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。     

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.     

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.     

Image-guided total marrow and total lymphatic irradiation using helical tomotherapy

PURPOSE: To develop a treatment technique to spare normal tissue and allow dose escalation in total body irradiation (TBI). We have developed intensity-modulated radiotherapy techniques for the total marrow irradiation (TMI), total lymphatic irradiation, or total bone marrow plus lymphatic irradiation using helical tomotherapy. METHODS AND MATERIALS: For TBI, we typically use 12 Gy in 10 fractions delivered at an extended source-to-surface distance (SSD). Using helical tomotherapy, it is possible to deliver equally effective doses to the bone marrow and lymphatics while sparing normal organs to a significant degree. In the TMI patients, whole body skeletal bone, including the ribs and sternum, comprise the treatment target. In the total lymphatic irradiation, the target is expanded to include the spleen and major lymph node areas. Sanctuary sites for disease (brain and testes) are included when clinically indicated. Spared organs include the lungs, esophagus, parotid glands, eyes, oral cavity, liver, kidneys, stomach, small and large intestine, bladder, and ovaries. RESULTS: With TBI, all normal organs received the TBI dose; with TMI, total lymphatic irradiation, and total bone marrow plus lymphatic irradiation, the visceral organs are spared. For the first 6 patients treated with TMI, the median dose to organs at risk averaged 51% lower than would be achieved with TBI. By putting greater weight on the avoidance of specific organs, greater sparing was possible. CONCLUSION: Sparing of normal tissues and dose escalation is possible using helical tomotherapy. Late effects such as radiation pneumonitis, veno-occlusive disease, cataracts, neurocognitive effects, and the development of second tumors should be diminished in severity and frequency according to the dose reduction realized for the organs at risk.     

基于螺旋断层治疗的儿童全骨髓全淋巴照射临床研究

目的 评价基于螺旋断层治疗的全骨髓全淋巴照射(TMLI)的预处理方案的可行性。方法 选取7例急性淋巴细胞白血病与再生障碍性贫血儿童患者作为研究对象,中位年龄为7岁。处方剂量方案12 Gy分6次,2 次/d。比较TMLI方案与基于螺旋断层治疗的全身照射技术(TBI)的靶区和危及器官受量,并对7例患者进行急性不良反应分级。结果 相比TBI方案,TMLI方案危及器官的平均剂量减少4.2%~40.6%。肾脏平均剂量减少最大。只有1-2级不良反应被观察到,其中2例恶心,5例呕吐,1例厌食,1例红斑,3例腹泻,1例口腔黏膜炎。结论 证实TMLI方案可行。与TBI方案相比,相同剂量TMLI方案的平均治疗时间并没有增加。TMLI方案的危及器官剂量减小,预测发病率减少,为清髓性预处理方案提供了一种策略。但TMLI方案的远期不良反应需要进一步临床评估。     

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.     

螺旋断层IMRT全骨髓照射流程可行性探讨

目的 探讨应用螺旋断层IMRT实施全骨髓照射(TMI)的流程可行性。方法 12例患者骨髓移植前1周均实施TMI预处理,处方剂量12 Gy分3次,1 次/d。按照TMI流程依次完成体位固定、CT定位、靶区勾画、计划设计及剂量验证等步骤,并实施治疗。统计靶区和正常组织的剂量参数,观察剂量验证结果与图像引导结果的相关性。结果 与全身照射(TBI)相比,TMI可显著降低正常组织受量,正常组织除口腔外中位数均<6.0 Gy,其中晶体D50(1.8±0.1) Gy,脑D50(5.7±0.2) Gy,双肺D50(5.2±0.2) Gy,肝D50(4.6±0.2) Gy。3 mm/3%标准下各部位γ通过率>95%,头颈段x轴摆位误差小于盆腔段,而z轴摆位误差则大于盆腔段。结论 应用螺旋断层IMRT可顺利实施TMI,剂量学优势明显,治疗流程合理可行。     

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.     

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.     

Single dose total lymphoid irradiation combined with cyclophosphamide as immunosuppression for human marrow transplantation in aplastic anemia.

Six patients with aplastic anemia underwent bone marrow transplantation following conditioning with high dose cyclophosphamide and single dose total lymphoid irradiation with 750 rad, 26 rad/min at the midplane of the patient. They all received bone marrow from human leukocyte antigens/mixed lymphocyte culture (HLA/MLC) matched siblings. Five of 6 patients were alive without complications at 12, 11, 7, 4 and 4 months respectively. The remaining patient died from sepsis which he had prior to transplantation. There were no graft rejection, graft-vs-Host Disease (GVHD) or interstitial pneumonitis among these patients. The procedure was well tolerated with minimal side effects. The results will be compared with those of groups whose bone marrow was previously transplanted with different immunosuppressive methods.     

Dosimetrie der Thoraxwandbestrahlung mit Elektronen bei Ganzkörper- und Ganzmarkbestrahlung

At total body irradiation the dose to the lung is normally reduced compared to the whole body. This is achieved by absorber materials which however reduce the dose to the thoracic wall as well. More severe this problem arises at total marrow irradiation where the dose to lung and liver should not exceed about 10 per cent of the whole body dose. In the first case an electron boost to the thoracic wall can be performed and in the second it shall be performed. The range of the electrons and hence their energy has to be adjusted according to the thickness of the thoracic wall. The technique of the electron boost in a source-surface distance of about 180 cm as well as the corresponding basic data measurements are presented in this paper.     

Autologous bone marrow transplantation in acute leukemia.

Twenty-one cases of relapsed acute leukemia were treated with high dose piperazindione and total body irradiation followed by infusion of autologous cryopreserved remission bone marrow. Evidence for engraftment was obtained in nineteen. Eleven patients achieved complete remission; of two to fourteen months duration (median 3+). Attempts to decrease leukemic contamination of the remission bone marrow by density separation did not influence the complete remission rate and duration.     

Systemic irradiation for selected stage IV and recurrent pediatric solid tumors: method, toxicity, and preliminary results

Eight patients with advanced pediatric solid tumors received either sequential upper and lower half-body irradiation (HBI) (7.5 rad/min to 500 rad total) or total body irradiation (TBI) (7.5 rad/min to 800 rad total) as part of two multimodality treatment regimens. All patients received combination chemotherapy; drugs were determined by the tumor type. The TBI regimen was selected for two patients who had progression of disease with conventional chemotherapy and for two patients with stage IV neuroblastoma. This intensive regimen consisted of bone marrow harvesting, followed by local radiation to gross disease, marrow-ablative chemotherapy, TBI, and re-infusion of the cryopreserved autologous marrow. Significant acute toxicity was followed by hematologic reconstitution in each patient within seven weeks. At this writing, two patients survive, one of whom is disease free two and one half years without maintenance chemotherapy. A less intensive, outpatient regimen was selected for four patients; three had a complete or good partial response to chemotherapy. The fourth patient had tumor-involved bone marrow not responsive to chemotherapy and was therefore ineligible for marrow cryopreservation and TBI. Each of these four patients received HBI after chemotherapy and local radiation to the primary and/or metastatic sites. Acute toxicity was limited to nausea and vomiting. Significant leukopenia and thrombocytopenia occured in three patients. All four patients were alive 10 to 26 months post HBI. This pilot study demonstrates that chemotherapy can be integrated with local fractionated radiation, and systemic radiation given as HBI or TBI with acceptable toxicity; sufficient bone marrow stem cells can be harvested after conventional chemotherapy and then cryopreserved to permit hematologic reconstitution of the patient who receives marrow ablative therapy.     

Comparative 60Co total body irradiation (220 cm SAD) and 25 MV total body irradiation (370 cm SAD) dosimetry

Adults with acute leukemia and malignant lymphoma in relapse after conventional therapy are treated with cyclophosphamide and total body irradiation (TBI) followed by autologous bone marrow transplants. For cobalt TBI, patients seated in a stand angled 45° above the floor are treated in a single fraction with sequential right and left lateral 87 cm ×87 cm fields at 220 cm source-axis distance (SAD) using a 5000 Ci cobalt unit. Typical lateral diameters, mid-plane dose rates, mid-plane doses, and maximum doses are: Hips, 34 cm, 8 rad/min, 900 rad, and 1050 rad; and shoulders, 38 cm, 7.7 rad/min, 800 rad, 1080 rad. The estimated lung dose is 1000 to 1100 rad. A compensator limits the dose to the head to 1000 rad. Estimated organ doses are: small intestine, liver and kidneys-1100 rad, and heart-1200 rad. Phantom dosimetry and dosimetry on patients treated reveals that these doses are delivered within 5 % accuracy. Patient tolerance of treatment, and some biological considerations of low dose rate therapy are reviewed. Certain dosimetry features of an alternate treatment at 370 cm SAD, using 25 MV photons are also presented.     

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.     

Lung function after bone marrow grafting

Results of a prospective lung function study are presented for 48 patients with acute myeloid leukemia (AML) treated with total body irradiation (TBI) and bone marrow transplantation (BMT) at the Royal Marsden Hospital between 1978 and 1980. Patients with active disease or who were in remission following cytoreductive chemotherapy had mildly impaired gas exchange prior to grafting. After TBI and BMT all patients studied developed progressive deterioration of lung function during the first 100 days, although these changes were subclinical. Infection and graft-versus-host disease (GvHD) were associated with further worsening of restrictive ventilatory defects and diffusing capacity (DLCO). Beyond 100 days, ventilatory ability returned to normal and gas transfer improved, although it failed to reach pre-transplant levels. There was no evidence of progressive pulmonary fibrosis during the first year after grafting.     

Magna-field irradiation and autologous marrow rescue in the treatment of pediatric solid tumors

Marrow ablative therapy has been given to pediatric patients with a variety of disseminated tumors. Eight patients with advanced neuroblastoma received autologous marrow reinfusion after intensive therapy. Three of eight are in continuous complete remission from 7 to 60 months. An additional four patients received allogeneic marrow transplantation and two remain in continuous complete response at 21 and 39 months. Intensive therapy and autologous marrow reinfusion have been applied to Ewing's sarcoma, but only preliminary results are available. Six patients with disseminated rhabdomyosarcoma and extra-osseous Ewing's sarcoma received conventional chemotherapy followed by sequential hemi-body irradiation. Four of six patients received autologous marrow rescue. Their median disease-free survival is 17 months. This preliminary experience demonstrates the feasibility of using marrow ablative therapy with autologous marrow transplantation in the treatment of pediatric solid tumors. Continuing Phase II studies are required to substantiate its efficacy.