Page 234 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 13 Radiation Oncology 213

For a tumor to be considered radiation induced, the following The normal tissue structures still receive the dose, and the dose per
criteria must be met: fraction is higher than for traditional RT; however, the total dose to
normal tissue structures is lower than what is typical for fractionated
1. The malignancy must arise within the irradiated field.
VetBooks.ir 2. Sufficient latency must have elapsed between the time of irradi- RT because of the steep dose drop-off between tumor and critical
ation and development of the tumor (typically at least 1 year).
normal tissue structures. Normal tissue tolerance data are just evolv-
3. The original tumor and the new tumor must have different ing for SRT, as are reports of long-term outcome, in both human
histologic diagnoses. and veterinary medicine. Estimates of tolerance have been based on
90
4. The tissue in which the new tumor forms must have been pre- limited clinical data, toxicity observation, and educated guessing.
viously normal before radiation exposure. It is inappropriate to extrapolate dose constraints from fraction-
The overall incidence of radiation-induced tumors in patients ated protocols. An additional clinical difference between SRT and
treated with RT is thought to be extremely low (up to 2% of fractionated RT is that with SRT, acutely responding normal tis-
patients treated). 78 sues in the surrounding region, such as skin, esophagus, and colon,
In veterinary patients, severe late reactions such as fibrosis and are susceptible to consequential late effects due to the short overall
tissue necrosis should be managed under the guidance of an onco- treatment time. 91,92 Dose constraints therefore must also be applied
logic surgeon and/or radiation oncologist experienced in dealing to these tissues. SRT is generally hypofractionated and delivered
with radiation injury. in one to five fractions over a period of 1 to 2 weeks, minimiz-
ing the effect of accelerated repopulation. Early stereotactic treat-
Chemical Modifiers of Radiation ment using a gamma-knife necessitated delivery in a single fraction
(referred to as stereotactic radiosurgery [SRS]). Current technology
Although rarely used clinically in veterinary medicine, many allowing precise repositioning makes limited fractionation feasible.
81
drugs can modify the cellular and tissue response to radiation. Even this minimal fractionation should allow higher total doses to
Radioprotectors (e.g., amifostine/WR-2721) are compounds that be administered safely to late-responding tissues in the region and
decrease the amount of radiation damage to targeted normal cells presumably take advantage of tumor reoxygenation and redistribu-
without providing similar protection to tumor cells. 82,83 Radio- tion. Biologic response after SRT has not been conclusively evalu-
sensitizers are chemicals that achieve greater tumor inactivation ated. Experimental data imply that direct tumor cell death cannot
than would be expected from the additive effect of treatment with account for the efficacy of SRT and SRS. Tumor cell death will be
either radiation or the chemical alone and have included common discussed later, but based on cell culture and rodent experiments,
chemotherapeutic agents such as carboplatin and gemcitabine. which suggest that 10 8–9 tumor cells must die to eradicate a 1-gram
82
Mechanisms of action also include targeting hypoxic cells by tumor, the doses used to obtain tumor control in human tumors
increasing sensitivity, increasing oxygen delivery, decreasing oxy- treated with SRS or SRT are far lower. 93–97 High dose, hypofrac-
gen consumption, and the use of hypoxia molecular target inhibi- tionated RT has been shown to cause vascular damage in mouse
84
tors. Newer concepts include employing gold nanoparticles and tumor models, which leads to greater-than-expected tumor control,
targeted therapies, including immune checkpoint inhibitors. 85,86 leading to the conclusion that tumor vascular injury leads to indi-
rect tumor cell death. 46,49
From a practical standpoint, SRT minimizes the number of
STEREOTACTIC RADIATION THERAPY: anesthesia episodes required in older and sometimes debilitated
BIOLOGIC AND ONCOLOGIC PRINCIPLES patients and is also generally more convenient for the owner;
however, these factors should not be the overarching rationale for
Although time, dose, and fraction size are still the underpin- prescribing SRT. Although acute effects are minimal and tumor-
nings of SRT, some of the biologic mechanisms appear to be associated signs, such as discomfort or dysfunction, often improve
different from conventionally fractionated RT. It can be confus- rapidly, the ultimate decision should be based on choosing the
ing, because the term “stereotactic RT technology” describes the modality that provides the best long-term tumor control and/or
physical equipment and software required to deliver focal treat- best quality of life. Long-term tumor control and late effects are
ment with location confirmation. Although generally associated still being quantified, but recent publications demonstrate compa-
with hypofractionated protocols, the technology can be used for rable survival times (STs) in nasal and brain tumors and improved
administration of traditionally fractionated RT. For instance, outcome in the treatment of feline acromegaly when compared
the use of image-guided and intensity-modulated RT has been with conventionally fractionated protocols. 8,9,98 SRT technology
87
described for the treatment of urinary tract tumors in dogs. For has also resulted in the improved treatment of tumor sites infre-
purposes of this chapter, the term SRT will refer to the use of high quently previously irradiated in veterinary medicine, including
doses per fraction (hypofractionation) using SRT technology and the adrenal gland, brachial plexus, and trigeminal nerve. 11,99,100
techniques. No all-embracing RT protocol exists. With increased under-
Unlike conventionally fractionated RT, which spares normal tis- standing of underlying biology, protocols continue to be manipu-
sues by improved repair, SRT overcomes the radiobiologic limita- lated to exploit tumor characteristics for improved control or to
tions by stereotactically verified positioning and treatment delivery increase sparing of normal tissues. Regardless of whether using
techniques that leave a minimal volume of normal tissue in the high finely fractionated RT or SRT, the protocol should be chosen
dose area. SRT, by definition, requires: (1) a tumor for targeting based on the specific normal tissues present in the irradiated field.
(not microscopic disease); (2) treatment planning and administra- For example, brain and spinal cord are less tolerant to the effects
tion that will provide a dramatic dose drop off between the tumor of irradiation than muscle or bone. Another factor that must be
and the surrounding normal tissue structures; and (3) a method of considered when selecting the appropriate dose is the volume
stereotactically verifying patient positioning. 88,89 The result is that of tissue in the field. Large volumes of normal tissues are more
normal late-responding tissue structures are spared through dose susceptible to damage from irradiation than smaller volumes.
avoidance rather than by administering small doses per fraction. For many tumor locations, a 5% probability for late effects is