ICRP Publication in progress:

Radiological protection in therapy with radiopharmaceuticals

Sören Mattsson Medical Radiation Physics, Lund University/Skåne University Hospital, Sweden

and Department of Physics, Kaunas University of Technology, Lithuania

Skåne University Hospital

Committee 3: Protection of persons and unborn children when ionising radiation is used for medical diagnosis, therapy, or for biomedical research. Assessment of the medical consequences of accidental exposures.

Main Commission Chair: Dr. Claire Cousins, Cambridge, UK (2009 - )

Scientific Secretary: Chris Clement, Ottawa, Canada

Task Groups Working Parties

Founded in 1928 “International X-ray and Radium Protection Committee”

Renamed “International Commission on Radiological Protection (ICRP) in 1950

Radiological Protection in Medicine

• Unique aspects of radiological protection for patients

– Deliberate exposure

– Voluntary exposure

• No dose limit

• Justification: more good than harm

– Three levels: general, procedure, individual patient

• Optimization: as low as reasonably achievable, but maintaining the

image quality for diagnosis or therapeutic outcome

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Recent Publications by ICRP • ICRP Publication 135: Diagnostic reference levels in medical imaging

• ICRP Publication 133: The ICRP computational framework for internal dose assessment for reference adults: specific absorbed fractions

• Publication 129: Radiological protection in cone beam computed tomography (CBCT).

• Publication 128: Radiation dose to patients from radiopharmaceuticals: A compendium of current information related to frequently used substances.

• Publication 127: Radiological protection in Ion beam radiotherapy.

• Publication 121: Radiological protection in paediatric diagnostic and interventional radiology.

• Publication 120: Radiological protection in cardiology.

• Publication 119: Compendium of dose coefficients based on ICRP Publication 60.

• Publication 117: Radiological protection in fluoroscopically guided procedures outside the imaging department.

• Publication 113: Education and training in radiological protection for diagnostic and interventional procedures.

• Publication 112: Preventing accidental exposures from new external beam radiation therapy technologies.

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The ICRP has been very active in relation to dosimetry for nuclear medicine diagnostics

… but has not yet any specific publication or recent detailed

advice on dosimetry or radiological protection for therapy with radiopharmaceuticals/molecular radiotherapy

ICRP Publication 53, 1987 ICRP Publication 62, 1991 ICRP Publication 80, 1998 ICRP Publication 106, 2008 ICRP Publication 128, 2015

Treatment planning

Individualised treatment planning is currently performed for cancer treatments using external radiotherapy and brachytherapy…

… but not for therapy with radiopharmaceuticals (now more and more called molecular radiotherapy)!!

…based on absorbed dose distributions delivered to target organs and to organs-at-risk

If no individual treatment planning is performed, a wide range of absorbed doses is delivered

Can we personalise treatment in line with other cancer treatments?

Treatment planning for therapy with radiopharmaceuticals Population based (like chemotherapy)!

I-131 NaI for thyroid remnant ablation (fixed activities): O’Connell et al (Radiother Oncol 1993) 7 – 3500 Gy Sgouros et al (J Nucl Med 2004) 1.2 – 540 Gy Flux et al (EJNM 2010) 6 – 570 Gy

Y-90 Zevalin for Non-Hodgkin´s lymphoma (555 MBq / kg) Wiseman et al (Cancer 2002) Red marrow 0.3 – 1.2 Gy Absorbed tumour dose 0.6 – 243 Gy I-131 mIBG for neuroblastoma (555 MBq / kg): Matthay et al (JNM 2002) Tumour absorbed doses: 3-305 Gy Y-90 DOTATOC for neuroendocrine tumours Bodei et al (EJNM 2004) Kidneys 6 - 46 Gy Marrow 0.2 – 1.9 Gy

(courtesy of Glenn Flux)

Therapy with radiopharmaceuticals

• Need to improve dosimetry

– To reach the same standard as in external radiotherapy

– EU: Council Directive 2013/59/Euratom (5 Dec. 2013) Article 56: For all medical exposure of patients for radiotherapeutic purposes, exposures of target volumes shall be individually planned and their delivery appropriately verified taking into account that doses to non-target volumes and tissues shall be as low as reasonably achievable and consistent with the intended radiotherapeutic purpose of the exposure.

Article 106: Member States shall bring into force the laws, regulations and administrative provisions necessary to comply with this Directive by 6 February 2018.

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Proposal 2011 Working Party 2012 Renewed Working Party 2013 Task Group 2016 (TG 101) Draft report to ICRP C3 and MC for review Sept. 2017 FMU-ICRP workshop and AOFNMB-ICRP symposium EANM, Vienna, MP Baltic States, Kaunas Approval of C3 and MC discussion October 2017 Public consultation and amendments 2018 Publication 2018?

We are here now

Progress of ICRP work

TG101: Radiological Protection in Therapy with Radiopharmaceuticals

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Full Members: Yoshiharu Yonekura (Chair, C3)

Sören Mattsson (Honorary Co-chair, C3)

Wesley E. Bolch (C2)

Laurence T. Dauer (C3)

Glenn Flux (UK)

Corresponding Members: Chaitanya Divgi (USA)

Mark Doruff (USA)

Darrell R. Fisher (USA)

Makoto Hosono (Japan)

Michael Lassmann (Germany)

Stig Palm (Sweden)

Pat Zanzonico (USA)

Personalised therapy with radiopharmaceuticals?

Dosimetry-based molecular radiotherapy allows visualisation of therapeutic agent in vivo (compare MVCT) – this offers a unique opportunity for personalised medicine

Personalised therapy with radiopharmaceuticals?

Requirements for treatment planning: • Accurate predictions of uptake and retention of radiopharmaceutical in vivo for organs-at-risk and target organs (or tumour)

• Response of tissue to continual low dose irradiation

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The goal of all radiation therapy is to optimise the relation between the probability for tumour control and normal tissue complications

Critical organs

Various organs at risk (OAR): • Kidney doses for peptide therapy • Liver doses for mIBG • Lung doses for metastatic thyroid therapy Is it sufficient to calculate mean doses to OAR with basic assumptions and

‘population’ dosimetry? (Standard phantoms, mean doses etc) Yes, if looking for rough estimate of dose for protection (or to satisfy the

FDA!) No, if considering short or long term toxicity Red marrow is the OAR for most therapies

(courtesy of Glenn Flux)

Key issues

• Improve dosimetry in the individual patient - Radiation absorbed dose to target (tumour) and normal healthy tissues - Should be estimated prior to therapy using a trace-labelled diagnostic administration or post-therapy on the basis of a retrospective assessment of the administration

• Improve quality of therapy with radiopharmaceuticals - Learn from external RT - Need systematic approach for treatment planning, monitoring the effect, and archiving the data

• Protection of workers and public - Patient release and waste management

The target audience includes: • Nuclear medicine physicians and oncologists • Medical physicists • Medical specialists (clinicians, practitioners and

prescribers/referrers) • Radiopharmacists and nuclear medicine technologists • Radiation protection officers • Regulatory authorities • Medical and scientific societies • Industry • Patients and patient representatives • Public protection officers

PREFACE, MAIN POINTS, GLOSSARY 1. INTRODUCTION 2. CURRENT ICRP RECOMMENDATIONS 3. RADIONUCLIDE THERAPY TREATMENT METHODS: JUSTIFICATION AND OPTIMISATION

4. BIOKINETIC DATA COLLECTION 5. METHODS FOR ABSORBED DOSE CALCULATIONS 4. SPECIFIC RADIATION PROTECTION ISSUES 5. SUMMARY OF RECOMMENDATIONS REFERENCES

3. RADIONUCLIDE THERAPY TREATMENT METHODS: JUSTIFICATION AND OPTIMISATION • Hyperthyroidism and other benign thyroid conditions

• Differentiated thyroid cancer (131I-iodide)

• Polycythaemia vera and essential thrombocythaemia (H2NaO4

32P and HNa2O432P)

• Skeletal metastases (89SrCl2, 153Sm-EDTMP, 223RaCl2) • Neuroblastoma in children and young adults (131I-mIBG)

• Radiolabelled peptide receptor radionuclide therapy (90Y-DOTATOC, 90Y-DOTATATE and 177Lu-DOTATATE)

3. RADIONUCLIDE THERAPY TREATMENT METHODS: JUSTIFICATION AND OPTIMISATION (continued)

• Radioimmunotherapy (131I-tositumomab and 90Y-

ibritumomab tiuxetan)

• Intra-arterial treatment of hepatocellular carcinoma and liver metastases (90Y-glass microspheres and -resin microspheres, 166Ho-microspheres )

• Radionuclide synovectomy (90Y-, 32P-, 186Re-colloids,

169Er-citrate, 177Lu-hydroxyapatite)

• Hypoxia (64Cu ATSM - copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone selective for hypoxic tissues)

New approaches

• Therapy with PSMA ligands 177Lu-PSMA, 225Ac-PSMA for prostate cancer (PSMA = Prostate Specific Membrane Antigen)

• Radioimmunotherapy with alpha-emitters 213Bi or 225Ac labelled anti-CD33 antibody for acute myeloid leukaemia • Pre-targeting techniques (how to enhance tumour-

to-normal concentration level)

Therapeutic agent Diagnostic agent Target disease

Candidate 177Lu-DOTA-TATE 68Ga-DOTA-TATE Neuroendocrine carcinoma

Established 111In-DOTA-TATE

Candidate 177Lu-PSMA ligand 223Ac-PSMA ligand

68Ga-PSMA ligand Prostate cancer

Candidate 211At-labeled compound

124I-labeled compound Various cancer

Established 90Y-labeled mAb 111In-labeled mAb Low-grade B-NHL

Example of developing agents for radiopharmaceutical therapy and diagnosis (theranostics)

RADIONUCLIDE THERAPY TREATMENT METHODS: JUSTIFICATION AND OPTIMISATION (organisation of the various chapters) • Introduction • Aim of treatment • Risks to patients • Radiation dose to friends and family • Radiation dose to staff and carers • Patient organ dosimetry • Treatment protocols • Recommendations

4. BIOKINETIC DATA COLLECTION • Whole-body activity • Activity in the blood • Organ and tumour activity

• Quantitative imaging • Planar imaging • SPECT/CT • PET/CT • Quantitative imaging protocols

• Pharmacokinetics and the integration of the time-activity curve

Delker A et al. Dosimetry for 177Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer. EJNMMI 43(1), 42-51, 2016 Planar imaging

SPECT/CT

1 h 24 h 48 h 72 h

Quantitative imaging

Activity concentrations in a patient: in one tumour metastasis (red), kidneys (cyan and dashed blue), spleen (orange) and liver (green)

From: Delker A et al. EJNMMI 43(1), 42-51, 2016

177Lu-DKFZ-PSMA-617

Activity concentration in blood samples (red) and the whole body (green) for calculation of the bone marrow dose

5. METHODS FOR ABSORBED DOSE CALCULATIONS • Purpose • Data acquisition • Absorbed dose • Time-integrated activity coefficient in a source region • Uncertainties in absorbed dose calculations • Equivalent dose • Effective dose • Biologically effective dose (BED) or Equieffective dose

(EQDX)

6. SPECIFIC RADIATION PROTECTION ISSUES • Introduction • Requirements for radiopharmaceutical therapy treatment rooms and wards • Patients (Medical exposure)

• Justification and optimisation of protection • Considerations prior to therapy • Pregnancy • Conception • Breastfeeding • Radioactive patients on dialysis • Prevention of medical errors with

radiopharmaceuticals

6. SPECIFIC RADIATION PROTECTION ISSUES (continued) • Staff (Occupational exposure)

• Protective equipment and tools • Individual monitoring • Contamination control procedures • Surveys and monitoring • Emergency patient care • Transfer of patients to another healthcare facility • Death of the patient following radionuclide therapy

• Relatives, comforters and carers (Medical exposure) and Members of the public (Public exposure)

• Release of the patient • Visitors to patients • Travel • Radioactive waste

Next Steps • Current draft

– Final approval of C3 in October 2017 (Paris meeting) and then approval of MC, hopefully beginning of next year

• Sharing information and discussion – Nuclear medicine, oncology and medical physics

communities; AOCNMB, EANM, JSNM, SNM, MPBS, etc. Need your support!

• Public consultation through the ICRP web site during 90 days. Comments are taken into account and modifications to the document made as appropriate

• Publication 2018

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Thank you for listening! soren.mattsson@med.lu.se