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Second malignancy after childhood NHL
Introduction
Second malignant neoplasms (SMN) represent a seri- ous long-term risk after treatment of children with can- cer. Reported cumulative incidences of SMN after child- hood cancer vary between 3 and 11% at 20-30 years depending on the first cancer, type of treatment and cumulative drug doses.1-5 No lifetime cumulative inci- dence has been established so far. A recently published study of the German Childhood Cancer Registry (GCCR) has shown a cumulative incidence of 8.3% within 35 years after first cancer in childhood.6 Analysis of SMN after treatment for childhood non-Hodgkin lym- phoma (NHL) showed cumulative incidences between 3 and 10% at 20-30 years after NHL diagnosis; the report- ed standard incidence ratios (SIR) for SMN varied between 2.4 and 12.0.1-5,6-10 Most information is derived from cancer registries in population-based studies on SMN after childhood cancer.1-9 These studies lack detailed information about the NHL-subtypes and spe- cific treatments. Two previous studies focused on SMN after childhood NHL.9,10 One of them limited the analysis to 5-year survivors of NHL, thus omitting most of the hematologic SMN that occur within 5 years of first diag- nosis.9 Two further studies about late health outcomes after treatment of childhood NHL included incidences of SMN, however, restricted the analysis to 5- and 10-year survivors of NHL, respectively.11,12
Studies on SMN after NHL in adulthood report an increased incidence of leukemia and solid tumors.13,14 A meta-analysis concerning the risk of SMN in adult NHL survivors detected a 1.88-fold increased risk for SMN in comparison with the general population.14
Treatment strategies for children with NHL differ from those used in adults with respect to the cumulative drug doses and the application of radiation. Whereas radio- therapy was largely omitted during the 1970s in the pediatric Berlin-Frankfurt-Muenster (BFM)-trials, it is nowadays applied in the treatment of most adults with NHL and bulky disease (Online Supplementary Tables S1 and S2).
In addition, the incidence of SMN may vary according to NHL subtype and treatment regimen, and may also be influenced by genetic and specific host factors.
We analyzed the incidence and type of SMN as well as risk factors for the development of SMN in a population- based large cohort of children treated for NHL with uni- form subtype-specific therapy regimens according to the NHL-BFM trials. Cumulative drug doses and the back- bone of the NHL-BFM trials remained stable over the analysis period of 30 years.
Methods
From 01/1981 to 06/2010, 4,184 children from 99 BFM-institu- tions diagnosed with NHL were registered in the studies ALL/NHL-BFM-81, -83, -86, NHL-BFM-90, -95, ALCL-99, EURO- LB-02, LBL-Register and B-NHL-BFM-04 after informed consent of the patient and/or guardians. The studies were conducted accord- ing to the Declaration of Helsinki. Approval was obtained from ethical committees of the investigators. 3,590 patients <15 years of age at diagnosis, were included in the analysis by 04/2017 (Figure 1).
NHL were classified using classifications at the time of diagno-
sis15,16,17 (see the Online Supplementary Appendix). Central reference pathology- and/or immunology-review was performed in over 90% of cases.
Patients were stratified according to the St Jude staging system18 and treated on one of the NHL-BFM-protocols listed above. Patients with lymphoblastic lymphoma (LBL) received an acute- lymphoblastic-leukemia (ALL)-type BFM-regimen consisting of eight drug inductions, consolidations, re-intensifications, and maintenance up to 2 years of therapy. Patients with mature B-cell- NHL or anaplastic large-cell-lymphoma (ALCL) received two to six courses of 5-day block-type chemotherapy as previously reported.19-23 All cumulative drug- and radiation doses are listed in the Online Supplementary Tables S1 and S2.
Long-term follow-up of patients was assured by the NHL-BFM datacenter and the GCCR (general information on data collection by the GCCR: www.kinderkrebsregister.de/english/). Details on follow-up are described in the Online Supplementary Appendix.
For the purpose of this evaluation, histopathology information about the first and second malignancy was re-reviewed in all patients. If required, complementary affirmative investigations were performed by the central reference pathology department. Non-lymphoid and lymphoid malignancies fulfilling the criteria depicted below were considered as proven SMN. In cases of mul- tiple SMN after NHL, only the first second cancer was counted.
Statistical analysis
The risk of SMN was estimated by cumulative incidence func- tions for SMN and death as competing events. Functions were compared using Gray test and 95% Confidence Intervals (CI) were calculated using standard methods.24
Survival after SMN was calculated from the date of SMN-diag- nosis to the date of death or last follow-up, respectively. Probability of survival was calculated according to Kaplan-Meier.25
SIR were calculated as the ratio of the observed SMN and the expected number of malignancies, as described by Scholz-Kreisel et al.6 Age-, sex-, and calendar year–specific rates from the GCCR were used to calculate the expected numbers for cases below 15 years. These data are complete and cover all diagnoses reported here. Population-based incidence rates for cases older than 15 years were not available for the entire period and all diagnoses. Therefore, the SIR was calculated for a subgroup of the cohort without basal cell carcinoma.
The contribution of factors to the development of SMN was estimated with the Cox proportional-hazards model. The clinical and biologic features analyzed included age at first diagnosis, sex, NHL-entity, -stage, therapy-type and known cancer-predisposing condition (CPC). The doses (as per protocol) of epipodophyllotox- ins, cyclophosphamide/ifosfamide (dose equivalence ratio 1:4), anthracyclines (dose equivalence ratio 1:1), cytarabine, asparagi- nase were analyzed, as well as stem-cell transplantation, and cra- nial radiotherapy. Statistical analysis was performed using SAS program (SAS, version 9.4; SAS Institute Inc, Cary, NC, USA).
Results
Patient characteristics
Patient characteristics are shown in Table 1. Because of the age restriction applied by the GCCR until 2008, we included only patients <15 years at first diagnosis of NHL in our analysis to ensure the most accurate assessment of the incidence of SMN in the study population. The ana- lyzed group included 57 patients with known CPC, name- ly primary and secondary immune deficiencies, Gorlin-, mismatch-repair-deficiency syndromes, neurofibro-
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