Alpha and Auger-emitting radionuclides in Therapeutic

Nuclear MedicineDr Ganesh Kumar

Deptt of Nuclear MedicineAIIMS

Currently the predominant class of radiopharmaceuticals that is used in nuclear medicine therapy

Have improved outcome of many benign and malignant lesions that are usually not amenable to other modalities of management

Beta emitter therapy

The emissions usually have a long range and energies distributed over a range rather than discrete single energy emissions

Beta-emitters: disadvantages

Also, the radiobiological effects at a cellular level lead to relatively lower cell-kill

A relatively long range and low LET account for more likelihood of unwanted side effects that can be dose-limiting

These properties have also been attributed to incidences of second malignancies in patients treated with beta emitters

Alpha emitters

Auger and conversion electron emitters

Positron emitters

comparatively short range of alpha particles in tissue

high LET

Therefore radiation burden to the surrounding healthy

tissues is low when compared to beta emitters

very effective treatment regimen for microscopic and small volume tumors

Alpha Emitters: properties

Alpha-emitters: radiobiology

Penetrating powers

Sources of alpha-emitters

Common therapeutic alpha-emitters

Discovered by Marie and Pierre Curie in 1898

Elemental form was isolated in 1910 by electrolysis

heaviest of the earth alkaline elements, and all isotopes are radioactive

Radium-226 has the longest half-life (t1/2 = 1600 years), is the most abundant radium isotope in nature

Radium (L. Radius, ray)

Otherwise known as Xofigo (Raclopride)

natural bone-seeker that decays with aphysical half-life of 11.4 days by releasing alpha-particles

Ra-223 dichloride

Source material: Ac-227; from irradiated samples of Ra-226

Separated by means of cation and anion exchange methods

Ra-223 eluted from the resin with high purity

Dissolved in physiologically compatible NaCl/Na-citrate buffer followed by sterile filtration

Ra-223: production

radium cations are incorporated within the bone matrix of metabolically active bone

probably by inclusion in the calcium phosphate and hydroxyapatite crystals

Biodistribution corresponds to Sr-89 chloride in pre-clinical and clinical models

Ra-223: Mechanism of Action

 indicated for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease

50 kBq/kg body wt q4wk; a course of upto 6 injections

ANC ≥ 1500/cc; Hb ≥ 10 g%; plt ≥ 1lac/cc prior to first administration

ANC ≥ 1000/cc and plt ≥ 50000/cc prior to subsequent dosages

Indications and dosage

6 cycles of Ra-223 (50 kBq/kg q4wk) in CRPC patients who did not respond to docetaxel

Interim analysis: 223Ra significantly improved survival versus placebo (14.0 months vs. 11.2 months; P = .00185)

Cross-over analysis (n = 528 deaths) of all randomized patients the median OS benefit was 3.6 months; P = .00007

Outcome (ALSYMPCA Trial)

With alpha-emitters, the endostealbone surface received high radiation doses

considerable fractions of the bone marrow were spared

much more energetic and localized radiation

Hence, produces densely ionizing tracks and predominantly non-reparable double DNA-strand breaks

Advantages over beta-emitters

Transient and mild myelosuppression (no cumulative toxicity over 6 months of Rx)

Neutropenia more common than thrombocytopenia (vs beta-emitters)

Other common side effects include nausea, diarrhoea, vomitign and pedal edema

Side effects

Has many desirable properties for RIT

Half-life of 7.2 hrs: reasonable match with the pharmacokinetics of mAbs, particularly in non-IV setting

More rapid exposure of the tumor cells to the labelled mAbs can be achieved

Astatine-211

Imaging can be done using polonium x-rays (70 – 90 keV)

Limited clinical data have been published to validate the role of At-211 immunoconjugates

Have shown promising results with a significant increase in survival of the study samples

At-211: clinical applications

Treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6 (Zalutsky et al, J Nucl Med. 2008 Jan;49(1):30-8)

GM + anaplastic ODG (n = 18) 71 – 347 MBq in post-surgical cavity Biodistribution with g-camera monitoring: 96.7 ±

3.6% decays within cavity; < 0.05% leakage into blood

Median OS: 54 wks vs 31 wks with no limiting dose toxicity

Bi-213

213Bi-CHX-DTPA conjugated with anti-PSMA mAb J591 has been experimentally shown effective in killing prostate cancer cell lines

Can potentially be employed as an effective therapeutic agent in CRPC and prostatic cancer with micro-metastatic disease

Potential clinical applications

often referred to as an in-vivo generator because it produces more potent daughter radionuclides after administration

Pb-212

Has been tried in pre-clinical studies as early as 1989 where intraperitoneal inoculation in mice bearing virulent Ovarian carcinoma cell line strain

Prolonged survival and eradicated tumor cells in 24% of the inoculated mice sample

Yet to find a mainstream clinical application in oncology management

Represent an attractive alternative to beta-emitters for cancer therapy

Auger electrons are emitted by isotopes that decay by electron capture (EC) or have internal conversion (IC) in their decay

In each decay of these isotopes, a cascade of very low energy electrons is emitted

Auger emitters

Multiplicity

Low energ

ies

Short range

in tissue

svery high energy density created in the immediate vicinity of the decay site

• “High LET-like” effect

highly localized absorbed radiation dose to the target region

Feasible option if they can be placed intracellularly, especially in close proximity to (or within) nuclear DNA

This has been experimentally achieved pre-clinical and phase I clinical studies by using 125IUDR (5-radioiodo 2’ deoxyuridine)

Cell-cycle specific radiosensitizer

Incorporated into the cellular DNA only in cells that are actively dividing in S-Phase

This can lead to toxicities when the radiolabelled compound is administered by systemic route

Circumvented by: loco-regional administration into the tumor volume/cavity

Co-administration with MTX (increase in % of cells in S-phase)

Problem with IUDR

Possible target tumor groups:

Brain Urinary bladder Ovarian Intra-capsular Liver Intra-arterial Gastric and colorectal Endoscopic Breast Sonography

Intra-cavitary

Production is expensive and the technology of source material enrichment is limited to a very limited number of nuclear reactors in the world

Availability is limited

Pre-clinical and clinical data are still evolving to validate their role for a more widespread clinical application

Why so less

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