Long-term analysis of children with metastatic neuroblastoma treated in the ENSG5 randomised clinical trial.

BACKGROUND: The European Neuroblastoma Study Group 5 (ENSG5) trial showed that time-intensive "rapid" induction chemotherapy (COJEC) was superior to "standard" 3-weekly chemotherapy for children with high-risk metastatic neuroblastoma. Long-term outcomes of the ENSG5 trial were analysed. PROCEDURE: Patients with metastatic neuroblastoma aged ≥12 months were randomly assigned to "standard" or "rapid" induction, receiving the same chemotherapy drugs and doses. Event-free survival (EFS) and overall survival (OS) were analysed and prognostic factors evaluated. Amongst patients surviving >5 years, a population of children with persistent metastatic disease after the end of treatment was identified and described. RESULTS: Ten-year EFS was 18.2% (95% confidence interval: 12.2-25.2) for the "standard" arm and 26.8% (19.5-34.7) for the "rapid" arm (hazard ratio [HR] 0.85, P = 0.28). Ten-year OS for the "standard" arm was 19.7% (13.4-26.8) and 28.3% (20.8-36.2) for the "rapid arm" (HR 0.83, P = 0.19). There was a trend for worse EFS and OS for patients having MYCN amplification (HR 1.37 and 1.40, respectively) and those with partial and mixed response to induction (HR 1.69 and 1.75 for EFS and 1.66 and 2.00 for OS, respectively). Among 69 patients who survived >5 years, six had persistent metastatic disease after the end of treatment. CONCLUSION: The benefit of the "rapid" induction regimen seems to be maintained in the long term, although the small number of survivors could justify the lack of statistical significance. MYCN amplification and poor metastatic response to induction could be associated with worse outcomes. A small group of patients with persistent metastatic disease that survived long term has been described.

Revised International Pediatric Non-Hodgkin Lymphoma Staging System.

PURPOSE: Treatment and prognosis of pediatric non-Hodgkin lymphoma (NHL) have improved dramatically in the last 30 years. However, the St Jude NHL staging classification for pediatric NHL was developed more than 35 years ago. The most recent Lugano lymphoma staging classification focused on adult lymphoma. Furthermore, major limitations of the current pediatric NHL staging classification include lack of consideration of new distinct pediatric NHL histologic entities; absence of recognition of frequent skin, bone, kidney, ovarian, and other organ involvement; and lack of newer precise methods to detect bone marrow and CNS involvement, minimal disease quantification, and highly sensitive imaging technologies. METHODS: An international multidisciplinary expert panel convened in Frankfurt, Germany, in 2009 at the Third International Childhood, Adolescent and Young Adult NHL Symposium to develop a revised international pediatric NHL staging system (IPNHLSS), addressing limitations of the current pediatric NHL staging system and creating a revised classification. Evidence-based disease distribution and behavior were reviewed from multiple pediatric cooperative group NHL studies. RESULTS: A revised IPNHLSS was developed incorporating new histologic entities, extranodal dissemination, improved diagnostic methods, and advanced imaging technology. CONCLUSION: This revised IPNHLSS will facilitate more precise staging for children and adolescents with NHL and facilitate comparisons of efficacy across different treatment strategies, various institutions, multicenter trials, and cooperative groups by allowing for reproducible pediatric-based staging at diagnosis and relapse.

International Pediatric Non-Hodgkin Lymphoma Response Criteria.

PURPOSE: Response criteria are well established for adult patients with non-Hodgkin lymphoma (NHL). A revised set of response criteria in adults with NHL was recently published. However, NHL in children and adolescents involves different histologies, primary sites of disease, patterns of metastatic spread, approaches to therapy, and responses to treatment compared with adult NHL. However, there are no standardized response criteria specific to pediatric NHL. Therefore, we developed international standardized methods for assessing response to therapy in children and adolescents with NHL. METHODS: An international multidisciplinary group of pediatric oncologists, pathologists, biologists, and radiologists convened during and after the Third and Fourth International Childhood, Adolescent and Young Adult NHL Symposia to review existing response and outcome data, develop methods for response evaluation that reflect incorporation of more sensitive technologies currently in use, and incorporate primary and metastatic sites of disease for the evaluation of therapeutic response in children and adolescents with NHL. RESULTS: Using the current adult NHL response criteria as a starting point, international pediatric NHL response criteria were developed incorporating both contemporary diagnostic imaging and pathology techniques, including novel molecular and flow cytometric technologies used for the determination of minimal residual disease. CONCLUSION: Use of the international pediatric NHL response criteria in children and adolescents receiving therapy for NHL incorporates data obtained from new and more sensitive technologies that are now being widely used for disease evaluation, providing a standardized means for reporting treatment response.

Long-term follow-up of children with high-risk neuroblastoma: the ENSG5 trial experience.

BACKGROUND: Therapy for high-risk neuroblastoma is intensive and multimodal, and significant long-term adverse effects have been described. The aim of this study was to identify the nature and severity of late complications of metastatic neuroblastoma survivors included in the ENSG5 clinical trial. PROCEDURE: The trial protocol included induction chemotherapy (randomized "Standard" OPEC/OJEC vs. "Rapid" COJEC), surgery of primary tumor and high-dose melphalan with stem cell rescue. Two hundred and sixty-two children were randomized, 69 survived >5 years, and 57 were analyzed. Data were obtained from the ENSG5 trial database and verified with questionnaires sent to participating centers. RESULTS: Median follow-up was 12.9 (6.9-16.5) years. No differences were found in late toxicities between treatment arms. Twenty-eight children (49.1%) developed hearing loss. Nine patients (15.8%) developed glomerular filtration rate <80 ml/min/1.73 m(2), but no cases of chronic renal failure were documented. Endocrine complications (28.1% of children) included mainly hypogonadism and delayed growth. Four children developed second malignancies, three of them 5 years after diagnosis: one osteosarcoma, one carcinoma of the parotid gland and one ependymoma. There were no hematological malignancies or deaths in remission. CONCLUSIONS: This study analyzed a wide cohort of high-risk neuroblastoma survivors from a multi-institutional randomized trial and established the profile of long-term toxicity within the setting of an international clinical trial.

Long-term outcome for immune suppression and immune related lymphoproliferative disorder: prospective data from the United Kingdom Children's Leukaemia and Cancer Group registry 1994-2004.

Prospective national registry data on 98 patients were studied to determine the long-term outcome of immune related lymphoproliferative disease (LPD) and define prognostic factors. Seventy-three developed LPD following organ transplant (26 liver, 21 heart, 15 kidney, nine bone marrow [BM], two bowel). Twenty-five had non-transplant related immunosuppression. Age was 1.1-17 years (median 8.6). Fifty-eight patients had lymphomatous, 21 systemic and 17 lymphadenopathic disease. Sixty (73%) were disseminated and 22 (27%) localized. Thirty-three (54%) were monoclonal. Seventy-three (83%) were Epstein-Barr virus (EBV) positive. Median follow-up was 7.6 years. LPD developed earlier after liver and BM as compared to heart or kidney transplant. Five-year overall survival (OS) was 58%. Prognosis was best after liver and kidney transplant (OS >77%). Mortality was higher following heart (2.5 times) and BM transplant (5 times). Adverse prognostic factors were disseminated or lymphomatous disease and lack of reduction of immunosuppression. With appropriate reduction of immunosuppression, rituximab and low-dose chemotherapy, long-term survival is high.

Relapsed intracranial ependymoma in children in the UK: patterns of relapse, survival and therapeutic outcome.

Relapsed ependymoma in children poses difficult dilemmas in management. Clinico-pathological and treatment data of 108 children with relapsed ependymoma in the United Kingdom (UK) treated between 1985 and 2002 were reviewed to identify prognostic factors affecting survival. The primary site was the most common site of relapse (84%). Overall 25% had metastatic relapse. Surgery at relapse was attempted in only 55%. Radiotherapy was delivered at relapse in 66% infants and 50% of older children were re-irradiated. Overall 5-year survival was 24% and 27% for children less than 3 years of age at initial diagnosis and older children, respectively. Multivariate analysis showed that, for infants, surgery (p=0.01) and radiotherapy (p=0.001) at relapse were independent predictors of survival. For older children regardless of the previous radiotherapy, repeat irradiation was associated with better outcome (p=0.05). Relapse was associated with poor outcome in both age groups. A survival advantage conferred by both radiotherapy and surgery at relapse is independently significant.

Randomised controlled trials of palliative care - a survey of the views of advanced cancer patients and their relatives.

PURPOSE: To determine if patients with advanced cancer are interested in participation in palliative care research, particularly RCTs, and the importance of demographic factors in decision making. It sought relatives' views towards supporting trial entry, and assessed if demographic factors can predict participation. METHODS: A questionnaire was developed through multiprofessional focus groups, patient and relative interviews and pilot studies. Consecutive patients known by the palliative care service to have advanced disease were approached. Relatives of consenting patients completed a parallel survey. K-means cluster analysis was used to differentiate between those willing and unwilling to participate. Multivariate logistic regression identified demographic factors predicting willingness. RESULTS: One hundred and one patients and 100 relatives were included. 92% of patients would participate in studies involving simple interventions, whereas only 26% would consider studies of complex interventions. A similar pattern was observed for relative support. Over 75% of participants expressed altruistic views. Concepts of 'randomisation', 'placebo-control' and 'blinding' deterred about one-half. Many were prepared to complete short questionnaires, accept extra medications, investigations, hospital visits or admissions within a trial context but the possibility of side-effects was a major deterrent. Patient age was the only significant predictor of willingness to participate, with older patients less likely to participate. CONCLUSION: Despite the likely absence of individual benefit, many patients appear willing to participate in palliative care research. Trial design and the possibility of side-effects proved very influential in their decision making. Clinical trials in palliative care are more likely to be successful if developed in accordance with the views of patients and their relatives.

High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial.

BACKGROUND: The current standard treatment for patients with high-risk neuroblastoma includes initial induction chemotherapy with a 21-day interval between induction treatments. We aimed to assess whether an intensive chemotherapy protocol that had a 10-day interval between treatments would improve event-free survival (EFS) in patients aged 1 year or over with high-risk neuroblastoma. METHODS: Between Oct 30, 1990, and March 18, 1999, patients with stage 4 neuroblastoma who had not received previous chemotherapy were enrolled from 29 centres in Europe. Patients were randomly assigned to rapid treatment (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], known as COJEC) or standard treatment (vincristine [O], cisplatin [P], etoposide [E], and cyclophosphamide [C], ie, OPEC, alternated with vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], ie, OJEC). Both regimens used the same total cumulative doses of each drug (except vincristine), but the dose intensity of the rapid regimen was 1.8-times higher than that of the standard regimen. The standard regimen was given every 21 days if patients showed haematological recovery, whereas the rapid regimen was given every 10 days irrespective of haematological recovery. Response to chemotherapy was assessed according to the conventional International Neuroblastoma Response Criteria (INRC). In responders, surgical excision of the primary tumour was attempted, followed by myeloablation (with 200 mg/m2 of melphalan) and haemopoietic stem-cell rescue. Primary endpoints were 3-year, 5-year, and 10-year EFS. Data were analysed by intention to treat. This trial is registered on the clinical trials site of the US National Cancer Institute website, number NCT00365755, and also as EU-20592 and CCLG-NB-1990-11. FINDINGS: 262 patients, of median age 2.95 years (range 1.03-20.97), were randomly assigned-132 patients to standard and 130 patients to rapid treatment. 111 patients in the standard group and 109 patients in the rapid group completed chemotherapy. Chemotherapy doses were recorded for 123 patients in the standard group and 126 patients in the rapid group. 97 of 123 (79%) patients in the standard group and 84 of 126 (67%) patients in the rapid group received at least 90% of the scheduled chemotherapy, and the relative dose intensity was 1.94 compared with the standard regimen. 3-year EFS was 24.2% for patients in the standard group and 31.0% for those in the rapid group (hazard ratio [HR] 0.86 [95% CI 0.66-1.14], p=0.30. 5-year EFS was 18.2% in the standard group and 30.2% in the rapid group, representing a difference of 12.0% (1.8 to 22.3), p=0.022. 10-year EFS was 18.2% in the standard group and 27.1% in the rapid group, representing a difference of 8.9% (-1.2 to 19.0), p=0.085. Myeloablation was given a median of 55 days earlier in patients assigned rapid treatment than those assigned standard treatment. Infective complications (numbers of patients with febrile neutropenia and septicaemia, and if given, time on antibiotic and antifungal treatment) and time in hospital were greater with rapid treatment. Occurrence of fungal infection was the same in both regimens. INTERPRETATION: Dose intensity can be increased with a rapid induction regimen in patients with high-risk neuroblastoma. There was no significant difference in OS between the rapid and standard regimens at 5 years and 10 years. However, an increasing difference in EFS after 3 years suggests that the efficacy of the rapid regimen is better than the standard regimen. A rapid induction regimen enables myeloablation to be given much earlier, which might contribute to a better outcome.

Efficacy and tolerability of high-dose methotrexate in central nervous system positive or relapsed lymphoproliferative disease following liver transplant in children.

Childhood post-transplant lymphoproliferative disease (PTLD) is a heterogeneous condition in which treatment varies, from the reduction of immunosuppression to moderately intensive chemotherapy. While low-dose chemotherapy/rituximab has been found to be effective, moderately intensive chemotherapy is required for patients who relapse, have classic non-Hodgkin lymphoma or have fulminant PTLD. Methotrexate (Mtx) is highly effective in lymphomas and crosses the blood-brain barrier. However, there are no data in the literature regarding its safety in post-liver transplant patients. We describe four cases of high-grade lymphomas (three diffuse large B cell and one T-cell lymphoblastic), post-liver transplant, for which chemotherapy including high-dose Mtx (HDMTX) was the treatment of choice. In total, 20 doses of HDMTX (1-5 g/m(2)) were given. The treatment was well tolerated and all four patients had a good response. One case of central nervous system (CNS) diffuse large B-cell lymphoma was treated with HDMTX alone. We conclude that, in the absence of significant organ damage, HDMTX can safely be given to liver transplant patients, but should only be administered in specialist oncology units. Proof of effectiveness as a single agent in CNS lymphoma needs further studies.

Outcome of children with nodular lymphocyte predominant Hodgkin lymphoma - a Children's Cancer and Leukaemia Group report.

This report describes the clinical outcomes and follow-up records of 42 children with nodular lymphocyte predominant Hodgkin lymphoma (LPHL) treated on United Kingdom Children's Cancer Study Group (UKCCSG) HD1 (1982-1992) and HD2 protocols (1992-2000). The clinical records of 42 children with LPHL treated between 1982 and 2000 were reviewed retrospectively. All 42 had histology reviewed centrally and confirmed as LPHL by an expert panel. In both trials, only patients with stage IA disease had the option of being treated with either involved field radiation alone or combination chemotherapy consisting of chlorambucil, vinblastine, procarbazine and prednisolone (ChlVPP). Patients with all other stages were treated with ChlVPP chemotherapy. Thirty-five patients (83%) presented with early stage disease (Stages I & II). All 42 patients achieved a complete remission (CR). Six children relapsed after primary therapy. The 5- and 10-year relapse-free survival rates were 87% and 82% respectively. Forty-one are currently alive in CR. In conclusion, children with low-stage LPHL treated between 1982 and 2000 according to the UK strategy for classical Hodgkin lymphoma (HL) had an excellent prognosis. There have been no second malignancies or transformations to B-cell non-Hodgkin lymphoma.

Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents.

The prognosis for higher risk childhood B-cell non-Hodgkin lymphoma has improved over the past 20 years but the optimal intensity of treatment has yet to be determined. Children 21 years old or younger with newly diagnosed B-cell non-Hodgkin lymphoma/B-cell acute lymphoblastic leukemia (B-NHL/B-ALL) with higher risk factors (bone marrow [BM] with or without CNS involvement) were randomized to standard intensity French-American-British/Lymphoma Malignancy B (FAB/LMB) therapy or reduced intensity (reduced cytarabine plus etoposide and deletion of 3 maintenance courses M2, M3, M4). All patients with CNS disease had additional high-dose methotrexate (8 g/m2) plus extra intrathecal therapy. Fifty-one percent had BM involvement, 20% had CNS involvement, and 29% had BM and CNS involvement. One hundred ninety patients were randomized. The probabilities of 4-year event-free survival (EFS) and survival (S) were 79% +/- 2.7% and 82% +/- 2.6%, respectively. In patients in remission after 3 cycles who were randomized to standard versus reduced-intensity therapy, the 4-year EFS after randomization was 90% +/- 3.1% versus 80% +/- 4.2% (one-sided P = .064) and S was 93% +/- 2.7% versus 83% +/- 4.0% (one-sided P = .032). Patients with either combined BM/CNS disease at diagnosis or poor response to cyclophosphamide, Oncovin [vincristine], prednisone (COP) reduction therapy had a significantly inferior EFS and S (P < .001). Standard-intensity FAB/LMB therapy is recommended for children with high-risk B-NHL (B-ALL with or without CNS involvement).

The development of functional imaging in the diagnosis, management and understanding of childhood brain tumours.

Imaging plays a fundamental role in the management of children with brain tumours. A series of new techniques, commonly grouped under the heading functional imaging, promise to give information on the properties and biological characteristics of tissues thereby adding to the structural information available from current imaging. The EPSRC funded a workshop to bring together clinicians from the UK Children's Cancer Study Group and scientific experts in the field to identify clinical problems in childhood brain tumours that may be addressed by functional imaging and to develop a clinical test bed for applying, evaluating and developing this new technology. The presentations and discussion sessions from the workshop are summarised and a review of the current 'state of the art' for this rapidly developing area provided. A key output of the workshop was agreement on a series of hypotheses which can be tested in carefully designed clinical studies.

Outcome after autologous hemopoietic stem cell transplantation in relapsed or refractory childhood Hodgkin disease.

OBJECTIVES: To determine the clinical outcome and prognostic factors for overall survival in children with recurrent and/or primary refractory Hodgkin disease (HD) after high-dose therapy and autologous hemopoietic stem cell transplantation (AHSCT). The survival outcome of this treatment was compared with conventional salvage therapy without stem cell transplantation. METHODS: Clinical records of 51 patients with relapsed or refractory HD who underwent AHSCT were reviewed. The source of the stem cells was bone marrow (n = 22) or peripheral blood (n = 29). At the time of high-dose therapy, 39 patients were in complete remission and 1 was in partial remission, while the remaining 11 had refractory disease. The records of 78 patients from the HD 1 trial who underwent conventional salvage treatment but without AHSCT for relapsed or refractory HD were also reviewed. All patients received HDT without radiation for conditioning. RESULTS: Overall survival from diagnosis of patients treated with AHSCT did not differ significantly from that of those treated with conventional salvage therapy (hazard ratio = 1.5; 95% confidence interval = 0.9-8.2; P = 0.4). There were also no statistically significant differences in survival data between the two approaches for patients whose duration of first remission was less than or greater than 1 year (P = 0.5; stratified log-rank). Of the 11 patients who received AHSCT for refractory disease, 9 remain alive and well with followups ranging from 2 to 18 years. No deaths due to treatment-related complications were seen in the AHSCT group. CONCLUSIONS: Stem cell transplantation does not offer any significant survival advantage over conventional salvage therapy in children with relapsed HD, although it may be of benefit for patients with primary refractory disease.

Acute neurotoxicity in children with advanced stage B-non-Hodgkin's lymphoma and B-acute lymphoblastic leukaemia treated with the United Kingdom children cancer study group 9002/9003 protocols.

We reviewed the pattern of acute neurotoxicity in children with B-non-Hodgkin's lymphoma (B-NHL) and B-acute lymphoblastic leukaemia (ALL) treated with the UKCCSG 9002/9003 protocols. Among 175 patients, 21 (12%) developed acute neurotoxicity: 9002 protocol (n=11/112) and 9003 (n=10/63). There were 20 boys and the median age was 10 years. Patients with neurological symptoms due to other causes were excluded. Acute neurological symptoms developed following induction chemotherapy in 7 patients, or after a more intensive course of chemotherapy containing high-dose methotrexate (n=14). Nine patients required their chemotherapy to be altered because of the acute neurotoxicity. One patient died of cerebral haemorrhage but none of the remaining six deaths was attributed to acute neurotoxicity. We conclude that acute neurotoxicity is common in children treated with the 9002/9003 protocols and tends to be transient. Intrathecal and systemic chemotherapy including high-dose methotrexate is probably the most common predisposing factor. Modification of subsequent chemotherapy is not invariably necessary.

Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer: report of an international compassionate use study.

BACKGROUND: Hyperuricemia and tumor lysis syndrome (TLS) are serious complications that can occur during chemotherapy for hematologic malignancies, even if standard management procedures, including administration of allopurinol, are undertaken. Rasburicase, a recombinant urate oxidase that converts uric acid (UA) into the soluble compound allantoin, has been shown to control hyperuricemia faster and more reliably than allopurinol.(1) METHODS: A compassionate use trial, running from January 1999 to December 2001, provided access to rasburicase for patients in nine countries who were at risk for TLS during the initiation of chemotherapy. Of the 280 patients enrolled in the study, 278 received rasburicase and were included in the analysis. A total of 166 pediatric patients who had leukemia (approximately 74%), lymphoma (approximately 24%), or solid tumors (approximately 3%) were treated with rasburicase. One hundred twelve adults with either leukemia (68%) or lymphoma (30%) also were treated. Rasburicase (0.20 mg/kg) was administered intravenously once a day for 1 to 7 days, at the investigator's discretion. Two doses daily could be administered during the first 3 days. A response was defined as a reduction in UA level or maintenance of a UA level less than 7.5 mg/dL (or less than 6.5 mg/dL, for children age < 13 years). RESULTS: UA levels at 24-48 hours after administration of the last dose of rasburicase were available for 122 pediatric patients and 97 adult patients. The mean UA level in 29 hyperuricemic children decreased from 15.1 mg/dL to 0.4 mg/dL, whereas in 27 hyperuricemic adults, the mean level decreased from 14.2 mg/dL to 0.5 mg/dL. Prophylactic administration of rasburicase to prevent TLS during chemotherapy reduced UA levels from a mean of 4.4 mg/dL to 0.8 mg/dL in 93 nonhyperuricemic children and from 4.8 mg/dL to 0.4 mg/dL in 70 nonhyperuricemic adults (for all reductions in UA levels, P < 0.001). The response rate was 100%. Rasburicase was very well tolerated. Serious adverse events related to rasburicase were observed in one patient. CONCLUSIONS: The results of the current study confirm that rasburicase is safe and highly effective in the prevention and treatment of chemotherapy-induced hyperuricemia in both children and adults.

Thalidomide after allogeneic haematopoietic stem cell transplantation: activity in chronic but not in acute graft-versus-host disease.

Thalidomide was used to treat acute (n=21) or chronic (n=59) graft-vs-host disease (GVHD) in 80 haematopoietic stem cell allograft recipients after failure to respond to the combination of cyclosporine and corticosteroids with or without other agents. The median time to onset of acute GVHD was 11 days, and thalidomide was started at a median of 48 days post transplant. In addition to corticosteroids and cyclosporine, 13 patients had also received other agents before thalidomide. None of the patients responded and all died of acute GVHD. For chronic GVHD (limited in 13, extensive in 46), thalidomide was started at a median of 385 days post transplant. In addition to corticosteroids and cyclosporine, 34 patients received azathioprine concomitantly. In all patients, thalidomide was added to the ongoing immunosuppressive regimen. The median duration of therapy with thalidomide was 60 days (range, 11-1210; <2 weeks in 11). In total, 13 patients (22%) had complete response, eight (14%) partial response and 38 (64%) no response. Response rates were comparable for limited (39%) and extensive (33%) chronic GVHD. At a median of 53 months, 19 patients are alive, 13 without evidence of chronic GVHD. Survival was significantly better in patients who responded to thalidomide. The principal causes of death were progressive chronic GVHD (n=29) and relapsed leukaemia (n=7). In conclusion, thalidomide has no activity in acute GVHD, but has some activity in chronic GVHD in combination with other agents.

Haploidentical vs autologous hematopoietic stem cell transplantation in patients with acute leukemia beyond first remission.

This is a retrospective comparison of partially mismatched related donor transplantation (PMRDT) and autotransplantation (ABMT) in advanced acute leukemia. Patients underwent T-cell-depleted PMRDT (n=164) or ABMT (n=131) for acute myeloid leukemia (n=130) or acute lymphoblastic leukemia (n=165). Fewer PMRDT patients were in remission (29 vs 85%; P<0.0001). The 5-year cumulative incidence of transplant-related mortality (TRM) was 52% after PMRDT and 16% after ABMT (P<0.0001). The 5-year cumulative incidence of relapse was 32% after PMRDT and 54% after ABMT (P=0.006). The actuarial unadjusted 5-year disease-free survival (DFS) was 16% after PMRDT and 30% after ABMT. In Cox's regression analysis, PMRDT (P<0.0001) and age >15 years (P=0.002) were associated with higher TRM, active disease (P=0.0021), ABMT (P=0.0074) and male sex (P=0.011) with higher relapse, and age >15 years (P=0.0007) and PMRDT (P=0.047) with lower DFS. Amongst second remission patients, TRM was higher after PMRDT (P=0.0003), relapse was higher after ABMT (P=0.034), and 5-year DFS was comparable (32% ABMT and 25% PMRDT). ABMT, if feasible, may be preferable to PMRDT in advanced acute leukemia patients since lower relapse after PMRDT is offset by higher TRM. If an autograft is not feasible because of nonavailability of autologous cells or very advanced disease, PMRDT is a potential alternative.

Recruiting children into cancer trials--role of the United Kingdom Children's Cancer Study Group (UKCCSG).

The UK Children's Cancer Study Group (UKCCSG), established in 1977, provides a highly organised structure for both service provision and research, and represents the model to which the adult cancer community is currently aspiring. Since childhood cancer is so rare, it is both essential and feasible for the vast majority of children to be referred into the network of specialist centres, and also for the maximum number of children to be recruited into national and international clinical trials. Over the last 30-40 years there have been major advances in treatment, such that now approximately 70% of children diagnosed with cancer will be cured of their disease. The conduct of clinical trials in this patient population does, however, raise a number of specific issues and these are discussed in the paper.

Potential role of magnetic resonance spectroscopy in assessment of tumour response in childhood cancer.

This brief review considers to what extent Magnetic Resonance Spectroscopy (MRS) can play a role in monitoring early tumour response with examples of preclinical studies and selected clinical studies in tumours of children and young adults. An early non-invasive indicator of tumour response to therapy would provide useful information regarding the effectiveness of therapy. This might be a relevant prognostic factor in new patients and in phase II studies could facilitate recommendations at an early stage as to whether to continue treatment. This review suggests that several markers and ratios are emerging as potential prognostic markers, but larger prospective studies are needed before translating this into clinical practice.

Role of itraconazole in haematology/oncology.

The antifungal agents most frequently used in prophylaxis and treatment are amphotericin B (and its new lipid forms) and azoles such as fluconazole, itraconazole, and more recently voriconazole. This review assesses the role of itraconazole in paediatric haematology/oncology practice. Its broader spectrum of activity and availability in oral and intravenous forms allow a flexible approach in the management of fungal infections.