03h0-3nih/%l $3.00 + .oo Copyright Cc 1990 Pergamon Prew plc
??Oncology Intelligence
TOTAL
BODY IRRADIATION
REGIMENS
FOR MARROW
GRAFTING
E.DONNALLTHOMAS,M.D. 1990Nobel Laureate Fred Hutchinson
Cancer Research Center and the University of Washington School of Medicine, Seattle, WA
When my colleagues and I first began to use total body irradiation for large animals and man in preparation for marrow grafting, high energy sources were not available. Therefore, we used opposing 6oCo sources in an effort to achieve a relatively homogenous total body irradiation (TBI) (8). Although we began with very low exposure rates, in the last 2 decades we have used rates of approximately 7 cGy per minute. Our studies in dogs showed that allogeneic grafts could not be achieved consistently with less than an 8 Gy exposure (21). To achieve consistent engraftment, we used 10 Gy in a single exposure followed immediately by an intravenous infusion of donor marrow. In patients with leukemia in relapse, our aim was to achieve a marrow graft as quickly as possible before the patient died of infection and bleeding problems. Using this approach, we were able to show that some patients with far-advanced refractory leukemia could be cured of their disease (25). We also showed that the possibility of cure could be increased to approximately 50% by transplantation of patients with acute leukemia in remission when they were in good clinical condition with a minimal body burden of leukemic cells (22). With patients in better condition and with improved supportive care techniques, it became feasible to consider fractionating the irradiation over a period of several days before the infusion of marrow. For patients with acute nonlymphoblastic leukemia (ANL) in first remission, we administered two doses of cyclophosphamide, 60 mg/kg on each of 2 days and then randomized the patients to receive either 10 Gy in a single exposure or 2 Gy per day for 6 days (24). Figure 1 shows the outcome of this study, demonstrating a superiority of the fractionated radiation regimen (p = 0.04). We studied several other irradiation regimens in human recipients of HLA-identical allografts. Most recently, we attempted to reduce the rate of leukemic relapse in patients transplanted for chronic myelogenous leukemia
(CML) in chronic phase by increasing the radiation exposure. We conducted a randomized study to compare 2 Gy per day on each of 6 days (12 Gy total) to 2.25 Gy per day for 7 days (15.75 Gy total). Although this study will require another year for complete evaluation, the present results are shown in Figures 2A, 2B, and 2C. In summary, the patients given the higher radiation exposure had a reduced incidence of recurrence of leukemia but a greater incidence of death from regimen-related toxicity so that overall disease-free survival was not different. We conclude that the total exposure of 15.75 Gy, as we administered it, is the maximum TBI exposure that can be tolerated without excessive regimen-related deaths. This conclusion is consistent with our earlier studies of irradiation regimens in dogs given autoiogous marrow grafts (7). Despite theoretical radiobiological consideration of TBI ( 14) different marrow transplant teams have used a variety of approaches to the administration of TBI, often dictated by the type and availability of radiation equipment (1, 2, 9- 12, 16, 18, 19,26). Some have used single “Co sources; others have used high energy sources. Different schemes of fractionation and hyperfractionation have been employed. Dose rates have varied from approximately 5 cGy/ minute to 26 cGy/minute. The Toronto team has used dose rates of 50 to 85 cGy/minute with a total exposure of 5.0 Gy. Some have used shielding of the lungs with electron boost to the chest wall. Others have also included total lymphoid irradiation. A survey of these approaches fails to disclose any regimen which is clearly superior, at least in the absence of controlled prospective trials. A major difficulty in the various approaches to TBI has been the fact that there are many confounding variables. Patients may die of idiopathic interstitial pneumonia which probably represents a direct radiation toxicity. However, there are many competing causes of death including the type and stage of disease being treated. the
Presented at the 17 International Congress of Radiology, Paris, France 1-8 July 1989. Reprint requests to: E. Donna11 Thomas, M.D., Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98 104.
This investigation was supported by PHS Grants CA 18029 and CA 3 1787 awarded by the National Cancer Institute, DHHS. Dr. Thomas is a recipient of a Research Career Award AI 02425 from the National Institute of Allergy and Infectious Diseases. Accepted for publication 24 May 1990. 1285
1286
1. J. Radiation Oncology 0 Biology 0 Physics
03
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November 1990, Volume 19, Number 5
I 9
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0.0
YEARS Fig. 1. Kaplan-Meier product limit estimates for event-free survival of patients with acute nonlymphoblastic leukemia in first remission, given cyclophosphamide 60 mg/kg on each of 2 days, randomized to receive 2 Gy on each of 6 days (n = 26) or 10 Gy (n = 27) in one exposure followed by an infusion of marrow from an HLA-identical sibling.
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complications of graft-versus-host disease, opportunistic infections, particularly cytomegalovirus interstitial pneumonia, venocclusive disease of the liver, and graft failure associated with T-cell depletion of donor marrow. One area of progress includes the prevention and control of graft-versus-host disease. The Seattle team has reported the use of a short course of methotrexate combined with cyclosporine with a significant decrease in the incidence and severity of graft-versus-host disease (20). Using this regimen along with a well-tolerated TBI regimen (2 Gy per day for 6 days) has resulted in an excellent survival and cure rate for patients with CML treated in the chronic phase of the disease (23). Figure 3 shows a survival and disease-free survival Kaplan-Meier analysis of these data for patients given an allogeneic graft from an HLA-identical donor with the transplant carried out within the first year after diagnosis. It is clear that, with this regimen, there is no reason to delay transplantation for patients with CML, since this disease has not been cured by any other approach. An intense area of current research involves other approaches to the prevention and treatment of graft-versus-host disease, including T-cell depletion of donor marrow and the use of various monoclonal antibodies. As regimens of promise are identified, it will be necessary to conduct randomized prospective trials to compare these regimens with the best immunosuppressive drug regimen described above. Late complications of TBI have been and continue to be a concern. However, these complications, after up to 2 decades of follow-up, do not appear to be prohibitive. Most patients are sterile following their previous chemotherapy and the marrow preparative regimen. Hair loss is not permanent. The incidence of cataracts has been reduced from approximately 60% to approximately 20% by fractionation of irradiation (5). Some patients have developed late pulmonary problems, but it is difficult to tell whether these problems are related to irradiation or to chronic graft-versus-host disease and opportunistic infections (3). Most leukemic children arrive for transplant
; E 0.4.
0
1
2 YEARS
N 1.0 :: R
E
’
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YEAR!3
Fig. 2. Kaplan-Meier product limit estimates for patients with CML in chronic phase, receiving cyclophosphamide, randomized to receive 2 Gy on each of 6 days (n = 5 1) or 2.25 Gy on each of 7 days (n = 56) and given a marrow graft from an HLAidentical sibling. Figure 2A shows survival, Figure 2B shows relapse, and Figure 2C shows death from nonleukemic causes.
having already received intensive chemotherapy, often with cranial irradiation as well. This previous therapy, when coupled with a transplant preparative regimen that includes TBI, often results in endocrine dysfunction and retarded growth and development ( 17). Alternative regimens which do not use TBI, such as busulfan and cyclophosphamide (26), have not yet been evaluated for these late effects. Studies of the incidence of second malignancies in canine and human irradiation chimeras suggest a slight increase over the expected incidence (6). Interpretation of these data is also difficult because of the frequent presence of some degree of chronic graft-versus-host disease. Recurrence of leukemia in donor type cells is an
TBI for marrow grafting 0 E. D. THOMAS
0.8. MNT-FREE
SURVlVAL
0 “A 0.6. B : , 0.4. T Y 0.2.
0
1
3
2
4
5
YEARS
Fig. 3. Kaplan-Meier product limit estimates for survival and event-free survival of patients with CML (n = 28) in chronic phase given cyclophosphamide, 2 Gy on each of 6 days followed by a marrow graft from an HLA-identical sibling, followed by a short course of methotrexate combined with a long course of cyclosporine. The patients were transplanted within I year of
diagnosis. infrequent, unexplained phenomena (4). A small fraction of patients, particularly those undergoing intensive treatment for graft-versus-host disease, have developed EBVassociated lymphoproliferative tumors which are often fatal (27). Overall, the incidence of second malignancies
1287
appears very low, with the major problem being the recurrence of the patient’s original malignant disease. Although some improvement in the use of TBI may be expected from exploration of various fractionation regimens and dose rates, it appears that the limits have been established and the results from fine-tuning will not be particularly impressive. Other approaches being explored include the use of radiolabeled heterospecific or monoclonal antibodies for a directed irradiation of malignant cells (13, 15). Other exploratory approaches use bone-seeking radioactive isotopes in an effort to achieve a higher radiation exposure for the marrow cavities without exposure of the lung. In the field of radiation biology, the established dogma states that the bone marrow is the most sensitive organ associated with lethal damage, followed closely by the gut. The accumulated experience with TBI when death is prevented by marrow transplantation shows that the limiting toxicity is not the gut but the lung (idiopathic interstitial pneumonia) and the liver (venocclusive disease). In many cases these organs also constitute the limiting toxicity for chemotherapy and combinations of chemotherapy with radiation therapy. In view of these limitations of chemoradiotherapy, other approaches under the broad heading of biological response modifiers are currently under intensive investigation.
REFERENCES I. Barrett, A.; Barrett, A. J.; Powles, R. L. Total body irradiation and marrow transplantation for acute leukaemia. The Royal Marsden Hospital experience. Path. Biol. 27:357359; 1979. 2. Baume, D.; Cosset, J. M.: Pica, J. L.; Girinski, T.; Le Bail. N.; Nabholtz, J. M.; Benhamou, E.; Dutreix, J.; Hayat, M. Comparaison entre irradiation totale en un temps et hyperfractionnee pour le conditionnement des greffes de moelle allogeniques. Une etude retrospective de 54 malades atteints d’hemopathies mahgnes. Bull. Cancer 75:361-372; 1988. 3. Beschorner, W. E.; Saral, R.; Hutchins, G. M.; Tutschka. P. J.; Santos, G. W. Lymphocytic bronchitis associated with graft-versus-host disease in recipients of bone-marrow transplants. N. Engl. J. Med. 299:1030-1036; 1978. 4. Boyd, C. N.; Ramberg, R. E.; Thomas, E. D. The incidence of recurrence of leukemia in donor cells after allogeneic bone marrow transplantation. Leuk. Res. 6:833-837; 1982. 5. Deeg, H. J.; Flournoy, N.; Sullivan, K. M.; Sheehan, K.; Buckner, C. D.; Sanders, J. E.; Storb, R.; Witherspoon, R. P.; Thomas, E. D. Cataracts after total body irradiation and marrow transplantation: a sparing effect of dose fractionation. Int. J. Radiat. Oncol. Biol. Phys. 10:957-964; 1984. 6. Deeg, H. J.; Sanders, J.; Martin, P.; Fefer, A.; Neiman, P.; Singer, J.; Storb, R.; Thomas, E. D. Secondary malignancies after marrow transplantation. Exp. Hematol. 12:660-666; 1984. 7. Deeg, H. J.; Storb, R.; Longton, G.; Graham, T. C.; Shulman, H. M.; Appelbaum, F.; Thomas, E. D. Single dose or fractionated total body irradiation and autologous marrow transplantation in dogs: effects of exposure rate, fraction size and fractionation interval on acute and delayed toxicity. Int. J. Radiat. Oncol. Biol. Phys. 15:647-653; 1988.
8. Ferrebee, J. W.; Thomas, E. D. Factors affecting the survival oftransplanted tissues. Am. J. Med. Sci. 235:369-386; 1958. 9. Findley, D. 0.; Skov, D. D.; Blume, K. G. Total body irradiation with a IO MV linear accelerator in conjunction with bone marrow transplantation. Int. J. Radiat. Oncol. Biol. Phys. 6:695-702; 1980. 10. Gluckman, E.; Devergie, A.; Lokiec, F. Use of cyclosporine for prevention of graft-versus-host disease after allogeneic bone marrow transplantation. Transplant. Proc. ZO(Suppl. 20):46 l-469; 1988. 11. Kim, T. H.; Kersey, J.; Sewchand, W.; Nesbit, M. E.; Krivit, W.; Levitt, S. H. Total-body irradiation with a high-doserate linear accelerator for bone-marrow transplantation in aplastic anemia and neoplastic disease. Radiology 122:523525; 1977. 12. Messner, H. A.; Curtis, J. E.; Minden. M. D.; Tritchler, D.; Lockwood, G.; Takahashi, T.; Lepine, J.; Jamal, N.; Tweeddale, M.; Wand], U. Clonogenic hemopoietic precursors in bone marrow transplantation. Blood 70:14251432; 1987. 13. Order, S. E.; Sleeper, A. M.; Stillwagon, G. B.; Klein, J. L.; Leichner, P. K. Current status of radioimmunoglobulins in the treatment of human malignancy. Oncology 3: I 15- 120: 1989. 14. Peters, L. J.; Withers, H. R.; Cundiff, J. H.; Dicke, K. A. Radiobiological considerations in the use of total-body irradiation for bone-marrow transplantation. Radiology 13 1: 243-247; 1979. 15. Press, 0. W.; Eary, J. F.; Badger, C. C.; Martin, P. J.; Appelbaum, F. R.; Levy, R.; Miller, R.; Brown, S.; Nelp, W. B.; Krohn, K. A.; Fisher, D.; DeSantes, K.; Porter, B.; Kidd. P.: Thomas, E. D.; Bernstein, I. D. Treatment of re-
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16. 17.
18.
19.
20.
I. J. Radiation Oncology 0 Biology 0 Physics
fractory non-Hodgkins lymphoma with radiolabeled MB- 1 (anti-CD37) antibody. J. Clin. Oncol. (In press). Quast, U. Total body irradiation-review of treatment techniques in Europe. Radiother. Oncol. 9:91-106; 1987. Sanders, J. E.; Buckner, C. D.; Sullivan, K. M.; Doney, K.; Appelbaum, F.; Witherspoon, R.; Storb, R.; Thomas, E. D. Growth and development in children after bone marrow transplantation. Horm. Res. 30:92-97; 1988. Shank, B.; Hopfan, S.; Kim, J. H.; Chu, F. C. H.; Grossbard, E.; Kapoor, N.; Kirkpatrick, D.; Dinsmore, R.; Simpson, L.; Reid, A.; Chui, C.; Mohan, R.; Finegan, D.; Q’Reilly, R. J. Hyperfractionated total body irradiation for bone marrow transplantation: I. Early results in leukemia patients. Int. J. Radiat. Oncol. Biol. Phys. 7: I 109-I 1IS; 198 I. Slavin, S.; Naparstek, E.; Cividalli, G.; Weshler, Z.; Weiss, L.; Mumcuoglu, M.; Brautbar, C.; Schlesinger, M.; Hale, G.; Waldmann, H.; Or, R. The use of Campath-l for prevention of graft vs host disease (GVHD) and total lymphoid irradiation (TLI) for abrogation of host resistance to T-cell depleted allografis. In: Gale, R. P.; Champ&n, R., eds. Progress in bone marrow transplantation. UCLA Symposia on Molecular and Cellular Biology, new series, Vol. 53. New York: Alan R. Liss, Inc.; 1987:399-402. Storb, R.; Deeg, H. J.; Whitehead, J.; Appelbaum, F.; Beatty, P.; Bensinger, W.; Buckner, C. D.; Clift, R.; Doney, K.; Farewell, V.; Hansen, J.; Hill, R.; Lum, L.; Martin, P.; McGuffin, R.; Sanders, J.; Stewart, P.; Sullivan, K.; Witherspoon, R.; Yee, G.; Thomas, E. D. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N. Engl. J. Med. 314:729-735; 1986.
November 1990, Volume 19, Number 5 21. Thomas, E. D.; Ashley, C. A.; Lochte, H. L., Jr.; Jaretzki, A., III; Sahler, 0. D.; Ferrebee, J. W. Homografts of bone marrow in dogs after lethal total-body radiation. Blood 14: 720-736; 1959. 22. Thomas, E. D.; Buckner, C. D.; Clift, R. A.; Fefer, A.; Johnson, F. L.; Neiman, P. E.; Sale, G. E.; Sanders, J. E.; Singer, J. W.; Shulman, H.; Storb, R.; Weiden, P. L. Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N. Engl. J. Med. 301:597-599; 1979. 23. Thomas, E. D.; Clift, R. A. Indications for marrow transplantation in chronic myelogenous leukemia. Blood 73:86 l864; 1989. 24. Thomas, E. D.; Clift, R. A.; Hersman, J.; Sanders, J. E.; Stewart, P.; Buckner, C. D.; Fefer, A.; McGuffin, R.; Smith, J. W.; Storb, R. Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. Int. J. Radiat. Oncol. Biol. Phys. 8: 817-821: 1982. 25. Thomas, E. D.; Flournoy, N.; Buckner, C. D.; Clift, R. A.; Fefer, A.; Neiman, P. E.; Storb, R. Cure of leukemia by marrow transplantation. Leuk. Res. 1:67-70; 1977. 26. Tutschka. P. J.; Elfenbein, G. J.; Sensenbrenner, L. L.; Saral, R.; Kaizer, H.: Order, S. E.; Beschorner, W. B.: Farmer, E.; Santos, G. W. Preparative regimens for marrow transplantation in acute leukemia and aplastic anemia. Baltimore experience. Am. J. Pediatr. Hematol. Oncol. 2:363-370; 1980. 27. Zutter, M. M.; Martin, P. J.; Sale, G. E.; Shulman, H. M.; Fisher, L.; Thomas, E. D.; Durnam, D. M. Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood 72:520-529; 1988.
??Oncology Intelligence
TOTAL
BODY IRRADIATION
REGIMENS
FOR MARROW
GRAFTING
E.DONNALLTHOMAS,M.D. 1990Nobel Laureate Fred Hutchinson
Cancer Research Center and the University of Washington School of Medicine, Seattle, WA
When my colleagues and I first began to use total body irradiation for large animals and man in preparation for marrow grafting, high energy sources were not available. Therefore, we used opposing 6oCo sources in an effort to achieve a relatively homogenous total body irradiation (TBI) (8). Although we began with very low exposure rates, in the last 2 decades we have used rates of approximately 7 cGy per minute. Our studies in dogs showed that allogeneic grafts could not be achieved consistently with less than an 8 Gy exposure (21). To achieve consistent engraftment, we used 10 Gy in a single exposure followed immediately by an intravenous infusion of donor marrow. In patients with leukemia in relapse, our aim was to achieve a marrow graft as quickly as possible before the patient died of infection and bleeding problems. Using this approach, we were able to show that some patients with far-advanced refractory leukemia could be cured of their disease (25). We also showed that the possibility of cure could be increased to approximately 50% by transplantation of patients with acute leukemia in remission when they were in good clinical condition with a minimal body burden of leukemic cells (22). With patients in better condition and with improved supportive care techniques, it became feasible to consider fractionating the irradiation over a period of several days before the infusion of marrow. For patients with acute nonlymphoblastic leukemia (ANL) in first remission, we administered two doses of cyclophosphamide, 60 mg/kg on each of 2 days and then randomized the patients to receive either 10 Gy in a single exposure or 2 Gy per day for 6 days (24). Figure 1 shows the outcome of this study, demonstrating a superiority of the fractionated radiation regimen (p = 0.04). We studied several other irradiation regimens in human recipients of HLA-identical allografts. Most recently, we attempted to reduce the rate of leukemic relapse in patients transplanted for chronic myelogenous leukemia
(CML) in chronic phase by increasing the radiation exposure. We conducted a randomized study to compare 2 Gy per day on each of 6 days (12 Gy total) to 2.25 Gy per day for 7 days (15.75 Gy total). Although this study will require another year for complete evaluation, the present results are shown in Figures 2A, 2B, and 2C. In summary, the patients given the higher radiation exposure had a reduced incidence of recurrence of leukemia but a greater incidence of death from regimen-related toxicity so that overall disease-free survival was not different. We conclude that the total exposure of 15.75 Gy, as we administered it, is the maximum TBI exposure that can be tolerated without excessive regimen-related deaths. This conclusion is consistent with our earlier studies of irradiation regimens in dogs given autoiogous marrow grafts (7). Despite theoretical radiobiological consideration of TBI ( 14) different marrow transplant teams have used a variety of approaches to the administration of TBI, often dictated by the type and availability of radiation equipment (1, 2, 9- 12, 16, 18, 19,26). Some have used single “Co sources; others have used high energy sources. Different schemes of fractionation and hyperfractionation have been employed. Dose rates have varied from approximately 5 cGy/ minute to 26 cGy/minute. The Toronto team has used dose rates of 50 to 85 cGy/minute with a total exposure of 5.0 Gy. Some have used shielding of the lungs with electron boost to the chest wall. Others have also included total lymphoid irradiation. A survey of these approaches fails to disclose any regimen which is clearly superior, at least in the absence of controlled prospective trials. A major difficulty in the various approaches to TBI has been the fact that there are many confounding variables. Patients may die of idiopathic interstitial pneumonia which probably represents a direct radiation toxicity. However, there are many competing causes of death including the type and stage of disease being treated. the
Presented at the 17 International Congress of Radiology, Paris, France 1-8 July 1989. Reprint requests to: E. Donna11 Thomas, M.D., Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98 104.
This investigation was supported by PHS Grants CA 18029 and CA 3 1787 awarded by the National Cancer Institute, DHHS. Dr. Thomas is a recipient of a Research Career Award AI 02425 from the National Institute of Allergy and Infectious Diseases. Accepted for publication 24 May 1990. 1285
1286
1. J. Radiation Oncology 0 Biology 0 Physics
03
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1 2
3
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November 1990, Volume 19, Number 5
I 9
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0.0
YEARS Fig. 1. Kaplan-Meier product limit estimates for event-free survival of patients with acute nonlymphoblastic leukemia in first remission, given cyclophosphamide 60 mg/kg on each of 2 days, randomized to receive 2 Gy on each of 6 days (n = 26) or 10 Gy (n = 27) in one exposure followed by an infusion of marrow from an HLA-identical sibling.
0
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complications of graft-versus-host disease, opportunistic infections, particularly cytomegalovirus interstitial pneumonia, venocclusive disease of the liver, and graft failure associated with T-cell depletion of donor marrow. One area of progress includes the prevention and control of graft-versus-host disease. The Seattle team has reported the use of a short course of methotrexate combined with cyclosporine with a significant decrease in the incidence and severity of graft-versus-host disease (20). Using this regimen along with a well-tolerated TBI regimen (2 Gy per day for 6 days) has resulted in an excellent survival and cure rate for patients with CML treated in the chronic phase of the disease (23). Figure 3 shows a survival and disease-free survival Kaplan-Meier analysis of these data for patients given an allogeneic graft from an HLA-identical donor with the transplant carried out within the first year after diagnosis. It is clear that, with this regimen, there is no reason to delay transplantation for patients with CML, since this disease has not been cured by any other approach. An intense area of current research involves other approaches to the prevention and treatment of graft-versus-host disease, including T-cell depletion of donor marrow and the use of various monoclonal antibodies. As regimens of promise are identified, it will be necessary to conduct randomized prospective trials to compare these regimens with the best immunosuppressive drug regimen described above. Late complications of TBI have been and continue to be a concern. However, these complications, after up to 2 decades of follow-up, do not appear to be prohibitive. Most patients are sterile following their previous chemotherapy and the marrow preparative regimen. Hair loss is not permanent. The incidence of cataracts has been reduced from approximately 60% to approximately 20% by fractionation of irradiation (5). Some patients have developed late pulmonary problems, but it is difficult to tell whether these problems are related to irradiation or to chronic graft-versus-host disease and opportunistic infections (3). Most leukemic children arrive for transplant
; E 0.4.
0
1
2 YEARS
N 1.0 :: R
E
’
0.6
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YEAR!3
Fig. 2. Kaplan-Meier product limit estimates for patients with CML in chronic phase, receiving cyclophosphamide, randomized to receive 2 Gy on each of 6 days (n = 5 1) or 2.25 Gy on each of 7 days (n = 56) and given a marrow graft from an HLAidentical sibling. Figure 2A shows survival, Figure 2B shows relapse, and Figure 2C shows death from nonleukemic causes.
having already received intensive chemotherapy, often with cranial irradiation as well. This previous therapy, when coupled with a transplant preparative regimen that includes TBI, often results in endocrine dysfunction and retarded growth and development ( 17). Alternative regimens which do not use TBI, such as busulfan and cyclophosphamide (26), have not yet been evaluated for these late effects. Studies of the incidence of second malignancies in canine and human irradiation chimeras suggest a slight increase over the expected incidence (6). Interpretation of these data is also difficult because of the frequent presence of some degree of chronic graft-versus-host disease. Recurrence of leukemia in donor type cells is an
TBI for marrow grafting 0 E. D. THOMAS
0.8. MNT-FREE
SURVlVAL
0 “A 0.6. B : , 0.4. T Y 0.2.
0
1
3
2
4
5
YEARS
Fig. 3. Kaplan-Meier product limit estimates for survival and event-free survival of patients with CML (n = 28) in chronic phase given cyclophosphamide, 2 Gy on each of 6 days followed by a marrow graft from an HLA-identical sibling, followed by a short course of methotrexate combined with a long course of cyclosporine. The patients were transplanted within I year of
diagnosis. infrequent, unexplained phenomena (4). A small fraction of patients, particularly those undergoing intensive treatment for graft-versus-host disease, have developed EBVassociated lymphoproliferative tumors which are often fatal (27). Overall, the incidence of second malignancies
1287
appears very low, with the major problem being the recurrence of the patient’s original malignant disease. Although some improvement in the use of TBI may be expected from exploration of various fractionation regimens and dose rates, it appears that the limits have been established and the results from fine-tuning will not be particularly impressive. Other approaches being explored include the use of radiolabeled heterospecific or monoclonal antibodies for a directed irradiation of malignant cells (13, 15). Other exploratory approaches use bone-seeking radioactive isotopes in an effort to achieve a higher radiation exposure for the marrow cavities without exposure of the lung. In the field of radiation biology, the established dogma states that the bone marrow is the most sensitive organ associated with lethal damage, followed closely by the gut. The accumulated experience with TBI when death is prevented by marrow transplantation shows that the limiting toxicity is not the gut but the lung (idiopathic interstitial pneumonia) and the liver (venocclusive disease). In many cases these organs also constitute the limiting toxicity for chemotherapy and combinations of chemotherapy with radiation therapy. In view of these limitations of chemoradiotherapy, other approaches under the broad heading of biological response modifiers are currently under intensive investigation.
REFERENCES I. Barrett, A.; Barrett, A. J.; Powles, R. L. Total body irradiation and marrow transplantation for acute leukaemia. The Royal Marsden Hospital experience. Path. Biol. 27:357359; 1979. 2. Baume, D.; Cosset, J. M.: Pica, J. L.; Girinski, T.; Le Bail. N.; Nabholtz, J. M.; Benhamou, E.; Dutreix, J.; Hayat, M. Comparaison entre irradiation totale en un temps et hyperfractionnee pour le conditionnement des greffes de moelle allogeniques. Une etude retrospective de 54 malades atteints d’hemopathies mahgnes. Bull. Cancer 75:361-372; 1988. 3. Beschorner, W. E.; Saral, R.; Hutchins, G. M.; Tutschka. P. J.; Santos, G. W. Lymphocytic bronchitis associated with graft-versus-host disease in recipients of bone-marrow transplants. N. Engl. J. Med. 299:1030-1036; 1978. 4. Boyd, C. N.; Ramberg, R. E.; Thomas, E. D. The incidence of recurrence of leukemia in donor cells after allogeneic bone marrow transplantation. Leuk. Res. 6:833-837; 1982. 5. Deeg, H. J.; Flournoy, N.; Sullivan, K. M.; Sheehan, K.; Buckner, C. D.; Sanders, J. E.; Storb, R.; Witherspoon, R. P.; Thomas, E. D. Cataracts after total body irradiation and marrow transplantation: a sparing effect of dose fractionation. Int. J. Radiat. Oncol. Biol. Phys. 10:957-964; 1984. 6. Deeg, H. J.; Sanders, J.; Martin, P.; Fefer, A.; Neiman, P.; Singer, J.; Storb, R.; Thomas, E. D. Secondary malignancies after marrow transplantation. Exp. Hematol. 12:660-666; 1984. 7. Deeg, H. J.; Storb, R.; Longton, G.; Graham, T. C.; Shulman, H. M.; Appelbaum, F.; Thomas, E. D. Single dose or fractionated total body irradiation and autologous marrow transplantation in dogs: effects of exposure rate, fraction size and fractionation interval on acute and delayed toxicity. Int. J. Radiat. Oncol. Biol. Phys. 15:647-653; 1988.
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