Affiliations of authors: Cochrane Haematological Malignancies Group, Cologne, Germany (ST, GH, TK, AE); Department I of Internal Medicine, University of Cologne, Germany (ST, AE).
Correspondence to: Sven Trelle, MD, Department I of Internal Medicine, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany (e-mail: sven.trelle{at}medizin.uni-koeln.de).
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INTRODUCTION |
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We begin by highlighting recent (July through December 2003) systematic reviews and protocols. We then outline six recently published trials that were selected by the editorial base of the CHMG on the basis of clinical relevance, methodological rigor, and anticipated impact. 1) The HD8 trial, conducted by the German Hodgkin's Lymphoma Study Group, showed that involved field irradiation is as effective as but less toxic than extended field irradiation in patients with Hodgkin lymphoma. 2) Ardeshna et al. provide data demonstrating that a watch-and-wait approach is adequate in asymptomatic patients with indolent lymphoma. 3) The Groupe d'Etude des Lymphomes de l'Adulte (GELA) trial, reported by Tilly et al., once more reveals that in patients with aggressive lymphoma more aggressive regimens may be limited by their toxicity. 4) The trial by Attal et al. suggests that a double autologous transplantation should be considered in selected patients with multiple myeloma. 5) The cooperative trial of the DutchBelgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON/SAKK) in patients with acute myeloid leukemia suggests that granulocyte colony-stimulating factor (G-CSF) may sensitize leukemic cells, but the data presented do not justify general use during induction therapy. 6) Cordonnier et al. present data that argue against the prophylactic use of immunoglobulins in allogeneic transplantation. We present all trial summaries in a structured format to assist practicing clinicians. Finally, we describe other recently published trials of potential interest and summarize other relevant ongoing trials.
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REVIEWS AND PROTOCOLS |
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Bohlius J, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma (Cochrane Review). In: The Cochrane Library. Issue 2, 2004. Chichester (UK): John Wiley & Sons [updated August 2003] [available at: http://www.cochrane.org/cochrane/revabstr/ab003189.htm].
Clinical background. Granulopoiesis-stimulating factors (G-CSF and granulocyte-macrophage colony-stimulating factor [GM-CSF]) are widely used to prevent febrile neutropenia and infections in the treatment of patients with malignant lymphoma. However, conclusions drawn from single studies are limited by the conflicting results of these trials.
Contribution. This systematic review and meta-analysis included 12 trials with 1823 randomized participants. Patients of at least 16 years of age with malignant lymphoma received either prophylactic G-CSF/GM-CSF or placebo/no prophylaxis during standard-dose chemotherapy. G-CSF and GM-CSF reduced the risk of neutropenia, febrile neutropenia, and infection. However, there was no evidence that either factor provides a statistically significant advantage in terms of complete tumor response, freedom from treatment failure, or overall survival.
Implications for practice. Prophylactic G-CSF/GM-CSF for all
lymphoma patients undergoing standard-dose chemotherapy cannot be recommended
based on the data reviewed. However, prophylaxis may be used in patients at
high risk of neutropenic complications (i.e., expected incidence 40%).
CHMG Protocols
Baldo P, Bearz A, Cannizzaro R, Canzonieri V, Dal Maso L, Di Lauro V, et al. Interferon-alpha for follicular lymphoma (Protocol for a Cochrane Review). In: The Cochrane Library. Issue 1. Chichester (UK): John Wiley & Sons; 2004.
Greb A, Bohlius J, Djulbegovic B, Wheatley K, Kober T, Engert A. High-dose chemotherapy and autologous stem cell transplantation for multiple myeloma (Protocol for a Cochrane Review). In: The Cochrane Library. Issue 1. Chichester (UK): John Wiley & Sons; 2004.
Murphy M, Stanworth S, Heddle N, Rebulla P, Brunskill S, Hyde C. Prophylactic platelet transfusion for haemorrhage after chemotherapy and stem cell transplantation in haematological malignancies (Protocol for a Cochrane Review). In: The Cochrane Library. Issue 1. Chichester (UK): John Wiley & Sons; 2004.
Ruggeri M, Rodeghiero F, Tosetto A. Steroids and intravenous immune globulines for the treatment of acute idiopathic thrombocytopenic purpura in adults (Protocol for a Cochrane Review). In: The Cochrane Library. Issue 1. Chichester (UK): John Wiley & Sons; 2004.
Steurer M, Pall G, Bohlius J, Schwarzer G, Greil R. Purine analogues in the treatment for chronic lymphocytic leukaemia. (Protocol for a Cochrane Review). In: The Cochrane Library. Issue 1. Chichester (UK): John Wiley & Sons; 2004.
Trelle S, Bohlius J, Skoetz N, Schwarzer G, Cornely O, Engert A. Antiviral agents for prophylaxis of herpesviridae infections in patients with haematological malignancies (Protocol for a Cochrane Review). In: The Cochrane Library. Issue 1. Chichester (UK): John Wiley & Sons; 2004.
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PUBLISHED TRIALS |
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Engert A, Schiller P, Josting A, Herrmann R, Koch P, Sieber M, et al. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 2003;21:36018.
Clinical background. Patients with early-stage unfavorable/intermediate-stage Hodgkin lymphoma have a good prognosis if treated with combined radio-chemotherapy. This good prognosis has increased the need to consider long-term side effects of the treatment and subsequently led to the development of therapies with reduced toxicity.
Contribution. This large multicenter trial recruited 1204 patients with early-stage unfavorable Hodgkin lymphoma (clinical stage [CS] IA/B and IIA with at least one risk factor, CS IIB with elevated ESR or more than two involved lymph nodes, CS IIIA without any risk factor) [Diehl V, Mauch P, Harris NL. Hodgkin's disease. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Vol 2. 6th ed. Philadelphia (PA): Lippincott; 2001. p. 233987]. At 5 years, both overall and event-free survival of patients randomly assigned to receive two cycles of cyclophosphamide, vincristine, procarbazine, prednisone and doxorubicin, bleomycin, vinblastine, dacarbazine (COPP/ABVD) plus involved field irradiation were similar to those in patients assigned to receive two cycles of COPP/ABVD plus extended field irradiation. The incidence of severe toxicities was clinically and statistically significantly lower in patients receiving involved field irradiation.
Implications for practice. Two cycles of COPP/ABVD plus involved field irradiation is as effective as two cycles of COPP/ABVD plus extended field irradiation but less toxic in patients with early-stage unfavorable Hodgkin lymphoma and should therefore be used in these patients.
Most interesting features. Large sample size with a heterogeneous group of centers.
Key study features are as follows.
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A number of clinically important figures were calculated from data in the original articles (labeled with an asterisk [*], inconsistencies in figures are caused by rounding). NNT/NNH = number needed to treat and number needed to harm, respectively. The numbers needed to treat or harm are translations of the absolute risk reduction (ARR) into clinical useful terms. They are calculated as the reciprocal of the ARR. The NNT is the average number of patients that needs to be treated with a particular therapy to prevent one additional bad outcome. The NNH is the average number of patients a clinician needs to treat for one additional patient to be harmed. For more information, see Barrowman NJ [Barrowman NJ. Missing the point (estimate)? Confidence intervals for the number needed to treat. CMAJ 2002;166:16767] and Cook and Sackett (Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995;310:4524).
Indolent Non-Hodgkin Lymphoma
Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan RE, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomized controlled trial. Lancet 2003;362:51622.
Clinical background. Randomized trials comparing a watch-and-wait approach with immediate treatment in patients with advanced low-grade lymphoma are limited by their small numbers of patients and short follow-up.
Contribution. In this multicenter trial, asymptomatic patients with stage III/IV low-grade lymphoma (mostly grade III follicular lymphoma) were followed for a median of 16 years. There was no difference, at 5, 10, and 15 years, in the overall survival of patients randomly assigned to watch-and-wait compared with the group of patients treated with chlorambucil (given continuously until disease progression or complete remission). At 10 years, the chance of not needing chemotherapy and of not dying of lymphoma was 19% (95% CI = 13% to 27%) in the watch-and-wait group.
Implications for practice. A watch-and-wait approach in asymptomatic, advanced stage low-grade non-Hodgkin lymphoma patients is adequate.
Most interesting features. Very long follow-up with very few losses to follow-up.
Key study features are as follows.
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Aggressive Non-Hodgkin Lymphoma
Tilly H, Lepage E, Coiffier B, Blanc M, Herbrecht R, Bosly A, et al. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 2003;102:42849.
Clinical background. Randomized trials in patients with aggressive non-Hodgkin lymphoma of more aggressive second- and third-generation regimens have failed to show any survival benefits compared with the cyclophosphamide, doxorubicin, vincristin, prednisone (CHOP) regimen.
Contribution. This large multicenter trial randomly assigned patients (aged 6169 years) with poor-prognosis aggressive non-Hodgkin lymphoma to either eight cycles of CHOP or to ACVBPa more aggressive regimen with additional central nervous system prophylaxis (induction: four cycles of doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone, and intrathecal methotrexate plus G-CSF [every 3 weeks]; sequential consolidation: two courses of methotrexate plus leucoverin rescue, four courses of etoposide, ifosfamide, two courses of cytosine-arabinoside [every course administered every other week]). Although results in participants randomly assigned to CHOP or to ACVBP were not different with regard to complete remission rates, event-free survival and overall survival in the ACVBP group was clinically and statistically significantly longer. However, the incidence of grade III/IV toxicities and the rate of treatment-related deaths were higher for patients treated with the more aggressive regimen.
Implications for practice. The survival benefit of ACVBP may be offset by the high incidence of severe side effects, and therefore this regimen cannot yet be generally recommended.
Most interesting features. Large sample size with a heterogeneous group of centers.
Key study features are as follows.
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Multiple Myeloma
Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. New Engl J Med 2003;349:2495502.
Clinical background. Multiple myeloma is an incurable malignancy, even with autologous stem-cell transplantation. Therefore, treatment options that prolong survival are needed.
Contribution. This randomized trial found that event-free survival and overall survival can be prolonged in patients younger than 60 years of age with previously untreated multiple myeloma treated with double autologous transplantation (two successive transplantations; in this study the transplantations were a median of 2.5 months apart) as compared with single transplantation. Treatment-related deaths and hematopoietic reconstitution were similar in both groups. Patients who relapsed after transplantation had the same probability of surviving 2 years after relapse, regardless of whether they received single or double transplantation.
Implications for practice. The possibility of a second autologous transplantation should be considered in patients who do not have a very good partial response or better after first transplantation but who tolerated the procedure well.
Most interesting features. Relatively long follow-up and large sample size.
Key study features are as follows.
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Acute Myeloid Leukemia
Lowenberg B, van Putten W, Theobald M, Gmur J, Verdonck L, Sonneveld P, et al. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. New Engl J Med 2003;349:74352.
Clinical background. High rates of relapse are common among patients with acute myeloid leukemia due to residual cells that escape cytotoxic chemotherapy. Administration of G-CSF during induction remission therapy may be beneficial, but clinical trials have been limited by their small numbers of patients.
Contribution. Disease-free survival was prolonged (both clinically and statistically significantly) in patients with acute myelogenous leukemia randomly assigned to G-CSF during induction remission therapy compared with those assigned to no G-CSF. However, overall survival and event-free survival were similar in both arms. The incidence of grade III/IV infections was also not different.
Implications for practice. Although improved disease-free survival may indicate sensitization of leukemic cells by G-CSF, the general application of G-CSF during induction remission therapy cannot be recommended based on these data.
Most interesting feature. Relatively large sample size.
Key study features are as follows.
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Supportive Care
Cordonnier C, Chevret S, Legrand M, Rafi H, Dhedin N, Lehmann B, et al. Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled, multicenter trial. Ann Intern Med 2003;139:818.
Clinical background. Prophylactic intravenous immunoglobulins are being widely used in patients undergoing allogeneic stem-cell transplantation despite a lack of evidence about effectiveness.
Contribution. This randomized, double-blind, placebo-controlled trial recruited 200 patientsmost of them with hematological malignancieswho underwent allogeneic stem-cell transplantation from human leukocyte antigen (HLA)identical sibling donors. At 6 months, the incidence of infections was not different between patients randomized to placebo (5% dextrose solution) or to intravenous immunoglobulins (given weekly from day 7 to day 100). There were also no differences in treatment-related mortality at 6 months and overall survival at 2 years.
Implications for practice. Administration of prophylactic intravenous immunoglobulins is not superior to dextrose solution in patients undergoing allogeneic stem-cell transplantation from HLA-identical siblings and should therefore not be used in these patients.
Most interesting feature. Placebo-controlled trial.
Key study features are as follows.
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Other Published Trials of Potential Interest
Cassileth BR, Vickers AJ, Magill LA. Music therapy for mood disturbance during hospitalization for autologous stem cell transplantation: a randomized controlled trial. Cancer 2003;98:27239.
This randomized, controlled, open-label trial assessed the effects of music therapy on mood in 69 patients undergoing stem cell transplantation. This trial found that music therapy appears to reduce mood disturbances in these patients.
Ganz PA, Moinpour CM, Pauler DK, Kornblith AB, Gaynor ER, Balcerzak SP, et al. Health status and quality of life in patients with early-stage Hodgkin's disease treated on Southwest Oncology Group Study 9133. J Clin Oncol 2003;21:35129.
This report of a randomized, controlled, open-label trial describes quality-of-life outcomes in 247 patients with early-stage Hodgkin lymphoma treated with either subtotal lymphoid irradiation or combined-modality therapy. Combined-modality therapy decreased short-term quality-of-life (6 months after treatment start), but quality of life after 1 year was similar in both treatment arms.
Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. New Engl J Med 2003;349:142332.
This report of a previously published randomized, controlled trial (IRIS)
shows the effect of imatinib mesylate on the molecular response rate in 1106
patients with chronic myeloid leukemia in chronic phase. A significantly
(clinically and statistically) greater proportion of patients treated with
imatinib had a reduction of BCR-ABL transcript levels (0.001 multiplied by
baseline value) after 12 months compared with patients treated with interferon
alfa plus cytarabine.
Schouten HC, Qian W, Kvaloy S, Porcellini A. Hagberg H, Johnson HE, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol 2003;21:391827.
This trial examined the effectiveness of high-dose chemotherapy followed by autologous stem-cell transplantation versus standard-dose chemotherapy in 89 patients with relapsed follicular non-Hodgkin lymphoma. It remains unclear if a change in the randomization ratio during the trial introduced bias (19 of the 89 patients were randomly assigned only between unpurged and purged stem-cell transplantation). Nevertheless, this trial showed that patients may benefit from high-dose chemotherapy in terms of progression-free survival and overall survival.
Solary E, Drenou B, Campos L, de Cremoux P, Mugneret F, Moreau P, et al. Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia. Blood 2003;102:120210.
This randomized controlled trial examined the effect of quinine in combination with induction chemotherapy versus induction chemotherapy alone on survival in adult de novo acute myeloid leukemia. Quinine did not improve either complete response rate or overall survival in these patients.
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ONGOING TRIALS |
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Phase III randomized study of chlorambucil alone versus fludarabine with or without cyclophosphamide in patients with newly diagnosed chronic lymphocytic leukemia. Catovsky D (Royal Marsden NHS Trust, London, U.K.) [available at: http://www.clinicaltrials.gov].
Question. In patients with previously untreated chronic lymphocytic leukemia, is fludarabine used alone or in combination with cyclophosphamide superior to chlorambucil (in terms of overall survival)?
Setting. Eighty-six centers in the United Kingdom, Argentina, Croatia, Greece, Ireland, Italy, New Zealand, and The Russian Federation (as of March 2004).
Design. Multicenter, randomized controlled phase III trial with a sample size of 750 participants.
Intervention. Participants are being randomly assigned to receive chlorambucil (daily for 7 days; repeated every 4 weeks until maximum response or up to 1 year), fludarabine (three to eight courses), or fludarabine plus cyclophosphamide (three to eight courses).
Acute Lymphocytic Leukemia
Phase III randomized study of allogeneic bone marrow transplantation or conventional consolidation and maintenance chemotherapy versus autologous bone marrow transplantation in patients with acute lymphoblastic leukemia in first remission. Rowe JM (University College Hospital, London, U.K.) [available at: http://www.clinicaltrials.gov].
Question. Is autologous bone marrow transplantation more effective than maintenance chemotherapy in adult acute lymphocytic leukemia patients in first remission ineligible for allogeneic bone marrow transplantation (in terms of duration of complete remission and overall survival)?
Setting. Forty-three centers in the United States and the United Kingdom (as of March 2004).
Design. Multicenter, randomized controlled phase III trial with a sample size of 550 participants.
Intervention. All patients receive the same two remission induction and intensification regimens. Participants are then randomly assigned to one of two different maintenance strategies. Arm 1: consolidation and maintenance therapy plus central nervous system prophylaxis; arm 2: autologous bone marrow transplantation plus interferon alfa-2b maintenance therapy for Philadelphia chromosomepositive patients.
Chronic Myeloid Leukemia
Phase II randomized study of imatinib mesylate at standard versus increased dose alone versus imatinib mesylate and cytarabine versus imatinib mesylate and PEG-interferon alfa-2a in patients with previously untreated chronic phase chronic myelogenous leukemia. Druker BJ (Oregon Health and Science University, Portland, OR) [available at: http://www.clinicaltrials.gov].
Question. Is increasing the dose of imatinib mesylate, or adding cytarabine or PEG-interferon alfa-2a to standard imatinib mesylate, superior to standard-dose imatinib mesylate in patients with previously untreated chronic phase chronic myelogenous leukemia (in terms of response rates)?
Setting. Not yet open for recruitment (as of March 2004).
Design. Multicenter, randomized controlled phase III trial with a sample size of 468 participants.
Intervention. Participants will be randomly assigned to standard-dose imatinib mesylate (once daily) or to one of three experimental arms: double-dose imatinib mesylate (i.e., twice daily), standard-dose imatinib mesylate plus PEG-interferon alfa-2a once weekly, or standard-dose imatinib mesylate plus cytarabine once daily for 14 days (repeated every 28 days). Treatment continues for 12 months in all arms.
Phase III randomized study of imatinib mesylate alone or with interferon alfa or low-dose cytarabine versus interferon alfa standard therapy followed by allogeneic stem cell transplantation in patients with newly diagnosed chronic phase chronic myelogenous leukemia. Hehlmann R (III. Medizinische Klinik Mannheim, Germany) [available at: http://www.clinicaltrials.gov].
Question. Is adding interferon alfa or adding low-dose cytarabine to standard-dose imatinib mesylate, or starting standard-dose imatinib mesylate after failure of initial interferon alfa treatment, superior to standard-dose imatinib mesylate in patients with previously untreated chronic phase chronic myelogenous leukemia (in terms of response rates and survival)?
Setting. Sixty-six centers in Germany and Switzerland (as of March 2004).
Design. Multicenter, randomized controlled phase III trial with a sample size of 1600 participants.
Intervention. Participants will be randomly assigned to standard-dose imatinib mesylate (once daily) or to one of three experimental arms: standard-dose imatinib mesylate plus interferon alfa (three times a week), standard-dose imatinib mesylate plus low-dose cytarabine (maximum of 10 x 10 mg/month), or initial combination treatment of interferon alfa plus hydroxyurea once daily followed by standard-dose imatinib mesylate (once daily) in case of treatment failure.
Stem Cell Transplantation
Standard follow-up compared with extended follow-up in treating patients who have undergone stem cell transplantation for cancer. Syrjala KL (Fred Hutchinson Cancer Research Center, Seattle, WA) [available at: http://www.clinicaltrials.gov].
Question. Is standard follow-up plus telephone counseling more effective than standard follow-up in patients who have undergone stem cell transplantation in terms of rehabilitation needs and psychological distress?
Setting. Nine centers in the United States (as of March 2004).
Design. Multicenter, randomized controlled phase III trial with a sample size of 412 participants.
Intervention. Participants will be randomized to standard care (preparation prior to discharge, receiving published material) or to standard care plus nine to 10 scheduled telephone appointments (lasting 1 hour each: identification of problems and specific support) in the first year after discharge.
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NOTES |
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The editorial base of the Cochrane Haematological Malignancies Group is funded, as part of the Competence Network Malignant Lymphomas, by the German Ministry of Education and Research (BMBF).
1 Calculation based on assumptions (e.g., response rate) not verified by
references.
2 "Drop-outs" refers to participants who withdrew consent, who
were unavailable for follow-up, or who were not evaluable.
3 "Protocol violations" refers to participants who did not
receive the intended treatment, switched arms, withdrew consent, were viewed
not eligible after randomization, etc.
4 Positive values favor experimental treatment, negative values favor control
arm.
5 Definition of event: progression during radiotherapy, lack of complete
remission at the end of protocol treatment, relapse, or death from any
cause.
6 Skin, nausea/emesis, pharynx, esophagus, larynx, gastrointestinal,
pulmonary, infection; some patients may have experienced more than one
toxicity.
7 Definition of event: disease progression, relapse, death from any cause, or
stopping of the trial.
8 Infections, mucositis, cardiac, and neurologic toxicities; some patients
may have experienced more than one toxicity.
9 Definition of event: progression of disease, relapse, or death.
10 Definition of event: failure to enter complete remission, death, or
relapse.
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