***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Purpose Relapsed high-risk neuroblastoma patients still have a poor prognosis . This phase-II trial assessed a new topotecan containing chemotherapy approach in patients with active disease . Methods Chemotherapy consisted of topotecan ( 1.0 mg/m2/day 168-h continuous infusion ) , cyclophosphamide ( 100 mg/m2/day 1-h-infusion days 1–7 starting 6 h prior to topotecan ) , and etoposide ( 100 mg/m2/day 1-h-infusion days 8–10 ) . Patients with relapsed neuroblastoma were scheduled for six cycles , untreated patients for two cycles followed by st and ard high-risk treatment . Results Main toxicity observed during 153 cycles were grade 3–4 leukopenia ( 97 % of cycles ) , thrombocytopenia ( 92 % ) , neutropenic fever ( 52 % ) , and mucositis ( 10 % ) . No treatment related fatal toxicity occurred . Complete or partial response was achieved in 19 of 31 ( 61 % ) evaluable relapsed patients and 8 of 11 ( 72 % ) untreated patients . Conclusions The combination of topotecan , cyclophosphamide , and etoposide is tolerable and effective in relapsed and untreated neuroblastoma . Myelotoxicity is the main side effect but seems justified in view of the encouraging response rates . A r and omized phase-III trial in primary disease has been commenced BACKGROUND Outcomes for children with relapsed and refractory neuroblastoma are dismal . The combination of irinotecan and temozolomide has activity in these patients , and its acceptable toxicity profile makes it an excellent backbone for study of new agents . We aim ed to test the addition of temsirolimus or dinutuximab to irinotecan-temozolomide in patients with relapsed or refractory neuroblastoma . METHODS For this open-label , r and omised , phase 2 selection design trial of the Children 's Oncology Group ( COG ; ANBL1221 ) , patients had to have histological verification of neuroblastoma or ganglioneuroblastoma at diagnosis or have tumour cells in bone marrow with increased urinary catecholamine concentrations at diagnosis . Patients of any age were eligible at first design ation of relapse or progression , or first design ation of refractory disease , provided organ function requirements were met . Patients previously treated for refractory or relapsed disease were ineligible . Computer-based r and omisation with sequence generation defined by permuted block r and omisation ( block size two ) was used to r and omly assign patients ( 1:1 ) to irinotecan and temozolomide plus either temsirolimus or dinutuximab , stratified by disease category , previous exposure to anti-GD2 antibody therapy , and tumour MYCN amplification status . Patients in both groups received oral temozolomide ( 100 mg/m2 per dose ) and intravenous irinotecan ( 50 mg/m2 per dose ) on days 1 - 5 of 21-day cycles . Patients in the temsirolimus group also received intravenous temsirolimus ( 35 mg/m2 per dose ) on days 1 and 8 , whereas those in the dinutuximab group received intravenous dinutuximab ( 17·5 mg/m2 per day or 25 mg/m2 per day ) on days 2 - 5 plus granulocyte macrophage colony-stimulating factor ( 250 μg/m2 per dose ) subcutaneously on days 6 - 12 . Patients were given up to a maximum of 17 cycles of treatment . The primary endpoint was the proportion of patients achieving an objective ( complete or partial ) response by central review after six cycles of treatment , analysed by intention to treat . Patients , families , and those administering treatment were aware of group assignment . This study is registered with Clinical Trials.gov , number NCT01767194 , and follow-up of the initial cohort is ongoing . FINDINGS Between Feb 22 , 2013 , and March 23 , 2015 , 36 patients from 27 COG member institutions were enrolled on this groupwide study . One patient was ineligible ( alanine aminotransferase concentration was above the required range ) . Of the remaining 35 patients , 18 were r and omly assigned to irinotecan-temozolomide-temsirolimus and 17 to irinotecan-temozolomide-dinutuximab . Median follow-up was 1·26 years ( IQR 0·68 - 1·61 ) among all eligible participants . Of the 18 patients assigned to irinotecan-temozolomide-temsirolimus , one patient ( 6 % ; 95 % CI 0·0 - 16·1 ) achieved a partial response . Of the 17 patients assigned to irinotecan-temozolomide-dinutuximab , nine ( 53 % ; 95 % CI 29·2 - 76·7 ) had objective responses , including four partial responses and five complete responses . The most common grade 3 or worse adverse events in the temsirolimus group were neutropenia ( eight [ 44 % ] of 18 patients ) , anaemia ( six [ 33 % ] ) , thrombocytopenia ( five [ 28 % ] ) , increased alanine aminotransferase ( five [ 28 % ] ) , and hypokalaemia ( four [ 22 % ] ) . One of the 17 patients assigned to the dinutuximab group refused treatment after r and omisation ; the most common grade 3 or worse adverse events in the remaining 16 patients evaluable for safety were pain ( seven [ 44 % ] of 16 ) , hypokalaemia ( six [ 38 % ] ) , neutropenia ( four [ 25 % ] ) , thrombocytopenia ( four [ 25 % ] ) , anaemia ( four [ 25 % ] ) , fever and infection ( four [ 25 % ] ) , and hypoxia ( four [ 25 % ] ) ; one patient had grade 4 hypoxia related to therapy that met protocol -defined criteria for unacceptable toxicity . No deaths attributed to protocol therapy occurred . INTERPRETATION Irinotecan-temozolomide-dinutuximab met protocol -defined criteria for selection as the combination meriting further study whereas irinotecan-temozolomide-temsirolimus did not . Irinotecan-temozolomide-dinutuximab shows notable anti-tumour activity in patients with relapsed or refractory neuroblastoma . Further evaluation of biomarkers in a larger cohort of patients might identify those most likely to respond to this chemoimmunotherapeutic regimen . FUNDING National Cancer Institute PURPOSE To determine the response rate ( RR ) of neuroblastoma ( NB ) in children to temozolomide ( TMZ ) , and evaluate the duration of response and tolerance of the drug in this patient population . PATIENTS AND METHODS A multicenter , phase II evaluation of an oral , daily schedule of TMZ ( 200 mg/m2/d x 5 days every 28 days ) was undertaken in children with refractory or relapsed high-risk NB ( metastatic or localized with Myc-N amplification ) . Response assessment was based on imaging with two-dimentional measurement of disease and meta-iodobenzylguanidine ( MIBG ) score . Activity was defined by a reduction in lesion size or isotope uptake at anytime . Methodology included a two-step design using Fleming 's method with a first step of 15 patients and a second of 10 additional patients if two to four responses had been observed in the first cohort . All data was central ly review ed by a panel . RESULTS Twenty-five assessable patients were recruited over a 14-month period in 14 centers and received 94 cycles of chemotherapy . Twenty-three patients had metastatic NB either refractory ( n = 9 ) or in relapse ( n = 14 ) .  Grade 3 or 4 thrombocytopenia was the most frequent toxicity ( 16 % of cycles ) . Myelosuppression result ed in treatment delays and dose reductions ( 24 % and 21 % of cycles , respectively ) . Response ( complete response , very good partial response , or partial response ) was observed in five patients ( RR = 20 % + /- 8 % ) with a median duration of 6 months and an objective or mixed response in five additional patients . CONCLUSION Temozolomide shows activity in heavily pretreated patients with NB , and deserves further evaluation in combination with another drug We initiated a phase 2 trial with a combination of topotecan and etoposide ( TE ) in patients with relapse after intensive first line chemotherapy for neuroblastoma .  TE chemotherapy consisted of topotecan ( schedule A : 1.0 mg/m2/d 30-minute – infusion days 1 to 5 , B : 0.7 mg/m2/d continuous infusion days 1 to 7 , and C : 1.0 mg/m2/d continuous infusion days 1 to 7 ) followed by etoposide ( 100 mg/m2/d 1-hour – infusion days 8 to 10 ) . TE was repeated every 28 days . The treatment was continued until severe nonhematopoietic toxicity or progression occurred or the treating physician chose alternative consolidation treatment after response to TE . Forty patients received 153 TE cycles . Grade s 3 to 4 leukopenia was frequently observed in all schedules ( A 51 % of cycles , B 48 % , and C 74 % , P=0.141 ) . Thrombocytopenia ( A 69 % , B 63 % , and C 93 % , P=0.004 ) and neutropenic fever ( A 12 % , B 29 % , and C 37 % , P=0.048 ) occurred more frequently in schedule C. No treatment-related fatal toxicity was observed . Among 36 patients evaluable for response , 4 patients achieved complete and 13 patients achieved partial remission ( 47 % ) . We conclude that the combination of TE is effective and tolerable in the treatment of relapsed high-risk neuroblastoma BACKGROUND Reports of responses and toxicities of salvage therapies for relapsed neuroblastoma are rare and often confounded by effects of additional treatments . Our objective was to describe the outcomes and toxicities for a topotecan and cyclophosphamide ( TOPO/CTX ) regimen for first relapse or progression of high-risk neuroblastoma . METHODS We retrospectively review ed charts of relapsed or refractory neuroblastoma patients treated between 1999 and 2009 with our st and ard-of-care outpatient TOPO/CTX ( 0.75 and 250 mg/m(2 ) /day × 5 days q3 - 4 weeks ) . RESULTS Twenty-seven patients received 343 cycles of TOPO/CTX ( median 10 cycles per patient , range 1 - 32 ) . Most patients ( N = 25 ) had undergone autologous stem cell transplantation . Seventeen ( 63 % ) patients had an objective response ( CR + PR + MR ) . The 3-year progression-free survival ( PFS ) after relapse was 11 ± 6 % and 3-year overall survival ( OS ) after relapse was 33 ± 9 % . The median PFS was 1.2 years and the median OS was 2.3 years . Five patients are alive with follow-up of 3.1 - 5.5 years . Shorter time from diagnosis to relapse ( 6 - 18 months ) was associated with shorter OS . The majority of patients experienced chemotherapy delays , transfusions , and febrile neutropenia , including eight bacterial infections . The mean number of hospitalized days was less than one per cycle . CONCLUSIONS TOPO/CTX was well tolerated and result ed in response rates and PFS similar to those reported for patients treated on COG 9462 . Our study provides additional toxicity , historical endpoints , and time-to-progression data against which new agents and combination therapies using TOPO/CTX as a backbone can be measured PURPOSE To assess objective response rate ( ORR ) after two cycles of temozolomide in combination with topotecan ( TOTEM ) in children with refractory or relapsed neuroblastoma . PATIENTS AND METHODS This multicenter , non-r and omised , phase II study included children with neuroblastoma according to a two-stage Simon design . Eligibility criteria included relapsed or refractory , measurable or metaiodobenzylguanidine ( mIBG ) evaluable disease , no more than two lines of prior treatment .  Temozolomide was administered orally at 150mg/m(2 ) followed by topotecan at 0.75mg/m(2 ) intravenously for five consecutive days every 28days . Tumour response was assessed every two cycles according to International Neuroblastoma Response Criteria ( INRC ) , and review ed independently . RESULTS Thirty-eight patients were enroled and treated in 15 European centres with a median age of 5.4years .  Partial tumour response after two cycles was observed in 7 out of 38 evaluable patients [ ORR 18 % , 95 % confidence interval ( CI ) 8 - 34 % ] . The best ORR whatever the time of evaluation was 24 % ( 95 % CI , 11 - 40 % ) 
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The response rate varied from 6 to 64 % ; however , because of heterogeneity , studies were not directly comparable , and no single treatment emerged as the most effective re-induction therapy .
To date , there is no clear superior re-induction therapy for 1st relapse of HRNB .