John Imeson

Results of a Randomized Study of Preradiation Chemotherapy Versus Radiotherapy Alone for Nonmetastatic Medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 Study

PURPOSE To determine whether preradiotherapy (RT) chemotherapy would improve outcome for Chang stage M0-1 medulloblastoma when compared with RT alone. Chemotherapy comprised vincristine 1.5 mg/m2 weekly for 10 weeks and four cycles of etoposide 100 mg/m2 daily for 3 days, and carboplatin 500 mg/m2 daily for 2 days alternating with cyclophosphamide 1.5 g/m2. PATIENTS AND METHODS Patients aged 3 to 16 years inclusive were randomly assigned to receive 35 Gy craniospinal RT with a 20 Gy posterior fossa boost, or chemotherapy followed by RT. RESULTS Of 217 patients randomly assigned to treatment, 179 were eligible for analysis (chemotherapy + RT, 90 patients; RT alone, 89 patients). Median age was 7.67 years, and median follow-up was 5.40 years. Overall survival (OS) at 3 and 5 years was 79.5% and 70.7%, respectively. Event-free survival (EFS) at 3 and 5 years was 71.6% and 67.0%, respectively. EFS was significantly better for chemotherapy and RT (P =.0366), with EFS of 78.5% at 3 years and 74.2% at 5 years compared with 64.8% at 3 years and 59.8% at 5 years for RT alone. There was no statistically significant difference in 3-year and 5-year OS between the two arms (P =.0928). Multivariate analysis identified use of chemotherapy (P =.0248) and time to complete RT (P =.0100) as having significant effect on EFS. CONCLUSION This is the first large multicenter randomized study to demonstrate improved EFS for chemotherapy compared with RT alone. It is anticipated that this regimen could reduce ototoxicity and nephrotoxicity compared with cisplatin-containing schedules. The importance of avoiding interruptions to RT has been confirmed.

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.

Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study.

PURPOSE To investigate the possibility that the substitution of ifosfamide for cyclophosphamide therapy for Ewings sarcoma will improve survival over that seen in the first United Kingdom Childrens Cancer Study Group (UKCCSG) Ewings tumor study (ET-1). PATIENTS AND METHODS Between 1987 and 1993,243 patients (138 men or boys) were entered onto the study. The median age was 13.5 years (range, 1.5 to 27 years). The median follow-up was 58 months. Chemotherapy included four courses of vincristine 2 mg/m2; ifosfamide 9 g/m2; and doxorubicin 60 mg/m2 administered every 3 weeks. Treatment of the primary tumor was with surgery and/or radiotherapy followed by ifosfamide 6 g/m2; doxorubicin 60 mg/m2; and vincristine 2 mg/m2; with actinomycin D 1.5 mg/m2 substituted for doxorubicin after a total dose of 420 mg/m2. RESULTS Two hundred one patients had no metastases. One hundred eighteen patients had tumors of the axial skeleton and 125 patients had limb primary tumors. The major toxicities were hematologic and infective, but there were no toxic deaths. The overall survival rate was 62% (95% confidence interval [CI], 56 to 69) and relapse-free survival (RFS) 56% (95% CI, 49 to 62). For those with no metastases at diagnosis, the RFS rate was 62% and for those with metastases, 23%. Multivariate analysis showed age and site to have a significant effect on RFS. Pelvic sites had the worst RFS rate of 41%; other axial sites, 55%; and extremity tumors, 73%. Age younger than 10 years had an RFS rate of 86% versus 55% for older patients. The local relapse rate for axial tumors was 20% and for limb primary tumors was 2.4%. CONCLUSION The 5-year survival rate of 62% is improved compared with the 44% survival rate achieved in ET-1. This is probably caused by the use of higher doses of ifosfamide compared with relatively low doses of cyclophosphamide in ET-1.

Anaplastic large cell lymphoma in childhood: analysis of 72 patients treated on The United Kingdom Children's Cancer Study Group chemotherapy regimens

Summary.  From June 1990 to June 1998, 72 patients with anaplastic large cell lymphoma (ALCL) were treated with short intensive multi‐agent regimens [non‐Hodgkins lymphoma (NHL) 9000 and 9602]. Diagnosis was based on morphological and immunophenotypic criteria. Treatment for stage I disease consisted of eight courses (2 × vincristine, doxorubicin, prednisolone; 2 × methotrexate; 2 × cytarabine, thioguanine; and 2 × methotrexate etoposide). For stage II, III and non‐central nervous system (CNS) stage IV, two COPADM (cyclophosphamide, doxorubicin, prednisolone, methotrexate, vincristine), two CYM (cytarabine methotrexate) and a COPADM was given. For CNS‐positive disease, treatment was intensified and contained methotrexate 8 g/m2 and cytarabine 3 g/m2. Fifty‐nine patients (82%) achieved a remission. Thirteen of these relapsed, with a median time to relapse from the start of treatment of 5 months (range 3–14). Relapse included a new site in 9/13 patients. The probabilities of overall and event free survival at 5 years were 65% (53–76%) and 59% (47–70%), respectively, with a median follow up of 4·3 years. Mediastinal and visceral involvement at presentation were found to be predictive of an increased risk of failure.

Circulating Neuroblastoma Cells Detected by Reverse Transcriptase Polymerase Chain Reaction for Tyrosine Hydroxylase mRNA Are an Independent Poor Prognostic Indicator in Stage 4 Neuroblastoma in Children Over 1 Year

PURPOSE In this prospective, multicenter study, the independent prognostic power of neuroblastoma cells detected by reverse transcriptase polymerase chain reaction (RT-PCR) for tyrosine hydroxylase (TH) mRNA was evaluated. PATIENTS AND METHODS The clinical significance of disease detected by RT-PCR in peripheral blood from children at diagnosis was compared with established prognostic markers [ie, age, lactate dehydrogenase (LDH), neuron-specific enolase, ferritin, and MYCN gene amplification] by multivariate analysis. The value of disease detection by RT-PCR during treatment and follow-up was also examined. RESULTS TH mRNA was detected in peripheral blood from 33 of 49 (67%) children with stage 4 neuroblastoma > 1 year old at diagnosis and was a significant predictive factor for overall survival [hazard ratio (HR) = 2.40, 95% confidence interval (CI) 1.19 to 4.84, P =.014) and event-free survival (HR = 2.09, 95% CI 1.06 to 4.17, P =.034) in a multivariate analysis. Detection of disease in blood from clinically disease-free children was related to increased risk of death (HR 2.54, 95% CI 1.42 to 4.55, P =.0014). CONCLUSION TH mRNA in peripheral blood of children with neuroblastoma is a poor prognostic indicator, reflecting the propensity for dissemination via the bloodstream. When combined with a serum LDH > 1500 IU/L, this is the most powerful poor prognostic model at diagnosis for children > 1 year old with stage 4 disease. The detection of TH mRNA in peripheral blood from clinically disease-free children is related to increased risk of relapse and death.

Improved cure rate in children with B-cell acute lymphoblastic leukaemia (B-ALL) and stage IV B-cell non-Hodgkin's lymphoma (B-NHL)--results of the UKCCSG 9003 protocol.

From June 1990 to February 1996, 35 patients with B-cell acute lymphoblastic leukaemia (B-ALL) 13 of whom had CNS disease and 28 patients with stage IV B-cell non-Hodgkins lymphoma (B-NHL) 22 of whom had CNS involvement were treated with a short, intensive multiagent chemotherapy regimen (UKCCSG 9003 protocol) based on the French LMB 86 regimen. Fifty-five were boys. The age range was 11 months to 16.5 years (median 8.4 years). Chemotherapy included cyclophosphamide, vincristine, daunorubicin, high-dose methotrexate (COPADM) and etoposide/high-dose cytarabine (CYVE) with frequent intrathecal (i.t.) triple therapy (methotrexate, cytarabine and hydrocortisone). Cranial irradiation (24 Gy in 15 fractions) was recommended in patients with overt CNS disease. One patient with Wiskott-Aldrich syndrome was withdrawn after entry and has been excluded from the analysis. Ten patients (16%) have relapsed (CNS, four; BM, two; combined CNS and BM, three; and jaw, one) 4-11 months after diagnosis and two patients never achieved complete remission (CR). All have died. In seven of the patients who relapsed, treatment had been modified or delayed because of poor clinical condition. Seven patients (11%) died of toxicity 11 days to 4 months after diagnosis. The cause of death was sepsis (n = 5) or sepsis with renal failure (n = 2). With a median follow-up of 3.1 years from diagnosis (range 9 months to 6.3 years), 43 patients (69%) survive in CR. This study confirms the effectiveness of this regimen with regard to the relapse rate (16%), although the rate of toxic death is of concern.

Prospective Validation of Renal Function–Based Carboplatin Dosing in Children With Cancer: A United Kingdom Children’s Cancer Study Group Trial

PURPOSE Carboplatin dosing in adults with cancer is based on renal function. The purpose of the current study was to validate a previously developed pediatric carboplatin-dosing formula. PATIENTS AND METHODS Thirty-eight pediatric patients were randomized to receive a carboplatin dose calculated according to surface area or a renal function-based dosing formula. On the next course of therapy, the alternative dosing method was used for each patient. Carboplatin pharmacokinetics (based on free plasma platinum concentrations) were measured after both courses. RESULTS The mean observed areas under the carboplatin concentration-versus-time curve (AUCs) after renal function- and surface area-based dosing were 98% and 95% of the target AUCs, respectively. The variation in the observed AUC was significantly less after renal function-based dosing (F test, P =.02), such that 74% of courses had an observed AUC within +/- 20% of the target value, versus 49% for courses after dosing according to surface area. Only one of 22 courses at the center with the most experience with renal function-based dosing was associated with an AUC outside +/- 20% of the target value, versus nine of 22 courses after surface area-based dosing in the same center. There was a relationship (r(2) =.71) between carboplatin AUC and thrombocytopenia in 10 neuroblastoma patients treated with a combination of carboplatin, vincristine, etoposide, and cyclophosphamide. CONCLUSION Renal function-based carboplatin dosing in children results in more consistent drug exposure than surface area-based drug administration.

Outcome of relapsed or refractory childhood B‐cell acute lymphoblastic leukaemia and B‐cell non‐Hodgkin's lymphoma treated with the UKCCSG 9003/9002 protocols

Twenty‐six children with B‐cell acute lymphoblastic leukaemia (B‐ALL) or Murphy Stage III or IV B‐cell non‐Hodgkins lymphoma (B‐NHL) progressed or relapsed after first‐line therapy with a short, intensive multiagent chemotherapy regimen [United Kingdom Childhood Cancer Study Group (UKCCSG) 9003] (n = 62) or a slightly less intensive regimen (UKCCSG 9002) (n = 112). Eight patients (4·6%) never achieved complete remission (CR) and 18 (10·3%) relapsed. Second‐line therapy resulted in remission for eight patients (30%). All patients initially treated with the 9003 protocol died. Three patients (11·5%) in the 9002 group, including one who never achieved CR in the primary site, are alive after second‐line therapy. This study confirms that the prognosis of relapsed or refractory B‐ALL/B‐NHL is poor and exceptionally so if relapse occurred less than 6 months from diagnosis. High‐dose therapy with stem cell rescue was used in only seven patients; its role needs to be studied further.

Long‐term follow‐up of children with high‐risk neuroblastoma: The ENSG5 trial experience

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.

Localized non‐Hodgkin's lymphoma with B‐cell histology: cure without cyclophosphamide? A report of the United Kingdom Children's Cancer Study Group on studies NHL 8501 and NHL 9001 (1985–1996)

Summary. We have examined the outcome for children treated on two consecutive United Kingdom Childrens Cancer Study Group studies of localized B‐cell non‐Hodgkins lymphoma (NHL). The first study (NHL 8501; 1985–1989) included cyclophosphamide in the treatment regimen at a total cumulative dose of 4 g/m2 whereas the regimen in the succeeding study (NHL 9001; 1990–1996) did not include cyclophosphamide. Ninety children with confirmed B‐cell NHL were treated in the two studies (NHL 8501, n = 33 and NHL9001, n = 57). With a median follow‐up of 7·5 years, overall survival for localized B‐cell NHL did not differ between the two regimens with observed 3‐year survivals of 94%[95% confidence interval (CI) 80–98%] and 89% (95% CI 79–95%) respectively (P = 0·47). There was also no difference in the event‐free survival between children treated on regimen NHL 8501 and NHL 9001 [91% (95% CI 76–97%) vs 84% (95% CI 73–92%) after 3 years; P = 0·34]. Although the difference in the number of failed remissions between NHL 8501 and 9001 (0/33 vs 6/57) approached statistical significance (P = 0·08, Fishers exact test), there was no overall statistical difference between the treatment failures on either regimen (P = 0·34). Substantial long‐term survival can be achieved for many children with localized B‐cell NHL without the use of cyclophosphamide. Further studies are needed to identify whether all clinical or histopathological subgroups will benefit equally from the omission of cyclophosphamide.