Tumor Growth Kinetics and Time, Dose and Fractionation in Radiotherapy Chapters 21 22

1. 1 Tumor Growth Kinetics and Time, Dose and Fractionation in Radiotherapy Chapters 21 & 22

2. 2 Overview The cell cycle Experimental measurements of cell cycle times Tumor doubling time The growth fraction Cell loss Pattern of tumor growth Growth kinetics of human tumors

3. 3 The Cell Cycle Mammalian cells replicate via mitosis The cell cycle, also called the mitotic cycle time (TC), is the average interval between two successive mitoses

4. 4 Mitotic Labeling Technique To determine duration of each cell-cycle phase Cell population is flash-labeled with tritiated thymidine At regular intervals thereafter, cell population samples are pulled, fixed, stained and autoradiographed Sampling procedure time > Tc for complete analysis

5. 5 Result of Mitotic Labeling

6. 6 Quantitative Assessment of Cell Cycle The population of cells at various stages can be quantified The percentage of cells in mitosis is given by the Mitotic Index (MI): The percentage of cells in S phase is given by the Labeling Index (LI):

7. 7 Measurements of Cell Cycle Times Once we know the labeling index, the average cell cycle time (TC) can be determined: Techniques (�flow cytometry�) allow for rapid (days) determination of tumor kinetics To better assess treatment planning

8. 8 Tumor Doubling The potential tumor doubling time (Tpot) is a measure of the maximum rate of increase in proliferating cells useful in determining the outcome of a fractionated radiotherapy treatment Tumors with a short Tpot may repopulate if the fractionations are delivered with too long of an interval between doses Tpot is calculated by:

9. 9 Tpot Used to divide patients into two groups fast-growing cancers (Tpot < 4 days) slow-growing cancers (Tpot > 4 days) Determines fractionation plan Patients with fast-growing cancers benefit from an accelerated treatment regime

10. 10 The Growth Fraction Cells are either proliferating or quiescent The growth fraction (GF) is the ratio of the number of proliferating cells (P) to the total number of cells (P+Q)

11. 11 Growth Fraction Estimated by injecting a tumor with tritiated thymidine after several cell generations the tumor is sectioned and autoradiographed radiographs are then evaluated to determine the number of labeled cells and those going through mitoses Growth fractions are typically in the range of 30-50%, and decrease to ~15% as the tumor outgrows the blood supply

12. 12 Cell Loss Tumor growth is determined by the balance of production and loss of cells The cell loss factor (F) is determined by: where Td is the actual doubling time The cell loss factor represents the rate ratio of cell-loss to cell-production

13. 13 Cell Loss Tumor cells are lost in various ways, for example: inadequate nutrition apoptosis immunologic attack metastasis exfoliation

14. 14 Pattern of Tumor Growth Pattern of tumor cells around a blood vessel The cells proliferate in the oxygen rich region around the vessel, but are pushed outward into anoxic regions where they perish

15. 15 Tumor Growth Pattern Tumor growth rates are determined by: time of the cell-cycle the growth factor rate of cell loss The proliferative cells of a tumor divide as rapidly as they are able to, limited only by their inherited characteristics and the availability of nutrients and oxygen

16. 16 Tumor Growth Tumors are not organized tissues and tend to outgrow their vascular supply, thus: areas of necrosis develop hypoxic cells (~15% of viable cells) are common The overstretched vascular supply of tumors often limits the growth fraction in areas away from the blood supply Growth fractions are typically ~ 30-50%

17. 17 Growth Kinetics in Human Tumors Data available on doubling times for more than a thousand different human tumors median ~ 2 months However, tumors of the same histologic type in different patients vary widely in growth rate Tumors with the most rapid mean growth rate and the highest growth fraction are the most radiosensitive

18. 18 Cell Cycle Times:Tumors vs. Normal Tissues Generally, the cell cycle times of malignant cells are considerably shorter than their normal counterparts exception: tumors arising from rapidly proliferating normal tissues Generally, irradiation ... � elongates the cycle for tumor cells � shortens the cycle for normal tissues

19. 19 Fractionation Developed in the 1920�s and 30�s - experiments with rams Single, large dose could not produce sterility without significant skin damage but, sterility could be induced with several smaller doses with no visible skin damage Fractionation thus: spares the normal tissues, allowing for repair of sublethal damage and repopulation increases tumor damage because of reoxygenation and reassortment Time between fractions is critical for tumor control In most cases, fractionation results in better tumor control (than single dose) for a given level of normal tissue toxicity

20. 20 Isoeffect Curves Strandquist plot - relation between total dose and overall treatment time (3-5 fractions/wk) Simple effect-equivalent relationships are attempted, but far from accurate example, treatment regimes of 4 d/wk vs. 5 d/wk

21. 21 Proliferation Proliferation of tumor cells and fractionation early-responding tissues (e.g. skin, intestinal epithelium) late-responding tissues (e.g. lung, spinal cord) Extra dose required to compensate for tumor proliferation, yet control normal-tissue damage, is sigmoidal over time in short time frames, none needed; at some point, large amt. needed Extending radiotherapy time has little sparing effect on late reactions, but a large sparing effect on early reactions

22. 22 Dose-Response Relationships:Early and Late Responding Tissues Tissue survival curves tend to have larger shoulders The dose-response relationship for late-responding tissues is more curved than for early responding tissues Thus, larger a/b dose value for early responding tissues In the linear-quadratic model, 2 components of cell injury are present. The linear-alpha component is responsible for the initial shoulder on the cell survival curve and is caused by repairable damage to the target. The quadratic-beta component represents nonrepairable damage. The linear component is proportional to the dose, while the quadratic component is proportional to the dose squared. Acute reacting tissues and tumors have a relatively larger alpha component and a larger a:b ratio. Smaller a:b ratios characterize late responding tissues. This difference between the tumor and late responding tissues is useful in designing schemes, which use multiple daily fractions rather than the conventional once daily treatments. Values for a:b are as follows: Early responding, normal tissue Skin Erythema - 10.6 Desquamation - 11.2 Oral mucosa Mucositis - 10.8 Tumor tissue Nasopharynx - 16 Oropharynx - 16 Vocal cord - 13 Tonsil - 7 Skin (squamous or carcinoma) - 8.5 Late responding, normal tissue Skin Telangiectasia - 2.7 Fibrosis - 1.7 Spinal cord Myelitis - 3.3 Cartilage Fibrosis - 4.5 In the linear-quadratic model, 2 components of cell injury are present. The linear-alpha component is responsible for the initial shoulder on the cell survival curve and is caused by repairable damage to the target. The quadratic-beta component represents nonrepairable damage. The linear component is proportional to the dose, while the quadratic component is proportional to the dose squared. Acute reacting tissues and tumors have a relatively larger alpha component and a larger a:b ratio. Smaller a:b ratios characterize late responding tissues. This difference between the tumor and late responding tissues is useful in designing schemes, which use multiple daily fractions rather than the conventional once daily treatments. Values for a:b are as follows: Early responding, normal tissue Skin Erythema - 10.6 Desquamation - 11.2 Oral mucosa Mucositis - 10.8 Tumor tissue Nasopharynx - 16 Oropharynx - 16 Vocal cord - 13 Tonsil - 7 Skin (squamous or carcinoma) - 8.5 Late responding, normal tissue Skin Telangiectasia - 2.7 Fibrosis - 1.7 Spinal cord Myelitis - 3.3 Cartilage Fibrosis - 4.5

23. 23 Late and Early Response In practice, treatment protocols requiring a few large fractions (to produce equal early effects) result in more severe late effects Fractionation greatly reduces late effects late-responding tissues are more sensitive to changes in fractionation patterns (recall SF curve) Isoeffect curves (Fig 22.7; pg 383) are steeper for late effects High-LET more effective for late effects As dose per fraction increases, late responding tissues can take less dose Conventional fractionation in the United States is considered to be 1.8-2 Gy per day, administered 5 days each week for 5-7 weeks, depending on the particular clinical situation. The alteration of this scheme has been evaluated for a variety of reasons, including time constraints, staff constraints, machine availability, and patient convenience. A variety of methods have been used to correlate different dose-fractionation schemes. These methods are rooted in an understanding of the dose-response curves and the association (or lack thereof) between acute reaction and long-term sequelae of treatment. Strandquist produced the first clinical isoeffect curve. He calculated the relationship between time, dose, cure, and skin reactions in the treatment of skin cancers. Later, Ellis recognized that the time factor was actually dependent on both the overall treatment time and the number of fractions. He devised the nominal standard dose (NSD) formula, ie, D = NSD X N0.24 X T0.11, where D = dose, N = number of fractions, and T = overall time. These formulas have been used in an attempt to adjust for the alterations in the standard fractionation schemes. Most contemporary isoeffect formulas make use of the linear-quadratic model as a basis for dose adjustments, ie, D1/D2 = (a/b + d2) / (a/b + d1), where D is the total dose and d is the dose per fraction. This formula assumes a complete repair of sublethal damage between the fractions. The major deficiency with these formulas is the lack of precision in determining a/b for the various tissue types, tumor types, and individual variations. One of the early attempts at altered fractionation was the use of split-course therapy. The attempt was to attain comparable or better levels of tumor control by allowing reoxygenation with reduced acute toxicity. A 2- to 3-week rest from the treatment was often used. However, this rest period resulted in poorer long-term control because repopulation and accelerated repopulation dominated. Other fractionation schemes include hyperfractionation, hypofractionation, and accelerated fractionation. In hyperfractionated regimens, the goal is to deliver higher tumor doses while maintaining a level of long-term tissue damage that is clinically acceptable. The daily dose is unchanged or slightly increased while the dose per fraction is decreased, and the overall treatment time remains constant. The a/b for the tumor must be greater than that of the dose-limiting tissue. An additional rationale for hyperfractionation is to allow radiosensitization through redistribution. With a greater number of fractions, the likelihood is greater that the tumor will be in a sensitive phase of the cell cycle at some time during the treatment. This strategy invariably results in more intense acute reactions when compared to conventional treatment. In the accelerated fractionation schemes, the dose per fraction is unchanged while the daily dose is increased, and the total time for the treatment is reduced. Three basic variations are possible. Continuous hyperfractionated accelerated radiation therapy (CHART) is an intense schedule of treatment, where multiple daily fractions are administered within an abbreviated period of time. An intense acute reaction develops in most patients. This reaction usually limits the total dose. In a concomitant boost technique, the first fraction of the day is administered in a larger volume, while the second fraction is targeted to a reduced-boost field of treatment. The boost may be administered early in the course of therapy or toward the end of treatment. This regimen is based upon the recognition that the treatment can induce an accelerated repopulation of the tumor cells so that reduction of the overall treatment time results in improved control. Clinical trials are in progress with the goal of evaluating these various altered fractionation patterns and comparing them to conventional treatment. Results from the recently completed randomized trial, RTOG-9003, supports the benefit of altered fractionation over conventional treatment for head and neck cancer. So far the benefit seems to be in local regional control. Further follow-up is necessary to determine if there is an overall survival benefit as wellConventional fractionation in the United States is considered to be 1.8-2 Gy per day, administered 5 days each week for 5-7 weeks, depending on the particular clinical situation. The alteration of this scheme has been evaluated for a variety of reasons, including time constraints, staff constraints, machine availability, and patient convenience. A variety of methods have been used to correlate different dose-fractionation schemes. These methods are rooted in an understanding of the dose-response curves and the association (or lack thereof) between acute reaction and long-term sequelae of treatment. Strandquist produced the first clinical isoeffect curve. He calculated the relationship between time, dose, cure, and skin reactions in the treatment of skin cancers. Later, Ellis recognized that the time factor was actually dependent on both the overall treatment time and the number of fractions. He devised the nominal standard dose (NSD) formula, ie, D = NSD X N0.24 X T0.11, where D = dose, N = number of fractions, and T = overall time. These formulas have been used in an attempt to adjust for the alterations in the standard fractionation schemes. Most contemporary isoeffect formulas make use of the linear-quadratic model as a basis for dose adjustments, ie, D1/D2 = (a/b + d2) / (a/b + d1), where D is the total dose and d is the dose per fraction. This formula assumes a complete repair of sublethal damage between the fractions. The major deficiency with these formulas is the lack of precision in determining a/b for the various tissue types, tumor types, and individual variations. One of the early attempts at altered fractionation was the use of split-course therapy. The attempt was to attain comparable or better levels of tumor control by allowing reoxygenation with reduced acute toxicity. A 2- to 3-week rest from the treatment was often used. However, this rest period resulted in poorer long-term control because repopulation and accelerated repopulation dominated. Other fractionation schemes include hyperfractionation, hypofractionation, and accelerated fractionation. In hyperfractionated regimens, the goal is to deliver higher tumor doses while maintaining a level of long-term tissue damage that is clinically acceptable. The daily dose is unchanged or slightly increased while the dose per fraction is decreased, and the overall treatment time remains constant. The a/b for the tumor must be greater than that of the dose-limiting tissue. An additional rationale for hyperfractionation is to allow radiosensitization through redistribution. With a greater number of fractions, the likelihood is greater that the tumor will be in a sensitive phase of the cell cycle at some time during the treatment. This strategy invariably results in more intense acute reactions when compared to conventional treatment. In the accelerated fractionation schemes, the dose per fraction is unchanged while the daily dose is increased, and the total time for the treatment is reduced. Three basic variations are possible. Continuous hyperfractionated accelerated radiation therapy (CHART) is an intense schedule of treatment, where multiple daily fractions are administered within an abbreviated period of time. An intense acute reaction develops in most patients. This reaction usually limits the total dose. In a concomitant boost technique, the first fraction of the day is administered in a larger volume, while the second fraction is targeted to a reduced-boost field of treatment. The boost may be administered early in the course of therapy or toward the end of treatment. This regimen is based upon the recognition that the treatment can induce an accelerated repopulation of the tumor cells so that reduction of the overall treatment time results in improved control. Clinical trials are in progress with the goal of evaluating these various altered fractionation patterns and comparing them to conventional treatment. Results from the recently completed randomized trial, RTOG-9003, supports the benefit of altered fractionation over conventional treatment for head and neck cancer. So far the benefit seems to be in local regional control. Further follow-up is necessary to determine if there is an overall survival benefit as well

24. 24 Fraction Size and Treatment Time Early effects: both fraction size and overall treatment time are important Late effects: number of fractions dominates overall treatment time has little influence Radiation effects on the normal tissues are divided into acute and chronic effects. Acute effects occur during the course of therapy and during the posttherapy period (approximately 2-3 weeks after the completion of a course of irradiation). Chronic effects can manifest anytime thereafter, from weeks to years after the treatment. Patients are usually most bothered by the acute effects, but physicians are at least equally concerned about the chronic effects. The acute effects can be quite uncomfortable but generally resolve. The chronic effects can be devastating, permanent, and progressive. Much of the effort that goes into the treatment planning regards minimizing the normal tissue effects of treatment. The tissues that divide rapidly (eg, mucous membranes) respond acutely to radiation and are responsible for much of the acute morbidity of the treatment. Two major theories are used to explain late injury. One theory attributes chronic injury to the damage of the microvasculature, while the other attributes injury to stem cell depletion. The mucous membranes of the oral cavity and the oropharynx respond early to fractionated radiation. Erythema is often evident after 1 week of treatment at conventional doses. This condition progresses over the next few weeks through various stages of mucositis, ranging from small patches to confluent or even ulcerated areas. Mucositis represents caking of the dead epithelial cells, fibrin, and inflammatory cells. Consider superimposed infection with yeast species or bacteria when patients report oral or throat pain during treatment. Healing begins while the patient is still undergoing treatment but may continue for several weeks after the radiation is completed. Loss of taste is a common acute effect of treatment. Taste loss begins early and progresses rapidly during the second 2 weeks of treatment. Patients may report diminished acuity, odd sensation, or complete absence of taste. Xerostomia is often present and exacerbates this loss of taste. This condition is often accompanied by a loss of appetite and weight loss. Recovery of taste is a slow and, frequently, an incomplete process. The major salivary glands (ie, parotid and submandibular glands) are responsible for nearly 80% of salivary production. The parotid glands primarily consist of serous acini, while the submandibular glands produce mucinous and serous secretions. The minor salivary glands, which are distributed throughout the oral mucosa, produce mostly mucinous secretions. Radiation affects the saliva volume and production and also alters the composition of the saliva. Decreased salivary pH and decreased volume are significant contributors to the altered oral mucosal flora and predispose patients to caries. Salivary production decreases rapidly with treatment, declining by nearly 50% after a week of treatment. Patients frequently describe thickened, tenacious, ropy saliva, which may make speech difficult in addition to affecting swallowing and taste. High-energy radiographs are skin sparing. Skin reactions, which were at one time dose limiting, are rarely a problem when high-energy radiographs are used. While erythema is common after several weeks of radiation, severe skin reactions, such as those observed in the orthovoltage era, are uncommon. When a need for skin irradiation exists (eg, skin involvement by the tumor or skin as the target in the treatment of basal cell cancers), the technique is adjusted so that a brisk skin reaction is produced. The use of less-penetrating orthovoltage radiographs, treatment with electrons, or the addition of tissue-equivalent bolus material placed over the radiation field can circumvent skin sparing. Even with megavoltage treatment, skin tanning and dry desquamation can occur. The addition of certain chemotherapeutic drugs can enhance skin and other effects. Radiation can induce melanin production, which is often first observed in the skin follicles because these skin invaginations receive a slightly higher dose as the beam enters tangentially to the surface. Skin sensitivity is increased because of the treatment. In situations where the skin is denuded, known as moist desquamation, the area must be kept clean to avoid superinfection. Re-epithelization moves centrally from the field edges and is generally completed within 3 weeks prior to the completion of treatment. Sweat glands and sebaceous glands may cease functioning, but the in-field hair loss usually is temporary. Regrowth is evident within a few weeks after cessation of therapy. The late effects of radiation can be a source of ongoing morbidity from a course of radiation therapy. Just as with the acute effects, the chronic effects are related to site, dose, volume, and time. Other therapies, such as surgery and chemotherapy, can increase the probability and severity of radiation-related morbidity. High doses of radiation to the neck can result in fibrosis. This condition is especially true in the postoperative setting where the neck may develop a woody texture and have limited movement. Likewise, the masticatory muscles may develop fibrosis, which can result in trismus. Instruct patients to begin stretching exercises of their jaw muscles as soon as possible after surgery. Obstruction of the cutaneous lymphatics results in lymphedema, which may be associated with episodes of intermittent erysipelas. Delayed wound healing can be a consequence of high-dose preoperative radiation. Telangiectasis may appear some time after the treatment in the areas that were treated without skin-sparing techniques such as with electrons, tangential irradiation, and deliberate addition of bolus material. The loss of salivary function is usually complete after modest doses of radiation to the parotid glands. The basal flow rates correlate with the response to radiation therapy. With 40-60 Gy, fewer than 20% of patients have a measurable salivary flow. For patients receiving fewer than 30 Gy, some function may return after 6-12 months. However, at dose levels exceeding 50 Gy, xerostomia usually is irreversible. Dry mouth is probably the most common problem for patients who receive therapeutic doses of radiation. Numerous approaches have been tried to address this problem. Pilocarpine 5 mg tid has been shown to stimulate residual salivary function. Some patients use artificial saliva substitutes, but most patients find them inadequate. Many patients must carry bottles of water to provide some relief. The US Food and Drug Administration (FDA) has recently approved the use of IV Amifostine (Ethyol) as a radioprotectant agent. Administered as a daily dose, Amifostine is to be used in the prevention of radiation-induced xerostomia in the postoperative setting. Concern about tumor protection appears to be unwarranted. Adverse effects, such as nausea and hypotension, the need for daily injections, and cost concerns may limit its wide acceptance. SQ administration, while not a labeled use, seems to be equally effective and associated with less toxicity. Intensity modulated radiation therapy (IMRT) is currently under investigation as a novel approach in preventing xerostomia. At the time of treatment planning, the radiation oncologist uses an inverse-planning algorithm that allows selective avoidance of critical normal tissues without compromising the tumor doses. Other potential uses for IMRT include the ability to administer biologically higher doses to target tissues and biologically lower doses to nontarget tissues and thus increase the therapeutic ratio. Several planning systems and systems of delivery are currently available or are in the testing phases. The initial reports are encouraging. As a consequence of oral pain and altered diet during treatment and xerostomia following treatment, the oral flora and pH can be altered significantly. Without meticulous dental care during and after radiation therapy, patients are prone to accelerated caries and decay. Oral and gingival tissue may atrophy following radiation, which results in a thin pale layer with evidence of telangiectatic vessels. Ulceration and bone exposure can occur. If serious injury to the underlying bone occurs, osteoradionecrosis may follow. Fortunately, this complication is uncommon. When it does occur, management of the condition may be difficult. While patience is important, some cases require intervention, which includes the use of antibiotics, hyperbaric oxygen treatment, and resection. Radiation to the spinal cord may result in a self-limited transverse myelitis, known as Lhermitte syndrome. The patient notes an electric shocklike sensation that is most notable with neck flexion. Rarely does this condition progress to a true transverse myelitis with associated Brown-S�quard syndrome. The dose to the spinal cord must be limited so as to avoid this devastating complication. A course of treatment often affects the thyroid gland either directly or secondarily via the hypothalamic-pituitary axis. Chemical hypothyroidism is often the only manifestation of an endocrinopathy and is treated readily with supplemental thyroid preparation. Other endocrinopathies are uncommon. Other structures that must be considered during the treatment planning are the visual apparatus, the auditory apparatus, and the apex of the lungs. Exceeding the tolerance of the lacrimal gland can result in dry-eye syndrome. The lens is highly sensitive to radiation. Direct irradiation of the lens with the most commonly used therapeutic doses results in cataract formation. Tolerance of the retina and optic nerve must also be respected during the treatment planning to avoid visual loss. Radiation to the auditory apparatus may result in serous otitis or possible sensorineural hearing loss at high doses of irradiation. Radiation-induced cancers are fortunately quite uncommon following therapeutic doses of radiation. A much greater risk of second malignancy is due to the same etiologic and genetic mechanisms that are responsible for the primary tumor.Radiation effects on the normal tissues are divided into acute and chronic effects. Acute effects occur during the course of therapy and during the posttherapy period (approximately 2-3 weeks after the completion of a course of irradiation). Chronic effects can manifest anytime thereafter, from weeks to years after the treatment. Patients are usually most bothered by the acute effects, but physicians are at least equally concerned about the chronic effects. The acute effects can be quite uncomfortable but generally resolve. The chronic effects can be devastating, permanent, and progressive. Much of the effort that goes into the treatment planning regards minimizing the normal tissue effects of treatment. The tissues that divide rapidly (eg, mucous membranes) respond acutely to radiation and are responsible for much of the acute morbidity of the treatment. Two major theories are used to explain late injury. One theory attributes chronic injury to the damage of the microvasculature, while the other attributes injury to stem cell depletion. The mucous membranes of the oral cavity and the oropharynx respond early to fractionated radiation. Erythema is often evident after 1 week of treatment at conventional doses. This condition progresses over the next few weeks through various stages of mucositis, ranging from small patches to confluent or even ulcerated areas. Mucositis represents caking of the dead epithelial cells, fibrin, and inflammatory cells. Consider superimposed infection with yeast species or bacteria when patients report oral or throat pain during treatment. Healing begins while the patient is still undergoing treatment but may continue for several weeks after the radiation is completed. Loss of taste is a common acute effect of treatment. Taste loss begins early and progresses rapidly during the second 2 weeks of treatment. Patients may report diminished acuity, odd sensation, or complete absence of taste. Xerostomia is often present and exacerbates this loss of taste. This condition is often accompanied by a loss of appetite and weight loss. Recovery of taste is a slow and, frequently, an incomplete process. The major salivary glands (ie, parotid and submandibular glands) are responsible for nearly 80% of salivary production. The parotid glands primarily consist of serous acini, while the submandibular glands produce mucinous and serous secretions. The minor salivary glands, which are distributed throughout the oral mucosa, produce mostly mucinous secretions. Radiation affects the saliva volume and production and also alters the composition of the saliva. Decreased salivary pH and decreased volume are significant contributors to the altered oral mucosal flora and predispose patients to caries. Salivary production decreases rapidly with treatment, declining by nearly 50% after a week of treatment. Patients frequently describe thickened, tenacious, ropy saliva, which may make speech difficult in addition to affecting swallowing and taste. High-energy radiographs are skin sparing. Skin reactions, which were at one time dose limiting, are rarely a problem when high-energy radiographs are used. While erythema is common after several weeks of radiation, severe skin reactions, such as those observed in the orthovoltage era, are uncommon. When a need for skin irradiation exists (eg, skin involvement by the tumor or skin as the target in the treatment of basal cell cancers), the technique is adjusted so that a brisk skin reaction is produced. The use of less-penetrating orthovoltage radiographs, treatment with electrons, or the addition of tissue-equivalent bolus material placed over the radiation field can circumvent skin sparing. Even with megavoltage treatment, skin tanning and dry desquamation can occur. The addition of certain chemotherapeutic drugs can enhance skin and other effects. Radiation can induce melanin production, which is often first observed in the skin follicles because these skin invaginations receive a slightly higher dose as the beam enters tangentially to the surface. Skin sensitivity is increased because of the treatment. In situations where the skin is denuded, known as moist desquamation, the area must be kept clean to avoid superinfection. Re-epithelization moves centrally from the field edges and is generally completed within 3 weeks prior to the completion of treatment. Sweat glands and sebaceous glands may cease functioning, but the in-field hair loss usually is temporary. Regrowth is evident within a few weeks after cessation of therapy. The late effects of radiation can be a source of ongoing morbidity from a course of radiation therapy. Just as with the acute effects, the chronic effects are related to site, dose, volume, and time. Other therapies, such as surgery and chemotherapy, can increase the probability and severity of radiation-related morbidity. High doses of radiation to the neck can result in fibrosis. This condition is especially true in the postoperative setting where the neck may develop a woody texture and have limited movement. Likewise, the masticatory muscles may develop fibrosis, which can result in trismus. Instruct patients to begin stretching exercises of their jaw muscles as soon as possible after surgery. Obstruction of the cutaneous lymphatics results in lymphedema, which may be associated with episodes of intermittent erysipelas. Delayed wound healing can be a consequence of high-dose preoperative radiation. Telangiectasis may appear some time after the treatment in the areas that were treated without skin-sparing techniques such as with electrons, tangential irradiation, and deliberate addition of bolus material. The loss of salivary function is usually complete after modest doses of radiation to the parotid glands. The basal flow rates correlate with the response to radiation therapy. With 40-60 Gy, fewer than 20% of patients have a measurable salivary flow. For patients receiving fewer than 30 Gy, some function may return after 6-12 months. However, at dose levels exceeding 50 Gy, xerostomia usually is irreversible. Dry mouth is probably the most common problem for patients who receive therapeutic doses of radiation. Numerous approaches have been tried to address this problem. Pilocarpine 5 mg tid has been shown to stimulate residual salivary function. Some patients use artificial saliva substitutes, but most patients find them inadequate. Many patients must carry bottles of water to provide some relief. The US Food and Drug Administration (FDA) has recently approved the use of IV Amifostine (Ethyol) as a radioprotectant agent. Administered as a daily dose, Amifostine is to be used in the prevention of radiation-induced xerostomia in the postoperative setting. Concern about tumor protection appears to be unwarranted. Adverse effects, such as nausea and hypotension, the need for daily injections, and cost concerns may limit its wide acceptance. SQ administration, while not a labeled use, seems to be equally effective and associated with less toxicity. Intensity modulated radiation therapy (IMRT) is currently under investigation as a novel approach in preventing xerostomia. At the time of treatment planning, the radiation oncologist uses an inverse-planning algorithm that allows selective avoidance of critical normal tissues without compromising the tumor doses. Other potential uses for IMRT include the ability to administer biologically higher doses to target tissues and biologically lower doses to nontarget tissues and thus increase the therapeutic ratio. Several planning systems and systems of delivery are currently available or are in the testing phases. The initial reports are encouraging. As a consequence of oral pain and altered diet during treatment and xerostomia following treatment, the oral flora and pH can be altered significantly. Without meticulous dental care during and after radiation therapy, patients are prone to accelerated caries and decay. Oral and gingival tissue may atrophy following radiation, which results in a thin pale layer with evidence of telangiectatic vessels. Ulceration and bone exposure can occur. If serious injury to the underlying bone occurs, osteoradionecrosis may follow. Fortunately, this complication is uncommon. When it does occur, management of the condition may be difficult. While patience is important, some cases require intervention, which includes the use of antibiotics, hyperbaric oxygen treatment, and resection. Radiation to the spinal cord may result in a self-limited transverse myelitis, known as Lhermitte syndrome. The patient notes an electric shocklike sensation that is most notable with neck flexion. Rarely does this condition progress to a true transverse myelitis with associated Brown-S�quard syndrome. The dose to the spinal cord must be limited so as to avoid this devastating complication. A course of treatment often affects the thyroid gland either directly or secondarily via the hypothalamic-pituitary axis. Chemical hypothyroidism is often the only manifestation of an endocrinopathy and is treated readily with supplemental thyroid preparation. Other endocrinopathies are uncommon. Other structures that must be considered during the treatment planning are the visual apparatus, the auditory apparatus, and the apex of the lungs. Exceeding the tolerance of the lacrimal gland can result in dry-eye syndrome. The lens is highly sensitive to radiation. Direct irradiation of the lens with the most commonly used therapeutic doses results in cataract formation. Tolerance of the retina and optic nerve must also be respected during the treatment planning to avoid visual loss. Radiation to the auditory apparatus may result in serous otitis or possible sensorineural hearing loss at high doses of irradiation. Radiation-induced cancers are fortunately quite uncommon following therapeutic doses of radiation. A much greater risk of second malignancy is due to the same etiologic and genetic mechanisms that are responsible for the primary tumor.

25. 25 Multiple Fractions Per Day Treatment prolongation advantages spare early reactions and allow reoxygenation in tumors disadvantages early reactions decrease, but no sparing of late injury allows for surviving tumor cells to proliferate during treatment Multiple fractions per day minimizes treatment prolongation (treatment to be completed as soon as practical) Two distinctly different multiple-fraction/day strategies: hyperfractionation accelerated treatment

26. 26 Hyperfractionation Intent is to further reduce late effects with equivalent tumor control (increases early effects) Overall treatment time remains conventional at 6 to 8 weeks but since two fractions are given daily, the total number of fractions is doubled (60-80) Further fractionation works as long as dose fraction is on curved portion of survival curve �flexure dose� (~ 0.1 a/b) is where significant bending starts

27. 27 Accelerated Treatment Intent is to reduce re-population in rapidly proliferating tumors Indicated when patients have fast growing tumors Involves a conventional total dose with a conventional fraction number but since two fractions a day are given, the overall time is nearly halved little or no change in late effects since number of fractions and dose/fraction are unaltered early response becomes limiting may need rest period during treatment

28. 28 Fractionation Regimes Must ensure that the two fractions are separated by adequate time for repair of sublethal damage Current convention dictates that the period between doses should be at least 6 hours There is a trade-off between relative benefits of: hyperfractionation to reduce late-effects accelerated treatment to improve tumor control

29. 29 Tpot and Accelerated Treatment Fast (Tpot < 4 days) and slow (Tpot > 4 days) growing tumors For slow growing tumors, no apparent difference between results of conventional and accelerated treatments For fast growing tumors, accelerated treatment results in substantially better local control comparable to those obtained for slow-growing tumors

30. 30 Effective Doses in Radiotherapy A linear-quadratic response assumption can be made in order to calculate the biological effectiveness of various radiotherapy protocols

31. 31 Calculating Equivalent Doses Bioeffect for a single acute dose, D: Bioeffect for n fractions of dose, d (D=dn):

32. 32 Calculating Effective Doses Biologically effective dose = E/a Relative effectiveness = 1 + d/[a/b] Late-responding tissues, a/b ~ 3 Gy Early-responding tissues, a/b ~ 10 Gy Equivalency should not be compared between early and late effects �Calculations � are not to be considered a substitute for clinical judgement and experience�

33. 33 Example Conventional Treatment n = 30; d = 2 Gy (5 d/wk); t = 6 wks E/a = 60 (1 + [2/10]) = 72 Gy10 E/a = 60 (1 + [2/3]) = 100 Gy3 Values are �equivalent doses� for early (10) or late (3) response Values are not �true� Gray

34. 34 Example Hyperfractionation n = 70; d = 1.15 Gy (twice daily; 5 d/wk) E/a = 80.5 (1 + [1.15/10]) = 89.8 Gy10 E/a = 80.5 (1 + [1.15/3]) = 111.4 Gy3 Biologically effective doses are higher than conventional method Thus, a more �effective� treatment schedule (early and late effects more pronounced)

35. 35 Tumor Proliferation Corrections for tumor growth during treatment schedule Growth of clonogens is exponential: And the rate constant is related to the tumor potential doubling time:

36. 36 Tumor Proliferation Factor Thus, the proliferation factor is derived as: a ~ 0.3 (initial slope of survival curve) Tpot ~ 5 days (median) t ~ 39 days (length of scheduled treatment) Thus, proliferation may reduce the biologically effective dose by 18 Gy10 (early effect!)