1. Predictive models validated by clinical data: new strategies for fractionation
Dr. M. Benassi
Dr. S. Marzi

2. Surviving Cell Fraction SF
N0= initia cell number
before irradiation
N = surviving cell number
after irradiation SF
SF =N/ N0
D(Gy)

3. Dose Fractionaction Schedules
LQ Model and
Dose Fractionaction Schedules
Surviving cell fraction
a fractionated delivery of total dose D in equal fractions of dose d is assumed
damage repair and cell proliferation are absent
a linear term attribuited to non-reparaible DNA lesions
b quadratic term attribuited to two reparaible lesions interacting to kill the cell
a/b involves the efficacy of different dose fractionations :
large values of a/b damage depends on D
small values of a/b damage is affected by both D and d

4. Dose Fractionaction Schedules
LQ Model and
Dose Fractionaction Schedules
Biological
Effective
Dose
for a single tissue:
same BED results in the same SF
a drops out of BED
BED depends only on the better-known a/b

5. to the dose per fraction
Hypofractionation
Schedules
Damage to the tumor
is sensitive
to the dose per fraction
Rationale
tumor a/b be 1.5 Gy (*)
late-responding tissue a/b be 3 Gy
same late complications
Dstd be the total dose in 2 Gy fractions
DHF be the total dose in 3 Gy fractions
Example:
Prostate
(*)FOWLER J., CHAPPELL R. and RITTER M., 2001 Is a/b for prostate tumors really low? Int. J. Radiation Oncology Biol. Phys., 50(4)

6. BED Calculations
Tumor:
Normal tissues:
same late complications ---> lower dose prescribtion
in spite of this the tumor BED increases

7. to the dose per fraction
Hyperfractionation
Schedules
Damage to the tumor
is insensitive
to the dose per fraction
Rationale
Example:
tumor a/b be 10 Gy
late-responding tissue a/b be 3 Gy
same late complications
Dstd be the total dose in 2 Gy fractions
DHF be the total dose in 1.2 Gy fractions
Head
and Neck

8. BED Calculations
Tumor:
Normal tissues:
same late complications ---> higher dose prescribtion
---> increased tumor BED
(!) acutely respondig tissues, for ex. mucosa, also experience increased BED

9. normalized to 2 Gy per fraction (NTD) using BED:
Normalized total dose
If the fraction size is different from dref = 2 Gy the physical total dose can be converted to the biologically equivalent total dose
normalized to 2 Gy per fraction (NTD) using BED:
NTD

10. dose-volume histogram
Normalized
dose-volume histogram
With the advent of 3DCRT (three dimensional conformal radiation therapy) the dose delivery is often characterized by steep dose gradients and inhomogeneous dose distributions, especially within sensitive structures;
NTD formulation may be used to take into account the actual fractionation for each structure at each voxel:
Normalized
DVH

11. A Time-dependent Effect:
Repopulation
number of fractions
lag time before accelerated repopulation begins
unperturbed doubling time
accelerated tumor clonogen doubling time
overall treatment duration
MOHAN R., WU Q., MANNING M., SCHMIDT-U. R., 2000 Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers Int J Radiat Oncol Biol Phys 46 (3)

12. Including Repopulation
NTD
Including Repopulation
For a given fractionation strategy for which repopulation is considered, the corresponding NTD can be derived from the new SF:
the equation system can be solved adopting an iterative search of nNTD and Tt,NTD
number of days in all the weekends

13. Simultaneous Integrated Boost Conventional treatments:
are often divided into two phases, initial large photon fields followed by a boost to a reduced volume
IMRT techniques:
allow a simultaneous treatment
(SIB simultaneous integrated boost)
produce more conformal dose distributions
reduce normal tissue doses
are biologically more effective

14. Head and neck (HN): Standard radiotherapy:
D  70 Gy to gross tumor (in 2 phases, photon + electron fields)
50 Gy  D  70 Gy to surrounding tissues (photons)
D  50 Gy to lymph nodes at risk (photons)
dose per fraction d = Gy
Treatment time Tt  7 weeks

15. Head and neck (HN): IMRT brainstem parotid spinal cord
GTV
Limph
nodes
7 or more IMRT fields

16. Head and neck (HN): tumor parameters
MOHAN R., WU Q., MANNING M., SCHMIDT-U. R., 2000 Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers Int J Radiat Oncol Biol Phys 46 (3)
WU Q., MANNING M., SCHMIDT-ULLRICH R. and MOHAN R., 2000 The potential for sparing of parotids and escalation of biologically dose with intensity-modulated radiation treatments of head and neck cancers: a treatment design study Int J Radiat Oncol Biol Phys 46 (1)

17. HN : normal tissue a/b values
dose per fraction is significant
are affected by the total dose
same or lower doses and lower dose per fraction are delivered to normal tissues outside the target volume
dose to normal tissues embedded within the target volume may be significantly higher and possible late effects need to be investigated
SIB:

18. Nasopharynx carcinoma
Example:
Nasopharynx carcinoma
GTV: 69.3 Gy/2.1Gy
CTV: 60 Gy/1.8 Gy
parotid
GTV
CTV
GTV
(positive nodes)

19. Dose-Volume Histograms
PTV 60 Gy
PTV 69.3Gy
spinal cord
right parotid
brainstem
left parotid

20. Dose-Volume Histograms
Normalized
Dose-Volume Histograms
spinal cord
right parotid
left parotid

21. Example: Prostate carcinoma Prostate: 77 Gy/2.2 Gy
Lymph nodes: 59.5 Gy/1.7 Gy
lymph nodes
prostate

22. Example: Pelvic irradiation
Uterus: 70.4 Gy/2.2 Gy
Lymph nodes: 57.5 Gy/1.8 Gy
bowel
lymph nodes
uterus

23. Pelvic and para-aortic irradiation
Example:
Pelvic and para-aortic irradiation
VisibleTumor: 66 Gy/2.2 Gy
Lymph nodes : 54 Gy/1.8 Gy
para-aortic
lymph nodes
Kidneys
GTV

24. Physical and Biolgical
Conformality
Rationale for the adoption of IMRT is also the ability to spatially customize 3D-dose delivery to supposed tumor foci of increased radioresistence or proliferative capabilities
new imaging techniques are necessary to define more precisely the edges of the visible tumor and its surroundings  BTV (biological target volume) is derived from metabolic, functional and genotypic data
a better knowledge of tumor radiobiologic characteristics not only improve the target identification but also support the choice of different dose prescribtions in each tumor subvolumes

25. Biologically conformal boost
dose optimization
Some approaches are described in literature to convert the physical dose into an “effective” dose transforming the biological image (PET, fMRI, ect) into a dose efficiency distribution;
a relative dose efficiency (0 <e(x)< 1) may be introduced to represent the radiation effect on the tumor at each point x (*) ;
the optimization algorithm can be forced to compensate for regionally variable radiosensitivity in order to achieve the best intensity modulation;
the assumption is that the effective dose should be homogeneous:
effective dose
(*) ALBER M., PAULSEN F., ESCHMANN S.M. and MACHULLA H. J., 2003 On biologically conformal boost dose optimization Phys. Med. Biol. 48 N31-N35

26. The cumulative dose-volume histogram of the target volume
and the histogram showing the effective dose distribution

27. Biologically conformal boost
dose optimization
A similar approach has been proposed(*) to integrate the information coming from metabolic and functional images within the inverse planning process:
conventional prescription dose
conventional tolerance dose
empirical coefficients
correlated with metabolic informations
correlated with functional informations
Tumor
Sensitive structures
(It was supposed a linear relation between the metabolic information and the prescribed dose but the formalism can be extended to any other relation)
(*) XING LEI et al., 2002 Inverse planning for functional image-guided intensity-modulated radiation therapy Phys. Med. Biol

28. Conclusions
LQ-model may be used to design the most appriopriate fractionation schedules (iperfractionation or ipofractionation depending on a/b values)
for some tumors (short doubling time) the repopulation effect has to be included on SF formalism
high conformality of IMRT plans allows to deliver simulateneous boost (SIB), that may be advantageous in different clinical situations
SIB techniques force to account for altered fractionations (different doses are delivered in the same number of fractions)
the lack of reliable radiobiological data has limited until now their use for making clinical predictions but
the integration of physical and biological conformality
will greatly improve the efficacy of radiotherapy