Therapeutic interventions for Burkitt's lymphoma in children

Joseph U Okebe; Toby J Lasserson; Martin M Meremikwu; Sue Richards

doi:10.1002/14651858.CD005198.pub2

Intervenciones terapéuticas para el linfoma de Burkitt en niños

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Referencias

Referencias de los estudios incluidos en esta revisión

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estudios excluidos
otras referencias

Anderson JR, Wilson JF, Jenkin DT, Meadows AT, Kersey J, Chilcote RR, et al. Childhood non‐Hodgkin's lymphoma. The results of a randomised therapeutic trial comparing a 4‐drug regimen (COMP) with a 10‐drug regimen (LSA2‐L2). The New England journal of medicine 1983;308(10):559‐65.

Brecher ML, Schwenn MR, Coppes MJ, Bowman WP, Link MP, Berard CW, et al. Fractionated cyclophosphamide and back to back high dose methrotrexate and cytosine arabinoside improves outcome in patients with stage III high grade small non‐cleaved cell lymphomas (snccl): a randomised trial of the pediatric oncology group. Medical and Pediatric oncology 1997;29(6):526‐33.

Cairo M.S, Gerrard M, Sposto R, Auperin A, Pinkerton R, Michon J, et al. Results of a randomised FAB LMB89 international study in children and adolescents (C+A) with advanced (bone marrow [BM] [B‐ALL] and/or CNS) B‐NHL (large cell [LCL], Burkitt's [BM] and Burkitt‐like [BLL]): Pts with L3 leukemia/ CNS‐ have an excellent prognosis.. Procdeedings of the American society of Clinical Oncology. 2003; Vol. 22:796.

Google Scholar

Magrath IT, Ziegler. Prophylaxis of meningeal Burkitt's lymphoma with CCNU. American association for cancer research 1973;14:67.

Google Scholar

Magrath IT, Ziegler JL. Failure of BCG immunostimulation to affect the clinical course of Burkitt's Lymphoma. British Medical Journal 1976;1:615‐8.

Magrath IT, Ziegler JL, Bluming AZ. Preliminary results of a randomized trial of BCG immunotherapy in Burkitt's lymphoma. Recent results in cancer research 1974;47:461‐5.

Ziegler JL, Magrath IT. BCG immunotherapy in Burkitt's lymphoma: preliminary results of a randomized clinical trial. National cancer institute monograph 1973;39:199‐202.

Ziegler JL, Magrath IT, Bluming AZ. BCG immunotherapy of Burkitt's lymphoma.. Proceedings of the American association for cancer research. 1972; Vol. 13:38.

Google Scholar

Neequaye J, Viza D, Pizza G, Levine P, De Vinci C, Ablashi D, Biggar R, Nkrumah F. Specific transfer factor with activity against Ebstein‐Barr virus reduces late relapse in endemic Burkitt's lymphoma. Anticancer research 1990;10(5A):1183‐7.

Olweny CLM, katongole‐Mbide E, Kaddu‐Mukassa A, Atine I, et al. Treatment of Burkitt's lymphoma: randomized clinical trial of single‐agent versus combination chemotherapy. Journal International du cancer 1976;17(4):436‐40.

Olweny CLM, Atine I, Kaddu‐Mukassa A, katongole‐Mbide E, Lwanda SK, Johansson B, et al. Cerebrospinal irradiation of Burkitt's lymphoma. Acta radiologica: therapy, physics, biology 1977;16(3):225‐31.

Patte C, Philip T, Rodary C, Zucker J, Behrendt H, Gentet J, et al. High survival rate in advanced‐stage B‐cell lymphomas and leukemias without CNS involvement with a short intensive polychemotherapy: results from the French pediatric oncology society of a randomized trial of 216 children. Journal of clinical oncology 1991;9(1):123‐32.

Sullivan MP, Brecher M, Ramirez I, Ragab A, Hvizdala E, Pullen J, et al. High‐dose Cyclophosphamide‐high‐dose methotrexate with coordinated intrathecal therapy for advanced nonlymphoblastic lymphoma of childhood: results of a pediatric oncology group study. The American journal of pediatric hematology /oncology 1991;13(3):288‐95.

Ziegler JL, Bluming AZ. Intrathecal chemotherapy in Burkitt's lymphoma. British medical journal 1971;3(773):508‐12.

Ziegler JL, Bluming AZ, Magrath IT, Carbone PP. Intensive chemotherapy in patients with generalized Burkitt's lymphoma. International journal of cancer 1972;10(2):254‐61.

Referencias de los estudios excluidos de esta revisión

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estudios incluidos
otras referencias

Adde M, Shad A, Venzon D, Arndt C, Gootenberg J, Neely J, et al. Additional chemotherapy agents improve treatment outcome for children and adults with advanced B‐cell lymphomas. Seminars in oncology 1998;25(2 suppl 4):33‐9.

Aviles A, Delgado S, Huerta‐Guzman J. Marginal zone B cell lymphoma of the parotid glands. European journal of cancer part B, oral oncology 1996;32B(6):420‐2.

Coiffier B, Brousse N, Peuchmaur M, Berger F, Gisselbrecht C, Bryon P A. et al. For the GELA group (Groupe d'Etude des lymphomas Aggressives). Peripheral T‐cell lymphocytes have a poorer prgnosis thab B‐cell lympomas: A prospective study of 361 immunotyped patients treated with LNH‐84 regimen. Journal of the European society for medical oncology/ESMO 1990;1(1):45‐50.

Gururagan S, Sposto R, Cairo MS, Meadows A T, Finlay J L. Outcome of CNS disease at diagnosis in disseminated small non‐cleaved cell lymphoma and B‐cell leukaemia: a children's cancer group study. Journal of clinical oncology 2000;18(10):2017‐25.

Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco AF. Maximising therapeutic effect of rituximab: maintenance treatment vs. re‐treatment at progression in patients with indolent non‐Hodgkin's lymphoma‐ a randomized phase two trial of the Minie Pearl research network. Journal of clinical oncology 2005;23(6):1088‐95.

Haioun C, Lepage E, Gisselbrecht C, Coiffier B, Bosly A, Tilly H, et al. Comparison of autologous bone marrow transplantation (BMT) with sequential chemotherapy for aggressive non‐Hodgkin's lymphoma in first remission: a study on 464 patients (LNH 87 protocol). 5th international conference on malignant lymphoma. 1993:85a.

Google Scholar

Hsu FJ, Casper CB, Czerwinski D, Kwak LW, Liles TM, Syrengelas A, et al. Tumor‐specific idiotype vaccines in the treatment of patients with B‐cell lymphoma‐ long term results of a clinical trial. Blood 1997;89(9):3129‐35.

Kaplan LD, Kahn JO, Crawe S, Northfelt D, Neville P, Grossberg H, et al. Clinical and virologic effects of recombinant human‐granulocyte colony stimulating factor in patients receiving chemotherapy for human immunodeficiency virus‐associated non‐Hodgkin's lymphoma: results of a randomized trial. Journal of clinical oncology 1991;9(6):929‐40.

Kimby E, Mellstedt H. Chlorambucil/prednisolone (CHP) versus CHOP in symptomatic low grade lymphomas. 5th international conference on malignant lymphoma. 1993.

Google Scholar

Levine AM, Wernz JC, Kaplan L, Rodman N, Cohen P, Metroka C, et al. Low‐dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS‐ related lymphoma. JAMA 1991;266(1):84‐8.

Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenburg J, Grillo‐lopez A, et al. Phase I clinical trial using escalating single‐dose infusion of chimeric Anti‐CD20 monoclonal antibody (IDEC‐C2B8) in patients with recurrent B‐cell lymphoma. Blood 1994;84(8):2457‐66.

Maloney DG, Grillo‐Lopez AJ, Bodkin DJ, White CA, Liles TM, Royston I, et al. IDEC‐C2B8: results of a phase I multiple‐dose trial in patients with relapsed non‐Hodgkin's lymphoma. Journal of clinical oncology 1997;15(10):3266‐74.

Olweny CLM, Ziegler JL. Treatment of histiocytic lymphoma in Ugandan adults. East African medical journal 1971;48(10):585‐91.

Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, et al. Two‐weekly or 3‐weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good prognosis (normal LDH) aggressive lymphomas: results of the NHL‐B1 trial of the DSNHL.. Blood 2004;104(3):626‐33.

Reiter A, Tiemann M, Ludwig WD, Wacker HH, Yakisan E, Schrappe M, et al. NHL‐BFM 90 therapy study in treatment of malignant non‐Hodgkin's lymphoma in children and adolescents. Part 1: classification and allocation to strategic therapy groups. BIF study group [Therapiestudie NHL‐BFM 90 zyr behandlung maligner non‐Hodgkin‐lymphome bei kindern und jugendlichen. tiel 1: klassifikation und einteilung in stategische therapiegruppen]. Klinische padiatrie 1994;206(4):222‐33.

Reiter A, Schrappe M, Yakistan E, Sauter S, Ebell W, Zimmermann M, et al. NHL‐BFM 90 therapy study in treatment of malignant non‐Hodgkin's lymphoma in children and adolescents. Part 3: an intermediate term analysis of the B‐NHL/B‐ALL. [Therapiestudie NHL‐BFM 90 zur behandlung maligner non‐Hodkin‐lymphome bei kindern und jugendlichen. Teil 3: eine zwischenanalyse der therapiegruppe B‐NHL/B‐ALL]. Klinische padiatrie 1994;204(4):242‐52.

Tilly H, Mounier N, Lederlin P, Dupriez B, Sebban C, Bosly A, et al. Randomized comparison of ACVBP and m‐BACOD in the treatment o patients with low‐risk aggressive lymphoma: the LNH87‐1 study. Journal of clinical oncology 2000;18(6):1309‐15.

Tura S, Mandelli F, Mazza P, Pileri S, Gherlinzoni F, Bocchia M, et al. MACOP‐B vs. MACHOP in the treatment of high‐grade non‐Hodgkin's lymphoma. Leukemia 1991;5((suppl 1)):74‐8.

Witzig TE. The use of Ibritumomab tiuxetan radioimmunology for patients with relapsed B‐cell non‐Hodgkin's lymphoma. Seminars in oncology 2000;27((suppl 12)):74‐8.

Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, et al. Randomized controlled trial of Yttrium‐90‐labeled Ibritumomab Tiuxetan radioimmunotherapy versus Rituximab immunotherapy for patients with relapsed or refractory low‐grade, follicular, or transformed B‐cell non‐Hodgkin's lymphoma. Journal of clinicaloncology 2002;20(10):2453‐63.

Referencias adicionales

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estudios incluidos
estudios excluidos

Bernheim A, Berger R, Lenoi G. Cytogenic studies on African Burkitt's lymphoma cell lines; t(8;14),t(2;8), and t(8;22) translocations. Cancer Genetics and Cytogenetics 1981;3:307‐15.

Burkitt. Sarcoma involving jaws in African children. British journal of surgery 1958;46:218‐23.

Cairo MS, Sposto R, Perkins SL, Meadows AT, Hoover‐Regan ML, Anderson JR, et al. Burkitt's and Burkitt‐like lymphoma in children and adolescents: a review of the Children's Cancer Group experience.. British Journal of Haematology 2003;4:660‐70. [MEDLINE: 12588354]

Goldstein J A, Berstein R L. Burkitt's lymphoma and the role of Ebstein‐ Barr virus. Journal of tropical paediatrics 1990;30:114‐9.

Google Scholar

Magrath IT, Ziegler JL, Bluming AZ. Preliminary results of a randomized trial of BCG immunotherapy in Burkitt's lymphoma.. Recent results in cancer research 1974;47:461‐5..

Magrath I T, Lwanga S, Carswell W, Harrison N. Surgical reduction of tumor bulk in management of abdominal Burkitt's Lymphoma. British Medical Journal 1974;2:308‐12.

Magrath IT. Malignant non‐Hodgkin's lymphomas in children. Hematology and oncology Clinics of North America 1987;1(4):577‐602. [MEDLINE: 3323174]

Magrath IT, Shiramizu B. Biology and treatment of small non‐cleaved cell lymphoma. Biology and treatment of small non‐cleaved cell lymphoma. Biology and treatment of small non‐cleaved cell lymphoma. Oncology 1989;3(11):41‐53. [MEDLINE: 2578020]

Meremikwu MM, Ehiri JE, Nkanga DG, Udoh EE, Ikpatt OF, Alaje EO. Socio‐economic constraints to effective management of Burkitt's lymphoma in south‐east Nigeria. Tropical medicine and international health2005 (in press).

Google Scholar

Norlin T, Clifford P, Einhorn J, et al. Conventional and superfractionated radiation therapy in Burkit's lymphoma. Acta Radiologica 1971;10:545‐57.

Google Scholar

Oguonu T, Emodi I, Kaine W. Epidemiology of Burkitt's lymphoma in Enugu, Nigeria. Annals of tropical paediatrics 2002;22(4):369‐74. [MEDLINE: 12530287]

Olweny CL, Katongole‐Mbidde E, Otim D, Lwanga SK, Magrath IT, Ziegler JL. Long‐term experience with Burkitt's lymphoma in Uganda. International journal of cancer 1980;26(3):261‐6. [MEDLINE: 7287207]

Smeland S, Blystad AK, Kvaloy SO, Ikonomou IM, Delabie J, Kvalheim G, et al. Treatment of Burkitt's/Burkitt‐like lymphoma in adolescents and adults: a 20‐year experience from the Norwegian Radium Hospital with the use of three successive regimens.. Annals of Oncology 2004;15(7):1072‐78. [MEDLINE: 15205201]

Sugimoto M, Tahara H, Ide T, Furuichi Y. Steps involed in immortalization and tumorigenesis of human b‐lymphoblastoid cell lines transformed by Epstein‐Barr virus. Cancer research 2004;64(10):3361‐4. [MEDLINE: 15150084]

Ziegler J L. Chemotherapy of Burkitt's lymphoma. Cancer 1972;30:1534‐40.

Ziegler J L, Magrath I T. Pathology annual. Ioachim H L. New York: Apleton‐Century‐Crofts, 1974.

Ziegler JL. Burkitt's Lymphoma. New England Journal of Medicine 1981;305:735‐45.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Anderson 1983

Methods	Randomised, parallel group, multicentre trial (North America) Method of randomisation: telephone call to central office (adaptive randomisation). Allocation concealment: adequate Blinding: not reported ITT: yes Withdrawals: stated
Participants	Baseline characteristics: 234 participants randomised (Regimen 1: 99; 106; 47 (20%) of participants had BL; M:F: 184:50). Mean age: not reported. Tumour staging: Rappaport. Diagnosis: Histopathological confirmation of childhood NHL Entry criteria: <18 years of age; no previous treatment for NHL; biopsy confirmed NHL Exclusion criteria: not stated
Interventions	COMP versus LSA2‐L2 (modified). See table 1 for details of treatment protocol. Treatment duration: 18 months Follow‐up: two‐four years
Outcomes	Overall survival (12‐24 months). Failure free survival @ 24mths. Relapse rate. Adverse events and toxicity.
Notes	Addional 23 participants followed during course of study but not randomly allocated to treatment group Full text publication Randomisation rating: A Withdrawal bias rating: B
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Brecher 1997

Methods	Randomised, parallel group, multicentre trial (North America) Method of randomisation: unclear Allocation concealment: unclear Blinding: not reported ITT: yes Withdrawals: stated
Participants	Baseline characteristics: 106 male, 17 female, all participants had stage III disease (Regimen A: 65; Regimen B: 58). Mean age: 8.6 yrs range 2.3‐20.3 yrs Tumour staging: Murphy classification Diagnosis: histo‐cytologic diagnosis of SNCCL Entry criteria: newly diagnosed stage III SNCCL, pathology confirmed Exclusion criteria :not stated
Interventions	Regimen A (prespecified duration) versus Regimen B:(duration determined by clinical response) Treatment duration: 9 months Follow‐up: 3‐8 years
Outcomes	Overall survival. Event‐free survival. Remission rate Relapse rate
Notes	Full text publication Randomisation rating: B Withdrawal bias rating: B Study type: remission induction
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Cairo 2003a

Methods	Randomised, parallel group, multicentre trial (Europe) Method of randomisation: unclear. Allocation concealment: unclear. Blinding: not reported ITT: unclear Withdrawals: unclear
Participants	Baseline characteristics: 241 participants screened (Burkitt's and Burkitt's‐like lymphoma: 51.3%), 195 randomised (standard dose: 96; reduced intensity: 99) Median age: 8 (range: 1‐19) Tumour staging: REAL Diagnosis: not reported Entry criteria: </=21 years; advanced disease (bone marrow and/or CNS, B‐NHL [LCL, BL and BLL]). Exclusion criteria: not described
Interventions	Standard dose versus reduced intensity chemotherapy Tretament duration: not reported Follow‐up: median 3.25 years
Outcomes	Overall survival. Event‐free survival.
Notes	Unpublished conference abstract Randomisation rating: B Withdrawal bias rating: B Study type: remission induction
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Magrath 1973

Methods	Randomised, parallel group, Method of randomisation: unclear Allocation concealment: unclear. Blinding: not reported ITT: unclear Withdrawals: stated
Participants	Baseline characteristics: 35 participants recruited (interim analysis). No other details reported. Mean age: Not reported Tumour staging: Not reported. Diagnosis: Not reported. Entry criteria: In remission from BL post cyclophosphamide
Interventions	CCNU (70mg/m2) administered orally once versus no treatment post treatment with C (two doses, 40mg/kg IV, two weeks apart). Treatment duration: 2 weeks Follow‐up: Unclear
Outcomes	CNS relapse
Notes	Unpublished conference abstract Randomisation rating: B Withdrawal bias rating: B Study type: remittance maintenance
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Magrath 1976

Methods	Randomised, parallel group, single centre trial (Uganda) Method of randomisation: unclear. Allocation concealment: unclear. Blinding: no ITT: unclear Withdrawals: stated.
Participants	Baseline characteristics: Screening population: 80. 45 participants randomised (40 evaluated BCG: 21; control: 19; M:F: BCG: 15:6; Control: 14:5) Mean age: BCG: 10; control: 6 Tumour staging: WHO. Diagnosis: Histopathology. Entry criteria: untreated BL; remission two weeks after treatment with C
Interventions	BCG versus no treatment. Participants randomised if in remission two weeks post C. Follow‐up: Median 1.75 years
Outcomes	Relapse. Overall survival. Event‐free survival. Toxicity.
Notes	Participants recruited if in remission. Randomisation rating: B Withdrawal bias rating: B Study type: remittance maintenance
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Neequaye 1990

Methods	Randomised, parallel group, single centre study (Ghana) Method of randomisation: randomised number list Allocation concealment: unclear Blinding: no ITT: unclear Withdrawals: stated
Participants	Baseline characteristics: 46 participants screened and given 3 courses of C (27 children randomised (M:F: 16:11)) Median age: 9 Tumour staging: Unclear Diagnosis: Histopathology Entry criteria: Stage III BL; adequate response to cyclophosphamide Exclusion criteria: not reported
Interventions	TF IM (once per month) versus no treatment. Incomplete administration of treatment due to limited supply of TF. Study duration: Maximum of one year Follow‐up: Median 3.3 years
Outcomes	Relapse. Overall survival.
Notes	Full text publication. Randomisation rating: A Withdrawal bias rating: B Study type: remittance maintenance
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Olweny 1976

Methods	Randomised, parallel group, single centre trial (Kenya). Method of randomisation: prepared cards. Concealment of allocation: unclear. Blinding: no ITT: no Withdrawals: stated
Participants	Baseline characteristics: 40 participants randomised Mean age: Not reported Tumour staging: Ziegler and Magrath Diagnosis: Histolopathology Entry criteria: Confirmed BL.
Interventions	C versus C,O, MTX Treatment duration: 2 weeks (or as soon as toxicity abated). A third dose was given to 3 participants in C group and in one participant in C.O.MTX group. Follow‐up: unclear
Outcomes	Relapse. Overall survival. Response (remission, reduction in tumour size or no response).
Notes	Full text publication Randomisation rating: A Withdrawal bias rating: A Study type: remission induction
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Olweny 1977

Methods	Randomised, parallel group, single centre trial (Kenya). Method of randomisation: prepared cards. Concealment of allocation: unclear. Blinding: no ITT: no Withdrawals: stated
Participants	Baseline characteristics: 25 participants randomised. Median age: Irradiation: 8; no irradiation: 5 (range: 4‐14). Tumour staging: Ziegler and Magrath Diagnosis: Histology or cytology Entry criteria: BL free of CNS involvement in remission post treatment with C, MTX, or O.
Interventions	Irradiation versus no irradiation. Dose given was 20 to 24 Gy (0.7 to 0.75 Gy per fraction). Treatnment duration: 2 x 5 days Follow‐up: 1.6 years
Outcomes	Relapse. Overall survival.
Notes	Full text publication Randomisation rating: A Withdrawal bias rating: A Study type: remittance maintenance
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Patte 1991

Methods	Randomised, parallel group, multicentre trial (Europe). Method of randomisation: central, balanced block randomisation. Allocation concealment: adequate. Blinding: no. ITT: unclear Withdrawals: stated
Participants	Baseline characteristics: 216 eligible (166 randomised; long duration: 84; short duration: 82). Age range : 6 months ‐17 years Tumour staging: Murphy Diagnosis: histology, cytology or immunotyping Entry criteria: Age <17 years, diagnosis of BL, stage III and IV disease Exclusion criteria: CNS involvement. After 1986, only those with abdominal or head‐neck primary tumours were included.
Interventions	Short course (5 weeks) versus long course (16 weeks plus 2 additional drugs) maintenance chemotherapy Follow‐up: unclear
Outcomes	Remission. Relapse. Toxicity. Overall survival. Event‐free survival
Notes	Full text publication. Randomisation rating: A Withdrawal bias rating: A Equivalence trial. Study type: remission induction
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Sullivan 1991

Methods	Randomised, parallel group, multicentre trial (North America) Method of randomisation: unclear. Allocation concealment: unclear. Blinding: no ITT: unclear Withdrawals: stated
Participants	Baseline characteristics: 168 participants registered, 148 were evaluable, 73 had BL. Median age: 8.7 years (range 0.7‐18.7), M:F; 4.4:1.0 Tumour staging: Murphy Diagnosis: unclear (institutional review) Entry criteria: stage III and IV non lymphoblastic NHL, age < 22 years Exclusion criteria: not stated
Interventions	Short term (2 months) versus long term (6 months) maintenance treatment Follow‐up: 3‐7 years
Outcomes	Complete remission. Event‐free survival. Toxicity
Notes	Full text publication. Randomisation rating: B Withdrawal bias rating: B Study type: remission induction
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Ziegler 1971

Methods	Randomised, parallel group, single site trial (Uganda) Method of randomisation: unclear Allocation concealment: unclear. Blinding: no ITT: unclear Withdrawals: not stated
Participants	Baseline characteristics: sample size; 20 evaluated for study Age range: 3‐14 years Tumour staging: Ziegler Diagnosis: unclear Entry criteria: BL at stage I‐III; no evidence of malignant pleocyotosis on admission Exclusion criteria: not stated
Interventions	Prophylactic IT therapy versus no treatment Treatment duration: 4 or 10 days Follow‐up: participants followed to relapse.
Outcomes	Relapse rate
Notes	Full publication Randomisation rating: B Withdrawal bias rating: B Method of remission induction not clear Study type: remittance maintenance
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Ziegler 1972a

Methods	Randomised, parallel group, single site trial (Uganda) Method of randomisation: unclear. Allocation concealment: unclear. ITT: no Withdrawals: stated
Participants	Baseline characteristics: sample size: 41 participants, 27 were evaluable for the study Age range: 3‐25 years Tumour staging: Ziegler Diagnosis: histopathologic Entry criteria: stage III or IV disease, untreated, histopathologic diagnosis Exclusion criteria: not stated
Interventions	C versus TRIKE regimen Follow‐up: Participants followed up until death.
Outcomes	Relapse. Remission. Overall survival.
Notes	2:1 allocation was used in randomisation. Full text publication Randomisation rating: B Withdrawal bias rating: C Study type: remission induction
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

NHL: Non‐Hodgkin's Lymphoma, LCL: Large cell lymphoma; BL: Burkit's lymphoma; BLL: Burkitt's‐like lymphoma; C: cyclophosphamide, O: vincristine, MTX: methotrexate, P: prednisolone, DAU: daunorubicin, CYT: cytarabine, THIO: thioguanine, ASP: asparaginase, CAR: carmustine, H:hydroxyurea, SNCCL: small noncleaved cell lymphoma, Ara‐C: cytosine arabinoside, DOX: doxorubicin, Cairo; conference proceedings; CCNU: Lomustine; CNS: central nervous system; TF: Transfer factor; HYD: hydrocortisone; CFR: citrovorum factor rescue; VP‐16: etoposide; SC: subcutaneously; CI: continuous infusion; IT: intrathecal;

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Adde 1998	There was no randomisation
Aviles 1983	The study was done in adults and the tumour type (marginal zone B‐cell lymphoma) is different
Coiffier 1990	The age group of the study participants were not stated but the tumour type is different and the study was not randomised
Gururagan 2000	This is a review article, no randomisation
Hainsworth 2005	No randomisation, tumour type is different
Haioun 1993	Study was done in adults
Hsu 1997	Age was above the cut off. The study was not randomised, tumour type is different
Kaplan 1991	The study was done in adults
Kimby 1993	The tumour type is different
Levine 1991	Age above cutoff, the study was not randomised
Maloney 1994	Age above cutoff, study was not randomised
Maloney 1997	Age above cutoff, study was not randomised
Olweny 1971	The study was done in adults
Pfreundschuh 2004	The study was done in adults
Reiter 1994a	Not randomised
Reiter 1994b	Not randomised
Tilly 2000	The study was done in adults
Tura 1991	The study was done in adults
Witzig 2000	The study was done in adults
Witzig 2002	The study was done in adults, tumour type is different

Data and analyses

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Comparison 1. COMP versus modified LSA2 L2 (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Open in table viewer

Comparison 2. Prespecified duration versus duration determined by clinical response (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	123	Odds Ratio (M‐H, Fixed, 95% CI)	1.58 [0.69, 3.63]
Open in figure viewer Analysis 2.1 Comparison 2 Prespecified duration versus duration determined by clinical response (remission induction), Outcome 1 Overall survival.
2 Event‐free survival Show forest plot	1	123	Odds Ratio (M‐H, Fixed, 95% CI)	2.10 [0.93, 4.74]
Open in figure viewer Analysis 2.2 Comparison 2 Prespecified duration versus duration determined by clinical response (remission induction), Outcome 2 Event‐free survival.
3 Remission rate Show forest plot	1	122	Odds Ratio (M‐H, Fixed, 95% CI)	0.24 [0.06, 0.89]
Open in figure viewer Analysis 2.3 Comparison 2 Prespecified duration versus duration determined by clinical response (remission induction), Outcome 3 Remission rate.
4 Toxicity and adverse events Show forest plot	1	123	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.02, 0.46]
Open in figure viewer Analysis 2.4 Comparison 2 Prespecified duration versus duration determined by clinical response (remission induction), Outcome 4 Toxicity and adverse events.

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Comparison 3. Standard versus reduced dose chemotherapy (remission inducing)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Open in table viewer

Comparison 4. C versus combination chemotherapy (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	2.75 [0.76, 9.95]
Open in figure viewer Analysis 4.1 Comparison 4 C versus combination chemotherapy (remission induction), Outcome 1 Overall survival.
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate Show forest plot	1	37	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.16, 5.39]
Open in figure viewer Analysis 4.3 Comparison 4 C versus combination chemotherapy (remission induction), Outcome 3 Remission rate.
4 Relapse Show forest plot	1	31	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.16, 2.87]
Open in figure viewer Analysis 4.4 Comparison 4 C versus combination chemotherapy (remission induction), Outcome 4 Relapse.
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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Comparison 5. Long versus short duration chemotherapy (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	166	Odds Ratio (M‐H, Fixed, 95% CI)	0.8 [0.30, 2.14]
Open in figure viewer Analysis 5.1 Comparison 5 Long versus short duration chemotherapy (remission induction), Outcome 1 Overall survival.
2 Event‐free survival Show forest plot	1	166	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.43, 3.20]
Open in figure viewer Analysis 5.2 Comparison 5 Long versus short duration chemotherapy (remission induction), Outcome 2 Event‐free survival.
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Toxicity and adverse events Show forest plot	1	166	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.78]
Open in figure viewer Analysis 5.5 Comparison 5 Long versus short duration chemotherapy (remission induction), Outcome 5 Toxicity and adverse events.

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Comparison 6. Two month versus six month maintenance regimen (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival Show forest plot	1	99	Odds Ratio (M‐H, Fixed, 95% CI)	0.59 [0.13, 2.60]
Open in figure viewer Analysis 6.2 Comparison 6 Two month versus six month maintenance regimen (remission induction), Outcome 2 Event‐free survival.
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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Comparison 7. C versus TRIKE (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	28	Odds Ratio (M‐H, Fixed, 95% CI)	2.6 [0.52, 13.04]
Open in figure viewer Analysis 7.1 Comparison 7 C versus TRIKE (remission induction), Outcome 1 Overall survival.
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	28	Odds Ratio (M‐H, Fixed, 95% CI)	2.55 [0.41, 15.65]
Open in figure viewer Analysis 7.4 Comparison 7 C versus TRIKE (remission induction), Outcome 4 Relapse.
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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Comparison 8. CCNU versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	1.0 [0.21, 4.86]
Open in figure viewer Analysis 8.4 Comparison 8 CCNU versus no treatment (remission maintenance), Outcome 4 Relapse.
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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Comparison 9. BCG versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.28, 4.51]
Open in figure viewer Analysis 9.1 Comparison 9 BCG versus no treatment (remission maintenance), Outcome 1 Overall survival.
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.8 [0.23, 2.79]
Open in figure viewer Analysis 9.4 Comparison 9 BCG versus no treatment (remission maintenance), Outcome 4 Relapse.
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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Comparison 10. TF versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	0.38 [0.06, 2.52]
Open in figure viewer Analysis 10.1 Comparison 10 TF versus no treatment (remission maintenance), Outcome 1 Overall survival.
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	0.34 [0.07, 1.68]
Open in figure viewer Analysis 10.4 Comparison 10 TF versus no treatment (remission maintenance), Outcome 4 Relapse.
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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Comparison 11. Irradiation versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	3.75 [0.32, 43.31]
Open in figure viewer Analysis 11.1 Comparison 11 Irradiation versus no treatment (remission maintenance), Outcome 1 Overall survival.
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	2.1 [0.38, 11.59]
Open in figure viewer Analysis 11.4 Comparison 11 Irradiation versus no treatment (remission maintenance), Outcome 4 Relapse.
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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Comparison 12. Intrathecal MTX versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	20	Odds Ratio (M‐H, Fixed, 95% CI)	1.5 [0.26, 8.82]
Open in figure viewer Analysis 12.4 Comparison 12 Intrathecal MTX versus no treatment (remission maintenance), Outcome 4 Relapse.
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Analysis 2.1

Comparison 2 Prespecified duration versus duration determined by clinical response (remission induction), Outcome 1 Overall survival.

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Analysis 2.2

Comparison 2 Prespecified duration versus duration determined by clinical response (remission induction), Outcome 2 Event‐free survival.

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Analysis 2.3

Comparison 2 Prespecified duration versus duration determined by clinical response (remission induction), Outcome 3 Remission rate.

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Analysis 2.4

Comparison 2 Prespecified duration versus duration determined by clinical response (remission induction), Outcome 4 Toxicity and adverse events.

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Analysis 4.1

Comparison 4 C versus combination chemotherapy (remission induction), Outcome 1 Overall survival.

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Analysis 4.3

Comparison 4 C versus combination chemotherapy (remission induction), Outcome 3 Remission rate.

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Analysis 4.4

Comparison 4 C versus combination chemotherapy (remission induction), Outcome 4 Relapse.

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Analysis 5.1

Comparison 5 Long versus short duration chemotherapy (remission induction), Outcome 1 Overall survival.

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Analysis 5.2

Comparison 5 Long versus short duration chemotherapy (remission induction), Outcome 2 Event‐free survival.

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Analysis 5.5

Comparison 5 Long versus short duration chemotherapy (remission induction), Outcome 5 Toxicity and adverse events.

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Analysis 6.2

Comparison 6 Two month versus six month maintenance regimen (remission induction), Outcome 2 Event‐free survival.

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Analysis 7.1

Comparison 7 C versus TRIKE (remission induction), Outcome 1 Overall survival.

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Analysis 7.4

Comparison 7 C versus TRIKE (remission induction), Outcome 4 Relapse.

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Analysis 8.4

Comparison 8 CCNU versus no treatment (remission maintenance), Outcome 4 Relapse.

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Analysis 9.1

Comparison 9 BCG versus no treatment (remission maintenance), Outcome 1 Overall survival.

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Analysis 9.4

Comparison 9 BCG versus no treatment (remission maintenance), Outcome 4 Relapse.

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Analysis 10.1

Comparison 10 TF versus no treatment (remission maintenance), Outcome 1 Overall survival.

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Analysis 10.4

Comparison 10 TF versus no treatment (remission maintenance), Outcome 4 Relapse.

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Analysis 11.1

Comparison 11 Irradiation versus no treatment (remission maintenance), Outcome 1 Overall survival.

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Analysis 11.4

Comparison 11 Irradiation versus no treatment (remission maintenance), Outcome 4 Relapse.

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Analysis 12.4

Comparison 12 Intrathecal MTX versus no treatment (remission maintenance), Outcome 4 Relapse.

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Table 1. Chemotherapy regimens

Study ID	Common treatment	Intervention 1	intervention 2
Anderson 1983	C; 1.2g/m2 IV on D1, O; 2.0mg/m2(max 2mg) IV on D3,10,17 and 24, MTX; 6.25mg/m2 IT on D5, 31,34. P; 15mg/m2 (max 60mg) orally qds on D3‐30 decreasing to zero on D31‐3. Radiation therapy. Tumour excision attempted in patients with localised disease. Laparotomy and biopsy in patients with non‐localised disease.	COMP Induction: MTX 300mg/m2 IV on D12, 7 Maintanance: C; 1g/m2 IV on D1, O; 1.5mg/m2 Iv on D1,4, MTX; 6.25mg/m2 IT on D1 (excluded from ist maintenance cycle), the 300mg/m2 IV on D15. Repeat maintenance cycle every 28 days	LSA2 L2 (modified) Induction: DAU; 60mg/m2 IV on D12 and 13 Consolidation: CYT; 100mg/m2 IV 5 days on ,2 days off x 2weeks, THIO; 50mg/m2 orally 8‐12 hrs post CYT injection, ASP; 6000IU/m2 IM daily x14 days post CYT and THIO. MTX; 6.25mg/m2 IT x2 3 days apart, 2‐3 days after last dose of ASP, CAR; 60mg/m2 IV single dose given 2‐3 days after completion of MTX Maintanance: THIO; 300mg/m2 orally on D1‐4, ; 600mg/m2 IV on D5, H; 2.4g/m2 orally on D1‐4, DAU 45mg/m2 orally on D5, CYT; 150mg/m2 IV D1‐5, O; 2.0 mg/m2 (max 2mg) IV on D5, MTX; 6.25 mg/m2 IT x2 doses 3days apart. Repeat maintenance cycles 1‐5
Brecher 1997	None	A Prespecified duration: Induction:C on D1 (dose not specified), MTX on D24 and 31 (dose not specified), O: wkly (x5weeks dose not specified), P: daily x4weeks (dose not specified) Consolidation(22 weeks): C: D52 and 102, MTX on D74,81,124, and 131, O: I hour prior to each MTX Maintanance(11 weeks): O and MTX on D174 and 216, CNS prophylaxis: Ara‐C;, MTX and hydrocortisone	B Duration determined by clinical response: Induction: fractionated C,O and DOX Infusion phase: sequential continuous infusion of MTX and Ara‐c (pending mucosal and bone marrow recovery) Repeat induction and infusion x 4 with dose of Ara‐c being doubled with each course CNS prophylaxis: MTX and Ara‐c
Cairo 2003	Prephase: C: 0.3g/m2 IV, O; 1mg/m2 IV on D1; P: 60mg/m2 IV or orally in 2 fractions on D1‐7, MTX+HYD+Ara‐C: 30mg IT on D1,3 and 5. Induction: COPADM 1 (started 1 wk after D1 of prephase) O: 2mg/m2 (max 2mg) IV, high dose MTX 8g/m2 IV x4 hours on D1, CFR: 15mg/m2 every 6 hrs orally on D2‐4; MTX+HYD+Ara‐C: 30mg IT on D2,4 and 6; DOX: 60mg/m2 IV on D2; C: 0.5g/m2 IV (in 2 fractions) on D2‐4; P: 60mg/m2 IV or orally on D1‐6 COPADM 2 similar to COPADM1 except for: 2nd O dose: 2mg/m2 (max 2mg) IV on D6; C: 1g/m2 IV (in 2 fractions) on D2‐4.	Reduced intensity Similar to standard dose except for consolidation drugs are given at 2/3 the standard doses and deletion of M2‐4 maintenance.	Standard dose Consolidation: (x2 courses) Ara‐C: 50mg/m2 CI x12hrs on D1‐5(8pm‐8am); high dose Ara‐C 3g/m2 IV x3hours on D2‐5(8‐11am); VP‐16: 200mg/m2 IV on D2‐5(2‐4pm). Maintenance (monthly alternating courses) M1: O: 2mg/m2(max 2mg) IV, high dose MTX 8g/m2 IVx4hours on D1; CFR: 15mg/m2 every 6hours orally on D2‐4; P: 60mg/m2 orally on D1‐5; MTX+HYD+Ara‐C: 30mg IT on D2; C: 0.5g/m2 IV on D1 and 2; DOX: 60mg/m2 IV on D2. M2/M4: VP‐16: 150mg/m2 IV on D1‐3; Ara‐C: 100mg/m2 SC(in 2 fractions) on D1‐5. M3: similar to M1 but without high dose MTX and IT
Olweny 1976	none	C: 40mg/kg IV on D1,repeated after 2 weeks or as soon as toxicity is abated	C: 30mg/kg IV on D1, O: 2mg/m2 IV on D1, MTX 15mg/m2 orally on D1‐3. This is repeated 12‐14 days later.
Patte 1991	Reduction phase: C: 0.3g/m2 IV, O; 1mg/m2 IV on D1; P: 2mg/kg orally on D1‐7, MTX+HYD: 15mg/m2 IT on D1. Induction: COPADM 1 (started 1 wk after D1 of prephase) O: 2mg/m2 IV, high dose MTX 3g/m2 IV x3 hours on D1, CFR: 15mg/m2 every 6 hrs orally on D2‐4; MTX+HYD: 15mg IT on D2 and 6; DOX: 60mg/m2 IV on D2; C: 0.5g/m2 IV (in 2 fractions) on D2‐4; P: 2mg/kg IV or orally on D1‐6 COPADM 2 similar to COPADM1 except for: addition of 2nd O dose: 2mg/m2 IV on D6; C: 1g/m2 IV (in 2 fractions) on D2‐4. CYM:high dose MTX 3g/m2 IV x3 hours on D1; CFR: 15mg/m2 every 6 hrs orally on D2‐4; Ara‐C: 100mg/m2 CI on D2‐6; Ara‐C+HYD: 30mg/m2 IT on D6 Maintenance (monthly alternating courses) M1: O: 2mg/m2 IV, high dose MTX 3g/m2 IVx3hours on D1; CFR: 15mg every 6hours orally on D2‐4; P: 2mg/kg orally on D1‐5; MTX+HYD: 15mg IT on D2; C: 0.5g/m2 IV on D1 and 2; DOX: 60mg/m2 IV on D2. M2: CCNU: 60mg/m2 orally on D28; Ara‐C: 100mg/m2 SC(in 2 fractions) on D28‐31; Ara‐C+HYD: 30mg/m2 IT on D28; THIO: 150mg/m2 orally on D28‐31	Long arm: CYM 1, Mini‐BACT:CCNU: 60mg/m2 orally on D1; Ara‐C: 100mg/m2 CI on D2‐6; THIO: 150mg/m2 orally on D2‐6; C: 0.5g/m2 IV on D2‐4. M1, M2, M1, M2	Short arm: CYM 1 and 2, M1
Sullivan 1991	Induction: C: 1.2g/m2 Iv on D1, repeat on D1 of weeks 7 and 14; O: 2.0mg/m2(max 2.omg) IV on D2 or 3 weekly x4 then 1.0mg/m2 IV given 1 hour before MTX infusion; P: 60mg/m2(max 60mg) orally daily from D1 x28 days; MTX: 2 6‐hour infusion starting from week 3, starting dose 50mg/kg increasing to 100mg/kg then to 200mg/kg throughout the rest of the treatment, given as 2 doses every 7 weeks during induction and consolidation and every 6 weeks during maintenance; CFR: 15mg IV 3hourly x9 doses then 15mg 6 hourly x8 doses after each MTX infusion; CNS prophylaxis: CYT: 45mg/m2 on D1 and 2, MTX 15mg/m2 on D3 starting on D2 of induction, subsequently given as triple therapy (CYT 60mg/m2, MTX 15mg/m2 (max 15mg, HYD 30mg/m2) at week 6 and 14, then 24 hours before each pair of MTX infusions. Maintenance: triple therapy, IV MTX, IV O	Maintenance regimen for 2 months	Maintenance regimen for 6 months
Ziegler 1971	unclear	MTX 25mg/m2 IT alternating with Ara‐C 50mg /m2 IT every 4 days. Two dose of each drug was given	No intrathecal therapy
Ziegler 1972a	none	C: 40mg/kg IV at 2 weekly intervals for 6 doses	TRIKE schedule C: 4omg/kg followed in two weeks by O: 1.4mg/m2 IV on D1 and MTX 15mg/m2 orally on D1‐4; Ara‐C: two weeks later; 250mg/m2 CI daily x3days.

Table 1. Chemotherapy regimens

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Table 2. Percentage of deaths (remission inducing studies)

Study	Comparison	Rx 1	Rx 2/control
Brecher 1997	Prespecified duration (1) versus duration determined by clinical response (2)	29	21
Olweny 1976	C: 40mg/kg IV on D1,repeated after 2 weeks or as soon as toxicity is abated (1) versus C: 30mg/kg IV on D1, O: 2mg/m2 IV on D1, MTX 15mg/m2 orally on D1‐3. This is repeated 12‐14 days later (2)	58	33
Patte 1991	Long duration chemotherapy (1) versus short duration chemotherapy (2)	10	12
Ziegler 1972a	C (1) versus TRIKE (2)	50	28

Table 2. Percentage of deaths (remission inducing studies)

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Table 3. Percentage of events (remission inducing studies)

Study	Comparison	Rx 1	Rx 2/control
Brecher 1997	Prespecified duration (1) versus duration determined by clinical response (2)	35	21
Patte 1991	Long duration chemotherapy (1) versus short duration chemotherapy (2)	11	13
Sullivan 1991	Two (1) versus six (2) month duration of maintenance chemotherapy.	6	10

Table 3. Percentage of events (remission inducing studies)

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Table 4. Percentage of remission (remission inducing studies)

Study	Comparison	Rx 1	Rx 2/control
Brecher 1997	Prespecified duration (1) versus duration determined by clinical response (2)	81	89
Patte 91	Long duration chemotherapy (1) versus short duration chemotherapy (2)	87	89
Olweny 76	Irradiation (1) versus no treatment (2)	83	84

Table 4. Percentage of remission (remission inducing studies)

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Table 5. Percentage of relapse (remission inducing studies)

Study	Comparison	Rx 1	Rx2/control
Brecher 1997	Prespecified duration (1) versus duration determined by clinical response (2)	15	15
Olweny 1976	C: 40mg/kg IV on D1,repeated after 2 weeks or as soon as toxicity is abated (1) versus C: 30mg/kg IV on D1, O: 2mg/m2 IV on D1, MTX 15mg/m2 orally on D1‐3. This is repeated 12‐14 days later (2)	53	62
Patte 1991	Long duration chemotherapy (1) versus short duration chemotherapy (2)	11	10
Ziegler 1972a	C (1) versus TRIKE (2)	80	61

Table 5. Percentage of relapse (remission inducing studies)

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Table 6. Percentage of toxicity (remission inducing studies)

Study	Comparisons	Rx1	Rx2/ control	type of toxicity
Brecher 1997	Prespecified duration (1) versus duration determined by clinical response (2)	74	96	Grade 3 and 4 toxicity; haematologic, neurotoxic, infections
Patte 1991	Long duration chemotherapy (1) versus short duration chemotherapy (2)	0	4	haematologic, multiorgan failure, infections

Table 6. Percentage of toxicity (remission inducing studies)

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Table 7. Percentage of deaths (remission maintaining studies)

Study	Comparison	Rx 1	Rx 2/control
Magrath 1976	BCG (1) versus no treatment (2)	29	26
Neequaye 1990	TF (1) versus no treatment (2)	14	31
Olweny 1977	Irradiation (1) versus no treatment (2)	27	9

Table 7. Percentage of deaths (remission maintaining studies)

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Table 8. Percentage of relapse (remission maintaining studies)

Study	Comparison	Rx 1	Rx 2/control	type of relapse
Neequaye 1990	TF (1) versus no treatment (2)	28	54	Not stated
Magrath 1976	BCG (1) versus no treatment (2)	52	58	Central nervous system
Magrath 1973	CCNU (1) versus no treatment (2)	38	38	Central nervous system
Olweny 1977	Irradiation (1) versus no treatment (2)	54	36	Central nervous system
Ziegler 1971	Intrathecal chemotherapy (MTX) (1) versus no treatment (2)	50	40	Central nervous system

Table 8. Percentage of relapse (remission maintaining studies)

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Comparison 1. COMP versus modified LSA2 L2 (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 1. COMP versus modified LSA2 L2 (remission induction)

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Comparison 2. Prespecified duration versus duration determined by clinical response (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	123	Odds Ratio (M‐H, Fixed, 95% CI)	1.58 [0.69, 3.63]

2 Event‐free survival Show forest plot	1	123	Odds Ratio (M‐H, Fixed, 95% CI)	2.10 [0.93, 4.74]

3 Remission rate Show forest plot	1	122	Odds Ratio (M‐H, Fixed, 95% CI)	0.24 [0.06, 0.89]

4 Toxicity and adverse events Show forest plot	1	123	Odds Ratio (M‐H, Fixed, 95% CI)	0.10 [0.02, 0.46]

Comparison 2. Prespecified duration versus duration determined by clinical response (remission induction)

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Comparison 3. Standard versus reduced dose chemotherapy (remission inducing)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 3. Standard versus reduced dose chemotherapy (remission inducing)

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Comparison 4. C versus combination chemotherapy (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	2.75 [0.76, 9.95]

2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate Show forest plot	1	37	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.16, 5.39]

4 Relapse Show forest plot	1	31	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.16, 2.87]

5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 4. C versus combination chemotherapy (remission induction)

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Comparison 5. Long versus short duration chemotherapy (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	166	Odds Ratio (M‐H, Fixed, 95% CI)	0.8 [0.30, 2.14]

2 Event‐free survival Show forest plot	1	166	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.43, 3.20]

3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Toxicity and adverse events Show forest plot	1	166	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.78]

Comparison 5. Long versus short duration chemotherapy (remission induction)

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Comparison 6. Two month versus six month maintenance regimen (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival Show forest plot	1	99	Odds Ratio (M‐H, Fixed, 95% CI)	0.59 [0.13, 2.60]

3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 6. Two month versus six month maintenance regimen (remission induction)

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Comparison 7. C versus TRIKE (remission induction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	28	Odds Ratio (M‐H, Fixed, 95% CI)	2.6 [0.52, 13.04]

2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	28	Odds Ratio (M‐H, Fixed, 95% CI)	2.55 [0.41, 15.65]

5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 7. C versus TRIKE (remission induction)

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Comparison 8. CCNU versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	1.0 [0.21, 4.86]

5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 8. CCNU versus no treatment (remission maintenance)

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Comparison 9. BCG versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.28, 4.51]

2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.8 [0.23, 2.79]

5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 9. BCG versus no treatment (remission maintenance)

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Comparison 10. TF versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	0.38 [0.06, 2.52]

2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	0.34 [0.07, 1.68]

5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 10. TF versus no treatment (remission maintenance)

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Comparison 11. Irradiation versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	3.75 [0.32, 43.31]

2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	2.1 [0.38, 11.59]

5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 11. Irradiation versus no treatment (remission maintenance)

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Comparison 12. Intrathecal MTX versus no treatment (remission maintenance)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Event‐free survival	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Remission rate	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Relapse Show forest plot	1	20	Odds Ratio (M‐H, Fixed, 95% CI)	1.5 [0.26, 8.82]

5 Toxicity and adverse events	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 12. Intrathecal MTX versus no treatment (remission maintenance)

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Referencias

Referencias de los estudios incluidos en esta revisión

Anderson 1983 {published data only}

Brecher 1997 {published data only}

Cairo 2003a {published data only}

Magrath 1973 {published data only}

Magrath 1976 {published data only}

Neequaye 1990 {published data only}

Olweny 1976 {published data only}

Olweny 1977 {published data only}

Patte 1991 {published data only}

Sullivan 1991 {published data only}

Ziegler 1971 {published data only}

Ziegler 1972a {published data only}

Referencias de los estudios excluidos de esta revisión

Adde 1998 {published data only}

Aviles 1983 {published data only}

Coiffier 1990 {published data only}

Gururagan 2000 {published data only}

Hainsworth 2005 {published data only}

Haioun 1993 {published data only}

Hsu 1997 {published data only}

Kaplan 1991 {published data only}

Kimby 1993 {published data only}

Levine 1991 {published data only}

Maloney 1994 {published data only}

Maloney 1997 {published data only}

Olweny 1971 {published data only}

Pfreundschuh 2004 {published data only}

Reiter 1994a {published data only}

Reiter 1994b {published data only}

Tilly 2000 {published data only}

Tura 1991 {published data only}

Witzig 2000 {published data only}

Witzig 2002 {published data only}

Referencias adicionales

Bernheim 1981

Burkitt 1958

Cairo 2003b

Goldstein 1990

Magrath 1974

Magrath 1974a

Magrath 1987

Magrath 1989

Meremikwu 2005

Norlin 1971

Oguonu 2002

Olweny 1980

Smeland 2004

Sugimoto 2004

Ziegler 1972

Ziegler 1974

Ziegler 1981

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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Instituciones a las que se accedió previamente

Usuarios institucionales

Instituciones a las que se accedió previamente

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