Cancer Clinical Trials Article: Review of Pulsed Reduced Dose Rate Re-irradiation for Recurrent Tumors
Journal of Cancer Clinical Trials is a Scholarly Open Access journal that deals with the study of cancer research and publishes original research articles, reviews, short reports, mini reviews, and letters to the editor.
Recurrent cancer after initial standard treatment is devastating for patients and physicians alike. In particular, treatment options following recurrence are often ill defined, sometimes with minimal data to support one approach over another. Moreover, utilization of reirradiation to treat recurrent cancer is frequently avoided due to concerns for exceeding normal tissue tolerances in the previous treatment area. Finally, re-irradiation is often employed in the palliative setting and less than definitive radiation doses are used. Therefore, data about tumor control following re-irradiation is often lacking.
Pulsed-Reduced Dose Rate (PRDR) is a re-irradiation technique that potentially overcomes volume and dose limitations in the setting of recurrent tumors. Tomé and Howard proposed a pulsed radiation strategy in glioma cell lines that exhibit Low-Dose Hyper- Radiosensitivity (LDHRS). In their analysis, models of glioma cell survival after low-dose, pulsed irradiation predicted greater tumor control than with standard dose-rates. In addition, their model predicted enhanced normal tissue repair as a result of longer treatment times inherent to PRDR.
Low-dose hyper-radiosensitivity is a radiobiological phenomenon whereby cells display higher sensitivity to lower doses of radiation than is expected from the linear quadratic model of cell survival. It has been demonstrated in vitro with doses<1 Gy . It is thought that low dose radiation fails to activate DNA damage repair mechanisms that would otherwise halt progression through the cell cycle and protect irradiated cells from radiation induced cell death, a process known as Increased Radioresistance (IRR). Specifically, cells that are irradiated above a threshold dose while in the G2 phase of the cell cycle will arrest at the G2 early checkpoint prior to mitosis in order to undergo DNA damage repair, leading to enrichment in this phase. Molecularly, the arrest of cells in this checkpoint is Ataxia Telangiectasia-Mutated (ATM) dependent; a kinase known to be involved in activation of DNA repair. Thus kinases like ATM may also regulate the transition of cellular response to radiation therapy from LDHRS at low doses to IRR at higher doses. These same mechanisms may also be implicated in the Inverse Dose Rate Effect (IDRE), a similar phenomenon of decreased cell survival over a range of low dose rates compared to high dose rates .
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