TITLE: The Principles of Radiation Oncology
SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
DATE: December 03, 2003
RESIDENT PHYSICIAN: Michael Underbrink, MD
FACULTY PHYSICIAN: Anna Pou, MD
SERIES EDITORS: Francis B. Quinn, Jr., MD and Matthew W. Ryan, MD
"This material was
prepared by resident physicians in partial fulfillment of educational
requirements established for the Postgraduate Training Program of the UTMB
Department of Otolaryngology/Head and Neck Surgery and was not intended for
clinical use in its present form. It was prepared for the purpose of
stimulating group discussion in a conference setting. No warranties,
either express or implied, are made with respect to its accuracy, completeness,
or timeliness. The material does not necessarily reflect the current or past
opinions of members of the UTMB faculty and should not be used for purposes of
diagnosis or treatment without consulting appropriate literature sources and
informed professional opinion."
Introduction
Radiation therapy either used alone or in combination
with surgery and/or chemotherapeutic modalities has become an important aspect
in the treatment of head and neck cancer.
A basic understanding of the principles of radiotherapy will benefit the
otolaryngologist in planning treatment strategies for these patients. The following discussion outlines the basic
principles of radiation oncology and is intended to provide a clear
understanding of the biologic basis for the use of ionizing radiation in
treating head and neck cancer.
Radiation Physics
The basis of radiation therapy is the interaction of
ionizing particles (x-rays, gamma rays or electrons) with tissues at the
molecular level. This interaction
depends on the energy created by the production of secondary charged particles,
usually electrons, which can break chemical bonds and inflict cellular
injury. Radiation therapy is delivered
by external beam, an interstitial implant, or combination of the two. External beam radiation therapy entails
generation of energy particles at some distance from the patient. Interstitial implants, or brachytherapy,
entails placement of radioactive sources near or within the tumor. Radiant energy is deposited in biologic
material in a discrete yet random fashion, and the biologic effects occur as a
result of the transfer of energy to atoms or molecules within the cell.
External Beam Irradiation
Dual-energy linear accelerators allow for the
generation of either low-energy megavoltage x-rays (4-6 MeV), high-energy
megavoltage x-rays (15-20 MeV) or electrons.
Most patients are treated with x-rays or gamma rays (photons) because of
the skin-sparing properties, penetration and beam uniformity. Due to the typical location of head and neck
cancers (7 to 8 cm deep) and regional lymph nodes (superficial), 4 to 6 MeV
x-rays or cobalt 60 gamma rays are typically used. Additional treatment (a boost) with 15 to 20
MeV x-rays can be used for the base of tongue or nasopharynx. Electron beams are useful for managing
superficial lesions, because of their finite range and deep tissue sparing
properties.
Brachytherapy
This is a technique in which radioactive sources are
placed directly into the tumor and surrounding tissues (interstitial implants),
within body cavities (intracavitary therapy), or onto epithelial surfaces
(surface molds). The advantages of this
therapy over external beam are that a greater dose can be delivered to the
tumor at a continuously low dose rate.
This allows for a theoretical advantage in the treatment of hypoxic or slowly
proliferating tumors and potentially, shorter treatment times. The tumor must be accessible and well demarcated. It should not be the only treatment modality
for tumors with a high risk of regional lymph node metastasis.
Radiobiology
The energy of therapeutic radiation is high enough to
eject an electron from a target molecule, thus, the term ionizing
irradiation. Ionizing energy is
distributed randomly within the cell so that the x-rays hit a wide array of molecules. A DNA double strand break is generally
believed to be responsible for cell death, which is determined by cells that
are no longer able to undergo cell division.
The injury responsible for cell death can occur directly or indirectly,
via free radicals (molecules with an unpaired electron, e.g., DNA à
DNA·). Free radicals are highly reactive and can
either be reduced by cellular mechanisms (repaired DNA) or stabilized by oxygen
(permanent DNA-OO·
damage). Inadequate repair of DNA
lesions, either nucleotide base damage or single/double strand breaks, can lead
to cell death or mutation.
Random Cell Death
The deposition of ionizing energy is a random event as
is the resultant radiochemical injury.
Therefore, any given cell within a tumor has an equal chance of being
hit by a given dose so that the same proportion of cells within the tumor is
damaged per dose. In other words, the
same dose of radiation will reduce the cell population from 100 cells to 10
cells as it will 10 billion cells to 1 billion cells. This means that a more radiation is needed to
eradicate larger tumors. Furthermore, a
tumor is no longer palpable when it is reduced to 105 cells, so
clinical response rates do not relate to effectiveness of the radiation
dose. Finally, this random nature of
cell death applies to normal tissue as well as tumor cells. A therapeutic advantage may be gained by one
of four hypothetical mechanisms: repair
of damage, reoxygenation of the tumor, redistribution within the cell cycle,
and repopulation of tumor cells. These
mechanisms are known as the classical four R’s of radiation biology.
Repair of sublethal injury
When a secondary electron passes through matter, a
cell may be exposed to either dense or sparse ionization. It is thought that cells are more likely to
repair damage inflicted by sparse ionization within the field of
radiation. This sublethal injury can be
repaired if no further hits are sustained.
Therefore, a greater total dose is needed to produce a biologic effect
when given in several fractions as opposed to a single fraction. The greater the number of fractions, the
greater is the opportunity for repair between dose fractions. However, the same biologic effect requires a
greater total dose. In most tissues,
sublethal injury is repaired within 3 hours, but up to 24 hours may be
necessary for some tissues. This concept
explains why radiation therapy is fractionated.
It allows repair of injured normal tissue, providing an overall
therapeutic advantage over tumor cells.
In contrast, this also may explain the radioresistance of certain
malignant cell types, which have a remarkable ability to repair sublethal
injury (i.e., melanoma).
Reoxygenation of Tumors
Oxygen, as discussed previously, is important for its
effects on stabilization of free radicals produced by ionizing radiation. Hypoxic cells generally require an increased
dose of radiation for lethal effect.
Hypoxic regions within cancerous tissue can occur secondary to temporary
constriction or collapse of capillaries or when tumors outgrow their blood
supply. During radiation treatment
hypoxic areas within the tumor decrease as the size of the tumor diminishes,
compressed blood vessels open, and hypoxic cells are brought closer to
capillaries. Reoxygenation is another
reason why radiation is given in fractionated doses. Tumor hypoxia is another potential cause of
radioresistance. Recently, hypoxic cell
radiosensitizers and agents selectively toxic to hypoxic cells have been
developed for clinical use with concurrent radiotherapy.
Redistribution within the Cell Cycle
Each individual cell’s position in the cell cycle
influences its radiosensitivity. Cells
undergoing DNA synthesis, the S phase, are much more radioresistant than are
cells in other phases of the cell cycle.
There is increasing evidence that the ability of a cell to be delayed in
the G2 phase of the cell cycle corresponds to its ability to survive
irradiation. Studies of the RAD9 gene
mutation producing radiosensitivity in yeast have shown these cells do not
undergo a delay in G2 following irradiation. In addition, radioresistant rat embryo cells
transformed with oncogenes, H-ras and c-myc, showed a G2 delay and
more radioresistance than control cells.
When radiation treatment is fractionated, surviving cells redistribute
into more sensitive phases of the cell cycle, making them more susceptible to
subsequent fractions. The sensitizing
effect of redistribution tends to offset sublethal injury repair. Furthermore, rapid cycling cells redistribute
better between fractions than slowly cycling cells. Skin and mucosa cells cycle rapidly and are
responsible for acute reactions to irradiation.
Connective tissue, brain and blood vessels cycle more slowly and are
responsible for late effects. It is the
tissues responsible for late complications that are spared more by
fractionation of treatment.
Repopulation
As cells are lost to radiation injury and death within
a given population of normal or tumor cells, the surviving cells respond by
increased regeneration or repopulation.
Repopulation is a greater problem with rapidly proliferating tumors than
slower growing neoplasms. Regeneration
is therefore one of the determinants for planning the length and timing of a
course of therapy, and a balance between adequate tumor control and sufficient
sparing of acutely reacting normal tissues to allow recuperation must be
reached. Accelerated treatment schedules
with twice-daily fractionation and combined accelerated-hyperfractionated
schedules have been developed to diminish the opportunity for tumor
repopulation. It is likewise, the reason
not to delay treatment after incomplete resection and to avoid protracted
courses of therapy or split-course treatment schedules.
Dose-Response Relations
The probability of controlling cancerous lesions with
radiotherapy depends on the size of the tumor and the dose of radiation
given. The dose-response relation for
small, well-vascularized neoplasms is steep, because they are relatively
homogeneous, are well oxygenated and have approximately the same number of
cells. Bulky tumors, however, are more
heterogeneous with considerable variability in number of cells and
oxygenation. Therefore, the
dose-response curve is much shallower.
The dose-response relation for normal tissue injury is the limiting
factor in the amount of irradiation that can be given. As the size of the tumor increases, and the
dose needed for local control likewise increases, the risk of injury to normal
tissue becomes greater.
Fractionation Schedules
Conventional fractionation schedules are typically in
increments of 1.8 to 2.0 Gy given five times per week for 6 to 8 weeks. Altered fractionation schedules have been
developed in an attempt to optimize treatment results under various clinical
circumstances. In essence, the objective
of altered fractionation is to improve the therapeutic ratio through an
alteration of time, dose, and/or fractionation based on the differential
response of tumors and normal tissues to these altered schedules. Accelerated fractionation involves two or
more dose fractions of the conventional size per day in an attempt to shorten
overall treatment time. In theory, this
may minimize tumor repopulation during treatment and, therefore, increase the
probability of tumor control for the same total dose. Hyperfractionation involves the administration
of two or more smaller dose fractions per day for a conventional or slightly
longer treatment time. Theoretically,
with hyperfractionation it is possible to increase the total dose, thereby
increasing the probability of tumor control without increasing late
complications.
Treatment
The treatment strategy for an individual patient with
head and neck cancer is based on the size and location of the primary lesion,
the presence or absence and extent of regional or distant metastatic disease,
and the general condition of the patient.
Early-stage head and neck cancer usually is effectively managed with
either surgery or radiation therapy alone.
The choice between these two modalities of treatment is often determined
by the functional deficit that would result from the proposed treatment. Larger cancers are generally managed with a
combination of surgery and radiation.
Radiation therapy alone is sometimes attempted, and in this case,
surgery is reserved for salvage of tumor recurrence. Surgical salvage of radiation failures is
generally more effective than radiation salvage of surgical failures.
A course of radiotherapy is usually delivered using a
shrinking field technique. This is based
on the concept that tumor cell killing by radiation is an exponential function
of dose and that the dose required for a particular tumor control probability
is proportional to the logarithm of the number of viable cells in the
tumor. For example, the initial tumor
dose of 45 to 50 Gy usually is delivered in 4.5 to 5 weeks through large
portals that cover the clinically involved region and areas of possible
regional lymph node metastasis. The
field is then reduced to encompass only gross tumor with a small margin (boost
fields) and an additional 15 to 25 Gy is delivered over the next 1.5 to 2.5
weeks to bring the total dose to 60 to 75 Gy in 6 to 7.5 weeks. With massive tumors, a second field reduction
at 60 to 65 Gy is performed. An additional
10 to 15 Gy is given through small fields for a total dose of 70 to 75 Gy in 7
to 8 weeks. The spinal cord should not
receive more than 45 Gy to avoid the risk or radiation myelitis.
When used
appropriately, combining surgery and radiotherapy complement one another very
well. Surgery is ideal for removal of
gross tumor, and most radiation failures are the result of an inability to
control bulky masses. Radiotherapy is
very effective in controlling microscopic disease, and often surgical failures
occur as a result of leaving subclinical tumor extensions, or microscopic disease,
behind. Intuitively, combining the two
modalities effectively counteracts the limitations of the other. Radiation can be administered either pre- or
post-operatively.
Preoperative radiotherapy may decrease tumor bulk to
facilitate dissection. Also, microscopic
disease may be more effectively controlled prior to disturbing its blood
supply. Tumor cell seed may be
diminished, and it may be possible to use smaller treatment portals
preoperatively. A typical preoperative
dose is 45 Gy in 4.5 weeks. This dose is
sufficient to eradicate subclinical disease among 85% to 90% of patients.
Postoperative radiotherapy, on the other hand, enables
more accurate surgical staging. The
dissection is much less difficult in tissues that have not been previously
irradiated, and surgical complications are often reduced because healing is
generally better. Finally, a larger dose
of radiation may be given postoperatively than preoperatively. The typical postoperative dose is 60 to 65 Gy
over 6 to 7 weeks. Postoperative
radiotherapy markedly reduces the risk of recurrence in the surgical field,
however the results are poorer is delayed more than 6 weeks.
Complications
Acute Tissue Reactions (Acute Toxicity) – The
time course for developing acute radiation reactions depends on the cycling
time of the cells affected. Mucosal
reactions begin to appear in the second week of irradiation. Skin reactions appear in the fifth week. Acute effects generally subside several weeks
after completion of treatment and are not a serious problem.
The Radiation Therapy Oncology Group (RTOG) considers
acute toxicities to occur within 90 days of the commencement of
radiotherapy. This definition reflects
the observations from conventional fractionation schedules of the 1980s when
this definition was created. Epithelial
surfaces generally heal within 20 to 40 days after completion of
treatment. With the development of
aggressive radiation and chemoradiation schedules in recent years, prolonged
acute effects have been noted which can last beyond the 90 day window.
Mucosal toxicity, or mucositis, is usually the
intensity-limiting side effect of aggressive radiation therapy schedules. Accelerated fractionation trials and
concurrent chemoradiation programs are associated with progressively higher
rates of mucosal toxicity. The
conservative approach to conventional fractionation schedules emphasized low
rates of severe acute reactions and recognition that the maximum tolerated
total dose should be limited by late tissue injury, not acute toxicities.
Late Tissue Reactions (Late Toxicity) – Late
effects from radiotherapy are a concern because the injury is often
permanent. These effects occur in
tissues composed of functional parenchymal cells with very low cell turnover
rate that retain the flexibility to regain reproductive function in the event
of tissue loss. Most late effects in the
head and neck develop within the first 3 years of treatment and a few appear or
progress after 3 years. The late effects
of radiation for head and neck cancer include xerostomia, damage to teeth,
fibrosis, soft-tissue necrosis, bone necrosis, cartilage necrosis, and damage
to the eye, ear, and central nervous system.
While chronic xerostomia is perhaps the best known late complication,
many patients also experience chronic fibrosis, edema, trismus, dysphagia, or
other organ dysfunction.
Xerostomia occurs from
injury to the serous cells within the salivary glands, and usually occurs with
doses larger than 35 Gy in 3.5 weeks.
Once lost, this function may or may not return, but no more than partial
recovery is typically expected. Dental
caries often results from the decrease in salivary flow and unlike other late
effects of radiation, teeth both inside and outside the radiation fields can be
affected.
Osteoradionecrosis results
from overlying soft tissue necrosis.
Cartilage necrosis can occur as well.
Soft tissue necrosis manifests as mucosal ulceration and is thought to
be caused by damage to vascular connective tissue.
Severe skin damage is relatively uncommon due to the
skin sparring properties of modern radiation therapy equipment. A serious problem, and the principle
dose-limiting factor of radiation, is fibrosis of the subcutaneous tissues and
muscle. In the most severe cases, the
tissue can develop a woody texture and become fixed. Large daily fractions and treatment of
massive neck disease increase the risk of fibrosis.
The potential ocular complications may include
cataracts, injury to the optic nerve, retinopathy, or damage of the lacrimal
gland. Otologic complications of serous
otitis media or even sensorineural hearing loss may occur with treatment of the
nasopharynx and ear, respectively.
Central nervous system complications of radiotherapy
are of special concern with regard to radiotherapy, because the results are
devastating to patients. Radiation
induced myelopathy can occur with doses as low as 30 Gy in 25 fractions, and is
characterized by electric shock sensations triggered by flexing the cervical spine
(Lhermitte sign). Transverse myelitis is
a rare complication after doses of 50 to 60 Gy.
Somnolence syndrome may appear months after therapy and is characterized
by lethargy, nausea, headache, cranial nerve palsy, or ataxia. This is usually a transient and self-limiting
condition. Brain necrosis is a permanent
injury that can develop after doses of 65 to 70 Gy.
Conclusions
Radiation therapy plays a key role in the treatment of
head and neck cancer as it is often used as in a primary or combined
fashion. The basic concepts of radiation
physics and radiobiology help to explain the rationale for radiation treatment
schedules and the reasons for associated complications. An understanding of these fundamentals is
essential to the otolaryngologist in order to adequately counsel head and neck cancer
patients regarding their treatment options and the possibility of serious side
effects after radiation therapy.
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