Javier El-Bietar, MD

Shahini Qureshi, MD

SUNY-Downstate Medical Center

Brooklyn, NY

Pre test

Q1. You are part of a research team associated with the NIH that is trying to convince the Federal Government to pass a bill that allows the fortification of all commercial cereals with folate. In your argument you site the importance of folate in the prevention of cancer. Choose best answer:

Folate is essential for:

A) Inhibition of DNA repair enzymes.

B) Mechanisms of chromosomal translocations.

C) methylation of DNA.

D) prevention of megaloblastic anemia.

Q2. According to recent studies, infants who are breast fed regularly by their mothers are associated with a decreased incidence of all of the following cancers EXCEPT:

A) Neuroblastoma

B) Acute lymphoblastic leukemia

C) Wilms Tumor

D) Ewing's Sarcoma

E) Hodgkin's Disease

Q3. You are working with a leukemic teenager who is receiving 7 days of cytoreduction therapy in preparation for a peripheral blood stem cell transplant. He is becoming increasingly more and more neutropenic as the therapy depletes his bone marrow production. You instruct him that while he still is comfortable eating, he should avoid fresh vegetables, egg/macaroni salads, deli meats, nuts, and unpasteurized milk products.

You explain that:

A) These food groups contain compounds that interact with chemotherapy.

B) These food groups may contain bacteria that lead to infection.

C) These food groups contain oxygen radicals that may increase mutations making leukemic cells more resistant to chemotherapy.

D) He will probably be too sick to eat but not to worry; we can give him nutrition through his veins.

Q4. Of the following pharmacological agents, which is not a treatment for chemotherapy induced nausea and vomiting:

A) Lorazepam

B) Metoclopramide

C) Granisetron

D) Amitriptyline

E) Dronabinol

Objectives

On completion of this section, the resident will be able to:

1. Identify and discuss relevant, documented nutritional measures that provide prevention from cancer in childhood.

2. Define cachexia, protein energy malnutrition in the pediatric cancer patient.

3. Define nutritional interventions for children receiving chemo-, radiation, or bone/stem cell transplant therapy.

4. Provide treatment for chemotherapy-induced nausea, vomiting, and wasting.

Facilitator's Preparation

Sala A, Pencharz P, Barr RD Children, cancer, and nutrition--A dynamic triangle Cancer. 2004 Feb 15;100(4):677-87. Review.

Mauer, AM, Burgess JB, Donaldson SS, Rickard KA, Stallings VA, Eys JV, Winick M. Special Nutritional Needs of Children with Malignancies-A Review. Journal of Parenteral and Enteral Nutrition. 1990 May-Jun;14(3):315-24.

Rivadeneira DE, Evoy D, Fahey TJ 3rd, Lieberman MD, Daly JM. Nutritional support of the cancer patient. CA Cancer J Clin. 1998 Mar-Apr;48(2):69-80.

Introduction

The pathogenesis of childhood malignancy is a complex multifactorial process that involves inherited susceptibility of hereditary (oncogenic) mechanisms, environmental factors, and lifestyle as well as the interaction of these variables. For as much as we know about oncogenesis, the intricate connections among these variables are still being elucidated. How one variable impacts the other for good or for bad is not well understood. Cancer is not a simple cause and effect disease model; however, based on our understanding of food's metabolically active byproducts and the trends of nutritional epidemiology, we are able to make recommendations for cancer prevention that are likely to decrease the risk for some pediatric malignancies.

The field of "nutrigenomics" demands an understanding of medical biochemistry and genetics and can allow us to create guidelines for a cancer preventative diet. Dr. Paul C. Rogers of the University of British Columbia defines nutrigenomics as a

"dynamic yet regulated manner in which bioactive food components interact with specific genes at multiple levels and vise versa." He reminds us that certain foods' components can "act on the human genome, either directly or indirectly, to alter the expression of genes and gene products." (1)

We hope to introduce the reader to some cancer preventative food components and related topics such as obesity, breast feeding, and fiber consumption.

It's imperative that the reader becomes comfortable identifying cachexia and protein energy malnutrition (PEM) in a cancer patient. Pediatricians must know:

The risks for PEM.
The patient's physiological factors that contribute to the pathogenesis of PEM: increased energy needs, increased losses, decreased intake.
The bedside and in-patient modalities that help assess the cancer patient's nutritional status.

By understanding how chemotherapy, radiation therapy, and bone marrow transplant regimens affect pediatric patients, physicians can predict the extent of physiologic damage and subsequent malnutrition. Understanding these effects, their pathogenesis, as well as an accurate assessment of a child's physiological state is crucial to properly tailoring an appropriate medical response.

The authors have provided a step-by-step discussion that allows the reader to design therapeutic interventions for the cachectic child patient. We discuss the importance of avoiding certain foods and the neutropenic diet. This is followed by concepts involving oral and enteral feedings, the indications for total parenteral nutrition, and glutamine supplementation during cancer therapy. This final discussion concludes with a review of the pharmacological agents and strategies that can help effectively treat the challenging symptoms of nausea and vomiting.

A Glossary of terms

Angiogenesis- the process of blood vessel growth into either viable physiological tissue/organ or benign/malignant tumor.

Apoptosis- programmed cell death.

Cytoreduction- chemo/radiation therapy induced destruction of the bone marrow's cell population. It is performed prior to a patient receiving bone marrow cell-, peripheral blood stem cell-, or cord blood stem cell transplation.

Graft-versus-host-disease (GvHD)- As pertaining to bone marrow, peripheral blood stem cell or cord blood stem cell transplant patients, when the immunological cells of the donor attack viable host tissue- usually involving the liver, skin, and GI tract.

Veno-occlussive disease (VOD)- As pertaining to bone marrow, peripheral blood stem cell or cord blood stem cell transplant patients, the development of thrombi in the smaller vasculature of the liver subsequently causing hepatic dysfunction, portal hypertension, and hepatomegaly. The patient gains weight acutely and appears jaundiced, ascitic, and complains of upper right quadrant pain.

Part 1. Prevention

A. Folic Acid and the methionine - methyl transfer pathway

Folic acid is a micronutrient essential for the passage of single carbon molecules in the production of DNA. Folate is converted to tetrahydrofolate in cells, which is involved in the methionine - methyl transfer pathway. This pathway involves the handing-off of methyl groups leading to the methylation of DNA. Methylation of DNA at promoter regions down regulates the expression of genes involved in cell proliferation. Moreover, DNA methylation directs cells in particular tissues towards differentiation (see Figure 1).

FIGURE 1

Figure 1- the process is as follows:

1. Dietary methionine, an essential amino acid derived from dietary protein is absorbed into cells.

2. In the same way, dietary folic acid is also absorbed into cells and joins this process.

3. Methionine is converted to S-adenosyl methionine (SAM).

4. Through the action of the enzyme methyl transferase, SAM donates its methyl group to DNA by converting to S-adenosyl homocysteine (SAH). This methylation of DNA is crucial in the pathways that lead to cellular differentiation.

5. SAH is then converted to homocysteine.

6. Homocysteine can receive a methyl group from 5-methyl tetrahydrofolate to reform methionine. This is catalyzed by the enzyme methionine synthase, which requires its cofactors- Vitamin B12 and zinc (See Part IV S8-c folic acid needs in pregnancy)

Although somewhat complex, the relaying of methyl groups allows elements of our diet to directly influence the genetic expression of genes that influence differentiation.

Deficiencies in folate, methionine, vitamin B12, or zinc may leave patients vulnerable to genetic mechanisms that condemn cells to proliferate indefinitely. Thompson and colleagues have shown that folate consumption and supplementation in pregnancy are associated with a decreased incidence of acute lymphoblastic leukemia. (2)

French and colleagues in Canada have shown that folic acid fortification in flour may have reduced the incidence of neuroblastoma. (3) Furthermore, other studies display the importance of folate in cancer chemotherapy. Although these studies do not address cancer prevention, they point out how important folate and the methyl pathway are implicated in cancer. (4-5)

Foods high in folate are liver, yeast, and green leafy vegetables. Eating a diet rich in fruits, vegetables, cereals/fiber and lean meats/poultry should provide an adequate intake of essential amino acids, B vitamins as well as zinc.

B. "Neutraceuticals"

When bioactive food components are shown to modulate gene function they display chemo-protective as well as chemo-preventative qualities. They are called "nutraceuticals." Many of these are also phytochemicals, or compounds derived from plants- fruits and vegetables. The largest of this group are the polyphenols:

TABLE 1 Phytochemicals in Foods

CAPTION: These compounds, have largely been studied in the basic science lab setting- rats, knock-out mice, cell tissue lines, and tumor cells. No formal guidelines exist that allow physicians to make a formal recommendation; nor are there weight, age or gender-based recommended dietary allowances for these compounds.

Other phytochemicals that have been shown to inhibit pathways of oncogenesis are diallyl sulfide and allicin (garlic and other allium vegetables), lycopene (found in colorful fruits and vegetables such as tomatoes, watermelon, pink grapefruit, and guava), capsaicin (pepper, jalapenos), limonene (citrus fruits), and beta-carotene (carrots, beets). (14-15)

In sum, phytochemicals should be consumed as part of a balanced diet that includes appropriate portions of fruits and vegetables.

C. Breast feeding, Obesity and Other Guidelines

Epidemiological case control studies by the National Institute of Environment Health Sciences and the Children's Oncology Group have elucidated interesting findings associated with breast-feeding. The first group found an association that there was an increased incidence of neuroblastoma in American and Canadian mothers who did not breast feed. (16) Similarly, COG found an inverse association between breast-feeding and the incidence of Wilms tumor. (17) Furthermore, a recent metanalysis evaluating breast-feeding concluded statistically significant decreased risk for acute lymphoblastic leukemia, Hodgkin's disease and neuroblastoma. (18). Breast-feeding should always be encouraged when counseling mothers about infant nutrition. These studies allow pediatricians an even more convincing argument when persuading mothers to adhere to AAP guidelines about breastfeeding.

Although most dietary recommendations for the prevention of cancer are based upon epidemiological studies performed in the adult population, their conclusions can easily be applied to the pediatric patient. More importantly, dietary habits adopted early in children's lives can impact their overall health later on. The US Department of Health, US Department of Agriculture, American Cancer Society, National Cancer Institute, and the American Institute for Cancer Research have all released nutritional guidelines. A summary of some of these is discussed below.

Obesity has been linked to cancers of the breast, colon, endometrium, esophagus, and kidney. It is also associated with cervical gallbladder, leukemic, ovarian, pancreatic, thyroidal, and prostate cancers. Every effort should be made to implement nutritional measures early on that lower children's risk of being obese. This includes discouraging early juice consumption, appropriate transitions to low fat milk, limiting sweets and fast food products, as well as controlling the consumption of foods high in saturated fats. Pediatricians must make a concerted effort to encourage physical activity and exercise. Again, reinforcing a well balanced diet by adhering to recommended daily allowances and eating a diet that is well balanced will not only decrease the risk of cancer, but create a healthier child patient.

Diets high in fiber have been associated with decreased incidences of rectal and colon cancers. The National Cancer Institute recommends between 20-30 grams of fiber daily. This means we must encourage our patients to eat fruits and vegetable as well as pastas, breads, and cereals made with whole-wheat flour of all kinds- wheat, corn, rye, bran, or oats. Another good source of fiber is dry peas and beans. [See Module on fiber PIV S5C]

A 2004 review in the Nutrition Journal compiled some other findings associated with recent research (19):

Foods made with refined sugar (foods with a high glycemic index) were associated with an increased risk of many adult cancers including upper GI (gastric, esophageal), endometrial, overian, and colorectal cancer.
Diabetics as well as obese patients predisposed towards developing diabetes, were at an increased risk of colorectal, endometrial, and pancreatic cancers
There is an increased risk of developing colorectal cancer and the consumption of a diet rich in red meat.
Foods high in the fatty acid omega-3 have been found to be associated with a decreased risk of breast cancer. Flax seed (see above) can increase the amount of omega-3 in the diet. Omega-6 fatty acids, on the contrary, may increase the risk of cancer development
Selenium is an essential mineral that is an important cofactor in physiological enzymes involved in reactions that induce tumor cell death, increase detoxification of carcinogenic molecules, and decrease the rate of tumor growth. A diet rich in selenium (found in many grains and vegetables grown in selenium rich soil) may be protective against cancer, prostate, and lung cancers.
Vitamin D may reduce the risk of many adult cancers including colon, bladder, genitourinary, non-Hodgkin's lymphoma, renal, and lung.

Finally, it is important to briefly mention alcohol- linked to hepatic, breast, esophageal, laryngeal, pharyngeal, and oral cancers. Alcohol can antagonize folate's action in the body- effectively reducing its protective mechanism. If a child or adolescent begins to drink, it is imperative (for a host of obvious reasons) that the pediatrician warn his/her patient of the risks involved.

A case study

Mrs. Campbell is 4 months pregnant. She has a strong family history of both breast and colon cancers on her mother's and father's side. She states that two years ago, her first cousin had a baby. Unfortunately, 6 months after it was born, her cousin's baby was diagnosed with "some kind of leukemia." Your patient cannot recall the exact cancer type. She wants to know if you have any recommendations to the prevention of leukemia in her baby. She presents a list of foods and supplements that you have never heard of as possible preventive modalities.

Have residents discuss in triads what guidance might be given to the mother.
Assign one resident to play the "mother" and another to play the "pediatrician." Let the "mother" and "pediatrician" discuss with an "observer" who gives feedback to the pediatrician at end of discussion.)

Part 2- Nutrition and the Pediatric Cancer Patient

A. Protein Energy Malnutrition in the Pediatric Cancer Patient.

It is imperative to differentiate between the concept of cachexia and wasting.

Cachexia is a severe state of malnutrition involving anorexia, weight loss, and muscle wasting. This definition can be further defined as an involuntary loss of fat-free mass with sometimes minimal or no overall weight loss. When the body enters a state of negative nitrogen balance, it begins to actively break down its protein stores. This is the cornerstone of protein energy malnutrition (PEM). Unfortunately, cancer patients with PEM will have a poor response to therapy, an increased risk of comorbidities, and a poor overall survival. This concept of cachexia differs from wasting, which is an involuntary weight loss that reflects fat loss and not protein stores. (20)

When the pediatric cancer patient develops PEM and cachexia, the physiological implications involved are shown in Table 2

TABLE 2. Pathophysiologic responses to Protein-energy malnutrition

Hypoalbuminemia
Hypoglycemia
Lactic acidosis
Hyperlipidemia
Impaired hepatic function
Glucose intolerance/Insulin Resistance
Elevated gluconeogenesis
Skeletal muscle atrophy
Visceral organ atrophy/damage
Immune dysfunction

Q1. What leads to PEM and cachexia?

A. Let resident make a listings (Table 3)

TABLE 3. Most common risk factors for PEM

a. an irradiated gastrointestinal tract,

b. intense frequent course of chemotherapy in the absence of steroids,

c. major abdominal surgery,

d. advanced disease at time of diagnosis, age (<2 months) and

e. the lack of a functional family or healthy care support. (1,20-21,23)

CAPTION: Note the important role that the physician must serve in recognizing risk and taking appropriate action.

PEM occurs when there is an increased energy deficit. The factors that increase the pediatric cancer patient's energy deficit are:

1. Increased energy needs- The pediatric cancer patient is a still a growing patient. In many respects their needs are greater than a pediatric patient not dealing with cancer. Their chemo or radiation therapy may have already stunted their growth, and they may be trying to catch up. They may be undergoing adolescence at the time of diagnosis. The tumor itself may be secreting cytokines that may increase the overall energy requirements. In other words, the total energy expenditure of a patient may be increased. When this energy expenditure is greater then the nutrient intake, the patient's energy deficit increases.

2. Increased losses- Chemo- and radiation therapy may cause mucositis, sloughing of the absorptive layers of the intestine, vomiting, diarrhea, as well as decreased functionality of digestive organs, thereby increasing the overall loss of nutrients. In addition, some tumors- such as neuroblastoma and pheochromocytoma- can secrete compounds (vasoactive intestinal peptide) that exacerbate GI symptoms like diarrhea. (See below for more discussion on the effects of therapy).

3. Decreased intake- Pediatric cancer patients may develop a psychogenically mediated anticipatory nausea and/or learned food aversion that progresses to overt anorexia. This is tremendously difficult to manage and control (see below). Mucositis, vomiting, diarrhea, and alterations in the sense of taste may also contribute to this anorexia. This overall decreased intake summates over time and further exacerbates the patient's energy deficit.

(21,23)

Pediatric cancer patients with PEM undergo changes in carbohydrate, lipid and protein metabolism that reflect a total catabolic state. Physiological cytokines produced further perpetuate these changes. Partly due to the presence of some solid tumors, insulin resistance can cause glucose intolerance. When the body cannot utilize available glucose, this results in a perceived starved-state. Furthermore, tumors actively metabolize available glucose into lactic acid. This lactic acid causes an increase in hepatic Cori cycling (the conversion of lactic acid back to glucose).

Some tumors cause increased gluconeogenesis by the liver- from the conversion of carbon skeletons derived from amino acids. These amino acids come from the increased turnover of muscle protein. In addition, there is an increase in fatty acid turnover, free fatty acid beta-oxidation (the conversion of short, medium and long chain fatty acids to carbon units available for energy), and hepatic and peripheral lipolysis. There is a decrease in lipogenesis. Fat stores are subsequently depleted. Finally, catabolic cytokines like tumor necrosis factor-alpha (TNF- ) are secreted actively by macrophages and lymphocytes in response to the tumor. TNF- increases fatty acid, glycerol, and whole body protein turnover. Ultimately, these cytokines contribute to the cachectic state. (1, 20-23)

B. Nutritional Status Assessment

When assessing the pediatric cancer patient, it is vital to perform an accurate history and physical. The type and stage of cancer when diagnosed is important, as well as the intensity of the current or planned intervention. Is the cancer in remission or not? Other important factors include current symptoms, past growth patterns, developmental status, food allergies, medications, family and social history, food preferences and religious beliefs. Physical exam should be careful and meticulous with special focus on signs of malnutrition- all mucosal surfaces for breakdown (mucositis), hair loss, stomatitis, peripheral fat store loss, and edema.

After a complete history and physical is performed, it is important to perform reliable bedside measures for overall nutritional status. The first measurement is the patient's weight. Acute malnutrition is defined by calculating the weight deficit:

Weight deficit (%) = actual wt (kg) x 100

expected wt. (kg) for actual height

First degree, second degree, or third degree acute malnutrition is defined as <90%, <80%, <70%, respectively. Chronic malnutrition utilizes a measured height and is defined by calculating the height deficit. [see Modules on Assessment of Nutritional Status (PII S2) and Failure to Thrive (PIV S2A]

Height deficit (%) = actual height (cm) x 100

Expected height (cm) = 50th percentile for chronological age and gender

First degree, second degree, or third degree chronic malnutrition is defined by a height-for-age estimate of <95%, <85%, <75%, respectively. (21)

It is important to note that a pediatric patient's weight, taken alone, may not necessarily reflect an accurate assessment of his/her protein status; especially if the evaluating physician strongly suspects PEM and cachexia. In addition to the above measurement, arm anthropometrics allow us to make bedside measurements that help clarify a patient's status. [Described in PII S2)

Other methods of measuring nutritional status are bioelectrical impedance (utilizing the difference an electrical charge moves through fat vs. lean tissue), and dual-energy x-ray absorptiometry (DEXA). In addition to these studies, the evaluating physician may measure serum prealbumin. It should be noted that the serum measure of albumin be discouraged. Albumin has a half-life of 20 days and is a poor indicator of acute changes in nutritional status. Pre-albumin has a half-life of 3-4 days and is a better marker. However, plasma proteins are also acute-phase reactants and may be skewed by coexisting complications associated with the pediatric patient's underlying malignancy- fever, infection. (1,20-21)

Surprisingly, in one study that looked at multiple centers, there were no consistent protocols for nutritional assessment of pediatric cancer patients being implemented. Further more, the study found that assessment of nutritional status of patients does not routinely occur. (24)

A comprehensive approach to Nutritional Status assessment can be found in Part II Section 2.

C. The Effects of Therapy

Pediatric patients undergo a variety of different treatment modalities with complex protocols defined by the Children's Oncology Group:

1) Chemotherapy

Chemotherapies used include alkyating agents, antimetabolites, anti-tumor antibiotics, plant derived alkyloids, and steroids. These can result in anorexia, changes in taste, nausea, vomiting, mucositis/ esophagitis, diarrhea, and constipation. Chemotherapy may also alter the metabolic environment. The immunosuppressive nature of chemotherapy causes neutropenia and pancytopenia; subsequently, increasing the risk of opportunistic infection. The risk of infection alone forces the clinician to make changes in nutritional intervention (see below). Infections to the GI tract increase energy losses via vomiting and diarrhea. Systemic infections alter metabolism (increasing energy expenditure) and contribute to poor intake (decreasing energy intake).

Steroids (eg. prednisone, dexamethasone) can contribute to alterations in protein metabolism by amplifying protein turnover.

Alkylating agents (eg. ifosfamide, cisplatin) and antimetabolites (eg. methotrexate, 6-mercaptopurine, and fludarabine) erode the absorptive mucosa and oral epithelium thereby contributing to the cancer patient's pain, loss of taste/appetite, and GI symptoms. Subtle changes in the enzymatic environment (loss of the intestinal brush border enzymes) as well as mucosal degeneration impair the gut's ability to properly absorb vital nutrients. Undigested sugars, such as lactose, can act to exacerbate an osmotic diarrhea. (22) Furthermore, alkylating agents and antimetabolites are processed by the liver and kidney and can be toxic to these organs. Impaired function can result in protein loss and inefficient processing/ storage/release of nutrients.

Plant alkyloids (eg. vincristine, vinblastine) can cause ileus. Narcotics, which are often prescribed when painful erosive mucositis/esophagitis occurs, only exacerbate the slowing of intestinal motility. (23,25,27-27)

2) Radiation Therapy

The extent of radiation therapy differs dramatically among cancer protocols.

It can range from total body irradiation, such as seen in bone marrow and peripheral blood stem cell transplantation, to targeted radiation (a particular organ or anatomical site). Regardless of the location, all patients undergoing radiation therapy are at risk for anorexia, changes in taste, nausea, vomiting, mucositis/esophagitis, diarrhea, and constipation.

If a child's radiation therapy is targeted at any area along the GI tract- mouth, salivary glands, throat, mediastinum, abdomen or pelvis- they are at risk for sequalae. Whether the changes are acute or chronic, the implications on nutritional status are severe. Mucositis can form anywhere along the GI tract- painful mouth/throat/esophageal sores as well as bleeding lesions in the stomach, small and large intestine. Xerostomia may occur, impacting the desire to eat. Taste buds may be affected- making food taste odd, bland, devoid of sweetness. Dysphagia/ swallowing may be impaired. Low intensity radiation to stomach affects acid secretion impacting protein digestion; high intensity can cause overt damage such as ulcers. Enteritis may evolve due to the attack on rapidly dividing gut epithelium. Chronic fibrosis, strictures, and scar tissue may form with bacterial overgrowth compounding the issue. All of these complications can directly or indirectly affect appetite, nausea/ vomiting, and contribute to diarrhea. (25,27,29)

3) Bone Marrow/Stem Cell Transplantation

Bone marrow and peripheral blood stem cell transplantation patients receive both chemotherapy and (sometimes) radiation therapy as part of their cytoreduction prior to transplant. The chemotherapy may continue on after they have received their transplant. As a result, they have an increased risk of developing all the aforementioned problems- anorexia, changes in taste, nausea, vomiting, mucositis/esophagitis, diarrhea, and constipation.

However, these patient are also at risk for both graft-versus-host-disease (GvHD) and veno-occlusive disease (VOD). GvHD can range from mild to severe- involving the skin, gut and liver. When the gut is involved, the pediatric patient may suffer from mild to severe diarrhea, detrimentally affecting energy intake. When the liver is involved, biliary secretion and subsequent fat metabolism is affected. VOD results in painful hepatomegaly, jaundice, weight gain, and ascites. This alters both the exocrine and metabolic functionality of the liver. Both entities can potentially cause increased protein catabolism, hyperglycemia, increased serum lipids (cholesterol, triglycerides), and vitamin and electrolyte deficiencies. (25-27)

D. Interventions

Mauer and colleagues (23) has stated "…nutritional intervention should be initiated in children in whom:

1. There is an interval or total weight loss of >5% of the pre-illness body weight

2. The relative weight for height is <90%; or the weight/height percentile determined from the National Center for Health Statistics (NCHS) growth charts is <10th percentile channel

3. Serum albumin is less than 3.2 mg/dl

4. The energy reserves as estimated by arm fat area of subscapsular skin fold (<1 year old) is less than the 5th percentile for age and sex.

5. The current percentile for weight and/or height has fallen 2 percentile channels…"

Mauer's team defined the goals of nutritional intervention to be increasing the ideal body weight, arm fat area (above 10th percentile for age and sex), and the serum albumin (above 3.2 mg/dl). These guidelines should remind the resident reader of the discussion above that calls into attention all the bedside tests and in-hospital techniques at assessing nutritional status.

E. Nutritional Support

Step 1. Avoid products likely to introduce bacteria.

Because chemo- and radiation therapy induces immunosuppression, hospitalized, neutropenic patients receive food that lowers the risk of exposure to bacteria. (Table 4).

TABLE 4 The "neutropenic" diet. Patients should avoid:

raw vegetables (avocado, salads, unpasteurized juices)
fruits with thin skins (fruits such as apples, oranges, pears with thick skins are appropriate but must be washed and peeled)
potato or pasta salads (which may have sat at inappropriate temperatures)
deli-style cut or undercooked meat
nuts
raw eggs
unpasteurized milk products (yogurt made with live cultures)
mold-containing French/ fresh farmer's/ Mexican/ goat's cheeses, or milk-based salad dressings

CAPTION: Foods likely to bring bacterial contamination into the gut should be eliminated from the diet

Foods should be kept refrigerated and for no more than 4 days. These practices remain under constant scrutiny because they have never been proven to decrease infection. However, many clinical centers still utilize them. (29,31)

Step 2. Every possible effort should be made to utilize a patient's own digestive tract- oral or enteral feedings. Children with mucositis may have too much pain. Therefore, appropriate analgesics (eg morphine sulfate) as well as soft or pureed food should be provided. Caloric intake should be maximized. This may require the usage of protein shakes and/or multiple small meals. Clinicians and dieticians need to find the nutrient-dense favorite foods of the child. Diaries and caloric counts need to be collected and studied. Mealtimes may need to be adjusted so as not to coincide with antineoplastic therapy. If a child exhibits nausea and vomiting, every effort to ameliorate these symptoms should be attempted (see below). (23, 26-28)

Step 3. If a child is unable to tolerate oral feedings and begins to manifest signs and symptoms of protein energy malnutrition/ cachexia, then enteral feeding should be implemented. This can be achieved by placing a nasogastric or percutaneous endoscopic gastrostomy tube. A determination of which type to use is (oftentimes) patient/case dependent. Enteral tube feeding is cost effective, stimulates the gut mucosa in the wake of chemotherapy, and may benefit the long-term efficacy of cancer therapy. The approach to patients and their parents is a delicate one. Tube feedings are associated with some stigma and can be perceived as punishment or a "step back." A thoughtful, slow and concise explanation should be offered and child-life specialists involved helping relieve some of the stress felt by the child. (26-28)

A slow infusion allows nutrients to be delivered over a longer period of time, maximizing absorbency in patients with limited absorptive capabilities. This is imperative in patients who have experienced surgical bowel resection or chemo/ radiation therapy-induced mucositis. If possible, the tube should be placed so the end is below the stomach and well into the small intestine. This reduces the risk of aspiration pneumonia or gastric ileus.(26-28)

The implementation of enteral feeds early can maintain an ideal weight/height in children during their in-hospital therapy. (31) Enteral feedings can effectively change the weight of children even in the face of acute intensive chemotherapy. One study showed that among 33 pediatric patients treated for both solid tumors and leukemias, 82% maintained an ideal body weight with PEG tube feedings. (32) Another study showed that amongst 25 pediatric patients treated for leukemias or solid tumors, all showed rebound of their weights after the placement of a PEG tube. 60% of these children were severely malnourished before the tube was placed. (33)

Step 4. Total Parenteral Nutrition (intravenous feeds) may be needed.

(See Module on PICU care).

Despite repeated attempts at implementing oral or enteral feeding, the damage induced by chemo-/radiation therapy can be so advanced that the patient must be placed on total parenteral nutrition. This is especially the case when a child has received total body irradiation (such as part of his bone marrow transplant cytoreduction) or focal radiation to the GI tract (radiation-induced strictures and enteritis). The absorptive lining of the GI tract may be covered with lesions from mucositis making efficient nutrient absorption impossible. Mucositis may also exacerbate nausea, pain, vomiting or diarrhea. Finally, graft-versus-host disease in its severest forms can involve extensive GI damage. (34) TPN has been shown to effectively reverse PEM in these multiple cancer settings (23). In addition, while undergoing peripheral blood stem cell-, cord blood stem cell-, or bone marrow transplant, TPN may actually help some patients' graft grow. (35)

When starting TPN, it is important to note:

The caloric distribution should be 40-60% carbohydrate (dextrose), 10-15% amino acids, and 20-30% lipids. (20)
TPN has risks!

1) Infection. The patients are already predisposed to infection because of immunosuppressant therapy. TPN through central venous catheters increases the likelihood of bacteremia and sepsis. Intravenous lipids increase the susceptibility to fungal infections.

2) Hepatotoxicity. TPN can cause biliary dysfunction and steatosis. This may present with all the clinical signs of inefficient bile secretion.

3) Delay oral intake/early satiety. Patients treated with TPN may experience early satiety. This may delay their transition back to enteral/oral feeding. (36)

Ideally, while patients receive TPN, they should have all the following parameters routinely checked (20,34):

- Weight, height, head circumference

- Arm Arthopometrics

- Intake/output

- Complete Metabolic Panel (including electrolytes, BUN, creatinine, glucose, liver function tests)

- Calcium, phosphorus, magesium

- Triglycerides

- Carnitine

- Vitamin levels: especially patients with acute lymphoblastic leukemia (ALL). One study showed appropriate Vitamin C levels were associated with fewer therapy delays, less toxicity, and fewer days in the hospital. Sufficient vitamin E levels were associated with lower incidences of infection. Finally, beta-carotene levels were associated with a decreased risk of toxicity from chemotherapy. (37)

Step 5. Supplementation with glutamine may be beneficial. Glutamine is an amino acid. One study showed that prophylactic glutamine, supplemented in enteral feeds, may slow the GI damage that occurs with radiation therapy. (38) More specifically, patients undergoing bone marrow transplant and cytoreduction/ immunosuppression, who receive glutamine, may have quicker resolution of their mucositis and enterocolitis. (39,40) Pediatric patients with solid tumors may benefit from less need of antibiotics, less frequent incidences of sepsis, and significant improvements in immunological function. (41)

Step 6. Aggressively treat nausea and vomiting.

Nausea and vomiting are difficult symptoms to treat in the pediatric cancer setting. They can be caused by chemotherapy, radiation therapy, infection or the underlying cancerous tumor or leukemia. Nausea can be subdivided into acute, delayed, or anticipatory. Acute nausea is felt within the first 24 hours of chemotherapy administration. Delayed nausea and vomiting occur 24 to 120 hours after the administration of therapy. Anticipatory nausea describes symptoms felt prior to the administration of chemotherapy. It is the hardest to treat because it may be a conditioned response learned by the patient over a period of time. This may involve other psychological manifestations such as anxiety, making their symptomatology complex. Finally, the central nervous system and the neuronal pathways of the GI tract are implicated in nausea and vomiting. These pathways involve the neuronal proteins serotonin, substance P, and the receptors to which they bind. These mechanisms are still poorly understood. The available anti-emetic agents target specific sites in these pathways, blocking the messages that ultimately cause emesis. (42)

TABLE 5. Impact on nutrition of various chemotherepeutic agents

A comment on Alternative diet therapies

The term "alternative" should be used in two of three ways. First, it may be an equally effective therapy to be used in a special circumstance. Think of Erythromycin therapy for strep throat in penicillin allergic individuals. Second it could derive from a folk custom that has not been subject to scientific evaluation or has evolved from a therapy taught to our ancestors and forgotten by contemporary physicians (see module on alternative diets). A third common usage is for therapies developed by charlatans as a scam to exploit desperate people. We encourage use of alternative and complimentary approaches under the first and usually the second definition. Keep your eyes, ears, and nose open to protect your patients from exploitation.

What has been called complementary/alternative medicine (CAM) has allotted relief for some pediatric patients dealing with nausea and vomiting. Pediatricians should be aware of the documented relief that hypnosis, massage therapy, guided imagery and acupuncture may provide. (52) One should be open to ideas that may help patients even when the therapies are not proven as they may derive from ancient regimens forgotten by modern practitioners (see module on alternative diets). Techniques such as these should be encouraged and supported. Most cancer centers have CAM and Child Life departments with trained personnel that can effectively implement strategies that complement medication regimens.

Summary

In this module we have provided an overview with some specifics of nutrition care for children with cancer beginning with possible prevention and concluding with therapies for both providing nutrition and preventing malnutrition (not necessarily the same thing). The topic is vast. The papers provided in the facilitator's preparation and in the bibliography below will help address needs in specific circumstances.

Reference List

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9. Liontas A, Yeger H. Curcumin and resvertrol induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma. Anticancer Research 2004 Mar-Apr; 24 (2B): 987-98.

10. Wieder T, Prokop A, Bagci B, Essmann F, Bernicke D, Schulze-Osthoff K, Dorken B, Schmalz HG, Daniel PT, Henze G. Piceatannol, a hydroxylated analog of chemopreventive agent resveratrol, is a potent inducer of apoptosis in the lymphoma cell line BJAB and in primary, leukemic lymphoblasts.

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16. Daniels JL, Olshan AF, Pollock BH, Shah NR, Stram DO. Breast-feeding and neuroblastoma, USA and Canada. Cancer Causes Control. 2002 Jun;13(5):401-5.

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18. Martin RM Gunnell D, Owen CG, Smith GD. Breast-feeding and childhood cancer: A systematic review with metaanalysis. Int J Cancer. 2005 Dec 20;117(6):1020-31.

19. Donaldson MS. Nutrition and cancer: A review of the evidence for an anti-cancer diet. Nutrition Journal. 2004, Oct 20. 3:19.

20. Berchard LJ, Adiv OE, Jaksic T, Duggan C. Chapter 42- Nutritional Supportive Care. Principles and Practice of Pediatric Oncology. Fifth Edition- 2006: 1330-1347.

21. Sala A, Pencharz P, Barr RD Children, cancer, and nutrition--A dynamic triangle Cancer. 2004 Feb 15;100(4):677-87. Review.

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24. Ladas EJ, Sacks N, Brophy P, Rogers PC. Standards of nutritional care in pediatric oncology: results from a nationwide survey on the standards of practice in pediatric oncology. A Children's Oncology Group study. Pediatr Blood Cancer. 2006 Mar;46(3):339-44

25. The National Cancer Institute Website. Nutritional Implications of Cancer Therapies: http://www.cancer.gov/cancertopics/pdq/supportivecare/nutrition/

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27. Barrera R. Nutritional support in cancer patients. JPEN J Parenter Enteral Nutr. 2002 Sep-Oct;26(5 Suppl):S63-71.

28. Adamson PC, Balis FM, Berg S, Blaney SM. Chapter 10- General Principles of Chemotherapy. Principles and Practice of Pediatric Oncology. Fifth Edition- 2006: 290-365

29. Donaldson SS: Nutritional consequences of radiotherapy. Cancer Res 37 (7 Pt 2): 2407-13, 1977.

30. Moody K, Charlson ME, Finlay J. The neutropenic diet: what's the evidence? Journal of Pediatric Hematology/Oncology. 2002 Dec; 24(9): 717-721.

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Annotated Answers

A1 The correct answer is C. Folate is converted to tetrahydrofolate in cells, which is involved in the methionine methyl transfer pathway. This pathway leads to the methylation of DNA and subsequent, cellular differentiation. Folate is not involved in any known process that affects the functionality of DNA repair enzymes. Although chromosomal translocations are implicated in the pathogenesis of and subsequent prognosis of cancer, folate is not involved in these processes. Although deficiencies in folate and B12 vitamins are associated with megaloblastic anemia, this is not been shown to be associated with an increased risk of cancer.

A2 The correct answer: D. According to recent epidemiological studies, infants who are breast-fed are associated with decreased incidences of neuroblastoma, ALL, Hodgkin's Disease, and Wilm Tumor. Occurrence of Ewing Sarcoma is unaffected

A3 The correct answer: B. Neutropenic patients are at increased risk of infection. The food groups listed in the question may contain bacteria that cause a serious infective process.

A4 The correct answer: D. Amitryptiline is utilized for neuroleptic pain and depression. Lorazepam is a benzodiazepine that is utilized in conjunction with other antiemetics to treat nausea and vomiting. Metoclopramide and granisetron act both centrally and peripherally to block the neuronal pathways involved in these symptoms. Dronabinol is a cannibinoid related to the active compound in marijuana and can effectively treat nausea and vomiting.