Newer Radionuclide Therapies

Dr. Sandip Basu

Radiation Medicine Center (BARC)

Tata Memorial Centre Annexe, Parel, Mumbai

NICSTAR-2018

5th -7th March, 2018

A. Receptor over-expression in Tumors as Target: 2 recent

success stories

Prostate Cancer

PSMA:

Prostate-specific

membrane antigen

Neuroendocrine Tumor

Somatostatin Receptor

B. Bone Targeted Therapies (Skeletal Metastasis): Chemi-adsorption of 177Lu-EDTMP (complex of Lu & ethylenediaminetetramethylene-

phosphonate) on the surface of newly formed calcium hydroxyapatite

crystals [Ca10(PO4)6(OH)2]

Lu-176

Yb-176

Lu-177

6.65 d

Yb-177

1.9 h

Lu-177m

160.5 d

+ (n, g)

(n, g)

σ = 2090 b

& 2.8 b

σ = 2.85 b

Direct Route

β- Indirect Route

(2.6% nat, enriched)

(12.7% nat, enriched)

Production of 177Lu in Research Reactor

Radiopharmaceutical Agent

Lutetium (Atomic number 71) is the last element in lanthanide series, and traditionally counted among the rare earths.

The structure of prostate-specific membrane antigen (PSMA), its

binding sites for PSMA ligands and the most frequently used

antibodies

Maurer, T. et al. (2016) Current use of PSMA–PET in prostate cancer management

Nat. Rev. Urol. doi:10.1038/nrurol.2016.26

Prostate specific membrane antigen

(PSMA), a type II transmembrane protein

expressed in all types of prostatic tissue (but

demonstrates 100-fold to 1,000-fold

overexpression on the cell membrane of

prostate cancer cells).

PSMA expression increases progressively in

higher-grade cancers, metastatic disease

and castration-resistant prostate cancer

(CRPC)

Urea-based small-molecule PSMA inhibitors

have produced most promising results. Glu-

NH-CO-NH-Lys(Ahx)-HBED-CC (68Ga-

PSMA-HBED-CC)

PSMA-DKFZ-617, has been used for both

imaging (68Ga) and molecular radiotherapy

(labeled with 177Lu).

PSMA/MR guided Prostatic Biopsy 68Ga-PSMA–PET–MRI of a 50-year-old patient who had a rising serum PSA value (16

ng/ml at imaging) and two tumour-negative previous biopsy samples

T2-weighted image showing a hypointense mass in the anterior fibromuscular stroma with

pronounced arterial enhancement. b | Typical pronounced arterial contrast enhancement

compared with the surrounding tissue. c | Intensity curve of the dynamic contrast enhanced

sequence shows a typical fast washin followed by washout in the late phase. d | Diffusion-

weighted imaging demonstrates markedly restricted diffusion. e | PET image and f | fused PET–

MRI showing intense prostate-specific membrane antigen (PSMA) expression in the

corresponding region. Targeted PET–MRI fusion biopsy revealed prostate cancer with Gleason

score 7 in this region.

68Ga-PSMA–PET–CT of a 52-year-old patient with primary

prostate cancer (serum PSA value of 19 ng/ml and Gleason score

7 at biopsy)

Maurer, T. et al. (2016) Current use of PSMA–PET in prostate cancer management

Nat. Rev. Urol. doi:10.1038/nrurol.2016.26

68Ga-PSMA–PET–CT of a 52-year-old patient with primary prostate cancer (serum PSA

value of 19 ng/ml and Gleason score 7 at biopsy). a | Contrast enhanced CT shows a

small lymph node (6 mm) adjacent to the right internal iliac artery. b | PET and c | fused

PET–CT images demonstrate intense prostate-specific membrane antigen (PSMA)

expression in this lymph node. Radical prostatectomy and lymphadenectomy revealed a

lymph node metastasis in the corresponding template field.

68Ga-PSMA–PET–CT in better staging in patient of Prostate Ca

Imaging of 65-year-old patient with prostate cancer and diffuse bone metastases

Imaging of 65-year-old patient with prostate cancer and diffuse bone

metastases. a | Bone scintigraphy demonstrates multiple bone

metastases predominantly in the pelvis and ribs. b | Corresponding

maximum-intensity projection of 68Ga-PSMA–PET shows considerably

more bone metastases than bone scintigraphy.

70-y-old patient with PSMA-avid lymph node metastases on 68Ga-PSMA PET/CT

before therapy (A) and on 177Lu-PSMA scintigraphy after first PSMA RLT (B), with

remarkable reduction in uptake after second PSMA RLT (C).

Richard P. Baum et al. J Nucl Med 2016;57:1006-1013

68Ga/177Lu Theranostic pair of Radiopharmaceuticals for prostate cancer

68Ga-PSMA PET-CT in a patient of metastatic Prostate Carcinoma with raised serum PSA level

68Ga-PSMA PET/CT Scan started on a regular basis in RMC after RPC approval in April 2017

177Lu-PSMA Therapy in Metastatic Castrate Resistant Prostate Carcinoma (mCRPC)

177Lu-PSMA in a patient of metastatic prostate carcinoma

10

Known case of metastatic cancer of prostate with bony pain, patient received 177Lu PSMA therapy and subsequently 68Ga PSMA scan show resolution of bony lesion with significant symptomatic improvement

68Ga PSMA scan 177Lu PSMA Post Therapy scan 68Ga PSMA scan

August 2017 Nov 2017

SST and SSTR: Neuroendocrine Tumors

Both SS 14 and SS 28 have biological activity, and they

have a tissue-specific distribution with a relative

dominance of SS 14 in the pancreas and stomach and

of SS 28 in the intestine

Five subtypes of SSTRs, 1-5, G protein-coupled

receptors SSTRs, have been cloned.

Of practical importance is the division of the five

receptor subtypes into two groups, where SSTRs 2, 3,

and 5 differ from SSTRs 1 and 4 regarding amino acid

homology and pharmacological profile.

SST and Analogues

68Ga-DOTA-TOC/NOC/TATE and 177Lu-

DOTATATE: Why Octreotide?

The clinical use of SST is limited because it has a short half-life

(about 2 minutes) in plasma.

Octreotide is an octapeptide that mimics natural somatostatin (The

biological activity of S-14 and S-28 resides in the cyclic region of the

mature peptide. The F-W-K-T portion of the ring structure is required

for receptor occupancy): absorbed quickly and completely after

subcutaneous application. Maximal plasma concentration is reached

after 30 minutes. The elimination half-life is 100 minutes (1.7 hours)

on average when applied subcutaneously.

Octreotide has its highest affinity to SSTR 2 and lower affinity to

SSTRs 3 and 5, while SS 14 and SS 28 bind to all subtypes with high

affinity

Science behind Radioligand Used: [177 Lu-DOTA 0 ,Tyr]

Octreotate

• Octreotate: differs from octreotide only in that the C-

terminal threoninol (corresponding amino alcohol) is

replaced with threonine.

• Nine-fold increase in affinity for the SSTR 2 for [DOTA

0 ,Tyr 3 ]octreotate when compared with [DOTA 0 ,Tyr

3 ]octreotide

• Translates into 6-to 7-fold increase in affinity for their

Radiolabeled counterparts and 4-5 times

enhancement in the tumor uptake

PRRT: A somatostatin receptor based targeted

radionuclide therapy

The goal of targeted radionuclide

therapy is to selectively deliver

radiation to cancer cells and/or

diseased tissue with minimal

toxicity to surrounding normal

tissues.

The basis for successful

radionuclide therapy is a

theranostic approach that

integrates diagnostic testing for

the presence of a molecular

target for which a specific

treatment/drug is intended

Krenning Scoring: A decision

making step (Score 1-4)

The range of tumors where PRRT employed

• NET : Gastroenteropancreatic and Pulmonary

• Medullary thyroid carcinoma: Preferred compared to

Vandetinib

• Merkel Cell carcinoma, Thymic NETs

• Non-iodine concentrating metastasis of DTC

• Pheochromocytomas, Paraganglioma, Neuroblastoma

56 years old female, liver biopsy suggestive of metastatic NET of liver, Mib 1 index:

<1%. The primary was undetected by conventional imaging. 68-Ga-DOTATATE PET/CT

scan showing multiple metastatic liver lesions and a focal tracer concentration in the

pelvic ileum. Final diagnosis: Ileal NET with bilobar hepatic metastases.

68Ga-DOTATATE PET/CT in Metastatic NET of Unknown Primary (CUP-

NETs)

Decision Making Scan Options for 177Lu-DOTATATE PRRT/Chemotherapy

Gamma Camera Based

Planar and SPECT

imaging

PET-CT Based Imaging

Somatostatin Receptor

Based Imaging: Significant

Advances towards

Management of NET

99mTc-

HYNIC-TOC

111In-

Pentetreotide 68Ga-DOTA-

TOC/NOC/TATE

Glucose Metabolism

Based FDG-PET/CT

SPECT and PET-CT agents

68 Ga

DOTATATE

PET

99m Tc

HYNIC-

TOC

SPECT

177 Lu

DOTATATE

post therapy

SPECT

Gratifying Experience

with BARC produced

Indigenous 99mTc-

HYNIC-TOC

Gratifying PRRT Results over last 7 years 70 year old male, NET of body and tail of pancreas with

hepatic metastasis, HPR 10-12%, no surgical intervention

68Ga-DOTATATE

PET-CT

FDG PET-CT

Baseline After 3 cycles

Before

1st PRRT

Before 3rd

PRRT

Timing of Test Ser CgA (ng/ml)

Before 1st PRRT 496.7

After 1st PRRT and before 2nd PRRT 243.1

53/F, diagnosed as a case of atypical carcinoid of lung (MiB1 index of 6-10%.), MiB 1

index of 6-10%. Multiple SSTR positive lesions in liver, both lungs, multiple rib & right

sided pelvis. received 3 cycles of chemotherapy with cisplatin and etoposide Reported a

dramatic decrease in symptoms which includes decrease in abdominal pain and

frequency of diarrhea. Also patient reports weight gain and overall improvement in

general condition. Received 2 # of PRRT and being worked up for the 3rd.

Eur J Nucl Med Mol Imaging. 2013 May;40(5):800-16.

Well-differentiated and moderately differentiated neuroendocrine carcinomas defined as

NET grade 1 or 2 according to the WHO 2010 classification (i.e. upto 20%)

26 /M, Bleeding PR, anorectal polyp excision in March

2013: HPR : High grade rectal NET with MiB 1 index of

22%.

•Took 5 inj of Long acting Octreotide injections . After

the 5th injection started complaining of abdominal pain

and flushing.

•68-Ga DOTATOC scan showed multiple SSTR positive

lesions in liver and pre sacral nodes. Seg III, Seg IV B

(SUVmax : 39.7), Seg VI and Seg VIII (SUVmax :

26.3). Presacral node at S1 (SUVmax : 45.6), 2

presacral node at 4 (SUVmax : 48.9 larger and smaller

is 22.5).

•Patient was treated with 166 mCi of 177-Lu based

PRRT. Follow up 68-Ga DOTATOC scan shows

complete resolution of lesions in Seg III and VI (no

documented lesion on CT). Other SSTR positive lesions

in liver and in pre sacral area have decreased in

metabolic intensity. Seg IV B (SUVmax : 24.9), Seg VIII

(SUVmax : 25), Presacral node at S1 (SUVmax : 32.9),

2 presacral node at 4 (SUVmax : 5.9 larger and smaller

is 16.8)

•Patient has overall reported a dramatic response with

total resolution of the abdominal pain and episodes of

flushing.

•Subsequently patient again received 2 more cycles of

PRRT with the scan findings being now almost same

with progressive decrease in the serum chromogranin A

Pre-1st cycle PRRT Pre-2nd cycle PRRT

Treatment algorithm.

Öberg K et al. Ann Oncol

ESMO Clinical Practice Guidelines for GEP-NETs

61/M, Post Whipple’s (Primary- Head and Proximal Body of Pancreas); Biopsy- Poorly

diff NE Ca; MiB1---20%; FDG-PET/CT: Total Discordance; CgA: 125.0193.47; with

excellent symptomatic response

Sunil Walke

Somatostatin Receptor Imaging 18F-FDG PET CT

Following 60 months after the 1st therapy the patient is alive, progression free and asymptomatic.

177Lu-DOTATATE

PRRT Beyond Neuroendocrine Tumors: Recurrent Skull-Base

Phosphaturic Mesenchymal Tumor Causing Osteomalacia

53/F, vitamin D resistant

hypophosphataemic osteomalacia:

bilateral groin pain and difficulty in walking.

Low serum phosphorus level & High serum

fibroblast growth factor 23 (FGF23) [(725

RU/ml; reference range: < or =180

RU/mL)]

Selective Internal Radiation Therapy with Transarterial

Radioembolization for Advanced Liver Cancer

Patients with unresectable intermediate stage—Barcelona Clinic

Liver Cancer (BCLC) stage B—hepatocellular carcinoma (HCC).

Special emphasis in patients with portal vein thrombosis (PVT), a

relative contraindication to TACE.

Other Indications: Cholangiocarcinoma and some metastases

(colorectal cancers, NET, breast, lung, etc.)

Radiopharmaceuticals:

90Y products are commercially available: TheraSphere® glass

microspheres (BTG, London, United Kingdom) and (Sirtex Medical,

North Sydney, Australia) SIR-Spheres resin microspheres

131I/188Re-LIPIODOL: Both are important cost-effective alternative

important in Indian settings

Radioembolization for the treatment of hepatocellular

carcinoma: example of efficacy

CT scan shows 13cm sized well-demarcated hypervascular tumor (arrows) in liver S4/8. (B) MR image 1 month after two sessions of TARE shows no

enhancement of tumor (arrows). Note shrinkage of tumor to 7cm

177Lu/153Sm-EDTMP in Metastatic Bone Pain Palliation

Suitable decay characteristics of

177Lu compared to 153Sm: •[T(1/2) = 6.73 d,

•E((max)) = 497 keV,

•E(γ) = 113 keV (6.4%), 208 keV (11%)]

In patients with breast cancer

and hormone refractory

prostate cancer with

skeletal metastases

Tc-99m MDP Bone Scan and Post Therapy 177Lu-EDTMP Scan

Tc-99m MDP Bone Scan (Left panel) and Post Therapy 177Lu-EDTMP Scan (right panel) of a 69 yr old male, known case of

adenocarcinoma of prostate (Gleason’s score 9) (operated primary) presented with multiple painful skeletal metastases. Patient

was on oral NSAIDS thrice a day (analgesic score 3) and had already received RT to pelvis 6 months back. Pre-therapy parameters

were: VAS- 9, BAP- 109.6, EORTC- 68, Karnofsky- 80 and ECOG- 2. Corresponding post 177Lu-EDTMP therapy value were:

VAS- 4, BAP- 87, EORTC- 40, Karnofsky- 80 and ECOG- 1. Post therapy analgesic score was zero.

Mean VAS pain score in responders treated with 153Sm-EDTMP and 177Lu-EDTMP

0

1

2

3

4

5

6

7

8

9

Pretherapy Week 4 Week 8 Week 12

Lu177-EDTMP

Sm153-EDTMP

0

10

20

30

40

50

60

Pretherapy Posttherapy

Lu177-EDTMP

Sm153-EDTMP

Graph demonstrating bone alkaline phosphatase

(BAP) parameters in responders

Acknowledgement to the Radiopharmaceutical Scientists,

Technologists & Physicians