M. Loes van Kempen-Harteveld

Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation.

Background and Purpose:Total-body irradiation (TBI) is an important part of the conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. The results after treatment with various TBI regimens were compared, and dose-effect relationships for the endpoints relapse incidence, disease-free survival, treatment-related mortality, and overall survival were derived. The aim was to define requirements for an optimal treatment schedule with respect to leukemic cell kill and late normal-tissue morbidity.Material and Methods:A literature search was performed. Three randomized studies, four studies comparing results of two or three TBI regimens, and nine reports with results of one specific TBI regimen were identified. Biologically effective doses (BEDs) were calculated. The results of the randomized studies and the studies comparing results of two or three TBI regimens were pooled, and the pooled relative risk (RR) was calculated for the treatments with high BED values versus treatments with a low BED. BED-effect relationships were obtained.Results:RRs for the high BED treatments were significantly lower for relapse incidence, not significantly different for disease- free survival and treatment-related mortality, and significantly higher for overall survival. BED-effect relationships indicate a decrease in relapse incidence and treatment-related mortality and an increase in disease-free and overall survival with higher BED values.Conclusion:“More dose is better”, provided that a TBI setting is used limiting the BEDs of lungs, kidneys, and eye lenses.Hintergrund und Ziel:Die Ganzkörperbestrahlung ist eine wichtige Komponente bei der Konditionierung des Patienten vor einer hämatopoetischen Stammzelltransplantation bei hämatologischen Malignomen. Die Therapieergebnisse verschiedener Ganzkörperbestrahlungs-Regime wurden verglichen und Dosis-Wirkungs-Beziehungen für die Endpunkte Rückfallinzidenz, krankheitsfreies Überleben, behandlungsbezogene Letalität und Gesamtüberleben abgeleitet. Ziel war, die Bedingungen eines auf Elimination von Leukämiezellen und Spätschäden von Normalgewebe optimierten Behandlungsplans zu definieren.Material und Methoden:Es wurde eine Literaturrecherche durchgeführt. Drei randomisierte Studien, vier Studien zum Vergleich von zwei oder drei Ganzkörperbestrahlungs-Regimen und neun Berichte über Ergebnisse eines spezifischen Ganzkörperstrahlungs-Regimes wurden gefunden. Es wurden die biologisch effektiven Dosen (BEDs) berechnet. Die Ergebnisse der randomisierten und der Studien, die zwei oder drei Ganzkörperbestrahlungs-Regime miteinander verglichen, wurden zusammengefasst und das gepoolte relative Risiko (RR) berechnet für Behandlungen mit hohen BED-Werten im Vergleich mit Behandlungen mit niedriger BED. Man erhielt BED-Wirkungs-Beziehungen.Ergebnisse:Die RR-Werte für Behandlungsformen mit hoher BED waren signifikant niedriger für die Rückfallinzidenz, nicht signifikant unterschiedlich hinsichtlich des krankheitsfreien Überlebens und der behandlungsbezogenen Letalität und signifikant höher, bezogen auf Gesamtüberleben. Die BED-Wirkungs-Relationen zeigen eine Abnahme der Rückfallinzidenz und der behandlungsbezogenen Letalität und eine Zunahme von krankheitsfreiem Überleben und Gesamtüberleben bei höheren BED-Werten.Schlussfolgerung:„Mehr Bestrahlung ist besser“—eine Ganzkörperbestrahlung vorausgesetzt, die die BEDs an Lungen, Nieren und Linsen begrenzt.

CATARACT-FREE INTERVAL AND SEVERITY OF CATARACT AFTER TOTAL BODY IRRADIATION AND BONE MARROW TRANSPLANTATION: INFLUENCE OF TREATMENT PARAMETERS

PURPOSE To determine prospectively the cataract-free interval (latency time) after total body irradiation (TBI) and bone marrow transplantation (BMT) and to assess accurately the final severity of the cataract. METHODS AND MATERIALS Ninety-three of the patients who received TBI as a part of their conditioning regimen for BMT between 1982 and 1995 were followed with respect to cataract formation. Included were only patients who had a follow-up period of at least 23 months. TBI was applied in one fraction of 8 Gy or two fractions of 5 or 6 Gy. Cataract-free period was assessed and in 56 patients, who could be followed until stabilization of the cataract had occurred, final severity of the cataract was determined using a classification system. With respect to final severity, two groups were analyzed: subclinical low-grade cataract and high-grade cataract. Cataract-free period and final severity were determined with respect to type of transplantation, TBI dose, and posttransplant variables such as graft versus host disease (GVHD) and steroid treatment. RESULTS Cataract incidence of the analyzed patients was 89%. Median time to develop a cataract was 58 months for autologous transplanted patients. For allogeneic transplanted patients treated or not treated with steroids, median times were 33 and 46 months, respectively. Final severity was not significantly different for autologous or allogeneic patients. In allogeneic patients, however, final severity was significantly different for patients who had or had not been treated with steroids for GVHD: 93% versus 35% high-grade cataract, respectively. Final severity was also different for patients receiving 1 x 8 or 2 x 5 Gy TBI, from patients receiving 2 x 6 Gy as conditioning therapy: 33% versus 79% high-grade cataract, respectively. The group of patients receiving 2 x 6 Gy comprised, however, more patients with steroid treatment for GVHD. So the high percentage of high-grade cataract in the 2 x 6 Gy group might also have been caused to a significant extent by steroid treatment. The percentage of patients with high-grade cataract was lower in allogeneic transplanted patients without steroid treatment for GVHD than in autologous transplanted patients: 35% versus 48%. An explanation for this could be pretransplant therapy containing high-dose steroids. CONCLUSIONS After high-dose-rate TBI in one or two fractions, steroids for GVHD influence latency time of a cataract and are of great importance for the severity the cataract finally attains. Although a cataract will develop in all patients, a clinically important high-grade cataract is relatively infrequent in patients not treated with steroids. Pretransplant therapy might also influence final severity of cataract.

Cataract after total body irradiation and bone marrow transplantation: degree of visual impairment.

PURPOSE To assess the degree of visual impairment as a result of cataract formation after total body irradiation (TBI) for bone marrow transplantation. METHODS AND MATERIALS The data from 93 patients who received TBI in 1 or 2 fractions as a part of their conditioning regimen for bone marrow transplantation were analyzed with respect to the degree of visual impairment as a result of cataract formation. The probability to develop severe visual impairment (SVI) was determined for all patients, and the degree of visual impairment was assessed for 56 patients with stabilized cataract, using three categories: no, mild, or severe. RESULTS For all 93 patients, the probability of developing a cataract causing SVI was 0.44. For allogeneic patients, it was 0.33 without and 0.71 with steroid treatment (p <0.001). All SVI-free probability curves reached a plateau distinct from the cataract-free curves. Apparently, cataracts developing late in the follow-up period rarely cause SVI. Of the patients with stabilized cataract, 32% had no visual impairment, 16% had mild, and 52% severe impairment. No or mild visual impairment was present in 61% of all patients with stable cataract and no steroid treatment compared with only 13% of the patients treated with steroids (p = 0.035). CONCLUSION SVI occurs in only some of the patients (52%) with stable cataract after TBI for bone marrow transplantation in 1 or 2 fractions. Steroid treatment markedly increases the probability of developing visual problems as result of a cataract after TBI.

Results of Hematopoietic Stem Cell Transplantation After Treatment With Different High-Dose Total-Body Irradiation Regimens in Five Dutch Centers

PURPOSE To evaluate results of high-dose total-body irradiation (TBI) regimens for hematopoietic stem cell transplantation. METHODS AND MATERIALS A total of 1,032 patients underwent TBI in one or two fractions before autologous or allogeneic hematologic stem cell transplantation for acute leukemia and non-Hodgkins lymphoma. The TBI regimens were normalized by using the biological effective dose (BED) concept. The BED values were divided into three dose groups. Study end points were relapse incidence (RI), non-relapse mortality (NRM), relapse-free survival (RFS), and overall survival (OS). Multivariate analysis was performed, stratified by disease. RESULTS In the highest TBI dose group, RI was significantly lower and NRM was higher vs. the lower dose groups. However, a significant influence on RFS and OS was not found. Relapses in the eye region were found only after shielding to very low doses. Age was of significant influence on OS, RFS, and NRM in favor of younger patients. The NRM of patients older than 40 years significantly increased, and OS decreased. There was no influence of age on RI. Men had better OS and RFS and lower NRM. Type of transplantation significantly influenced RI and NRM for patients with acute leukemia and non-Hodgkins lymphoma. There was no influence on RFS and OS. CONCLUSIONS Both RI and NRM were significantly influenced by the size of the BED of single-dose or two-fraction TBI regimens; OS and RFS were not. Age was of highly significant influence on NRM, but there was no influence of age on RI. Hyperfractionated TBI with a high BED might be useful, assuming NRM can be reduced.