Extreme heterogeneity of myeloablative total body irradiation techniques in clinical practice: A survey of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Authors

  • Sebastian Giebel MD,

    Corresponding author
    1. Department of Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
    • Corresponding author: Sebastian Giebel, MD, Department of Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Str. Wybrzeze Armii Krajowej 15, Poland; Fax: (011) 48-322789149; sgiebel@io.gliwice.pl

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  • Leszek Miszczyk MD,

    1. Department of Radiotherapy, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
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  • Krzysztof Slosarek MD,

    1. Department of Radiotherapy and Brachytherapy Planning, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
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  • Leila Moukhtari,

    1. European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Office, Saint-Antoine Hospital, Paris, France
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  • Fabio Ciceri MD,

    1. Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Italy
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  • Jordi Esteve MD,

    1. Hematology Department, IDIBAPS, Hospital Clinic, Barcelona, Spain
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  • Norbert-Claude Gorin MD,

    1. European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Office, Saint-Antoine Hospital, Paris, France
    2. Clinical Hematology and Cellular Therapy Department, Saint-Antoine Hospital, Public Hospital System, Paris, France
    3. Pierre and Marie Curie University, Paris, France
    4. INSERM UMRS 938, Paris, France
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  • Myriam Labopin MD,

    1. European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Office, Saint-Antoine Hospital, Paris, France
    2. Clinical Hematology and Cellular Therapy Department, Saint-Antoine Hospital, Public Hospital System, Paris, France
    3. Pierre and Marie Curie University, Paris, France
    4. INSERM UMRS 938, Paris, France
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  • Arnon Nagler MD,

    1. Division of Hematology, Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel
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  • Christoph Schmid MD,

    1. Department of Hematology and Oncology, Augsburg Clinic, Ludwing-Maximilinas University Munich, Augsburg, Germany
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  • Mohamad Mohty MD

    1. European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Office, Saint-Antoine Hospital, Paris, France
    2. Clinical Hematology and Cellular Therapy Department, Saint-Antoine Hospital, Public Hospital System, Paris, France
    3. Pierre and Marie Curie University, Paris, France
    4. INSERM UMRS 938, Paris, France
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  • The participation of the following European Group for Blood and Marrow Transplantation (EBMT) centers is kindly acknowledged: CIC 160, Necker Hospital, Paris, France; CIC 726, University of Liege, Liege, Belgium; CIC 810, University of Freiburg, Freiburg, Germany; CIC 183, National Center of Bone Marrow Transplant, Tunis, Tunisia; CIC 202, University Hospital, Basel, Switzerland; CIC 751, St. Savas Oncology Hospital, Athens, Greece; CIC 428, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland; CIC 859, National Hospital of Hematological Diseases, Sofia, Bulgaria; CIC 323, University Hospital Virgen de la Arrixaca, Murcia, Spain; CIC 544, San Gerardo Hospital, Monza, Italy; CIC 208, University Hospital, Zurich, Switzerland; CIC 206, Rigshospitalet, Copenhagen, Denmark; CIC 682, University of Pecs, Pecs, Hungary; CIC 727, Lnico Hospital, Salamanca, Spain; CIC 259, University Hospital, Essen, Germany; CIC 728, Puerta de Hierro University Hospital, Madrid, Spain; CIC 240, Bologna University, Bologna, Italy; CIC 926, CHU Lapeyronie, Montpellier, France; CIC 283, University Hospital, Lund, Sweden; CIC 576, Carlos Haya Hospital, Malaga, Spain; CIC 546, University Medical Center Groningen, Groningen, the Netherlands; CIC 755, Schneider Children's Medical Center of Israel, Petach-Tikva, Israel; CIC 237, Radboud University-Nijmegen Medical Centre, Nijmegen, the Netherlands; CIC 749, Oldenburg Clinic, Oldenburg, Germany; CIC 661, Rennes University Medical Center, Rennes, France; CIC 640, University Medical Center, Ljubljana, Slovenia; CIC 996, Antwerp University Hospital, Antwerp, Belgium; CIC 244, West of Scotland Cancer Centre, Glasgow, Scotland, United Kingdom; CIC 625, Nurnberg Clinic, Nurnberg, Germany; CIC 295, Hannover Medical School, Hannover, Germany; CIC 710, RP Group, Royal Perth Hospital, Perth, Western Australia, Australia; CIC 754, Chaim Sheba Medical Center, Tel-Hashomer, Israel; CIC 266, University Hospital, Uppsala, Sweden; CIC 672, Hautepierre Hospital, Strasbourg, France; Paul Strauss Center, Strasbourg, France; CIC 241, Leon Berard Center, Lyon, France; CIC 169, Gazi Universitesi Tip Fakültesi Hastanesi, Ankara, Turkey; CIC 152, Augsburg Clinic, Augsburg, Germany; CIC 613, Germans Trias i Pujol University Hospital, Barcelona, Spain; CIC 659, CHU Morvan, Brest, France; CIC 246, Erasmus Medical Center-Daniel den Hoed Cancer Centre, Rotterdam, the Netherlands; CIC 257, St James Hospital, Trinity College, Dublin, Ireland; CIC 242, Marques de Valdecilla University Hospital, Santander, Spain; CIC 265, Maggiore di Milano Hospital, Milan, Italy; CIC 813, San Raffaele Scientific Institute, Milan, Italy; CIC 432, Henri-Mondor Hospital, Creteil, France; CIC 397, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; CIC 232, La Sapienza University, Rome, Italy; CIC 227, Wien Medical University, Vienna, Austria; CIC 260, Santa Creu i Sant Pau Hospital, Barcelona, Spain; CIC 658, Riuniti di Bergamo Hospital, Bergamo, Italy; CIC 646, Heilig Hartziekenhuis, Roeselare, Belgium; CIC 217, San Martino Hospital, Genoa, Italy; CIC 261, University Hospital of Geneva, Geneva, Switzerland; CIC 409, Beilinson Hospital, Petach-Tikva, Israel; CIC 302, University Hospital Center Rebro, Zagreb, Croatia; CIC 800, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; CIC 505, Pediatric Clinic/Outpatient Department, Department of Radiotherapy-Radiooncology, Munster, Germany.

Abstract

BACKGROUND

Total body irradiation (TBI) is widely used for conditioning before hematopoietic cell transplantation. Its efficacy and toxicity may depend on many methodological aspects. The goal of the current study was to explore current clinical practice in this field.

METHODS

A questionnaire was sent to all centers collaborating in the European Group for Blood and Marrow Transplantation and included 19 questions regarding various aspects of TBI. A total of 56 centers from 23 countries responded.

RESULTS

All centers differed with regard to at least 1 answer. The total maximum dose of TBI used for myeloablative transplantation ranged from 8 grays (Gy) to 14.4 Gy, whereas the dose per fraction was 1.65 Gy to 8 Gy. A total of 16 dose/fractionation modalities were identified. The dose rate ranged from 2.25 centigrays to 37.5 centigrays per minute. The treatment unit was linear accelerator (LINAC) (91%) or cobalt unit (9%). Beams (photons) used for LINAC were reported to range from 6 to 25 megavolts. The most frequent technique used for irradiation was “patient in 1 field,” in which 2 fields and 2 patient positions per fraction are used (64%). In 41% of centers, patients were immobilized during TBI. Approximately 93% of centers used in vivo dosimetry with accepted discrepancies between the planned and measured doses of 1.5% to 10%. In 84% of centers, the lungs were shielded during irradiation. The maximum accepted dose for the lungs was 6 Gy to 14.4 Gy.

CONCLUSIONS

TBI is an extremely heterogeneous treatment modality. The findings of the current study should warrant caution in the interpretation of clinical studies involving TBI. Further investigation is needed to evaluate how methodological differences influence outcome. Efforts to standardize the method should be considered. Cancer 2014;120:2760–2765. © 2014 American Cancer Society.

INTRODUCTION

Allogeneic and autologous hematopoietic stem cell transplantation (HSCT) is widely used for the treatment of many myeloid and lymphoid malignancies. Transplantation is preceded by the administration of a conditioning regimen with the objective of eliminating malignant cells and, in the case of allogeneic HSCT, preventing graft rejection. Conditioning may include either total body irradiation (TBI), usually administered in combination with chemotherapy, or chemotherapy alone. The choice of the regimen depends on disease type as well as recipient and donor characteristics.

Historically, the combination of TBI (12 grays [Gy]) with cyclophosphamide was the most frequently used conditioning regimen.[1, 2] The antineoplastic effect of TBI was documented as dose-dependent with fewer instances of leukemia recurrence after escalated dose treatment.[3, 4] In the 1980s, a radiation-free regimen (ie oral busulfan combined with cyclophosphamide) was developed for patients with leukemia.[5, 6] However, prospective and retrospective comparisons suggested TBI was a preferable option in this setting.[7] The advantages of TBI over high-dose chemotherapy include: 1) no sparing of “sanctuary” sites such as the testicles and the central nervous system; 2) high-dose homogeneity to the whole body regardless of blood supply; 3) less possibility of cross-resistance with other antineoplastic agents; 4) no problems with excretion or detoxification; and 5) the ability to tailor the dose distribution by either shielding or “boosting” sites of interest.

Unfortunately, TBI is also associated with the risk of significant adverse effects. Early, usually reversible, postradiation effects include mucositis, nausea, vomiting, loss of appetite, diarrhea, headache, fatigue, and parotits.[8] Late effects such as interstitial pneumonitis, renal dysfunction, cataracts, infertility, hypothyroidism, growth retardation in children, and secondary malignancies may be long-lasting or irreversible and may affect the patient's lifespan and the quality of life.[9-11] The incidence of nonrecurrence mortality increases with increased doses of TBI.[3, 4]

Although the delivery of chemotherapy is relatively easy and uniform, applying TBI has many technical and procedural requirements which in turn may be the cause of the significant diversity of the treatment options. Potential heterogeneity may affect the doses used for myeloablative TBI, the method of fractionation, the modes of delivering the dose, the type of immobilization, the methods of dosimetry, and organ shielding. To our knowledge to date, few attempts have been made to standardize the methodology. Reports of clinical studies usually provide only general information regarding the total dose and the number of TBI fractions, whereas all other variables remain unknown. To the best of our knowledge, there are no data to date reflecting current practice in the field of TBI techniques. Because methodological differences may influence both the efficacy and safety of the therapy, a detailed description of the current status across centers and countries appears essential. The goal of the current study was to explore this area of clinical practice. For this purpose, the European Group for Blood and Marrow Transplantation (EBMT) designed and performed a survey among its member centers.

MATERIALS AND METHODS

The survey was performed from February to July 2013. The questionnaire included 19 questions regarding various aspects of TBI methodology. We focused solely on high-dose regimens used in adults and considered myeloablative therapy according to the responder's evaluation. All 205 EBMT transplant centers known to use TBI were approached, 57 of which responded (28% return). Because 2 responding transplant centers collaborated with the same radiotherapy department, the responses actually reflected clinical practice in 56 TBI centers. The centers were located in 23 countries, including 19 European countries as well as Australia, Israel, Saudi Arabia, and Tunisia (of 32 countries approached; 72% return rate).

Data were collected by the Acute Leukemia Working Party of the EBMT in Paris, France and analyzed in the Maria Sklodowska-Curie Memorial Cancer and Institute of Oncology in Gliwice, Poland.

RESULTS

Dose and Fractionation of Myeloablative TBI

All centers differed with regard to at least 1 of the methodological aspects of TBI.

The total dose of TBI used for myeloablative transplantation was reported to range from 8 Gy to 14.4 Gy. The number of fractions ranged from 1 to 8, whereas the dose per fraction was between 1.65 Gy and 8 Gy. A total of 14 dose/fractionation modalities were identified, with 6 fractions of 2 Gy each found to be the most frequent modality used (n = 36; 64%). The treatment duration was reported to be between 1 day and 6 days. Detailed results are presented in Figure 1.

Figure 1.

Dose and fractionation of myeloablative total body irradiation are shown. A total of 12 grays (Gy) in 6 fractions was found to be the most frequently used modality (41 centers). It was administered in 3 days (2 fractions per day) in all but 1 center, in which the treatment duration was 6 days (1 fraction per day). A total of 12 Gy in 2 fractions for 2 days was reported by 2 centers as well as a dose of 13.2 Gy in 8 fractions administered for 4 days. Other options are represented by single centers.

The dose rate in the axis of the beam ranged from 2.25 centigrays to 37.5 centigrays per minute, with large variety noted among the centers. A total of 36 modalities were recognized, with 16 centigrays per minute being most frequently used (3 of 46 responding centers; 6.5%). Combining total dose, fractionation, and dose rate, 40 variants were reported. Five combinations used in at least 2 centers are listed in Table 1.

Table 1. The Most Frequent Combinations of the Total Dose, Number of Fractions, and Dose Rate of TBIa
Total Dose, GyNo. of Fractions (Dose per Fraction, Gy)Dose Rate in the Axis of the Beam, cGy/MinuteNo. of Centers (%)
  1. Abbreviations: cGy, centigrays; Gy, grays, TBI, total body irradiation.

  2. a

    All other modalities were represented by single centers.

126 (2)163 (5.4)
126 (2)82 (3.6)
126 (2)112 (3.6)
126 (2)10-152 (3.6)
126 (2)20-302 (3.6)

Treatment Unit

A total of 51 centers (91.1%) used linear accelerator (LINAC) as a treatment unit, whereas the remaining 5 centers (8.9%) use cobalt unit. In addition, 2 centers reported using helical tomotherapy unit as an alternative to regular LINAC. Beams (photons) used for LINAC were 6 to 25 megavolts (MV). Nine various modalities of beam energy were recognized, among which 6 MV was the most frequent (26 centers; 51%).

Treatment Technique

Although the most frequent technique used for irradiation was found to be “patient in 1 field” with 2 fields per fraction and 2 patient positions per fraction (36 of 56 centers; 64%), a total of 11 modalities were described with regard to the technique, number of fields, and positions per fraction (Table 2). The source-to-surface distance was reported to range from 2 to 5 m (most frequently 4 meters, which was reported in 10 centers; 18%). In 23 centers (41%), the patients were immobilized during TBI. Nine different types of device were reported to be used for immobilization, most frequently vacuum (6 centers) or thermoplastic (3 centers). The irradiation time was reported to be calculated directly using a homemade device (38 of 53 centers responding to this question; 71.7%) or using a commercial treatment planning system (15 centers; 28.3%).

Table 2. Treatment Technique
TechniqueNo. of Fields per FractionNo. of Patient Positions per FractionNo. of Centers (%)
  1. Abbreviation: SSD, source-to-surface distance.

  2. a

    A combination of “patient in 1 field” (4 fractions; 2 fields per fraction and 2 patient positions per fraction) followed by “segmented fields” (2 fractions; 6 fields per fraction and 1 patient position per fraction).

Patient in 1 field2236 (64.3)
 445 (8.9)
Multiple isocenters6 (10.7)
Moving strips2 (3.6)
Segmented fields1221 (1.8)
SSD (3 parts)621 (1.8)
Sweeping beam1021 (1.8)
Moving couch221 (1.8)
Patient in 1, 2, or 3 fields2-621 (1.8)
Patient sitting (A) or laying (B)(A) −1(B) −2(A) −1(B) −21 (1.8)
Individual approacha1 (1.8)

Dosimetry

The delivered radiation dose was measured in 52 centers (92.9%). For this purpose, 5 types of detectors for in vivo dosimetry were used including semiconductors (37 centers; 71.2%), thermoluminescent dosimeters (8 centers; 15.4%), metal oxide semiconductor field effect transistor (4 centers; 7.7%), ionization chambers (2 centers; 3.8%), and alanine dosimeters (1 center; 1.9%). The accepted discrepancy between the planned and measured entrance doses varied from 1.5% to 10%, with a median of 5%.

Organ Shielding

The maximum accepted total delivered dose for the lungs was reported to range from 6 Gy to 14.4 Gy. A dose of 8 Gy was reported most frequently (12 centers; 21.4%) but a total of 18 various options have been reported. Lung density was reported to be considered for treatment planning in 43 centers (79.6% of the 54 centers that responded to this question).

In 47 centers (84%), the lungs were shielded during irradiation. The position of the lung shield was reportedly verified before each fraction in 44 centers (97.8% of the 45 responding centers). Chest wall compensation was reported to be performed in 10 of 47 centers (21.3%) using either electrons (6 centers; 12.8%), photons (3 centers; 6.4%), or both (1 center; 2.1%).

In addition, in some centers the lenses, thyroid gland, larynx, kidneys, and/or salivary glands were reportedly shielded (Table 3). In those centers, the maximum accepted total delivered dose was reported to be 6 Gy to 11 Gy for lenses, 12.5 Gy for the thyroid gland, 10 Gy for the larynx, and 4.25 Gy to 12 Gy for the kidneys.

Table 3. Organs Routinely Shielded During TBI
OrganNo. of Centers
  1. Abbreviation: TBI, total body irradiation.

Lungs33 (58.9%)
Lungs + lenses6 (10.7%)
Lungs + thyroid gland3 (5.4%)
Lungs + larynx2 (3.6%)
Lungs + kidneys2 (3.6%)
Lungs + lenses + salivary glands + thyroid gland1 (1.8%)
Lenses1 (1.8%)
None8 (14.3%)

DISCUSSION

TBI was introduced for conditioning before HSCT in the late 1950s by the Seattle group.[12] At that time, it was delivered using cobalt-60 unit with 2 opposite fields, and initially the dose was approximately 10 Gy applied as a single fraction.[1, 2] Gradually, the Cobalt units have been substituted by regular LINACs and the doses have become fractionated. The treatment techniques evolved as well, leading to a high variety of treatment options as documented by Quast based on a European survey in 1987.13 Since that time, the issue has not been systematically approached. German and more recently American groups of experts published guidelines on the use of TBI.[14, 15] However, these guidelines provided only general requirements and expressed preconditions for TBI while not specifying detailed methodological recommendations. Furthermore, they did not reflect the real clinical practice, which, in turn, was the scope of our analysis disclosing the extreme heterogeneity of TBI across centers and countries. In fact, we could not identify any pair of centers performing TBI in exactly the same way. The heterogeneity affected all methodological aspects.

The TBI doses used for conditioning reported in the literature range from 2 Gy to 15.75 Gy.[16] Lower doses were introduced in the late 1990s, considered to be reduced-intensity conditioning, and allowed for durable engraftment with various antitumor activity. Due to the high diversity of this relatively new approach, we decided to focus solely on high-dose regimens, asking centers for the maximum dosage and respective fractionation they used in the case of myeloablative conditioning. Even then, however, the answers were very inconsistent across the entire survey from total dose, the number of fractions, and the dose per fraction. There was further diversity with regard to the dose rates. In the current survey we identified 40 various combinations of the total dose, fractionation, and dose rate.

The optimal TBI dosage and fractionation have been the subject of many debates, but to our knowledge only 4 randomized studies have been performed to date to address this issue.[17] Clift et al conducted 2 trials among patients with acute myeloid leukemia and chronic myeloid leukemia, comparing a dose of 12 Gy of TBI with dose-escalated 15.75 Gy TBI.[3, 4] In both cases, higher doses were found to be associated with a reduced risk of disease recurrence, although this finding was counterbalanced by a higher incidence of severe or fatal toxicities involving mainly the liver, lungs, and mucosa. Therefore, no effect on the overall survival could be demonstrated. Thomas et al compared a 10-Gy single dose with 12 Gy delivered in 6 fractions.[18] Despite the low number of patients (27 patients and 26 patients, respectively), reduced toxicity in the fractionation arm could be demonstrated without a negative effect noted on the recurrence rate. Long-term follow-up analysis suggested a survival advantage for fractionated TBI.[19] In a study by Girinsky et al, a 10-Gy single dose was compared with 14.75 Gy of fractionated TBI among 147 patients with various hematologic malignancies.[20] Cause-specific survival was found to be significantly higher whereas the incidence of venoocclusive disease of the liver was found to be reduced in the fractionated arm. Altogether it was concluded that dose escalation above 12 Gy does not provide an apparent survival benefit whereas fractionation results in reduced toxicity while preserving the antileukemic effect. The safety and efficacy of TBI may be affected further by the dose rate. Although in a randomized trial comparing “high” and “low” dose rates no effect on outcome could be demonstrated,[21] in a retrospective analysis the dose rate was found to be an independent factor influencing the incidence of renal toxicity.[22] In view of the above observations, it must be assumed that heterogeneity regarding total dose, fractionation, and dose rate as identified in the current survey may influence both the antileukemic activity and tolerance of the procedure and may affect the overall outcome.

Although regular LINACs are predominantly used for TBI, as demonstrated in the current survey, the beam energy varies significantly. In a retrospective analysis by Thomas et al, a dose of 15 MV was associated with a higher risk of pulmonary complications compared with a dose of 9 MV.[23] However, to the best of our knowledge, the effect of beam energy (used voltage) on general and specific outcomes has not been extensively studied. In addition, there was no direct comparison of TBI based on regular LINACs with cobalt units, with the latter still being used in several centers in Europe. Two centers reported helical tomotherapy as an alternative to regular LINAC. This option is postulated to allow for better control over dose distribution and homogeneity.[24] It also provides an opportunity to individually spare organs at risk. Further investigation is needed to establish its possible effect on the rate of disease recurrence and nonrecurrence mortality.

The majority of centers use the “patient-in-1-field” technique, with 2 fields and 2 patient positions per fraction. However, 10 other modalities were reported, most likely resulting from the individual experience of the respective centers. Some retrospective analyses demonstrated that patient position may influence toxicity, with a higher rate of pulmonary complications noted among patients treated in the prone and supine positions versus those treated in the lateral position.[23] However, the effect of the treatment technique on outcome requires further investigation. It is interesting to note that in less than one-half of the centers, patients were immobilized during irradiation and various types of devices were used for this purpose. It may be assumed that this diversity influences the precision of the dose delivery.

According to the guidelines published by the American College of Radiology and American Society for Radiation Oncology, in vivo dosimetry should be used to assess dose homogeneity and every effort should be made to maintain dose inhomogeneity within ± 10%.[15] The dosimetry should also be checked against department protocols to verify dose delivery. According to the current survey, not all centers reported using the in vivo dosimetry. Furthermore, dosimetry techniques as well as accepted discrepancies between planned and delivered doses vary strongly. To the best of our knowledge, the possible impact of dosimetry on outcome has not been studied to date in the case of TBI. However, data from other fields of radiotherapy have suggested its relevance also among recipients of HSCT.[25]

Several organs are particularly susceptible to TBI-related toxicities, providing the rationale for reducing the dose by appropriate shielding. Results of retrospective analyses have indicated that lung shielding reduces the risk of pulmonary dysfunction and, among patients with poor preirradiation functional parameters, may improve survival.[26, 27] According to our analysis, 16% of centers do not use lung shielding, 20% do not consider lung density for treatment planning, and the accepted dose for lungs varies strongly.

The frequency of late ocular complications reported in the literature is up to 30% for fractionated TBI and 80% for single-dose TBI.[23, 28] There is evidence from a randomized trial that a reduction in the irradiation dose to the lenses may reduce the risk of cataracts.[29] Despite this finding, the results of the current survey indicated that only 14% of centers reported shielding lenses during TBI. Shielding of other critical organs such as the kidneys, thyroid glands, or salivary glands is applied by single centers.

Conclusions

The results of the current survey indicate that, in contrast to myeloablative chemotherapy, for which the application is rather uniform, the delivery of TBI varies strongly among centers, with potential implications for both the efficacy and safety of the procedure. In view of these findings, the interpretation of any prospective or retrospective multicenter studies comparing TBI-based and chemotherapy-based protocols appears problematic because these protocols usually rely on a mixture of TBI modalities according to individual center preferences. The potential bias is difficult to estimate because methodological aspects of TBI are rarely reported. Furthermore, because TBI techniques apparently evolve, conclusions from studies performed in the past may not necessarily be correct at the current date. Hence, the findings of the current study should warrant caution in the interpretation of clinical studies involving TBI.

Most of the questions regarding the influence of the methodological aspects of TBI on outcome remain unanswered. To the best of our knowledge, few prospective studies have been performed to date, and those that were included relatively small populations and were performed mostly > 20 years ago. Because it is difficult to design multicenter randomized trials focused on TBI techniques, every effort should be made to perform large retrospective studies addressing these issues. The results of the current survey may be useful for the planning of such analyses because we were able to identify the areas of particular heterogeneity. Finally, based on the results of postulated retrospective analyses, attempts should be made to standardize the method to further improve results of the treatment.

FUNDING SUPPORT

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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