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Journal of the National Cancer Institute Advance Access originally published online on August 28, 2007
JNCI Journal of the National Cancer Institute 2007 99(17):E1; doi:10.1093/jnci/djm110
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© The Author 2007. Published by Oxford University Press.

ONLINE COMMENTARY

Sixth Biannual Report of the Cochrane Haematological Malignancies Group—Focus on Non-Hodgkin Lymphoma

Olaf Weingart, Fareed A. Rehan, Holger Schulz, Frauke Naumann, Ina Knauel, Corinne Brillant Julia Bohlius, Andreas Engert

Affiliations of authors: Cochrane Haematological Malignancies Group (CHMG) Department of Internal Medicine 1 (OW, FAR, HS, FN, IK, CB, JB), Department of Internal Medicine 1 (AE), University Hospital of Cologne, Cologne, Germany

Correspondence to: Olaf Weingart, Cochrane Haematological Malignancies Group (CHMG) Department of Internal Medicine 1, University Hospital of Cologne, Kerpener Street 62, D- 50924 Cologne (Köln), Germany (e-mail: olaf.weingart{at}uk-koeln.de).


   Introduction
Top
 Introduction
Published trials on rituximab...
 Published trial on interferon...
 Published trial on hdc...
 Methodologic aspects
 The cochrane library
 References
 Notes
 
The Cochrane Haematological Malignancies group (CHMG), based at Cologne, Germany, searches continuously and systematically for clinical trials in the field of hemato-oncology. Randomized controlled trials (RCTs) are identified through 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 July 2006 to March 2007.

In these 9 months, 65 controlled clinical trials (RCTs and nonrandomized clinical trials) were published on therapeutic interventions in several hematologic malignancies (e.g., acute leukemia, chronic lymphocytic leukemia, follicular lymphoma). The majority of important trials focused on the addition of rituximab to CHOP-like multiagent chemotherapy (i.e., cyclophosphamide, doxorubicin, vincristine, and prednisone) for non-Hodgkin lymphoma.

In our present summary of key features of recent RCTs, we focus on non-Hodgkin lymphoma. We will discuss three recently published trials of rituximab that have implications in clinical practice for non-Hodgkin lymphoma patients. We also discuss two other trials that addressed the role of interferon in patients with relapsing follicular lymphoma and high-dose chemotherapy for non-Hodgkin lymphoma.

After a short overview of the clinical relevance and the selection of patients for these trials, we discuss important methodologic aspects of each trial, e.g., randomization, loss to follow-up, dropout rate, and statistical analysis. We also discuss the results of the primary efficacy endpoints and the methods used to evaluate adverse effects (toxicities).

The main objective of this summary report is to provide the knowledge in a way that busy practitioners can easily interpret it.


   Published Trials on Rituximab and Non-Hodgkin Lymphoma
Top
 Introduction
 Published trials on rituximab...
Published trial on interferon...
 Published trial on hdc...
 Methodologic aspects
 The cochrane library
 References
 Notes
 
Non-Hodgkin lymphoma has been classified into two types: aggressive (i.e., fast growing) and indolent (i.e., slow growing). Patients with aggressive B-cell lymphoma are potentially curable when treated with multiagent chemotherapy such as CHOP. The standard of care for patients with aggressive lymphoma has changed with the advent of the monoclonal antibody rituximab. Rituximab, an anti-CD20 IgG, binds to the CD20 antigens on the surface of B cells, flagging them for destruction by the immune system. This eliminates B cells (including cancerous ones) from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.

Rituximab was approved by the Food and Drug Administration in 1997 for the treatment of B-cell lymphoma in adults. Currently, it is indicated for the first-line treatment of diffuse large B-cell, CD20-postive, non-Hodgkin lymphoma in combination with CHOP or other anthracycline-based chemotherapy regimens. Rituximab is also used in the treatment of B-cell leukemia, moderate to severe rheumatoid arthritis, and some autoimmune disorders.

In this section, we provide structured summaries for three RCTs on rituximab. The results of further relevant RCTs (1,2) are summarized in a recently published meta-analysis of RCTs that included 1943 patients (3) and examined the efficacy of combined immunochemotherapy (rituximab plus chemotherapy) compared with the identical chemotherapy alone in patients with indolent or mantle cell lymphoma.

Good-Prognosis Diffuse Large B-Cell Lymphoma

Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomized controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379–91 (NCT 00064116, available at http://www.ClinicalTrials.gov). (4)

Clinical background. It is assumed that young patients (aged 18–60 years) with no risk factor or with one risk factor according to age-adjusted International Prognostic Index (IPI) have a good prognosis. These patients might also benefit from rituximab. In this context, the MInT Group analyzed the efficacy of rituximab in combination with different CHOP-like chemotherapy regimens in young patients with good-prognosis diffuse large–B-cell lymphoma.

Contribution. This prospective trial, conducted in 18 countries, recruited 824 untreated patients (aged 18–60 years) with CD20-positive diffuse large–B-cell lymphoma defined by the local pathologist according to WHO criteria, who had no risk factors or one risk factor according to age-adjusted IPI, stage II–IV disease, or stage I disease with bulk. Patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n = 413) or to six cycles of CHOP-like chemotherapy alone (n = 411). Patients with primary bulky disease received additional radiotherapy. Radiotherapy to extranodal sites was given at the treating physician's discretion.

The primary endpoint was event-free survival (EFS), defined as time to progressive disease under therapy. The events for this endpoint were progressive disease, no achievement of complete remission, no achievement of unconfirmed complete remission, partial remission associated with treatment in excess of that stipulated in the protocol (e.g., more than six cycles of chemotherapy, radiotherapy to nonbulky areas, or use of rituximab in chemotherapy-only group), no change, relapse after achievement of complete remission or unconfirmed complete remission, or death from any cause, whichever came first.

Implication for practice. The addition of rituximab increased 3-year event-free survival compared with that in patients assigned to chemotherapy alone (79% [95% confidence interval [CI] = 75 to 83] versus 59% [95% CI = 54 to 64]) and had also increased 3-year overall survival (OS) (93% [95% CI = 90 to 95] versus 84% [95% CI = 80 to 88]). Thus, the authors concluded that rituximab added to six cycles CHOP is an effective treatment for young patients with good-prognosis diffuse large–B-cell lymphoma. However, long-term follow-up considering late recurrences and second malignancies is needed.

Most interesting feature. The detailed subgroup analysis of different chemotherapies was performed.


Key study features are as follows.

 Sample size calculation        • Yes, assumptions justified.      
 Randomization        • Central allocation with balanced randomization      
 Blinding        • Open label (unmasked)      
 Setting        • 172 centers in 18 different countries      
 Follow-up        • Median follow-up 34 months (range 0.03–64)      
 Lost to follow-up        • 59 patients were not evaluable due to early termination of the trial      
 Analysis        • Intention-to-treat analysis      
 Primary endpoint (Note 1)        • Event-free survival      
 Comparability of groups        • There were 2% more patients with extranodal involvement and B-symptoms in the chemotherapy-alone group (control).      
 • Performance status (0–4) was worse in the control group.      
 • There were 2% more patients with bulky disease in the intervention group.      
 Data of primary endpoint and survival        Patients assigned to chemotherapy and rituximab had increased:      
 • 3-year EFS (79% [95% CI = 75 to 83] vs 59% [95% CI = 54 to 64], log-rank P = .0001); with chemotherapy alone;      
 • 3-year OS (93% [95% CI = 90 to 95] vs 84% [95% CI = 80 to 88], difference between groups 9% [95% CI = 3 to 13], log-rank P = .0001);      
 • 3-year progression-free survival (PFS) (95% [95% CI = 81 to 89] vs 68% [95% CI = 62 to 73], difference between groups 17% [95% CI = 11 to 24], log-rank P = .0001)      
 Severe adverse events        • No difference in frequency of common toxic effects (grade 3,,4 US National Cancer Institute [NCI] Common Toxicity Criteria) were found.      
 Potential conflict of interest        • Explanation of sponsor's role and potential influence on trial. Two authors are full-time employees of the pharmaceutical company.      
 Of note        • Four different chemotherapy regimens were used (in both groups)      

Maintenance Rituximab in Older Patients

Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006;24:3121–7. (5)

Clinical background. More than 60% of patients with diffuse large–B-cell lymphoma are older than 60 years at the time of diagnosis. The CHOP regime is considered as standard therapy in this high-risk group because other second-generation regimens have shown limited advantage, raising the question about the benefit of adding rituximab to standard CHOP chemotherapy. In addition to the failure of therapy during induction, the failure to maintain the response is a second major area of treatment failure. So this trial also addressed the impact of rituximab as a drug for maintenance.

Contribution. This prospective trial recruited 632 patients older than 60 years with untreated diffuse large–B-cell lymphoma. After central pathologic review, 76 patients were excluded because of follicular or marginal zone subtype, and 10 patients were excluded due to other reasons. In the first randomization, 267 patients were assigned to R-CHOP and 279 to the control (CHOP) for induction therapy. In the second part of this two-stage RCT, 174 patients who reached partial or complete remission after induction were randomly assigned to maintenance therapy with rituximab (MR) and 178 to observation (control). No additional radiotherapy was administered. The primary endpoint was failure-free survival (FFS), defined as time from random assignment to relapse, nonprotocol treatment, or death. In the second part, failure-free survival rates were calculated for responders only.

Implication for practice. The addition of rituximab to the standard chemotherapy (CHOP) increased the failure-free survival. A statistically significant difference of maintenance therapy with rituximab was found only in the group with CHOP induction. No improvement in failure-free survival was observed with maintenance rituximab after R-CHOP. Regarding overall survival, induction therapy with R-CHOP was better than CHOP only in patients who did not receive maintenance rituximab. However, no statistically significant differences were observed with maintenance rituximab after R-CHOP or CHOP.

We conclude from this trial that addition of rituximab to the therapy of older patients with diffuse large–B-cell lymphoma might be an improvement. However, further trials will be needed to determine the best time of application and duration of rituximab.

Most interesting feature. Sequential analysis of two interventions with the same drug.


Key study features are as follows.

 Sample size calculation        • Yes, the aimed differences are described      
 Randomization        • Two-stage random assignment. In first part, stratification for IPI risk factors      
 Blinding        • Not stated      
 Setting        • Unclear (intergroup or multicenter?)      
 Follow-up        • Median follow-up 42 months      
 Lost to follow-up        • Only missing data for selected information was reported      
 Analysis        • Intention-to-treat analyses was not described, but the description of graphs included all randomized patients      
 Primary endpoint (Note 1)        • Failure-free survival      
 Comparability of groups        • The groups were balanced after the first randomization for induction therapy (CHOP vs R-CHOP). Performance status (0–4) was slightly worse in the intervention group I (R-CHOP)      
 Data of primary endpoint and survival        Intervention        FFS: hazard ratio (HR) [CI]; P        OS: HR [CI]; P      
 R-CHOP vs CHOP (all)        0.78 [0.61 to 0.99]; .04        0.83 [0.63 to 1.09]; 1.09      
 R-CHOP vs CHOP (not MR)        0.64 [0.47 to 0.85]; .03        0.72 [0.52 to 1.00]; .5      
 MR vs no maintenance        0.63 [0.44 to 0.90]; .09        0.96 [0.63 to 1.47]; .85      
 MR vs no maintenance after CHOP        0.45 [0.29 to 0.71]; .004        not statistically significant; .27      
 MR vs no maintenance after R-CHOP        0.93 [0.53 to 1.66]; .03        not statistically significant; .48      
 Severe adverse events        • No significant difference for common side effects and toxic effects for first randomization was found      
 • Significant grade 3/4 neutropenia was reported in patients receiving MR      
 Potential conflict of interest        • Standardized table with disclosure of conflicts for authors      
 Of note        • A two-stage randomization resulting in four main groups of different therapeutic regimens was performed.      
 • For some subgroups, the data were only partly reported or were reported with different parameters.      

Concurrent and Sequential Treatment With Rituximab

Ogura M, Morishima Y, Kagami Y, Watanabe T, Itoh K, Igarashi T, et al. Randomized phase II study of concurrent and sequential rituximab and CHOP chemotherapy in untreated indolent B-cell lymphoma.Cancer Sci 2006;97:305–12. (6)

Clinical background. The results of many randomized trials have shown that the addition of rituximab to standard chemotherapy is beneficial for patients with different types of lymphoma.

How to add rituximab in the treatment protocols? This question was not answered by Habermann, et al. 2006 (5)(see above). Therefore, this phase II randomized trial tried to answer this question in patients with untreated indolent B-cell lymphoma with six courses of rituximab given concurrently with standard therapy (CHOP) and patients receiving six courses of rituximab after they completed CHOP therapy.

Contribution. The trial recruited 69 patients (aged 20–70 years) with newly diagnosed indolent B-cell non-Hodgkin lymphoma, defined by the local pathologist according to the revised European-American lymphoma classification (REAL) classification (7). Thirty-four patients were allocated to the concurrent arm (Arm C) and 35 patients were allocated to the sequential arm (Arm S). The primary endpoint was overall response rate (ORR), defined for eligible patients achieving a complete, uncertain complete, or partial response (PR) according to International Workshop Response Criteria for non-Hodgkin lymphoma. The primary endpoint was analyzed as intention-to-treat and per-protocol analyses.

Implication for practice. With both schedules, the addition of rituximab to standard chemotherapy resulted in a sufficient response rate without a statistically significant. The improved progression-free survival and rate of side effects seemed to be better for the patients receiving six courses of rituximab after having completed CHOP therapy, but these findings were not statistically significant. This trial with 69 patients was underpowered for any conclusion about efficacy of different regimens of rituximab.

Most interesting features.

Results were presented for per protocol and intention-to-treat analyses.
Hematologic toxicities related to rituximab according to Japan Clinical Oncology Group (JCOG) (8), which are an expanded version of the Common Toxicity Criteria of the National Cancer Institute.were evaluated.


Key study features are as follows.

 Sample size calculation        • Yes, the aimed differences were described      
 Randomization        • Randomization by an independent center recognizing performance status, clinical stage, and center      
 Blinding        • Not stated      
 Setting        • 21 hospitals in Japan      
 Follow-up        • 28.2 months      
 Lost to follow-up        • Four patients stated as being not evaluable      
 Analysis        • Intention-to-treat analyses. Per-protocol analysis was also used for ORR and CR-rate. For this three patients were ineligible and excluded in the but were included in the full analysis set      
 Primary endpoint See remark "of note" below) (Note 1)        • Overall response rate (ORR)      
 Comparability of groups        • Stated as "very similar," but the results of statistical tests were not reported      
 Data of primary endpoint and survival        • ORR for concurrent: 97% (95% CI = 95 to 100) and 94% (95% CI = 84 to 99) for sequential.      
 • One patient in the sequential arm died. No more data were available for overall survival.      
 • Median progression-free survival for patients in concurrent arm (n = 32) was 34.2 months [95% CI = 27.1 months—inestimable], whereas that for patients in sequential arm (n = 33) had not yet been reached, with a median follow-up time of 28.2 months.      
 Severe adverse events        • Serious adverse events were reported in detail in tabular form.      
 • Slightly more adverse events were identified in the arm with concurrent therapy.      
 Potential conflict of interest        • Not stated      
 Of note        • Overall response rate (ORR), defined as the sum of partial and complete responses, was selected as the primary endpoint for efficacy of the intervention. The adequacy of such an endpoint is dependent on other factors such as effect size, effect duration, and benefits of other available therapy (9).      


   Published Trial on Interferon and non-Hodgkin lymphoma
Top
 Introduction
 Published trials on rituximab...
 Published trial on interferon...
Published trial on hdc...
 Methodologic aspects
 The cochrane library
 References
 Notes
 
Role of Interferon in Patients With Relapsing Follicular Lymphoma

Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 2006;108:2540–4. (10)

Clinical background. Chemotherapy with combined interferon {alpha} (Intron A) has improved survival of patients with follicular lymphoma in comparison with chemotherapy alone, but it did not cure the patients (11). High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) gave encouraging results in phase II studies on relapsing patients with follicular lymphoma. This trial concluded that high-dose therapy should be reserved for the treatment of relapsing patients when compared with standard chemotherapy combined with interferon (i.e., interferon with standard chemotherapy should be preferred).

Contribution. Four hundred one patients (<61 years, median = 49 years) were included according to eligibility criteria from July 1994 to March 2001. Of these, 209 patients received 12 cycles of CHVP (cyclophosphamide, doxorubicin, vincristine, and prednision) plus interferon {alpha} for 18 months (CHVP-I arm) and 192 patients received 4 cycles of CHOP followed by high-dose therapy with total body irradiation and autologous stem cell transplantation (CHOP-HDT arm). Overall response rate, overall survival and event free survival were estimated in both arms.

Whether patients in the CHVP-I arm received interferon maintenance therapy was not clear. In the treatment section, it was stated that after a 6-month course of CHVP, patients were given interferon. Patients then achieving a complete or partial response received six courses of CHVP plus interferon every 2 months for 1 year.

Implication for practice. Overall response rate were similar in both groups (79% in CHVP-I arm and 78% in CHOP-HDT arm after induction therapy). Of the 151 patients eligible for high-dose therapy, 131 underwent transplantation. Intention-to-treat analysis after a median follow-up of 7.5 years showed that there was no difference between the two arms for overall survival (P = .53) or event-free survival (P = .11).The study did not show statistically significant benefit in favor of first-line high dose therapy for patients with follicular lymphoma.

Most interesting feature. Analysis according to Follicular Lymphoma International Prognostic Index (FILIPI). Outcomes were stratified according to the FILIPI score. Among patients with an intermediate or high-risk FILIPI score (12), event-free survival seemed to be longer in the CHOP-HDT arm (37% [95% CI = 26% to 43%] for 130 patients) than the CHVP-I arm (29% [95% CI = 15% to 30%] for 135 patients), P = .057, but overall survival did not differ.

Interferon-related chronic grade 3 or 4 toxicities were observed.


Key study features are as follows.

 Sample size calculation        • Yes      
 Randomization        • Randomization by an independent center recognizing clinical stage and center      
 Blinding        • Not stated      
 Setting        • 71 centers in France and Belgium      
 Follow-up        • Median follow-up of 7.5 years (92 months)      
 Lost to follow-up        • Based on ITT analysis, 273 of 401 (93%) of randomized patients have been seen in the last 9 months before the final analysis. Only for eight patients was information lost for more than 2 years.      
 Analysis        • Intention-to treat analysis      
 Primary endpoint (Note 1)        • Event-free survival, overall survival      
 Comparability of groups        • No substantive difference for patient characteristics were reported      
 Data of primary endpoint and survival.        • 7-year EFS estimates were 28% (95% CI = 21% to 34%) in CHVP-I arm compared with 38% (95% CI = 31% to 45%) in the CHOP-HDT arm (P = .11)      
         •Overall survival was similar in both treatment groups: 7-year OS of 70% (95% CI = 65% to 71%) for CHVP-I arm compared with 76% (95% CI = 69% to 82%) for CHOP-HDT arm (P = .4)      
 Severe adverse events        • Two cases of secondary myelodysplastic syndrome, two cases of secondary AML were observed in the CHVP-I arm.      
         • Two cases of myelodysplastic syndrome were reported in CHOP-HDT arm.      
         • Ten solid tumors in CHVP-I arm and nine in CHOP-HDT arm      
 Potential conflict of interest        • Not stated      
 Of note        • Analysis according to FILIPI, late toxicities (LT)      


   Published Trial on HDC and non-Hodgkin lymphoma
Top
 Introduction
 Published trials on rituximab...
 Published trial on interferon...
 Published trial on hdc...
Methodologic aspects
 The cochrane library
 References
 Notes
 
High-Dose Chemotherapy for non-Hodgkin lymphoma

Betticher DC, Martinelli G, Radford JA, Kaufmann M, Dyer MJS, Kaiser U, et al. Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol 2006;17:1546–52. (13)

Clinical background. Sequential high-dose (SHiDo) chemotherapy with stem cell support has been shown to prolong event free survival in patients with diffuse large–B-cell lymphoma. The current randomized multicenter trial aimed to confirm this by comparing SHiDo chemotherapy with standard CHOP therapy in patients with aggressive lymphoma.

Contribution. The trial recruited 136 patients between 1997 and November 2003 (aged 18–61 years) with untreated, histologically documented aggressive lymphoma (diffuse large–B-cell, primary mediastinal-thymic B-cell and anaplastic large-cell lymphoma) according to the REAL classification. Four ineligible and three other patients were excluded.

Initially, a 2:1 randomization in favor of SHiDo was chosen. After revision of the trial protocol, randomization was changed to 1:1 due to the collaboration with the UK Coordinating Committee on Cancer Research (UKCCCR) lymphoma subcommittee. Fifty-nine patients were enrolled in the CHOP arm and 70 in the SHiDo arm. The trial closed in 2003 (after 6.5 years) because the results of the interim analysis (in regard to efficacy, safety, and power calculation) did not show any possibility more to detect relevant differences in overall survival (primary endpoint) and because of the high incidence of severe toxicity in the experimental arm (ShiDo). Furthermore in the meanwhile, new strategies for this patient population were developed.

Implication for practice. The trial did not confirm earlier results that had implied better outcome of SHiDo regimen in patients with untreated aggressive lymphoma. There was a higher rate of toxicity complications, so SHiDo therapy should not be recommended as the standard therapy for previously untreated patients.

Most interesting feature.

Single relevant outcome parameter was overall survival.
Subgroup analysis regarding age, bulky disease, and bone marrow involvement was performed.


Key study features are as follows.

 Sample size calculation        • During the trial, there was a change of sample size calculation, in view of collaboration with UKCCCR lymphoma subcommittee resulting in a change from 1:2 randomization to 1:1      
 Randomization        • Central randomization stratified by center, number of IPI risk factors, and absence of bone marrow infiltration      
 • First planed 1:2, later changed to 1:1 randomization      
 Blinding        • Not stated      
 Setting        • Multicenter (28 centers in 5 countries)      
 Follow-up        • 48 months (median follow-up)      
 Lost to follow-up        • Four of 136 patients were stated as ineligible, one refused, and documentation of two got lost      
 Analysis        • Intention-to-treat analyses      
 Primary endpoint (Note 1)        • Overall survival      
 Comparability of groups        • For first 1:2 randomization, there was a slight imbalance, with greater proportion of patients in the high intermediate and high-risk IPI groups in CHOP arm.      
 Data of primary endpoint (and survival).        Data for 3-year overall survival, no statistically significant difference was found (P = .48)      
 • SHiDo 39 death (46%; CI = 34% to 58%)      
 • CHOP 28 death (53%; CI = 39% to 67%)      
 • Data for the secondary endpoint, i.e., 3-year event-free survival, showed also no significant difference (33% vs 39%; P = .67)      
 Severe adverse events        3% of patients in CHOP and 4% in SHiDo arm died due to the toxic side effects. Overall toxicity was also higher in the SHiDo arm      
 Potential conflict of interest        • Trial was partly supported by Amgen and Roche.      
 • Conflicts of interest for authors were not stated.      
 Of note        • Trial was closed in 2003 (after 6.5 years) due to absence of the potential to detect relevant differences in overall survival between the treatment arms and the high incidence of severe toxicity in SHiDo arm.      
 • Data of protocol adherence were reported.      
 • Subgroup analysis was performed.      


   Methodologic Aspects
Top
 Introduction
 Published trials on rituximab...
 Published trial on interferon...
 Published trial on hdc...
 Methodologic aspects
The cochrane library
 References
 Notes
 
In the last biannual report, we described the definitions of different efficacy endpoints (mainly primary outcome measures) used in different oncology trials. In this report, we concentrate on intervention-related adverse events (toxicities) and treatment-related deaths, reported in the above-mentioned five trials, according to criteria used. Each trial reported intervention-related adverse effects (toxicities of grades 0–5).

A brief summary in tabular form provides an overview of the criteria (methods) used to evaluate the toxicities and the toxicities that were related to different interventions (only grade 3–5 toxicities will be discussed). For detail, please see the related publications. We divide the toxicities in three main groups, along with a fourth group of treatment-related deaths, as follows:

Hematologic toxicities
Nonhemotologic toxicities
Late toxicities or secondary malignancies
Treatment-related deaths (Deaths)

Pfreundschuh et al. 2006 (4)

This study used US-NCI Common Toxicity Criteria to evaluate the adverse effects and toxicities (Table 1). Only grade 3–5 adverse effects (toxicities) were reported.


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  		Table 1. CHOP versus CHOP-R adverse effects and toxicities*

 
Habermann et al. 2006 (5)

Reported were grade 0–4 toxicities, including some information about lethal toxicities. Whether these lethal toxicities resulted in death was not described. There were no statistically significant differences in adverse events between induction arms (P>.18; Table 2). Only adverse effects (toxicities) with grades 3–5 are given here.


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  		Table 2. R-CHOP versus CHOP in older patients with diffuse large B-cell lymphoma*

 
The trial showed that grade 3 or 4 granulocytopenia was more common in maintenance rituximab patients (n = 23, 12%) than in observation patients (n = 8, 4%), P = .008. Overall grade 3 or 4 nonhemotologic toxicities of all types were reported in 36 patients (18%) randomly assigned to maintenance therapy with rituximab and 32 patients (17%) randomly assigned to observation (P = .69).

Ogura et al. 2006 (6)

The trial reported both hematologic and nonhematologic toxicities for grades 0–5. Overall grade 3 or greater hematologic toxicities in Arm C were 32 cases (94%) compared with Arm S with 33 cases (100%). Grade 3 or greater nonhematologic adverse events were seven cases (21%) in Arm C compared with four cases (12%) in Arm S (Table 3). Only adverse effects (toxicities) with grades 3–5 are described here.


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  		Table 3. Randomized phase II study of concurrent and sequential rituximab and CHOP chemotherapy in untreated indolent B-cell lymphoma*

 
Sebban et al. 2006 (10)

In this trial, author described only late toxicities, including secondary malignancies (Table 4).


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  		Table 4. CHVP-I versus CHOP followed by HDT with ASCT in advanced follicular lymphoma*

 
Betticher et al. 2006 (13)

Three percent of the patients in the CHOP arm and 4% in the SHiDo arm died due to toxic side effects of therapy. The most frequent nonhematologic toxicities in CHOP-I arm were myelotoxicity, infections, and nausea/vomiting (>10% of patients). Overall toxicities were higher in the SHiDo arm (Table 5).


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  		Table 5. CHOP versus SHiDo for aggressive non-Hodgkin lymphoma*

 
Two trials (Pfreundschuh and Ogura) (4,6) described two slightly different criteria, US-NCI-CTCAE and JCOG toxicity criteria, respectively, for evaluating the adverse events. Two trials (Habermann and Betticher) (5,13) did not describe the criteria for grading the adverse effects, and one (Sebban) (10) described only the late toxicities.

This analysis highlights the fact that it is important to check the criteria and methods used when comparing the level of adverse effects and toxicities for the same intervention in different trials.


   The Cochrane Library
Top
 Introduction
 Published trials on rituximab...
 Published trial on interferon...
 Published trial on hdc...
 Methodologic aspects
 The cochrane library
References
 Notes
 
New Reviews

In the new issue of the Cochrane Library (Issue II 2007 published online April 18, 2006; available at http://www.thecochranelibrary.com/), no new review was published.

New Protocols

There were four new protocols approved through the editorial process:

Antiplatelet drugs for polycythemia vera and essential thrombocythemia by Squizzato A, Romualdi E, Middeldorp S
Immunoglobulin prophylaxis in hematologic malignancies and hematopoietic stem cell transplantation by Raanani P, Ben-Bassat I, Gafter-Gvili A, Leibovici L, Paul M, Shpilberg O
Rituximab as maintenance therapy for patients with follicular lymphoma by Vidal L, Gafter GA, Leibovici L, Shpilberg O
Vaccines for prophylaxis of viral infections in patients with hematologic malignancies by Cheuk DKL, Chiang AKS, Lee TL, Chan GCF, Ha SY, YL Lau

However, several other review and protocol manuscripts are in the editorial process and are expected to be published in forthcoming issues of the Cochrane Library. Currently, the CHMG maintains 10 published reviews, 21 protocols, and 20 registered titles.


   NOTES
Top
 Introduction
 Published trials on rituximab...
 Published trial on interferon...
 Published trial on hdc...
 Methodologic aspects
 The cochrane library
 References
 Notes
 
CHMG Editorial Base is funded under the auspices of the German Federal Ministry of Education and Research (BMBF): FKZ: 01GH0501.


   REFERENCES
Top
 Introduction
 Published trials on rituximab...
 Published trial on interferon...
 Published trial on hdc...
 Methodologic aspects
 The cochrane library
 References
Notes
 

(1) Forstpointner R, Unterhalt M, Dreyling M, Bock HP, Repp R, Wandt H, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood (2006) 108(13):4003–4008.[Abstract/Free Full Text]

(2) van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood (2006) 108(10):3295–3301.[Abstract/Free Full Text]

(3) Schulz H, Bohlius J, Trelle S, Skoetz N, Reiser M, Kober T, et al. Immunochemotherapy With Rituximab and Overall Survival in Patients With Indolent or Mantle Cell Lymphoma: A Systematic Review and Meta-analysis. J Natl Cancer Inst (2007) 99(9):706–714.[Abstract/Free Full Text]

(4) Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncology (2006) 7(5):379–391.[CrossRef][ISI][Medline]

(5) Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol (2006) 24(19):3121–3127.[Abstract/Free Full Text]

(6) Ogura M, Morishima Y, Kagami Y, Watanabe T, Itoh K, Igarashi T, et al. Randomized phase II study of concurrent and sequential rituximab and CHOP chemotherapy in untreated indolent B-cell lymphoma. Cancer Science (2006) 97(4):305–312.[CrossRef][Medline]

(7) Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood (1994) 84(5):1361–1392.[Free Full Text]

(8) Tobinai K, Kohno A, Shimada Y, Watanabe T, Tamura T, Takeyama K, et al. Toxicity grading criteria of the Japan Clinical Oncology Group. The Clinical Trial Review Committee of the Japan Clinical Oncology Group. Jpn J Clin Oncol (1993) 23(4):250–257.[Free Full Text]

(9) U.S. Department of Health and Human Services Food and Drug Administration - Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologies. (2007) Rockville MD: U.S. Department of Health and Human Services Food and Drug Administration.

(10) Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood (2006) 108(8):2540–2544.[Abstract/Free Full Text]

(11) Rohatiner AZS, Gregory WM, Peterson B, Borden E, Solal-Celigny P, Hagenbeek A, et al. Meta-Analysis to Evaluate the Role of Interferon in Follicular Lymphoma. J Clin Oncol (2005) 23(10):2215–2223.[Abstract/Free Full Text]

(12) Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, et al. Follicular Lymphoma International Prognostic Index. Blood (2004) 104(5):1258–1265.[Abstract/Free Full Text]

(13) Betticher DC, Martinelli G, Radford JA, Kaufmann M, Dyer MJS, Kaiser U, et al. Sequential high dose chemotherapy as initial treatment for aggressive sub-types of Non-Hodgkin Lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol (2006) 17(10):1546–1552.[Abstract/Free Full Text]


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