Medical and Radiation Oncology

Carole Havrila, RD, CSO Paul W. Read, MD, PhD David Mack, M D INTRODUCTION

An estimated 1,437,000 people will be diagnosed with cancer and 565,000 people will die of cancer in the United States in 2008. Cancer is second only to heart disease as the cause of death in the United States, accounting for one-fourth of all deaths in this country. Men have a 50% chance of developing cancer during their lifetime and women have a 33% chance, with half of all cancer diagnoses involving breast, prostate, lung, or colon cancer. With earlier detection and more advanced treatments, two-thirds of all cancer patients will live at least 5 years.1

Cancer treatments have become increasingly more complicated over the past two decades, with many patients being treated with combinations of surgery, chemotherapy, and radiation in a multidisciplinary approach requiring coordination of care among many healthcare professionals. Newer chemotherapy drugs hold the promise of reduced toxicity and target novel cancer pathways, offering new hope to cancer patients. Advancements in radiation therapy planning and delivery have reduced acute and late toxicity by reducing the dose delivered to normal adjacent tissues.

This chapter reviews the basics of chemotherapy and radiation therapy and outlines the role of nutrition and the registered dietitian in the care of cancer patients in modern cancer centers.

Background

With the evolution of multicellular life from less complex ancestors, cancer became possible. Early life forms were likely similar to extant simple bacteria.

Their growth and division were limited only by their food sources and the need to avoid toxic concentrations of their own wastes. More than a billion years after the emergence of primitive bacterial cells, nucleated cells appeared in the fossil record, although their original forms may have been closer to those of the bacteria.2 Some lineages of nucleated cells found survival advantages in forming colonial assemblies for part or all of their life cycles; from these lineages, true multicellular organisms likely developed.

The cells composing a multicellular organism needed to develop an entire repertoire of molecular machinery to interact and communicate with one another, derived from precursors used by their unicellular ancestors. Adhesion molecules were modified from less specialized precursors, as were surface, cytoplasmic, and nuclear receptors. Signal transduction pathways that relayed, amplified, or attenuated signals from the external environment to the cell’s interior became more complex, allowing for a host of graduated responses to external stimuli or the lack thereof. The genome of cells grew in complexity, and new methods of controlling and regulating cellular division and gene expression evolved, allowing for the new organisms to radiate beyond the niches occupied by their unicellular cousins.

With multicellularity came the need for the individual cells within an organism to regulate their growth, division, and gene expression in response to both the external environment and signals from adjoining and distant cells. Multicellularity allowed cells the potential to differentiate into increasingly specialized forms, then to form tissues and organs—and even obligated them to commit a form of cellular suicide in response to the proper signals for the benefit of the survival of the organism. When the ancient control systems regulating the cells of a multicellular organism go significantly awry, cancer is the result.

A brief overview of cellular information flow is necessary to understand how malignancy can arise and the conceptual framework for its therapy. Deoxyribonucleic acid (DNA) is the material encoding genetic information in all living cells. DNA exists as immensely long sequences of purine bases— adenine (A) and guanine (G)—and pyrimidine bases—thymine (T) and cytosine (C). Each base is linked to a sugar (deoxyribose) and phosphate backbone. By convention, the linkage of a base with a sugar molecule is called a nucleoside (e.g., adenine + sugar = adenosine; similarly for guanosine, thymidine, and cytidine). The phosphorylation of a nucleoside yields a nucleotide (e.g., adenosine monophosphate—AMP, diphosphate—ADP, or triphosphate—ATP). Each sequence of DNA has a complementary sequence coupled to it through hydrogen bonds acting across paired bases: Adenine associates with thymine, and cytosine associates with guanine. From the sequence of one strand, the sequence of its complementary partner can be determined easily, as shown in Figure 4.1.

Figure 4.1 Deoxyribonucleic Acid Strand As complementary sequences associate, they spontaneously wind into the famous double helix described by Watson and Crick, which earned them the Nobel Prize. More than 3 billion bases in the DNA sequence code for a human being. These bases are packaged into 23 pairs of chromosomes carried within the nucleus of almost every one of the 60 trillion cells in the body, with each instruction set encoding an estimated 25,000 to 30,000 genes.

Even though almost every human cell carries the entire instruction set to build a human being, vast stretches of DNA are quiescent and inactive. Some DNA is tightly coiled around small proteins, known as histones, silencing it; other stretches are modified by methylation of cytosine bases as a silencing mechanism. Only the DNA that is necessary for each cell’s particular function is normally transcriptionally active. A common set of instructions is necessary for any nucleated cell: to synthesize proteins involved in energy utilization, intracellular transport, membrane synthesis, and destruction of damaged structures. Other instructions tell the cell to become a certain subtype—for example, colonic epithelial, breast ductal, or cardiac muscle. Certain cells are multipotent; that is, they are able to differentiate into multiple types. For example, a hematopoietic stem cell is able to differentiate into an array of cells to reconstitute the blood-forming tissues and immune system.

Transcriptionally active DNA is loosely packaged within the nucleus to allow access for transcription proteins. Thus information encoded in the DNA can be transcribed into short stretches of messenger ribonucleic acid (mRNA), which then translocates to the cell’s cytoplasm, where it is translated into proteins the cell requires to function. An entire repertoire of additional proteins, nucleic acids, and organelles is necessary for this process: gene enhancers, gene promoters, initiation factors, transcription factors, RNA polymerases, topoisomerases, free RNA bases, transfer RNAs, and ribosomes, just to start. Genes can be constitutively activated (i.e., always “on” and being used to synthesize RNA and then protein), or they can be switched on or off depending on the needs of the cell.

There are also times when cells must die for the benefit of the organism as a whole. For example, during a certain period in utero, a fetus’s eyelids are fused shut and its fingers are webbed. These states would impose a selective disadvantage to a newborn infant. Particular instructions expressed in development cause those extraneous cells to die off—a controlled, energy-requiring process called apoptosis—at the right time to allow for the proper human form to develop. Besides regulating development, apoptosis can occur as a result of a cell’s failing to replicate properly, in response to other external “death signals,” or when certain thresholds of cellular damage are exceeded, especially damage to DNA. Repair enzymes constantly scan the genome, excising mismatches in DNA bases and correcting them, replacing missing bases that have spontaneously hydrolyzed off the sugar-phosphate backbone, and repairing single- and double-stranded breaks. The process is not perfect, however, and mistakes occur, which is part of why cancer is usually (but not always) a disease of aging, and probably part of why aging itself occurs. Maintaining the fidelity of a sequence of 3 billion bases over decades of life and use requires a great deal of cellular effort.

When a cell is ready to divide, as dictated by its environment and genetic program, it normally does so in a controlled fashion (Figures 4.2 and 4.3). First, the cell moves from a relatively quiescent state called G0, to a growth phase, G:, in which it enlarges its contents and synthetic pool of raw materials (e.g., amino acids, ATP) and synthesizes the replication machinery. It then moves to S (for synthesis) phase, where its DNA is replicated with the aid of DNA polymerases and ligases (enzymes that link stretches of DNA), to phase G2, preparatory to mitosis, the actual phase where division occurs. Mitosis occurs in the familiar live-stage pattern:

1. Prophase: the condensation of loosely organized DNA into discrete chromosomes.

2. Metaphase: where chromosomes line up in the center of the cell, attached to a microtubule spindle apparatus that will separate them.

3. Anaphase: where the chromosomes are pulled to opposite poles of the dividing cell.

4. Telophase: where the daughter cells’ DNA starts to decondense and new nuclear envelopes form around them.

5. Cytokinesis: where the cells finally separate and become independent entities.

As with protein synthesis, this process is tightly regulated at checkpoints during G1, allowing entry into the S phase, and at G2, allowing entry into

Figure 4.2 Mitosis Not

Figure 4.3 The Cell Cycle mitosis. Failure to progress through these checkpoints, or through mitosis, normally triggers apoptosis.

surprisingly given the complexity of the cell, both genetic errors and dysregulation may occur. When a cell acquires a threshold amount of genetic damage, it has the potential to become cancerous. The amount of damage can be as small as a single gene, as happens with chronic myelogenous leukemia, but is usually much larger. The cell may become semiautonomous, with growth and replication pathways fixed in the “on” position, and the cell becoming increasingly unresponsive to external signals that would normally halt its division, cell-cycle checkpoints, and apoptotic signals telling it to die. Note that this condition may not be frankly malignant—malignancy is a continuum, not a binary condition—but the same genetic damage that allows for release from normal growth restraints also tends to result in increasing genetic instability with each cellular replication.

Over time, the premalignant cell can give rise to a family of closely related subclones, each competing for resources to outgrow its competitors. Eventually—and this may take many decades—one or more subclones may gain a growth advantage over their neighbors and acquire first the ability to avoid immune surveillance and elimination, then the ability to grow through tissue compartments otherwise limiting them from access to surrounding structures, then the ability to recruit blood vessels to bring oxygen and nutrients and take away wastes, and finally the ability to metastasize—that is, to send forth cells in the circulation and lymphatic system to implant themselves in other tissues to grow. This is cancer.

Fundamentally, then, cancer is a collection of genetic diseases. Scientists and physicians have made great strides in understanding and treating some of these diseases, whereas other diseases have proved very resistant to all forms of therapy to date. Surgery, radiation, and chemotherapy deployed in different combinations have been the mainstays of treatment for decades, supplemented by (for some diseases) hormonal therapy, immunotherapy with monoclonal antibodies, and, most recently, rationally designed small-molecule inhibitors of the signaling pathways driving a cancer’s growth.

Cancers are characterized according to their organ of origin (e.g., lung, colon, breast), and their treatment and prognosis are guided by the degree of advancement of disease at discovery, categorized into stages. Stages are usually defined based on a combination of tumor size, nodal involvement, and presence or absence of metastases—the so-called TNM classification system. For the example of breast cancer, a T1 tumor is 2 centimeters or less and does not involve the skin or chest wall; a T2 tumor is greater than 2 centimeters and not more than 5 centimeters and does not involve the previous structures. N1 disease is present in fewer than four nodes, N2 in four to nine nodes, and so on. Metastases are either absent (M0) or present (M1). Various TNM combinations are empirically grouped together, based on large data sets that correlate to the prognosis of the disease: Stage I breast cancer is T1N0M0; stage II can be T0N1M0, T1N1M0, T2N0M0, T2N1M0, or T3N0M0. Unsurprisingly, the aforementioned live stage II breast cancers are not identical diseases—what is it about a particular T1 tumor that allows it to spread to lymph nodes at a small size, and why don’t all T3 tumors do so? A great deal of research is directed toward unraveling the genetic basis for a particular cancer’s behavior and propensity to recur after definitive treatment.

As a general principle of solid malignancies, stage I disease is localized and often curable by some form of surgery alone: Examples include a stage I melanoma or a stage I colon cancer. Depending on the tumor type, adjuvant therapy might be deployed, which is therapy designed to increase the chances for cure after the primary surgical treatment. For example, small breast cancers often are treated with lumpectomy alone, with consideration given to using an individualized combination of chemotherapy, immunotherapy, radiation, and endocrine therapy afterward, depending on the size of the cancer, the receptors it expresses, the desire the patient has to retain the breast, and the age and health of the patient.

Stage II and III disease usually involve tumors that have grown larger than a certain size or have approached or invaded adjacent structures or have spread to nearby lymph nodes—the specifics depend on the cancer type. The prognosis for stage II and III disease is increasingly poorer than that for stage I, and aggressive adjuvant therapy is often used to give the patient the best chance for long-term disease-free survival after surgery.

Stage IV disease is usually metastatic; in other words, the cancer— regardless of the primary tumor size or nodal involvement—has succeeded in seeding itself in other organs or outside of lymph nodes in the vicinity of the primary tumor. Stage IV cancer is usually not treated surgically for cure, as undetectable micrometastatic disease generally coexists with radiologically apparent metastases. Instead, its treatment normally involves some combination of chemotherapy and radiation (with immunotherapy and/or hormonal therapy if the cancer is susceptible) delivered with palliative intent, so as to improve survival or to reduce symptoms. Many exceptions to this general system exist, however: Stage IV testicular cancer is usually highly curable, and other stage IV cancers can occasionally be treated with good results, especially if a long time has passed between treatment of the primary malignancy and the appearance of a distant metastasis.

The staging system is somewhat different for the hematologic malignancies that originate in lymphoid tissue or bone marrow and have immediate access to the circulatory system. These conditions tend to be (but are not always) disseminated diseases at the outset, as opposed to solid tumors. Also, their treatment is rarely surgical; rather chemotherapy, immunotherapy,

and radiation are deployed for cure or to relieve symptoms (refer to Chapter 12).

Overview of Radiation Oncology

Radiation therapy is the clinical subspecialty in which cancer is treated with high-energy photons or particles. These photons and particles deposit energy into the patient’s tissues, resulting in biochemical reactions that cause cell injury or cell death.3, 4 Radiation oncologists prescribe radiation to patients in units of energy per unit mass called a gray (Gy; 1 gray = 1 joule/kilogram body weight). Radiation therapy has been used for more than a century to treat cancer5 and is a critical component in curative protocols for many patients with diverse diagnoses.6 It is also widely used as a palliative measure for patients with advanced cancer symptoms such as pain, luminal obstruction, and bleeding. Radiation causes characteristic side effects depending on which tissues are being irradiated,7 and these iatrogenic toxic-ities can significantly affect the nutritional status of patients.

Historical Development of Radiation Therapy as a Major Cancer Treatment

X-rays were first generated by electricity in the laboratory of Roentgen in

1895.8 Two years later, in 1897, a case using x-rays to treat a skin lesion was reported at the Vienna Medical Society.5 In 1898, Becquerel and the Curies discovered radioactivity,9 which is the ability of natural elements to emit energy in the form of gamma rays or particles. The potential biologic consequences of gamma rays were discovered accidentally when Becquerel left a container with 200 mg of radium in his vest pocket for 6 hours and subsequently developed a chest wall ulcer, which took several weeks to heal.5 Physicians soon thereafter purified and concentrated radium and implanted it adjacent to tumors in patients to treat head and neck, gynecologic, and breast malignancies with high local radiation doses.10 This regimen ushered in the practice of brachytherapy, which is described in greater detail later in this chapter. Although x-rays and gamma rays come from different sources— they are created from electrical devices and natural radioactive material, respectively—both are highly energetic photons with identical properties. Both sources of photon radiation are currently used in the treatment of cancers in radiation therapy departments.

In the 1920s, x-ray units were built to treat cancer patients with photon energies of as much as 100—200 kilovolts.10 This effort marked the beginning of external beam radiation, also known as teletherapy. Due to complex physics, higher-energy photon beams penetrate more deeply into tissues and deliver a lower relative skin dose exposure than do low-energy photons. The early treatment units resulted in very high skin dose exposures, causing skin erythma (redness) and moist desquamation (blistering). These side effects limited the tolerable total radiation dose deliverable to deep-seated tumors in the chest, abdomen, and pelvis and, therefore, the effectiveness of radiation treatments.

In an effort to improve the efficacy and reduce the toxicity of radiation therapy, higher-energy photon beams were required to reduce the skin dose exposure and allow for higher doses of radiation to be delivered to tumors. Cobalt-60 was concentrated to have a very high activity, and the first megavoltage (MeV) teletherapy units were built in the 1950s.5 The cobalt units used large quantities of high-activity cobalt-60, which reliably produced a clinically stable high-dose rate beam with photon energies of approximately 1.25 MeV. They dramatically reduced the skin dose for patients, allowing curative doses of radiation to be delivered to tumors deep within the body. These units are still routinely used in many countries around the world owing to their dependability and clinical utility—indeed, few other medical devices can claim a 60-year lifespan with relatively few major changes.

In the 1950s and 1960s, the first linear accelerators were built to deliver megavoltage radiation beams with even higher photon energy capabilities as well as a new clinical option, the electron beam.5 Electrons travel into tissues to an energy-specific distance and then deliver essentially no dose to tissues that are deeper within the body, with a rapid dose fall-off from 100% to 0% dose over a span of 1-8 centimeters.11 When used properly, linear accelerators can be extremely useful for high-dose treatment of superficial tumors such as head and neck cancers, breast cancers, and skin cancers while sparing deeper tissues.12 During the 1950s and 1960s time period, which included the Cold War, both the United States and the Soviet Union performed a tremendous amount of scientific research to study the biologic effects of radiation. Since the 1980s, most cancer patients in the United States have been treated with linear accelerators, which are now capable of producing photon energies in the range of 6-18 MeV photons.

Radiation therapy has advanced to the point of providing wide-scale proton particle beam units, a technology being pioneered at major universities with large cancer centers.13 Proton therapy is unique because of the ability of the proton to penetrate deeply into tissues with relatively little dose being delivered to entrance tissues; instead, it delivers its dose over the narrow distance range where the tumor lies without any dose being delivered beyond that point. Therefore, proton beam treatments result in less radiation to adjacent organs and hold the promise of less treatment-related toxicity compared to treatments delivered with photons.

Radiation Biology: Biologic Effects of Radiation

The physical interaction of photons with biologic tissues lasts less than a nanosecond and results in the photon either being absorbed and depositing energy in the tissue, or passing straight through the patient without interaction or energy delivery to the tissues.8 When high-energy photons are absorbed by atoms in cells, they cause electrons to be knocked out of their atomic orbits and to move, a process called ionization. These highly energetic moving electrons cause DNA damage.7 With this treatment method, the physical interaction of radiation with biologic material is converted into biochemistry capable of killing tumor cells and potentially injuring normal tissues. The basic biologic rationale for treating tumors with radiation is that tumor cells are less capable of repairing DNA injury and are preferentially killed compared to normal cells.7 The physics and biochemistry of this interaction are completed in less than a millisecond, well before the patient gets off the treatment table.

The subsequent biologic consequences of the radiation-induced biochemical reactions on adjacent organs, or treatment-related toxicities, depend on the total dose of radiation, the type of tissue or organ irradiated, and the volume of tissue treated.7 The side effects are divided into acute and late toxici-ties, based on when they develop. Acute toxicities generally occur during the course of treatment or shortly thereafter, resolve within three months of completing treatment, and are related to temporary depletion of stem cells resulting in mucosal injury as well as congestion of the microvasculature resulting in edema (swelling) and erythema.7 Late toxicities occur three or more months after the completion of treatment and are generally related to reduced blood flow secondary to radiation damage to the microvasculature and to reduced numbers of stem cells that are normally present for regenerating the mucosa and skin and for healing injured tissue. Both of these conditions predispose patients to infection and ulceration and can lead to serious late complications involving heavily irradiated tissues. Radiation can also result in secondary cancers in the irradiated tissues, which can develop years or even decades after treatment.

In general, the risk of acute and late radiation toxicity increases with higher daily doses of radiation. To minimize this risk, radiation treatments are usually divided into many smaller daily treatments, a strategy called fractionated radiation therapy. Curative treatments are usually given on a daily basis Monday through Friday over 3-8 weeks (depending on the total dose of radiation to be delivered), with a daily fractionated dose of 1.8-2.0 Gy being delivered with each treatment. Each radiation treatment generally takes 10-15 minutes per day.

Medications can be given to patients either to protect normal tissues from the effects of radiation (radiation protectors) or to make the radiation more effective at killing cancers (radiation sensitizers), thereby resulting in improved eradication of tumors. Currently the only FDA-approved radiation protector is amifostine, which has been shown to reduce radiation injury to the salivary glands.14 Many chemotherapy agents are used as radiation sensitizers. In fact, the combination of concurrent chemotherapy with radiation (given at the same time), called chemoradiation, is considered the standard of care for many brain tumors, head and neck cancers, lung cancers, gastrointestinal cancers, and cervical cancer.6 For other tumors, such as breast cancer and lymphomas, chemotherapy and radiation are given sequentially (one and then the other) instead of concurrently.6 The improvement in local control provided by combining chemotherapy and radiation generally comes at the cost of increased toxicity for patients compared to treatment with radiation alone.

Modern Radiation Delivery Techniques

Radiation can be delivered to patients in one of three basic ways: teletherapy, brachytherapy, or radioactive nucleotides.

The vast majority of patients are treated with teletherapy—that is, the use of external beam units. With teletherapy, external beams of radiation are generated either by large amounts of cobalt-60 that create the beam via radioactivity, or by photons that are electrically generated via a linear accelerator. Protons are generated in a cyclotron or synchrotron. In this method of treatment, the beam is created outside the patient and then is targeted to travel into the patient and hit the tumor. The radiation beam can be collimated or focused for various medical purposes. Wide beams are used to treat large-volume tumors or even for total body irradiation (TBI) prior to hematopoietic cell transplantation. Very narrow radiation beams can be used to treat small, subcentimeter-sized tumors in the body; with this approach, one to five high-precision ablative treatments are delivered, called stereotactic radiosurgery.15

Modern photon beam linear accelerators are built with arrays of paired multi-leaf collimators consisting of thin 3- to 10-mm tungsten blocks that can be independently moved to block portions of the radiation beam. These blocks are used to create customized radiation treatments for individual patients. Intensity-modulated radiation therapy (IMRT) utilizes many different multi-leaf collimator positions and beam entry angles calculated by sophisticated radiation treatment planning software to deliver highly focused or conformal radiation treatments. With this approach, the high radiation doses conform to the tumor-containing tissues and adjacent normal tissues are spared, thereby minimizing toxicity.

Modern linear accelerators are also equipped with fluoroscopic or CT scan capabilities built into the treatment units. This capability allows daily imaging prior to each treatment so as to ensure accurate treatment delivery, a process known as image-guided radiation therapy (IGRT). Tumors in the lung and abdomen, for example, move secondary to breathing. Some treatment units are capable of tracking or synchronizing the radiation beam delivery with patient breathing to ensure the accurate treatment of a moving tumor with the least amount of adjacent normal tissue being irradiated. This process is called respiratory gated radiation therapy.

Brachytherapy is the second way to deliver radiation therapy. It involves physically implanting sources of high radioactivity into patients’ tissues or body cavities via seeds, plastic catheters, and various applicators; these sources then deliver high doses of radiation to adjacent tumors, with the radiation dose rapidly falling off with distance from the source. Frequently the placement of seeds or applicators is performed in the operating room as a surgical procedure. Brachytherapy is further characterized by the dose rate, with low-dose-rate (LDR) implants treating patients for hours or days and high-dose-rate (HDR) implants treating patients for just a few minutes. Some brachytherapy implants involve the permanent placement of radioactive seeds into patients, such as prostate seed implants. Other brachytherapy implants involve the temporary placement of radioactive sources into plastic catheters or applicators, with all radioactive sources being removed upon completion of treatment.

The third method of delivering radiation to patients is to treat them with oral or intravenous unsealed radioactive nucleotides. Examples include oral administration of iodine-131 for thyroid cancer, intravenous administration of radioactive-labeled monoclonal antibodies to treat lymphoma (Bexxar and Zevalin), and use of radioactive microspheres infused into the livers of patients with tumors (TheraSpheres or SIR-Spheres). Radionuclide administration can occur in a radiation therapy department or in the nuclear medicine and interventional radiology divisions of radiology departments.

Radiation Therapy Department Personnel

Radiation oncology departments include a diverse group of healthcare personnel working together as a team. These personnel may include radiation oncologists, oncology nurses, radiation therapists, medical physicists, dosimetrists, clerical staff, social workers, and registered dietitians (RD).

A radiation oncologist is a physician specializing in the treatment of cancers with radiation. He or she is ultimately responsible for the safety and welfare of the patients. In addition to prescribing the dose of radiation and the tumor volumes in the patient to be treated, the radiation oncologist is responsible for: ensuring that adjacent critical organs do not receive excessive radiation, managing treatment-related toxicities, evaluating tumor response to treatment, and coordinating patient care with other oncology specialists.

Oncology nurses perform initial and weekly patient assessment; identify issues such as patient malnutrition, social problems, or psychiatric problems that may interfere with treatment; and help coordinate consultations with appropriate healthcare professionals to facilitate optimal care. They also assist in brachytherapy procedures, give medications and infusions, and maintain code carts and departmental medications.

Radiation therapists are specially trained to assist in the treatment planning simulation process and administration of daily radiation treatments. Medical physicists ensure that treatment units and brachytherapy sources are properly calibrated and maintained; they also commission all new equipment and review all treatment planning calculations to verify their accuracy prior to treatment. Dosimetrists run the treatment planning software and work with physicians to create individualized radiation treatment plans based on the prescribed dose to the tumor volume and the dose constraints to adjacent critical organs. The clerical staff is involved in scheduling, processing insurance preauthorization, and maintaining departmental charts. Social workers help solve complex social problems such as transportation difficulties, childcare requirements, requirements for local temporary housing, lack of insurance requiring application for Medicaid and/or disability benefits, and, in general, they work to mitigate the potential negative impacts of these issues on patient care.

Registered dietitians meet with patients initially, and in an ideal setting, they perform weekly follow-up assessments. The RD assesses the patient’s nutritional status, changes in the patient’s caloric requirements, the need for tube feeding, and refeeding risks. He or she frequently works with the social worker to obtain nutritional supplementation if patients cannot afford to pay for these products.

Radiation Oncology Work Flow

The patient care process for most cancer patients undergoing radiation therapy is a fairly standard one. Patients undergoing radiation therapy are first registered by the clerical staff and then undergo a consultation including an initial assessment by the oncology nurse and a complete history and physical by the radiation oncologist. In general, patients are seen in the radiation oncology department, although hospitalized patients may be seen in consultation in their hospital rooms. Social workers and RDs may then be asked to see patients for assessments.

If it is determined that the patient would benefit from external beam radiation therapy, the patient is scheduled to undergo a treatment planning simulation. This procedure generally consists of a special CT scan performed by the radiation therapists and radiation oncologists in which personalized immobilization equipment is used to ensure reproducible daily treatment setup. It is called simulation because the patient immobilization and positioning simulate how the patient will be treated on the actual treatment unit. In the simulation, the physician uses a laser to place marks or tattoos on the patient or marks the immobilization equipment to guide daily patient alignment prior to treatment. PET, CT, or MRI scans may also be used for treatment planning simulation.

Following simulation, the patient goes home, and the physician digitally contours or draws the target volumes for radiation treatment and the adjacent critical organs on the simulation scan, prescribes a target tumor dose, and places constraints or limits for the maximum radiation dose to be received by adjacent critical organs. The dosimetrist then uses this contoured treatment planning CT scan and the tumor prescription and adjacent organ dose constraints to create an individualized treatment plan for each patient. The physician approves the dosimetrist’s plan if it meets all the required criteria, and the medical physicist checks the plan for accuracy and performs all necessary quality assurance tests to ensure safe delivery of the plan. The plan is then imported into the treatment unit software, and the radiation therapist subsequently uses this information for daily patient treatment. In total, this radiation planning process generally takes three to five days.

Modern treatment units have imaging capabilities that are used by radiation therapists and physicians to ensure that the patient setup maintains millimeter accuracy on a daily basis. Special consideration must be given to pediatric patients, such as construction of specialized immobilization equipment or even the need for daily anesthesia, to make treatment possible for small children and infants. During the treatment course, the patient is seen at least once a week for toxicity assessment and management and assessment of tumor response by the physicians and nurses. Ideally, a RD also sees the patient weekly to assess his or her nutritional status and the need for intervention with supplementation or enteral feedings. Following completion of the course of radiation, the patient is followed by the healthcare team to manage the acute and then late treatment-related toxicities, for evaluation of tumor response, and for surveillance of tumor recurrence.

Radiation therapy may be given with the intention of curing patients of their cancer and is frequently combined with surgical resection and/or chemotherapy. In contrast, palliative radiation is used to reduce symptoms such as bleeding, obstruction, or pain, with the twin goals of minimizing distressing symptoms and improving quality of life. Curative treatment courses frequently last three to eight weeks, whereas palliative treatment courses last one to two weeks.

Standard curative external beam radiation prescriptions for common tumors have been developed based on the optimal dose to cure a given tumor and the dose limitations of adjacent organs. Table 4.1 lists common tumors, standard external beam radiation prescription doses, and treatment durations, and identifies whether concurrent chemotherapy is administered for the most commonly treated adult tumors.

Overview of Medical Oncology

Physicians have attempted to treat cancers with pharmacologic agents for millennia, almost entirely without success until the last century.16-18 Early successes in the prevention and treatment of bacterial diseases in the nineteenth century led researches to hypothesize that malignancies could be treated with chemical compounds as well. During World War I, young men Table 4.1 Frequently Used Radiation or Chemoradiation Treatment Regimens for Common Adult Malignancies

Cancer Primary Site

Common Prescribed Dose (Gy)

External Beam Treatment

Duration

Concurrent Chemotherapy

Breast

60-66 Gy

6 weeks

No

Prostate

72-78 Gy or brachytherapy

implant

7-8 weeks 5 weeks

No (hormonal—yes)

Lung

60-74 Gy

6-7.5 weeks

Yes

Head and neck

60-72 Gy

6-7 weeks

Yes

Gastrointestinal

50-56 Gy

5-6 weeks

Yes

Gynecologic

45-50 Gy +

brachytherapy implant

5 weeks

Yes

Brain

50-60 Gy

5-6 weeks

Yes

Sarcoma

60-74 Gy

6-7.5 weeks

No

Lymphoma

30-50 Gy

3-5 weeks

No

Source: Treatment recommendations data from National Comprehensive Cancer Network clinical practice guidelines in oncology. © 2008 National Comprehensive Cancer Network, Inc. http://www.nccn.org.

exposed to mustard agents (named for their odor) were sometimes found to have a paucity of normal bone marrow cells at autopsy.18 In the early 1940s, Gilman and Philips conducted studies of nitrogen mustard derivatives in patients with lymphoma. Their work was spurred by a 1943 German air attack on U.S. ships—one of which was loaded with mustard agents—at the port of Bari, Italy, which injured hundreds of seamen, soldiers, and civilians who were exposed to the gas, and caused the deaths of dozens of people. The survivors were found to develop lymphoid and myeloid bone marrow suppression.

Gilman and Philips’ work was classified at the time it was being conducted, as was the release of chemical weapons in Italy. Nevertheless, the line of research they began led to a publication in 1946 by Goodman and colleagues containing the first description of the use of recognizably modern chemotherapy in humans.19 This work was quickly followed by breakthroughs in treating certain leukemias with the antifolate agent methotrexate, and the first cure of a cancer (choriocarcinoma) with this compound. The growth of knowledge in molecular biology over subsequent decades has led to increasingly effective and less toxic interference with different cellular processes using chemotherapy.

Traditional cytotoxic chemotherapy agents can be categorized by the mechanisms used to interrupt cell division and cause cell death (see Table

4.2). Classical alkylators include mechlorethamine, cyclophosphamide, and ifosfamide, all of which are descendants of the original mustard agents. These compounds bind directly to DNA, either causing cross-links across complementary strands or within the same strand, and resulting in irreparable damage and preventing the proper unwinding of DNA during replication or gene expression. Chemically unrelated compounds with similar mechanisms of action include the platinum agents. The first platinum agent was cis-diaminodichloroplatinum (CDDP), also known as cisplatin, which is used frequently to treat lung cancer. Its cousins, oxaliplatin and carboplatin, are often used in combination with other agents to treat colorectal cancer and lung cancer, respectively.20

Nucleoside analogs are compounds that chemically resemble the constituent bases of DNA or RNA. The prototypes of this class of compounds are 6-mercaptopurine, which is used to treat certain types of leukemia, and 5-fluorouracil (5-FU), which was synthesized more than 50 years ago as an analog of uracil; uracil is an RNA base and a substrate for thymidine synthesis. A relatively new compound, capecitabine, is an oral agent that is converted to 5-FU within the body; it is increasingly being used to replace infusional 5-FU. Other pyrimidine nucleoside analogs include gemcitabine and cytarabine. Purine nucleoside analogs commonly used in cancer therapy include fludarabine, 2-chlorodeoxyadenine (2-COA), and pentostatin. These compounds work against cancer cells in different ways. For example, they Table 4.2 Representative Types of Chemotherapeutic Agents in Common Use

Class

Examples

Mechanisms of Action

Alkylators

Cyclophosphamide, ifosfamide, platinum agents

Bind directly to DNA, resulting in irreparable damage and preventing the proper unwinding of DNA during replication or gene expression

Nucleoside analogs

5-Fluorouracil, capecitabine, gemcitabine, cytarabine, fludarabine, 2-CDA, pentostatin

Become incorporated into a growing DNA sequence, causing chain termination and triggering apoptosis; alternatively, inhibit enzymes involved in DNA and/or RNA synthesis

Topoisomerase inhibitors

Etoposide, topotecan, irinotecan

Interfere with enzymes involved in uncoiling DNA to allow for replication and gene expression

Microtubule inhibitors

Paclitaxel, docetaxel, vinorelbine, vinblastine

Prevent assembly or disassembly of microtubules necessary for mitosis

Multifunctional

Daunorubicin, idarubicin, doxorubicin

Free radical generators; physically interfere with DNA replication; topoisomerase inhibition

Tyrosine kinase inhibitors

Imatinib, erlotinib, sunitinib, sorafenib

Bind to proteins involved in cellular signaling

Monoclonal antibodies

Rituximab, bevacizumab, cetuximab

Bind to proteins involved in cellular signaling, activate the immune system against target cells

become integrated into a growing DNA sequence, causing chain termination and triggering apoptosis. Some also competitively inhibit enzymes involved in DNA or RNA synthesis, arresting the cell’s ability to replicate or produce needed proteins from messenger RNA.20

In contrast to chemotherapeutic agents that inflict direct damage on DNA, the topoisomerase inhibitors block enzymes involved in DNA uncoiling. As an illustration of this principle, picture a double helix that is fixed on both ends. Pulling on the strands in the middle to uncoil and separate them, as must occur during DNA replication or gene expression, increases coiling both upstream and downstream of the separation point; it also increases tension on the strands. Topoisomerases are enzymes that induce single- or double-stranded breaks in DNA upstream and downstream of an uncoiled region, allow the strands to rotate to relieve the tension, and then anneal the break. Not surprisingly, compounds have been developed to interfere with these enzymes. Etoposide (used to treat testicular and lung cancer), topotecan

(used for lung and ovarian cancer), and irinotecan (used in lung cancer) are all topoisomerase inhibitors that are commonly used as chemotherapeutic agents.20

Other compounds have multiple functions. For example, the anthracycline antibiotics, which include doxorubicin and epirubicin (often used to treat breast cancer), are derived from natural antibacterial compounds. These compounds posses topoisomerase-inhibiting activity, but also interact directly with DNA to hinder its replication; in addition, they are free radical generators of other DNA-damaging species.20

A wide array of agents has been developed to interfere with cytoplasmic processes outside the cell’s nucleus, including the taxanes paclitaxel and docetaxel. Taxanes bind to and stabilize microtubules, and prevent the dynamic changes necessary for the spindle apparatus to accurately separate chromosomes during mitosis, inducing mitotic arrest and apoptosis. The taxanes’ cousins, vinca alkaloids (e.g., vincristine, vinblastine, and vinorelbine), have the opposite effect: They prevent the synthesis of microtubules from tubulin monomers, with similar catastrophic effects on cellular division.20

Besides the development of new cytotoxic agents, another major advance in treating malignancies over the last decades has been the combination of agents with different mechanisms of action and non-overlapping toxicities to minimize the chances for cancer cells developing resistance to treatment. This approach led to curative regimens for Hodgkin’s lymphoma and childhood acute lymphoblastic leukemia in the 1960s. With rare exceptions, modern chemotherapy regimens deployed for cure rely on two or more agents for maximum effectiveness.20

Traditional cytotoxic chemotherapy acts on the replicative machinery of a cell. Other cellular processes have now been sufficiently characterized to allow for the development of agents to disrupt them. The prototype for these compounds is imatinib, which was developed to treat chronic myelogenous leukemia (CML). The genetic defect in CML arises from a translocation between chromosomes 9 and 22, giving rise to an abnormal stretch of DNA called the Philadelphia chromosome. A particular gene product of the Philadelphia chromosome is the chimeric protein BCR-ABL. BCR-ABL is the fusion product of two genes, bcr and abl, which normally do not interact. The fusion protein is constitutively active and drives the cell containing it to replicate without end, giving rise to CML. If CML is left untreated, additional genetic errors accumulate over the course of several years, and the disease moves first to an accelerated phase, then an acute leukemic phase that is usually rapidly fatal. Imatinib binds to the BCR-ABL protein, preventing its activity and causing the death of the cell by means of a still-unclear process.21 An entire cohort of agents targeted against specific cellular proteins involved in intracellular signaling has been developed since imatinib, and these drugs are becoming increasingly important in treating cancer.

Monoclonal antibody-based therapy against cell-surface proteins is another area under development. Monoclonal antibodies work in a variety of ways. Some trigger the immune system to destroy the malignant cells by antibody-dependent cellular cytotoxicity (ADCC), which recruits natural killer cells and macrophages to the tumor. Others cause the deposition of complement proteins (complement-dependent cytotoxicity [CDC], a form of innate immunity), which leads to the death of the targeted cell. Still other monoclonal antibodies indirectly downregulate the cell’s growth by activating or inhibiting signaling pathways, possibly potentiating the effectiveness of cytotoxic chemotherapy. The prototypic monoclonal antibody agents are rituximab and trastuzumab. Ritux-imab is directed against the protein CD20, which is expressed on normal B lymphocytes as well as on the B cells of malignant disorders. Trastuzumab works against HER-2, a cell-surface protein that is expressed on certain breast cancers and portends very aggressive behavior of the cancer. The use of trastuzumab has dramatically improved the treatment of this type of breast cancer, providing approximately a 50% relative reduction in the relapse risk after local treatment and chemotherapy. Another extremely promising agent of this type is bevacizumab, which is an antibody to circulating vascular endothelial growth factor (VEGF). Bevacizumab binds to VEGF, clearing it from the circulation and decreasing the rate at which a malignancy can recruit new blood vessels to supply its growth needs.22

Not surprisingly, other classes of agents are in use or in development for cancer therapy. Examples include histone deacetylase inhibitors and hypomethylating agents, which alter genetic expression directly, by activating genes that have aberrantly become silenced during the process of carcinogenesis.23, 24

The complexity of modern cancer therapy reflects both the difficulty and the advances in treating the heterogeneous collection of diseases lumped together as cancer. A full review of all the types of pharmaceutical agents now being deployed or being developed to work against malignancies is beyond the scope or purpose of this text. Nevertheless, the growing number of agents active against cancer is testament to the progress that has been made over the last 60 years.

Oncologists are often asked why it is so difficult in many cases to treat or cure advanced malignancy, especially when compared to other superficially similar conditions, such as infectious diseases. The answer is that the rogue cells of cancer arose from normal cells around them, and the differences between the cancerous cells and healthy ones are not enormous. Both cancerous cells and healthy cells make use of the same cellular processes to survive, grow, and replicate, and most of our current therapies are limited by the toxicity to normal cells, and thus to the organism as a whole. Bacteria, in contrast, have been evolving apart from humans for billions of years, and their cellular machinery is much more vulnerable to our treatments—not only because it is less complex and redundant than our own cellular machinery, but also because it is evolutionarily divergent, allowing us to develop agents that are extremely toxic to bacterial processes yet relatively innocuous to the human body.

The final goal of chemotherapy is to cure cancers at any stage with a minimum of toxicity—or better still, to prevent them from occurring in the first place. Until this goal can be achieved, an interim step that many scientists and oncologists are working toward is to convert advanced cancers into manageable chronic diseases. Toward that end, the medical oncologist has a number of increasingly effective tools at his or her disposal. Cytotoxic chemotherapies have been used for decades and are still being developed, but as the understanding of cellular processes evolves, the ability to exploit the differences between malignant and healthy cells will advance as well.

Nutritional Implications of Medical and Radiation Oncology

Advancements in cancer therapies achieved over the past two decades have led to better treatment outcomes and improved survival rates for many cancers.25 However, side effects associated with cancer treatments continue to afflict patients during these treatments and beyond. Many side effects are nutrition related and should be managed as soon as possible. Today, many patients receive treatments with combined radiation and chemotherapy, and such treatments can cause significant weight loss in as many as 70% of patients.26

Regardless of cancer diagnosis, unintentional weight loss of more than 5% predicts a poor prognosis even after adjusting for performance sta-tus.27 It is well accepted that malnourished patients with cancer are more likely to have infections and treatment toxicities with associated increases in healthcare costs and decreases in treatment response.28 Today, quality of life is paramount as more patients are being treated, but not necessarily with the goal of obtaining a cure. Because malnutrition can significantly influence response to treatment, it should be the goal of all RDs working with cancer patients to provide tailored nutritional interventions throughout cancer treatment and into survivorship to maximize quality of life. Other clinicians should screen and refer patients at nutritional risk to the RD for individualized care.

Nutritional Implications of Radiation Therapy

Radiation therapy is widely used to treat a number of malignancies, including those affecting the lung, head and neck, brain, cervix, prostate, gastrointestinal tract, and breast. As mentioned earlier in this chapter, high-dose radiation is delivered via radiotherapy, brachytherapy, or radiopharmaceutical therapy. Radiation therapy is given in precise, fractionated doses to the site of disease. Despite this narrowing of the scope of therapy, radiation affects healthy tissue, in addition to cancer cells, in the targeted treatment field it is given. Radiation to any part of the gastrointestinal tract or pelvic area, for example, leaves a patient vulnerable to nutrition-related side effects (see Table 4.3).29

Radiation to the cervix, colon/rectum, stomach, and pancreas can lead to side effects of nausea, vomiting, and diarrhea. Medically, diarrhea is typically managed with antidiarrheal medicines such as Imodium (loperamide hydrochloride) and Lomotil (diphenoxylate/atropine). Bulk-forming agents such as psyllium (Metamucil) and the amino acid glutamine may also be used alongside these medications.30 According to the American Dietetic Association’s (ADA) Oncology Evidence Analysis guidelines, glutamine has not been proven effective to reduce radiation-associated diarrhea, and its usage warrants further study. In addition, limiting dietary fiber, lactose, and spicy foods is sometimes helpful to decrease symptoms of bloating, cramping, and diarrhea. In some patients, radiation enteritis can develop as an early (developing within two to three weeks of treatment) or late (several weeks, months, or years after the end of treatment) side effect. In severe cases, malabsorption of nutrients and severe fluid losses can occur. In those Table 4.3 Acute Nutrition-Related Side Effects of Radiation29- 31

Area in Which Radiation is Applied

Nutrition-Related Side Effects

Central nervous system

Fatigue, hyperglycemia associated with steroids

Head/neck/thorax

Mucositis, stomatitis, thick saliva, xerostomia, loss of taste, altered taste, dysphagia, odynophagia, esophagitis, nausea and vomiting, fatigue

Abdomen/pelvis

Nausea, vomiting, diarrhea, gas, malabsorption, lactose intolerance, fatigue

Sources: Unsal D, Mentes B, Akmansu M, et al. Evaluation of nutritional status in cancer patients receiving radiotherapy: A prospective study. Am J Clin Oncol. 2006;29:183-188; Chencharick JD, Mossman KL. Nutritional consequences of the radiotherapy of head and neck cancer. Cancer.

1983;51:811-815.

patients who develop severe enteritis, the use of nutrition support is often warranted to treat severe weight loss and vitamin/mineral deficiencies.29

Cancers of the head and neck and thorax treated with radiation therapy are associated with many nutritional challenges.31 Many patients have tumors that physically prevent eating or limit intake, and many patients have a history of heavy alcohol and tobacco abuse, which further compromises nutritional status prior to treatment. Given that radiation fields involve rapidly dividing tissues, this population may experience significant mucositis, stomatitis, xerostomia, thick saliva, altered taste and smell, dysphagia, and nausea and vomiting. The incidence of malnutrition in this population is common, with as many as 57% of patients with head and neck cancer experiencing weight loss before starting radiation.32

Today, multimodality (radiation therapy and concurrent chemotherapy) treatment is being used more often for these malignancies. The increased toxicities associated with such therapy can cause significant weight loss, which can in turn lead to frequent treatment interruptions, hospital or emergency room admissions for hydration and nutritional support, and, most importantly, decreased treatment response.26 Many cancer centers routinely place percutaneous gastrostomy tubes in patients who receive concurrent chemotherapy and radiation. Such early and aggressive nutrition intervention has been shown to decrease weight loss and deterioration of nutritional status in these patients.26

Most side effects associated with radiation therapy are acute, beginning around the second to third week into the course of radiation treatment, and then declining two to three weeks after the completion of treatment. Regardless of the body area being treated with radiation therapy, universal side effects include fatigue, loss of appetite, and skin changes. Some side effects become chronic, such as with radiation enteritis or osteonecrosis, and may last weeks to months beyond the completion of treatment.33

Nutritional Implications of Chemotherapy

More than 90 chemotherapy agents are used to treat a variety of cancers.34 Chemotherapy agents are classified based on their mechanism of action and are administered either intravenously or in the form of an oral drug. Chemotherapy treatments may take minutes or hours. Certain chemotherapy agents have more toxic effects on kidney and liver function owing to their elimination or metabolism pathways. These regimens require aggressive hydration and hospital admission to carefully monitor vital signs and deliver intravenous fluids along with the chemotherapy. Chemotherapy can be given as one single agent or a combination of agents, depending on the type of cancer. Chemotherapy given concurrently with radiation is the standard of care for a variety of cancers. Patients receiving such treatments experience more severe side effects and, therefore, must be considered at high nutritional risk.34

Because chemotherapy is a systemic treatment, it affects the entire body. As a consequence, it has the potential to cause more side effects than radiation therapy or surgery alone.34, 35 The side effects associated with chemotherapy typically depend on the specific treatment regimen, including the dose of medication(s), the length of planned treatment, and the patient’s stage of disease and health status. Normal gastrointestinal function may be affected by damage to the cells lining the digestive tract, leading to nausea, vomiting, diarrhea, and altered gastric motility. Chemotherapy drugs are graded for their emetogenic potential, and a variety of medicines are used to mitigate treatment-related nausea and vomiting, including Compazine (prochlorperazine) , Emend (aprepitant), and Zofran (ondansetron).36, 37

When faced with gastrointestinal side effects, patients benefit from education on low-fat, bland foods that are easily digested. Dry toast, broth-based soups, fresh fruit, and Popsicles are some examples of foods that are better tolerated during periods of nausea and vomiting. Small, frequent snacks are encouraged, rather than the typical three meals per day, as many patients are overwhelmed at the sight of food and become anorexic. Oftentimes, patients benefit from being given a written meal schedule including meal/snack times, sample foods, and amounts needed. Some may benefit from setting a kitchen timer or a watch alarm to sound when the next snack time approaches. Patients with anorexia or little caregiver support find this strategy particularly helpful. Providing information on daily calorie requirements is often too intense for the patient, whereas giving patients approximate amounts of foods to be eaten, 6-8 times daily, is more realistic and helpful for obtaining adequate calories. If counseling interventions alone are not helpful, appetite stimulants should be considered. Patients must also be counseled on appropriate fluid intake to prevent dehydration.34, 36

It is crucial to reassess patients often to assure adequate control of nausea and vomiting with nutrition and medication interventions. Weight loss can be significant in patients who follow the correct dietary modifications, yet do not receive adequate medical management of symptoms. Regular weight checks at each chemotherapy or oncologist appointment are needed to document progressive weight loss. In some cases, the doses of chemotherapy drugs may be reduced or the drugs changed if the toxicity of nausea and vomiting is severe.36, 37

Myelosuppression is another significant side effect of many chemotherapy drugs. Decreases in the number of white blood cells, red blood cells, and platelets leave patients at higher risk for infections, anemia, and bleeding.36 In most cases, blood cell counts return to normal approximately 21-24 days after chemotherapy. Severe neutropenia, however, increases a patient’s susceptibility to life-threatening infection.34, 36 The oncology RD should counsel patients and caregivers on the importance of cooking meats well, avoiding foods past their expiration date, and washing fruits and vegetables thoroughly during this time period. Dietitians must monitor patients for diet adequacy as some patients—being fearful of infection—may limit their food intake unnecessarily. Anemia associated with chemotherapy may be treated with erythropoietic factors to improve red cell return to the bone marrow.36 Oncology RDs are frequently asked if there are particular foods or dietary supplements that can hasten the return of bone marrow cells. Patients need to be encouraged to consume adequate calories and protein to facilitate recovery of their bone marrow cells. Any patient with inadequate intake will suffer immune dysfunction, and this will impair recovery of the bone marrow post chemotherapy. Due to limited evidence-based research for many dietary supplements, use of these supplements is typically discouraged for this purpose.37

Altered taste is another common side effect of chemotherapy, and is associated most commonly with treatment consisting of cisplatin, carboplatin, cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), 5-fluorouracil (5-FU), and methotrexate.34-36 The use of antifungal medicines for treatment-induced thrush worsens alterations in the sense of taste, as do some antidepressants and analgesics.37 Attention to meticulous mouth care (brushing, flossing, mouth wash or baking soda rinses) is often helpful to reduce offending tastes. Also, using plastic utensils is often effective to reduce the “metallic” taste many patients report with platinum-based chemotherapies.36 Ongoing and aggressive counseling is necessary to recommend less offending foods and liquids. For some patients, using a straw with liquids is helpful to limit exposure of the liquid on the tongue. Others complain that the altered taste is more pronounced after swallowing. Patients must be encouraged to persevere in finding less offensive foods to maintain caloric intake. Many patients must have a feeding tube placed to avoid severe weight loss.

Table 4.4 provides a summary of recommendations for managing nutrition-related side effects of chemotherapy.

The side effect of cancer treatment universally reported by patients is fatigue.34, 35 For some, this fatigue is debilitating and unrelenting. After ruling out anemia and other possible causes such as pain and depression, RDs can assess their patients’ diets for adequate calories, protein, and fluid, and provide appropriate counseling.34, 35

Ongoing nutritional intervention throughout cancer diagnosis and treatment can prevent or decrease complications and the severity of side effects.38 Maintaining good nutritional status and a healthy weight during treatment increases the likelihood of successful treatment completion. Indeed, the identification of nutritional problems and implementation of interventions for

Side Effect

Strategy

Nausea/vomiting/poor appetite

Clear liquids taken in small amounts; high-carbohydrate foods such as fruit and Popsicles. Set meal patterns/schedules to provide 6—8 small meals/snacks daily.

Thickened saliva

Seltzer and tonic waters, papaya nectar may help thin secretions; increased fluid intake; Consider guaifenesin

(Mucinex).

Diarrhea

Avoid high-fat foods; avoid dairy if it worsens diarrhea. Eat bananas. Consider soluble fiber supplements such as Benefiber.

Weight loss

Eat smaller, frequent scheduled meals with nutrient-dense foods. Use calorie/protein supplements.

Neutropenia

Encourage safe food preparation/handling/cooking to avoid food-borne infections. Ensure adequate calorie/protein intake to support weight maintenance.

Altered taste

Provide regular dental care (brushing/flossing), and use baking soda/water rinses. Use plastic eating utensils if metallic taste is bothersome. Use sugar-free mints/candies or gum; use sauces/marinades on meats; try colder foods versus warm foods; use straws with liquids.

Fatigue

Assure adequate calorie, protein, and fluid intake; engage in activity as tolerated.

Sources: Byron J. Nutrition implications of chemotherapy. In: Elliott L, Molseed LL, McCallum PD, Grant B, eds., The Clinical Guide to Oncology Nutrition. 2nd ed. Chicago, IL: American Dietetic Association; 2006:72—87; Fishman M, Mrozek-Orlowski M, eds., Cancer Chemotherapy Guidelines and Recommendations for Practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Press; 1999; Camp-Sorrell D. Chemotherapy: Toxicity management. In: Yarbro, MH, Frogge MH, Goodman M, et al, eds., Cancer Nursing: Principles and Practice. 5th ed. Sudbury, MA: Jones and Bartlett; 2000:412^55.

nutrition-related symptoms have been shown to stabilize or reverse weight loss in patients with cancer.39 If a patient is unable to tolerate therapy due to side effects, the intent of treatment, whether curative or palliative, is compromised. The goals of nutritional care for all patients receiving chemotherapy or radiation therapy should include preserving lean body mass, preventing or reversing any known deficiencies, minimizing nutrition-related side effects, improving tolerance to treatment, protecting immune function, and maximizing quality of life.40

Patients receiving chemotherapy and radiation therapy should be screened for nutritional risk as soon as possible after their initial diagnosis (see Table 4.5). Those deemed to be at nutritional risk must be assessed and

Anthropometrics

Laboratory Values

Weight

Albumin

Height

Complete blood count

Body mass index (BMI)

Serum electrolytes, creatinine, blood urea nitrogen

Recent weight changes

Liver function tests

Usual body weight

Micronutrient levels

Patient History

Physical Findings

Diet history

Muscle and fat stores

Pertinent medical history

Oral health

Medicine/supplement usage Gastrointestinal symptoms

Skin appearance

Sources: Blackburn GL, Bistrian BR, Maini BS, et al. Nutritional and metabolic assessment of the hospitalized patient. J Parenter Enteral Nutr. 1977;1:11-22; McCallum PD. Nutrition screening and assessment in oncology. In: Elliott L, Molseed LL, McCallum PD, Grant B, eds., The Clinical Guide to Oncology Nutrition. 2nd ed. Chicago, IL: American Dietetic Association, 2006:44-53.

followed throughout treatment according to their needs.41 Screening includes reviewing a patient’s height, weight, any recent weight loss or gain in relation to usual body weight, current dietary intake, labs, and any significant nutrition-related symptoms. Nutrition assessment then assigns a level of nutritional risk reflecting the patient’s nutrient needs and the plan to manage the problem or improve symptoms.

Currently, a number of tools are available to help the oncology RD assess patients.41 These include institution-specific guidelines, Subjective Global Assessment (SGA) and the Patient-Generated Subjective Global Assessment (PG-SGA).42, 43 The PG-SGA is a validated tool for use in the oncology population that allows the RD to measure nutritional status and then to track changes in status, based on nutritional intervention, over a short period of time.42, 43 The form consists of one part to be completed by the patient or caretaker, including questions related to weight history, recent eating patterns, nutrition-related symptoms, and functional status. After the patient or caretaker fills out the form, the RD or other member of the healthcare team evaluates the patient for weight loss, disease status, and metabolic stress. Next, a nutrition-related physical exam is performed looking for visible nutritional deficiencies, and the need for nutritional involvement is quantified by assigning a score to the patient. Patients deemed at significant nutritional risk are counseled and monitored closely throughout treatment and into recovery.

A system such as the PG-SGA requires a multidisciplinary commitment to the nutritional care of patients. In the face of today’s nursing shortage, many clinics have difficulty implementing such a thorough screening tool. In some cases, the oncology RD must identify patients at nutritional risk via his or her own screening methods and institution-specific criteria. This can be accomplished by attending patient rounds and tumor boards, or being available during certain clinic times to identify patients at nutritional risk.

Determining the nutritional needs of patients receiving chemotherapy and/or radiation therapy can be done using a variety of methods.44 Most RDs are quite familiar with the Harris-Benedict equation (HBE),45 which uses a patient’s height, weight, age, and sex to determine resting energy expenditure. Activity or stress/injury factors are also integrated into this equation to give the final tally of calories needed daily. Compared to indirect calorimetry, HBE often overestimates calorie needs for many patients.46 Of note, one study found that HBE underestimated the resting energy expenditure of patients with head and neck cancer receiving radiation therapy when compared to indirect calorimetry.47

Although indirect calorimetry is a well-established method of determining energy needs of patients, it requires the use of equipment that is more often used and housed in the inpatient/critical care setting. Many cancer centers do not have access to this equipment. Recent studies have validated the use of Mifflin-St. Joer formula to more accurately assess the energy expenditure of healthy outpatients,48 but this formula has not yet been validated in oncology patients or acutely ill individuals.

In the end, dietitians must use clinical judgment when assessing the calorie needs of cancer patients. And, because calorie needs can and do change throughout the course of therapy, it is important to track weights in relation to caloric intake to assess whether goals are being met or need to be changed. Current treatment intensity, the patient’s general health, and performance status at the start of treatment should be considered when estimating calorie and protein needs.

It is a common misconception that all patients with cancer have increased calorie needs. Studies have shown this is not the case: Only some 30% of cancer patients actually have increased needs.4449 Some data support increased calorie needs in patients with cancers of the head and neck.47 Weekly weights and careful record keeping of calories eaten by the patient are necessary to accurately determine the level of calorie support needed by the patient. Because patients are typically quite fatigued and suffering treatment-related side effects, family members and friends are often enlisted to help with this process. In one study conducted within the head and neck cancer population receiving radiotherapy, patients reported increased intake with the support and encouragement of family.50

Nutrition counseling has been shown to improve nutritional status and quality of life significantly in patients with head and neck and gastrointestinal cancers.51 Individual counseling may be the most effective nutrition intervention to affect nutritional status. This type of interaction involves giving patient-specific information to help the individual manage nutrition-related symptoms. Some studies have indicated that intensive nutrition counseling can significantly improve dietary intake in patients receiving radiation therapy.52 Other studies have shown that medical nutrition therapy can improve calorie/protein intake, help maintain weight, and increase quality of life.53

To be effective, nutrition counseling must be thorough and frequent. For example, patients receiving combined chemotherapy and radiation for cancer of the head and neck can lose weight rapidly when symptoms of mucositis and dysphagia begin, which typically occur by the second week of treatment. Ideally, the RD should counsel the patient on the need for aggressive nutritional intake prior to the onset of the side effects. Weekly follow-up visits are crucial for managing side effects as they develop. The oncology RD must identify nutrient-dense foods that the patient will and can eat, and then provide specific information about the recommended amounts to eat daily. This process involves lengthy discussions regarding food preferences, identification of tolerances, and clear instructions regarding serving sizes and types of foods to buy and eat. Patient-specific meal patterns can illustrate the types and amounts of foods needed to meet nutritional needs, in conjunction with the medical management of pain, nausea, and other side effects. Weekly weights and symptom assessments will help to identify problems that affect patient intake. Food records kept by patients may be evaluated to determine whether patients are meeting their estimated nutritional needs.

Nutrition Support During Oncologic Therapies

Ideally, patients undergoing treatment for cancer will meet their nutritional needs via oral intake. The oral route is physiologically superior and should be maintained as long as possible.38 Recommending modified textures, fortifying calories in liquids and soft solids, and spacing out eating times are important management tips to help patients complete treatment with minimal nutritional compromise. Liquid medical food supplements are widely used today to boost calorie and protein intake. These flavored supplements, which often replace some or most of a meal’s calories and protein content, can minimize large weight losses. This, in turn, is helpful in preventing treatment interruptions.3839 Modular carbohydrate, protein, and fat products are also available and can be added to a variety of common foods to boost caloric, protein, or fat intake. While patients should always be encouraged to maintain some level of oral intake of foods, many become reliant on the use of supplements as a significant source of calories and protein during treatment.

Simply telling patients to drink a nutritional supplement is rarely enough. Patients are more likely to meet their nutritional needs if they are given a number of cans or supplements to consume daily. This type of education also makes patients more accountable in the management of their care.

Although many patients are willing to use nutritional supplements early on, taste fatigue and aversion after prolonged use of these products are quite common.38 The nutritional supplements typically used by cancer patients are flavored milk-type supplements (although most are lactose-free). Juice-type calorie/protein-fortified medical food supplements are available as well. Given that the side effects associated with radiation continue one to two weeks after completion of treatment, ongoing follow-up after treatment ends is important to assure continued attention to adequate nutrition. Weight monitoring and symptom tracking are often useful in adjusting supplement requirements post treatment.

Despite the widespread availability and relatively modest cost of nutritional supplements, many patients are unable to afford them. Generic formulas, which are nutritionally comparable to the brand-name products, are available and less expensive. It is vital that the entire multidisciplinary team, but especially the social worker, be prepared to assist with issues that can affect intake and ultimately nutritional status, such as ability to purchase nutritional supplements. The oncology RD can also provide patients with recipes for homemade supplements. These mixtures are frequently better tolerated if patients have caregiver support or the energy to prepare drinks, shakes, or fortified foods.

Patients receiving radiation and/or chemotherapy—and especially those being treated for cancers of the head and neck, thorax, and gastrointestinal tract—may require nutritional support beyond what medical food supplements and food can provide. Tumor-related symptoms, increased metabolic needs, and the inability to meet nutritional needs orally are all indications for nutrition support.54 The use of nutrition support in individuals with cancer is still the subject of debate, with some researchers suggesting that it may have detrimental effects on outcomes and length of life. However, when used appropriately, enteral and parenteral nutrition support have been shown to be an effective way to nourish cancer patients who cannot maintain adequate oral intake.54, 55 Malnourished cancer patients may benefit from nutrition support by achieving increased energy, strength, activity level, and weight gain.54 Patients with cancers (especially those of the head and neck) that are treated with radiation alone or with chemoradiation often develop significant mucositis, taste changes, thickened saliva, nausea, and vomiting that preclude oral intake as a sole source of nutrient intake. Prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement before treatment begins is becoming more accepted when the toxicity of treatment is expected to be severe.25, 31 Patients with cancer who may benefit from nutrition support include those with recent significant weight loss (more than 10% usual body weight within the previous 6 months), those unable to eat or drink for more than 5 days, and those with known malabsorption, small bowel obstruction, or fistulas affected by oral intake.47

Enteral nutrition is the preferred nutrition support route, as it is the most physiologic. Feeding into the gut maintains the integrity of the gastrointestinal tract, thereby avoiding the risk of bacterial translocation.38 The translocation of bacteria into the systemic circulation can lead to sepsis, organ failure, and death.56 PEG tubes are often used in patients receiving cancer treatment when the expected duration of use is greater than 2 weeks. PEG tubes have a larger diameter than nasogastric tubes, so they allow for easier passage of tube feeding products as well as medications. PEG tubes also reduce the risk of aspiration compared to nasogastric tubes.55

The primary oncologist should present the option of feeding tube placement as part of a patient’s overall treatment plan. The psychological effects of PEG tubes are variable and not well studied; however, they may include depression, stress, and change in lifestyle.50 Early discussion with the patient and caregivers at the time of diagnosis and education regarding the indi-cations for the tube, expected length of use, and benefits of aggressive nutritional intervention are helpful to reduce anxiety related to these tubes. Often, patients have fears based on past experiences with family members or friends, and education and reassurance may be helpful in overcoming their trepidation. It is this author’s experience that feeding tubes placed in patients who are undergoing treatment are less effective owing to an increased rate of complications, more pain associated with the procedure, and less tolerance to tube feedings after placement. Patients who undergo gastrostomy tube placement prior to head and neck radiation treatment, by contrast, lose less weight during the treatment course and have increased quality of life.2657

Enteral formulas are typically infused via a bolus method by syringe (over 10-30 minutes) or through a continuous feeding pump. Although enteral nutrition is not risk free, it is considered to be safer than parenteral feeding.58 Patients can usually tolerate standard polymeric formulas, either isocaloric (1 cal/mL) or calorically dense (2 cal/mL) for those with volume intolerances. Carbohydrates are usually the major calorie source, with whey or casein supplying the protein content. Fat is typically provided via vegetable oils or triglycerides.

Specialty formulas are available, but their benefits and drawbacks should be weighed carefully relative to standard formulas. Many are difficult to obtain through local pharmacies or home health companies, and they are usually quite expensive compared to standard formulas. Immuno-enhanced enteral feeding (formulas with added omega-3 fatty acids, arginine, and nucleotides) may decrease postoperative complications from gastrointestinal surgeries when given preoperatively to very malnourished cancer patients.24 Currently, there is limited support for tube feeding (and oral) products formulated for cancer patients and enriched with eicosopentanoic acid (EPA). While some research has shown that EPA can be an effective modulator of cancer cachexia, this relationship has not been proven in larger, well-designed studies.59

Parenteral nutrition (PN) delivers nutrients directly into the circulation via a central vein or a peripheral vein. PN may be necessary in a select population of cancer patients receiving treatment, including those with gut dysfunction receiving aggressive treatment, short bowel syndrome, intractable nausea and vomiting with enteral feedings, bowel obstruction, or enterocuta-neous fistulas requiring bowel rest. Contraindications for PN include a functional gut, poor prognosis, or nutritional support that is needed for less than five days.

PN carries more risk than enteral feedings. Because it is administered via vein, there is a higher risk of infection with both peripheral and central parenteral nutrition support. Most patients requiring PN are weaned off and transitioned back to an oral diet as soon as possible.

The use of PN in patients with cancer is controversial. Some studies support the use of preoperative PN in malnourished patients with gastrointestinal cancer.38, 60 Those receiving such nutrition support develop fewer surgical complications and infection and have decreased mortality.38, 60 Other studies have shown contradictory results, likely due to small sample sizes, variations in the patient populations studied, and differences in treatment plans.60 Despite the inconsistent results, the risks of overfeeding associated with PN have been identified and new practice recommendations made.60 It appears that PN during chemotherapy is most appropriate for those patients with significant weight loss and malnutrition who are responding to the prescribed treatment.60 Limited studies are available on PN use during radiation therapy; the ones that have been published do not show any survival benefit or reduction in treatment toxicity with this type of nutritional therapy.60 Patients with radiation enteritis may require bowel rest, and a course of PN may be warranted in such cases to prevent nutritional decline.

Clearly, the advantages and disadvantages of PN should be considered carefully before such treatment is undertaken in cancer patients. The American Society for Parenteral and Enteral Nutrition and the American Dietetic Association Oncology Evidence Analysis Library provide guidelines for appropriate use of PN in this population to help guide the oncology RD and other clinicians.

SUMMARY Chemotherapy and radiation therapy are key components in the care of many patients with cancer who cannot be treated by surgery alone. Advances in these cancer treatments continue to emerge, yet these therapies still cause significant toxicities that negatively affect many patients. Because this population has unique nutritional needs, early and ongoing intervention by a RD is essential to assist in the multidisciplinary care of these patients. The oncology RD provides individualized counseling to patients and families, and helps guide other members of the healthcare team regarding the nutritional status of those treated. This type of nutritional counseling can improve both quality of life and outcomes in patients with cancer. This chapter should equip healthcare professionals working with oncology patients with a better understanding of both radiation and chemotherapy principles, and assist them in understanding the nutrition screening, assessment, and counseling processes. Ultimately, the goal is to provide cancer patients with the best nutritional care centered on evidence-based practice.

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