Normal organ Biological Effective Dose (Saving kidney, bone marrow and liver)

Safety and toxicity

Azmal/Su/Jamila

BED: Introduction

• Radiobiological model

• Can help predict clinical outcomes when treatment parameters are altered

• base on:

– linear quadratic model

– radiobiological data for patients

• assumes:

– full repair between two fractions

– no proliferation of tumor cells

BED: Definition

Biologically effective dose (of a given schedule) is:

• the total dose required to give the same log cell kill as the schedule being studied,

• at an infinitely low dose-rate or with infinitely small fractions well spaced out;

• with an overall time factor for repopulation during continued irradiation

• for a tissue with a particular α/β ratio only

BED: Formula

BED=nd(1+d/[α/β]) - loge2 (T-Tk)/αTp

• n fractions of

• d Gy are given

• in an overall time of T days

• and tumour repopulation doesn’t start until day Tk

(using k for kick-off, or onset, of the delayed repopulation during fractionated irradiation)

• assuming a constant repopulation rate or cell doubling time Tp up to the end of the RT

α and β

• tissue specific coefficients for radiation damage

• α proportional to dose (one single event is lethal)

• β proportional to dose squared (two sublethalevents required for lethal damage)

• α/β ratio

- repair capacity

- quantifies the sensitivity of a given tissue to changes in fractionation

Dose limiting organ(organ with largest absorbed dose)

• nonmyeloablative radionuclide therapy: red marrow

• 90Y-ibritumomab tiuxetan therapy: liver

• 131I-tositumomab: lung, liver and kidney

• peptide receptor radionuclide therapy (PRRT): red marrow and kidney

• 90Y-glass or resin microsphere: liver and lung

• 11C-docetaxel: liver and gall bladder

• 89Sr, 153Sm, 186/188Re- RP: bone surface, red marrow

• 223 RaCl2 : bone surface

Dose limiting organ(organ with largest absorbed dose)

• nonmyeloablative radionuclide therapy: red marrow

• 90Y-ibritumomab tiuxetan therapy: liver

• 131I-tositumomab: lung, liver and kidney

• peptide receptor radionuclide therapy (PRRT): redmarrow and kidney

• 90Y-glass or resin microsphere: liver and lung

• 11C-docetaxel: liver and gall bladder

• 89Sr, 153Sm, 186/188Re- RP: bone surface, red marrow

• 223 RaCl2 : bone surface

Red marrow

Non specific/?SSRT mediatedUptakeβ or γ range

Mild transient myelotoxicityMyelodysplastic syndrome

Blood basedImage based

2-3 Gy

Indv. dosimetryα emitter

Figure: Penetration of γ-rays, β particles and α particles into bone marrow

Cancer J 2013;19: 71-78

Kidney

Megalin/ cubilinSSRTPinocytosisOrganic anion transporter

Radiation nephropathy: Acute/chronic

PlanarSPECT3D RBD

28 vs 40 Gy<7.4GBq/m2

L-lys & L-arg 25g/25g Fractionation

111In-DTPA-exendin-4

40-50

MBq

Megalin deficient : 20-40 Gy/kidney

Wild type: 70 Gy/kidney

↓Body wt.

↑uri. protein

↑U&C

Histopath

16-19 weeks

Thickening and necrosis of tubular basal lamina Glomerulo-sclerosisMelis et al. J NuclMed. 2010 (51)

Megalin

• 600 kD, member of LDL protein family

• Also known as LRP2

• A multiligand binding receptor

• Expressed in plasma membrane of absorptive epithelial cells: lungs, oviducts, thyroid, parathyroid, eyes & ears

• Present as Megalin/Cubilin complex, a scavenging protein receptor in apical membrane of renal proximal tubular cells.

Megalin

• Facilitates renal re absorption (endocytosis) of peptides, (binding) proteins, hormones, drugs, toxins and enzymes.

• Re absorption of radio-labeled octreotide in mice.

• ↓uptake and ↓renal retention of 111In-SSTR analogue is seen in absence of megalin.

Figure: Abdominal scintigraphy in a patient

after 220MBq 111DTPA-octreotide:

(A) without and (B) with coinfusion of LysArg

Renal activity 52% controlled with LysArg

A B

Eur J Nucl Med (2003) 30:9-15

Liver

Portal triaditisLow gr pHTN

RE Induced Liver Disease (REILD)

99mTc-MAA3D voxelBremsstrahlung SPECT90Y PETSPECT/MR

35-520 Gy

Lobar/segmental RE Fractionation

Dose delivered to liver

Figure : Liver absorbed dose and tolerability Front Oncol 2014 4: 210

Lung

β radiation mediated damage

Prog. pul. insuf, Pul. fibrosisRadiation pneumonitis

99mTc-MAA

<20-30 Gy

Multicompartmentalmethod

Dose delivered to lung

Figure : Lung absorbed dose and tolerability Front Oncol 2014 4: 210

Suggested normal limits from literature

RN Disease Max Limit131I DTC, Benign thyroid, NB, BCL 2Gy to blood90Y Liver NET 2Gy to BM

Radiopeptide

NET 28Gy and 40Gy for kidneys

90Y-microspheres

HCC, metastatic liver tumors Variable ?35-520Gy

Zevalin NHL, Follicular lymphoma WB AD 1.3-2.4mGy/MBq

Bexxar NHL. Folliclar lymphoma WB AD 0.65-0.75 Gy

Suggested safety measures from literature

RN Organ safety measures131I, 90Y Bone marrow Individual dose optimization

radiopeptide

Kidney Co administratin of amino acids

90Y-microspheres

Liver Selective placement of catheter to hepatic artery, targeting of least possible number of segments

90Y-microspheres

Lung LS 20%, <20 or 30Gy

References

Fowler. Br J Radiol, 2010; 83:554-568

Jones et al. Clin Oncol, 2001;13:71-81

Brady et al. Cancer J 2013;19: 71-78

Cremonesi et al. J Nucl Med, 2007;48:1871-1879

Rajendran et al. J Nucl Med, 2008;49:837-844

van der Veldt et al. Eur J Nucl Med Mol Imaging, 2010;37:1950-1958

Rolleman et al. Eur J Nucl Med, 2003;30:9-15

Cremonesi et al. Front Oncol, 2014;4:210

Forrer et al. Eur J Nucl Med Mol Imaging, 2009;36:1138-1146

Baroneet al. J NuclMed. 2005;46:99s-106s

Bodeiet al. EurJ NuclMed Mol Imaging. 2008;35:1847-1856

Otte et al. Eur J Nucl Med,1999;26: 1439-1447

Fisher et al. J Nucl Med, 2009;50:644-652

Zevalin prescribing information; http://www.zevalin.com/v3/pdf/

Bexxar prescribing information; http://us.gsk.com/products/assets/ us_bexxar.pdf.

O’Donoghue et al. Cancer Biother Radiopharm, 2002;17:435-443

Boucek et al. Eur J Nucl Med Mol Imaging, 2005;32:458-469