Radiobiological considerations in magna-field irradiation

Radiobiological considerations are described for total body irradiation (TBI) as given to patients undergoing bone marrow transplantation (BMT). Although much progress has been made in the use of BMT for refractory leukemias, many patients still die from interstitial pneumonia and relapse. Fractionated TBI has been introduced in order to improve leukemic cell kill, while increasing the degree of normal tissue tolerance. Traditionally, bone marrow stem cells, leukemic cells and immunocytes have been considered as having a limited ability to repair radiation damage while cells of lung tissue and intestinal epithelial cells have a greater capacity. During fractionated radiation therapy or continuous low-dose rate exposure, repair of sublethal damage between fractions allows greater recovery in the cells of lung tissue compared to those in the bone marrow. Clinically, the potential benefit of six fractions over one fraction or low dose-rate TBI has yet to be proved, although there is suggestive evidence for a reduced incidence of interstitial pneumonitis. However, other extraneous factors such as doses to the lung, differences in conditioning regimens, effect of increased delay in BMT for patients receiving fractionated TBI, and the immeasurable differences between institutions make definite conclusions impossible. Despite this, a consensus for dose fractionation has developed and most centers are moving away from the use of large single dose TBI.     

Interstitial pneumonitis following total body irradiation for bone marrow transplantation using two different dose rates

A total of 22 patients with leukemia (10 ALL, 11 AML, 1 CML) have undergone allogeneic bone marrow transplantation (BMT) by the Quebec Co-operative Group for Marrow Transplantation from 1980 to 1982. All patients received 900 cGy total body irradiation (TBI), in a single fraction, on the day preceding BMT. The first 11 patients were treated on a cobalt unit at a constant dose rate of 4.7 to 6.3 cGy/min. Six of these patients developed interstitial pneumonitis (IP). The clinical course of three patients, two with idiopathic and one with drug-induced pneumonitis, was mild and recovery was complete in all. The other three patients developed severe infectious IP and two died. The next 11 patients were treated with a sweeping beam technique on a 4 MV linear accelerator delivering a total tumor dose of 900 cGy at an average dose rate of 6.0 to 6.5 cGy/min but an instantaneous dose rate of 21.0 to 23.5 cGy/min. Eight patients developed severe IP. Five of these were idiopathic and four died. Three were infectious and all died. The fatality of interstitial pneumonitis appeared to be greater in the group treated with the sweeping beam technique.     

螺旋断层治疗用于全骨髓照射的初步结果

目的：评估全骨髓照射作为异基因外周血干细胞移植（ Allo－PBSCT）前预处理方式的疗效及安全性。方法2014—2015年6例患者Allo－PBSCT前均采用HT联合环磷酰胺（60 mg／kg1次／d共2 d）的预处理方式。采用HT技术实施。结果6例患者中位年龄18．5岁。处方剂量（12 Gy分3次3 d完成）精确覆盖全部骨骼区域,OAR受量较全身照射降低13％～60％。头颈、胸腹、盆腔部位剂量验证通过率分别为（95．8±1．2）％、（96．2±1．1）％、（98．9±0．8）％。上、下部分的HI和平均治疗时间分别为1．18、1．17和39．2、14．3 min。放疗期间5例患者出现1—2级恶心、呕吐,2例患者出现1—2级疼痛,1例患者出现1级腹泻,1例患者出现2级肠炎。所有患者均未出现3—4级非血液学不良反应,并且成功植入骨髓。结论 HT技术应用于全骨髓照射是可行的,靶区适形度高,剂量均匀性好,安全性高且不良反应较传统TBI明显减低,可作为新的骨髓移植前预处理方式。     

Lung damage following bone marrow transplantation: I. The contribution of irradiation

High dose whole body irradiation is commonly included in conditioning regimens for bone marrow transplantation for treatment of patients with hematological malignancies. Interstitial pneumonitis is a major complication after BMT. About one-fourth of all BMT patients die from IP. In about half of these cases, an infectious agent, particularly cytomegalovirus, is involved. When no infectious cause is found, it is classified as idiopathic IP (IIP). Total body irradiation is often associated with the induction of IIP; however, extrapolation of animal data from the experiments presented indicates that this is not the only factor contributing to IIP in man. Brown Norway (BN/Bi) rats were bilaterally irradiated to the lungs with 300 kV X rays at a high dose rate (HDR; 0.8 Gy/min) and at a low dose rate (LDR; 0.05 Gy/min). The dose-response curves found were very steep. In the LDR group, lung function studies were performed. There was a strong correlation between the increase in ventilation rate and the death pattern. The LD50 at 180 days was 13.3 Gy for HDR and 22.7 Gy for LDR. The ratios of LD50/180 at 0.05 Gy/min to that at 0.8 Gy/min is 1.7, which indicates a great repair capacity of the lungs. Extrapolation of animal data to patient data leads to an estimated dose of about 15-16 Gy at a 50% radiation pneumonitis induction for low dose rate TBI. As the absorbed dose in the lungs of BMT patients rarely exceeds 10 Gy, additional factors such as remission-induction chemotherapy, cyclophosphamide, methotrexate, cyclosporin A, graft-versus-host disease, etc., might be involved in the high incidence of IIP in man after BMT.     

Eradication of leukaemic marrow and prevention of leukaemia relapse with total body irradiation and bone marrow transplantation

A series of studies was carried out to determine the effect of allogeneic bone marrow transplantation (BMT) on leukaemia. The study aimed at two different, but strictly linked issues: (1) identification of the eradication capability of BMT, and (2) evaluation of the effect of BMT, both in preventing relapse and in producing long-term disease-free survival. Fifty-four patients allografted for leukaemia were evaluated at various intervals, after bone marrow transplantation, for the presence of host haemopoiesis using red-blood-cell and cytogenetic markers. Among 40 patients in remission, 10 showed functional host and donor haemopoiesis (mixed chimerism), while in 30, host haemopoiesis was never detected (complete chimerism). Seven of the 14 evaluable patients who relapsed showed the reappearance of host haemopoiesis at the time of relapse. The records of received doses of TBI indicate that patients who achieved mixed chimerism, either relapsing or not, received significantly lower doses than complete chimeras. However, some patients with complete chimerism received a TBI dose equivalent to the dose received by those with mixed chimerism, suggesting that the TBI dose is not the only factor determining the reappearance of host haemopoiesis. The data on chimerism and relapse suggest that there is heterogeneity in radiosensitivity between normal marrow cells and leukaemic cells, and further, within the different types of leukaemia. The incidence/severity of acute and chronic graft-vs-host disease (GvHD) was significantly higher in complete chimeras than in mixed chimeras suggesting that mixed chimerism may play a role in the development of tolerance; however, it could be the tolerance (i.e. absence of GvHD) which is responsible for the persistence of host haemopoietic cells. One-hundred-and-sixty-eight patients undergoing allogeneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) and chronic myeloid leukaemia were analyzed for risk factor associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120mg/kg and total body irradiation (TBI) of 330 cGy on days -3, -2, -1. There was a difference of ±18% between the nominal total dose of 990 cGy and the actual received dose as indicated by dosimetric recordings. While interstitial pneumonitis had minimal impact on survival there was a considerable difference in the incidence of relapses. The incidence of relapse was higher in patients receiving less, than in patients receiving more than 1000 cGy respectively and this had a major impact on survival. However, transplant-related mortality was slightly higher in the group of patients receiving higher doses of TBI. These results suggest that a higher dose of TBI, within this schedule, produced long-term disease-free survival in the majority of acute myeloid leukaemia and chronic myeloid leukaemia with minor radiobiological side-effects which, however, tended to be higher as the TBI dose increased. Moreover, a small reduction of the dose may significantly increase the risk of relapse. In addition, the disease status significantly influences the probability of relapse and this is mainly seen in chronic myeloid leukaemia. Moreover, the prevention of graft-vs-host disease plays a relevant role both in relapse as well as in the transplant-related mortality. It is therefore concluded that fine tuning of the conditioning protocol, and of the therapy for graft-vs-host prevention, is needed to improve the results in allogeneic bone marrow transplant.     

Interstitial pneumonitis following bone marrow transplantation after low dose rate total body irradiation

Idiopathic and infective interstitial pneumonitis (IPn) is a common complication after bone marrow transplantation (BMT) in many centers and carries a high mortality. We report here a series of 107 patients with acute leukemia grafted at the Royal Marsden Hospital in which only 11 (10.3%) developed IPn and only 5 died (5%). Only one case of idiopathic IPn was seen. Factors which may account for this low incidence are discussed. Sixty of 107 patients were transplanted in first remission of acute myeloid leukemia (AML) and were therefore in good general condition. Lung radiation doses were carefully monitored and doses of 10.5 Gy were not exceeded except in a group of 16 patients in whom a study of escalating doses of TBI (up to 13 Gy) was undertaken. The dose rate used for total body irradiation (TBI) was lower than that used in other centers and as demonstrated elsewhere by ourselves and others, reduction of dose rate to less than 0.05 Gy/min may be expected to lead to substantial reduction in lung damage. Threshold doses of approximately 8 Gy for IPn have been reported, but within the dose range of 8 to 10.5 Gy we suggest that dose rate may significantly affect the incidence. Data so far available suggest a true improvement in therapeutic ratio for low dose rate single fraction TBI compared with high dose rate.     

Magna-field irradiation: Physical consideration

Magna-field radiotherapy in the form of total body, half body and total nodal irradiation is becoming increasingly prominent and involves dosimetric problems that are much more pronounced than they are for conventional field sizes. In this review of the physical considerations of magna-field irradiation, a number of possible alternate methods of producing large radiation fields are outlined, the basic beam dosimetry is reviewed and the factors producing dose variation in the patient are considered. Since the lung contains large regions of low density tissues and has a lower tolerance to radiation than most other tissues, special consideration is given to methods of dose determination and dose reduction to this organ. The question of accuracy in dose delivery is briefly discussed and the concept of delivering a radiation dose ‘as precisely as readily achievable (APARA), technological and biological factors being taken into account' is introduced.     

Idiopathic interstitial pneumonia following bone marrow transplantation: The relationship with total body irradiation

Interstitial pneumonia is a frequent and often fatal complication of allogenic bone marrow transplantation. Thirty to 40 percent of such cases are of unknown etiology and have been labelled as cases of idiopathic interstitial pneumonia. Idiopathic cases are more commonly associated with the use of total body irradiation; their occurrence appears to be independent of immunosupression or graft versus host disease. Evidence is presented from the literature suggesting that the development of idiopathic interstitial pneumonia is related to the absolute absorbed dose of radiation to lung. The similarity of idiopathic pneumonia to radiation paeumonitis seen in a different clinical setting is described.     

Effect of dose-rate on total body irradiation: lethality and pathologic findings

The effect of low dose-rate total body irradation (TBI) on hemopoietic and nonhemopoietic lethality has been studied in BALB/c mice using dose-rates ranging from 25 to 1 cGy/min. Deaths were scored at 10 days, 30 days, and one year after irradiation, and dose-response curves were constructed to determine the dose-rate dependence of deaths from the gastrointestinal syndrome, hemopoietic syndrome, and late lethal syndrome(s), respectively. A plot of the LD50S for each of these lethal syndromes versus dose-rate showed the dose-rate dependence for late lethality to be somewhat greater than that for gut death, but both of these endpoints were markedly more dose-rate dependent than was hemopoietic lethality, particularly at dose rates less than 5 cGy/min. To determine which late responding normal tissues might be critical for low dose-rate TBI, complete necropsies were performed on all mice dying later than 60 days after irradiation and on all mice surviving at one year; all tissues were examined histologically. Morphologic evidence of radiation injury was present in only three tissues, lung (fibrosis and scarring) kidney (tubule depletion), and liver (presence of mitoses). Subjectively, the lung changes were most severe up to 9 months while kidney changes became more prominent after this time, suggesting that late death after low dose-rate TBI may not be entirely attributable to lung injury. However, regardless of which late responding normal tissue is dose-limiting, it is clear that low dose-rate TBI preferentially spares these tissues compared with hemopoietic stem cells.     

Hyperfractionated total body irradiation for bone marrow transplantation: I. early results in leukemia patients

Bone marrow transplantation following cytoreduction with total body irradiation and cyclopbospbamide has previously been shown to be of value in treating refractory leukemias. Major problems, however, have been fatal interstitial pneumonitis and leukmmac relapse. In an attempt to minimize these problems, we initiated a new hyperfractionsted regimen for total body irradiation, with partial long sparing. From May, 1979 throughJuly, 1980, we treated 48 leukemia patients according to this regimen, varying in age from 1.5 to 42 years old (mead age: 18 y). Analysis in September, 1980, with follow-up from 2–16 mos, showed that we have a significantly reduced incidence of interstitial pneumonitis compared with single dose (1000 rad) irradiation (33 vs 70%), as well as decreased deaths attributable to interstitial pneumonitis (23 vs 50%). This is reflected in the survival curves, with loss of the early drop in survival previously observed with single dose irradiation. One year actuarial survival was 65% for acute lympbocytic leukemia (n - 16) and 72% for acute non-lymphocytic leukemia (n - 29). This compares with only 17% for acute non-lympbocytic leukemia patients (n = 12) on our previous single dose regimen. Age was: also found to be an important parameter for both survival and interstitial pneumonitis.     

Total body irradiation in bone marrow transplantation: the influence of fractionation and delay of marrow infusion

Bone marrow transplantation (BMT) after total body irradiation (TBI) and cyclophosphamide is being employed increasingly in the therapy of end stage leukemia. Interstitial pneumonitis (IP) represents a major acute toxicity after allogeneic transplantation. A more rapid reconstitution of lymphoid organs and bone marrow post transplant may result in increased immune competence and hence fewer opportunistic pulmonary infections and IP. By delaying the infusion of marrow to 72 hr after TBI (1250 rod at 7.5 rad/min) instead of the customary 24 hr, we can demonstrate an increase in initial repopulation of thymus, spleen and marrow, with syngeneic transplants in Lewis rats.Interstitial pneumonitis may also be caused, in part, by the pulmonary toxicity of large single exposures of TBI. Clinical and laboratory data suggest that fractionated TBI may be less toxic to the lung. When fractionated TBI (625 rad × 2, 7.5 rad/min) is compared to single dose TBI (1250 rad, 7.5 rad/min), an increased initial repopulation of lymphoid organs is observed when fractionated therapy is employed. Delay in marrow infusion and fractionation of TBI exposure may have clinical advantages in patients who receive BMT.     

Fractionated Total Body Irradiation in Bone Marrow Transplantation – An Emphasis on Lung Dosimetry

The use of fractionated total body irradiation is now replacing the large single dose technique originally used in many centres. Twenty-three patients have received this form of therapy prior to marrow transplantation at St. Vincent's Hospital. Doses of 12 to 14 Gray are delivered over 3 to 3 days treating twice daily. Particular emphasis is placed on the amount of radiation received by the lungs and the prescribed dose is related directly to this. The rationale of this technique is discussed, together with the methods of dose calculation, set-up, and incidence of side-effects. Fractionation results in a regime that is very well tolerated with a lower morbidity than that seen with single dose irradiation.     

The effect of fractionated versus unfractionated total body irradiation on the growth of the bn acute myelocytic leukemia

The efficacy of various total body irradiation (TBI) regimens prior to bone marrow transplantation was evaluated in a rat model for acute myelocytic leukemia (D₀ = 85.1 cGy gamma; N = 3.7). Using high dose rate gamma irradiation (115 cGy/min), fractionated TBI with large total daily doses (400 - 600 cGy), either given as acute doses or as split doses at 8 hr intervals, was most effective. Split doses (2 fractions per day) offered no additional advantage. At the most, a 4 log leukemic cell kill was induced. No lethal toxicity was observed. Nine Hundred cGy “flash” TBI had a similar anti-tumor effect, but with this regimen almost half of the rats died from radiation-induced toxicity (lungs and gastro-intestinal tract). The results are explained in terms of differences between normal and leukemic cells as regards (a) repair of sublethal damage; and (b) repopulation. Low dose rate continuous gamma-irradiation (0.26 cGy/min) with total doses ranging from 900 to 2000 cGy was also quite effective. Maximally a 4 log cell kill was obtained. With 2000 cGy, 50 % of the rats died from the gastro-intestinal tract-syndrome.In addition to the major role played by chemotherapy, TBI is mainly of importance in sterilizing the various sanctuaries in the body which contain leukemic cells “anatomically resistant” to most cytostatic agents.     

Cell survival kinetics in peripheral blood and bone marrow during total body irradiation for marrow transplantation

Cell survival kinetics in both peripheral blood and in bone marrow have been studied over the time course of hyperfractionated total body irradiation (TBI) for bone marrow transplantation. Our unique TBI regimen allows the study of the in vivo radiation effect uncomplicated by prior cyclophosphamide, since this agent is given after TBI in our cytoreduction scheme. Peripheral blood cell concentrations were monitored with conventional laboratory cell counts and differentials. Absolute bone marrow cell concentrations were monitored by measuring cell concentrations in an aspirate sample and correcting for dilution with blood by a cell cycle kinetic method using cytofluorometry. In the entire group of patients, time to engraftment with donor marrow was found to be 16.6 × 4.4 days and more rapid when a nucleated donor cell dose of ≥4.0 × 10⁸ cells/kg was given. For lymphocytes in peripheral blood in patients in remission, the effective D₀ ranged from 373 rad in 10 children ≤10 y old, to 536 rad in the four patients between 11–17 y old, while n = 1.0 in all groups. There was no trend observed according to age. Granulocytes had a much higher effective D₀, approximately 1000 rad in vivo. Absolute nucleated cell concentration in marrow dropped slowly initially, due to an increased lymphocyte concentration in marrow during a concurrent drop in lymphocyte concentration in peripheral blood, but eventually fell on the last day of TBI ranging from 7–44 % of the initial marrow nucleated cell concentration. Marrow myeloid elements, however, dropped continuously throughout the course of TBI.     

Toxicity and dosimetry of fractionated total body irradiation prior to allogeneic bone marrow transplantation using a straightforward radiotherapy technique

Since 1989, we have used a relatively straightforward technique for giving total body irradiation (TBI), using anterior and posterior parallel opposed fields with the arms and fists acting as compensators. The dosimetry, toxicity and outcome of 48 patients (26 adults, 22 children) treated with TBI using this technique have been audited. A dose of 14.4 Gy in eight fractions over 4 days was prescribed to all patients with an unrelated donor and 12 Gy in six fractions over 3 days to those with a sibling donor. From May 1994, all children received 14.4 Gy because of a recommendation from the United Kingdom Children's Cancer Study Group. The range of lung dosimetry was −6% to +7% when the dose was specified to the lung maximum. The trunk doses were all within ±10% of the prescribed dose. Doses to other regions of the body were less homogeneous but clinically acceptable in that the minimum doses were never less than −10% of the prescribed dose. Mucositis was the most common side effect; its treatment with opioids was more frequent after 14.4 Gy than after 12 Gy (P = 0.0004) and in adults than in children (P = 0.01). No cataracts have yet been seen in these patients. The radiation was not found to be a proven cause of clinical pneumonitis, although there was one death due to interstitial pneumonitis, which was likely to have been caused by cytomegalovirus infection in which radiation pneumonitis could not be excluded. There were no other suspected TBI-related deaths.In conclusion, this straightforward technique achieved acceptable dosimetry and was well tolerated.     

Osteochondroma after Total Body Irradiation in Bone Marrow Transplant Recipients: Report of Two Cases

We present two cases of osteochondroma after total body irradiationin bone marrow recipients, the first in a 6-year-old boy withjuvenile chronic myelogenous leukemia and the second in a 13-year-oldboy with acute myelogenous leukemia. The patients developedmultiple osteochondromas three years and seven years, respectively,after 12 Gy of total body irradiation. Neither had a familyhistory of hereditary multiple osteochondromatosis. A reviewof the English literature revealed only one report describingfive cases of osteochondroma after 12 Gy of total body irradiationin bone marrow transplant recipients. Osteochondroma shouldbe considered as an additional adverse effect of total bodyirradiation.     

Total body irradiation with a 10 MV linear accelerator in conjunction with bone marrow transplantation

Total body irradiation (1000 rad, single dose) in conjunction with chemotherapy and bone marrow transplantation is a therapy for acute leukemia. We show that a 10 MV linear accelerator is a suitable source of radiation for these procedures. Dosimetric and clinical results are presented for 25 patients who were treated between $\text{l5}\text{76}$ and $\text{12}\text{78}$.     

Modified total body irradiation as a planned second high-dose therapy with stem cell infusion for patients with bone-based malignancies

PURPOSE: To estimate the maximum tolerated dose of hyperfractionated total marrow irradiation (TMI) as a second consolidation after high-dose chemotherapy with autologous or syngeneic blood stem cell transfusion for patients with bone/bone marrow-based malignant disease. PATIENTS AND METHODS: Fifty-seven patients aged 3-65 years (median, 45 years), including 21 with multiple myeloma, 24 with breast cancer, 10 with sarcoma, and 2 with lymphoma, were treated with 1.5 Gy administered twice daily to a total dose of 12 Gy (n = 27), 13.5 Gy (n = 12), and 15 Gy (n = 18). Median time between the 2 transplants was 105 days (range, 63-162 days). RESULTS: All patients engrafted neutrophils (median, Day 11; range, Day 9-23) and became platelet independent (median, Day 9; range, Day 7-36). There were 5 cases of Grade 3-4 regimen-related pulmonary toxicity, 1 at 12 Gy, and 4 at 15 Gy. Complete responses, partial responses, and stabilizations were achieved in 33%, 26%, and 41% of patients, respectively. Kaplan-Meier estimates of 5-year progression-free survival and overall survival for 56 evaluable patients are 24% and 36%, respectively. Median time of follow-up among survivors was 96 months (range, 77-136 months). CONCLUSION: Total marrow irradiation as a second myeloablative therapy is feasible. The estimated maximum tolerated dose for TMI in a tandem transplant setting was 13.5 Gy. Because 20% of patients are surviving at 8 years free of disease, further studies of TMI are warranted.