Radiation Biology
Radiobiological Considerations in the Use of Total-Body Irradiation for Bone-Marrow Transplantation 1 Lester J. Peters, M.D., H. Rodney Withers, M.D., Ph.D., Jackson H. Cundiff, B.Sc., and Karel A. Dicke, M.D., Ph.D.
On radiobiological grounds, a therapeutic advantage should result when total body irradiation (TBI) in preparation for bone-marrow engraftment is given as a fractionated course, rather than as a single exposure at logistically reasonable dose rates. This is because cells of hemopoietic origin in general show less capacity for repair of sublethal radiation injury than do cells of other organs. Dose-limiting lung tolerance, in the context of fractionated TBI, is estimated to be at least 12 Gy (without correction) in increments of 2 Gy regardless of dose rate. A practical method for delivering TBI using a high-energy linear accelerator is described. INDEX TERMS: Leukemia, therapeutic radiology • Radiobiology, blood and hematopoietic studies • Therapeutic radiology, dosimetry. Therapeutic radiology, total-body irradiation
Radiology 131:243-247, April 1979
HE FEASIBILITY of using high-dose chemotherapy and total-body irradiation (TBI) followed by bone-marrow engraftment in the management of certain malignant and nonmalignant hemopoietic disorders is now established (1). By far the most frequent application is in the treatment of refractory leukemia, where successful bone-marrow reconstitution permits the administration of drugs and radiation in doses that are well in excess of the lethal limit for hemopoietic death. The rationale for the use of TBI in addition to chemotherapy is based on the efficacy of radiation in killing cells of Iymphohemopoietic origin and its ability to sterilize "privileged sites", such as the central nervous system and testes. With bone-marrow rescue, the upper limit of radiation dose that can be used is set by the tolerance of organs such as the gut and lungs, to acute or late radiation sequelae. Historically, TBI has been administered in a single sitting largely because patients considered for marrow transplantation were usually very ill, and because of a desire to expedite marrow engraftment. Techniques commonly employed deliver single midplane doses of around 10 Gy (1,000 rad) at less than 0.1 Gy (10 rad)/min (2), the dose rate usually being limited by the machine output and treatment geometry required for TBI. Low-dose-rate treatment has several disadvantages: (a) treatment time is long, (b) radiation sickness develops during exposure, and (c) immediate tolerance to treatment of both patients and staff is poor. In an effort to circumvent these practical problems, the use of high-dose-rate exposures using high-energy linear accelerators has been recommended
T
(3). The purpose of this report is to suggest that highdose-rate single exposures are likely to adversely affect the therapeutic ratio for TBI, and that fractionated TBI is a much sounder approach radiobiologically. Target Cells
In the treatment of leukemia, the target cells are the leukemic stem cells surviving chemotherapy as well as the normal hemopoietic and lymphoid cells that must be ablated to permit successful bone-marrow engraftment when allogeneic marrow is used. When syngeneic or autologous bone-marrow reconstitution is employed, it is obvious that only the leukemic stem cells need be eliminated. Conversely, in patients with aplastic anemia or immune-deficiency disorders, only the resistance to marrow engraftment must be overcome. The radiation survival characteristics of bone-marrow stem cells in the mouse were first measured in vivo by McCulloch and Till using the exogenous spleen-colony assay system (4). The survival curve had a Do of 0.95 Gy (95 rad) and an extrapolation number of 1.5, the latter implying that these cells have a limited capacity to accumulate (and repair) sublethal injury. Similar survival curves have been produced by other investigators for both hemopoietic stem cells and spleen cells (5,6), and it appears to be a general characteristic of these cell types to have relatively low Do's and little or no shoulder on their radiation survival curves. A strictly exponential radiation survival curve has also been demonstratedfor human bone-marrow cells cultured in vitro (7). With regard to experimental
1 From the Section of Experimental Radiotherapy (L.J.P., H.R.W.),Department of Physics (J.H.C.), and Department of Developmental Therapeutics (K.A.D.), University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston, TX. Received Aug. 23, 1978; accepted and revision requested Nov. 9; revision received Dec. 8. This investigation supported in part by Grants #CA-06294 and #CA-11138, awarded by the National Cancer Institute, DHEW. jr
243
244
LESTER J. PETERS AND OTHERS
1.5
~
14
':3
I 3
~
1.2
g
I I
Critical Normal Tissues
o
•
o
•
I.O'--------------L---------'------1I~"O__O__1L'>___-O______----'
01
10 Dose Rate (Rod /min)
100
1000
Fig. 1. Dose-rate factors for LDso/3o in mice reported by difFeola et al. (12), ~ Pure and Clark (11), 0 ferent authors . • Thomson and Tourtellotte (9),0 Tubiana and Boisserie (13), • = Kallman (10).
=
=
TABLE
I:
=
=
EFFECT OF DOSE FRACTIONATION ON THE
LDso/3o OF
BALB/C MICE *
No. of Fractions t
LDso
Dose Ratio
1 2
770 870 920 920
1.00 1.13 1.20 1.20
4 8
* Data of Tubiana and Boisserie (13)
t Delivered within 48 hours
TABLE
April 1979
II: ACTUARIAL INCIDENCE OF PNEUMONITIS IN PATIENTS
RECEIVING RADIOTHERAPY TO THE UPPER HALF OF THE BODY *
Uncorrected Lung Dose (0.3-0.5 Gy/min [30-50 rad/min)) 10 8
(1000) (800)
6
'~ ~
if)
Human Lung Tolerance When the whole of both lungs are irradiated for prophylaxis or treatment of metastatic disease, lung tolerance (defined as
Radiobiological Considerations in the Use of Total-Body Irradiation for Bone-Marrow Transplantation 1 Lester J. Peters, M.D., H. Rodney Withers, M.D., Ph.D., Jackson H. Cundiff, B.Sc., and Karel A. Dicke, M.D., Ph.D.
On radiobiological grounds, a therapeutic advantage should result when total body irradiation (TBI) in preparation for bone-marrow engraftment is given as a fractionated course, rather than as a single exposure at logistically reasonable dose rates. This is because cells of hemopoietic origin in general show less capacity for repair of sublethal radiation injury than do cells of other organs. Dose-limiting lung tolerance, in the context of fractionated TBI, is estimated to be at least 12 Gy (without correction) in increments of 2 Gy regardless of dose rate. A practical method for delivering TBI using a high-energy linear accelerator is described. INDEX TERMS: Leukemia, therapeutic radiology • Radiobiology, blood and hematopoietic studies • Therapeutic radiology, dosimetry. Therapeutic radiology, total-body irradiation
Radiology 131:243-247, April 1979
HE FEASIBILITY of using high-dose chemotherapy and total-body irradiation (TBI) followed by bone-marrow engraftment in the management of certain malignant and nonmalignant hemopoietic disorders is now established (1). By far the most frequent application is in the treatment of refractory leukemia, where successful bone-marrow reconstitution permits the administration of drugs and radiation in doses that are well in excess of the lethal limit for hemopoietic death. The rationale for the use of TBI in addition to chemotherapy is based on the efficacy of radiation in killing cells of Iymphohemopoietic origin and its ability to sterilize "privileged sites", such as the central nervous system and testes. With bone-marrow rescue, the upper limit of radiation dose that can be used is set by the tolerance of organs such as the gut and lungs, to acute or late radiation sequelae. Historically, TBI has been administered in a single sitting largely because patients considered for marrow transplantation were usually very ill, and because of a desire to expedite marrow engraftment. Techniques commonly employed deliver single midplane doses of around 10 Gy (1,000 rad) at less than 0.1 Gy (10 rad)/min (2), the dose rate usually being limited by the machine output and treatment geometry required for TBI. Low-dose-rate treatment has several disadvantages: (a) treatment time is long, (b) radiation sickness develops during exposure, and (c) immediate tolerance to treatment of both patients and staff is poor. In an effort to circumvent these practical problems, the use of high-dose-rate exposures using high-energy linear accelerators has been recommended
T
(3). The purpose of this report is to suggest that highdose-rate single exposures are likely to adversely affect the therapeutic ratio for TBI, and that fractionated TBI is a much sounder approach radiobiologically. Target Cells
In the treatment of leukemia, the target cells are the leukemic stem cells surviving chemotherapy as well as the normal hemopoietic and lymphoid cells that must be ablated to permit successful bone-marrow engraftment when allogeneic marrow is used. When syngeneic or autologous bone-marrow reconstitution is employed, it is obvious that only the leukemic stem cells need be eliminated. Conversely, in patients with aplastic anemia or immune-deficiency disorders, only the resistance to marrow engraftment must be overcome. The radiation survival characteristics of bone-marrow stem cells in the mouse were first measured in vivo by McCulloch and Till using the exogenous spleen-colony assay system (4). The survival curve had a Do of 0.95 Gy (95 rad) and an extrapolation number of 1.5, the latter implying that these cells have a limited capacity to accumulate (and repair) sublethal injury. Similar survival curves have been produced by other investigators for both hemopoietic stem cells and spleen cells (5,6), and it appears to be a general characteristic of these cell types to have relatively low Do's and little or no shoulder on their radiation survival curves. A strictly exponential radiation survival curve has also been demonstratedfor human bone-marrow cells cultured in vitro (7). With regard to experimental
1 From the Section of Experimental Radiotherapy (L.J.P., H.R.W.),Department of Physics (J.H.C.), and Department of Developmental Therapeutics (K.A.D.), University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston, TX. Received Aug. 23, 1978; accepted and revision requested Nov. 9; revision received Dec. 8. This investigation supported in part by Grants #CA-06294 and #CA-11138, awarded by the National Cancer Institute, DHEW. jr
243
244
LESTER J. PETERS AND OTHERS
1.5
~
14
':3
I 3
~
1.2
g
I I
Critical Normal Tissues
o
•
o
•
I.O'--------------L---------'------1I~"O__O__1L'>___-O______----'
01
10 Dose Rate (Rod /min)
100
1000
Fig. 1. Dose-rate factors for LDso/3o in mice reported by difFeola et al. (12), ~ Pure and Clark (11), 0 ferent authors . • Thomson and Tourtellotte (9),0 Tubiana and Boisserie (13), • = Kallman (10).
=
=
TABLE
I:
=
=
EFFECT OF DOSE FRACTIONATION ON THE
LDso/3o OF
BALB/C MICE *
No. of Fractions t
LDso
Dose Ratio
1 2
770 870 920 920
1.00 1.13 1.20 1.20
4 8
* Data of Tubiana and Boisserie (13)
t Delivered within 48 hours
TABLE
April 1979
II: ACTUARIAL INCIDENCE OF PNEUMONITIS IN PATIENTS
RECEIVING RADIOTHERAPY TO THE UPPER HALF OF THE BODY *
Uncorrected Lung Dose (0.3-0.5 Gy/min [30-50 rad/min)) 10 8
(1000) (800)
6
'~ ~
if)
Human Lung Tolerance When the whole of both lungs are irradiated for prophylaxis or treatment of metastatic disease, lung tolerance (defined as
