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Total body irradiation
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
12.
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
19.
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
