Jeffrey Y. C. Wong - Total Marrow Irradiation: A Comprehensive Review

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Since the initial pioneering efforts of Thomas and colleagues [], radiation therapy continues to be an important part of conditioning regimens in patients undergoing hematopoietic cell transplantation (HCT). Radiation therapy is used primarily as a form of systemic therapy utilizing high energy photons and large fields to deliver total body irradiation (TBI). TBI is often part of the conditioning regimen in patients with leukemia undergoing allogeneic HCT. The primary indications for allogeneic HCT in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) are patients in first remission with intermediate to high risk features, induction failure, and relapse, or in second remission or beyond. Patients with myelodysplastic syndrome (MDS) with high risk features or evolving to an acute state are also candidates for allogeneic HCT. The role of TBI in patients with multiple myeloma undergoing HCT is less frequent but has been used in patients undergoing autologous or allogenic HCT.

There are a number of advantages to using TBI as part of the conditioning regimen. TBI is effective at eradicating malignant cells, which for most hematologic malignancies are very radiosensitive. TBI also provides a powerful means of immunosuppression to prevent rejection of donor hematopoietic cells in patients undergoing allogeneic HCT. TBI offers distinct advantages compared to chemotherapy. Delivery of radiation therapy to the tumor site is not dependent on blood supply or influenced by interpatient variability of drug absorption, metabolism, biodistribution, or clearance kinetics. Radiation therapy can reach potential sanctuary sites, such as testes and brain. Chemotherapy resistant clones that develop may still be sensitive to irradiation. Finally, non-TBI chemotherapy-only conditioning regimens offer no obvious advantage in reducing toxicities or improving control rates compared to TBI containing regimens [].

Understanding the limitations of TBI in the context of evolving strategies being used in HCT provides the basis for developing new more-targeted radiotherapy approaches. A major limitation is that the recent technological advances in image-guided organ-sparing IMRT delivery have not been applied to the delivery of TBI. The traditional methods of delivering TBI developed more than 30 years ago, utilize large opposed whole body fields, and are the least conformal in radiation oncology []. Although lung blocking has reduced the risks of pneumonitis and lethal pulmonary toxicity, recent studies have demonstrated that mean lung doses below 8 Gy, which are challenging to achieve using conventional TBI delivery methods, are needed to further reduce lung toxicity risks and improve overall survival.

A second challenge is the utilization of TBI is declining due to lack of new strategies to reduce TBI toxicities and the introduction of alternative non-TBI approaches. In a survey of the Center for International Blood and Marrow Transplant Research (CIBMTR) Database which surveyed 596 centers in 52 countries and included 219,341 patients from 1995 to 2010, TBI utilization decreased for both autologous (13% to 2%, p < 0.0001) and allogeneic HCT (53% to 39%, p < 0.0001) []. Patients older than 60 years, with comorbidities or with poor performance status, are not able to undergo TBI. As a result, there has been increasing use of chemotherapy-only myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens. In addition, the perspective of hematologists has evolved from viewing allogeneic HCT primarily as a cytotoxic tool to more of an immunologic tool which relies more on graft versus tumor effects for disease control. In an increasing number of clinical scenarios, TBI is no longer the primary modality but is added when increased cytoreduction and immunosuppression are needed, and only if it can be added without significant additional toxicity.