Total Body Irradiation R4 洪逸平 Bone Marrow Transplantation (2011) 46, 475–484 Best Practice & Research Clinical haematology (2007) Current Opinion in Hematology 2008, 15:555–560 財團法人台灣癌症臨床研究發展基金會

Total Body Irradiation  The first examples of human surviving supralethal TBI in leukemia with BM infusion and grafting was in 1965 Cancer Res 1965; 25: 1525–1531.

Goals of TBI  Eradicating diseased marrow  Reducing tumor burden  Immunosupressive  TBI may be particularly important in the setting of matched-unrelated donor transplants, when adequate immunosuppression is essential  Deplete the BM to allow physical space for engraftment of healthy donor marrow

Total Body Irradiation  Dual opposing 60Co  Advantages: highly homogenous radiation exposure which allows the patient some freedom of movement  Disadvantages: cost, difficulties in organ shielding, and the problem of delivering higher dose rates  Linear accelerators  a higher dose rate as well as organ shielding can easily be administered.  Major concerns: the dose rate, the fractioning and the total dose

Dose, fractionation and dose rate employed during TBI Myeloablative regimens  Early-myeloablative TBI regimens used single, large fractions of 8–10 Gray (Gy)  High risk of death from interstitial pneumonitis  Fractionation and reduction od dose  Dose rates <10–12 cGy/min are associated with reduced rates of pneumonitis, nausea and vomiting  TBI in daily or twice-daily fractions appears to improve the therapeutic ratio, allowing higher radiation doses  inconvenient

Dose rate  Most of the clinically used TBI regimens the radiation is given at low dose rates (5 – 8 cGy/min)  High dose rates (60 – 80 cGy/min) in canine models showed more GI and marrow toxicity with more intense immunosuppressive effect  High dose rate increases the risk of interstitial pneumonitis and cataract  If TBI was fractioned, the toxicity reduced.  Lower dose rates permitted higher total doses

Fractionating  Fractionating was applied to increase the irradiation dose  The total dose of fractionated TBI needs to be increased to have a similar Immunosuppressive effect as single-dose TBI  Risk for late organ toxicity decreased and long- term survival improved in animal model  In clinical trials, Fractionated TBI showed less veno-occlusive disease (VOD) of the liver, a trend for fewer relapses and improved survival. International Journal of Radiation Oncology, Biology, Physics 1988; 15: 647e653. Journal of Clinical Oncology 2000 Bone Marrow Transplantation 1986; 1:

Dose, fractionation and dose rate in Myeloablative TBI  In the latter half of 20 th century, myeloablative regimens delivering 12 Gy, twice daily, over 3 days, in combination with chemotherapy were most commonly employed  15-16Gy showed no improvement of OS (may be due to increased mortality unrelated to relapse) Blood 1990; 76: Blood 1991; 77:

Reduced-intensity conditioning regimens  In the 1990s, feasibility of reduced-intensity conditioning (RIC) regimens consisting of lower-dose TBI and/or fludarabine  Cytotoxic effect from such regimens is minimal – tumor cell death is largely dependent on a graft vs tumor effect  McSweeney et al. employing 2 Gy delivered as a single dose, with or without fludarabine, with cyclosporine and mycophenolate mofetil as GVHD prophylaxis in older patients  Other group use 2 Gy, single-dose, low-dose rate (7 cGy/min) TBI in the setting of both related and unrelated donor transplantation Blood 2001; 97: 3390–3400 Blood 2004; 104: 961–968. Blood 2003; 102: 756–762 J Clin Oncol 2005; 23: 1993–2003.

Reduced-intensity conditioning regimens  Kahl et al. found better relapse free survival in CLL, MM, non-Hodgkin’s lymphoma patients  Graft rejection risk is higher in CML and MDS patients  Marks et al. compared cohorts of patients receiving myeloablative therapy vs RIC in ALL and showed no difference in mortality. However relapse rate increased in RIC group Biol Blood Marrow Transplant 2005; 11: 272–279. Blood 2007; 110: 2744–2748.

Morbidity associated with current regimens for TBI  interstitial pneumonitis  In ~50% if single, large fraction of 8-10 Gy, with 50% fatal  25% in fractioned and low-dose-rate TBI  CMV infection may take a role

Acute toxicities associated with TBI  Nausea and vomiting  Preventable with modern anti-emetic agents  Parotitis  Occur after the first 1-2 fractions, subsided within 1 – 2 days  Unique to TBI  Dry mouth and mucositis  5 – 10 days after TBI

End-organ damage and late effects after TBI  Cataract  Gonadal failure  Thyroid dysfunction  Kidney dysfunction  Decreased bone mineral density  Xerostomia  Short stature and endocrine dysfunction in child  Increased risk for cardiometabolic traits, including central adiposity, hypertension, insulin resistance and full-blown metabolic syndrome  Venoocclusive disease of the liver may occur in 10–70% of patients

Second malignant neoplasms  Two large, recent, analyses demonstrated the risk of solid tumor after BMT to range from 3 to 7% at 15 years following transplant  A recent multi-institutional analysis of allogeneic transplant recipients allogeneic transplant recipients demonstrated a 3.3% incidence of development of a solid tumor 20 years  This risk was increased for the 67% of patients who received irradiation compared with those who did not  This excess risk was observed only in patients who received radiation ≦ 30 years old  Curtis et al. 58 observed the risk of solid tumor to be 2.2% 10 years after BMT, and 6.7% 15 years Blood 2009; 113: 1175–1183. N Engl J Med. 1997; 336 (13): 897–904.

Second malignant neoplasms  Radiotherapy was observed to increase the risk of second cancers, this risk is significantly higher in receiving >10 Gy than <10Gy  Patients are also at risk for further hematological malignancies, including MDS and AML J Clin Oncol 2000; 18: 348–357.

Protection of normal tissue during TBI  Physical blocks  TLI for immunosuppression during BMT  TLI may result in increased proportions of natural killer T cells  Prevent GVHD by inhibit conventional T cell  Lowsky et al. described 37 patients with lymphoid malignancies or acute leukemia treated with 800 cGy total TLI, over 10 fractions, 3% ≧ grade II GVHD with increased odds of early CMV viremia

Future directions: increased conformality and potential for dose escalation  Potential use of helical tomotherapy  Potential use of proton beam radiotherapy  Potential use of radioimmunotherapy

ALL  The most commonly used regimen for transplantation of patients with ALL is CY plus TBI  Retrospective analysis from the IBMTR found that a conventional CY/TBI regimen was superior to a non- TBI-containing regimen of BU plus CY, with a 3-year survival of 55 versus 40% for BU/CY. With similar relapse risk  A recent study of BU, Fludarabine and 400 cGy of TBI showed a low TRM(3%) and a projected DFS of 65% J Clin Oncol 2000; 18: 340–347.

ALL  A comparative analysis of TBI combined with either CY or etoposide chemotherapy showed no TRM differences  In CR1, no significant differences in relapse, leukemia-free survival or survival by conditioning regimen  In CR2, the risks of relapse, treatment failure and mortality tended to be lower with etoposide (regardless of TBI dose) or with TBI doses 413 Gy. Biol Blood Marrow Transplant 2006; 12: 438–453.

AML  Cy-TBI appears to be superior to Bu-Cy in terms of survival and LFS, especially in patients with advanced disease  Both TRM and relapse are reduced in patients undergoing TBI  Early toxicity is an important problem with Bu, and higher incidences of VOD and hemorrhagic cystitis are reported Experimental Hematology 31 (2003) 1182–1186 IBMTR

BUCY and CyTBI Best Practice & Research Clinical Haematology Vol. 20, No. 2, pp. 295 e 310, 2007

Best Practice & Research Clinical Haematology Vol. 20, No. 2, pp. 295 e 310, 2007

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