Feasibility Trial of Diffusing Alpha-emitter Radiation Therapy (DaRT) for Malignant Skin & Superficial Soft Tissue Tumors

Diffusing Alpha-emitter Radiation Therapy is a form of interstitial brachytherapy which

may be effective in treating malignant skin and superficial soft tissue tumors for

several reasons. First, alpha-emitting radionuclides have a high linear energy transfer

(LET), which produces a dense track of ionization events within cells and DNA, which

produce complex DNA damage and more effective cell kill than more sparsely ionizing forms

of radiation, such as gamma-rays or x-rays. Second, alpha-emitting radionuclides exhibit

a higher relative biologic effect (RBE) compared to gamma-rays or x-rays, due to the

relative insensitivity to cancer cellular radiosensitivity associated with cell cycling.

Finally, alpha-emitting radionuclides are relatively insensitive to hypoxia, which is

common as malignant skin and superficial soft tissue tumors become larger (Hall 2000).

Alpha particles have been considered unsuitable for treatment of solid tumors, since no

practical method to effectively irradiate a macroscopic tumor with these short-range

particles (penetration range in human tissue of ≤0.1 mm) has been found.

The "Diffusing Alpha-emitter Radiation Therapy (DaRT)", based on the interstitial

intratumoral placement of an encapsulated Radium-224 source (3.7 days half-life), is

described in this study. These sources release short-lived alpha-emitting atoms into the

tumor microenvironment by recoil. These atoms are dispersed in the immediate surrounding

tumor microenvironment both by convection through tumor interstitial fluid and by thermal

diffusion. The decay of Radium-224 in the capsule results in the release of the

short-lived (half-life of about 1 minute) radioisotope Radon-220. Radon-220 migrates in

the tumor microenvironment until it decays. This is followed by the decay of its daughter

radioisotope, Polonium-216. Lead-212, the result of this last decay, gives rise to

Bismuth-212, which emits yet another alpha particle. The result of these decay events is

the release of alpha particles (Kelson 1994 and Kelson 1995). DaRT will be used in this

study for the treatment of malignant skin and superficial soft tissue tumors.

This study has been designed to determine the feasibility of performing the procedure

required to deliver radiotherapy to the tumor. At the same time, the safety of the

treatment, tumor response, radiation safety, device placement stability, and patient

reported quality of life, and molecular and histologic effects on the tumor will be

assessed.

The DaRT sources will be inserted using preplanned radiotherapy parameters, with a

specified number and size of DaRT sources. Approximately 2-3 weeks after placement of the

DaRT sources, the placement of the sources will be reassessed by volumetric imaging, and

then they will be removed. Tumor response to DaRT will be assessed periodically 3 months

after removal of the device.

This is a single-institution pilot feasibility trial in which 10 subjects will be

enrolled.

The primary objectives are is to explore the feasibility of delivering radiotherapy for

malignant skin and superficial soft tissue tumors using DaRT (Alpha Tau Medical, Tel

Aviv, Israel), a form of interstitial brachytherapy which uses a novel radioisotope

delivery system, as well as to determine the frequency and severity of acute adverse

events. Secondary objectives will include assessments of radiotherapy-related adverse

events, tumor response, radiation safety, stability of device placement, and associations

with quality of life.