Total body irradiation: techniques, dosimetry, and complications]

Total-body irradiation (TBI) has an established role in many preparative regimens used before bone marrow transplantation (BMT) in the treatment of hematological malignancies in children and adults. Better choice in TBI techniques and dosimetry have permitted better homogeneity of dose, and therefore a significant sparing of critical tissues. Advances in treatments over the past 20 years have greatly improved survival; therefore, the evaluation of early and late complications, with a sufficient follow-up, according to different conditioning regimens is important. In this article, we review and compare different TBI techniques and dosimetry, and their influence on the distribution and homogeneity of dose, and the possible relationship to the risk of complications. We also describe the acute and late effects of TBI in children and adults appearing in the first month post-BMT as veno-occlusive disease, interstitial pneumonitis, or after 3 months, i.e., endocrinal late effects and growth in children, cataracts, neurological and bone or other complications, secondary tumors and alteration in the quality of life. The responsibility of TBI in the increased rate of certain complications is difficult to assess from chemotherapy or allograft side effects (chronic graft vs. host disease) or from other associated medical treatments, such as long term steroid therapy.     

A practical approach to uniform total body photon irradiation

Photon total body irradiation (TBI) has been applied to treat several systemic malignancies. However, TBI studies have been limited by nonuniform dosimetry. A 16 MV technique was initiated to improve uniformity of dose in a practical manner. For high dose TBI, missing tissue compensators are designed from lateral tissue separations, intra-lung separations, average CT numbers of lung regions, tissue phantom ratios, and off axis ratios. A few days before treatment, CT scans are obtained and TBI is simulated in the treatment room. In the treatment room, back projections of the patient's lateral silhouette, arm outline, and CT levels are traced on a compensatory tray. Lead sheets are scribed through a schematic of the tray, cut, and fixed to their appropriate positions on the tray. Doses are verified with thermoluminescent dosemeters and ion chambers. Most measurements at the temple, chest wall, mid-thighs, and mid-knees have been within 10% of prescribed doses. About 4 hours are required for compensator fabrication and dose verification. This approach has been found practical, substantially improving dose uniformity relative to prior 60Co techniques applied at this institution.     

In-vivo dosimetry by diode semiconductors in combination with portal films during TBI: reporting a 5-year clinical experience.

BACKGROUND AND PURPOSE: In-vivo dosimetry is vital to assure an accurate delivery of total body irradiation (TBI). In-vivo lung dosimetry is strongly recommended because of the risk of radiation-induced interstitial pneumonia (IP). Here we report on our 5-year experience with in-vivo dosimetry using diodes in combination with portal films and assessing the effectiveness of in-vivo dosimetry in improving the accuracy of the treatment. Moreover, we wished to investigate in detail the possibility of in-vivo portal dosimetry to yield individual information on the lung dose and to evaluate the impact of CT planning on the correspondence between stated and in-vivo measured doses. MATERIALS AND METHODS: From March 1994 to March 1999, 229 supine-positioned patients were treated at our Institute with TBI, using a 6 MV X-rays opposed lateral beam technique. 146 patients received 10 Gy given in three fractions, once a day (FTBI), shielding the lungs by the arms; 70 received 12-13.2 Gy, given in 6-11 fractions, 2-3 fractions per day (HFTBI): in this case about 2/3 of the lungs were shielded by moulded blocks (mean shielded lung dose equal to 9 or 9.5 Gy). Thirteen patients received 8 Gy given in a single fraction (SFTBI, lung dose: 7 Gy). For all HFTBI and FTBI patients, midline in-vivo dosimetry was performed at the first fraction by positioning two diodes pairs (one at entrance and one at the exit side) at the waist (umbilicus) and at the pelvis (ankles). If at least one of the two diodes doses (waist-pelvis) was outside +/-5% from the prescribed dose, actions could be initiated, together with possible checks on the following fractions. Transit dosimetry by portal films was performed for most patients; for 165 of them (117 and 48, respectively for FTBI and HFTBI) the midline in-vivo dose distribution of the chest region was derived and mean lung dose assessed. As a CT plan was performed for all HFTBI patients, for these patients, the lung dose measured by portal in-vivo dosimetry was compared with the expected value. RESULTS: Concerning all diodes data, 528 measurements were available: when excluding the data of the first fraction(s) of the patients undergoing corrections (n = 392), mean and SD were respectively 0.0% and 4.5% (FTBI: -0.3 +/- 4.8%; HFTBI: 0.4 +/- 3.9%). In total 105/229 patients had a change after the first fraction and 66/229 were controlled by in-vivo dosimetry for more than one fraction. Since January 1998 a CT plan is performed for FTBI patients too: when comparing the diodes data before and after this date, a significant improvement was found (i.e. rate of deviations larger than 5% respectively equal to 30.7% and 13.1%, P = 0.007). When considering only the patients with a CT plan, the global SD reduced to 3.5%. Concerning transit dosimetry data, for FTBI, the mean (midline) lung dose was found to vary significantly from patient to patient (Average 9.13 +/- 0.81 Gy; range 7.4-11.4 Gy); for the HFTBI patients the mean deviation between measured and expected lung dose was 0.0% (1 SD = 3.8%). CONCLUSIONS: In vivo dosimetry is an effective tool to improve the accuracy of TBI. The impact of CT planning for FTBI significantly improved the accuracy of the treatment delivery. Transit dosimetry data revealed a significant inter-patient variation of the mean lung dose among patients undergoing the same irradiation technique. For patients with partial lung shielding (HFTBI), an excellent agreement between measured and expected lung dose was verified.     

Renal dysfunction after total body irradiation: dose-effect relationship

PURPOSE: Late complications related to total body irradiation (TBI) as part of the conditioning regimen for hematopoietic stem cell transplantation have been increasingly noted. We reviewed and compared the results of treatments with various TBI regimens and tried to derive a dose-effect relationship for the endpoint of late renal dysfunction. The aim was to find the tolerance dose for the kidney when TBI is performed. METHODS AND MATERIALS: A literature search was performed using PubMed for articles reporting late renal dysfunction. For intercomparison, the various TBI regimens were normalized using the linear-quadratic model, and biologically effective doses (BEDs) were calculated. RESULTS: Eleven reports were found describing the frequency of renal dysfunction after TBI. The frequency of renal dysfunction as a function of the BED was obtained. For BED>16 Gy an increase in the frequency of dysfunction was observed. CONCLUSIONS: The tolerance BED for kidney tissue undergoing TBI is about 16 Gy. This BED can be realized with highly fractionated TBI (e.g., 6x1.7 Gy or 9x1.2 Gy at dose rates>5 cGy/min). To prevent late renal dysfunction, the TBI regimens with BED values>16 Gy (almost all found in published reports) should be applied with appropriate shielding of the kidneys.     

In vivo dosimetry during external photon beam radiotherapy

In this critical review of the current practice of patient dose verification, we first demonstrate that a high accuracy (about 1-2%, 1 SD) can be obtained. Accurate in vivo dosimetry is possible if diodes and thermoluminescence dosimeters (TLDs), the main detector types in use for in vivo dosimetry, are carefully calibrated and the factors influencing their sensitivity are taken into account. Various methods and philosophies for applying patient dose verification are then evaluated: the measurement of each field for each fraction of each patient, a limited number of checks for all patients, or measurements of specific patient groups, for example, during total body irradiation (TBI) or conformal radiotherapy. The experience of a number of centers is then presented, providing information on the various types of errors detected by in vivo dosimetry, including their frequency and magnitude. From the results of recent studies it can be concluded that in centers having modern equipment with verification systems as well as comprehensive quality assurance (QA) programs, a systematic error larger than 5% in dose delivery is still present for 0.5-1% of the patient treatments. In other studies, a frequency of 3-10% of errors was observed for specific patient groups or when no verification system was present at the accelerator. These results were balanced against the additional manpower and other resources required for such a QA program. It could be concluded that patient dose verification should be an essential part of a QA program in a radiotherapy department, and plays a complementary role to treatment-sheet double checking. As the radiotherapy community makes the transition from the conventional two-dimensional (2D) to three-dimensional (3D) conformal and intensity modulated dose delivery, it is recommended that new treatment techniques be checked systematically for a few patients, and to perform in vivo dosimetry a few times for each patient for situations where errors in dose delivery should be minimized.     

Modification of radiation-induced damage to bone marrow stem cells by dose rate, dose fractionation, and prior exposure to cytoxan as judged by the survival of CFUs: application to bone marrow transplantation (BMT)

The relative importance of the effects of dose rate, dose fractionation, and prior exposure to Cytoxan on the recovery of cells in the bone marrow, following conditioning for BMT, remains controversial. Traditionally, bone marrow stem cells and leukemic cells have been considered as having a limited ability to repair radiation-induced damage following total body irradiation (TBI) compared to cells of the lung (the dose-limiting tissue for TBI). We examined the survival response of the bone marrow stem cells of mice (CFUs) at three TBI dose rates (0.47, 0.25 and 0.08 Gy/min). The radiation response of CFUs (compilation Do = 0.75 Gy) was independent of dose rate. One TBI dose fractionation was chosen: two fractions per day, separated by 6 hours, for 3 days. The radiation survival curve of CFUs showed a compilation Do of 1.09 Gy, compared to 0.75 Gy for the one-fraction case. The recovery of CFUs following 2 days of Cytoxan demonstrated an "overshoot," whereas recovery of CFUs was incomplete, even by day 23, following the initiation of the complete conditioning regimen of Cytoxan plus TBI. These data demonstrate no significant effect of dose rate, at least in the range 0.08 to 0.48 Gy/min, on the survival of CFUs following either single or six fractionated TBI doses. However, the statistically significant difference in the Do of CFUs in going from one to six fractions has direct application to bone marrow transplantation techniques. Moreover, Cytoxan, at least at 200 mg/kg for 2 days, prior to TBI, appears to have only a marginal modifying effect on the eventual recovery of CFUs.     

Toxicity and dosimetry of fractionated total body irradiation prior to allogeneic bone marrow transplantation using a straightforward radiotherapy technique

Since 1989, we have used a relatively straightforward technique for giving total body irradiation (TBI), using anterior and posterior parallel opposed fields with the arms and fists acting as compensators. The dosimetry, toxicity and outcome of 48 patients (26 adults, 22 children) treated with TBI using this technique have been audited. A dose of 14.4 Gy in eight fractions over 4 days was prescribed to all patients with an unrelated donor and 12 Gy in six fractions over 3 days to those with a sibling donor. From May 1994, all children received 14.4 Gy because of a recommendation from the United Kingdom Children's Cancer Study Group. The range of lung dosimetry was −6% to +7% when the dose was specified to the lung maximum. The trunk doses were all within ±10% of the prescribed dose. Doses to other regions of the body were less homogeneous but clinically acceptable in that the minimum doses were never less than −10% of the prescribed dose. Mucositis was the most common side effect; its treatment with opioids was more frequent after 14.4 Gy than after 12 Gy (P = 0.0004) and in adults than in children (P = 0.01). No cataracts have yet been seen in these patients. The radiation was not found to be a proven cause of clinical pneumonitis, although there was one death due to interstitial pneumonitis, which was likely to have been caused by cytomegalovirus infection in which radiation pneumonitis could not be excluded. There were no other suspected TBI-related deaths.In conclusion, this straightforward technique achieved acceptable dosimetry and was well tolerated.     

Effect of dose-rate on total body irradiation: lethality and pathologic findings

The effect of low dose-rate total body irradation (TBI) on hemopoietic and nonhemopoietic lethality has been studied in BALB/c mice using dose-rates ranging from 25 to 1 cGy/min. Deaths were scored at 10 days, 30 days, and one year after irradiation, and dose-response curves were constructed to determine the dose-rate dependence of deaths from the gastrointestinal syndrome, hemopoietic syndrome, and late lethal syndrome(s), respectively. A plot of the LD50S for each of these lethal syndromes versus dose-rate showed the dose-rate dependence for late lethality to be somewhat greater than that for gut death, but both of these endpoints were markedly more dose-rate dependent than was hemopoietic lethality, particularly at dose rates less than 5 cGy/min. To determine which late responding normal tissues might be critical for low dose-rate TBI, complete necropsies were performed on all mice dying later than 60 days after irradiation and on all mice surviving at one year; all tissues were examined histologically. Morphologic evidence of radiation injury was present in only three tissues, lung (fibrosis and scarring) kidney (tubule depletion), and liver (presence of mitoses). Subjectively, the lung changes were most severe up to 9 months while kidney changes became more prominent after this time, suggesting that late death after low dose-rate TBI may not be entirely attributable to lung injury. However, regardless of which late responding normal tissue is dose-limiting, it is clear that low dose-rate TBI preferentially spares these tissues compared with hemopoietic stem cells.     

Late toxicity of total body irradiation with bone marrow transplantation in a rat model

In defined-flora, barrier-maintained rats, radiation nephritis is the principle late toxicity seen after high dose-rate total body irradiation (TBI), when hematologic toxicity is prevented by bone marrow transplantation (BMT). Pneumonitis develops only if rats are placed in a conventional microbiological environment during and after BMT. Low dose-rate TBI gives qualitatively similar late toxicity, but at radiation doses twice as large. Fractionation of the TBI has little effect on the bone marrow ablation doses, but results in increased gastrointestinal and renal tolerance. The addition of immunosuppressive or cytotoxic drugs (cyclosporine-A, methotrexate, cis-platinum) after TBI and BMT greatly decreases the dose of TBI that can be tolerated. The use of a cyclophosphamide plus cytosine arabinoside conditioning regimen prior to TBI and BMT increases the bone marrow ablation dose, but has no effect on acute gastrointestinal toxicity or on renal toxicity. These results indicate that substantial late toxicity may be associated with the TBI conditioning regimens used for BMT even in the absence of cytotoxic and antibiotic drugs, immunosuppressive agents, infection and graft-versus-host disease; and that radiation may be a contributing factor in the nephritis sometimes observed after TBI and BMT.     

Uniformity and standardization of single and opposing cobalt 60 sources for total body irradiation

The use of total body irradiation (TBI), chemotherapy, and allogeneic bone marrow transplantation in the management of relapsing leukemia has been established with dual source cobalt irradiation. In many facilities in order to reproduce the clinical results with single source irradiation, dosimetry must be compared under situations of varying configurations in order to standardize TBI techniques. Once intercomparison is achieved by on site dosimetric evaluation, recommendations are made for patient position, length of exposure in different positions and average thickness and beam data used to calculate absorbed dose. Homogeneity of single and opposing cobalt sources is also compared.     

Reduction of organ motion effects in IMRT and conformal 3D radiation delivery by using gating and tracking techniques.

Respiration-gated radiotherapy offers a significant potential for improvement in the irradiation of tumour sites affected by respiratory motion such as lung, breast and liver tumours. An increased conformality of irradiation fields leading to decreased complications rates of organs at risk (lung, heart) is expected. Four main strategies are used to reduce respiratory motion effects: integration of respiratory movements into treatment planning, breath-hold techniques, respiratory gating techniques, and tracking techniques. Measurements of respiratory movements can be performed either in a representative sample of the general population, or directly on the patient before irradiation. The measured amplitude could be applied to a geometrical margin or integrated into dosimetry. However, these strategies remain limited for very mobile tumours, in which this approach results in larger irradiated volumes. Reduction of breathing motion can be achieved by using either breath-hold techniques or respiration synchronized gating techniques. Breath-hold can be achieved with active techniques, in which a valve temporarily blocks airflow of the patient, or passive techniques, in which the patient voluntarily breath-holds. Synchronized gating techniques use external devices to predict the phase of the respiration cycle while the patient breaths freely. Another category is tumour tracking, which consists of two major aspects: real-time localization of, and real-time beam adaptation to, a constantly moving tumour. These techniques are presently being investigated in several medical centres worldwide. Although promising, the first results obtained in lung and liver cancer patients require confirmation. This paper describes the most frequently used gating and tracking techniques and the main published clinical reports.     

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.     

Physical aspects of total body irradiation of bone marrow transplant patients using 18 MV x rays

The physical aspects of a total body irradiation (TBI) treatment are described. Patients seated in a special chair with their legs bent backwards are irradiated anteriorly and posteriorly (AP/PA). The chair reduces patient movement and facilitates positioning patients during 9 fractions of TBI over a 3-day period. The dose to lower extremities are monitored and raised to the total body dose. A conventional linear accelerator in a standard size treatment room is used to deliver 18 MV x-ray beams at a dose rate of approximately 20 cGy/min at a 350 cm treatment distance. Results of dose distribution, field flatness, dose uniformity, in vivo and in vitro dosimetry, and boost irradiation techniques are described.     

Total body irradiation using helical tomotherapy: Set-up experience and in-vivo dosimetric evaluation

PurposeHelical Tomotherapy (HT) appears as a valuable technique for total body irradiation (TBI) to create highly homogeneous and conformal dose distributions with more precise repositioning than conventional TBI techniques. The aim of this work is to describe the technique implementation, including treatment preparation, planning and dosimetric monitoring of TBI delivered in our institution from October 2016 to March 2019.Material and methodPrior to patient care, irradiation protocol was set up using physical phantoms. Gafchromic films were used to assess dose distribution homogeneity and evaluate imprecise patient positioning impact. Sixteen patients’ irradiations with a prescribed dose of 12 Gy were delivered in 6 fractions of 2 Gy over 3 days. Pre-treatment quality assurance (QA) was performed for the verification of dose distributions at selected positions. In addition, in-vivo dosimetry was carried out using optically stimulated luminescence dosimeters (OSLD).ResultsPlanning evaluation, as well as results of pre-treatment verifications, are presented. In-vivo dosimetry showed the strong consistency of OSLD measured doses. OSLD mean relative dose differences between measurement and calculation were respectively +0,96% and ?2% for armpit and hands locations, suggesting better reliability for armpit OSLD positioning. Repercussion of both longitudinal and transversal positioning inaccuracies on phantoms is depicted up to 2 cm shifts.ConclusionThe full methodology to set up TBI protocol, as well as dosimetric evaluation and pre-treatment QA, were presented. Our investigations reveal strong correspondence between planned and delivered doses shedding light on the dose reliability of OSLD for HT based TBI in-vivo dosimetry.     

Pretransplant pulmonary function tests predict risk of mortality following fractionated total body irradiation and allogeneic peripheral blood stem cell transplant

PURPOSE: To determine the value of pulmonary function tests (PFTs) done before peripheral blood stem cell transplant (PBSCT) in predicting mortality after total body irradiation (TBI) performed with or without dose reduction to the lung. METHODS AND MATERIALS: From 1997 to 2004, 146 consecutive patients with hematologic malignancies received fractionated TBI before PBSCT. With regimen A (n=85), patients were treated without lung dose reduction to 13.6 gray (Gy). In regimen B (n=35), total body dose was decreased to 12 Gy (1.5 Gy twice per day for 4 days) and lung dose was limited to 9 Gy by use of lung shielding. In regimen C (n=26), lung dose was reduced to 6 Gy. All patients received PFTs before treatment, 90 days after treatment, and annually. RESULTS: Median follow-up was 44 months (range, 12-90 months). Sixty-one patients had combined ventilation/diffusion capacity deficits defined as both a forced expiratory volume in the first second (FEV1) and a diffusion capacity of carbon dioxide (DLCO)<100% predicted. In this group, there was a 20% improvement in one-year overall survival with lung dose reduction (70 vs. 50%, log-rank test p=0.042). CONCLUSION: Among those with combined ventilation/diffusion capacity deficits, lung dose reduction during TBI significantly improved survival.     

Multicentre dosimetric comparison of photon‐junctioning techniques in head and neck radiotherapy

Because many head and neck radiotherapy treatment techniques rely on a junction between X‐ray fields, it was the aim of the present study to investigate the use of different junctioning techniques and the affect on the dose across the junction. Techniques in use at nine radiotherapy centres in Australia were investigated using thermoluminescence dosimetry (TLD). The techniques could broadly be divided into two groups: (i) use of the light field to match the fields after moving the patient; and (ii) use of asymmetric collimation to create a single isocentre located in the junction. The mean dose at the junction and its reproducibility was studied in five consecutive treatments in each centre using 25 TLD chips placed throughout the junction in an anthropomorphic phantom. There was a tendency for the mono‐isocentric technique to deliver a lower, more accurate mean dose at the junction (Group I: 1.22 Gy (n = 8) vs Group II: 0.96 Gy (n = 5) for 1 Gy planned, some centres contributed to both technique) with greater reproducibility (Group I: 9.6%, Group II: 5.1% of the mean dose). We conclude that a mono‐isocentric treatment technique has the potential to deliver a more accurate and reproducible dose distribution at the field junction of photon beams in head and neck treatment.     

Calibration of a MOSFET Detection System for 6-MV In Vivo Dosimetry

Purpose: Metal oxide semiconductor field-effect transistor (MOSFET) detectors were calibrated to perform in vivo dosimetry during 6-MV treatments, both in normal setup and total body irradiation (TBI) conditions.Methods and Materials: MOSFET water-equivalent depth, dependence of the calibration factors (CFs) on the field sizes, MOSFET orientation, bias supply, accumulated dose, incidence angle, temperature, and spoiler-skin distance in TBI setup were investigated. MOSFET reproducibility was verified. The correlation between the water-equivalent midplane depth and the ratio of the exit MOSFET readout divided by the entrance MOSFET readout was studied. MOSFET midplane dosimetry in TBI setup was compared with thermoluminescent dosimetry in an anthropomorphic phantom. By using ionization chamber measurements, the TBI midplane dosimetry was also verified in the presence of cork as a lung substitute.Results: The water-equivalent depth of the MOSFET is about 0.8 mm or 1.8 mm, depending on which sensor side faces the beam. The field size also affects this quantity; Monte Carlo simulations allow driving this behavior by changes in the contaminating electron mean energy. The CFs vary linearly as a function of the square field side, for fields ranging from 5 × 5 to 30 × 30 cm². In TBI setup, varying the spoiler-skin distance between 5 mm and 10 cm affects the CFs within 5%. The MOSFET reproducibility is about 3% (2 SD) for the doses normally delivered to the patients. The effect of the accumulated dose on the sensor response is negligible. For beam incidence ranging from 0° to 90°, the MOSFET response varies within 7%. No monotonic correlation between the sensor response and the temperature is apparent. Good correlation between the water-equivalent midplane depth and the ratio of the exit MOSFET readout divided by the entrance MOSFET readout was found (the correlation coefficient is about 1). The MOSFET midplane dosimetry relevant to the anthropomorphic phantom irradiation is in agreement with TLD dosimetry within 5%. Ionization chamber and MOSFET midplane dosimetry in inhomogeneous phantoms are in agreement within 2%.Conclusion: MOSFET characteristics are suitable for the in vivo dosimetry relevant to 6-MV treatments, both in normal and TBI setup. The TBI midplane dosimetry using MOSFETs is valid also in the presence of the lung, which is the most critical organ, and allows verifying that calculation of the lung attenuator thicknesses based only on the density is not correct. Our MOSFET dosimetry system can be used also to determine the surface dose by using the water-equivalent depth and extrapolation methods. This procedure depends on the field size used.