The impact of severe late-effects after 12 Gy fractionated total body irradiation and allogeneic stem cell transplantation for childhood leukemia (1988-2010).

This study consists of a retrospective study including 71 childhood leukemia survivors (36 females) treated with allo-HSCT 12 Gy fractionated total body irradiation (fTBI) conditioning, with a median age of 25.0 y at time of follow-up and a median delay of 14.8 y since the graft. The recovery ratio was 90%. The number of severe late-effects was specified for each patient: 21 with growth deficiency (final height <162.5 cm for 12/35 men and <152.0 cm for 9/36 women - Growth deficiency was correlated to young age at the time of the allograft); 5 with sclerodermic chronic graft vs. host disease; 9 with osteonecrosis; risk of impaired fertility for 25 women and 28 men (only 2 women had a child); 8 with diabetes; 5 with pulmonary late-effects including 1 death; 5 with chronic renal insufficiency including 1 death; 2 with cardiac late-effects; 2 with arterial high blood pressure; 11 (8 women) declared 14 subsequent cancers (7 with thyroid carcinomas, 3 with multiple squamous cell carcinomas, 2 with epidermoïdis carcinomas of the tongue or the lip, 1 with bone sarcoma, and 1 with carcinoma of the breast); 6 with chelating treatments of hemochromatosis; 14 with important educational underachievement; 11 with depression at adult age; 1 with hepatitis B virus infection; 4 with other severe late-effects, including 2 with blindness. The average number of severe late-effects was 2.3 with a positive correlation according to delay from fTBI (p < 0.0002). Two-thirds had at least 2 late-effects. These results emphasize the urgent abandonment of conditioning by TBI in children.

Age at Birth of First Child and Fecundity of Women Survivors of Childhood Acute Lymphoblastic Leukemia (1987-2007): A Study of the Childhood Cancer Registry of the Rhône-Alpes Region in France (ARCERRA).

We studied the fecundity of 174 successive ALL (1987-2007) in females of the Childhood Cancer Registry of the Rhône-Alpes Region (ARCERRA) with a median age at follow-up of 25.6 years (18.0-37.4). We distinguished five treatment groups: Group Ia, chemotherapy only (n = 130); Ib, chemotherapy with cranial radiotherapy (n = 10); II, TBI conditioning allograft (n = 27); III, chemotherapy conditioning allograft (n = 4); IV, TBI conditioning autograft (n = 3). Twenty-three women had their first child at the mean age of 25.8 ±3.0 years, i.e., 2.0 ±2.9 years earlier than the general population of the Rhône-Alpes region (P = 0.003). The standardized fertility ratio (SFR), expressed as the number of actual births observed (O) to the number that would be expected in women of the same age in the general population (E) (SFR = O/E) was decreased for Group Ia (0.62; 95%CI, 0.52-0.74) and collapsed in Group II (0.17; 0.11-0.25). In univariate analysis, TBI (P = 0.013) and alkylating agents (P = 0.01) were negatively correlated with fecundity, but not with the age at diagnosis or the anthracyclines doses. In multivariate analysis including TBI and alkylating agents, we still found a negative correlation between TBI (P = 0.035), as well as alkylating agents (P = 0.028), and fecundity. More precisely, fecundity was negatively correlated with cumulative cyclophosphamide equivalent dose (P = 0.001), with a fecundity decreased for ≥1g/m(2), but without any dose effect; results not found in the Group Ia. Age at first child seems younger but the young median age of the cohort not allows concluding; fecundity is collapsed after fractionated total body irradiation and decreased after chemotherapy without any demonstrable cause. A delay of fertility is not excluded.

Academic difficulties and occupational outcomes of adult survivors of childhood leukemia who have undergone allogeneic hematopoietic stem cell transplantation and fractionated total body irradiation conditioning.

We studied academic and employment outcomes in 59 subjects who underwent allogeneic hematopoietic stem cell transplantation (a-HSCT) with fractionated total body irradiation (fTBI) for childhood leukemia, comparing them with, first, the general French population and, second, findings in 19 who underwent a-HSCT with chemotherapy conditioning. We observed an average academic delay of 0.98 years among the 59 subjects by Year 10 of secondary school (French class Troisième), which was higher than the 0.34-year delay in the normal population (P < .001) but not significantly higher than the delay of 0.68 years in our cohort of 19 subjects who underwent a-HSCT with chemotherapy. The delay was dependent on age at leukemia diagnosis, but not at fTBI. This delay increased to 1.32 years by the final year of secondary school (Year 13, Terminale) for our 59 subjects versus 0.51 years in the normal population (P = .0002), but did not differ significantly from the 1.08-year delay observed in our cohort of 19 subjects. The number of students who received their secondary school diploma (Baccalaureate) was similar to the expected rate in the general French population for girls (observed/expected = 1.02) but significantly decreased for boys (O/E = 0.48; CI: 95%[0.3-0.7]). Compared with 13.8% of the general population, 15.3% of the cancer survivors received no diploma (P = NS). Reported job distribution did not differ significantly between our cohort of childhood cancer survivors and the general population except that more female survivors were employed in intermediate-level professional positions. Academic difficulties after fTBI are common and their early identification will facilitate educational and professional achievement.

Final height and body mass index after fractionated total body irradiation and allogeneic stem cell transplantation in childhood leukemia.

Impaired linear growth has been reported in patients treated during childhood with allogeneic stem cell transplantation and fractionated total body irradiation (fTBI). The objective of this study was to determine the final height and body mass index (BMI) achieved. Forty-nine patients with leukemia were included and surveyed for more than 5 years. Median age at follow-up was 24.3 years (range, 18.9-35.8) and median follow-up time from allograft was 14.4 years (range, 4.5-21.9). Mean height standard deviation score (s.d.s.) at final examination (-1.1 ± 1.3,) was significantly lower than at fTBI (0.3 ± 1.2; P = .001). Final height s.d.s. was significantly correlated with age at diagnosis, age at fTBI, and target height (P = .001; P < .001; P < .001, respectively). Final height was significantly lower in children transplanted before age 5 (P = .006). Growth hormone treatment (n = 6) had only a modest effect on growth velocity. Mean BMI at follow-up was normal at 19.6 kg/m(2) for boys and 21.2 for girls, but with a significant decrease since allograft only for boys (-1.2 ± 1.5 s.d.s.) (P = .003). In conclusion, final height is decreased; BMI is normal but decreased from fTBI in boys.

Second malignant neoplasms following childhood cancer: a study of a recent cohort (1987-2004) from the childhood cancer registry of the Rhône-Alpes region (ARCERRA) in France.

Studies of second malignant neoplasms (SMNs) in childhood are generally conducted in old cohorts. The aim of this study was to determine the actual incidence of all SMNs in a recent cohort. The authors studied a cohort of 2907 children included in the population-based Childhood Cancer Registry of the Rhône-Alpes Region for a first cancer diagnosed between 1987 and 2004. Total follow-up was 22,722 person-years, with a median follow-up of 9.8 years (range, 00.0-22.8 years). Fifty-four SMNs were reported in 52 patients. Overall median latency was 5.9 years. Cumulative incidence rates were 2.2% at 10 years and 3.9% at 15, with an overall standardized incidence ratio (SIR) of 13.9 (95% confidence interval [CI], 10.4-18.3) and absolute excess risk of 2.2. The SMNs were 12 thyroid carcinomas (SIR 57.1); 9 bone tumors (SIR 32.0); 8 leukemias (SIR 11.9); 5 lymphomas, all related to Epstein-Barr virus following allograft, (SIR 6.7); 5 CNS tumors (SIR 10.5); 4 soft tissue sarcomas (SIR 17.4); 4 carcinomas (no breast cancer); and 7 other cancers. Twelve SMNs appeared after total body irradiation, 16 after focal radiotherapy, and 8 leukemias after chemotherapy. The risk of secondary cancer was highest after retinoblastomas (SIR 41.8), Hodgkin lymphomas (SIR 20.8), leukemias (SIR 18.4), soft tissue sarcomas, CNS tumors, and bone tumors. These recent cohort findings show, on one hand, a high incidence of SMNs but do not capture breast cancers because of the relatively short follow-up and, on the other hand, a different distribution of first and second cancers.

Trends in treatment-related deaths (TRDs) in childhood cancer and leukemia over time: a follow-up of patients included in the childhood cancer registry of the Rhône-Alpes region in France (ARCERRA).

BACKGROUND: We assessed the number and causes of treatment-related deaths (TRDs) in childhood cancer over time and correlated them with adherence to therapeutic guidelines. PROCEDURE: We compared two cohorts of children of the Childhood Cancer Registry of the Rhône-Alpes Region: Cohort I (1987-1992, 909 patients) and Cohort II (1996-1999, 648 patients). RESULTS: In all cancers together, 75 TRDs were reported in Cohort I and 24 in Cohort II (P = 0.001). Cumulative incidence at 5 years declined from 7.9% to 4.1%, and overall survival (OS) increased from 71.0% to 77.2%. TRDs declined by nearly 10-fold in patients with solid malignant tumors (P = 0.02) and central nervous system tumors (P = 0.001), but OS improved for patients with solid malignant tumors only (P = 0.01). No difference was observed in treatment- and transplantation-related deaths in patients with acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML), but OS was better in patients with AML (P = 0.02). Between the two cohorts, transplantation-related mortality did not decrease and was higher at 5 years in patients with ALL who received unrelated-matched donor transplants (41.3%) than in those receiving sibling-matched donor transplants (18.7%). OS improved in the respective transplant groups (37.0% and 64.2%). Severe graft-versus-host disease was also observed among patients with ALL (P = 0.036). The decrease in TRDs was correlated with compliance to therapeutic guidelines. CONCLUSION: Although mortality declined, improved adherence to therapeutic guidelines and more restricted indications of allograft are needed to preclude further treatment- and transplantation-related deaths, particularly among those with leukemia.

Childhood cancer survival in France, 1990-1999.

The aim of this study was to describe the overall survival after childhood cancer in France using follow-up data from regional population-based registries. The survival of children (aged under 15 years) diagnosed with a cancer during 1990-1999 was analysed. For all cancers, the survivals were, respectively, 90.3% [89.4-91.3] at 1-year, 75.2% [73.8-76.6] at 5 years and 72.2% [70.7-73.7] at 10 years. During the 1990s, the average improvement in the 5-year survival was +1.2% per year. Adjusted for gender, age, area of residence and stage, children with cancer diagnosed between 1995 and 1999 had a 0.80 reduced risk of dying compared with those whose cancer had been diagnosed between 1990 and 1994. The increase of survival at the population level reflects a global improvement in childhood cancer care. The Paediatric Registries, in association with the French Society of Childhood Cancer, are now collecting data to quantify on a national basis the other events, at least relapse and second cancers.

Cancer incidence among children in France, 1990-1999.

BACKGROUND: Cancer is the second most important cause of death for children aged less than 15 years in France, unintentional injuries being the leading cause. The aim of the present study was to estimate the incidence of childhood cancer from six Childhood Cancer Registries covering 32% of France. PROCEDURE: Incident cancer cases diagnosed between 1990 and 1999 in children (0-14 years) resident in the administrative areas covered by each Registry were included. Annual age-standardized rates (ASRs) were adjusted by the world population. The estimated annual percent change (EAPC) was used to measure trend towards changes in the annual age-standardized incidence rate. RESULTS: With 4234 registered cases, the ASRs per million children were 137.5 for all cancers combined, 42.3 for leukemia, 29.1 for central-nervous-system tumors, 15.6 for lymphomas, 14.1 for sympathetic-nervous-system tumors, and 9.1 for renal tumors. The ASR of all cancers combined was slightly higher in males (145.8 per million children) than in females (128.7 per million children) with an M/F ratio of 1.2. No significant incidence trend was observed, with an EAPC of +0.2% [IC 95% (-2.5; +3.0); P = 0.89]. CONCLUSIONS: The estimated incidence rates are similar to those reported in previous studies in European and North American countries. These results will contribute to the development of National Registration of Childhood Cancer in France and support the national research program on childhood cancer.