Whole-Body Irradiation

All individuals in Southern Sweden with a cancer diagnosis occurring between the ages of 0–18 years of age from 1970–01–01 -2016–12–31 were identified in the national cancer registry. The starting point of enrollment of patients into the registry was chosen due to the low survival rates of childhood cancer before 1970. Since its start in 1958, Swedish law mandates that all cancer cases be reported to the national registry which registers all cancer diagnoses (primary and subsequent) but not details on treatment. The vital status and personal details of the childhood cancer patients were retrieved from the Swedish population registry. Together this data formed the basis for the manual data collection of treatment history and details of the primary malignancy found in the medical records of each individual. In order for the treatment data to be collected and entered into BORISS, the medical records were manually gathered from the archives of the children’s clinic in Lund. Records were also found in the departments of Neurosurgery, Pediatric surgery, Medicine, Oncology and Pathology in Lund and in other hospitals in Southern Sweden.
The diagnosis of a malignancy was verified by an experienced pediatric oncologist (TW), by assessment of the pathology report. The diagnosis of malignancy is coded according to ICD-7, ICD-9, C24, ICD-O version 3 and ICD-10. The registry contains 219 different histological diagnoses, divided in 12 categories according to ICCC. Details of chemotherapy were extracted from prescription documents and later on from separate chemotherapy records. The dates and administration routes of all chemotherapy was recorded. All cytostatic agents (conventional drugs and more recently introduced drugs e.g. tyrosine kinase inhibitors, protein kinase inhibitors and antibodies) were recorded. The chemotherapy drugs (n = 91) are coded by a 3-digit number. Cumulative doses of each drug (mg/m² body surface area) were calculated. From the Radiation clinic, details of target organ(s), total irradiation dose (Gy) and fractionation was gathered. The target organ which received radiation therapy is coded by a 3-digit number and the target list covers 150 targets. When surgery was performed, details of the procedure, microscopic surgical margins, removal of organ(s) or an extremity, if any, were recorded. For stem cell treatment, details of conditioning therapy (with chemotherapy and/or total body irradiation), and dates of the procedure were recorded.
All entered data was cross-checked by two separate individuals. The registry contains personal data, diagnosis (in plain text and in code; ICD-7, ICD-9, C24, ICD-10 and ICD-0 version 3), and date of diagnosis. Phenotypic and cytogenetic data for leukemia, as well as cytogenetic aberrations with regards to solid tumors were gathered from medical records. Where available, data was recorded on other serious diseases, previous treatments, constitutional chromosomal aberrations, and other possible immunosuppressive treatments (pre-dating the cancer diagnosis), as was heredity for malignancies, and data on relapses. By annual updating of the database from the national cancer registry and the population registry, the development of secondary and subsequent primary neoplasms and vital status, are obtained.
Prospective collection of treatment data is carried out from 2016–01–01 and onwards under the governance of the Council of Skåne.

The disease stage at HSCT for hematological malignancies was defined according to the European Group for Blood and Marrow Transplantation (EBMT) risk score (31 (link)). The disease stage for nonmalignancies was defined as the hematopoietic cell transplant comorbidity index (HCT-CI) (32 (link)). The myeloablative conditioning regimen was defined as total body irradiation ≥ 8 Gy, busulfan 16 mg/kg, or melphalan 140 mg/m² (53 (link)). All patients were treated according to the standard myeloablative protocols based on chemotherapy and radiation dosing, as previously described (46 (link), 54 (link)). GVHD prophylaxis was performed with tacrolimus. Additional GVHD prophylaxis included mycophenolate mofetil for the matched unrelated donor (MUD), with the addition of posttransplant cyclophosphamide from 2013 in the case of a haploidentical donor. Serotherapy with anti-thymocyte globulin was also assessed as an independent variable. Prevention and treatment of infection and other elements of transplant-specific supportive care were performed according to institutional standard practices. Duration of follow-up was defined as the time from HSCT to last contact or death. Acute and cGVHD were diagnosed and graded using standard criteria (55 , 56 (link), 57 (link)).
The study’s primary endpoints were comparing the incidence of aGVHD and chronic GVHD-free survival between the defibrotide group and the control group. The incidence of GVHD was defined as any GVHD requiring systemic immune suppressive therapy. The secondary endpoints evaluated the influence of defibrotide prophylaxis on the incidence of early and late transplant-related complications. Early transplant-related complications were defined as events occurring within 100 d after HSCT unrelated to primary disease recurrence.

We used the dose of exposure to radiation from neutrons and gamma rays estimated by using the Atomic Bomb Survivor 1993 Dose (ABS93D). ABS93D was described in detail in a previous report (28 (link)). Briefly, radiation dose calculated by ABS93D is based on individual exposure status such as distance from the hypocenter, shielding and age at time of bombing. Hoshi et al. (28 (link)) showed that the dose evaluation of ABS93D was close to that of the Dosimetry system 1986 (DS86) by Radiation Effects Research Foundation. We used the weighted radiation dose of the colon, which is often chosen as the whole-body irradiation exemplary organ, by calculating the sum of the gamma ray dose and 10 times the neutron dose considering the biological effectiveness of neutrons.