Affiliations of authors: Cochrane Haematological Malignancies Group, Cologne, Germany (TK, ST, JB, AE); Department of Internal Medicine I, University of Cologne, Germany (ST, JB, AE); Cologne Coordinating Centre of Clinical Studies, Germany (NS)
Correspondence to: Thilo Kober, MNA, Level 4 (Neubau), Department of Internal Medicine I, University Hospital Cologne, Kerpener Str. 62, Cologne 50924, Germany (e-mail: thilo.kober{at}medizin.uni-koeln.de).
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INTRODUCTION |
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The work of Palumbo et al. (2004) provides data from a multicenter randomized study that suggests that intermediate dosages of oral melphalan improved survival of myeloma patients aged 5070 years. Hunault et al. (2004) report a trial that suggests a better outcome for adult patients with acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than following late high-dose therapy and autologous BMT. Lenz et al. (2005) provide results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group (GLSG), showing that immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) statistically significantly improved response and time to treatment failure but not long-term outcome in patients with previously untreated mantle cell lymphoma. Markus et al. (2005) compared the combination of cyclophosphamide, vincristine, and prednisone plus rituximab chemotherapy regimen (R-CVP) with CVP alone as first-line treatment for advanced follicular lymphoma and found that patients treated with R-CVP had a statistically significantly prolonged time to progression. On behalf of The Australasian Leukemia and Lymphoma Group, Bradstock et al. (2005) report on the value of administering high- versus conventional-dose cytarabine in consolidation therapy for acute myeloid leukemia in adults, which showed no difference between the two consolidation arms for relapse-free survival (RFS) at 3 years. Reyes et al. (2005) compared two chemotherapy schedules (i.e., cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] plus involved-field radiotherapy with chemotherapy alone [i.e., doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP]), showing that in patients under 61 years of age, chemotherapy with ACVBP followed by sequential consolidation is superior to CHOP plus radiotherapy for the treatment of low-risk localized lymphoma. Hainsworth et al. (2005) and Ghielmini et al. (2005) investigated the efficacy of maintenance rituximab given at standard dose versus re-treatment and of single-dose rituximab versus prolonged treatment in indolent non-Hodgkin lymphoma and mantle cell lymphoma, respectively. Maintenance treatment or re-treatment with single-agent rituximab seemed to substantially enhance progression-free survival and response rates. Monotherapy with rituximab is active in mantle cell leukemia, but the addition of four single doses at 8-week intervals does not seem to significantly improve response rate, duration of response, or event-free survival after treatment with standard schedule. Walsh et al. (2004) compared the antiemetic agent granisetron with ondansetron for prevention of nausea and vomiting in hematopoietic stem cell transplant patients and found that both agents are equally effective. Finally, Kimmick et al. (2005) tested an educational intervention to improve the accrual of cancer patients aged 65 and older to clinical trials and found that accrual was not increased.
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COCHRANE REVIEWS |
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Sasse EC, Sasse AD, Brandalise SR, Clark OAC, Richards S. Colony stimulating factors for prevention of myelosuppressive therapy induced febrile neutropenia in children with acute lymphoblastic leukaemia. The Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD004139. DOI: 10.1002/14651858.CD004139.[CrossRef]
Clinical background. Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood, and febrile neutropenia is a potentially life-threatening side effect of ALL treatment. Current treatment consists of supportive care plus antibiotics. Clinical trials have attempted to evaluate the use of colony-stimulating factors (CSFs) as additional therapy to prevent febrile neutropenia in children with ALL. Individual trials have not shown whether there is a substantial benefit, and meta-analysis provides the most reliable assessment and the best recommendations for practice.
Contribution. The authors scanned more than 5500 citations and included six trials with 332 participants; 161 children with (ALL) were randomly assigned to CSF as the treatment group, and 171 were allocated to the control group (placebo or no treatment). Children with ALL treated with CSF experienced shorter hospitalizations and fewer infections. The main results indicate that the use of CSF statistically significantly reduced the number of episodes of febrile neutropenia (rate ratio = 0.63; 95% confidence interval [CI] = 0.46 to 0.85; P = .003), the length of hospitalization (weighted mean difference [WMD] = 1.58; 95% CI = 3.00 to 0.15; P = .03), and the number of infectious diseases episodes (rate ratio = 0.44; 95% CI = 0.24 to 0.80; P = .002). Nevertheless, CSF did not influence the length of episodes of neutropenia (WMD = 1.11; 95% CI = 3.55 to 1.32; P = .4) or delays in chemotherapy courses (rate ratio = 0.77; 95% CI = 0.49 to 1.23; P = .28). However, there was no evidence for a shortened duration of neutropenia or fewer treatment delays and no useful information about survival.
Implications for practice. There is evidence that the prophylactic administration of CSF reduces length of hospitalization and rate of infections during treatment. There is no evidence that CSF reduces the length of neutropenia episodes or diminishes delay of chemotherapy courses in pediatric patients with ALL undergoing myelosuppressive chemotherapy. Although there were statistically significant fewer febrile neutropenia episodes in the CSF group, substantial heterogeneity between trials prevents a conclusion being drawn from this finding, and no useful information on survival is available.
CHMG Protocol
Okebe J, Richards S, Meremikwu M. Therapeutic interventions for endemic Burkitt's lymphoma in children. The Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD005198. DOI: 10.1002/14651858.CD005198.[CrossRef]
The main objective of this systematic review, which is currently in progress, is to assess the relative effects of chemotherapy, surgery, radiotherapy, and immunotherapy in the treatment of endemic Burkitt lymphoma. Randomized controlled trials with children aged up to 20 with cancer confirmed by clinical and histopathologic features to be Burkitt lymphoma will be identified and analyzed.
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PUBLISHED TRIALS |
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I. Advanced Follicular Lymphoma
Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:141723.
Clinical background. Follicular lymphoma is the most common form of indolent lymphoma, accounting for about 70% of indolent lymphoma and 20%25% of all cases of non-Hodgkin lymphoma (NHL). Most patients with advanced disease, i.e., stage III/IV, cannot be cured with currently available therapy. However, both single-agent chlorambucil and cyclophosphamide, vincristine, and prednisone (CVP) have become standard treatments in many treatment centers. The addition of rituximab, a chimeric monoclonal antibody against CD20, is active in follicular lymphoma, both as monotherapy and in combination chemotherapy, and is currently being clinically evaluated.
Contribution. This prospective trial recruited 322 patients with untreated CD20+ and stages IIIIV follicular lymphoma (National Cancer Institute [NCI] Working Formulation Groups B, C, D; WHO follicular lymphoma Grades 13 confirmed by lymph node biopsy) who were randomized to receive eight cycles of either CVP plus rituximab (R-CVP) or CVP alone. The CVP treatment schedule comprised a combination of intravenous cyclophosphamide 750 mg/m2, 1.4 mg/m2 vincristine, up to a maximal dose of 2 mg on day 1; and 40 mg/m2 of prednisone per day orally on days 15. Patients treated with R-CVP received in addition intravenous rituximab 375 mg/m2 on day 1 of each therapy cycle. Fatigue, neutropenia, and back pain were the most common severe adverse events and occurred at a slightly higher frequency in the R-CVP arm. Five of 162 patients experienced a total of six life-threatening events following R-CVP. No details were provided.
Implications for practice. Combination R-CVP chemotherapy statistically significantly improves clinical outcome in previously untreated patients with follicular lymphoma. Severe adverse events are possible, especially in patients receiving rituximab, and close clinical monitoring is therefore mandatory.
Key study features are as follows.
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II. Diffuse Large B-cell Lymphoma
Reyes F, Lepage E, Ganem G, Molina TJ, Brice P, Coiffier B, et al., for the Group d'Etude des Lymphomes de I'Adulte (GELA). ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005;352:1197205.
Clinical background. Radiotherapy was once considered the standard treatment for limited-stage aggressive lymphoma. Over time, the approach has evolved to a combination of chemotherapy and radiotherapy to control systemic disease and to reduce the size of irradiation fields. More recently, new approaches using intensified chemotherapy schedules plus radiotherapy are being explored to determine the optimal therapy for patients under 61 years of age with localized stage I or II aggressive lymphoma
Contribution. This large study randomly assigned 647 previously untreated patients under 61 years with localized stage I or II aggressive lymphoma according to the Working Formulation and the Kiel classification (mainly diffuse large B-cell lymphoma) to either chemotherapy (ACVBP) alone or to combined treatment modality consisting of CHOP and irradiation. ACVBP treatment consisted of three cycles doxorubicin 75 mg/m2 and cyclophosphamide 1200 mg/m2 on day 1, 2 mg/m2 vindesine and 10 mg/m2 bleomycin on days 1 and 5, and 60 mg/m2 prednisone on days 15 given at 2-week intervals, followed by sequential consolidation therapy of two cycles of methotrexate 3 g/m2 plus leucovorin rescue, four cycles of etoposide 300 mg/m2 and ifosfamide 1500 mg/m2, and two cycles of cytarabine 100 mg/m2 given subcutaneously for 4 days at 2-week intervals. Chemoradiotherapy consisted of three cycles of CHOP repeated at 21-day intervals (doxorubicin 50 mg/m2, cyclophosphamide750 mg/m2, vincristine 1.4 mg/m2 (up to a maximal dose of 2 mg/m2) on day 1 and prednisone 60 mg/m2 on days 15. The prescribed dose of irradiation commenced 1 month after the last CHOP cycle and was 40 Gy given in 22 fractions of 1.8 Gy, 5 days per week.
Implications for practice. In patients under 61 years old, chemotherapy with three cycles of ACBP followed by sequential consolidation is more beneficial than three cycles of CHOP plus radiotherapy for the treatment of low-risk aggressive lymphoma.
Key study features are as follows.
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Mantle Cell Lymphoma
Lenz G, Dreyling M, Hoster E, Wörmann B, Dührsen U, Metzner B, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005;23:198492.
Clinical background. Mantle cell lymphoma is characterized by poor prognosis with a low to moderate sensitivity to chemotherapy and a median survival of only 34 years. New randomized trials compare combination immunochemotherapy treatment schedules to improve previously observed outcomes.
Contribution.
In this cooperative multicenter study, 122 untreated patients with advanced-stage mantle cell lymphoma were randomly assigned to six cycles of either CHOP (intravenous doxorubicin 50 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 [up to a maximal dose of 2 mg/m2] on day 1 and prednisone 100 mg/m2 orally on days 15, or R-CHOP [i.e., CHOP plus rituximab 375 mg/m2 intravenously]). Patients up to 65 years old achieving partial or complete remission underwent a second random assignment to either myeloablative radiochemotherapy followed by autologous stem-cell transplantation(ASCT) or interferon-alfa maintenance (INF-). Patients in the ASCT arm received Dexa-BEAM, i.e., dexamethasone, BCNU, etoposide, cytarabine, melphalan 48 weeks after induction therapy. Subsequent high-dose therapy consisted of total-body irradiation (TBI; 12 Gy on days 6 to 4) and high-dose i.v. cyclophosphamide (60 mg/kg of body weight, days 3 and 2). Patients assigned to IFN-
received it at a maintenance dose of 6 x 106 U subcutaneously three times weekly within 4 weeks after the last therapy cycle. Treatment-associated adverse events included hematotoxicity (i.e., anemia, thrombocytopenia, leukocytopenia; granulocytopenia occurred more frequently after R-CHOP) and infectious complications.
Implications for practice. New developed combined immunochemotherapy schedules with R-CHOP may constitute an encouraging new baseline regimen for advanced-stage mantle cell lymphoma but need to be further improved by novel strategies in remission.
Key study features are as follows.
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Multiple Myeloma
Palumbo A, Bringhen S, Petrucci MT, Musto P, Rossini F, Nunzi M, et al. Intermediate-dose melphalan improves survival of myeloma patients aged 5070. Results of a randomized controlled trial. Blood 2004;104:30527.
Clinical background. Conventional chemotherapy in the treatment of multiple myeloma has been replaced by high-dose therapy followed by stem cell rescue because of increased response and remission rates. To improve 5-year survival, modification of the current standard chemotherapy with intermediate dose regimen needs to be explored further because high-dose therapy may be too toxic for patients older than 70 years.
Contribution. This Italian multicenter study randomly assigned 194 untreated patients with confirmed diagnosis of multiple myeloma aged 5070 years. Patients received either oral melphalan (MP arm) or intermediate-dose therapy (MEL 100 arm). The MP regimen consisted of oral melphalan 6 mg/m2 and prednisone 60 mg/m2 on days 17 of each course, repeated every 4 weeks for a total of six courses. Patients in the MEL 100 arm received melphalan 100 mg/m2, followed by stem cell support.
Near-complete remission rate was 6% after MP and 25% after MEL100 (P < .0012). Severe hematologic toxicity was shorter in the MP group. After MEL100 administration, the median duration of severe neutropenia (range 113) and thrombocytopenia (range 018) was 5 and 3 days, respectively. Other adverse events included fever, fatigue, diabetes, hypertension, and mucositis.
Implications for practice. Three-year event free survival (EFS) and overall survival (OS) is positively influenced by the administration of melphalan 100 and stem cell support in patients aged 5070 years with multiple myeloma, especially in those aged 6570 years.
Key study features are as follows.
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Acute Myeloid Leukemia
Bradstock KF, Matthews JP, Lowenthal RM, Baxter H, Catalano J, Brighton T, et al., for the Australasian Leukemia and Lymphoma Group. A randomized trial of high- versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood 2005;105:4818.
Clinical background. Despite more than 30 years of clinical investigation, the optimal treatment of acute myeloid leukemia (AML) in adults remains to be defined. The value of administering sequential courses of chemotherapy containing high-dose cytarabine in both induction and consolidation therapy for AML has, up to recently, not been assessed in a prospective randomized trial.
Contribution. To clarify some of these questions, this randomized study treated 292 adult patients with AML with identical induction therapy (ICE). This regimen consisted initially of idarubicin 12 mg/m2 by intravenous bolus daily on days 1, 2, and 3; cytarabine 3 g/m2 by 3 hoursintravenous infusion at 12-hour intervals on days 1, 3, 5, and 7), and etoposide 75 mg/m2 administered intravenously daily over 1 hour on days 17 inclusive. Complete remission was achieved in 234 (80%) patients. From these, 202 patients were then randomly assigned to either a single cycle of ICE or two diluted courses (IcE): idarubicin 9 or 12 mg/m2 intravenously on days 1 and 2, cytarabine 100 mg/m2 daily on days 15 inclusive, and etoposide 75 mg/m2 i.v. daily on days 15 inclusive. Following concerns of toxicity grade 3 or 4 (n = 44), the dose of idarubicin was reduced to 9 mg/m2.
Implications for practice. High-dose cytarabine is effective for induction of complete remission in patients with de novo AML. However, high-dose cytarabine as consolidation treatment is not more effective as lower-dose cytarabine but is associated with more nonhematologic toxicity, particularly gastrointestinal.
Key study features are as follows.
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Other Published Trials of Potential Interest
Kimmick GG, Peterson BL, Kornblith AB, Mandelblatt J, Johnson JL, Wheeler J, et al. Improving accrual of older persons to cancer treatment trials: a randomized trial comparing an educational intervention with standard information: CALGB 36001. J Clin Oncol 2005;23:22017.
This randomized study examined the effects of a multifaceted educational intervention directed to physicians and other members of the medical research team at Cancer and Leukemia Group B (CALGB) to improve accrual of cancer patients age 65 and older to phase II and III clinical trials. In summary, the educational intervention (educational information and a seminar) studied did not improve accrual of older cancer patients. Educating physicians to change practice is considered an enormous task.
Walsh T, Morris AK, Holle LM, Callander N, Bradshaw P, Valley AW, et al. Granisetron vs ondansetron for prevention of nausea and vomiting in hematopoietic stem cell transplant patients: results of a prospective, double-blind, randomized trial. Bone Marrow Transplant 2004;34:9638.[CrossRef][ISI][Medline]
This trial of 110 randomly assigned patients undergoing autologous or allogeneic hematopoietic stem cell transplantation (HSCT) compared two serotonin type 3 (5-HT3) antagonists to prevent acute nausea and vomiting (N/V) from highly emetogenic chemotherapy. The study purports both agents to be equally effective in preventing acute N/V and demonstrate comparable adverse events. However, it should be noted that the reported dosage of daily granisetron 10 mg/kg may vary with respect to dosages given in clinical settings in Europe.
Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco FA. Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphomaa randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2005;23:108895.
A total of 114 patients who received previous chemotherapy for indolent non-Hodgkin lymphoma were treated with a standard 4-week course of rituximab (weekly 375 mg/m2). Ninety patients (79%) with response were then randomly assigned to either maintenance treatment (i.e., standard 4-week courses administered at 6-month intervals) or rituximab re-treatment at progression. Progression-free survival (PFS) was prolonged in the maintenance group (31.3 versus 7.4 months; P = .007). There were no treatment-related hospitalizations, and no patient discontinued therapy because of toxicity.
Ghielmini M, Schmitz SH, Cogliatti S, Bertoni F, Waltzer U, Fey MF, et al. Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK).J Clin Oncol 2005;23:70511.
This randomized trial evaluated the effect after induction treatment of standard rituximab regimen (375 mg/m2 weekly for 4 weeks) in 104 patients with newly diagnosed or refractory or relapsed mantle cell lymphoma (MCL). Patients with objective response or stable disease at week 12 from start of treatment were assigned to no further treatment (arm A) or prolonged rituximab administration (375 mg/m2) every 8 weeks (arm B). Median event-free survival (EFS) was 6 months in arm A versus 12 months in arm Bbut the difference was not significant (P = .1). Prolonged treatment seemed to improve EFS, that is 5 months in arm A versus 11 months in arm B (P = .04). Thirteen percent of patients in arm A and 9% in arm B presented with grade 34 hematologic toxicity.
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NOTES |
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2 "Protocol violations" refers to participants who did not receive the intended treatment, switched arms, withdrew consent, were viewed not eligible after randomization, etc.
The editorial base of the Cochrane Haematological Malignancies Group is funded as part of the Competence Network Malignant Lymphoma by the German Ministry of Education and Research (BMBF).
Thilo Kober is the CHMG Executive Officer and Andreas Engert the CHMG Coordinating Editor. Nicole Skoetz, Sven Trelle, and Julia Bohlius are members of the CHMG editorial base.
There is no conflict of interest by the authors associated with this report.
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