Background

Non-Hodgkin’s lymphoma (NHL) is a cancer of the lymphatic tissue, causing enlargement of lymph nodes and generalised symptoms. Follicular lymphoma (FL), a clinical subtype of NHL, develops slowly and often without symptoms for many years. FL takes a relapsing and remitting course, and median survival is 8–10 years, although more recent evidence suggest it could be as high as 15–20 years. In 2008, the incidence of FL in England and Wales was 3.4 per 100,000 persons. Over 70% of FLs are diagnosed in persons aged > 60 years, and 85–90% present with advanced disease, which is defined as lymph nodes on both sides of the diaphragm being involved (stage III) or disease is disseminated with one or more extralymphatic organ involved (stage IV).

Advanced FL is not curable, thus the aim of disease management is to both increase patient life expectancy and to increase patient health-related quality of life. For the majority of patients (90%), first-line therapy in stage III–IV FL is rituximab (R) (MabThera^®, Roche Products) plus chemotherapy (R-chemotherapy), with around two-thirds receiving the cyclophosphamide, vincristine and prednisolone (CVP) regimen as the chemotherapy component of treatment. The next most frequent chemotherapy regimen is cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP), which accounts for 16% of other chemotherapy regimens. Patients who are less fit and/or elderly may receive chlorambucil (Leukeran^®, Aspen) as single-agent chemotherapy. The National Institute for Health and Clinical Excellence reviewed the use of rituximab in Technology Appraisal (TA) no. 110 in 2006, subsequently recommending the use of R-CVP as first-line treatment for symptomatic stage III–IV FL. Since TA110, the licence for rituximab has been extended so that rituximab can be administered in combination with any chemotherapy for first-line treatment of symptomatic stage III–IV FL. Rituximab monotherapy as a maintenance treatment may follow for patients who have responded to first-line treatment with R-chemotherapy, which aims to delay relapse by stabilising response to initial therapy, eradicating any residual disease and maintaining remission after successful remission induction therapy.

Objectives

The aim of this assessment is to systematically evaluate and appraise the clinical effectiveness and cost-effectiveness of rituximab (in its licensed indication) in combination with chemotherapy compared with non-rituximab-containing chemotherapy, for the first-line treatment of symptomatic stage III–IV FL.

Methods

Eleven electronic databases were searched from inception to September/October 2010: MEDLINE, including MEDLINE In-Process & Other Non-Indexed Citations; Cumulative Index to Nursing and Allied Health Literature (CINAHL); EMBASE; The Cochrane Library, including the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED) and Health Technology Assessment (HTA) databases; Science Citation Index (SCI); and BIOSIS. Ongoing research was searched using clinical trials databases and registers. Relevant conference proceedings were searched and the reference lists of relevant articles and sponsor submissions were handsearched.

Comparative studies were selected for review if they addressed the clinical effectiveness or cost-effectiveness of adding rituximab to chemotherapy. In addition, comparative studies that involved either an intervention or comparator defined in the decision problem (i.e. R-chemotherapy or chemotherapy alone) were selected for potential use in a network meta-analysis. The studies had to include patients with symptomatic III–IV FL and to be of randomised controlled trial (RCT) design. Outcomes had to include one or more of the following: response rates, response duration, overall survival (OS), progression-free survival (PFS) or duration of disease remission. The quality of the studies was assessed using criteria based on those proposed by the NHS Centre for Reviews and Dissemination. Data were abstracted into standardised data extraction forms. Findings were tabulated and discussed in a narrative synthesis.

A systematic review of economic evaluations addressing the cost-effectiveness of the addition of rituximab to chemotherapy compared with chemotherapy alone was conducted. There was also one manufacturer submission (Roche) for this assessment, which included an economic model. In addition, a systematic review of the quality of life in FL was performed.

A probabilistic model was developed by the Assessment Group (AG) to assess the cost-effectiveness of the addition of rituximab to CVP, CHOP and MCP (mitoxantrone, chlorambucil and prednisolone) from a NHS perspective. The model has four health states: PFS after first line (PFS1), PFS after second line (PFS2), progressive disease and death. Patients start in PFS1 and receive first-line induction with chemotherapy with or without rituximab. Patients who relapse move on to PFS2 and are assumed to receive second-line treatment with or without maintenance rituximab. After progression, patients enter a progressive state and remain in that state until death. The model uses a 25 years time horizon and costs and benefits are discounted at 3.5%. A scenario analysis is presented incorporating first-line maintenance in responder to first-line induction with R-chemotherapy.

Results

Discussion

The results from four randomised trials (of good quality) comparing R-chemotherapy with chemotherapy alone showed an improvement in a number of clinical effectiveness outcomes. These benefits are achieved with minimal clinically relevant additional adverse events or toxicity. It is noted that data for outcomes such as OS are compromised in three of the studies owing to the use of additional treatments. Longer OS data follow-up would strengthen the findings, as the median OS has not yet been reached in any of the trials.

This assessment provides an indication of the cost-effectiveness of the addition of rituximab to CVP, CHOP and MCP in a UK setting. The model developed by the AG extends the analysis undertaken in previous economic models in terms of a greater level of detail in the modelled treatment pathway. A wide range of assumptions have also been examined in SAs. However, there are some limitations relating to the sources of data used in the AG model for the effectiveness in first and second line and the assumed utility values. There is little evidence available regarding the effectiveness of R-CHOP and R-MCP in first-line induction. There is also uncertainty about the effect of salvage treatment in patients previously treated with an anthracycline regimen. Finally, there is uncertainty whether or not rituximab is as effective in second line when patients have been previously treated with rituximab. The context for care and the mode of delivery is identical with the comparator therapies; thus, there are no implications that do not also apply to chemotherapies alone.

Conclusions

The addition of rituximab to CVP, CHOP and MCP is likely to be clinically effective in the first-line treatment of stage III–IV FL. The cost per QALY gained is estimated to be < £25,000 for all three comparisons under our base-case assumption and is considerably lower if first-line rituximab maintenance is not assumed. The main uncertainties in terms of influencing the ICER relate to the effectiveness of rituximab retreatment (i.e. resistance) and the effect of salvage treatment in patients previously treated with anthracycline regimens. Assumptions were made and the best evidence identified was used when appropriate and available. Therefore, results have to be interpreted in line with the assumptions made and the quality of the evidence available.

Funding

Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

Publication

• Papaioannou D, Rafia R, Rathbone J, Stevenson M, Buckley Woods H, Stevens J. Rituximab for the first-line treatment of stage III–IV follicular lymphoma (review of Technology Appraisal No. 110): a systematic review and economic evaluation. Health Technol Assess 2012;16(37). [PubMed: 23021127]

NIHR Health Technology Assessment programme

The Health Technology Assessment (HTA) programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. ‘Health technologies’ are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.

The research findings from the HTA programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the ‘National Knowledge Service’.

The HTA programme is needs led in that it fills gaps in the evidence needed by the NHS. There are three routes to the start of projects.

First is the commissioned route. Suggestions for research are actively sought from people working in the NHS, from the public and consumer groups and from professional bodies such as royal colleges and NHS trusts. These suggestions are carefully prioritised by panels of independent experts (including NHS service users). The HTA programme then commissions the research by competitive tender.

Second, the HTA programme provides grants for clinical trials for researchers who identify research questions. These are assessed for importance to patients and the NHS, and scientific rigour.

Third, through its Technology Assessment Report (TAR) call-off contract, the HTA programme commissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring together evidence on the value of specific technologies.

Some HTA research projects, including TARs, may take only months, others need several years. They can cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence, undertaking a trial, or other research collecting new data to answer a research problem.

The final reports from HTA projects are peer reviewed by a number of independent expert referees before publication in the widely read journal series Health Technology Assessment.

Criteria for inclusion in the HTA journal series

Reports are published in the HTA journal series if (1) they have resulted from work for the HTA programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.

Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.

The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 09/141/01. The protocol was agreed in September 2010. The assessment report began editorial review in April 2011 and was accepted for publication in December 2011.The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Editor-in-Chief: Professor Tom Walley CBE

Series Editors: Dr Martin Ashton-Key, Professor Aileen Clarke, Dr Peter Davidson, Dr Tom Marshall, Professor William McGuire, Professor John Powell, Dr Rob Riemsma, Professor Helen Snooks and Professor Ken Stein