Dosimetry of single fraction high dose total body irradiation as measured by thermoluminescent dosimeters

Eighty-five patients with acute myelogenous or acute lymphoblastic leukemia were treated at the City of Hope National Medicine Center with chemotherapy, total body irradiation, and bone marrow transplant. The average mid-line dose to these patients was 1002 rad with a uniformity of 8%.     

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.     

Calculation of lung shielding for total body irradiation

The radiation absorbed dose to the lung is calculated for patients receiving total body irradiation. Based on this calculation the thickness of lead attenuators required to reduce the lung dose is determined. To calculate accurately the dose the lung density as well as the lung dimensions of individual patients must be considered. For total body irradiations all calculations of attenuator thicknesses should be based on measured data obtained for the large radiation field.     

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.     

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.     

Calculation and prescription of dose for total body irradiation

The use of large total body fields creates a unique set of problems that stress the accuracy of techniques routinely used for dose calculation. This paper discusses an approach suggested by the Children's Cancer Study Group (CCSG) for both prescribing the total body irradiation (TBI) dose and calculating the beam-on time or meter set needed to deliver it. It is aimed at guaranteeing the accuracy of the calculations, while at the same time ensuring a high degree of compliance for the various CCSG protocols using TBI. Data supporting the various CCSG recommendations are presented.     

Cyclic,low-dose total body irradiation for metastatic neuroblastoma

Total body irradiation (TBI) can be thought of as a systemic anticancer agent. It therefore might best be given like an adjuvant drug, i.e. in tolerable doses, cyclically. The therapeutic ratio between normal bone marrow stem cells and suitably sensitive cancer cells should be widened by these means. Fourteen children with advanced (Stage IV) neuroblastomas were given 100–150 rad TBI in 50 rad daily fractions along with each three-week cycle of standard triple-agent chemotherapy (vincristine, DTIC, cyclophosphamide). Two patients died of toxicity and one is still undergoing therapy. Four of the remaining 12 survive free of disease for 12+ to 31 + months. The regimen is well tolerated, but prolonged, pronounced bone marrow depression, especially thrombocytopenia, commonly occurs after doses of 300–450 rad.     

Myeloablative combination chemotherapy without total body irradiation for neuroblastoma

Myeloablative treatment intensification in 25 patients diagnosed when older than 12 months of age with stage IV neuroblastoma included sequential delivery of cisplatin 120 mg/m2 x 1, hyperfractionated radiation (2,100 cGy) to the primary site and adjacent lymph nodes, carmustine (BCNU) 200 mg/m2 x 1, melphalan 60 mg/m2/d x 3 (n = 13) or thiotepa 300 mg/m2/d x 3. (n = 12), and etoposide (VP 16) 300 mg/m2/d x 3. Seventy-two hours after the last dose of VP 16, histologically tumor-free and 4-hydroperoxycyclophosphamide (4-HC; 100 mumol/L)-purged autologous bone marrow (ABMT) was infused. Acute toxicities included grade 3 to 4 oral mucositis, grade 1 to 2 diarrhea, and fevers. No patient required infusion of unpurged reserve autografts. At ABMT, 16 patients (group I) were progression-free 6.5 months to 14 months (median, 9 months) from diagnosis: seven remain progression-free 20 months to 46 months (median, 39 months) off therapy, six relapsed 4 months to 17 months post-ABMT, and three died of toxicity (candidiasis, metabolic derangement, and venoocclusive disease [VOD]). The event-free survival of group I patients is 44% at 24 months post-ABMT. Nine patients (group II) were in second remission at ABMT, including three who had relapsed after other transplant procedures: two are progression-free 24 months and 41 months off therapy, four relapsed 3 months to 12 months post-ABMT, and three died of toxicity (aspergillosis, hemorrhagic cystitis, VOD). Only one of 10 relapses involved a primary site, suggesting a beneficial effect of local radiation. In terms of survival or toxicity, an advantage for melphalan or thiotepa was not evident. Regimens such as this may prolong the survival of selected patients with poor-risk neuroblastoma, but concerns over late relapses and toxicity mandate continuing efforts to devise alternative, less risky, and more clearly beneficial approaches for definitive ablation of neuroblastoma.     

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.     

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.     

A total body irradiation stand for bone marrow transplant patients

A stand designed for the immobilization of patients standing during total body irradiation (TBI) with horizontal 10 MV X rays is described. The stand reduces patient movement and facilitates the initial positioning and repositioning of patients during 11 fractions of TBI over a 3 2/3 day period. Details of design and use are presented. The stand is regularly used to treat TBI patients.     

A simple dose calculation method for total body photon irradiation

A simple technique for calculation of the prescribed dose for total body irradiation (TBI) is presented. The technique uses a standard calibration procedure and applies standard correction methods to account for variations in the field size, depth, and treatment distance. Since the scattering volume (the entire body) is smaller than the X ray field for this treatment, the change in output with field size is handled separately from changes due to scatter within the phantom. The latter is shown to be a function of the phantom size (corresponding to the frontal area of the trunk of the body for patient irradiation) rather than the size of the field opening. Dosimetric tests of this technique have been conducted and the errors determined. For these tests, three different phantom sizes were used to represent the upper body sizes of a 2-year old child, an 8-year old, and an adult, and three linear accelerator energies (6, 10, and 15 MV) were included. Calculations were performed using the technique and compared to measurements for the same phantom sizes. Differences of less than 1.3 were found.     

Therapeutic use of fractionated total body and subtotal body irradiation

Ninety-one patients were treated using fractionated subtotal body (STBI) or total body irradiation (TBI). These patients had generalized lymphomas, Hodgkin's disease, leukemias, myelomas, seminomas, or oat-cell carcinomas. Subtotal body irradiation is delivered to the entire body, except for the skull and extremities. It was expected that a significantly higher radiation dose could be administered with STBI than with TBI. STBI was given when there was a reasonable likelihood that malignancy did not involve the shielded volumes. A five- to ten-fold increase in tolerance for STBI was demonstrated. Many of these patients have had long-term (up to 17 year--?permanent) remissions. There is little or no treatment-induced symptomatology, and no "sanctuary sites." STBI and TBI are useful therapeutic modalities for many of these malignancies.     

Long-term complications of total body irradiation in adults

PURPOSE: To report long-term pulmonary, thyroid, and ocular complications in patients who had conditioning regimens including total body irradiation (TBI) before bone marrow transplantation (BMT). METHODS AND MATERIALS: Between June 1986 and December 1995, 478 patients received TBI in our institution. The present study includes 186 adult patients who had complete remission lasting one year or more after BMT. There were 108 males and 78 females. Median age was 36.5 years (range 15-60). Initial diagnoses were lymphomas (50%), acute lymphoid leukemias (16%), acute myeloid leukemias (16%), chronic myeloid leukemia (13%), aplastic anemia (3%), and myelodysplasia (2%). At the time of BMT, 43.5% of patients were in complete response and 56.5% in partial response. Treatment consisted of a single dose TBI at 10 Gy in 9% and fractionated TBI delivering 12 to 13.5 Gy in 6 fractions in 91%. From 1986 to October 1991, TBI was performed in lateral position with 9 MV energy (57% of patients) and thereafter in alternate prone and supine positions with 15 MV energy (43%). Chemical conditioning regimen was cyclophosphamide (60 mg/kg at D-4 and D-3) in 69% and CBV (cyclophosphamide 1500 mg/m(2) from D-6 to D-3, BCNU 300 mg/m(2) at D-6, VP-16 200 mg/m(2) from D-6 to D-4) in 25%. Fifty eight percent of patients received autologous and 42% allogeneic BMT. All patients had clinical, biologic, and functional examinations at one-year intervals. RESULTS: Median follow-up from BMT was 49 months (range 12-136). Late pulmonary effects were observed only in functional explorations, without clinical effect, including restrictive syndrome in 8% and alteration in the diffusing capacity of carbon monoxide in 12%. No patient showed clinical thyroid symptoms, and 10% developed biologic dysfunction: hypothyroidism (6.5%), thyroiditis (3%), and Basedow disease (0.5%). Ocular complications occurred in 29.5%, including cataract (15%), dry syndrome (13%), and keratitis (1.5%). In univariate and multivariate analysis, pulmonary complications were statistically increased by chronicle graft vs. host disease (GVHD) vs. no (p = 0.02), prone and supine vs. lateral TBI position (p = 0.02), and with 15 MV vs. 9 MV beam energy (p = 0.02). Cataract occurred less frequently with fractionated than with single-dose TBI (p = 0.000002). No differences were observed regarding age, sex, initial diagnosis, status at the time of BMT, conditioning chemotherapy regimen, and total dose of TBI. CONCLUSION: From this retrospective study it was shown that long-term complications of TBI were not symptomatic in most patients. The role of parameters of irradiation and especially position of treatment and beam energy should be emphasized and assessed with a longer follow-up.     

Acute and delayed toxicities of total body irradiation

Total body irradiation is being used with increasing frequency for the treatment of lymphopoietic malignancies and in preparation for marrow transplantation. Acute toxicities include reversible gastroenteritis, mucositis, myelosuppression and alopecia. As the success of treatment improves and more patients become long-term survivors, manifestations of delayed and chronic toxicity become evident. These include impairment of growth and development, gonadal failure and sterility, cataract formation and possibly secondary malignancies. The contribution of total body irradiation to the development of pneumonitis and pulmonary fibrosis is still poorly understood. Some of these changes are reversible or correctable, whereas others are permanent. Nevertheless, until equally effective but less toxic regimens become available, total body irradiation appears to be the treatment of choice to prepare patients with leukemia for marrow transplantation.