EN TERAPIA METAByLICA NO ESTrNDAR CON 177 Lu, 90 Y y 223 Ra

Jornada científica RADIOFuSICA DE LA DOSIMETRuA INTERNA EN LOS PROCEDIMIENTOS TERAPÉUTICOS CON RADIOFrRMACOS DOSIMETRIA FuSICA Y CLuNICA EN TERAPIA METAByLICA NO ESTrNDAR CON 177 Lu, 90 Y y 223 Ra Pablo Mínguez Gabi!a Unidad de Protecci"n Radiol"gica y Radiofísica H. U. Cruces/Gurutzeta (Barakaldo) H. U. Puerta de Hierro Majadahonda, 06-Junio-2016

Introduction In radionuclide therapy (RNT), 131 I is the most often used radionuclide. 131 I-NaI Hyperthyroidism Differentiated thyroid cancer 131 I-mIBG (metaiodobenzylguanidine) Neuroblastoma Adult neuroendocrine tumours 131 I-antibody Radioimmunotherapy

There are many other radionuclides which can be used in RNT 177 Lu and 90 Y labelled to somatostatin analogues (Peptide Receptor Radionuclide Therapy) for neuroendocrine tumours 177 Lu labelled to the monoclonal antibody J591 for PSMA (Prostate-specific membrane antigen) therapy of castration-resistant prostate cancer 90 Y glass or resin microspheres for intra-arterial treatments in the liver 90 Y, 169 Er, 186 Re for synovectomy.

153 Sm, 89 Sr (palliative) and 223 Ra (therapeutic, ALSYMPCA study) for bone metastases. 32 P chromic phosphate for myeloproliferative diseases. 90 Y Zevalin (monoclonal antibody) for B-cell lymphoma. TTT.

177 Lu labelled to the molecule DOTA-(Tyr3)- octreotate or DOTATATE 90 Y microspheres for intra-arterial treatments of the liver SIRT (Selective Internal Radiation Therapy) 223 Ra-dichloride to treat bone metastases in patients with castration resistent prostate cancer (CRPC)

Production of 177 Lu: -direct pathway: irradiation of an enriched 176 Lu target with neutrons: 176 Lu(n, γ) 177 Lu (there is 177m Lu). The specific activity is about 1000 GBq/mg (more than three stable Lu atoms for every 177 Lu). -indirect pathway: irradiation of 176 Yb to produce 177 Yb (T 1/2 =1.9 h) which decays to 177 Lu 176 Yb(n, γ) 177 Yb(β-) 177 Lu. The specific activity is about 4000 GBq/mg (nearly every Lu atom is 177 Lu).

Radiation protection issues: The air-kerma rate constant @ 1 m is 7.636 @Sv h -1 GBq -1 (for radioiodine it is 51.0 @Sv h -1 GBq -1 @ 1 m) Outpatient or inpatient? Outpatient or inpatient? In our hospital the protocol consists of hospitalising patients one night to collect the urine but it may not be necessary.

177 Lu decays by β - emission to the fundamental level and to excited levels of 177 Hf with a physical half-life of 6.647 d. There are 6 γ emissions from the excited levels of 177 Hf with energies: 112,9498 kev (6,20%) 136,7245 kev (0,05%) 249,6742 kev (0,20%) 71,6418 kev(0,17%) 208,3662 kev(10,38%) 321,3159 kev(0,22%) There are also X-ray emissions, Auger electrons, and bremsstrahlung.

The maximum kinetic energy of the β - particles is of 498.3 kev with a maximum range in soft tissue of 1.7 mm. The mean kinetic energy is of 134 kev with a mean range in soft tissue of 0.23 mm.

Which collimator should we use? Compromise between increasing the sensitivity in order to improve the SNR and the necessity of minimising the septal penetration of high energy photons. For energy windows of 112.9498 kev and 208.3662 kev, the sensitivities of a GE Infinia gamma camera have been studied with SIMIND Monte Carlo simulations using a Petri dish with a radius of 5 cm and a source collimator distance of 10 cm. MIRD Pamphlet No. 26. Ljungberg et al.

Sensitivity values (cps/mbq) crystal thickness of 3/8 66 Collimator 113 kev 208 kev 15% 20% 15% 20% HE 6.8 (3.0%) 7.5 (3.1%) 7.0 (6.8%) 7.2 (6.9%) ME 5.8 (3.3%) 6.3 (3.5%) 6.0 (7.8%) 6.1 (8.0%) LEGP 16.1 (31.8%) 18.6 (35.4%) 71.5 (84.7%) 74.6 (84.9%) LEHR 12.0 (43.5%) 14.3 (47.9%) 70.3 (90.4%) 73.2 (90.5%) In parenthesis there is the contribution due to the scatter in the collimator and to the septal penetration. MIRD Pamphlet No. 26. Ljungberg et al.

The sensitivity is higher for the LE collimators than for the ME and HE collimators. The HE collimator has a slightly higher sensitivity than the ME collimator because it has bigger collimator holes, but it has worse spatial resolution. Thus, it is preferable to use the ME collimator and the energy window of 208 kev because in the case of LE collimators (energy window 113 kev) there is a too high contribution of scattered photons and of septal penetration photons. Both energy widths 15% and 20% can be used. MIRD Pamphlet No. 26. Ljungberg et al.

Calibration of the gamma camera (cps/mbq) Planar acquisitions (when corrections such as attenuation and scatter correction are accurate) -point source or Petri dish in air. The calibration factor will be the count rate in the appropriate ROI (correction for scatter and septal penetration may be necessary) divided by the activity in the source. MIRD Pamphlet No. 26. Ljungberg et al.

SPECT acquisitions (when corrections are not that accurate) -Tank of uniform activity or tank with hot spheres. Acquisition protocol and reconstruction procedure must be the same as with patients. The calibration factor will be the count rate in the appropriate VOI divided by the activity. MIRD Pamphlet No. 26. Ljungberg et al.

OLINDA S-values of unit-density spheres for tumour dosimetry

OLINDA S-values for organ dosimetry

Image acquisitions in patients: -Planar images. Short acquisition times. -SPECT/CT images. More accurate activity quantification. Long acquisition times. A compromise is the hybrid SPECT-conjugate view method: -Planar images in all the time-points and a SPECT/CT acquisition to renormalise the time-activity curve. Dead-time correction is usually not necessary in treatments with 177 Lu.

Recommended acquisition times: Recommended acquisition times: -1d, 4d, 7d (Choose the administration day!) -Early acquisition (1h) for a fast-washout phase. -Late acquisition may be necessary as activity in the tumour has been measured even 1 month after administration.

Integration method (it may depend on the number of time-points): -Exponential curve (1 washout phase). -Trapezoidal + exponential curve. -Combination of exponential curves.

Rationale for therapeutic use: The 177 Lu is usually labelled to the molecule DOTA- (Tyr3)-octreotate or DOTATATE, which is an analogue of somatostatin. Thus, the somatostatin receptors, especially sstr2, in neuroendocrine tumours will take up DOTATATE.

Most often used treatment protocol: -4 activity administrations of 7.4 GBq of 177 Lu with a time interval between administrations of about 8 weeks.

In the clinical dosimetry the OARs are: -Kidneys. Absorbed-dose constraints between 21 Gy-27 Gy. BED can be used as a reference with a constraint value of 40 Gy. DVH to study the heterogeneity. -Bone marrow (2 Gy). There are no data for tumour-absorbed dose prescription

Absorbed doses per administered activity: [kidneys. Values between 0.62 Gy/GBq and 0.9 Gy/GBq. (18.35 Gy to 26.64 Gy) [bone marrow. Values between 0.02 Gy/GBq and 0.07 Gy/GBq. (0.59 Gy to 2.07 Gy) [liver. Values between 0.13 Gy/GBq and 0.21 Gy/GBq. (3.85 Gy to 6.22 Gy) The joint IAEA, EANM, and SNMMI practical guidance... Zaknun et al.

The acquisition is performed in the energy window of 208 kev. Acquisition times for planar imaging are (0.5h), 24h, 96h and (168h) after treatment administration. For SPECT, the acquisitions times are at 24h and/or 96h. 177Lu-[DOTA0,Tyr3] Octreotate Therapy... Garkavij et al.

Kidney dosimetry: 4 dosimetric methods are used in order to determine the absorbed dose to kidneys: -1. Planar images: 1A. Background/Overlapping correction with a ROI adjacent to the kidneys due to the intestinal uptake. 1B. Background/Overlapping correction with a ROI outside the abdominal cavity. 177Lu-[DOTA0,Tyr3] Octreotate Therapy... Garkavij et al.

-2. SPECT/CT 2A. The absorbed dose obtained from Method 1A is normalised with SPECT/CT acquisitions. 2B. The absorbed dose is determined at a voxel level and the median absorbed dose is chosen as the representative absorbed dose. 177Lu-[DOTA0,Tyr3] Octreotate Therapy... Garkavij et al.

Results for absorbed dose to kidneys per administered activity in the 4 methods: 1A 1B 2A 2B 0.97 Gy/GBq 1.15 Gy/GBq 0.81 Gy/GBq 0.90 Gy/GBq 177Lu-[DOTA0,Tyr3] Octreotate Therapy... Garkavij et al.

The main reason for the differences between planar imaging and SPECT/CT imaging lies in the background/overlapping correction. In Method 1B the ROI is chosen outside the abdominal cavity and the absorbed dose to kidneys seems to be overestimated. The absorbed dose to kidneys per administered activity is similar in each of the cycles of the treatment. 177Lu-[DOTA0,Tyr3] Octreotate Therapy... Garkavij et al.

The whole-body absorbed dose is of 0.07<0.02 Gy/GBq. Thus, for one cycle of 7.4 GBq the whole-body absorbed dose is of 0.52 Gy, and for the 4 cycles of 2.08 Gy. The tumour-absorbed dose per administered activity lies in a very wide range: 0.1 Gy/GBq to 20 Gy/GBq. After 4 cycles: 2.96 Gy to 592 Gy 177Lu-[DOTA0,Tyr3] Octreotate Therapy... Garkavij et al.

The conjugate view method is used. Mean absorbed dose to kidneys per administered activity is 0.80 Gy/GBq. For 4 cycles of 7.4 GBq the total absorbed dose would be 23.68 Gy. A wide range of values obtained: 0.33 Gy/GBq to 2.4 Gy/GBq Individualised dosimetry. Estimation of the absorbed dose to the kidneys... Larsson et al.

Radiobiological considerations: The ratio of tumour BED to OAR BED has been suggested as a clinically useful metric to choose between different treatment schedules (Number of activity administrations and time interval between administrations). Kidneys are considered to be late reacting organs α/β about 3 Gy.

Biologically effective dose in fractionated... Minguez et al.

If the ratio of the tumour BED to kidneys BED is calculated for a different number of treatment administrations and different time intervals between administrations, the schedule with the highest ratio would lead to the higher tumour BED for the same toxicity to the kidneys (e. g. adjusting the kidneys BED to the toxicity limit)

90 Y production 90 Y is a decay product of 90 Sr, which is a long-lived fission waste product. 90 Y can thus be obtained from a 90 Sr / 90 Y generator.

Decay scheme of 90 Y

-The maximum range in soft tissue is 11 mm (E max =2.2798 MeV) and the mean range is 2.5 mm (E mean =0.933 MeV). -The physical half-life is 64.041 h (2.6684 d). -In principle there are no radiation protection issues for members of the public.

99m Tc-MAA (Macro-Aggregated Albumin) imaging Previous to the treatment. Dosimetry with 99m Tc-MAA images is performed relying on the same behaviour for the 90 Y-microspheres. Calculate lung shunting. Calculate tumour involvement.

99m Tc-MAA SPECT/CT based dosimetry is accurate. It is mentioned that some studies have found a high correlation between microspheres distribution for 99m Tc-MAA and 90 Y-microspheres, when injected in the same way. A correlation between tumour absorbed dose and overall survival is demonstrated.

90 Y imaging -Gamma camera (planar imaging or SPECT/CT). Using the bremsstrahlung caused by the β - particles. -PET/CT. Using the emission of β + particles from the 0 + 0 + transition.

90 Y gamma camera imaging. -Acquisitions are performed using a ME (or even a a HE) collimator with energy windows lower than 200-250 kev and with different energy window widths.

90 Y PET/CT imaging.

The treatment with microspheres can be delivered for: -hepatocellular carcinoma. -liver metastases. Two types of 90 Y-microspheres: -Resin microspheres with sizes between 20 μm and 60 μm. The microspheres can be delivered to the tumour via the hepatic artery, but they cannot leave the arterial circulation. Activity per microsphere 50 Bq. -Glass microspheres with sizes between 20 μm and 30 μm. Activity per microsphere 2500 Bq.

% Tumour involvement Activity (GBq) > 50% 3.0 GBq 25 % - 50% 2.5 GBq < 25% 2.0 GBq

ii) Body Surface Area (BSA) Method. The most often used method to prescribe the activity to administer. In this method the activity to administer is adjusted according to the size of the tumour within the liver (tumour involvement) and the size of the patient (BSA). Adjustments are made for the amount of lung shunting in the patient.

Activity constraints in the empirical and the BSA methods: Percent lung shunting Activity <10% As calculated 10% - 15% Reduce activity by 20% 15% -20% Reduce activity by 40% >20% Contraindicated therapy In patients with a reduced liver function a decrease of activity of 25% should be considered.

iii) Partition model In this model the maximum activity that does not exceed the constraints for the absorbed doses to liver and lungs is calculated. D max liver parenchyma between 50 Gy and 80 Gy. D max lungs between 20 Gy and 30 Gy. Alternatively a tumour absorbed dose can be prescribed.

Dosimetric techniques in 90 Y-Microsphere Therapy... Gulec et al.

Higher absorbed doses reported with glass microspheres (117 Gy right lobe 108 Gy left lobe) than with resin microspheres (50.8 Gy right lobe 44.5 Gy left lobe). However, 92% (glass microspheres) and 94% (resin microspheres) of patients with partial response or stable disease at 6 months after treatment.

As normal liver tissue is a late reacting tissue then a radiobiological optimisation can be performed. (α/β=10 Gy for tumour and α/β=2.5 Gy for liver) Multi-cycle treatments would allow administering higher activities than a single cycle. Higher tumour BED keeping constant the liver BED.

Production of 223 Ra: 223 Ra can be obtained by irradiating 226 Ra with neutrons to produce 227 Ra. 227 Ra decays to 227 Ac which decays via 227 Th to 223 Ra. Thus 223 Ra can be obtained in a generator eluting it from 227 Ac.

223 Ra 11.43 d α 5.61MeV 5.72MeV 219 Rn 3.96 s α 6.82MeV 215 Po 1.78 ms α 7.39MeV 2.17 min 516 ms 211 Bi β- 211 Po 211 Pb 36.1 min β- α 6.62MeV β- 207 Tl α 207 Pb 4.77 min stable

In order to obtain the calibration factor (cps/mbq) a Petri dish may be used. The images are acquired with an activity of 3.9 MBq for 5 minutes. 82 kev ME 82 kev LEHR 154 kev ME Energy width 20%

A problem in relation to image acquistion: The administered activities are very low. 50 kbq/kg for a patient of 70 kg means an activity of 3.5 MBq. For the dosimetry static planar images have to be acquired. Acquisitions last about 30 minutes.

Recommended acquisition times: -1 st. Between 1 h and 5 h. -2 nd. Between 18 h and 24 h. -3 rd. Between 48 h and 60 h. -4 th. Between 7d and 15 d. The first acquisition may be skipped and a monoexponential curve fitting performed. Patients are treated on an outpatient basis.

OLINDA S-values for organ dosimetry

OLINDA S-values of unit-density spheres for tumour dosimetry

In the dosimetry of alpha particles, which are high- LET radiation, instead of calculating the mean absorbed dose to tumour/oar it may be necessary to perform dosimetry at a lower scale. MIRD dosimetry may be applied and S-values for dosimetry of alpha particles at cellular and subcellular level are available (e.g. S nucleus cytoplasm, S nucleus cell surface ). Microdosimetry. Specific energy. However, for the target absorbed doses delivered in therapeutic applications (they may be about 100 Gy), calculation of the mean absorbed dose may be a reasonable approximation to study the clinical effects.

Relative Biological Effectiveness (RBE) A value of 20 has been given in different documents, but this may be too conservative and aimed to be used in radiation protection issues. In the therapy, values between 3 and 5 have been In the therapy, values between 3 and 5 have been reported, and a value of 5 is recommended until further studies are performed.

ALSYMPCA study concludes that 223 Ra improves overall survival. Treatment schedule: 6 administrations of 50 kbq/kg every four weeks.

223 Ra mimics the biokinetic behaviour of calcium, strontium and barium. Most 223 Ra is eliminated by faeces and only a small percentage by urine.

Organ Bone endosteum Lower large intestine wall D alpha (Gy/Bq) D alpha (Gy/Bq) (RBE=5) D alpha (Gy/Bq) (RBE=20) D beta/ Gamma (Gy/Bq) 7.5E-07 3.8E-06 1.5E-05 1.1E-08 1.3E-08 1.1E-07 3.0E-07 4.0E-08 Liver 3.6E-08 1.8E-07 7.2E-07 1.5E-09 Red marrow 7.2E-08 3.7E-07 1.5E-06 5.5E-09 50 kbq/kg for a patient of 70 kg means an activity of 3.5 MBq, and for a protocol of 6 activity administrations it means an activity of 21 MBq. Thus, 16 Gy to the bone endosteum and 1.5 Gy to the red marrow. Dosimetry of 223Ra chloride:... Lassmann et al.

Energy window Sensitivity (cps/mbq) 82 kev (20%) 69 154 kev (20%) 31 270 kev (20%) 34 A Phase 1, open-label study of the biodistribution, pharmacokinetics and dosimetry of Radium-223 dichloride... Chittenden et al.

Energy spectrum for 223 Ra measured in a Philips Forte gamma camera A Phase 1, open-label study of the biodistribution, pharmacokinetics and dosimetry of Radium-223 dichloride... Chittenden et al.

Insert AP PA Cylinder 93% 92% Sphere 78% 62% A Phase 1, open-label study of the biodistribution, pharmacokinetics and dosimetry of Radium-223 dichloride... Chittenden et al.

AP PA Images acquired at 48 h after administering 10 MBq WBS are acquired at a speed of 6 cm/min for 30 min A Phase 1, open-label study of the biodistribution, pharmacokinetics and dosimetry of Radium-223 dichloride... Chittenden et al.

In these studies 50 kbq/kg are administered and the count rate is too low to acquire WBS. Static planar images are acquired. A Wiener filter may improve the contrast and the SNR. Unfiltered Filtered A case report of image-based dosimetry of bone metastases... Pacilio et al.

Dosimetry of bone metastases... Pacilio et al. Coregistration of 99m Tc-MDP (Methyl Diphosphonate) and 223 Ra images. In 8 of 9 patients, good correlation between 99m Tc- MDP and 223 Ra uptake. 99m Tc-MDP 223 Ra

Future perspective: Therapy with 177 Lu-DOTATATE. -SPECT/CT based dosimetry (at least the hybrid method). -The schedule of 4 activity administrations of 7.4 GBq may be too rigid. Individualisation of treatments. Different absorbed dose to kidneys per administered activity are obtained. -Optimisation using BED values.

Future perspective: Therapy with 90 Y-microspheres. -PET/CT imaging. -More studies on correlation between 99m Tc-MAA and 90 Y-microspheres uptake. -More studies on a dose-effect correlation. -Optimisation using BED values.

Future perspective: Therapy with 223 Ra-dichloride. -Individualisation of the treatment schedule. A higher activity per cycle may be beneficial from a radiobiological viewpoint and better images could be acquired. -Attention should be paid to the bone-marrow toxicity and other possible toxicities.

Future perspective: Therapy with 223 Ra-dichloride. -Correlation between 99m Tc-MDP and 223 Radichloride uptake. -Focus on microdosimetry in order to better understand treatment outcome and toxicities.

Muchas gracias / Thank you very much