Radiotherapy and High-Dose Chemotherapy in Advanced Ewing's Tumors

Background: Ewing's tumors are sensitive to radio- and chemotherapy. Patients with multifocal disease suffer a poor prognosis. Patients presenting primary bone marrow involvement or bone metastases at diagnosis herald a 3-year disease-free survival below 15%. The European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) has established the following indications for high-dose therapy in advanced Ewing's tumors: Patients with primary multifocal bone disease, patients with early (<2 years after diagnosis) or multifocal relapse. Patients and Method: As of 1987, 83 patients have been treated in the EICESS group, 39 of them at the transplant center in Düsseldorf, who have been analyzed here. All individuals received 4 courses of induction chemotherapy with EVAJA and stem cello collection after course 3 and 4. Consolidation radiotherapy of the involved bone compartments was administered in a hyperfractionated regimen 2 times 1.6 Gy per day, up to 22.4 Gy simultaneously to course 5 and 22.4 Gy to course 6 of chemotherapy. The myeloablative chemotherapy consisted of melphalan and etaposide (ME) in combination with 12 Gy TBI (Hyper-ME) or Double-ME with whole lung irradiation up to 18 Gy (without TBI). Results: The survival probability at 40 months was 31% (44% DOD; 15% DOC). Pelvic infiltration did not reach prognostic relevance in this cohort. Radiotherapy encompassed 75% of the bone marrow at maximum (average 20%). Engraftment was not affected by radiotherapy. Conclusion: High-dose chemotherapy can improve outcome in poor prognostic advanced Ewing's tumors. The disease itself remains the main problem. The expected engraftment problems after intensive radiotherapy in large volumes of bone marrow can be overcome by stem cell reinfusion. Hintergrund: Ewing-Tumoren sind radio- und chemosensibel. Im metastasierten Stadium ist die Prognose schlecht. Patienten mit Knochen- oder Knochenmarkinfiltration haben nach drei Jahren eine erkrankungsfreie Überlebenswahrscheinlichkeit von weniger als 15%. Die EICESS-Gruppe hat folgende Indikationen für die Hochdosistherapie bei fortgeschrittenen Ewing-Tumoren etabliert: Patienten mit primären multifokalen Knochenmetastasen und Patienten mit einem frühen (<2 Jahren) oder multifokalen Rezidiv. Patienten und Methode: Seit 1987 wurden 83 Patienten in der EICESS-Gruppe behandelt, 39 von ihnen in Düsseldorf, deren Analyse hier vorgestellt werden soll. Alle Patienten erhielten vier Kurse einer Induktionschemotherapie mit EVAJA und nachfolgender Stammzellasservation. Anschließend erfolgte eine konsolidierende Bestrahlung aller befallenen Knochenkompartimente, hyperfraktioniert, 2mal 1,6 Gy pro Tag bis zu einer Zielvolumendosis von 22,4 Gy simultan zu Kurs 5 und 6 der Chemotherapie, entsprechend 44,8 Gy Gesamtdosis. Die myeloablative Therapie bestand aus Melphalan und Etoposid (ME) und 12 Gy TBI (Hyper-ME) oder bei zusätzlichem Lungenbefall aus zwei Kursen ME und Ganzlungenbestrahlung bis 18 Gy (Double-ME). Ergebnisse: Die Überlebenswahrscheinlichkeit nach 40 Monaten betrug 31% (44% starben am Tumor und 15% an Komplikationen). Beckentumoren hatten in dieser Gruppe keine prognostische Relevanz. Im Durchschnitt wurden 20% des Knochenmarkvolumens (maximal 75%) bestrahlt. Das Engraftment wurde durch die Bestrahlung nicht beeinflußt. Schlußfolgerung: Die Prognose bei multifokalen, fortgeschrittenen Ewing-Tumoren kann durch die Hochdosistherapie verbessert werden. Das Hauptproblem bleibt die Krankheit selbst. Die nach intensiver Strahlentherapie großer Knochenmarkvolumia erwarteten Engraftment-Probleme können durch Stammzellreinfusion überwunden werden.     

Re-186 HEDP conditioning therapy in patients with advanced acute lymphoblastic leukemia before allogeneic bone marrow transplantation

The authors present their experience with dose calculation of Retin1,1-hydroxyethylidene-186-diphosphonate (Re-186 HEDP) therapy used as part of an intensified conditioning regimen before allogeneic stem cell transplantation in 2 patients with advanced acute lymphoblastic leukemia during the second partial or third complete remission. Kidneys were shielded during total-body irradiation (TBI) to limit the TBI-mediated renal radiation dose to 7 Gy. The aim of this dose calculation of Re-186 HEDP therapy was to deliver additional radiotherapy to the red bone marrow without exposing more than an additional 5 Gy to the kidneys in addition to the TBI standard dose of 12.6 Gy. Pretherapeutic kidney scintigraphy (Tc-99m mercaptoacetyltriglycine) showed normal results. Thus, dynamic Tc-99m methylene diphosphonate bone scintigraphy was used to calculate the expected bone marrow and kidney doses. A total amount of 8.8 GBq (238 mCi) Re-186 HEDP was given to patient no. 1 and 14.3 GBq (387 mCi) Re-186 HEDP was given to patient no. 2. Re-186 HEDP activity was monitored based on its gamma radiation measurement daily for 5 days in patient no. 1 and 7 days in patient no. 2. Therapeutic Re-186 isotope distribution and biologic half-life correlated well with the prediction by a pretherapeutic Tc-99m methylene diphosphonate scan. The calculated effective Re-186 bone marrow dose was 3.3 Gy for patient no. 1 and 5.6 Gy for patient no. 2. Effective kidney doses were 1.6 Gy and 2.1 Gy respectively. No unexpected complications occurred after completing conditioning and allogeneic stem cell transplantation. Posttransplant kidney function remained normal. Patient no. 1 remains in a second complete remission of his advanced acute lymphoblastic leukemia 18 months after HEDP therapy. Patient no. 2 relapsed 5 months after transplantation and eventually died as a result of progressive disease. The authors conclude that Re-186 HEDP will be able to increase the total additional bone marrow dose. In patients in whom the kidney dose is limited to 5 Gy in addition to TBI, doses near 10 Gy can be achieved on the bone marrow.     

Vulnerability of folate in plasma and bone marrow to total body irradiation in mice

PURPOSE: To examine how folate status in a body is influenced by oxidative stress. MATERIAL AND METHODS: Mice were given total body irradiation (TBI) by X-ray, and changes in the concentration of folate were compared to those in vitamins C and E. RESULTS: In a time-dependent study, folate in plasma and bone marrow decreased from 5 h until 120 h post-TBI at 3 Gy. Folate in plasma and bone marrow decreased in a dose-dependent manner at 24 h. Marked decreases of vitamins C and E were also detected in bone marrow, but not in plasma even at 10 Gy of TBI. The susceptibility of plasma folate by irradiation was confirmed by an in vitro exposure study. Neither vitamins C and E nor folate were decreased in the liver by TBI. CONCLUSION: It is suggested that folate is vulnerable to oxidative stress, and folate may need to be evaluated, particularly for TBI or radiotherapy.     

脑干肿瘤的放射治疗及预后分析

 目的 回顾性分析20例脑干肿瘤放射治疗效果,探讨影响放疗效果的因素。方法 20例患者均接受单纯8mV-X线放疗,放射剂量40～60 Gy／(4～7)周。Kaplan-Meier法计算生存率并绘制生存曲线。结果 1 a生存14例,3 a生存5例,5 a生存2例,中位生存期为22.4个月。就诊前症状持续时间长及首发无颅神经损害者预后好。结论 就诊前症状持续时间及首发有无颅神经损害可能是影响脑干肿瘤预后的重要因素。建议肿瘤靶区放射剂量至少为50 Gy。     

Primary spinal epidural extraosseous Ewing's sarcoma: report of five cases and literature review

Ewing's sarcoma is the most common malignant bone tumour occurring in children and adolescents and exists in two different clinicopathological entities: osseous Ewing's sarcoma (OES) and extraosseous Ewing's sarcoma (EES). Five cases of primary epidural EES are described, which presented with non-specific symptoms leading to a long diagnostic delay. The median age at diagnosis was 22 years (range 13-36 years). The median diagnostic delay was 3 months. All patients had one or more neurological deficits. All underwent surgical exploration with a laminectomy and partial resection followed by adjuvant radiotherapy to a dose of 46-50 Gy and chemotherapy with VAC (vincristine, adriamycin and cyclophosphamide) alternating with ICE (ifosphamide, cisplatin and etoposide) for at least six cycles. The mean follow-up period is 21.2 months (range 11-32 months). Four of the five patients achieved a complete remission and are disease free at the time of writing this report. Two patients have a residual neurological deficit--both having presented with long history of neurological deficit. Primary spinal epidural EES should be suspected whenever young patients present with back pain and/or radicular pain, have abnormal neurology and an extradural mass is demonstrated on MRI. Surgical excision followed by adjuvant radiotherapy (50 Gy) and combination chemotherapy (VAC alternating with ICE) achieved local and systemic control in these patients. A greater number of patients and longer follow up are required to evolve a generally accepted treatment policy for this aggressive but potentially curable malignancy.     

Multimodality Diagnostics and Megatherapy in Poor Prognosis Ewing's Tumor Patients

BACKGROUND: The prognosis of Ewing's tumor patients has been improved gradually through cooperative therapy studies, so that meanwhile 55 to 65% of the patients survive relapse-free in the long term. Patients with multifocal primary, early or multiply-relapsed Ewing's tumors have a dismal prognosis. Megatherapy with subsequent stem cell transplantation seems to improve outcome in this patient cohort. Feasibility of this intense megatherapy regimen is crucially dependent on collaboration and multidisciplinary coordination of radiologists, radiotherapists, surgeons and oncologists. PATIENTS AND METHODS: Since 1988, 25 patients were treated with megatherapy consisting of melphalan, etoposide and total-body irradiation followed by stem cell transplantation. All patients received 6 courses of an induction therapy. Before the fourth therapy block, tumors that were bulky at initial diagnosis (> 200 ml) were excised, as well as lung metastases which could still be detected after the third chemotherapy block. During the fifth and sixth chemotherapy block, patients received local irradiation on all infiltrated sites. Persisting immunosuppression after high-dose treatment may facilitate the incidence of relapse. To improve proliferation and cytotoxic activity of early regenerating NK-cells, adoptive immunotherapy with systemic IL-2 therapy after megatherapy is part of the treatment protocol. RESULTS: Of 25 patients treated with megatherapy, 10 patients are still alive with a follow-up time of 6 months to 9 years after megatherapy. The time up to engraftment was decreased from 15 +/- 6 days down to 9 +/- 2 days through the use of G-CSF and CD34+ selected stem cells. At the same time, erythrocyte and platelet replacement was shortened. Frequently occurring complications were mucositis and infections. One patient died after developing septicemia and multi-organ failure, another patient developed a myelodysplastic syndrome 4.5 years after megatherapy. However, relapse is still the major cause of death. The influence of IL-2 on event-free survival cannot valued because 21 of 25 patients were treated with adoptive immunotherapy. CONCLUSION: The complex diagnostic and therapeutic strategy renders and EFS of 34% for a patient group with otherwise dismal prognosis. To clarify the efficiency of megatherapy in patients with advanced Ewing's tumors, a standardized treatment strategy is necessary to accumulate a sufficient number of patients for large cooperative studies in this subject.     

Prognostic Value of Hemoglobin Concentrations in Patients with Advanced Head and Neck Cancer Treated with Combined Radio-Chemotherapy and Surgery

PURPOSE: Hemoglobin levels are currently the focus of interest as prognostic factors in patients with head and neck cancer. Most published clinical trials have confirmed hemoglobin to possess a significant influence on survival in patients treated with radiotherapy. In our study we have investigated the prognostic value of hemoglobin in a combined modality schedule. PATIENTS AND METHODS: Forty-three patients with advanced head and neck tumors were treated with combined radio-chemotherapy. The therapy comprised 2 courses of induction chemotherapy with ifosfamide (1,500 mg/m2, day 1 to 5) and cisplatin (60 mg/m2, day 5) followed by hyperfractionated accelerated radiotherapy with a total dose of only 30 Gy. Surgery involved tumor resection and neck dissection. RESULTS: The 1-year overall survival rate and the 2-year survival rate were 79% and 56%, respectively. The 1- and 2-year recurrence-free survival rates were 68% and 49%, respectively. Prognostic factors with an impact on survival were seen in tumor size (T3 vs T4, p = 0.0088), response to radio-chemotherapy at the primary site (no vital tumor rest vs vital tumor rest, p = 0.045), response to lymph node radio-chemotherapy (no vital tumor cells vs vital tumor cells, p = 0.013) and level of hemoglobin after radio-chemotherapy (Hb > or = 11.5 g/dl vs < 11.5 g/dl, p = 0.0084). CONCLUSION: In our study hemoglobin level after radio-chemotherapy was identified for the first time to be also a significant prognostic factor (univariate analysis) in head and neck cancer patients who underwent combined radio-chemotherapy. Besides chemotherapy plus low-dose irradiation achieved similar results in comparison with radical resection and high-dose radiotherapy at least for the first 2 years after therapy. Relapsing disease could be treated with 1 additional course of radiotherapy which is supposed to be well tolerated.     

Prognostic factors in the treatment of inoperable orofacial tumors with simultaneous radiotherapy and intra-arterial chemotherapy

Between January 1973 and April 1982 66 evaluable patients with advanced inoperable orofacial tumours underwent intraarterial Bleomycin and Methotrexate with simultaneous radiotherapy in a prospective study. 32 patients had no previous treatment, 34 patients had initial surgery, radiotherapy and/or chemotherapy. 15 mg Bleomycin were administered through a catheter into the arteria externa carotis daily in the morning. 25 mg Methotrexate were given in the same way at night followed by 3 mg Calcium-Leucovorin i.m. every 8 hours. The cumulative dose was 300 mg Bleomycin and 500 mg Methotrexate. Four hours after the administration of Bleomycin the target volume was irradiated (single fraction 2 Gy, total dose 60 to 65 Gy). The overall response rate was 65% containing 17% complete and 48% partial remission. Destruction of the bone appeared to be the most important index at the start of the therapy. Further prognostic determinants as previous treatment, localisation of the primary tumours (maxilla and mandibula respectively oral cavity and oropharynx) and local regional lymphnode stage missed statistically significance in the survival time, may be due to a possible radiosensitizing effect of the simultaneous chemotherapy. Complete remission turned out to be the most important prognostic factor after the end of treatment. Patients responding with complete remission show a median disease free survival of 56+ months and a median survival time of 82 months. Acute reactions were reversible. Only in 14% of the patients the treatment could not be finished. Better results could be obtained by electron-affinic radiosensitizers and high LET radiation.     

Involved-Field Irradiation in Combination with Total-Body Irradiation (TBI) Does Not Increase Short-Term Toxicity Compared to TBI Alone in Patients with Advanced-Stage Low-Grade Non-Hodgkin Lymphoma

PURPOSE: High-dose therapy (HDT) is currently under investigation for patients with advanced low-grade non-Hodgkin lymphoma (NHL). We report on the toxicity of a modified HDT that combines total-body irradiation (TBI) with involved-field irradiation (IF-RT) for patients with bulky disease or residual lymphomas > 2 cm after induction chemotherapy. PATIENTS AND METHODS: 41 patients received HDT which consisted of high-dose cyclophosphamide and fractionated TBI (6 x 2 Gy) followed by autologous stem cell transplantation. Eleven patients received IF-RT prior to TBI, three patients had already received another radiotherapy treatment prior to HDT. RESULTS: After a medium follow-up of 19 months we observed an overall survival rate of 100%, and a relapse-free survival rate of 78%. Severe toxicity was observed only in one patient who developed a myelodysplastic syndrome, and another patient who showed signs of pneumonitis. About two thirds of the patients claimed minor toxicity of grade I-II according the LENT-SOMA scale, predominantly as a decrease in concentration, reduced sexual functioning, and musculo-skeletal pain. Correspondingly, laboratory tests showed grade I-II changes of blood counts, liver enzymes, hormone levels, and lung function. There was no excess toxicity in the patients who received IF-RT additional to TBI. CONCLUSIONS: HDT including TBI and prior IF-RT is feasible without excess morbidity. Careful follow-up is required to detect myelodysplastic syndrome or endocrine changes of ovarian or testicular function.     

Radiation dose as a factor in host preparation for bone marrow transplantation across different genetic barriers.

Engraftment of donor bone marrow in relation to total body irradiation (TBI) dose was studied in syngeneic (B6----B6), MHC-compatible (BALB.B----B6) and MHC-incompatible allogeneic (BALB/c----B6) murine bone marrow transplantation (BMT) models. For each BMT combination radiation dose-response curves were obtained from stable long-term bone-marrow chimerism using Gpi-1 phenotyping and this was compared with the growth of exogenous CFU-S. Syngeneic engraftment required the lowest TBI doses limited to ablation of host haemopoietic stem cells. Resistance against H-2-compatible allogeneic engraftment was evident at low radiation doses (less than 5.5 Gy) but at 6 Gy and above the level of chimerism was comparable to syngeneic transplants, which indicated effective immunosuppression. Higher TBI doses were needed for engraftment as the immunological barrier was increased using fully H-2-incompatible allogeneic transplants. The high TBI dose (9.5 Gy) needed for suppression of spleen endocolonies in the CFU-S assay meant that rejection of exogenous bone marrow was evident only across the larger immunological barriers. When the fully allogeneic combination was reversed (B6----BALB/c) both CFU-S and chimerism data showed less rejection. The steep dose-response relationships show how engraftment is critically dependent on TBI dose, as well as the genetic disparity between donor and host.     

Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation

Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates (188Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2+/-2.1 (range 6.9-15.8) GBq 188Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4+/-5.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking 188Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia.     

Ergebnisse der multidisziplinären Behandlung lokalisierter Ewing-Sarkome bei Kindern und Jugendlichen

PURPOSE: To identify results and prognostic factors on long-term survival and local control following treatment of localized Ewing's sarcoma. PATIENTS AND METHODS: Between 1979 and 2004, a total of 60 children and young adults with Ewing's sarcoma were treated. Patients with distant metastases at presentation (n = 6) and recurrent cases (n = 2) were excluded from this analysis. Patients were exclusively treated within ongoing national and international protocols CESS-81, CESS-86, EICESS-92, EURO-EWING-99. All patients received local irradiation with a total dose of 45-60 Gy; in addition, 41 (79%) of the patients had local surgical procedures, 27 (52%) of them with clear margins. RESULTS: Overall survival rates at 5 and 10 years were 56% and 45%, respectively. Patients 相似文献   

紫杉醇与替尼泊苷联合化疗治疗脑恶性胶质瘤

目的评价紫杉醇与替尼泊苷联合化疗方案对恶性脑神经胶质瘤的治疗效果和毒副作用,探讨有效的辅助化疗方案,以提高恶性脑神经胶质瘤的疗效,延长患者的生存期.方法不能手术、术后残留或复发的恶性脑神经胶质瘤患者,随机分为两组,试验组(21例):紫杉醇135 mg/m2,静脉滴注,第1天;替尼泊苷 200 mg/m2,分 3 d(d1-3),静脉滴注,3周可重复;对照组(19例):司莫司汀100 mg/m2,第1天 ,晚顿服;替尼泊苷用法同前,4～6周可重复.第1周期化疗后常规局部外放疗,肿瘤组织量 50～60 Gy.结果 40例患者有效28例,总有效率70.0%;其中大脑半球胶质瘤有效率65.5%(19/29), 脑干胶质瘤有效率88.9%(8/9),小脑胶质瘤有效率50%(1/2).经χ2检验,两种化疗方案有效率差异无显著性.主要毒性为骨髓抑制,特别是中性粒细胞减少;其中Ⅲ、Ⅳ度毒性反应5例,占12.5%;经对症处理均恢复正常.远期疗效正在观察中.结论紫杉醇与替尼泊苷联合化疗治疗恶性脑胶质瘤安全、有效,为脑瘤辅助化疗提供了新方案.     

Helical Tomotherapy as a New Treatment Technique for Whole Abdominal Irradiation

PURPOSE: To describe a new intensity-modulated radiotherapy (IMRT) technique using helical tomotherapy for whole abdominal irradiation (WAI) in patients with advanced ovarian cancer. MATERIAL AND METHODS: A patient with radically operated ovarian cancer FIGO stage IIIc was treated in a prospective clinical trial with WAI to a total dose of 30 Gy in 1.5-Gy fractions as an additional therapy after adjuvant platinum-based chemotherapy. The planning target volume (PTV) included the entire peritoneal cavity. PTV was adapted according to breathing motion as detected in a four-dimensional respiratory-triggered computed tomography (4D-CT). Inverse treatment planning was done with the Hi-Art tomotherapy planning station. Organs at risk (OARs) were kidneys, liver, bone marrow, spinal cord, thoracic and lumbosacral vertebral bodies, and pelvic bones. Daily control of positioning accuracy was performed with megavoltage computed tomography (MV-CT). RESULTS: Helical tomotherapy enabled a very homogeneous dose distribution with excellent sparing of OARs and coverage of the PTV (V90 of 93.1%, V95 of 86.9%, V105 of 1.9%, and V110 of 0.01%). Mean liver dose was 21.57 Gy and mean kidney doses were 9.75 Gy and 9.14 Gy, respectively. Treatment could be performed in 18.1 min daily and no severe side effects occurred. CONCLUSION: Helical tomotherapy is feasible and fast for WAI. Tomotherapy enabled excellent coverage of the PTV and effective sparing of liver, kidneys and bone marrow.     

Systemic Mast Cell Disease (SMCD) and Bone Pain A Case Treated with Radiotherapy

BACKGROUND: Systemic mast cell disease (SMCD) is a rare disease characterized by a multitopic proliferation of cytologically and/or functionally abnormal tissue mast cells. SMCD preferentially involves the skin, spleen, liver, lymph nodes and the bone marrow. The cause of SMCD is unknown. Bony pain, caused by mast cell infiltration of the marrow cavity, is present in up to 28% of cases and is frequently chronic and difficult to palliate with medical therapy. CASE REPORT: We report one case of refractory bone pain in a 54-year-old female Caucasian patient with advanced SMCD and associated bony involvement, which was treated with radiotherapy for pain palliation. Between 1995 and 1998, the patient was irradiated at four different locations: 1) right shoulder and proximal right humerus, 2) both hands, 3) both knees, 4) left humerus with a total dose of 40 Gy in 2.0 or 2.5 Gy daily fractions. RESULTS: Different results of pain palliation were achieved. In one location the pain was reduced for 55 months until her death due to disease progression, whereas in two other locations a pain control was maintained for 3 and 6 months after radiotherapy. In one location, no pain reduction was achieved. Severe side effects were not observed. CONCLUSION: Palliative radiotherapy has a role in the control of severe intractable bone pain in patients with advanced SMCD, though in some cases the effect may be short or incomplete. The observed palliation of pain can even differ in the same patient.     

Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation

Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates (¹⁸⁸Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2DŽ.1 (range 6.9-15.8) GBq ¹⁸⁸Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4LJ.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking ¹⁸⁸Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia.     

Combined External Beam and Intraluminal Radiotherapy for Irresectable Klatskin Tumors

BACKGROUND: In most cases of proximal cholangiocarcinoma, curative surgery is not possible. Radiotherapy can be used for palliative treatment. We report our experience with combined external beam and intraluminal radiotherapy of advanced Klatskin's tumors. PATIENTS AND METHODS: 30 patients were treated for extrahepatic proximal bile duct cancer. Our schedule consisted of external beam radiotherapy (median dose 30 Gy) and a high-dose-rate brachytherapy boost (median dose 40 Gy) delivered in four of five fractions, which could be applied completely in twelve of our patients. 15 patients in the brachytherapy and nine patients in the non-brachytherapy group received additional low-dose chemotherapy with 5-fluorouracil. RESULTS: The brachytherapy boost dose improved the effect of external beam radiotherapy by increasing survival from a median of 3.9 months in the non-brachytherapy group to 9.1 months in the brachytherapy group. The effect was obvious in patients receiving a brachytherapy dose above 30 Gy, and in those without jaundice at the beginning of radiotherapy (p < 0.05). CONCLUSIONS: The poor prognosis in patients with advanced Klatskin's tumors may be improved by combination therapy, with the role of brachytherapy and chemotherapy still to be defined. Our results suggest that patients without jaundice should be offered brachytherapy, and that a full dose of more than 30 Gy should be applied.     

Interstitial pneumonitis after allogeneic bone marrow transplantation following total body irradiation.

The records of 40 patients who received allogeneic bone marrow transplantation (BMT) at Hyogo College of Medicine under the same conditioning regimen using cyclophosphamide and total body irradiation (TBI) from January 1984 to August 1989 were analyzed. The dose rate of TBI was 10 cGy per minute, and the total dose was 10 Gy (2.5 Gy daily for 4 days). Interstitial pneumonitis (IP) occurred in 13 of 40 patients, and was fatal in five patients. The probability of developing IP during the first year was 31%. We performed univariate analysis on the following factors but did not find any significant risk factors for IP: age and sex of patient, sex mismatch, ABO mismatch, grade of acute graft-versus-host disease, post immunosuppression regimen, and number of marrow cells transfused.     

Results of whole lung irradiation and chemotherapy in comparison with partial lung irradiation in metastasizing, undifferentiated soft tissue sarcomas

The poor prognosis of patients with unresectable pulmonary metastases of soft tissue sarcoma is well known. In order to evaluate the beneficial effect of radiotherapy, we have treated 44 patients with pulmonary metastases of grade 3 soft tissue sarcoma from 1980 to 1986. In 36 patients the treatment volume was restricted to the single metastases up to a dose of 50 to 60 (9 to 10 Gy/week). The survival rate at one year was 18% and at two years 6%. Eight patients were treated with a combined regimen, consisting of cisplatin and ifosfamide with simultaneous whole lung irradiation. Irradiation was performed with 8 or 16 MV photons at a hyperfractionation of 2 x 0.8 Gy/day (8 Gy/week). After a dose of 12 Gy, the single metastases were boosted up to 50 to 60 Gy, with a second course of chemotherapy. In six of eight patients complete remissions were achieved, one patient showed a partial remission. The survival rate at 27 months was 50%. The patients with partial remission died from pulmonary progression at 23 months. One patient died after twelve months from a loco-regional recurrence in the tonsillar fossa without evidence of pulmonary disease. Side effects included alopecia and moderate bone marrow suppression approximately twelve days after each chemotherapy cycle. Pulmonary fibrosis was observed only at the high dose volume without impairment of respiratory function. From these observations the conclusion is drawn that whole lung irradiation simultaneously with cisplatin and ifosfamide chemotherapy provides good palliative results without relevant morbidity in patients with high grade unresectable pulmonary metastases of soft tissue sarcomas.     

Whole Lung Irradiation in Patients with Exclusively Pulmonary Metastases of Ewing Tumors

BACKGROUND: In the European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) 92, whole lung irradiation (WLI) was performed in patients with primary lung metastases. This retrospective analysis evaluates the pulmonary function and the outcome of patients with exclusively pulmonary metastases. PATIENTS AND METHODS: Between 1990 and 1999, 99 patients were registered into the EICESS-92-study trial with exclusively pulmonary metastases of Ewing tumors. The multimodal treatment regimen included polychemotherapy and local therapy to the primary tumor. WLI was performed with a dose between 12-21 Gy. 70 patients were treated with WLI, 13 of them received a further boost to their primary tumor in the thorax up to a cumulative dose of 54 Gy. RESULTS: Pulmonary function tests were available for 37 patients treated with WLI (+/- boost). None, mild, moderate or severe pulmonary complications were seen in 43%, 29%, 21% and 7% of patients treated with WLI without further boost (median follow-up 25.2 months). Patients with an additional radiation boost or surgery to the thorax showed slightly higher rates of complications. Overall survival (OAS) showed a trend towards better results for patients with WLI (5-year-OAS: 0.61 for WLI vs. 0.49 for no WLI, p = 0.36). CONCLUSION: These data indicate a benefit and acceptable toxicity for WLI in the presented collective of patients. As long as there is no randomized prospective analysis, the present data confirm the indication for WLI in Ewing tumor patients with primary exclusively lung metastases.