31 Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation

31 Total Body Irradiation Conditioning Regimens in Stem Cell Transplantation

Kathryn E. Dusenbery and Bruce J. Gerbi

K. E. Dusenbery, MD

University of Minnesota Medical School, Department of Ra- diation Oncology, MMC436, 420 Delaware St. S.E., Minneapo- lis, MN 55455, USA

B. J. Gerbi, PhD

Associate Professor, Therapeutic Radiology – Radiation On- cology, University of Minnesota, Mayo Mail Code 494, 420 Delaware St SE, Minneapolis, MN 55455, USA

CONTENTS

31.1 Conditioning Regimen 786 31.2 Fractionation and Dose Rate 787 31.3 Sequence 788

31.4 Technical Aspects 788 31.5 Right and Left Lateral TBI 788

31.6 Simulation and Patient Measurements 788 31.6.1 Compensators for TBI 790

31.7 Compensator Design 791 31.7.1 Patient Treatment 793 31.7.2 Dose Verification 793 31.7.3 Dose Prescription 794 31.8 Anteroposterior TBI 794 31.8.1 Patient Treatment Technique 797 31.9 Normal Tissue Shielding 798 31.9.1 Lung Shielding 798

31.9.2 Kidney Shielding 799 31.10 Gonad Shielding 800 31.10.1 Thymus Shielding 800 31.10.2 TomoTherapy 800

31.10.2.1 Special Considerations for TBI in Young Children 801

31.10.2.2 Complications Following Preparation With TBI 802 References 802

immune (Thomas 1997) or genetic disorders are being offered transplantation (Iannone et al. 2003;

Peters et al. 2003). The rationale for SCT differs depending on the disease treated and the source of bone marrow cells. In both autologous and alloge- neic SCT for malignant diseases, the rationale for SCT is to allow chemotherapeutic dose escalation.

The SCT “rescues” the patient from what otherwise would be a lethal dose of chemotherapy.

In an allogeneic SCT, a healthy donor marrow regenerates in its place and the infused donor lymphocytes have a proven anti-tumor effect (graft versus leukemic effect) (Schleuning 2000;

Remberger et al. 2002; Zecca et al. 2002). Donor lymphocytes can also serve to supply absent enzyme for patients with inborn errors of metabo- lism. In autologous SCT, the infused marrow may be contaminated with malignant cells. Various methods have been used to purge the marrow of residual malignant cells (Freedman et al. 1998;

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 autologous transplantation (Hawley et al. 1996;

Imamura et al. 1996; Klingemann 1996; Leshem et al. 2000). In the future, the autologous cells may be manipulated with genes that confer relative che- motherapeutic resistance (Wood and Prior 2001), thus allowing for additional post transplantation chemotherapy with little damage to the new bone marrow (Heslop et al. 1995).

The development of HLA (human lymphocyte antigen) and MLC (mixed lymphocyte culture) assays allowed physicians to determine whether potential marrow donors were “histocompatible”

(i.e., matched by HLA antigens and non-reactive to MLC cultures) and therefore less likely to develop graft-versus-host disease (GVHD) (Mahmoud et al. 1985; Parr et al. 1991; Petersdorf et al.

1998). Initially, transplants were only performed between HLA-matched related donors, but, with Since the first successful bone marrow transplanta-

tion was performed at the University of Minnesota

in 1960 (Gatti et al. 1968), bone marrow and stem

cell transplantation (SCT) has gained prominence

as a therapy for a variety of diseases as outlined in

Table 31.1. The majority of bone marrow transplants

are carried out in an effort to eradicate malignant

disease, but a growing number of patients with auto-

the advent of effective therapies directed at decreas- ing the probability and severity of GVHD, matched unrelated donor transplants have become more common. The National Marrow Donor Program (NMDP) types potential bone marrow and stem cell donors. More than 16,000 transplants have been performed using unrelated donors provided by the NMDP (McCullough et al. 1989; Karanes 2003;

Cornetta et al. 2005). With more than four million donors listed in the registry, over 70% of patients can now find an HLA-A, -B, -DR phenotypic match at the initial search.

In recent years, in addition to related and unre- lated bone marrow donor sources, additional sources of pluripotential stem cells have been inves- tigated, including the use of umbilical cord blood (Cornetta et al. 2005), a rich source of stem cells.

A bank of HLA typed umbilical cord blood harvests has also been established (Krishnamurti et al.

2003).

Another source of pluripotential stem cells are circulating blood stem cells. These cells can be har- vested through leukapheresis, frozen for later use, then thawed and reinfused. In addition to sparing the donor the discomfort of a bone marrow har- vest, these peripheral stem cell harvests usually result in a more prompt engraftment than occurs with bone marrow infusions, resulting in a shorter period of pancytopenia and thus less risk of infec- tion (Korbling et al. 1991; Steingrimsdottir et al.

2000).

31.1

Conditioning Regimen

Presumed desired endpoints of the pre-transplan- tation conditioning regimen are to eradicate the recipient’s native bone marrow, immune suppress the recipient sufficiently to avoid rejection of the donor transplant, and to do this with minimal toxic- ity to other tissues. In some situations, these three goals are attainable with a chemotherapy-only con- ditioning regimen; however, multiple variables need to be considered including the age of the patient, the underlying disease, the source of the donor marrow, and whether the donor marrow is manipulated (i.e., T depleted) (Fehr and Sykes 2004).

At the University of Minnesota, total body irradia- tion (TBI) is generally part of the conditioning regi- mens for the situations outlined in Table 31.2. These situations include unrelated marrow or cord blood donor transplants, certain underlying malignancies that are considered radiosensitive [acute lymphocytic leukemia (ALL), multiple myeloma], and for patients in whom a TBI-containing conditioning regimen has been shown to be superior to a chemotherapy-only conditioning regimen [acute myeloid leukemia (AML) in second remission] (Dusenbery et al. 1996).

There are theoretical advantages and disadvan- tages of a TBI-containing preparative regimen. Most often patients undergoing SCT have been exposed to multiple chemotherapeutic regimens; therefore, potential SCT recipients may be relatively chemo- therapy “resistant.” As most patients undergo- ing SCT have not been irradiated previously, their malignant cells may be more radiation sensitive than chemotherapy sensitive. Additionally, there are known sanctuary sites where chemotherapy does not penetrate well, such as the central nervous system (CNS) or testicles. There are no sanctuary sites for irradiation and, in certain situations such as relapsed ALL, a TBI-containing regimen may be especially beneficial. Lastly, chemotherapy which is usually given intravenously (busulfan may be given orally) needs to be metabolized and eliminated from the body. It is known that chemotherapy pharma- cokinetics differ among patients resulting in some areas of the body exposed to higher or lower con- centrations of drug. TBI requires no metabolism for clearance and all areas of the body receive the same dose of irradiation. The disadvantages of using a TBI regimen are the potential late side effects, such as sterility, cataracts, and growth retardation, as well as the potential neurological toxicity that may occur with irradiation.

Table 31.1. Diseases treated by stem cell transplantation Acute myeloid leukemia

Acute lymphoblastic leukemia Chronic myelogenous leukemia Chronic lymphocytic leukemia Myelodysplasia

Lymphoma Non-Hodgkin‘s Hodgkin‘s disease Multiple myeloma Aplastic anemia Idiopathic Fanconi

Paroxysmal nocturnal hemoglobinuria Congenital/immunodeficiency

SCIDS

Autoimmune disease Rheumatoid arthritis

Systemic lupus erythematosus Osteopetrosis

Leukencephalopathies Hurlers syndrome

Other inborn errors of metabolism

Sickle cell anemia/thalassemia

31.2

Fractionation and Dose Rate

Initial trials with TBI use a single fraction of up to 10 Gy. Subsequently, it was suggested that the thera- peutic ratio (i.e., increased leukemic cell kill and decreased toxicity of late responding tissues, such as lung, heart, spinal cord, kidney, and CNS) of TBI might be improved by either going to a very low dose rate (not practical since treatment times of up to 24 h would be required) or using a fractionated schema.

This was based on radiobiological data suggesting that leukemic cells (and their normal counterparts, the hematopoietic stem cells) were relatively radio- sensitive, with a narrow “shoulder” on the survival curve and with little capacity of sublethal radiation damage repair capacity (Hall 1994). However, late responding tissues are better able to repair sublethal damage and have a relatively “broad shoulder” on the dose–response curve. Formulations based on dose survival models have been proposed to evalu- ate the biological equivalence of various doses and fractionation schedules. Assumptions are based on the linear-quadratic model that takes into account the α and β (non-reparable and reparable) compo- nents of cell kill. The values for the α and β compo- nents of cell kill can be derived experimentally, but are not available for many human tissues. Extrapo- lating from animal data and cell cultures, it has been found that the ratio of α/ β is a useful indicator of the effect of fractionation on cell damage. Tissues with a high α/ β include the gastrointestinal tract,

skin, and bone marrow cells (“early” responding);

whereas, tissues with a low α/ β include spinal cord, kidney, brain, and lung (“late” responding) (Hall 1994).

Although not completely applicable in the setting of TBI schemes, the biological effective dose (BED) of one TBI regimen can be compared with another regimen if several estimates are taken into consider- ation. The units are arbitrary but allow one to com- pare the theoretical effects of different TBI regimens on different tissues.

BED = n × d (1+d/(α/β))

where n=number of fractions, d=dose per fraction (Gy/fraction) and α/β=estimate (10 for early tissues, 3 for late tissues).

In engineering an optimal TBI regimen, the goal is to cause minimal damage to late responding tis- sues, while having a high probability of damaging the early responding bone marrow cells (and malig- nant cells). Regimens can be evaluated for their potential effect on late responding tissues or on early responding tissues. If evaluating for late effects of different TBI regimens:

Assume an α/β of 3 BED 750 cGy in 1 fraction 26 750 cGy in 3 fractions 14 1200 cGy in 6 fractions 20 1320 cGy in 8 fractions 20 1395 cGy in 12 fractions 19

One can see that fractionation would be expected to spare late effects. One could go to a higher total dose, without increasing the probability of late effects. If considering the early effects of different TBI regimens:

Assume an α/β of 10 BED 750 cGy in 1 fraction 13 750 cGy in 3 fractions 9 1200 cGy in 6 fractions 14 1320 cGy in 8 fractions 15 1375 cGy in 12 fractions 16

It becomes apparent that fractionation spares early effects. Since bone marrow ablation is desired, the total dose must be increased to 1200 cGy or more to get the same myeloablative effects as a single frac- tion of 750 cGy.

These theoretical equations are supported by data from reports of bone marrow transplantation

Table 31.2. University of Minnesota protocols utilizing total body irradiation or total lymphoid irradiation in the condi- tioning regimen (CR)

1320 cGy in eight fractions over 4 days:

– Acute lymphoblastic leukemia in second or subsequent CR – Acute lymphoblastic leukemia high risk in first CR – Chronic myelogenous leukemia

– Acute myeloid leukemia (some children receive chemo- therapy only conditioning)

– Myelodysplastic syndrome

– Non-Hodgkin‘s lymphoma (depending on dose of prior irradiation)

– Unrelated donor transplantation – Cord blood transplantation Other regimens

– Fanconi anemia: 450 cGy in single fraction, ±thymus block – Non-myeloablative transplants: 200 cGy in a single fraction – Sickle cell anemia or thalassemia: total lymphoid irradiation,

block gonads

– Osteopetrosis: TLI to include spleen, liver and mesenteric

lymph nodes

regimens. For example, the risk of cataract for- mation (a late responding tissue) is substantially higher when the TBI is given in a single fraction of TBI than when it is fractionated (Aristei et al.

2002).

Although no randomized clinical trials exist, the majority of retrospective reviews looking at the rate of interstitial pneumonitis after single fraction TBI compared with multiple fraction TBI strongly suggest an advantage for a fractionated TBI schedule (Shank et al. 1983; Cardozo et al.

1985; Kim et al. 1985; Molls et al. 1986; Standke 1989; Valls et al. 1989; Carlson et al. 1994). One must keep in mind the fact that these trials are non-randomized and usually compare recently transplanted patients on fractionated schemas with former single fraction patients. Numerous variables are potentially implicated in the devel- opment of interstitial pneumonitis, including other TBI variables such as dose rate, use of lung shielding, and timing of the TBI (before or after chemotherapy) (Molls et al. 1986).

Initially single fraction TBI was delivered with cobalt units at extended distances. The dose rate achievable was only 5–10 cGy/min and it required 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 pneumo- nitis may be higher with higher dose rate (Kim et al. 1985; Carruthers and Wallington 2004).

However, most institutions have kept the dose rate low (under 10 cGy/min), since a fraction of 200 cGy can be delivered in a reasonable amount of time (20 min in this case).

31.3 Sequence

TBI can either precede or follow the chemotherapy portion of the conditioning regimen. An advantage to delivering the TBI first is that, with the appro- priate use of antiemetics, it can be given as an out- patient treatment and thus reduce inpatient costs.

Following completion of TBI, patients are then hos- pitalized for the chemotherapy portion of the condi- tioning regimen. Clinical data are lacking, however, on whether TBI is less toxic or more effective when given before chemotherapy, although it is theoreti- cally possible that the variety of cytokines released during chemotherapy may influence the incidence of pneumonitis.

31.4

Technical Aspects

Numerous techniques for irradiation of the entire body are described in the literature. At the Univer- sity of Minnesota, two general TBI techniques are currently in use, with modifications of the tech- niques for certain situations. The vast majority of our patients are treated using the first technique, which involves right and left lateral fields with the patient semi-recumbent at an extended distance on a specially designed couch. The second tech- nique is an anterior–posterior treatment technique patterned after that developed at Memorial Sloan Kettering (Shank et al. 1983). For the latter, adult patients are treated in a standing position with ante- rior and posterior beams, while younger (smaller) patients are treated in a reclined position if they can fit within the available field size at the floor of the treatment room. The goal of both of these techniques is to deliver a uniform dose to the entire body within ±10% of the dose at the prescription point. This second technique has the advantage that certain organs such as the thymus or testicles can be blocked.

31.5

Right and Left Lateral TBI

This technique uses lateral photon beams with the patient in a semi-recumbent position, as described 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 used to produce a uniform dose through all body regions to within +10% of the dose specified at the umbilicus.

31.6

Simulation and Patient Measurements

Pretreatment measurements for TBI are performed

in the simulator room to accurately reproduce the

treatment position within the treatment room and to

calculate the size and thickness of the compensating

filters. The simulation procedure consists of three

steps. During the first step, an anterior chest film is

taken to determine the amount of lung traversed by

the treatment fields. The radiograph is taken with the patient seated on the simulator couch with his or her back resting against the film cassette holder.

The source–skin distance (SSD) to the patient’s chest is measured and because the source–film distance (SFD) is known, the magnification factor for the size of the lungs can be determined. Using this informa- tion, the thickness of the lung inhomogeneity can be computed. This information is used later when the need for lung compensation is evaluated.

The second step is to establish the patient treat- ment position so that the entirety of the body fits within the 95% isodose line. An overhead projector is used to cast an isodose pattern that represents the uniformity of the actual treatment field (Fig. 31.1).

The head and back of the patient are positioned within the 98% line, while the toes of the feet are within the 95% isodose line of the radiation field.

Once this position has been established, setup mea- surements are recorded on the form, as illustrated in Figure 31.2.

To describe the position of the lower extremities, measurements are made from our reference point [the anterosuperior point of the iliac spine (ASIS)] to 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 is used to produce a representation of the treatment fi eld

Fig. 31.2. The form used to document the patient treatment position when the bilateral body technique is used

the distance from the middle of the shoulder to the top of the head is measured. The latter information is used to scale the size of the head compensator. The chin extension, measured from the sternal notch to the point of the chin, is also recorded. Additionally, the need for positional devices, such as pillows for the back of the head, foam sponges underneath the hips, or sandbags under the feet, is recorded on the form. For future reference, the names of the indi- viduals who made and checked the measurements are recorded.

The third step is to measure the right–left lateral

thickness of the patient at certain anatomical loca-

tions. These measurements are recorded on the form

shown in Figure 31.3 and constitute the basic data

needed to determine the thickness of the compensa-

tors at these locations. The key measurement is the

width of the patient at the umbilicus since this is the

location where the dose is prescribed. Values of lat-

eral thickness are also measured at the head, neck,

shoulders, mid-mediastinum, pelvis, knees, and

ankles. The mid-mediastinal thickness is measured

midway between the sternal notch and the xiphoid

and includes the thickness of the arms.

simulation. The form shown in Figure 31.3 also serves as the calculation sheet for the determi- nation 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-mediasti- num 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 prescrip- tion point (which in our case is the umbilicus) and the other locations. The following equation is used to calculate tissue deficit:

TD = L

− + − L ( 1 ρ

) L

⁽¹⁾

where L

is the lateral separation at the umbili- cus, L is the lateral separation at that particular anatomical location, L

is the separation of the lung determined from the anterior radiograph, and ρ

is the density of the lung. For ρ

, a value of 0.25 g/cm

is used as the average lung density for healthy lung tissue (Van Dyk et al. 1982). Equa- tion 1 is used only for the mid-mediastinal location where lung tissue is present. At all other locations, L

is zero and the tissue deficit can be obtained using Eq. 2:

TD = L

− L ⁽²⁾

L

is determined using the anterior chest radio- graph that was taken in the simulator. The lung thickness is determined at a point midway between the sternal notch and the most superior aspect of the domes of the diaphragms as seen on the radiograph.

As shown in Figure 31.4, two lateral measurements are made for both the right and left lobes of the lung:

the first measurement, represented by L

and L

, extends from the most lateral aspect to the most medial portion of the lung. The second measure- ment, represented by L

and L

, spans from the most lateral extent of the lung to the mediastinum.

The lung thickness is calculated using the following equation:

L L L L l SSD SFD

lung

SFD

rt rt lt lt

= ( + + + ) _× ^⎛ ⎝ ⎜⎜⎜ ^{× +} ⎞

⎠ ⎟⎟⎟

1 2 1 2

2

1

2 ( )

(3)

Fig. 31.3. The form used to record the values of right–left lateral thickness of the patient. This information is used to calculate the tissue defi cits that exist at various body locations versus the umbilicus thickness. Values of compensator thickness are subsequently calculated from these data. The fi nal column pro- vides a location to document the percentage of the prescribed dose delivered to the midline of the indicated regions

Once the lateral separations are recorded, the point where the lower extremities compensator is to start must be determined. Since the dose is pre- scribed for the midline thickness at the umbilicus, and the pelvis is usually of greater thickness, the compensator must be started at some point below the pelvis. The location where the compensator is to begin is that point on the legs that has the same sep- aration as the umbilicus. As final documentation, a photograph is taken with the patient in the treat- ment position with respect to the radiation field.

31.6.1

Compensators for TBI

Compensator thickness determination is calcu-

lated from measurements taken at the time of

where SSD is the source–skin distance and SFD is the source–film distance measured when the anterior chest radiograph was obtained during the first step of the simulation. In Eq. 3, the terms in the second parentheses serve to de-magnify the lung dimen- sions measured on the chest radiograph to life-size at the midplane of the patient.

The compensator thickness, L

, is determined using the following equation:

L TD K

c

comp eff comp

= × × − ⎛ ×

⎝ ⎜⎜⎜

⎜

⎞

⎠ ⎟⎟⎟

⎟⎟

1 2

τ

ρ µ

τ ρ

ln (4)

In this expression, τ is the thickness ratio (Khan et al. 1970; Kirby et al. 1988). For beam energies from cobalt 60 (Co-60) to 10 MV, a value for τ of 0.70 is a good approximation for compensator distances greater than 20 cm from the surface (Khan et al.

1980). The density of the compensating material is p

(aluminum in this case), K is the off axis cor- rection factor that accounts for both the decreases in beam intensity away from the central axis and effec- tive scattering field size for the various locations, and µ

is the broad-beam linear attenuation coefficient in tissue for this beam energy. The effective field size at various locations can be determined by Clarkson integration. The data in Table 31.3 were calculated in this manner for a Rando phantom and represents the equivalent scattering field at various locations of the body as a function of beam energy for an average adult (Kirby et al. 1988). This data can be used to determine accurate values for K in Eq. 4.

An alternate method to determine compensator thickness for TBI has been suggested by the Ameri- can Association of Physicists in Medicine (AAPM) (1986). Comparisons made between the system of

compensator thickness determination described above and that suggested by the AAPM (1986) show that the two systems produce compensators the thickness of which varies by less than 1 mm of alu- minum. Finally, the percentage difference in dose between the prescription point and other locations of the body are calculated and recorded in the last column of the form.

31.7

Compensator Design

The compensators are designed to be located at a distance of 72 cm from the virtual source of the accelerator so that appropriate compensation can be provided without the devices becoming excessively large and difficult to handle. Thus, the measurements recorded on the setup sheet in Figure 31.2 must be de-magnified from the treatment distance to the location of their use. Using the information supplied in Figures 31.2–31.4, the size of the compensators is determined in the following manner. For the lower extremities compensator, the base length for section A in Figure 31.5 is obtained by taking the ASIS to knee distance, subtracting the distance below the ASIS that the compensator is to start, and multiplying that dimension by the lateral magnification factor:

Lateral magnification factor = Source-Compensator tray distance

Source-axis distance- L

2

⎛⎛

⎝ ⎜⎜⎜ ⎞

⎠ ⎟⎟⎟

(5) Section B of the lower extremities compensator is the 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 adequate coverage of the feet. Section D is simply an additional 2 cm of aluminum that is needed to clamp the compensator to the compensator tray during the actual treatment. The thickness of the compensator is obtained from the compensator thickness column as shown on Figure 31.3 for the corresponding ana- tomical location.

The head and neck compensator is designed in much the same manner. The base length of section E of this compensator is the de-magnified distance from the middle of the shoulder to the top of the head. Section F is an additional 1 cm of material to ensure adequate coverage, while section G is pro- vided for clamping. The thicknesses of the compen-

Table 31.3. The equivalent square field size for various ana- tomical locations. Determined at midline in a Rando phantom.

The lateral dimensions of the phantom at these locations is also listed in addition to the equivalent lengths required to obtain the calculated field sizes by equivalent square calcula- tion. Reproduced from Khan et al. (1970)

Photon energy Side of equivalent square (cm)

Head Neck Chest Umbilicus Hips

Co-60 17 22 31 30 28

4 MV 16 20 30 29 23

6 MV 18 23 29 27 26

10 MV 17 22 33 27 26

18 MV >18 >18 >18 >18 >18

Mean 17 22 31 28 26

Lateral dimension 15 12–16 31 27 31

Equivalent length 19 30 31 29 20

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 H

from the chest radiograph (Fig. 31.4) to life size using (1/2)(SSD–SFD)/SFD, then again de-magnifying these dimensions to the treat- ment 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 compensa- tor, 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 that is sent to the machine shop for fabrication. Fig- ure 31.7a shows the finished aluminum compensa- tors 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.

1999). To determine the total number of monitor units (MUs) for TBI, the calculation is done as an isocentric treatment at an extended distance. Equa- tion 6 is used in the determination as follows:

MU = TD STF

k S r S r TMR d,r f

c o p o e

f

×

× × × × ⎛ ′

⎝ ⎜⎜⎜ ⎞

⎠ ⎟

( ) ( ) ( ) ⎟⎟⎟

⎛

⎝

⎜⎜⎜ ⎜⎜⎜

⎜⎜⎜ ⎜⎜

⎞

⎠

⎟⎟⎟ ⎟⎟⎟

⎟⎟⎟ ⎟⎟⎟

2

(6) In this equation, k is the machine calibration factor equal to 1 cGy per MU in tissue at d

depth at the standard calibration distance, which is f, for the calibration field size of 10 ×10 cm

; S

(r

) represents the collimator scatter correction factor for r

; the collimator field size, S

(r

), is the phantom scatter factor for the effective scattering field, r

; at the umbilicus, (f/f’)

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,r

) 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 that support the compensators is included.

The beam spoiler or degrader is necessary because of the large degree of skin sparing that is still present

Fig. 31.4a,b. a The anterior chest radiograph obtained during simulation indicating the lateral measurements taken to de- termine lung thickness, L

. Also shown is the level where these measurements are taken, the midpoint between the sternal notch and the xiphoid. This dimension, H

, is also the one used if a lung compensator is required. b The inset, which is a diagrammatic representation of a transverse CT scan through the chest, illustrates the rationale behind these measurements

a

b

Fig. 31.5. A schematic diagram showing the relationship

between the compensators used for the bilateral total-body

technique and the patient treatment position

for the large field sizes and extended treatment dis- tances 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 d

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.

31.7.1

Patient Treatment

To ensure that all the information is accurately transferred to the treatment room, the first setup of every patient is rigorously checked. The treat- ment 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 region. For the lower extremities compensator, posi- tioning 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 com- pensator 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 irra- diation is to make sure that the beam spoiler is in place and that it is 20 cm or closer to the patient’s most proximal surface.

31.7.2

Dose Verification

The dose delivered to the patient during TBI has been verified using both lithium fluoride (LiF) thermolu-

Fig. 31.6. The compensator design from showing the informa- tion provided to the machine shop for fabrication of the alu- minum compensators. For the position on the lower extremi- ties compensator indicated by “Mark”, a small peg is inserted into the side of the compensator. This peg aids in aligning the compensator with the knee and the ankle when the patient is in the treatment position

Fig. 31.7a,b. The completed aluminum compensators used for the bilateral total body technique. a The aluminum compensa- tors for the lower extremities, lung, and head and neck (from left to right). b An illustration of the aluminum compensa- 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 using double-sided tape

a

b

minescent dosimetry (TLD) chips and encapsulated powder. The dosimeters for the head and neck region were taped to the side of these regions and covered by 2.5 cm of wax bolus. The location of the TLDs for the mid-mediastinal readings was between the upper arm and the chest wall. The TLDs for the lower extremities were all placed between the legs at the indicated locations. The results of these measure- ments shown in Table 31.4 illustrates that there is fairly good dose uniformity throughout the entire treatment region when using parallel-opposed high- energy photon beams.

For routine treatment, TLD powder capsules embedded between 1-cm slabs of plastic are placed between the patient’s legs as close to the groin for the first treatment. This is done to ensure that the proper dose is being delivered.

31.7.3

Dose Prescription

The usual dose prescribed using this technique is 165 cGy twice daily for 4 days for a total of eight frac- tions. This results in a cumulative dose of 1320 cGy.

Each fraction is separated by at least 6 h. The dose rate is between 10 Gy/min and 19 cGy/min. A sum- mary of the patient treatment schedule is shown in Table 31.5.

31.8

Anteroposterior TBI

An anteroposterior (AP) TBI technique used at the University of Minnesota is adapted from that developed at the Memorial Sloan Kettering Hospital in New York (Shank et al. 1983). The patients are treated in either a standing or reclining position, alternating anterior and posterior surfaces for each fraction. The prescription dose is 1375 cGy to the

midplane of the pelvis delivered in 11 125-cGy frac- tions using 3 fractions per day at approximately 4.5- h intervals. 6-MV X-rays are used at a dose rate of 10–19 cGy/min at the midline of the pelvis, which is the prescription point. For each X-ray treat- ment, 2.1-cm thick cerrobend lung blocks are used to reduce the dose to the lungs by approximately 50%. The chest wall overlying the lungs, which were shielded by the lung blocks, are given an additional 600 cGy to d

using electron beams of appropri- ate energy. The electron energy used for these chest wall boost fields is selected to place the 90% isodose line at the lung–chest wall interface. In addition, all male patients receive a testicular boost of 400 cGy to d

on day 1. The electron energy for this boost is chosen to set the 90% isodose at the posterior 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 simulation procedure to obtain lung block shape and position during treatment, measurements of patient thickness, and locating the CT scan region that will be used to determine the optimum electron energy for the chest wall boost. Details of the patient workup and treatment procedures are given below.

Simulation and patient measurements. Three steps are associated with the simulation of the patient: (1) fit the patient within the available field 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.

Patient positioning within the treatment field.

The simulation of the patient is performed inside the treatment room with the gantry rotated to the lateral treatment position. The gantry is rotated to provide the best coverage of the patient within the visible field. However, the gantry angulation should not deviate by more than 2 ° from the lateral treat- ment position so that the proper treatment distance is maintained. The treatment room is preferred over the simulator because fitting the patient within

Table 31.4. Lithium fluoride thermoluminescent chip and disposable powder capsule measurement showing percentage of pre- scribed 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

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 25-MV X-rays, 165 cGy/frac- tion

TBI fractions 3, 4: 18-MV or 25-MV X-rays, 165 cGy/frac- tion

TBI fractions 4, 6: 18-MV or 25-MV X-rays, 165 cGy/frac- tion

TBI fractions 7, 8: 18-MV or 25-MV X-rays, 165 cGy/frac- 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 X-rays, 125 cGy/fraction

TBI fractions 4, 5, 6: 6-MV X-rays, 125 cGy/fraction

TBI fractions 7, 8, 9: 6-MV X-rays, 125 cGy/fraction

TBI fractions 10, 11: 6-MV X- rays, 125 cGy/fraction Fraction 1: testicular electron

boost, 400 cGy/fraction

Fraction 7: electron chest wall boost, 300 cGy/fraction

Fraction 10: electron chest wall boost, 300 cGy/fraction

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 d

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

a b

the available field size is a crucial step at our insti- tution. For our treatment distance of 410 cm, the diagonal field size is 170 cm (5'8") inside the 90%

isodose line. Patients shorter than 170 cm (5'8") can be easily treated in the standing position. However, it is necessary for taller patients to sit on the seat of the treatment stand in order to fit within the treat- ment field. Although this is not the optimum treat- ment position, acceptable dose uniformity can still be achieved.

Films for lung blocks. Once the position of the

patient within the treatment field has been deter-

mined, chest radiographs are taken. The anterior

film is taken with a small BB placed at the tops of

the diaphragms. The distance of this BB below the

sternal notch is measured and recorded on the form

illustrated in Figure 31.9. Additionally, a posterior

radiograph is taken with a BB placed at C7. The loca-

tion of the BB is indicated on the form and marked

with a tattoo. Also recorded are the gantry angle

of the accelerator, the seat extension and height, the separation of the supports located under the arms, and the position of the hand rests. For shorter patients, an additional wooden platform is placed below their feet to position them more in the center

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, umbi- licus, 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 the patient lying supine compared with in the stand- ing position are significantly different, for instance in women with pendulous breasts.

Once the scanning is completed, computerized treatment planning is performed to determine the appropriate electron beam energy for the electron chest wall boost. This is done by placing the 90%

isodose line at the lung chest wall interface. A typi- cal treatment plan is illustrated in Figure 31.10.

Fig. 31.9. The form used to document the patient treatment position when using the standing total body technique

Fig. 31.10. A computerized

treatment plan done to deter-

mine 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

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).

31.8.1

Patient Treatment Technique

Total body photon irradiation. The treatment is deliv- ered 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 posi- tion resting against the back plate of the total body treatment stand that was specifically designed for this treatment (Fig. 31.12). The treatment distance for this particular setup is 410 cm source–axis dis- tance (SAD) to the midline of the pelvis.

The lungs are shielded with the appropriate lung blocks throughout the total body photon portion of the treatment. The lung blocks are hung by a Lexan hook from the anterior plate of the total body treat- ment stand. The location of the top of the 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 treat- ments (Fig. 31.13). The prescribed dose is 600 cGy to d

, delivered in two 300-cGy fractions. The selection of electron energy and the need for bolus is based on the results of computerized treatment planning using the CT scan so that the 90% isodose line is placed at the lung–chest wall interface.

b a

Fig. 31.11a,b. The apparatus used to shield the lungs during standing total body irradiation. a The proper separation of the two cerrobend lung blocks is maintained by the acrylic plate.

The Lexan hook is used to suspend the blocks from the plastic plate that is placed in front of the patient when positioned in the total body treatment stand. This arrangement allows easy adjustment of both the height of the blocks and their right–left placement with respect to the patient. b The cerrobend insert that is used for the chest wall electron boost treatment exactly matches the shape of the cerrobend lung blocks

Fig. 31.12. The standing total body treatment position with the

back of the patient resting against the back plate of the total

body treatment stand. The lung blocks are shown, in position,

hanging from the front acrylic plate

Testicular boost. Male patients are given a testicu- lar electron boost on the first day of treatment. The prescribed dose is 400 cGy to d

in one fraction.

The patient is treated in the supine position with a sheet of lead placed under the testes to minimize the dose to the rectal area. A 6-mm-thick sheet of wax bolus is placed between the lead and the pos- terior 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 approxi- mately 20 cm above the torso of the patient both to provide a high surface dose and to support the lung blocks used for the anterior and posterior X-ray fields.

The lower extremities are simply bolused to provide a high skin surface dose (Fig. 31.14). The chest wall

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 d

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- ered in TBI because shielding may potentially reduce the dose to the target volume (bone marrow cells, leukemic cells, and circulating stem cells). Despite this concern, there are situations in which partial shielding of critical tissues, including the lungs, kid- neys, eyes (lens), and brain, is considered.

31.9.1

Lung Shielding

Because pneumonitis is a leading cause of death after SCT, with total dose of TBI implicated as a potential contributing cause, partial blocking of the lung has been advocated. The dose received by the

Fig. 31.13. A special couch extension designed to reproduce the standing TBI treatment position when treating the electron chest wall boost fi elds. The device is separated into two pieces for ease of handling and, since it is attached directly to the couch, it has the same range of motion as the couch. Patients up to approximately 5 feet tall can be treated in the standing position, while taller patients are treated in a seated position.

This style of chair keeps the back of the patient in about the same orientation when seated as when they are standing

Fig. 31.14. An illustration showing the treatment position used

for pediatric patients. The lung blocks are placed on top of

the acrylic beam spoiler. The lower extremities are bolused to

provide a high dose at the surface

of pneumonitis, omit the electron beam chest wall boost. No increased risk of leukemia relapse has been noted, but a prospective trial is lacking.

31.9.2

Kidney Shielding

The risk of renal injury after SCT is dependent on multiple factors, including previous chemother- apy

use of nephrotoxic antibiotics, and therapies directed at the prevention and treatment of GVHD (Moulder et al. 1987, 1988; Lawton et al. 1989, 1992; Moulder and Fish 1989, 1991; Emminger et al. 1991; Cowen et al. 1992; Cole et al. 1994;

Miralbell et al. 1996). In a recent review of the incidence of acute renal failure in patients treated at the University of Minnesota SCT program, up to 30% of patients undergoing SCT in 1993 had acute renal failure, defined as a doubling of creatinine over the baseline creatinine (Lane et al. 1994). Of these patients, 10% required dialysis.

Late-onset renal failure occurs in up to 20% of survivors of SCT. On the beneficial effect of partial kidney blocking in the setting of T-depleted SCT, Lawton (Lawton et al. 1992) found that the inci- dence of chronic renal failure was reduced from 26% to 6% when posterior 1-HVL renal blocks were placed, reducing the estimated kidney dose from 14 Gy to 12 Gy (given at 200 cGy twice a day). In another series of 79 patients transplanted with TBI- containing regimens, Miralbell et al. (Miralbell et al. 1996) reported that the 18-month probability of

Table 31.7. Lithium fluoride thermoluminescent dosimeters (TLD) establish homogene- ity of dose for standing TBI technique. The TLD chips were covered by approximately 1 cm of bolus to indicate the dose at d

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 as well as lung density. At the University of Minne- sota, when delivering TBI with right and left lateral 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 lung dose to within 10% of the dose received at the prescription point (level of the umbilicus at mid- plane). Often no additional compensation is needed to achieve this goal, but if needed, tissue compensa- tors are placed to reduce the lung dose to within 10%

of the prescription dose.

Using a similar right and left lateral technique, in addition to using the arms to decrease lung dose, some institutions use partial blocks to reduce the lung dose further, usually to an arbitrary amount (for instance 1000 cGy).

For AP–posteroanterior (PA) fields, partial atten- uation blocks (80–90% transmission) or thicker blocks (usually one half-value layer; HVL) can be placed in front of the beam to decrease the lung dose to the desired amount. With one HVL block, the underlying ribs receive approximately half of the prescription dose and electron beams of the appro- priate energy can be used to “boost” the underly- ing ribs. A CT scan through the lung can be used to determine the appropriate electron energy. This technique was initially reported at Memorial Sloan Kettering Cancer Center (Shank et al. 1983) and was used at the University of Minnesota for about 10 years, although has now largely been abandoned as it is considerably more difficult to administer.

Some institutions, in an effort to decrease the risk

renal dysfunction-free survival decreased from 95, to 74, to 55% for patients conditioned with 10, 12, and 13.5 Gy, respectively. The other factor that pre- dicted for renal dysfunction was the risk of develop- ing GVHD. Renal dysfunction-free survivals were 93% for patients at lower risk of GVHD and 52% for patients with a high GVHD risk (e.g., unrelated allo- geneic SCT, absence of T-cell depletion).

31.10

Gonad Shielding

A common late complication after SCT is sterility.

In certain diseases, such as acute lymphoblastic leu- kemia, the gonads are considered sanctuary sites, and shielding would possibly increase the risk of relapse (Quaranta et al. 2004). In other situations, especially SCT for non-malignant diseases, there is probably less risk. The challenge in shielding either of the testes is to use sufficient attenuating material and to do it in such as way as to minimally shield marrow sites. The challenges in shielding the ova- ries are even more complicated because they lie in the pelvis near a rich supply of marrow; they are difficult to visualize, especially in young girls; and they are mobile and may move between the planning process and treatment days. Despite these obstacles, 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 irradia- tion 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- plantation (Storek et al. 2003). The thymus is diffi- cult to visualize, especially in older children. For this protocol, a treatment planning CT scan is performed

with the patient in the TBI treatment position, if pos- sible. Intravenous contrast is given and the thymus is delineated. Patients treated via this protocol are treated with AP and PA total body fields with 5- HVL cerrobend thymus blocks positioned over the thymus gland in both the anterior and posterior fields (Fig. 31.15). To design these blocks, a 1-cm margin is placed around the outline of the thymus on the AP and PA CT contours. Additionally, alumi- num compensators are placed over the lungs with both the AP and PA fields to diminish the lung dose to be no more than the prescription point dose. Thus far, only a handful of patients have been treated on this regimen and whether there is speedier immune reconstitution remains to be seen.

31.10.2 TomoTherapy

It is theoretically desirable to deliver radiation only to the immune organs and bone marrow spaces while sparing sensitive structures such as the brain, lens, lung, and kidneys. Intensity modulated radio- therapy (IMRT) planning could accomplish this, but most systems are limited by field size issues.

Additionally, accurate IMRT depends on a repro- ducible patient position, which is complicated when considering treating the entire marrow spaces. The

Fig. 31.15. Distally reconstructed radiograph showing location

of thymus block (5 HVL) and lung block (1 HVL) used in

Fanconi anemia

technology to accomplish this is now available with TomoTherapy (Mackie et al. 2003; Beavis 2004).

The TomoTherapy radiation system is a linear accel- erator 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 treat- ment 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 accom- plish 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 whether the patient willingly leaves his or her par- ents for the measurements, whether they listen to the instructions the therapist gives, and how anxious 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- thesia, we sometimes arrange for a potential TBI patient come to the department for several consecu- tive days so he or she can become acquainted with our therapists. The therapist will spend 10–15 min with the patient in the treatment room practicing for the TBI treatment. As there are intercoms and video monitors, the therapist can place the patient in the treatment position, leave the room, and talk to the patient over the intercom. With practice, even young patients are often able to be spared anesthesia.

Obviously, there are situations where anesthesia is necessary. Anesthesia for TBI presents unique situations not ordinarily encountered by most anes- thesiologists. Foremost is the fact that the anesthe- siologist cannot be in the treatment room during the TBI. Additionally, for the AP/PA technique, the

Fig. 31.16. Example of the isodose distribution achieved with TomoTherapy. Because this is delivered locally, an extremely conformal dose distribution can be achieved, thus delivering the dose only to the narrow spaces, while avoiding irradiation of sensitive structures (lung, kidney, liver)

patient is prone, and the airway is more difficult to keep patent.

If TBI under general anesthesia is scheduled, the patient fasts for 6 h before the scheduled procedure.

For infants, an interval of 4 h from intake of for- mula is sufficient. On arrival to the radiation ther- apy room, atropine and propofol are administered intravenously. Dolasetron is effective at preventing nausea during and after the treatment.

As the patient loses consciousness, a blood pres-

sure cuff is placed around the upper arm and the

electrocardiogram (ECG) is monitored continu-

ously. Pulse oximetry is used for continuous moni-

toring of oxygen saturation. Supplemental oxygen

is administered with nasal prongs. A continuous

drip of propofol is started. The patient is placed

in the treatment position. The child’s head is fixed

firmly in position by a sponge rubber donut or Sty- rofoam. Adhesive tape is used to secure the head in the appropriate position so that airway patency and 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 attendant personnel withdraw from the treatment room. During the treatment, airway and respira- tory adequacy are observed constantly by means of a zoom television monitor system, while blood pres- sure, ECG, and pulse oximetry are monitored on the second television monitor.

After the treatment is complete, the patient is trans- ferred to the post-anesthetic recovery room, where surveillance is continued until full arousal occurs.

Patients who receive several treatments on consecu- tive days show increased tolerance to propofol and the dose may need to be increased accordingly.

31.10.2.2

Complications Following Preparation With TBI The major causes of morbidity and mortality follow- ing a SCT are infectious complications (Auner et al.

2002). Additionally, interstitial pneumonitis devel- ops in up to 20% of transplanted patients depend- ing on the source of the marrow and previous thera- pies received (Cardozo et al. 1985; Abraham et al.

1999; Emmanouilides et al. 2003; Carruthers and Wallington 2004). Acute side effects of TBI include nausea and vomiting, alopecia, diarrhea, low grade fever, mucositis, and pancytopenia. Intermediate side effects include interstitial pneumonitis, veno-occlu- sive disease, and nephrotoxicity. Late side effects include restrictive lung disease, possible decreased growth, endocrine abnormalities (especially hypo- thyroidism) sterility, cataracts, chronic renal failure, and neurological damage. Sanders reported that boys given single-fraction TBI were significantly shorter than boys given fractionated TBI (P<0.03). The same (non-significant) trend was demonstrated in girls.

Few studies of neuropsychiatric testing of patients treated after TBI exist. One might expect lower cumulative doses to be associated with less impair- ment, but data are lacking. Younger patients seem to be at a higher risk of neurological damage (Faraci et al. 2002; Rubin et al. 2005).

The incidence of second tumors after SCT is low;

Seattle reported 4 in 1800 patients. At the Univer- sity of Minnesota, 53 second malignant neoplasms developed among 2150 patients for an estimated risk

of 9.9% at 1–3 years after transplantation (Bhatia et al. 1996). Second neoplasms were more common in patients likely to have GVHD.

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