Dr Ishita B Sen, Director and Head, Department of Nuclear Medicine, Fortis Memorial Research Institute, Gurgaon
The possibility of pinpointing biological targets, and thereby potentially targeting and eradicating tumors or even single cancer cells without any harm to the surrounding tissue is a tantalizing concept. This concept is now feasible through the use of highly specific immune-complexes, which are labeled with alpha ray emitting ()-particles. Alpha emitters deliver exceedingly high ionizing density radiation, killing cells along its track in tissue. These alpha emitters are conjugated to highly specific immune conjugates, which selectively target the tumor cells. Alpha emitters work by inducing clusters of DNA damage such as double-stranded DNA breaks and base chemical modifications that evoke a large number of cellular responses and pathways that include apoptosis, autophagy, and necrosis and cell-cycle arrest. This type of damage is difficult to repair by the cell. Since the range of the alpha emitters is in millimeters in tissue, the surrounding normal tissue is unaffected by alpha emitters. Targeted alpha therapy often called the magic bullet therapy thus has the potential to eradicate cancer cells with minimal damage to normal tissue.
TAT in Prostate Cancer
Targeted Alpha Therapy (TAT) of prostate cancer uses PSMA-617, an anti-PSMA (prostate specific membrane antigen) peptide that specifically binds to prostate cancer cells, but not to normal, healthy cells. The peptide is labeled with the alpha-emitting radionuclides like 213Bismuth and 225Actinium that generate high-energy alpha particles during its decay. With the range of alpha particles in human tissue nearing 0.1 mm, the method allows selective irradiation, killing the tumor cells with minimal damage to healthy tissue. TAT is being successfully used in metastatic prostate cancer patients, who have failed all other conventional hormonal therapy. In a study done in the University Hospital, Heidelberg, Germany, scientists have seen several long-lasting full responses at times surpassing two years without relapse. The therapeutic responses observed in the majority of patients to date indicate that TAT with Alpha-PSMA-617 has the potential to change the future treatment of metastatic prostate cancer.
TAT in Neuroendocrine Tumors
213Bi-DOTATOC, an alpha-emitting radiocomplex targeting the somatostatin receptors expressed in neuroendocrine tumors, has been used in patients with metastatic neuroendocrine tumors. TAT was shown to be able to overcome resistance against beta radiation and resulted in a high number of long-lasting anti-tumor responses. 213Bi-DOTATOC was associated with moderate acute hematological toxicity, even in a patient with highly disseminated bone marrow involvement. Chronic kidney impairment remained in the acceptable range, and no other organ toxicity was observed. 213Bi-DOTATOC was administered both systemically and directly into the liver through selective intra-arterial administration.
TAT in Gliomas
Functionally critically located gliomas represent a challenging subgroup of intrinsic brain neoplasms. Standard therapeutic recommendations often cannot be applied, because radical treatment and preservation of neurological function are contrary goals. Targeted local radiotherapy using
213Bi-DOTA-substance P represents an innovative and effective treatment for critically located gliomas. In a study done in Basel, Switzerland, 213Bi-DOTA-substance P showed high retention at the target site. MR imaging was suggestive of radiation-induced necrosis of the tumors, which was validated by subsequent resection. Primarily nonoperable gliomas become resectable with this treatment, thereby improving the prognosis.
TAT in India
TAT is now available in India at two tertiary care cancer hospitals, one in the nuclear medicine department at Fortis Memorial Research Institute, Gurugram, and the other at the HCG Cancer Centre, Bengaluru. Targeted alpha therapy (TAT) is gaining more attention as new targets, chemical labeling techniques, and -particle emitters are made available. Results and improvements are now being published at an increasing rate and the number of conceivable applications is rapidly expanding in the field of cancer treatment.