TBI During BM and SCT: Review of the Past, Discussion of the Present and Consideration of Future Directions

REVIEW TBI during BM and SCT: review of the past, discussion of the present and consideration of future directions

CE Hill-Kayser, JP Plastaras, Z Tochner and E Glatstein

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

TBIhasbeenusedwidelyinthesettingofBMToverthe described survivors of accidental irradiation who received past 3 decades. Early research demonstrated feasibility matched marrow infusions.7 Clinical and animal research and efficacy in the myeloablative setting, in preparation continued over the next decade, in parallel with the first for allogenic BMT and later for autologous stem cell development of clinical measures to support patients with rescue. As experience with TBI increased, its dual roles of decreased marrow function: these included antibiotic and myeloablation and immunosuppression came to be recog- antifungal agents, parenteral nutrition and blood transfusion nized. Toxicity associated with myeloablative TBI remains technology that prolonged survival during the acute pretrans- significant, and this treatment is generally reserved for plant and post transplant phases of treatment. In the 1970s, younger patients with excellent performance status. Reduced several groups demonstrated strong clinical results in leukemic intensity conditioning regimens may be useful to provide patients receiving allogeneic BMT following chemoradiation8– immunosuppression for patients who are not candidates for 11 (Table 1). At this time, BMT were limited to patients with a myeloablative treatment. Efforts to reduce toxicity through sibling or related donor found to be histocompatible based on protection of normal tissue using methods of normal tissue human leukocyte antigen (HLA) typing. blocking and use of TLI, rather than TBI, continue. In the As survival rates after hematological malignancies future, modalities such as helical tomotherapy, proton radio- increased with use of BMT, attention turned to methods therapy and radioimmunotherapy, may have roles in delivery of reducing toxicity and expanding potential therapeutic of radiation to the BM and lymphoid structures with reduced value. Single, large-fraction treatment was associated with normal tissue toxicity. With further investigation, these death due to toxicity, most notably pneumonitis.12 Several efforts may expand the therapeutic ratio associated with TBI, groups reported on methods of reduction of risk of lung allowing safer delivery to a broader range of patients. toxicity, including fractionated treatment and use of lung- Bone Marrow Transplantation (2011) 46, 475–484; blocking devices. Unrelated donor transplants were under- doi:10.1038/bmt.2010.280; published online 29 November 2010 taken for patients without matched, related donors. Keywords: TBI; autologous stem cell rescue; reduced Finally, largely to address problems identifying donors, as intensity conditioning; TLI; TRM well as higher side-effect profiles for patients receiving unrelated donor marrow, research in the 1980s led to development of autologous SCT techniques. These allowed patients to receive their own stem cells with no concern for immunocompatibility13–16 (Table 1). Introduction and historical perspective Understanding of the extremely important role of BMT in treatment of potentially fatal conditions culminated in Interest in the use of radiation as part of BMT arose in the receipt of the 1990 Nobel Prize in Physiology and Medicine mid-twentieth century. With the use of radioactive substances by Dr E Donnell Thomas for his work on ‘Organ and Cell came the recognition that death from exposure to low-dose Transplantation in the Treatment of Human Disease.’ The TBI was commonly due to marrow failure. Animal studies use of TBI as a part of conditioning regimens for this type subsequently demonstrated the potential role of hematological of treatment continues in the modern era, and appears to 1–5 infusions as rescue therapy after BM damage or eradication. provide benefit over conditioning with chemotherapy alone The first examples of humans surviving supralethal TBI in the in many settings17–20 (Table 1). Although huge amounts of setting of leukemia with the use of BM infusion and grafting progress have been made with regard to optimal BMT 6 were published in 1965. During the same year, other groups methods in the past 50 years, myriad questions regarding technique and outcome remain.

Correspondence: Dr CE Hill-Kayser, Department of Radiation Onco- logy, University of Pennsylvania School of Medicine, 3400 Spruce Street, Goals of TBI 2 Donner, Philadelphia, PA 19146, USA. E-mail: [email protected] Received and accepted 6 October 2010; published online 29 November TBI may be given as a part of BMT with therapeutic goals 2010 that are single or multifold. The ﬁrst uses of TBI were with TBI in BMT CE Hill-Kayser et al 476 Table 1 Inﬂuential studies examining the role of TBI in BMT

Study lead author No. of Population type Comment and year of patients publication

Early human studies Mathe´et al.6 10 ALL Described regimen of 8 Gy TBI delivered in 2 fractions with allogeneic marrow transplantation; 3/10 patients experienced CR. 7/10 died within 30 days of BMT. Andrews et al.7 5 Accidental exposure Described survivors of accidental irradiation after treatment with allogeneic marrow infusion

Benefit of TBI in the allogenic BMT setting Thomas et al.9 100 AML/ALL Examined 100 patients surviving advanced leukemia treated with TBI and BMT, and demonstrated that patient condition at the time of BMT influenced outcomes. Thomas et al.10 19 ANLL Described improved outcomes in AML after first remission, using HLA-matched donors. Demonstrated importance of low-leukemic cell burden, patient clinical condition and HLA-matching. Thomas et al.11 22 ALL Demonstrated improved outcomes in patients undergoing BMT in remission compared with those in relapse. Recommended BMT before terminal relapse for patients with HLA-identical sibling donors. Ringdeń et al.17 1060 ALL/AML Retrospective comparison of patients treated with Bu/Cy vs TBI/Cy BMT regimens; demonstrated improved outcomes with TBI in ALL patients only. Davies et al.18 627 Pediatric ALL Demonstrated improved survival for children with ALL treated with TBI/Cy vs Bu/Cy for HLA-identical allogenic BMT. Kro¨ger et al.19 50 CML Demonstrated similar antitumor efficacy of Bu/Cy and TBI/Cy regimens for unrelated BMT, but showed higher incidence of liver and bladder toxicity with Bu/Cy. Shi-Xia et al20 3172 Leukemia Meta-analysis demonstrating improved DFS with TBI/Cy over Bu/Cy in ALL and AML. Lower TRM was seen in all groups with TBI/Cy compared with Bu/Cy.

Beneﬁt of TBI in the autologous BMT setting Ravindranath 232 Pediatric AML Demonstrated lower relapse rate after autologous BMT with TBI compared with intensive et al.13 consolidation chemotherapy in childhood AML. TRM was increased in BMT group. Vaidya et al.14 31 Pediatric ALL Long-term follow-up of childhood ALL patients in second remission treated with autologous BMT with TBI, in absence of matched sibling donor. Demonstrated improved survival compared with historic controls after relapsed ALL. Dusenberry 35 AML Demonstrated improved outcomes with TBI/Cy over Bu/Cy for patients with relapsed AML et al.15 undergoing autologous BMT.

Toxicity reduction: fractionation and dose-rate Altschuler et al.21 108 ALL Demonstration of low risk of pneumonitis with fractionated TBI (11 Gy in 5 fractions) Kim et al.24 22 ALL/AML/CML Demonstrated increased death from pneumonitis with higher dose rate TBI. Shank et al.28 76 ALL/ANLL Demonstrated reduced incidence of pneumonitis (18 vs 50%) with 13.2 Gy in 11 fractions compared with 10 Gy in a single fraction. Thomas et al.29 53 ANLL Demonstrated survival advantage after 12 Gy in 6 fractions compared with 10 Gy in 1 fraction Reduced-intensity conditioning regimens Giralt et al.35 15 AML/MDS Demonstrated feasibility of RIC regimens in patients ineligible for myelablative regimens. McSweeney 45 450 years, various Demonstrated usefulness of graft vs tumor effect in patients not eligible for myeloablative et al.36 malignancies therapy; utilized mycophenolate mofetil for GVHD prophylaxis Sorror et al.37 144 Various malignancies Retrospective analysis demonstrating decreased incidence of grade III–IV toxicities in patients undergoing RIC vs myeloablative therapy. Higher pretransplant comorbidity scores were correlated with increased toxicity and mortality. Mielcarek et al.38 96 Various malignancies Retrospective analysis demonstrating decreased acute GVHD after RIC vs myeloablative regimens, but described association of RIC with ‘late-onset GVHD.’ Baron et al.39 322 Various malignancies Showed potential improved graft vs tumor outcomes in patients with chronic GVHD after RIC, which was not apparent in association with acute GVHD. Kahl et al.40 834 Various malignancies Described improved outcomes after RIC for patients with low-grade disease (CLL, MM, NHL) compared with those with advanced myeloid/lymphoid disease. Baron et al.41 21 CML Demonstrated concern for increased risk of graft rejection in CML. Marks et al.42 1521 ALL Demonstrated higher relapse but similar age-adjusted survival in ALL patients treated with RIC vs myeloablative regimens. Underscored importance of PS and age in decisions regarding TBI regimen.

Abbreviations: ANLL ¼ acute nonlymphoblastic leukemia; Bu/Cy ¼ busulfan/cytoxan; DFS ¼ disease-free survival; Gy ¼ Gray; MDS ¼ myelodysplastic syndrome; MM ¼ multiple myeloma; NHL ¼ non-Hodgkin’s lymphoma; PS ¼ performance status; RIC ¼ reduced intensity conditioning; TBI/Cy ¼ total body irradiation/cytoxan.

the intent of eradicating diseased marrow and/or reducing suppressive.23 This approach may allow an immunother- tumor burden.8,21,22 This is still a common goal of TBI in apeutic effect of a donor graft (graft vs tumor) to take both the allogeneic and autologous settings. After the place, targeting diseased marrow in the setting of malignant myeloablative role of TBI had been established, several disease. Although TBI itself is not serving a myeloablative groups recognized the potential of TBI as an immuno- role in this setting, it is used as a means of dampening the

Bone Marrow Transplantation TBI in BMT CE Hill-Kayser et al 477 host immune response from which GVHD may result; TBI performance status. In the 1990s, feasibility of reduced- may be particularly important in the setting of matched- intensity conditioning (RIC) regimens consisting of lower- unrelated donor transplants, when adequate immunosuppres- dose TBI and/or fludarabine was published by several sion is essential. A related potential goal of TBI in either groups.35,36 These regimens appeared to allow donor the allogeneic or autologous settings may be to deplete the engraftment with reduced risk of acute, life-threatening BM to allow physical space for engraftment of healthy donor toxicity; the cytotoxic effect from such regimens is minimal, marrow. For many patients, the goals of TBI are multifold. and they are delivered in order to provide immune Individual therapeutic goals may significantly alter decisions suppression and allow donor marrow engraftment—tumor with regard to treatment regimen and technique used, several cell death is largely dependent on a graft vs tumor effect. aspects of which are discussed below. McSweeney et al.36 demonstrated the feasibility of use of a regimen employing 2 Gy delivered as a single dose, with or without fludarabine, with cyclosporine and mycophenolate Dose, fractionation and dose rate employed during TBI mofetil as GVHD prophylaxis in older patients. Other groups have demonstrated acceptable rates of donor Myeloablative regimens engraftment and decreased toxicity with 2 Gy, single-dose, Data regarding optimal prescribed dose and optimal dose per low-dose rate (7 cGy/min) TBI in the setting of both related fraction prescribed as part of TBI are relatively limited. Early- and unrelated donor transplantation.37–39 Overall relapse- myeloablative TBI regimens used single, large fractions of 40 8,21,22 free survival rates were examined by Kahl et al., who 8–10Gray(Gy). As described earlier, these regimens noted that subsets of patients, including those with were associated with high risk of death from interstitial 12,24 diagnoses of CLL, multiple myeloma and non-Hodgkin’s pneumonitis. Both fractionation and reduction in lymphoma appeared to fare better than others after this dose rate were subsequently shown to potentially reduce this 24–28 type of regimen. Other groups have found that risk of graft risk (Table 1). Data in both rodents and humans appear rejection may be higher for patients with myelodysplastic to indicate that dose rates o10–12 cGy/min are associated syndrome and CML.41 Marks et al.42 compared cohorts of with reduced rates of pneumonitis, nausea and vomit- 25,29,30 patients receiving myeloablative therapy vs RIC for adult ing. Other groups have shown that delivery of TBI ALL, and found no difference in mortality on multivariate in daily or twice-daily fractions appears to improve analysis—although relapse rates were increased with RIC the therapeutic ratio, allowing higher radiation doses to be 21,29,31,32 regimens, age-adjusted survival was the same. Various delivered safely. These data support use of both other reduced-intensity fractionation regimens have been reduced dose-rate and fractionated TBI; however, these investigated at centers worldwide. Generally speaking, benefits may be offset by decreased convenience—low-dose relapse rates appear to be higher when non-myeloablative rate treatment regimens may require up to 30 min per fraction regimens are employed; however, increased disease-related to deliver, and twice-daily fractions may be inconvenient for mortality may be offset by decreased death from toxicity. both patients and treatment centers. These logistic issues may As RIC regimens rely more heavily on graft vs tumor discourage some practitioners from using TBI as part of BMT response, providing immune suppression so that donor regimens, and further work with regard to convenient delivery marrow may engraft and relying on the graft marrow for of TBI in the modern era of expansive supportive care (for tumor cell destruction, effectiveness varies across disease example, modern anti-emetics) to further understanding of type, as would be expected. With the currently available maximum tolerated dose and dose-rate is warranted. treatment options, myeloablative regimens appear to In the latter half of the 20th century, based largely on data provide benefit to patients who can tolerate such aggressive supporting use of fractionation and reduced dose-rate, treatment, when relapse-free survival benefit outweighs risk myeloablative regimens delivering 12 Gy, twice daily, over 3 of death from toxicity, and are still commonly employed. days, in combination with chemotherapy were most com- Clearly, however, no perfect TBI prescription currently monly employed. These regimens were designed to provide exists, and many questions regarding dose requirements both immunosuppressive and cytotoxic effects as part of and optimal dose rate and fractionation exist. allogeneic BMT, and are still frequently used with these goals. Efforts to further reduce disease relapse rate through dose escalation to 15–16 Gy have not improved OS—although Morbidity associated with current regimens for TBI higher doses have been shown to decrease relapse rates, this benefit appears to be offset by increased mortality unrelated 31,33,34 Clearly, toxicity associated with TBI remains one of the to relapse. Thus, more, cannot simply be presumed to most important factors in determining treatment regimens be better. Interestingly, the noted increase in death from for individual patients. During radiation of the entire body, toxicity appears to be restricted to the 6–12 month period post 32 toxicity to essentially every organ system must be transplant. Various other regimens, including modest dose considered; however, understanding toxicity associated escalation to 13–14 Gy, and single daily treatments, have been uniquely with radiotherapy is complicated by the many studied without clear impact on patient outcomes. other treatments that are simultaneously received by patients undergoing BMT—these may include antibiotic, Reduced-intensity conditioning regimens antifungal and antiviral agents, immunosuppressive drugs, In their various forms, myeloablative regimens are asso- pain medications, chemotherapeutics and myriad others. ciated with significant risk and toxicity, and access is often As described previously, interstitial pneumonitis was limited to patients who are o50 years of age with excellent observed to occur in B50% of patients receiving TBI via

Bone Marrow Transplantation TBI in BMT CE Hill-Kayser et al 478 Table 2 Acute and long-term toxicities resulting from TBI

Toxicity Methods of Risk Reduction and Intervention

Acute Parotitis Generally subsides in 1–2 days without intervention Nausea/vomiting Use of low dose-rate TBI Antiemetics

5HT3 receptor agonists (ondansetron, granisetron) Dopamine agonists (metoclopramide, prochloperazine) NK1 receptor antagonists (aprepitant)

H1 histamine receptor antagonists (diphenydramine, meclizine) Benzodiapepines (midazolam, lorazepam) Steroids (dexamethazone)

Sub-acute Interstitial pneumonitis Use of low-dose rate TBI Use of lung blocks Fractionation Avoidance of chemotherapies associated with lung toxicity Avoidance of infection, notably CMV

Late and long-term Venoocclusive Avoidance of concurrent use of drugs that are sources of toxic metabolites disease of the liver and/or modify the endothelium: Myeloablative drugs (BU, BCNU, MTX) Immunosuppressants (sirulimus, cyclosporine) Antimicrobials (ketoconazole, amphotericin B, vancomycin, acyclovir) Avoidance of BMT in the setting of active hepatitis or cirrhosis Close monitoring of ﬂuid: sodium balance post transplant Role of heparin prophylaxis remains unclear Cataract formation Fractionation Eye shielding Gonadal failure Pretransplant sperm/oocyte banking or harvest Hormone replacement therapy if indicated Renal toxicity/chronic kidney disease Monitoring of blood urea nitrogen, creatinine, and GFR Treatment of post transplant chronic disease if indicated Osteopenia/porosis Bone density monitoring and treatment, if indicated Xerostomia Use of artiﬁcial salivary products Monitoring of nutrition and impact on quality of life Dental complications Frequent professional cleaning and care Addressing of sequelae that may impact self-care, including xerostomia, mucosal pain, and/or trismus Endocrine dysfunction Comprehensive endocrine monitoring with hormone replacement as indicated Short staturea Monitoring of growth hormone level during pubertal growth Cardiometabolic traits Hypertension screening, treatment if indicated Dyslipidemia screening, treatment if indicated Close monitoring of wt, body mass index and adipose distribution Screening for insulin resistance/diabetes mellitus, treatment if indicated Second malignancy Age-appropriate cancer screening Yearly pap smear Colonscopy and/or fecal occult blood testing Yearly mammogram with consideration of screening breast MRI Close monitoring of patient-reported symptoms

Abbreviations: GFR ¼ glomerular ﬁltration rate; MRI ¼ magnetic resonance imaging. aDocumented only in pediatric survivors.

a single, large fraction of 8–10 Gy, with 50% of cases proving different factors, they are particularly difﬁcult to fully fatal.12 Even when fractionated and low-dose-rate TBI is understand and prevent. employed with concurrent chemotherapy, the rate of interstitial pneumonitis may approach 25%.43 Clearly, Acute toxicities associated with TBI fractionation and dose-rate reduction lower the risk of The most common acute toxicities following TBI, listed in development of this life-threatening toxicity; however, Table 2, include nausea and vomiting, although these are analysis is complicated by further observation that CMV largely preventable with modern anti-emetic drugs. Par- is associated with many cases of interstitial pneumonitis, otitis may occur after the ﬁrst 1–2 fractions, and generally and transplant patients are at high risk for contraction or subsides within 1–2 days.44 Dry mouth and mucositis may reactivation of CMV.43 The multifactorial nature of occur 5–10 days after TBI. Parotitis appears to be a side interstitial pneumonitis developing during or after BMT effect uniquely associated with TBI; however, other acute serves as an example that can be likened to many toxicities side effects are generally due to combinations of agents and occurring in this setting—because they result from so many illness experienced by patients in the acute BMT setting.

Bone Marrow Transplantation TBI in BMT CE Hill-Kayser et al 479 End-organ damage and late effects after TBI As demonstrated time and time again, risk of severe end- Many of the toxicities associated with TBI may result in organ toxicity and development of SMN are multifactorial end-organ damage. These can include cataract formation in in this patient population. Fractionation and reduced dose- 30–40% (80–90% of those receiving a single fraction of rate TBI appear to decrease risk of interstitial pneumonitis 8–10 Gy),20,45 gonadal failure,46 thyroid dysfunction, kidney and cataract formation, and most acute toxicities appear dysfunction47,48 and decreased bone mineral density.49 Survi- to be related to overall TBI dose and dose-rate. Some vors are at known risk for chronic oral and dental complica- population-based data demonstrate a direct relationship tions after TBI, with xerostomia being reported by patients between TBI dose and development of SMN. Further large as having a major impact on quality of life 1 year after BMT.50 studies and long-term comparison studies may help to In a recent analysis of late effects and quality of life of further elucidate the optimal balance between aggressive childhood cancer survivors, TBI was strongly associated with treatment of the primary malignancy, and reducing risk of short stature and endocrine dysfunction.51 Survivors of child- life-threatening toxicity and SMN. hood ALL treated with TBI have also been demonstrated to be at increased risk for cardiometabolic traits, including central adiposity, hypertension, insulin resistance and full-blown Protection of normal tissue during TBI metabolic syndrome compared with survivors treated with conventional chemotherapy.52 Venoocclusive disease of the As the delicate balance between the need for aggressive liver may occur in 10–70% of patients,53 although risk appears treatment and limiting toxicity associated with this treat- to be modulated by use of concurrent drugs,20,54,55 concurrent ment becomes increasingly clear in the setting of TBI, the liver disease and development of GVHD.56 need for consideration of methods of toxicity-reduction beyond dose and dose-rate is emphasized. One method for Second malignant neoplasms potentially reducing the risk profile associated with TBI is Second malignant neoplasms (SMN) are recognized as reduction of the volume of exposed normal tissue. Current late effects of BMT that may be devastating. Two large, methods for delivery of TBI require the target volume to recent, analyses have demonstrated the risk of solid tumor encompass the entire body, using either an anterior– after BMT to range from 3 to 7% at 15 years following posterior/posterior–anterior (AP-PA) or opposed lateral transplant. In a recent multi-institutional analysis of 28 874 approach. For individuals other than babies and small allogeneic transplant recipients, Rizzo et al.57 demonstrated children, this generally requires an extended source to a 3.3% incidence of development of a solid tumor 20 years surface distance so that the entire body may be encom- after BMT. This risk was increased for the 67% of patients passed in the beam. This type of treatment requires each who received irradiation compared with those who did not; and every organ to be considered an ‘organ at risk’ during however, interestingly, this excess risk was observed only delivery of radiotherapy; in keeping with the nomenclature, in patients who received radiation at 30 years of age or ‘total body irradiation’ is delivered, when radiation of only younger.57 In another large analysis of 19 299 BMT the BM, lymphoid regions and central nervous system patients, Curtis et al.58 observed the risk of solid tumor (CNS) might be adequate from a therapeutic standpoint. to be 2.2% 10 years after BMT, and 6.7% 15 years after. Use of physical blocks to reduce normal tissue exposure Again, an inverse relationship was observed between the Current methods for reducing the volume of total tissue frequency of second cancer and age at time of transplanta- exposed include placement of blocks to reduce dose to tion. Radiotherapy was observed to increase the risk of critical normal structures. With recognition of the poten- second cancers, with this risk being significantly higher for tially fatal nature of interstitial pneumonitis associated with patients receiving at least 10 Gy to the total body compared TBI has come use of lung blocks, designed to include the with those receiving 10 Gy.58 This is potentially of o pulmonary volumes identified on AP-PA films, and interest in light of the risks and benefits observed with reduction of dose delivered to the mid-plane of the lungs. RIC regimens that may employ single fractions of 2 Gy. Animal studies have demonstrated that lung blocks may Socieét al.59 have published similar findings in a cohort of protect resident cell populations within the lungs, while still 3182 children undergoing allogeneic BMT for acute permitting full marrow engraftment,61 and reduction of leukemia. The incidence of secondary solid cancers was lung dose has been demonstrated to improve OS after TBI found to be 11% at 15 years, with increased risk among in patients with compromised pulmonary function before patients who received high-dose TBI, and those 5 years o BMT.62 Along the same lines, eye shields may be employed of age at the time of transplantation.59 In addition to solid to reduce risk of cataract formation,63 and kidney shields tumors, patients are also at risk for further hematological are occasionally used.28,64,65 Although physical blocks are malignancies—one of the most dreaded of these is therapy- useful in specific settings such as those described above, related myeloid neoplasm, including myelodysplasia and many vital organs cannot feasibly be blocked during AML. Krishnan et al.60 analyzed 612 patients having delivery of TBI as this blocking would also block areas of undergone high-dose chemoradiotherapy with autologous marrow and lymph nodes requiring treatment. stem cell rescue for Hodgkin’s disease and non-Hodgkin’s lymphoma; on multivariate analysis, the contribution of TBI to risk of therapy-related myeloid neoplasm was not TLI for immunosuppression during BMT statistically significant; however, this risk was notably Recent work has demonstrated that limiting radiation dose increased for patients who underwent priming with VP-16 to lymphoid tissue may serve an immunosuppressive role for peripheral stem cell collection.60 and protection from GVHD, with reduced toxicity when

Bone Marrow Transplantation TBI in BMT CE Hill-Kayser et al 480 compared with TBI. TLI has been shown in animal studies reduced with this technique.72 Treatment planning time did to cause changes in the constitution of the T-cell popula- not appear to differ significantly between the two techni- tion; explicitly, TLI may result in increased proportions ques, although treatment delivery took a longer period of of natural killer T cells as compared with conventional time when tomotherapy was employed. Wong et al.73 T cells.66,67 Natural killer T cells, in turn, may prevent performed a similar study evaluating use of tomotherapy to GVHD by inhibiting actions of conventional T cells treat the total marrow (target region skeletal bone) as well that mediate GVHD.66,68 Clinical studies in humans using as the major lymph node chains, spleen and sanctuary sites. TLI-based regimens have been very promising. Lowsky They demonstrated a 1.7–7.5-fold reduction in median et al.69 described 37 patients with lymphoid malignancies organ dose with these techniques compared with conven- or acute leukemia who were treated with 800 cGy total tional TBI. Additionally, dose-volume histogram analysis TLI, over 10 fractions. All patients were of age and/or predicted that dose escalation up to 20 Gy could potentially co-morbidity status that rendered them unsuitable for be feasible and safe with this technique. Total marrow myeloablative BMT. Radiation was delivered using fields irradiation using helical tomography was delivered to one to encompass major lymph node regions, as well as the patient, who experienced a blood count nadir followed by thymus and spleen, and patients received concurrent successful engraftment, accompanied by limited nausea and antithymocyte globulin. Those authors report very low vomiting, and no erythema, oral mucositis or esophagitis.73 incidence of acute GVHD (3% grade II or higher), which Certainly, these preliminary studies support further in- they note to be considerably lower than that described in vestigation into clinical feasibility of use of helical most studies of RIC regimens. The TLI regimen appeared tomotherapy for delivery of TBI with sparing of critical to allow engraftment, and did not appear to adversely normal structures. This technique may allow delivery of affect the antitumor properties of the graft. TLI regimens myeloablative doses to a broader range of patients if may have the appeal of offering improved protection toxicity to normal critical structures can be limited from GVHD when compared with RIC regimens, while clinically (Table 3). also limiting the volumes of normal tissue exposed when compared with any TBI regimen. Certainly, further study is Potential use of proton beam radiotherapy warranted; increased odds of early CMV viremia have Proton beam radiotherapy is a second potential technol- been demonstrated following TLI,70 and other potential ogy, which may eventually allow total marrow and/or toxicities have yet to be explored. Having said this, TLI lymphoid irradiation to be delivered with minimal toxicity represents an appealing alternative to TBI in certain (Table 3). The heavy, charged nature of protons causes populations. Efforts to further improve TLI regimens are them to stop within tissue and deposit the majority of their underway, with use of combinations of chemotherapy and energy at their stopping point—this produces the observed TLI to optimize tumor control and reduce TRM71 ‘Bragg-peak.’ The Bragg-peak may be placed within a described in the literature. delineated target volume, allowing dose to be deposited within the target with minimal exit dose. This stands in stark contrast to photon-based treatment, when exit dose is Future directions: increased conformality and potential unavoidable. Proton radiotherapy is employed for delivery for dose escalation of craniospinal radiation in pediatric malignancies at several centers; this type of treatment allows radiation to Potential use of helical tomotherapy be delivered to the brain and spinal cord with minimal exit As techniques for delivery of radiotherapy continue to dose through the heart, lungs and gastrointestinal and progress, options for delivering more conformal treatment genitourinary organs.74,75 Potential exists for the target to either the ‘total body’ (BM, nodal regions and CNS) or volume to be expanded to include all of the skeletal bones only the lymphoid regions, may potentially become as well as lymphoid groups and organs. To our knowledge, available. Helical tomotherapy is one potentially attractive the dosimetric feasibility of this type of treatment has not technology that employs a megavoltage linear accelerator been explored. mounted on a computed tomography gantry. This type of device allows the beam source to continually rotate around the patient. Simultaneously, the couch, or patient Potential use of radioimmunotherapy placement device, moves perpendicularly to the beam Perhaps the ultimate conformal approach to delivery of source. This allows the beam to move in a spiral or helical radiotherapy involves use of radionucleotides conjugated to pattern relative to the patient. The beam can be modulated antibodies that recognize cell-surface Ags. Such agents, with a multileaf collimator. During treatment planning, recognizing and binding to CD20, are currently available these qualities allow large volumes to be delineated and for patients with B-cell non-Hodgkin’s lymphoma, and treated, while neighboring volumes may be spared. Zhuang have been employed as part of RIC regimens for allogeneic et al.72 recently performed a dosimetric comparison of TBI BMT in the phase II setting.76 An agent targeted to BM delivered via helical tomotherapy compared with the more would be penultimate in allowing directed delivery of traditional, extended SSD approach. The target volume for radiation. Extensive work to extend the success of radio- treatment was the entire body less the right and left lungs. immunotherapy to other forms of cancer is currently After treatment planning with both techniques, the average underway with goals of expanding cell surface targeting, dose delivered to the target volume was improved with and tailoring radionucleotides employed to specific clinical tomotherapy, and median right and left lung doses were situations 77 (Table 3).

Bone Marrow Transplantation TBI in BMT CE Hill-Kayser et al 481 Table 3 Potential future methods of reduction of radiation to normal tissue during radiation as part of BMT

Method Description Extent of current study Potential beneﬁts

Helical tomotherapy Rotating beam source with Dosimetric studies demonstrating Reduction of dose to normal tissues multileaf collimator moving in reduction in median organ dose Safe escalation of dose to BM, LN and spiral pattern relative to patient DVH analysis showing potential for safe spleen dose escalation to marrow and other Delivery of myeloablative doses to regions broader range of patients through Treatment delivered to one patient with limiting toxicity successful engraftment and limited toxicity Proton radiotherapy Heavy, charged particles that stop Studied and applied clinically for delivery Reduction of dose to normal vital in tissue, producing Bragg-peak. of CSI organs through elimination of exit dose The majority of radiation is Allows reduction of dose to most vital Specific dose deposition in the BM, LN delivered within the Bragg-peak organs during CSI and spleen. region, and may be delivered to the Studies in TBI have not been published target vol with minimal exit dose Radioimmunotherapy Radionucleotides conjugated to Agents recognizing CD20 clinically An agent targeted to BM could allow antibodies that recognize specific available delivery of entire radiation dose to cell-surface Ags allows delivery of Used widely to treat B-cell NHL outside of marrow alone radiation to specific cell-types BMT setting All cells not expressing a specific surface Phase II data demonstrating efficacy as part marker could then be spared, allowing of RIC regimens during BMT for NHL extreme ‘conformality’ of radiation Laboratory-based expansion of cell-surface delivery. targeting is currently underway.

Abbreviations: CSI ¼ craniospinal irradiation; DVH ¼ dose vs histogram; LN ¼ lymph nodes; NHL ¼ non-Hodgkin’s lymphoma; RIC ¼ reduced-intensity conditioning.

Fractionated, low dose-rate 10–12 Gy Myeloablative Normal-tissue-sparing, dose escalated, Single fraction, Excellentage < PS 50 myeloablative therapy high dose rate Older age intermediate 8-10 Gy

Reduced-intensity, Selected low dose-rate patients 2 Gy Immunosuppressive Reduced-intensity, immunosuppressive goal

• Unacceptable • Significant toxicity from myeloablative • Improved conformality with tomotherapy, toxicity regimens remains protons, or radioimmunotherapy may allow • No longer • Aggressive myeloablative regimens dose escalation of myeloablative regimens employed reserved for young, excellent PS • Normal tissue sparing may allow more patients patients to tolerate myeloablative treatment

Past Current Future

Figure 1 Schematic of past, current and potential future regimens for delivery of TBI as part of BMT. Hatched areas represent patients receiving TBI with immunosuppressive intent; solid areas represent myeloablative intent. Gy ¼ Gray; PS ¼ performance status.

Use of increasingly conformal radiotherapy for delivery irradiation’ rather than ‘total body irradiation’ may allow of treatment to the BM and related sites has potential myeloablative dose delivery with reduced or minimal to widen the therapeutic ratio currently associated with normal tissue effects, and stands to potentially beneﬁt radiation in the setting of BMT: employment of ‘total many subsets of patients—both those who cannot tolerate marrow irradiation’ or ‘total marrow and lymphoid myeloablative therapy with current techniques, and those

Bone Marrow Transplantation TBI in BMT CE Hill-Kayser et al 482 who may benefit from dose escalation that is currently 7 Andrews GA. Criticality accidents in Vinca, Yugoslavia, and unacceptably toxic (Figure 1). Certainly, it seems that Oak Ridge, Tennessee. Am J Roentgenol Radium Ther Nucl further research and clinical trials examining the role of Med 1965; 93: 56–74. tomotherapy, proton therapy and/or radioimmunotherapy 8 Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, Neiman for delivery of this type of treatment are warranted PE et al. Bone-marrow transplantation. N Engl J Med 1975; (Table 3). 292: 832–843, 895–902. 9 Thomas ED, Buckner CD, Banaji M, Clift RA, Fefer A, Flournoy N et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and Conclusions and areas for future investigation allogeneic marrow transplantation. Blood 1977; 49: 511–533. 10 Thomas ED, Buckner CD, Clift RA, Fefer A, Johnson FL, Over the past 60 years, the role of BMT has expanded from Neiman PE et al. Marrow transplantation for acute non- a desperate rescue effort to a treatment modality that is lymphoblastic leukemia in first remission. N Engl J Med 1979; 301: 597–599. used broadly. Work in the late 20th century demonstrated 11 Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner the multiple ways in which TBI as part of BMT may be CD, Clift RA et al. Marrow transplantation for patients with employed—as a myeloablative therapy, an immunosup- acute lymphoblastic leukemia in remission. Blood 1979; 54: pressive component, or both. Unfortunately, the therapeu- 468–476. tic ratio associated with BMT remains very narrow— 12 Keane TJ, Van Dyk J, Rider WD. Idiopathic interstitial although higher radiation doses appear to offer improved pneumonia following bone marrow transplantation: the survival from the primary malignancy, doses are limited by relationship with total body irradiation. Int J Radiat Oncol normal tissue toxicity. Comparisons between treatment Biol Phys 1981; 7: 1365–1370. regimens remain difficult because of lack of randomized 13 Ravindranath Y, Yeager AM, Chang MN, Steuber CP, comparisons within the literature, and because most Krischer J, Graham-Pole J et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy investigations are done retrospectively by single institu- for acute myeloid leukemia in childhood. Pediatric Oncology tions. Still, radiation dose and dose-rate appear to correlate Group. N Engl J Med 1996; 334: 1428–1434. directly with both relapse-free survival and overall toxicity, 14 Vaidya SJ, Atra A, Bahl S, Pinterton CR, Calvagna V, Horton including risk of SMN. As we approach research goals C et al. Autologous bone marrow transplantation for child- regarding TBI in the 21st century, modalities to improve hood acute lymphoblastic leukaemia in second remission: long- conformality may offer new opportunities with regard to term follow-up. Bone Marrow Transplant 2000; 25: 599–603. this therapy. Reducing normal tissue exposed may allow 15 Dusenberry KE, Daniels KA, McClure JS, McGlave PB, escalation of myeloablative TBI doses, and may allow Ramsay NK, Blazar BR et al. Randomized comparison of patients who cannot currently tolerate myeloablative cyclophosphamide-total body irradiation versus busulfan- radiation to do so. Randomized, cooperative, clinical cyclophosphamide conditioning in autologous bone marrow transplantation for acute myeloid leukemia. Int J Radiat Oncol investigations with regard to these opportunities are Biol Phys 1995; 31: 119–128. certainly warranted and necessary. 16 Biagi E, Rovelli A, De Lorenzo P, Uderzo C. Autologous hematopoetic stem cell transplantation (AHSCT) as consolidation therapy for childhood acute myelogenous leukemia in 1st Conflict of interest complete remission. Pediatr Hematol Oncol 2001; 18: 359–362. 17 Ringdeń O, Labopin M, Tura S, Arcese W, Iriondo A, Zittoun R et al. A comparison of Busulphan versus total body The authors declare no conflict of interest. irradiation combined with cyclophosphamide as conditioning for autograft or allograft bone marrow transplantation in patients with acute leukaemia. Acute Leukaemia Working Party of the References European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 1996; 93: 637–645. 1 Nowell PC, Cole LJ, Habermeyer JG, Roan PL. Growth and 18 Davies SM, Ramsay KC, Klein JP, Weisdorf DJ, Bolwell B, continued function of rat marrow cells in x-radiated mice. Cahn JY et al. Comparison of preparative regimens in Cancer Res 1956; 16: 258–261. transplants for children with acute lymphoblastic leukemia. 2 Vos O, Davids JAG, Weyzen WWH, van Bekkum DW. J Clin Oncol 2000; 18: 340–347. Evidence for cellular hypothesis in radiation protection by 19 Kro¨ger N, Zabelina T, Kru¨ger W, Renges H, Stute N, Kabisch bone marrow cells. Acta Physiol Pharmacol Neerland 1956; 4: H et al. Comparison of total body irradiation vs busulfan in 482–486. combination with cyclophosphamide as conditioning for 3 Lindsley DL, Odell TT, Tausche FG. Implantation of unrelated stem cell transplantation in CML patients. Bone functional erythropoietic elements following total-body irra- Marrow Transplant 2001; 27: 349–354. diation. Proc Soc Exp Biol Med 1955; 90: 512–515. 20 Shi-Xia X, Xian-Hua T, Hai-Qin X, Bo F, Xiang-Feng T. Total 4 Makinodan T. Circulating rat cells in lethally irradiated mice body irradiation plus cyclophosphamide versus busulphan with protected with rat bone marrow. Proc Soc Exp Biol Med 1956; cyclophosphamide as conditioning regimen for patients with 92: 174–179. leukemia undergoing allogeneic stem cell transplantation: a meta- 5 Barnes DWH, Corp MJ, Loutit JF, Neal FE. Treatment of analysis. Leuk Lymphoma 2010; 51 (1): 50–60. murine leukaemia with x-rays and homologous bone marrow. 21 Altschuler C, Resbeut M, Blaise D, Maraninchi D, Preliminary communication. Br Med J 1956; 2: 626–627. Stoppa AM, Lagrange JL et al. Fractionated total body 6 Mathe´G, Amiel JL, Schwarzenberg L, Catton A, Schneider irradiation and bone marrow transplantation in acute lympho- M. Adoptive immunotherapy of acute leukemia: experimental blastic leukemia. Int J Radiat Oncol Biol Phys 1990; 19: and clinical results. Cancer Res 1965; 25: 1525–1531. 1151–1154.

Bone Marrow Transplantation TBI in BMT CE Hill-Kayser et al 483 22 Gale RP, Butturini A, Bortin MM. What does total body nonmyeloablative versus conventional hematopoietic stem cell irradiation do in bone marrow transplants for leukemia? Int J transplantation. Blood 2003; 102: 756–762. Radiat Oncol Biol Phys 1991; 20: 631–634. 39 Baron F, Maris MB, Sandmaier BM, Storer BE, Sorrer M, 23 Gough MJ, Crittenden MR. Combination approaches to Diaconescu R et al. Graft-versus-tumor effects after allogeneic immunotherapy: the radiotherapy example. Immunotherapy hematopoietic cell transplantation with nonmyeloablative 2009; 1 (6): 1025–1037. conditioning. J Clin Oncol 2005; 23: 1993–2003. 24 Kim TH, Rybka WB, Lehnert S, Podgorsak EB, Freeman CR. 40 Kahl C, Storer BE, Sandmaier BM, Mielcarek M, Maris MB, Interstitial pneumonitis following total body irradiation for Blume KG et al. Relapse risk in patients with malignant bone marrow transplantation using two different dose rates. diseases given allogeneic hematopoietic cell transplant- Int J Radiat Oncol Biol Phys 1985; 11: 1285–1291. ation after nonmyeloablative conditioning. Blood 2007; 110: 25 Barrett AJ. Bone marrow transplantation. Cancer Treat Rev 2744–2748. 1987; 14: 203–213. 41 Baron F, Maris MB, Storer BE, Sandmaier BM, Stuart MJ, 26 Barrett AJ, Depledge MH, Powles RL. Interstitial pneumonitis McSweeney PA et al. HLA-matched unrelated donor hema- following bone marrow transplantation after low dose rate topoietic cell transplantation after nonmyeloablative condi- total body irradiation. Int J Radiat Oncol Biol Phys 1983; 9: tioning for patients with chronic myeloid leukemia. Biol Blood 1029–1033. Marrow Transplant 2005; 11: 272–279. 27 Cosset JM, Girinsky T, Malaise E, Chaillet MP, Dutreix J. 42 Marks DI, Wang T, Pe´rez WS, Antin JH, Copelan E, Gale RP Clinical basis for TBI fractionation. Radiother Oncol 1990; et al. The outcome of full-intensity and reduced-intensity 18(Suppl 1): 60–67. conditioning matched sibling or unrelated donor transplanta- 28 Shank B, Chu FC, Dinsmore R, Kapoor N, Kirkpatrick D, tion in adults with Philadelphia chromosome-negative acute Teitelbaum H et al. Hyperfractionated total body irradiation lymphoblastic leukemia in first and second complete remission. for bone marrow transplantation. Results in seventy leukemia Blood 2010; 116: 366–374. patients with allogeneic transplants. Int J Radiat Oncol Biol 43 Pecego R, Hill R, Appelbaum FR, Amos D, Buckner CD, Phys 1983; 9: 1607–1611. Fefer A et al. Interstitial pneumonitis following auto- 29 Thomas ED, Clift RA, Hersman J, Sanders JE, Stewart P, logous bone marrow transplantation. Transplantation 1986; Buckner CD et al. Marrow transplantation for acute 42: 515–517. nonlymphoblastic leukemia in first remission using fractio- 44 Deeg HJ. Delayed complications and long-term effects after nated or single-dose irradiation. Int J Radiat Oncol Biol Phys bone marrow transplantation. Hematol Oncol Clin North Am 1982; 8: 817–821. 1990; 4: 641–657. 30 Katz R, Sharma SC, Homayoonfar M. Irradiation equiva- 45 Benyunes MC, Sullivan KM, Deeg HJ, Mori M, Meyer W, lence. Health Phys 1972; 23: 740–741. Fisher L et al. Cataracts after bone marrow transplantation: 31 Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen long-term follow-up of adults treated with fractionated total FB, Fisher LD et al. Allogeneic bone marrow transplantation body irradiation. Int J Radiat Oncol Biol Phys 1995; 32: in patients with acute myeloid leukemia in first remission: a 661–670. randomized trial of two irradiation regimens. Blood 1990; 76: 46 Tauchmanova` L, Selleri C, DeRosa G, Pagano L, Orio F, 1867–1871. Lombarde G et al. High prevalence of endocrine dysfunc- 32 Clift RA, Buckner CD, Appelbaum FR, Sullivan KM, Storb tion in long-term survivors after allogeneic bone marrow R, Thomas ED. Long-term follow-up of a randomized trial of transplantation for hematologic diseases. Cancer 2002; 95: two irradiation regimens for patients receiving allogeneic 1076–1084. marrow transplants during first remission of acute myeloid 47 Gerstein J, Meyer A, Sykora KW, Fru¨hauf J, Karstens JH, leukemia. Blood 1998; 92: 1455–1456. Bremer M. Long-term renal toxicity in children following 33 Clift RA, Buckner CD, Appelbaum FR, Bryant E, Bearman fractionated total-body irradiation (TBI) before allogeneic SI, Petersen FB et al. Allogeneic marrow transplantationin stem cell transplantation (SCT). Strahlenther Onkol 2009; 185: patients with chronic myeloid leukemia in the chronic phase: a 751–755. randomized trial of two irradiation regimens. Blood 1991; 77: 48 Abboud I, Porcher R, Robin M, de Latium RP, Glotz D, Socie´ 1660–1665. G et al. Chronic kidney dysfunction in patients alive without 34 Bieri S, Helg C, Chapuis B, Miralbell R. Total body irradiation relapse 2 years after allogeneic hematopoietic stem cell before allogeneic bone marrow transplantation: is more dose transplantation. Biol Blood Marrow Transplant 2009; 15: better? Int J Radiat Oncol Biol Phys 2001; 18: 1071:1077. 1251–1257. 35 Giralt S, Estey E, Albitar M, van Besien K, RondońG, 49 Benmiloud S, Steffens M, Beauloye V, de Wandeleer A, Anderlini P et al. Engraftment of allogeneic hematopoietic Devogelaer JP, Brichard B et al. Long-term effects on bone progenitor cells with purine analog-containing chemotherapy: mineral density of different therapeutic schemes for acute harnessing graft-versus-leukemia without myeloablative ther- lymphoblastic leukemia or non-hodgkin lymphoma during apy. Blood 1997; 89: 4531–4536. childhood. Horm Res Paediatr 2010; 74: 241–250. 36 McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, 50 Brand HS, Bots CP, Raber-Durlacher JE. Xerostomia and Molina AJ, Maloney DG et al. Hematopoietic cell transplan- chronic oral complications among patients treated with tation in older patients with hematologic malignancies: haematopoietic stem cell transplantation. Br Dent J 2009; replacing high-dose cytotoxic therapy with graft-versus-tumor 207: E17. effects. Blood 2001; 97: 3390–3400. 51 Ishida Y, Sakamoto N, Kamibeppu K, Kakee N, Iwai T, 37 Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu Ozono S et al. Late effects and quality of life of childhood R, Flowers C et al. Comparing morbidity and mortality of cancer survivors: Part 2. Impact of radiotherapy. Int J Hematol HLA-matched unrelated donor hematopoietic cell transplan- 2010; 92 (1): 95–104. tation after nonmyeloablative and myeloablative conditioning: 52 Chow EJ, Simmons JH, Roth CL, Baker KS, Hoffmeister PA, influence of pretransplantation comorbidities. Blood 2004; 104: Sanders JE et al. Increased cardiometabolic traits in pediatric 961–968. survivors of acute lymphoblastic leukemia treated with total 38 Mielcarek M, Martin PJ, Leisenring W, Flowers ME, Maloney body irradiation. Biol Blood Marrow Transplant 2010 DG, Sandmaier BM et al. Graft-versus-host disease after (e-pub ahead of print).

Bone Marrow Transplantation TBI in BMT CE Hill-Kayser et al 484 53 Ayash LJ, Hunt M, Antman K, Nadler L, Wheeler C, lymphoid irradiation protects against graft-versus-host disease: Takvorian T et al. Hepatic veno-occlusive disease in auto- ‘natural suppressor’ cells. J Immunol 2001; 167: 2087–2096. logous bone marrow transplantation of solid tumors and 67 Lan F, Zeng D, Higuchi M, Higgins JP, Strober S. Host lymphomas. J Clin Oncol 1990; 8: 1699–1706. conditioning with total lymphoid irradiation and antithymo- 54 Cutler C, Stevenson K, Kim HT, Richardson P, Ho VT, cyte globulin prevents graft-versus-host disease: the role of Linden E et al. Sirolimus is associated with veno-occlusive CD1-reactive natural killer T cells. Biol Blood Marrow disease of the liver after myeloablative allogeneic stem cell Transplant 2003; 9: 355–363. transplantation. Blood 2008; 112 (12): 4425–4431. 68 Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. 55 Carreras E. Veno-occlusive disease of the liver after Donor-type CD4(+) CD25(+) regulatory T cells suppress hematopoetic cell transplantation. Eur J Haematol 2000; 64 lethal acute graft-versus-host disease after allogeneic bone (5): 281–291. marrow transplantation. J Exp Med 2002; 196: 389–399. 56 Kusumi E, Kami M, Kanda Y, Murashige N, Seki K, 69 Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Fujiwara M. Hepatic injury following reduced intensity Grumet FC, Shizuru JA et al. Protective conditioning for unrelated cord blood transplantation for adult patients with acute graft-versus-host disease. New Engl J Med 2005; 353 hematological diseases. Biol Blood Marrow Transplant 2006; (13): 1321–1331. 12: 1302–1309. 70 Schaenman JM, Shashidhar S, Rhee C, Wong J, Navato S, 57 Rizzo JD, Curtis RE, Socie´G, Sobocinski KA, Gilbert E, Wong RM et al. Early CMV viremia is associated with Landgren O et al. Solid cancers after allogeneic hematopoetic impaired viral control following nonmyeloablative hemato- cell transplantation. Blood 2009; 113: 1175–1183. poetic cell transplantation with a total lymphoid irradiation 58 Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie´G, and antithymocyte globulin preparative regimen. Biol Blood Travis LB et al. Solid cancers after bone marrow transplanta- Marrow Transplant 2010 (e-pub ahead of print). tion. N Engl J Med. 1997; 336 (13): 897–904. 71 Nakamae H, Terada Y, Nakane T, Koh H, Nakamae M, 59 Socie´G, Curtis RE, Deeg HJ, Sobocinski KA, Filipovich AH, Aimoto R et al. A modified myeloablative conditioning Travis LB et al. New malignant diseases after allogeneic regimen for allogeneic hematopoietic stem cell transplantation, marrow transplantation for childhood acute leukemia. J Clin consisting of intravenous busulfan, cyclophosphamide and Oncol 2000; 18: 348–357. total lymphoid irradiation, in advanced leukemia. Gan To 60 Krishnan A, Bhatia S, Slovak ML, Arber DA, Niland JC, Kagaku Ryoho 2010; 37: 1691–1695. Nademanee A et al. Predictors of therapy-related leukemia and 72 Zhuang AH, Liu A, Schultheiss T, Wong YC. Dosimetric myelodysplasia following autologous transplantation for study and verification of total body irradiation using helical lymphoma: an assessment of risk factors. Blood 2000; 95: tomotherapy and its comparison to extended SSD technique. 1588–1593. Medical Dosimetry (e-pub ahead of print). 61 Janssen WJ, Muldrow A, Kearns MT, Barthel L, Henson PM. 73 Wong JY, Liu A, Schultheiss T, Popplewell L, Stein A, Development and characterization of a lung-protective method Rosenthal J et al. Targeted total marrow irradiation using of bone marrow transplantation in the mouse. J Immunol three-dimensional image-guided tomographic intensity-modu- Methods 2010; 357: 1–9. lated radiation therapy: an alternative to standard total body 62 Singh AK, Karimpour SE, Savani BN, Guion P, Hope AJ, irradiation. Biol Blood Marrow Transplant 2006; 12: 306–315. Mansueti JR et al. Pretransplant pulmonary function tests 74 Lee CT, Bilton SD, Famiglietti RM, Riley BA, Mahajan A, predict risk of mortality following fractionated total body Chang EL et al. Treatment planning with protons for pediatric irradiation and allogeneic peripheral blood stem cell trans- retinoblastoma, medulloblastoma, and pelvic sarcoma: how do plant. Int J Radiat Oncol Biol Phys 2006; 66 (2): 520–527. protons compare with other conformal techniques? Int J 63 van Kempen-Harteveld ML, van Weel-Sipman MH, Emmens Radiat Oncol Biol Phys 2005; 63: 362–372. C, Noordijk EM, van der Tweel I, Re´ve´sz T et al. Eye shielding 75 Timmermann B, Lomax AJ, Nobile L, Grotzer MA, Weiss M, during total body irradiation for bone marrow transplantation Kortmann RD et al. Novel technique of craniospinal axis in children transplanted for a hematological disorder: risks and proton therapy with the spot-scanning system: avoidance of benefits. Bone Marrow Transplant 2003; 31: 1151–1156. patching multiple fields and optimized ventral dose distribu- 64 Broerse JJ, Dutriex A, Noordijk EM. Physical, biological, tion. Strahlenther Onkol 2007; 183: 685–688. and clinical aspects of TBI. Radiother Oncol 1990; 18(Suppl 1): 76 Bethge WA, Lange T, Meisner C, von Harsdorf S, Bornhaeu- 11–162. ser M, Federmann B et al. Radioimmunotherapy with yttrium- 65 Harden SV, Routsis DS, Geater AR, Thomas SJ, Coles C, 90-ibritumomab tiuxetan as part of a reduced-intensity Taylor PJ et al. Total body irradiation using a modified conditioning regimen for allogeneic hematopoietic cell trans- standing technique: a single institution 7 year experience. plantation in patients with advanced non-Hodgkin lymphoma: Br J Radiol 2001; 74: 1041–1047. results of a phase 2 study. Blood 2010; 116 (10): 1795–1802. 66 Lan F, Zeng D, Higuchi M, Huie P, Higgins JP, Strober S. 77 Barbet J, Chatal JF, Kraeber-Bode´re´F. Radiolabeled anti- Predominance of NK1.1+TCR alpha beta+ or DX5+TCR bodies for cancer treatment. Med Sci (Paris) 2009; 25: alpha beta+ T cells in mice conditioned with fractionated 1039–1045.

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