Tumor Burden and Intraosseous Metabolic Activity as Predictors of Bone Marrow Failure during Radioisotope Therapy in Metastasized Prostate Cancer Patients.

RATIONALE: Radium-223-Dichloride (Ra-223) is an alpha-emitter, used to treat bone metastases. Patients with high metastatic burden and/or with increased trabecular bone uptake could present a higher incidence of hematologic toxicity. We hypothesized that these two factors are predictors of bone marrow failure. MATERIAL AND METHODS: A computer algorithm discriminated between trabecular bone (BVol) and tumor metastases (MVol) within pretherapeutic whole-body skeletal SPECT/CT (N = 47). The program calculated the metastatic invasion percent (INV%) as the MVol/(MVol + BVol) ratio and extracted the BVol mean counts. BVol counts were correlated to % drop of hemoglobin (Hb), leukocytes (WBC), and platelets (PLT) after 3/6 Ra-223 cycles. Patient-specific and computational-derived parameters were tested as predictors of hematologic toxicity with MANOVA. RESULTS: BVol counts correlated with drop of Hb (R = 0,65, p < 0.01) and PLT (R = 0,45, p < 0.01). Appendicular BVol counts showed a better correlation (p < 0.05, p < 0.01, and p < 0.001 for Hb, WBC, and PLT, resp.). INV% directly correlated with BVol counts (R = 0.68, p < 0.001). At MANOVA, grade III/IV toxicity was predicted by INV% (p < 0.01), by long-bone invasion (p < 0.005), and by BVol counts (p < 0.05). CONCLUSIONS: In patients with significant bone tumor burden, degree of bone invasion and trabecular bone uptake are predictors of subsequent bone marrow failure.

Radiosensitivity in lymphoblastoid cell lines derived from Shwachman-Diamond syndrome patients.

Shwachman-Diamond syndrome is an autosomal-recessive disorder characterised by bone marrow failure and a cumulative risk of progression to acute myeloid leukaemia. The Shwachman-Bodian-Diamond syndrome (SBDS) gene, the only gene known to be causative of the pathology, is involved in ribosomal biogenesis, stress responses and DNA repair, and the lack of SBDS sensitises cells to many stressors and leads to mitotic spindle destabilisation. The effect of ionising radiation on SBDS-deficient cells was investigated using immortalised lymphocytes from SDS patients in comparison with positive and negative controls in order to test whether, in response to ionising radiation exposure, any impairment in the DNA repair machinery could be observed. After irradiating cells with different doses of X-rays or gamma-rays, DNA repair kinetics and the residual damages using the alkaline COMET assay and the γ-H2AX assay were assessed, respectively. In this work, preliminary data about the comparison between ionising radiation effects in different patients-derived cells and healthy control cells are presented.

Verification of dose distribution for volumetric modulated arc therapy total marrow irradiation in a humanlike phantom.

PURPOSE: Volumetric modulated arc therapy (VMAT) treatment planning studies have been reported to provide good target coverage and organs at risk (OARs) sparing in total marrow irradiation (TMI). A comprehensive dosimetric study simulating the clinical situation as close as possible is a norm in radiotherapy before a technique can be used to treat a patient. Without such a study, it would be difficult to make a reliable and safe clinical transition especially with a technique as complicated as VMAT-TMI. To this end, the dosimetric feasibility of VMAT-TMI technique in terms of treatment planning, delivery efficiency, and the most importantly three dimensional dose distribution accuracy was investigated in this study. The VMAT-TMI dose distribution inside a humanlike Rando phantom was measured and compared to the dose calculated using RapidArc especially in the field junctions and the inhomogeneous tissues including the lungs, which is the dose-limiting organ in TMI. METHODS: Three subplans with a total of nine arcs were used to treat the planning target volume (PTV), which was determined as all the bones plus the 3 mm margin. Thermoluminescent detectors (TLDs) were placed at 39 positions throughout the phantom. The measured TLD doses were compared to the calculated plan doses. Planar dose for each arc was verified using mapcheck. RESULTS: TLD readings demonstrated accurate dose delivery, with a median dose difference of 0.5% (range: -4.3% and 6.6%) from the calculated dose in the junctions and in the inhomogeneous medium including the lungs. CONCLUSIONS: The results from this study suggest that RapidArc VMAT technique is dosimetrically accurate, safe, and efficient in delivering TMI within clinically acceptable time frame.

Low-dose total body irradiation, fludarabine, and antithymocyte globulin conditioning for nonmyeloablative allogeneic transplantation.

Nonmyeloablative allogeneic peripheral blood progenitor cell transplantation with low-dose total body irradiation (TBI; 200 cGy) plus fludarabine followed by cyclosporine and mycophenolate mofetil results in modest graft rejection rates. Acute and chronic graft-versus-host diseases (GVHD) are also seen and may not differ substantially from those that occur after fully ablative transplantation. Adding antithymocyte globulin (ATG) to pretransplant conditioning produces substantial immunosuppression. Because of its persistence in the circulation, ATG can achieve in vivo T-cell depletion. Twenty-five patients who were not eligible for conventional fully ablative allogeneic stem cell transplantation by virtue of age or comorbidities underwent nonmyeloablative allogeneic transplantation with ATG 15 mg/kg/d days -4 to -1, TBI 200 cGy on a single fraction on day -5, and fludarabine 30 mg/m(2)/d on days -4 to -2. Oral mycophenolate mofetil 15 mg/kg every 12 hours and cyclosporine 6 mg/kg every 12 hours were started on day -5. Grafts were unmanipulated peripheral blood progenitor cells mobilized with filgrastim 10 microg/kg/d and collected on day 5. The median age of the recipients was 57 years (range, 30-67 years); diagnoses were non-Hodgkin lymphoma (n = 11), acute myeloid leukemia (n = 6), multiple myeloma (n = 3), acute lymphoblastic leukemia (n = 2), severe aplastic anemia (n = 1), paroxysmal nocturnal hemoglobinuria (n = 1), and myelodysplastic syndrome (n = 1). The median CD34(+) and CD3(+) contents of the grafts were 7.6 x 10(6)/kg and 1.6 x 10(8)/kg, respectively. Five patients received voluntary unrelated donor grafts. Three patients, 2 with voluntary unrelated donor grafts and 1 with a sib donor, received a 1 antigen-mismatched graft. The rest were fully matched. Twenty-two of 25 patients were evaluable for chimerism. Sixteen had >/=95% donor chimerism. Four patients displayed 80% to 90% donor chimerism, 1 displayed 78%, and 1 displayed 64%. Eleven patients relapsed with their original disease. One patient rejected the graft at 180 days. The median hospital stay was 27 days. Complications included GVHD in 6 patients (3 patients had grade I or II GVHD of skin and liver, and 3 patients had grade III or IV GVHD of liver and gut). Two of the patients with GVHD had mismatched grafts. Transplant-related toxicity was seen in 4 patients and infection in 5 patients. The median length of follow-up was 162 days (range, 17-854 days). Complete remissions were seen in 10 patients. Four patients remained in complete response (CR) at 280 to 595 days. One patient relapsed with non-Hodgkin lymphoma after a CR of 728 days. Of the 25 patients, 16 died (6 of relapsed disease, 4 of GVHD, 3 of infection, and 3 of transplant-related toxicity) and 9 are alive (6 with CR-2 of them after donor leukocyte infusion-and 3 with relapsed disease). The addition of ATG to low-dose TBI and fludarabine nonmyeloablative conditioning was well tolerated and resulted in >80% donor engraftment in this small cohort. As in other series of truly nonmyeloablative transplantation, a high rate of relapse was observed. Donor engraftment may be facilitated by the addition of ATG to low-dose TBI and fludarabine conditioning.

Timing of elective brain irradiation: a critical factor for brain metastasis-free survival in small cell lung cancer.

Risk factors for brain metastasis in small cell lung cancer were studied in 260 patients without brain metastasis at presentation who were treated on 5 protocols. The first three protocols offered elective brain irradiation (EBI) to all available patients after 2 or 3 courses of chemotherapy (early EBI), whereas the other two offered it after 5 or 6 courses of chemotherapy (late EBI). The overall incidence of brain metastasis was higher in the late EBI group than in the early EBI group (23.6% vs. 14.3%, p = 0.08), primarily due to higher incidence of brain metastasis developing before EBI in the former. There was a higher incidence of brain metastasis in patients without than in patients with bone marrow metastasis (21.4% vs. 6.8%, p = 0.04), in patients less than 60 years old than in patients 60 years or older (23.4% vs. 13.4%, p = 0.06), and in patients with than in patients without bone metastasis (30.2% vs. 16.8%, p = 0.07). Major risk factors for short brain metastasis-free survival were bone metastasis (p = 0.008), late EBI (p = 0.03), and failure to achieve complete remission after induction chemotherapy (p = 0.001) or as a best response (p = 0.0001). The early EBI group had a longer brain metastasis-free survival than the late EBI group, even among patients with bone metastasis (p = 0.02) or bone marrow metastasis (p = 0.05) and those who achieved complete remission after induction chemotherapy (p = 0.06) or as a best response (p = 0.05). These results indicate that timing of EBI is a critical factor in brain metastasis in patients with small cell lung cancer. There was no difference in overall survival between the two groups, however, even among patients who achieved complete remission as a best response.

89Sr radionuclide therapy: dosimetry and haematological toxicity in two patients with metastasising prostatic carcinoma.

We present dosimetry for spinal metastases and red bone marrow in two patients who received 89Sr therapy for disseminated prostatic carcinoma. Absorbed dose to metastases was estimated by combining 85Sr gamma camera studies with computed tomographic measurements of bone mass, and doses of 20 cGy/MBq and 24 cGy/MBq were found for vertebral metastases that uniformly involved the bodies of L3 and D12 respectively. Absorbed dose to red bone marrow was estimated from total body strontium retention studies using the ICRP model for bone dosimetry, and a ratio of metastatic to marrow dose of around 10 was found in each patient. Although they received comparable treatment activities of around 200 MBq, the patients showed markedly different haematological response, this difference being confirmed when each received a second 89Sr treatment 6 months after the first. As a result, clinically significant thrombocytopenia occurred in one patient which prevented further radiostrontium therapy being given.

Magnetic resonance imaging of bone marrow disorders.

The sensitivity of MRI to marrow infiltration together with the ability to perform multiplanar imaging allows evaluation of the bone marrow in a manner that has never been feasible before. The clinical impact of this has yet to be fully realized. However, detection of focal marrow infiltration by MRI with concurrently normal conventional imaging studies has important clinical implications for staging and therapy. Proper staging of marrow-based neoplasms such as leukemia and lymphoma is fundamental to the determination of treatment and prognosis. MRI can be used to increase diagnostic certainty when a question exists concerning primary or metastatic marrow disease when other imaging studies are inconclusive. Chemical shift imaging may further improve the sensitivity and clinical utility of magnetic resonance imaging in patients with hematologic disorders involving the bone marrow.

[Use of 131I-meta-iodobenzylguanidine in pediatric oncology]. / Aspekte der Anwendung von 131J-Metajodbenzylguanidin aus Sicht der pädiatrischen Onkologie.

The detection of specific trapping of MIBG by neuroblastoma cells is of great importance for the diagnosis and management of neuroblastoma in childhood. The specificity and sensitivity of the test has been demonstrated by Kimmig and Feine in a multi-center study. Moreover, MIBG might be used in the therapy of neuroblastoma. The first therapeutic cases allow slight optimism. There remain however still a number of questions to be answered. In vitro investigations of uptake kinetics and cytotoxicity of MIBG performed by our group provided valuable information for clinical investigations.

Treatment of meningeal relapse in childhood acute lymphoblastic leukemia. I. Results of craniospinal irradiation.

Fourteen children were treated for isolated meningeal relapse occurring seven to 44 months (median, 14 months) after prophylactic cranial irradiation (2,400 rad/12 fractions) and intrathecal methotrexate (IT MTX, 12 mg/m2 for four doses during cranial irradiation). Eight had "high-risk" acute lymphocytic leukemia with age less than 2 years, white blood cell counts greater than 20,000, or T cell markers. Treatment for central nervous system leukemia included IT MTX (12 mg/m2 twice weekly until clearance of spinal fluid cytology) followed by craniospinal irradiation (CSI, 3,000 rad/20 fractions to the cranium and 1,800 rad/12 fractions to the spine). No maintenance IT MTX was given. Systemic chemotherapy was continued or reinstituted for a minimum of one year after CSI. No instance of second meningeal relapse has occurred. Five patients remain in secondary complete remission 66+, 54+, 36+, 26+, and 24+ months after meningeal relapse. Disease-free survival was limited by marrow relapse in eight patients (2-20 months after CSI) and testicular relapse in one. No acute toxicities were noted with CSI. Myelosuppression occurred in seven patients. Infections within two months of CSI were noted in five. No neurologic sequelae are apparent. Serial neuropsychometric studies in 10 patients revealed a significant decline in mean values on Global IQ scales. Long-term survival with acceptable toxicity is possible following aggressive, prompt treatment of meningeal relapse occurring after prophylactic cranial irradiation. Hematologic relapse remains the major obstacle to long-term disease-free survival.

Hypopyon in acute lymphoblastic leukemia.

A child with acute lymphoblastic leukemia had central nervous system relapse 23 months after diagnosis while in bone marrow remission. This was followed by leukemic involvement of the eye as the only site of relapse 7 months later. Leukemic cells layered out in the anterior chamber and cytologic examination was the only way to make a definitive diagnosis of leukemic hypopyon. Topical treatment is generally ineffective and radiotherapy is the treatment of choice. The prognosis with this complication depends on whether it occurs during therapy or after therapy has been discontinued.

[Combination of chemotherapy and radiotherapy. II. Differential effect on the medullary syndrome of irradiation combined with the drug administered in fractional doses and at various times]. / Association de chimiothérapie et de radiothérapie. II. Effet différentiel sur le syndrome médullaire de l'association de l'irradiation et du fractionnement dans le temps de la drogue.

We have studied the effect of 5-Fu in fractional doses on the medullar syndrome after a single whole body cobalt irradiation in mice. The bone marrow is not sensitive to the fractionation of 5-Fu and it is the single dose of 5-Fu injected 72 hours after the irradiation which is the most effective.

Management of generalized malignant lymphomata with "systemic" radiotherapy.

The natural history of lymphocytic lymphomata is such that anatomical generalization of disease is usually present at the time of diagnosis. Tumour infiltration of extralymphatic sites such as the liver and bone marrow is identifiable with particular frequency in those cases presenting with lymph node manifestations of disease. Even in the absence of detectable extralymphatic dissemination, the lymphatic involvement is often sufficiently diffuse to mitigate against extensive lymph node irradiation "à la Hodgkin's disease" as appropriate or technically feasible form of treatment. Rather, systemic treatment must be recognized as imperative for the majority of newly diagnosed patients and we have investigated "systemic" radiotherapy as an alternative to chemotherapy during the past decade. Our experience with 57 consecutive patients with lymphocytic lymphoma has been reviewed. Total body irradiation (TBI) has been found to yield high remission rates despite a lack of serious toxicity or constitutional reactions. Rigorous diagnostic staging was not employed but despite the advanced stage of disease which was clinically obvious in most cases, survival rates have been strikingly high. Actuarially calculated 5-year survival rates for the well differentiated (diffuse and nodular combined), nodular poorly differentiated and diffuse poorly differentiated subtypes are 85%, 69% and 51% respectively. Furthermore, initial management with radio-therapy as described has not negated with effective use of subsequent chemotherapy when selectively required.