Radiobiological and Clinical Bases for Total Body Irradiation in the Leukemias and Lymphomas Jean Marc Cosset, GgrardSoci~, TModore Girinsky, Bernard Dubray, Alain Fourquet, and Eliane Gluckman In spite of the recent introduction of conditioning regi- mens consisting of chemotherapy alone, therapeutic total body irradiation (TBI) remains a powerful antileuke- mic and immunosuppressive tool in preparative regi- mens for bone marrow transplantation. However, the question of the "best" TBI schedule has not been answered. Available radiobiological and clinical data show that (1) the role of fractionation (or dose rate) on leukemia cell killing may vary with the leukemia type. Acute myeloid leukemia cells have been found to be insensitive or only slightly sensitive to fractionation, whereas chronic myeloid leukemia cells appear to be sensitive. Data are still controversial for acute lympho- cytic leukemia and the non-Hodgkin's lymphomas; (2) the immunosuppressive effect of TBI is very fraction- ation sensitive; end (3) most normal tissues at risk are also highly sensitive to fractionation and dose rate. These data permit some cautious adaptations of the TBI schemes to the type of leukemia, use of T-cell-depleted donor marrow, end potential normal tissue toxicity. However, we still lack data concerning the precise intrinsic and fractionation radiosensitivity of the leuke- mia/lymphoma of a given patient. Recent improve- ments in leukemia-cell cultures allowing the generation of dose survival curves and the study of in vitro radiation- induced apoptosis (mainly for lymphomes) may soon provide radiation oncologists with the data to allow further refinement and individualization of TBI sched- ules. Copyright 91995 by W.B. Saunders Company I n the late 1950s, E.D. Thomas, recipient of the 1990 Nobel prize in Medicine, introduced total body irradiation (TBI) in the preparative regimen for allogeneic bone marrow transplantation.l He initially delivered 10 Gy in a single fraction, at a dose rate considered "low" at that time, 0.07 to 0.10 Gy/ minute. This schedule remained the gold standard for TBI for almost two decades. In the late 1970s, new radiobiological data chal- lenged the use of low dose rate single dose TBI. Based on these data, Peters et al 2,3 pointed out the marked sensitivity of most normal tissues to alter- ations of fractionation and dose rate, in contrast to the minor (if any) effects on bone marrow progeni- tors and leukemic cells. Consequently, it was con- eluded that with the same total dose an improved therapeutic ratio (same antileukemic effect, but reduced toxicity) could be expected from a reduction in the dose rate of single dose TBI or by TBI fractionation. With a slight increase in total dose, one could expect superior efficacy with reduced (or simi- lar) toxicity. From the D~paaement d'Oncologie RadiotMrapique, Institut Curie, Paris, France; Unit~ de Greffe de Moelle Osseuseet Laboratoire d'Etude des Cellules Souches, CEA/ DSV-Hdpital St Louis, Paris, France; and the D(partement de RadiotMrapie, Institut GustaveRoussy, Villejuif, France. Address reprint requests to Jean Marc Cosset, MD, D~partement d'Oncologie RadiaMrapique, Institut Curie, 26 Rue D'Ulm, 75231 Paris, France. Copyright 9 1995 by W.B. Saunde~ Company 1053-4296/95/0504-000555.00/0 The first issue was the choice between a very low dose rate and a fractionated schedule. In principle, it should be possible to identify a low dose rate single dose TBI scheme equivalent to a fractionated sched- ule. Calculations were made for various fractionation schemes and dose rates, based on an extension of the linear quadratic model. 4q~ These calculations sug- gested that an exceedingly low dose rate, with an impractical irradiation time of 20 to 24 hours, would be necessary to be radiobiologically equivalent to common fractionated TBI schedules. Therefore, supported by radiobiology and practi- cality, a wide variety of fractionated TBI sched- ules tl-13 began to he used. However, after more than I5 years of studies testing a variety of TBI schemes, the conclusions are inconclusive. Thomas himself wrote in 1990 that "a survey of these (various) approaches ... fails to disclose any regimen which is clearly superior, ''14 while Appelbaum et al, t5 also from the Seattle group, wrote 2 years later that "there is little evidence that methods for delivering TBI have been improved since the initial trials of Thomas in the late 60s." Actually, it was probably too optimistic to expect a therapeutic breakthrough by the introduction of fractionated TBI. The outcome of allogeneic or autologous bone marrow transplantation is governed by an impressive number of confounding variables. 16 Irradiation-related, disease-related, patient-related, and transplant-related parameters, among others, contribute to an extremely complex problem. One Seminars in Radiation Oncology, Vol 5, No 4 (October), 1995: pp 301-315 30 1