Affiliations of authors: Cochrane Haematological Malignancies Group, Cologne, Germany (TK, JB, ST, AE); Department of Internal Medicine I, University of Cologne, Germany (JB, ST, AE).
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 Bonnadonna et al. (2004) presents long-term findings that suggest that adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by involved-field radiation therapy (IFRT) is considered an effective and safe treatment in early Hodgkin disease. Ghielmini et al. (2004) report that prolonged treatment with rituximab in patients with follicular lymphoma statistically significantly increases event-free survival and response rate compared with the standard weekly schedule. Forstpointner et al. (2004) show that the addition of rituximab to a combination of fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) prolongs survival when compared with FCM alone in patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL). Thomas et al. report the results of the LALA-94 trial, which found that allogeneic stem cell transplantation (SCT) improves disease-free survival (DFS) in high-risk adult lymphoblastic leukemia (ALL) patients. Pfreundschuh et al. (2004) advocate biweekly CHOP-14 (cyclophosphamidedoxorubicin hydrochloride [adriamycin]vincristine [Oncovin]prednisolone) as new standard chemotherapy regimen for patients 60 or older because of its favorable efficacy and toxicity profile. Greenberg et al. (2004) found that complete remission (CR) rates and overall survival are not improved by using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC) compared with MEC alone in patients with relapsed or refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome. Based on the results of a clinical trial they conducted, Lee et al. (2004) advise against using the combination of corticosteroids (methylprednisolone) with a monoclonal antibody (daclizumab) as initial therapy for acute graft-versus-host disease (GvHD). Finally, Spielberger et al. (2004) tested the ability of a recombinant human growth factor (palifermin) to decrease oral mucosal injury and achieved a substantial reduction in the incidence of oral mucositis in patients with hematologic cancers.
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COCHRANE REVIEWS AND PROTOCOL |
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Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennet C, et al. Erythropoietin for patients with malignant disease. In: The Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD003407. DOI: 10.1002/14651858.CD003407.pub2.[CrossRef]
Clinical background. Anemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (EPO) and red blood cell transfusions.
Contribution.
This systematic review included 27 trials with 3287 randomized adult patients. Intervention was Epoetin- or Epoetin-ß administered subcutaneously or intravenously at doses of at least 300 U per kilogram of body weight perweek, given for at least 4 weeks. Dose adaptation of erythropoietin depending on hematological response was allowed. Studies on new erythropoiesis-stimulating substances like Darbepoetin-
were not considered for this review. Collectively, the trials provide strong evidence that treatment with erythropoietin decreases the relative risk and the volume of red blood cell transfusion. The current evidence is insufficient to determine whether initiating treatment at higher baseline hemoglobin levels is associated with better treatment outcomes.
Implications for practice. In view of the inconclusive evidence presently available, EPO should not be used to increase tumor response or overall survival outside clinical trials. EPO may be used routinely outside of clinical trials to increase hemoglobin levels and reduce the need for transfusion in patients with falling hemoglobin levels, i.e.,approaching 10 g/dL. Adverse events such as thromboembolic complications and hypertension should be monitored. (This systematic review is currently being updated through a financial grant provided by the UK Department of Health known as Cochrane Review Update Incentive Scheme.)
Stanworth SJ, Hyde C, Heddle N, Rebulla P, Brunskill S, Murphy MF. Prophylactic platelet transfusion for haemorrhage after chemotherapy and stem cell transplantation. In: The Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD004269. DOI: 10.1002/14651858.CD004269.pub2.[CrossRef]
Clinical background. Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in thrombocytopenic patients with bone marrow failure. Although considerable advances have been made in platelet transfusion therapy in the last 30 years, some questions continue to provoke debate, especially that of whether prophylactic platelet transfusions should be used for the prevention of thrombocytopenic bleeding.
Contribution. This systematic review included eight completed published trials with a total of 390 participants in the intervention and 362 participants in the control groups. All trials included small numbers of patients. Three trials evaluated prophylactic transfusions versus therapeutic transfusions and found no difference. However, these three trials may have been underpowered to detect clinically meaningful differences. Three other trials evaluated different thresholds for prophylactic transfusions (10 x 109/L versus 20 x 109/L). Again, no statistically significant difference was observed, but these studies may also have been underpowered.
Implications for practice. There are no reasons to change current practice, consistent with guidelines recommending platelet count prophylactic thresholds of 10 x 109/L. However, uncertainty about the practice of prophylactic transfusion therapy should be recognized. In the light of concerns that blood products, including platelets, could become an increasingly scarce and costly resource in the future and for which adequate alternatives do not exist, adequately powered trials in transfusion medicine are still needed.
CHMG Protocols
Quellmann S, Bohlius J, Greb A, Hübel K, Schwarzer G, Engert A. Corticosteroids for preventing graft-versus-host disease. In: The Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD004885. DOI: 10.1002/14651858.CD004885.[CrossRef]
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PUBLISHED TRIALS |
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Bonadonna G, Bonfante V, Viviani S, Di Russo A, Villani F, Valagussa P. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results. J Clin Oncol 2004;22:283541.
Clinical background. Radiation therapy (RT) can cure more than 80% of patients with pathological stage IA, IB, and IIA Hodgkin disease. However, evaluation of the optimal extent of RT fields to use in combination with chemotherapy (CT) is required to improve treatment outcomes in those patients with unfavorable prognostic factors.
Contribution. This prospective trial recruited 140 patients with early-stage Hodgkin disease to assess efficacy and tolerability of four cycles of ABVD followed by either subtotal nodal plus spleen irradiation (STNI) or IFRT. There were no statistically significant differences in estimated 12-year freedom from progression (FFP) and overall survival (OS) rates between the treatment arms. However, the trial was not powered to establish noninferiority; its purpose was descriptive, not inferential. Secondary malignancies occurred in three patients in the STNI arm. Neutropenia was the most common hematologic toxicity, with grade 3 in 9% of patients and grade 4 in 0.9% (no absolute numbers given).
Implications for practice. IFRT after four cycles of ABVD can be considered an effective and safe treatment modality in early Hodgkin disease with both favorable and unfavorable presentations. However, conclusions are limited because of the small sample size.
Most interesting features. Long follow-up.
Key study features are as follows.
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Indolent Non-Hodgkin Lymphoma
Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004;103:441623.
Clinical background. The anti-CD20 antibody rituximab is one of the most effective single-agent treatments for non-Hodgkin lymphoma (NHL), with a reputation of achieving good response rates, even in pretreated patients. The standard treatment schedule (375 mg/m2 each week for 4 weeks) may be enhanced by additional doses to improve clinical efficacy.
Contribution. A total of 202 patients with primary or refractory follicular lymphoma (FL) received rituximab standard treatment. At week 12, 151 patients with stable disease (SD), partial remission (PR), or complete remission (CR) were then randomly assigned to receive no further treatment (arm A) or to receive prolonged rituximab treatment (four single rituximab infusions given at 8-week intervals; arm B). Extended rituximab administration led to clinically and statistically significantly improved 3-year event-free survival.
Implications for practice. A prolonged rituximab dosage regimen may be considered in patients with FL.
Most interesting features. Relatively long follow-up, heterogenous group of participating centers.
Key study features are as follows.
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Indolent and Aggressive Non-Hodgkin Lymphoma
Forstpointner R, Dreyling M, Repp R, Hermann S, Hanel A, Metzner B, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2004;104:306474.
Clinical background. Follicular lymphomas (FLs) and mantle cell lymphomas (MCLs) represent two challenging malignant conditions because they cannot be cured by conventional therapeutic approaches. Monoclonal antibodies (MAbs) may offer a more specific, less toxic, and more broadly applicable treatment modality than other approaches.
Contribution. In this cooperative multicenter study, 147 patients age 18 and older with relapsed or refractory FL or MCL (according to WHO classification) were randomized to daily fludarabine (25 mg) on days 13, cyclophosphamide (200 mg daily on days 13), and mitoxantrone (one 8 mg dose every 4 weeks for a total of four cycles; FCM arm), alone or combined with rituximab (375mg/m2) once-only on the day before the respective FCM course (R-FCM arm). A total of 128 patients were evaluable. Patients in the R-FCM arm showed a statistically and clinically significantly higher overall response rate (CR + PR was seen in 52/66 patients, or 79%) than patients in the FCM arm (36/62, or 58%); the CR rate was also higher in the R-FCM arm (33% versus 13%). Patients in the R-FCM arm showed clinically and statistically significantly superior progression-free survival (16 months, compared with 10 months for patients in the FCM arm). Estimated overall survival (OS) at 2 years was 73% among patients in the R-FCM arm, compared with 53% in the FCM arm (median survival in R-FCM not reached after 3 years versus 2 years for FCM; P = .003). Side effects, particularly myelosuppression and granulocytopenia grades &3by4;, were similar in both treatment arms.
Implications for practice. Adult patients with FL or MCL benefit from the addition of rituximab to a fludarabine, cyclophosphamide, and mitoxantrone chemotherapy regimen.
Most interesting features. Large size of participating centers.
Key study features are as follows.
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Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC, Rube C, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004;104:63441.
Clinical background. More than 50% of patients with newly diagnosed aggressive lymphomas are older than 60 years and have a worse prognosis than younger patients. To improve 5-year survival, modification of the current standard chemotherapy regimen (CHOP) needs to be explored.
Contribution. This large multicenter study randomly assigned 689 patients with a confirmed diagnosis of aggressive or very aggressive lymphoma (advanced stage III/IV and bulky disease), aged between 61 and 75 years. Patients received six cycles of CHOP-21 (cyclophosphamide, doxorubicin, vincristine, and prednisolone every 3 weeks), CHOP-14 (every 2 weeks plus G-CSF 300 µg/d or 480 µg/d pending on body weight, beginning on day 4 to 13), CHOEP-21 (CHOP plus etoposide every 3 weeks) or CHOEP-14 (every 2 weeks plus G-CSF from day 4). Five-year event-free and overall survival, relative to those in patients receiving the CHOP-21 regimen, were statistically and clinically significantly better in patients receiving CHOP-14 but not in those receiving CHOEP-14 or CHOEP-21. CHOEP-14 and CHOEP-21 were more toxic than CHOP-14 and CHOP-21, which had similar toxicities. Adverse events included leukocytopenia grade 3/4, anemia, and thrombocytopenia.
Implications for practice. Long-term treatment results in elderly patients can be improved by a "dose-densified" CHOP-14 regimen and should be considered the new standard chemotherapy regimen for patients aged 60 or older with aggressive lymphoma.
Most interesting features. Large sample size with a heterogeneous group of participating centers.
Key study features are as follows.
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Acute Myeloid Leukemia
Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, et al. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol 2004;22:107886.
Clinical background. Relapsed patients with acute myeloid leukemia (AML) or those with high-risk myelodysplastic syndromes (MDS) have poorer response and prognosis to chemotherapy than those with de novo AML. Moreover, patients with AML often display multidrug resistance.
Contribution. This phase III randomized study investigated the efficacy of valspodar (PSC 833), a modulator of the multidrug resistance gene 1 (MDR-1), in combination with polychemotherapy for treatment of AML. The trial compared the efficacy of mitoxantrone, etoposide, and cytarabine (MEC) with that of MEC plus valspodar (PSC-MEC). The median disease free-survival (DFS) among patients achieving CR was 10 months in the PSC-MEC arm (95% CI = 5.5 to 15) and 9.3 months in the MEC arm (95% CI = 4 to 14).
Implications for practice. The MDR-modulating agent valspodar does not improve response rates or survival in poor-risk AML patients (aged 1570 years) treated with chemotherapy.
Most interesting features. Clinical setting (high-risk AML/MDS).
Key study features are as follows.
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Acute Lymphoblastic Leukemia
Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol 2004;22:407586.
Clinical background. Although clinical trials have demonstrated an improved response rate in adult lymphoblastic leukemia (ALL), the duration of remission has been disappointingly short. Trials that test different treatment approaches based on risk groups of patients are indicated.
Contribution. This prospective multicenter study included 922 adult patients with ALL. Patients were stratified in four risk groups (1 = standard risk ALL; 2 = high-risk ALL; 3 = Philadelphia chromosomepositive ALL; 4 = CNS-positive ALL). Patients were assigned to allogeneic stem cell transplantation (alloSCT). All groups received 4-week induction chemotherapy of prednisone (60 mg), vincristine (2 mg), and cyclophosphamide (750 mg) (CPM) plus either daunorubicin (30 mg) (DNR) or idarubicin (9 mg) (IDA) (first randomization). Patients from group 1 achieving complete remission (CR) were further randomly assigned to intensive consolidation chemotherapy or less intensive consolidation chemotherapy. Those achieving CR after salvage therapy were included in group 2. Patienst in groups 2, 3, and 4 with a human leukocyte antigenidentical sibling were assigned to allogeneic stem cell transplantation (alloSCT). If no sibling donor was available, patients in group 2 were randomly assigned to autologous stem cell transplantation (autoSCT) or chemotherapy; patients in groups 3 and 4 underwent auto SCT without further randomization. Overall, 660 (72%) patients achieved a complete remission (CR) after one course of chemotherapy (induction) with no difference between DNR and IDA. However, the IDA arm showed statistically and clinically significantly higher treatment-related mortality. After salvage therapy, CR rate improved to 84% (771/992). For patients in group 1, there were no differences in disease-free or overall survival between patients receiving intensive and less intensive consolidation. For patients in group 2 there was no statistically significantly difference between autoSCT and chemotherapy. However, this treatment arm was underpowered to detect any meaningful differences. Disease-free survival was clinically and statistically significantly improved by alloSCT compared with the other treatment modalities.
Implications for practice. AlloSCT shows promising results in high-risk patients. However, optimal therapy for standard-risk patients and patients not feasible for alloSCT remains unclear.
Most interesting features. Large patient sample, complex treatment schedule.
Key study features are as follows.
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Stem Cell Transplantation
Lee SJ, Zahrieh D, Agura E, MacMillan ML, Maziarz RT, McCarthy PL Jr, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood 2004;104:155964.
Clinical background. Acute graft versus host disease (GvHD) remains one of the major complications of allogeneic hematopoietic stem cell transplantation (HSCT). Daclizumab (Zenapax) is a humanized monoclonal antibody used as prophylactic agent in solid-organ transplantation.
Contribution. This multicenter, randomized, placebo-controlled trial of 102 participants aimed to investigate whether the addition of daclizumab to initial corticosteroid therapy for GvHD improved outcomes. Daclizumab was given at 1 mg/kg intravenously over 15 minutes on study days 1, 4, 8, and then weekly up to 100 days posttransplantation. The study was discontinued following the second interim analysis (October 2003), which showed that 50% of evaluable participants in the group receiving corticosteroids plus daclizumab had a statistically significantly worse 100-day survival than patients receiving corticosteroids alone (77% versus 94%; P = .02). Toxic effects in the daclizumab arm included grade 35 of the renal, pulmonary, neurologic, and cardiac systems, as well as infections.
Implications for practice. Daclizumab should not be added to corticosteroids as initial therapy for GvHD.
Most interesting features. Termination of trial after interim analysis.
Key study features are as follows.
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Supportive Care
Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004;351:25908.
Clinical background. Oral mucositis results from injury to the oral cavity and requires treatment in approximately 70%80% of transplant patients receiving radiation-based conditioning regimens. Serious consequences of debilitating mucositis include pain requiring opioid analgesia, potentially life-threatening infections, inadequate nutrition, and prolonged hospitalization.
Contribution. This double-blind randomized study compared the effect of palifermin, a recombinant human keratinocyte growth factor, with placebo in 212 patients aged older than 18 years with Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma, or leukemia. The study population received either palifermin (60 µg/kg daily) or placebo for 3 consecutive days 3 days before fractionated total-body irradiation. After conditioning (irradiation plus cyclophosphamide), patients received three additional doses of palifermin or placebo. Incidence of grade 3/4 oral mucositis was clinically and statistically lower in the palifermin arm than the placebo arm (63% versus 98%). Adverse side effects, including rash, pruritis, erythema, mouth and tongue disorders, and taste alteration, were mild to moderate and transient.
Implications for practice. The administration of palifermin is a promising therapeutic approach in the reduction of oral mucositis associated with intensive chemotherapy and radiotherapy for hematologic malignant conditions.
Most interesting features. Innovative drug.
Key study features are as follows.
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Other Published Trials of Potential Interest
Cohen L, Warneke C, Fouladi RT, Rodriguez MA, Chaoul-Reich A. Psychological adjustment and sleep quality in a randomized trial of the effects of a Tibetan yoga intervention in patients with lymphoma. Cancer 2004;100:225360.[CrossRef][ISI][Medline]
This randomized study examined the effects of Tibetan yoga (TY), which incorporates controlled breathing and visualization, mindfulness techniques, and low-impact postures, in 39 patients with lymphoma. Patients in the TY group had statistically significantly lower sleep disturbance scores during follow-up compared with patients in the wait-list control group (5.8 versus 8.1; P<.004).
Kluin-Nelemans HC, Buck G, le Cessie S, Richards S, Beverloo HB, Falkenburg JH, et al. Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups. Blood 2004;103:440815.
This randomized trial conducted jointly by The Dutch Hemato-Oncology Association (HOVON) and the British Medical Research Council (MRC) in 407 newly diagnosed chronic myeloid leukemia (CML) patients compared high-dose interferon (IFN)-alfa (5 MIU/m2 daily) with low-dose (3 MIU/m2, five times a week). There was no evidence of benefit for high-dose IFN compared with low-dose IFN for the treatment of CML. At a median follow-up of 53 months, there were no statistically significant differences in overall survival (odds ratio = 1.09, 95% CI = 0.81 to 1.46), progression-free survival, or complete hematologic or major cytogenetic responses. Quality-of-life data showed comparable results in both arms for most factors.
Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 2004;101:532835.
All-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) are considered effective in the treatment of acute promyelocytic leukemia (APL). In this study, 61 patients with newly diagnosed APL were randomly assigned to one of three treatment groups, i.e., ATRA, As2O3, and the combination of both drugs. Although CR rates in all three groups were high (90%), the time to achieve CR differed statistically significantly, with that of the combination group being shortest. Importantly, all 20 cases in the combination group remained in CR, whereas seven of 37 cases treated with monotherapy relapsed (P<.05) after a follow-up of 830 months (median: 18 months). The authors conclude that the ATRA/As2O3 combination for remission/maintenance therapy of APL brings much better results than either of the two drugs used alone.
A Plea for CONSORT
During our scrutiny of the full-text articles of studies described in this report, it became apparent that, despite several decades of educational effort, randomized controlled trials (RCTs) are often not reported properly in medical journals. Particularly, the description of the flow of trial participants (i.e., their allocation and movement) is often ambiguous and confusing. Furthermore, authors are inconsistent in providing absolute numbers, which is frustrating for those attempting to interpret the data. Moreover, the vocabulary of clinical trial reports is often a hybrid mixture of terms and phrases originating from medicine, statistics, biostatistics, epidemiology, and bioethics. In most cases it also is the product of clinical trial specialists, methodologists, and theoreticians concerned with the design, conduct, and analysis of clinical studies and who are not trained in technical writing.
DerSimonian and colleagues (1) suggested that reporting of clinical trials could be greatly improved by providing authors with a list of items that are expected to be reported. The outcome was the publication of the CONSORT statement (Consolidated Standards of Reporting Trials) in 1996. Work on a revised checklist began in 1999, which on completion featured 22 descriptors dealing with various aspects of items to include when reporting a randomized trial (2).
Our experience in the data extraction process of recently published clinical trials in hematology and oncology reinforce the need to apply the CONSORT checklist as mandatory publication requirement by all authors reporting on clinical trials in the medical literature.
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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 sponsored (funding number 01 GIO491) as part of the Competence Network Malignant Lymphoma by the German Ministry of Education and Research (BMBF).
Julia Bohlius is the first author of a CHMG review and coreviewer of a CHMG protocol mentioned in this report.
Andreas Engert is a coauthor of a CHMG review and CHMG protocol mentioned in this report.
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REFERENCES |
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(1) DerSimonian R, Charette LJ, McPeek B, Mosteller F. Reporting on methods in clinical trials. N Engl J Med 1982;306:13327.[Abstract]
(2) Altman DG, Schulz KF, Moher D, Egger M, Davidhoff F, Elbourne D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001;134:66394.
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