Barrett: Total body irradiation.

TOTAL BODY IRRADIATION

Barrett A

Beatson Oncology Centre, Radiation Oncology, Western Infirmary, Glasgow, Scotland.

Received 23 March; accepted 5 April 2000.

Key words: Total body irradiation.

INTRODUCTION of safe bone marrow transplantation (BMT), which removed the dose limiting toxicity of total The potential of systemic irradiation for the body irradiation (TBI) and permitted the use of treatment of disseminated malignant disease much higher doses. Increasing experience has was recognised almost immediately after the led to better ways to preventing graft versus discovery of radioactivity by Madame Curie in host disease (GvHD) and enabled rescue after 1897. By 1905, a German physicist, Frederic high dose therapy to be extended to the majority Dessauer, had designed an arrangement of x ­ of patients who do not have a fully compatible ray sources, which would give a homogenous sibling (Kernan et aI., 1993). dose of radiation to the whole body. The From the early 1970s, the pioneering work of treatment of 3 patients with leukemia was Donal Thomas, mostly in Seattle, has led to the reported by Adalar Eifer in a Hungarian journal increasing use of total body irradiation as a in 1907. In 1923, Chaoul & Lange from the therapeutic method for many different University Clinic of Surgery in Munich treated 12 conditions. Initially patients with the most patients with Hodgkin's disease, of whom 8 radiosensitive tumours such as leukaemias and showed responses which lasted at least 7 lumphomas were treated (Thomas et al.; 1979), months (Chaoul and Lange, 1923). but subsequently, systemic irradiation has been Special equipment for total body irradiation tried with many other types of cancer and the was installed at the Memorial Hospital, New indications for treatment have been greatly York, in May 1931 and by June of the next year, extended. Patients with haematological or Heublein reported results with 185 kV x - rays congenital metabolic diseases. where bone given at a dose rate of 0.67 to 1.26 cGy per hour marrow transplantation may correct the to patients at a distance of 18-14 feet (5.5 - 7.5 underlying abnormality, have also been metres). He concluded that the safe whole body irradiated, although preparation for dose was 25% of an erythema dose (7.5 Gy transplantation in these cases is more usually measured in air) and noticed "encouraging given by chemotherapy alone. improvement" in 3 out of 10 patients, but no A scientific basis for total body irradiation has pronounced "beneficial clinical manifestations" been difficult to establish because interacting (Heublein, 1932). Nevertheless, this work factors affect outcome of treatment. The effect continued and, in 1942, an analysis of 270 of high doses of 8 Gy or more to the whole body patients was presented by Medinger and Craver on systems other than the bone marrow cannot (Medinger and Craver, 1942). be studied unless fatality is prevented by bone Doses were limited to 3 Gy because of marrow transplantation or other stem cell haematological toxicity and research soon support. However, BMT produces problems, (of started to find ways of overcoming this limitation. which graft versus host disease is the most Thomas et al. (Thomas et al.; 1957) reported severe), which may influence complications the use of intravenous infusion of bone marrow such as interstitial pneumonitis in which to patients receiving radiation and radiation plays an important part. It is also chemotherapy. The discovery of leuco ­ difficult to determine how much radiotherapy agglutinating antibodies by Dausset (Dausset contributes to control of diseases in a multi­ and Nenna, 1952) stimulated much research modality treatment and it is unsatisfactory to which led to the recognition of leukocyte compare results between centres where many histocompatibility antigens. An understanding of aspects of patient management may differ. these was essential for the initial development However, over the last 10 years, our

This paper was first prepared as a chapter for the Oxford textbook of oncology and presented at st 1 Congress of Polish Society of Roadiation Oncology in Krak6w 27 - 29 May 1999.

Rep. Pract. Oncol. Radiother. 4 (3) 1999 47 Barrett: Total body irradiation.

understanding of how to improve TBI schedules A TYPES OF "RESCUE" AFTER HIGH DOSE has increased, particularly because of the THERAPY studies undertaken in the large number of In the early days of high dose therapy, bone patients recorded by the International and marrow was used for "rescue" and could be European Bone Marrow Transplant Registries obtained from a number of sources. Identical and through the continuing pioneering work of twin grafts (syngeneic bone marrow) offered the Seattle Group (Bortin et al.; 1992; Petersen etal., 1992). apparent advantages in being well tolerated by the recipient. However, these grafts may be associated with a higher rate of relapse because A AIMS OF TOTAL BODY IRRADIATION of loss of a "graft versus leukaemia" effect which offsets the advantage of a lower incidence of At doses of 6 to 15 Gy, total body irradiation transplant related complications. will produce bone marrow ablation. For benign Allogeneic grafts from a fully compatible family disease, the intent of such treatments is to member are usually preferred when available, provide enough immuno - suppression to allow although these may cause graft versus host an infused marrow or stem cells to engraft disease. The scope of high dose therapy has satisfactorily so that the underlying defect can been widened by using partly compatible family be corrected. For patients with diffuse members or fully compatible unrelated donors, malignancies, the aim is to eradicate malignant although graft versus host disease and rejection cells by high dose systemic radiotherapy (in are major problems with these type of grafts. T conjunction with chemotherapy) and to rescue cell depletion of allogeneic "mismatched" or the patient from the inevitable bone marrow unrelated grafts reduces graft versus host toxicity by bone marrow transplantation or stem disease, but leads to a higher incidence of graft cell infusion. rejection and leukaemic relapse. Thus, in the first situation, the therapeutic Reinfusion of autologous marrow (harvested agent is the transplant and in the second, it is during remission) has been widely used. The the high dose therapy which includes total body risk of persisting malignant cells being returned irradiation. Obviously, the optimal scheduling of to the body and leading to relapse may be total body irradiation Jor the two situations may reduced by "purging" the marrow in-vitro to be different. Broadly speaking, chemotherapy remove tumour cells and has been reported to alone is often adequate to permit marrow improve outcome ina number of situations engraftment in patients with benign diseases, (Brenner et aI., 1994). A major clinical problem although increased immune suppression however remains the failure to eliminate all obtained by adding total body irradiation is tumour cells from the patient rather than from sometimes necessary after rejection of a first the marrow for reinfusion. . graft or when HLA matching is less close. For More recently, peripheral blood progenitor those with malignant disease however, the cells (PBPC) have been harvested after search for ways of intensifying treatment stimulation by appropriate colony stimUlation continues because in many situations relapse of factors. This procedure, which can be the initial disease remains the major problem, undertaken on a out-patient basis, appears to and many regimens still include TBI as well as be satisfactory for ensuring engraftment. Early high dose chemotherapy. results suggest that allogeneic peripheral blood stem cells from a sibling donor may also be For each disease treated the following should used satisfactorily (Korbling et aI., 1995). be defined: Manipulation of PBPC may be used to improve 1. The target cell population for the outcome further, either by purging autologous treatment (that is part of the normal PBPC or by attempting to expand particular immune system or a malignant cell progenitor cell populations in vitro before population). reinfusion (Moolten, 1995). Though some 2. The biological behaviour and radiation success has been reported, such manipulation response characteristics of the target always leads to an increased risk of graft failure. cell population. Another potential source of stem cells for 3. The dose needed to achieve the engraftment is cord blood. planned effect. 4. The most appropriate schedule of A INDICATIONS FOR HIGH DOSE THERAPY irradiation. WITH TBI 5. The interaction of radiation with other B LEUKAEMIA elements of the management of the patients. Most intensive treatments with haemopoietic 6. The complications likely to occur. support are undertaken for leukaemia.

48 Rep. Praet. Oneol. Radiother. 4 (3) 1999 Barrett: Total body irradiation.

C ACUTE LYMPHOCYTIC LEUKEMIA phase, the survival falls and in accelerated phase disease, the survival after bone marrow Children with acute lymphocytic leukaemia at transplantation is less than 30%. This approach high risk of relapse should be considered for is ineffective in patients who are treated in blast treatment in first complete remission. This group crisis. Autologous transplantation is being includes those who fail to remit by day 28 of investigated and may prolong survival, although standard therapy, those with biphenotypic elimination of Ph+ cells is unlikely. At the onset leukaemia or who have Ph+ cells, infants with of the disease, marrow purging may be possible MLL gene rearrangement and those with high since there will be a residual population of hazard scores. Allogeneic matched related normal Ph- cells which declines as the disease donors should be used when available, but progresses. Attempts are being made to select allogeneic unrelated matched or related partially benign primitive progenitor cells from marrow mismatched grafts may be considered for those obtained early in the disease to use for marrow at highest risk. Other children in the standard reconstitution after conventional induction of risk group should be considered for remission (Applebaum et aI., 1995). transplantation if they relapse after second complete remission has been obtained. In this B NON - HODGKIN'S LYMPHOMA group long - term survival may be expected in C HIGH GRADE 50 - 70% of patients (Barrett et aI., 1994). Relapse remains a major problem and attempts A large number of patients with lymphoma have to intensify preparation regimens have largely been treated with autologous bone marrow resulted in increased toxicity without significant transplantation at different stages of their disease. improvement in survival rates. A sub-set of patients with poor prognosis after In adults, results are less satisfactory because conventional therapy can be identified at of high relapse and complication rates, (four presentation and should be considered for high year actuarial survival rates of 30 - 40%) and dose therapy. This includes patients with BMT is reserved for those with Ph+ disease or intermediate or high grade disease with poor who are in second remission (Zhang et aI., prognosis features (bone marrow or CNS 1995). involvement and high LDH levels) who may be considered for transplantation in first CR. Patients C ACUTE NON LYMPHOCYTIC LEUKAEMIA in second remission, but whose disease remains (ANLL OR AML) sensitive to chemotherapy may also be transplanted with good results. This approach has Patients with acute myeloid leukaemia (AML) improved long term survival in this group from may be transplanted in first remission if they 20% to 50% overall (Philip et aI., 1995). Relapse have a matched sibling donor. Relapsing rates appear to be higher when autologous rather patients should be considered for autologous than allogeneic support is used, but this bone marrow or PBPC, or unrelated matched disadvantage is offset by the higher transplant bone marrow support after high dose therapy in related morbidity seen with allogeneic second remission. Disease free survival rates ·of transplants. Allogeneic procedures may also offer 50 - 80% at 5 years can be expected in a the advantage of a graft versus lymphoma effect selected young group of patients (Zittoun et aI., and relapse and progression rates are lower in 1995). patients who develop chronic graft versus host disease (GvHD). Because of the toxicity of this C CHRONIC MYELOID LEUKAEMIA approach, it is more suitable for young patients «55) (Sweetenham et aI., 1994). Allogeneic bone marrow transplantation after high dose therapy is the only curative option for C LOW GRADE patients with CML, although it is only feasible in younger patients (aged < 55). Patients with Patients with short first or second remissions chronic phase disease are treated with from chemotherapy or those in whom only hydroxyurea, busulfan or interferon alpha to partial remission can be obtained may have obtain complete remission with disappearance improved survival after high dose therapy and of Ph+ cells. Conditioning before bone marrow autografting (Rohatiner et aI., 1994). However, transplantation is usually with cyclophospha­ this should not be the first approach because of mide/busulfan or cyclophosphamide and TBI. In the risk of myelodysplasia after transplantation patients transplanted in chronic phase within 1 and the long natural history of the disease. year of diagnosis, 5 year survival rates of There is no clear evidence of benefit from between 40 - 70% may be obtained. If· the purging the graft. Allogeneic transplantation may transplant is delayed to later in the chronic improve control rates (Van Besien et al., 1995).

Rep. Praet. Oneol. Radiother. 4 (3) 1999 49 Barrett: Total body irradiation.

B HODGKIN'S DISEASE A TECHNIQUES FOR TOTAL BODY IRRADIATION Patients with high risk or relapsed Hodgkin's disease may also be appropriately treated by To obtain a large enough field to encompass high dose chemotherapy with or without TBI the whole body using a conventional treatment (Nademanee et aI., 1995). Early transplantation unit, the machine must be used with an is recommended to avoid drug resistant disease extended source - patient distance as the developing and to minimise cumulative toxicity. largest field size available at normal workin~ distances is usually of the order of 40 cm . B MULTIPLE MYELOMA Under these working conditions, data obtained for standard treatments cannot be used and Young patients «55) with good initial simple extrapolation is inaccurate. Depth dose response to chemotherapy should be data must be obtained by direct measurement in considered for high dose therapy with PBPC or a finite phantom at an extended distance used. autologous bone marrow, or allogeneic The flatness of the beam at extended source ­ transplant following high dose therapy with patient distance must be determined. Scatter melphalan alone or without TBL This approach contributed from walls, floor and treatment improves 5 year survival rates and, using couch must also directly measured and will be allogeneic marrow, a plateau in survival at different for each treatment room. Dose approximately 40% has been reported. distributions can be calculated from tissue air Regiments containing TBI appear to give better ratios or computerized tomographic density results than those using chemotherapy alone. measurements. Special TBI planning systems This plateau in survival has not been seen in have been developed which incorporate patients treated with PBPC. Even in those anatomical information from CT scanning with patients who relapse after high dose therapy parameters of dose calculation such as depth, with TBI, survival after relapse may be backscatter, tissue thickness, thickness of prolonged (Varterasian et aI., 1997). inhomogeneity, off axis distance and source to skin distance to give accurate predictions of B OTHER TUMOURS dose distribution (Van Dam et aI., 1988; C NEUROBLASTOMA Sanches-Nieto et aI., 1997). In vivo dosimetry can be performed with Only 12-20% of patients with stage 4 disease thermoluminescent lithium fluoride monitors, will survive for more than 2 years after diodes or other in vivo dosimeters and only conventional chemotherapy. Long term survival these direct readings will fully take into account rates of up to 40% may be obtained with intensive variations in body dimensions at different levels, initial therapy, appropriate local surgery or differences between individual patients, the radiotherapy, and early autologous or allogeneic effect of positioning of the body with regard to bone marrow transplantation after high dose the beam ahd the loss of internal scatter melphalan alone or with TBI. because the fields is larger than the patient. Patients over the age of 1 or with n-myc The maximum field sizes that can be obtained amplification should be considered (Stram et aI., depend on the size and the geometry of the 1996). Purging of autologous marrow or PBPC treatment room and are often unsatisfactorily has been shown to reduce relapse rates. Current small, even when the patient is treated lying 131 studies are looking at ways of incorporating 1 along the diagonal of the beam to increase the MIBG therapy, conventional chemotherapy and effective field size. Many centres will have no high dose chemotherapy with TBI to improve choice of machine for total body irradiation and outcome in this group of patients. will have to use either cobalt or linear Patients with disseminated Ewing's sarcoma, accelerator eqUipment chosen primarily by the PNET or rhabdomyosarcoma, where conventional characteristics of the room in which it is situated. treatment has a low chance of producing cure, are The patient may need to be confined within the now being transplanted in well defined research available size by a device such as a specially protocols. designed treatment chair or a perspex box of Very selected young patients with breast the same dimensions as the field size (Barrett, cancer may also benefit from high dose therapy. 1982; Quast, 1987; Lutz et aI., 1988). Patients with high grade brain tumours are With the patient in the supine position and being treated with high dose therapy, usually treating with lateral fields, a more homogenous with chemotherapy alone. In patients with solid dose distribution may be obtained using higher tumours such as these, radiotherapy is used for energies of photons, such as 18 MV. If lung local control rather than as part of the shielding is used and the patient is treated with conditioning for high dose therapy. AP/PA fields, 6 MV irradiation may give a more

50 Rep. Praet. Oneol. Radiother. 4 (3) 1999 Barrett: Total body irradiation. satisfactory distribution (Ekstrand et aI., 1997). that the incidence of testicular relapse can be There is no clinical evidence of a difference in reduced by giving an additional dose to the outcome of treatment whether a cobalt machine testes before total body irradiation. This does or linear accelerator at various energies is used not influence the overall survival rate. Since (Bortin et aI., 1982). doses of 24 Gy are needed to prevent testicular relapse after testicular involvement, attempts B HOMOGENEITY have been made to boost testicular dose so that when given in conjunction with total body By analogy with conventional radiation irradiation, doses are high enough to ensure treatment, it has been assumed that the aim of local control. Doses of 4 - 6 Gy fractionated total body irradiation should be to obtain as over 2 - 4 days are most commonly used. We homogenous a dose as possible to the whole have recommended 3 doses of 1.8 Gy on body. If open and unmodified beams are used, sequential days immediately prior to inhomogeneities of up to 15% may be found. In cyclophospamide and total body irradiation. thinner regions of the body such as the neck and ankles, doses may be larger than mid ­ C CENTRAL NERVOUS SYSTEM abdominal doses by up to 15%. Doses in the lung are variable, but may be up to 10% higher Similar boosts have been used in some because of increased transmission in air. Doses centres to minimize the risk of CNS relapse. to the head may be low because they may be There are insufficient data to establish whether within the penumbral region if the field size is this approach is effective, although, as for the small or because of loss of internal scatter. The testicular boosts, a dose of 1.8 Gy given on 3 patient's position also affects dose distribution. successive days before total body irradiation For example, flexion of the neck to bring the has proved safe and apparently effective in chin onto the chest will reduce doses to the minimizing CNS relapse. neck, and lung doses may be modified by varying the position of the arms. C SPLENIC IRRADIATION Many centres use compensators to decrease doses to the lung or lower limbs or bolus around Patients with massive splenomegaly from neck or ankles to act as compensators. Lung chronic myeloid leukaemia may be left with shields are used either as compensators to limit residual splenic enlargement after the lung dose to that received elsewhere in the chemotherapy and additional radiation may be body or to reduce the dose even lower to given to the spleen. This -is best localised by minimise pulmonary complications of total body ultrasound and its position marked on the skin irradiation. Some centres have considered immediately before treatment. Treatment should applying shielding of the kidneys or liver to limit be avoided if possible when platelet counts are late toxicity (Miralbell et aI., 1996). low and daily fractions sizes are usually of the order of 0.5 to 1.5 Gy per day (Lapidot et aI., B BOOSTS 1988).

The assumption that homogeneity is desirable C NODAL AREAS may be questioned. The most effective treatment may be one which delivers the highest With the increasing use of high dose therapy dose feasible to the areas most likely to contain in the treatment of lymphomas, additional disease. In practice, this approach has been treatment to initial or residual areas of nodal used when boosts are given to various parts of disease may be considered advisable since the body known to harbour residual disease or after bone marrow transplantation, most to areas at high risk because of poor lymphoma relapse occur in sites of previous chemotherapy access. disease. Local radiotherapy may be given before or after high dose chemotherapy or TBI. C TESTICULAR IRRADIATION Full therapeutic doses (35 Gy) have been reasonably well tolerated after bone marrow Prophylactic testicular irradiation after the transplantation, although leukopenia and induction of remission in acute lymphatic mucositis may be troublesome (Abrams et aI., leukaemia is not considered beneficial. Although 1997). It may be more convenient to plan to isolated testicular relapse may occur, it is often deliver boosts to local nodal areas before TBI the herald of systemic relapse for which further using doses of 20 Gy to involved sites. chemotherapy is indicated. However work from Particular care should be taken when irradiating North American centres such as Seattle and the mediastinum which may result in Memorial Sloan Kettering Hospital have shown pneumonitis (Rosalia et aI., 1996). If local

Rep. Praet. Oneol. Radiother. 4 (3) 1999 51 Barrett: Total body irradiation. treatment and TBI are given close to one 8 SPECIFIC TECHNIQUES another, it is safest to restrict total cumulative doses to 35 Gy. Most groups giving total body irradiation treatments use a standard cobalt unit or linear 8 SHIELDING accelerator (4 - 18 MV) operating at a source C LUNG SHIELDING skin distance (SSD) of approximately 4 metres which will usually give field sizes from 128 - 160 Lung shielding is used by approximately 80% em. Within this field size, patients may lie of European centres (Quast, 1987) undertaking supine, on their side or be seated with knees total body irradiation. Lead blocks are usually bent up on a special chair. made individually for each patient from suitable Perspex of up to 2 cm in thickness is usually planning films or from CT measurements to placed next to the patient, both on the beam cover the lung from the clavicle to the dome of side (entry) to prevent skin sparing, which would the diaphragm following the inner contour of the occur with high energy irradiation and is chest wall. This arrangement shields only undesirable because leukaemic cells may approximately 60% of lung tissue and also infiltrate the skin, and on the exit side to absorb unavoidably 5% of bone marrow (Dutreix et aI., backscatter from walls which increases skin 1986). Some techniques shield the lung for the dose without adding usefully to mid plane doses main part of the TBI treatment and then add a (Van Dam et aI., 1988). boost to the bone - marrow - containing ribs Special total body irradiation units have been using electrons (Shank et aI., 1983). This is a installed in a number of centres. In Toronto, a complex arrangement and additional lung dose single source wide angled collimator unit from the electron boosts are inevitable. permits large field irradiation at a short Scattered irradiation within the lung may also be treatment distance. Dual source treatment significant, but it is difficult to quantitate. facilities have been available for many years in Shields are placed either close to the machine Seattle, where 2 opposing cobalt sources are head, which may make alignment with the mounted on floor rails to allow adjustment of patient difficult, or in direct contact or very close treatment distances as sources decay (Thomas to the patient. Positioning may then be more et aI., 1979). The patient is placed between the accurate, but may cause some discomfort to the 2 horizontal beams. At the Royal Marsden patient. It is difficult to ensure the accuracy of Hospital (RMH) in London dual cobalt sources shielding especially if treatments are prolonged are mounted vertically and provide field sizes of or if patients are restless or uncooperative; the 2 x 0.65 m at 2 m SSD; in Boston, proximity of the mediastinum, liver and spleen, Massachusetts, two 4 MV linear accelerators to which full doses must be given, makes similarly mounted give field sizes of 80 x 220 2 accuracy very important. However, from the cm , These special facilities provide tfle work of Dutreix it can be seen that shielding is possibility for varying the parameters of only effective for at most 60% of the lung treatment which are fixed with most single volume; 30% lies within the mediastinal fields source units because of field size constraints and 5% in the apex where shielding is difficult, (Lutz et aI., 1988; Lewis and Rosenbloom, although lung doses may be highest. For this 1988). reason and because of concerns about Where there is no room large enough for total accuracy in placing shields, some centres prefer body irradiation, some centres have used a to use no lung shielding, but to restrict doses to scanning cobalt beam, to cover the whole body. those known to be within tolerance. This has the theoretical disadvantage that not all A reduction in the incidence of interstitial the malignant cell population is being irradiated pneumonitis when shielding was introduced has at the same time and that the incident dose rate been claimed by many groups, but often this is higher than when whole body treatment is change coincided with a reduction in effective given at extended distances. In practice, there is whole body doses by fractionation or more little evidence to suggest that this technique is careful measurement of lung doses. It is not less effective, although a higher incidence of clear whether the development of interstitial interstitial pneumonitis has been reported with a pneumonitis can be provoked by high doses to sweeping beam technique than with a static part of the lung only or whether partial protection beam (Kim et al., 1985). is effective. The role of lung shielding, except to Most patient are treated with postero-anterior provide compensation if homogeneity of and antero-posterior fields because the treatment is being sought, therefore remains increased thickness of the body when lateral unclear. Similar rates of interstitial pneumonitis fields are used leads to less satisfactory dose are reported by groups using techniques with distributions. This effect is less obvious in and without lung shielding (Bortin et aI., 1982). children. High energy accelerators (>18 MV)

52 Rep. Pract. Oncol. Radiother. 4 (3) 1999 Barrett: Total body irradiation. may give a better dose distribution if lateral A SCHEDUUNG OF TOTAL BODY fields are used to treat the supine patient. If IRRADIATION vertical treatment units are used with the patient supine, it is possible to place lung shielding In conventional radiotherapy, regimens can more accurately. With the patient lying on his only be considered isoeffective if they produce side, careful positioning of the arms may the same degree of tumour control for the same contribute to compensation for increased lung level of toxicity to normal tissue. In practice, the transmission. acute tolerance of normal tissues is likely to limit Some centres in the United States and Europe the doses that can be given, although late have adopted the technique first developed at damage may be more critical. For total body the Memorial Hospital in New York where irradiation, three endpoints must be considered patients are treated standing supported by a if regimens are to be compared. modified bicycle seat and arm supports, with 1. Effect on cells of the immune lung shields suspended from their shoulders. system. Additional boost treatments are then given with 2. Control of leukaemic or other electrons to the chest wall to increase the dose tumour cell population. to bone marrow bearing ribs (Shank et aI., 3. Effect on normal tissues other than 1983). bone marrow (whose function can From analysis of treatment results notified to be effectively replaced by the the International and European Bone Marrow transplant procedure). Transplant Registries, there is no evidence for After bone marrow, the next most sensitive superiority of one treatment technique over organ to damage from total body irradiation is another and factors such as the dose given and the lung, with liver and kidney also at risk from the sCheduling of total body irradiation are likely similar or higher doses. For proper comparison to be much more important (Bortin et aI., 1982). of one schedule with another the question must be asked, do these two regimens produce equal rates of engraftment, control of initial disease and incidence of interstitial pneumonitis (and B TOTAL LYMPHOID IRRADIATION other normal tissue toxicity)? One treatment can only be proved to be better than another if it can Total lymphoid irradiation (TLI) was proposed be shown that, for equal rates of normal tissue by Slavin et aI. (Slavin et aI., 1983) as a way of toxicity, tumour control or engraftment producing immuno - supression without the lung (whichever is the most significant clinical factor) toxicity of total body irradiation. It permitted is improved. Unfortunately not all studies are stable chimerism after bone marrow constructed in this way and it may be difficult to transplantation and was widely used to facilitate conclude that a particular schedule is better organ engraftment. Initially, beneficial than another if only one of the parameters is symptomatic response in auto-immune diseases reported. such as systemic lupus erthymatosis and Analysis of treatment results is further rheumatoid arthritis was reported (Strober et aI., complicated by the timescales of the different 1985), but these responses may not be long­ endpoints. Failure of engraftment will be obvious lasting and a relatively high incidence of within 2 to 3 weeks and interstitial pneumonitis secondary B- cell malignancy has indicated occurs most commonly up to 100 days after that this approach should be used with caution. total body irradiation. Leukaemic or other TLI has been used for conditioning patients with tumour cell relapse however may occur at any aplastic anaemia after graft rejection, but it is a time up to several years after treatment. complicated technique and appears to offer little Because patients who have died early with advantage over low dose total body or thoraco ­ interstitial pneumonitis will be lost to the total abdominal irradiation. With TLI, doses of 20 ­ analysis of tumour relapse, its true incidence 34 Gy with conventional daily fractionation have with that schedule will be impossible to been used. It has also been used in some determine. Because of these problems, rates of centres before or after total body irradiation to interstitial pneumonitis have commonly been produce additional immune suppression for used as the single endpoint for comparison of patients receiving T-cell depleted marrow schedules of total body irradiation. grafts. However, using data from large reported Shaped fields such as mantle and inverted Y series of TBI treatment and derived alpha bete (used more commonly in the treatment of ratios for each of the normal tissues and the Hodgkin's disease) or thoraco - abdominal tumour population at risk (in so far as these can fields with lung shielding may be used to deliver be determined from the literature) it should doses of 5 - 6 Gy. theoretically be possible to calculate an optimal

Rep. Praet. Oneal. Radiother. 4 (3) 1999 53 Barrett: Total body irradiation. schedule for TBI. In practice, because tumour relapse. The mechanism for the failure of cell populations and normal tissues vary in engraftment after T cell depletion is not clear, radiosensitivity both within patients and in although host natural killer cells and T different organs as well as between patients, it lymphocytes have been implicated. Empirical may not be possible to demonstrate a single intensification of conditioning for bone marrow "best treatment". Most of the currently used transplantation with T cell depleted marrow has schedules have been shown empirically to be resulted in increased rates of graft versus host reasonably well tolerated. Differences in tumour disease. There are differences in radiosensitivity cell population control are difficult to in-vitro for the various lymphocyte subsets (T, B, demonstrate since quantitation of residual OKT4 , OKTa) which may be responsible for disease after induction chemotherapy has not these outcomes (Uckun et aI., 1992). Further been possible up till now and there may be studies are needed to determine which cell is considerable variation in total tumour cell responsible for graft rejection and to elucidate numbers in different patients who are apparently the role of increased doses of total body in complete clinical remission. Quantitative PCR irradiation in the abrogation of graft failure. of bone marrow may help to elucidate this situation. B RADIOSENSITIVITY OF LEUKAEMIC AND OTHER MALIGNANT CELLS B RADIOSENSITIVITY OF CELLS OF THE NORMAL HAEMOPOIETIC AND IMMUNE O'Donoghue in his review of the literature of SYSTEMS the in-vitro radiosensitivity of human leukaemic cell lines has found descriptions of 8 different Early work by Till and McCulloch (Till and lines (including 3 lymphomas) and McCulloch, 1962) using the exogenous spleen measurements of bone marrow or peripheral colony assay system in mice showed that bone blood leukaemic progenitor cells from 20 marrow stem cells have a limited capacity to patients (O'Donoghue, 1986). These studies repair sub - lethal damage. Similar radiation confirmed that leukaemic cells are highly survival curves have been obtained with human radiosensitive with a low capacity for the bone marrow cells cultured in -vitro (Senn and accumulation and repair of sub-lethal damage. McCulloch, 1970). Because of these typical cell As for normal stem cells, little effect of changes survival curves, little effect is expected from in dose rate or fractionation would therefore be changes in radiation schedule and this has been expected. However for this cell population, the confirmed in a number of experimental systems. doubling time must also be considered. This However, Tarbell et al. (Tarbell et aI., 1989) would be likely to be insignificant for continuous have shown Do values of 80 cGy for single low dose radiation, but if a doubling time of 2.5 fraction high dose rate treatment, 85 cGy for low days is considered, fractionation over a period dose rate single fractions and 55 - 65 cGy for of 5 days could result in a reduction in log cell fractionated regimens, suggesting increased kill of 0.6. Direct studies of the effects of various sensitivity to fractionated treatment. schedules of total body irradiation on leukaemic Nevertheless, overall it seems reasonable to cell in-vitro have been reported. There is some conclude that the effect of variations in dose evidence of increased survival of leukaemic rate and fractionation are insignificant for the cells in-vitro when radiation is given as a split killing of normal bone marrow cells which course compared with continuous radiation to represent a very radiosensitive population. the same total dose. The LDso for man from bone marrow ablation For control of leukaemia and other is 4 Gy and in patients with nonmalignant malignancy, it can be assumed from general disease undergoing bone marrow experience in radiotherapy that increasing dose transplantation, doses of 6 Gy appear of radiation will produce increased tumour cell necessary to ablate host marrow adequately to kill. This can be shown using the same allow engraftment of donor marrow. This is technique and scheduling of total body below the Jevel at which lung damage will occur irradiation, by demonstrating reduction in rates and scheduling therefore is not critical if killing of relapse as the dose is escalated and has normal stem cells is the only consideration. been confirmed by studies from various groups. The complication of graft versus host disease In a study of escalating single fraction low dose after bone marrow transplantation can be rate total body irradiation in 238 patients at the greatly reduced by the in-vitro manipulation of Royal Marsden Hospital, London, a lower harvested bone marrow to reduce T cell relapse rate was noted after 10.5 Gy than 9.5 numbers. The use of T cell depleted bone Gy although at a higher dose of 11.5 Gy any marrow however results in a markedly increased benefit in preventing leukaemic relapse was rate of graft rejection as well as of leukaemic offset by a high early death rate from lung

54 Rep. Pract. Oncol. Radiother. 4 (3) 1999 Barrett: Total body irradiation. damage. Similarly the Seattle group have shown reduced incidence of pneumonitis with a lower rate of leukaemic relapse with 15.7 Gy fractionated total body irradiation but in many compared with 12 Gy, although at the expense cases all that has been accomplished effectively of a higher transplant related mortality (Petersen is a reduction in overall dose. If fractionated et aI., 1992). However, for other tumour types radiotherapy is to be used, it is likely that the whose radiobiological characteristics will be most benefit will be obtained using relatively different, dose should not be considered in small doses per fraction «2 Gy) although even isolation (Peters et aI., 1979). lower fraction sizes (1.2 Gy) may be beneficial In addition, other biological factors such as in terms of lung sparing and clinically feasible total body burden of tumour may outweigh an and effective (Shank et aI., 1983). Within the possible advantage of increasing dose within range of dose used per fraction, little additional the range feasible because of normal tissue benefit is gained using low dose rate as damage. opposed to the standard output of most machines, although additional sparing with very B NORMAL TISSUES low dose rates has been reported experimentally. Similar dose response curves A direct effect of increasing the total irradiation and a beneficial effect of fractionation in dose on the incidence of damage to normal reducing late damage have also been tissue can also be demonstrated. For the lung, demonstrated for liver, kidney and lens. the dose limiting tissue in total body irradiation, In summary therefore, toxicity to normal the response curve using upper half body tissue, efficacy against tumour population and irradiation for disseminated malignant disease feasibility in term of delivery must be shows an apparent threshold below which lung considered, as well as overall treatment time damage is not clinically apparent, with a very and time between fractions. Regimens such as steep increase in incidence with dose over the those from Seattle, UK MRC and US Memorial range 9 -10 Gy (Keane et aI., 1981). For single Sloan Kettering regimens all offer the advantage fraction low dose treatments in the RMH of high dose, low dose per fraction and experience, the incidence of interstitial reasonable overall treatment time and therefore pneumonitis rose from 30% with 10.5 Gy to 69% appear to be the most satisfactory at present. with 11.5 Gy. Similar steep responses have Clinical trials from Seattle have recommended a been with high dose total body irradiation in the total dose of 14.4 Gy in children and 13.2 Gy in range of 7 - 8 Gy. Work from Seattle suggests adults and this corresponds very well with the that when fractionated total body irradiation with UK experience with the MRC protocol of 14.4 2 Gy fractions is used, maximum tolerated lung Gy (maximum lung dose in 8 fractions of 1.8 Gy doses are of the order 14 -15 Gy. given over 4 days) (Demirer et aI., 1995). Isoeffective schedules of total body irradiation Further experience with treating patients with for the endpoint of clinical lung damage other tumours may lead to a change in these manifested as interstitial pneumonitis are recommendations, but this is unlikely since the reasonably well established as 7.5 Gy single parameters of normal tissue toxicity will not vary. fraction high dose rate, 10.5 Gy single low dose rate and 14 - 15 Gy with fractionated TBI. A DRUG-RADIATION INTERACTIONS Several experiments and clinical studies have now suggested that although considerable As total body irradiation is only one element of sparing of normal tissue damage may be the conditioning regiment, drug-radiation achieved in single fraction treatments by interactions must be considered in assessing lowering the dose rate, regimens using small the effectiveness or tOXicity of a particular dose fractions are likely to be best, since for treatment. For many years, the combination equivalent toxicity, dose rate for a single fraction developed by the Seattle Group of would have to be very low leading to very cyclophosphamide 120 mg/kg given on days 4 prolonged treatment times which are not and 3 before total body irradiation has been feasible in practice. Fractionated TBI is widely used (Thomas et aI., 1979). The therefore now widely used, although there is continuing problem of leukaemic relapse after great variation in the dose per fraction. bone marrow transplantation has led to attempts The response of the lung to fractionated to intensify conditioning before grafting in radiotherapy is dependent much more on various ways. Radiation dose and fractionation fraction size than duration of treatment. The half may be modified (Petersen et aI., 1992), or more time for repair of lung is estimated to be commonly alternative drugs or several approximately 1.5 h hours and a minimum of 6 chemotherapeutic agents have been used in hours is needed between fractions to ensure combination. Unfortunately most of these that repair is complete. Many groups report a studies have either found no improvement in

Rep. Praet. Oneol. Radiother. 4 (3) 1999 55 Barrett: Total body irradiation. relapse rates or have found that an prophylaxis appears to be with a combination of improvement in relapse rate is offset by an a 5 hydroxy triptamine (5HT) antagonist such as increase in transplant related morbidity and ondansetron with dexamethasone (Spitzer et aI., mortality (Ringden et aI., 1983; Gorgon et aI., 1994). 1997; Kumar et aI., 1997; Hjiyiannakis et aI., Acute damage to the gut may be reflected by 1997). severe diarrhoea, anorexia, and cramping Attempts to replace total body irradiation with abdominal pain occurring within 4 or 5 days of drugs have been made and the most widely irradiation. Histologically, there is evidence of used chedule is that developed by Santos of flattening of crypt epithelium and degeneration cyclophosphamide (60 mg/kg x 2) and busulfan of crypt cells by 10 days after treatment. Repair (4 mg/kg x 4) (Santos et aL, 1983). Results occurs usually within 20 days. Damage to the comparable with those from total body villi may result in malabsorption, although irradiation containing regiments are obtained. complete recovery normally occurs. Both total body irradiation and busulphan are Total body irradiation may also cause potent stem cell killers. The spectrum of hypotension and pyrexia which may be morbidity is defferent and the optimum schedule worsened by the use of drugs such as must be determined taking these factors into chlorpromazine and ameliorated with steroids. consideration (Ringden et aI., 1994). Bilateral parotitis is common after total body For the radiation oncologist directing TBI irradiation, but usually resolves within 24 hours. treatments, one of the persisting challenges is to It is associated with a rise in the parotid iso­ assist in developing more effective, but less enzyme serum amylase with no change noted in toxic preparatory regiments. In many cases, the pancreatic amylase (Barrett et aI., 1982). Values effects of individual drugs given in conjuction return to normal by 6 days and there are with radiation are well known, and potentially normally no sequelae although xerostomia may toxic drugs such as cytosine arabinoside, persist for up to a year after the treatment. methotrexate and cisplatin can be avoided. As Pilocarpine may help to stimulate saliva flow new drugs are developed and added to after treatment. Careful attention to dental conditioning regimens, constant vigilance and hygiene is necessary if the mouth remains dry to careful observation' are needed to detect any prevent further complications. Graft versus host unforeseen interactions. disease will exacerbate the oral sequelae of treatment (Dahllof et aI., 1997). A COMPLICATIONS OF TOTAL BODY In treatments uncomplicated by graft versus IRRADIATION host disease or drug tOXicity, no immediate changes in serum urea, electrolytes, liver B ACUTE EFFECTS function tests, calcium, phosphate or alkaline phosphatase have been noted. There is a rapid Nausea and/or vomiting may be expected in fall in the lymphocyte count to 50% by the end of most, but not all, patients after total body treatment with single fraction total body irradiation. After single fraction exposures at low irradiation with a half time of 30 hours, and to dose rate, vomiting occurred in 75% of patients 60% 13 hours after the first fraction of a after a dose of 2- 3 Gy had been received fractionated course. Rises in granulocyte (Westbrook et aL, 1987). When fractionated concentrations may be very marked (200 ­ total body irradiation is used, vomiting may be 400% of initial value) after only 10 minutes of less marked, but occurs in most patients total body irradiation, although numbers then between 1Y2 - 8 hours after the start of the decline rapidly to initial or lower values. No treatment. It is difficult to separate the emetic changes in platelets or red cell numbers were effects of chemotherapy and radiotherapy in this noted up to 72 hours after the start of total body situation when chemotherapy is given before irradiation (Girinsky et aL, 1991). Increased TBI. Data from patients treated with levels of adrenaline and especially cyclophosphamide after TBI suggest that this noradrenaline may be seen after total body drug does play a major role in the nausea! irradiation. No short term changes in /vomiting that is seen with high dose therapy. concentrations of Ts or T4 are noted, although Nausea and vomiting may continue up to 4 days TSH values are lowered after 10 Gy in most after irradiation and may be associated with cases. diarrhoea related to direct toxicity on the gut. Reversible alopecia would be expected from Children under 10 years of age may experience the dose levels used for total body irradiation. less vomiting than adults. Vomiting may be This factor cannot be separated from the effects precipitated by movement and general of chemotherapy and permanent impairment of discomfort and reduced by fasting and anti­ hair regrowth may occur. Changes in colour or emetics. The most effective anti - emetic texture of regrowing hair are common.

56 Rep. Praet. Oneal. Radiother. 4 (3) 1999 Barrett: Total body irradiation.

B LATE EFFECTS grafting, older age, presence of severe graft versus host disease, long interval from In radiobiological terms, effects on lung, liver diagnosis to transplantation, poor performance and kidney may be termed late, although in status pre-transplant and high dose rate total practice, damage to these organs from total body irradiation (Pino et aI., 1982). In the IBMTR body irradiation may manifest itself within 1 to 6 series, for patients with none of these factors, weeks of irradiation. the probability of developing interstitial pneumonitis was 8% compared with 94% in CLUNG patients with all these factors. There was no evidence from this study of an advantage for Interstitial pneumonitis and graft versus host fractionated radiation in reducing pneumonitis disease are the two most important factors and no dose response relationship was detected contributing to early death after bone marrow for radiation doses to lung between 5.6 and 12.8 transplantation. Interstitial pneumonitis is Gy (Bortin et aI., 1982). characterized by fever, dyspnoea, cough and Methotrexate appears to have more direct hypoxia within the period up to 100 days after toxicity for lung than cyclosporin. This may be transplantation. Chest radiographs show because of a potentiating effect of radiation characteristic bilateral changes of diffuse damage. The cyclosporin syndrome of adult interstitial infiltrates, and lung function testing respiratory distress (ARDS) may be seen after shows a reduction in diffusing capacity. renal toxicity has developed from high dose Histological changes of oedema, cellular treatment. Increasing age may increase risk of infiltrates, alveolar exudation, type 2 pneumonitis because there is a greater pneumocyte proliferation and later collagen likelihood of prior infection with cytomegalovirus. deposition are seen. Graft versus host disease also increases the The clinical syndrome of pneumonitis is due to risk of pneumonitis by immunological and an accumulation of activated T cells in the lung infective processes. with an associated population of macrophages The lack of correlation in the study above of and neutrophils (Nakayama et aI., 1996). There pneumonitis with total dose contrasts strongly is an increase in cells expressing messenger with data presented by Keane et al. (Keane et RNA for inflammatory proteins such as tumour aI., 1981) who showed a clear dose response necrosis factor alpha, interleukin 1 beta, and relation over the range of 7-100 Gy. This may transforming growth factor beta (TFG beta). The have been obscured in the data from the host MLC class II expressing cells are increased International Bone Marrow -Transplant Registry in lung after lBI and this process is potentiated by different ways of reporting doses or by the in patients undergoing allogeneic transplant or fact that some of the schedules were delivering those with lesser degree of matching whereas it doses below the threshold for lung damage. is rare with syngeneic transplants or autologous grafts. These acute changes lead to a process CLIVER of type 2 pneumocyte proliferation and collagen deposition with fibrosis. Liver damage in recipients of bone marrow In many cases, specific aetiological factors transplants may be related to the conditioning may be detected. Up to 40% of cases are regiment, to graft versus host disease or to associated with cytomegalovirus or other infection either previously or neWly acquired. infection. Cytomegalovirus infection can be The clinical picture of radiation or chemotherapy diagnosed by culture of lung tissue, by bronchial associated liver damage develops within a few alveolar lavage or by identifying the weeks of treatment with weight gain, jaundice, characteristic viral inclusion bodies in lung abdominal pain, hepatomegaly, ascites and, in biopsies. The mortality from this condition is severe cases, encephalopathy. This condition is high. Other possible infective agents are associated with a high mortality rate and is more pneumocystis, (which may largely be prevented often seen after preparation of patients with by prophylactic administration of trimethoprin­ busulfan than with TBI. sulpha methoxasole), herpes simplex or zoster, Histopathological changes are of veno­ aspergillus, candida and other fungi and a occlusive disease, where the terminal hepatic variety of bacteria. In approximately 60% of venules and sub-lobular veins are narrowed by patients with interstitial pneumonitis, no sub-endothelial fibrosis and thickening with infectious agent can be detected and a trapping of cells, including hepatocytes, within diagnosis of idiopathic pneumonitis is made. the lumen resulting in obstruction to sinusoidal The risk of interstitial pneumonitis is increased blood flow. Although factors other than radiation by the use of methotrexate rather than are usually more important in its causation, the cyclosporin for immunosuppression after incidence is reported to be lower after

Rep. Pract. Oncol. Radiother. 4 (3) 1999 57 Barrett: Total body irradiation. fractionated than high dose-rate single fraction CEYE TBI. Low dose heparin and tissue plasminogen activators such as alteplase have been used to Marked changes are observed in transplanted try to reduce the severity of this problem. patients who develop chronic graft versus host Spontaneous resolution within 3 to 4 weeks may disease with kerato-conjunctivitis and changes occur (Baglin, 1994). in lacrimal gland secretions. Retinitis may result from conditioning with cytosine arabinoside and C KIDNEY TBL In uncomplicated survival after total body irradiation, the only change to be observed is There are many factors which may contribute to the development of cataract. In the Seattle renal damage during the preparation for and series reported in 1984 (Deeg et aL, 1984), the recovery from bone marrow transplantation risk of developing cataract was 18% and 19% in including the use of chemotherapeutic agents patients treated with chemotherapy or such as ifosfamide, antibiotics and cyclosporin. fractionated total body irradiation and 80% in Tests of glomerular function after bone marrow those receiving single fraction total body transplant f TBI usually show only minor irradiation. All cases were bilateral and the risk impairment. Tubular defects and haemolytic increased for 3 years after transplantation uremic syndrome are more likely to occur, but are before stabilizing. Surgical excision was more related to drugs than radiation exposure necessary in half the patients. Chronic graft (Patzer et aI., 1997). Endothelial injury is versus host disease and steroid therapy were characteristic of acute radiation nethropathy also associated with a higher risk of developing which is related to dose of radiation. The doses cataracts. With low dose single fraction total used for TBI should be below the threshold for body irradiation, the incidence is lower than after overt damage. Although renal failure is a common high dose single fraction treatment, but higher problem of multi-factorial aetiology after bone than with fractionated irradiation being of the marrow transplantation, it is difficult to quantitate order of 58% at 10 years (Fife et aI., 1994). precisely the contribution of TBI. Mirabell however has shown a dose dependent effect in CTEETH his patients (Mirabell-et aI., 1996). Radiation nephritis is a well recognized entity Disturbances in tooth development and size after local field irradiation to doses in excess of 20 are seen after BMT with TBI with a severity Gy and may occur many years after exposure. inversely proportional to age at the time of The first report of radiation nephritis after total treatment (Nasman et aL, 1997). body irradiation was by Bergstein et aL (Bergstein et aL, 1986). Two children developed hypertension, haematuria and impaired renal C CENTRAL NERVOUS SYSTEM DAMAGE· function 6 months after treatment. Histologically the kidney showed expanded mesangial zones, A syndrome of somnolence with lassitude, thickening of capillary and arteriolar walls, focal anorexia and sometimes vomiting, may be areas of tubular atrophy and interstitial oedema expected at about six weeks after TBI. A similar and fibrosis. One of the patients had received picture is seen after cranial irradiation for ALL cyclosporin and acyclovir, drugs with known renal and is believed to be due to transient toxicity. Tarbell et aL (Tarbell et al., 1988) found demyelination. No treatment is needed as the evidence of renal dysfunction in 11 out of 29 condition improves spontaneously (within seven survivors of transplantation for acute to ten days). It does not correlate with any lymphoblastic leukaemia or neuroblastoma persisting or late damage. between 1980 and 1986. Conditioning regimens Leukoencephalopathy may occur within days had included drugs with renal toxicity such as or months of transplantation and may be related cisplatin teniposide and ifosfamide. Patients to drug administration (especially high dose presented with anaemia, haematuria and a rising methotrexate), radiation or viral infection. It is creatinine: biopsy in 2 patients showed changes uncommon after total body irradiation unless consistent with radiation nephritis or the previous cranial irradiation has been given and haemolytic uremic syndrome. the incidence is inversely correlated with age. It thus appears that the tolerance of the The characteristic appearance on computerised kidney to radiation may be diminished when tomographic scanning is of dilated ventricles, multi agent chemotherapy is used cerebral atrophy, hypodense areas and concomitantly and children may be especially calcification. susceptible. Because of the late onset of Damage to the spinal cord has been reported radiation nephritis, this problem may increase anecdotally but is rare. in severity with longer follow - up of survivors By extrapolation from results of prophylactic of bone marrow transplantation. cranial irradiation for leukaemia, impairment of

58 Rep. Pract. Oneol. Radiother. 4 (3) 1999 Barrett: Total body irradiation. cognitive function and learning ability would be progress normally through puberty. Young age expected, although there are few detailed long at the time of treatment may be relatively term studies yet (Peper et aI., 1993). protective. Most boys will probably be azoospermic, but patients who progress through C QUALITY OF LIFE puberty with normal gonadotrophin and sex hormone levels may be fertile (Sarafoglou et aI., Quality of life after bone marrow 1997; Sanders, 1997). transplantation may be impaired. In a study from Although the probability of fertility cannot yet Toronto, many patients reported low grade be accurately predicted, pregnancies have been symptoms such as fatigue, pain, joint stiffness reported after T81 given to males and females. and sleep disturbance. Patients studied at less No abnormalities in offspring of these patients than 3 years from the time of transplant have been reported, although the rate of experienced considerable impairment, while spontaneous abortion may be increased longer term survivors were indistinguishable (Sanders et aI., 1996). from the normal population in most areas studied. However, 81 % of patients were D THYROID FUNCTION prepared to recommend a transplant for somebody in similar circumstances (Sutherland The most common abnormality seen after et aI., 1997). 8MT with T81 conditioning is compensated or over thypothyroidism with elevated TSH levels C HORMONAL CHANGES with or without low free serum thyroxine or tri­ D GONADAL FUNCTION iode thyronine levels. Thyroid abnormalities, which are commonly first detected between 12 Gonadal function and fertility are known to be and 60 months after treatment, have been affected by high dose chemotherapy and total reported in 2 - 56% of patients treated with T81, body irradiation. The degree of impaired but hypothyroidism may also occur in up to 10% function depends on age, sex and dose and of patients conditioned without T81 (Toubert et type of therapeutic agent used. aI., 1997). Replacement therapy is given early to In adult women, the usual pattern seen after try to reduce the risk of induction of thyroid T81 is ovarian failure with amenorrhea, low malignancy. plasma oestradiol levels with raised gonadotrophins, and infertility. Low androgen o GROWTH levels may be found, probably also resulting from ovarian damage. A direct effect on the Growth may be affected by T81 in two ways. adrenal gland may occur although no 1. By damage to the hypothalamus abnormalities of plasma cortisol levels have and pituitary gland leading to been reported. Since androgen is needed to impaired growth hormone (GH) sustain increased muscle activity during production. exercise, low levels may help to explain the 2. 8y a direct effect on the epiphyseal easy fatiguability reported by patients after T81 plate leading to early epiphyseal (Hovi et aI., 1997). fusion. In very young but post - pubertal females, Studies comparing effects of T81 with thoraco­ ovarian recovery may be seen in 10 - 25% at 2 abdominal irradiation have shown that the - 7 years after 8MT. Recovery is not affected by central effect is the most significant. Cranial hormone replacement therapy and this may be irradiation given before T81 increases the risk of temporarily discontinued to assess whether failure of GH production (Huma et aI., 1995). recovery has occurred. It is possible that this Normal levels of GH may be maintained after group of patients may undergo early T81, especially if this is fractionated, or a pattern menopause (as has been reported after of normal plasma levels with low GH peaks after chemotherapy). stimulation may be seen. Growth hormone In men, the most common pattern is of should be administered if GH levels are infertility (due to a direct effect on the testes) but measured to be low, if there is a low GH peak with normal testosterone and gonadotrophin after 2 stimulation tests and a loss of height levels. If additional radiation is given by a SDS of 1 SD or more (shown by measurement testicular boost so that total doses are greater of sitting rather than standing height). Low GH than 20 Gy, testosterone levels may be low with peaks have been reported in 20 - 70% of raised gonadotrophins and replacement therapy patients and graft versus host disease and poor may then be necessary. nutritional status increase the risk of GH failure. Studies in pre - pubertal children suggest that Administration of growth hormone at an early many boys and some girls receiving T81 may stage as soon as growth velocity starts to fall off

Rep. Praet. Oneol. Radiother. 4 (3) 1999 59 Barrett: Total body Irradiation. prevents further decrease in height, although 4.6 times, whereas over the age of 39 the risk "catch - up" growth does not occur. was nearly the same as in a normal population. Appropriate sex hormone administration is Cumulative incidence was 0.7% at 5 years, also essential to obtain the full growth potential 2.2% at 10 years and 6.7% at 15 years. Patients of the pubertal growth spurt. with ALL were most likely to develop brain tumours whereas melanoma occurred more C HEART often in those treated for AML. Patients treated with thoraco-abdominal or total body irradiation Cardiac toxicity is not a major problem after had a higher risk than those conditioned without total body irradiation, although it has been radiation. No difference was seen whether TBI observed after high dose cyclophosphamide was given as a single fraction or in several therapy. Myocardial fibrosis and constrictive fractions. The risk of brain tumours was highest pericarditis are late effects occurring many in those who had received cranial as well as years after conventional radiotherapy, and total body irradiation (9 of the 13 patients with careful follow-up of patients receiving total body brain tumours). irradiation is necessary to determine whether Other factors which are possibly associated these same complications will develop. In one with increased risk may be determined by study of 28 patients with leukaemia, serial echo immunological abnormalities: T cell depletion cardiography and radionuclide ventriculography possibly related to melanoma induction, immune showed abnormalities in only 4, in whom the abnormalities with oral mucositis and chronic resting ejection fraction was reduced after graft versus host disease for buccal cavity treatment. Animal studies have shown acute tumours, cyclosporin administration (for skin changes in the pattern of isoenzymes in mice tumours), papilloma virus infection in squamous after total body irradiation and these enzyme cell carcinomas of skin and buccal mucosa. changes may lead to functional alterations. On Buccal cavity tumours are commonest in men. the basis of experience from conventional The three parotid tumours observed were muco­ radiotherapy it seems possible that coronary epidermoid carcinomas - the type also artery disease or myocardial infarction may observed in survivors of the atomic bomb. occur at an earlier -age than normal in this It is interesting to compare this pattern of patient population (Kupari et aI., 1990). second tumour incidence with that seen after treatment of leukaemia without bone marrow B SECOND TUMOUR INDUCTION transplant when the cumulative incidence of second tumours at 20 years is 2.9 - 4%. A In the first year or two after bone marrow similar pattern of brain, thyroid, skin and transplantation, the commonest malignancies connective tissue tumours occurs, but the seen are recurrence of the original disease or greatest risk (27 times expected) is of brain lymphoproliferative disorders which seem to be tumours in those treated with cranial irradiation related to immune suppression and Epstein Barr (Nygaard et aI., 1991). virus infection (Darrington et aI., 1994). These data underline the risk of radiation and A large study from the Seattle Group and the the need for prolonged follow-up. Patients International Bone Marrow Transplant Registry should be encouraged to avoid exposure to has followed nearly 20,000 patients treated with known carcinogens (such as tobacco) which bone marrow transplantation to determine the may potentiate the effects of radiation. risk of developing a new solid cancer. 9,501 patients survived longer than 1 year and 73% of the patients had TBI as part of the initial conditioning for BMT. 3,200 patients have survived for 5 years or more and in this group REFERENCES 80 second tumours were diagnosed. These included 17 carcinomas of the buccal cavity or Abrams R A, Liu P J C, Ambinder RF et al. Hodgkin pharynx, 11 brain tumours, 11 melanomas, 8 and Non-Hodgkin Lymphoma: Local-regional radiation thyroid carcinomas, 9 bone and connective therapy after bone marrow transplantation. Radiology tissue and 3 liver tumours. The overall risk of 1997,203: 865-870. developing a second tumour was inversely Applebaum F R, Clift R, Radich J, Anasetti C, related to the age at the time of bone marrow Buckner C D. Bone marrow transplantation for chronic transplant and directly related to time since myelogenous leukaemia. Seminars in Oncology 1995, treatment, original tumour type and dose of 22 (4): 405-411. radiation (Curtis et aI., 1997). Risk in children treated before the age of 10 Baglin T P. Veno-occlusive disease of the liver was increased 36.6 times and at age 20 - 29 complicating bone marrow transplantation. Bone Marrow Transplantation 1994, 13:1.

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