31 Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation

Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 785 31 Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation

Kathryn E. Dusenbery and Bruce J. Gerbi

CONTENTS immune (Thomas 1997) or genetic disorders are being offered transplantation (Iannone et al. 2003; 31.1 Conditioning Regimen 786 Peters et al. 2003). The rationale for SCT differs 31.2 Fractionation and Dose Rate 787 31.3 Sequence 788 depending on the disease treated and the source of 31.4 Technical Aspects 788 bone marrow cells. In both autologous and alloge- 31.5 Right and Left Lateral TBI 788 neic SCT for malignant diseases, the rationale for 31.6 Simulation and Patient Measurements 788 SCT is to allow chemotherapeutic dose escalation. 31.6.1 Compensators for TBI 790 The SCT “rescues” the patient from what otherwise 31.7 Compensator Design 791 31.7.1 Patient Treatment 793 would be a lethal dose of chemotherapy. 31.7.2 Dose Verification 793 In an allogeneic SCT, a healthy donor marrow 31.7.3 Dose Prescription 794 regenerates in its place and the infused donor 31.8 Anteroposterior TBI 794 lymphocytes have a proven anti-tumor effect 31.8.1 Patient Treatment Technique 797 (graft versus leukemic effect) (Schleuning 2000; 31.9 Normal Tissue Shielding 798 Remberger Zecca 31.9.1 Lung Shielding 798 et al. 2002; et al. 2002). Donor 31.9.2 Kidney Shielding 799 lymphocytes can also serve to supply absent 31.10 Gonad Shielding 800 enzyme for patients with inborn errors of metabo- 31.10.1 Thymus Shielding 800 lism. In autologous SCT, the infused marrow may 31.10.2 TomoTherapy 800 be contaminated with malignant cells. Various 31.10.2.1 Special Considerations for TBI in methods have been used to purge the marrow of Young Children 801 Freedman 31.10.2.2 Complications Following Preparation With TBI 802 residual malignant cells ( et al. 1998; References 802 Colombat et al. 2000; Schouten et al. 2000; van Besien et al. 2003). As there is no anti-tumor (graft versus leukemia) effect, various cytokines are being tried in an effort to mimic the graft versus leukemia effect and improve the efficiency of Since the first successful bone marrow transplanta- autologous transplantation (Hawley et al. 1996; tion was performed at the University of Minnesota Imamura et al. 1996; Klingemann 1996; Leshem in 1960 (Gatti et al. 1968), bone marrow and stem et al. 2000). In the future, the autologous cells may cell transplantation (SCT) has gained prominence be manipulated with genes that confer relative che- as a therapy for a variety of diseases as outlined in motherapeutic resistance (Wood and Prior 2001), Table 31.1. The majority of bone marrow transplants thus allowing for additional post transplantation are carried out in an effort to eradicate malignant chemotherapy with little damage to the new bone disease, but a growing number of patients with auto- marrow (Heslop et al. 1995). The development of HLA (human lymphocyte antigen) and MLC (mixed lymphocyte culture) assays allowed physicians to determine whether K. E. Dusenbery, MD potential marrow donors were “histocompatible” University of Minnesota Medical School, Department of Ra- (i.e., matched by HLA antigens and non-reactive to diation Oncology, MMC436, 420 Delaware St. S.E., Minneapo- MLC cultures) and therefore less likely to develop lis, MN 55455, USA Mahmoud Gerbi graft-versus-host disease (GVHD) ( B. J. , PhD Parr Petersdorf Associate Professor, Therapeutic Radiology – Radiation On- et al. 1985; et al. 1991; et al. cology, University of Minnesota, Mayo Mail Code 494, 420 1998). Initially, transplants were only performed Delaware St SE, Minneapolis, MN 55455, USA between HLA-matched related donors, but, with 786 K. E. Dusenbery and B. J. Gerbi

Table 31.1. Diseases treated by stem cell transplantation 31.1 Acute myeloid leukemia Conditioning Regimen Acute lymphoblastic leukemia Chronic myelogenous leukemia Presumed desired endpoints of the pre-transplan- Chronic lymphocytic leukemia tation conditioning regimen are to eradicate the Myelodysplasia Lymphoma recipient’s native bone marrow, immune suppress Non-Hodgkin‘s the recipient sufficiently to avoid rejection of the Hodgkin‘s disease donor transplant, and to do this with minimal toxic- Multiple myeloma Aplastic anemia ity to other tissues. In some situations, these three Idiopathic goals are attainable with a chemotherapy-only con- Fanconi ditioning regimen; however, multiple variables need Paroxysmal nocturnal hemoglobinuria Congenital/immunodeficiency to be considered including the age of the patient, the SCIDS underlying disease, the source of the donor marrow, Autoimmune disease and whether the donor marrow is manipulated (i.e., Rheumatoid arthritis Fehr Sykes Systemic lupus erythematosus T depleted) ( and 2004). At the University of Minnesota, total body irradia- Osteopetrosis tion (TBI) is generally part of the conditioning regi- Leukencephalopathies Hurlers syndrome mens for the situations outlined in Table 31.2. These Other inborn errors of metabolism situations include unrelated marrow or cord blood Sickle cell anemia/thalassemia donor transplants, certain underlying malignancies that are considered radiosensitive [acute lymphocytic leukemia (ALL), multiple myeloma], and for patients the advent of effective therapies directed at decreas- in whom a TBI-containing conditioning regimen has ing the probability and severity of GVHD, matched been shown to be superior to a chemotherapy-only unrelated donor transplants have become more conditioning regimen [acute myeloid leukemia (AML) common. The National Marrow Donor Program in second remission] (Dusenbery et al. 1996). (NMDP) types potential bone marrow and stem cell There are theoretical advantages and disadvan- donors. More than 16,000 transplants have been tages of a TBI-containing preparative regimen. Most performed using unrelated donors provided by the often patients undergoing SCT have been exposed NMDP (McCullough et al. 1989; Karanes 2003; to multiple chemotherapeutic regimens; therefore, Cornetta et al. 2005). With more than four million potential SCT recipients may be relatively chemo- donors listed in the registry, over 70% of patients therapy “resistant.” As most patients undergo- can now find an HLA-A, -B, -DR phenotypic match ing SCT have not been irradiated previously, their at the initial search. malignant cells may be more radiation sensitive In recent years, in addition to related and unre- than chemotherapy sensitive. Additionally, there lated bone marrow donor sources, additional are known sanctuary sites where chemotherapy sources of pluripotential stem cells have been inves- does not penetrate well, such as the central nervous tigated, including the use of umbilical cord blood system (CNS) or testicles. There are no sanctuary (Cornetta et al. 2005), a rich source of stem cells. sites for irradiation and, in certain situations such A bank of HLA typed umbilical cord blood harvests as relapsed ALL, a TBI-containing regimen may be has also been established (Krishnamurti et al. especially beneficial. Lastly, chemotherapy which is 2003). usually given intravenously (busulfan may be given Another source of pluripotential stem cells are orally) needs to be metabolized and eliminated from circulating blood stem cells. These cells can be har- the body. It is known that chemotherapy pharma- vested through leukapheresis, frozen for later use, cokinetics differ among patients resulting in some then thawed and reinfused. In addition to sparing areas of the body exposed to higher or lower con- the donor the discomfort of a bone marrow har- centrations of drug. TBI requires no metabolism for vest, these peripheral stem cell harvests usually clearance and all areas of the body receive the same result in a more prompt engraftment than occurs dose of irradiation. The disadvantages of using a TBI with bone marrow infusions, resulting in a shorter regimen are the potential late side effects, such as period of pancytopenia and thus less risk of infec- sterility, cataracts, and growth retardation, as well tion (Korbling et al. 1991; Steingrimsdottir et al. as the potential neurological toxicity that may occur 2000). with irradiation. Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 787

Table 31.2. University of Minnesota protocols utilizing total skin, and bone marrow cells (“early” responding); body irradiation or total lymphoid irradiation in the condi- whereas, tissues with a low α/ β include spinal cord, tioning regimen (CR) kidney, brain, and lung (“late” responding) (Hall 1320 cGy in eight fractions over 4 days: 1994). – Acute lymphoblastic leukemia in second or subsequent CR Although not completely applicable in the setting – Acute lymphoblastic leukemia high risk in first CR of TBI schemes, the biological effective dose (BED) – Chronic myelogenous leukemia of one TBI regimen can be compared with another – Acute myeloid leukemia (some children receive chemotherapy only conditioning) regimen if several estimates are taken into consider- – Myelodysplastic syndrome ation. The units are arbitrary but allow one to com- – Non-Hodgkin‘s lymphoma (depending on dose of prior pare the theoretical effects of different TBI regimens irradiation) on different tissues. – Unrelated donor transplantation – Cord blood transplantation BED = n × d (1+d/(α/β)) Other regimens – Fanconi anemia: 450 cGy in single fraction, ±thymus block where n=number of fractions, d=dose per fraction – Non-myeloablative transplants: 200 cGy in a single fraction α β – Sickle cell anemia or thalassemia: total lymphoid irradiation, (Gy/fraction) and / =estimate (10 for early tissues, block gonads 3 for late tissues). – Osteopetrosis: TLI to include spleen, liver and mesenteric In engineering an optimal TBI regimen, the goal lymph nodes is to cause minimal damage to late responding tissues, while having a high probability of damaging the early responding bone marrow cells (and malig- 31.2 nant cells). Regimens can be evaluated for their Fractionation and Dose Rate potential effect on late responding tissues or on early responding tissues. If evaluating for late effects Initial trials with TBI use a single fraction of up to of different TBI regimens: 10 Gy. Subsequently, it was suggested that the therapeutic ratio (i.e., increased leukemic cell kill and Assume an α/β of 3 BED decreased toxicity of late responding tissues, such 750 cGy in 1 fraction 26 as lung, heart, spinal cord, kidney, and CNS) of TBI 750 cGy in 3 fractions 14 might be improved by either going to a very low dose 1200 cGy in 6 fractions 20 rate (not practical since treatment times of up to 24 h 1320 cGy in 8 fractions 20 would be required) or using a fractionated schema. 1395 cGy in 12 fractions 19 This was based on radiobiological data suggesting that leukemic cells (and their normal counterparts, One can see that fractionation would be expected the hematopoietic stem cells) were relatively radio- to spare late effects. One could go to a higher total sensitive, with a narrow “shoulder” on the survival dose, without increasing the probability of late curve and with little capacity of sublethal radiation effects. If considering the early effects of different damage repair capacity (Hall 1994). However, late TBI regimens: responding tissues are better able to repair sublethal damage and have a relatively “broad shoulder” on Assume an α/β of 10 BED the dose–response curve. Formulations based on 750 cGy in 1 fraction 13 dose survival models have been proposed to evalu- 750 cGy in 3 fractions 9 ate the biological equivalence of various doses and 1200 cGy in 6 fractions 14 fractionation schedules. Assumptions are based on 1320 cGy in 8 fractions 15 the linear-quadratic model that takes into account 1375 cGy in 12 fractions 16 the α and β (non-reparable and reparable) compo- nents of cell kill. The values for the α and β compo- It becomes apparent that fractionation spares nents of cell kill can be derived experimentally, but early effects. Since bone marrow ablation is desired, are not available for many human tissues. Extrapo- the total dose must be increased to 1200 cGy or more lating from animal data and cell cultures, it has been to get the same myeloablative effects as a single frac- found that the ratio of α/ β is a useful indicator of tion of 750 cGy. the effect of fractionation on cell damage. Tissues These theoretical equations are supported by with a high α/ β include the gastrointestinal tract, data from reports of bone marrow transplantation 788 K. E. Dusenbery and B. J. Gerbi regimens. For example, the risk of cataract for- 31.4 mation (a late responding tissue) is substantially Technical Aspects higher when the TBI is given in a single fraction of TBI than when it is fractionated (Aristei et al. Numerous techniques for irradiation of the entire 2002). body are described in the literature. At the Univer- Although no randomized clinical trials exist, sity of Minnesota, two general TBI techniques are the majority of retrospective reviews looking at currently in use, with modifications of the tech- the rate of interstitial pneumonitis after single niques for certain situations. The vast majority of fraction TBI compared with multiple fraction TBI our patients are treated using the first technique, strongly suggest an advantage for a fractionated which involves right and left lateral fields with the TBI schedule (Shank et al. 1983; Cardozo et al. patient semi-recumbent at an extended distance 1985; Kim et al. 1985; Molls et al. 1986; Standke on a specially designed couch. The second tech- 1989; Valls et al. 1989; Carlson et al. 1994). One nique is an anterior–posterior treatment technique must keep in mind the fact that these trials are patterned after that developed at Memorial Sloan non-randomized and usually compare recently Kettering (Shank et al. 1983). For the latter, adult transplanted patients on fractionated schemas patients are treated in a standing position with ante- with former single fraction patients. Numerous rior and posterior beams, while younger (smaller) variables are potentially implicated in the devel- patients are treated in a reclined position if they opment of interstitial pneumonitis, including can fit within the available field size at the floor other TBI variables such as dose rate, use of lung of the treatment room. The goal of both of these shielding, and timing of the TBI (before or after techniques is to deliver a uniform dose to the entire chemotherapy) (Molls et al. 1986). body within ±10% of the dose at the prescription Initially single fraction TBI was delivered with point. This second technique has the advantage that cobalt units at extended distances. The dose rate certain organs such as the thymus or testicles can achievable was only 5–10 cGy/min and it required be blocked. several hours to deliver the dose. When using fractionated TBI, it is not clear that the dose rate needs to be this low, although the risk of pneumonitis may be higher with higher dose rate (Kim et 31.5 al. 1985; Carruthers and Wallington 2004). Right and Left Lateral TBI However, most institutions have kept the dose rate low (under 10 cGy/min), since a fraction of 200 cGy This technique uses lateral photon beams with the can be delivered in a reasonable amount of time patient in a semi-recumbent position, as described (20 min in this case). by Khan et al. (1980). The treatment is delivered at a source to patient midline distance of 410 cm, which produces a field approximately 120 cm wide at the 95% isodose line. Aluminum compensators are 31.3 used to produce a uniform dose through all body Sequence regions to within +10% of the dose specified at the umbilicus. TBI can either precede or follow the chemotherapy portion of the conditioning regimen. An advantage to delivering the TBI first is that, with the appropriate use of antiemetics, it can be given as an out- 31.6 patient treatment and thus reduce inpatient costs. Simulation and Patient Measurements Following completion of TBI, patients are then hos- pitalized for the chemotherapy portion of the condi- Pretreatment measurements for TBI are performed tioning regimen. Clinical data are lacking, however, in the simulator room to accurately reproduce the on whether TBI is less toxic or more effective when treatment position within the treatment room and to given before chemotherapy, although it is theoreti- calculate the size and thickness of the compensating cally possible that the variety of cytokines released filters. The simulation procedure consists of three during chemotherapy may influence the incidence steps. During the first step, an anterior chest film is of pneumonitis. taken to determine the amount of lung traversed by Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 789 the treatment fields. The radiograph is taken with the distance from the middle of the shoulder to the the patient seated on the simulator couch with his top of the head is measured. The latter information or her back resting against the film cassette holder. is used to scale the size of the head compensator. The The source–skin distance (SSD) to the patient’s chest chin extension, measured from the sternal notch to is measured and because the source–film distance the point of the chin, is also recorded. Additionally, (SFD) is known, the magnification factor for the size the need for positional devices, such as pillows for of the lungs can be determined. Using this informa- the back of the head, foam sponges underneath the tion, the thickness of the lung inhomogeneity can be hips, or sandbags under the feet, is recorded on the computed. This information is used later when the form. For future reference, the names of the indi- need for lung compensation is evaluated. viduals who made and checked the measurements The second step is to establish the patient treat- are recorded. ment position so that the entirety of the body fits The third step is to measure the right–left lateral within the 95% isodose line. An overhead projector thickness of the patient at certain anatomical loca- is used to cast an isodose pattern that represents the tions. These measurements are recorded on the form uniformity of the actual treatment field (Fig. 31.1). shown in Figure 31.3 and constitute the basic data The head and back of the patient are positioned needed to determine the thickness of the compensa- within the 98% line, while the toes of the feet are tors at these locations. The key measurement is the within the 95% isodose line of the radiation field. width of the patient at the umbilicus since this is the Once this position has been established, setup mea- location where the dose is prescribed. Values of lat- surements are recorded on the form, as illustrated eral thickness are also measured at the head, neck, in Figure 31.2. shoulders, mid-mediastinum, pelvis, knees, and To describe the position of the lower extremities, ankles. The mid-mediastinal thickness is measured measurements are made from our reference point midway between the sternal notch and the xiphoid [the anterosuperior point of the iliac spine (ASIS)] to and includes the thickness of the arms. the knee and to the back of the heel. The length of the feet is also recorded. The distance from the sternal notch to the top of the knee or patella is documented to describe how compressed the patient is within the field. Finally, with the arms in the treatment position,

Fig. 31.1. For the bilateral technique, the patient is positioned within the homogeneous portion of the beam. The simulation is performed in the simulator room and an overhead projector Fig. 31.2. The form used to document the patient treatment is used to produce a representation of the treatment ﬁ eld position when the bilateral body technique is used 790 K. E. Dusenbery and B. J. Gerbi

simulation. The form shown in Figure 31.3 also serves as the calculation sheet for the determination of compensator thickness at the different locations. The compensators are usually designed in three pieces: one for the lower extremities, one for the head and neck region, and one for the lungs. In most cases, a lung compensator is not required since the effective thickness at the mid-mediastinum is usually greater than that at the umbilicus. The arms are deliberately positioned in line with the lungs and act to increase the total thickness in this region. The first step in designing tissue compensators is to determine the tissue deficit (TD), the difference in tissue-equivalent thickness between the prescription point (which in our case is the umbilicus) and the other locations. The following equation is used to calculate tissue deficit:

=−+−ρ (1) TD Lref L()1 lung L lung

where Lref is the lateral separation at the umbilicus, L is the lateral separation at that particular anatomical location, Llung is the separation of the lung determined from the anterior radiograph, and ρ ρ lung is the density of the lung. For lung, a value of 0.25 g/cm3 is used as the average lung density for healthy lung tissue (Van Dyk et al. 1982). Equa- Fig. 31.3. The form used to record the values of right–left lateral thickness of the patient. This information is used to calculate tion 1 is used only for the mid-mediastinal location the tissue deﬁ cits that exist at various body locations versus where lung tissue is present. At all other locations, the umbilicus thickness. Values of compensator thickness are Llung is zero and the tissue deficit can be obtained subsequently calculated from these data. The ﬁ nal column pro- using Eq. 2: vides a location to document the percentage of the prescribed dose delivered to the midline of the indicated regions =− TD Lref L (2)

Once the lateral separations are recorded, the Llung is determined using the anterior chest radio- point where the lower extremities compensator is graph that was taken in the simulator. The lung to start must be determined. Since the dose is pre- thickness is determined at a point midway between scribed for the midline thickness at the umbilicus, the sternal notch and the most superior aspect of the and the pelvis is usually of greater thickness, the domes of the diaphragms as seen on the radiograph. compensator must be started at some point below As shown in Figure 31.4, two lateral measurements the pelvis. The location where the compensator is to are made for both the right and left lobes of the lung: begin is that point on the legs that has the same sep- the first measurement, represented by LRt1 and LLt1, aration as the umbilicus. As final documentation, extends from the most lateral aspect to the most a photograph is taken with the patient in the treat- medial portion of the lung. The second measurement position with respect to the radiation field. ment, represented by LRt2 and LLt2, spans from the most lateral extent of the lung to the mediastinum. The lung thickness is calculated using the following 31.6.1 equation: Compensators for TBI ⎛1 ⎞ ⎜ ×+()SSD SFD ⎟ ()LLLl+++ ⎝⎜ ⎠⎟ Compensator thickness determination is calcu- = rt1212 rt lt lt × 2 Llung (3) lated from measurements taken at the time of 2 SFD Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 791 where SSD is the source–skin distance and SFD is the compensator thickness determination described source–film distance measured when the anterior above and that suggested by the AAPM (1986) show chest radiograph was obtained during the first step that the two systems produce compensators the of the simulation. In Eq. 3, the terms in the second thickness of which varies by less than 1 mm of alu- parentheses serve to de-magnify the lung dimen- minum. Finally, the percentage difference in dose sions measured on the chest radiograph to life-size between the prescription point and other locations at the midplane of the patient. of the body are calculated and recorded in the last The compensator thickness, Lc, is determined column of the form. using the following equation: ⎛ ⎞ 1 τ ⎜lnK τ ⎟ LTD=× × −⎜ × ⎟ (4) 31.7 c ρµ⎜ ρ ⎟ 2 comp⎝ eff comp ⎠ Compensator Design

In this expression, τ is the thickness ratio (Khan et The compensators are designed to be located at a al. 1970; Kirby et al. 1988). For beam energies from distance of 72 cm from the virtual source of the cobalt 60 (Co-60) to 10 MV, a value for τ of 0.70 is accelerator so that appropriate compensation can be a good approximation for compensator distances provided without the devices becoming excessively greater than 20 cm from the surface (Khan et al. large and difficult to handle. Thus, the measurements 1980). The density of the compensating material is recorded on the setup sheet in Figure 31.2 must be pcomp (aluminum in this case), K is the off axis cor- de-magnified from the treatment distance to the rection factor that accounts for both the decreases in location of their use. Using the information supplied beam intensity away from the central axis and effec- in Figures 31.2–31.4, the size of the compensators is tive scattering field size for the various locations, and determined in the following manner. For the lower µ eff is the broad-beam linear attenuation coefficient extremities compensator, the base length for section in tissue for this beam energy. The effective field size A in Figure 31.5 is obtained by taking the ASIS to knee at various locations can be determined by Clarkson distance, subtracting the distance below the ASIS that integration. The data in Table 31.3 were calculated in the compensator is to start, and multiplying that this manner for a Rando phantom and represents the dimension by the lateral magnification factor: equivalent scattering field at various locations of the body as a function of beam energy for an average Lateral magnification factor = adult (Kirby et al. 1988). This data can be used to Source-Compensator tray distance ⎛⎛ ⎞ determine accurate values for K in Eq. 4. ⎜ Lref ⎟ ⎜Source-axis distance- ⎟ An alternate method to determine compensator ⎝ 2 ⎠ (5) thickness for TBI has been suggested by the Ameri- can Association of Physicists in Medicine (AAPM) Section B of the lower extremities compensator is the (1986). Comparisons made between the system of de-magnified distance from the knee to the back of the heels, while section C is the de-magnified length of the feet plus an additional 2 cm to ensure Table 31.3. The equivalent square field size for various anatomical locations. Determined at midline in a Rando phantom. adequate coverage of the feet. Section D is simply an The lateral dimensions of the phantom at these locations is additional 2 cm of aluminum that is needed to clamp also listed in addition to the equivalent lengths required to the compensator to the compensator tray during the obtain the calculated field sizes by equivalent square calcula- actual treatment. The thickness of the compensator Khan tion. Reproduced from et al. (1970) is obtained from the compensator thickness column Photon energy Side of equivalent square (cm) as shown on Figure 31.3 for the corresponding ana- Head Neck Chest Umbilicus Hips tomical location. Co-60 17 22 31 30 28 The head and neck compensator is designed in 4 MV 16 20 30 29 23 much the same manner. The base length of section 6 MV 18 23 29 27 26 E of this compensator is the de-magnified distance 10 MV 17 22 33 27 26 18 MV >18 >18 >18 >18 >18 from the middle of the shoulder to the top of the Mean 17 22 31 28 26 head. Section F is an additional 1 cm of material to Lateral dimension 15 12–16 31 27 31 ensure adequate coverage, while section G is pro- Equivalent length 19 30 31 29 20 vided for clamping. The thicknesses of the compen- 792 K. E. Dusenbery and B. J. Gerbi

sator are again obtained from Figure 31.3 for the head and neck regions. The length of the lung compensator is obtained by de-magnifying Hcomp from the chest radiograph (Fig. 31.4) to life size using (1/2)(SSD–SFD)/SFD, then again de-magnifying these dimensions to the treatment position of the compensators using Eq. 5. The compensator thickness is obtained from Figure 31.3. The width of the compensators (the dimension of the compensator that is not shown in Fig. 31.5) is typically 11 cm for the lower extremities compensator, 6.5 cm for the head and neck compensator, and 7.5 cm for the lung compensator. Figure 31.6 shows the compensator design form a that is sent to the machine shop for fabrication. Fig- ure 31.7a shows the finished aluminum compensators and Figure 31.7b illustrates the compensators in use and how they are attached to the tray using specially designed clamps. The lung compensator, when required, is attached to the tray with double- sided tape. Machine calibration and treatment calculation. The linear accelerator is calibrated according to the protocol outlined by the AAPM (Almond et al. b 1999). To determine the total number of monitor units (MUs) for TBI, the calculation is done as an Fig. 31.4a,b. a The anterior chest radiograph obtained during isocentric treatment at an extended distance. Equa- simulation indicating the lateral measurements taken to de- tion 6 is used in the determination as follows: termine lung thickness, Llung. Also shown is the level where these measurements are taken, the midpoint between the ⎛ ⎞ ⎜ ⎟ sternal notch and the xiphoid. This dimension, Hcomp, is also ⎜ ⎟ ⎜ TD × STF ⎟ the one used if a lung compensator is required. b The inset, MU = ⎜ ⎟ which is a diagrammatic representation of a transverse CT ⎜ ⎛ ⎞2 ⎟ ⎜ ×××() () () ×⎜ f ⎟ ⎟ scan through the chest, illustrates the rationale behind these ⎜k Srco Sr po TMRd,r e ⎜ ⎟⎟⎟ ⎟ ⎝⎜ ⎝f ′⎠ ⎠⎟ (6) measurements In this equation, k is the machine calibration factor equal to 1 cGy per MU in tissue at dmax depth at the standard calibration distance, which is f, for the × 2 calibration field size of 10 10 cm ; Sc (ro) represents the collimator scatter correction factor for ro; the collimator field size, SP(re), is the phantom scatter factor for the effective scattering field, re; at the umbilicus, (f/f’)2 is the inverse square factor from the calibration distance, f, to the treatment distance, f’, set to the midline of the patient; and TMR(d,re) is the tissue maximum ratio for the midline depth, d, for the effective field size. The accuracy of the TMR values taken at 100 cm source-axis distance has been verified at the extended treatment distance. Finally, a combined spoiler plus tray factor (STF) for both the 1-cm acrylic beam spoiler and the blocking trays Fig. 31.5. A schematic diagram showing the relationship that support the compensators is included. between the compensators used for the bilateral total-body The beam spoiler or degrader is necessary because technique and the patient treatment position of the large degree of skin sparing that is still present Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 793

for the large field sizes and extended treatment distances employed in TBI. Figure 31.8a illustrates the buildup characteristics of 10-MV X-rays for a single incident beam with and without the beam spoiler in place. The measurements are normalized to dmax for the single field in this figure. Figure 31.8b shows the percentage surface dose for parallel-opposed 10-MV beams, for both open and degraded fields, normalized to the dose delivered to the midplane of a 25-cm thick patient. For both data sets, the beam spoiler was placed at a distance of 20 cm from the phantom surface. With- out the beam spoiler, the dose delivered to the superfi- cial regions of the patient could be inadequate.

Fig. 31.6. The compensator design from showing the information provided to the machine shop for fabrication of the alu- 31.7.1 minum compensators. For the position on the lower extremi- Patient Treatment ties compensator indicated by “Mark”, a small peg is inserted into the side of the compensator. This peg aids in aligning the To ensure that all the information is accurately compensator with the knee and the ankle when the patient is in the treatment position transferred to the treatment room, the first setup of every patient is rigorously checked. The treatment position is checked for accuracy versus the data recorded on the setup sheet (Fig. 31.2). Next, it is verified that the patient is positioned within the uniformly flat portion of the radiation field. It is verified that the upper arms are properly positioned to provide shielding for the lungs so that they do not receive excessive dose, and that the forearms and hands are in line with the thighs. The fit, size, and positioning of the compensating filters are also checked to ensure that the proper amount of compensation is being applied to each anatomical a region. For the lower extremities compensator, positioning is accomplished by aligning the pegs on the side of the compensator (indicated by “Mark” on the compensator design form, Fig. 31.6) with the knee and the back of the heel. The head and neck compensator is positioned so that compensation begins at the mid-shoulder and extends beyond the top of the head. The lung compensator, when required, is placed with the superior border of the compensator at the sternal notch and perpendicular to the back of the treatment couch. The final check before irradiation is to make sure that the beam spoiler is in place and that it is 20 cm or closer to the patient’s b most proximal surface. Fig. 31.7a,b. The completed aluminum compensators used for the bilateral total body technique. a The aluminum compensators for the lower extremities, lung, and head and neck (from 31.7.2 left to right). b An illustration of the aluminum compensa- Dose Verification tors attached to the block tray of the linear accelerator. The head and lower extremities compensators are attached using clamps while the lung compensator is mounted on the tray The dose delivered to the patient during TBI has been using double-sided tape verified using both lithium fluoride (LiF) thermolu- 794 K. E. Dusenbery and B. J. Gerbi minescent dosimetry (TLD) chips and encapsulated midplane of the pelvis delivered in 11 125-cGy frac- powder. The dosimeters for the head and neck region tions using 3 fractions per day at approximately 4.5- were taped to the side of these regions and covered h intervals. 6-MV X-rays are used at a dose rate of by 2.5 cm of wax bolus. The location of the TLDs 10–19 cGy/min at the midline of the pelvis, which for the mid-mediastinal readings was between the is the prescription point. For each X-ray treat- upper arm and the chest wall. The TLDs for the lower ment, 2.1-cm thick cerrobend lung blocks are used extremities were all placed between the legs at the to reduce the dose to the lungs by approximately indicated locations. The results of these measure- 50%. The chest wall overlying the lungs, which were ments shown in Table 31.4 illustrates that there is shielded by the lung blocks, are given an additional fairly good dose uniformity throughout the entire 600 cGy to dmax using electron beams of appropri- treatment region when using parallel-opposed high- ate energy. The electron energy used for these chest energy photon beams. wall boost fields is selected to place the 90% isodose For routine treatment, TLD powder capsules line at the lung–chest wall interface. In addition, all embedded between 1-cm slabs of plastic are placed male patients receive a testicular boost of 400 cGy between the patient’s legs as close to the groin for to dmax on day 1. The electron energy for this boost the first treatment. This is done to ensure that the is chosen to set the 90% isodose at the posterior proper dose is being delivered. surface of the scrotum. A summary of the patient treatment schedule is shown in Table 31.6. The workup for the TBI patients consists of a 31.7.3 simulation procedure to obtain lung block shape Dose Prescription and position during treatment, measurements of patient thickness, and locating the CT scan region The usual dose prescribed using this technique is that will be used to determine the optimum electron 165 cGy twice daily for 4 days for a total of eight frac- energy for the chest wall boost. Details of the patient tions. This results in a cumulative dose of 1320 cGy. workup and treatment procedures are given below. Each fraction is separated by at least 6 h. The dose Simulation and patient measurements. Three rate is between 10 Gy/min and 19 cGy/min. A sum- steps are associated with the simulation of the mary of the patient treatment schedule is shown in patient: (1) fit the patient within the available field Table 31.5. size, (2) take both an anterior and a posterior chest radiograph for the location of lung blocks, and (3) measure and record AP patient thickness at specific anatomical sites. 31.8 Patient positioning within the treatment field. Anteroposterior TBI The simulation of the patient is performed inside the treatment room with the gantry rotated to the An anteroposterior (AP) TBI technique used at lateral treatment position. The gantry is rotated to the University of Minnesota is adapted from that provide the best coverage of the patient within the developed at the Memorial Sloan Kettering Hospital visible field. However, the gantry angulation should in New York (Shank et al. 1983). The patients are not deviate by more than 2° from the lateral treat- treated in either a standing or reclining position, ment position so that the proper treatment distance alternating anterior and posterior surfaces for each is maintained. The treatment room is preferred over fraction. The prescription dose is 1375 cGy to the the simulator because fitting the patient within

Table 31.4. Lithium fluoride thermoluminescent chip and disposable powder capsule measurement showing percentage of prescribed dose to various anatomical locations for the right and left lateral TBI technique. Aluminum compensators were used to account for differences in thickness. These results are for the 10-MV right–left lateral technique Anatomical location Head Neck Chest wall Pelvis Thigh Knee Ankle Oral cavity Mean 095.5 099.8 097.8 102.1 097.3 097.2 099.9 109.0 Standard deviation 005.94 007.20 005.76 005.11 006.04 006.54 006.63 010.6 Maximum 110 122 116 111 118 113 116 143 Minimum 084 088 083 090 087 085 088 093 Number 036 035 035 036 036 036 035 020 Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 795

Table 31.5. Summary of patient treatment schedule for right and left lateral total body irradiation treatment Radiation therapy: BMT day Day 1: -4 Day 2: -3 Day 3: -2 Day 4: -1 TBI fractions 1, 2: 18-MV or TBI fractions 3, 4: 18-MV or TBI fractions 4, 6: 18-MV or TBI fractions 7, 8: 18-MV or 25-MV X-rays, 165 cGy/frac- 25-MV X-rays, 165 cGy/frac- 25-MV X-rays, 165 cGy/frac- 25-MV X-rays, 165 cGy/fraction tion tion tion

Table 31.6. Summary of patient treatment schedule for standing total body technique showing timing of total body X-ray and electron treatments BMT day Day 1: -7 Day 2: -6 Day 3: -5 Day 4: -4 TBI fractions 1, 2, 3: 6-MV TBI fractions 4, 5, 6: 6-MV TBI fractions 7, 8, 9: 6-MV TBI fractions 10, 11: 6-MV X- X-rays, 125 cGy/fraction X-rays, 125 cGy/fraction X-rays, 125 cGy/fraction rays, 125 cGy/fraction Fraction 1: testicular electron Fraction 7: electron chest wall Fraction 10: electron chest wall boost, 400 cGy/fraction boost, 300 cGy/fraction boost, 300 cGy/fraction

a b

Fig. 31.8a,b. a The buildup characteristics of 10-MV X-rays for a single incident beam both with and without the beam spoiler in place. The measurements are normalized to dmax for the single fi eld in this fi gure. b The percentage surface dose for parallel- opposed 10-MV beams for both open and degraded fi elds normalized to the dose delivered to the midplane of a 25-cm-thick patient

the available field size is a crucial step at our insti- Films for lung blocks. Once the position of the tution. For our treatment distance of 410 cm, the patient within the treatment field has been deter- diagonal field size is 170 cm (5'8") inside the 90% mined, chest radiographs are taken. The anterior isodose line. Patients shorter than 170 cm (5'8") can film is taken with a small BB placed at the tops of be easily treated in the standing position. However, the diaphragms. The distance of this BB below the it is necessary for taller patients to sit on the seat of sternal notch is measured and recorded on the form the treatment stand in order to fit within the treat- illustrated in Figure 31.9. Additionally, a posterior ment field. Although this is not the optimum treat- radiograph is taken with a BB placed at C7. The loca- ment position, acceptable dose uniformity can still tion of the BB is indicated on the form and marked be achieved. with a tattoo. Also recorded are the gantry angle 796 K. E. Dusenbery and B. J. Gerbi

of the beam. The information on this form is later used to duplicate the patient treatment position. Patient thickness measurements. Following the radiographs, AP separations are measured at the head, neck, sternal notch, mid-mediastinum, umbilicus, pelvis, knees, and ankles. The target dose is prescribed at the midplane thickness of the pelvis. The names of the individuals who made and checked the measurements are recorded. Treatment planning computed tomography (CT) scans. The staff physician next outlines the lung blocks on both the anterior and posterior chest radiographs. For adult patients, the blocks are drawn so that there is a 2-cm margin between both the dia- phragm and edge of the vertebrae and a 1.5-cm gap between the edge of the block and the rib cage. Once these lung blocks are indicated on the films, the patient is taken for treatment planning CT scans. A CT scan is then taken through the region of the lung blocks. Treatment planning is performed on the CT scans to ensure proper dose coverage. Ultra- sound scans are occasionally performed instead of CT scans, when the values of chest wall thickness of Fig. 31.9. The form used to document the patient treatment the patient lying supine compared with in the stand- position when using the standing total body technique ing position are significantly different, for instance in women with pendulous breasts. Once the scanning is completed, computerized of the accelerator, the seat extension and height, treatment planning is performed to determine the the separation of the supports located under the appropriate electron beam energy for the electron arms, and the position of the hand rests. For shorter chest wall boost. This is done by placing the 90% patients, an additional wooden platform is placed isodose line at the lung chest wall interface. A typi- below their feet to position them more in the center cal treatment plan is illustrated in Figure 31.10.

Fig. 31.10. A computerized treatment plan done to determine the proper electron energy for the chest wall boost ﬁ elds. The objective is to place the 90% isodose line at the lung–chest wall interface Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 797

Construction of lung blocks and electron cut- outs. The lung blocks are constructed from the outlines drawn on the anterior and posterior chest films and are held together by a plastic plate that maintains the proper block separation (Fig. 31.11a). The cerrobend blocks are 2.1 cm thick, which is approximately the half-value thickness, including scatter, for 6-MV photons. The cerrobend cut-out used for the electron chest wall boost fields is an exact negative of the anterior and posterior lung blocks (Fig. 31.11b). a

31.8.1 Patient Treatment Technique

Total body photon irradiation. The treatment is delivered using 6-MV X-rays with a dose rate between 10 cGy/min and 19 cGy/min at the midplane of the pelvis. The patient is treated in the standing position resting against the back plate of the total body b treatment stand that was specifically designed for this treatment (Fig. 31.12). The treatment distance Fig. 31.11a,b. The apparatus used to shield the lungs during for this particular setup is 410 cm source–axis dis- standing total body irradiation. a The proper separation of the tance (SAD) to the midline of the pelvis. two cerrobend lung blocks is maintained by the acrylic plate. The Lexan hook is used to suspend the blocks from the plastic The lungs are shielded with the appropriate lung plate that is placed in front of the patient when positioned in blocks throughout the total body photon portion of the total body treatment stand. This arrangement allows easy the treatment. The lung blocks are hung by a Lexan adjustment of both the height of the blocks and their right–left hook from the anterior plate of the total body treat- placement with respect to the patient. b The cerrobend insert ment stand. The location of the top of the lung blocks that is used for the chest wall electron boost treatment exactly matches the shape of the cerrobend lung blocks is positioned at the level of the skin tattoos and is verified with measurements from bony landmarks. Verification films confirm the positioning of the blocks during the photon treatments. A 1-cm-thick acrylic beam spoiler is placed between the patient and the beam to produce a high dose on the patient’s skin surface. The screen is located 20 cm or less from the patient surface. The skin dose with this location of the beam spoiler is approximately 92% of the delivered midline dose for the 6-MV beam. Electron chest wall boost. For fractions 7 and 10, an electron chest wall boost is given to that portion of the chest wall that was shielded by the lung blocks. A special couch extension has been designed so that both adult and pediatric patients are in the same upright treatment position for the chest wall boost fields as they were for the standing total body treatments (Fig. 31.13). The prescribed dose is 600 cGy to dmax, delivered in two 300-cGy fractions. The selection of electron energy and the need for bolus is based on the results of computerized treatment Fig. 31.12. The standing total body treatment position with the back of the patient resting against the back plate of the total planning using the CT scan so that the 90% isodose body treatment stand. The lung blocks are shown, in position, line is placed at the lung–chest wall interface. hanging from the front acrylic plate 798 K. E. Dusenbery and B. J. Gerbi

electron boost is also delivered with the patient in the supine position. LiF TLD was performed on several patients to establish the homogeneity of dose throughout the treatment field. The TLD chips were covered by approximately 1 cm of bolus to indicate the dose at dmax at these locations and were placed at the same locations for both anterior and posterior treatments. The results of the measurements, shown in Table 31.7, indicate an acceptable level of dose homogeneity for this treatment technique.

31.9 Normal Tissue Shielding

Shielding of normal tissues must be carefully consid- Fig. 31.13. A special couch extension designed to reproduce the ered in TBI because shielding may potentially reduce standing TBI treatment position when treating the electron the dose to the target volume (bone marrow cells, chest wall boost ﬁ elds. The device is separated into two pieces leukemic cells, and circulating stem cells). Despite for ease of handling and, since it is attached directly to the this concern, there are situations in which partial couch, it has the same range of motion as the couch. Patients up to approximately 5 feet tall can be treated in the standing shielding of critical tissues, including the lungs, kid- position, while taller patients are treated in a seated position. neys, eyes (lens), and brain, is considered. This style of chair keeps the back of the patient in about the same orientation when seated as when they are standing 31.9.1 Lung Shielding Testicular boost. Male patients are given a testicular electron boost on the first day of treatment. The Because pneumonitis is a leading cause of death prescribed dose is 400 cGy to dmax in one fraction. after SCT, with total dose of TBI implicated as a The patient is treated in the supine position with a potential contributing cause, partial blocking of the sheet of lead placed under the testes to minimize lung has been advocated. The dose received by the the dose to the rectal area. A 6-mm-thick sheet of wax bolus is placed between the lead and the posterior surface of the scrotum to reduce the amount of backscatter from the lead. The electron energy is based on the thickness of the testes and is chosen so that the 90% isodose line is at the posterior surface of the scrotum. Infant irradiation. Total body treatments for infants are done with the patient supine on a sep- arate treatment couch positioned on the floor. We have found that the treatments are best performed with sedation or anesthesia. The gantry is directed vertically down for these cases and the collimator is rotated 45° to produce the largest available field size. A 1-cm acrylic beam spoiler is positioned approximately 20 cm above the torso of the patient both to provide a high surface dose and to support the lung Fig. 31.14. An illustration showing the treatment position used blocks used for the anterior and posterior X-ray fields. for pediatric patients. The lung blocks are placed on top of The lower extremities are simply bolused to provide the acrylic beam spoiler. The lower extremities are bolused to a high skin surface dose (Fig. 31.14). The chest wall provide a high dose at the surface Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 799

Table 31.7. Lithium fluoride thermoluminescent dosimeters (TLD) establish homogeneity of dose for standing TBI technique. The TLD chips were covered by approximately 1 cm of bolus to indicate the dose at dmax at these locations. The chips were in place during both anterior and posterior treatments. SD standard deviation, D deviation Anatomical Location Prescription dose (%) Mean SD Highest D Lowest D n Umbilicus 097.4 04.21 104 090 27 Right palm – opposite knuckles 113.9 09.15 134 095 27 Right palm – heel of hand 104.7 08.76 117 090 06 Between breasts 101.0 05.97 118 092 27 Right hip 113.0 09.41 137 098 26 Left inner thigh 107.9 09.59 131 093 25 Perineal 105.2 06.38 120 093 23 Left outer ankle 112.3 11.6 130 103 07 Sternal notch 103.6 06.36 113 085 27 Forehead 097.0 07.44 109 083 26 Left lateral calf 111.7 08.77 128 092 27 Top of head 109.7 11.6 136 096 18 Under lung block 062.5 09.79 086 048 26 Neck-thyroid notch 100.8 06.37 110 092 06

lungs is influenced by both the irradiation geometry of pneumonitis, omit the electron beam chest wall as well as lung density. At the University of Minne- boost. No increased risk of leukemia relapse has sota, when delivering TBI with right and left lateral been noted, but a prospective trial is lacking. fields, the arms are placed at the sides; the thickness of the arms is considered in determining whether additional compensation is needed to reduce the 31.9.2 lung dose to within 10% of the dose received at the Kidney Shielding prescription point (level of the umbilicus at midplane). Often no additional compensation is needed The risk of renal injury after SCT is dependent on to achieve this goal, but if needed, tissue compensa- multiple factors, including previous chemother- tors are placed to reduce the lung dose to within 10% apy, use of nephrotoxic antibiotics, and therapies of the prescription dose. directed at the prevention and treatment of GVHD Using a similar right and left lateral technique, (Moulder et al. 1987, 1988; Lawton et al. 1989, in addition to using the arms to decrease lung dose, 1992; Moulder and Fish 1989, 1991; Emminger some institutions use partial blocks to reduce the et al. 1991; Cowen et al. 1992; Cole et al. 1994; lung dose further, usually to an arbitrary amount Miralbell et al. 1996). In a recent review of the (for instance 1000 cGy). incidence of acute renal failure in patients treated For AP–posteroanterior (PA) fields, partial atten- at the University of Minnesota SCT program, up to uation blocks (80–90% transmission) or thicker 30% of patients undergoing SCT in 1993 had acute blocks (usually one half-value layer; HVL) can be renal failure, defined as a doubling of creatinine placed in front of the beam to decrease the lung over the baseline creatinine (Lane et al. 1994). Of dose to the desired amount. With one HVL block, these patients, 10% required dialysis. the underlying ribs receive approximately half of the Late-onset renal failure occurs in up to 20% of prescription dose and electron beams of the appro- survivors of SCT. On the beneficial effect of partial priate energy can be used to “boost” the underly- kidney blocking in the setting of T-depleted SCT, ing ribs. A CT scan through the lung can be used Lawton (Lawton et al. 1992) found that the inci- to determine the appropriate electron energy. This dence of chronic renal failure was reduced from technique was initially reported at Memorial Sloan 26% to 6% when posterior 1-HVL renal blocks were Kettering Cancer Center (Shank et al. 1983) and placed, reducing the estimated kidney dose from was used at the University of Minnesota for about 14 Gy to 12 Gy (given at 200 cGy twice a day). In 10 years, although has now largely been abandoned another series of 79 patients transplanted with TBI- as it is considerably more difficult to administer. containing regimens, Miralbell et al. (Miralbell et Some institutions, in an effort to decrease the risk al. 1996) reported that the 18-month probability of 800 K. E. Dusenbery and B. J. Gerbi renal dysfunction-free survival decreased from 95, with the patient in the TBI treatment position, if pos- to 74, to 55% for patients conditioned with 10, 12, sible. Intravenous contrast is given and the thymus and 13.5 Gy, respectively. The other factor that pre- is delineated. Patients treated via this protocol are dicted for renal dysfunction was the risk of develop- treated with AP and PA total body fields with 5- ing GVHD. Renal dysfunction-free survivals were HVL cerrobend thymus blocks positioned over the 93% for patients at lower risk of GVHD and 52% for thymus gland in both the anterior and posterior patients with a high GVHD risk (e.g., unrelated allo- fields (Fig. 31.15). To design these blocks, a 1-cm geneic SCT, absence of T-cell depletion). margin is placed around the outline of the thymus on the AP and PA CT contours. Additionally, aluminum compensators are placed over the lungs with both the AP and PA fields to diminish the lung dose 31.10 to be no more than the prescription point dose. Thus Gonad Shielding far, only a handful of patients have been treated on this regimen and whether there is speedier immune A common late complication after SCT is sterility. reconstitution remains to be seen. In certain diseases, such as acute lymphoblastic leukemia, the gonads are considered sanctuary sites, and shielding would possibly increase the risk of 31.10.2 relapse (Quaranta et al. 2004). In other situations, TomoTherapy especially SCT for non-malignant diseases, there is probably less risk. The challenge in shielding either It is theoretically desirable to deliver radiation only of the testes is to use sufficient attenuating material to the immune organs and bone marrow spaces and to do it in such as way as to minimally shield while sparing sensitive structures such as the brain, marrow sites. The challenges in shielding the ova- lens, lung, and kidneys. Intensity modulated radio- ries are even more complicated because they lie in therapy (IMRT) planning could accomplish this, the pelvis near a rich supply of marrow; they are but most systems are limited by field size issues. difficult to visualize, especially in young girls; and Additionally, accurate IMRT depends on a repro- they are mobile and may move between the planning ducible patient position, which is complicated when process and treatment days. Despite these obstacles, considering treating the entire marrow spaces. The we have attempted to decrease the dose to the gonads on occasion, usually at the request of a parent or as part of a protocol. For patients transplanted for sickle cell anemia or thalassemia, the SCT goal is to provide a supply of normal red blood cells. Even partial engraftment ameliorates the symptoms of the disease. For this protocol, we localize the ovaries by ultrasound and use five HVL cerrobend blocks anteriorly and posteriorly to decrease the dose to the ovaries. The testicles are placed in a cerrobend “clam shell”. Instead of TBI, total lymphoid irradiation to a dose of 500 cGy is used.

31.10.1 Thymus Shielding

At the University of Minnesota, we are conducting a trial in which the thymus is blocked in the hopes of speeding immune reconstitution in patients with Fanconi Anemia undergoing unrelated donor trans- Storek plantation ( et al. 2003). The thymus is diffi- Fig. 31.15. Distally reconstructed radiograph showing location cult to visualize, especially in older children. For this of thymus block (5 HVL) and lung block (1 HVL) used in protocol, a treatment planning CT scan is performed Fanconi anemia Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 801 technology to accomplish this is now available with TomoTherapy (Mackie et al. 2003; Beavis 2004). The TomoTherapy radiation system is a linear accelerator mounted in the head of a spiral CT unit. IMRT can be delivered as beams spiral down the axis of a patient supine on the treatment couch. The beams can be planned to deliver dose to the bones and bone marrow, liver and spleen as well as major nodal groups and to relatively spare the lungs and kidneys (Fig. 31.16). Prior to treatment, a conformation CT is performed and the patients position on the treatment couch verified and adjusted, so as to match the position the patient was in for planning. There are technical hurdles to overcome in order to accomplish this, but it holds the promise of possibly being able to decrease the toxicity of TBI and increase the dose to the tumor and marrow sites thus decreasing the risk of non-engraftment or relapse.

31.10.2.1 Special Considerations for TBI in Young Children

A fundamental requirement for TBI is immobility during treatment. Whereas many children even as young as 3 years of age are able to cooperate and remain immobile with the encouragement of their parents, many children must be anesthetized. We usually try to determine at the time of simulation whether a patient will require anesthesia. Clues about whether a patient will be cooperative include Fig. 31.16. Example of the isodose distribution achieved with TomoTherapy. Because this is delivered locally, an extremely whether the patient willingly leaves his or her par- conformal dose distribution can be achieved, thus delivering ents for the measurements, whether they listen to the the dose only to the narrow spaces, while avoiding irradiation instructions the therapist gives, and how anxious of sensitive structures (lung, kidney, liver) they appear. Additionally, the parents usually have a good indication of how their child has done with other medical procedures. In an effort to avoid anes- patient is prone, and the airway is more difficult to thesia, we sometimes arrange for a potential TBI keep patent. patient come to the department for several consecu- If TBI under general anesthesia is scheduled, the tive days so he or she can become acquainted with patient fasts for 6 h before the scheduled procedure. our therapists. The therapist will spend 10–15 min For infants, an interval of 4 h from intake of for- with the patient in the treatment room practicing for mula is sufficient. On arrival to the radiation ther- the TBI treatment. As there are intercoms and video apy room, atropine and propofol are administered monitors, the therapist can place the patient in the intravenously. Dolasetron is effective at preventing treatment position, leave the room, and talk to the nausea during and after the treatment. patient over the intercom. With practice, even young As the patient loses consciousness, a blood pres- patients are often able to be spared anesthesia. sure cuff is placed around the upper arm and the Obviously, there are situations where anesthesia electrocardiogram (ECG) is monitored continu- is necessary. Anesthesia for TBI presents unique ously. Pulse oximetry is used for continuous moni- situations not ordinarily encountered by most anes- toring of oxygen saturation. Supplemental oxygen thesiologists. Foremost is the fact that the anesthe- is administered with nasal prongs. A continuous siologist cannot be in the treatment room during drip of propofol is started. The patient is placed the TBI. Additionally, for the AP/PA technique, the in the treatment position. The child’s head is fixed 802 K. E. Dusenbery and B. J. Gerbi firmly in position by a sponge rubber donut or Sty- of 9.9% at 1–3 years after transplantation (Bhatia et rofoam. Adhesive tape is used to secure the head in al. 1996). Second neoplasms were more common in the appropriate position so that airway patency and patients likely to have GVHD. ventilation are secured. Two closed-circuit television cameras are focused on the patient and on the physiological monitor con- sole. When the patient is ready for irradiation, all References attendant personnel withdraw from the treatment room. During the treatment, airway and respira- AAPM, American Association of Physicists in Medicine (task tory adequacy are observed constantly by means of Group 2) (1986) The physical aspects of total and half body photon irradiation. AAPM Report no 17 a zoom television monitor system, while blood pres- Abraham R et al. (1999) Intensification of the stem cell trans- sure, ECG, and pulse oximetry are monitored on the plant induction regimen results in increased treatment- second television monitor. related mortality without improved outcome in multiple After the treatment is complete, the patient is trans- myeloma. Bone Marrow Transplant 24:1291–1297 ferred to the post-anesthetic recovery room, where Almond PR et al. (1999) AAPM’s TG-51 protocol for clinical reference dosimetry of high-energy photon and electron surveillance is continued until full arousal occurs. beams. Med Phys 26:1847 Patients who receive several treatments on consecu- Aristei C et al. (2002) Cataracts in patients receiving stem cell tive days show increased tolerance to propofol and transplantation after conditioning with total body irradia- the dose may need to be increased accordingly. tion. Bone Marrow Transplant 29:503–507 Auner HW et al. (2002) Infectious complications after autologous hematopoietic stem cell transplantation: comparison of patients with acute myeloid leukemia, malignant lym- 31.10.2.2 phoma, and multiple myeloma. Ann Hematol 81:374–377 Complications Following Preparation With TBI Beavis AW (2004) Is tomotherapy the future of IMRT? Br J Radiol 77:285–295 The major causes of morbidity and mortality follow- Bhatia S et al. (1996) Malignant neoplasms following bone Auner marrow transplantation. Blood 87:3633–3639 ing a SCT are infectious complications ( et al. Cardozo BL et al. (1985) Lung damage following bone marrow 2002). Additionally, interstitial pneumonitis devel- transplantation: I. the contribution of irradiation. Int J ops in up to 20% of transplanted patients depend- Radiat Oncol Biol Phys 11:907–914 ing on the source of the marrow and previous thera- Carlson K et al. (1994) Pulmonary function and complications pies received (Cardozo et al. 1985; Abraham et al. subsequent to autologous bone marrow transplantation. 1999; Emmanouilides 2003; Carruthers Bone Marrow Transplant 14:805–811 et al. and Carruthers SA, Wallington MM (2004) Total body irradiation Wallington 2004). Acute side effects of TBI include and pneumonitis risk: a review of outcomes. Br J Cancer nausea and vomiting, alopecia, diarrhea, low grade 90:2080–2084 fever, mucositis, and pancytopenia. Intermediate side Cole CH et al. (1994) Intensive conditioning regimen for bone effects include interstitial pneumonitis, veno-occlu- marrow transplantation in children with high-risk haema- tological malignancies. Med Pediatr Oncol 23:464–469 sive disease, and nephrotoxicity. Late side effects Colombat P et al. (2000) Value of autologous stem cell trans- include restrictive lung disease, possible decreased plantation with purged bone marrow as first-line therapy for growth, endocrine abnormalities (especially hypo- follicular lymphoma with high tumor burden: a GOELAMS thyroidism) sterility, cataracts, chronic renal failure, phase II study. Bone Marrow Transplant 26:971–977 and neurological damage. Sanders reported that boys Cornetta K et al. (2005) Umbilical cord blood transplantation in adults: results of the prospective Cord Blood Transplanta- given single-fraction TBI were significantly shorter tion (COBLT). Biol Blood Marrow Transplant 11:149–160 than boys given fractionated TBI (P<0.03). The same Cowen D et al. (1992) Regimen-related toxicity in patients (non-significant) trend was demonstrated in girls. undergoing BMT with total body irradiation using a sweep- Few studies of neuropsychiatric testing of patients ing beam technique. Bone Marrow Transplant 10:515–519 treated after TBI exist. One might expect lower Dusenbery KE et al. (1996) Autologous bone marrow transplantation in acute myeloid leukemia: the University cumulative doses to be associated with less impair- of Minnesota experience. Int J Radiat Oncol Biol Phys ment, but data are lacking. Younger patients seem to 36:335–343 be at a higher risk of neurological damage (Faraci Emmanouilides C et al. (2003) Localized radiation increases et al. 2002; Rubin et al. 2005). morbidity and mortality after TBI-containing autologous The incidence of second tumors after SCT is low; stem cell transplantation in patients with lymphoma. Bone Marrow Transplant 32:863–867 Seattle reported 4 in 1800 patients. At the Univer- Emminger W et al. (1991) Is treatment intensification by sity of Minnesota, 53 second malignant neoplasms adding etoposide and carboplatin to fractionated total developed among 2150 patients for an estimated risk body irradiation and melphalan acceptable in children Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation 803

with solid tumors with respect to toxicity? Bone Marrow phocyte deplete bone marrow transplantation in adult Transplant 8:119–123 patients. Int J Radiat Oncol Biol Phys 23:681–686 Faraci M et al. (2002) Severe neurologic complications after Leshem B, Vourka-Karussis U, Slavin S (2000) Correlation hematopoietic stem cell transplantation in children. Neu- between enhancement of graft-versus-leukemia effects fol- rology 59:1895–1904 [erratum (2003) 60:1055] lowing allogeneic bone marrow transplantation by rIL-2 Fehr T, Sykes M (2004) Tolerance induction in clinical trans- and increased frequency of cytotoxic T-lymphocyte pre- plantation. Transplant Immunology 13(2): p. 117–30. cursors in murine myeloid leukemia. Cytokines Cell Mol Freedman AS et al. (1998) High-dose chemoradiotherapy and Ther 6:141–147 anti-B-cell monoclonal antibody-purged autologous bone Mackie TR et al. (2003) Image guidance for precise conformal marrow transplantation in mantle-cell lymphoma: no evi- radiotherapy. Int J Radiat Oncol Biol Phys 56:89–105 dence for long-term remission (comment). J Clin Oncol Mahmoud HK et al. (1985) Bone marrow transplantation for 16:13–18 chronic granulocytic leukaemia. Klin Wochenschr 63:560– Gatti RA et al. (1968) Immunological reconstitution of sex- 564 linked lymphopenic immunological deficiency. Lancet McCullough J et al. (1989) The National Marrow Donor Pro- 2:1366–1369 gram: how it works, accomplishments to date. Oncology Hall EJ (1994) Radiobiology for the radiologist, 4th edn. J.B. (Huntingt) 3:63–68 Lippincott, Philadelphia. xii, p 478 Miralbell R et al. (1996) Renal toxicity after allogeneic bone Hawley RG et al. (1996) Retroviral vectors for production marrow transplantation: the combined effects of total- of interleukin-12 in the bone marrow to induce a graft- body irradiation and graft-versus-host disease. J Clin versus-leukemia effect. Ann NY Acad Sci 795:341–345 Oncol 14:579–585 Heslop HE, Rooney CM, Brenner MK (1995) Gene-marking Molls M, Budach V, Bamberg M (1986) Total body irradiation: and haemopoietic stem-cell transplantation. Blood Rev the lung as critical organ. Strahlentherapie und Onkologie 9:220–225 162:226–232 Iannone R et al. (2003) Results of minimally toxic nonmy- Moulder JE, Fish BL (1989) Late toxicity of total body irradia- eloablative transplantation in patients with sickle cell tion with bone marrow transplantation in a rat model. Int anemia and beta-thalassemia. Biol Blood Marrow Trans- J Radiat Oncol Biol Phys 16:1501–1509 plant 9:519–528 Moulder JE, Fish BL (1991) Influence of nephrotoxic drugs on Imamura M, Hashino S, Tanaka J (1996) Graft-versus-leuke- the late renal toxicity associated with bone marrow trans- mia effect and its clinical implications. Leuk Lymphoma plant conditioning regimens. Int J Radiat Oncol Biol Phys 23:477–492 20:333–337 Karanes C (2003) Unrelated donor stem cell transplant: donor Moulder JE, Fish BL, Abrams RA (1987) Renal toxicity fol- selection and search process. Pediatr Transplant 7[Suppl lowing total-body irradiation and syngeneic bone marrow 3]:59–64 transplantation. Transplantation 43:589–592 Khan FM, Moore VC, Burns DJ (1970) The construction of com- Moulder JE, Fish BL, Holcenberg JS, Cheng M (1988) Effect of pensators for cobalt teletherapy. Radiology 96:187–192 total-body irradiation with bone marrow transplantation Khan FM et al. (1980) Basic data for dosage calculation and on toxicity of cisplatin. NCI Monogr 6:29–33 compensation. Int J Radiat Oncol Biol Phys 6:745–751 Parr MD, Messino MJ, McIntyre W (1991) Allogeneic bone Kim TH et al. (1985) Interstitial pneumonitis following total marrow transplantation: procedures and complications. body irradiation for bone marrow transplantation using Am J Hospital Pharmacy 48:127–137 two different dose rates. Int J Radiat Oncol Biol Phys Peters C et al. (2003) Hematopoietic cell transplantation for 11:1285–1291 inherited metabolic diseases: an overview of outcomes and Kirby TH, Hanson WF, Cates DA (1988) Verification of total practice guidelines. Bone Marrow Transplant 31:229–239 body photon irradiation dosimetry techniques. Med Phys Petersdorf E et al. (1998) Effect of HLA matching on outcome 15:364–369 of related and unrelated donor transplantation therapy for Klingemann HG (1996) Role of postinduction immunotherapy chronic myelogenous leukemia. Hematol Oncol Clin North in acute myeloid leukemia. Leukemia 10[Suppl 1]:S21–S22 Am 12:107–121 Korbling M et al. (1991) Autologous blood stem cell (ABSCT) Quaranta BP et al. (2004) The incidence of testicular recur- versus purged bone marrow transplantation (pABMT) in rence in boys with acute leukemia treated with total body standard risk AML: influence of source and cell composi- and testicular irradiation and stem cell transplantation. tion of the autograft on hemopoietic reconstitution and Cancer 101:845–850 disease-free survival. Bone Marrow Transplant 7:343–349 Remberger M et al. (2002) The graft-versus-leukaemia effect in Krishnamurti L et al. (2003) Availability of unrelated donors haematopoietic stem cell transplantation using unrelated for hematopoietic stem cell transplantation for hemoglo- donors. Bone Marrow Transplant 30:761–768 binopathies. Bone Marrow Transplant 31:547–550 Rubin J et al. (2005) Acute neurological complications after Lane PH et al. (1994) Outcome of dialysis for acute renal fail- hematopoietic stem cell transplantation in children. Pedi- ure in pediatric bone marrow transplant patients. Bone atr Transplant 9:62–67 Marrow Transplant 13:613–617 Schleuning M (2000) Adoptive allogeneic immunotherapy Lawton CA et al. (1989) Technical modifications in hyperfrac- – history and future perspectives. Transfusion Sci 23:133– tionated total body irradiation for T-lymphocyte deplete 150 bone marrow transplant. Int J Radiat Oncol Biol Phys Schouten HC et al. (2000) The CUP trial: a randomized study 17:319–322 analyzing the efficacy of high dose therapy and purging Lawton CA et al. (1992) Influence of renal shielding on the in low-grade non-Hodgkin’s lymphoma (NHL). Ann Oncol incidence of late renal dysfunction associated with T-lym- 11[Suppl 1]:91–94 804 K. E. Dusenbery and B. J. Gerbi

Shank B et al. (1983) Hyperfractionated total body irradia- Thomas ED (1997) Pros and cons of stem cell transplantation tion for bone marrow transplantation. Results in seventy for autoimmune disease. J Rheumatol 48[Suppl]:100–102 leukemia patients with allogeneic transplants. Int J Radiat Valls A et al. (1989) Total body irradiation in bone marrow Oncol Biol Phys 9:1607–1611 transplantation: fractionated vs single dose. Acute toxicity Standke E (1989) Fundamentals, trends and our experiences and preliminary results. Bulletin du Cancer 76:797–804 with total body irradiation (TBI) before bone marrow van Besien K et al. (2003) Comparison of autologous and allo- transplantation (BMT). Folia Haematologica – Internation- geneic hematopoietic stem cell transplantation for follicu- ales Magazin fur Klinische und Morphologische Blutforsc- lar lymphoma. Blood 102:3521–3529 hung 116:481–485 Van Dyk J, Keane TJ, Rider WD (1982) Lung density as mea- Steingrimsdottir H et al. (2000) Immune reconstitution after sured by computerized tomography: implications for autologous hematopoietic stem cell transplantation in rela- radiotherapy. Int J Radiat Oncol Biol Phys 8:1363 tion to underlying disease, type of high-dose therapy and Wood KJ, Prior TG (2001) Gene therapy in transplantation. infectious complications. Haematologica 85:832–838 Curr Opin Mol Therapeut 3:390–398 Storek J et al. (2003) Interleukin-7 improves CD4 T-cell recon- Zecca M et al. (2002) Chronic graft-versus-host disease in chil- stitution after autologous CD34 cell transplantation in dren: incidence, risk factors, and impact on outcome. Blood monkeys. Blood 101:4209–4218 100:1192–1200