The Bethesda Handbook of Clinical Oncology

Basic Principles of Radiation Oncology 43

Chirag Shah, Nikhil P. Joshi, and Bindu Manyam

INTRODUCTION

Radiation therapy represents an essential modality in the treatment of patients with many different types of malignancy and differs significantly from other commonly used modalities such as surgery and systemic therapy in its delivery and mechanism of action. The purpose of this chapter is to provide a review of the basics of radiation oncology, including an introduction to radiation biology and radiation physics, a summary of patient workflow and treatment delivery and finally, an evaluation of alternative radiation techniques beyond conventional external beam radiation therapy.

RADIATION BIOLOGY AND PHYSICS

Radiation therapy is primarily delivered using external beam radiation therapy via a linear accelerator with the predominant treatment mode being high-energy photons or x-rays. These photons represent ionizing radiation and are part of the electromagnetic spectrum. Alternatives to photons exist including electrons (available on linear accelerators) and to a lesser degree protons and neutrons (seperate devices). Photon-based radiation therapy is considered indirectly ionizing, in that it does not produce damage directly for the most part but instead has its energy transferred to secondary particles (usually electrons), which produce DNA damage. This primarily occurs through the Compton process for photons. Heavy charged particles, though less frequently used, are directly ionizing and can cause damage without secondary particles. Radiation therapy causes biologic effects through DNA damage, in particular double stranded DNA breaks. DNA damage occurs through interactions between particles and DNA, which can occur directly or indirectly. Direct action occurs when the photon transfers energy to an electron, which subsequently interacts with the DNA. Indirect action occurs when the secondary electron interacts to produce free radicals, which can then damage DNA. Photon-based radiation therapy works primarily through indirect action while heavy charged particles work primarily through direct action. Radiation therapy is typically delivered via fractionation, with multiple small radiation doses delivered, allowing for a higher total dose to be delivered, increasing tumor control probability while reducing the risk of normal tissue toxicity. It should be noted that with improvements in treatment planning, treatment delivery, and image guidance, there is a renewed interest in hypofractionation (larger doses per fraction); further the development of stereotactic body radiotherapy (SBRT) allows for the delivery of radiation therapy in five fractions or less using large doses per fraction.

The four fundamental radiobiologic principles guiding standard fractionation and clinical radiation oncology are 1) repair, 2) re-assortment, 3) repopulation, and 4) reoxygenation. Repair is essential and one of the key reasons for fractionation. After receiving photon-based radiation therapy, normal tissue cells are able to repair sublethal damage, limiting toxicity while cancer cells are limited in their abilities to repair sublethal damage, allowing for an improvement in the therapeutic ratio with fractionation. Re-assortment is important because cancer cells have varying degrees of radiosensitivity based on the stage of the cell cycle they are in, with the G2-M phase being the most radiosensitive and the S phase being the least sensitive. As such, fractionation allows for re-assortment of cells into more radiosensitive phases of the cell cycle, enhancing cell kill. Repopulation is important for two reasons; repopulation with fractionation allows for normal tissues to recover if an adequate time interval is introduced. More importantly, some malignancies have been shown to clinically demonstrate repopulation (e.g., head and neck cancer, cervical cancer) during treatment requiring clinicians to complete treatment within a certain duration of time or risk suboptimal local control and outcomes. Finally, reoxygenation represents a key principle of radiation sensitivity and damage. As most radiation is delivered with photons, the primary mechanism of DNA damage is indirect action via free radicals. The presence of oxygen allows “fixation” of the DNA damage caused by free radicals enhancing the impact of the radiation. Fractionation enhances reoxygenation, increasing radiation sensitivity of tumors.

TREATMENT WORKFLOW AND DELIVERY

Regardless of treatment location, radiation oncology workflows are fairly consistent. Patients are initially seen in consultation to discuss the role of radiation therapy and inform patients regarding the potential benefits of treatment as well as acute, sub-acute, and chronic toxicities associated with treatment to allow for informed decision making. This is followed by radiation therapy planning, which begins with a simulation or planning scan. The simulation typically consists of some form of imaging; traditionally, this was done with 2-D films or fluoroscopy but this has been replaced primarily with a CT simulator. At the time of simulation, immobilization is created to achieve reproducible patient positioning, depending on location (e.g., mask for CNS and head and neck cases). Immobilization can also be dependent on the type of treatment; for example, more rigid immobilization may be used when high dose treatments (e.g., SBRT) are performed. At the time of simulation, contrast can be used to enhance assessment of vasculature and lymph nodes and 4D scans are performed to assess the impact of respiratory motion on target and organ at risk volumes. The patient is scanned and an isocenter is placed; additionally, tattoos are commonly placed to facilitate patient setup daily.

Once simulation is complete, the images obtained are transferred to a treatment planning computer. The physician will then draw in contours or volumes for the target including the gross tumor volume (GTV), the clinical target volume (CTV), and the planning target volume (PTV) based on physical exam, imaging, and any other procedures (e.g., Colonoscopy, EGD, nasopharyngoscopy). Additionally, if a 4D scan is performed, an internal target volume (ITV) can be created to account for organ motion. Contours are also made for all critical normal tissue structures in the treatment field. A radiation plan is then created by a dosimetrist and reviewed by the physician. Once approved by the physician, a medical physicist reviews the treatment plan and it undergoes quality assurance checks which are dependent on the technique utilized.

Modern radiation therapy is typically delivered with a linear accelerator. A linear accelerator generates high-energy photons by accelerating electrons and having them approach a target. The x-rays/photons are primarily produced when the electrons are deflected (Bremsstrahlung radiation); additionally, electrons can be used as the therapeutic particle when the target is removed. Inside the head of the linear accelerator are several structures designed to allow to for safe and efficient treatment delivery. In patients treated with photons, beyond the x-ray target is a flattening filter, which creates a more uniform radiation field as well as ion chambers, which measure radiation dose, and subsequently jaws, which can shape the beam. There is a light field to visualize the treatment field as well as an optical distance indicator to measure the source to surface distance. Modern linear accelerators also include a multileaf collimator, which can be used to shape the beam. A similar set of structures is used for electron treatments with the exception of the target being removed and the use of scattering foils rather than flattening filter. Radiation therapists perform treatment delivery; treatment plans created in the treatment planning system are sent to information systems that communicate with the linear accelerator while also serving as an electronic medical record to document daily treatment.

Multiple treatment techniques can be utilized to deliver external beam radiation therapy. Modern radiation therapy primarily utilizes a CT simulator for treatment planning and therefore a three-dimensional approach. Beams can then be shaped using the jaws in the linear accelerator or with leaves within a multi-leaf collimator. Such approaches are known as three-dimensional conformal radiotherapy (3D-CRT). Over the past two decades, an alternative technique to 3D-CRT has emerged known as intensity modulated radiation therapy (IMRT). IMRT allows for the modulation of the intensity of the beam, providing clinicians the ability to preferentially give dose to one area while sparing another. This is accomplished primarily through inverse treatment planning algorithms where the treatment planning system is provided dose constraints for the target and normal tissue structures (with weighting for each objective provided), as well as beam angles. IMRT is routinely performed in the treatment of many different malignancies including CNS malignancies, head and neck cancers, cancers of the thorax and abdomen, sarcomas, and genitourinary as well as gynecologic malignancies.

External beam radiation therapy can be utilized in many different scenarios. Definitive radiation therapy can be utilized in the management of some CNS tumors, lymphomas, and prostate cancers. Definitive radiation in conjunction with chemotherapy can also be utilized in the treatment of some CNS malignancies, head and neck cancers, inoperable lung cancers, esophageal cancers, pancreas cancers, gynecologic malignancies, and bladder cancers allowing for organ preservation and the potential for improved toxicity and quality of life. Radiation therapy can also be delivered post-operatively for patients at high risk for recurrence or residual microscopic disease following surgery; this is most commonly seen in breast cancers but is also used in CNS malignancies, head and neck cancers, pancreatic cancer, sarcomas, genitourinary, and gynecologic malignancies. Finally, radiation therapy can be utilized for palliation, most commonly for bone metastases, brain metastases, lung masses, and bleeding. Common oncologic emergencies where radiation therapy is utilized include spinal cord compression, airway compromise, superior vena cava syndrome, and symptomatic brain metastases not amenable to surgery. Radiosensitizers can be used with radiation therapy to increase the response to treatment. Clinically, this is most commonly done with the addition of concurrent chemotherapy. However, alternatives have been studied including halogenated pyridmidines and hypoxic radiosensitizers, though both are used sparingly in the clinic at this time. Radioprotectors, compounds that protect the body from radiation, have also been explored. At this time, the only clinically utilized radioprotector is amifostine, which is utilized to prevent xerostomia with data demonstrating no difference in clinical oncologic outcomes when using amifostine in head and neck cancers.

Radiation therapy can be associated with acute, subacute, and chronic toxicities. The most common toxicities noted during treatment are fatigue and skin erythema/irritation. Additional acute toxicities are typically dependent on the area of the body being irradiated. Common acute and subacute side effects are listed based on treatment site: CNS (headache, nausea, alopecia, tinnitus), head and neck (mucositis, xerostomia, altered taste, dysphagia), thorax (esophagitis, pneumonitis), gastrointestinal (nausea, vomiting, diarrhea), genitourinary/gynecologic (urinary frequency/urgency, dysuria, diarrhea, vaginal irritation). Acute and subacute side effects tend to resolve within weeks to months of the completion of treatment. Chronic toxicities can be long-lasting; however, use of normal tissue toxicity constraints can limit the risk of chronic toxicities based on treatment site.

ADDITIONAL TECHNIQUES

As noted above, stereotactic radiation therapy is a technique that allows for the delivery of highly conformal radiation treatments, allowing for large doses per fraction. With respect to terminology, stereotactic radiosurgery (SRS) is usually associated with a single fraction while stereotactic body radiation therapy (SBRT) typically is more than one fraction and usually up to five fractions. SRS is best known for its use in the central nervous system and can be performed with a linear accelerator or more specialized treatment machines (e.g., Gamma Knife). While most commonly associated with the treatment of brain metastases, SRS can also be used for pituitary adenomas, trigeminal neuralgia, acoustic neuromas, meningiomas, and arteriovenous malformations as well. More recently, SRS has been incorporated into the management of spine metastases as well, replacing standard radiation therapy in some cases and offering the potential for improved local control and pain control.

SBRT is most commonly associated with the treatment of inoperable early stage non-small cell lung cancers. Promising initial data from Indiana University led to a multi-institutional study, which confirmed excellent rates of local control and an acceptable toxicity profile. Moving forward, current trials are evaluating optimal dose and fractionation schemes for peripheral and central tumors as well as comparing SBRT to surgery in operable patients. SBRT is also being utilized in the management of prostate cancer with trials evaluating five fraction regimens with promising results leading to comparisons to standard and hypofractionated radiation therapy. More recently, SBRT has been utilized to treat liver metastases and HCC’s with encouraging preliminary outcomes with respect to local control and liver toxicity as well as pancreatic cancers. Additionally, SBRT is being evaluated in a number treatment sites including soft tissue sarcoma and head and neck cancers.

Brachytherapy is a radiation therapy technique where radioactive sources are implanted on or inside a patient. Brachytherapy can be performed with low dose rate (LDR) implants typically associated with prostate seed implants, or high dose rate (HDR) implants typically associated with temporary gynecologic or breast implants. Brachytherapy is a commonly utilized treatment in the management of prostate cancer. As noted above, many are familiar with LDR brachytherapy for prostate cancer with excellent clinical outcomes and toxicity profiles reported. Additionally, increasing data are available supporting HDR brachytherapy in prostate cancer, which, unlike LDR, allows for modulation of dose once catheters are in place and the potential for improved toxicity profiles. While treatment with brachytherapy in prostate cancer is primarily monotherapy, recent data are available on the use brachytherapy boost in patients with higher-risk prostate cancer.

Brachytherapy (placing radioactive material inside or on the surface of the body) has also emerged as a standard of care treatment option in appropriately selected women with early stage breast cancer via accelerated partial breast irradiation (APBI), which treats the lumpectomy cavity with a margin. Initial studies evaluated APBI using multi-catheter interstitial HDR; however, more recent studies have evaluated single entry applicators, increasing the ability for patients to receive this treatment. At this time, multiple randomized trials comparing brachytherapy with standard whole breast irradiation have been performed, with no difference in local recurrence noted. Intraoperative radiation therapy (IORT) represents a form of partial breast irradiation different from APBI and can be delivered with multiple techniques at the time of surgery; however, two randomized trials evaluating the technique have demonstrated increased rates of local recurrence compared with whole breast irradiation and as such this technique should not be considered off-protocol at this time. Brachytherapy remains an essential component in the management of gynecologic cancers; in patients with endometrial cancer, post-operative vaginal cylinder brachytherapy is routinely used based on clinical and pathologic factors while brachytherapy remains essential in the management of cervical cancers. Brachytherapy can also be utilized in head and neck cancers, as well as soft tissue sarcomas.

Traditionally, radiation therapy was delivered with photons (high energy x-rays) or electrons for superficial treatments. Photons, which are the most commonly utilized form of radiation therapy, are uncharged and are known for characteristics including the need for a build up region and dose deposition over several centimeters. Protons, on the other hand, are different than photons in that the majority of dose is deposited within a small range (few millimeters) known as the Bragg peak, which can be modulated by changing the energy of the protons. It should be noted however, this range is typically too small for clinical utilization and as such, a spread out Bragg peak is used. The biology of protons is considered similar to photons with the advantage being primarily improved dose distribution rather than greater biologic effect as seen with neutrons for example. While previously limited to a few centers throughout the United States, the past two decades has seen a significant expansion in the number of proton centers. One of the challenges associated with proton therapy is the amount of resources required to deliver treatment and therefore, the cost of treatment. However, proton therapy is particularly attractive for pediatric malignancies with data available supporting the utilization of protons in pediatric cancers, particularly CNS malignancies. With respect to other malignancies, much has been made of the role of protons in the management of prostate cancer. However, at this time, the data does not consistently support the utilization of protons in the management of prostate cancer and should be only performed on-protocol. Similarly, there is limited data supporting the role of protons in breast cancer; while recent data suggests protons can be used for APBI and may be cost-effective, the limited number of patients treated with this technique mandates further study before patients are routinely treated off-protocol. Moving forward, further technological advances including intensity modulated proton therapy and advanced image guidance may allow for further improvement in outcomes with proton therapy; in the interim, in light of the limited data suggesting comparable or improved outcomes and the lack of data demonstrating cost-effectiveness, outside of accepted indications (e.g., pediatric cancers), proton therapy should be limited to use on-protocol primarily.