Renal toxicity after total body irradiation

PURPOSE: To evaluate the incidence of renal dysfunction after total body irradiation (TBI). METHODS AND MATERIALS: Between 1990 and 1997, 64 patients (median age 50 years) received TBI as part of the conditioning regimen before bone marrow transplantation (BMT). Five patients with abnormal renal function at the beginning of treatment or with incomplete data were excluded. All patients received a total of 12 Gy (6 fractions twice daily for 3 consecutive days) prescribed to the peak lung dose (corrected for lung transmission) at a dose rate of 7.5 cGy/min. Renal shielding was not used. Renal dysfunction was assessed on the basis of the serum creatinine levels measured at the start and end of TBI and at 6, 12, 18, and 24 months after completion of BMT. Cox proportional hazard analysis was used to evaluate the various factors known to affect renal function. RESULTS: Only 4 patients had elevated serum creatinine levels at 12 months and subsequently only 2 of the 33 surviving patients had persistent elevated renal serum creatinine levels 24 months after BMT. A fifth patient developed proteinuria and mildly elevated serum creatinine levels at 2.5 years. In 2 patients, the elevation coincided with disease relapse and normalized once remission was achieved. In the third patient, the elevation in serum creatinine levels coincided with relapse of multiple myeloma and the presence of Bence-Jones proteinuria. The fourth patient was the only patient who developed chronic renal failure secondary to radiation nephritis at 2 years. The etiology of the fifth patient's rise in creatinine was unknown, but may have been secondary to radiation nephritis. On univariate analysis, but not on multivariate analysis, a significant correlation was found between TBI-related renal dysfunction and hypertension before and after BMT. CONCLUSION: A dose of 12 Gy at 2 Gy/fraction resulted in only 1 case of radiation nephritis in the 59 patients studied 24 months after the completion of TBI and BMT.     

Survival after total body irradiation: effects of irradiation of exteriorized small intestine.

Rats receiving lethal irradiation to their exteriorized small intestine with pulsed 18 MVp bremsstrahlung radiation live about 4 days longer than rats receiving a dose of total-body irradiation (TBI) causing intestinal death. The LD50 for intestinal irradiation is approximately 6 Gy higher than the LD50 for intestinal death after TBI. Survival time after exteriorized intestinal irradiation can be decreased, by adding abdominal irradiation. Adding thoracic or pelvic irradiation does not alter survival time. Shielding of large intestine improves survival after irradiation of the rest of the abdomen while the small intestine is also shielded. The kinetics of histological changes in small intestinal tissue implicate the release of humoral factors after irradiation of the abdomen. Radiation injury develops faster in the first (proximal) 40 cm of the small intestine and is expressed predominantly as shortening in villus height. In the last (distal) 40 cm of the small intestine, the most pronounced radiation effect is a decrease in the number of crypts per millimeter. Irradiation (20 Gy) of the proximal small intestine causes 92% mortality (median survival 10 days). Irradiation (20 Gy) of the distal small intestine causes 27% mortality (median survival greater than 30 days). In addition to depletion of crypt stem cells in the small intestine, other issues (humoral factors, irradiated subsection of the small intestine and shielding of the large intestine) appear to influence radiation-induced intestinal mortality.     

Idiopathic interstitial pneumonia following bone marrow transplantation: The relationship with total body irradiation

Interstitial pneumonia is a frequent and often fatal complication of allogenic bone marrow transplantation. Thirty to 40 percent of such cases are of unknown etiology and have been labelled as cases of idiopathic interstitial pneumonia. Idiopathic cases are more commonly associated with the use of total body irradiation; their occurrence appears to be independent of immunosupression or graft versus host disease. Evidence is presented from the literature suggesting that the development of idiopathic interstitial pneumonia is related to the absolute absorbed dose of radiation to lung. The similarity of idiopathic pneumonia to radiation paeumonitis seen in a different clinical setting is described.     

Dose-effect relationship for cataract induction after single-dose total body irradiation and bone marrow transplantation for acute leukemia

PURPOSE: To determine a dose-effect relationship for cataract induction, the tissue-specific parameter, alpha/beta, and the rate of repair of sublethal damage, mu value, in the linear-quadratic formula have to be known. To obtain these parameters for the human eye lens, a large series of patients treated with different doses and dose rates is required. The data of patients with acute leukemia treated with single-dose total body irradiation (STBI) and bone marrow transplantation (BMT) collected by the European Group for Blood and Marrow Transplantation were analyzed. METHODS AND MATERIALS: The data of 495 patients who underwent BMT for acute leukemia, who had STBI as part of their conditioning regimen, were analyzed using the linear-quadratic concept. The end point was the incidence of cataract formation after BMT. Of the analyzed patients, 175 were registered as having cataracts. Biologic effective doses (BEDs) for different sets of values for alpha/beta and mu were calculated for each patient. With Cox regression analysis, using the overall chi-square test as the parameter evaluating the goodness of fit, alpha/beta and mu values were found. Risk factors for cataract induction were the BED of the applied TBI regimen, allogeneic BMT, steroid therapy for >14 weeks, and heparin administration. To avoid the influence of steroid therapy and heparin on cataract induction, patients who received steroid or heparin treatment were excluded, leaving only the BED as a risk factor. Next, the most likely set of alpha/beta and mu values was obtained. With this set, the cataract-free survival rates were calculated for specific BED intervals, according to the Kaplan-Meier method. From these calculations, cataract incidences were obtained as function of the BED at 120 months after STBI. RESULTS: The use of BED instead of the TBI dose enabled the incidence of cataract formation to be predicted in a reasonably consistent way. With Cox regression analysis for all STBI data, a maximal chi-square value was obtained for alpha/beta = 1.75 Gy and mu = 0.75 h(-1). When Cox regression analysis was applied for patients who had no steroid treatment after BMT, a maximal chi-square value was obtained for alpha/beta = 1 Gy and mu = 0.6 h(-1). Cox regression analysis was repeated using the data of patients who had not received posttransplant steroid treatment and also no heparin administration; we found alpha/beta = 0.75 Gy and mu= 0.65 h(-1). An increased cataract incidence was observed after steroid treatment of >14 weeks and heparin administration. CONCLUSION: The alpha/beta value of 0.75 Gy and mu value of 0.65 h(-1) found for the eye lens are characteristic for late-responding tissues. The incidence of cataract formation can now be quantified, taking into account the values calculated for alpha/beta and mu, TBI dose, and dose rate. Also, the reduction in cataract incidence as a result of lens dose reduction by eye shielding can be estimated.     

Lung damage following bone marrow transplantation after hyperfractionated total body irradiation

From July 1985 to December 1989, 72 evaluable patients aged between 6 and 51 (median age 27 years) suffering from haematological malignancies received an allogeneic bone marrow transplant (BMT) depleted of T-lymphocytes to reduce the risk of graft-versus-host-disease (GvHD); 57 were matched and 15 mismatched. Three different conditioning regimens were used in an effort to enhance cytoreduction without increase extramedullary toxicity. Mismatched patients were treated with more immunosuppressive regimens. Total body irradiation (TBI) was given in three doses per day, 5 h apart, over 4 days for a total of 12 fractions. The dose to the lungs was 14.4, 15.6 and 9 Gy according to the conditioning regimen. The incidence of interstitial pneumonia (IP) was 12.3% in matched and 46.7% in mismatched patients. Our results seem to indicate that lung toxicity is correlated with the intensity of the conditioning regimen, the stage of disease and, in mismatched patients, with the degree of human leucocyte antigen (HLA) disparity and the poor post-BMT reconstitution, rather than the radiotherapy dose delivered to the lungs. On the contrary, the hyperfractionated scheme adopted, the absence of GvHD and, perhaps, the post-TBI administration of cyclophosphamide all seem to have contributed to the low incidence of IP in our matched patients.     

Late effects of total body irradiation

Late effects of chemo-radiotherapy conditioning before bone marrow transplantation (BMT) are being increasingly recognised in long-term survivors, particularly children. They can be divided into two categories: those affecting hormonal status and those affecting specific organ function. All women treated develop ovarian failure with low levels of beta-oestradiol and raised values of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In males, raised FSH and LH values are found with normal testosterone levels but most patients have azoospermia. In children, puberty is usually but not invariably delayed by treatment but can be induced by appropriate hormone replacement. Compensated hypothyroidism was found in 6/30 children. Growth hormone secretion may be impaired especially if previous cranial irradiation has been given. In children, a reduction in sitting height has been observed. Cataract has occurred in 20% of children between 3 and 6 years after treatment. Two second tumours have been observed. No other major organ toxicities have been encountered.     

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

: To assess the degree of visual impairment as a result of cataract formation after total body irradiation (TBI) for bone marrow transplantation.

: 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.

: 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).

: 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.     

Cataracts after total body irradiation and marrow transplantation: a sparing effect of dose fractionation

We examined 277 patients, who have been followed for 1 to 12 years after marrow transplantation, for cataract development. In preparation for transplantation, 96 patients with aplastic anemia were conditioned with chemotherapy only, usually cyclophosphamide 50 mg/kg X 4 intravenously, while 181 patients (two with aplastic anemia and 179 with a hematologic malignancy) were conditioned with a regimen of total body irradiation (TBI) and chemotherapy. TBI was delivered from two opposing 60Co sources at an exposure rate of 4 to 8 cGy/min, either as a single dose of 10 Gy (105 patients) or in fractions (76 patients), usually at increments of 2 to 2.25 Gy/day for 6 to 7 days for cumulative doses of 12 to 15.75 Gy. To date, 86 patients have developed cataracts. Kaplan-Meier product limit estimates of the incidence of cataracts for patients given chemotherapy only and no TBI, single-dose TBI, and fractionated TBI are 19, 80, and 18%, respectively. On the basis of proportional hazards regression analyses, patients given single-dose TBI had a relative risk of developing cataracts that was 4.7-fold higher than in patients given fractionated TBI or chemotherapy only (p less than 0.00005), suggesting a significant sparing effect with use of TBI dose fractionation. Addition significant risk factors included the chronic use of steroids posttransplant (highly associated with the presence of chronic graft-versus-host disease), and the diagnoses of acute lymphoblastic or chronic myelogenous leukemia.     

Blood cell kinetics and total body irradiation

The early response of blood cells to irradiation has been studied in leukemia patients who received total body irradiation (TBI) prior to cyclophosphamide and bone marrow transplantation. After a single session treatment (10 Gy in 4 h) the most dramatic variation was observed in the granulocytes. At the end of the irradiation their concentration was 2 to 6 times higher. Because of a subsequent rapid decline, the peak may be overlooked if the blood counts are delayed. Lymphocytes decreased to 50% at the end of the single session TBI and continue to decrease exponentially, with a half time of 30 h. During a fractionated irradiation (11 X 1.2 Gy in 4 days) the lymphocyte number dropped to 60%, 13 h after the first fraction and this decline continued with a half time of 30 h during the treatment. From the data obtained in vivo, a lymphocyte D0 value of 1.2 Gy was computed. The lymphocyte subsets (B.T. OKT4 OKT8) did not exhibit different radiosensitivities either in vivo or in vitro. The disappearance of lethally hit lymphocytes from the blood exhibits a biphasic kinetic: 50% of the cells disappear in a few hours and 50% with a half time at 30 h. Lymphocytes irradiated either in vitro or in vivo when in culture disappear slowly, contrasting with the in vivo findings. It may suggest that lethally hit lymphocytes are quickly removed from the circulating pool in vivo.     

Fractionated total body irradiation for metastatic neuroblastoma

Twelve patients over one year old with neuroblastoma (NBL) metastatic to bone and bone marrow entered a study of adjuvant low-dose, fractionated total body irradiation (TBI). Six children who achieved a “complete clinical response” following chemotherapy (cyclophosphamide and adriamycin) and surgical resection of the abdominal primary received TBI (10 rad/fraction to totals of 100–120 rad/10–12 fx/12–25 days). Two children received concurrent local irradiation for residual abdominal tumor. The intervals from cessation of chemotherapy to documented progression ranged from 2–16 months, not substantially different from patients receiving similar chemotherapy and surgery without TBI. Three additional children with progressive NBL received similar TBI (80–120 rad/8–12 fx) without objective response.     

Biological basis of total body irradiation]

A comprehensive understanding of the radiobiological bases of total body irradiation (TBI) is made difficult by the large number of normal and malignant tissues that must be taken into account. In addition, tissue responses to irradiation are also sensitive to associated treatments, type of graft and a number of patient characteristics. Experimental studies have yielded a large body of data, the clinical relevance of which still requires definite validation through randomized trials. Fractionated TBI schemes are able to reduce late normal tissue toxicity, but the ultimate consequences of the fractional dose reduction do not appear to be equivocal. Thus, leukemia and lymphoma cells are probably more radiobiologically heterogeneous than previously thought, with several cell lines displaying relatively high radioresistance and repair capability patterns. The most primitive host-type hematopoietic stem cells are likely to be at least partly protected by TBI fractionation and may hamper late engraftment. Similarly, but with possibly conflicting consequences on the probability of engraftment, the persistence of a functional marrow stroma may also be fractionation-sensitive, while higher rejection rates have been reported after T-depletion grafts and fractionated TBI. In clinical practice (as for the performance of relevant clinical trials), the influence of these results are rather limited by the heavy logistic constraints created by a sophisticated and time-consuming procedure. Lastly, clinicians are now facing an increasing incidence of second cancers, at least partly induced by irradiation, which jeopardize the long-term prospects of otherwise cured patients.     

Biological dosimetry after total body irradiation (TBI) for hematologic malignancy patients

PURPOSE: Biological dosimetry based on scoring chromosomal aberrations in peripheral lymphocytes was compared to physical dosimetry done for total body irradiation (TBI) before bone marrow transplantation (BMT) in patients with hematologic malignancies. PATIENTS AND METHODS: Fifteen patients undergoing TBI were included in the study. A total dose of 12 Gy in 2.5 days was fractionated into 2 or 3 daily doses of 1.8 Gy delivered by a 18 MV linear accelerator (dose rate: 15.8 cGy x min(-1)). Blood samples were obtained from patients before irradiation and after the first fraction of 1.8 Gy. A standard dose-effect curve was established by in vitro irradiation of healthy volunteer lymphocytes. Chromosomal aberrations were scored by the conventional cytogenetics (CCG) method for unstable anomalies and by fluorescent in situ hybridization (FISH) for stable anomalies. RESULTS: Healthy donor lymphocytes before irradiation yielded 0.1% dicentrics and 0.3% translocations of chromosome 4 (Chr. 4), that is 2.5% for the whole genome. Patients before irradiation had 2% of dicentrics and 1.1% of chromosome 4 translocations. The biologically estimated dose of the 15 patients after exposure to 1.8 Gy was 1.93 Gy (95% CI: 1.85-2.05) according to CCG, and 2.06 Gy (95% CI: 1.75-2.15) by FISH. CONCLUSION: The dose estimated by biological dosimetry, in this case of homogeneously distributed radiation of TBI agrees well with the absorbed radiation dose calculated by physical dosimetry.     

Renal insufficiency in patients with hematologic malignancies undergoing total body irradiation and bone marrow transplantation: a prospective assessment

PURPOSE: Patients with malignant hematologic disorders undergoing bone marrow transplantation (BMT) may develop renal insufficiency. A study was undertaken to assess prospectively the subclinical renal function changes with radioisotopic methods in patients undergoing BMT for hematologic malignancies. METHODS AND MATERIALS: We studied 71 patients with normal renal function undergoing BMT for various hematologic malignancies, mostly leukemias. Conditioning included chemotherapy and 12 Gy (45 patients) or 13.5 Gy (26 patients) fractionated total-body irradiation (TBI). In 21 patients receiving 12 Gy TBI, the kidney dose was limited to 10 Gy using partial transmission blocks fabricated after renal opacification with nonionic, hypo-osmolar contrast medium. The glomerular filtration rate (GFR) and effective renal plasmatic flow (ERPF) were determined radioisotopically before conditioning and at 4, 12, and 18 months, using (51)Cr ethylene-diamine-tetra-acetic acid and (131)I ortho-iodo-hippurate, respectively. Renal insufficiency was defined as a decrease of >/=30% in GFR or ERPF compared with the baseline values. The potential influence of patient- and treatment-related variables on renal dysfunction was assessed. RESULTS: At 4 (early) and 12-18 (late) months, a >/=30% GFR drop was observed in 54% and 49% of patients and a >/=30% ERPF drop in 44% and 34% of patients, respectively. After stepwise logistic analysis, a GFR reduction at 4 months correlated significantly with age (<40 years old, worse), TBI using kidney blocks (partial kidney shielding to 10 Gy was associated with a higher rate of renal dysfunction at 4 months compared with the full TBI dose), and days of aminoglycoside/vancomycin use. An ERPF drop at 4 months was independently related with the days of amphotericin use and days of prostaglandin E(1) use (prophylaxis against hepatic venoocclusive disease). A GFR and ERPF reduction at 12-18 months correlated with days of amphotericin use and days of prostaglandin E(1) use, respectively. CONCLUSION: Early post-BMT renal dysfunction is associated with the administration of potentially nephrotoxic drugs. An inverse correlation with the prescribed TBI dose was observed; patients whose kidneys received 10 Gy through the use of partial shielding blocks had significantly greater renal dysfunction at 4 months. The administration of potentially nephrotoxic contrast agents used in radiotherapy treatment planning may be responsible for the latter observation. Prostaglandin E(1) use correlated with a significant reduction in ERPF at both 4 and 12-18 months.