Treatment outcome in children and adolescents with relapsed Hodgkin lymphoma--results of the UK HD3 relapse treatment strategy.

The purpose of this national retrospective study was to evaluate the outcome in children with relapsed or primary refractory Hodgkin lymphoma [HL] after a primary chemotherapy alone treatment strategy. Between 2000 and 2005, 80 children with relapsed [n = 69] or primary refractory [n = 11] HL were treated on a standardized treatment protocol of 4-6 cycles of EPIC [etoposide, prednisolone, ifosfamide and cisplatin] chemotherapy. Radiotherapy was recommended to all relapsed sites. High dose therapy with stem cell rescue [SCT] was recommended for patients with poor response. The 5-year overall survival [OS] and progression-free survival from relapse was 75·8% [64·8-83·9] and 59·9% [48·3-69·7] respectively. Duration of first remission was strongly associated with OS; risk of death was decreased by 53% [Hazard ratio (HR): 0·47, 95% confidence interval (CI): 0·19-1·18] for those with a time from end of treatment to relapse of 3-12 months (compared to <3 months) and reduced by 80% (HR 0·20, 95% CI: 0·04-0·90) for those >12 months after end of treatment. Other poor prognostic factors included advanced stage disease at relapse and B symptoms at first diagnosis. The most important factor associated with salvage failure was time to relapse. Survival outcome in children with primary refractory HL is poor.

DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome.

BACKGROUND: Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). AIM: To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. METHODS AND RESULTS: The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli-Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli-Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli-Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. CONCLUSION: Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition 'DICER1 syndrome'. ACCESSION NUMBERS: The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2.

Opioid use in palliative care of children and young people with cancer.

OBJECTIVE: Identify opioids prescribed, preferred routes, and doses among children with incurable cancer. STUDY DESIGN: Prospective survey with monthly questionnaires regarding patients 0 to 19 years old from oncology centers. Data were collected by professionals on each patient for 6 months or until death, and analyzed from patients who died. Impact of tumor was analyzed with Kruskal-Wallis and Mann-Whitney tests. Major opioid dosages are expressed as oral morphine equivalents. RESULTS: Of 185 children recruited, 164 (88 boys, 76 girls) died. Mean palliative care duration was 67 days. One hundred forty-seven (89.6%) received major opioids. Morphine, diamorphine, and fentanyl were prescribed in 75%, 57.9%, and 11.6%, respectively. Seventy-three (44.5%) received >1 major opioid. Median monthly maximum doses prescribed rose from 2.1 mg/kg/24 h (study entry) to 4.4 mg/kg/24 h (death) (P < .001); overall variable (0.09-1500 mg/kg/24 h, median 3.7 mg/kg/24 h). Opioids were given by the oral (117/164, 71.3%), intravenous (68/164, 41.5%), subcutaneous (40, 28%), rectal (20, 12.2%), and transdermal (18, 11%) routes. There was a shift to intravenous use as death approached. Numbers within each tumor group were too small to show significance. Children with solid tumors outside the central nervous system were likely to receive more opioids, be given multiple different opioids, and receive opioids in the last month. CONCLUSIONS: The study shows the United Kingdom practice of opioid use and provides comparator data for practice in children's palliative medicine.

Long-term outcome in children with Hodgkin's lymphoma: the United Kingdom Children's Cancer Study Group HD82 trial.

BACKGROUND: The aim of United Kingdom Children's Cancer Study Group (UKCCSG) HD82 was to establish the efficacy of chlorambucil/vinblastine/procarbazine/prednisolone (ChlVPP) in the treatment of childhood Hodgkin's lymphoma stages II-IV and radiotherapy (RT) alone in stage I patients. We report on the status of these patients to a follow-up of 20 years. METHODS: Treatment consisted of 35Gy involved-field RT for stage I and ChlVPP alone for stages II-IV. Adjuvant RT (35Gy) was administered to those with bulky mediastinal disease. RESULTS: Of the 358 patients, the 10-year EFS/OS per stage is I (65.4%/92.6%), II (80.0%/93.3%), III (68.8%/85.0%), IV (45.5%/72.7%). The corresponding 20-year OS rates are similar with a combined (all stage) rate dropping from 89.3% to 89.0% over the decade. The cumulative 20-year malignancy rate is 7.29%. CONCLUSION: Single modality treatment provided relatively low EFS at 10-years but comparable long-term OS, relative to contemporary published combined modality regimens, for stages I-III but not for stage IV patients.

Hodgkin's lymphoma in children aged 5 years or less - the United Kingdom experience.

PURPOSE: The aim of this study is to describe the natural history of Hodgkin's Lymphoma (HL) in a large unselected group of children aged 5 years or below at diagnosis, who were treated on a standard treatment programme in the United Kingdom between 1982 and 2000. METHODS: Eighty-one unselected children with HL aged 5 years or under at diagnosis, treated on the United Kingdom Children's Cancer Study Group (UKCCSG) Hodgkin's trials HD1 (1982-1992) and HD2 (1992-2000), were included in the study. RESULTS: Sixty-one patients (81%) presented with early stage disease (n=66). Fifty-three patients (65%) received combination chemotherapy, 28 (34%) received involved field radiotherapy (IF-RT) and 4 patients were treated with combined modality therapy. Eighteen children relapsed after primary therapy. CONCLUSIONS: Children treated with IF-RT had a higher rate of primary treatment failures as well as increased late treatment-related morbidity.

Clinical outcome in children and adolescents with Hodgkin lymphoma after treatment with chemotherapy alone - the results of the United Kingdom HD3 national cohort trial.

PURPOSE: To assess the efficacy of a standardised hybrid chemotherapy treatment programme for Hodgkin lymphoma (HL) in a national series of children and adolescents. PATIENTS AND METHODS: The 381 assessable patients, treated between March 2000 and April 2005 in the United Kingdom Children's Cancer Study Group trial, were reviewed to evaluate overall survival (OS), disease free survival (DFS) and deaths. Protocol treatment for stages 2-4 offered a hybrid programme of ChlVbPP (chlorambucil, vinblastine, prednisolone, procarbazine) alternating with ABVcD (doxorubicin, bleomycin, vincristine, dacarbazine). Patients with stage I disease only were offered involved field radiation alone or hybrid chemotherapy. RESULTS: With a median follow up of 5.1 years (range 0.5-8.4 years), the 5 years OS and DFS for all patients was 97% and 78%, respectively. By multivariate analysis, mediastinal and stage IV disease at presentation were the only factors that affected achieving a complete response. The 5-year DFS rate for patients with stage IV disease was 55% whilst patients with mediastinal disease had a 2-fold higher risk of an event. CONCLUSIONS: This study demonstrated that multi-agent chemotherapy alone is insufficient treatment for patients with mediastinal and stage IV disease.

A genome-wide association study identifies susceptibility loci for Wilms tumor.

Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor, we conducted a genome-wide association study in 757 individuals with Wilms tumor (cases) and 1,879 controls. We evaluated ten SNPs in regions significantly associated at P < 5 × 10(-5) in two independent replication series from the UK (769 cases and 2,814 controls) and the United States (719 cases and 1,037 controls). We identified clear significant associations at 2p24 (rs3755132, P = 1.03 × 10(-14); rs807624, P = 1.32 × 10(-14)) and 11q14 (rs790356, P = 4.25 × 10(-15)). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate association signals at 5q14, 22q12 and Xp22.

Symptoms in children/young people with progressive malignant disease: United Kingdom Children's Cancer Study Group/Paediatric Oncology Nurses Forum survey.

AIM: The purpose of this study was to survey symptoms in children/young people with progressive cancer and identify which are the most important and which are the most difficult to treat effectively. PATIENTS AND METHODS: This was a questionnaire survey of 22 United Kingdom Children's Cancer Study Group centers. Data were collected by clinical nurse specialists in pediatric oncology regarding children/young people between 0 and 20 years of age, using 2 questionnaires. The first collected demographic details and the second data about the occurrence and perceived impact of symptoms. RESULTS: There were 185 children/young people from 20 centers registered in the study, aged 4 months to 19 years (mean: 8.7 years), who received palliative care for a median of 34 days (range: 0-354 days). Data were analyzed for 164 children/young people who died during the study. Between referral to palliative care and death, there were significant increases in the number of symptoms reported and children/young people experiencing pain (70.6% vs 91.5%). Symptoms included some that often go unrecognized in children/young people, for example, anorexia, weight loss, and weakness. The nature of the underlying malignancy significantly influenced the prevalence of some symptoms. There were significant differences between the symptoms associated with central nervous system tumors and other groups. Pain other than headache occurred more commonly in children with solid tumors (98.4%) than in others (87%). Neurologic symptoms, including headache, were universal among those with central nervous system tumors. CONCLUSION: This study documents the frequency of symptoms and contrasts the experiences of children/young people with different groups of malignant disease. With access to skilled symptom control, pain can be effectively treated in most children/young people. Some other symptoms often remain intractable. The study highlights the need for further research to establish the effectiveness of therapeutic interventions for symptom control and their impact on the quality of life for children/young people dying from cancer.

ChlVPP chemotherapy in children with stage IV Hodgkin's disease: results of the UKCCSG HD 8201 and HD 9201 studies.

We reviewed the results of two consecutive United Kingdom Childrens' Cancer Study Group (UKCCSG) studies of children with stage IV Hodgkin's Disease (HD) treated between January 1982 and December 1999. Among 697 children with HD, 67 were diagnosed to be stage IV. The median age at diagnosis was 12.7 years (range 4.4-16.2). Thirty-five (52%) were boys. Thirty-nine patients (58%) had B symptoms at diagnosis. All were treated with 6-8 cycles of ChlVPP chemotherapy regimen (Chlorambucil, Vinblastine, Procarbazine and prednisolone) and only 12 had radiotherapy. The overall survival (OS) at 5 and 10 years was 80.8% and 77.2%, respectively, whilst the event-free survival (EFS) at the same time intervals was 55.2% and 48.8% respectively. Twenty-eight patients (41.79%) relapsed/progressed, 18 (64%) survived after further chemotherapy with or without high-dose therapy and stem cell rescue. Twelve patients died, seven of HD, three from infections and one from secondary acute myeloblastic leukaemia (AML). Although the EFS in this study was lower than other studies, 64% of relapsed patients were salvaged with second-line therapy. It is also anticipated that survivors treated with this non-anthracycline-containing regimen will have less long-term toxicity.