The Role of Radiation Therapy in Cancer Management

Surgery is complemented by the modality of radiation therapy as part of a multimodal approach for

many types of cancer. Like surgery, radiotherapy is typically focused on locoregional disease control.

For that reason, many of the same principles apply to surgery and radiation oncology, such as patient

selection, recognition of the behavior or tumor biology for a particular patient and cancer, and

assessment of both short-term and long-term toxicities of therapy.

Mechanisms of Radiation Delivery

Energy emitted from a source travelling through space is termed “radiation.” As the energy passes

through materials it interacts with those substances in one of two forms: photons or freely propagating

particles. Photons are packets of electromagnetic fields travelling through space at the speed of light.

The shorter the wavelength of the photon the greater the frequency of the oscillation and the higher the

energy contained within the photon packet. Lower-energy photons make up the energy in visible light

and only interact with the surfaces of objects. Higher-energy photons are used in diagnostic and

therapeutic radiology and can pass through tissues to interact with deeper material and either reveal or

impact underlying structures. Freely propagating particles carrying kinetic energy can be protons,

electrons, or alpha-particles. These charged particles interact with other charged particles as they travel

along their path. As photons or charged particles interact with biologic materials within the target area

in the setting of therapeutic radiation, the interactions lead to ionization and subsequent biologic

damage.

Linear accelerators (linacs) are the most common means for generating radiation in a manner

allowing focused delivery of energy to a target tissue. Linacs can be used to generate either photon

radiation or electron particles to be used as the ionizing agent. The linac uses oscillating electric fields

to accelerate electrons toward a metal target converting the electron beam into a spray of photons. The

photons are focused through filters and shaping elements to sharpen the beam of energy being

delivered. A higher energy level of the photons travelling through the shaping process will lead to a

higher level of energy delivered to the surface of the treatment target. As the photon beam travels

across distance through a material, the dose will attenuate as the depth of penetration increases.

Photons with higher energy penetrate more deeply into any given material and maintain the energy

level for a greater distance. As this ionizing radiation travels through tissues, the photons deposit

energy into the materials through which it passes. The total amount of energy delivered to a biologic

system is measured in terms of joules per kilogram. The dose corresponding to the amount of energy

delivered is expressed in terms of Gray (units of dose).

Tissue Response to Radiation

The therapeutic effects of radiation are contingent on the damage caused to the cells through which the

ionizing radiation beam passes. The mechanism of action of cellular damage can be categorized into

direct and indirect effects of radiation (Fig. 14-6). Both effects lead to the damage of DNA molecules.

The direct effect of ionizing radiation is ionization of DNA molecules and the downstream effects of the

damage to this critical cellular molecule. The indirect effect of ionizing radiation is best exemplified by

the radiolysis of water molecules leading to the generation of free radicals. Free reactive species

interact with DNA molecules causing indirect damage. The majority of total DNA damage is from this

second, indirect effect. The proportional relationship between oxygen tension within tissues and the

resultant damage caused by ionizing radiation is termed the oxygen effect.152 The phenomenon is

explained by the capacity to generate a greater concentration of free radicals in oxygen-rich tissues than

in hypoxic environments.

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Figure 14-6. The mechanism of action of cellular damage can be categorized into direct and indirect effects of radiation.

Ionizing radiation can lead to multiple types of DNA damage: cross-linking of two DNA strands, loss

of a DNA base or entire nucleotide, and breakage of the sugar-phosphate backbone.153 Many of these

types of damage are actually a failed attempt to eliminate unpaired electrons resulting from free radical

generation. The mammalian cell has multiple DNA repair mechanisms operating with remarkable

fidelity under typical conditions. In the setting of therapeutic radiation delivery, the DNA disruption is

either too complex or too widespread to allow for normal mechanisms of repair. The generation of

flawed versions of the original DNA molecule can lead to ineffective mitosis and failed cell division.

Many cancer types are characterized by deficits in the DNA repair mechanism process.154,155 When these

processes function suboptimally, the impact of radiation-induced damage can be more potent on the

mutated cancer cells than on the DNA-repair intact nonneoplastic cells. Disruption of DNA synthesis by

fluoropyrimidines such as 5-fluorouracil and capecitabine likely contributes to the therapeutic benefit of

combining these agents to radiation. Fluoropyrimidines interfere with the capacity of cellular DNA

repair mechanisms to correct DNA lesions induced by ionizing radiation.

Of course, ionizing radiation is relatively nonselective in terms of its deposition of energy packets

into the tissues it traverses. Both normal and neoplastic cells are targets for the effects of radiation if

the tissues lie in the beam of delivery. Different types of normal tissues demonstrate different levels of

sensitivity to radiation. Breast tissue, intestinal mucosa, stem cells, lymphocytes, and bone marrow cells

are considered radiosensitive based on their response to a given dose of radiation. Conversely, muscle

cells, large arteries and veins, the heart, and neurons are considered more radioresistant based on the

relatively low degree of cell death induced by radiation. Given a high enough radiation dose, nearly any

malignancy can be destroyed. One of the key challenges of radiation therapy treatment planning is

balancing the cytotoxic dose delivered to a given tumor with the impact that treatment will have on

surrounding tissues. The therapeutic ratio is relationship between tumor killing and normal tissue

complication rates.

Strategies to broaden the therapeutic ratio have focused on both increasing effective tumor killing

and limiting the toxicity to normal tissues associated with a given dose of radiation. Approaches for

increasing effective tumor killing include the use of radiosensitizers, preoperative radiation in a high

oxygen tension environment, and fractionation. Fractionation is the division of a total therapeutic dose

of radiation into multiple radiation treatments generally given daily. The biologic impact of dividing the

total treatment dose is related to several cellular behaviors within the treatment field (Table 14-11).

Fractionation increases the effectiveness of a radiation dose by allowing for reoxygenation and cell cycle

redistribution within the tumor. Alternatively, approaches for reducing normal tissue toxicity include

rotating gantry delivery systems using multiple beams reaching a single point via different routes

through normal tissue, collimation allowing delivery of a narrow beam of energy, and fractionation.

Fractionation decreases normal tissue toxicity by allowing initiation of DNA repair mechanisms and by a

compensatory increase in cell proliferation in tissues such as stem cells in response to injury. The injuryinduced increase in cell proliferation is termed repopulation. Since repopulation does not typically start

until 4 weeks of radiation injury, most treatment plans are kept short to avoid tumor repopulation.

Understanding the deleterious effects of ionizing radiation on normal tissues is critical to

understanding the therapeutic ratio for any radiation treatment plan. Desired cytotoxic effects on

tumors are accompanied by undesirable cytotoxic effects on normal cells. Typically, treatment plans are

developed to allow for the maximum tolerated dose (MTD) to be delivered to the structures within the

treatment field. The MTD is based on the radiation tolerance of each structure or tissue type within that

field. Plans incorporating shielding or avoidance of radiosensitive normal tissues can lead to safer and

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more effective therapy. Although radiosensitive cells generally have a lower tolerance dose than

radioresistant cells, this principle does not always hold true. The early and late effects of ionizing

radiation may not be wholly determined by the degree of cell killing. Downstream effects, such as

compensatory proliferation, cytokine-mediated responses, and radiation-induced gene expression can

lead to undesirable tissue effects within the treatment field.156

An important, although relatively uncommon, normal tissue effect of therapeutic radiation is the

development of a second cancer. Approximately 20% of these second malignancies are leukemias. The

majority of radiation-associated tumors are solid malignancies arising in the treatment field. These

cancers typically develop many years after the original treatment. The increasing number of patients

surviving disease free after an initial radiation treatment course may lead to an increasing number of

these late second cancer events. Children and immunocompromised adults are more likely to develop

second cancers.157 Importantly, the risk of developing a second cancer within the radiation field is

relatively low. In clinical scenarios where the benefit of therapeutic radiation is clearly demonstrated,

the incidence of second malignancies does not generally skew the risk/benefit assessment against

therapeutic radiation. However, an awareness of the potential for the development of a second cancer is

critical for those who care for long-term cancer survivors.

Table 14-11 The Biologic Impact of Dividing the Total Treatment Dose is Related

to Several Cellular Behaviors Within the Treatment Field

Radiation Therapy Delivery Modalities

Ionizing radiation can be delivered to an intended treatment area in a number of ways. The choice

regarding the proper treatment modality includes decisions regarding the timing of radiation, the use of

concurrent chemotherapy, and the delivery system for the radiation energy. Just as with surgical

therapy, the primary determinant for all of these decisions is the intent of any radiation treatment plan.

Therapeutic radiation can be employed as a part of a nonsurgical definitive treatment plan, as a

palliative therapy, or as a means to complement the locoregional control of a surgical resection.

Radiation Treatment Approaches

Perioperative radiation therapy with or without chemotherapy sensitizers is commonly employed for

tumors, such as rectal cancers, gastroesophageal cancers, and soft tissue sarcomas.158–160 When surgical

therapy is combined with radiation and chemotherapy, this is often referred to as trimodality therapy. In

these scenarios, radiation provides an additional element of local control by treating potential

postsurgical residual disease in the tumor bed and lymphatic system. Preoperative radiation is generally

preferred over postoperative radiation for several reasons. The normal tissue toxicity associated with

any radiation treatment is largely within a planned field of resection when radiation is delivered

preoperatively. Radiation delivered postoperatively is delivered entirely to a healing surgical bed.

Additionally, treatment of a target field with an intact vascular supply and associated increased oxygen

tension, theoretically enhances the indirect effects of the radiation energy. In clinical settings where the

tumor is large or abuts major structures, such as major blood vessels, nerves, or bony structures, the

reduction in size of a tumor may allow for preservation of critical structures and their function.

Chemotherapy is often combined with radiation as a definitive therapy for cancers that are either

unresectable or exquisitely radiosensitive. Patients with anal cancer can avoid an abdominoperineal

resection the majority of time due to the extremely high complete response rates of combined

chemoradiotherapy.161 Locally advanced cancers such as pancreas adenocarcinoma or esophageal cancer

may be treated with concurrent chemoradiation in order to alleviate local symptoms and limit the impact

of local progression.

Definitive radiation therapy is not commonly employed for these locally advanced cancers. A more

typical application of radiation alone is in the setting of certain small, radiosensitive cancers such as

prostate cancer or nonmelanoma skin cancers.162 Cutaneous tumors in sensitive areas such as the face or

head are good candidates for this approach in order to avoid the need for significant soft tissue

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