1. Total Body Irradiation
R4洪逸平
Current Opinion in Hematology 2008, 15:555–560
Bone Marrow Transplantation (2011) 46, 475–484
Best Practice & Research Clinical haematology (2007)

2. 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.

3. 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

4. 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

5. 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

6. 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

7. 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
International Journal of Radiation Oncology,
Biology, Physics 1988; 15: 647e653.
 In clinical trials, Fractionated TBI showed less
veno-occlusive disease (VOD) of the liver, a
trend for fewer relapses and improved
survival. Journal of Clinical Oncology 2000
Bone Marrow Transplantation 1986; 1: 151-

8. 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: 1867-18
Blood 1991; 77: 1660-16

9. 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 Blood 2001; 97: 3390–3400
 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 2004; 104: 961–968.
Blood 2003; 102: 756–762
J Clin Oncol 2005; 23: 1993–200

10. Reduced-intensity conditioning
regimens
 Kahl et al. found better relapse free
survival in CLL, MM, non-Hodgkin’s
lymphoma patients 2007; 110: 2744–2748.
Blood
 Graft rejection risk is higher in CML and
MDS patients Biol Blood Marrow Transplant 2005; 11: 272–279.
 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

11. 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

13. 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

14. 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

15. 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 Blood 2009; 113: 1175–1183.
 Curtis et al. 58 observed the risk of solid tumor to be
2.2% 10 years after BMT, and 6.7% 15 years
N Engl J Med. 1997; 336 (13): 897–

16. 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.

17. 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

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

20. 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 J Clin Oncol 2000; 18: 340–347.
 A recent study of BU, Fludarabine and 400 cGy of
TBI showed a low TRM(3%) and a projected DFS
of 65%

21. 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.

22. 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
IBMTR
Experimental Hematology 31 (2003) 1182–1186

23. BUCY and CyTBI
Best Practice & Research Clinical
Haematology

24. Best Practice & Research Clinical
Haematology

26. Thanks For Your Attention!!