Clinical Application of �Cyclotron-based Radiopharmaceuticals� �

Hendra Budiawan

Department of Nuclear Medicine & Molecular Theranostics

Hasan Sadikin General Hospital / Universitas Padjadjaran

Bandung

�Cyclotron produced Radiopharmaceutical�

• Short half-lives, not suitable for long transport times.

95% of radiopharmaceuticals used in PET

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• Fluorine-18, Carbon-11, Oxygen-15 and Nitrogen-13

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•  IAEA, 2022:

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Over 1,200 cyclotrons worldwide: increasing the availability of nuclear medicine — ultimately providing better and more effective diagnosis.

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Portugal (population10 million) perform over 50,000 PET procedures per year.

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�Radiopharmaceutical Production with Cyclotrons�

Yoo RJ, et al.. KSNM60: The History of Radiopharmaceutical Sciences in Korea. Nucl Med Mol Imaging. 2022 Jun;56(3):114-126.

• Ga-68
• Tc-99m

Positron Emission Tomography

• PET is a powerful metabolic imaging technique utilising possibly the best radiopharmaceutical that has ever been used FDG (F-18 fluorodeoxyglucose).

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• Excellent quality images 🡪appreciated by non-nuclear medicine clinicians & has an enormous clinical impact.

• Change the practise of medicine, especially in oncology.

Every cancer center has Nuclear Medicine facilities.

The Warburg effect means higher glucose uptake of cancer cells compared to normal tissues, whereas a smaller fraction of this glucose is employed for oxidative phosphorylation

F-18 Fluorodeoxyglucose (FDG)

“Molecule of the 20^th century”

glucose

deoxyglucose

Fluorodeoxyglucose

F-18 Fluorodeoxyglucose (FDG)

Glucose

Transporter

Polypeptides�GLUT 1 - 4 ↑↑

K₃

K₄

Hexokinase ↑

Tumor Cell

Glucose-6-

Phosphatase ↓

¹⁸FDG-1-P

Glycogen

¹⁸F-fru-6-P

Glycolysis

¹⁸FDG-6-

phospho-

glucono-lactone

HMP

shunt

¹⁸FDG

Blood

K₁

K₂

¹⁸FDG

¹⁸FDG-6P

[¹⁸F] FDG – the Molecule of the Century

Uptake and Metabolism

Why PET ?

• PET displays biochemical, metabolic, and molecular processes
• Metabolic changes generally preceed anatomical abnormalities
• Specific metabolic pathways
• Possibility of quantification, response monitoring, prognostication

Positron Emission Tomography

¹⁸F

• ⁺

• ^-

+

p

γ

γ

511 KeV

511 KeV

PET/CT

• CT gives morphological information

• FDG PET gives functional and metabolic information

• Fusion of both imaging modalities gives additional information in more than 50% of patients

FDG PET indication

• Helping in confirming early diagnose.

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• More accurate and effective determination of the spread of cancer and staging.

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• More precise therapy planning.

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• Therapy response can be assessed earlier, so therapy plan can be also changed earlier as needed.

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• Early detection of cancer recurrence,residual massess.

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• Assisting clinician in differentiating benign and malignant tumor.

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• Determination of biopsy localisation

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• Raise biomarker but negative physical exam and anatomic imaging

• Helping in confirming early diagnose.

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• More accurate and effective determination of the spread of cancer and staging.

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• More precise therapy planning.

​

• Therapy response can be assessed earlier, so therapy plan can be also changed earlier as needed.

​

• Early detection of cancer recurrence,residual massess.

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• Assisting clinician in differentiating benign and malignant tumor.

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• Determination of biopsy localisation

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• Raise biomarker but negative physical exam and anatomic imaging

FDG PET indication

• Helping in confirming early diagnose.

​

• More accurate and effective determination of the spread of cancer and staging.

​

• More precise therapy planning.

​

• Therapy response can be assessed earlier, so therapy plan can be also changed earlier as needed.

​

• Early detection of cancer recurrence,residual massess.

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• Assisting clinician in differentiating benign and malignant tumor.

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• Determination of biopsy localisation

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• Raise biomarker but negative physical exam and anatomic imaging

FDG PET indication

Lung ca gr IV

PET-CT as whole body staging

• Helping in confirming early diagnose.

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• More accurate and effective determination of the spread of cancer and staging / restaging.

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• More precise therapy planning.

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• Therapy response can be assessed earlier, so therapy plan can be also changed earlier as needed.

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• Early detection of cancer recurrence,residual massess.

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• Assisting clinician in differentiating benign and malignant tumor.

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• Determination of biopsy localisation

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• Raise biomarker but negative physical exam and anatomic imaging

FDG PET indication

Astrocytoma

• Helping in confirming early diagnose.

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• More accurate and effective determination of the spread of cancer and staging.

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• More precise therapy planning.

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• Therapy response can be assessed earlier, so therapy plan can be also changed earlier as needed.

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• Early detection of cancer recurrence,residual massess.

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• Assisting clinician in differentiating benign and malignant tumor.

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• Determination of biopsy localisation

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• Raise biomarker but negative physical exam and anatomic imaging

FDG PET indication

Response Monitoring

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text

Comparison of the FDG-PET/CT images before and after 2 cycles of neoadjuvant chemotherapy shows:

• SUV of 11.0 and 2.8 (before and after therapy)

before chemoth/

after chemoth/

RP Baum, Zentralklinik Bad Berka

Lung Carcinoma (squamous cell)�follow-up after 6 cycles chemotherapy (too late !!)

before th/ after therapy

Scar vs Viable Mass

FDG PET measures metabolic changes which are earlier

than structural changes

before chemotherapy

after 2 cycles

no FDG uptake in the mass

Metabolism

precedes

morphology !

Monitoring Response to Therapy

RP Baum, Zentralklinik Bad Berka

• Helping in confirming early diagnose.

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• More accurate and effective determination of the spread of cancer and staging.

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• More precise therapy planning.

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• Therapy response can be assessed earlier, so therapy plan can be also changed earlier as needed.

​

• Early detection of cancer recurrence / residual mass

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• Assisting clinician in differentiating benign and malignant tumor.

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• Determination of biopsy localisation

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• Raise biomarker but negative physical exam and anatomic imaging

FDG PET indication

structure vs function

dead tissue

vital metastasis

MRI

PET

• Helping in confirming early diagnose.

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• More accurate and effective determination of the spread of cancer and staging.

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• More precise therapy planning.

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• Therapy response can be assessed earlier, so therapy plan can be also changed earlier as needed.

​

• Early detection of cancer recurrence, residual massess.

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• Assisting clinician in differentiating benign and malignant tumor.

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• Determination of biopsy localisation

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• Raise biomarker but negative physical exam and anatomic imaging

FDG PET indication

Biopsy localisation

Equivocal nodule

• Helping in confirming early diagnose.

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• More accurate and effective determination of the spread of cancer and staging.

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• More precise therapy planning.

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• Therapy response can be assessed earlier, so therapy plan can be also changed earlier as needed.

​

• Early detection of cancer recurrence, residual massess.

​

• Assisting clinician in differentiating benign and malignant tumor.

​

• Determination of biopsy localisation

​

• Raise biomarker but negative physical exam and anatomic imaging

FDG PET indication

History of breast ca with elevated tumor marker

Summary

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• Main indication : staging and restaging of oncologic patients in addition to morphological methods, therapy response, follow-up, beside some indications in primary tumor diagnosis.

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• FDG PET is the method of choice in restaging oncologic patients

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Peter Lind

FDGP PET: Incidentaloma

Check-up ??

FDGP PET: Incidentaloma

NaF-18 PET vs Tc-99m Bone Scan

12

NaF-18 PET

Tc-99m Bone Scan

F-18 FDG: Myocardial Viability

Matsunari I et al.,2003

Healthy

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Alzheimer’s disease

Neurologi: Dementia

F18-DOPA

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1. Parkinson’s disease
2. Alzheimer’s disease vs Lewy body dementia
3. Neuroendocrine tumors
4. Brain tumors / Glioma

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Normal Parkinson’s disease

�Radiopharmaceutical Production with Cyclotrons�

Yoo RJ, et al.. KSNM60: The History of Radiopharmaceutical Sciences in Korea. Nucl Med Mol Imaging. 2022 Jun;56(3):114-126.

• Ga-68
• Tc-99m

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Diagnostic PSMA scan

🡪 resolution of metastases.

Diagnostic PSMA scan

(Tc-PSMA or Ga-PSMA or F-18 PSMA)

• progressive bone and lymph node metastases.

Therapy

3 cycle Lutetium-177 PSMA

Prostate Cancer Theranostics

Theranostics

(see & treat)

Current Status of Nuclear Medicine in Asia

China

PET: 427, PET/MR:23, Cyclotron: 120

Mongolia

PET: 2, Cyclotron: 1

Japan

PET: 464, PET/MR: 12, PEM: 12

Philippines

PET: 22, Cyclotron: 5

Malaysia

PET: 22, Cyclotron: 8

Singapore

PET: 18, PET/MR: 2, Cyclotron: 3

Thailand

PET: 15, PEM: 1, Cyclotron: 6

ROK

PET: 264, PET/MR: 4, Cyclotron: 35

Myanmar

PET: 2, Cyclotron: 1

Nepal

PET: 3

India

PET: ~400, Cyclotron: 39

Pakistan

PET: 7

Bangladesh

PET: 9, Cyclotron: 2

Vietnam

PET:11, Cyclotron: 5

Indonesia

PET: 5, Cyclotron: 4

Theranostics

The biggest continent; population: > 4.6 B

�275 million, 38 provinces�17,000 islands (5 big islands, 6,000 inhabited)

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1. Hasan Sadikin GH (Bandung)

Center for NM Speciality Education & Training Program National Referral Center for Nuclear Medicine

2. Santosa

1. Cipto Mangunkusumo
2. Pertamina
3. Gatot Subroto
4. Dharmais (PET)
5. Jantung Harapan Kita
6. Gading Pluit (PET)
7. MRCCC (PET)
8. Mandaya

Adam Malik GH (SPECT/CT)

Kariadi (Semarang)

Moewardi

(Solo)

Sardjito (Yogyakarta)

Sutomo

(Surabaya)

M Djamil (Padang)

Abdul Wahab Sjahranie

(Samarinda)

Kandou (Manado)

Bali Mandara (Bali)

Fatmawati (Jakarta)

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?

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?

2022: 16 NM department (13 in Java, 2 in Sumatera, 1 in Kalimantan)

None in easteran part.

2 theranostics centre (Bandung & Jakarta)

2023: 20 NM department (Solo-Central Java, Manado-North Sulawesi, Bali, Jakarta).

Following year: New capital city in Central Kalimantan, South Kalimantan, South Sulawesi, Papua)

INDONESIA

Current condition

1. Lack of facilities with inhomogenous spread.

• Several new NM departments are planned

🡪 including PET & cyclotron facilities

🡪 spreading to the eastern part (until now mostly in western part)

🡪 encourage surrounding hospitals to have NM facilities

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2. Not yet a priority in hospital agenda in most places

3. Policy

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Matur Nuwun

Dopaminergic Imaging

C-11 methionine

MPIfnF Köln

Low Grade

Glioma

High Grade

Glioma

C-11 methionine (MET) positron emission tomography (PET)/CT has potential as an additional imaging tool for brain tumors [12]. Methionine easily crosses the intact blood-brain barrier via the neutral amino acid transporter and is incorporated into active tumor 

(A-C) 71 yo male with HCC of Edmondson & Steiner’s grade 1�(D-F) 65 yo male with HCC of Edmondson & Steiner’s grade 3

Hepatocellular Carcinoma

18F-FDG PET alone not sensitive enough for the evaluation of HCC primary tumor, but has a reasonable sensitivity in the detection of HCC metastasis.

🡪 dual-tracer protocol (11C-acetate and 18F-FDG)

• mutual complementary advantage

(Ho et al. J Nucl Med 2007; 48:902–909)

Multifocal bone metastases: a 62-y-old patient with previous liver resection for HCC. 18F-FDG and 11C-acetate PET/CT showed multifocal lung and bone metastases. 11C-acetate revealed more bone metastasis are significantly more intense. Largest left iliac lesion (large arrows) showed typical osteolytic pattern on CT bone window.