The State of the Art in Radiation Therapy

The State of the Art in Radiation Therapy

212 Seminars in Oncology Nursing, Vol 22, No 4 (November), 2006: pp 212–220 OBJECTIVES: To describe the modalities used to administer radiation ther...

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Seminars in Oncology Nursing, Vol 22, No 4 (November), 2006: pp 212–220

OBJECTIVES: To describe the modalities used to administer radiation therapy and discuss the acute effects and longterm survivorship issues experienced by patients who receive radiation therapy.

DATA SOURCES: Radiation oncology, surgical, and oncology nursing journals, textbooks, electronic resources.

CONCLUSION: New technology and state-of-theart equipment has resulted in improved treatment modalities, thereby expanding traditional treatment paradigms and exploring new frontiers.

IMPLICATIONS PRACTICE:

FOR

NURSING

It is critical that oncology nurses remain cognizant of advanced technology and its influence on treatment outcomes and patient toxicity. Such knowledge will better serve patients and hopefully influence evidence-based treatment interventions.

From University of Pittsburgh Medical Center, Passavant Cancer Center, and La Roche College, Department of Nursing, Pittsburgh, PA. William P. Hogle, RN, MSN, OCN®: Clinical Manager, University of Pittsburgh Medical Center-Passavant Cancer Center; and Adjunct Faculty, La Roche College, Department of Nursing, Pittsburgh PA. Address correspondence to William P. Hogle, RN, MSN, OCN®, University of Pittsburgh Medical Center, Passavant Cancer Center, 9100 Babcock Blvd, Pittsburgh, PA 15237; e-mail: [email protected]

© 2006 Elsevier Inc. All rights reserved. 0749-2081/06/2204-$30.00/0 doi:10.1016/j.soncn.2006.07.004

THE STATE OF THE ART IN RADIATION THERAPY WILLIAM P. HOGLE

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UCH LIKE the technologic advancements made in the consumer electronics industry over the past decade, advanced computer software and imaging technology have propelled the field of radiation oncology well into the 21st century. The pioneering work of Roentgen, Curie, Becquerel, and others have given way to treatment techniques that were once unimaginable. Although the basic underlying principles of radiation therapy and radiobiology have changed little over the past 100 years, the means by which radiation is administered has continually evolved so as to improve overall outcomes and minimize side effects. Since nearly two thirds of all cancer patients receive radiation at some point during their disease trajectory,1,2 it is imperative that continued improvements through technological advancements and knowledge gained from clinical trials and preclinical experimentation continue to be realized. Although a small percentage of benign diseases or non-malignant conditions are treated with radiation therapy, the primary goal in the administration of therapeutic radiation is to destroy malignant cells in a treated volume of tissue while minimizing damage to normal tissues.3 The purposes of administering radiation vary according to disease and patient or practitioner intent (Table 1).3,4 There are primarily two types of ionizing radiation therapy, that which produces electromagnetic radiation; such as x-rays (photons) from a linear accelerator or gamma rays emitted from a radiation source (eg, cobalt-60, cesium-137, iridium-192) and particulate radiation, which consists of particles including alpha particles, beta particles, electrons, neutrons, and protons (Table 2).3 Brachytherapy and radioimmunotherapy utilize radionuclides that emit radiation in the form of alpha and beta particles or gamma rays. Therefore, brachytherapy and radio-

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TABLE 1. Purpose of Administering Radiation Therapy Definitive treatment Prescribed as the primary treatment modality, with or without chemotherapy, for the treatment of cancer with the intent to cure. Neoadjuvant treatment Prescribed before standard or definitive treatment, usually surgery, in patients with local disease to improve the chance of successful resection. Adjuvant treatment Administered after definitive treatment (either surgery or chemotherapy) to improve local control. Prophylaxis treatment Prescribed to treat asymptomatic, high-risk areas so as to prevent growth of cancer. Control Prescribed to limit the growth of cancer cells to extend the symptom-free time period for the patient. Palliation Noncurative treatment to relieve pain and suffering (ie, bleeding, airway obstruction, neurologic compromise) when the disease has reached a stage at which a cure is no longer possible. Data from references 3 and 4.

immunotherapy may be considered electromagnetic or particulate in nature. Regardless of its source, ionizing radiation damages a number of intracellular components. The key molecule in the nucleus of the cell for radiation damage is thought to be deoxyribonucleic acid (DNA).5 One form of damage involves the alteration of or loss of one or more of the four nitrogen containing bases: adenine (A), thymine (T), cytosine (C), and guanine (G). A second form of damage may involve the destruction of hydrogen bonds between A-T and C-G base pairs, which function to keep the two DNA strands together. Other types of damage include breaks in one or both chains of the DNA molecule and cross-linking of the chains after breakage. When

the strands are broken, resulting in damage to the DNA, consequences can vary. Major or minor effects on protein synthesis may occur, resulting in a change in the genetic material of the cell or mutation, thus resulting in impaired cellular function and cell death.6 Other cellular structures that are both direct and indirect targets of radiation include chromosomes, which play a key role in various stages of cellular mitosis; cell plasma and cell membrane; mitochondrial and lysosomal membranes; and cellular components such as proteins, enzymes, carbohydrates, and lipids. The combined effects of damage to chromosomes and other cellular components may contribute to the ultimate effect of radiation at the cellular level.

TABLE 2. Types of Particulate Radiation Alpha particles Large, positively charged particles with poor penetrating ability; emitted during decay of a radioactive source. Electrons Small, negatively charged particles accelerated to high energies by an electrical machine (linear accelerator). Beta particles Electrons emitted during decay of radioactive sources. Protons Large, positively charged particles that may be generated by a linear accelerator. Neutrons Large, uncharged particles that may be generated by a large machine, such as a cyclotron. Data from reference 3.

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TABLE 3. Biological Factors that Influence Cellular Response to Radiation Therapy Oxygen effect Theorized that oxygen effect is related to the ability of oxygen to combine with the free radicals formed during ionization thereby producing new and toxic combinations. Another theory suggests that the presence of oxygen at the time of irradiation prevents the reversal, and thus repair, of some of the chemical changes that occur as the result of ionization. Linear energy transfer Rate at which energy is lost from different types of radiation while traveling through matter. Low energy transfer radiations have a random pathway resulting in few direct hits within the cell nucleus. High energy transfer radiations more likely to interact with matter and produce more direct hits within the cell. High energy transfer is more dependable when administering radiation therapy. Relative biological Compares a dose of test radiation with a dose of standard radiation that produces the same biological response. Expressed by the formula: Dose of reference radiation to produce a given biologic effect divided by dose of test radiation to produce the same biologic effect. Dose rate Refers to the rate at which a given dose is administered Low dose rates are less effective in producing lethal cell damage than high dose rates. Low dose rates permit cell repair to occur before the lethal dose is reached in fractionated therapy. Fractionation Takes the total dose of radiation and divides it into equal fractions. Total dose may need to be higher due to the plan of delivering multiple fractions. Data from reference 6.

CELLULAR RESPONSE

C

TO

RADIATION

ellular effects from radiation appear to be maximized during the M and G2 phases of the cell cycle.7 This would suggest maximum effect from radiation should occur just before and during cell division. In addition, research by Bergonie and Tribondeau8 has supported that the sensitivity of cells to irradiation is directly proportional to their reproductive activity and inversely proportional to their degree of differentiation. Because the effect of radiation is known to be greatest during mitosis, undifferentiated cell populations are generally most sensitive to radiation. In contrast, well-differentiated cells are relatively radioresistant.6 In addition to cell cycle phase and cell sensitivity, other biological factors that influence cellular response include: oxygen effect, linear energy transfer, relative biological effectiveness, dose rate, and fractionation. Table 3 provides an explanation of these concepts.6 Fractionation is the practice of administering daily radiation treatments over an extended period of time, usually over several weeks, so that a high dose is given to the tumor, while ideally sparing normal tissue.9 A fractionated dose of radiation is biologically less efficient than a single dose, but also is less toxic to

healthy surrounding tissue. Therefore, higher total doses are necessary during fractionation to produce the same damage compared with a single dose. The biologic effects on tissue from fractionated radiation therapy depend on the four “Rs” of radiobiology, which include: repopulation, redistribution, repair, and reoxygenation (Table 4).6,10

RADIATION TREATMENT MODALITIES

R

adiation therapy is primarily delivered utilizing three different modalities: external beam radiation therapy (EBRT), brachytherapy, or radioimmunotherapy. EBRT is the backbone of therapeutic irradiation and is considered a linear accelerator-based modality. The radiation is produced in the form of high-energy x-rays by a machine that uses high-frequency electromagnetic waves to accelerate charged particles, such as photons and electrons, through a linear tube. Linear accelerators have the ability to treat with shallow depth penetration (electrons) or deep depth penetration (photons). Technologic advancements for linear accelerator-based treatment modalities over the past decade have allowed practitioners greater flexibility in treatment planning and presumed improvement in treat-

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TABLE 4. The Four “Rs” of Radiobiology and Their Influence on Dose Fractionation Repair Replacement of damaged cells by a different cell type. Resulting in scar formation or fibrosis. Some tumor cells may be repaired between daily doses of radiation. Redistribution Redistribution of cell age is advantageous and desired as more tumor cells are made radiosensitive. Succeeding daily doses of radiation, more tumor cells are delayed in the cycle and reach the mitotic phase as the next dose is given, thereby increasing cell kill. Repopulation Takes place through cell division during a multifractionated treatment plan. Allows repopulation to occur in normal tissues, sparing them from some of the late consequences that might arise if repopulation was inhibited. Tumor cells that succeed in dividing while undergoing a fractionated course of treatment are usually incapable of surviving because of the radiation effect. As a result, fractionation favors normal tissue while killing tumor cells. Reoxygenation Normal cells are usually well oxygenated and tumor cells are characteristically in a normal to hypoxic to anoxic state. Hypoxic or anoxic cells are generally radioresistant. Oxygenated cells are radiosensitive. Fractionating the dose allows the cells to become oxygenated as the tumor shrinks. Data from references 6 and 10.

ment outcomes while hopefully decreasing overall toxicity. Three- and 4-dimensional treatment planning systems and conformal radiation therapy, inclusive of intensity modulated and image-guided radiation therapy techniques, are replacing fluoroscopyguided simulation and once standard 2-dimensional treatment fields. Three-dimensional treatment planning and conformal radiation therapy deliver radiation to a target with an improved margin for sparing normal tissue. Computer software and advanced computed tomography (CT) imaging are used during the treatment planning process to digitally reconstruct a 3-dimensional image of the patient’s anatomy, inclusive of a tumor or tumor bed, so as to guide highly accurate conformal beams of radiation. Beam shape can also be customized by using multi-leaf collimator units to accommodate irregularly shaped tumors or treatment fields. Intensity Modulated Radiation Therapy As the name implies, intensity modulated radiation therapy (IMRT) allows for the modulation in intensity of each beam of radiation so that each field can have multiple areas of high- and lowintensity radiation within the same field. This ability to modulate the radiation dose allows al-

most limitless possibilities to customize each patient’s treatment prescription. IMRT is augmented through the use of multi-leaf collimators and improved treatment planning software to determine optimal distribution of beam intensities across the treatment area. Conventional external radiation cannot treat a tumor surrounding a vital organ without dosing that particular organ. Conversely, 3-dimensional planning and IMRT provide for separation and safe treatment of the tumor from the adjacent structures and tissue.11 It is believed that IMRT may prove beneficial in escalating the dose to the tumor volume while reducing the dose to normal tissue.12 Image-Guided Radiotherapy Although IMRT is a powerful cancer treatment tool, its overall effectiveness can be limited by organ movement or errors in patient positioning. Image-guided radiotherapy uses technologic advancements developed over the past 5 years to incorporate sophisticated imaging systems onto linear accelerators, thus allowing for consideration of the fourth dimension of patient treatment planning, movement. Among the innovative accelerator-based imaging advancements are: conebeam CT, radiographic kV imaging, and gated CT (Table 5).13 Cone-beam CT and radiographic kV

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imaging allow practitioners to compare planning images with images acquired right before treatment and adjust the location and frequency of the multiple beams of radiation as needed. Gated CT accounts for patient movement from respirations during treatment administration. Stereotactic Radiosurgery Linear accelerator-based stereotactic radiosurgery techniques have traditionally been used to treat central nervous system tumors. The process combines stereotactic localization techniques, 3-dimensional planning imagery, and a sharply focused beam of radiation aimed at a specific, well-defined intracranial lesion. When treating central nervous system tumors, patients are positioned in a halo device used for immobilization, so as to ensure accuracy and reproducibility of the treatment set-up. Target volumes should ideally be spherical and treatment administration usually takes place in a single fraction (treatment). In addition to accelerator-based stereotactic radiosurgery, a gamma knife utilizing multiple cobalt-60 sources or a cyclotron, which uses neutrons or protons, can be used to administer this type of treatment. Image Guided CyberKnife Radiosurgery This technology uses a frameless approach to radiosurgery and can be used to treat extracranial lesions throughout the body. CyberKnife (Accuray, Inc, Sunnyvale, CA) technology consists of

an advanced, relatively lightweight linear accelerator used to produce high-energy beams of radiation. The accelerator is attached to a highly versatile robotic arm capable of delivering radiation from 1,200 different beam angles. The technology also engages the use of several x-ray cameras, along with advanced software imaging used to track and compensate for patient movement (be it movement from respiratory motion or otherwise). This image-guided technology essentially acts to replace the use of a frame to restrict patient movement. Current research has focused CyberKnife technology in treating malignant tumors of the head and neck, spine, lung, abdomen, and pelvis.14 –17 When treating extracranial lesions, it may be necessary to place interstitial fiducial markers by way of CT guidance to provide a target upon which the image-guided software can focus. Brachytherapy This modality involves the temporary or permanent placement of selected radioactive sources directly into a body cavity (intracavitary), into the tissue (interstitial), into a passageway (intraluminal), or onto a tissue surface (plaque). Brachytherapy delivers a prescribed treatment dose to a specified tumor volume with a rapid fall-off in radiation dose to adjacent normal tissues. Highdose-rate or low-dose-rate brachytherapy can be used to treat a number of malignancies including gynecologic, breast, lung, esophageal, and head and neck cancers, brain and prostate tumors, cho-

TABLE 5. Linear Accelerator-Based Imaging Advancements Cone beam CT This technology brings the power of CT imaging to the point of delivery. It provides real-time volumetric images of soft tissue, organs, and bony structures and their alignment in a three dimensional plane. Cone beam technology is integrated into the linear accelerator by using a lower energy x-ray source that can display images right before treatment. This allows for any last minute adjustments in treatment position to be made and can minimize the treatment margin around the tumor. Radiographic kV imaging Similar to cone-beam CT, this technology provides high-quality x-ray images that are 2-dimensional projection images. Such capability allows images of lung tumors and tumors that do not overlay adjacent bony features. Gated CT Gating systems use CT images acquired during simulation and are incorporated into the treatment planning phase. The CT images show the location of tumors and organs at different phases of the respiratory motion cycle. Beam delivery is then adjusted so it is turned on and off at specific intervals based on the stability of the tumor during a portion of the respiratory cycle. Data from reference 13.

THE STATE OF THE ART IN RADIATION THERAPY

roidal melanoma, and others.18 Brachytherapy can be used as primary treatment or in combination with EBRT to cure or palliate certain malignancies. By irradiating a small volume of tissue, complications are minimized and organ function is preserved.19,20 Brachytherapy is most often performed using reactor-produced radionuclides such as cesium-137, iridium-192, iodine-125, palladium-103, and gold-198. Recent advances in ultrasonic imaging have refined prostate brachytherapy techniques, thereby allowing this form of treatment to be safe and highly effective. In addition, 3-dimensional planning and novel delivery techniques, such as balloon-tipped catheters, have revolutionized breast brachytherapy techniques and treatment of some recurrent brain tumors. Intraoperative Radiation Therapy This modality uses a single, large fraction of radiation administered to an exposed tumor or resected tumor bed during a surgical procedure.21 Intraoperative radiation therapy (IORT) uses highenergy electrons from a portable “mini-accelerator,” a traditional fixed-linear accelerator, or a high-doserate gamma-emitting isotope. When IORT is used it usually is necessary to attach specially designed applicators to the accelerator unit. Considerations when using IORT include shielding of adjacent normal tissue as well as shielding of the operating room staff from radiation exposure. In addition, when using a non-portable accelerator unit, logistic considerations of patient transfer and infection control are legitimate concerns. These concerns can be negated if a fixed linear accelerator exists within the operating room. IORT provides aggressive treatment to the tumor bed during surgery, thus allowing the potential for reduction of subsequent postoperative doses of radiation and allows for dose escalation if deemed necessary.22 IORT is typically used in the treatment of gastrointestinal, gynecologic, and genitourinary cancers,23 as well as some types of breast cancers.24

ACUTE EFFECTS

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RADIATION THERAPY

s presented, there are a number of different methods in which radiation therapy can be administered. Effects from radiation therapy refer to visible (detectable) structural and functional changes that a dose produces within a certain period of time. With the exception of cataracts of

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the ocular lens, radiation-induced changes are neither unique nor distinguishable from biologic effects caused by trauma.5 Structural or morphologic response after irradiation is usually grouped into three phases: early or acute, subacute, and late or chronic effects. Acute effects vary with each patient, are site specific and generally short term, and resolve after completion of treatment. The time to complete resolution of acute effects depends on the tissues treated and the degree of reaction from the radiation.25 Subacute effects are toxicities that are clinically evident within weeks to a few months after completing radiation. Late or chronic effects are generally considered those that occur 6 months following treatment completion. The appearance of late effects is a consequence of early changes that were irreversible and progressive.5 Acute side effects are expected during radiation therapy and correlate with the specific normal tissues and structures within the path of the radiation beam. Table 6 represents a list of site specific acute reactions.25–29 Although there are sitespecific effects, there are also acute effects that are considered general in nature; these include fatigue and radiodermatitis. Myelosuppression is also a general acute effect of radiation but is likely seen only when significant portions of the pelvis, sternum, or long bones are irradiated or when radiation is combined with chemotherapy. Fatigue related to radiation therapy is usually selflimiting. King et al30 found that fatigue was experienced by 60% of patients during the first week of radiation therapy and by 93% during the third week of treatment. Acute skin reactions such as erythema and dry or moist desquamation are common and occur to some degree within the treated field in many patients who receive radiation. Body areas with thinner skin and skin folds are more susceptible to radiodermatitis, as are areas that have had previous radiation exposure.31

LONG-TERM SURVIVORSHIP ISSUES

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atients who experience acute effects from radiation could potentially experience these same effects well past the acute and sub-acute phases of recovery, thus making them late effects. There is no conclusive method to predict the extent one will experience a late effect from radiation therapy. In addition to acute effects becoming late effects, the radiation therapy patient faces

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TABLE 6. Selected Site Specific Acute Toxicities of Radiation Therapy Site Toxicities Central nervous system Brain

Spinal cord Head and neck

Chest/Lung

Breast Abdomen/Pelvis

Scalp, forehead erythema, alopecia, external auditory canal irritation causing ear aches, transient increased cerebral edema, which can result in headaches, dizziness, nausea and vomiting, acute myelopathy, acute somnolence syndrome Lhermitte’s syndrome (subacute) Skin erythema, oral mucositis which may include oral candidiasis, laryngitis, esophagitis manifested as dysphagia or odynophagia, xerostomia, dysgeusia, and ageusia Skin erythema, esophagitis manifested as dysphagia or odynophagia, dysgeusia resulting in anorexia, gastric reflux, cough, shortness of breath, blood tinged sputum, acute pericarditis, pneumonitis (subacute) Skin erythema which may result in dry or moist desquamation, breast edema, nipple irritation Skin erythema, dyspepsia, nausea, vomiting, anorexia, diarrhea, proctitis symptoms, cystitis symptoms, perianal mucositis, vaginal dryness, decreased libido

Data from references 25–29.

issues such as increased post-treatment anxiety, depression, functional disability, and changes in quality of sleep.32,33 The prevalence of anxiety and depression among radiation patients may be as high as 50%.34 Many cancer survivors experience symptoms of post-traumatic stress disorder and live in continual fear of a disease recurrence.35 In addition to psychosocial issues, many longterm survivors suffer from some degree of sexual side effects. Most patients treated with radiation to the pelvis have reported varying degrees of sexual dysfunction.36 Narrowing and obliteration of the pelvic vasculature and fibrosis of perivaginal tissue contribute to vaginal stenosis in women treated with pelvic radiotherapy.37 In males, radiation accelerates atherosclerotic changes in the pelvis and eventually interferes with the arterial blood supply of the penis. Fibrosis of the neurovascular bundles also contributes to decreased erectile capacity.38 Patients treated with radiation for breast cancer and head and neck cancer were also found to experience sexual dysfunction.39 – 41 Radiation-induced malignancies are another concern for long-term survivors. Carcinogenesis from radiation depends on a number of variables, but is directly related to the exposure to radiation. Such variables include: a latent period of 1 to 30 years, radiation dose, concomitant factors in the radiated organism’s environment, and the actual

fate of the cell as it responds to radiation.42 Secondary malignancies that have been associated with radiation exposure include skin carcinoma, leukemia, sarcoma, thyroid cancer, lung cancer, and possibly breast cancer.7,43,44 Because of the potential for secondary malignancies, it is important that patients who have received radiation therapy continue with follow-up care and take part in an active cancer screening program as recommended by the American Cancer Society.45 Though the past several years have brought many technical advances in the field of radiation therapy, the basic principles of radiobiology have remained unchanged. Dosage and dose rate, radiosensitivity, fractionation, and the four “Rs” of radiobiology remain the foundation upon which newer treatment modalities are based. Many treatment protocols now use chemotherapy and radiation therapy. When combined modality is used, acute side effects are usually intensified. In addition, radioimmunotherapy is evolving as a viable treatment option that combines the targeting power of monoclonal antibodies with the cellkilling ability of radiation therapy. Therefore, nurses skilled in the administration of chemotherapy should have a fundamental knowledge base of radiation therapy and its overall effect on patients. The role of the radiation oncology nurse continues to evolve, with a central focus on patient

THE STATE OF THE ART IN RADIATION THERAPY

education and side-effect management. It is hoped that improving treatment efficiency and effectiveness through advanced technology will yield improved patient outcomes and decrease toxicity.

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Radiation oncology nurses must remain knowledgeable of treatment advances so as to apply evidence-based clinical knowledge and interventions toward improved patient care management.

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39. Lamb MA. Effects of cancer on the sexuality and fertility of women. Semin Oncol Nurs 1995;11:120-127. 40. Bruner DW, Berk L. Altered body image and sexual health. In: Yarbro CH, Frogge MH, Goodman M, eds: Cancer Symptom Management. Ed 3. Sudbury, MA: Jones & Bartlett: 2004;596-603. 41. Monga U, Tan G, Ostermann H, et al. Sexuality in the head and neck cancer patient. Arch Phys Med Rehab 1997; 78:298-304. 42. Bucholtz JD. Radiation carcinogenesis. In: Hassey-Dow K, Bucholtz JD, Iwamoto R, Fieler V, Hilderly L, eds: Nursing Care in Radiation Oncology. Ed 2. Philadelphia, PA: Saunders: 1997;57-68. 43. March HC. Leukemia in radiologists in a twenty-year period. Am J Med Sci 1950;220:282-286. 44. Myrden JA, Hiltz JE. Breast cancer following multiple fluoroscopies during artificial pneumothorax treatment of pulmonary tuberculosis. Can Med Assoc J 1969;100: 1032-1034. 45. American Cancer Society. Cancer Detection Guidelines. Available at. http://www.cancer.org/docroot/PED/content/ PED_2_3X_ACS_Cancer_Detection_Guidelines_36.asp (accessed January 2006).