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Total Body Irradiation
R4洪逸平
Bone Marrow Transplantation (2011) 46, 475–484Best Practice & Research Clinical haematology (2007). 295-310
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: 151-157
Dose, fractionation and dose rate in Myeloablative TBI
In the latter half of 20th 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: 1867-1871
Blood 1991; 77: 1660-1665
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 28 874 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 HaematologyVol. 20, No. 2, pp. 295 e 310, 2007
Best Practice & Research Clinical HaematologyVol. 20, No. 2, pp. 295 e 310, 2007
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