Alpha-emitting Radionuclides:

Ra-223

prof. dr. K. Goffin

Nuclear Medicine and Molecular Imaging

Department of Imaging & Pathology

UZ Leuven – KU Leuven

Belgium

International Course on Theranostics and

Molecular Radiotherapy Brussels, 06-10-2017

Background

• Bone metastases are present in

– CRPC (castration resistant prostate cancer) patients: > 90%

– MBC (metastatic breast cancer): up to 80%

• Bone metastases are a major cause of mortality, pain,

morbidity (decrease of quality of life)

• Bone metastases cause skeletal events

(need for radiation of bone or for orthopedic surgical intervention,

spinal cord compression, pathological bone fracture)

Need for effective and tolerable therapies that improve survival and reduce skeletal events

http://www.loc.gov

/pictures/item/985

17525/ PRINTED SEP 1938

Radium-223

• Alfa (223Ra)

• Helium-nucleus

• High LET: 80 keV/µm

• Short range (~µm)

• 2000-7000 ionpairs/µm

• Double strand DNA breaks

• Irrepairable

• 2-3 tracks kill cell

• Beta (electronen – 89Sr / 153Sm)

• Elementary particle

• Low LET: 0,2 keV/µm

• Longer range (~mm)

• 5-20 ionpairs/µm

• DNA damage can be repaired

• Cross-fire necessary

• +/- 1000-10000 tracks kill cell

Alfa versus Beta

Nilsson, Am Soc Clin Oncol Educ Book, 2014

a-particle radiation

α-particle tracks in different bone areas

Spongious bone Osteoblastic zone

Note the short track

length

Bruland, Clin Cancer Res, 2006

Decay scheme radium-223

Total energy emitted by

radium-223 and daughters is

28,2 MeV

- 95,3% as a particles

- 3,6% as b particles

- 1,1% as g

Henriksen, Cancer Res, 2002

Radionuclides for therapy of bone M+

Radionuclides/radiopharmaceuticals used for the therapy of bone metastases

Isotope Radiopharmaceutical Half-life (days)

Energy (MeV) (maximum/mean)

γ-Energy (keV) (%)

Soft-tissue range (mm) (maximum/mean)

Usual Activity

32P

32P-orthophosphate 14.3 1.7/0.70(β) - 8.5/3(β) 5-10 mCi i.v. 10-

12mCi p.o.

89Sr

89SrCl2 50.5 1.46/0.58 (β) 0.91 (0.01) 7/2.4 (β) 4 mCi i.v. 40-60

µCi/kg i.v.

153Sm

153Sm-EDTMP 1.9 0.81/0.23 (β) 103 (28) 3.4/0.6 (β) 1 mCi/kg i.v.

186Re

186Re-HEDP 3.7 1.07/0.35 (β) 137 (9) 3.7/1.1 (β) 35 mCi i.v.

223Ra

223RaCl2 11.4 5.64 (α) (mean) 154 (5.6)

269 (13.6) 0.05-0.08 1.4 µCi/kg i.v.

117mSn

117mSn-DTPA 13.6 0.127.0.129 and 0.152

(conversion electrons) 159 0.2-0.3 (conversion

electrons) 0.05-0.27 mCi/kg i.v.

Goldsmith, Nuclear Medicine Therapy, 2013

Bone surface to red bone marrow ratio

Bruland, Clin Cancer Res, 2006

Imaging of 223RaCl2

Carrasquillo, EJNMMI, 2013

Small bowel

Colon

No liver

No gallblader

Bone targetting one day after injection

Carrasquillo, EJNMMI, 2013

ALSYMPCA trial

Alpharadin in Symptomatic Prostate Cancer Patients

Parker, NEJM, July 2013

ALSYMPCA – trial design

Parker, NEJM, 2013

• Male

• EB: White

• ~30% > 75 years

• ~40% on

bisphosphonates

• ~45% docetaxel

naive

• ~55% docetaxel

pretreated

• ~55% on opiates

• ~10% superscan

ALSYMPCA – Patients characteristics

Overall: balanced

Parker, NEJM, 2013

ALSYMPCA – Patients characteristics

• ~15% EBRT within 3

months

• High Hb: median 12.1

Overall: balanced

Parker, NEJM, 2013

ALSYMPCA

• Effect on pain palliation

Nilsson, ASCO GU, 2013

QOL score

ALSYMPCA – Overall Survival

Δ 3.6 months

Parker, NEJM, 2013

ALSYMPCA – Skeletal events

Δ 5.8 months

Parker, NEJM, 2013

ALSYMPCA – secondary endpoints

ALSYMPCA – side effects

Patients with AEs, % (n) Ra-223

n = 600

Placebo

n = 301

All grade AEs 93 (558) 96 (260)

Grade 3 or 4 AEs 57 (339) 63 (188)

Serious AEs 57 (281) 60 (181)

Discontinuation due to AEs 17 (99) 21 (62)

Fewer AEs associated with Ra-223

ALSYMPCA – AEs of interest

All grades Grade 3 or 4

Patients with AEs

% (n)

Ra-223

n = 600

Placebo

n = 301

Ra-223

n = 600

Placebo

n = 301

Hematologic

Anemia 31 (187) 31 (92) 13 (77) 13 (39)

Neutropenia 5 (30) 1 (3) 2 (13) 1 (2)

Thrombocytopenia 12 (69) 6 (17) 6 (38) 2 (6)

Nonhematologic

Bone pain 50 (300) 62 (187) 21 (125) 26 (77)

Diarrhea 25 (151) 15 (45) 2 (9) 2 (5)

Nausea 36 (213) 35 (104) 2 (10) 2 (5)

Vomiting 19 (111) 14 (41) 2 (10) 2 (7)

Constipation 18 (108) 21 (64) 1 (6) 1 (4)

Ra-223 associated with highly favorable safety profile

and low incidence of myelosuppression

Ra-223 in clinical routine

Nilsson, Clin Genitourin Cancer, 2013

Ra-223 in clinical routine

• Survival after 24 months

– 30% Ra-223 vs. 13% placebo

• Most frequent cause of death was disease progression

• No treatment-related AEs or long-term hematologic

toxicity during the 12- to 24-month follow-up

Nilsson, Clin Genitourin Cancer, 2013

Ra-223 in heavily pretreated mCRPC

• 29 patients with mCRPC

– 70% had received at least 3 lines of prior therapy

• Median of 4 cycles Ra-223 (range 1-6, 38% 6 cycles)

Modi, Clin Genitourin Cancer, 2016

Ra-223 in heavily pretreated mCRPC

• 70% of patients had increase of PSA during treatment

• 5 patients (17%) developed visceral metastases

Modi, Clin Genitourin Cancer, 2016

Can we predict outcome after Ra-223?

• Baseline prognostic factors for worse overall survival

– Poor ECOG performance status

– Elevated tALP

– Elevated LDH

– Elevated PSA

• Post-treatment changes (at 12 weeks) from baseline

ALSYMPCA Sartor, Ann Oncol, 2017

Can we predict outcome after Ra-223?

• Post-treatment changes (at 12 weeks) from baseline

ALSYMPCA Sartor, Ann Oncol, 2017

ALP LDH PSA

Can we predict outcome after Ra-223?

• Baseline factors associated with worse outcome

1. Prior chemotherapy

2. > 5 bone metastases

3. Elevated baseline ALP (> 115 U/L)

4. No ALP response after Ra-223 treatment

Wong, Clin

Genitourin Cancer,

2017

Can we predict outcome after Ra-223?

• Bone scan index

– Prognostic biomarker

• OS: 8.2 months - BSI > 5 vs. 15.0 months - BSI ≤ 5

• Hematological toxicity: odds ratio of 3.0 for BSI > 5

– Tool for response assessment

• BSI decrease in 84% after 6 cycles

Fosbol, JNM, 2017

Can we predict outcome after Ra-223?

• 68Ga-PSMA PET as gate keeper

– To exclude patients with bone marrow involvement, large lymph

nodes (> 2 cm), extensive lymph node mesatsases and visceral

metastases from Ra-223 therapy

– More effective and higher success regarding PSA changes

Ahmadzedehfar, JNM, 2017

Bone scan for therapy response?

• Changes on bone scans assessed before and after 6 cycles of Ra-

223 in 12 patients with mCRPC with bone metastases

• In 10 patients: uptake on post-treatment bone scan was reduced in

lesions with high pretreatment uptake

• In 11 patients: development of new or expanded bone lesions

Nome, Scan J Urol, 2014

BS during Ra-223: bone flare may occur ≠ progression

Imaging for therapy response?

• Hypothesis

– Ra-223 kills tumor cells in metastases surrounded by highly

proliferating osteoblasts, consistent with survival benefit.

– Insufficient radiation effect in small tumor deposits, not surrounded by

increased osteoblast activity, thus allowing continuous tumor growth

– To improve overall anticancer effect, Ra-223 might be a valuable

component of combination treatment

Nome, Scan J Urol, 2014 Uprimny, EJNMMI, 2014 Ahmadzedehfar, Clin Nucl Med, 2016

68Ga-PSMA PET

XOFIGO

Practical issues

Administration of Xofigo

Dosing and Administration:

1. Calculate the patient dose

volume (55 kBq/kg body weight

after implementation of NIST

update on April 18th 2016)

2. Draw up the desired volume

into a syringe

3. Inject the product into the

patient (slow i.v. injection)

Activity calibration can be done with standard

dose calibrator – activity on volume

Dose calibrator linearity 5.6 – 0.03 MBq (150 – 0.8 μCi)

Carrasquillo, EJNMMI, 2013

Detection of radium-223

Radiation exposure to others

Patient is immediately releasable from hospital

Ra-223 in urine and faeces

Carrasquillo, EJNMMI, 2013

Conclusion Ra-223 in mCRPC

• 223RaCl2 has similar pain palliation as β- therapy, but less

myelotoxicity well tolerated

• 223RaCl2 is easy to administer

• 223RaCl2 is safe in pre-treated patients and advanced disease

Demonstrated survival benefit in phase III RCT

– OS: 3.6 months

– Time to first SRE: 5.8 months

• Outcome can be predicted using baseline characteristics/markers

and marker dynamics after treatment

• 223RaCl2 has been approved in the US, EU and other regions for

treatment of CRPC and symptomatic bone metastases and no

known visceral metastases

Ra-223 in breast cancer

• open-label, phase IIa nonrandomized study (4 cycles)

• 23 advanced BC patients with progressive bone dominant

disease, and no longer candidates for further endocrine

therapy

Coleman, Breast Cancer Res Treat, 2014

N-telopeptide

of type 1

bALP

wk 9 wk 17

-33%

-42%

Ra-223 in breast cancer

• 20 patients had FDG PET/CT identifying 155

hypermetabolic osteoblastic bone lesions at baseline

– 50 lesions showed metabolic decrease after 2 cycles

– 32.3 % metabolic response rate (mRR) at week 9

– persisting after the treatment period (41.5 % mRR at week 17)

Coleman, Breast Cancer Res Treat, 2014 Radium-223 was safe and well tolerated.

Ra-223 in osteosarcoma

• Shows great potential since high osteoblastic activity as

intrinsic feature of osteosarcoma

• Studies ongoing

Anderson, Current Advances in Osteosarcoma, 2014

pre post

Ra-223 in osteosarcoma

• Young man with lung and brain metastatic

osteosarcoma of left femur

• Ra-223 after standard surgery, chemotherapy

Subbiah, JAMA Oncol, 2015

pre

post

Thank you for your attention