Radiation Therapy
Content
Uses of Radiation: Radiation Therapy Introduction
1. Introduction Since we know radiation can kill cells, both functionally and reproductively, we can use radiation to kill disease. Cancer is the disease that is almost always treated when using radiation. When using radiation to treat cancer we are attempting to cause reproductive cell death, not functional cell death. 2. Cancer 2.1 Overview and Definitions • One person in three will get cancer. • One person in five will die from cancer. • Cancer is the second leading cause of death but exceeds all other diseases in terms of years of working-life lost. • What is cancer? Superficially, cancer seems to be a range of diseases rather than a single entity: after all, tumors arise at different sites, grow at different rates and may be benign or lethal. But such a wide range of clinical manifestations conceals the fact that all tumor cells show the same fundamental defect: an abnormal response to the physiological mechanisms that regulate cell multiplications. Webster’s Medical Dictionary defines cancer as: Cancer – A malignant tumor of potentially unlimited growth that expands locally by invasion and sytemically by metastasis. Tumor – an abnormal mass of tissues that arises from cells of pre-existent tissue, and serves no useful purpose. Malignant – dangerous and likely to be fatal (as opposed to “benign,” which refers to a non-dangerous growth). Unlimited Growth – cancer cells do not exhibit the regulating mechanism called “contact inhibition,” a mechanism through which cells detect their neighbors and stop dividing when a certain density is reached. Thus cancer cells multiply in an unregulated manner independent of normal control mechanisms. If this occurs in an organ such as the liver, kidney, lung or brain then a solid mass results while uncontrolled multiplication of bone marrow stem cells gives rise to leukemia in which the malignant progeny are detectable in the blood.
Figure 1. Diagrammatic representation of a slice through a large solid tumor.
Solid tumors may be present in the body for months or years before clinical symptoms develop. Tumors can be managed and the patient often cured provided there has been no significant invasion of vital organs. Patients do not often die of primary tumors. Metastases – the more usual causes of death are the effects of metastasis which refers to the spread of tumor cells from one part of the body to another, usually by the blood or lymph systems (see figure). Metastases are especially common in the bone marrow, liver, lungs and brain.
Figure 2. The early development and metastatic spread of a tumor.
2.2 Cancer Treatment Modalities A. Surgery B. Chemotherapy (cell-destroying drugs) C. Hyperthermia (application of heat) D. Immunotherapy (mobilization of the body’s natural resistance to foreign cells). This is not clinically practiced. E. Radiation • Of all the patients seen each year with invasive cancer, 40% are cured by surgery, radiation therapy, chemotherapy or some combination of the above. “Cure” usually is defined as disease free for five years.
• •
Radiotherapy and surgery are methods used to eliminate primary tumor or perhaps a well-defined secondary. The aim of eliminating a tumor entirely is called the “radical” approach. If cancer is more advanced, an alternative aim is to prevent pain and other symptoms and to delay the growth of the tumor and its secondary spread (metastasis), sometimes for many years. This approach is called “palliative.”
A. Surgery • Very important. • For some tumors, surgery is the only or greatest chance for a complete cure - colorectal, - small and large bowel cancer, - some lung, ovarian, thyroid, testicular, stomach and uterine cancers. • Often chemotherapy or radiation therapies are used to augment surgery. B. Chemotherapy • Drugs carried throughout the body (not like surgery or radiation, which are usually local). • The only effective way, so far, of dealing with widespread, multiple metastases. • Very successful against cancer of the blood-forming organs such as leukemias. • Not very good at eliminating primary tumors or other solid lumps of malignancies greater than a few millimeters in diameter. • About 30 chemotherapeutic drugs are in regular use in the treatment of cancer (but over 800,000 compounds have been tested). • Usually used in combination with other treatment methods. C. Hyperthermia • Long reported that tumors stop growing during a fever bout. • Not well studied; conflicting results. • Difficult to quantitatively measure heat delivery and absorption, etc. • Used in combination with other modalities. D. Immunotherapy • The immune system is felt to be important in preventing the development of cancer through immune surveillance and may also help to eliminate established disease. Therefore, methods of stimulating the immune system are being investigated. • Not in clinical practice. E. Radiation • One half of all cancer patients in the U.S. receive radiation therapy at some point during the course of disease. One half of these patients are potentially curable. (The rest receive radiation either as adjuvant or palliative treatment.) • Any improvements to radiotherapy, even small improvements, will benefit a great many people.
3. Standard Radiotherapy Radiotherapy is typically carried out in the radiation oncology unit of a hospital using photons or electrons from a linear accelerator (shown below). A linear accelerator (linac) generates high energy electrons and photons (typically 5-25 MeV). They have gradually replaced units using the isotope 60Co which emits photons of just over 1 MeV.
Figure 3. A radiotherapy linear accelerator. The linac is isocentrically mounted so that when the tumor is placed at the axis of the treatment arm, the beam will be directed at the tumor from all angles.
Standard radiotherapy is “fractionated”. That is, therapy is carried out, five days a week for about 5-7 weeks. [The patient attends the hospital for about one hour, each visit.]
Why Fractionate? Answer: “The 4-R’s of Radiotherapy”. The problem, as illustrated in the first figure below, is that there is no intrinsic difference in the radiosensitivity of normal cells and tumor cells. The four "R's" attempt to exploit some of the differences in the "living conditions" of tumors and healthy tissues.
Figure 4. X-ray dose -response curves of normal (N12) and transformed (T7) Chinese hamster cells
Figure 5. Growth curve for RF-1 tumors implanted into unirradiated tumor beds (circles) or into irradiated (20 Gy) beds (squares).
(i) Repair of DNA damage It is assumed that tumor cells are less able to repair DNA damage.
Although this is not true in vitro (tumor cells and normal cells grown in culture dishes have the same repair capability as shown in the plot above), tumor cells are often oxygen and nutrient deficient.
Figure 6. Schematic illustration of the effect of fractionated radiotherapy on normal (--) and tumor ( __ ) cell populations.
(ii) Reoxygenation The proliferative cells of a tumor, unrestrained as they are by any homeostatic control, divide and proliferate as rapidly as they are able to, limited only by their own inherited characteristics and the availability of an adequate supply of nutrients. Since a tumor is not an organized tissue, it tends to outgrow its own blood supply. Areas of necrosis often develop and are frequently accompanied by hypoxic cells, which often constitute about 15% of the total viable cells. As the tumor outgrows its vascular system, rapid cell proliferation near capillaries will push other cells into regions remote from a blood supply, where there is an inadequate concentration of oxygen and other nutrients. These cells will die, giving rise to a progressively enlarging necrotic zone. Another manifestation of the overstretched vascular supply is that only a portion of the viable cells are actually proceeding through the cell cycle and multiplying. Figure 7.
A single large dose of radiation to a tumor area will tend to kill off the healthy, oxygenated tumor cells, but may not affect the hypoxic cells. The death of the wellvascularized cells will make more room for the surviving hypoxic cells, and these will now get a good supply of oxygen. The initial large dose of radiation will not kill the tumor.
Figure 8. The percentage of hypoxic cells in a transplantable mouse sarcoma as a function of time after a dose of 1000 rad (10 Gy) of x-rays. Immediately after irradiation, essentially 100% of the viable cells are hypoxic because a dose of 1000 rad (10 Gy) kills a large proportion of the aerated
cells. In this tumor the process of reoxygenation is very rapid. By 6 hours, the percentage of hypoxic cells has fallen to a value close to the pre-irradiation level.
Figure 9. The process of reoxygenation. Tumors contain a mixture of aerated and hypoxic cells. A dose of x-rays kills a greater proportion of aerated than hypoxic cells because they are more radiosensitive. Immediately after irradiation, most cells in the tumor are hypoxic. But the preirradiation pattern tends to return because of reoxygenation. If the radiation is given in a series of fractions separated in time sufficiently for reoxygenation to occur, the presence of hypoxic cells does not greatly influence the response of the tumor.
Why are hypoxic ells less sensitive to radiation-induced damage than oxygenated cells? The answer seems to be that oxygen acts at the level of free radicals. Recall from the lecture dealing with biological effects of radiation, that the “indirect” effect of radiation is a result of water radioloysis. That is, when ionizing radiation ionizes/excites water molecules, we get the creation of free radicals. [Free radicals are atoms/molecules with an unpaired electron. Radicals are indicated with a “dot” beside the symbol for the species. For example, Hx is a hydrogen free radical, OHx is a hydroxy free radical. Both are produced when ionizing radiation interacts with water. Radicals are quite reactive as they are attempting to form a covalent bond with another species. That is, they can break an existing bond within another molecule. For example: RH + OHx Æ Rx + H2O Here we have let R symbolize any organic molecule in the cell.] If oxygen is present it can interact with the organic free radical that was created in the exampl,e above: Rx + O2 Æ RO2x RO2x is a non-restorable change in R.
Figure 10. Schematic illustration of the “oxygen fixation theory” of oxygen sensitivity occurring following a photon interaction in water.
If oxygen is not present, restoration of the original molecule is possible by grabbing a hydrogen from another molecule (eg water). Rx Æ RH R O2x is a non-restorable change in R.
Thus oxygen sensitizes the cells by “fixing” in place the radiation damage. (iii) Redistribution Recall the 4 phases of the cell cycle: M, G1, S, G2.
Cells are more sensitive to radiation during some phases of their cycle than others.
Figure 11. Cell survival curves for Chinese hamster cells at various stages of the cell cycle. The survival curve for cells in mitosis is steep and has no shoulder. The curve for cells late in S phase is shallower and has a large initial shoulder. G1 and early S phases are intermediate in sensitivity. The broken line is a calculated curve expected to apply to mitotic cells under hypoxia.
A radiation fraction will kill mainly the more sensitive cells. The remaining cells will be somewhat “synchronized” (i.e. all at the same part of the cycle). Then, at a later time these synchronized cells will move into a more sensitive phase and this is the time to deliver the next fraction of radiation. (iv) Repopulation Radiation will often stimulate cell division. In normal tissues this is kept under control by normal homeostatic mechanizing but this is not true for tumors. Thus we need to deliver another dose to counteract the repopulation.
Using the 4 R’s, fractionated radiotherapy attempts to rely on biological effects to get more cell kill in the tumor than in the surrounding tissue.
How large is the difference in radiation response between normal and tumor tissues? Not large. Usually tumor "cure" can't occur without also causing damage to normal tissues
Figure 12. Theoretical dose-effect relationships for the percentage of local control of one particular type of tumor and the appearance of complications in the irradiated normal tissues. a) tumor of average radiosensitivity; (b) a more radioresistant tumor than (a), cure without complication is possible only for a small proportion of tumors. At A, cure without complication; B, the optimal dose; C, cure of all tumors but with a high proportion of complications. TCD50 is the dose to cure 50 % of the tumors, DC50 is the dose resulting in a complication in 50% of the patients.
Figure 13.
Radiation therapy can be performed in ways other than using a linac or 60Co source. These ways all attempt to improve the radio of tumor to healthy tissue dose. 3.1 Brachytherapy Based on the Greek word for ‘short distances’, brachytherapy is the use of radioactive seeds or needles placed directly inside the tumor or inside a cavity. [Contrast this to standard radiotherapy which is called ‘teletherapy’, ie irradiation over a distance.] Examples include: 192-Iridium with a half-life of 74 days and photons of 130-1060 keV. 125-Iodine with a half-life of 60 days and photons of 27-36 keV 103-Palladium with a half-life of 17 days and photons of 20-23 keV
3. Non-Standard Radiotherapy
Historically, 226-Radium was used (half-life of 1600 years).
Figure 14. Examples of radioactive seeds/wires in applicators designed for treatment of tumors in various anatomical regions via the brachytherapy approach.
3.2 Use of Heavy Charged Particles (e.g. Proton Therapy)
Recall that the dose versus depth curve for heavy charged particles in tissue (water) shows a sharp peak (the Bragg peak) at the end of its range. Note also the very abrupt end to dose delivery due to the particle’s finite range.
Figure 15. Dose versus distance in water for a heavy particle beam.
The primary rationale for proton therapy is the idea of superimposing this peak on the tumor. Thus tumor-to-healthy-tissue dose ratio will be large. In reality the Bragg peak is spread out a bit because of the size of the tumor.
Figure 16. Spread out Bragg peak using either a variable filter in front of the patient, or a variable energy beam.
Figure 17. With particles heavier than protons the Bragg peak gets narrower and the dose drop-off at the end of the range even steeper.
One of the major drawbacks of heavy particle therapy is the high cost of the accelerators used to generate the heavy particle beams. The heavier the particle, the more expensive the accelerator since more energy is needed to make the particles penetrate to depth in the body. To date, the cyclotron at Harvard University has performed the most heavy ion therapies. Over 8000 proton therapy treatments had been performed by July 1999 (see below). This, however is a physics machine with no rotating gantry and with a fixed energy. The Loma Linda facility is the only dedicated proton therapy facility in the world. The second will begin treating patients soon – this one is a Massachusetts General Hospital right next to the Charles T stop. The tables below show the facilities in the world involved in treating patients with heavy particles (proton, pi-mesons (pions), and heavier ions), as well as new facilities planned or under construction.
3.4
Boron Neutron Capture Therapy
BNCT offers a means of treating individual tumor cells, possibly cells unconnected with a main tumor mass. BNCT is a binary therapy involving a boron-10-labeled drug (which is tumor seeking) followed by irradiation with a beam of low-energy neutrons. The reaction we get is:
10
B + n → (11B)* → 4He + 7Li* Q = 2.7 MeV
The alpha and lithium particles have high LET and high RBE. If the boron went to tumor cells only, then we have very tumor-cell-specific cell death. The neutron capture cross-section of 10B is highest at thermal energies. The cross-section shows a 1/v behaviour with energy, thus we get the most capture reactions if thermal neutrons interact with the tumor. Need: 1. a boron-labeled pharmaceutical that is taken up only by, or retained only by, tumor cells. [This is difficult.] 2. a low energy neutron source. So far reactors are the only neutron sources used. Accelerator sources are under development. The goal is to use neutrons with energies somewhat higher than thermal. Then we rely on the hydrogen in the tissue that overlies the tumor to ‘moderate’ the neutron energies down to the thermal energy range. So, we start with an ‘epithermal’ neutron beam. FDA-approved clinical trials using epithermal neutron beams have been conducted at the MIT Reactor and at Brookhaven National Lab. Trials recently began in Europe as well.
1. Introduction Since we know radiation can kill cells, both functionally and reproductively, we can use radiation to kill disease. Cancer is the disease that is almost always treated when using radiation. When using radiation to treat cancer we are attempting to cause reproductive cell death, not functional cell death. 2. Cancer 2.1 Overview and Definitions • One person in three will get cancer. • One person in five will die from cancer. • Cancer is the second leading cause of death but exceeds all other diseases in terms of years of working-life lost. • What is cancer? Superficially, cancer seems to be a range of diseases rather than a single entity: after all, tumors arise at different sites, grow at different rates and may be benign or lethal. But such a wide range of clinical manifestations conceals the fact that all tumor cells show the same fundamental defect: an abnormal response to the physiological mechanisms that regulate cell multiplications. Webster’s Medical Dictionary defines cancer as: Cancer – A malignant tumor of potentially unlimited growth that expands locally by invasion and sytemically by metastasis. Tumor – an abnormal mass of tissues that arises from cells of pre-existent tissue, and serves no useful purpose. Malignant – dangerous and likely to be fatal (as opposed to “benign,” which refers to a non-dangerous growth). Unlimited Growth – cancer cells do not exhibit the regulating mechanism called “contact inhibition,” a mechanism through which cells detect their neighbors and stop dividing when a certain density is reached. Thus cancer cells multiply in an unregulated manner independent of normal control mechanisms. If this occurs in an organ such as the liver, kidney, lung or brain then a solid mass results while uncontrolled multiplication of bone marrow stem cells gives rise to leukemia in which the malignant progeny are detectable in the blood.
Figure 1. Diagrammatic representation of a slice through a large solid tumor.
Solid tumors may be present in the body for months or years before clinical symptoms develop. Tumors can be managed and the patient often cured provided there has been no significant invasion of vital organs. Patients do not often die of primary tumors. Metastases – the more usual causes of death are the effects of metastasis which refers to the spread of tumor cells from one part of the body to another, usually by the blood or lymph systems (see figure). Metastases are especially common in the bone marrow, liver, lungs and brain.
Figure 2. The early development and metastatic spread of a tumor.
2.2 Cancer Treatment Modalities A. Surgery B. Chemotherapy (cell-destroying drugs) C. Hyperthermia (application of heat) D. Immunotherapy (mobilization of the body’s natural resistance to foreign cells). This is not clinically practiced. E. Radiation • Of all the patients seen each year with invasive cancer, 40% are cured by surgery, radiation therapy, chemotherapy or some combination of the above. “Cure” usually is defined as disease free for five years.
• •
Radiotherapy and surgery are methods used to eliminate primary tumor or perhaps a well-defined secondary. The aim of eliminating a tumor entirely is called the “radical” approach. If cancer is more advanced, an alternative aim is to prevent pain and other symptoms and to delay the growth of the tumor and its secondary spread (metastasis), sometimes for many years. This approach is called “palliative.”
A. Surgery • Very important. • For some tumors, surgery is the only or greatest chance for a complete cure - colorectal, - small and large bowel cancer, - some lung, ovarian, thyroid, testicular, stomach and uterine cancers. • Often chemotherapy or radiation therapies are used to augment surgery. B. Chemotherapy • Drugs carried throughout the body (not like surgery or radiation, which are usually local). • The only effective way, so far, of dealing with widespread, multiple metastases. • Very successful against cancer of the blood-forming organs such as leukemias. • Not very good at eliminating primary tumors or other solid lumps of malignancies greater than a few millimeters in diameter. • About 30 chemotherapeutic drugs are in regular use in the treatment of cancer (but over 800,000 compounds have been tested). • Usually used in combination with other treatment methods. C. Hyperthermia • Long reported that tumors stop growing during a fever bout. • Not well studied; conflicting results. • Difficult to quantitatively measure heat delivery and absorption, etc. • Used in combination with other modalities. D. Immunotherapy • The immune system is felt to be important in preventing the development of cancer through immune surveillance and may also help to eliminate established disease. Therefore, methods of stimulating the immune system are being investigated. • Not in clinical practice. E. Radiation • One half of all cancer patients in the U.S. receive radiation therapy at some point during the course of disease. One half of these patients are potentially curable. (The rest receive radiation either as adjuvant or palliative treatment.) • Any improvements to radiotherapy, even small improvements, will benefit a great many people.
3. Standard Radiotherapy Radiotherapy is typically carried out in the radiation oncology unit of a hospital using photons or electrons from a linear accelerator (shown below). A linear accelerator (linac) generates high energy electrons and photons (typically 5-25 MeV). They have gradually replaced units using the isotope 60Co which emits photons of just over 1 MeV.
Figure 3. A radiotherapy linear accelerator. The linac is isocentrically mounted so that when the tumor is placed at the axis of the treatment arm, the beam will be directed at the tumor from all angles.
Standard radiotherapy is “fractionated”. That is, therapy is carried out, five days a week for about 5-7 weeks. [The patient attends the hospital for about one hour, each visit.]
Why Fractionate? Answer: “The 4-R’s of Radiotherapy”. The problem, as illustrated in the first figure below, is that there is no intrinsic difference in the radiosensitivity of normal cells and tumor cells. The four "R's" attempt to exploit some of the differences in the "living conditions" of tumors and healthy tissues.
Figure 4. X-ray dose -response curves of normal (N12) and transformed (T7) Chinese hamster cells
Figure 5. Growth curve for RF-1 tumors implanted into unirradiated tumor beds (circles) or into irradiated (20 Gy) beds (squares).
(i) Repair of DNA damage It is assumed that tumor cells are less able to repair DNA damage.
Although this is not true in vitro (tumor cells and normal cells grown in culture dishes have the same repair capability as shown in the plot above), tumor cells are often oxygen and nutrient deficient.
Figure 6. Schematic illustration of the effect of fractionated radiotherapy on normal (--) and tumor ( __ ) cell populations.
(ii) Reoxygenation The proliferative cells of a tumor, unrestrained as they are by any homeostatic control, divide and proliferate as rapidly as they are able to, limited only by their own inherited characteristics and the availability of an adequate supply of nutrients. Since a tumor is not an organized tissue, it tends to outgrow its own blood supply. Areas of necrosis often develop and are frequently accompanied by hypoxic cells, which often constitute about 15% of the total viable cells. As the tumor outgrows its vascular system, rapid cell proliferation near capillaries will push other cells into regions remote from a blood supply, where there is an inadequate concentration of oxygen and other nutrients. These cells will die, giving rise to a progressively enlarging necrotic zone. Another manifestation of the overstretched vascular supply is that only a portion of the viable cells are actually proceeding through the cell cycle and multiplying. Figure 7.
A single large dose of radiation to a tumor area will tend to kill off the healthy, oxygenated tumor cells, but may not affect the hypoxic cells. The death of the wellvascularized cells will make more room for the surviving hypoxic cells, and these will now get a good supply of oxygen. The initial large dose of radiation will not kill the tumor.
Figure 8. The percentage of hypoxic cells in a transplantable mouse sarcoma as a function of time after a dose of 1000 rad (10 Gy) of x-rays. Immediately after irradiation, essentially 100% of the viable cells are hypoxic because a dose of 1000 rad (10 Gy) kills a large proportion of the aerated
cells. In this tumor the process of reoxygenation is very rapid. By 6 hours, the percentage of hypoxic cells has fallen to a value close to the pre-irradiation level.
Figure 9. The process of reoxygenation. Tumors contain a mixture of aerated and hypoxic cells. A dose of x-rays kills a greater proportion of aerated than hypoxic cells because they are more radiosensitive. Immediately after irradiation, most cells in the tumor are hypoxic. But the preirradiation pattern tends to return because of reoxygenation. If the radiation is given in a series of fractions separated in time sufficiently for reoxygenation to occur, the presence of hypoxic cells does not greatly influence the response of the tumor.
Why are hypoxic ells less sensitive to radiation-induced damage than oxygenated cells? The answer seems to be that oxygen acts at the level of free radicals. Recall from the lecture dealing with biological effects of radiation, that the “indirect” effect of radiation is a result of water radioloysis. That is, when ionizing radiation ionizes/excites water molecules, we get the creation of free radicals. [Free radicals are atoms/molecules with an unpaired electron. Radicals are indicated with a “dot” beside the symbol for the species. For example, Hx is a hydrogen free radical, OHx is a hydroxy free radical. Both are produced when ionizing radiation interacts with water. Radicals are quite reactive as they are attempting to form a covalent bond with another species. That is, they can break an existing bond within another molecule. For example: RH + OHx Æ Rx + H2O Here we have let R symbolize any organic molecule in the cell.] If oxygen is present it can interact with the organic free radical that was created in the exampl,e above: Rx + O2 Æ RO2x RO2x is a non-restorable change in R.
Figure 10. Schematic illustration of the “oxygen fixation theory” of oxygen sensitivity occurring following a photon interaction in water.
If oxygen is not present, restoration of the original molecule is possible by grabbing a hydrogen from another molecule (eg water). Rx Æ RH R O2x is a non-restorable change in R.
Thus oxygen sensitizes the cells by “fixing” in place the radiation damage. (iii) Redistribution Recall the 4 phases of the cell cycle: M, G1, S, G2.
Cells are more sensitive to radiation during some phases of their cycle than others.
Figure 11. Cell survival curves for Chinese hamster cells at various stages of the cell cycle. The survival curve for cells in mitosis is steep and has no shoulder. The curve for cells late in S phase is shallower and has a large initial shoulder. G1 and early S phases are intermediate in sensitivity. The broken line is a calculated curve expected to apply to mitotic cells under hypoxia.
A radiation fraction will kill mainly the more sensitive cells. The remaining cells will be somewhat “synchronized” (i.e. all at the same part of the cycle). Then, at a later time these synchronized cells will move into a more sensitive phase and this is the time to deliver the next fraction of radiation. (iv) Repopulation Radiation will often stimulate cell division. In normal tissues this is kept under control by normal homeostatic mechanizing but this is not true for tumors. Thus we need to deliver another dose to counteract the repopulation.
Using the 4 R’s, fractionated radiotherapy attempts to rely on biological effects to get more cell kill in the tumor than in the surrounding tissue.
How large is the difference in radiation response between normal and tumor tissues? Not large. Usually tumor "cure" can't occur without also causing damage to normal tissues
Figure 12. Theoretical dose-effect relationships for the percentage of local control of one particular type of tumor and the appearance of complications in the irradiated normal tissues. a) tumor of average radiosensitivity; (b) a more radioresistant tumor than (a), cure without complication is possible only for a small proportion of tumors. At A, cure without complication; B, the optimal dose; C, cure of all tumors but with a high proportion of complications. TCD50 is the dose to cure 50 % of the tumors, DC50 is the dose resulting in a complication in 50% of the patients.
Figure 13.
Radiation therapy can be performed in ways other than using a linac or 60Co source. These ways all attempt to improve the radio of tumor to healthy tissue dose. 3.1 Brachytherapy Based on the Greek word for ‘short distances’, brachytherapy is the use of radioactive seeds or needles placed directly inside the tumor or inside a cavity. [Contrast this to standard radiotherapy which is called ‘teletherapy’, ie irradiation over a distance.] Examples include: 192-Iridium with a half-life of 74 days and photons of 130-1060 keV. 125-Iodine with a half-life of 60 days and photons of 27-36 keV 103-Palladium with a half-life of 17 days and photons of 20-23 keV
3. Non-Standard Radiotherapy
Historically, 226-Radium was used (half-life of 1600 years).
Figure 14. Examples of radioactive seeds/wires in applicators designed for treatment of tumors in various anatomical regions via the brachytherapy approach.
3.2 Use of Heavy Charged Particles (e.g. Proton Therapy)
Recall that the dose versus depth curve for heavy charged particles in tissue (water) shows a sharp peak (the Bragg peak) at the end of its range. Note also the very abrupt end to dose delivery due to the particle’s finite range.
Figure 15. Dose versus distance in water for a heavy particle beam.
The primary rationale for proton therapy is the idea of superimposing this peak on the tumor. Thus tumor-to-healthy-tissue dose ratio will be large. In reality the Bragg peak is spread out a bit because of the size of the tumor.
Figure 16. Spread out Bragg peak using either a variable filter in front of the patient, or a variable energy beam.
Figure 17. With particles heavier than protons the Bragg peak gets narrower and the dose drop-off at the end of the range even steeper.
One of the major drawbacks of heavy particle therapy is the high cost of the accelerators used to generate the heavy particle beams. The heavier the particle, the more expensive the accelerator since more energy is needed to make the particles penetrate to depth in the body. To date, the cyclotron at Harvard University has performed the most heavy ion therapies. Over 8000 proton therapy treatments had been performed by July 1999 (see below). This, however is a physics machine with no rotating gantry and with a fixed energy. The Loma Linda facility is the only dedicated proton therapy facility in the world. The second will begin treating patients soon – this one is a Massachusetts General Hospital right next to the Charles T stop. The tables below show the facilities in the world involved in treating patients with heavy particles (proton, pi-mesons (pions), and heavier ions), as well as new facilities planned or under construction.
3.4
Boron Neutron Capture Therapy
BNCT offers a means of treating individual tumor cells, possibly cells unconnected with a main tumor mass. BNCT is a binary therapy involving a boron-10-labeled drug (which is tumor seeking) followed by irradiation with a beam of low-energy neutrons. The reaction we get is:
10
B + n → (11B)* → 4He + 7Li* Q = 2.7 MeV
The alpha and lithium particles have high LET and high RBE. If the boron went to tumor cells only, then we have very tumor-cell-specific cell death. The neutron capture cross-section of 10B is highest at thermal energies. The cross-section shows a 1/v behaviour with energy, thus we get the most capture reactions if thermal neutrons interact with the tumor. Need: 1. a boron-labeled pharmaceutical that is taken up only by, or retained only by, tumor cells. [This is difficult.] 2. a low energy neutron source. So far reactors are the only neutron sources used. Accelerator sources are under development. The goal is to use neutrons with energies somewhat higher than thermal. Then we rely on the hydrogen in the tissue that overlies the tumor to ‘moderate’ the neutron energies down to the thermal energy range. So, we start with an ‘epithermal’ neutron beam. FDA-approved clinical trials using epithermal neutron beams have been conducted at the MIT Reactor and at Brookhaven National Lab. Trials recently began in Europe as well.
