Editorial [Hot topic:Targeted Alpha Particle Therapy (Guest Editors: Ganesan Vaidyanathan and Roy Larsen)]

In this thematic issue of Current Radiopharmaceuticals the research and development in the field of internal radionuclide therapy with alpha-particle emitters is addressed. Targeted radionuclide therapy is a viable alternative to external beam radiation therapy, at least for some cancer forms, and can deliver selectively curative doses of radiation to cancer cells. The radiopharmaceuticals in vogue for these applications are labeled with radionuclides that emit β-particles such as 131I and 90Y. Beta-particles have a relatively long range in tissues and therefore deposit their energy over several millimeters. As a result of this, the fraction of absorbed radiation dose in tumor decreases with the decreasing size of the tumor. Thus β-particle radiations are appropriate for the treatment of larger tumors and those in which the uptake of the radiopharmaceuticals is not homogeneous. But radiopharmaceuticals tagged with β-particle emitting radionuclides can be detrimental to normal tissues adjacent to tumors. On the other hand, alpha-emitters, which deliver a much more energetic and localized radiation, are ideal for the treatment of minimal residue diseases, settings in which the targeted radiotherapy has the greatest chance of success. Such diseases include micrometastatic lesions, residual tumor margins that remain after debulking the primary tumor by surgery, skeletal metastases which appear in close vicinity to radiosensitive bone-marrow cells, and tumors in circulation including lymphoma and leukemia. In addition, targeted alpha particle therapy may be ideal for the treatment of local metastases in body cavities, e.g., ovarian cancer and neoplastic meningitis which spread as thin sheets of compartmental tumor often accompanied by free-floating cells. Alpha-particles are radiations of high linear energy transfer (LET) and have a number of radiobiological advantages. These include high relative biological effectiveness, less dependence of cytotoxicity on dose rate, and the ability to treat both normoxic and hypoxic cell populations. Also, the cytotoxic effect of high-LET radiations is only modestly affected, if at all, by the cell cycle status. Another positive feature of alpha-particle emitting radionuclides is that it is easy to shield hospital staff and families of patients from receiving radiation exposure since most alpha-emitters are associated with relatively little gammas and x-rays. High LET radiations like α-particles, are in general considered more carcinogenic than beta particles and conventional external beam irradiation. However, this problem can be reversed in clinical applications of targeted alpha therapy, since the short alpha-particle range facilitates the exposure of smaller normal tissue volumes, thus minimizing the number of normal cells at risk. The translational research in this field has for many years been hampered by lack of funding and supply of α-emitting radionuclides in clinically relevant amounts, but results of four clinical trials have been reported. A phase I dose escalation study with a 213Bi-labeled anti-CD33 monoclonal antibody for the treatment of patients with recurrent acute myeloid leukemia was presented in 2002. Yet another phase I study was performed in evaluating the therapeutic efficacy of an 211At-labeled chimeric anti-tenascin antibody in the treatment of patients with recurrent brain tumors. Results from a phase I study evaluating the usefulness of dissolved [223Ra]radium dichloride for the treatment of patients with prostate and breast carcinoma and skeletal metastases have been reported. A phase II trial of this compound is completed and a large scale phase III study, estimated to include 750 patients randomized two-to-one in favor of 223Ra, has recently been initiated. If this phase III study becomes successful, it could attract the interest for alpha-emitters among larger commercial players and secure a basis for further development of this exciting field of nuclear medicine. As mentioned above, the lack of availability of alpha particle-emitting radionuclides is one of the major impediments for the successful application of this mode of therapy. Fisher has dwelt on the commercial availability of various alpha-emitters and has made several recommendations to improve their supply. Morgenstern et al. have reviewed the production aspects describing the pros and cons of various processes..........