Getting Ahead of the Expanding Landscape: Radiopharmaceutical Dosimetry
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In this webinar, Medpace experts explore the medical, operational, imaging, and regulatory considerations for radiopharmaceutical dosimetry.
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Getting Ahead of the Expanding Landscape: Radiopharmaceutical Dosimetry
- 1. GETTING AHEAD OF THE EXPANDING LANDSCAPE: RADIOPHARMACEUTICAL DOSIMETRY JULY 8, 2021
- 2. M A K I N G T H E C O M P L E X S E A M L E S S LEARNING OBJECTIVES • Define dosimetry: external beam radiation, brachytherapy, radiopharmaceutical therapy (RPT) • Methods of dosimetry: ‒ Absorbed fraction method (S value, MIRD) ‒ Voxel level dosimetry ‒ Direct MC methods ‒ Dose point Kernel method ‒ Voxel S method ‒ Bioeffect Modeling • Dosimetry in pre-clinical testing and early phase trials • Imaging challenges for RPT • Challenges of site imaging qualification and scanner calibration 2
- 3. M A K I N G T H E C O M P L E X S E A M L E S S PRINCIPLES OF RADIATION THERAPY • Ionizing radiation employs particles to kill cancer cells by directly or indirectly damaging cancer cell DNA Conventional External Beam Radiation (EBRT) • Small daily doses, fractionated over time (15-40) Ablative EBRT (Stereotactic Radiosurgery, SRS) • Higher dose delivered in fewer treatments (1-5) Brachytherapy (intracavitary, interstitial) • Radioactive sources placed directly into tumors or nearby to deliver radiation close to tumor Radiopharmaceutical therapy (RPT, theranostics) • Radio-isotopes linked to biologics and delivered to target specific cells, delivered orally, IV, intraperitoneally, intrathecally 3
- 4. M A K I N G T H E C O M P L E X S E A M L E S S INCREASING APPLICATIONS FOR RADIATION • 1.9 Million Cancer Diagnoses in US/year • 1.3 Million (>60%) treated with RT • Significant growth anticipated • RT for metastatic cancers historically limited to short, palliative EBRT directed at single site of disease • A major opportunity for radiation expansion, radiopharmaceuticals and novel theranostics 4 http://cebp.aacrjournals.org/content/cebp/early/2017
- 5. M A K I N G T H E C O M P L E X S E A M L E S S WHAT IS DOSIMETRY? • Radiation dosimetry is used to estimate the absorbed dose (Gy/GBq) of a radioactive compound in critical organs and/or tumors ‒ Helps to define a treatment dose without damaging the critical organs ‒ Helps to define a treatment dose that will treat the cancer ‒ Helps to predict a treatment dose based on a diagnostic agent using the same pharmaceutical 5 Relative radiotracer uptake (%ID/g or Bq/g) Absorbed dose value (Gy/GBq) 0 0.5 1 1.5 2 2.5 Absorbed dose per unit of injected activity (Gy/GBq) 0 5 10 15 20 25 30 35 15 60 120 240 Normalized Organ Activity (MBq/g) Mins p.i. Normalized Organ Time-Activity Curves Lungs Liver Spleen Marrow Bladder Heart
- 6. M A K I N G T H E C O M P L E X S E A M L E S S DOSE QUANTITIES IN SI UNITS FOR RADIATION 6 Human Body Equivalent Dose (Sv) The magnitude of effects on the human body Hoefnagel et al., 1993 “Phantom” Device to model and calculate the absorbed dose for an irradiated subject Sources of external radiation • Monitored quantities • Instrument responses Measured in practice by Radiological Protection Instruments Physical quantities • Fluence, Φ • Kerma, K (gray) • Absorbed dose, D (gray) Operational quantities • Ambient dose equivalent, H* (d) • Directional dose equivalent, H’ (d, Ω ) • Personal dose equivalent, Hp (d) Unit = sievert Protection quantities • Organ absorbed dose, DT (gray) • Organ equivalent dose, HT (sievert) • Effective dose, E (sievert)
- 7. RADIATION DOSIMETRY: CANCER CLINICAL TRIALS
- 8. M A K I N G T H E C O M P L E X S E A M L E S S FOCUS ON CLINICAL RADIATION AND RADIONUCLIDE THERAPY IN CANCER CLINICAL TRIALS 8 Cancer Imaging External beam radiation Brachytherapy Radiopharmaceutical therapy Skowronek et al., 2017 Sgouros et al., 2020
- 9. M A K I N G T H E C O M P L E X S E A M L E S S EXTERNAL BEAM RADIOTHERAPY (EBRT) • Ionizing radiation eradicates cancer cells (high energy photons, electrons, or protons) • Linear accelerator (LINAC) • Standardized dosimetry plans • Advanced imaging, immobilization, sophisticated treatment planning systems optimize dose distribution and provide personalized patient dosimetry 9 Definitions 3DCRT: 3D conformal radiotherapy IMRT: intensity modulated radiotherapy IGRT: image guided radiotherapy SRS: stereotactic radiosurgery IORT: intra-operative radiotherapy “Phantom” Device calculates absorbed dose Kosmin et al., 2020
- 10. M A K I N G T H E C O M P L E X S E A M L E S S BRACHYTHERAPY 10 CT pelvis, coronal view; isodose curves HDR intracavitary brachytherapy in cervical cancer patient • Radioligand isotopes: • 192Ir • 137Cs • 125I • 1900s- Pierre Curie observed shrinkage of tumor radioactive sources implanted directly into mass • Sealed, radioactive sources directly into tumor or nearby • High radiation dose delivered directly to the tumor • Dosimetric advantages: ‒ Optimal tumor-to-normal tissue gradients while minimizing the integral dose to the rest of the patient ‒ Differs from conventional EBRT • Sharp radiation dose gradients • Rapid dose fall-off at distance from the sources, limiting dose exposure of surrounding tissues • Radiation source moves with the tumor during procedure • Does not require additional margins for clinical tumor volume set-up as there are no organ motion uncertainties Chargari et al., 2019 Skowronek et al., 2017
- 11. M A K I N G T H E C O M P L E X S E A M L E S S RADIOPHARMACEUTICALS: RADIOLIGAND THERAPY • Radioligand isotopes ‒ 177Lu ‒ 225Ac ‒ 212Pb • Advantages ‒ Delivery of higher radiation doses to concentrated tumor volumes ‒ Decreased integral radiation dose ‒ Less Damage to normal tissues/cells ‒ May be combined with EBRT and chemotherapy • Disadvantages ‒ Less effective for large tumors; best suited for smaller lesions ‒ Inhomogeneous dose distribution ‒ Binding may be non-specific which could inadvertently damage normal tissues ‒ Dosimetry not as well established or standardized 11
- 12. M A K I N G T H E C O M P L E X S E A M L E S S RADIOPHARMACEUTICAL DOSIMETRY 12 DOSIMETRY FOR RADIONUCLIDES • Absorbed dose delivered per cell influenced by range of emissions • Targets disseminated metastases and smaller lesions • Methods: ‒ Absorbed fraction method (S value, MIRD) ‒ Voxel level dosimetry ‒ Direct MC methods ‒ Dose point Kernel (DPK) ‒ Voxel S method Huizing et al., 2018 Sgouros et al., 1990
- 13. M A K I N G T H E C O M P L E X S E A M L E S S PRECLINICAL TOXICITY & DOSIMETRY IN TRIALS • Preclinical testing to identify toxicity ‒ Increase radiation dose and activity until toxicity occurs ‒ Perform histopathology to determine which organ responsible for dose limiting toxicity ‒ Absorbed dose to organ calculated ‒ Identify optimal dose for Phase I • Phase 1 ‒ Dosimetry allows for efficient escalation schemes ‒ Patient specific 3D imaging dosimetry calculation ‒ Other endpoints include PK analysis and imaging data for dosimetry ‒ Expedite time to Phase 2 Phase 3 clinic 13
- 14. M A K I N G T H E C O M P L E X S E A M L E S S RADIATION DOSE CONSIDERATIONS FOR RPT • Radiation Dose Constraints to Normal Organs ‒ Extrapolated from historic EBRT dose constraints ‒ Alpha emitters verses Beta emitters ‒ Organ dose limits for RPT • Kidney • Bone marrow • Brain 14 Example of kidney dosimetry Bodei et al., 2015 Huizing et al., 2018
- 15. M A K I N G T H E C O M P L E X S E A M L E S S SUMMARY/KEY TAKEAWAYS • Many advantages of incorporating image-based dosimetry in RPT clinical trials • Image based dosimetry calculations decrease uncertainty in absorbed dose (BEDS) tumors and organs at risk • Tools and techniques available for calculating absorbed radiation dose • Dosimetry helps reduce time to bring novel RPT agents to clinic • Efficient dose escalation schemes and careful patient selection is key • Unify RPT dosimetry with “old school” radiation techniques • With integration of image based dosimetry, RPT may become leading therapeutic weapon for treating solid tumors 15
- 17. M A K I N G T H E C O M P L E X S E A M L E S S NUCLEAR MEDICINE • Introduce radioactive substance into the body ‒ Different ‘tracer’ for Diagnosis or Therapy • Functional imaging ‒ Can observe physiological or pathological processes by uptake. • Detection by gamma camera or detector array • Therapy isotopes imaged with SPECT/CT • Planar and 3D images possible 17 https://www.gehealthcare.fr/products/ molecular-imaging/nuclear- medicine/nm-ct-850
- 18. M A K I N G T H E C O M P L E X S E A M L E S S NUCLEAR MEDICINE • Radiotracers produce gamma rays (one photon in random directions at a time) • Capture photons in single direction per detector • 5-10 mm resolution; whole body planar scan time 15-20 min • Whole gantry can rotates to image from multiple directions or be fixed for planar • 3D Image covering 40cm field of view; 15 min (x3 for full coverage) 18 https://www.gehealthcare.fr/products/ molecular-imaging/nuclear- medicine/nm-ct-850
- 19. M A K I N G T H E C O M P L E X S E A M L E S S NUCLEAR MEDICINE 19 Radio-Isotope Emitted Photon Energy (keV) 99mTc 141 Low 123I 159 67Cu 93, 184 177Lu 113, 208 111In 171, 245 67Ga 93, 184, 296, 388 131I 364 High • Gamma emission occurs across a range of energies, with some isotopes emitting more than one energy of photon. ‒ Higher energy photons require different camera optimization and produce images with worse resolution.
- 20. M A K I N G T H E C O M P L E X S E A M L E S S NUCLEAR MEDICINE 20 • Gamma emission occurs across a range of energies, with some isotopes emitting more than one energy of photon. ‒ Higher energy photons require different camera optimization and produce images with worse resolution. ‒ Photons can also deflect (scatter) and lose some energy D’Arienzo et al., 2016
- 21. M A K I N G T H E C O M P L E X S E A M L E S S SUMMARY / KEY TAKEAWAYS • Single Photon detection techniques present challenges for quantitative imaging • Collimators which are necessary, limit spatial resolution and sensitivity ‒ Hard to quantify because there is low detection efficiency (~0.01%). • Certain isotopes emit a selection of photons ‒ Different detection responses, difficult to optimize • Majority of the challenge of utilizing dosimetry in a trial is derived from the specific needs of SPECT quantification 21
- 23. M A K I N G T H E C O M P L E X S E A M L E S S SITE IMAGING QUALIFICATION • Step #1: Feasibility questionnaire • Has to be done along with the clinical operation team • It evaluates: ‒ If the site has the appropriate machines/equipement • Scanners with appropriate collimators • Dose calibrator • Gamma counter ‒ If the site has experience with the given istotope ‒ The knowledge of the imaging team at site for the imaging aquisition parameters to be used ‒ If the site imaging technologist(s) speak English well or not 23
- 24. M A K I N G T H E C O M P L E X S E A M L E S S SITE IMAGING QUALIFICATION • Step #2: Site training • Step #3: Scanner calibration 24 Feasibility Site Training Mock Shipment IMP Site Qualification First Patient First Visit Teleconference Site Training Module Site Refresher Training 1 month
- 25. M A K I N G T H E C O M P L E X S E A M L E S S SITE IMAGING QUALIFICATION • Step #3: Scanner calibration • Qualification scans are required prior to site activation and imaging of study participants to: ‒ Assess equipment set-up and image quality ‒ Assess site capability to transfer images electronically to Medpace Imaging Core Labs ‒ Calibrate the scanner(s) for future dosimetry calculation • The following qualification scans and data should be collected by the Imaging Core Labs: ‒ Gamma counter and dose calibrator calibration certificates ‒ Phantom scan using the studied istotope 25
- 26. M A K I N G T H E C O M P L E X S E A M L E S S QUALIFICATION – GAMMA COUNTER & DOSE CALIBRATOR Well/Gamma Counter: ‒ Used to determine the radioactivity in blood, plasma and urine samples • Dose Calibrator: – Used to measure radioactivity and injected radioactivity in the reference source • Both should be calibrated per sites standard practice for the use of the studied istotope • Calibration should be maintained throughout the trial 26 https://www.perkine lmer.com/product/w izard2-gamma- counter-w-2-det- 550-smpl-2470- 0020 https://capintec.com/product/crc-77thr-dose-calibrator/ https://scienze.nz/gamma-counter/
- 27. M A K I N G T H E C O M P L E X S E A M L E S S QUALIFICATION – PHANTOM SCAN • Required to obtain comparable quantification in multicenter settings ‒ Maintaining accuracy and precision of quantitation ‒ Aim to standardize the acquisition parameters including energy window photopeaks • Uses phantom scans (NEMA) with a source of known activity • Mandatory for clinical trials with dosimetry calculation 27 http://www.spect.com/products-nema.html
- 28. M A K I N G T H E C O M P L E X S E A M L E S S QUALIFICATION – PHYSICAL PARAMETERS EXAMPLE FOR 177Lu • Example SPECT/CT acquisition guidelines: ‒ All acquisitions utilizing 177Lu should utilize MEGP collimator ‒ Use 2 primary energy windows: 20% windows at 113 and 208 KeV ‒ Windows collected separately because different energy equals different physical properties therefore: • Different amount of attenuation through tissue • Different detection characteristics • Overall, different quantification required WINDOW LOWER ENERGY (keV) UPPER ENERGY (keV) CENTER (keV) FULL WIDTH (%) 1 101.7 124.3 113 20 2 187.2 228.8 208 20 28
- 29. M A K I N G T H E C O M P L E X S E A M L E S S SUMMARY / KEY TAKEAWAYS • Qualification is needed for: ‒ Scanner calibration • Sensitivity factor calculation (for SPECT quantification) ‒ QA and validation of additional devices (Dose Calibrator/Gamma Counter) ‒ Prepare site for the nuanced requirements for quantitative imaging ‒ Be sure the site is able to upload images electronically without delay ‒ Use and save the acquisition protocol in their system 29
- 31. M A K I N G T H E C O M P L E X S E A M L E S S IMAGING TIME POINTS • For dosimetry calculation: ‒ Between 3 to 5 time points needed ‒ Early and late time points are the most important ones • Challenging for patient / site to acquire several images ‒ Depends on patient’s illness and pain ‒ Require several visits 31 Relative radiotracer uptake (%ID/g or Bq/g) 0 5 10 15 20 25 30 35 15 60 120 240 Normalized Organ Activity (MBq/g) Mins p.i. Normalized Organ Time-Activity Curves Lungs Liver Spleen Marrow Bladder Heart
- 32. M A K I N G T H E C O M P L E X S E A M L E S S ANATOMICAL COVERAGE • Images should focus on primary disease as well as on disease extension body parts • For dosimetry, image field of view should cover all critical organs (full bladder included) • Two fields of view usually covers the chest, abdomen and pelvis • Three fields of view will also cover the brain 32 http://www.sfu.ca/~psa43/Project_2/data/body.jpg 175 cm 40 cm 40 cm 40 cm
- 33. M A K I N G T H E C O M P L E X S E A M L E S S • The imaging protocol should be strictly followed by each site • No deviation permitted, if so, the scan will not be used for calculation (dosimetry, qualitative analysis) • No re-scan of a patient is permitted for therapeutic imaging • Sites should be pro-active and send images to Medpace Imaging Core Lab asap for further dosimetry analysis if any ‒ Allowing treatment dose calculation for example IMAGING PROTOCOL 33
- 34. M A K I N G T H E C O M P L E X S E A M L E S S DIAGNOSTIC / THERAPEUTIC RADIOPHARMACEUTICALS EXAMPLE 68Ga-PSMA PET/CT AND 177Lu-PSMA PLANAR 34 A. Image showing multiple bone and lymph node metastases in a patient with metastatic prostate cancer B. Post-therapeutic images showing high uptake within lesions corresponding to those seen on PET image Rahbar et al., 2016 PSMA is an antigen overexpressed by prostate’s cancer cells 68Ga-PSMA PET 177Lu-PSMA Planar Therapy
- 35. M A K I N G T H E C O M P L E X S E A M L E S S DOSIMETRY FOR DIAGNOSTIC AGENTS • Requires a series of images post injection • Most of the time PET/CT, low-dose, toxicity is minimal • The goal here is to estimate the predicted effective dose of therapeutic agent (from the diagnostic agent) to: ‒ Treat the patient ‒ Not damage the critical organs 35
- 36. M A K I N G T H E C O M P L E X S E A M L E S S DOSIMETRY FOR THERAPEUTIC AGENTS • Requires a series of SPECT/CT and/or planar images post injection • Dose delivered by treatment is intended to be cytotoxic • Radiation dosimetry is used to estimate the absorbed dose (Gy/GBq) (quantity of radiation received) of a radioactive compound in critical organs and/or tumors • The goal is to find the: ‒ Maximum tolerated dose ‒ Optimally effective dose 36
- 37. M A K I N G T H E C O M P L E X S E A M L E S S SUMMARY / KEY TAKEAWAYS • Image acquisition protocol is NOT standard of care and will be challenging to both sites and patients • Site must follow strictly the image acquisition protocol to ensure data can be used for quantification • Dosimetry of Therapy for two main purposes: ‒ Find the maximum dose that is safe, ‒ Find the optimally effective dose • Dosimetry of corresponding diagnostic agent for predictive purposes 37
- 39. M A K I N G T H E C O M P L E X S E A M L E S S PHARMACOKINETICS (PK) BLOOD/PLASMA AND URINE SAMPLES • PK is the study of the time course of drug absorption, distribution, metabolism, and excretion • Primary goals of clinical PK include enhancing efficacy and decreasing toxicity of a patient’s drug therapy • Simplifications of body processes are necessary to predict a drug’s behavior in the body ‒ Compartmental models (one-compartment, two-compartment, and multi- compartment model) ‒ Non-compartmental analysis (NCA) • NCA commonly used as standard 39
- 40. M A K I N G T H E C O M P L E X S E A M L E S S PHARMACOKINETICS (PK) BLOOD/PLASMA AND URINE SAMPLES • PK analysis relies on observed drug concentration measurements over time in biological samples (blood, urine, plasma…) • Steps for PK calculation: ‒ Sample gamma count (CPM) and conversion to concentration (Bq/mL) ‒ Pharmacokineticist receives drug concentration (Bq/mL) ‒ PK software package (e.g., Phoenix WinNonlin) to estimate relevant PK parameters • From the concentration versus time plot, a pharmacokineticist can begin to understand the absorption and elimination characteristics of the drug 40
- 41. M A K I N G T H E C O M P L E X S E A M L E S S PHARMACOKINETICS (PK) BLOOD/PLASMA AND URINE SAMPLES • PK parameters: ‒ Cmax and Tmax ‒ Area under the concentration-time curve (AUC) ‒ Volume of distribution (Vd) ‒ Systemic clearance (CL) ‒ Terminal half-life (t1/2) 41 https://www.lexjansen.com/phuse/2012/is/IS05.pdf
- 42. M A K I N G T H E C O M P L E X S E A M L E S S DOSIMETRY - BLOOD/PLASMA SAMPLES • Blood and Plasma gamma count data used for: ‒ PK ‒ Bone marrow dosimetry calculation • Bone marrow is the most radiosensitive tissue in the body • Activity in the bone marrow can be determined from the activity concentration in the blood or plasma if there is no specific uptake in the bone marrow cells • Blood samples should be drawn from the arm opposite the injection site to eliminate the risk of contamination 42 https://www.cancer.gov/publications/dictionaries/ cancer-terms/def/bone-marrow?redirect=true Hindorf et al., EANM 2010
- 43. M A K I N G T H E C O M P L E X S E A M L E S S DOSIMETRY - URINE SAMPLES • Urine gamma count data used for: ‒ PK ‒ Bladder wall dosimetry calculation • Bladder is the most exposed organ to radiation • Activity in the Bladder wall can be determined from the activity concentration in the urine • If 3D images are performed, there is no need to collect urine samples • If only 2D images are perfomed, then urine collection is needed: ‒ Before infusion ‒ Before imaging ‒ After infusion for several days, depending on the istotope 43 Gnesin et al., 2017
- 44. M A K I N G T H E C O M P L E X S E A M L E S S COUNTS • Most commonly a well counter is used (single or multiple wells) • The response of the detector should be well characterized for the given radionuclide so that corrections for sensitivity, dead time and volume dependence can be applied 44 • Fixed volume into the tubes (samples volume measured by a pipette) • Acquisition time to be chosen so that the acquired, background corrected, number of counts is higher than 104 so that the statistical inaccuracy is less than 1% https://www.perkinelmer.com/ product/wizard2-gamma- counter-w-2-det-550-smpl- 2470-0020 https://scienze.nz/gamma-counter/
- 45. M A K I N G T H E C O M P L E X S E A M L E S S SUMMARY / KEY TAKEAWAYS • PK is the study of the time course of drug absorption, distribution, metabolism, and excretion • It uses biological samples radioactivity count done by the site • Non-compartmental analysis (NCA) usually used • Blood / Plasma used for: ‒ Bone marrow dosimetry calculation • Urine used for: ‒ Bladder wall dosimetry calculation (for studies using planar only) 45
- 47. M A K I N G T H E C O M P L E X S E A M L E S S SITE IMAGING AND DATA COLLECTION • Data needed for dosimetry calculation are collected directly by the nuclear medicine team at site and entered in EDC ‒ Injected activity value (decay corrected) ‒ Date and Time of scans ‒ Biological sample counts • Procedure and communication system in place to receive the data from the nuclear medicine department • Ask for source data asap (injected activity) • If pediatric population, ask for the weight asap and verify the source 47
- 48. M A K I N G T H E C O M P L E X S E A M L E S S SITE IMAGING AND DATA COLLECTION • Risks / Challenges: ‒Late image upload because site’s standard procedure for image de-anonimization takes fews weeks ‒Data entry delayed because of bad communication between the nuclear medicine department and the CRC/nurse ‒Late data entry for gamma counts: better to collect source data asap and make the site complete a sheet directly ‒Unverified data (injected activity) will lead to: • Wrong dosimetry calculation • Wrong estimation of the injected dose for next cycle/patient 48
- 49. M A K I N G T H E C O M P L E X S E A M L E S S SITE IMAGING AND DATA COLLECTION 49 Data acquisition at site Send data for anonymisation Transfer data to the CRC or equivalent and enter data within EDC. In parallel, upload images into the eCRF The CRA verifies the data Dosimetrist can start using the data for dosimetry calculation 1 to 5 business days 1 to 10 business days 5-10 business days 10 business days
- 50. M A K I N G T H E C O M P L E X S E A M L E S S SUMMARY / KEY TAKEAWAYS • Data used for dosimetry calculation have to be entered in EDC asap and: ‒ Be verified urgently if dosimetry data are expected within few days after the injection ‒ Be verified following the standard procedure timeline if dosimetry data are not required urgently • Take into account possibility of data entry / image upload delay and anticipate the risks 50
- 51. M A K I N G T H E C O M P L E X S E A M L E S S CONCLUSIONS • The following considerations are important for any radiopharmaceutical trial: ‒ Communication between: • the Imaging Core Labs and the clinical operation team • the nuclear medicine department and the CRC/nurse (at site) ‒ Scanner calibration and site qualification ‒ Imaging protocol to be strictly followed • Dosimetry and PK calculation are powerful tools and can help physicians on their clinical decision for treatment dose 51
- 52. M A K I N G T H E C O M P L E X S E A M L E S S ADDITIONAL REFERENCES • Dale, R. & Carabe-Fernandez, A. The radiobiology of conventional radiotherapy and its application to radionuclide therapy. Cancer Biother. Radiopharm. 20, 47–51 (2005). • O’Donoghue, J. A., Bardies, M. & Wheldon, T. E. Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J. Nucl. Med. 36, 1902–1909 (1995). Demonstrates that, in contrast to external-beam radiotherapy, in RPT fewer cells do not lead to greater tumour control probability. • Radiopharmaceutical therapy in cancer: clinical advances and challenges. George Sgouros. Nature Reviews.Drug Discovery. Published online July 29 2020 • Michael Kosmin MD. Radiotherapy for pituitary tumors. http://creativecommons.org/licenses/by-nc-nd/2.0/. https://www.ncbi.nlm.nih.gov/books/NBK278955/. Feingold KR, Anawalt B, Boyce A, et al., editors. South Dartmouth (MA): MDText.com, Inc.; 2000-. • Brachytherapy: An overview for clinicians. Cyrus Chargari MD, PhD, Eric Deutsch MD, PhD, Pierre Blanchard MD, PhD, Sebastien Gouy MD, PhD, Hélène Martelli MD, PhD, Florent Guérin MD, PhD, Isabelle Dumas PhD … See all authors • CA: A Cancer Journal for Clinicians. First published: 30 July 2019. Chargari C, Magne N, Guy JB, et al. Optimize and refine the therapeutic index in radiation therapy: overview of a century. Cancer Treat Rev. 2016; 45: 58- 67. • Chargari C, Van Limbergen E, Mahantshetty U, Deutsch E, Haie-Meder C. Radiobiology of brachytherapy: the historical view based on linear quadratic model and perspectives for optimization. Cancer Radiother. 2018; 22: 312- 318. • Skowronek J. Current status of brachytherapy in cancer treatment—short overview. J Contemp Brachytherapy. 2017; 9: 581- 589. • Bentzen, S. M. et al. Quantitative analyses of normal tissue effects in the clinic (QUANTEC): an introduction to the scientific issues. Int. J. Radiat. Oncol. Biol. Phys. 76, S3–S9 (2010). Summary of radiation dose versus response data from radiotherapy experience. 52
- 53. M A K I N G T H E C O M P L E X S E A M L E S S ADDITIONAL REFERENCES CONT’D • Radiopharmaceutical therapy in cancer: clinical advances and challenges. George Sgouros. Nature Reviews.Drug Discovery. Published online July 29 2020 • Sgouros, G. et al. Treatment planning for internal radionuclide therapy: three-dimensional dosimetry for nonuniformly distributed radionuclides. J. Nucl. Med. 31, 1884–1891 (1990). Imaging-based patient specific dosimetry for RPT treatment planning. • Sgouros, G. et al. MIRD Monograph: Radiobiology and Dosimetry for Radiopharmaceutical Therapy with Alpha-Particle Emitters (ed. Sgouros, G.). (SNMMI, 2015). Comprehensive review of radiobiology and dosimetry for α-emitter RPT • Back, T. & Jacobsson, L. The alpha-camera: a quantitative digital autoradiography technique using a charge-coupled device for ex vivo high resolution bioimaging of alpha-particles. J. Nucl. Med. 51, 1616–1623 (2010). α-Camera imaging technique to assess distribution of α-particles in tissues. • Bolch, W. E., Eckerman, K. F., Sgouros, G. & Thomas, S. R. MIRD pamphlet no. 21: a generalized schema for radiopharmaceutical dosimetrystandardization of nomenclature. J. Nucl. Med. 50, 477–484 (2009). Mathematical • Bodei, L. et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur. J. Nucl. Med. Mol. Imaging 42, 5–19 (2015). Study that demonstrates the toxicity profile of PRRT with 90Y, 177Lu or their combination in a large series of patients 53
Editor's Notes
- Michael Introduction of Molecular Imaging Fundamentals Imaging Equipment – SPECT/CT vs PET/CT Physics of Radiopharmaceuticals
- 1)Reference: Radiopharmaceutical therapy in cancer: clinical advances and challenges. George Sgouros. Nature Reviews.Drug Discovery. Published online July 29 2020 www.nature.com/nrd 2) Wikipedia picture 3) Author: Janusz Skowronek, titel : Brachytherapy in breast cancer: an effective alternative. Prz Menopauzalny. 2014 Mar; 13(1): 48–5 4) Reference: Radiopharmaceutical therapy in cancer: clinical advances and challenges. George Sgouros. Nature Reviews.Drug Discovery. Published online July 29 2020 www.nature.com/nrd
- Reference: Michael Kosmin MD. Radiotherapy for pituitary tumors. http://creativecommons.org/licenses/by-nc-nd/2.0/. https://www.ncbi.nlm.nih.gov/books/NBK278955/ Feingold KR, Anawalt B, Boyce A, et al., editors. South Dartmouth (MA): MDText.com, Inc.; 2000-. Michael Kosmin, MDDepartment of Oncology, University College London Hospitals NHS Foundation Trust, London UKEmail: ten.shn@nimsok.leahcim Naomi Fersht, MDDepartment of Oncology, University College London Hospitals NHS Foundation Trust, London UKEmail: ten.shn@thsref.imoan Corresponding author.
- Brachytherapy: An overview for clinicians Cyrus Chargari MD, PhD, Eric Deutsch MD, PhD, Pierre Blanchard MD, PhD, Sebastien Gouy MD, PhD, Hélène Martelli MD, PhD, Florent Guérin MD, PhD, Isabelle Dumas PhD … See all authors CA: A Cancer Journal for Clinicians. First published: 30 July 2019 https://doi.org/10.3322/caac.21578 Chargari C, Magne N, Guy JB, et al. Optimize and refine the therapeutic index in radiation therapy: overview of a century. Cancer Treat Rev. 2016; 45: 58- 67. Chargari C, Van Limbergen E, Mahantshetty U, Deutsch E, Haie-Meder C. Radiobiology of brachytherapy: the historical view based on linear quadratic model and perspectives for optimization. Cancer Radiother. 2018; 22: 312- 318. Skowronek J. Current status of brachytherapy in cancer treatment—short overview. J Contemp Brachytherapy. 2017; 9: 581- 589.
- Bentzen, S. M. et al. Quantitative analyses of normal tissue effects in the clinic (QUANTEC): an introduction to the scientific issues. Int. J. Radiat. Oncol. Biol. Phys. 76, S3–S9 (2010). Summary of radiation dose versus response data from radiotherapy experience.
- Reference: Radiopharmaceutical therapy in cancer: clinical advances and challenges. George Sgouros. Nature Reviews.Drug Discovery. Published online July 29 2020 Sgouros, G. et al. Treatment planning for internal radionuclide therapy: three-dimensional dosimetry for nonuniformly distributed radionuclides. J. Nucl. Med. 31, 1884–1891 (1990). Imaging-based patient specific dosimetry for RPT treatment planning. Sgouros, G. et al. MIRD Monograph: Radiobiology and Dosimetry for Radiopharmaceutical Therapy with Alpha-Particle Emitters (ed. Sgouros, G.). (SNMMI, 2015). Comprehensive review of radiobiology and dosimetry for α-emitter RPT www.nature.com/nrd Back, T. & Jacobsson, L. The alpha-camera: a quantitative digital autoradiography technique using a charge-coupled device for ex vivo high resolution bioimaging of alpha-particles. J. Nucl. Med. 51, 1616–1623 (2010). α-Camera imaging technique to assess distribution of α-particles in tissues. Bolch, W. E., Eckerman, K. F., Sgouros, G. & Thomas, S. R. MIRD pamphlet no. 21: a generalized schema for radiopharmaceutical dosimetrystandardization of nomenclature. J. Nucl. Med. 50, 477–484 (2009). Mathematical
- Example of kidney dosimetry after PRRT in PLANET ® Dose. Isodose lines superimposed on anatomical images provide a detailed view of (upper left) whereas the summary table (lower left) and dose –volume histogram (lower right) enable a quick assessment) Current dosimetry requirements in radiopharmaceutical programs; how this impacts your clinical development plans and overall strategy Integrating dosimetric data into Phase 1 trials and SRC discussions
- Michael Introduction of Molecular Imaging Fundamentals Imaging Equipment – SPECT/CT vs PET/CT Physics of Radiopharmaceuticals
- Michael Nuclear Medicine or Molecular imaging are catch all terms for the imaging of unsealed radioactive sources administered to a patient’s body. Different tracers can be selected based on their biochemical actions or on the physical properties of their isotopes. In this way we can investigate different functions within the body. Be that motility of bile acid or specific binding to a tumor-expressing receptor. Detection of the radioactivity is complicated and involves highly specialised devices. These fall into two categories PET for Positron emission and SPECT for Single Photon emission.
- Michael Radioisotopes used for therapy are imaged on SPECT/CT or Gamma Cameras. Single gamma emission is random, and so to make it deterministic (aka. un-random) the detectors, have what we call a collimator to only detect photons that hit at the perfect angle to form a coherent image. This design requirement of a gamma camera limits the resolution, and because it is very selective over which photons form the image, the sensitivity is low so it can take a long time to image a patients. Approximately 45 minutes from Skull to thigh.
- Michael Unlike PET, whose Positrons annihilate to always create photons with the same energy. Single Photon emitters emit across a broad range of energies. The different energy of the photons affects their detection. As I said the camera must only accept photons travelling in one direction (this is called collimation). Higher energy photons can pass through thin collimators so the collimator must be thicker which reduces the resolution. Some isotopes have complicated decays and so emit more than one type of photon at high percentages. Lutetium-177 is an example we’ll come to later.
- Michael On the diagram, you can see that there are 2 main peak and below that is low energy or x-ray noise. This spectrum is of the energies detected by a gamma camera. So while the emissions may be always exactly the same from the isotope, the response to it is less precise.
- Michael Quantitative imaging of the therapy isotope is the cornerstone of internal dosimetry. If you can’t quantify how much, where and when the tracer is then, you’ve no information to determine the amount of radiation was delivered. So SPECT imaging poses us significant challenges because of its inherent limitations. However, in the next sections we will discuss how with good practice these limitations can be mitigated.
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- Alexia So the first step should be to include imaging in the site feasibility process. Given the challenge, it is important right out of the gate to know whether a site is going to have any issues collecting the data. Having the necessary equipment is obviously important, but having experience with the isotopes is also vital. There may be updates required for equipment, education needed and depending on the country, possible environmental licences required. Due to the complicated qualification and patient acquisition requirements, it is important to understand exactly what the linguistic needs of the site are. Nuclear medicine specific vocabulary is not well supported by Google Translate.
- Alexia Once feasibility has been established, and any possible pitfalls have been identified, then the site training can be developed. For involved imaging, a teleconference is absolutely essential. It provides an opportunity to bring together the Clinical Trial team, for the site staff to engage and ask questions. Here, if english is not the best language to communicate, country dedicated Clinical Research Associates can assist in translation and liaison. Once the site has received the training then a mock delivery of the IMP can be a great opportunity to provide the isotope necessary for the site to calibrate their scanner with. Finally, once a site has been qualified, there may be yet time between qualification and the first patient arriving. Therefore on a case by case basis, depending on the time window, refresher training on the imaging protocols may be worthwhile.
- Alexia Because the imaging protocols, especially on the SPECT/CT scanners, are highly specific, It’s important that a scan is performed to verify that all of the parameters have been met. Not only that but because of the challenges of quantifying SPECT isotopes, calibration and determination of scanner-specific sensitivity values underlie all future quantification. Time sensitive transmission of data is incredibly important so testing the ability of the sites with their internal data pipeline to provide images and adjunct data to the CRO is necessary.
- Michael Two additional pieces of equipment for a radionuclide therapy trial will be the well gamma counter and the dose calibrator. The first is a common piece of equipment in nuclear medicine departments and the latter is absolutely essential. Both pieces of equipment are involved in quantifying radioactivity and so per site’s practice should be maintained to a high level as part of their QA regimen. They should be configured according to manufacturer recommendations for any new isotopes that are not installed.
- Michael Performing a phantom scan with the studied isotope allows the sensitivity and the response of the camera to that isotope to be determined, to allow the quantification of activity in a patient. It requires the precise amount of activity within to be measured and the phantom must be scanned on the exact same parameters as a patient scan. In this way the parameters can be verified, but the scanning protocol can be saved onto the camera, ready to use with patients.
- Michael To give an example of the kind of specialist requirements, here is an example of the energy windows for Lutetium. As we saw previously, the energies emitted are not uniformly detected by the camera so we need to define a range of energies that will be accepted for that emission. Known as an energy window. The reason for collecting both is because they interact differently inside the patient and the camera so quantifying them separately is important. Also, if you only quantify 1 peak, you are losing almost half the information which further reduces your detection sensitivity. The point of capturing these energy windows into separate images is one that sites may not be familiar with so the training and qualification importance is further emphasized.
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- Michael When imaging patients for Dosimetry there are a few key points that add extra challenge when compared to a normal clinical scan. In order to determine the time that the isotopes spends in the body, it needs to be imaged at a range of timepoints. Early time points so estimating the start of the time activity curve, and late time points for observing the washout. Different tissues will wash out the tracer at different times so having more time points in the middle gives a better estimation. However, as mentioned, imaging that covers the whole body is time consuming and for patients who are receiving targetted radiotherapy for cancer, one must consider how many procedures can be tolerated. For therapy isotopes with long half-lives, typically imaging will be conducted over a week for dosimetry.
- Michael Where to image is a key point. This can be flexible depending on the extent of the disease to evaluate tumor uptake. However, targeted radiotherapy is an exciting prospect for metastatic disease particularly, so tumor location may not necessarily be predictable. Likewise, for dosimetry for safety, there are a number of critical organs that will need to be captured. Brain, Heart, Kidney, Bone Marrow. Likely SPECT/CT from Skull to Mid-thigh will be the safest to gain maximal coverage. But 45 minutes up to 5 times is a lot. Fields of view should ideally have small overlap. Missing part of an organ or lesion can degrade significantly the accuracy of the quantification
- Michael Imaging protocols for dosimetry must be followed closely. Unlike Standard of Care imaging, if images are unevaluable not only is there incredibly limited data that can be derived from them, but also they cannot be re-performed. If images are unsatisfactory, another dose of therapy cannot be administered just for one missing image timepoint. In training, sites are informed of the necessity to be fast with data turnaround. If safety review or dose adjustment is to be performed, timelines for dosimetry analysis are short so sites should engage closely with us and work to mitigate issues pre-emptively where possible.
- Michael A- MIP 68Ga-PSMA PET image showing multiple bone and lymph node metastases. B- Post-therapeutic planar scintigraphic images showing high 177Lu-PSMA-617 uptake within lesions corresponding to those seen on PET image... Now, a break from words with a great pair of pictures. Obviously one of the great benefits of modern targeted therapeutics is that a binding agent or ligand can be paired with diagnosis and treatment isotopes. Here too you can see a difference between resolution between PET on the left and SPECT or Planar on the right. This example is of PSMA, which has been a diagnostic tool and now is having success as a therapeutic tool. Novartis have recently published their results of the phase 3 trial with PSMA-617. PSMA is over expressed by prostate cancer cells, even after they spread to other parts of the body so you see here some normal organs like liver, kidneys, salivary and lacrimal glands but diffuse prostate cancer cells in the spine, shoulders, pelvis, and many many lymph nodes. Where the Lutetium tracer is, is where there is therapy being delivered.
- With that example we saw uptake in normal and tumor tissue. By analyzing images over a number of time points one can evaluate the amount of activity in tissue over time, and from there determine how much ‘dose’ was absorbed by the tissue over that time. Now with any radiotherapy, the intention is to deliver the maximum amount of cell killing radiation to tumors, while limiting as much as possible the dose to healthy tissue. In Clinical trials, with novel treatments, in early phases, the intention is to gain evidence that the treatment is effective, so the highest dose that can be safely tolerated is likely to provide the greatest anti-tumor effect However, with all radiotherapy treatment, the long term aim is to optimize the dose to get the best treatment with the lowest possible dose so as to minimize the long term risks of radiation while still effectively controlling or eliminating the disease.
- Michael As discussed, the imaging for Dosimetry is involved. Inclusion of dosimetry into a clinical trial takes careful consideration of the imaging requirements. Inability of sites to follow the imaging protocol can have a significant effect on the validity and the strength of the data acquired and that comes back to our key tenets of Good clinical practice. Finding the dose of the product that keeps the patient the safest while also treating them effectively is the goal of any therapy. What having such an effective quantification tool as Image based dosimetry may allow is more and better dose optimization.
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- One way to make these simplifications is to apply mathematical principles to the various processes. To apply mathematical principles, a model of the body must be selected. A basic type of model used in pharmacokinetics is the compartmental model. Compartmental methods consider the body to consist of a finite number of interconnected, well-mixed, and kinetically homogeneous compartments (e.g., blood and other tissues/organs). Based upon this view, the pharmacokineticist makes certain assumptions and develops models based upon nonlinear regression analysis to describe the PK of the drug. As a result of this approach, there is the potential for variability in the output of the analysis from one analyst to another, since the assumptions used to build the PK model may be somewhat different. In contrast, noncompartmental analysis (NCA) methods are model-independent, meaning they do not rely upon assumptions about body compartments, and they tend to provide more analyst-to-analyst consistency. In addition, an NCA relies almost exclusively upon algebraic equations to estimate PK parameters, making the analysis less complex than compartmental methods. As such, NCAs often prove faster and more cost-efficient to conduct, especially when compared to more complex compartmental analyses (e.g., where compartmental models are applied to population PK analyses that rely upon sparse sampling techniques).
- https://www.nuventra.com/resources/blog/what-is-nca/
- https://www.nuventra.com/resources/blog/what-is-nca/
- Bone marrow is the most radiosensitive tissue in the body and without stem cell support it is commonly the dose-limiting tissue for radionuclide therapy Ideally the activity concentration in the blood and plasma, as well as the patient’s haematocrit (HCT, the proportion of the total blood volume that is occupied by blood cells), should be determined to allow certification of the absence of specific activity uptake in any component of the blood.
- https://ejnmmires.springeropen.com/articles/10.1186/s13550-017-0288-x Urine containers The whole volume of urine excreted in the 72 hours post IMP1 administration must be collected). Urines will be collected in separate containers for each voiding. Ideally the time of the voiding should be recorded on the container. The whole urine container should be scanned along with the patient at the end of the feet (or next to the legs if patient is too tall) at the first planar time point (D1: 1-3h). This should be collected when the patient has voided after injection and before the first planar scan.
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- The type you have depends on your cancer type and where it is in your body.
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- Example of kidney dosimetry after PRRT in PLANET ® Dose. Isodose lines superimposed on anatomical images provide a detailed view of (upper left) whereas the summary table (lower left) and dose –volume histogram (lower right) enable a quick assessment) Current dosimetry requirements in radiopharmaceutical programs; how this impacts your clinical development plans and overall strategy Integrating dosimetric data into Phase 1 trials and SRC discussions
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- Reference: Radiopharmaceutical therapy in cancer: clinical advances and challenges. George Sgouros. Nature Reviews.Drug Discovery. Published online July 29 2020 Sgouros, G. et al. Treatment planning for internal radionuclide therapy: three-dimensional dosimetry for nonuniformly distributed radionuclides. J. Nucl. Med. 31, 1884–1891 (1990). Imaging-based patient specific dosimetry for RPT treatment planning. Sgouros, G. et al. MIRD Monograph: Radiobiology and Dosimetry for Radiopharmaceutical Therapy with Alpha-Particle Emitters (ed. Sgouros, G.). (SNMMI, 2015). Comprehensive review of radiobiology and dosimetry for α-emitter RPT www.nature.com/nrd Back, T. & Jacobsson, L. The alpha-camera: a quantitative digital autoradiography technique using a charge-coupled device for ex vivo high resolution bioimaging of alpha-particles. J. Nucl. Med. 51, 1616–1623 (2010). α-Camera imaging technique to assess distribution of α-particles in tissues. Bolch, W. E., Eckerman, K. F., Sgouros, G. & Thomas, S. R. MIRD pamphlet no. 21: a generalized schema for radiopharmaceutical dosimetrystandardization of nomenclature. J. Nucl. Med. 50, 477–484 (2009). Mathematical
- Reference: Radiopharmaceutical therapy in cancer: clinical advances and challenges. George Sgouros. Nature Reviews.Drug Discovery. Published online July 29 2020 Sgouros, G. et al. Treatment planning for internal radionuclide therapy: three-dimensional dosimetry for nonuniformly distributed radionuclides. J. Nucl. Med. 31, 1884–1891 (1990). Imaging-based patient specific dosimetry for RPT treatment planning. Sgouros, G. et al. MIRD Monograph: Radiobiology and Dosimetry for Radiopharmaceutical Therapy with Alpha-Particle Emitters (ed. Sgouros, G.). (SNMMI, 2015). Comprehensive review of radiobiology and dosimetry for α-emitter RPT www.nature.com/nrd Back, T. & Jacobsson, L. The alpha-camera: a quantitative digital autoradiography technique using a charge-coupled device for ex vivo high resolution bioimaging of alpha-particles. J. Nucl. Med. 51, 1616–1623 (2010). α-Camera imaging technique to assess distribution of α-particles in tissues. Bolch, W. E., Eckerman, K. F., Sgouros, G. & Thomas, S. R. MIRD pamphlet no. 21: a generalized schema for radiopharmaceutical dosimetrystandardization of nomenclature. J. Nucl. Med. 50, 477–484 (2009). Mathematical
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