IART and EBRT, an innovative approach

Transcription

1 External beam radiotherapy and nuclear medicine therapy: which kind of integration? Mahila Ferrari mahila.ferrari A different NM and RT integration... Radionuclide therapy combined to EBRT an example: IART and EBRT, an innovative approach 1

2 The physicist contribution in the IART studies Dosimetric protocol: biodistribution, internal dosimetry (Gy/GBq), constraints for the therapeutic protocol Therapeutic protocol: internal dosimetry evaluation (Gy), EBRT treatment planning Dosimetric study To assess doses of 90 Y-DOTA-biotin to target (breast tumor bed) and non-target organs, we set up a dosimetric study with 111 In-DOTA-biotin in 10 pts undergoing conservative breast surgery. Immediately after quadrantectomy, avidin (100 mg) was injected in the tumour bed. One day after, 111 In-DOTAbiotin ( 111 MBq) was administered (iv) after chase (biotinylated albumin - 20 mg) to remove circulating avidin. 2

3 Pharmacokinetics and biodistribution study * Transmission image for attenuation correction * Blood samples, complete urine collection * Scintigraphic images 5 ant-post WB + 1 SPECT/CT * CT analysis to evaluate the patient specific organ masses on all images scatter corrected, ROI drawing of sources organs and counts analysis (conjugate view) background, attenuation, decay correction counts activity conversion time-activity curve absorbed doses IART : scintigraphic images >5 % IA 1 h 4 h 20 h 26 h pt n. 11 3

4 IART : Pharmacokinetics % IA Blood clearance time - h - %IA %IA eliminated via the kidneys time - h- IART : Uptake in breast % IA in the breast area % IA time - h - 4

5 Gy/GBq The breast area - ISODOSE High uptake: 170 g Gy/GBq Mean uptake: 220 g Gy/GBq Low uptake: 490 g Gy/GBq Gy/GBq Gy (3.7 GBq) pt n. 11 High uptake Mean uptake Low uptake 5.5 ± ± ± ± ± ± 4.1 IART : absorbed doses High uptake Mean uptake Low uptake Urinary Bladder Kidneys Heart Wall Lungs Total Body Red Marrow Other organs...it s closer to a locoregional than a systemic therapy... 5

6 % incidence IART : TD 5/5 and TD 5/50 threshold doses Gy (3.7 GBq) TD 5/5 * TD 50/5 * u. bladder 5.1 ± Kidneys 4.6 ± * According to the experience gained in EBRT doses associated respectively to a 5% (TD 5/5 ) and 50% (TD 50/5 ) of chance to cause deterministic late side effects within 5 years Correlation of dose with symptomatic radiation nephropathy % Incidence of nephritis 100% 80% 60% 40% Thompson Dewit Avioli Lux ton Kim LeBourgeois ; Dewit ; Kim NTCP curve XRT Barone NTCP curve Y-90 IART 20% 0% kidneys dose (Gy) Kidney dose (Gy) Cassady JR. In J Radiation Oncology Biol Phys 1995 Barone et al. J Nucl Med

7 IART : phase I approach Designing the therapeutic protocol of phase I, we have decided to start the therapy phase applying IART in order to release to a boost of radiation before EBRT Rational The dose to release with the IART, even better the activity to be injected, has been evaluated using the linear quadratic model to obtain a BED equivalence between IART and EBRT BED: biologically effective dose 7

8 BED RT BED RT = n D RT 1 + D RT (α/β) D RT released dose in one single fraction EBRT n number of fraction (= 1) α/β radiosensitivity parameter (for tumours = 10 Gy) provide a quantitative indication of the sensitivity of a given tumour to change in fraction or dose rate. BED IART BED IART = D IART 1 + D IART λ (µ + λ)(α/β) D IART absorbed dose in the breast area due to injection of 90 Y-biotin µ damage recovery constant (0.5 h -1 ) λ effective dose rate constant (patient specific α/β dosimetry evaluation; h -1 ) radiosensitivity parameter (for tumours = 10 Gy) 8

9 IART : activity BED IART 20 Gy D IART = 20 Gy A 90 Y-biotin = 3.7 ± 0.7 GBq Phase I-II I II study: IART + EBRT Primary objectives of this study were to determine the optimal dose of avidin with a fixed activity (3.7 GBq) of 90 Y-biotin in order to provide a boost of 20 Gy (BED 21 Gy), followed by standard EBRT of 40 Gy in 20 times (2 Gy/fraction), to assess local and systemic toxicity From the scintigraphic images acquired up to 24 hours after the injection, we estimated the BED release with the injection of 3.7 GBq of 90 Y-DOTA-biotin 9

10 Phase I-II I II study Level Avidin (mg) HSA chase (mg) Biotin L1 (n = 5) Y- biotin (3.7 L2 (n = 5) 50 5 GBq) spiked with L3 (n = 5) In (185 MBq) To analyze the differences between the three consecutive cohorts of patients some parameters related to the breast area were compared: - maximum uptake (max %IA in the breast area) - number of decays in the breast area (max uptake region) - absorbed dose in the breast area (max uptake region) Phase I-II I II study: IART + EBRT cohort I (100 mg) cohort II (50 mg) cohort III (150 mg) uptake% ND(h) Gy/GBq The dose of 100 mg of avidin resulted to be the more appropriate for the target area, without influencing the biodistribution of non target organs 10

11 Conclusions and further developments The phase I-II study is ongoing Possible switch from 90 Y to 177 Lu-biotin Increase the specific activity (MBq/mg) of 90 Y- biotin to improve the absorbed dose to the breast region Perform PET 68 Ga-Biotin Introduce Voxel dosimetry 11