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Shortly after the observation in the late 1800s that radioactive emissions could be used to treat cancer, it became apparent that increasing the dose of radiation delivered to tumors resulted in greater local control and a potential cure, but that the ultimate limiting factor in dose delivery was the frequently low tolerance of normal tissues. Unlike the tissue reactions produced secondary to many other medical interventions, radiation damage to normal tissue was often irreversible and onset was frequently noted long after the radiation had been administered. Early techniques in brachytherapy (radioactive implants directly into tumors) reduced doses to normal tissues somewhat, but employed isotopes of such high energy (e.g. radium and cesium) that normal tissue damage was still inevitable in many cases, and normal tissue tolerance remained a limiting factor in radiation applicability for almost a century.
The Holy Grail in the use of radiation for cancer therapy became the elusive agent(s) that could selectively target tumor tissue and spare normal tissue. Progress in external beam radiation therapy (EBRT) equipment and techniques, first with high-energy beams from linear accelerators, then three-dimensional (3-D) conformal radiation, intensity-modulated radiation therapy (IMRT), and, more recently, proton beam radiation produced dramatically reduced doses to normal ‘transit’ tissues, but limitations persisted.
In the 1940s, the availability of iodine-131 (131I) in the sodium iodide form ushered in a new era and potential for radiation management of cancer and certain benign disorders of the thyroid gland. The nature of selective physiologic/metabolic localization of iodine in the thyroid gland, with rapid excretion of residual iodine, was the prototype for subsequent investigation and utilization of systemic radionuclides. Iodine fulfilled most of the characteristics of the ideal systemic targeted radionuclide therapy (STaRT) agent in that it localized selectively in the target tissue, had a favorable physical profile (physical and biological half life and decay scheme), had a gamma component that permitted imaging for dosimetry and documentation of localization, was reliably and readily available, and was inexpensive.
The fact that no carrier molecule or carrier-binding agent was necessary only added to the isotope’s potential and effectiveness. Unfortunately, the use of the unbound isotope was limited to the relatively uncommon well-differentiated thyroid cancers that demonstrated iodine affinity, such as the follicular and papillary variants.1,2
In the 1960s through the 1980s, interest peaked in the use of phosphorus-32 (32P) in both aqueous and colloidal formulations. Intravenous aqueous 32P (as Na2PO3) proved to be effective in the systemic management of polycythemia vera and chronic myelogenous leukemia, as well as for palliative treatment of metastatic disease in bone.
Use in the hematological malignancies was soon eclipsed by the introduction of more effective chemotherapeutic compounds, and other radioactive agents proved to be more efficacious and more easily administered for management of bone metastases.
The intra-cavitary use of 32P for control of malignant pleural effusions and ascites was highly effective, and the agent was employed routinely in this regard. In the 1980s, there was also considerable interest and investigation related to the use of the agent for subclinical mesothelial disease from ovarian malignancies when used in conjunction with debulking surgery or as adjuvant management. Studies carried out by the Gynecologic Oncology Group and individual centers proved efficacy, but in the presence of inhomogeneous abdominal distribution of isotope, as was often the case post- operatively, complications proved to be unacceptable. 32P use waned in the late 1980s, until Order and others suggested the potential for direct tumor instillation of the agent in association with materials to produce arteriolar/capillary blockade and, therefore, promote isotope retention. High tumor doses were demonstrated with anecdotal evidence of efficacy.More recently, the agent has been used for management of recurrent joint effusions in hemophiliacs and patients with rheumatoid arthritis (radiosynovectomy).3-10