Total Body Irradiation

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15 Total Body Irradiation

Total body irradiation (TBI) is a radiotherapy technique that has been applied to treat various benign and malignant diseases since the early twentieth century. The technique has evolved in parallel with an increase in the knowledge of the biologic response to ionizing radiation, and because of a result of improvements in radiation dosimetry and treatment delivery. TBI remains an important component of hematopoietic stem cell transplant (HSCT), with the goal of eradicating residual malignant cells and modulating the immune system of the transplant recipient. In the context of HSCT, TBI is advantageous because biologic effects can be exerted uniformly, without sparing of “sanctuary” sites like the nervous system or testes and without interference from metabolic or resistance processes.

History

Only a decade after Roentgen described the “x-ray,” German biophysical engineer Friedrich J. Dessauer first described a “new technique of radiotherapy” that involved homogenous irradiation of the entire body. In his initial report describing the technique in 1905, he proposed irradiating a supine patient using three simultaneously active low-voltage Roentgen ray sources (Fig. 15-1).1,2 In 1907, Aladár Elfer, a medical professor in Hungary, reported his experience using a TBI technique that spared the head in three patients with leukemia.3 Although there is a paucity of data regarding the early use of the technique, some have speculated that untoward hematologic toxicity probably limited its application.4

Early success using TBI to treat hematopoietic and lymphoid malignancies in Europe (there named the Teschendorf method) prompted development of the technique in the United States.57 Arthur C. Heublein, in collaboration with Gioacchino Failla, is credited with the development of the first TBI unit in North America, located at Memorial Hospital in New York City. In the United States, the technique became known as Heublein therapy.8 A specially constructed treatment ward was designed to treat four patients at an extended distance (5-7 meters) simultaneously at an exposure rate of 0.7 R per hour for approximately 20 hours per day, typically over 1 to 2 weeks, using a 185 kV x-ray tube at 3 mA, with a 2-mm copper filter. The goal was to deliver 25% of erythema dose (750 R). Remarkably, in Heublein’s initial report, no hematopoietic toxicity was noted with this treatment schedule. Of 12 patients with advanced lymphomas and leukemias, 7 (58%) demonstrated some form of improvement after treatment; 2 of 8 patients (25%) with metastatic breast, melanoma, and kidney cancers were also noted to demonstrate some form of improvement.9,10 A later report of the experience with 270 cancer patients from Memorial Hospital treated with TBI between 1931 and 1940 confirmed that the technique was more successful in patients with hematopoietic and lymphoid malignancies, compared with patients with carcinomas or sarcomas, for whom it was ineffective. The authors emphasized that the technique was safe if doses were prescribed cautiously. They did not recommend exposures greater than 300 R, and noted hematopoietic and gastrointestinal toxicity with exposures as low as 50 to 100 R.8

In the early 1940s, World War II prompted the Manhattan Project, an initiative to develop nuclear weapons. Part of this endeavor sponsored research into the human biologic response to ionizing radiation, including TBI. The military’s interest in TBI was primarily to help understand human tolerance for radiation exposure during occupational duties and warfare, and to develop radiation biodosimetric assays. Several research studies coordinated through the Manhattan Project were initiated in patients with advanced malignancies,1113 as well as in patients with benign diseases.13 For example, studies of dose escalation, radiation biologic dosimetry, and cognitive and psychomotor function were carried out at M.D. Anderson Hospital for Cancer Research.14 A detailed report of 30 patients treated at the maximum exposure level (200 R) in the initial study concluded that side effects primarily consisted of nausea, vomiting, and myelosuppression, and that intervention was necessary in 10% of patients treated with this dose of TBI.15 At Baylor University College of Medicine, studies using 25 to 250 R of TBI with 250 kV to 2 MV energy machines were performed to find a biologic dosimeter, as well as to study acute effects of radiotherapy.16 The Sloan-Kettering Institute for Cancer Research also participated in similar studies of at least 20 patients, although the results were never published. The military conducted similar studies at the Naval Hospital in Bethesda, Maryland, and reported palliation of patients with radiosensitive diseases treated with fractionated TBI.17

The most recent Department of Defense–sponsored research study of TBI was at the University of Cincinnati and focused on identifying biochemical markers in the urine that predicted response to TBI. Later, studies of the neuropsychiatric effects of TBI were initiated. Ultimately, only results regarding the palliation of advanced malignancies were reported.18 Patients with advanced metastatic radioresistant malignancies for whom chemotherapy was unavailable were often treated with TBI in the absence of any clear anticipated benefit. Patients treated with TBI in this manner were included in research studies, often without consenting to participate. The ethics of this practice were called into question by a report written in 1995 by the United States Department of Energy’s Advisory Committee on Human Radiation Experiments,19 which could be a contributor to the public’s uneasiness with radiation in general.20

TBI was used not only in malignant diseases; it was considered the critical immunosuppressant in the first successful solid organ transplant. In 1959, a kidney was successfully transplanted between dizygotic twins after TBI to 450 R to the recipient.21 Around the same time in France, successful kidney transplants after TBI were being reported.22,23 Of the first seven patients who underwent kidney transplant following TBI or pharmacologic immunosuppression worldwide between 1959 and 1962, the two who did not experience kidney failure were treated with TBI alone (without chemical immunosuppression) prior to transplant, and each survived in excess of 20 years after transplant.2123 However, successful preclinical studies with pharmacologic therapy prompted the use of chemical immunosuppressants (corticosteroids, 6-mercaptopurine, and azathioprine) for solid organ transplantation after 1963.24

With an increased understanding of the human response to TBI, and a rapidly growing body of preclinical in vivo studies of TBI, therapeutic protocols were developed to maximize benefit in patients with malignant diseases. In 1957, Nobel laureate E. Donnall Thomas first reported the use of bone marrow infusion in humans following whole-body irradiation or chemotherapy,25 and less than one year later he published his experience using TBI with exposures up to 600 R, followed by bone marrow transplantation.26 In the series of the first five patients with leukemia treated with TBI, who then received intravenous infusion of normal donor marrow, Thomas et al. noted the difficulty of acute myelosuppression and resultant hemorrhage and infection during the period leading up to engraftment. The report also comments that low dose rates (delivery over 2-3 days) appeared preferable to higher dose rates, for metabolic and immunologic reasons. In addition, patients receiving 200 to 300 R fared better than those receiving 400 to 600 R. The problem of delivering an adequately homogenous dose was raised, and suggestions to use higher-energy photons were proposed.26 Thomas et al. later reported on syngeneic bone marrow transplantation in two children after 850 to 1140 R was delivered in a single fraction over 22 to 25 hours, using 60Co sources. The authors concluded that 1000 R of TBI did not produce “troublesome” acute radiation sickness, and produced remission of leukemia, but not cure.27 The first report of successful cure of a patient with leukemia with allogeneic transplantation after TBI was reported in 1969. The technique involved opposed 60Co sources, which operated at 5.8 R per minute, to a total exposure of 1620 R, calculated to be 954 rad at midline. With appropriate supportive care, no major acute radiation sickness was noted, but the patient died of overwhelming cytomegalovirus (CMV) infection, without evidence of leukemia.28

Over the next several years, techniques of combining chemotherapy and TBI were developed and refined, with promising results.29,30 Success in the treatment of advanced leukemias and severe aplastic anemia (AA) was achieved. Departure from the use of TBI alone was primarily fostered by the development of more effective cytotoxic chemotherapeutics and immunologic therapies, which, when combined with TBI, yielded fewer leukemic recurrences.29 Although the use of TBI without HSCT has largely been abandoned, primarily for fear of inducing secondary malignant neoplasms (SMNs) and limiting later therapeutic options, some question the validity of this fear and still contend that very low-dose TBI (1.5-2 Gy in 10-20 fractions over several weeks) is a viable option for upfront therapy in advanced indolent lymphomas.31 Fig. 15-2 demonstrates how the use of TBI during HSCT has remained constant or increased during preceding years.32

Background on Hematopoietic Stem Cell Transplant

HSCT has evolved into a highly complex clinical discipline, firmly rooted in immune system and cancer biology, the details of which are beyond the scope of this chapter. When HSCT was initially performed (see “History”), bone marrow was extracted from the donor, filtered, and infused intravenously to the recipient. Later, peripheral blood stem cells, instead of bone marrow, were collected from the donor, and found to be an alternative to bone marrow grafts. For this reason, “bone marrow transplants” are now more appropriately termed hematopoietic stem cell transplants, because the critical component of the graft is the hematopoietic stem cell (HSC), independent of the source. Oftentimes, peripheral blood stem cells are “mobilized” from the donor using hematopoietic growth stimulating factors, and removed from the donor by apheresis. In addition, recent success using HSCs derived from human umbilical cord blood has been described. Depending on the source of HSCs, various postcollection processing measures (cell selection and depletion) may be undertaken to optimize the outcome of the transplant.

When transplant occurs between different individuals, the hematopoietic graft is said to be allogeneic. This is in contradistinction to reinfusion of native HSCs back into the donor in an “autologous” transplant, more appropriately termed an autoplant, because nothing is being transferred between different individuals.33 A rare but alternative situation is of a patient with a genetically identical twin in the case of a “syngeneic” transplant. Of these three methods of HSCT, autologous and syngeneic transplant are generally associated with less risk because issues related to immunocompatibility are minimized. Allogeneic transplants requiring the “matching” of donor and recipient are typically carried out through identification of human leukocyte antigen compatibility. The donor may be related to the recipient, or identified through registries of volunteers, such as the National Marrow Donor Program.

Prior to undergoing HSCT, most patients require intensive antineoplastic or immunosuppressive therapy in preparation for HSCT, often referred to as conditioning. Conditioning can involve cytotoxic chemotherapy, immunosuppressants, antibody therapy, or radiation therapy. The nature of the conditioning regimen can be referred to as high or reduced intensity, myeloablative, submyeloablative, or nonmyeloablative, to carry out conventional or mini transplants.33 Although agreed-upon formal definitions of these regimens do not exist,34 the goal of high-intensity, myeloablative, or conventional transplant is to completely eliminate the recipient’s native HSC compartment, which necessitates HSCT (autologous or allogeneic) for survival. High-intensity, myeloablative, or conventional transplants may or may not involve TBI, to high doses (>5 Gy in a single fraction, >8 Gy in multiple fractions). Reduced-intensity, nonmyeloablative, or mini-transplant conditioning regimens are often used for older patients or for those with medical problems for whom a high-intensity, myeloablative, or conventional transplant would cause excessive morbidity or mortality, and may or may not involve TBI to lower doses. During and immediately after conditioning, the transplant recipient is at significant risk of infections and other hematologic complications. For this reason, the supportive care of HSCT recipients is very complex, and should only be undertaken in specialized facilities. Nonetheless, some groups have developed reduced-intensity and myeloablative HSCT regimens, including TBI, which have been safely undertaken on an outpatient basis.35,36

After undergoing conditioning and HSCT, the major challenges are related to engraftment, the permanent reconstitution of the recipient’s hematopoietic system, and preventing graft rejection and associated postengraftment complications. The former process can be facilitated through the use of hematopoietic growth stimulating factors, and the latter can be mitigated with chemical and biologic immunosuppressants. Once the graft has successfully taken, the recipient is at risk of developing graft-versus-host disease (GVHD), which is a complication that describes engrafted HSCs recognizing the host’s native, non-HSC tissues as foreign and attacking them. Specific organs at risk are the skin, gastrointestinal tract, and liver. The risk of GVHD is only present in patients undergoing allogeneic HSCT. Moreover, it has been recognized that part of the beneficial effect of transplant is the graft-versus-tumor (GVT) effect, a fundamental component of the therapeutic effect of HSCT, which can occur in autologous or allogeneic transplants.

According to data summarized by the Center for International Blood and Marrow Transplant Research (CIBMTR) in 2005, the diseases most commonly treated with HSCT are (in decreasing order of frequency): multiple myeloma (MM); non-Hodgkin lymphoma (NHL); acute myelogenous leukemia (AML); Hodgkin disease (HD); acute lymphoid leukemia (ALL); myelodysplastic and myeloproliferative disease (MDS); chronic myelogenous leukemia (CML); AA, and various other leukemias, cancers, and nonmalignant diseases.37 The 2009 National Comprehensive Cancer Network (NCCN) guidelines for therapy indicate that allogeneic or autologous HSCT may be a treatment option for AML, MM, MDS, CML, HD, and NHL, depending on the clinical situation. Detailed discussion of these diseases and their management is beyond the scope of this chapter, and the reader is referred to appropriate chapters in this text and others for further review.3841 The role of TBI in nonmalignant diseases is discussed further below.

Radiobiology

Experimental radiobiologists have described much of what is known regarding the fundamental biologic effects of TBI, and clinicians have applied these principles to optimize the therapeutic benefit for patients. The essential rationale for TBI in the context of HSCT is to eradicate malignant or dysfunctional cells or modulate immune system function. Therefore, the critical radiobiologic in vitro data related to efficacy of treatment deals with normal and malignant hematopoietic cells.

Preclinical studies have helped define some of the fundamental radiobiologic properties of the normal lymphocytes. The D0 of normal lymphocytes has been reported to be 0.5 to 1.4 Gy,4245 depending on the in vitro or in vivo model used to calculate this parameter. This D0 suggests that normal lymphocytes cells are very sensitive to ionizing radiation. A very small shoulder on the radiation cell survival curve has been noted,46,47 suggesting little repair between fractions of radiation. Clinical data have revealed similar findings in patients undergoing hyperfractionated TBI (HTBI), with lymphocyte survival demonstrating an effective D0 of 3.8 Gy according to one study.48 Other radiobiologic phenomena have been ill-defined in other normal hematopoietic cells. Radiobiologically relevant levels of hypoxia are unlikely in the hematopoietic compartment. Repopulation is not likely to influence hematopoietic cell survival, given the short duration of most TBI regimens (1-5 days), although, given the variable lifespan of leukocytes (days to years), it may be of some relevance. Redistribution appears to be of significance, given the time scale for TBI; however, this has been difficult to assess.49

The radiobiology of malignant hematopoietic cells has been described. The D0 of leukemic cells generally ranges between 0.8 and 1.5 Gy, however, compared with normal hematopoietic cells, a wider range of radiosensitivities have been described.5061 Many have cited the technical nuances and variations in assay technique for this great range.49,62 Similar to normal hematopoietic cells, their malignant counterparts are thought to demonstrate little sublethal damage repair,6367 although split-dose and low-dose-rate experiments have demonstrated the capacity for leukemic cells to repair radiation-induced damage.55,58,68,69 Generally, leukemic cells are believed to have a cell survival curve with minimal or no shoulder, although this varies across cell types and cell lines.47,51,54 For example, Cosset and colleagues summarized preclinical and clinical findings, concluding that AML demonstrates little repair, whereas CML does demonstrate repair, and ALL, myeloma, and lymphomas have not been well studied but appear to demonstrate a wide range of repair capacity.62,70 Similar to normal hematopoietic cells, reoxygenation is unlikely to be radiobiologically relevant to malignant hematopoietic cells during TBI. Redistribution and repopulation, however, may be relevant, but have not been systematically studied.

In vivo preclinical research laid the foundation for the first successful HSCT in humans. Studies in rats,71 dogs,72 and nonhuman primates73 demonstrated that reconstitution of the hematopoietic system was possible after TBI with supralethal doses of radiation. Later work in animals revealed that delivering TBI in several fractions required a higher total dose relative to the biologically isoeffective dose given in a single fraction.7476 Another model demonstrated no significant difference in the effect of a low-dose-rate (0.04 Gy/min) single fraction of TBI compared with a hyperfractionated course of TBI given thrice daily to the same total dose.77

Although the hematopoietic system is the target of TBI, normal tissues effectively limit the dose that can be safely delivered. The sparing of normal tissues with fractionated TBI was proposed by Peters and colleagues,63,64 and subsequently supported by preclinical data in mice78,79 and dogs80 showing less lung injury with fractionated TBI regimens.

Immediate Toxicity and Management

Although a good deal of what has been learned about the acute in vivo biologic effects of TBI is derived from laboratory-based animal studies, whole-body irradiation also has been studied in people exposed during accidental or wartime nuclear events.81,82 These large-scale studies are valuable because they deal with apparently normal subjects; however, the retrospective nature limits the quality of the data. The reader is referred to several excellent texts for a review of the acute and fatal radiation syndromes (gastrointestinal, hematopoietic, and cerebrovascular) that can be caused by TBI in an uncontrolled setting.8385

Acute side effects of therapeutic TBI can be difficult to distinguish from other HSCT-related morbidity. However, Chaillet and colleagues conducted a very informative prospective clinical study of the symptoms and signs that occur in patients after TBI, prior to the initiation of any other HSCT related therapy.86 Thirty-one patients between 4.5 and 55 years of age were treated using parallel-opposed anteroposterior (AP) 18 MV photons from a linear accelerator (linac). Shielding was used to limit the lung dose to 8 Gy. A total dose of 10 Gy was given as a “single dose” as six discrete fractions of 1.6 Gy, each given over 15 minutes, with a 30-minute break between fractions, for a mean dose rate of 0.04 Gy per minute and instantaneous dose rate of 0.11 to 0.12 Gy per minute. Symptoms and signs were assessed regularly during the 4 hour TBI, and for 20 hours after the completion of TBI. Antiemetics, but no chemotherapy or steroids, were given prior to the start of TBI. Table 15-1 displays the symptoms and signs experienced by patients during the 4 hours of TBI, and within 24 hours of starting TBI. Fever was a very common finding, and a maximum of 40.8° C was noted in one patient. Tachycardia frequently paralleled febrile episodes; a maximum rate of 130 beats per minute was noted. Drowsiness was noted only in patients who received sedating antiemetics. Parotid gland pain was common, and bilateral parotid swelling was noted in 29% of patients. Marked lacrimation was noted in 6% of patients, whereas 16% of patients experienced ocular dryness. Two patients experienced mild conjunctival edema. Hypertension was noted only during TBI. The results of a similar study conducted by Buchali and colleagues of patients who were treated with a fractionated course of TBI delivered mostly to a total dose of 12 Gy using 2 Gy per fraction, twice daily, 8 hours apart, with lung doses limited to 10 Gy, is also summarized in Table 15-1.87

A prospective clinical study showed that fractionation of TBI can reduce acute nausea, vomiting, mucositis, diarrhea, and parotitis, although these differences were not statistically significant. Late cutaneous eruptions were more common in patients undergoing fractionated TBI, although this was not statistically significant. This same study, which randomized patients to high- or low-dose-rate TBI, revealed no differences in the acute toxicities mentioned when comparing dose rate.88 Another randomized controlled trial (RCT) reported that fractionating TBI revealed “no apparent difference in acute toxicity” compared with single-fraction TBI, with both regimens being “well-tolerated.”89

Older studies cite nausea and vomiting as frequent side effects of TBI. These symptoms have been substantially minimized with the advent of more effective antiemetics, such as the 5-hydroxytryptamine (serotonin) receptor-3 (5HT-3) antagonists. Several small, high-quality controlled clinical studies support the prophylactic use of 5HT-3 antagonists to reduce nausea and vomiting during TBI, and are summarized in Table 15-2.9094 The use of corticosteroids in conjunction with 5-HT3 antagonists is supported by a trial listed in Table 15-2; however, given the toxicity associated with this approach, consensus regarding routine administration in conjunction with TBI is lacking.9597 Of note, less nausea and vomiting has been noted in myeloablative conditioning regimens involving TBI, compared with those which use chemotherapy alone, even with modern antiemetics.98

Oral mucositis is a side effect of TBI in up to 75% of patients undergoing myeloablative TBI, causing mouth pain, odynophagia, necessitating intensive supportive care such as total parenteral nutrition and opioid analgesics.99 In one study, intensive dental hygiene conferred a reduction in the rate of moderate and severe mucositis, although the authors felt it to be clinically insignificant.100 Topical oral agents, such as chlorhexidine digluconate and neutral calcium phosphate in conjunction with topical fluoride treatments, can decrease the duration and severity of oral mucositis as well as pain and the need for opioid analgesics.101103 Similarly, prophylactic oral sucralfate and clarithromycin have reduced moderate and severe oral mucositis rates.104,105 When given prophylactically, one study showed that amifostine limited the duration of mucositis, with an associated decrease in the rate of moderate and severe infections, with no effect on HSCT outcome.106 One study noted that short-term intravenous recombinant granulocyte-macrophage–colony stimulating factor decreased rates of moderate to severe mucositis,107 whereas another found no effect when this agent was delivered topically.108 Recently, Spielberger et al. reported the results of a trial of the recombinant human keratinocyte growth factor, palifermin, given before and after conditioning with 12 Gy of fractionated TBI. Palifermin reduced the rate and duration of moderate and severe mucositis by 35% and 3 days, respectively, and decreased mouth and throat pain, as reflected in reduced morphine usage and decreased the need for total parenteral nutrition (by 24%).109 This study dealt only with patients undergoing autologous HSCT; however, in the setting of TBI for allogeneic HSCT, palifermin may also confer a protective effect on the mucosa, although this has not been studied in an RCT.110

Skin erythema may also be noted toward the end of a course of TBI; desquamation is rare. Hyperpigmentation may be noted in the long term. Alopecia typically occurs 7 to 14 days after TBI is complete, and hair typically returns 3 to 6 months after treatment.111 Changes in the color or texture of regrown hair have been noted by some. Of note, myeloablative conditioning regimens using chemotherapy alone have noted a significantly higher incidence of permanent alopecia.112

Later Toxicity and Management

As previously mentioned (see “Radiobiology”), the hematopoietic system is particularly sensitive to TBI, and lymphopenia is often seen with doses of 0.5 Gy, and can be seen with doses of 0.3 Gy. Lymphopenia is typically followed by neutropenia, thrombocytopenia, and finally anemia. Soon after a TBI dose of 4 to 6 Gy, lymphocytosis can be seen, but typically is followed by neutropenia within 1 week. Neutrophils fall to their minimum 3 to 4 weeks after TBI (Fig. 15-3).113 Regeneration of the HSC compartment depends on the total dose used, because higher doses cause more rapid myelosuppression, of greater duration. Administration of hematopoietic growth factors after TBI have the theoretical potential to alter hematopoietic system reconstitution, although reports in the setting of allogeneic HSCT have demonstrated an increased risk of GVHD and compromised survival,114 and therefore routine use is controversial.115,116 Of note, hematopoietic growth factors have only been used in the post-TBI period, given the concerns raised by a trial in lung cancer, in which growth factors increased pulmonary toxicity and thrombocytopenia when given concurrent with chemoradiation therapy.117

image

FIGURE 15-3 • Representative hematologic response to total body irradiation, given as a single fraction of 200 cGy on day 0.

(From Andrews GA: Radiation accidents and their management, Radiat Res Suppl 7:390–397, 1967.)

As noted previously, salivary glands frequently are affected by TBI. Although acute parotitis is typically self-limited and can be managed with anti-inflammatory medicines, long-term salivary gland dysfunction can result in xerostomia, which may lead to dental caries. In a study of children who underwent allogeneic HSCT, the risk of developing impaired salivary function was 22% in those who receive TBI as part of conditioning versus 1% in those who did not.118 Studies have shown that salivary flow can improve up to 1 year after the completion of TBI.119 Fractionating TBI was shown to reduce salivary dysfunction by 54% in one study.120 Myeloablative conditioning regimens with and without TBI have been associated with tooth development abnormalities in children.120122 In one series, myeloablative conditioning regimens using chemotherapy alone were associated with significantly higher rates of tooth developmental abnormalities than those involving TBI, although rates of salivary gland dysfunction were highest amongst the patients treated with single-fraction TBI.123 Because of the increased risk of oral pathologic conditions associated with TBI, careful pretransplant evaluation by a dental specialist is recommended to minimize the risk of serious morbidity.124 Pilocarpine has been noted to help relieve symptoms of xerostomia in patients treated with TBI.125

The major dose-limiting toxicity of TBI is pneumonopathy, which can manifest early as pneumonitis and later as pulmonary fibrosis. In the setting of HSCT, radiation pneumonopathy can be difficult to distinguish from other causes of pathologic conditions of the lung; moreover, lung damage is likely multifactorial, with risk of acute lung complications estimated to be 30% to 60%, depending on factors like infection, conditioning regimen, GVHD, age, and diagnosis (see Peters and Afessa126 for review). Likewise, late pneumopathy occurs in 10% to 26% of patients, and is associated with underlying lung dysfunction, type of conditioning regimen, acute and chronic GVHD and prophylaxis, donor and recipient age and immunocompatibility, stage of disease, and genetic predisposition (see Patriarca et al.127 for review). TBI has been shown to be a risk factor for the idiopathic pneumonia syndrome128 as well as diffuse alveolar hemorrhage.129 Although rates of pneumonopathy in patients receiving TBI vary widely (10%-84%),130 some series have reported pneumonitis in up to 20% of HSCT patients who never received TBI.131 In the modern era, with appropriate TBI techniques, the risk of pneumonopathy in patients treated with TBI may not be increased at all.132 Nevertheless, the significance of the problem is clear, given that mortality related to interstitial pneumonitis in patients treated with TBI can be 60% to 80%.131,133,134

Several TBI-specific factors (total dose, fractionation, dose rate, and the use of lung shielding) have been shown to have significant bearing on the development of pulmonary complications. The total dose used during TBI has frequently been cited as a major factor influencing lung complications.130,135,136 In two prospective RCTs using 12 Gy versus 15.75 Gy, higher rates of mortality were noted within the first 6 months in patients treated with 15.75 Gy, although pulmonary complications were not specifically cited as the excess cause of deaths.137140 In a retrospective dosimetric study, mean lung dose larger than 9.4 Gy was found to be an independent predictor for lethal pulmonary complications in patients receiving TBI to a total dose of 10 Gy in three daily fractions, at 0.055 Gy per minute using parallel opposed lateral fields.141 Two RCTs have demonstrated that fractionated TBI can reduce pneumonitis, compared with single-fraction TBI, although only one study was statistically significant.89,142,143 A retrospective study found no difference in pneumonitis rates when comparing a single fraction of 6 Gy and three daily fractions of 3.33 Gy, suggesting that total doses smaller than 10 Gy may not require fractionation to prevent toxicity, although no randomized data support this.144 The necessity of hyperfractionation to prevent lung toxicity is unclear: a comparison of two prospective single-arm trials at the same institution revealed that conventional fractionation given with AP fields and lung blocks to a total dose of 12 Gy in daily 3-Gy fractions may not be any different than HTBI given twice daily with 1.7 Gy per fraction to a total dose of 10.2 Gy for 3 days, using parallel opposed lateral fields and no blocks.145 Sampath et al. recently reviewed 26 studies involving 1096 patients to create a dose-response model to predict risk of pneumonitis from TBI, taking other factors into consideration. Although unable to estimate the risk of pneumonitis for hyperfractionated regimens, they were able to determine the effect of fractionation and cyclophosphamide (CY) and busulfan (Bu) on the risk of developing pneumonitis, in a dose-response model, as seen in Fig. 15-4.146 Pneumonitis rates were not significantly different in a trial that randomized patients to high- or low-dose-rate TBI.88 However, there is an abundance of retrospective clinical data suggesting that lowering the dose rate (<0.025-0.09 Gy/min) does decrease the likelihood of pulmonary complications,130,136,140,147,148 especially if TBI is delivered as a single fraction.149 If TBI is fractionated, some report that low dose rate (<0.069 Gy/min) is not necessary,134 although others found a beneficial effect.150,151 Studies of patients receiving fractionated TBI with lung shielding have demonstrated a reduction in pneumonopathy152,153; however, one RCT found no difference in pneumonopathy if the shielding allowed a lung dose of either 6 or 8 Gy in a single fraction.154

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FIGURE 15-4 • Incidence of pneumonitis based on dose-response model accounting for total body irradiation fractionation, as well as chemotherapy effects. Cy and Cyc, Cyclophosphamide; fx, fraction(s); Bu, busulfan.

(From Sampath S,et al: Dose response and factors related to interstitial pneumonitis after bone marrow transplant, Int J Radiat Oncol Biol Phys 63[3]:876–884.)

Pulmonary function tests (PFTs; spirometry and diffusion capacity) are often helpful in the assessment of patients with pulmonary symptoms or radiographic abnormalities. Studies of PFTs in patients treated with HSCT have demonstrated a deleterious effect on spirometry and diffusion capacity, which often resolves in the absence of other complicating factors,155157 and is related to TBI dose.158 A retrospective study found that lung shielding had a small but significantly beneficial effect on PFTs one year after HSCT, especially in patients with abnormal function prior to HSCT.159 In one study, Bu, but not TBI, was not associated with a negative effect on PFTs.160 There is no evidence that PFTs improve pulmonary outcome after HSCT in adulthood, and for this reason, they are not recommended.161 However, some groups recommend baseline PFTs as part of long-term follow-up care for children treated with TBI.162 Counseling patients regarding smoking cessation is of critical importance in all patients, especially those who are at increased risk of developing lung injury. In the event of acute pneumonitis, high-dose steroids (30-60 mg of prednisone/day) typically alleviate symptoms within 24 to 48 hours.

Cardiovascular toxicity as a result of HSCT has been relatively rare, given the stringent selection criteria for patients treated with this aggressive therapeutic modality. Nevertheless, among patients who survive HSCT, cardiac events were responsible for 2.4% and 3.0% of deaths in patients that underwent autologous and allogeneic HSCT, respectively, which represents a greater than expected occurrence in some patients.163,164 Most of the recent literature has identified no association between TBI and development of cardiovascular disease.165,166 Several detailed prospective analyses using plasma cardiac troponin and brain natriuretic peptide levels, electrocardiography and echocardiography revealed no evidence of cardiac dysfunction in previously healthy individuals treated with TBI.167,168 However, a prospective study of children who underwent allogeneic HSCT found a 12% and 26% cumulative incidence of abnormalities in ejection fraction (<30%) on echocardiography prior to and five years after HSCT, respectively. This study revealed that TBI was associated with abnormalities in cardiac function on univariate analysis, but not multivariate analysis; the five-year cumulative incidence of cardiac abnormality was 26% in children treated with TBI with prior anthracycline therapy and 2% in children treated with TBI without prior anthracycline therapy.169 For these reasons, it appears prudent to screen patients who have undergone HSCT for cardiovascular disease or risk factors, whether or not this involved TBI, to minimize late morbidity and mortality.

Hepatotoxicity from TBI manifests primarily as veno-occlusive disease (VOD), also known as sinusoidal obstructive syndrome, of the liver. This clinicopathologic phenomenon was first described in 1977 by Shulman et al.,170 who noted the onset of weight gain from ascites, painful hepatomegaly, and jaundice from centrilobular liver acinus necrosis 1 to 4 weeks after HSCT. Overall, up to 70% of patients that undergo HSCT can be affected by VOD. TBI, along with many other risk factors, has been implicated in the development of VOD (see Wadleigh et al.171 for review). Notably, a RCT and meta-analysis found that patients treated with Bu instead of TBI were significantly more likely to develop VOD.172,173 Two RCTs have concluded that fractionated TBI reduces the incidence of VOD compared with single-dose TBI.142,143 Another RCT found no difference in the rate of VOD when the dose rate was either 0.06 Gy per minute or 0.15 Gy per minute,88 although a retrospective study of single-dose TBI found that dose rates of 0.07 Gy per minute were associated with less VOD than dose rates of 0.18 to 1.2 Gy per minute.174 TBI dose greater than 13.2 Gy has been reported to be associated with higher rates of VOD on univariate analysis,175 although dose greater than 12 Gy was not associated with VOD in another retrospective study.176 Lawton et al. reported a non–statistically significant 10% decrease in the rate of fatal VOD in patients treated with TBI as part of HSCT, when a 10% attenuation liver block was employed.177 Ursodeoxycholic acid was effective in preventing VOD in a RCT of patients undergoing TBI followed by HSCT,178 although another RCT did not support this finding.179 Reduced-intensity conditioning regimens may also prevent VOD. Treatment of VOD can include the fibrinolytic antithrombotic agent, defibrotide; decompressing the sinusoids by a transjugular intrahepatic portosystemic shunt and liver transplantation are more invasive options for management of severe disease.180

Cataracts are one of the most common complications of TBI. Patients may present with painless vision loss, and may be noted to have opacification of the lens on examination. In one series of patients treated with TBI in one or two fractions, severe visual impairment was noted in approximately half of patients.181 This problem has been noted to arise in a large proportion of patients treated with TBI, depending on total dose, fractionation, and dose-rate used. When considering risk factors associated with HSCT, steroid use,182184 prior cranial irradiation,185,186 and the development of GVHD184 have been shown to predispose to cataractogenesis, whereas heparin use appears to be protective.187 Delivering TBI in a single fraction is the single biggest risk factor for developing a cataract after HSCT.187192 High dose rate (>0.035-0.048 Gy/min) TBI also appears to increase the risk of cataract formation.185,187,190,193 A prospective study that randomized patients to high- or low-dose-rate TBI found that the incidence of cataract 5 years after treatment was 12% and 34% in the low- and high-dose-rate arms, with 13% and 39% of the cataracts occurring in patients who received fractionated or single-dose TBI, respectively.194 Kal and van Kempen-Harteveld recently reviewed the subject of TBI-induced cataracts and concluded that a biologically equivalent dose of 40 Gy yields a 10% chance of developing cataracts, using linear-quadratic modeling that included corrections for dose rate, with an α/β of 0.65 for late effects on the lens. On the basis of this, they suggest considering lens shielding for single-fraction TBI regimens,195 although this is controversial in the setting of malignant disease.196 Given the frequency of cataracts occurring after TBI, patients should be monitored for the development of this complication.197 Management of cataracts that impair vision or degrade quality of life may involve phacoemulsification or extraction; recent data suggest these procedures are safe, with an adverse event rate of 0.1% for experienced surgeons,198 and effective, with a 90% chance of 20/40 vision postoperatively.199

Kidney dysfunction occurs in approximately 17% of survivors of HSCT,200 and can manifest in a number of ways, with the most- to least-frequent syndromes being idiopathic chronic kidney disease, nephrotic syndrome, thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome), and acute renal failure (see Hingorani201 for review). The syndrome best associated with TBI is thrombotic microangiopathy, which can manifest as nephritis, hypertension, proteinuria, or anemia 6 to 12 months after HSCT. HSCT-related risk factors for nephropathy can include GVHD, infections with CMV or BK virus, nephrotoxic medications like cytotoxic chemotherapy (cytarabine, CY, ifosfamide, cisplatin, retinoic acid, carmustine, actinomycin D, melphalan), antibiotics (acyclovir, ganciclovir, foscarnet, vancomycin, amphotericin, aminoglycosides), and immunosuppressants (cyclosporine, tacrolimus, methotrexate). It is worth noting that the larger and more contemporary studies of chronic kidney disease after HSCT, have not demonstrated an association with TBI.202206 Total dose has been implicated as the most important in predicting renal morbidity from TBI; a retrospective study found that GVHD and high dose (13.5 Gy) was associated with elevated serum creatinine.207 A prospective evaluation of renal function using radioisotopes found that early nephropathy was associated with age younger than 40 years, use of kidney blocks (possibly related to nephrotoxic contrast media given during simulation), and nephrotoxic drug use, while late nephropathy was associated with nephrotoxic drug used, but not TBI dose.208 The benefit of kidney shielding has been assessed in two retrospective studies, which both demonstrated significant improvement in long-term kidney function, with no evidence of dysfunction when the hyperfractionated dose was limited to 9.8 to 10 Gy.209,210 Two recent dose-effect modeling studies have demonstrated that nephropathy is unlikely after a biologically equivalent total dose of 16 Gy (calculated using a linear quadratic model, with corrections for dose rate and an α/β of 2.5 Gy) and that fractionating TBI and delivering a low dose rate (<0.10 Gy/min) prevent kidney dysfunction.195,211 Monitoring blood chemistry and counts, as well as blood pressure and urine studies are advised given the prevalence of kidney disease after HSCT. Although there are no proven therapies to treat HSCT-related nephropathy, medical therapies (antihypertensives, corticosteroids), plasma exchange, hemodialysis and renal transplant, and are possible options for management (see Hingorani201 for review). The angiotensin-converting enzyme inhibitor captopril is known to prevent chronic nephropathy from diabetes212 and was been hypothesized to reduce the risk of radiation nephropathy from TBI in preclinical studies.213,214 A small RCT of captopril to mitigate chronic renal failure in patients undergoing 12 Gy of fractionated TBI (with kidney dose of 9.8 Gy) prior to HSCT revealed less nephropathy; however, this was not statistically significant.215

Primary hypothyroidism is the most common endocrinopathy following TBI with an incidence of approximately 25% after fractionated therapy.216 The incidence is significantly higher in series of single-dose TBI and is known to increase with longer follow-up. It has been suggested that adults have a lower risk of hypothyroidism than children and that some patients develop only transient hypothyroidism. This condition is easily managed with thyroid hormone replacement. Following TBI, central hypothyroidism caused by thyrotropin (thyroid-stimulating hormone) deficiency is rare, as is deficiency of corticotropin (adrenocorticotrophic hormone), and hypogonadotropic hypogonadism.

Impaired growth and loss of adult height has been described as a consequence of TBI during childhood. This effect is multifactorial because radiation can cause poor nutritional conditions, skeletal dysplasia, and also temporary or permanent growth hormone (GH) deficiency. The effects of TBI on growth are inversely related to patient age at the time of treatment. Both the total dose and dose per fraction of TBI have shown to be related to the risk of growth impairment. These factors are also important when considering GH replacement for children proven to have deficiency. Sanders et al. observed that GH replacement was not effective after single-dose TBI or when TBI was delivered after age 10 years.217

Typical TBI regimens allow preservation of testicular Leydig cell function and therefore normal testosterone levels. However, almost all males will develop azoospermia as a result of germ cell irradiation during TBI. Although male patients are universally counseled to expect infertility, there are rare reports of spermatogenic activity in men many years after exposure to TBI during childhood. Age plays an even more important role in female fertility following TBI. Although approximately half of prepubescent girls who receive TBI will undergo spontaneous puberty, many will experience premature menopause in their twenties or thirties.218 Ovarian failure is expected in virtually all females receiving TBI after age 10 years. For the small percentage of women who become pregnant after TBI, some investigators have reported an increased risk for spontaneous abortion, whereas others do not.

Other endocrine and metabolic complications of HSCT include insulin resistance, lipid disorders and hypertension. Both type 1 and type 2 diabetes mellitus are associated with TBI.219The possible mechanisms involved are active areas of investigation.

Declines in neuropsychiatric function following TBI have been observed, but are subtle because of relatively low doses and modern fractionation. A recent prospective study at St. Jude tracked 158 children who had undergone HSCT, of whom 80 had received full-dose fractionated TBI. Patients were given a battery of neurocognitive examinations at 1, 3, and 5 years after transplant. Although TBI was associated with a 3-point decline in IQ compared with non-TBI patients, this difference was small compared with the 20 point difference observed between children from high and low socioeconomic groups.220

Beyond organ-specific toxicities, the risk of developing SMNs is increased in patients that have undergone HSCT. Typically, three groups of SMNs after HSCT are described, and follow a distinct pattern of development (Fig. 15-5):221 MDS and AML, post-transplant lymphoproliferative disorder (PTLD), and solid tumors.222 There are multiple risk factors that may predispose to development of a SMN after HSCT, including but not limited to genetic aberrations, pre-HSCT therapy, conditioning regimen, graft source and processing, post-transplant immunosuppression, and GVHD (for review see DeVita et al.38); only the association of TBI with SMNs is discussed here.

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FIGURE 15-5 • Relative risk and chronology of second malignancies after allogeneic hematopoietic stem cell transplant. GvHD, Graft-verus-host disease; HD, Hodgkin disease; NHL, non-Hodgkin lymphoma.

(From Adès L, et al: Second malignancies after allogeneic hematopoietic stem cell transplantation: new insight and current problems, Blood Rev 16:135–146.)

Secondary MDS or AML after HSCT has been reported to occur at rates between 1.1% at 20 months to 24.3% at 43 months. The World Health Organization classifies secondary MDS and AML as alkylating agent– or radiation-related, typically occurring 4 to 7 years after treatment, or topoisomerase-II inhibitor–related, typically occurring 6 months to 5 years after treatment.223 Several studies have attempted to quantify the risk of developing secondary MDS or AML after undergoing TBI, with conflicting results. Studies from research groups from Minnesota,224 Newcastle,225 the City of Hope,226 and France227 have demonstrated no increase in rates of MDS or AML after myeloablative HSCT using TBI. Other studies from Nebraska,228 the European Group for Bone Marrow Transplantation (EBMT),229 Paris,230 Barcelona,231 and France232 have found weak associations of borderline or no statistical significance. One study found an association of secondary MDS or AML with TBI on multivariate analysis when TBI was used with etoposide and CY.233 One of the more recent and detailed studies that investigated this subject found that, among 4000 patients treated with autologous HSCT for lymphoma, 57 developed MDS or AML, with a cumulative incidence rate of 3.7% 7 years after HSCT. A case-control analysis revealed a weak association of TBI and the subsequent development of MDS or AML, which was not statistically significant. In a small, subgroup analysis, a TBI dose of 13.2 Gy was associated with MDS or AML, but the authors cautioned that this group of patients may represent a population that shared other, non-TBI related factors that could have contributed to leukemogenesis. Older age also appeared to increase the risk.234 The dose threshold effect was not supported by a more recent study that found no differences in the rate of MDS or AML after TBI whether 12 or 14 Gy of TBI was given.235

The association of TBI with the subsequent development of a PTLD has been described in several studies. Because it is thought to be a consequence of immune system dysfunction, PTLD occurs primarily in patients that have undergone allogeneic, not autologous, HSCT. The cumulative incidence of PTLD at 12 years varies by the number of risk factors harbored by the patient, and ranged from 0.2 to 8.1%.236 Small, early studies from Seattle222 and the CIBMTR237 suggested an association between TBI use during HSCT and subsequent development of a PTLD. However, subsequent research from Minnesota,224 Vancouver,238 and Nebraska239 suggested no association of TBI and PTLD. A follow-up study from the CIBMTR, the largest and most comprehensive study available, involving 26,000 patients who underwent allogeneic HSCT over a 30-year period clearly demonstrated that no association between PTLD and TBI exists, in contrast to their previous findings.236

The risk of solid tumors after HSCT involving TBI has been studied extensively.240250 The largest, and most recently updated analysis from the CIMBTR suggests that among patients who undergo allogeneic HSCT, the cumulative incidence of developing a solid malignancy (including non-skin carcinoma in situ carcinomas) is 1%, 2.2%, and 3.3% at 10, 15, and 20 years after transplant, based on the competing risk analysis method.251 The number of secondary solid tumors was double what would have been expected in this population; significantly higher rates of oral cavity and pharyngeal, liver, central nervous system (CNS), thyroid, bone, soft tissue cancers, and melanomas were observed. TBI was found to be a risk factor for developing a secondary solid tumor, with risk increased in those who survived more than 5 years from the HSCT, and those less than 30 years old at the time of HSCT. Although an earlier study found that TBI doses less than 10 Gy were associated with fewer secondary solid tumors,240 this dose association was not maintained in the subsequent analysis.251 There was no difference in secondary solid tumors in patients treated with fractionated or single-dose TBI. There was no increased risk of squamous cell carcinomas in patients treated with TBI. There was no increased risk of secondary solid tumors in patients treated with TBI after age 30. Chronic GVHD and male sex were also associated with the development of secondary solid tumors and squamous cell carcinoma, respectively.251

Given the increased risk of second malignant neoplasms after TBI, careful surveillance of long-term survivors is a desirable (but not yet proven effective) strategy to minimize secondary morbidity and mortality. Guidelines published by the American Cancer Society,252 the NCCN (www.nccn.org), and the Children’s Oncology Group162 provide important references when assessing patients at higher risk of developing a secondary solid tumor.

Physical Principles

A report in 1980 highlighted the fact that different institutions carry out TBI in a variety of ways.253 In fact, the physics of TBI has not changed significantly since 1986 when the American Association of Physicists in Medicine published “The Physical Aspects of Total and Half Body Photon Irradiation.”254 The data, formulas, and recommendations in this comprehensive report are still relevant today.

TBI differs from conventional radiation therapy in several unique ways, which determine the physical design of a TBI technique. As the name implies, to treat the entire body is paramount, although it is complicated by the limited maximum apertures available from teletherapy machines. Dose uniformity is compromised by tissue inhomogeneities (i.e., variations in both body part thickness and tissue density). If the skin and the bone marrow are targeted for treatment, then the buildup region becomes a concern, especially for linac energies. Critical organ shielding must balance toxicity and control of circulating leukemic cells. Similarly, protocols often specify low dose rates to minimize toxicity. These aspects of TBI are interdependent; a comprehensive solution must optimize treatment geometry, beam parameters, and individual needs of the patient.

Geometry

The most common TBI technique, developed at Memorial Sloan-Kettering Cancer Center (MSKCC), uses opposing AP-posteroanterior (PA) fields with the patient standing several meters from the source and the beam pointed horizontally.255 AP-PA fields delivered using higher linac energies are recommended to optimize dose uniformity.254 A beam spoiler placed upstream from the patient’s surface showers the skin with electrons to reduce skin sparing. A TBI stand developed at MSKCC and commercially available provides support and comfort for the patient and reproducibility of setup; an acrylic scatter spoiler positioned upstream is available as an option. The stand also provides facility for lung blocks, film verification, and in vivo dosimetry (Fig. 15-6).

Although the upright patient position is preferred to achieve full body coverage, this is not practical for all patients. Young children may not be able to stand and may require anesthesia for an accurate and reproducible treatment. For this group of patients, the standard geometry is lying on the floor with the gantry pointing downward. Other features of TBI (i.e., spoiler and blocks) are maintained. For taller children and adults who cannot tolerate the standing position, treatment on the floor is an option with abutting fields. Similarly, in some clinics where a large treatment room is unavailable, combinations of gantry or patient motion, possibly involving matching fields, are used.254,256

Alternatively, patients can be irradiated using right and left lateral fields.257 This technique has the advantage that the treatment distance can be reduced with the patient treated in a sitting position or partly reclining position on a stretcher. As the body part thickness variation is much greater for lateral fields than for the AP-PA fields, compensators attached to the head of the machine are used to improve the uniformity, especially for lower energies (≤6 MV). Arm positions are important to achieve the proper lung dose through self-shielding.

Planning

Two-dimensional images of the thorax using computed radiography (CR) plates are acquired for adult patients standing in the treatment position in the treatment room to design the lung block shapes. Magnification is determined by a marker placed on the patient laterally at about midline; a second marker identifies the level of the suprasternal notch where the patient is subsequently tattooed. Block margins are drawn on the image 2 cm from the diaphragm and vertebral body edge and 1.5 cm from the lateral and superior rib cage. A similar procedure is done for the posterior field. The patient’s height and AP separation at the suprasternal notch, chest, abdomen and pelvis are measured at this time. A computed tomography (CT) scan is also acquired to optimize the electron energy for the chest wall boost and assess the lung dose. Anesthetized pediatric patients are simulated in the CT only because they are treated AP supine and PA prone on the floor. Lungs are shielded (50%) for all patients for each fraction.

Electron boosts compensate the anterior and posterior chest walls for the blocked photons. Electron energy and surface bolus is based on CT planning of the chest wall-lung region such that the interface is 80% to 95% of Dmax, and the mid-lung dose is limited to 10 Gy for the photon-electron composite. A typical electron boost dose distribution is shown in Fig. 15-7.

Treatment

A variety of TBI protocols are followed at MSKCC. The total dose is prescribed to midplane pelvis.

Adult patients are treated in the standing position with 15 MV, AP-PA fields at 440 cm source-axis distance (SAD) with a dose rate of 0.08 to 0.17 Gy per minute. The gantry is tilted 5 degrees off the horizontal to place the central axis at approximately the level of the umbilicus for an average adult patient. At 440 cm, a collimator setting of 40 × 40 cm2, and a 45-degree collimator angle, the diamond-shaped field accommodates a 200 cm (≈6.5 ft) patient with ample margins. All treatments incorporate a beam spoiler, 1.2 cm acrylic, 15 to 25 cm from the patient’s surface to increase the skin dose to 90% of prescription. Handles and supports on the TBI stand serve to restrict the patient movement and help maintain a relaxed, but reproducible, position.

Pediatric patients who are too young to stand are treated supine and prone lying on the floor with 6 or 15 MV, AP-PA fields at approximately 220 cm SAD, and a dose rate of 0.13 to 0.17 Gy per minute. This low midplane dose rate on the floor is attained with a dynamic multileaf collimator pattern having one peripheral leaf in motion such that the beam hold-offs reduce the repetition rate to approximately 70 monitor units (MU) per minute. Maximum patient length on the floor is approximately 110 cm with a 45-degree collimator rotation. An acrylic beam spoiler is used in this geometry as well. In most of these cases, anesthesia is administered for each treatment to restrict movements during simulation and treatment.

Lung blocks are attached to a plastic holder and are positioned at the surface of the patient using the tattoo or marker position as reference. Because of broad beam-scatter conditions, the thicknesses of lung shields are 2.2 cm. AP and PA images verify block positioning on the first treatment.

The chest wall boost is delivered with the patient seated on the couch at 105 cm source-surface distance (SSD) and the gantry at 90 degrees. The electron cutouts match the photon blocks at the skin surface and are also aligned to the tattoo or marker.

Male patients may receive a testicular electron boost of 4 Gy. The patient is treated in the recumbent position with a dual polystyrene-lead shield under the testes to protect the rectum and to minimize backscattered electrons. The physician prescribes the energy based on scrotal thickness.

Role of Total Body Irradiation in Contemporary Hematopoietic Stem Cell Transplant

The role of TBI in HSCT has been refined over the preceding several decades. High-level evidence guides some of the rationale for using TBI, whereas in some situations institutional and practitioner preference dictates the use of the technique. Major questions that have been answered deal with the necessity of using TBI during HSCT, as well as dose, fractionation, and shielding.

Necessity of Total Body Irradiation in Hematopoietic Stem Cell Conditioning

Although the earliest studies of HSCT for malignant hematopoietic diseases involved both chemotherapy and radiotherapy (see “History”), in the 1970s several non-TBI (chemotherapy only) regimens were developed, largely for logistical reasons—adequate facilities to perform TBI were not widely available.258 Soon thereafter, the availability of conditioning regimens for HSCT without TBI (primarily involving Bu and CY; see Santos259) gave rise to several important clinical studies that investigated the necessity of TBI in HSCT in various hematopoietic diseases.

Acute Myelogenous Leukemia

There have been two RCTs comparing TBI-based conditioning regimens to non-TBI–based conditioning regimens for AML. In 1987, the Groupe d’Etude des Greffes de Moelle Osseuse initiated a prospective, multicenter, RCT to evaluate whether TBI could be replaced by Bu in an effort to limit toxicity in allogeneic HSCT.260 A similar single-institution study was initiated at the University of Minnesota for patients receiving autologous HSCT, but accrual was poor and the study was terminated early.261 As noted in Table 15-3, superior overall survival, disease-free survival, survival, and fewer relapses were noted with the TBI conditioning regimen in both trials, with only the French trial demonstrating a statistically significant difference.260,262 An updated, combined analysis of three trials of allogeneic HSCT for AML that randomized patients to conditioning with or without TBI found marginally significant improvements in overall survival and disease-free survival. Patients treated with or without TBI had an estimated 10-year survival of 63% or 51% (P = 0.068), and 10-year disease free survival of 57% or 47% (P = 0.051). On multivariate analysis, TBI was associated with significantly less hair loss and no difference in the rates of GVHD, cataracts, avascular necrosis, or pulmonary complications.263 A retrospective analysis by the CIBMTR revealed that TBI-based conditioning yields fewer relapses (especially in extramedullary and CNS sites) and less hepatic VOD than Bu-based conditioning.264

Chronic Myelogenous Leukemia

Two RCTs have compared the efficacy and toxicity of allogeneic HSCT in patients with CML, preceded by conditioning with either TBI and CY or Bu and CY (see Table 15-3).265267 Both studies showed no significant difference in overall survival, event-free survival, or transplant-related mortality. The French study found more relapses in patients treated with TBI (especially fractionated TBI), but this was not seen in the study from Seattle, which used fractionated TBI exclusively. The Seattle trial did show significantly longer fevers, more blood cultures revealing bacteria or fungi, more hospitalizations in the 100 days after transplant, and higher incidence of grade 2 through 4 GVHD in patients treated with TBI. An updated, combined analysis of three studies that randomized patients with CML to different conditioning regimens prior to allogeneic HSCT confirmed no significant difference in survival (65% and 63%) and disease-free survival (52% and 42%) for patients treated with Bu-CY and CY-TBI, respectively. No differences in the 5-year cumulative incidence of chronic GVHD (37% and 39%). However, cataracts were more common among patients treated with TBI.263 Retrospective data also suggest that Bu-CY conditioning regimens prior to allogeneic HSCT for CML may be favored because of lower relapse rates,268 although higher rates of GVHD, hepatotoxicity, and hemorrhagic cystis have been reported with chemotherapy alone.269

Acute Lymphoid Leukemia

The Pediatric Blood and Marrow Transplant Consortium conducted the only RCT comparing the effect of preallogeneic HSCT conditioning using Bu or TBI, in children with ALL. A CNS boost of 6 Gy was given to patients with history of prior CNS disease, but no prior CNS irradiation if randomized to TBI; if randomized to Bu, patients with history of CNS disease received 18 Gy of CNS radiation therapy prior to Bu. The study showed no difference in overall survival; however, longer event-free survival was noted for patients treated with TBI. Patients 6 years old or younger, as well as those in first complete remission, appeared to experience the most benefit from the TBI regimen.270 A retrospective study using the CIBMTR data by Davies and colleagues of 627 children with ALL that underwent HSCT after conditioning with CY and TBI, or Bu and CY found that the risk of relapse was not significantly different in the two cohorts. However, the risk of treatment-related mortality was significantly greater in the Bu-CY group. The use of CY-TBI was associated with superior overall survival and leukemia-free survival. Based on this data, the authors concluded that less treatment-related mortality in the CY-TBI group led to greater overall survival and leukemia free survival.271 A multivariate analysis of adults with ALL who underwent HSCT preceded by conditioning with fractionated TBI to 12 Gy (lung dose of 9 Gy) or Bu found that shorter event-free survival and disease relapse were more likely among patients that did not receive TBI on multivariate analysis. There were no differences in the rates of transplant related mortality, hepatic VOD, or GVHD.272

Mixed Diseases

Two prospective trials of conditioning have been carried out in groups of patients with leukemias and lymphomas. As these trials included a heterogenous group of diseases, results should be interpreted with caution. Nevertheless, in 1988 the Nordic Bone Marrow Transplantation Group initiated a multicenter, RCT of 167 children (n = 27) and adults (n = 140) with AML (n = 68), ALL (n = 38), CML (n = 57), or lymphoma (n = 4) prior to allogeneic HSCT.172 With 7 years of follow-up, the authors found a survival benefit in the TBI group among patients with “advanced” disease, with less toxicity compared with Bu regimens; no differences were identified in the subset analysis of the different diseases that were treated.112 The Southwest Oncology Group’s RCT 8612 also investigated the role of TBI prior to allogeneic HSCT for ALL (n = 48), AML (n = 40), and CML (n = 34) not in the first remission. This regimen substituted etoposide for CY in the TBI group only, making a meaningful comparison difficult. Although overall survival and disease-free survival appeared superior for “good-risk” patients in the TBI group, these differences were not statistically significant.274

In conclusion, a meta-analysis by Hartman et al.173 summarizes how TBI influences the outcome of conditioning regimens prior to allogeneic HSCT.173 As demonstrated in Fig. 15-8, overall survival and disease-free survival are slightly better with TBI-based regimens, although this was not statistically significant. As noted in Fig. 15-9 and Fig. 15-10, GVHD was roughly equivalent in the studies, whereas hepatic VOD was clearly more common with Bu-based regimens. Interstitial pneumonitis appeared to also be very similar in both groups. In the setting of autologous HSCT, a non-TBI-based conditioning regimen is preferred for MM; however, no other trials have randomized patients to a TBI or non-TBI conditioning regimen prior to autologous HSCT, and therefore institutional preference primarily dictates use of the technique in these situations.

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FIGURE 15-8 • Odds ratio and 95% confidence intervals of survival and disease-free survival in a meta-analysis of total body irradiation (TBI)–based conditioning versus non-TBI–based conditioning in five randomized controlled trials.

(From Hartman AR, et al: Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs. total body irradiation: a meta-analysis, Bone Marrow Transplant 22:439–443, 1998.)

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FIGURE 15-9 • Odds ratio and 95% confidence intervals of acute and chronic GVHD in a meta-analysis of total body irradiation (TBI)–based conditioning versus non-TBI–based conditioning in five and four randomized controlled trials, respectively. GVHD, Graft-versus-host disease.

(From Hartman AR, et al: Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs. total body irradiation: a meta-analysis, Bone Marrow Transplant 22:439–443, 1998.)

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FIGURE 15-10 • Odds ratio and 95% confidence intervals of hepatic veno-occlusive disease and interstitial pneumonitis in a meta-analysis of total body irradiation (TBI)–based conditioning versus non-TBI–based conditioning in four and three randomized controlled trials, respectively.

(From Hartman AR, et al: Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs. total body irradiation: a meta-analysis, Bone Marrow Transplant 22:439–443, 1998.)

Total Body Irradiation Dose

The appropriate radiation dose to use during conditioning with TBI has been investigated by several groups. In 1985, researchers in Seattle conducted a RCT of two TBI regimens as part of HSCT for AML. Seventy-one patients were randomized to receive 12 Gy in six daily fractions (2 Gy/fraction/day), or to 15.75 Gy in seven daily fractions (2.25 Gy/fraction/day). TBI was delivered using opposed 60Co sources, at 0.06 to 0.07 Gy per minute. The use of shielding was not described. Higher-dose (15.75 Gy) TBI was associated with higher rates of mortality in patients that did not relapse, and higher rates of grade 2 through 4 acute GVHD (P = 0.02). Patients receiving higher-dose TBI were less likely to receive adequate immunosuppression. Nonetheless, patients treated with lower-dose TBI (12 Gy) appeared to be more likely to relapse, although this finding was marginally significant (P < 0.06).137 A report of the long-term results (minimum follow up of 7.5 years) of the trial revealed no difference in overall survival between the two TBI groups. Again, relapse was noted to be more common in patients with lower-dose TBI, with marginal statistical significance (P = 0.06). Nonrelapse mortality was again noted to be significantly higher in the higher-dose TBI group, although the authors note that this was limited to the first 6 months after transplant.139

In a similar trial, also from Seattle, 116 patients with CML were randomized to receive either 12 or 15.75 Gy, as described previously. Higher-dose (15.75 Gy) TBI was associated with a superior relapse-free survival. Higher-dose TBI was also associated with more grade 2 through 4 acute GVHD, although this was not statistically significant (P = 0.15). Initially, survival appeared superior in patients receiving lower-dose (12 Gy) TBI; however, further follow-up revealed no significant difference in survival. Similar to the experience with AML, the authors conclude that higher-dose TBI was associated with greater relapse-free survival at the cost of more acute GVHD, which likely led to transplant-related mortality that offset the survival benefit.138

Retrospective data do suggest a benefit to higher-dose (>12 Gy) TBI in certain clinical scenarios. Although the highest doses of TBI reported in the literature are 20 Gy prior to autologous HSCT,275 at least one study has reported lower relapse rates and less transplant-related mortality in a subset of patients with ALL who received a TBI dose larger than 13 Gy.276 Although modeling studies suggest that higher biologically effective doses are associated with lower relapse rates and longer overall survival,277 excess toxicity with higher doses in clinical dose-escalation studies does warrant caution.278281 For these reasons, fractionated TBI doses used prior to myeloablative HSCT often range between 12 and 15 Gy.

Reduced-intensity conditioning regimens have been used more often over the preceding decade for patients that might not be able to tolerate a myeloablative HSCT because of advanced age or comorbidities, but could benefit from the GVT effects of allogeneic HSCT. The role of TBI as part of reduced intensity regimens is ill-defined, as prospective RCTs of reduced intensity conditioning regimens involving TBI have not been completed. Likewise, the optimal dose of TBI as part of reduced intensity autologous HSCT has not been defined in an RCT. Several notable studies of allogeneic HSCT have employed TBI doses of 2 to 8 Gy, often in conjunction with chemotherapy.282296 Table 15-4 lists some representative allogeneic HSCT regimens using low-dose TBI.

Fractionation and Total Body Irradiation Dose Rate

Laboratory-based radiobiological data (see “Radiobiology”) and clinical observations prompted trials investigating fractionation and dose-rate delivery in TBI. Thomas and colleagues were the first to conduct an RCT of single-dose or fractionated TBI in patients with AML. In this study, 53 patients with AML were randomized to receive TBI in a single 10 Gy dose, or 12 Gy in six daily fractions after receiving CY. TBI was delivered using opposed 60Co sources, at a rate of 80 R per minute in air at midpoint (≈0.06 Gy/min). Disease-free survival was significantly longer in the patients who were treated with fractionated TBI. There was no apparent difference in acute toxicity in the two treatment groups.89 A follow-up report also described the outcome of patients treated with the same transplant regimen prior to the RCT, but using a single fraction of 9.2 Gy using opposed 60Co sources at 0.04 Gy per minute. Among the patients randomized, those who received fractionated TBI survived significantly longer than those receiving single-fraction TBI. Patients receiving single-fraction TBI experienced twice as many leukemic recurrences, compared with those receiving fractionated TBI, although this was not statistically significant (P = 0.09). VOD of the liver was significantly more common in patients receiving single-fraction TBI (P = 0.02).142

Ozsahin et al.88 conducted a study investigating the effect of dose rate in patients undergoing single-dose or fractionated TBI as part of autologous or allogeneic HSCT for a variety of hematologic and lymphoid malignancies. In this trial, 157 patients receiving single-dose or multiple fractions of TBI were randomized to low dose rate (0.06 Gy/min or 0.03 Gy/min, respectively) or high dose rate (0.15 Gy/min or 0.06 Gy/min, respectively). Radiotherapy was delivered with 60Co or 6-MV photons from a linac. Single-dose TBI was delivered to a total dose of 10 Gy while limiting the lung dose to 8 Gy. Fractionated TBI was delivered to a total dose of 12 Gy in six fractions over 3 days, while limiting the lung dose to 9 Gy. A variety of chemotherapies were used. The authors found no significant differences in overall or relapse-free survival, pneumonitis, VOD, or GVHD. Cataracts were significantly more common among patients receiving single-fraction, high-dose-rate TBI.88 In a follow-up report of this study, with a median follow-up of 50 months, it was demonstrated that TBI in a single fraction or at a high-dose-rate was associated with the development of cataracts.194

Girinsky and colleagues conducted an RCT of 160 patients older than 15 years, undergoing autologous or allogeneic HSCT for a variety of hematologic and lymphoid malignancies. Patients were treated with a single fraction of TBI (STBI) with 10 Gy during 4 hours (average dose rate of 0.045 Gy/min; instantaneous dose rate of 0.125 Gy/min), or HTBI with 14.85 Gy in 11 fractions during 5 days at a dose rate of 0.25 Gy per minute. A linac was used to deliver 18-MV photons with lung shielding; patients receiving STBI received a lung dose of 8 Gy, and HTBI patients received a lung dose of 9 Gy. After TBI, CY or melphalan were given, followed by HSCT. With a median follow-up of 8 years in 147 assessable patients, overall survival and cause-specific survival were higher in the HTBI group; this was not statistically significant. However, a multivariate analysis that controlled for prognostic variables revealed greater cause-specific survival but not overall survival was longer in patients treated with HTBI (P = 0.04). There was no significant difference in the rates of lethal pneumonitis, hepatic VOD, GVHD, graft failure, infection, or organ failure. However, the rate of hepatic VOD was significantly higher in the STBI group.143

The necessity of hyperfractionation versus conventional fractionation has never been tested in a prospective trial. Investigators from M.D. Anderson Cancer Center compared the outcome of patients on different prospective HSCT protocols, and found that fewer recurrences occurred in the conventionally fractionated group. These results should be interpreted with caution, because this study was not randomized, and other factors not related to TBI may have influenced the results.145 Investigators in Seattle have conducted phase I and II studies of twice- and thrice-daily hyperfractionation protocols that did not suggest a significant benefit with hyperfractionation versus conventional fractionation when compared with historical results.280,297

Organ Shielding During Total Body Irradiation

The necessity of shielding to prevent normal tissue toxicity has been investigated in several studies; because pneumonopathy has been considered the dose-limiting toxicity of TBI, the studies have primarily been concerned with lung shielding. Labar et al.152 conducted a trial in 64 patients with AML, ALL, and CML undergoing TBI and CY conditioning. Patients were treated with 12 Gy of TBI in three fractions given once daily and were randomized to TBI with or without lung shielding, after stratifying by age group (<20, 21-30, 31-40, >40 years), sex, underlying disease, GVHD prophylaxis, and donor-recipient sex combination. TBI was delivered using a 60Co source, and blocks were used to limit the estimated lung dose to 9 Gy in the group of patients treated with lung shields. There was no difference in leukemia-free survival or rate of relapse. Although interstitial pneumonitis was more common in the group of patients treated without lung blocks (12%) compared with those treated with lung blocks (4%), this difference was not statistically significant.152

Girinsky et al.154 conducted a similar study in a group of 85 patients with various lymphoid or hematopoietic malignancies. Each patient received TBI with a dose of 10 Gy given in a single fraction during 4 hours (average dose rate 0.04 Gy/min, instantaneous dose rate 0.125 Gy/min). Patients were randomly assigned to receive a 6 or 8 Gy lung dose. The authors observed no differences in overall survival, or lung complications. However, chronic GVHD and infections were significantly less common in the low lung dose group. Interestingly, there were significantly more leukemia relapses in the low lung dose group. The authors speculated whether the additional lung shielding may have fostered survival of leukemic cells, which led to higher rates of relapse.154

Retrospective data support the benefit of shielding. Weshler et al.153 reported a series of 44 consecutive patients who received 12 Gy of TBI; the first 23 patients were treated with opposed lateral fields and had no lung shielding in place, whereas the subsequent 21 patients had half-value layer transmission block after 6 Gy. Pneumonitis occurred in 26% of patients without lung shielding, whereas no pneumonitis was noted in those who had lung shielding.153 Investigators from Wisconsin have demonstrated sparing of renal and hepatic function with shielding.177,209

Total Body Irradiation in Nonmalignant Diseases

Because radiotherapy is most commonly employed in the treatment of malignant diseases dealt with in other sections of this book, special attention is paid in this chapter to the role of TBI as part of HSCT for nonmalignant diseases. The basis of this role lies in preclinical studies, which have demonstrated that among the highest tolerable doses of TBI, CY or Bu, TBI was the most effective single conditioning agent in a rat model of autoimmune arthritis treated with pseudo-autologous HSCT.298 Although no RCT data exist to support the use of TBI in the conditioning regimen of patients undergoing autologous HSCT for nonmalignant, autoimmune conditions, several pilot studies have prompted the execution of phase III studies incorporating TBI.

Saccardi et al. summarized the results of phase I and II trials carried out by the EBMT using HSCT for multiple sclerosis (MS), which revealed stabilization or improvement of neurologic symptoms in 63% of patients who generally had severe or progressive disease.299 Collectively, TBI was part of the conditioning regimen in 16 of the 178 patients. Statistical analysis revealed that Bu, and not TBI, was associated with transplant-related mortality. Interestingly, Nash et al., studied 26 patients in a pilot study using high-dose myeloablative conditioning prior to autologous HSCT, including 8 Gy of TBI, and found that 3-year progression free survival was 73%, with 91% overall survival, with minimal toxicity.300 Concerns about the use of TBI in HSCT for MS were brought up by Samijin et al.301 and Burt et al.302 who speculated that radiotherapy may have contributed to axonal injury or caused dysfunction of neural precursor cells, although direct evidence of this is lacking. For these reasons, the ongoing RCT to compare autologous HSCT with mitoxantrone drug therapy for severe MS will not involve TBI (http://www.astims.org/). Similar concerns regarding the toxicity of radiotherapy in patients with inflammatory bowel disease has prompted investigators to omit TBI from ongoing RCTs of autologous HSCT in Crohn disease.303

Similar to MS and Crohn disease, autologous HSCT has been explored recently for patients with systemic sclerosis (SSc, scleroderma) in several pilot studies. Binks et al.304 reported the results of a phase I and II trial of autologous HSCT for poor prognosis SSc using a variety of conditioning regimens, some of which included TBI. In their initial report, two of nine patients who underwent 8 Gy of TBI died of interstitial pneumonitis 1 and 3 months after TBI.304 This prompted investigators to minimize TBI dose during further investigations of HSCT in this disease.305 After two of the first eight patients in a study by Nash et al. died of pneumonitis, these investigators shielded the lungs with five half-value layers after the first 2-Gy fraction.306 With shielding in place, no further TBI-related pulmonary mortality has occurred; however, two patients developed MDS and a former smoker was diagnosed with stage I lung cancer.307 Autologous HSCT for SSc is currently being studied in two RCTs; in the United States, the Scleroderma Cyclophosphamide or Transplantation (NCT00114530) trial will incorporate 8 Gy of TBI, whereas in the Autologous Stem Cell Transplantation International Scleroderma (http://www.astistrial.com) trial in Europe, TBI will not be used.

HSCT has been used successfully for management of a few of the varied genetically acquired metabolic diseases in children. Dramatic improvements after HSCT have been published for certain lysosomal storage diseases including Hurler syndrome and early cerebral adrenoleukodystrophy.308 Although typical TBI-containing regimens were used early in the experience, the trend is now for HSCT using umbilical cord blood without TBI in these very young children.309 Similarly, reduced-intensity allogeneic transplants without TBI have shown promise for children with disorders such as sickle cell disease, thalassemia, and other hemoglobinopathies as well as immunodeficiencies (SCID), and bone marrow failure syndromes.310 HSCT protocols for Fanconi anemia show great promise and continue to use TBI. Because the underlying disorder in this disease is characterized by an inability to repair sublethal DNA damage, patients are exquisitely sensitive to radiotherapy and do not derive benefits of fractionation. A prospective dose-escalation study revealed that no benefit was derived from 6 Gy; therefore, a low single dose of 4.5 Gy is the standard.311

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