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

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

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

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

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) 1021-1031

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

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

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

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

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

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) 619-630

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

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

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 = 1.8 - 2 Gy Treatment time Tt  7 weeks

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

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) 619-630 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) 195-205

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:

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

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

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

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

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

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

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

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

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

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. 47 3567-3578

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