The document discusses the radiobiology behind dose fractionation in radiation therapy. It provides an overview of the linear quadratic model which describes how cell survival changes with dose and is used to determine biologically equivalent doses for different fractionation schedules. The model assumes equal effect per fraction but may not be accurate at high or low doses. Fractionation takes advantage of the four R's - repair, repopulation, redistribution, and reoxygenation - to better kill tumors while sparing normal tissues. The alpha/beta ratio indicates a tissue's sensitivity to fractionation and is used to estimate equivalent total doses for different fraction sizes.
This is a made easy summary of ICRU 89 guidelines for gynecological brachytherapy. Extra practical questions for MD/DNB Radiotherapy exams are also attached.
This is a made easy summary of ICRU 89 guidelines for gynecological brachytherapy. Extra practical questions for MD/DNB Radiotherapy exams are also attached.
24° CORSO RESIDENZIALE DI AGGIORNAMENTO
con il patrocinio dell’Associazione Italiana di Radioterapia Oncologica (AIRO)
Moderna Radioterapia, Nuove Tecnologie e Ipofrazionamento della Dose
17 marzo 2014: Oltre l’alfa/beta: ipotesi di coinvolgimento dell’endotelio e modelli predittivi dell’effetto nei trattamenti ultra-ipo-frazionati (lineare-cubico ecc.)
describes relationship between radiation dose and the fraction of cells that “survive” that dose
model of cell killing
target model
linear quadratic model
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
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Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
1. The Radiobiology Behind Dose
Fractionation
Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los Angeles, Ca.
wmcbride@mednet.ucla.edu
WMcB2009
www.radbiol.ucla.edu
2. Objectives
•
•
•
•
•
•
To understand the mathematical bases behind survival curves
Know the linear quadratic model formulation
Understand how the isoeffect curves for fractionated radiation
vary with tissue and how to use the LQ model to change dose
with dose per fraction
Understand the 4Rs of radiobiology as they relate to clinical
fractionated regimens and the sources of heterogeneity that
impact the concept of equal effect per fraction
Know the major clinical trials on altered fractionation and their
outcome
Recognize the importance of dose heterogeneity in modern
treatment planning
WMcB2009
www.radbiol.ucla.edu
3. Relevance of Radiobiology to Clinical
Fractionation Protocols
Conventional treatment:
Tumors are generally irradiated with 2Gy dose per fraction delivered
daily to a more or less homogeneous field over a 6 week time period to
a specified total dose
The purpose of convenntional dose fractionation is to increase dose to
the tumor while PRESERVING NORMAL TISSUE FUNCTION
• Deviating from conventional fractionation protocol impacts outcome
• How do you know what dose to give; for example if you want to change dose
per fraction or time? Radiobiological modeling provide the guidelines. It uses
– Radiobiological principles derived from preclinical data
– Radiobiological parameters derived from clinical altered fractionation
protocols
• hyperfractionation, accelerated fractionation, some hypofractionation schedules
The number of non-homogeneous treatment plans (IMRT) and extreme hypofractionated
treatments are increasing. Do existing models cope?
WMcB2009
www.radbiol.ucla.edu
4. In theory, knowing relevant radiobiological parameters
one day may predict the response for
• Dose given in a single or a small number of fractions
• SBRT, SRS, SRT, HDR or LDR brachytherapy, protons,
cyberknife, gammaknife
• Non-uniform dose distributions optimized by IMRT
• e.g. dose “painting” of radioresistant tumor subvolumes
•
•
Combination therapies with chemo- or biological agents
Different RT options when tailored by molecular and
imaging theragnostics
• If you know the molecular profile and tumor phenotype, can you
predict the best delivery method?
• Biologically optimized treatment planning
WMcB2009
www.radbiol.ucla.edu
5. The First Radiation Dosimeter
prompted the use of dose fractionation
WMcB2009
www.radbiol.ucla.edu
6. In general, history has shown
repeatedly that single high
doses of radiation do not allow
a therapeutic differential
between tumor and critical
normal tissues.
Dose fractionation does.
SBRT/SRS often aims at TISSUE ABLATION
WMcB2009
www.radbiol.ucla.edu
7. How to modify a treatment
schedule
WMcB2009
www.radbiol.ucla.edu
8. Modeling Radiation Responses
Assumes that ionizing ‘hits’ are random events in space
Which are fitted by a Poisson Distribution
P of x = e-m.mx/x!
where m = mean # hits, x is a hit
P survival
(when x = 0)
100 targets 100 hits m=1 e-1=0.368
100 targets 200 hits m=2 e-2=0.137
100 targets 300 hits m=3
e-3=0.05
N.B. Lethal hits in DNA are not really randomly
distributed, e.g. condensed chromatin is more
sensitive, but it is a reasonable approximation
WMcB2009
www.radbiol.ucla.edu
9. This Gives a Survival Curve Based on a Model
where one hit will eliminate a single target
•
When there is single lethal hit per target
1.0
•
S.F.= e-1 = 0.37
This is the mean lethal dose D0
0.37
•
D10 = 2.3 xD0
•
In general, S.F. = e-D/D0
S.F.
0.1
or LnS.F. = -D/D0
0.01
0.001
or S.F. = e-αD , i.e. D0 = 1/α
D0
D 10
DOSE Gy
Where α is the slope of the curve and D0 the
reciprocal of the slope
How many logs of cells would be killed
by 23 Gy if D0 = 1 Gy?
WMcB2009
www.radbiol.ucla.edu
10. Mean Inactivation Dose (Do)
•
•
•
•
Virus D0 approx. = 1500 Gy
E. Coli D0 approx. = 100 Gy
Mammalian bone marrow cells D0 = 1 Gy
Generally, for mammalian cells D0 = 1-1.5 Gy
Why the differences?
WMcB2009
www.radbiol.ucla.edu
11. Puck and Marcus, J.E.M.103, 563, 1956
First in vitro mammalian survival curve
Eukaryotic Survival Curves are
Exponential, but have a ‘Shoulder’
Two component model
single
lethal
hits
n
1.0
0.1
0.01
Accumulation of
sub-lethal
damage
0.001
dose
WMcB2009
www.radbiol.ucla.edu
12. Two Component Model
single
lethal
hits
n
1.0
D0 =
1
reciprocal
initial slope
S.F.
0.1
• Two Component Model
(or single target, single hit +
multi-target (n), single hit)
• S.F.=e-D/1D0[1-(1-e-D/nD0)n]Extrapolation
Number
Single hit
0.01
Accumulation
of sublethal
damage
0.001
Accumulate
d
damage
D0 =
n
reciprocal
final slope
DOSE Gy
WMcB2009
www.radbiol.ucla.edu
13. 1
limiting slope/
low dose rate
S.F.
Multi-fraction survival curves can be
considered linear if sublethal damage is
repaired between fractions
they have an extrapolation number (n) = 1.0
5 fractions
•The resultant slope is the effective D0
•e D 0 is often 2.5 - 5.0Gy and e D 10 5.8 - 11.5Gy
.1
•S.F. = e-D/eD0
3 fractions
Single dose
.01
0
4
8
12
16
Dose (Gy)
20
•If S.F. after 2Gy = 0.5, eD0 = 2.9Gy; eD10 =
6.7Gy and 30 fractions of 2 Gy (60Gy) would
reduce survival by (0.5)30 = almost 9 logs (or
60/6.7)
•If a 1cm tumor had 109 clonogenic cells, there
would be an average of 1 clonogen per tumor
and cure rate would be about 37%
24
WMcB2009
www.radbiol.ucla.edu
14. Linear Quadratic Model
•
1.0
αD
S.F. = e-αD
Single lethal hits
βD2
S.F. 0.1
Cell kill is the result of single lethal hits
plus accumulated damage from 2
independent sublethal events
S.F. = e-(αD+βD2)
Single lethal hits plus
accumulated damage
0.01
•
The generalized formula is E = αD + βD2
•
0.001
α/β in Gy
DOSE Gy
For a fractionated regimen E= nd(α + βd) = D (α + βd)
Where d = dose per fraction and D = total dose
∀
α/β is dose at which death due to single lethal
lesions = death due to accumulation of sublethal
lesions i.e. αD = βD2 and D = α/β in Gy
WMcB2009
www.radbiol.ucla.edu
15. • Over 90% of radiation oncologists use the LQ model:
– it is simple and has a microdosimetric underpinning
α/β is large (> 6 Gy) when survival curve is almost
exponential and small (1-4 Gy) when shoulder is
wide
– the α/β value quantifies the sensitivity of a
tissue/tumor to fractionated radiation.
• But:
– Both α and β vary with the cell cycle. At high doses,
S phase and hypoxic cells become more important.
– The α/β ratio varies depending upon whether a cell
is quiescent or proliferative
– The LQ model best describes data in the range of 1 6Gy and should not be used outside this range
WMcB2009
www.radbiol.ucla.edu
16. Thames et al Int J Radiat Oncol Biol Phys 8: 219, 1982.
•The slope of an isoeffect curve changes
with size of dose per fraction depending on
tissue type
• Acute responding tissues have flatter
curves than do late responding tissues
• α/β measures the sensitivity of tumor or
tissue to fractionation i.e. it predicts how total
dose for a given effect will change when you
change the size of dose fraction
Douglas and Fowler Rad Res 66:401, 1976
Showed and easy way to arrive at an α/β
ratio
Reciprocal
total dose
for an isoeffect
Slope = β
Intercept = α
Dose per fraction
WMcB2009
www.radbiol.ucla.edu
17. Response to Fractionation Varies
With Tissue
1
1
Acute Responding
Acute
Tissues α/β = 10Gy
S.F.
Late Responding
Tissues - α/β = 2Gy
0
4
8
12
Dose (Gy)
Fractionated
Acute Effects
Single Dose
Late Effects
α/β = 2Gy
α/β is high (>6Gy) when survival
curve is almost exponential and low
(1-4Gy) when shoulder is wide
.01
Fractionated
Late Effects
.1
.1
S.F.
Single Dose
Acute Effects
α/β = 10Gy
.01
16
0
4
8
12
16
Dose (Gy)
20
Fractionation spares late responding tissues
WMcB2009
www.radbiol.ucla.edu
19. What are α/β ratios for human
cancers?
In fact, for some tumors e.g. prostate, breast, melanoma, soft tissue
sarcoma, and liposarcoma α/β ratios may be moderately low
Prostate
– Brenner and Hall IJROBP 43:1095, 1999
• comparing implants with EBRT
∀ α/β ratio is 1.5 Gy [0.8, 2.2]
– Lukka JCO 23: 6132, 2005
• Phase III NCIC 66Gy 33F in 45days vs 52.5Gy 20F in 28 days
• Compatible with α/β ratio of 1.12Gy (-3.3-5.6)
Breast
– Owen, J.R., et al. Lancet Oncol, 7: 467-471, 2006 and Dewar et al JCO,
ASCO Proceedings Part I. Vol 25, No. 18S: LBA518, 2007.
• UK START Trial
– 50Gy in 25Fx c.w. 39Gy in 13Fx; or 41.6Gy in 13Fx [or 40Gy in 15Fx (3
wks)]
• Breast Cancer α/β = 4.0Gy (1.0-7.8)
• Breast appearance α/β = 3.6Gy; induration α/β
If fractionation sensitivity of a cancer is similar to = 3.1Gy
dose-limiting
healthy
tissues, it may be possible to give fewer, larger fractions without
compromising effectiveness or safety
WMcB2009
www.radbiol.ucla.edu
20. What total dose (D) to give if
the dose/fx (d) is changed
New
Dnew (dnew + α/β )
Old
= Dold (dold + α/β )
So, for late responding tissue, what total dose in 1.5Gy
fractions is equivalent to 66Gy in 2Gy fractions?
Dnew (1.5+2) = 66 (2 + 2)
Dnew = 75.4Gy
NB: Small differences in α/β for late responding tissues can make a
big difference in estimated D!
WMcB2009
www.radbiol.ucla.edu
21. Biologically Effective Dose (BED)
S.F. = e-E = e-(αD+βD2)
E = nd(α + βd)
E/α = nd(1+d/α/β)
Biologically
Effective Dose
Total dose
Relative
Effectiveness
35 x 2Gy = B.E.D.of 84Gy10 and 117Gy3
NOTE: 3 x 15Gy = B.E.D.of 113Gy10 and 270Gy3
Equivalent to 162 Gy in 2Gy Fx -unrealistic!
(Fowler et al IJROBP 60: 1241, 2004)
Normalized total dose2Gy
= BED/RE
= BED/1.2 for α/β of 10Gy
= BED/1.67 for α/β of 3Gy
www.radbiol.ucla.edu
WMcB2009
23. Does this Matter?
Prescribed Dose:
25 fractions of 2Gy = 50Gy
Hot spot: 110%
Physical dose: 55Gy
Biological dose: 60.5Gy
“Double
Trouble”
www.radbiol.ucla.edu
WMcB2009
24. The Linear Quadratic Formulation
• Does not work well at high dose/fx
• Assumes equal effect per fraction
WMcB2009
www.radbiol.ucla.edu
25. HT29 cells
N.B. Survival curves may
deviate from L.Q. at low and
high dose!!!!
• Certain cell lines, and tissues, are
hypersensitive at low doses of 0.050.2Gy.
• The survival curve then plateaus over
0.05-1Gy
• Not seen for all cell lines or tissues, but
has been reported in skin, kidney and
lung
• At high dose, the model probably does not
fit data well because D2 dominates the
equation
Lambin et al. Int J Radiat Biol 63:639 1993
www.radbiol.ucla.edu
WMcB2009
26. The Linear Quadratic Formulation
• Does not work well at low or high dose/fx
• Assumes equal effect per fraction
WMcB2009
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27. 4Rs OF DOSE FRACTIONATION
• Assessed by varying the
time between 2 or more
doses of radiation
700R
1500R
Repopulation
Redistribution
Repair
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28. 4Rs OF DOSE FRACTIONATION
These are radiobiological mechanisms that
impact the response to a fractionated course of
radiation therapy
• Repair of sublethal damage
– spares late responding normal tissue preferentially
• Redistribution of cells in the cell cycle
– increases acute and tumor damage, no effect on late
responding normal tissue
• Repopulation
– spares acute responding normal tissue, no effect on late
effects,
– danger of tumor repopulation
• Reoxygenation
– increases tumor damage, no effect in normal tissues
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29. Repair
•
•
•
•
“Repair” between fractions should be complete - N.B. we are
dealing with tissue recovery rather than DNA repair
– Correction for incomplete repair is possible (Thames)
In general, time between fractions for most tissues should
be >6 hours
Some tissues, such as CNS, recover slowly making b.i.d.
treatment inadvisable
Bentzen - Radiother Oncol 53, 219, 1999
– CHART analysis HNC showed that late morbidity was
less than would be expected assuming complete recovery
between fractions
– Is the T1/2 for recovery for late responding normal
tissues 2.5-4.5hrs?
WMcB2009
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30. Regeneration in Normal Tissues
•
•
The lag time to regeneration varies with the tissue
In acute responding tissues,
– Regeneration has a considerable sparing effect
• In human mucosa, regeneration starts 10-12 days into a
2Gy Fx protocol and increases tissue tolerance by at least
1Gy/dy
– Prolonging treatment time has a sparing effect
– As treatment time is reduced, acute responding tissues
become dose-limiting
•
In late responding tissues,
– Prolonging overall treatment time beyond 6wks has little effect,
but
prolonging time to retreatment may increase tissue tolerance
WMcB2009
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31. Repopulation in Tumor Tissue
Rat rhabdosarcoma
Human SCC head and neck
T2
70
Total
Dose
(2 Gy equiv.)
55
T3
local control
no local control
40
Treatment Duration
Hermens and Barendsen, EJC 5:173, 1969
4 weeks to start of accelerated
repopulation.
Thereafter T1/2 of 4 days = loss of 0.6Gy
per day
Treatment breaks are often “bad”
Withers, H.R., Taylor, J.M.G., and Maciejewski, B.
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Acta Oncologica 27:131, 1988
32. Other Sources of Heterogeneity
•
Biological Dose
– Cell cycle
– Hypoxia/reoxygenation
– Clonogenic “stem cells” (G.F.)
•
•
•
•
S.F
hypoxic
oxic
Dose
Number
Intrinsic radiosensitivity
Proliferative potential
Differentiation status
Phillips, J Natl Cancer Inst 98:1777, 2006
•
Physical Dose
– Need to know more about the importance of dose-volume constraints
WMcB2009
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33. • Heterogeneity within and between between
tumors in dose-response characteristics, often
resulting in large error bars for α/β values
• In spite of this, the outcome of clinical studies of
altered fractionation generally fit the models,
within the constraints of the clinical doses used
WMcB2009
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35. Players
•
•
•
•
•
•
•
Total dose (D)
Dose per fraction (d)
Interval between fractions (t)
Overall treatment time (T)
Tumor type
Acute reacting normal tissues
Late reacting normal tissues
WMcB2009
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36. Definitions
• Conventional fractionation
– Daily doses (d) of 1.8 to 2 Gy
– Dose per week of 9 to 10 Gy
– Total dose (D) of 40 to 70 Gy
• Hyperfractionation
–
–
–
–
The number of fractions (N) is increased
T is kept the same
Dose per fraction (d) less than 1.8 Gy
Two fractions per day (t)
Rationale: Spares late responding tissues
WMcB2009
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37. Definitions
• Accelerated fractionation
– Shorter overall treatment time
– Dose per fraction of 1.8 to 2 Gy
– More than 10 Gy per week
Rationale: Overcome accelerated tumor repopulation
• Hypofractionation
– Dose per fraction (d) higher than 2.2 Gy
– Reduced total number of fractions (N)
Rationale: Tumor has low α/β ratio and there is no
therapeutic advantage to be gained with respect to late
complications
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38. TCP
or NTC
Tumor control
Late responding tissue
complications
Complication-free cure
TCP
or
NTC
Accelerated
Fractionation
Hyperfractionation
Dose
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39. Conventional
70 Gy - 35 fx - 7 wks
Hyperfractionated
81.6 Gy - 68 fx - 7 wks
Very accelerated
with reduction of dose
54 Gy - 36 fx - 12 days
Moderately
accelerated
72 Gy - 42 fx - 6 wks
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40. Hyperfractionated
Barcelona (586), Brazil (112), RTOG 90-03 (1113), EORTC 22791 (356),
Toronto (331)
Very accelerated
CHART (918), Vancouver (82), TROG 91-01 (350),GORTEC 94-02 (268)
Moderately accelerated
RTOG 90-03 (1113), DAHANCA (1485), EORTC 22851 (512) CAIR (100),
Warsaw (395)
Other
EORTC 22811 (348), RTOG 79-13 (210)
7623 patients in 18 randomized phase III trials !!
HNSCC only will be discussed
WMcB2009
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41. EORTC hyperfractionation trial in
oropharynx cancer (N = 356)
Oropharyngeal Ca T2-3, N0-1
80.5 Gy - 70 fx - 7 wks
LOCAL CONTROL
Years
Horiot 1992
control: 70 Gy - 35-40 fx - 7-8 wks
p = 0.02
SURVIVAL
p = 0.08
Years
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42. Very Accelerated: CHART (N = 918)
Dische 1997
54 Gy - 36 fx - 12 days
control: 66 Gy - 33 fx - 6.5 wks
Loco-regional control
conventional
CHART
Favourable outcome with CHART:
www.radbiol.ucla.edu
Survival
conventional
CHART
well differentiated tumors
larynx carcinomas
WMcB2009
43. CHART: Morbidity
Dische 1997
54 Gy - 36 fx - 12 days
control: 66 Gy - 33 fx - 6.5 wks
P = 0.04
P = 0.003
Moderate/severe subcutaneous
fibrosis and oedema
Mucosal ulceration and
deep necrosis
P = 0.04
P = 0.009
Laryngeal oedema
Moderate/severe dysphagia
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44. Moderately Accelerated
Overgaard 2000
DAHANCA 6: only glottic, (N = 694)
DAHANCA 7: all other sites, + nimorazole (N = 791)
66-68 Gy - 33-34 fx - 6 wks
control: 66-68 Gy - 33-34 fx - 7 wks
Actuarial 5-year rates
Local control
DAHANCA 6
DAHANCA 7
Nodal control
DAHANCA 6 + 7
Disease-specific survival
DAHANCA 6 + 7
5 fx/wk
6 fx/wk
73%
56%
81% p=0.04
68% p=0.009
Overall survival
Late effects (edema, fibrosis)
n.s.
n.s.
87%
65%
.
89% n.s.
72% p=0.04
WMcB2009
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45. Moderately Accelerated
CAIR: 7-day-continuous accelerated irradiation (N = 100)
Skladowski 2000
66-72 Gy - 33-36 fx - 5 wks
68.4-72 Gy - 38-40 fx - 5.5 wks
control: 70-72 Gy - 35-36 fx - 7 wks
control: 66.6-72 Gy - 37-40 fx - 7.5-8 wks
OVERALL SURV IV AL
Probability
CAIR
CONTROL
log-rank
p=0.00001
Follow-up (months)
WMcB2009
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46. RTOG 90-03, Phase III comparison of
fractionation schedules in Stage III and IV
SCC of oral cavity, oropharynx, larynx,
hypopharynx (N = 1113)
Fu 2000
Conventional
70 Gy - 35 fx - 7 wks
Hyperfractionated
81.6 Gy - 68 fx - 7 wks
Accelerated with split
67.2 Gy - 42 fx - 6 weeks (including 2-week split)
Accelerated with
Concomitant boost
72 Gy - 42 fx - 6 wks
WMcB2009
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50. Toxicity of RT in HNSCC
Acute effects in accelerated or hyperfractionated RT
Author
Regimen
Grade 3-4 mucositis
Cont
Exp
Horiot (n=356)
HF
49%
67%
Horiot (n=512)
Acc fx + split 50%
67%
Dische (n=918)
CHART
43%
73%
Fu (n=536)
Acc fx(CB)
25%
46%
Fu (n=542)
Acc fx + split 25%
41%
Fu (n=507)
HF
25%
42%
Skladowski (n=99) Acc fx
26%
56%
WMcB2009
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51. Altered fractionation in head and
neck cancer: meta-analysis
Randomized trials 1970-1998 (no postop RT)
15 trials included (6515 patients)
Bourhis, Lancet 2006
Survival benefit: 3.4% (36%
39% at 5 years, p = 0.003)
Loco-regional control benefit: 7% (46.5%
53% at 5 years, p < 0.0001)
WMcB2009
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52. Conclusions for HNSCC
•
•
•
•
•
Hyperfractionation increases TCP and protects late responding tissues
Accelerated treatment increase TCP but also increases acute toxicity
What should be considered standard for patients treated with radiation
only?
– Hyperfractionated radiotherapy
– Concomitant boost accelerated radiotherapy
Fractions of 1.8 Gy once daily when given alone, cannot be considered
as an acceptable standard of care
TCP curves for SSC are frustratingly shallow … selection of tumors?
WMcB2009
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53. Conclusions for HNSCC
• The benefit derived from altered fractionation is consistent
with can be of benefit but should be used with care
• In principle, tumors should be treated for an overall
treatment time that is as short as possible consistent with
acceptable acute morbidity, but with a dose per fraction
that does not compromise late responding normal tissues,
or total dose.
• Avoid treatment breaks and treatment prolongation
wherever possible – and consider playing “catch-up” if
there are any
• Start treatment on a Monday and finish on a Friday, and
consider working Saturdays
• Never change a winning horse!
WMcB2009
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54. Other Major Considerations
• Not all tumors will respond to hyper or accelerated
fractionation like HNSCC, especially if they have a low
α/β ratio.
• High single doses or a small number of high dose per
fractions, as are commonly used in SBRT or SRS
generally aim at tissue ablation. Extrapolating based on a
linear quadratic equation to total dose is fraught with
danger.
• Addition of chemotherapy or biological therapies to RT
always requires caution and preferably thoughtful preconsideration!!!
• Don’t be scared to get away from the homogeneous field
concept, but plan it if you intend to do so.
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56. Modeling of radiation responses are based
on
1. Random events occurring in cell nuclei
2. Random events in space as defined by
the Poisson distribution
3. A Gaussian distribution
4. Logarithmic dose response curves
WMcB2009
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57. D0 is
1. Is a measure of the shoulder of a survival
curve
2. Is the mean lethal dose of the linear
portion of the dose-response curve
3. Represents the slope of the log linear
survival curve
4. Is constant at all levels of radiation effect
WMcB2009
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58. Dq is
1. A measure of the inverse of the terminal
slope of the survival curve
2. A measure of the inverse of the initial
slope of the survival curve
3. A measure of the shoulder of the survival
curve
4. A measure of the intercept of the terminal
portion of the survival curve on the y axis
WMcB2009
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59. If Dq for a survival curve is 2Gy, what dose
is equivalent to a single dose of 6Gy given in
2 fractions, assuming complete repair and
no repopulation between fractions.
1. 4 Gy
2. 6 Gy
3. 8 Gy
4. 10 Gy
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60. A whole body dose of 7 Gy of x‑rays would produce severe,
potentially lethal hematologic toxicity. Assuming that the Do of
the hematopoietic stem cells is 1 Gy and that these cells have
a negligible capacity to repair sublethal radiation damage,
what is the surviving fraction of these stem cells after this dose
of radiation?
1. 0.0001
2. 0.001
3. 0.025
4. 0.067
5. 0.1167
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61. If 90% of a tumor is removed by surgery,
what does this likely represent in term of
radiation dose given in 2 Gy fractions?
1. 1-2 Gy
2. 3-4 Gy
3. 6-7 Gy
4. 9-12 Gy
5. 20-30 Gy
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62. What is true for the α/β ratio
1. It is unitless
2. It is a measure of the shoulder of the
survival curve
3. It measures the sensitivity of a tissue to
changes in size of dose fractions
4. It is the ratio where the number of nonrepairable lesions equals that for
repairable lesions
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63. The alpha component in the linear quadratic
formula for as radiation survival curve
represents
1. Unrepairable DNA double strand breaks
2. Lethal single track events
3. Multiply damaged sites in DNA
4. Damage that can not be altered by
hypoxia
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64. Which parameter is most relevant for
standard clinical regimens in RT
1. The α/β ratio
2. Do
3. Alpha
4. Beta
5. The extrapolation number
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65. If cells have a Do of 2 Gy, assuming no shoulder,
what dose is required to kill 95% of the cells?
1. 6 Gy
2. 12 Gy
3. 18 Gy
4. 24 Gy
5. 30 Gy
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66. The extrapolation number N for a multifraction survival curve, allowing complete
repair between fractions and no repopulation
is
1. 1
2. < 1
3. >1
4. Dependent on the size of the dose per
fraction
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67. The extrapolation number N for a single
dose neutron survival curve is
1. 1
2. < 1
3. >1
4. Dependent on the size of the dose per
fraction
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68. The extrapolation number N for a low dose
rate survival curve is
1. 1
2. < 1
3. >1
4. Dependent on the size of the dose per
fraction
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69. The inverse of the slope of a multifraction
survival curve (effDo) is generally within the
range
1. 1.0-1.5 Gy
2. 1.5-2.5 Gy
3. 2.5-5.0 Gy
4. 5.0-10.0 Gy
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70. If the effDo for a multifraction survival curve is
3.5 Gy, what dose would cure 37% of a
series of 1cm diameter tumors (109
clonogens).
1. 56 Gy
2. 64 Gy
3. 72 Gy
4. 80 Gy
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71. If the effDo for a multifraction survival curve is
3.5 Gy, what dose would cure 69% of a
series of 1cm diameter tumors (109
clonogens).
1. 56 Gy
2. 64 Gy
3. 72 Gy
4. 80 Gy
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72. If a tumor has an effective Do of 3.5 Gy,what is the
S.F. after 70 Gy?
1. 2 x 10-11
2. 2 x 10-9
3. 2 x 10-7
4. 2 x 10-5
5. 2 x 10-3
WMcB2009
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73. If 16 x 2 Gy fractions reduce survival by 10-4, what
dose would be needed to reduce survival to 10-10?
1. 50 Gy
2. 60 Gy
3. 64 Gy
4. 70 Gy
5. 80 Gy
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74. If 16 x 2 Gy fractions reduce survival by 10-4, what is
the effective D0?
1. 2.0 Gy
2. 2.3 Gy
3. 3.0 Gy
4. 3.5 Gy
5. 3.8 Gy
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75. The α/β ratio for mucosal tissues is closest
to
1. 2 Gy
2. 4 Gy
3. 6 Gy
4. 8 Gy
5. 10 Gy
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76. Which of the following human tumors Is
thought to have an α/β ratio of 1-2 Gy
1. Oropharyngeal Ca
2. Prostate Ca
3. Glioblastoma
4. Colorectal Ca
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77. The TD5/5 for a certain tissue irradiated at 2
Gy/fraction is 60 Gy whereas at 4 Gy/fraction it is 40
Gy. Assuming that the linear quadratic equation,
‑lnSF= N (αD + βD2), accurately represents cell survival
for this tissue, what is the value of α/β?
1. 1 Gy
2. 2 Gy
3. 4 Gy
4. 10 Gy
5. 20 Gy
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78. It is decided to treat a patient with hypofractionation at 3
Gy/fraction instead of the conventional schedule of 60 Gy
in 2 Gy fractions. What total dose should be delivered in
order for the risk of late normal‑tissue damage to remain
unchanged according to the linear‑quadratic model with
α/β for late damage = 3 Gy?
1. 40 Gy
2. 48 Gy
3. 50 Gy
4. 55.4 Gy
5. 75 Gy
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79. A standard treatment for HNSCC tumors is 70 Gy delivered at 2
Gy/fraction. Hyperfractionation is being attempted with a fraction
size of 1.2 Gy. What total treatment dose should be used to
maintain the same complication rate for the late responding
normal tissues. Assume full repair of sublethal damage between
fractions and an α/β of 3 Gy.
1. 42 Gy
2. 58 Gy
3. 70 Gy
4. 83 Gy
5. 117 Gy
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80. A standard treatment for HNSCC tumors is 70 Gy delivered at 2
Gy/fraction. Hyperfractionation is being attempted with a fraction
size of 1.2 Gy. What total treatment dose should be used to
maintain the same complication rate for the late responding
normal tissues. Assuming no proliferation and complete repair
between fractions, an α/β of 3 Gy for late responding tissue and
12 Gy for tumor, what would be the therapeutic gain.
1.
6%
2. 12%
3. 18%
4. 24%
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81. Which of the following sites is the least
suitable for b.i.d. treatment
1. Head and neck
2. Brain
3. Lung
4. Prostate
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82. The rationale behind accelerated
fractionation is
1. To spare late responding normal tissue
2. To combat encourage tumor
reoxygenation
3. To exploit redistribution in tumors
4. To combat accelerated repopulation in
tumors
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83. The CHART regimen for HNSCC of 54Gy in 36 fractions over
12 days compared with 66 Gy in 33 fractions in 6.5 weeks,
overall showed
1. Superior locoregional control, no increase in overall
survival, increased late effects
2. Superior locoregional control that translated into an
increase in overall survival, no change in late effects
3. No change in locoregional control and overall survival,
decreased late effects
4. Superior locoregional control, no increase in overall
survival, increased acute effects
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84. DAHANCA 6 and 7 clinical trials with 6668Gy given in 6 compared to 7 weeks
1. Was a hyperfractionation trial
2. Treated 6 days a week
3. Showed no increase in local control
4. Showed no increase in disease-specific
survival
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85. RTOG 90-03, which compared hyperfractionation,
accelerated fractionation with a split, and
accelerated fractionation with a boost showed
1. Hyperfractionation to be superior in terms of
loco-regional control and late effects
2. Accelerated fractionation with a split to be
equivalent to hyperfractionation in terms of locoregional control
3. There to be no advantage to altered fractionation
4. Accelerated fractionation to be superior to
hyperfractionation
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Radiation Biology is study of the effects of radiation on living things. For the most part, this course deals with the effects of radiation doses of the magnitude of those used in radiation therapy.
The mathematical bent of early radiobiologists led them to describe survival curves by the mean lethal dose (D37 or D0), which is the dose required to cause on average one lethal hit per cell and result in 37% survival. In practice D10, the dose that would reduce survival to by one log10, which is 2.3x D0 is easier to use. The slope of the curve is given by , where D0 is 1/. Bacterial killing and protein inactivation follow this log-linear curve, although the D0 values are high compared with mammalian cells.
In 1956 Puck and Marcus published the first survival curve for mammalian cells and noted that the D0 was 100-150cGy. Furthermore, it had a shoulder region before the logarithmic decline. It is easiest to think of this as single-hit and multi-hit killing (another assumption!). At low doses, the rate of deposition of energy by a charged particle is inversely proportional to its energy, and as it loses energy through collisions and scattering the distribution of ionizing events become more dense and the probability of a lethal lesion being formed by a single track increases. At higher doses, accumulation of injury from other tracks (intertrack) becomes a more likely cause of a lethal lesion. Note that the nature of the chromosomal lesions will go from being predominantly deletions to more exchange-type (two-hit) lesions. Note that with doses of around 2Gy, the former will dominate.
Adenocarcinoma may be fractionation sensitive, like LRT
Fractionation alpha nd beta
An additional complication has been reported by Joiner et al, who have shown that certain cell lines show a hypersensitivity zone at 0.05-0.2 Gy that flattens out over 0.05-1 Gy, before showing the normal shape of survival curve. The basis for this is not well established but hypersensitivity is thought to be associated with increased apoptosis and lack of G2 arrest.
Fractionation benefits
Fractionation spare late tissues
Fractionation and time prolongation
Alternative or supplemental indicator of treatment outcome
Conventional empirically developed Fletcher
Radiosensitive tumors can be controlled with low doses (seminoma and lymphoma), low incidence of normal tissue damage
GBM very radioresistant
Most tumors intermediate sensitivity SCC, adenoca
Tumor size also plays a role
Conformal radiotherapy: dose escalation with sparing of normal tissues but when done in a conventional way, lengthening OTT
Hyperfractionation: escalate dose, improve tumor control without increasing risk of late complications.
Exceptions of tumors with low a/b: melanoma, prostate, liposarcoma
Applied in the palliative setting, limited life expectancy, late side effects not an issue
Moderate hypofractionation used in some countries, total dose usually lower but OTT also shorter which may compensate for the expected reduction in local tumor control
A way to escalate dose in trials of CRT? SIB
Accelerated fractionation:early normal tissue reactions are expected to increase. If interval between fractions is long enough late normal tissue side effects should be the same or less if fractionsize is lower than 1.8 or 2 Gy and/or total dose is decreased
Pooled grade 2 and 3 side effects
Increase of about 19 %in long term local tumor control
Interfraction interval 4 to 6 hours
12 consecutive days, 3 fractions per day, interval 6 hours, 1.5 Gy, total dose 54 Gy, total dose is lower to remain within tolerance of acutely responding tissues
918 patients
OTT reduced by 33 days, total dose is 12 Gy less but LC is the same.
Mucositis occured earlier but settled sooner as well, skin reactions were less severe.