TITLE: PRINCIPLES OF RADIATION ONCOLOGY
Source: UTMB Dept. Otolaryngology Grand Rounds
Date: January 29, 1997
Faculty: Christopher Rassekh, M. D.
Resident: Kyle Kennedy, M. D.
Series Editor: Francis B. Quinn, Jr., M.D.
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The radiation administered in radiotherapy is in the form of electromagnetic waves or charged or neutral particles. Electromagnetic waves are represented by x-rays or gamma rays. Charged particles may take the form of electrons, protons, or heavy ions, while neutrons are an example of neutral particles. During a course of therapy, the radiation may be administered by external beam, an interstitial implant, or a combination of the two. Radiant energy is deposited in biologic material in a discrete yet random fashion, and its biologic effects occur as a result of the transfer of energy to the atoms or molecules within a cell.
The deposition of this energy may result in the displacement of an orbital electron and subsequent ionization. These secondary electrons may then interact with various cellular components to cause cellular injury or death. As a given secondary electron passes through matter, its passage along a particular path results in clusters of dense and sparse ionization. If a cluster of dense ionization interacts with a critical target within a cell, irreparable damage may occur and cause cell death.
Importantly, it is possible to administer a given dose of radiation to a patient, and the absorption is a crucial measure of this dose. The rad and Gray are the usual units of measure. A dose of one rad for any type of radiation results in the absorption of 100 ergs of energy per gram of target tissue, and one Gray is equal to 100 rads. Therefore, one centiGray (cGy) is equivalent to one rad.
From a radiobiologic standpoint, a viable tumor cell is one in which the capacity for unlimited division is present. A tumor cell must lose this reproductive or clonogenic capability to be considered killed. Radiotherapeutic tumor control is achieved by the elimination of all viable cells within a tumor, and a given dose of radiation will result in the death of a certain proportion (not number) of viable cells with each administration. Therefore, the larger the volume of tumor, the larger the total dose of radiation required for tumor control. A tumor cell which has been sterilized or killed with radiotherapy may not necessarily have been morphologically altered and typically manifests cell death at the time of mitosis. It is important to note that this mitotic death may not occur with the first cell division following irradiation. Several apparently successful cell cycles may take place before cell death becomes overtly manifest, but the cell is still considered no longer viable in that its unlimited reproductive potential has already been lost.
The subcellular events following radiation injury which may ultimately lead to cell death are incompletely understood but are thought to involve the interaction of radiant energy with a critical target within the cell. As mentioned previously, this critical target is most likely DNA. Several mechanisms have been proposed to account for injury to the cell's genetic apparatus. Ionizing radiation may result in the formation of a secondary electron which then directly interacts with a molecule of DNA to irreparably damage its structure or alter its content. An indirect effect may occur if the secondary electron alters another intracellular molecule leading to the formation of a free radical which subsequently damages a molecule of DNA. The plasma membrane and enzymes are other possible sites where radiation injury is thought to occur.
Irradiation of cells may not only lead to cell death but to other changes as well. Radiation has been shown to alter a cell's progression through the cell cycle. The delay occurs at particular points in the cell cycle, such as early G2 and the G1/S interface. Multiple factors affect this kinetic alteration, including the radiation dose, dose rate, and cell type. The cell's position in the cell cycle is a factor also.
The doses of radiation administered during conventional therapy do not appear to significantly alter the vegetative functions of most cells. Therefore, the loss of tissue function which may be seen to occur during radiotherapy is thought to occur as a function of the total number of cells lost, not the incremental loss of function for an individual cell. Acute tissue reactions are typically displayed in tissues with high cell turnover rates and significant stem cell, maturational, and functional compartments. Examples would include most epithelia and bone marrow. Late reactions are seen in tissues with a low cell turnover rate and prominent functional compartment of cells that have retained the capability for reversion to a reproductive phase in the event cells are lost due to injury. Examples include bone, some neuroglia, and endocrine tissues.
Cell killing by radiation occurs exponentially as a function of dose. For this reason, cell survival curves are typically graphed on semilogarithmic coordinates with cell survival on a logarithmic scale as a function of radiation dose on a linear scale. When graphed in this fashion, exponential cell survival appears as a straight line whose slope is dependent upon Do or the mean lethal dose of radiation. Do represents the dose of radiation that would be required to kill all cells in a given population if the dose were directed to the critical target of each individual cell. In reality, the mean lethal dose kills an average of 63% of the cells in a population with cell survival reduced to 37%. It may be noted that for most mammalian cells, cell killing over the first few hundred rads is not exponential but rather downward curving on a semilogarithmic scale. As the dose of radiation is increased and cell killing becomes more efficient, this "shoulder" gradually slopes into the straight line terminal exponential portion of the curve.
The above description applies to the administration of a single dose of radiation, and several biophysical models have been proposed to account for the shoulder portion of the graph. The true significance of the shoulder becomes apparent when the dose of radiation is fractionated, however. During fractionation, an interval of time elapses between dose fractions, and it may be seen that the shoulder on the cell survival curve reconstitutes itself between dose fractions. This implies repair of sublethal injury such that the surviving cells respond to subsequent fractions as if they had not received a previous dose of radiation. With equal fraction sizes and complete recovery between fractions, the net cell survival curve appears exponential. If the size of the dose fractions is progressively decreased, the shoulders on the curves will gradually become shallower until a point is reached at which further reduction of fraction size does not result in a further increase in cell survival.
The repair of sublethal injury between dose fractions has important implications for radiotherapy. The biologic effects of radiation are dependent upon the fractionation schedule. The larger the number of fractions, the greater is the opportunity for repair of sublethal injury and the higher the total dose of radiation necessary to kill a given number of tumor cells.
The radiosensitivity of tumor cells is influenced by many factors. Not long ago, tumor histology and location were thought to play major roles in the potential control of tumors with radiotherapy. Squamous cell carcinomas were considered radiosensitive and adenocarcinomas radioresistant. A primary lesion of the oral tongue was considered radiosensitive while metastases to the regional lymph nodes of the neck were radioresistant. There is no doubt that certain tumors are more difficult to control with radiotherapy, but histology is no longer felt to be as important. The differing radiosensitivities of tumors in various locations has been attributed to previously available radiotherapeutic equipment or techniques, and metastatic lesions are now known to be no less sensitive than the primary lesion.
The number of viable tumor cells and the proportion of hypoxic cells within a tumor are major contributors to radiosensitivity, and both of these are a function of the size of a given tumor. Exophytic, infiltrative, and ulcerative lesions of the head and neck differ in their response irradiation as well. Exophytic tumors are usually more easily controlled with radiation while infiltrative and ulcerative lesions are more radioresistant. The infiltrative and ulcerative lesions are more likely to be larger than clinically apparent and contain a larger proportion of hypoxic cells.
It has been apparent for many years that oxygen plays an important role in tumor sensitivity to radiation therapy. That hypoxic tumor cells are more radioresistant is well-established. While the mechanism for this phenomenon is incompletely understood, the presence of oxygen is thought to fix radiation injury within cells which is labile and would otherwise have been repaired. The maximum change in radiosensitivity occurs over the range of 0-20mm of Hg. It is obvious that this is well below the venous pO2, and there was initially some question as to the clinical applicability of tumor cell hypoxia. However, significant hypoxia has been demonstrated in experimental solid tumors, and significant indirect evidence indicates that hypoxic conditions within human tumors as well. Hypoxic conditions may develop because tumors often outgrow their existing blood supply, and shunting of blood via arteriovenous anastomoses may result in regions of marginally hypoxic cells within a tumor. Vascular compression may also play a role. The oxygen enhancement ratio (OER) demonstrates that the dose of radiation which results in a given level of cell survival is greater by a constant factor under hypoxic conditions than when cells are well-oxygenated. For most mammalian cells, the OER is 2.5 to 3. In other words, 2.5 to 3 times the dose of radiation required to kill well-oxygenated cells is necessary to kill hypoxic cells.
The position of tumor cells within the cell cycle confers radiosensitivity or resistance. For instance, the late G2 and M phases are the most radiosensitive, whereas the late S phase is the most radiosresistant. This should not be confused with phase-specific killing such as that seen with some types of chemotherapy, because cells throughout the cell cycle are subject to being killed by radiation.
As mentioned previously, there are different types of radiation used in radiotherapy, and the biologic effect is considerably affected by the form of radiation administered. The relative biologic effect compares a given beam to a reference standard and is calculated by dividing the reference standard by the beam being evaluated to produce the same effect. Linear energy transfer (LET) is another comparative measure for the various types of radiation and defines the degree of energy deposition per unit of distance traveled. X-rays, gamma rays, electrons, and protons are all low LET forms of radiation in that their density of ionization is sparse. In general, they penetrate tissues deeply and result in less intracellular radiation injury. High LET forms of radiation, such as heavy nuclear particles (e.g. fast neutrons), penetrate tissues less deeply and cause more radiation injury to biologic material. Substantial differences may be noted between the survival curves for high versus low LET forms of radiation. High LET forms of radiation display survival curves with a narrower shoulder and steeper terminal slope. Cell killing by high LET radiation is less affected by the position of the cells in the cell cycle and their oxygen status, and cells have little ability to repair the radiation injury inflicted by high LET radiation. Therefore, dose fractionation has much less effect with high LET radiation.
Many drugs act to modify the response to radiotherapy, and these interactions may be considered independent, additive, synergistic, or antagonistic. An analysis of the interaction between drugs and irradiation is complex and difficult at best. The potential outcome is often hard to define, particularly with concurrent administration of cytotoxic agents and radiotherapy. Care should be taken to avoid adverse reaction or overdosage of either form treatment.
It has been noted that hyperthermia enhances the radiosensitivity of tumor cells, and it is an investigational therapeutic adjunct. Hyperthermia is toxic to cells in a low pH environment and those in the S phase of the cell cycle. It reduces the shoulder of the survival curve and increases the terminal slope. The use of hyperthermia in the treatment of head and neck tumors is often impractical due to difficulty in monitoring the therapy and the discomfort involved.
Fractionation refers to the administration of a dose of radiation in small increments of the total dose over a specific time period with intervals between the dose fractions. It has long been noted that therapeutic improvements are made in tumor control with fractionated doses of radiotherapy as opposed to a single large dose or a few large fractions. The reasoning behind the practice of fractionation is best described in terms of the concepts of repair, reoxygenation, redistribution, and regeneration (repopulation).
The cellular repair of sublethal injury results in the reconstitution of the shoulder of the survival curve between radiotherapy dose fractions. The opportunity for repair improves as the number of dose fractions increases, thus resulting in a sparing effect. This sparing effect is especially notable among the late-reacting normal tissues.
The presence of oxygen results in increased tumor cell radiosensitivity with hypoxia having the opposite effect. During a fractionated course of radiotherapy, a process of reoxygenation has been shown to occur, thus making the cells of a given tumor more susceptible to killing by radiation. The means by which this phenomenon occurs are unclear, but several possibilities exist. As well-oxygenated tumor cells are killed, hypoxic cells would then come into closer proximity with adjacent blood vessels, or the effective diffusion capacity of oxygen could increase as cells are killed and oxygen consumption decreases. Alterations in blood flow could also take place within tumor vessels. The basic principle in reoxygenation is that during a fractionated course of radiotherapy, a given tumor cell's oxygen status has an increased chance of improving such that it will become more radiosensitive and subsequently be killed.
Tumor cells are more vulnerable to injury as they enter certain portions of the cell cycle. Fractionation allows an opportunity for progression of a cell from a more to a less sensitive phase of the cell cycle. This is especially true for rapidly cycling cells such as those of acutely reacting normal tissues as well as tumor cells. Late-reacting normal tissues have a low cell turnover rate and therefore are not as affected by redistribution.
As cells are lost due to radiation injury and death within a given population of cells (normal or tumor), the surviving cells respond by an increased regeneration or repopulation. As with redistribution, this is especially true for tissues with rapid cell turnover such as acutely reacting normal tissues and tumors and less so for late-reacting normal tissues, which have low cell turnover. While protracting the course of radiotherapy has the effect of sparing the acutely reacting normal tissues, it also incurs the risk of allowing regenerating tumor cells to proliferate. Regeneration is therefore a major determinant in planning the length of a course of therapy, and a balance must be reached to allow adequate tumor control with sufficient sparing of acutely reacting normal tissues to allow their recuperation during treatment. Unnecessarily protracted courses of therapy or split courses of therapy are best avoided if possible.
Isoeffect curves can be a useful tool in understanding the complex interactions of dose, fractionation, and length of therapy in producing a given biologic effect. The curves are plotted such that a given biologic effect is defined in terms of the total radiation dose required to produce the effect as a function of number of fractions or treatment time. When the log dose is plotted as a function of log number of fractions (with treatment time held constant), the slope of the curve defining the late tissue effects is noted to be significantly steeper than that for acute reactions. This indicates the degree of repair capacity of these tissues. If the log dose is then plotted as a function of the log treatment time (with the number of fractions held constant), the slope of the curve defining the acute tissue reactions is steeper. This represents the regenerative capacity of these tissues. It also becomes apparent from these plots that with both hypofractionation and protraction of treatment time, isoeffective doses based on acute tissue reactions may lead to excessive radiation dosage with subsequent adverse late-reacting tissue responses.
In the United States, a conventional fractionation schedule is typically in increments of 180-200cGy 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.
Accelerated fractionation involves two or more dose fractions of approximately conventional size per day with the net effect of shortening overall treatment time. Such a schedule would be most applicable in the treatment of rapidly proliferating tumors with increased regenerative potential.
Hyperfractionation involves two or more small dose fractions per day for a conventional or slightly longer treatment time. The results in an overall increase total dose. This technique is an attempt to minimize late-reacting normal tissue responses while maintaining a greater effect on tissues which are kinetically similar to acutely reacting normal tissues (e.g. tumors).
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. A choice of treatment modality or combination of modalities is the made to fit the patient's needs.
As mentioned previously, ionizing radiation may be delivered by external beam, interstitial implant (brachytherapy), or a combination of the two. The choice depends on the size and location of the tumor and the presence or likelihood of regional metastatic disease.
Interstitial radiotherapy is a form low-dose-rate continuous irradiation with the advantages of hyperfractionation and accelerated fractionation in that it is similar to a very large number of small dose fractions. Continuous irradiation shortens the length of treatment. This technique allows a small high-dose volume of radiation and rapid fall-off in the adjacent tissues with sparing of normal structures. The method is quite effective for appropriate accessible tumors. However, there are risks of inadequate dosing to a portion of a given tumor as well as normal tissue injury in areas of localized "hot spots" in the implant sources.
For the majority of smaller tumors of the head and neck, a course of radiotherapy consisting of 6000 to 6500cGy over 6 to 6.5 weeks is adequate. Doses of 6500 to 7000cGy over 6.5 to 7.5 weeks may be necessary to control larger masses with even higher doses required for bulky disease. It has been shown that a dose of 5000cGy over 5 weeks will control subclinical disease in 90 to 95% of patients.
Dose-response curves display a steep slope for most smaller tumors and indicate that even modest increases in radiation dose may increase the probability of control from 25% to 75%. The sigmoidal shape of the curve is a result of the heterogeneity among the tumor cell population for a given neoplasm with regard to the number of viable tumor cells and the proportion of cells that are hypoxic. The curve is not as steeply sloped for larger tumors due to the increased heterogeneity of the cell population in these larger cancers.
The therapeutic ratio relates the dose-response curves for tumor control probability and normal tissue injury. For smaller tumors, the curves are typically separated from one another, indicating a relatively high probability of tumor control without injury to adjacent normal tissues. On the other hand, the curves for larger tumors lie closer together and may even overlap, indicating a significant likelihood of injury to adjacent normal tissues even with a modest increase in radiation dose.
A course of radiotherapy is usually delivered using a shrinking field technique. The concept is based on the notion 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. The idea is to administer a dose of radiation which provides a homogeneous tumor control probability throughout a given volume of tumor. An example would be to deliver a dose 5000cGy over 5 weeks via fields which encompass the gross tumor with adjacent areas of potential regional lymph node metastases. This would be followed by a dose 2000cGy over 2 weeks to the remaining detectable tumor with a margin for a total dose of 7000cGy over 7 weeks.
As a general rule, the most rapidly proliferating tumors (those with the highest cell turnover) display the most rapidly visible response to radiotherapy. By contrast, tumors which are more indolent regress more slowly. As already noted, tumor cells are no longer considered viable when they have lost their reproductive or clonogenic capacity, but they may be morphologically unchanged. Several apparently successful cell divisions may take place before mitotic death of the cell occurs. The clinical significance of regression varies from tumor to tumor, and most squamous cell carcinomas of the head and neck are felt to have a modest rate of cell turnover. For this reason, residual tumor which persists after an apparently adequate course of radiation therapy is generally considered to have a decreased probability of tumor control. This raises the question of appropriate timing for post-radiation biopsies of residual tumor masses. These patients require close follow-up, and unless there is overt clinical evidence of tumor growth, it is best to postpone biopsy until 3 months post-radiation. This is particularly important since it is morphologically impossible to distinguish a viable tumor cell from one which may have already been sterilized.
When used appropriately, the combined modalities of surgery and radiotherapy complement one another very well. Surgery is ideal for removal of gross tumor, and most radiation failures are the result of the inability of radiation to control bulky masses. Radiation therapy is effective in controlling microscopic disease, and most surgical failures occur as a result of an inability to remove all subclinical tumor extensions. The use of each modality is effective in counteracting the limitations of the other. For the most part, radiotherapy, when combined with surgery for management of head and neck cancer, is administered postoperatively. However, each sequence has its merits.
Preoperative radiotherapy may decrease tumor bulk to facilitate dissection. Microscopic disease is more effectively controlled preoperatively, prior to disturbance of its blood supply and oxygenation. Seeding of tumor cells during surgical dissection with the risk of subsequent metastasis may be diminished. Finally, it may be possible to smaller treatment portals preoperatively.
Postoperative radiotherapy may allow more accurate surgical staging of the tumor and definition of tumor margins. This information is vital in planning the dosage and administration of postoperative radiotherapy. Surgical dissection is less difficult overall in tissues which have not been previously irradiated, and a larger dose of radiation may be given postoperatively than preoperatively.
Failure of radiation therapy to achieve tumor control may result from numerous causes, many of which have been mentioned previously. A few of the more common reasons radiotherapy fails include volume of tumor, tumor hypoxia, tumor regeneration, and inadequate dosage among others.
Xerostomia results from radiation injury to the serous cells within the salivary glands. Once lost, this function may or may not return, but no more than partial recovery is typically expected. A corollary to the loss of salivary flow may be the onset of dental caries, particularly in teeth previously in poor repair. Dental extraction is often necessary prior to the initiation of radiotherapy.
Osteoradionecrosis is typically the result of radionecrosis of the overlying mucosal soft tissues. There may be cartilage involvement as well. Skin changes including erythema and breakdown are usually no longer severe with current radiotherapeutic techniques. However, fibrosis of the underlying subcutaneous tissues may become a substantial problem and even limit therapy.
The potential ocular complications of radiotherapy may include cataracts, injury to the optic nerve, retinopathy, or injury to the lacrimal gland. Otologic complications of serous otitis media, sensorineural hearing loss, or vestibular dysfunction may arise.
The CNS complications of radiotherapy can be devastating, and radiotherapists take many precautions to avoid these serious problems. Complications may involve the spinal cord or brain. A transient radiation myelopathy may occur which consists of electric shock-like sensations with flexion of the cervical spine and transverse myelitis is rare. Somnolence syndrome may appear months after therapy in patients receiving radiation to the sinuses or nasopharynx. It is transient and consists of lethargy, nausea, and headaches among other complaints. Brain necrosis is irreversible and may require resection.
Radiation oncology is a complex field involved with the administration of ionizing radiation for the treatment of neoplastic diseases. Radiotherapy plays a prominent role in the treatment of tumors of the head and neck region. This presentation has attempted to provide a general overview of the fundamental concepts of radiobiology applicable to the management of head and neck cancer. It is hoped that this basic knowledge will be of some benefit to those concerned with the care of these patients with the ultimate goal of evaluating and planning the most effective treatment strategies possible.
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