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Page 1: Fractionation in Radiotherapy

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Page 2: Fractionation in Radiotherapy

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Fractionation in Radiotherapy

By: A. Haghbin

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Radiation fractionation as cancer treatment. Fractionation also refers to a method of treating cancer with radiation therapy. When the total dose of radiation is divided into several, smaller doses over a period of several days, there are fewer toxic effects on healthy cells.

“FRACTIONATED” Radiation Therapy

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4 Historical Review

Earlier some radiotherapists believed that fractionated treatment was inferior & single dose was necessary to cure cancer.

While radiobiological experiments conducted in France favored fractionated regimen for radiotherapy which allows cancerocidal dose to be delivered without exceeding normal tissue tolerance.

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5 Radiobiological rationale for Fractionation

The five (historically four) R's of radiobiology are concepts that explain the rationale behind fractionation of radiotherapy.

The 5 R's Of Fractionation:- Repair- Redistribution- Reoxygenation- Repopulation- Radiosensitivity

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6   5th R and LQ model – conventional RT

Linear-Quadratic Model assumes that there are two components to

cell killing by radiation one that is proportional to dose (Linear) one that is proportional to the square of

the dose (Quadratic)

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7 Linear-Quadratic Model

The ‘bendiness’ is determined by α/β ratio

SF = e-(αD+βD2)

S is the fraction of cells surviving a dose (D)

α and β are constants. D is the dose in Gy If at a dose D, αD = βD2 then: D = α/β

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8 5th R and LQ model – conventional RT

The LQ model is simple and convenient

– better fit in the low dose–high survival region

– α (lethal/non-repairable) & β (sub-lethal/reparable)

– α/β ratio for early and late reactions in human normal

tissues consistent with results from experimental models

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9 Repair Repair is the one of the primary reasons to fractionate radiotherapy. As

discussed in DNA Damage and Repair There are three types of damage that ionising radiation can cause to

cells:-Lethal Damage :which is irreversible and irreparable and leads irrevocably to cell death -Potentially Lethal Damage(PLD):The component of radiation damage that can be modified by postirradiation environmental conditions-Sublethal Damage(SLD):which under normal circumstances can be repaired in hours unless additional sublethal damage is added

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10 Repair of Sublethal Damage

Dose rate effect Type radiation Cell in different cell cycle phase Type cell

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11Dose-rate effect

If a radiation dose is delivered in a series of equal fractions, separated by sufficient time for repair of sublethal damage to occur between doses, the effective dose-survival curve becomes an exponential function of dose.

EFFECTIVE SURVIVAL CURVE FOR A MULTIFRACTION REGIMEN

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12 Type radiation

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14 Cell in different cell cycle phase

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15 Type cell Cell survival is a function of cell type and radiation type

Non- or slowly proliferating cells (nerve, muscle, secretory) are less susceptible to radiation damage.

Highly-proliferating cells (epithelial, stem cells) are more susceptible.

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16 Repair and Low Dose Rate treatment

If the dose rate is sufficiently low, repair may be able to take place during radiotherapy treatment. This considerably reduces the cell death due to sublethal damage and is one reason low dose treatments show reduced effectiveness at identical doses to high dose rate treatment.

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17 Repair Half Life

Intefraction interval and the repair half life is an important consideration when fractionating radiotherapy. Some tissues, notably the spinal cord, appear to have a slow repair mechanism with a half life of about 4 hours. It is important to separate dose by at least 6 hours and preferably 8 hours if two fractions are given on the same day.

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18 Redistribution

Cells move to more radiosensitive phase in the cell cycle between fractions.

M and G2 most sensitive phases. Late S most resistant phase

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19Redistribution

Redistribution of proliferating cell populations throughout the cell cycle increases cell kill in fractionated treatment relative to a single session treatment.

Cells are most sensitive during M & G2

phase & are resistant during S phase of cell cycle .

Redistribution can be a benefit in fractionated course of RT if cells are caught in sensitive phase after each fraction

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20 Reoygenation

Cells at the center of tumor are hypoxic & are resistant to low LET radiation.

Hypoxic cells get reoxygenated occurs during a fractionated course of treatment, making them more radiosensitive to subsequent doses of radiation.

Tumours may be acutely or chronically hypoxic. This oxygenation status may change during treatment.

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21 Reoygenation

In this particular tumor, the process of reoxygenation is very rapid indeed.

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22 Conventional RT and Reoxygenation

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23 Repopulation

Tends to increase cell survival. Occurs when fraction interval

length greater than cell cycle doubling time.

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24 Summery of Dose Rate Effect

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25 Radiosensitivity

Radiosensitivity is a newer member of the R's It reminds us, that apart from repair pathways, redistribution of

cells, reoxygenation of malignant cells and repopulation there is an intrinsic radiosensitivity or radioresistance in different cell types.

Radio sensitivity expresses the response of the tumor to irradiation.

Malignant cells have greater reproductive capacity hence are more radiosensitive.

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26Factors affecting the radiosensitivity

Physical LET (linear energy transfer): RS Dose rate: RS

Chemical Increase RS: OXYGEN, cytotoxic drugs. Decrease RS: SULFHYDRL compounds (cys,

cysteamine…) Biological

Cycle status: RS: G2, M RS: S

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28 Radiation Response

Response of all normal tissues to radn is not same

Depending on their response tissues are either Early responding – constitute fast

proliferating cells such as skin, mucosa, intestinal epithelium, colon, testis etc.

Late responding – have large no. of cells in the resting phase e.g. spinal cord, bladder, lung, kidneys etc.

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29 Various Fractionation Schedule

Fractionated radiation exploits difference in 4R’s between tumors and normal tissue thereby improving therapeutic index Types

Conventional Altered • Hyper fractionation • Accelerated fractionation • Split course• Hypofractionation

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30 Conventional fractionation

Division of dose into multiple spares normal tissue through repair of SLD & repopulation of cells.

Concurrently , fractionation increases tumor damage through reoxygenation & redistribution of tumor cells.

Hence a balance is achieved the response of tumor & early & late reacting normal tissue.

Most common fractionation for curative radiotherapy is 1.8 to 2.2Gy

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31 Conventional fractionation

Evolved as conventional regimen because it is Convenient (no weekend treatment) Efficient (treatment every weekday) Effective (high doses can be delivered without exceeding either

acute or chronic normal tissue tolerance) Allows upkeep of machines.Rationale for using conventional fractionation Most tried & trusted method Both tumorocidal & tolerance doses are well documented

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32 Hyperfractionation

 the delivery of radiation in small-dose fractions( 2-3 times per day) aims to improve the therapeutic ratio, reducing the dose given in

each fraction, so as to reduce the late side effects while also permitting an increased total dose to the tumor

 hyperfractionation provided the greatest benefit to patients with head and neck cancer 

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33 Hyperfractionation

A hyper fractionated schedule of 80.5Gy/70(1.15Gy twice/day)/7wks compared with 70Gy/35/7wks in head & neck cancer.

Implications • Increased local tumor control at 5yr from 40 to59%• Reflected in improved survival• No increase in side effects

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34 Accelerated Treatment

Alternative to hyper fractionation Rationale – To reduce repopulation in rapidly proliferating

tumors by reducing overall treatment time. Pure accelerated treatment – same total dose delivered in half

the overall time by giving 2or more s/day. but it is not possible to achieve as acute effects become limiting factor.

Impure accelerated treatment – dose is reduced or rest period is interposed in the middle of treatment.

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35 Types of accelerated fraction

Comparison of head & neck cases accelerated regimen 72Gy/45 (1.6Gy,3/day)/5wks with 70Gy/35/7wks

Implications – 15% increase in loco regional control No survival adv. Increased acute effects Unexpected increase in late complications

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36CHART

(Continuous Hyperfractionated RT)

With CHART treatments 6hrs apart delivered 3times a day,7daya a wk. with dose of 1.5Gy, total dose of 54Gy can be delivered in 36 over 12 consecutive days including weekends.

Characteristics Low dose Short treatment time No gap in treatment, 3/day at 6hr interval

Implications Better local tumor control Acute reactions are brisk but peak after treatment is completed Dose small hence late effects acceptable Promising clinical results achieved with considerable trauma to pt.

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37 Split-Corse

Total dose is delivered in two halves with a gap in b/w with interval of 4wks.

Purpose of gap is to allow elderly pts. to recover from acute reactions of

treatment further morbidity who have poorly tolerated or disease

progressed despite treatment. Applied to elderly pts. in radical treatment of ca bladder &

prostate & lung cancer.

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38 Hypofractionation

High dose is delivered in 2-3/ wk Rationale Treatment completed in a shorter period of time.Machine time well utilized for busy centers.Higher dose gives better control for larger tumors.Higher dose also useful for hypoxic fraction of large tumor. Disadv. Higher potential for late normal tissue complications.

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