Radiation Therapy Use of radiation to kill diseased cells. Cancer is the disease that is almost always treated when using radiation. ? One person in three will develop some form of cancer in their lifetime. ? One person in five will die from that cancer. ? Cancer is the second leading cause of death but exceeds all other diseases in terms of years of working-life lost. Diagrammatic representation of a slice through a large solid tumor. Image removed. From Webster’s Medical Dictionary: 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). 1 Unlimited Growth: ? Cancer cells multiply in an unregulated manner independent of normal control mechanisms. ? Formation of a solid mass in organs. ? Multiplication of bone marrow stem cells gives rise to leukemia, a cancer of the blood. Image removed. Solid tumors: ? Primary tumor may be present in the body for months or years before clinical symptoms develop. ? Some 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---brain tumors are the exception. Metastases: ? The spread of tumor cells from one part of the body to another, usually by the blood or lymph systems. ? Metastases are more usually the cause of death. ? Metastases are especially common in the bone marrow, liver, lungs and brain. 2 Cancer Treatment Modalities Surgery ? Very important. ? For some tumors, surgery is the only or greatest chance for a complete cure o 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. Chemotherapy ? Drugs carried throughout the body (not like surgery or radiation, which are usually local). ? The only effective way, so far, for treatment of widespread, multiple metastases. ? Most successful against leukemias. ? Limited effectiveness against primary tumors or tumors 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. 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. Immunotherapy and Radioimmunotherapy ? Methods of stimulating the immune system are being investigated. ? Still experimental, not in clinical practice. Radiation ? 50% of all cancer patients in the U.S. receive radiation therapy. 50% 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. Stats: 40% of all cancer patients “cured” by surgery, chemo, and radiation in various combinations. “Cure” usually means 5 year survival. Surgery and radiation used with curative intent vs primary. ? Palliation: non-curative intent for more advanced disease. 3 The problem: ? Destroy the tumor with minimal damage to the normal tissues. ? However, normal tissues and tumor can have the same radiosensitivity. X-ray dose-response curves of normal (N12) and transformed (T7) Chinese hamster cells Image removed. Fractionation ? Standard radiotherapy is “fractionated” (usually five days a week for ~ 6 weeks). ? Fractionated radiotherapy relies on biological effects to obtain more cell kill in the tumor than in the surrounding normal tissue. The 4 R’s of fractionated radiation therapy ? Repair ? Reoxygenation ? Redistribution ? Repopulation 4 Standard Radiation Therapy Low-LET, electrons or photons, 5-25 MeV 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. Image removed. Image removed. 1) Repair of DNA damage Schematic illustration of the effect of fractionated radiotherapy on normal (--) and tumor ( __ ) cell populations. Image removed. Normal tissues repair damage more efficiently than tumors. Fractionation schedules developed empirically. Typical: 1.8-2.0 Gy/day, 5 days/week for 6 weeks. Idealized fractionation experiment. With each fraction, the shoulder or repairable damage is repeated. Multiple small fractions approximate to a continuous low dose rate. Image removed. 5 Normal Tissue Tolerance Image removed. Tolerance of various normal tissues versus total number of fractions (left) or dose per fraction (right). Skin: dry desquamation in humans; bone marrow, intestine, lung: LD 50 in mice. Fractionation spares normal tissues Greater total doses can be delivered if fractionated. Tolerance doses can vary considerable for various normal tissues. Note bone marrow: very little sparing with fractionation. Bone marrow stem cells radiosensitive, little or no shoulder on survival curve means no repair. 6 2) Reoxygenation Oxygen must diffuse from the capillary. Image removed. Fig. 6.8 in Hall, Eric J. Radiobiology for the Radiologist, 5 th ed. Philadephia PA: Lippincott Williams & Wilkins, 2000. Diffusion limit ~ 70 μm. Hypoxic cells may limit the radiocurability of the tumor. Image removed. Fig. 6.9 in [Hall]. Tumor blood supply is dynamic. Vessels may open and close periodically, affecting the oxygen distribution Low-LET radiation is more effective at killing well-oxygenated cells: “Direct vs indirect” effect Percent of hypoxic cells in a transplanted mouse tumor after a single dose of 10 Gy X rays. Reoxygenation is rapid in this tumor. Image removed. Fig. 6.13 in [Hall]. 7 Image removed. Fig. 6.12 in [Hall]. Tumors “outgrow” their blood supply. Large tumors develop hypoxic/necrotic centers. Fractionation, given at the proper intervals to allow reoxygenation will continue to kill the reoxygenated fraction of cells. 3) Redistribution ? Radiation will kill cells in the more sensitive phases of the cell cycle. ? Radiation will also cause a G 2 /M delay or block. ? Cells become partially synchronized after a dose of radiation. ? As these cells enter the more sensitive stages of the cell cycle together, the next fraction can kill more cells as the Survivors of the initial dose are primarily in the radioresistant S phase. Six hours later this population of cells is in the radiosensitive G 2 M phase. Image removed. Fig. 5.4 in [Hall]. This split-dose experiment illustrates three of the 4 “R’s” of radiobiology. 1) Prompt repair of sublethal damage within 2 hours. 2) Progression and redistribution of partially synchronized surviving cells through the cell cycle. 3) Increase in surviving population resulting from cell division (repopulation) if the interval between fractions is > the cell cycle time. 8 4) Repopulation ? Radiation can stimulate cell division in both tumor and normal tissues. ? Normal tissues have control mechanisms in place and will benefit from the repopulation. Tumor cells may show accelerated repopulation during treatment. Surviving tumor cells divide faster as overall tumor volume decreases. Image removed. Fig. 22.8 in [Hall]. ? Situation is more complicated during fractionated radiation therapy. ? Extra dose per fraction, or more fractions, may be needed to counteract tumor accelerated repopulation. ? Fractionation schedules may not be optimal from the radiation biology point of view: e.g., 1 fraction/day, 5 days/week, for 6 weeks. ? Experimental fractionation schedules (3 fractions/day, 12 days in a row) show improved tumor control with the same or less normal tissue complications. 9 Normal tissue complication probability (NTCP) Tumor control probability (TCP) 10% NTCP is often considered the maximum allowable. Image removed. Fractionated RT spares normal tissues because of repair and repopulation, but increases tumor damage because of reoxygenation and redistribution. Radioresistant tumors: the 2 curves may be very close together. Tumor response is a function of total treatment time and total dose. Image removed. 10 Other Radiation Therapy modalities Brachytherapy: implant radioactive “seeds”, or insert radioactive needles. BNCT Particles Advantages of high-LET radiation ? Less, or no, oxygen effect ? Bragg Peak allows better dose localization Images removed. Protons Image removed. Fig. 6-11 in Turner J. E. Atoms, Radiation, and Radiation Protection, 2 nd ed. New York: Wiley-Interscience, 1995. Dose localization Normal tissue sparing SOBP: spread out Bragg Peak Images removed. 11 Protons Image removed. Stereotactic Radiosurgery: Uses accelerator Gamma Knife: Uses fixed Co-60 sources Image removed. 12 ? Protons are by far the most extensively used particle therapy. ? Heavier ions: carbon, neon, ? Clinical results not yet dramatic enough to justify the considerable cost of the accelerator required. 13