334Radiation Therapy
RADIATION TYPES
There are different types of radiation currently used in medicine.
• X-rays are extranuclear radiation. They occur from the bombardment of an atom/target by another source—usually high-speed electrons.
• The alpha particle demonstrates cluster decay where a parent atom ejects a defined daughter collection of nucleons. These have a typical kinetic energy of 5 MeV. Because of their relatively large mass, their +2 electric charge, and relatively low velocity, alpha particles are very likely to interact with other atoms and lose their energy. Their forward motion is effectively stopped within a few centimeters of air or paper. This particle is the same as a helium-4 particle (two protons and two neutrons).
• Beta particles are high-energy, high-speed electrons emitted by certain types of radioactive nuclei. Beta particles are ionizing radiations. They are stopped by millimeters of tissue. The production of beta particles is termed beta decay.
• Gamma particles are a form of ionizing radiation that originates from the decay of the nucleus of a radioactive isotope. Energies range from 10,000 (104) to 10,000,000 (107) electron volts.
• An isotope is one of two or more atoms having the same number of protons but a different number of neutrons. This makes the nucleus unstable. The atom then spontaneously decomposes/decays and excess energy is given off by emission of a nuclear electron or helium nucleus and radiation, to achieve a stable nuclear composition. Some of these isotopes include radium-226, cesium-137, iridium-192, cobalt-60, and gold-198.
• Electron energy comes from outside the nucleus. Electrons are used to treat tumors en face—close to the skin.
DEFINITIONS
• Roentgen is the amount of photon radiation that causes 0.001293 g of air to produce one electrostatic unit of positive or negative charge. It can also be defined as: the amount of photon energy required to produce 1.61 × 1012 ion pairs in 1 cm3 of dry air at 0 degree C. It is a unit of exposure, not an amount of energy that ionizing radiation imparts to matter.
• Kinetic energy related to mass (KERMA) is the transfer of energy from photons to particles. Particles transfer this energy to tissue and this is defined as absorbed dose.
• Radiation Absorbed Dose (Rad): is the amount of energy that radiation imparts to a given mass. A rad is a dose of 100 ergs of energy per gram of given material. The SI unit for rad is the gray (Gy) which is defined as a dose of one joule per kilogram. One joule equals 107 ergs, and one kilogram equals 1,000 grams, thus 1 Gy equals 100 rads
• Relative biologic effectiveness (RBE) is the ratio of the dose required for a given radiation to produce the same biologic effect induced by 250 kV of x-rays.
• Isodose is the line that connects structures, which receive equal radiation dose.
• Source to skin distance (SSD) is usually defined at 80 to 100 cm from the machine to the patient. Radiation is dosed at a fixed point from the patient and thus there needs to be standardization of distance for treatment.
• Isocenter is a fixed point in the patient around which treatment is rotated.
• Dmax is the point where the maximum amount of dose from one beam is deposited. The dose at Dmax is defined at 100%. The depths of Dmax for some common energies are 4 MV, 1.2 cm; 6 MV, 1.5 cm; 10 MV, 2.5 cm; and 18 MV, 3.2 cm.
• Percent depth dose is the change in dose with depth within the patient.
• Gross tumor volume (GTV): direct tumor volume by measurement. The GTV requires a high dose of radiation to treat the primary or bulky tumor. This dose is usually 80 to 90 Gy.
• Clinical target volume (CTV): this includes any region that has a high likelihood of harboring malignancy but appears clinically normal. The CTV requires a lower dose than GTV. This dose is usually around 45 to 54 Gy and is adequate to treat occult or microscopic disease.
• Planning target volume (PTV) is a margin added to account for organ motion and daily setup error.
RADIATION EFFECTS
There are two basic types of energy transfer that may occur when x-rays interact with matter:
• Ionization, in which the incoming radiation causes the removal of an electron from an atom or molecule leaving the material with a net positive charge.
• Excitation, in which some of the x-ray’s energy is transferred to the target material leaving it in an excited (or more energetic) state.
There are three important processes that can occur when x-rays interact with matter. These processes are the photoelectric (PE) effect, the Compton effect, and pair production
• The PE effect produces energy in the eV to keV range. This type of radiation occurs when atoms absorb energy from light and emit electrons. This form of radiation is used for diagnostic x-rays and to simulate radiation treatment beams. The PE effect occurs when photons interact with matter with resulting ejection of electrons from the matter. PE absorption of x-rays occurs when the x-ray photon is absorbed resulting in the ejection of electrons from the atom. This leaves the atom in an ionized state. The ionized atom then returns to the neutral state with the emission of an x-ray characteristic of the atom. Photoelectron absorption is the dominant process for x-ray absorption up to energies of about 500 keV.
• Pair production occurs when the x-ray photon energy is greater than 1.02 MeV. An electron and positron are created with the annihilation of the x-ray photon. Positrons are very short lived and disappear (positron annihilation) with the formation of two photons of 0.51 MeV energy. Pair production is of particular importance when high-energy photons pass through materials with high atomic numbers. This type of energy is not used clinically.
• The Compton effect is when an incident photon interacts with an outer electron. The energy that results is shared between the ejected electron and the scattered photon. Compton scattering is important for low atomic number specimens. At energies of 100 keV to 10 MeV, the absorption of radiation is mainly due to the Compton effect. This type of energy is used for the radiation treatment of cancers. Photons are harvested from the decay of a source. First, the source has intrinsic decay. The electrons from this decay are used to bombard tungsten causing the Compton effect. The resultant photon is the radiation we use in linear accelerator machines.
ENERGY EQUIVALENCES
1 Gray (Gy) is equal to 1 J/kg of tissue.
1 Gy is equal to 100 cGy.
100 radiation absorbed doses (Rads) are equal to 1 Gy.
1 Rad is equal to 1 cGy.
RADIATION DELIVERY
• External beam radiation is delivered using a linear accelerator machine. These machines deliver 4 to 24 MeV. Total radiation dose is administered via a daily divided dose called a fraction. Common daily doses/fractions are 1.8 to 2 Gy. A total dose of 90 Gy is needed to sterilize most tumors. Noncancerous tissues cannot tolerate this total dose from external beam radiation, so brachytherapy is needed to locally deliver radiation directly to the tumor.
• Brachytherapy is the local, and often internalized, delivery of radiation. For gynecologic cancers, radiation is often delivered using tandem and ovoids, vaginal cylinders, or interstitial needles. Brachytherapy is delivered at a low-dose rate (LDR) or a high-dose rate (HDR).
LDR is defined as 0.4 to 2 Gy/hr; HDR is defined as a dose greater than 12 Gy/hr or greater than 20 to 250 cGy/min (12–15 Gy/hr). The dose conversion from LDR to HDR is 0.6.
HDR is more common now because of a number of patient-based reasons: treatment time is shorter, treatment is delivered on an outpatient basis, there is no need for bed rest, there is better ability to retract the rectum for shorter periods of time, and therefore better patient acceptance and comfort. Clinically, there is better implant reproducibility and a greater degree of certainty that the sources will remain stable during treatment. The HDR applicators are less bulky, so patients with narrow vaginas do not necessarily have to be treated with interstitial implants. The smaller source size also allows for finer increments in source location and weighting and a better ability to shape the dose distribution.
Isotopes: Iridium-192 is the most commonly used isotope. The half-life of iridium is 74 days. Cesium-137 is no longer available but its half-life is 30 years. Cobalt-60 is also no longer used but its half-life is 5.26 years. Radium-226 has a half-life of 1,626 years and has little use in modern radiation oncology.
337TUMORICIDAL BASICS
• Radiation dose is proportional to the time the patient is exposed to the dose. The dose is also proportional to the distance from the source (the inverse square law): 1/r2. Dosing used to be mg/hr based. It is now dosimetry based.
• In the log cell kill model, each dose—called a fraction—kills a fixed amount of cells. Radiation works by causing breaks in the DNA backbone via one of two types of energy, a photon or a charged particle (an electron). This damage is either direct or indirect with ionization of the atoms that make up the DNA chain. Indirect ionization is the result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA. Direct ionization is the result of electrons causing single-stranded DNA breaks. These single-stranded breaks need to be on opposing strands of DNA in close proximity to each other in order to create a double-stranded break. Oxygen free radicals modify radiation damage making it irreparable. Oxygen is transported to tumors via the blood system, so adequate hemoglobin (Hg) levels are needed. Without oxygen, the cell survival curve shifts to the right.
• There are two cell survival/dose-response curves, the linear and the linear-quadratic. The linear “curve” is a straight line and this is represented by LDR. LDR is delivered over a protracted period of time and cell kill is by a single electron. The linear quadratic curve demonstrates cell kill caused by two breaks in the DNA from either by the same electron or by two different electrons. This cell survival curve is straight initially and then curves, representing HDR-type delivery.
• The linear quadratic equation: –ln S = alphaD + betaD2. The alpha component is the nonreparable damage, whereas the beta component represents reparable damage. S is the surviving fraction of cells. The dose at which the cell kill is due to equal linear and quadratic components is called the alpha beta ratio.
• The biologically equivalent dose (BED) is used as a guide to determine optimal dosing. The BED = D[1 + d/(alpha/beta)], where D is the total dose and d is the dose per fraction. Early side effects demonstrate an alpha/beta ratio of 10 whereas late side effects and tumor control assume an alpha/beta of 3.
• The cell can respond to radiation differently depending on its phase in the cell cycle. Late S phase is the most radioresistant phase and M phase is most radiosensitive. There are two possible outcomes after exposure to radiation: survival or death. If the cell survives there is cell cycle arrest and DNA repair.
• There are three types of cell death. The first is apoptotic, which is ordered programmed cell death. A lot of tumors have mutations in apoptotic pathways and thus do not respond to apoptotic signals easily. The second type of cell death is mitotic. Mitotic death may take days. The third is senescence. Senescence is when cell proliferation is irreversibly arrested and death eventually ensues.
THE FOUR R’S OF RADIATION
• Repair: radiation in fractionated doses is not as lethal as if it were delivered in one high dose. Sublethal repair occurs when a certain percentage of cells are killed, and those that survive can repair their damage and continue to divide.
• Reassortment: radiation kills cells best when they are in the late G2 and M phases, which are the most radiosensitive cycles. Other cycles are relatively radioresistant. After a dose of fractional radiation, the cells that were in the more radioresistant phases (and survived) reassort themselves into their next cell cycle. They then become more radiosensitive and when the next dose of radiation is delivered, they have a higher likelihood of death.
• Repopulation is when the surviving population of cells that are not lethally damaged divide and replace those that were killed.
• Reoxygenation is when the tumor generates new blood vessels to bring in a higher oxygen tension via Hg. Oxygen must be present during radiation to generate the free radical that yields DNA damage. Low oxygen tension makes cells more radioresistant.
DISEASE SITE RADIATION TREATMENT
Cervical Cancer
All stages of cervical cancer can be treated with definitive radiation therapy (XRT).
• Anatomical dosing is based on the paracervical triangle—the lateral vaginal fornices and the apex of the anteverted uterus. Dosing is directed at two common points. Point A is 2 cm superior and 2 cm lateral to the external cervical os. This correlates anatomically to where the ureter and the uterine artery cross. Point B is 2 cm superior and 5 cm lateral to the external cervical os. This point corresponds to the obturator lymph node (LN) basins. Point T is inside point A. It is 1 cm superior to the external cervical os and 1 cm lateral to the tandem; it receives a dose 2 to 3× the dose to point A. Point P is located along the bony pelvic sidewall at its most lateral point and represents the minimal dose to the external iliac LNs. Point C is 1 cm lateral to point B and is approximate to the pelvic sidewall. Point H is an HDR point: it originates from a line that connects the mid-dwell position of the ovoids and intersects with the tandem. Then move superiorly the radius of the ovoids (to top of ovoids) + 2 cm, and then 2 cm perpendicularly. The vaginal surface is where the lateral radius of the ovoid and ring applicator falls. This receives a dose 1.4 to 2.0 times the point A dose.
• CT-based planning and conformal blocking is the current standard of care. External beam radiation therapy (EBXRT) volumes should cover gross disease, parametria, uterosacral ligaments, at least 3 cm of vaginal margin, presacral nodes, and other nodal basins at risk. If negative LN are determined via surgical staging or imaging, the radiation volume should include all of the internal and external iliac, and the obturator LN basins. If bulky or residual tumor is present or there were positive pelvic LN found at surgical staging, the radiation volume should cover the common iliacs as well. If common iliac or PA LN involvement is identified, extended field pelvic and para-aortic radiation therapy (PA-XRT), up to the renal vessels is advised.
• Intensity-modulated radiation therapy (IMXRT) is a highly conformal dosing method, which can minimize the dose to vital pelvic organs (bowel, bladder) while maximizing dose at risk of involved sites.
• Current definitive dosing for cervical cancer prescribes a total dose to point A of 85 to 90 Gy with 60 Gy dosed to point B.
External beam radiation provides 45 to 50.4 Gy to point A via whole pelvic radiation therapy (WP-XRT) with a 15-Gy boost when appropriate. The dose to point A is brought up from 50.4 Gy using external beam radiation to the total desired dose of 80 Gy in small volume, and 85 to 90 Gy for large volume tumors, with brachytherapy.
If LDR is used, the brachytherapy dose is 50 to 60 cGy/hr with 40 Gy total given. If HDR is used, the dose is 30 Gy. The brachytherapy dose per HDR fraction to point A is 3 to 10.5 Gy. The total number of fractions is 2 to 13. The number of fractions per week is 1 to 3. The morbidity is lower for fractions less than 7 Gy.Gynecologic Oncology Group (GOG) protocols use 6 Gy × 5 fractions to point A. Radiation Therapy Oncology Group (RTOG) protocols allow more variation depending on the external beam radiation dose with brachytherapy fraction sizes of 5.3 to 7.4 Gy using 4 to 7 fractions. Platinum-based chemotherapy should be used in the definitive management of cervical cancer.
Microscopic nodal disease demands an EBXRT dose of 45 to 50.4 Gy in 1.8 to 2 Gy daily fractions. 10- to 15-Gy boosts can be given to residual disease, bulky adenopathy, or the parametria.
Sequencing of brachytherapy with external beam radiation is based on tumor size, patient anatomy, and practitioner discretion. For nonbulky disease, HDR is often integrated after 20 Gy of external beam therapy around the second week of treatment. Alternatively, some deliver WP-XRT to 50.4 Gy followed by five HDR insertions.
Brachytherapy most commonly uses the tandem and ovoid system. There are 48 dwell positions in the tandem. The radiation sources are usually spaced 2.5 to 5 mm apart. The dwell position is where the source is driven to stop. The longest tandem possible should be used. The tandem should be loaded so the sources reach the uterine fundus. This enables adequate distribution to the lower uterine segment, the paracervical tissues, and obturator LNs. The tandems have three curvatures (15°, 30°, and 45°); the greatest curvature is used in cavities measuring greater than 6 cm. A flange is added to the tandem after insertion into the uterine cavity and approximates the exocervix. The keel is then added and prevents rotation of the tandem after packing.
Vaginal ovoids come in four different sizes. The largest sized ovoid that the patient can tolerate is placed as far laterally and cephalad as possible. This gives the highest tumor dose possible. The mini-sized ovoid is 1.6 cm in diameter, the small is 2 cm in diameter, the medium is 2.5 cm in diameter, and the large is 3 cm in diameter. The mini does not have any shielding to protect the bladder. A wide separation of the ovoids is desired as this increases the dose to the pelvic sidewall. A 10-mg protruding source is recommended if the vaginal ovoids are separated by more than 5 cm. Optimal positioning is: on the AP view, the tandem is midline and unrotated, the tandem is midway between the colpostats, the keel is in close proximity to the gold seed markers fiducials placed in the cervical stroma, and the colpostats are placed high in the vaginal fornices; on the lateral view, the tandem bisects the colpostat, there is sufficient anterior and posterior packing, and the tandem is equidistant from the sacral promontory and the pubis.
The anterior bladder point is determined by placement of a Foley catheter with 7 mL of radiopaque material placed into the balloon. The balloon is then pulled down against the urethra creating this point.
The posterior rectal point is determined by packing the vagina with radiopaque packing and moving 5 mm posterior to that line.
The vaginal surface dose should be kept below 140 Gy.
• In the postoperative posthysterectomy setting, patients can be broken into two risk categories: (a) those with intermediate-risk factors (LVSI, DOI, and tumor size), per GOG 92 and (b) those with high-risk factors (2+ positive LNs, lesion size >2 cm, margins ≤5 mm, positive margins, or parametrial involvement proven histologically) per GOG 109. WP EBXRT should be considered for those with intermediate-risk factors, and concurrent platinum-based chemotherapy in addition to WP EBXRT for those with high-risk factors. Some centers treat both groups with combination therapy. The adjuvant dose is 45 to 50.4 Gy EBXRT. The fields include the upper 4 cm of vaginal cuff, the parametria, and the internal and external iliac LN basins. If LN metastasis is documented, the upper border of the field should be increased to the next nodal basin or 7 cm higher than the involved LN and bulky LN should be boosted with an additional 10 to 15 Gy.
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