Therapy: An introduction Prof John Buscombe

Therapy: An introduction Prof John Buscombe

What is radionuclide therapy Different terms used Unsealed sources Defined for radiation protection and legal reasons Internal radiotherapy Could be confused with radioactive seeds and wires Targeted (radio) therapy Much liked by NM community but may be confusing

General principles If you can see it you can treat it If the patient has the right disease you can treat it You can image the patient to see you have targeting-gamma only High activity in the target tissues, low in other tissues

What can these therapies offer? Cure-maybe Tumour control-sometimes Symptom control-frequently Side effects-sometimes Patient intolerance-rarely Hope-always

Types of treatment P-32 I-131 I-131 MIBG I-131/Re-188 Lipiodol, Y-90 Sir spheres, Re-186/8 Ho-166 MAA Lu-177/Y-90 Octreotate I-131 Bexxar,Y-90 Zevalin, I-131 Ritux I-131 CHT25 I-131 SIP Sm-153 EDTMP/Sr-89/Re-188/ Re-186 HEDP/Sn-177m/ Ra-223 Y-90/Re-186/Er-169 colloids PCV, Cavity therapies Thyrotoxicosis, thyroid cancer NETs HCC NETs Follicular NHL Hodgkin s disease Solid tumours Palliation of bone pain, treatment of bone mets synovectomy

Changes in supplier 1988 P-32 Amersham I-131Amersham I-131 mibg Mallinckrodt Y-90 colloids Amersham Sr-89 Amersham 2010 P-32 Polatom Y-90 Dotatate/toc Polatom/Perkin Elmer, Molecular imaging Lu-177 Dotatate Covidien Y-90 Zevalin Bayer Ra-223 Bayer I-131 SIP Philogen

Change in attitude Small market Limited use Except for I-131 palliation only Single agent Small but growing market Use expanding to more common conditions Aim for cure Combination with chemo/immunotherapy

Who can we cure? This category includes one of the oldest treatments I-131 can be used to ablate thyroid remnants and treat metastatic disease Lymphoma

63 year old women 6 weeks after total thyroidectomy Spot views performed 72 hours after administratio n of 140 MBq of I-131 Ant Post

Imaging performed 72 hours after administration of 3.5 GBq of I-131

After 3 further treatments of 5GBq of I-131, whole body imaging with 140MBq of I-131 fails to show any uptake in tumour and TBG is normal and remains so

Can we control disease P-32 in polycythaemia rubra-vera Y-90 particulates in liver tumours

P-32 Biological half life in marrow is 8 days Beta emitter most radiation in 3-8 mm Cheap isotope Given as 74-114 Mbq/m 2 to max 185 MBq Marrow dose 2.2mGy/Mbq No special rad proc just care with urine for 7 days May be given orally

Chemo vs P-32 A few randomised studies Results very similar Some suggestion rate of strokes and MIs less with P-32?significance Cost less if treated for more than 1 year Rate of final leukaemic transformation same at 20% at 10 years Results in ET same as PCV

Y-90 particulates 2 main types From Australia Y-90 resin balls SIRspheres From Canada Y-90 integrated glass balls Theraspheres

Y-90 particulates non resectable liver tumour is a management challenge External beam radiation unable to deliver an effective dose (90Gy for most adenocarcinoma) without damaging surrounding parenchyma Y-90 is a beta emitter, deliver a target dose of > 100Gy, penetrates about 11mm in soft tissue Half life 64.1 hour

Indications-general In reality treatment is palliative When to treat 2 nd line 3 rd line Not able to have curative treatment RFA Surgery What about guidelines

Pivotal study van hazel JSO 2004 Phase II RCT from Australia 21 patients metastatic CRC <25% liver mets >80% mets in liver All patients received 4 cycles of 5F-U and leucovorin Half randomised to additional Y-90 Sir spheres

van Hazel et al 2004 Median PFS (p=0.005) 18 16 14 12 10 8 6 Chemo Chemo +y90 4 2 0 Chemo Chemo +y90

Confirmation Hendlisz et al J Clin Onc 2010 Belgian study phase III 5FU vs 5FU+Y-90 SIRT 46 patients with unresectable CRC mets in the liver recruited but 44 assessed Median TTP was 2.1 months for 5FU and 4.5 months for 5FU and Y-90 SIRT (those not given SIRT were then given SIRT) Median OS was 7.3 months for 5FU vs 10 months for 5-FU and Y-90 SIRT

Time to progression-hendlisz JCO

Treatment Schedule-SIRFLOX Control arm: mfolfox6 (+ bevacizumab) (1) Cycle 1 Cycle 2 Cycle 3 Cycle 4 F O LF F O LF F O LF F O LF O X O X O X O X OX = 85 mg/m 2 OX = 85 mg/m 2 OX = 85 mg/m 2 OX = 85 mg/m 2 Bev Bev Bev Bev Treatment arm: mfolfox6 (+ bevacizumab) (1) + SIRT (2) Preparation Cycle 1 Cycle 2 Cycle 3 Cycle 4 Work up for SIRT On day -14 to -3 F O LF O X SIRT On day 3 or 4 F O LF O X F O LF O X F O LF O X OX = 60 mg/m 2 OX = 60 mg/m 2 OX = 60 mg/m 2 OX = 85 mg/m 2 1. Bevacizumab allowed at investigator s discretion, per institutional practice. 2. Work-up procedure at Day (D) -14 to D-3 prior to SIRT; SIR-Spheres Y-90 resin microspheres administered on either D3 or D4, of either Cycle 1 or Cycle 2. Bev

CONSORT Diagram-SIRFLOX Stratification Intent to use bevacizumab (1) : Yes: 292 (55%) No: 238 (45%) Randomised n = 530 October 2006 April 2013 Intention to Treat (ITT) Population mfolfox6 n = 263 mfolfox6 + SIRT n = 267 Stratified to receive Bevacizumab (1) bev n = 147 (56%) no bev n = 116 (44%) bev n = 145 (54%) no bev n = 122 (46%) 1. Patients stratified to receive (bev) or not receive (no bev) treatment with bevacizumab, at the investigator s discretion.

PFS in the Liver: SIRFLOX Cumulative Incidence of Liver Progression 0.7 Probability of Hepatic Progression 0.6 0.5 0.4 0.3 0.2 0.1 n Median FOLFOX (+ bev) 263 12.6 months FOLFOX (+ bev) + SIRT 267 20.5 months HR: 0.69 (95% CI: 0.55 0.90), p=0.002 7.9 month improvement in median PFS in the liver 31% reduction in risk of disease progression in the liver 0.0 0 12 24 36 48 60 Time from Randomization (months) Number at risk FOLFOX (+ bev) 263 96 29 9 5 2 FOLFOX (+ bev) + SIRT 267 106 33 11 5 2

Progression-Free Survival at Any Site 1.00 Proportion Not Progressing 0.75 0.50 0.25 n Events Median FOLFOX (+ bev) 263 225 10.2 months FOLFOX (+ bev) + SIRT 267 217 10.7 months HR: 0.93 (95% CI: 0.77 1.12), p=0.43 0.00 0 12 24 36 48 60 Time from Randomization (months) Number at risk FOLFOX (+ bev) 263 96 29 9 5 2 FOLFOX (+ bev) + SIRT 267 106 33 11 5 2

One patient s result

Can we palliate symptoms? The pain and swelling of Rheumatoid arthritis in the knee Pain from bone metastases Pain from liver metastases Reduction in carcinoid symptoms

Radiation synovectomy Uses radionuclides with destructive radiation to damage and destroy synovium Used as an alternative to chemical or operative synovectomy Needs to be used to treat a primary synovial problem

Indications for radiation synovectomy RA PA Baker s cyst Inflammatory OA Haemophiliac synovitis Pigmented villous synovitis Most need an effusion Normally failed at least 1 treatment with steroids

Isotopes used Isotope T1/2 (days) B- energy MeV penetration gamma P-32 14.3 0.695 2.2mm nil Y-90 2.8 0.935 10.8 mm nil Re-186 3.8 0.309 4.5 mm 137keV Er-169 9.4 0.098 1.0mm nil Sm-153 1.9 0.081 3.1 103keV

Joints and the isotopes used Joint Knee Shoulder Elbow Fingers Hip Isotopes/pharms Y-90 silicate, Y-90 colloid, Re-186 HEDP, SM-153 HYDA Y-90 silicate, Y-90 colloid, Sm-153 HYDA Y-90 silicate, Y-90 colloid, Re-186 HEDP Er-169 colliods Er-169 colloids Y-90 colloid, Y-90 silicate

Preparation of the patient Explain procedure Explain that a needle will be put into the joint Explain that their knee will be immobilised for at least 24 hours (so we can only do one) Response is unlikely for 14 days and there may be transient increase in pain Non-treated joints will not get better! No surgery can be performed for 2 weeks

Principles of synovectomy

Assessment of response Normally made at about 6 weeks Should include assessment of joint clinically, use of pain killers and ultrasound of joint Only if no pain improvement at this point is a treatment failure defined

How well does it work? Though there are >70 studies Few randomised controlled trials Only 9 in full random controlled trials Most studies agree that 80% of patients get good pain relief Similar to surgical synevectomy Better than steroids alone Clunie et al

Bone metastses Often feared in cancer Tends to mean advanced disease Often painful Normally predict that death (possibly unpleasant) will come soon

Which cancers? The 5 Bs go to bones Breast (B)rostate Bronchus (B)ryroid (B)idney

Bone/BM metastases Though we call them bone mets Really bone marrow mets Nearly always need red marrow Adult-axial skeleton & prox humerus/femur Neg bone scan MRI, PET positive

Bone/bone marrow mets Metastases starts to grow Will impinge on bone Bone will try to remodel Increased uptake of Tc-99m MDP As bone affected Osteoclasts breakdown damaged bone, osteoblasts and fibroblasts try to reform bone

Bone/bone marrow mets The bone may be breached-#s Fibroblasts release PGs These PGs produce local pain Other inflammatory cells involved PG, Other pain mediators HIS may be released SRS Direct involvement of nerve fibres PG

Therapy of bone metastases Uptake of radionuclide in sclerotic zone (orange) with irradiation within that zone and some into the tumour

Radium-223 Dichloride is an Alpha-particle Emitting Radiopharmaceutical in Development for Cancer Patients with Prostate Bone Metastases Radium belongs to the same group of elements as Calcium Radium is a calciummimetic element Radium (Ra-223) is quickly taken up in newly forming bone 20 Ca Ra 88 SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213-23. 42

Short Range of α-emitters Reduces Bone Marrow Exposure 1 Marrow Marrow Radium Ra 223 dichloride β-emitter Bone Range of α-particle: (short range 2 to 10 cell diameters 2 ) Bone Range of β-particle: (long range 10 to 1000 cell diameters 2 ) SOURCE: 1. Henriksen G, et al. Cancer Res. 2002;62:3120 3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.

Decay of Radium-223 Dichloride Radium-223 dichloride emits mainly α-particles t½ = 11.43 days Of the total decay energy 95.3% emitted as α- particles 3.6% emitted as β- particles 1.1% emitted as γ- or X-rays SOURCE 1. Henriksen G, et al. Cancer Res 2002;62:3120-3125. α 5.78 MeV α 6.88 MeV 223 Ra 11.43 d 219 Rn 3.96 s 215 Po 1.78 ms α 7.53 MeV 211 Pb 36.1 min β - Radium-223 decay chain 1 211 Bi 2.17 min α 1.37 MeV 6.68 MeV (99.73%) 207 Tl 4.77 min β - (0.27%) 584keV α 6.68 MeV β - 1.42 kev 211 Po 516 ms 207 Pb stable 44

ALSYMPCA Updated Analysis: Radium-223 Significantly Improved Overall Survival The updated analysis confirmed the 30% reduction in risk of death (HR=0.70) for patients in the radium-223 group compared with placebo. Survival % 100 80 60 40 20 Increase OS =3.6 mos MEDIAN OS (months) Radium-223: 14.9 Placebo: 11.3 HR (95% CI): 0.70 (0.58 0.83) P <0.001 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Since Randomisation Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0 Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0 CI, confidence interval; HR, hazard ratio; OS, overall survival. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213-23. 45

Radiopeptides Based on somatostatin system Peptides converted from commercial sources: Lanreotide Octreotide Octreotate Normally DOTA linker Isotopes In-111, Y-90, Lu-177

Affinity of radiolabelled somatostatin analogues to somatostatin-receptors Radiopharmaceuticals Sst1 Sst2 Sst3 Sst4 Sst5 Na1ve somatosta1n SS- 28 5.2±0.3 2.7±0.3 7.7±0.9 5.6±0.4 4.0±0.3 111 In- DTPA- octreo1de >10000 22±3.6 182±13 >1000 237±52 90 >10000 ( Y- DOTATOC Y- DOTA- Tyr 3 octreo1de ( 90 11±1.7 389±135 >10000 114±29 90 >10000 ( Y- DOTATATE Y- DOTA- Tyr 3 octreotate ( 90 1.6±0.4 >1000 523±239 187±50 90 ( Y- DOTALAN Y- DOTA- lanreo1de ( 90 >10000 23±5 290±105 >10000 16±3.4 177 Lu- DOTA- Tyr 3 octreotate ( 177 Lu- DOTATATE) >10000 15 >10000 453 547 IC 50 ± SEM, nm Reubi JC et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000, 27:273-82. de Jong M et al. Comparison of 111 In-labeled somatostatin analogues for tumor scintigraphy and radionuclide therapy. Cancer Res. 1998, 58:437-41. 47

Preclinical development De Jong M et al. Somatostatin receptortargeted radionuclide therapy of tumors: preclinical and clinical findings. Semin Nucl Med. 2002, 32:133-40. 48

Practical points Patient selection Positive study on In-111 oct, Tc-99m DOTANOC or Ga-68 DOTATATE Must have progressive disease on CT or MRI or symptoms not controlled by sandostatins WHO performance status 0,1 If on LAR time treatment for week before or after injection If sub cut stop 24 hours

Ga-68 PET/CT more lesions than In-111 Oct In-111 Oct WB Ga-68 PET/CT SPECT

Tc- 99m HYNIC octreo3de Foregut, pancreas non-secretor, NECLM (WHO 2)

Y-90 octreotate Newer peptide Higher affinity for SSR2 Minimal side effects as renal and bone marrow uptake low Patients treated in Poland, UK and Germany

Foregut, pancreas secretor (gastrinoma) NECLM (WHO 2)

61 yrs old female; FPI, WHO 2, G2; CS IV, nonsecretor Ini3al SRS ( 99 Tc TOC) Ini3al CT CT 12 M aler PRRT SRS 12 M aler PRRT, ( 99 Tc TOC) 54

Treatment with Y-90 DOTATATE Cwikla et al (Ann Oncol 2010) 35 patients with proven GEP-NET All treated patient had evidence of PD before therapy 4x3-4GBq Y-90 DOTATATE with aminoacid cover 12 weeks apart Response measure by CT and symptom relief Good correlation between symptom relief and survival Correlation with imaging less clear

What is a response with Y-90 Cwikla et al Waterfall plot at 6 weeks Waterfall plot at 6 months Pre-therapy 6 months post last cycle 12 months after last cycle

Lutetium-DOTATATE development From a somatostatin-receptor ligand to a registered drug (?) A series of analogues synthesized and studied by academic teams in various tumour models (mice and rats) Successfully transferred to the clinic by academia for imaging (indium-111, gallium-68) and therapy (yttrium-90, lutetium-177) Thousands of patients included in clinical trials and treated by compassionate use A concern: risks of kidney failure and myelotoxicity Finally a company (AAA) completed a phase III 57 registration trial

Lu-177 Octreotate Developed by Krenning JCO 2005 151 patients treated with cum activities of 22-30 GBq of Lu-177 octreotate Given with renal protection Toxicity bone marrow and in some men reduction in testosterone Follow up data in 125 patients

Lu-177 in GEP (Krenning-JCO 2005) 35 30 25 20 15 10 CR PR MR SD DP 5 0 Response

Krenning et al JCO 2005

Lu-177 octreotate (n=310) Kwekkeboom JCO 2008 Carcinoid n=188 1% CR, 22% PR, 17% MR, 42% SD, 20%DP PET non func n=72 6% CR, 36% PR, 18%MR, 26% SD, 14% DP PET func n=19 0% CR 60% PR, 20% MR, 30% DS, 10% PD

Survival post Lu-177 oct n=310

Post therapy with Lu-177tate Image courtesy of Dr S Navalkissoor Royal Free Hospital London

PPRT DOTATATE Navilkissor et al 2011 Y-90 Author (n) CR PR SD DP Symptom relief Baum (75) 0 28 39 8 64 Cwikla (57) 0 14 44 0 51 Toupanakis (85) 0 11 66 11 62 TOTAL (217) 0 0% 49 23% 149 69% 19 8% 167 77% Lu-177 Author (n) CR PR SD DP Symptom relief Kwekenboom (310) 5 86 158 61 21/36 Gabriel (55) 0 15 27 13 Total (365) 5 2% 101 27% 185 51% 74 20% 58%

NETTER-1 study Randomized multicentre phase III study comparing 177 Lu-DOTATATE + Sandostatin LAR Depot (LAR octreotide) 30 mg to LAR octreotide 60 mg in patients with grade 1-2, inoperable, progressive under LAR octreotide intestinal neuroendocrine tumour 30 mg 4 administrations of 7.4 GBq de 177 Lu-DOTATATE every 8 weeks (LAR octreotide 30 mg) 229 patients included showing a 79 % reduction of progression or death risk (p < 0.0001) Overall response : 18 versus 3 % (p = 0.0008) Overall survival (interim analysis): 13 vs. 22 deaths (p = 0.0186) Progression-free survival Reasonable tolerance Response 65 177 LAR Octreotide Lu-DOTATATE 60 mg (n = 101)* (n = 100)* CR 1 0 PR 17 3 All patients 116 113 Progression (%) 6 (5) 27 (24) Stable disease (%) 77 (66) 70 (62) * Excluding patients with no centralized assessment Months Strosberg JR et al. NETTER-1 phase III: progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177 Lu-Dotatate. J Clin Oncol 2016; 34:194. Survival 177 Lu-DOTATATE Octreotide LAR 60 mg

Summary Radionuclide therapy can treat a range of benign and malignant conditions Beginning to be involved in more common tumours Area of research which is active New treatments like Lu-177 PSMA Radiologists do not do therapy