Total Body Irradiation

History of Total Body Irradiation

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. 23.1 ). 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. 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.

Early success using TBI to treat hematopoietic and lymphoid malignant tumors in Europe (there named the Teschendorf method) prompted the development of the technique in the United States. 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. A specially constructed treatment ward was designed to treat four patients at extended distance (5 to 7 m) simultaneously at an exposure rate of 0.7 roentgen (R)/hour, for about 20 hours/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 the erythema dose (750 R).

In Heublein's initial report, no hematopoietic toxicity was noted with this treatment schedule. Seven of 12 patients (58%) with advanced lymphomas and leukemias and 2 of 8 patients (25%) with metastatic breast, melanoma, and kidney cancers were noted to demonstrate some improvement after treatment. A later report of the experience with 270 patients with cancer from Memorial Hospital treated with TBI between 1931 and 1940 confirmed that the technique was more successful in patients with hematopoietic and lymphoid cancers compared with those 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.

In the early 1940s, World War II prompted an initiative to develop nuclear weapons, known as the Manhattan Project. 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 cancers, as well as patients with benign diseases. For example, studies of dose escalation, radiation biologic dosimetry, and cognitive and psychomotor function were carried out at the M. D. Anderson Hospital for Cancer Research. 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. At Baylor University College of Medicine, studies using 25 R to 250 R of TBI with 250 kV to 2 MV photons were performed to find a biologic dosimeter, as well as to study acute effects of radiotherapy. The military conducted similar studies at the Naval Hospital in Bethesda, Maryland, and reported palliation of patients with radiosensitive diseases treated with fractionated TBI. The most recent research study of TBI sponsored by the U.S. Department of Defense was conducted at the University of Cincinnati. It 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 cancers were reported. Patients with advanced metastatic radioresistant malignant tumors, 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 was called into question by a report written in 1995 by the U.S. Department of Energy's Advisory Committee on Human Radiation Experiments, which may have contributed to the public's general uneasiness regarding radiation.

Not only used in malignant diseases, TBI was also considered the critical immunomodulator in the first successful solid organ transplant. In 1959, a kidney was successfully transplanted between dizygotic twins after TBI at exposures of up to 450 R (given to the recipient). Around the same time in France, successful kidney transplants after TBI were being reported. Of the first seven patients who underwent kidney transplant following TBI or pharmacologic immunomodulation worldwide between 1959 and 1962, the two who did not experience kidney failure were treated with TBI alone (without chemical immunosuppression) before transplant, and each survived for more than 20 years after transplant. However, successful preclinical studies with pharmacologic therapy prompted the use of chemical immunosuppressants (corticosteroids, 6-mercaptopurine, and azathioprine) for solid organ transplantation after 1963.

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; less than 1 year later he published his experience in using TBI with exposures up to 600 R followed by bone marrow transplantation. 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 commented that low dose rates (delivery over 2 to 3 days) appeared preferable to higher dose rates, for metabolic and immunologic reasons. In addition, patients receiving 200 R to 300 R fared better than those receiving 400 R to 600 R. The problem of delivering an adequately homogenous dose was raised, and suggestions about using higher-energy photons were proposed. Thomas et al. later reported on syngeneic bone marrow transplantation in two children after 850 R to 1140 R was delivered in a single fraction over 22 to 25 hours, using cobalt-60 ( ⁶⁰ Co) sources. The authors concluded that 1000 R of TBI did not produce “troublesome” acute radiation sickness; it did produce remission of leukemia, but did not cure the disease. The first report of successful cure of a patient with leukemia with allogeneic transplantation after TBI was reported in 1969. The technique involved opposed ⁶⁰ Co sources, which operated at 5.8 R/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 infection, without evidence of leukemia.

Over the next several years, techniques of combining chemotherapy and TBI were developed and refined, with promising results. Success in the treatment of advanced leukemias and severe aplastic anemia 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. Although the use of TBI without HSCT has largely been abandoned, primarily for fear of inducing secondary malignant tumors and limiting later therapeutic options, some question the validity of this fear and still contend that low dose TBI (1.5 Gy to 2 Gy in 10 to 20 fractions over several weeks) is a viable option for initial therapy in advanced indolent lymphomas. Fig. 23.2 demonstrates how the use of TBI during HSCT has changed over a recent 15-year period.

Hematopoietic Stem Cell Transplant

Hematopoietic stem cell transplant 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 bone marrow was extracted from the donor and infused intravenously into the recipient. Later, peripheral blood stem cells, instead of bone marrow, were collected from the donor as an alternative to bone marrow grafting. 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. The peripheral blood stem cells are often “mobilized” from the donor using hematopoietic growth-stimulating factors and are 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 (e.g., cell selection and depletion) may be undertaken to optimize the outcome.

When transplant occurs between different individuals, the hematopoietic graft is said to be an allogeneic graft. 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. A rare but alternative situation is when an organ from a genetically identical twin of a patient is transplanted (syngeneic transplant). Of these three methods of HSCT, autologous and syngeneic transplantations are generally associated with less risk because issues related to immunocompatibility are minimized. Allogeneic transplantations require the “matching” of donor and recipient and are typically carried out through identification of human leukocyte antigen (HLA) compatibility. The donor may be related to the recipient or may be identified through registries of volunteers, such as the National Marrow Donor Program.

Before undergoing HSCT, most patients will require intensive antineoplastic or immunomodulatory therapy, often referred to as conditioning, in preparation for HSCT. Conditioning can involve cytotoxic chemotherapy, immunomodulators, antibody therapy, or radiation therapy. The nature of the conditioning regimen can be referred to as of high or reduced intensity or as myeloablative, submyeloablative, or nonmyeloablative, to carry out conventional or mini-(ature) transplants. Although agreed-on formal definitions of these regimens do not exist, the goal of high-intensity/myeloablative/conventional transplant is to eliminate completely the recipient's native HSC compartment, which necessitates HSCT (autologous or allogeneic) for survival. High-intensity, myeloablative, and 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, minitransplant conditioning regimens are often used for older patients or for those with medical problems, for whom a high-intensity, myeloablative, and 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 for infections and other hematologic complications. For this reason, the supportive care of HSCT recipients is complex and should only be undertaken in specialized facilities. Nonetheless, some groups have developed reduced-intensity and myeloablative HSCT regimens, including TBI, that have been safely undertaken on an outpatient basis.

After undergoing conditioning and HSCT, the major challenges are related to engraftment, the permanent reconstitution of the recipient's hematopoietic system, and prevention of 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 immunomodulators. Once the graft has successfully taken, the recipient is at risk of developing graft-versus-host disease (GVHD), in which engrafted HSCs recognize the host's native, non-HSC tissues as foreign and attack 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 Worldwide Network for Blood and Marrow Transplantation in 2006, the diseases most commonly treated with HSCT are lymphoproliferative disorders (54.5%, most often multiple myeloma [MM]; non-Hodgkin lymphoma [NHL], and Hodgkin lymphoma [HL]); leukemias (33.8%, most often acute myelogenous leukemia [AML]; acute lymphocytic leukemia [ALL]; myelodysplastic syndrome [MDS]; chronic myeloid leukemia [CML] and chronic lymphocytic leukemia [CLL]); solid tumors (5.8%); and nonmalignant disorders (5.1%). The 2014 National Comprehensive Cancer Network (NCCN) guidelines for therapy indicate that allogeneic or autologous HSCT may be a treatment option for testicular cancer, AML, MM, MDS, CML, HL, and NHL, depending on the clinical situation. HSCT with or without TBI-based conditioning has also been described in the treatment of solid tumors, including breast cancer, germ cell tumors, renal cell carcinoma, melanoma, neuroblastoma, and other pediatric cancers. Detailed discussion of these diseases and their management is beyond the scope of this chapter, and the reader is referred to other chapters in this text and other reviews. The role of TBI in nonmalignant diseases will be discussed in subsequent sections of this chapter.

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 deal with normal and malignant hematopoietic cells.

Preclinical studies have helped define some of the fundamental radiobiologic properties of the normal lymphocytes. The D ₀ (radiation dose that reduces survival to e ^{− 1} [0.37] on the exponential portion of the survival curve) (see Chapter 1 ) of normal lymphocytes has been reported to be 0.5 Gy to 1.4 Gy, depending on the in vitro or in vivo model used to calculate this parameter. This D ₀ suggests that normal lymphocyte cells are sensitive to ionizing radiation. A small shoulder on the radiation cell survival curve has been noted, suggesting little repair between fractions of radiation. Clinical data have revealed similar findings in patients undergoing hyperfractionated TBI, with lymphocyte survival demonstrating an effective D ₀ of 3.8 Gy, according to one study.

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 to 5 days), although given the variable life span of leukocytes (days to years), it may be of some relevance. Redistribution would appear to be of significance, given the time scale for TBI; however, this has been difficult to assess.

The radiobiology of malignant hematopoietic cells has been described. The D ₀ of leukemic cells generally ranges from 0.8 Gy to 1.5 Gy; however, compared with normal hematopoietic cells, a wider range of radiosensitivities has been described. Many have cited the technical nuances and variations in assay technique for this great range. Similar to normal hematopoietic cells, their malignant counterparts are thought to demonstrate little sublethal damage repair, although split-dose-rate and low-dose-rate experiments have demonstrated the capacity of leukemic cells to repair radiation-induced damage. Generally, leukemic cells are thought to have a cell survival curve with a minimal shoulder or no shoulder, although this varies across cell types and cell lines. For example, Cosset et al. summarized preclinical and clinical findings, concluding that AML demonstrates little repair, whereas CML does demonstrate repair; ALL, myeloma, and lymphomas have not been well studied, but appear to demonstrate a wide range of repair capacity.

Similar to that in 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. Recent molecular studies suggest a significant effect of TBI on peripheral blood mononuclear cell immune-related gene expression in patients.

In vivo preclinical research laid the foundation for the first successful HSCT in humans. Studies in rats, dogs, and nonhuman primates 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. Another model demonstrated no significant difference in the effect of a low-dose-rate (0.04 Gy/minute), single-fraction of TBI compared with a hyperfractionated course of TBI given three times a day to the same total dose.

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 et al. and subsequently was supported by preclinical data in mice and dogs that showed that less lung injury occurred with fractionated TBI regimens.

Immediate Toxicity and Management in Total Body Irradiation

Although a good deal of what has been learned about the acute in vivo biologic effects of TBI has been derived from laboratory-based animal studies, whole-body irradiation also has been studied in people exposed during accidental or wartime nuclear events. 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 reviews of acute and fatal radiation syndromes (gastrointestinal, hematopoietic, and cerebrovascular syndromes) that can be caused by TBI in an uncontrolled setting.

Acute side effects of therapeutic TBI can be difficult to distinguish from other HSCT-related morbidities. However, Chaillet et al. conducted an informative prospective clinical study of the symptoms and signs that occur in patients after TBI, before the initiation of any other HSCT-related therapy. Thirty-one patients, 4.5 to 55 years of age, were treated using parallel-opposed anteroposterior 18-MV photons from a linear accelerator. 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/minute and an instantaneous dose rate of 0.11 Gy/minute to 0.12 Gy/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 before the start of TBI. Table 23.1 displays the symptoms and signs experienced by patients during the 4 hours of TBI and within 24 hours of starting TBI. Fever was a common finding, and a maximum of 40.8° C (105.4° F) was noted in one patient. Tachycardia frequently paralleled febrile episodes; a maximum rate of 130 beats/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 et al. 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, are also summarized in Table 23.1 .

A prospective clinical study showed that fractionation of TBI can reduce acute nausea, vomiting, mucositis, diarrhea, and parotitis, although the differences were not statistically significant. Late cutaneous eruptions were more common in patients undergoing fractionated TBI, although the numbers were not statistically significant. The same study, which randomized patients to either high- or low-dose rate TBI, revealed no differences in the acute toxicities mentioned when comparing dose rate. 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.”

Older studies cite nausea and vomiting as frequent side effects of TBI. These symptoms have been substantially lessened with the advent of more effective antiemetics, such as the 5-hydroxytryptamine (serotonin) receptor-3 (5-HT3) antagonists. Several small but high-quality controlled clinical studies support the prophylactic use of 5-HT3 antagonists to reduce nausea and vomiting during TBI ; they are summarized in eTable 23.1 . The use of corticosteroids in conjunction with 5-HT3 antagonists is supported by a trial listed in eTable 23.1 . However, given the toxicity associated with this approach, consensus regarding routine administration in conjunction with TBI is lacking. Of note, less nausea and vomiting have been noted in myeloablative conditioning regimens involving TBI compared with those that use chemotherapy alone, even with modern antiemetics.

Oral mucositis is a side effect of TBI in up to 75% of patients undergoing myeloablative TBI, causing mouth pain and odynophagia and necessitating intensive supportive care such as total parenteral nutrition and opioid analgesics. In one study, intensive dental hygiene conferred a reduction in the rate of moderate and severe mucositis, although the authors thought the rate to be clinically insignificant. Topical oral agents, such as chlorhexidine digluconate and neutral calcium phosphate in conjunction with topical fluoride treatments, can decrease pain duration and severity of oral mucositis, as well as pain and need for opioid analgesics. Similarly, prophylactic oral sucralfate and clarithromycin have reduced moderate and severe oral mucositis rates. One study showed that when given prophylactically, amifostine limited the duration of mucositis, with an associated decrease in the rate of moderate and severe infections, with no effect on HSCT outcome. Low-level laser (650 nm) therapy has been reported to reduce the incidence of oral mucositis in an RCT.

In one study, researchers noted that short-term intravenous recombinant granulocyte-macrophage colony–stimulating factor decreased rates of moderate to severe mucositis, but in another study, no effect was found when this agent was delivered topically. 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 need for total parenteral nutrition (by 24%). 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 studies suggesting this have been small and inadequately designed.

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, and hair typically returns 3 to 6 months after treatment. Changes in the color or texture of regrown hair have been noted. Of note, myeloablative conditioning regimens using chemotherapy alone have produced a significantly higher incidence of permanent alopecia.

Later Toxicity and Its Management in Total Body Irradiation

Hematopoietic Toxicity

As previously mentioned (see Radiobiology section), the hematopoietic system is particularly sensitive to TBI; 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 Gy to 6 Gy has been given, lymphocytosis can be seen, but it typically is followed by neutropenia within 1 week. Three to 4 weeks after TBI, neutrophils fall to their minimum ( Fig. 23.3 ). 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 has 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 and, therefore, routine use is controversial. Of note, hematopoietic growth factors have only been used in the period following TBI, given the concerns raised by a trial in lung cancer, where growth factors increased pulmonary toxicity and thrombocytopenia when given concurrently with chemoradiation therapy.

Pulmonary Toxicity

The major dose-limiting toxicity of TBI is pneumonopathy (restrictive or obstructive lung disease), which can manifest early as pneumonitis or later as pulmonary fibrosis. In the setting of HSCT, radiation pneumonopathy can be difficult to distinguish from other causes of lung pathology; moreover, lung damage is likely multifactorial, with the risk of acute lung complications estimated to be 30% to 60%, depending on factors such as infection, conditioning regimen, GVHD, age, and diagnosis. Likewise, late pneumonopathy 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. TBI is a risk factor for idiopathic pneumonia syndrome, as well as for diffuse alveolar hemorrhage. Although rates of pneumonopathy in patients receiving TBI vary widely (10% to 84%), some series have reported pneumonitis in up to 20% of patients undergoing HSCT who never received TBI. In the modern era, with appropriate TBI techniques, the risk of pneumonopathy in patients treated with TBI may not be increased at all. 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%.

Several TBI-specific factors (e.g., total dose, fractionation, dose rate, and use of lung shielding) have been shown to have a 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. 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 cause of excess deaths. In a retrospective dosimetric study, a mean lung dose of more 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/minute using parallel opposed lateral fields. Two RCTs have demonstrated that fractionated TBI can reduce pneumonitis compared with single-fraction TBI, although only one study showed differences that were statistically significant. 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 of less than 10 Gy may not require fractionation to prevent toxicity, although no randomized data support this. 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 anteroposterior fields and lung blocks to a total dose of 12 Gy in daily 3-Gy fractions may not differ from hyperfractionated TBI given twice daily with 1.7 Gy per fraction to a total dose of 10.2 Gy over 3 days, using parallel opposed lateral fields and no blocks. An RCT suggested that the angiotensin-converting enzyme inhibitor, captopril, may mitigate pulmonary toxicity associated with TBI.

Sampath et al. reviewed 26 studies involving 1096 patients to create a dose-response model for predicting the risk of pneumonitis from TBI while 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, cyclophosphamide, and busulfan on the risk of developing pneumonitis, in a dose-response model, as seen in Fig. 23.4 .

Pneumonitis rates did not differ significantly in a trial that randomized patients to high- or low-dose-rate TBI. However, an abundance of retrospective clinical data suggest that lowering the dose rate (<0.025 to 0.09 Gy/minute) does decrease the likelihood of pulmonary complications, especially if TBI is delivered as a single fraction. If TBI is fractionated, some report that a low dose rate (<0.069 Gy/minute) is not necessary, whereas others found a beneficial effect. Studies of patients receiving fractionated TBI with lung shielding have demonstrated a reduction in pneumonopathy ; however, one RCT found no difference in pneumonopathy rates if the shielding allowed a lung dose of either 6 Gy or 8 Gy in a single fraction.

Pulmonary function tests (PFTs), such as 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 and is related to the TBI dose. A retrospective study found that lung shielding had a small but significantly beneficial effect on PFTs 1 year after HSCT, especially in patients with abnormal function before HSCT. In one study, busulfan and not TBI, was associated with a negative effect on PFTs. No evidence indicates that obtaining PFTs improves pulmonary outcome after HSCT in adulthood and, for this reason, they are not recommended. However, some groups recommend baseline PFTs as part of long-term follow-up care for children treated with TBI. Counseling regarding smoking cessation is of critical importance for all patients, especially those who are at increased risk of developing lung injury. In the event of acute pneumonitis, high-dose steroids (30 mg to 60 mg of prednisone/day) typically alleviate symptoms within 24 to 48 hours.