1. Dose regime Models &Gap correction factor Presented by Jyoti Bisht (Medical Physicist) Swami Ram Cancer Hospital & Research Center Haldwani,Nainital
2.  Radio-Biology: Radio-biology is the branch of Radiation Physics in which thebiological effects of Radiation are observed, measured and evaluatedwith respect of irradiation time. Basically We need Radiobiology to know Normal Tissue Tolerance Tumor lethality Dose and Toxicity Dose optimization Consequential Dose
3.  Need for time-dose models- The main aim of radiotherapist is to obtain a high probability of tumor control without exceeding tolerance of normal tissue. Not all diseases are treated with the same time-dose schedule and not all radiotherapists will treat similar disease similarly. Since, typical treatment plans are quite complicated to compare. With the help of these time-dose models the treatment regimes now can be easily modified.
4.  BIOEFFECT DOSE MODELS CLINICAL HUMAN EXPERIMENTAL TISSUE REACTIONS ANIMAL TISSUE REACTIONS CELL SURVIVAL THEORIES TIME – DOSE THEORY
5.  Strandquist model. In 1944 Strandqvist has published a graphical representation, describing the result of 280 patients of different type of skin cancers. He plotted an isoeffect line on log-log scale between total dose D and total treatment time T. The isoeffect line on logarithmic co-ordinates was drawn, which was as a straight line with a slope of 0.22. Mathematically, the total dose D is related to overall treatment time, T, as; D=KT0.22 Where K is a constant.
6. Isoeffect curves relating total dose to theoverall treatment time
7.  Cohen model Cohen had analyzed three sets of data of skin damage, the end points were taken as skin erythema and skin tolerance. Similar isoeffect lines were plotted for Tumor Lethal Dose (TLD) of squamous cell carcinoma and basal cell carcinoma in skin cancer also. He further evaluated an exponent of 0.33 for skin erythema / skin tolerance and 0.22 for skin cancers. According to Cohen’s result, the relationship between total dose and overall treatment time, for normal tissue tolerance and tumors can be written as :-
8. Dn = K1T0.33And Dt = K2T0.22Where K1 and K2 are proportionality constants. Dn, Dt andT are normal tissue tolerance dose, tumor lethal doseand overall treatment time respectively.
9.  Nominal Standard Dose (NSD) formula It is given by Ellis(1965). The exponent of T in normal tissue is higher than that of tumor, which indicates that the repair capacity of normal tissue is higher than that of tumors. This difference is termed as “Differential Recovery Rate”. The normal tissues are having two types of repair / recovery capabilities. i.e., (i) intracellular recovery and (ii) extra-cellular recovery. He had investigated that the number of fractions (N) were more important than the overall treatment time (T).
10. This led Ellis to an important realization that the time factor wasactually a composite effect of N and T The exponents forintracellular and homeostatic recoveries are 0.22 and 0.33-0.22= 0.11 respectively. Now equation may be transformed to; D = KT0.22Now T0.22 can be replaced by N0.22 as intracellular recoverycompletes within few hours of irradiation, the equation can berewritten as; D = KN0.22T0.11
11. The conventional treatment schedule is delivered 5 fractionsper week; therefore exponent 0.22 of N replaced by 0.24and the proportionality constant is replaced by a term NSD.Hence the final formula, comprising total dose D, at normaltissue tolerance, number of fractions N and overalltreatment time T, is given by D = NSD N0.24T0.11And can be written as NSD = D N-0.24 T-0.11Where NSD (the nominal standard dose) is a constant, unitof NSD is ret(radiation effect therapy).
12.  Drawbacks of NSD concept .The problems encountered in the application of NSD conceptand its derivatives quoted by Barendsen are as follows :- Doubts have been raised concerning the validity of these models with respect to the type of the tissue involved. Evidence revealed that for different tissues, the dependence of tolerance dose fractionation is not the same. The doubts have also been raised concerning the validity of these models with respect to different effects in the same tissue or organ.
13.  The cumulative Radiation effect (CRE) NSD formulas do not say anything about tumor response and the part of the treatment schedule, which has already been completed. The fact that a portion of a treatment schedules, which has already been completed, might have reached some level of tolerance. Kirk et al have extended the NSD concept to the cumulative radiation effect (CRE) for such type of treatment schedules. This was based on the concept of sub-tolerance of normal tissue, which was subjected to irradiation .
14.  In practice, the concept of partial tolerance is very important in the analysis of a complex treatment protocol, which includes many number of treatment parts, and is combined together. The partial tolerances is additive in nature. i.e.; PT = (PT)1 + (PT)2 +…………+(PT)n The basic NSD formula was written in terms of total dose D, overall treatment time T and total number of fraction N. However, in general practice, the dose per fraction d is often the starting point so that the total dose may be written as D = N.d and total treatment time T= x.N, where x is the function of number of fractions per week.
15.  Time, Dose, Fractionation Factor (TDF) Given by Orton and Ellis. The effectiveness of the treatment should be described in terms of partial tolerance and its expression is given as; PT (partial tolerance) = NSD x n/N Where, N is the number of fractions of the chosen size and, frequency, which would result in full connective tissue tolerance, and n is the number of such fraction actually given.
16. Now, the equation of NSD may be written as NSD = N.d.N-0.24 (x.N)-0.11Or NSD = d.N0.65 x-0.11Or N = [(NSD/d). x-0.11]1.538Now, substituting the value of N in equation of partialtolerance, we get PT = n (NSD)-0.538 d1.538 x-0.169
17. Now equation PT can be written as; PT = (NSD)-0.538. (TDF). 103Where,• TDF is defined as, TDF = n. d1.538 x-0.169. 10-3• 10-3 is simply a scaling factor that makes TDF valuesmore convenient to handle.• x is the function of number of fractions per week. (5 fractions in7 days.)
18.  Gap correction factor In some situations, it became necessary to interrupt a continuous treatment schedule by interposing a rest period due to many reasons. In such type of treatment schedules, the effectiveness of the first part of the treatment will have decayed by the time second part of the treatment is started. The two parts of the treatment are well separated, therefore the TDF values of these two parts of the plan cannot be added until a decay correction has applied to the TDF values of first part of the treatment.
19. Orton suggested the use of decay factor.The decay correction factor is based on the timecomponent of the basic NSD formula and is given by Decay / Gap correction Factor (GF) = {T/(T+G)}0.11Where, the duration of the first part of split course is Tdays, and the rest period is G days.
20.  Calculation Process - Calculate the normal tissue BED for the prescribed schedule. This calculation should make use of the dose actually received by the critical normal tissue.Eq (A). Determine the respective pre-gap normal-tissue BED. Find the difference between them to determines the late-normal BED ,still to give’ (the post-gap BED). Review the various option (for ex- twice daily fractionation and hyperfractioonation, increased fraction size) to ascertain which will be likely to produce the minimum extension to the treatment time,then calculate required dose per fraction. For the selected option , calculate the associated tumour BED using Eq (B). Review the final tumour and normal tissue BEDs which will preferred compensation option.
21.  Formulas -----BED= n d [ 1+d/(a/b)] ….Eq(A)BED= n d[1+d/(a/b)] –K*(T-T delay) ….Eq(B)where, n= no. of fractions d= dose per fraction a/b= Dose (given in literature) T= Total treatment time Tdelay= delay in treatment or prolonged time K= proportionality constant
22.  Effects of the Gap -4 R’s of Radiotherapy – Repair of sublethal damage of normal cells. Reassortment of cells within the cell cycle. Repopulation of normal cells. Reoxygenation of tumour tissue.Prolongation of treatment are to spare early reactions andto allow adequate reoxygenation in tumours.
23.  Data on the basis of a servey in Manchaster, UK and Toronto, Canada in three years reported for Gap - 1994 2000 2005 Department-related Planned Public holiday/statutory days 46% ---- 39% Machine service time 31% 37% 35% Unplanned 7% ---- ---- Machine breakdown ---- 13% 9% Patient-related Radiotherapy reactions 16% 8% 8% Patient unwillingness ---- 5% 4% Unspecified ---- 37% 5% Total 100% 100% 100%
24.  Factors that can affect the tumours control outcome due to Gap- Tumour proliferation (ex: Slow growing tumours & fast growing tumours) Prolongation length . Interruption time ((initially breakage or in middle or at last of the treatment).
25.  Tumour Proliferation - Glioblastoma are very fast growing tumours, and there is evidence that delay in starting therapy affects outcome. 75,76. Carcinoma of bladder : Two small reports favor that prolongation may affect outcome.78,79Two large reports shows no significant affect of prolongation on outcome.77,80 Prolongation of slow growing tumours for five days does not significantly affect patient outcome (Local control and survival) applicable on Ca anus81-83 and Ca prostate 84-87 For Ca breast shows adverse effect on local control and survival if treatment prolonged for more than seven days in a five-week course of treatment.22,23For shorter courses there is no published data. But prolongation should not be more than two days. In palliative cases the prolongation may reduce the effect of benefit for ex-Management of cord compression and superior vena cava obstruction(SVCO).
26.  Prolongation length - The minimum length of an interruption which result in prolongation of treatment time is difficult to determine. Data from different course studies show that 14-16 day interruption definitely effect treatment outcome. Prolongation of one week may arise loss of tumour control from 3 to 25%(Median 14%). Mathematical modeling of squamous cell carcinoma oh head and neck, cervix, and lung shows that an unscheduled interruption of one day(uncompensated) reduces local tumour control by 1 to 1.4%10,15,16. For locally advanced cervical cancer the overall treatment time should not exceed 56 days for squamous carcinoma. Ca breast (postoperative) shows that prolongation of more than seven days for five week treatment increases risk of local recurrence and death. 22,23
27. Does the timing of interruption matter?Studies are going on this topic. Gap arising in short course of treatment (3-4 days). Gap arising earlier than 28 days in a long course of therapy. Gap arising after 28 days treatment.Biological correction for these events will be different . Correction for interruption arising later in a long course of therapy is more difficult because it require the patient to receive a large no. of fractions over a short time of period and this may increase the risk of long term late effect. According to a study on pig skin it is suggested that an interruption on a Monday or Friday have a more serious adverse effect than an interruption mid-week.95,46
28.  Compensatory Methods -Transfer to a second machineAccelerated SchedulingBiological allowanceIncreased total dose
29.  Implementation -Availability of resourcesPatient-specific reminders at the time of prescription or treatmentCommunicationQuality assuranceFundingResearchSupervisionTeachingRadiobiology Support
30. Reference -These all references has been taken from the report -The Timely delivery of radical radiotherapy: standardsand guidelines for the management of unscheduledtreatment interruptions, Third edition, 2008Published by :Board of faculty of Clinical Oncology The Royal College of Radiologists