© Oxford University Press 2006.
ONLINE COMMENTARY |
Fifth Biannual Report of the Cochrane Haematologic Malignancies Group—Focus on Multiple Myeloma
Affiliations of authors: Cochrane Haematological Malignancies Group (FN, OW, EK, HS, JB, HH, AE), Department of Internal Medicine, University of Cologne (HS, JB, AE), Cologne, Germany
Correspondence to: Frauke Naumann, PhD, Department of Internal Medicine (CHMG), University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany (e-mail: frauke.naumann{at}uk-koeln.de).
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INTRODUCTION |
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 TopNotes Introduction Published trialsOther published trials of...New chmg protocols and... |
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The Cochrane Haematological Malignancies group (CHMG) searches continuously and systematically for clinical trials in the field of hemato-oncology. Randomized controlled trials (RCTs) are identified by electronic search of Medline (OVID gateway) using a broad search filter that covers all topics in hemato-oncology (http://www.chmg.de/html/pdf/topic.pdf) combined with a highly sensitive search filter for randomized studies (Cochrane Handbook for systematic reviews of interventions 4.2.5; Appendix 5b.2—phase 1 and phase 2; The Cochrane Collaboration 2005 [updated May 2005] http://www.cochrane.dk/cochrane/handbook/hbook.htm). The search presented here covers publications from November 2005 to mid-June 2006. In these 6 months, 65 controlled clinical trials (RCTs and clinical trials with a control group not determined by randomization) were published on therapeutic interventions in several hematological malignancies (e.g., acute leukemia, chronic lymphocytic leukemia, follicular lymphoma), with a clear majority of important trials in multiple myeloma. In our concise summary of key features of recent trials, we therefore focus on five recently published trials in multiple myeloma that have been chosen for their implications for clinical practice. We then mention four other RCTs of interest on interventions in hemato-oncology and conclude this fifth biannual report by summarizing the latest additions to the Cochrane Library (see www.thecochranelibrary.com).
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PUBLISHED TRIALS |
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Focus on Multiple Myeloma
Multiple myeloma is a generally incurable malignant disease of plasma cells. Most patients are diagnosed when they are older than 65 years of age. Both clinical course and survival time vary widely and depend on the time of diagnosis, stage of disease, and prognostic factors. Therapeutic options include chemotherapy using either established (e.g., melphalan) or newly available (e.g., thalidomide) drugs and high-dose treatment with stem cell support (autologous as well as allogeneic). Recent research has focused on defining the target population for the different therapeutic approaches, taking into account pretreatment characteristics of patients (e.g., age), and aims to balance treatment benefit with potential adverse events.
In this section, we provide structured summaries for five RCTs. After a short overview of the clinical relevance and the selection of patients for these trials, we list important methodologic aspects of each trial, e.g., randomization, drop-out rate, and statistical analysis. For the presentation of results, we chose the primary outcome data and statistically significantly different serious adverse events. The interested reader is referred to the original publication for further results. Finally, we illustrate the effect of non-standardized reporting of comparable outcomes (here, survival data) by juxtaposing the definitions used in each trial.
By highlighting important methodologic aspects in a structured format, these summaries are aimed at assisting busy medical practitioners to form their own opinion during the interpretation of study results.
Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354:1021–30. (NTC00083551, available at http://www.ClinicalTrials.gov)
Clinical background. Thalidomide as a single agent has shown activity against advanced and refractory myeloma. Intensive dexamethasone and melphalan–based chemotherapy and tandem autologous transplantation led to an increase in overall survival (OS). Here, the authors assessed the safety and efficacy of the combination of thalidomide with intensive chemotherapy in newly diagnosed multiple myeloma patients of all age groups.
Contribution. This prospective trial recruited 668 patients (age < 75 years, with 20% older than 65 years) with newly diagnosed progressive or symptomatic multiple myeloma who had received no more than one cycle of prior therapy. Patients were randomly assigned to receive a treatment protocol consisting of four steps (induction chemotherapy and melphalan-based tandem autotransplant followed by consolidation and maintenance therapy), alone or in combination with thalidomide. According to the authors, baseline characteristics were similar between the two groups.
The addition of thalidomide resulted in a statistically significantly higher 5-year event-free survival (EFS) rate without statistically significantly improving OS. Adverse events—especially thromboembolic events, syncopal episodes, and severe peripheral neuropathy—were more frequent in the thalidomide group. Subgroup analysis revealed that the incidence of adverse events varied in different phases of treatment and in different age groups.
Implications for practice. The addition of thalidomide to high-dose therapy for multiple myeloma increased the EFS rate without improving OS. The higher incidence of adverse events in the thalidomide group during induction therapy and in patients older than 65 may guide future therapeutic decisions with respect to the target population or timing of administration.
Most interesting feature. Detailed analysis of adverse events.
Key study features are as follows.
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Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, Garcia-Laraña J, et al, and the Programa para el Estudio de la Terapeutica en Hemopatia Maligna (PETHEMA). High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 2005;106:3755–9.
Clinical background. There is conflicting evidence for the beneficial effect of high-dose melphalan with stem cell transplantation on survival. In this prospective trial, conventional chemotherapy (CCT) was compared with high-dose therapy (HDT) in a preselected population of patients who had all responded (with complete, partial, or minimal responses) to initial chemotherapy.
Contribution. In this prospective RCT, 216 newly diagnosed and previously untreated patients younger than 65 years with symptomatic stage II or III multiple myeloma were enrolled (median age 56 and 57 years in the CCT and HDT groups, respectively). Eighty-nine percent of responders to initial chemotherapy consisting of vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, adriamycin, and dexamethasone were randomly assigned to receive either additional conventional chemotherapy or high-dose therapy with autologous stem cell support. The two groups were similar, apart from statistically significant differences in the type of M-protein and a statistically significant higher percentage of patients with hemoglobin level lower than 100g/L in the chemotherapy arm. In univariate analysis, this hemoglobin level was associated with statistically significantly shorter survival.
Progression-free survival (PFS) was not statistically significantly different between high-dose regimen followed by autologous stem cell transplantation and conventional chemotherapy. Despite a long follow-up of more the 4,5 years, there was no impact on OS.
Implications for practice. In this trial, higher complete remissions rates (not described) did not translate into prolonged OS. Other treatment options, including new drugs in either induction or maintenance therapy or different stem cell transplantation regimens, e.g., tandem transplantation, will have to be clinically evaluated and analyzed for benefit.
Most interesting feature. Long-term results.
Key study features are as follows.
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Facon T, Mary JY, Pegourie B, Attal M, Renaud M, Sadoun A, et al, for the Intergroupe Francophone du Myelome (IFM) group. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 2006;107:1292–8.
Clinical background. Melphalan and prednisone are regarded as standard therapy in patients ineligible for high-dose chemotherapy. Dexamethasone-based regimens were of interest as a potential alternative for both single and combination therapies. Toxicities are of concern especially in elderly patients. Here, the efficacy and safety of dexamethasone-based regimens compared to standard therapy are assessed in an unselected elderly population (65–75 years) with newly diagnosed multiple myeloma.
Contribution. In this prospective randomized trial, 500 patients aged between 65 and 75 years and ineligible for high-dose therapy were randomized to compare melphalan–prednisone (MP) with dexamethasone-based regimens: melphalan–dexamethasone (M-DEX), dexamethasone alone (DEX), and dexamethasone–interferon alpha-2b (DEX-IFN). Survival curves were compared between the four individual treatment groups and between groups with or without melphalan (M group = MP, M-DEX; DEX without M group = DEX, DEX-IFN). According to the authors, there were no differences in pretreatment characteristics among any of the treatment groups.
Interim analysis lead to stopping of enrollment in the dexamethasone arm and finally to the stopping of the complete trial after 3 years because of of the poor rate and length of PFS among patients receiving dexamethasone without melphalan. There was no statistically significant disadvantage with respect to OS, however. Whereas hematologic toxicities were similar between groups, a significantly higher incidence of severe nonhematologic complications was observed in all three groups receiving dexamethasone.
Implications for practice. Melphalan and prednisone have been confirmed as the best treatment choice in elderly patients. Due to the toxicities of dexamethasone-based therapies, future trials should focus on combining melphalan-containing regimens with new drugs, e.g., thalidomide, bortezomib, or lenalidomide.
Most interesting feature. RCT with elderly patients (65–75 years) with follow-up of 7 years.
Key study features are as follows.
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Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol 2005;23:9227–33.
Clinical background. High-dose therapy with autologous stem cell support is the standard treatment for patients with multiple myeloma and good performance status. In patients between 55 and 65 years of age, who may be more vulnerable for the toxicity of the high-dose treatment, the benefit of high-dose therapy compared with conventional chemotherapy is unclear.
Contribution. This prospective trial recruited 190 patients (aged 55–65 years) with newly diagnosed stage II or III multiple myeloma without previous treatment who were randomly assigned to receive conventional chemotherapy or high-dose therapy with autologous stem cell support. A second randomization step allocated a busulfan- or a melphalan-based preparative regimen to the patients in the high-dose therapy group. According to the authors, there were no differences in the baseline characteristics of the study arms.
The long-term results of this clinical trial did not provide evidence for superiority of high-dose therapy over conventional chemotherapy in the patients of the selected age group in terms of OS, although EFS indicated a benefit for high-dose therapy. High-dose therapy was not performed in 24% of the allocated patients but was performed in 22% of the patients of the conventional chemotherapy arm as rescue treatment (not planned in the trial protocol).
Implications for practice. In patients aged 55–65 years, high-dose therapy as first-line therapy is feasible and of benefit in terms of EFS but not OS. High-dose therapy represents a therapeutic option in this group of patients on an individual basis and remains to be challenged by future results of newly available drugs.
Most interesting feature. Long-term results.
Key study features are as follows.
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Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, et al. Italian multiple myeloma network G. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006;367:825–31.[CrossRef][ISI][Medline]
Clinical background. Therapeutic options for elderly patients with multiple myeloma (>65 years), who represent the majority of multiple myeloma patients, usually exclude high-dose therapy or hematopoeitic stem cell transplantation. The addition of thalidomide to standard melphalan and prednisone therapy may improve their prognosis.
Contribution. In this prospective trial, 255 patients with previously untreated multiple myeloma between 65 and 80 years were evaluated for EFS, OS, and adverse events. Patients were randomly assigned to receive melphalan and prednisone either alone (MP) or in combination with thalidomide (MPT). Patients have been followed for at least 6 months, with a median follow-up of 17.6 months. Thalidomide treatment was discontinued in one-third of the evaluated patients; in another one-third, the dose was reduced. Only 75% of evaluated patients have completed the six cycles scheduled by the trial protocol. Furthermore, 21% of the patients in the standard treatment arm switched to the combination therapy for salvage therapy.
The combination therapy of thalidomide, melphalan, and prednisone statistically significantly improved 2-year EFS. Due to the short follow-up, it is too early to assess the effect on OS. Thalidomide increased rates of thromboembolic events, neuropathy, and infections.
Implications for practice. Adding thalidomide to the standard regimen of melphalan and prednisone may also be of benefit in elderly patients. Close clinical monitoring and anticoagulant prophylaxis are necessary for the control of adverse events.
Most interesting feature. RCT with elderly patients.
Key study features are as follows.
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20 patients at risk)
Interpretation of Survival Data
To illustrate the problem of nonstandardized reporting of clinical trials for the comparability of therapeutic options, we have extracted here the definitions provided for each survival endpoint.
The five trials summarized above used different endpoints, such as OS, EFS, and PFS, for the evaluation of treatment outcomes. Because the event and the starting point of measurement are defined by the investigator and may be influenced by ascertainment bias, great care has to be applied when interpreting data, especially when comparing the results of different trials.
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Although in all five trials, there was no statistically significant difference in OS, in three of them a statistically significant benefit was achieved in either EFS or PFS. The OS outcome is more easily influenced by short follow-up or too small a sample size. Furthermore, high switch rates between the arms may mask the effect on overall survival in an intent-to-treat analysis.
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OTHER PUBLISHED TRIALS OF INTEREST |
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Chronic Lymphocytic Leukemia
Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006;107:885–91.
In this RCT, the German CLL Study Group reports results of 375 patients aged 18–65 years (recruitment 1999–2003) suffering from chronic lymphocytic leukemia, most of who have advanced-stage disease. Combination chemotherapy with fludarabine and cyclophosphamide (FC) is compared with fludarabine monotherapy.
Data sets are sufficiently complete for the analysis performed and methodologic assessment criteria are mostly fulfilled, although for neither group median OS has been reached.
Both treatment response and PFS were significantly better in the fludarabine and cyclophosphamide arm: complete remission rate for fludarabine and cyclophosphamide, 16.5%, and for fludarabine, 4.9% (P = .001); median PFS 48 months and 20 months, respectively (P = .001). However, 3-year OS rates were similar, at 80.3% and 80.7%, respectively. Toxicity was statistically significantly more frequent in the fludarabine and cyclophosphamide arm (72.6% versus 54.0%, P = .001).
In outcomes relevant to quality of life (response, PFS, treatment-free survival), combination therapy with fludarabine and cyclophosphamide was superior to fludarabine alone. This result is clinically important especially because younger patients were included in the study, for many of whom being fit for work is vital.
Hodgkin Lymphoma
Gobbi PG, Levis A, Chisesi T, Broglia C, Vitolo U, Stelitano C, et al. ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 2005;23:9198–207.
This study compares three different chemotherapy regimens for the treatment of advanced-stage Hodgkin Lymphoma: Stanford V, MOPPEBVCAD, and ABVD, each combined with reduced radiotherapy. Included in this RCT were 355 patients aged 15—69 years between 1996 and 2000.
The methods section is well described; patient flow is transparent. Treatment groups varied slightly in disease stage. Response was best in the MOPPEBVCAD and ABVD groups (81% and 71%) and reached 56% in the Stanford V group. After radiotherapy, complete response rates were 94%, 89%, and 76%, respectively. There were statistically significant differences in hematologic toxicity between the three groups (P<.01), which was mild in ABVD, moderate in Stanford V, and substantial in MOPPEBVCAD. Five-year OS was similar in the three groups at 90%, 89%, and 82% for ABVD, MOPPEBVCAD, and Stanford V, respectively; 5-year failure-free survival was 78%, 81%, and 54%, respectively. The differences between Stanford V and each of the other two regimens were statistically significant (P<.01 in both cases).
In this study, both ABVD and MOPPEBVCAD were superior to Stanford V regarding response and survival. Taking into account the higher toxicity of MOPPEBVCAD, ABVD can be regarded as the first-choice regimen in combination with limited radiotherapy.
Aggressive Non-Hodgkin Lymphoma
Schmitz N, Kloess M, Reiser M, Berdel WE, Metzner B, Dorken B, et al. Four versus six courses of a dose-escalated cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen plus etoposide (megaCHOEP) and autologous stem cell transplantation: early dose intensity is crucial in treating younger patients with poor prognosis aggressive lymphoma. Cancer 2006;106:136–45.[CrossRef][ISI][Medline]
Between 1999 and 2001, this study carried out by the German High-Grade Non Hodgkin's Lymphoma Study Group enrolled 67 patients with aggressive lymphoma aged 18–60 years. The aim was to compare a four-course high-intensity megaCHOEP regimen with a six-course megaCHOEP regimen, both supported by autologous stem cell transplantation.
Patients were randomly assigned to groups at the beginning only; from an unknown timepoint on, enrollment in the six-course arm was stopped due to frequent disease progression. In the four-course arm (arm A), 90.2% of patients were able to receive all doses but only 69.2% of patients in arm B (six-course regimen) were able to receive all doses. Response rates were 65.8% and 50.0%, respectively. OS was 70% (95% CI = 54.9% to 85.0%) in arm A and 46.2% in arm B (95% CI = 27.0% to 65.3%), P = .037. Toxicity in general was higher in arm A, and there was a statistically significant difference in the occurrence of stomatitis (P<.001) and liver toxicity (P = .032).
Results obtained in this study show an advantage for the four-course high-intensity regimen (arm A) regarding response and OS. There seems to be a benefit in receiving high-dose therapy early in the course of chemotherapy, as represented here by the four-course regimen.
Supportive Therapy
Abdelkefi A, Torjman L, Ladeb S, Othman TB, Achour W, Lakhal A, et al. Randomized trial of prevention of catheter-related bloodstream infection by continuous infusion of low-dose unfractionated heparin in patients with hematologic and oncologic disease. J Clin Oncol 2005;23:7864–70.
Patients aged 4-60 years, suffering from some hemato-oncologic disease and carrying a nontunneled central venous line were included in this Tunisian RCT between 2002 and 2004. Continuous intravenous fractionated heparin was compared with continuous intravenous normal saline solution for the prevention of catheter-related bloodstream infections.
The descriptions in the methods section are thorough and the patient flow transparent; a sample size calculation based on center experience was done.
Catheter-related bloodstream infections occurred in 6.8% of patients in the heparin group and 16.6% of those in the saline solution group (P = .03). This was a statistically significant 59% decrease (relative risk = 0.41; 95% CI = 0.18 to 0.95). The number of catheter-related thromboses was statistically significantly higher in the control group: 2 of 102 versus 10 of 102 (P = .017). The frequency of patients experiencing bleeding was similar in both groups, four in the heparin group versus five in the control group (P = .7).
These data show that continuous intravenous heparin infusion is an effective prophylaxis for catheter-related infections without an increase in complications.
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NEW CHMG PROTOCOLS AND REVIEWS |
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New Reviews
In the new issue of the Cochrane Library (Issue III 2006 published online July 19, 2006; see http://www.thecochranelibrary.com/), one new review and a major update was published.
The new review "Purine Antagonists for Chronic Lymphocytic Leukaemia" (by Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R) analyzed data from five trials with 1838 randomized patients. The results confirm that greater response rates are achievable by using purine antagonists but at the cost of greater complications, mainly infections. There is inconclusive evidence about whether treatment with purine antagonists improves survival. None of the studies included quality-of-life data. More research is needed to fully explore the role of purine antagonists in the treatment of B-CLL and their potential impact on survival.
The update of our review "Erythropoietin or Darbepoetin for patients with cancer" (by Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Brunskill S, Djulbegovic B, Benett CL, Langensiepen S, Hyde C, Engert E) showed consistent evidence that erythropoietin or darbepoetin reduces the risk for blood transfusions and the number of units transfused in anemic cancer patients. Quality of life might be improved following those treatments. But the risk for thrombotic complications is increased, and it remains uncertain whether and how erythropoietin or darbepoetin affect tumor control and survival.
Thus, caution is advised when using erythropoietin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thromboembolic events.
First results of this update, which include data from 57 trials, were also published in the print issue of the JNCI in May 2006. (Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98:708–14.)
New Protocols
There were two new protocols. The first, "Corticosteroids versus other single drugs or drug combinations for treatment of acute and chronic graft versus host disease (GvHD) after allogeneic stem cell transplantation" (by H Salmasian, S Banihosseini, JLM Ferrara, T Hahn, P McCarthy, Anari M Rabbani, Darabad R Rahimi, M Rohanizadegan, A Shakiba in The Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005565. DOI: 10.1002/14651858.CD005565), focuses on the effects of corticosteroids for the treatment of graft versus host disease after myeloablative stem cell transplantation.
The second protocol, on "Different threshold levels for red blood cell transfusions in patients with hematological malignancy" (by Pawson R, Brunskill S, Murphy MF, Doree C, Hyde C, Daly J), will add to the information on supportive care provided by the review "Erythropoietin or Darbepoetin for patients with cancer" (see above). After clarification of evidence for raising low-level hemoglobin in cancer patients with different methods, the results will provide additional guidance for giving red blood cell transfusions.
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NOTES |
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TopNotesIntroductionPublished trialsOther published trials of...New chmg protocols and... |
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(1) Here, only the primary endpoint is listed. For all other outcomes, please refer to the original publication.
CHMG Editorial Base is funded under the auspices of the German Federal Ministry of Education and Research (BMBF) through its Health Research Division (DLR e.V.): FKZ: 01GH0501. CHMG is part of the Competence Network Malignant Lymphomas.
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