1. Peptide receptor radionuclide therapy (PRRT) involves administering radiolabeled peptides like octreotide that target somatostatin receptors overexpressed on neuroendocrine tumors. 2. PRRT with beta-emitting radionuclides like yttrium-90 and lutetium-177 is an effective treatment for inoperable or metastatic neuroendocrine tumors. 3. PRRT has shown symptomatic improvement, tumor growth control, and regression in around 30% of patients with neuroendocrine tumors.

1. The Emerging Role of Peptide
Receptor Radionuclide Therapy
(PPRT) in Oncology Treatment
Dr Mahayuddin Abd Manap
Medical Lecturer (Nuclear Medicine)
Oncological & Radiological Sciences Cluster
IPPT Bertam

2. Lecture Outline
1. Introduction to PPRT
2. Neuroendocrine tumour (NET) as basis
a. Classifications
b. Diagnosis
c. Treatment
d. Future trend
3. Summary

3. Introduction
• Peptides a promising therapeutic agents in
the treatment of cancer, diabetes, and
cardiovascular diseases
• Application of peptides in a variety of other
therapeutic areas are growing rapidly
• 3 main peptides in the market (with sales over
$1 billion) are used in treating cancer directly
or in the treatment of episodes associated
with certain tumors (leuprolide, goserelin and
octreotide)

4. • In conventional cancer therapy, common
problems encountered are:
– Drug resistance
– Altered biodistribution
– Biotransformation
– Drug clearance
– Systemic toxicity
• "Molecularly targeted cancer therapies"•
using
proteins, peptides and related biomolecules
are more relevant due to the possibility of
improved drug potency, efficiency and
minimal side effects.

5. .
• Peptides can be used as:
– Direct anti-cancer drugs
– Cytotoxic drug carriers,
– Vaccines,
– Hormones
– Radio-nuclide carriers
– Drug targets
• Advantages of using
peptides are:
– small size
– ease of synthesis and
modification
– tumor penetrating ability
– good biocompatibility

6. Peptide Receptor Radionuclide
Therapy (PRRT)
• A molecularly targeted radiation therapy
• Involved the systemic administration of β-
emitting radionuclide chelated to a
radiolabelled peptide
• Target with high affinity and specificity
receptors overexpressed on tumours e.g.
somatostatin receptor (sstr) subtype 2 (sstr2)
that is overexpressed on the cell surface of
NETs

10. Somatostatin receptors (SSTR)
•Expressed on
surface of NET
•5 different
subtypes of SSTR
•Exerts its action
by inhibiting G-
protein-
dependent cAMP
•SSTR2 is
overexpressed in
NETs

11. Adapted from Reubi et al. (2001)

12. Neuroendocrine tumour (NET)
• Heterogenous group of neoplasms
• Arise from cells of the endocrine (hormonal) and
nervous systems
• Can be benign or malignant
• Incidence 50/million population
• Location:
– GI (70%) ; GEP NET
– Bronchopulmonary(25%)
– Other sites (5%)

13. Neuroendocrine tumours

14. Incidence of NET

15. Neuroendocrine Neoplasms: NENs of the
Gastroenteropancreatic (GEP) System
WHO 1980 WHO 2000 WHO 2010
I. Carcinoid 1. Well-differentiated
endocrine tumor (WDET)*
2. Well-differentiated
endocrine carcinoma
(WDEC)*
3. Poorly differentiated
endocrine carinoma/small-
cell carcinoma (PDEC)
a. NET G1 (carcinoid)
b. NET G2*
c. NEC G3 large-cell or
small-cell type
II. Mucocarcinoid
III. Mixed forms
carcinoid-
adenocarcinoma
4. Mixed exocrine-endocrine
carcinoma (MEEC)
d. Mixed
adenoneuroendocrine
carcinoma (MANEC)
IV. Pseudotumor
lesions
5. Tumor-like lesions (TLL) e. Hyperplastic and
preneoplastic lesions
NET, neuroendocrine tumor–well differentiated; NEC, neuroendocrine carcinoma–poorly differentiated;
G, Grade
*If the Ki67 index exceeds 20%, this NET may be labeled G3
Bosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.

17. Somatostatin analogues
•Different analogs of somatostatin
•2 active forms-14 and 28 amino acids (peptides)

18. Octreotide
• Analog of somatostatin
• Made up of 8 amino acids (octapeptide)
• Binds to SSTR
• Can be labeled with a variety of radioactive
compounds for:
• Diagnoses:
– 111In-octreotide (Octreoscan) and 68Ga –DOTATATE
• Therapy :
– 90Yttrium and 177Lutetium

21. Normal octreotide scan
Posterior
Anterior

22. Abnormal octreotide scan

23. 68Ga-PET (DOTA-octreotate)
PET imaging of neuroendocrine tumors

24. Accuracy of OctreoScan
• Carcinoid 80%
• Insulinoma 31
• Gastrinoma 95
• Glucagonoma 73
• SCLC 100
• Pheochromocytoma 100
• Paraganglioma 86
• Medullary thyroid Ca 54
• VIPoma 86
• Pituitary adenoma 80

26. Management of NET
• Multimodality multidisciplinary management
• Surgical removal of primary tumour is treatment
of choice
• 20% of cases present with metastases
• 50% in this group have no identifiable primary
lesion
• Treatments include:
– “Cold” somatostatin analogues
– Chemotherapy
– Liver direct therapies (RFA/bland or chemo
embolisation/radioembolization (SIRTEX)
– Biological agents eg Sunitinib or Everolimus

27. PRRT
• A molecularly targeted
radiation therapy
• Involved the systemic
administration of β-
emitting radionuclide
chelated to a
radiolabelled peptide
• Target with high affinity
and specificity receptors
overexpressed on
tumours e.g.
somatostatin receptor
(sstr) subtype 2 (sstr2)
that is overexpressed on
the cell surface of NETs

28. PRRT for NET
• First attempted in the 1990's
• Initial trial used high doses of 111In–DTPA–
octreotide
• 1996 : 90Y-DOTATOC used in first patient in
Basel, Switzerland. Excellent response
following few cycles of treatment
• 2000 : 90Y-DOTATATE used
• Lutetium based compounds introduced later

29. Targeted molecular imaging and therapy

30. 90Y-DOTATATE/DOTATOC
Administered activity 2.78 – 4.44 Gbq (100mCi)/m2
177Lu-DOTATATE/DOTATOC
Administered activity 5.55 – 7.4 Gbq (100mCi)/m2

31. PRRT for NET
• Progressive metastatic disease
• Other therapies are not likely to be successful
or appropriate
• Tumours subjected to high radiation dose
• Kidneys critical organ in PRRT
– Proximal tubular reabsorption and retention in the
interstitium
– Pre-existing risk factors for nephrotoxicity (HTN
and DM)

33. • Positive SSTR receptor expression on Octreoscan
or GaPET scan
• Well/moderately differentiated NET
• Metastatic, progressive, symptomatic disease
• Absolute contraindications:
– Pregnancy
– Severe acute illness/unmanageable psychiatric illness
• Relative contraindications:
– Breast feeding (if not discontinued)
– Severely compromised renal or bone marrow function

34. • In-patient hospital stay for 1-2 nights in
purpose built lead lined rooms
• Treatment given as a drip over 30-60 min
• 1 L of amino acids (Lysine/Arginine comtained
solution) over 4 hr through drip for renal
protection
• Anti-sickness, pain medication
• Post-therapy scan the next day
• Discharge home following scan if feeling well
• Follow-up blood tests at regular intervals

35. Radiation protection
• Vast majority of radiation remains in body
• Some high energy radiation exit the body
• Restrict close contact (< 1 m) with children and
pregnant women for up to 1 week
• Sleep in a separate bed for up to 5 days
• Double flush toilet for up to 7 days, observe
proper toilet hygiene
• Do not return to work for 7 days
• Avoid pregnancy for up to 6 months

36. Amino acid infusion – kidney protection

37. Side effects of PRRT
• Early (up to 1 week)
– Nausea (30%), vomiting (15%), abdominal symptoms,
tiredness, tumour discomfort, allergic reaction, carcinoid
crisis (SOB, neuro symptoms)
• Intermediate (4-6 weeks)
– bone marrow suppression (low Hb,WBC,platelets),
increased risk of infection, bleeding , anaemia, hair loss
• Late (many weeks –months)
– renal dysfunction (less than 1%), reduced with
administration of amino acids during PRRT,
myelodysplastic syndrome (3 out 500)

38. PRRT Outcomes
• Resulted in:
–Symptom improvement
–Control tumour growth
–Tumour regression
• 30% response rate
• Post therapy monitoring
– renal profile

40. Treatment response assessment

43. New Avenues To Improve PRRT In Future
• DUO-PRRT (routine at some center)
• TANDEM-PRRT (concurrent Lu-177/Y-90 PRRT
Kunikowska et al.)
• Intra-arterial PRRT (> 100 i.a. treatments up to now)
• Combined PRRT (in combination with other
treatment modalities)
– TACE, SIRT, RFA (Hörsch et a. ASCO 2010)
– chemotherapy (e.g. Capecitabine, Doxorubicin)
– kinase inhibitors (e.g. Sunitinib, Sorafenib)
• Intra-operative use of probes after PRRT with Lu-177
• Improved dosimetry and radioprotection
• Improved peptides (e.g. antagonists) and novel
molecules

44. Summary
• Diagnostic and radiotherapeutic targeting of
neuroendocrine tumors with peptide-based
nuclear probes has been proven useful