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© 2000 American Society for Clinical Oncology Prospective Randomized Comparison of Single-Dose Versus Hyperfractionated Total-Body Irradiation in Patients With Hematologic MalignanciesFrom the Departments of Radiation Oncology, Biostatistics and Epidemiology, and Medicine, Institut Gustave Roussy, Villejuif; Department of Oncology and Radiotherapy, Institut Curie; and Department of Hematology, Hôpital Saint-Louis, Paris, France. Address reprint requests to Theodore Girinsky, MD, Département of Radiation Oncology, Institut Gustave Roussy, Villejuif, 94805, France; email girinski{at}igr.fr
PURPOSE: Fractionated total-body irradiation (HTBI) is considered to induce less toxicity to normal tissues and probably has the same efficacy as single-dose total-body irradiation (STBI) in patients with acute myeloid leukemia. We decided to determine whether this concept can be applied to a large number of patients with various hematologic malignancies using two dissimilar fractionation schedules. PATIENTS AND METHODS: Between December 1986 and October 1994, 160 patients with various hematologic malignancies were randomized to receive either a 10-Gy dose of STBI or 14.85-Gy dose of HTBI. RESULTS: One hundred forty-seven patients were assessable. The 8-year overall survival rate and cause-specific survival rate in the STBI group was 38% and 63.5%, respectively. Overall survival rate and cause-specific survival rate in the HTBI group was 45% and 77%, respectively. The incidence of interstitial pneumonitis was similar in both groups. However, the incidence of veno-occlusive disease (VOD) of the liver was significantly higher in the STBI group. In the multivariate analysis with overall survival as the end point, the female sex was an independent favorable prognostic factor. On the other hand, when cause-specific survival was considered as the end point, the multivariate analysis demonstrated that sex and TBI were independent prognostic factors. CONCLUSION: The efficacy of HTBI is probably higher than that of STBI. Both regimens induce similar toxicity with the exception of VOD of the liver, the incidence of which is significantly more pronounced in the STBI group.
TOTAL-BODY IRRADIATION (TBI) given before blood or bone marrow hematopoietic stem-cell transplantation remains an important component of conditioning regimens given to patients with various hematologic malignancies. Earlier randomized studies conducted by Thomas et al1 suggested that fractionated total-body irradiation ([FTBI] delivering 12 Gy in 6 fractions) led to better overall survival in patients with acute nonlymphocytic leukemia in first remission than single-dose total-body irradiation ([STBI] delivering 10 Gy in 1 fraction). These results were corroborated in a second published study with a longer follow-up.2 Significantly better overall survival was confirmed for patients who underwent FTBI than STBI, with fewer leukemia recurrences and complications (notably less hepatic toxicity). Therefore, it was plausible to assume that moderate FTBI with a slightly higher dose than that of STBI was the best treatment. We decided to investigate this concept further by comparing hyperfractionated TBI (HTBI) with STBI in patients with various hematologic malignancies. The highly fractionated schedule, which delivered a large number of fractions (HTBI in 11 fractions), was initially devised by the team at the Memorial Sloan-Kettering Cancer Center3 but was never compared with STBI in a randomized study. Two additional reasons prompted us to undertake this study. First, we were doubtful about the alleged efficacy of the highly fractionated schedules because new experimental evidence was suggesting that the normal and leukemic self-renewing stem-cell population of the host were capable of repairing radiation damage.4,5 Secondly, we wanted to determine whether HTBI, which is logistically difficult to carry out and time consuming, was a viable option in centers performing TBI routinely.
Between December 1986 and October 1994, 160 patients with various hematologic malignancies were entered onto the study. All patients were randomized to receive either a 10-Gy single dose or 14.85-Gy hyperfractionated dose of TBI. Patient accrual in this study represented 75% of the total number of patients treated in the bone marrow transplantation unit.
Patient Eligibility
Preparative Regimens
Posttransplantation Immunosuppression Blood CSP levels were monitored, and adjustments were made according to renal and hepatic function. The methotrexate dose was adjusted for mucositis and according to liver function tests. Acute graft-versus-host disease (GVHD) was treated with methylprednisolone 2 mg/kg bolus, and extensive chronic GVHD was treated with corticosteroids alone or in combination with CSP.
Causes of Death
Statistical Analysis
Analyses were carried out according to the intent-to-treat principle. Differences between groups were evaluated by the
Patient and Treatment Characteristics Of the 161 randomized patients, 147 received bone marrow transplants according to the protocol and are, therefore, assessable. Fourteen patients were not treated with radiotherapy because a relapse occurred before bone marrow transplantation. Table 1 lists patient and treatment characteristics. There were more female patients in the STBI group, but the difference is not significant. Various hematologic diseases were evenly distributed between the STBI and HTBI groups. Preparative regimens with cyclophosphamide and TBI were delivered in 66% and 73% of patients in the STBI and HTBI group, respectively. The other patients received melphalan and TBI as their conditioning regimen. Approximately two thirds of the patients in each group were given an allogeneic blood or bone marrow hematopoietic stem-cell graft, and the remaining patients received an autologous blood or bone marrow hematopoietic stem-cell graft. Eighty percent of donors and recipients were tested for cytomegalovirus (CMV). Negative CMV serology in donors and recipients was 28% and 29% in the STBI and HTBI groups, respectively. Positive CMV serology in donors and recipients was 52% and 48% in the STBI and HTBI groups, respectively.
Patients with acute lymphatic leukemia (ALL) and acute myelogenous leukemia (AML) in first complete remission, chronic myeloid leukemia (CML) in the chronic phase, or lymphoma with chemosensitive recurrent disease accounted for 42% and 46.5% of the patients in the STBI and HTBI groups, respectively. The median interval from diagnosis to the transplantation was similar in both groups (7 months in both groups). Eighty-one of the 147 assessable patients have died. The remaining 66 were known to still be alive between 34 and 138 months (median, 96 months) after bone marrow transplantation. The causes of death are listed in Table 2. The total number of deaths was similar in both groups (60% and 50% of the patients in the STBI and HTBI groups, respectively). Death caused by relapse and by VOD of the liver was higher in the STBI group compared with the HTBI group. Deaths resulting from other causes were similar in both groups. The estimated distributions of overall survival and cause-specific survival are shown in Figs 1 and 2. The 8-year overall survival and cause-specific survival rates in the STBI group were 38% (95% CI, 28% to 50%) and 63.5% (95% CI, 50% to 75%), respectively. The 8-year overall survival and cause-specific survival rates in the HTBI group were 45% (95% CI, 32% to 59%) and 77% (95% CI, 63% to 87%), respectively. As shown in Fig 3, the incidence of IP was not significantly different in the STBI and HTBI groups (19% and 14%, respectively). Figure 4 shows that VOD of the liver was significantly more frequent in the STBI group than the HTBI group (14% v 4%, P = .04). It is noteworthy that the 8-year overall survival rates were identical in patients given an allogeneic or an autologous blood or bone marrow hematopoietic stem-cell graft (39% and 43%, respectively). Results were not different when only patients with acute leukemia (AML and ALL) were considered. Among the 91 allograft recipients, no significant difference was observed in the incidence of grade 2 to 4 acute GVHD between the two treatment groups (28% and 33% in the STBI and HTBI groups, respectively). A subgroup analysis of allograft and autograft recipients was carried out to determine whether a higher dose of TBI (10 Gy v 14.85 Gy) would reduce the incidence of relapses. In the allogeneic setting, the cause-specific survival rate was 74% (95% CI, 56% to 86%) and 84% (95% CI, 65% to 94%) in the STBI and HTBI groups, respectively (Fig 5). In the autologous setting, the 8-year cause-specific survival rate was 50% (95% CI, 30% to 69%) and 69% (95% CI, 47% to 84%) in the STBI and HTBI groups, respectively (Fig 6). It is noteworthy that the 8-year overall survival rates were similar among allograft recipients (39%; 95% CI, 28% to 50%) and autograft recipients (43%; 95% CI, 31% to 56%). In the univariate analysis, good-risk patients (namely patients with leukemia in first complete remission, with CML in the chronic phase, and with chemosensitive recurrent lymphoma) and female sex (females fared better than their male counterparts) were significant prognostic factors.
In the multivariate analysis, the relative risk of death was significantly lower for female patients and of borderline significance for good-risk patients. Patients with CML fared better than patients with other hematologic malignancies (Table 3). Interestingly, a multivariate analysis using cause-specific death as the end point demonstrated that sex and TBI schedules (patients who received HTBI fared significantly better than patients treated with STBI) were significant prognostic factors (Table 4).
Of the 161 patients enrolled onto this single-institution study over a period of 8 years, 147 patients received TBI and are, therefore, assessable. Patient accrual in the study represents 75% of all patients who underwent bone marrow transplantation during that period of time. Patients deemed unable to abide by a long rigorous follow-up schedule and children under the age of 15 were excluded from the study. The median follow-up of our patient cohort is 8 years (range, 34 to 138 months). This long follow-up allows us to draw firm conclusions about the comparison of two dissimilar TBI regimens in terms of toxicity and efficacy. The main conclusion is that both regimens yielded similar results in terms of overall and cause-specific survival. Although the 8-year overall survival rate was higher in the group of patients who received HTBI than in the group treated with STBI, the difference was not significant (Fig 1). Of note, although total radiation doses were different in the two TBI schedules (14.85 Gy in HTBI v 10 Gy in STBI), cause-specific survival rates were similar in both groups (Fig 2). There was, however, a trend toward a higher 8-year relapse rate in the STBI group compared with the HTBI group (36.5% v 23%, respectively). When relapse rates were analyzed according to the type of bone marrow graft, relapse rates were similar for allograft recipients after both STBI and HTBI (26% v 16%, respectively)(Fig 3). In contrast, autograft recipients experienced a higher relapse rate after STBI compared with HTBI (50% v 31%, respectively)(Fig 4). Two earlier prospective studies performed by Clift et al10,11 demonstrated fewer relapses among patients with AML in first complete remission and CML allograft recipients after high-dose TBI (15.75 Gy) (14% and 0%, respectively) than in patients after a dose of 12 Gy (39% and 19%, respectively). Ozsahin et al12 reported a relapse rate of 42% and 40% in the STBI and FTBI group, respectively. In the study by Deeg et al,2 AML allograft recipients had a relapse rate of 22% and 12% after 10 Gy and 12 Gy of TBI, respectively. Although heterogeneous, the above data suggest that fewer relapses occur with higher TBI doses. Moreover, our study suggests that high doses of TBI may be particularly beneficial to autograft recipients who are not exposed to a graft versus leukemia effect. Concerning the possible detrimental effects of fractionation, Socié et al13 found a higher relapse rate in CML patients treated with a 12-Gy dose of FTBI compared with those who received 10 Gy of STBI. Our results seem to contradict these earlier results. In the small subgroup of CML patients, treatment with HTBI led to an 8-year overall survival rate of 70% versus 30% in the STBI group (P = .085). Uckun et al5 demonstrated that leukemic progenitor cells from patients with ALL possessed a capacity to repair radiation damage. An analysis of our small subgroup of patients with ALL showed that the 8-year overall survival rate was similar in both groups (48% in the STBI group and 42% in the HTBI group). The difference in the total dose between the two TBI schedules probably compensated for the fractionation in the HTBI group. The nonrelapse mortality rate was identical in both groups, 34% and 35% in the STBI and HTBI group, respectively. These rates are similar to those obtained by Deeg et al2 (37% in the 12-Gy FTBI group) and in two studies by Clift et al10,11 (34% and 38% in the group treated with 15.75 Gy). However, Clift et al10,11 also showed a significantly lower nonrelapse mortality rate in CML and AML patients given 12 Gy of FTBI (approximately 20%). These data seem to suggest that a 12-Gy dose of FTBI might be better tolerated. Down et al4 demonstrated that FTBI required higher total doses for engraftment than STBI in both syngeneic and allogeneic bone marrow transplantation in mice. In our experience, only one patient in each group experienced a graft failure, and this may be attributable to a much higher dose in the hyperfractionated schedule. Indeed, the higher dose in the HTBI group may have offset the radiation dose–sparing effect of fractionation. The incidence and mortality rates caused by IP were comparable for STBI (8 Gy given in a single fraction to the lungs) and HTBI (9 Gy given in 11 fractions) groups. Our study suggests that as long as the radiation dose to the lungs remains low, fractionation seems to play a limited role in the prevention of lung complications. This finding is slightly at variance with the study by Deeg et al2 in which a nonsignificant decrease in idiopathic IP was observed in patients treated with FTBI. This discrepancy could be imputed to a lack of shielding from irradiation in the latter study, exposing the lungs to a higher dose than that delivered to our patients. In a multivariate analysis of risk factors, Weiner et al14 showed that an instantaneous dose rate of more than 0.04 Gy/min carried a higher risk of IP. They reported an incidence of approximately 20% when dose rates were below 0.04 Gy/min. In our experience, a similar incidence of IP (approximately 15% to 20%) was found using higher instantaneous dose rates (0.125 Gy/min in the STBI group and 0.25 Gy/min in the HTBI group). This suggests that fractionation and/or dose rates do not impact on the incidence of IP markedly in patients treated with TBI as long as doses to the lungs do not exceed 8 to 9 Gy. Similar findings were obtained by Ozsahin et al,12 who showed a comparable incidence of IP in groups of patients with a low and a high instantaneous dose rate whose lungs had partially been shielded from irradiation. In our study, the incidence and mortality caused by VOD of the liver was significantly higher in the STBI group. Deeg et al2 noted the same finding in their study. In contrast, Ozsahin et al12 found a similar incidence of VOD in patients treated with either STBI or FTBI. These findings suggest that a single 10-Gy dose of TBI may give increase to more liver injury than a higher dose given with a fractionated schedule. Multivariate analysis, using overall survival as the end point, demonstrated that the only independent prognostic factor was the female sex. Because this has not been demonstrated in other studies, its significance remains doubtful. The fact that good-risk patients fared better than other patients is not surprising per se because complete remission in leukemia and lymphoma patients is a strong independent prognostic factor.15-17 The TBI schedule was not a prognostic factor. It is noteworthy, however, that although overall survival in the HTBI group was similar to that of the STBI group, there were fewer female patients, and two patients had received a T-cell–depleted bone marrow graft in the former group. Interestingly, when multivariate analysis was performed using cause-specific survival as the end point, HTBI was a significant prognostic factor. Therefore, it is possible that HTBI is a more efficient and/or less toxic treatment, but this remains to be demonstrated. The comparative cost of both TBI schedules shows that there is a $1,000 difference (estimated costs, STBI = $4,500 and HTBI = $5,500). In conclusion, the incidence of IP was similar in both groups, but a significantly higher incidence of VOD of the liver was noted in patients treated with 10 Gy of STBI. Overall and cause-specific survival rates were higher in the group of patients given HTBI, but differences were not significant. In the multivariate analyses, sex was always a significant independent prognostic factor and the TBI schedule was prognostic when cause-specific survival was considered. A randomized study is needed to demonstrate a possible beneficial effect of a higher dose in autograft recipients.
We thank Lorna Saint Ange for editing the manuscript and Dr C. Levy-Piedbois for determining the financial cost of the TBI schedules.
1. Thomas ED, Clift RA, Hersman J, et al: Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. Int J Rad Biol Phys 8:817-821, 1981 2. Deeg HJ, Sullivan KM, Buckner CD, et al: Marrow transplantation for acute nonlymphoblastic leukemia in first remission: Toxicity and long-term follow-up of patients conditioned with single-dose or fractionated total body irradiation. Bone Marrow Transplant 1:151-157, 1986[Medline] 3. Shank B, O’Reilly RJ, Cunningham I, et al: Total body irradiation for bone marrow transplantation: The Memorial Sloan-Kettering Cancer Center experience. Radiother Oncol 1:68, 1990 (suppl)
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Down JD, Tarbell NJ, Thames HD, et al: Syngeneic and allogeneic bone marrow engraftment after total body irradiation: Dependence on dose, dose rate, and fractionation. Blood 77:661-669, 1991 5. Uckun FM, Chandan-Langlie M, Jaszcz W, et al: Radiation damage repair capacity of primary clonogenic blasts in acute lymphoblastic leukemia. Cancer Res 553:1431-1436, 1993 6. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomised clinical trials requiring prolonged observations of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977[Medline] 7. Rothman KJ: Estimation of confidence limits for the cumulative probability of survival in life table analysis. J Chronic Dis 31:557-560, 1978[Medline] 8. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc A 135:185-207, 1972 9. Cox DR: Regression models and life-tables. J R Stat Soc B 34:187-220, 1972
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Clift RA, Buckner CD, Appelbaum FR, et al: Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimens. Blood 76:1867-1871, 1990
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Clift RA, Buckner CD, Appelbaum FR, et al: Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: A randomized trial of two irradiation regimens. Blood 77:1660-1665, 1991 12. Ozsahin M, Pene F, Touboul E, et al: Total-body irradiation before bone marrow transplantation: Results of two randomized instantaneous dose rates in 157 patients. Cancer 69:2853-2865, 1992[Medline] 13. Socie G, Devergie A, Girinsky T, et al: Influence of the fractionation of total body irradiation on complications and relapse rate for chronic myelogenous leukemia. Int J Radiat Oncol Biol Phys 20:397-404, 1991[Medline] 14. Weiner RS, Bortin MM, Gale RP, et al: Interstitial pneumonitis after bone marrow transplantation: Assessment of risk factors. Ann Intern Med 104:168-175, 1986
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Horning SJ, Chao NJ, Negrin RS, et al: High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin’s disease: Analysis of the Stanford University results and prognostic indices. Blood 89:801-813, 1997 16. Vernant JP, Marit G, Maraninchi D, et al: Allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia in first complete remission. J Clin Oncol 6:227-231, 1998[Abstract] 17. Hurd DD: Allogeneic and autologous bone marrow transplantation for acute nonlymphocytic leukemia. Semin Oncol 14:407-415, 1987[Medline] Submitted August 13, 1999; accepted November 3, 1999.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher’s exact test for categorical variables and the Student’s t test for continuous variables (two-sided tests). Survival probabilities were estimated using the Kaplan-Meier method.
