radiaton_therapy

Radiation Therapy

Use of rad i ation to kill diseased cells.

Cancer is t h e disease that is al most always treated when using radiation.

 One person in three will develop som e form of can cer in their lifetime.

 One person in five will die from that can cer.

 Cancer is the second leading cause of d eath but exceeds all other diseases in term s of years of wo rking-life lost.

Diagramm atic representation of a slice through a large solid tum o r.

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Webster’s Medical Dictionary:

Cancer – A malignan t tum o r of potentiall y unlim ite d growth that expands locally by invasion and sytem i cally by met a s t as i s .

Tumor – an abnormal mass of tissues that aris es from cells of pre-existent tissue, and serves no useful purpose.

Malignant – dangerous and li kely to be fatal (as opposed to “benign,” which refers to a non-dangerous growth).

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Unlimit ed Grow th:

 Cancer cel ls m u ltiply in an unregulated manner independent of norm a l control mechanisms .

 Form ation of a solid m a ss in organs.

 Multiplication of bone marrow stem cells gives rise to leukemia, a cancer of the blood.

Solid tum ors:

 Prim a ry tum o r may be present in th e body for m onths or years before clinical sym p to m s d e velop.

 Som e tumors can be managed and the pa tient often cured provi d ed there has been no significant i nvasion of vital organs.

 Patients do not often die of primary tum o rs--- brai n tumors are the exception .

Metastases:

 The spread of tum o r cells from one part of the body to another, usually by the blood or lym ph system s.

 Metast ases are mor e usua lly the cause of death.

 Metastases are especia lly comm on in the bone m a rrow, liver, lungs and brain.

Cancer Treatment Modalities Surgery

 Very im portant.

 For som e tum o rs, surgery is the only or great est chance for a complet e cure

o colorectal, sm all and large bowel ca ncer, some lung, ovarian, thyroi d, testicular, stom ach and uterine cancers.

 Often chem otherapy or radiation ther apies ar e used to augment surgery.

Chemotherapy

 Drugs carried throughout the body (not li ke surgery or radiation, which are usually loc a l).

 The only effective way, so far, for treatment of widespread, multiple metast ases .

 Most successful against leukemias.

 Li mited effectivenes s against primary tu mors or tumors great er than a few m illimeters in diameter.

 About 30 chem otherapeutic drugs are in regular use in the treatm ent of cancer (but over 800, 000 com p ounds have been tested).

 Usually used in combination with other treatment methods.

Hyp erth ermi a

 Long reported that tum o rs stop growing during a fever bout.

 Not well studied; conflicting results.

 Difficult to quantitatively measure h eat delivery and absorption, etc.

 Used in co m b ination with other m odalities.

Immunotherapy and Radioimmunotherapy

 Methods of stim ulating the imm une system are being investi g ated.

 Still experimental, n o t in clinical practice.

Radiation

 50% of all can cer pat i ents in the U.S. receive radiat ion therapy. 50% of these patients are potentially curable. ( T he rest receive radiation either as adjuvant or palliative treatment.)

 Any im provem e nts to radiotherapy, even small im provement s, will benefit a great many people.

Stats: 40% of all cancer patients “cured” by surgery, chem o, and radiation in various com b inations. “Cure” usually m e ans 5 year survi v al.

Surgery and radiation used with curative intent vs pri m ary.

 Palliation: non-curative intent for m o re advanced disease.

The problem:

 Destroy the tu m o r with m i nimal damage to the normal tissues.

 However, norm a l tissues and tum o r ca n have the same radiosensitivity.

X- ray dose-response curves of norm a l (N12) and transform e d (T7) Chinese hamster cells

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Fracti on ation

 Standard radiotherapy is “fractionated” (usually five days a week for ~ 6 weeks).

 Fractionated radiotherapy relies on biological effects to obtain m o re cell kill in the tumor than in the surrounding normal tissue.

The 4 R’ s of f r act i onat ed radi ation therap y

 R epair

 R eoxygenation

 R edistribution

 R epopulation

Standard Radiation Therapy

Low-LET, electrons or phot ons, 5-25 MeV

A radiotherapy linear accel erator. The linac is isocentrically m ounted so that when the tum o r is placed at t h e axis of the treatment arm , the beam will be directed at the tu mor from all angles.

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1) Rep a i r of DNA damage

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Schematic illustration of the effect of fractionated radiotherapy on normal (--) and tum o r ( ) cell populations.

Normal tissues repair damage m o re efficiently than tum o rs. Fractionation schedul es developed em pirically.

Typical: 1.8-2.0 Gy/day, 5 days/week for 6 weeks.

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Idealized f r actionati on experimen t. With ea ch fraction, the shoulder or repairable damage is repeated. Multiple small fractions approximate to a continuous low dose rate.

Normal Tissue Tolerance

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Tolerance of various norm a l tissues versus to tal num b er of fractions (left) or dose per fraction (right). Skin: dry desquama tion in hum ans; bone marrow, intestine, lung: LD 50 in mice.

Fractionation spares norm a l tissues

Greater total doses can be delivered if fractionated.

Tolerance doses can vary consi d er able for various norm al tissues.

Note bone m a rrow: very little sparing with fractionation. Bone marrow stem cells radiosensitive, little or no shoulder on survival curve means n o repair.

2) Reoxygenation

Oxygen must diffuse from the capillary.

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Diffusion limit ~ 70 µ m .

Hypoxic cells m a y lim it the radiocurability of the tum o r.

Tum o r blood suppl y is dynam i c.

Vessels may open and close periodically, affecting the oxygen distri buti o n

Low-LET radiation is more eff ective at killing well-oxygenated cells:

“Direct vs indirect” effect

(Right)

Percent of hypoxic cells in a transplant e d mouse tumor after a single dose of 10 Gy X rays.

Reoxygenation is rapid in this tumor.

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Tum o rs “outgrow” their blood supply.

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Large tumors develop hypoxic/necrotic centers.

Fractionation, given at the proper inte rvals to allow reoxygenation will continue to kill the reoxygenated fraction of cells.

3) Redistribution

 Radiation will kill cells in the m o re sensitive phases of the cell cycle.

 Radiation will also cause a G 2 /M delay or block.

 Cells become p a rtially synchroni zed after a dose of radiation.

 As these cells enter the m o re sensitive stages of the cell cycle together, the next fraction can kill m o re cells as the

Survivors of the initi al dose are primarily in the radioresist ant S phase. Six hours l a ter this population of cells is in the radiosensitive G 2 M phase.

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This split-dose experiment illustrates th ree of the 4 “R’s” of radiobiology.

1) Prom p t repair of sublethal damage within 2 hours.

2) Progression and redistribution of part ially synchronized survivi ng cells through the cell cy cle.

3) Increase in surviving population resulti ng from cell divisi on ( repopulation ) if the interval between fractions is > the cell cycle time.

4) Repopulation

 Radiation can sti m ul ate cell di vision in both tum o r and norm a l tissues.

 Normal tis sues have control mechanis ms i n place an d will benefit from t h e repopulati on.

Tum o r cells may show accelerat ed repopulation duri ng treatm e nt. Survi v ing tum o r cells divide faster as overall tumor volume decreas es.

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 Situation is m o re co m p licated durin g fra ctionated radi ation therapy.

 Extra dose per fraction, or m o re frac tions, may be needed to counteract tum o r accelerate d repopulation.

 Fractionation schedul es may not be optim al from the radiation biology poi nt 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 im proved tum o r control with the same or less norm a l tissue co mplicati ons.

Normal tissue co m p lication probability (N TCP) Tu m o r co ntrol probability (TCP)

10% NTCP is often consider ed the maximu m allowable.

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Fractionated RT spares normal tissues because of repair and repopulation , but increases t u mor dam a ge becaus e of reoxygenation a nd redistribution .

Radioresistant tumor s : the 2 cu rves m a y be very close together. Tum o r response is a function of tota l treatment tim e and total dose.

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Other Radiation Therapy modalities

Brachytherapy: i m plant radioactive “seeds”, or insert radioactive needles.

BNCT

Particles

Advantages of high-LET radiation

 Less, or no, oxygen effect

 Bragg Peak allows better dose localizatio n

Protons

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Dose local ization Normal tis sue sparing

SOBP: spread out Br agg Peak

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Protons

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Stereotactic Radiosurgery:

Uses accel erator

Gamma Knife:

Uses fixed Co-60 sources

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 Protons are by far the most extens ively used particle therapy.

 Heavier ions: carbon, neon,

 Clinical results not yet dramatic enough to justify the considerable cost of the accelerator required.