[2 X transferrin (g/L)]-[5.8 X delayed hypersensitivity index](8)

A value of 40% or greater indicates a patient at high risk of perioperative morbidity and mortality. In summary, I do think it's worthwhile for the physician to find a way to categorize their patients as either well nourished (or mildly malnourished) as opposed to being moderately to severely malnourished.

Is Nutritional Support Beneficial?

Russell

Trials using aggressive nutritional support have been rather disappointing with regard to cancer patient outcomes. Often, the nutritional support has not been shown to have any efficacy in terms of reducing morbidity or mortality rates, and there is some evidence that aggressive nutritional support could even feed the cancer and make the situation worse. This goes back to the question of assessment.

If it can be shown that nutritional support is effective in the treatment of these patients, as part of the armamentarium, it would be important to categorize the patients by degree of malnutrition. But if it's not effective, why is it worthwhile for the physician to categorize the patient and consider aggressive nutritional support? Are there situations where nutritional support, in fact, has been shown to be efficacious in cancer patients?

Mason

An excellent point. Because of what you say, I'd like to reiterate that it is particularly important for the physician to categorize their patient as 'well-nourished' or 'malnourished' because there are only a few situations where aggressive nutritional support has been shown to actually improve the patient's outcome among cancer patients. This is determined, in part, by their nutritional status.

The first situation where there is good evidence that aggressive nutritional support can positively affect the outcome of a cancer patient is among those patients who are about to undergo major surgery. Furthermore, it is important to qualify this statement -- only the moderately and severely malnourished patients with cancer who are about to undergo major surgery seem to benefit. There are now many large prospective randomized trials that substantiate this point. Two recent meta-analyses also suggest that the malnourished patient undergoing major surgery can benefit from aggressive nutritional support and in each instance these meta-analyses provided sub-analyses of only those studies that included cancer patients and the same conclusions were reached.(9),(10) I would like to further emphasize that in order for aggressive nutritional support to be efficacious in this setting, it needs to be given preoperatively.

Russell

How many days or weeks of nutritional support prior to surgery are optimal?

Mason

If one considers the literature as a whole, there's a strong suggestion that 8 to 10 days of preoperative nutritional support can positively affect the outcome in this setting. I'd like to underline that the physician will likely see no overt improvement in nutritional status during those 10 days. Nevertheless, there is good evidence that enzyme systems are improved and that physiology is improved during the course of those 10 days, and this is what is responsible for the improved clinical outcome.

I'd like to further emphasize that this nutritional support can be provided either as an outpatient or inpatient, and it need not be provided through a high technology approach. Sometimes, nutritional support with oral liquid nutritional supplements is sufficient, so long as the patient is able to ingest enough of the supplements. With regard to the question of whether an enteral versus perenteral approach ought to be pursued, I think there is increasing evidence that if the gut is functioning, it is worthwhile to pursue an enteral approach as the first choice. Again, there are recent meta-analyses that substantiate this point -- and a sub-analysis of those studies that are predominantly filled with cancer patients further confirms these observations.(11)

The second situation where there is some evidence that a cancer patient can benefit from aggressive nutritional support is among those patients who are about to embark on chemotherapy or radiation therapy. In both these situations, the prospective randomized trials suggest that improved nutritional status can be obtained by aggressive nutritional support. Nevertheless, in this situation, morbidity and mortality have not been shown to improve as a result of administration of aggressive nutritional support. Benefits for patients about to undergo chemotherapy appear to be confined to those who are malnourished.

The utility of aggressive nutritional support in radiation therapy has been most extensively studied in individuals with head and neck cancer, since these patients tend to have mechanical swallowing difficulties and a very high prevalence of malnutrition. In such individuals, there is now reasonable evidence that placement of a percutaneous endoscopic gastrostemy tube (PEG), and administration of supplemental tube feedings during and after the course of radiation prevent further deterioration in nutritional status and actually improve the quality of life. Again, there is no clear demonstration of a decrease in morbidity and mortality, but the end points mentioned above might alone justify the use of aggressive nutritional support.

The last situation where there is good evidence that aggressive nutritional support can benefit a cancer patient is for those patients who are undergoing a bone marrow transplant. For reasons that are not entirely clear, even among well-nourished individuals, there is a benefit to prophylactic use of total parenteral nutrition (TPN).(12) Perhaps this is because bone marrow transplantation is such a potent catabolic force on the body and its effects are so long lasting that it is likely that even a well-nourished patient will have nutritional deterioration during a recovery from their transplant.

These studies demonstrate that the use of TPN during and immediately after the transplant, until the time of significant recovery, benefits the patients in terms of not only improved nutritional status, but also decreased morbidity. Usually, the support with TPN must last at least two weeks after the time of transplant. There continues to be considerable reluctance to utilize enteral tube feedings in this setting because the feeding tube is thought to interfere possibly with mucosal integrity in an upper gastrointestinal mucosa that is already affected by mucositis. Nevertheless, compared to TPN in perspective randomized trials, the two feeding regimes seemed to be just as efficacious.

Summary

Russell

So, in summary, there is evidence that aggressive nutritional support is warranted in malnourished patients prior to major surgery and in patients who are undergoing bone marrow transplantation. Malnourished patients who are undergoing chemotherapy and/or radiotherapy may also benefit but in this situation the benefits to be expected are not in terms of decreased morbidity or mortality, but rather in an increased quality of life: feeling better, as well as improved functional and nutritional status.