IN THE NAME OF HIM

Z.MANSORI

Z.DOORANDISH

E.GHASEMLOY

E.MAROUFZADE

APRIL2014

THE DOSE RATE EFFECT

DNA DAMAGES

LETHAL DAMAGE: LD

SUB-LETHAL DAMAGE: SLD

POTENTIAL LETHAL DAMAGE: PLD

SURVIVAL CURVE

A CELL SURVIVAL CURVE IS A PLOT OF SURVIVING FRACTION AGAINST DOSE

INITIAL PORTION HAS A SHOULDER AND TERMINAL PORTION BECOME STRAIGHT LINE

S = E-(AD + BD2)

SURVIVAL CURVE

SURVIVAL CURVEAT HIGH LETS, SUCH AS Α-

PARTICLES OR LOW-ENERGY NEUTRONS, THE CURVE IS A STRAIGHT LINE

FOR LOW LETS,STARTS OUT STRAIGHT WITH A FINITE INITIAL SLOPE

• INCREASING LET:

• INCREASES THE STEEPNESS OF THE SURVIVAL CURVE

• SHOULDER DISAPPEARS DUE TO INCREASE OF KILLING BY SINGLE-EVENTS

SURVIVAL CURVELINEAR AND QUADRATIC

CONTRIBUTIONS TO CELL KILLING ARE EQUAL WHEN THE DOSE IS EQUAL TO THE RATIO OF A TO B

AD = B D2 D = A/ B

A COMPONENT IS REPRESENTATIVE OF DAMAGE CAUSED BY A SINGLE EVENT

B COMPONENT IS REPRESENTATIVE OF DAMAGE CAUSED BY MULTIPLE EVENTS

DOSE RATE D° =D/T

DOSE RATE. LDR

MDR

HDR

THE DOSE-RATE EFFECT

FOR X- OR R-RAYS, DOSE RATE IS ONE OF THE PRINCIPAL FACTORS THAT DETERMINE THE BIOLOGIC CONSEQUENCES OF A GIVEN ABSORBED DOSE.

THE CLASSIC DOSE-RATE EFFECT RESULTS FROM THE REPAIR OF SLD THAT OCCURS DURING A LONG RADIATION EXPOSURE.

THE DOSE-RATE EFFECT• CONTINUOUS LOW-DOSE-

RATE(LDR) IRRADIATION MAY BE CONSIDERED TO BE AN INFINITE NUMBER OF INFINITELY SMALL FRACTIONS.• NO SHOULDER, SHALLOWER THAN

FOR SINGLE ACUTE EXPOSURES.

THE DOSE-RATE EFFECTTHE LINEAR COMPONENT

OF CELL DAMAGE WILL BE UNAFFECTED BY DOSE RATE SINCE THE TWO CHROMOSOME BREAKS THAT INTERACT TO FORM A LETHAL LESION ARE CAUSED BY A SINGLE ELECTRON TRACK

THE DOSE-RATE EFFECTTHE QUADRATIC COMPONENT,

HOWEVER, IS CAUSED BY TWO SEPARATE ELECTRON TRACKS; IF THERE IS A LONG TIME INTERVAL BETWEEN THE PASSAGE OF THE TWO ELECTRON TRACKS, THEN THE DAMAGE CAUSED BY THE FIRST MAY BE REPAIRED BEFORE THE SECOND ARRIVES

SUB-LETHAL DAMAGE REPAIR

THE DOSE-RATE EFFECT

• CELLS CHARACTERIZED BY A SURVIVAL CURVE FOR ACUTE EXPOSURES THAT HAS A SMALL INITIAL SHOULDER EXHIBIT A MODEST DOSE-RATE EFFECT

• CELL LINES CHARACTERIZED BY A SURVIVAL CURVE FOR ACUTE EXPOSURES WHICH HAS A BROAD INITIAL SHOULDER EXHIBIT A DRAMATIC DOSE-RATE EFFECT

THE DOSE-RATE EFFECT IN HELA CELLS

SURVIVAL CURVES FOR HELA CELLS CULTURED IN VITRO OVER A WIDE RANGE OF DOSE RATES – FROM 7.3 GY/MIN TO 0.535 CGY/ MIN

THE DOSE-RATE EFFECT CAUSED BY REPAIR OF SUBLETHAL DAMAGE IS MOST DRAMATIC BETWEEN 0.01 GY/MIN AND 1 GY/MIN

HELA CELLS ARE CHARACTERIZED BY A SURVIVAL CURVE FOR ACUTE EXPOSURES THAT HAS A SMALL INI- TIAL SHOULDER, WHICH GOES HAND IN HAND WITH A MODEST DOSE-RATE EFFECT

SURVIVAL CURVES FOR HELA CELLS

THE DOSE-RATE EFFECT IN(CHO)CELLSCHINESE HAMSTER (CHO) CELLS HAVE A BROAD

SHOULDER TO THEIR ACUTE X-RAY SURVIVAL CURVE AND SHOW A CORRESPONDING LARGE DOSE-RATE EFFECT

THIS DIFFERENCE IN SHOULDER SIZE AND CORRESPOND- ING MAGNITUDE OF THE DOSE-RATE EFFECT CORRELATES WITH THE DOMINANT MECHANISM OF CELL DEATH

SURVIVAL CURVES FOR CHINESE HAMSTER

THE DOSE-RATE EFFECT

survival curves for 40 different cell lines of human origin, cultured in vitro and irradiated at HDR and LDR

THE INVERSE DOSE-RATE EFFECT

DECREASING THE DOSE RATE RESULTS IN INCREASED CELL KILLING

AN INVERSE DOSE-RATE EFFECT IS OFTEN SEEN OVER A NARROW RANGE OF DOSE RATES, WHEREBY DECREASING THE DOSE RATE ACTUALLY INCREASES THE EFFICACY OF CELL KILLING

THE INVERSE DOSE-RATE EFFECT

DECREASING THE DOSE RATE FOR THIS CELL LINE FROM 1.53 GY/H TO 0.37 GY/H. INCREASES THE EFFICIENCY OF CELL KILLING, SO THAT THIS LDR IS ALMOST AS EFFECTIVE AS AN ACUTE EXPOSURE.

THE INVERSE DOSE-RATE EFFECTTHE EXPLANATION OF THIS

PHENOMENON IS ILLUSTRATED AT THIS PICTURE.

AT ABOUT 0.3 GY/H, CELLS TEND TO PROGRESS THROUGH THE CYCLE AND BECOME ARRESTED IN G2, A RADIOSENSITIVE PHASE OF THE CYCLE

THE DOSE-RATE EFFECT SUMMARIZED

1.HDR

FOR ACUTE EXPOSURES AT HDR, THE SURVIVAL CURVE HAS A SIGNIFICANT INITIAL SHOULDER.

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2.LDR THE SURVIVAL CURVE

BECOMES PROGRESSIVELY SHALLOWER, AND THE SHOULDER TENDS TO DISAPPEAR.

REPAIRsu

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REPAIR

• REPAIR OF SUBLETHALLY DAMAGED DNA CAN OCCUR IF THE CELL CONTAINS THE FULL COMPLEMENT OF DNA DAMAGE DETECTION PROTEINS AND REPAIR ENZYME SYSTEMS, BUT THERE MUST ALSO BE SUFFICIENT TIME FOR THESE MECHANISMS TO OPERATE.

3. FOR LOWER DOSE RATEWHAT IS EXPECTED: RESULT:

REDISTRIBUTION / REASSORTMENT

• WITH MULTIPLE DOSES, CELLS PROGRESS THROUGH TO A NEW PHASE OF THE CELL CYCLE (SENSITIVE)

• “SENSITIZATION DUE TO RE-ASSORTMENT” CAUSES THERAPEUTIC GAIN.

3. BELOW CRITICAL DOSE RATE:

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EARLY RESPONDING TISSUES

EARLY-RESPONDING TISSUES ARE USUALLY SELF-RENEWING TISSUES AND ARE CHARACTERIZED BY A RAPIDLY PROLIFERATING STEM CELL COMPARTMENT THAT PROVIDES CELLS TO DIFFERENTIATE AND BECOME THE MATURE FUNCTIONING CELLS.

EXAMPLES: SKIN, INTESTINAL EPITHELIUM, BONE-MARROW

LATE RESPONDING TISSUES

LATE-RESPONDING TISSUES ARE MUCH LESS ABLE TO TOLERATE RETREATMENT BECAUSE THEY DO NOT HAVE THE ABILITY TO RECOVER FROM THE INITIAL DAMAGE INASMUCH AS THEY DO NOT HAVE A RAPIDLY PROLIFERATING STEM CELL COMPARTMENT.

EXAMPLES : SPINAL CORD, LUNG, KIDNEY

EARLY AND LATE RESPONDING TISSUES

THE DOSE–RESPONSE RELATIONSHIP FOR LATE-RESPONDING TISSUES IS MORE CURVED THAN THAT FOR EARLY RESPONDING TISSUES.

THE DOSE-RATE EFFECT AND CLINICAL DATA

PATERSON IN THE 1960S POINTED THAT THE DOSE-LIMITING FACTOR IN THE CASE OF INTERSTITIAL IMPLANTS IS THE TOLERANCE OF NORMAL TISSUES.

60 GY IN7 DAYS AS THE STANDARD, THE EXPERIENCE WAS BASED ON TREATMENT WITH RADIUM NEEDLES IMPLANTED ACCORDING TO THE MANCHESTER SYSTEM.

ELLIS PROPOSED AN ESSENTIALLY IDENTICAL SCHEME FOR USE IN CLINICAL PRACTICE

IR-192 INESTED OF RA-226

PATIENT COMFORT , BUT ALSO RESULTED IN A MUCH LARGER VARIATION OF DOSE RATE BETWEEN INDIVIDUAL IMPLANTS. FOR TOW REASONS:

1. SHORT HALF-LIFE OF IRIDIUM-192 (74 DAYS) THE LINEAR ACTIVITY WILL VARY.

2. IRIDIUM-192 IMPLANTS, WHERE ALL SOURCES HAVE THE SAME LINEAR ACTIVITY WITH VARYING SEPARATION BETWEEN WIRES FOR DIFFERENT LENGTHS.

IR-192 INESTED OF RA-226

BECAUSE ALL WIRES IN AN IRIDIUM-192 IMPLANT HAVE THE SAME LINEAR ACTIVITY, THERE IS A CORRELATION BETWEEN IMPLANTED VOLUME AND DOSE RATE

IR-192 INESTED OF RA-226

PIERQUIN AND HIS COLLEAGUES (1973) SAID THAT IN IRIDIUM-192 IMPLANTS, THE DOSE RATE WAS UNIMPORTANT.

THE PARIS SCHOOL RECOMMENDED THE SAME PRESCRIBED DOSE IRRESPECTIVE OF OVERALL TIME WITHIN THE RANGE 3–8 DAYS.

MANY HUNDREDS OF PATIENTS WERE TREATED WITH IR-192 IMPLANTS USING STANDARD DOSES UNCORRECTED FOR DOSE RATE,IT DOES NOT AGREE WITH THE EXPERIMENTAL RADIOBIOLOGICAL DATA(PATTERSON & ELLIS)

DOSE-RATE EFFECTS FROM ANANALYSIS OF THE IRIDIUM IMPLANT

DATAIN THE FIRST, MAZERON AND COLLEAGUES(1991B)

STUDIED TUMOR CONTROL & NECROSIS OF T1 AND T2 SCC OF THE MOBILE TONGUE AND FLOOR OF MOUTH TREATED WITH INTERSTITIAL IR-192.

THE DATA ARE COMPARE TUMOR CONTROL AND NECROSIS IN PATIENTS TREATED AT DOSE RATES ABOVE OR BELOW 0.5 GY/H.

RESULTS

TWO PRINCIPAL CONCLUSIONS CAN BE DRAWN FROM THIS ANALYSIS:

1. THERE IS LITTLE OR NO DIFFERENCE IN LOCAL CONTROL BETWEEN THE TWO DOSE-RATE RANGES PROVIDED A SUFFICIENTLY HIGH TOTAL DOSE IS USED (65–70 GY), BUT THERE IS A CLEAR SEPARATION AT LOWER DOSES (AROUND 60 GY) WITH THE LOWER DOSE RATE BEING SIGNIFI CANTLY LESS EFFECTIVE.

2. OVER THE ENTIRE RANGE OF DOSES USED, THERE WAS A HIGHER INCIDENCE OF NECROSIS ASSOCIATED WITH THE HIGHER DOSE RATE RANGE

MAZERON ET AL. NEXT STUDY

THEY STUDIED CARCINOMA OF THE BREAST WHO RECEIVED AN

IR-192 IMPLANT AS A BOOST TO EBRT.

A FIXED STANDARD TOTAL DOSE WAS USED,REGARDLESS OF THE DOSE RATE, A FIXED STANDARD TOTAL DOSE WAS USED(IR:37GY)

A CLEAR DIFFERENCE IN TUMOR CONTROL COULD BE SEEN BETWEEN 0.3 GY/H AND 0.9 GY/H

THE BIAS OF TUMOR SIZE AND DOSE RATE

FOR INTERSTITIAL IMPLANTS, THE DOSE RATE TENDS TO INCREASE AS THE SIZE OF THE IMPLANT INCREASES.

THIS CORRELATION IS PARTICULARLY TRUE IN THE PARIS SYSTEM, BUT LESS TO PARKER-PATTERSON.

PIERQUIN AND HIS COLLEAGUES (1973) POINTED THAT LARGER TUMORS BEING ASSOCIATED WITH HIGHER DOSE

RATES, WHILE SMALLER TUMORS ARE ASSOCIATED WITH LOWER DOSE RATES

THE BIAS OF TUMOR SIZE AND DOSE RATE

LARGER TUMORS OF COURSE REQUIRE A LARGER DOSE FOR A GIVEN LEVEL OF LOCAL CONTROL, WHILE THE THE MAXIMUM DOSE THAT CAN BE TOLERATED BY NORMAL TISSUES DECREASES AS THE VOLUME IMPLANTED INCREASES. THIS WILL TEND TO FLATTEN THE ISOEFFECT CURVE FOR TUMOR CONTROL AND STEEPEN THE ISOEFFECT CURVE FOR NORMAL TISSUE TOLERANCE.

• THE PATERSON/ELLIS RECOMMENDATIONS WERE BASED ON EQUALIZING ONLY LATE EFFECTS & RA NEEDLES ,& PARIS RECOMMENDATIONS WERE BASED ON EQUALIZE LATE AND EARLY EFFECTS & IR WIRES .

•THANKS FOR YOUR ATTENTION