**Photon Total Body Irradiation for Leukemia Transplantation Therapy: Rationale and Technique Options**

Brent Herron, Alex Herron, Kathryn Howell, Daniel Chin and Luann Roads *PSL Medical Center, Denver USA* 

#### **1. Introduction**

532 Advances in Cancer Therapy

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**9. References** 

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Leukemia is a classification of disease in which the two major defects are unregulated proliferation and incomplete maturation of the hemopoietic progenitors (Scheinberg, Maslak, & Weiss, 2001). Leukemia originates in the marrow, although leukemia cells may infiltrate lymph nodes, liver, spleen, and other tissues. Scheinberg et al. (2001) describe the principal clinical manifestation is the decrease of red cells and platelets as a result of the suppression of normal hemopoiesis or turnover and repopulation of blood components. In the chronic leukemias, unregulated proliferation of leukemia cells and elevated white cell count dominate. Differentiation and maturation of the leukemia cells may be largely preserved. Scheinberg further characterizes acute leukemias with unregulated proliferation also, but the maturation of the leukemia progenitors is profoundly impaired.

Transplantation of blood products, in particular stem cells, has become a common treatment procedure for various types of leukemias since the early 1990's (Scheinberg, Maslak, & Weiss, 2001). Cells void of leukemia are transplanted into the leukemia patient. The purpose of the transplant is the repopulation of the non-cancerous cells. Urbano-Ispizua et al. (2002) describes the current practice of stem cell transplantation for hematological diseases, solid tumors and immune disorders. Definitions, abbreviations and classifications described in this review are summarized here.

Hemopoietic stem cell transplantation (HSCT) refers to any procedure where hemopoietic cells of any donor type and any source are given to a recipient with the intention of repopulation/replacing the hemopoietic system of the recipient in total or in part (Urbano-Ispizua et al., 2002). Human Leukocyte Antigen (HLA) matching is a six point scoring system that identifies antigens and antibodies for both donor and recipient. Allogenic and autologous implants are also characterized by Urbano-Ispizua, et al (2002). Allogenic implants are procedures in which the recipient receives stem cells from a related or unrelated donor whose HLA score is identical (HLA score=6) or nearly identical (HLA score=5) to the recipient. Autologous implants refer to procedures in which the recipient receives stem cells from a collection performed while the patient is in remission or leukemiafree.

Photon Total Body Irradiation

with +/- 10% accuracy and uniformity criteria.

acquired or fabricated.

adequate dose.

100cm.

for Leukemia Transplantation Therapy: Rationale and Technique Options 535

volume from various angles. A criterion for field arrangement is accounting for dose uniformity within the tumor volume. That is, large variations in dose throughout the tumor are rarely acceptable. Bentel continues by specifying that additional beams will aid with dose uniformity. Beam angulation is determined by the desire to "spare" or reduce the radiation dose to non-malignant or non-cancerous tissue or organs. In most cases, the delivered radiation dose to the tumor is limited by normal tissue or organ tolerance in areas surrounding or close to the tumor volume (Bentel, 1997). Radiation doses are expressed in units of centigray (cGy) which is equivalent to the more common unit rad. Typical dose levels for standard non-TBI treatments are 4500-7000 cGy. Field dimensions are usually 100- 200 sq.cm therefore; the fields are roughly 5 inches by 5 inches. Dose uniformity criteria is typically +/- 5%. The standard treatment distance from the housing of the accelerator is

Van Dyk (2000) addresses the degree of accuracy required for total body irradiation treatments. As the specification of dose becomes less certain, disease control can be affected. In addition, undesirable radiation induced side effects can be pronounced. Van Dyk cites research that a 5% change in dose could result in a 20% change in the incidence of radiation pneumonitis. Under such circumstances, it is difficult to argue that +/- 5% accuracy is sufficient. Conversely, if the prescribed dose is well below the onset of radiation pneumonitis and if the dose is sufficient for adequate tumor control, then perhaps the guideline of +/- 5% accuracy can be relaxed and +/- 10% or even +/- 15% may be sufficiently accurate. The beam arrangement for total body irradiation is typically chosen

For large field radiotherapy, the delivery of a uniform dose of radiation over the entire target volume is not a trivial task. The irradiation method must be devised to produce radiation fields large enough to cover the entire body adequately. With this larger field size requirement, the patient is positioned further from the linear accelerator than the standard 100cm treatment distance. The increased distance takes advantage of the spread or divergence of the radiation field from the accelerator. The treatment distance can vary depending on the accelerator vault size, but is typically 350 to 500cm. The treatment distance for the TBI procedure represents a few additional problems (Lindsey & Deeg, 1998). These distances can be difficult to achieve in some linear accelerator vaults. Counter tops or other equipment will need to be removed. Since the patient will not be on the standard treatment couch at this extended distance, another adjustable patient support table must be

Dose uniformity is a major concern for the TBI process and the technique option chosen (Bradley et al., 1998). Bentel (1992) describes the principle of radiation absorption. The absorption of radiation is exponentially proportional to the thickness of the different body sections of the patient. The variance between absorption and dose between thinner and thicker body sections is more pronounced as the x-ray energy is decreased. Therefore, higher x-ray energy aids the dose uniformity criteria. Fletcher describes a negative side to the use of higher x-ray energy. Unfortunately, higher x-ray energies provide decreased entrance dose with the first 2cm of the patient. That is, high energy x-rays will provide a more uniform dose in tissue only after the first 2cm. Therefore, the use of a x-ray energy greater than 4MV require the addition of an acrylic sheet placed in close proximity to the patient (Bradley et al., 1998). This acrylic sheet serves as a "beam spoiler" and produces scatter radiation that allows the entrance 2cm of tissue to receive a higher and more

Bone marrow and cerebral spinal fluid peripheral cells are standard sources of hemopoietic stem cells (Urbano-Ispizua et al, 2002). For autologous HSCT, peripheral blood has become the preferred choice in view of its more rapid hemopoietic reconstitution. For allogenic HSCT, both sources are used. Both methods have their specific advantages and disadvantages. There are marked differences in toxicity concerning the donors. For recipients, the final issue concerning long-term outcome remains open. Peripheral blood is associated with more rapid engraftment or repopulation in the recipient. Urbano-Ispizua (2002) warns of a major concern with allogenic transplantation with peripheral blood is the high incidence of chronic graft-versus-host disease. That is, the recipient's immune system rejects the donor cells. In general, cord blood transplantation is recommended when patients require allogenic transplantation and do not have an HLA identical or a one-antigen mismatched donor.

Both allogenic and autologous implants are performed subsequent to subjecting the leukemia patient to intensity conditioning regimens (Shank, 1998). Despite the classification of the patient as in remission or disease-free, there is still significant opportunity that undetected leukemia cells are still present and will repopulate along with the transplanted stem cells. Shank describes the conditioning regimen's intent is to reduce the likelihood of the leukemia cell re-growth. Conditioning regimens include intense chemotherapy or radiation therapy or a combination of both. The intensity of these treatments is severe. Shank cautions of the fine balance between transplant-related mortality and the risk of relapse or repopulation of the leukemia cells.

The role of radiation therapy in the preparation of patients for bone marrow transplantation is the primary focus of this chapter. The primary utilization of radiation in oncology management is the use of small (less than 100 sq.cm) beams or fields directed at localized solid tumors (Bentel, 1992). Since leukemia cells are present throughout the body, large fields encompassing the entire body are necessary. This type of radiation treatment is referred to as Total Body Irradiation (TBI) or sometimes as Magna Field Irradiation (Shank, 1998). In her review article, Shank cites sole use TBI did not eradicate all leukemia cells. The addition of chemotherapy such as cyclophosphamide (CY) provides a reduced recurrence rate. Shank notes that although a large number of regimens now combine chemotherapeutic agents with and without TBI for marrow ablation, combined therapy of CY and TBI remains the standard for comparison.

Irradiation holds several advantages over chemotherapy as a systemic agent (Shank, 1998). These advantages include a lack of crossreactivity with other agents, dose homogeneity independent of blood supply, no requirements for detoxification and excretion, and the ability to tailor dose distribution within the body by shielding areas of greater sensitivity or boosting the radiation dose in areas that may contain additional disease. This discussion will focus primarily on the clinical aspects of TBI. Technical aspects of providing these large fields will also be addressed..

### **2. Total body irradiation: Criteria and nuances**

Bentel (1992) describes standard methodology of radiation oncology treatments. Standard radiation therapy treatments are provided utilizing a linear accelerator with x-ray energies approximately 100 times greater than conventional machines used for chest or dental x-rays. The accelerator is capable of rotating 360 degrees about a patient with the center of rotation placed within the tumor volume. Typically, 2-6 fields or beams are directed at the tumor

Bone marrow and cerebral spinal fluid peripheral cells are standard sources of hemopoietic stem cells (Urbano-Ispizua et al, 2002). For autologous HSCT, peripheral blood has become the preferred choice in view of its more rapid hemopoietic reconstitution. For allogenic HSCT, both sources are used. Both methods have their specific advantages and disadvantages. There are marked differences in toxicity concerning the donors. For recipients, the final issue concerning long-term outcome remains open. Peripheral blood is associated with more rapid engraftment or repopulation in the recipient. Urbano-Ispizua (2002) warns of a major concern with allogenic transplantation with peripheral blood is the high incidence of chronic graft-versus-host disease. That is, the recipient's immune system rejects the donor cells. In general, cord blood transplantation is recommended when patients require allogenic transplantation and do not have an HLA identical or a one-antigen

Both allogenic and autologous implants are performed subsequent to subjecting the leukemia patient to intensity conditioning regimens (Shank, 1998). Despite the classification of the patient as in remission or disease-free, there is still significant opportunity that undetected leukemia cells are still present and will repopulate along with the transplanted stem cells. Shank describes the conditioning regimen's intent is to reduce the likelihood of the leukemia cell re-growth. Conditioning regimens include intense chemotherapy or radiation therapy or a combination of both. The intensity of these treatments is severe. Shank cautions of the fine balance between transplant-related mortality and the risk of

The role of radiation therapy in the preparation of patients for bone marrow transplantation is the primary focus of this chapter. The primary utilization of radiation in oncology management is the use of small (less than 100 sq.cm) beams or fields directed at localized solid tumors (Bentel, 1992). Since leukemia cells are present throughout the body, large fields encompassing the entire body are necessary. This type of radiation treatment is referred to as Total Body Irradiation (TBI) or sometimes as Magna Field Irradiation (Shank, 1998). In her review article, Shank cites sole use TBI did not eradicate all leukemia cells. The addition of chemotherapy such as cyclophosphamide (CY) provides a reduced recurrence rate. Shank notes that although a large number of regimens now combine chemotherapeutic agents with and without TBI for marrow ablation, combined therapy of CY and TBI remains

Irradiation holds several advantages over chemotherapy as a systemic agent (Shank, 1998). These advantages include a lack of crossreactivity with other agents, dose homogeneity independent of blood supply, no requirements for detoxification and excretion, and the ability to tailor dose distribution within the body by shielding areas of greater sensitivity or boosting the radiation dose in areas that may contain additional disease. This discussion will focus primarily on the clinical aspects of TBI. Technical aspects of providing these large

Bentel (1992) describes standard methodology of radiation oncology treatments. Standard radiation therapy treatments are provided utilizing a linear accelerator with x-ray energies approximately 100 times greater than conventional machines used for chest or dental x-rays. The accelerator is capable of rotating 360 degrees about a patient with the center of rotation placed within the tumor volume. Typically, 2-6 fields or beams are directed at the tumor

mismatched donor.

relapse or repopulation of the leukemia cells.

the standard for comparison.

fields will also be addressed..

**2. Total body irradiation: Criteria and nuances** 

volume from various angles. A criterion for field arrangement is accounting for dose uniformity within the tumor volume. That is, large variations in dose throughout the tumor are rarely acceptable. Bentel continues by specifying that additional beams will aid with dose uniformity. Beam angulation is determined by the desire to "spare" or reduce the radiation dose to non-malignant or non-cancerous tissue or organs. In most cases, the delivered radiation dose to the tumor is limited by normal tissue or organ tolerance in areas surrounding or close to the tumor volume (Bentel, 1997). Radiation doses are expressed in units of centigray (cGy) which is equivalent to the more common unit rad. Typical dose levels for standard non-TBI treatments are 4500-7000 cGy. Field dimensions are usually 100- 200 sq.cm therefore; the fields are roughly 5 inches by 5 inches. Dose uniformity criteria is typically +/- 5%. The standard treatment distance from the housing of the accelerator is 100cm.

Van Dyk (2000) addresses the degree of accuracy required for total body irradiation treatments. As the specification of dose becomes less certain, disease control can be affected. In addition, undesirable radiation induced side effects can be pronounced. Van Dyk cites research that a 5% change in dose could result in a 20% change in the incidence of radiation pneumonitis. Under such circumstances, it is difficult to argue that +/- 5% accuracy is sufficient. Conversely, if the prescribed dose is well below the onset of radiation pneumonitis and if the dose is sufficient for adequate tumor control, then perhaps the guideline of +/- 5% accuracy can be relaxed and +/- 10% or even +/- 15% may be sufficiently accurate. The beam arrangement for total body irradiation is typically chosen with +/- 10% accuracy and uniformity criteria.

For large field radiotherapy, the delivery of a uniform dose of radiation over the entire target volume is not a trivial task. The irradiation method must be devised to produce radiation fields large enough to cover the entire body adequately. With this larger field size requirement, the patient is positioned further from the linear accelerator than the standard 100cm treatment distance. The increased distance takes advantage of the spread or divergence of the radiation field from the accelerator. The treatment distance can vary depending on the accelerator vault size, but is typically 350 to 500cm. The treatment distance for the TBI procedure represents a few additional problems (Lindsey & Deeg, 1998). These distances can be difficult to achieve in some linear accelerator vaults. Counter tops or other equipment will need to be removed. Since the patient will not be on the standard treatment couch at this extended distance, another adjustable patient support table must be acquired or fabricated.

Dose uniformity is a major concern for the TBI process and the technique option chosen (Bradley et al., 1998). Bentel (1992) describes the principle of radiation absorption. The absorption of radiation is exponentially proportional to the thickness of the different body sections of the patient. The variance between absorption and dose between thinner and thicker body sections is more pronounced as the x-ray energy is decreased. Therefore, higher x-ray energy aids the dose uniformity criteria. Fletcher describes a negative side to the use of higher x-ray energy. Unfortunately, higher x-ray energies provide decreased entrance dose with the first 2cm of the patient. That is, high energy x-rays will provide a more uniform dose in tissue only after the first 2cm. Therefore, the use of a x-ray energy greater than 4MV require the addition of an acrylic sheet placed in close proximity to the patient (Bradley et al., 1998). This acrylic sheet serves as a "beam spoiler" and produces scatter radiation that allows the entrance 2cm of tissue to receive a higher and more adequate dose.

Photon Total Body Irradiation

be accounted.

Dyk, 2000).

discussion.

**3.1 Accelerator room** 

based on Computerized Tomography scans.

**3. Representative Total Body Irradiation program** 

for Leukemia Transplantation Therapy: Rationale and Technique Options 537

Verification of the attenuation of the beam should be made with anthropomorphic or tissue equivalent phantoms. Scatter radiation from other components within the room, such as walls and equipment, will apply to this extended distance large field treatment and should

One of the major complications of large field radiotherapy is radiation pneumonitis (Corns et al., 2000). For total lung radiation, this syndrome is lethal in 80% of the patients who develop it. Because of this effect, Corns et al. (2000) warns that it is imperative that the dose to the lung be precisely controlled to ensure the probability of its occurrence is minimal. Even in standard radiation treatments, a calculation of the lung dose requires density corrections to the standard attenuation data (Bentel, 1992). The lower density lungs will transmit more radiation than regular more dense tissue. Several methods have been developed to correct for the lower density lung tissue and provide an accurate accounting of dose in this region (Bentel, 1992). Unfortunately, these calculations vary in ease of use as well as in the resulting correction factor. Van Dyk (2000) has calculated the correction factor from four of the most popular methodologies and observed a +/-12% variation. Despite this variation in accounting accuracy, methods of lung dose reduction is often required (Van

When a prescribed tumor dose is well above lung tolerance, the dose to lung will have to be reduced to minimize the probability of lung complication. Several methods can be used to reduce the dose. The techniques vary in complexity of design and application. All techniques incorporate one common concept: the use of an attenuator (Van Dyk, 2000). The attenuator absorbs radiation prior to delivering dose to the lungs. The decreased dose delivered to the lungs coupled with the increased transmission of dose within the lungs because of their lower density provides a dose comparable to rest of the body. Van Dyk describes several methods for the design of these attenuators. These methods vary from shielding the lungs with arm positioning to full or partial-transmission shielding blocks

A representative TBI program is described here as an aid to the development of similar programs. Room modifications, technique selection, energy choice, and equipment necessary to achieve adequate dose uniformity in a comfortable setting are included in this

TBI treatments should be performed with a high energy accelerator capable of providing photons of 15MV or greater. Lower x-ray energies can be utilized, but as the energy is decreased, dose homogeneity becomes more difficult to achieve with opposed fields. The distance to the closest wall with the gantry angled at 90 or 270 degrees will dictate the maximum field size to encompass the patient. Offset of the isocenter in the treatment vault design may allow for a greater treatment distance. Unfortunately, the desire to add TBI to the radiation therapy services may occur after a vault has been constructed. Most vaults are configured with a 20 foot width. Without an isocenter offset, this room width provides a source-wall distance of approximately 4m. Our institution's vault design provided a sourcewall distance of slightly less than 4m. A 40x40 cm2 field at 1m projects to 1.58m2 without collimator rotation and 2.2m2 with a 45° collimator rotation. Only a minor room

Even with the use of high-energy x-rays and beam spoilers, the dose uniformity across the patient and from thicker to thinner body sections may not meet the +/- 10% criteria (Bredeson et al., 2002). Dose uniformity will improve if opposed beams are used. As shown and described in Figure 1, the beam can be directed from different sources (item d) or by changing the patient position from supine to prone. If a two-beam arrangement is utilized, half of the radiation dose is provided by one beam. The patient is rotated or the source of radiation is moved and the remaining dose is provided. Typically, two fields are adequate to provide acceptable dose homogeneity for TBI treatments (Bredeson et al., 2002).

Fig. 1. Front view of TBI table used for opposed lateral treatments with couch sections angled at 45°.

Large variations in patient thickness, e.g. head thickness compared to shoulder thickness, pose problems with dose uniformity that multiple fields cannot resolve (Bredeson et al., 2002). Galvin and D'Angio and Walsh (2000) and Lin and Chu (2001) have described methods for compensating for the lack of patient thickness in certain areas such as the head or feet. The addition of rice bags or water-filled bags serves as adequate substitutes in these areas of decreased thickness. Rice or water exhibits the same attenuation characteristics as human tissue. Therefore, packing the patient or filling voids with these materials presents the patient as a uniform thickness. Therefore absorption variations are minimized.

The parameters used to characterize the x-ray beam at the standard 100cm distance will not necessarily apply to the extended distance (Van Dyk, 2000). Beam profiles and output calibration of the linear accelerator at the treatment position will need to be measured.

Even with the use of high-energy x-rays and beam spoilers, the dose uniformity across the patient and from thicker to thinner body sections may not meet the +/- 10% criteria (Bredeson et al., 2002). Dose uniformity will improve if opposed beams are used. As shown and described in Figure 1, the beam can be directed from different sources (item d) or by changing the patient position from supine to prone. If a two-beam arrangement is utilized, half of the radiation dose is provided by one beam. The patient is rotated or the source of radiation is moved and the remaining dose is provided. Typically, two fields are adequate to

provide acceptable dose homogeneity for TBI treatments (Bredeson et al., 2002).

Fig. 1. Front view of TBI table used for opposed lateral treatments with couch sections

the patient as a uniform thickness. Therefore absorption variations are minimized.

Large variations in patient thickness, e.g. head thickness compared to shoulder thickness, pose problems with dose uniformity that multiple fields cannot resolve (Bredeson et al., 2002). Galvin and D'Angio and Walsh (2000) and Lin and Chu (2001) have described methods for compensating for the lack of patient thickness in certain areas such as the head or feet. The addition of rice bags or water-filled bags serves as adequate substitutes in these areas of decreased thickness. Rice or water exhibits the same attenuation characteristics as human tissue. Therefore, packing the patient or filling voids with these materials presents

The parameters used to characterize the x-ray beam at the standard 100cm distance will not necessarily apply to the extended distance (Van Dyk, 2000). Beam profiles and output calibration of the linear accelerator at the treatment position will need to be measured.

angled at 45°.

Verification of the attenuation of the beam should be made with anthropomorphic or tissue equivalent phantoms. Scatter radiation from other components within the room, such as walls and equipment, will apply to this extended distance large field treatment and should be accounted.

One of the major complications of large field radiotherapy is radiation pneumonitis (Corns et al., 2000). For total lung radiation, this syndrome is lethal in 80% of the patients who develop it. Because of this effect, Corns et al. (2000) warns that it is imperative that the dose to the lung be precisely controlled to ensure the probability of its occurrence is minimal. Even in standard radiation treatments, a calculation of the lung dose requires density corrections to the standard attenuation data (Bentel, 1992). The lower density lungs will transmit more radiation than regular more dense tissue. Several methods have been developed to correct for the lower density lung tissue and provide an accurate accounting of dose in this region (Bentel, 1992). Unfortunately, these calculations vary in ease of use as well as in the resulting correction factor. Van Dyk (2000) has calculated the correction factor from four of the most popular methodologies and observed a +/-12% variation. Despite this variation in accounting accuracy, methods of lung dose reduction is often required (Van Dyk, 2000).

When a prescribed tumor dose is well above lung tolerance, the dose to lung will have to be reduced to minimize the probability of lung complication. Several methods can be used to reduce the dose. The techniques vary in complexity of design and application. All techniques incorporate one common concept: the use of an attenuator (Van Dyk, 2000). The attenuator absorbs radiation prior to delivering dose to the lungs. The decreased dose delivered to the lungs coupled with the increased transmission of dose within the lungs because of their lower density provides a dose comparable to rest of the body. Van Dyk describes several methods for the design of these attenuators. These methods vary from shielding the lungs with arm positioning to full or partial-transmission shielding blocks based on Computerized Tomography scans.
