Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: A review

Critical Reviews in Oncology / Hematology 123 (2018) 138–148

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Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: A review

T

Adrien Paixa, Delphine Antonia,b, Waisse Waissia,b, Marie-Pierre Ledouxc, Karin Bilgerc, ⁎ Luc Forneckerc, Georges Noela,b, a

Radiation Oncology Department, Centre Paul Strauss 3 rue de la Porte de l’hôpital, 67065, Strasbourg Cedex, France Radiobiology Laboratory, EA3430, Strasbourg University, 3 rue de la Porte de l’hôpital, 67000, Strasbourg, France c Hematology Department, CHU Hautepierre, 1, rue Molière, 67000, Strasbourg, France b

A R T I C L E I N F O

A B S T R A C T

Keywords: Bone marrow transplantation Total body irradiation IMRT Tomotherapy

Hematologic malignancies may require, at one point during their treatment, allogeneic bone marrow transplantation. Total body irradiation combined with chemotherapy or radiomimetic used in allogeneic bone marrow transplantation is known to be very toxic. Total body irradiation (TBI) induces immunosuppression to prevent the rejection of donor marrow. TBI is also used to eradicate malignant cells and is in sanctuary organs that are not reached by chemotherapy drugs. TBI has evolved since its introduction in the late fifties, but acute and late toxicities remain. Helical tomotherapy, which is widely used for some solid tumors, is a path for the improvement of outcomes and toxicities in TBI because of its sparing capacities. In this article, we first review the practical aspects of TBI with patient positioning, radiobiological considerations and total dose and fractionation prescriptions. Second, we review the use of intensity modulated radiation therapy in bone marrow transplantation with a focus on helical tomotherapy TBI, helical tomotherapy total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) and their dosimetric and clinical outcomes. Finally, we review the perspective of dose escalation and the extension to older patients and patients with comorbidity who do not benefit from a standard bone marrow transplantation conditioning regimen.

1. Introduction Radiotherapy in bone marrow transplantation conditioning regimens was introduced in the late fifties by Nobel Prize Laureate E.D. Thomas (Ferrebee and Thomas, 1958). Since that time, total body irradiation (TBI) has been widely used in bone marrow transplantation. TBI induces immunosuppression to prevent the rejection of donor marrow. TBI aims to eradicate malignant cells in the same area that chemotherapy does (Bortin et al., 1992; Vriesendorp et al., 1991) and in sanctuary organs that are not reached by chemotherapy drugs, which are mainly the brain and testes. TBI is an important part of conditioning regimens for bone marrow transplantation for hematological malignancies. Regimens containing TBI seem to achieve better outcomes than regimens not containing TBI (Hartman et al., 1998; Blaise et al., 2001; Dusenbery et al., 1995; Michel et al., 1994; Bunin et al., 2003; Clift et al., 1998; Ringden et al., 1994). Even though TBI is an efficient part of bone marrow transplantation conditioning treatment, it is responsible for many side effects. The acute

⁎

toxicities include nausea, vomiting, diarrhea, stomatitis, temporary loss of taste, parotitis and rash. The late toxicities include interstitial pneumonitis (IP), hepatic veno-occlusive disease (VOD), cataracts, infertility, hormone-related disorders, bone toxicity (osteoporosis), growth retardation and secondary malignancies (Bolling et al., 2011; Van Dyk et al., 1981; Blaise et al., 1992; Leiper, 1995; Shank, 1996; Ringden et al., 1999; Socie et al., 2001; Della Volpe et al., 2002; Schenken and Hagemann, 1975; Thomas et al., 1993; Curtis et al., 1997; Hasegawa et al., 2005). In this article, we review the literature about TBI techniques in bone marrow transplantation, from two-dimensional to intensity modulated radiotherapy (IMRT) techniques. 2. Total body irradiation 60 C and linear accelerator based techniques were the first techniques of TBI that were described, and they are still widely used (Giebel et al., 2014).

Corresponding author at: Radiation Oncology Department, Centre Paul Strauss 3 rue de la Porte de l’hôpital, 67065, Strasbourg Cedex, France. E-mail address: [email protected] (G. Noel).

https://doi.org/10.1016/j.critrevonc.2018.01.011 Received 3 July 2017; Received in revised form 28 September 2017; Accepted 24 January 2018 1040-8428/ © 2018 Elsevier B.V. All rights reserved.

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compared to 45% for the STBI10Gy schedule (p = .05). No acute toxicity difference was observed between the two treatments (Thomas et al., 1982). Shank et al. experimented, in a prospective non-randomized trial, FTBI13.2Gy in 11 fractions of 1.2 Gy three times a day during four consecutive days compared to STBI10Gy. Even if it was not the primary endpoint of this study, the authors observed a lower incidence of IP with the hyperfractionated schedule, 24% vs. 70%. In acute non-lymphocytic leukemia (ANLL) patients, the authors found a significant difference in favor of the FTBI compared to the STBI schedule for oneyear relapse-free survival (RFS) and OS rates at 53% vs. 17% (p < .001) and 61% vs. 17% in (p < .01), respectively (Shank et al., 1983). In another study using a large retrospective analysis in 21 French institutions, Socie et al. compared a STBI10Gy vs. several fractionated schemes of FTBI12Gy, mainly 2 Gy twice daily (BID) for 3 days or 4 Gy once daily for 3 days (Socie et al., 1991). The study did not demonstrate a significant difference in OS, but the fractionation significantly reduced the incidence of chronic GVHD (41.3% vs. 22.2%; p = .01) and IP (37.5% vs. 1.7%; p = .02). The Seattle team published a randomized trial evaluating another FTBI15.75Gy with 7 consecutive daily fractions of 2.25 Gy, which demonstrated to have a better RFS rate than the FTBI12Gy with 6 consecutive daily fractions of 2 Gy. The probability of relapse at 4 years was 0.25 for the 12 Gy arm vs. 0 for the 15.75 Gy arm (p = .008). There was not a significant difference in OS rates because of an increase of non-relapse mortality induced by acute GVHD complications, hepatic VOD or infection (Clift et al., 1998; Thomas, 1990; Clift et al., 1991). Others study reported a decrease of relapse with a higher TBI dose threshold, which ranged from 9.9 Gy to 13 Gy (Scarpati et al., 1989; Marks et al., 2006). Several studies investigated the use of a reduced intensity conditioning regimen (RIC) in bone marrow transplantation for patients who were not eligible for a myeloablative conditioning regimen (MAC) due to age or comorbidities. Aoudjhane et al., in a retrospective registry based study including patients older than 50 years, compared MAC in combination with TBI with doses > 10 Gy or busulfan with doses > 8 mg/kg and others drugs and RIC combining fludarabine and TBI doses < 2 Gy or busulfan doses < 8 mg/kg. No significant difference in the 2-year RFS and OS rates were observed (Aoudjhane et al., 2005). Bornhäuser et al., in a prospective phase 3 trial with AML patients, compared an RIC consisting of FTBI8Gy (BID fraction of 2 Gy) and fludarabine with a FTBI12Gy (6 BID fractions of 2 Gy) and cyclophosphamide. No significant differences were observed in the OS, RFS and disease-free survival (DFS) rates (Bornhauser et al., 2012). In patients younger than 35 years, Sébert et al. compared MAC and RIC regimens in a retrospective study and did not demonstrate any significant differences in the OS and RFS rates between the two regimens (Sebert et al., 2015). Ozsahin et al. evaluated the influence of low dose rate (6cGy/min) versus high dose rate (200cGy/min) in TBI. They did not find significant difference in OS, 4 years RFS, GVHD, 4 years IP and VOD incidence rate. However, 4 years cataract incidence was higher in patient treated with high dose rate STBI or FTBI (Ozsahin et al., 1992).

2.1. Patient positioning (Roberts et al., 2013) (Fig. 1) Few dedicated systems exist, but, today, TBI is mostly performed with standard linear accelerators. The primary limitation of standard linear accelerators is the maximum field size of 40 × 40 cm at a standard source-surface distance (SSD). However, positioning patients at a superior SSD, generally 200–600 cm, allowed for an enlarging of the field size. If the size of the treatment room allows it, patients are treated by a single field. Otherwise, multiple fields are required. Two main techniques are used. 1) Antero-posterior directed fields are the simple technique. The patient is treated in alternative dorsal and ventral decubitus, and gantry remains at the 0° position. Patients are treated lying down in a couch or on the floor. This position is convenient for children or for those patients with a height that allows for it. It is also the position of choice for children who need anesthesia. 2) If this position is not usable or not optimal, lateral decubitus is an alternative set up, in which the gantry is turned at 90° with a collimator rotation of 45°. 3) The third position and the less used is that of a seated position, and irradiation is performed with parallel lateral fields. Shields are positioned relative to tattoos on the patient skin, and the shielding position is then verified by means of MV imaging on a photostimulable phosphor cassette. A hard copy of the radiography is printed and evaluated by the physician. This time consuming and poorly accurate procedure is being improved by direct imaging systems such as the Theraview TBI imager, which allows for real time shielding positioning, in which shielding positioning could be controlled faster before irradiation and during irradiation. 2.2. Radiobiological considerations One of the aims of TBI is to eradicate the bone marrow in the recipient to allow for the donor bone marrow to engraft in the recipient. D0 values (dose required to reduce survival cells to 37%) of bone marrow cells range from 0.3 to 1.6 Gy, demonstrating a high radiosensitivity (Hendry, 1985; Uckun and Song, 1989). The antileukemic effect of TBI has been explored by experiments on leukemia cells, which reported a wide range of heterogeneity of radiosensitivity. As reviewed by Cosset et al. (1994), leukemia cell D0 values are in the range of 0.8–1.5 Gy, which make them as radiosensitive as bone marrow cells. However, some studies report extreme D0 values, ranging from 0.3 Gy to 4 Gy. The most commonly accepted conclusion of those studies is that there are differences in hypersensitivity between the different leukemia lines. However, the authors stated that it could be a bias caused by differences in cloning techniques that were used in these experiments. Unexpectedly, leukemic cells certainly have a capacity for repairing sublethal lesions, and several studies demonstrated an increase in the survival of leukemic cells with fractionated irradiation schedules (Cosset et al., 1994). Animal studies reported a better immunosuppressive effect in an equivalent dose single-fraction regimen compared to that of fractionated schedules (Storb et al., 1989; Storb et al., 1994; Salomon et al., 1990). 2.3. Total dose, fractionation and dose rate

2.4. Indications of TBI As in many treatment plans, the total dose and fractionation have to be balanced between the relapse rate, side effects and complications. Ten grays in a single fraction TBI (STBI) has been the first widely used regimen (Thomas et al., 1975a, 1975b). To improve the outcomes of the TBI regimen, reducing relapse rates, graft versus host disease (GHVD) and toxicities, especially lung pneumonitis, were required. Since the early eighties, several studies comparing fractionated and hyperfractionated TBI regimens have been published. Thomas et al., in a prospective randomized trial, compared STBI10Gy with fractionated TB (FTBI) 12 Gy in six consecutive daily fractions of 2 Gy and demonstrated superiority of the FTBI schedule in terms of overall survival (OS). The two-year OS rate was 65% for the FTBI12Gy schedule,

Acute lymphoid leukemia (ALL) remains as the main indication of a TBI based conditioning regimen in bone marrow transplantation. Several studies compared TBI containing regimens with non-TBI containing regimens in bone marrow transplantation. A prospective randomized study compared busulfan–cyclophosphamide (BuCY) and TBI–cyclophosphamide (CyTBI) in children. The results demonstrated a better event-free survival (EFS) rate from the TBI-CY regimen compared with the BuCY regimen, with a 3-year EFS of 58% vs. 29%, respectively (p = .03). Additionally, the OS rates were not significantly different between the two regimens (Bunin et al., 2003). Davies et al., in a retrospective study, demonstrated a better DFS from the CY-TBI regimen 139

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Fig. 1. TBI patient positionning.

indications remain controversial (Belkacémi et al., 1998).

compared to the BuCY conditioning regimen (50% vs. 35%; p = .005) and a better OS as well (55% vs. 40%; p = .003) (Davies et al., 2000). Kato et al., in a national registry based study, compared TBI-based bone marrow transplantation conditioning regimens: cyclophosphamide (CY), melphalan, cyclophosphamide + etoposide (CY-VP16), cyclophosphamide + cytarabine (CY-AraC) and others. TBI-melphalan demonstrated a 5-year EFS rate of 71.4%, vs. 62.2% for CY, 67.6% for CY + VP16, 52.6% for CY + AraC and 59.1% for others (p = .009) (Kato et al., 2015). Finally, Marks et al., in a registry-based comparison, evaluated CY-TBI vs. etoposide-TBI with two dose levels in each arm: < 13 Gy and ≥ 13 Gy. This study did not show any differences in RFS, DFS and OS rates between the regimens for the patient with the first complete response. For the patient with the second complete response, data suggests that etoposide could improve DFS compared to Cy-TBI for a dose of < 13 Gy, but not compared to CY-TBI with a dose ≥13 Gy (Marks et al., 2006). Other diseases, such as acute myelogenous leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma (MM), and Hodgkin’s disease, might benefit from a TBI-based conditioning regimen, but the

2.5. Side-effects and complications The dominant side effects in patients undergoing a TBI-containing conditioning regimen for bone marrow transplantation are nausea and vomiting, which occur in 35% to 66% of patients, usually after 3–5 Gy (Thomas et al., 1982; Ozsahin et al., 1992; Buchali et al., 2000; Valls et al., 1989; Cosset et al., 1989; Barrett, 1982; Chaillet et al., 1993). However, nausea and vomiting are easily manageable with oral granisetron and ondansetron (Spitzer et al., 2000; Belkacémi et al., 1996). Acute side effects also include diarrhea, stomatitis, temporary loss of taste and appetite, parotitis, rash and asthenia. VOD is a life-threatening side effect of TBI. However, its diagnosis can only be made on biopsy, and the clinical criteria for the diagnosis of VOD have been proposed. McDolnald et al. suggested that VOD could be clinically diagnosed when 2 or more of the following criteria are present: bilirubin ≥2 mg/dL, hepatomegaly or right upper quadrant pain, and ascites with or without unexplained weight gain > 2% over baseline 140

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overall incidence ranging from 3% to 43% for a total dose of FTBI that was from 12 Gy to 14 Gy (Chou et al., 1996; Borg et al., 2002; Gerstein et al., 2009; Miralbell et al., 1996). Miralbell et al. found a significant relationship between TBI dose and renal dysfunction (Miralbell et al., 1996). A prospective study reported that young age, TBI using kidney blocks and days of aminoglycoside/vancomycin use were significantly associated with a decrease of the glomerular filtration rate. The same study reported that the days of amphotericin or prostaglandin E1 use were significantly associated with a decrease of the effective renal plasmatic flow (Miralbell et al., 2004). Bone impairment following a TBI-containing regimen, including osteoporosis, has a reported incidence ranging from 4% to 31.6% (Majhail et al., 2007; Savani et al., 2007; Marnitz et al., 2014). In addition to osteoporosis, aseptic osteonecrosis occurred in 3% to 12% of patients who were treated by a TBI containing regimen. Two case control studies reported a significant relationship between TBI and the incidence of osteonecrosis, with an odds ratio (OR) of 3.2 (CI 95%: 1.1–9.7) and 5.73 (CI 95%: 2.38–13.83). However, aseptic necrosis was also strongly associated with steroid use, with an OR of 14.4 (CI 95%: 2.8–73.2) (Socie et al., 2001; Majhail et al., 2007; Fink et al., 1998; Robin et al., 2005; Faraci et al., 2006). TBI in a bone marrow transplantation regimen is known to be associated with growth impairment and is frequently associated with growth hormone deficiency (Thomas et al., 1993; Cohen et al., 1999; Shinohara et al., 1993). Cohen et al., in a multicentric retrospective study, reported a mean standard deviation difference of genetically estimated height of −0.94 SD. Moreover, the authors reported that STBI has poorer outcomes in growth impairment than does FTBI (Cohen et al., 1999). Shinohara et al., in a retrospective study, reported a 56% growth retardation of more than −1.0 SD and a 16% growth retardation of more than −2.0 SD (Shinohara et al., 1993). Sanders et al., in a prospective study, demonstrated that growth hormone therapy significantly improved the height of children at 10 years (Sanders et al., 2005). Among endocrinal impairments following bone marrow transplantation, thyroid dysfunction is frequently reported, in retrospective studies, with an incidence ranging from 20% to 57%. The most frequently reported thyroid dysfunctions are subclinical hypothyroidism and euthyroid sick syndrome (ETS). Retrospective studies reported age at bone marrow transplantation and acute GVHD as predictive factors of thyroid troubles. Thyroid dysfunction incidence was not reported as being related to conditioning regimens, as studies reported similar rates between TBI containing and TBI non-containing regimens (Toubert et al., 1997; Sanders et al., 2009; Jung et al., 2013; Madden et al., 2015). Infertility in both men and women is also reported in TBI related endocrinal dysfunction (Ozsahin and Cosset, 1994). Claessens et al. reported that 59% of patients experienced deterioration of their sexual relationships, with 47% of men having erectile dysfunction and 53% of women having vaginal dryness (Claessens et al., 2006). Curtis et al., in a retrospective study of 19,229 patients who received bone marrow transplantation, reported a total of 80 new cases of cancer vs. 29.8 that were expected in the general population. Although the observed difference is statistically significant (p < .001), its clinical implication remains low. Moreover, a multivariate analysis of these data reported that the risk of secondary malignancies was increased only for an FTBI dose over 14 Gy (relative risk = 4.4; CI 95%: 1.1–10.1). The results also showed that children undergoing bone marrow transplantation seem to be more likely to develop secondary malignancies than adults (Curtis et al., 1997). Two retrospective studies reported that people undergoing a TBI containing conditioning regimen for bone marrow transplantation experienced a decrease in their quality of life (QoL). However, these studies did not allow for the determination of the specific contribution of TBI in the decrease in QoL (Claessens et al., 2006; Sundberg et al., 2013). Claessens et al. reported a decrease of the QoL in 44% of patients undergoing TBI, with 41% of patients having a deterioration in their job

(McDonald et al., 1984). A meta-analysis of 135 studies that recorded VOD in stem cell transplantation reported a mean incidence of 13.7%. However, it did not take into account the type of conditioning regimen, and it is likely that some of the studies reported VOD incidences of nonTBI conditioning regimens. Moreover, the authors reported conflicting data about the relevance of heparin prophylaxis for VOD (Coppell et al., 2010). A retrospective study reported that male sex and conditioning chemotherapy consisting of cyclophosphamide alone were significantly associated with higher rates of VOD (Belkacémi et al., 1995). Among TBI complications, IP is the most frequent dose limiting complication. The reported incidence rate for IP in TBI containing conditioning regimens ranges from 6% to 30% (Dusenbery et al., 1995; Ringden et al., 1994; Bolling et al., 2011; Blaise et al., 1992; Ozsahin et al., 1992; Devergie et al., 1995). Volpe et al., in a retrospective study, reported an increase of lethal lung complications from 3.8% to 19.2% when the mean lung dose was ≤9.4 Gy vs. > 9.4 Gy (Della Volpe et al., 2002). In a meta-analysis of 20 studies and 26 conditioning regimens, Sampath et al. identified lung dose, total dose, dose per fraction, cyclophosphamide dose and use of busulfan as predictive factors of IP (Sampath et al., 2005). A retrospective study reported that instantaneous dose rate and the age were associated with higher rates of IP (Ozsahin et al., 1996). To decrease the dose in the lungs, lung shielding has been developed using full transmission blocks after a certain number of fractions or a partial block during the entire treatment. Shank et al. reported an IP incidence reduction from 50% with 10 Gy STBI without lung shielding to 18% for 13.2 Gy in 11 fractions of 1.2 Gy over 4 days with partial lung shielding and anterior and posterior chest wall electron boosts (6 Gy in 2 fractions) (Shank et al., 1990). Lawton et al., in a retrospective analysis, reported a decrease of lethal pulmonary events when partial lung shielding was increased from 50% to 60% for a total prescribed dose of 14 Gy in 3 daily fractions over 3 days (Lawton et al., 1989). One retrospective study reported an increase of the relapse of refractory anemia when lung shielding had been used (Anderson et al., 2001). In both techniques, transmission blocks are used to shield the lungs to reduce the dose received by the lungs, and the chest wall is supplemented with electron beams with the energy and dose being such that the prescribed dose is delivered to the lung–chest interface. Shields have been widely used to decrease the mean dose to critical organs such as lungs. However, it has been demonstrated that lung shielding is not an accurate way of lowering the dose to lungs and that it could also lead to an underdose to the bone marrow at the manubrium and ribs (Anderson et al., 2001; Hui et al., 2004). Neurologic complications occur in 11% to 59% of patients undergoing hematopoietic stem cell transplantation. They include hemorrhage, fungal infections, encephalopathy and peripheral neuropathy. A recent review stated that the incidence of neurologic complications could be correlated to the human leukocyte antigen (HLA) disparity. Encephalopathy is mainly due to sepsis and to the use of sedative drugs. A TBI dose over 12 Gy within the first 100 days after transplantation has been demonstrated as a risk factor of neurological complications, but no correlation has been demonstrated between that dose after 100 days after transplantation and neurological complications (Rodriguez, 2014). Cataract is a frequent late effect of conditioning regimens that contain TBI. In a registry based retrospective study, the estimated overall 10-year incidence of cataracts was 50%, with a significant higher rate with a STBI than with a FTBI (60% with a STBI, 43% with a FTBI with ≤6 fractions and 7% with a FTBI with > 6 fractions; p < .0001). Higher dose rate, age > 23 years, allogeneic BMT and steroid administration are associated with higher rates of cataract, whereas FTBI provide lower rates of cataract. Moreover, this study reported that heparin in VOD prophylaxis was a protective factor, since the incidence of cataracts dropped from 55% to 33% (p = .04) (Belkacemi et al., 1998). Renal toxicity of TBI has been reported in several studies, with an 141

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Fig. 2. Helical Tomotherapy TBI mean lungs D50 (Gy) for a prescribed dose of 12 Gy.

treatment report should include the total dose administered, prescription scheme, beam-on-time, dose to organ-at-risk including at least dose to lungs, shield used, and toxicities observed. Finally, quality accuracy includes long-term follow-up (Wolden et al., 2013; Nelligan et al., 2015; International Commission on Radiation Units and Measurement, 1993; International Commission on Radiation Units and Measurements, 1999).

situation and 35% of patients experiencing a decrease of intellectual capacity (Claessens et al., 2006). Moreover, the authors demonstrated that 59% of the patients experienced sexual relationship deterioration, with 47% of men having erectile dysfunction and 53% of women having vaginal dryness (Claessens et al., 2006). Although, using FTBI schemes in bone marrow transplantation improved the overall survival by lowering the side effects and non-relapserelated mortality, such as fatal IP and GHVD, and a TBI containing regimen remains associated with significant side effects, such as the lowering of the quality of life of patients. Moreover, studies have demonstrated that raising the total dose of TBI reduces the relapse rate, but it increases non-relapse mortality.

3. Intensity modulated radiotherapy in bone marrow transplantation 3.1. General concept

2.6. Quality accuracy

As TBI has improved from its introduction in the fifties to the late nineties, as described before, an axis of progression for this technique remains. The primary limitation of TBI is its toxicity to organs at risk, especially to the lungs, heart, liver and kidneys. Helical tomotherapy (HT) allows for the performance of in IMRT which leads to a better organ-at-risk sparing.

The TBI process involves a close interdisciplinary cooperation between radiation oncologists, haemato-oncologists, qualified medical physicists, dosimetrists, radiation therapists, nurses, and dieticians. The first step of the TBI process involves a clinical evaluation that includes the medical history of the patient and any conditions that may influence the TBI delivery, such as pulmonary, renal and hepatic diseases or pregnancy. Informed consent requires disclosure, understanding, capacity and voluntariness from the patient. TBI prescription must take into account the specific transplant program that is determined depending on the patient’s condition and the bone marrow transplantation indication. The radiation oncologist’s prescription includes total dose, dose to lungs, dose per fraction, number of doses per day, delay between two fractions, if suitable, number of treatment days per week, beam energy, planning target volume, patient positioning and immobilization, source-to-skin distance (SSD) and organ shielding. According to the ACPSEM ROSG, the TBI working group and American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) guidelines, the simulation of treatment, including shield placement, should be done in the treatment position. Reference points for the patient and shield positioning should be marked on the patient’s body for setup accuracy. Data from whole body computed tomography are useful for dose calculation and for taking into account the shape of the lungs. In accordance with the ICRU 50 and 62 reports, the dose prescription is delivered to a relevant point, which is often at the umbilicus or pelvic region. Moreover, dose homogeneity requires that 95% of the PTV receives at least 95% of the prescribed dose and that no more than 107% of the prescribed dose should be delivered at one point of the PTV. Actually, because of dosimetric uncertainties when performing the TBI without simulated CT, most teams accept from a 1.5–10% discrepancy between the planned and the delivered doses (Giebel et al., 2014). In vivo dosimetry verification should be performed on the first fraction of treatment with diodes or MOSFETs detectors. Thermo luminescent dosimeter of film could be used for post treatment analysis. During the entire treatment duration, specific attention should be paid to body variation, including weight loss or gain, to adapt beam-on-time duration and deliver an accurate treatment. The

3.2. TBI with helical tomotherapy Two studies report the feasibility of TBI performed with HT. They both defined planning treatment volumes (PTV) as the whole body excluding organs at risk (OARs) (Penagaricano et al., 2011; Gruen et al., 2013). Gruen et al. defined only lungs as OARs, whereas Peñagarícano et al. also include kidneys as OARs. Peñagarícano et al. took into account the mobility of the lungs and kidneys according to breathing by performing a 4D CT-scan. The dose prescription to the PTV was, in both studies, a single 2 Gy dose delivered BID for a total of 12 Gy. The average dose delivered to the lungs (Fig. 2) ranged from 7.3–9.3 Gy, which remained below the 9.4 Gy cut-off (Della Volpe et al., 2002). The average mean dose to the kidneys was 7.3 Gy. Moreover, the studies reported a grade V acute GHVD in 10–50% of the patients, but this rate has to be carefully considered considering the small sample sizes (n = 4–10). No acute toxicities ≥grade 3 have been reported.

3.3. TBI with volumetric arc therapy (VMAT) TBI with VMAT seems to provide significant decrease of the dose to OAR. A recent study evaluating TBI with VMAT in 7 patients reported a reduction of the mean dose received by the lungs of 13–27%. In one patient, presenting with renal insufficiency, the mean dose to the kidneys has been reduced of 43–52%. Every patient suffered from grade 3 mucositis and one from bladder inflammation. With a mean follow-up time of 8 monts (2.3–15 months), one patient died from refractory disease, one from relapse and the five others live disease free (Springer et al., 2016). 142

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3.4. Total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI)

Table 1 Helical Tomotherapy TMLI OARs mean D50 (Gy) for a prescribed dose of 12 Gy.

Because of the ability of HT to perform a targeted radiotherapy with a better conformation of the dose delivery to targeted structures with a better sparing of critical structures, the concepts of TMI and TMLI emerged (Mackie et al., 1993). This ability is combined with the delivering of the dose without multiple fields and with an easy patient setup on the machine couch. Immobilization is the key to treatment accuracy and is mostly performed with a five point thermoplastic mask and a body vacuum (Schultheiss et al., 2007). For TMI, the clinical target volume (CTV) includes the entire bony skeleton. To take into account chest mobility, three CT scans are performed with different breathing patterns: shallow breathing, inspiration and expiration. Inspiration and expiration CT scans are used to determine a contouring margin for the ribs and sternum. For TMLI, the CTV includes the CTV from the TMI and every major lymph node, the spleen, the liver and sanctuary sites such as the brain or testes. For a conventional total dose of 12 Gy, a reduction of the average mean dose to the lungs ranges: 25–51%, for HT-TMI vs. TBI. A similar mean dose reduction is observed for major critical organs, such as the liver (41–52%), the heart (46–47%), the kidneys (40–63%) and the lenses (70–87%) (Fig. 3-a). Three studies report similar dose reductions to OARs with HT-TMLI (Table 1) (Schultheiss et al., 2007; Wong et al., 2009; Rosenthal et al., 2011). Moreover, the studies report a good acute tolerance of HT-TMI for bone marrow transplantation (BMT) in patients with multiple myeloma (MM) (Gruen et al., 2013; Wong et al., 2009; Shueng et al., 2009; Somlo et al., 2011). No grade 4 toxicities have been reported. Wong et al. reported infrequent grade 3 fatigue and anorexia. Grade 1–2 toxicities were mostly digestive toxicities (Wong et al., 2009). Fig. 4 is an example of color wash dosimetry performed for a TMI at

Study

Lungs

Eyes

Lens

Kidneys

Liver

Heart

Schultheiss et al. (2007) Wong et al. (2009) Rosenthal et al. (2011)

4,9 5,7 5,8

5,8 6,2 5,8

1,8 2,5 2,4

6,5 6,7 6,8

Not OAR 9,2 7,4

4,8 6,2 6,6

our institution.

3.5. Dose escalation Considering the dose reduction to the OARs, the good tolerance of HT TMI and TMLI, and that several trials showed a decrease of relapse in AML and CML with higher total dose (Clift et al., 1998; Clift et al., 1991; Scarpati et al., 1989; Marks et al., 2006), several studies evaluated the feasibility of a dose escalation in HT TMI and TMLI (Wong et al., 2009; Somlo et al., 2011; Wong et al., 2013). Somlo et al. conducted a prospective dose escalation trial using HT in a bone marrow transplantation conditioning regimen in patients with MM (Somlo et al., 2011). The escalation dose schema started from 10 Gy, with an increment of 2 Gy per cohort. The patients also received 1.5 mg/m2 cyclophosphamide and 200 mg/m2 G-CSF and melphalan. The first limited toxicity effect, reversible grade 3 pneumonitis, was observed at a total dose of 18 Gy. The median average radiation dose to organs at risk ranged from 11 to 81% of the total prescribed dose. These results have been confirmed by another phase I study (Patel et al., 2014). Moreover, a median follow-up of 1126 days, an overall survival of 50% and a relapse free survival of 43% were reported.

Fig. 3. OARs mean D50 (Gy) for a prescribed dose of 12 Gy.

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Fig. 4. Example of color wash of a TMI dosimetry performed in the radiation oncology unit of Paul Strauss Cancer Center, Strasbourg, France.

chemotherapy of fludarabine and melphalan combined with HT-TMI at a total dose of 12 Gy in 2 Gy single fractions of BID in patients who were not eligible for standard TBI due to age or comorbidities (Rosenthal et al., 2011). The dosimetric study demonstrated acceptable outcomes,

3.6. TMI and TMLI conditioning regimen in advanced and poor prognosis hematological malignancies A phase 1–2 study evaluated the feasibility of a reduced intensity 144

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with an average median dose to the lungs of 5.8 Gy (Fig. 3-b). The clinical outcomes revealed that the incidence of aGVHD ≥ grade III was 27%. Acute toxicities ≥grade 3 were mainly pulmonary (15%), gastrointestinal (9%), renal (9%) and CNS toxicity/confusion (9%). No grade 4 toxicities were reported. Wong et al. also conducted a combined trial evaluating dose escalation of TMI in association with higher-intensity chemotherapy in patients under 55 years old with advanced ALL or AML who were not eligible for standard BMT. This dosimetric study showed that for a total delivered dose from 12 to 15 Gy, the average median dose to the OARs were 15–45% of the prescribed dose. Two higher intensity chemotherapy regimens have been evaluated. In the first trial, the arm combining TMI + busulfan and etoposide was proposed for treating ALL and AML. In the second trial, TMI + busulfan and etoposide was used for treating AML. The first regimen was tolerated well with no toxicity ≥grade 3 reported for a total dose of < 15 Gy and grade 3 mucositis and fatigue at 15 Gy but no dose limiting toxicities. The second regimen’s toxicities were more important, with grade 3 mucositis at 12 Gy, and dose limiting toxicities at 13.5 Gy, with hepatic VOD and grade 4 mucositis (Wong et al., 2013).

creating a transition planning target volume between the upper and lower plan, the resulting dose that was delivered at the junction was ± 10% of the prescribed dose (Zeverino et al., 2012). Finally, treatment plan verification is a key point of quality assurance in IMRT, and two main approaches can be used. The first approach is by using a flat homogeneous water equivalent phantom to independently measure the dose distribution from radiation fields. The second approach consists of an irradiated phantom with ionization chambers and radiographic film by all of the beam portals. To verify the dose delivered, in vivo dosimetry is performed. It seems that film, thermoluminescent dosimeters and diodes might not be accurate enough and that real time 2D dosimetry using portal imaging is most efficient (Chao et al., 2013).

3.7. Advantages and drawback

4. Conclusion

The HT maximum field is limited to 60 × 160 cm (Beavis, 2004), which imposes a treatment in two parts for most of the patients. Most of the team have chosen to treat the upper body with HT and the lower body (limbs) with AP-PA fields, which leads to junction field uncertainties in the dosimetry calculation. Moreover, a recent case of radiation dermatitis has been reported and is an example of the uncertainties of the fields junction (Takenaka et al., 2016).

Since its introduction in the fifties by Thomas et al., TBI used in a BMT conditioning regimen has evolved widely. Traditional TBI is performed with 1.5–2 Gy fraction BID to a total dose of 12–13.5 Gy, with a chest wall boost with electrons so that the prescribed dose is delivered to the lung-chest interface. Phase I and II trials demonstrate the technical feasibility and clinical good tolerance of TMI and TMLI. The early results demonstrate a significant dose reduction to the OARs and the feasibility of dose escalation in a BMT conditioning regimen. Early results in the field of HT-TMI and HT-TMLI suggest the possibility that advanced hematological malignancies and those with a poor prognosis will benefit from an alternative BMT conditioning regimen with TMI and TMLI, which was previously impossible with TBI. The outcomes of HT for TMI and TMLI should be confirmed by the results of phase III trials.

3.9. Treatment duration Nevertheless, TMI and TMLI request a long contouring time: 8 h for HT-TMI and 12–16 h for HT-TMLI. Studies report an average in-room time of 2 h, which could be decreased to 90 min with experience and a mean beam on time approximately 50 min (Schultheiss et al., 2007; Wong et al., 2009; Rosenthal et al., 2011; Shueng et al., 2009).

3.8. Quality accuracy The use of HT for performing intensity modulated TMI requires a specific quality assurance (QA) to ensure treatment accuracy. First, quality assurance of the multileaf collimator calibration of the MLC operation requires specific procedures (Chui et al., 1996; LoSasso et al., 2001). Another important aspect of QA in TMI and TMLI is the accuracy of patient positioning. Due to a highly conformational radiation delivery, patient positioning must be highly reproducible in interfraction delivery to ensure that the prescribed dose adequately covers the planning target volume. Most of the team that performs the TMI and TMLI use a five point mask for head and neck immobilization and a body vacuum for body immobilization. Patients undergo either three CT scans with different breathing patterns (inspiration, expiration, free breathing) or 4D CT, which determine the margin for taking into account the organs motion, such as the ribs, lungs, kidneys, spleen, liver, and a shallow breathing CT to determine the target structure and OARs. Image guided radiotherapy (IGRT) in TMI and TMLI is usually performed daily. Most of the teams performed megavoltage CT (MVCT) of the pelvic region and head and neck regions for fusion with the planning CT (Schultheiss et al., 2007; Wong et al., 2009; Rosenthal et al., 2011; Shueng et al., 2009; Somlo et al., 2011). Recently, Takahashi et al. published a multi-institutional feasibility study to decrease patient localization and repositioning by generating an MV topogram (MVtopo) instead of a MVCT. This procedure seems to be a fast and accurate alternative to MVCT and decreases image acquisition, from over 15 min for MVCT to less than 1 min for MVtopo (Takahashi et al., 2015). Due to the HT field size limitation, the treatment plan has to be split into two segments. Accuracy of dose homogeneity resulting in the match of the two plans is challenging. Some teams managed the dose junctioning between the two plans by overlapping the 50% isodose (Schultheiss et al., 2007; Wong et al., 2009; Rosenthal et al., 2011; Shueng et al., 2009; Somlo et al., 2011), whereas other teams did not report how they managed that field junction (Somlo et al., 2011; Hui et al., 2007). Zeverino et al. reported the use of a novel field junction in HT-TMI. By

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Dr Adrien Paix, MD, MSc resident in radiation oncology at Paul Strauss Cancer Center. Dr Delphine Antoni, MD, MSc associate professor of radiation oncology at Strasbourg medical school. Physician at the radiation oncology department of Paul Strauss cancer center. Master of Science in radiobiology and Philisophiae Doctor candidate at Strasbourg university radiobiology laboratory. Involve in hematologic malignancies treatment especially total body irradiation. Dr Waisse Waissi, MD, MSc resident in radiation oncology at Paul Strauss Cancer Center. Master of Science in radiobiology and Philisophiae Doctor candidate at Strasbourg university radiobiology laboratory. Dr Marie-Pierre Ledoux, MD assistant professor in hematology at Strasbourg medical school. Fellow in the hematology department of Strasbourg university hospital. Dr Karin Bilger, MD physician in the hematology department of Strasbourg university hospital. Head of the bone marrow transplantation unit. Dr Luc Fornecker, MD, PhD physician in the hematology department of Strasbourg university hospital. Philisophiae Doctor in analytical chemistry. Pr Georges Noel, MD, PhD Professor in radiation oncology at Strasbourg medical school. Chairman of the radiation oncology residency program. Physician in the radiation oncology department of Paul Strauss cancer center.

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