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
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Radium-223
Alfa versus Beta Alfa ( 223 Ra) 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 89 Sr / 153 Sm) 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
a-particle radiation Nilsson, Am Soc Clin Oncol Educ Book, 2014
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 32 P 32 P-orthophosphate 14.3 1.7/0.70(β) - 8.5/3(β) 5-10 mci i.v. 10-12mCi p.o. 89 Sr 89 SrCl2 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. 153 Sm 153 Sm-EDTMP 1.9 0.81/0.23 (β) 103 (28) 3.4/0.6 (β) 1 mci/kg i.v. 186 Re 186 Re-HEDP 3.7 1.07/0.35 (β) 137 (9) 3.7/1.1 (β) 35 mci i.v. 223 Ra 223 RaCl2 11.4 5.64 (α) (mean) 154 (5.6) 269 (13.6) 0.05-0.08 1.4 µci/kg i.v. 117m Sn 117m Sn-DTPA 13.6 0.127.0.129 and 0.152 159 0.2-0.3 (conversion (conversion electrons) 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 223 RaCl 2 Small bowel Colon No liver No gallblader Carrasquillo, EJNMMI, 2013
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
ALSYMPCA Patients characteristics Male EB: White ~30% > 75 years ~40% on bisphosphonates ~45% docetaxel naive ~55% docetaxel pretreated ~55% on opiates ~10% superscan 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 QOL score Nilsson, ASCO GU, 2013
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 Patients with AEs % (n) Hematologic Ra-223 n = 600 All grades Grade 3 or 4 Placebo n = 301 Ra-223 n = 600 Placebo n = 301 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 ALP LDH PSA ALSYMPCA Sartor, Ann Oncol, 2017
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? 68 Ga-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 BS during Ra-223: bone flare may occur progression Nome, Scan J Urol, 2014
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 68 Ga-PSMA PET Uprimny, EJNMMI, 2014 Ahmadzedehfar, Clin Nucl Med, 2016 Nome, Scan J Urol, 2014
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 18 th 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 223 RaCl 2 has similar pain palliation as β - therapy, but less myelotoxicity well tolerated 223 RaCl 2 is easy to administer 223 RaCl 2 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 223 RaCl 2 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 wk 9 wk 17 N-telopeptide of type 1-33% balp -42% Coleman, Breast Cancer Res Treat, 2014
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) Radium-223 was safe and well tolerated. Coleman, Breast Cancer Res Treat, 2014
Ra-223 in osteosarcoma Shows great potential since high osteoblastic activity as intrinsic feature of osteosarcoma Studies ongoing pre post Anderson, Current Advances in Osteosarcoma, 2014
Ra-223 in osteosarcoma Young man with lung and brain metastatic osteosarcoma of left femur Ra-223 after standard surgery, chemotherapy pre post Subbiah, JAMA Oncol, 2015
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