British Journal of Radiology 74 (2001),1041-1047 © 2001 The British Institute of Radiology
Total body irradiation using a modified standing technique: a single institution 7 year experience
S V Harden, BCh, MRCP, FRCR,
D S Routsis, BSc, DCRT,
A R Geater, MA, MSc,
S J Thomas, MA, MSc,
P J Taylor, BSc, DCRT,
R E Marcus, BS, FRCP, FRCPath and
M V Williams, MD, FRCR, FRCP
Department of Clinical Oncology, Box 193, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
Correspondence: M V Williams
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Abstract
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We describe a simple standing technique for delivering total body irradiation (TBI) using large horizontal fields, made possible by the off-centre installation of a non-dedicated treatment unit in a pre-existing bunker. Patients are treated using anterior and posterior fields with customized lung compensators. This technique enables the dose to the lung to be accurately calculated and modified to avoid overdose and to minimize the risk of pneumonitis. From February 1991 to December 1997, 94 patients with a variety of haematological malignancies were given fractionated TBI using this technique prior to allogenic or autologous bone marrow transplantation. Patients received a total dose of 14.4 Gy given in eight fractions over 4 days, with at least 6 h between fractions. The prescribed dose to the lungs was reduced to 12 Gy in eight fractions. The technique was well tolerated, took less than 10 min to set up and did not disrupt the daily routine use of the machine. Doses to all measured points on the trunk and head were within ±6% of the prescribed dose. Doses to the lungs were within ±5% of the prescribed dose. There were no early respiratory deaths in the 37 autologous transplant patients. There were 10 (17%) respiratory deaths in the 57 allogeneic transplant patients, 3 of confirmed infectious aetiology.
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Introduction
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Over the last 30 years, total body irradiation (TBI) has become widely used in combination with chemotherapy in conditioning regimens for the treatment of haematological malignancies prior to bone marrow or peripheral blood stem cell transplantation (PBSCT). TBI contributes to the eradication of tumour cells, particularly from sanctuary sites, and also acts to cause severe immunosuppression allowing subsequent engraftment of the transplanted stem cells. TBI also causes toxicity to normal tissues. Short-term side effects include mucositis, dysphagia, diarrhoea, parotitis, erythema, pneumonitis, veno-occlusive disease and all the attendant risks of prolonged pancytopaenia. In the longer term, side effects include cataracts, reduced pituitary function, neurological sequelae, infertility and increased risk of second malignancy [1–4].
TBI was originally delivered as a single fraction. Toxicity was influenced by dose rate and total dose. The total dose was predominantly limited by fatal pulmonary toxicity from interstitial pneumonitis [5]. Fractionated and hyperfractionated TBI techniques were subsequently introduced to improve anti-leukaemic effect without further increasing toxicity, based on the radiobiological principles of preferential normal tissue repair with fractionation. A number of comparative series have suggested that the use of fractionated TBI can reduce toxicity without compromising outcome [6, 7]. There has been only one randomized controlled trial comparing single and fractionated TBI and, although there was a trend towards reduced interstitial pneumonitis in the fractionated group, this did not reach significance [8, 9]. Dose escalation studies for fractionated TBI show that fatal hepatic veno-occlusive disease and fatal interstitial pneumonitis are the main dose-limiting toxicities [10, 11].
There are many different techniques in use for the delivery of TBI [12]. Factors influencing choice of technique include dose homogeneity, accurate delivery, reproducibility, ease of set up and local constraints on field size, room size and whether a treatment unit can be dedicated for TBI or is also required for conventional radiotherapy.
Prior to 1991, patients in our institution were given TBI as a single 9.5 Gy fraction, at a dose rate of 7.5 cGy min-1 over a period of 2–6 h. The patient was treated supine using lateral fields. Thermoluminescent dosemeters (TLDs) were used to calculate dose received. Set up took a long time, requiring the use of bolus bags and careful positioning to achieve dose homogeneity. In particular, it was difficult to measure accurately the dose to the lungs. In view of these points, a new technique of delivering TBI was developed, which coincided with the installation of a new linear accelerator. The aim was to introduce a more simple technique with a rapid and easily reproducible set up, using anteroposterior (AP) fields to minimize separation distances and differences as well as to improve dose homogeneity. The use of AP fields would also allow accurate measurement of lung dose. Individualized lung compensators were designed to improve dose homogeneity and to allow dose adjustment to the lungs based on in vivo dosimetry. A fractionated TBI regimen of 14.4 Gy in eight fractions given over 4 days replaced the single fraction regimen, based on consensus opinion that fractionation can reduce toxicity (in particular pneumonitis) whilst preserving anti-leukaemic effect [8, 9, 13]. The (total) lung dose was reduced from 14.4 Gy to a total of 12 Gy in eight fractions using lead compensators, based on experience from Glasgow [14]. This paper describes the TBI technique and retrospectively reviews the outcome, engraftment, disease control and major pulmonary toxicities in 94 patients who were consecutively treated using this technique. A brief description of the technique has been reported previously [15].
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Materials and methods
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Patients
Between February 1991 and December 1997, 94 consecutive patients were treated with fractionated TBI as part of their conditioning for bone marrow transplantation or PBSCT. Patient details are shown in Table 1
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57 patients received allografts, 46 from sibling donors and 11 from matched unrelated donors. 37patients received autologous bone marrow transplants. In 76 patients, cyclophosphamide was used with the TBI as conditioning. Of the remaining patients, eight received etoposide, eight received melphalan and two received combination chemotherapy (cytarabine, cyclophosphamide and methotrexate x 1 and carmustine, etoposide and melphalan x 1).
Data on these patients were collected prospectively on a transplant database. This was supplemented by retrospective case notes review. The incidence of major pulmonary toxicity, days to engraftment and outcome were noted for each case.
Treatment unit
An Asea Brown Boveri LA20 linear accelerator (Baden, Switzerland) was installed in a large pre-existing bunker 7.33 m in width. The installation was off-centre, with the isocentre 3.00 m from one wall and 4.33 m from the other, giving a maximum focus-to-wall distance of 5.33 m. This meant that whilst the maximum field size at the isocentre was a 0.4 m x 0.4 m full square field, by making use of the off-centre installation a horizontal beam could produce a field size of 2.0 m x 2.0 m at 5 m. This field size could easily cover a standing patient at the wall. By angling the gantry 5° past the horizontal and rotating the collimators through 45°, it was possible to ensure that the patient's feet were encompassed in the radiation beam. The linear accelerator was used to produce beams of 16 MV X-rays (quality index 0.771) at a dose rate of 300 cGy min-1 at 1 m (isocentre) and 12 cGy min-1 at 5 m. The set-up is shown in Figure 1.
TBI technique
Patients were treated with anterior and posterior fields in a supported, standing position. A 2 cm PMMA (Perspex) screen was used to provide radiation build-up. Individualized lead lung compensators were designed and supported on the screen. Patients stood facing the machine for anterior fields and facing the wall for posterior fields, with their arms held by their sides. A bicycle saddle mounted on a height-adjustable support fixed to the wall was used to provide stability and lateral support. For the treatment, the patients wore simple unwired underwear to preserve dignity and modesty. A bolus bag containing paraffin jelly was wrapped round the anterior side of the neck to compensate for the decreased thickness of tissue in this part of the body. No other bolus or compensators were used. A photograph of a patient in the treatment position is shown in Figure 2.
The prescribed dose was 14.4 Gy given in eight fractions over 4 days, prescribed to the mean of the abdomen and hip mid-separation doses. Treatment was given twice daily with a minimum of 6 h between fractions [15, 16]
Lung compensators
During the planning stage, a mobile X-ray set placed at the position of the linear accelerator focus was used to take AP and posteroanterior (PA) films, covering the thoracic region, with the patient in the treatment position. The films were used to design lung compensators made from multiple layers of 0.5 mm lead sheet. The full extent of the lungs was outlined on the films. To allow for patient movement and for the attenuating effect of the heart and abdominal contents, a second outline was drawn skirting these structures, 8 mm within the first outline. These outlines were simply based on the planning radiographs and were not assessed from quantitative measurements of cardiac or abdominal dimensions. To simplify planning and treatment, the AP and PA films were overlaid by the physicist and a combined outline was obtained (see Figure 3). The inner line was used to define full thickness compensation (approximately 7 mm lead) and the outer line marked the limit of half thickness compensation (approximately 4.5 mm lead). Portal films were routinely obtained for the first fraction to evaluate the positioning of the compensators (see Figure 4).
Dosimetry
Absolute dosimetry was performed following the IPSM code of practice for high energy photon dosimetry [17]. Depth doses were measured in a water tank at a source-to-surface distance of 4.7 m. Tissue maximum ratios (TMRs) were calculated from measured depth doses using the method of Burns [18].
A standard number of monitor units were given for the first fraction of each patient's treatment, calculated from the results of dose measurements for previous patients. Doses were measured using TLDs during the first fraction. TLD measurements were made of the doses to the head, neck, abdomen, right hip, right ankle and four positions on the chest (superior and inferior for each lung). The TLDs were placed on the anterior and posterior surfaces of the patient under 1 cm wax build up. With the exception of the chest points, the TLDs remained in place for both the anterior and posterior fields, to give the sum of the entry and exit doses. For the chest measurements, separate dosemeters were used for the two fields, to give separate readings of entry and exit doses. The positions of the chest TLDs were determined from measurements taken from the planning films. Patient separations were measured at the TLD sites. The points of interest are shown in Figure 5.
At the points of interest, the ratio of the dose at mid-separation to the sum of the entry and exit doses was calculated. These ratios were calculated using TMRs and the measured separations. In the chest, an effective separation was calculated from the ratio of the entry dose to the exit dose. From these ratios and the TLD measurements, a set of mid-separation doses was calculated.
The doses measured on the first fraction were used to modify the monitor units for the remaining fractions and to modify the number of layers of lead required for the lung compensators. Typical compensators had 14 layers (7 mm) at the centre of the compensator, reducing to 9 layers (4.5 mm) at the edge of the compensator. Alterations to the lead of more than three layers were rare. The aim was to give a total dose of 14.4 Gy to the mean of the abdomen and hip and to give 12.0 Gy throughout the lungs. Further TLD measurements were made to confirm the modified values.
All TLD measurements were made using TLD chips, read using either a NE Rialto (NE, Beenham, UK) or a Vinten TOLEDO (Vinten, Sandy, UK). The doses were calibrated by irradiating standards with doses of close to 1 Gy and 2 Gy. Corrections were made for supralinearity. The dose to the standards was traceable to measurements made with ionization chambers following the IPSM code of practice for high energy photon dosimetry [17].
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Results
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Almost all the patients reported in this study were able to maintain the supported standing position for the duration of the treatment. For the small minority of patients who were unable to maintain this position, a similar technique was developed based on a kneeling chair (not described here).
This technique was quick to set up, usually less than 10 min. For a dose per fraction of 1.8 Gy, typical irradiation times were 7–8 min per beam. Each fraction therefore required a 25 min time slot. The total length of time needed on the linear accelerator per patient for a course of treatment, including planning time, was approximately 5 h.
Doses to all measured points on the trunk and head were within ±6% of the prescribed dose. Apart from the thoracic region surrounding the lungs, which received a total dose of 12 Gy, there were no sanctuary sites of low dose. Doses to the ankles and neck were higher than the prescribed dose. Typical values were 10% above prescription to the ankles and 5% above prescription to the neck. Doses to the lungs were within ±5% of the prescribed dose.
In 89 of 94 patients, TBI was given as planned in eight fractions over 4 days with no interruption in scheduling for acute toxicity or machine breakdown. Four patients were treated over 5 days owing to machine breakdown and one patient had a 3 day gap between the first and the remaining seven fractions owing to concomitant medical problems. Outcomes, median days to engraftment and pulmonary complications for allografts and autografts are shown in Table 2.
Most patients tolerated the treatment very well, with only minor problems during the eight fractions. The fractionated technique was felt to be better tolerated than the previously used single fraction semi-supine technique. Acute side effects included dysphagia, mucusitis, skin erythema, parotitis, diarrhoea, nausea, tiredness and lethargy.
In the 37 patients receiving autografts, there was only one treatment-related death, which was due to failure of engraftment. 15 patients remain alive and free from relapse. 5 patients have relapsed but are still alive and 16 patients have died from their disease.
In the 57 patients receiving allografts, there have been 28 deaths, 9 of these due to disease relapse or progression. 19 deaths were due to complications of the transplant process, which subdivide into 10 respiratory deaths, 2 cases of graft rejection, 3 deaths from graft-versus-host disease and 1 death from each of thrombotic thrombocytopaenic purpura, veno-occlusive disease and renal failure, systemic fungal sepsis, and neurological degeneration.
The 10 respiratory deaths all occurred in the first few months following transplantation. Eight cases had sibling donors and two had unrelated donors. Three had a confirmed infectious aetiology: one cytomegalovirus pneumonitis, one pneumocystis pneumoniae and one aspergillus infection. The remaining seven deaths were recorded as being due to pneumonia and/or pulmonary haemorrhage. Three of these cases were conditioned with melphalan and seven had been conditioned with cyclophosphamide. There were two documented cases of radiation pneumonitis, one of whom died of bilateral pulmonary haemorrhage shortly after the diagnosis of pnemonitis was made, and one who recovered from the pnemonitis but subsequently died 10 months post transplant from neurological degeneration. This patient had received an allograft from an unrelated donor and had had no other radiotherapy apart from TBI. No definitive cause for his deterioration was found on either MRI of the brain or analysis of cerebrospinal fluid. The follow-up for survivors ranged from 1 year to 8 years.
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Discussion
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TBI is routinely used as part of the conditioning for transplantation in patients with haematological malignancies. A balance needs to be struck between potentially fatal toxicities from normal tissue damage and the anti-tumour and immunosuppressive effects. In this series, we have treated 94 patients with fractionated TBI using a simple standing technique. The use of anterior and posterior fields to deliver the TBI allowed quick and reproducible set up. Set-up times were typically under 10 min, compared with our previous technique that took over 1 h. This means that the day-to-day treatment of routine radiotherapy patients is not disrupted. The use of AP fields rather than lateral fields also improved dose homogeneity and reduced separation distances and differences. Whilst use of a combination of fields can further improve dose homogeneity, we feel this straightforward technique achieves a good balance between quick set-up and treatment time and dose homogeneity [19]. Although this technique reduces radiographer and machine time, the use of lung compensators does entail more work for the mould room and physics department compared with our previous technique. However, the added work is relatively low volume and allows accurate measurement and adjustment of lung dose.
The relapse and disease progression figures for our patients are similar to those in other series. Shielding the lungs to receive a dose of 12 Gy did not appear to adversely affect control of disease, an observation also noted in other series [13, 20, 21]. However, since 1998, the lung dose has been increased to 14.4 Gy in accordance with national treatment protocols. However, lung compensators are still used to improve dose homogeneity across the lungs and to allow adjustments to be made depending on in vivo dosimetry.
The incidence of respiratory deaths and pneumonitis in the allogenic transplant group is low using this technique at our centre. There were no cases of pneumonitis in the autograft group. These results compare well with other series [13, 22, 23]. In the first few weeks, particularly after allogenic transplantation, there are often multiple factors contributing to respiratory symptoms, including infections, pancytopaenia and radiation pneumonitis. Graft-versus-host disease is also implicated in the severity of pneumonitis [24]. However, in our series there was no significant difference in the proportion of respiratory deaths between those patients with a sibling donor (8/46) and those with unrelated donors (2/11). There were only 2 documented cases of radiation pneumonitis out of the 57 patients who underwent allografting, although radiation cannot be easily excluded as a contributory factor in the 9 other documented respiratory deaths. It is interesting to note that of the nine patients conditioned with melphalan and TBI prior to allografting, three died from respiratory complications. However, the numbers are too small to comment further.
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Conclusion
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This standing TBI technique using a non-dedicated treatment unit installed off-centre is simple to set up, well tolerated by patients, easily and efficiently incorporated into the routine workload of our radiotherapy department, and allows accurate measurement of lung dose. In the first 94 patients treated with this technique, we have seen a low incidence of major pulmonary complications and no compromise of disease control rates.
Received for publication March 21, 2000.
Revision received March 16, 2001.
Accepted for publication June 4, 2001.
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References
|
|---|
-
Fife K, Milan S, Westbrook K, Powles R, Tait D. Risk factors for requiring cataract surgery following total body irradiation. Radiother Oncol 1994;33:93–8.[Medline]
-
Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, Travis LB, et al. Solid cancers after bone marrow transplantation [see comments]. N Engl J Med 1997;336:897–904.[Abstract/Free Full Text]
-
Sullivan KM, Mori M, Sanders J, Siadak M, Witherspoon RP, Anasetti C, et al. Late complications of allogeneic and autologous marrow transplantation. Bone Marrow Transplant 1992;10(Suppl. 1):127–34.
-
Benyunes MC, Sullivan KM, Deeg HJ, Mori M, Meyer W, Fisher L, et al. Cataracts after bone marrow transplantation: long-term follow-up of adults treated with fractionated total body irradiation. Int J Radiat Oncol Biol Phys 1995;32:661–70.[Medline]
-
Thomas ED, Buckner CD, Banaji M, Clift RA, Fefer A, Flournoy N, et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 1977;49:511–33.[Abstract/Free Full Text]
-
Cosset JM, Socie G, Dubray B, Girinsky T, Fourquet A, Gluckman E. Single dose versus fractionated total body irradiation before bone marrow transplantation: radiobiological and clinical considerations. Int J Radiat Oncol Biol Phys 1994;30:477–92.[Medline]
-
Shank B, Chu FC, Dinsmore R, Kapoor N, Kirkpatrick D, Teitelbaum H, et al. Hyperfractionated total body irradiation for bone marrow transplantation. Results in seventy leukemia patients with allogeneic transplants. Int J Radiat Oncol Biol Phys 1983;9:1607–11.[Medline]
-
Thomas ED, Clift RA, Hersman J, Sanders JE, Stewart P, Buckner CD, et al. Marrow transplantation for acute nonlymphoblastic leukemic in first remission using fractionated or single-dose irradiation. Int J Radiat Oncol Biol Phys 1982;8:817–21.[Medline]
-
Deeg HJ, Sullivan KM, Buckner CD, Storb R, Appelbaum FR, Clift RA, 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 1986;1:151–7.[Medline]
-
Petersen FB, Deeg HJ, Buckner CD, Appelbaum FR, Storb R, Clift RA, et al. Marrow transplantation following escalating doses of fractionated total body irradiation and cyclophosphamide—a phase I trial. Int J Radiat Oncol Biol Phys 1992;23:1027–32.[Medline]
-
Demirer T, Petersen FB, Appelbaum FR, Barnett TA, Sanders J, Deeg HJ, et al. Allogeneic marrow transplantation following cyclophosphamide and escalating doses of hyperfractionated total body irradiation in patients with advanced lymphoid malignancies: a Phase I/II trial. Int J Radiat Oncol Biol Phys 1995;32:1103–9.[Medline]
-
Quast U. Total body irradiation—review of treatment techniques in Europe. Radiother Oncol 1987;9:91–106.[Medline]
-
Lohr F, Wenz F, Schraube P, Flentje M, Haas R, Zierhut D, et al. Lethal pulmonary toxicity after autologous bone marrow transplantation/peripheral blood stem cell transplantation for hematological malignancies. Radiother Oncol 1998;48:45–51.[Medline]
-
Tait RC, Burnett AK, Robertson AG, McNee S, Riyami BM, Carter R, et al. Subclinical pulmonary function defects following autologous and allogeneic bone marrow transplantation: relationship to total body irradiation and graft-versus-host disease. Int J Radiat Oncol Biol Phys 1991;20:1219–27.[Medline]
-
Geater A, Williams MV. Addenbrooke's total body irradiation technique. In: Proceedings of the British Institute of Radiology: Total Body Irradiation; 1996 Nov 28; London: Br J Radiol 1997;70:1309–13.
-
Doughty D, Lambert GD, Hirst A, Marks AM, Plowman PN. Improved total-body irradiation dosimetry. Br J Radiol 1987;60:269–78.[Abstract]
-
IPSM. Code of Practice for high energy photon dosimetry based on the NPL absorbed dose calibration service. Phys Med Biol 1990;35:1355–60.
-
Burns JE. Conversion of PDD for photon beams from one SSD to another and calculation of TAR,TMR and TPR. Br J Radiol 1996;(Suppl. 25):153–7.
-
Lawrence G, Rosenbloom ME, Hickling P. A technique for total body irradiation in the treatment of patients with acute leukaemia. Br J Radiol 1980;53:894–7.[Medline]
-
Altschuler C, Resbeut M, Maraninchi D, Guillet JP, Blaise D, Stoppa AM, et al. Fractionated total body irradiation and allogeneic bone marrow transplantation for standard risk leukemia. Radiother Oncol 1989;16:289–95.[Medline]
-
Labar B, Bogdanic V, Nemet D, Mrsic M, Vrtar M, Grgic-Markulin L, et al. Total body irradiation with or without lung shielding for allogeneic bone marrow transplantation. Bone Marrow Transplant 1992;9:343–7.[Medline]
-
Goolden AW, Goldman JM, Kam KC, Dunn PA, Baughan AS, McCarthy DM, et al. Fractionation of whole body irradiation before bone marrow transplantation for patients with leukaemia. Br J Radiol 1983;56:245–50.[Abstract]
-
Ozsahin M, Belkacemi Y, Pene F, Laporte J-P, Rio B, Lebond V, et al. Interstitial pneumonitis following autologous bone-marrow transplantation conditioned with cyclophosphamide and total-body irradiation. Int J Radiat Oncol Biol Phys 1996;34:71–7.[Medline]
-
Latini P, Aristei C, Aversa F, Checcaglini F, Maranzano E, Raymondi C, et al. Lung damage following bone marrow transplantation after hyperfractionated total body irradiation. Radiother Oncol 1991;22:127–32.[Medline]
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Abstract
Introduction
