Positron emission tomography (PET)-adapted therapy for Hodgkin lymphoma patients

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of interim [18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging for treatment modification in patients with Hodgkin lymphoma by critical, systematic and statistical analysis of randomised controlled trials, regarding overall survival, progression-free survival, response rate, adverse events and quality of life.

Background

Description of the condition

Hodgkin lymphoma (HL) is a cancer of the lymphatic system of the body, involving the lymph nodes, spleen, and other organs such as the liver, lung, bone or bone marrow depending on the tumour stage (Lister 1989). It is a B-cell lymphoma which accounts for less than 1% of all neoplasms throughout the world (Fraga 2007). Hodgkin lymphoma is characterised by a small proportion of tumour cells, known as Hodgkin- and Reed-Sternberg-cells. The malignant cells usually account for only about 1% of cells in the tumour tissue surrounded by a specific inflammatory microenvironment (Diaz 2011; Shenoy 2011).

In western countries HL typically shows a bimodal age distribution with a first peak around the age of 30 and a second peak after the age of 50. It accounts for 10% to 15% of all lymphoma in industrialised countries with an incidence of 2 to 3 per 100,000 inhabitants. Therefore it can be regarded as a relatively rare disease, but nevertheless, it is one of the most common malignancies in young adults (Caporaso 2009; Swerdlow 2003; Thomas 2002).

There is a distinction between two types of HL according to the Revised European-American Lymphoma/World Health Organization (REAL/WHO) classification: lymphocyte predominance HL (LP-HL) representing about 5% of all HL, and classical HL (˜95%). They differ in morphology, phenotype, molecular features and therefore in clinical behavior as well as clinical presentation (Harris 1999; Re 2005). Classical HL is further divided into four subtypes (nodular sclerosis, mixed cellularis, lymphocyte-rich classical Hodgkin lymphoma, and lymphocyte depleted Hodgkin lymphoma) all of which are treated similarly (Fraga 2007).

The disease usually develops in lymph nodes of the upper part of the body, mostly in the latero-cervical lymph nodes which results in painless swelling of the lymphatic tissue involved. Normally HL appears within certain parts of the body with peripheral extranodal involvement being rare. As a sign of large tumour size or spreading, 25% of patients present themselves with B-symptoms such as fever of unknown origin, heavy sweating during nighttime and loss of more than 10% of body weight (Connors 2009; Pileri 2002).

For staging, the Ann Arbor Classification and the International Prognostic Index (IPI) (only for advanced stages) is used. Referring to Ann Arbor, we distinguish between four different tumour stages summarised as limited (˜40% of patients) and advanced (˜60% of patients) disease. Stages one to three indicate the degree of lymph node involvement, while stage four indicates disseminated organ involvement and can be found in 20% of cases. Factors influencing the prognosis of Hodgkin lymphoma are, for example, large mediastinal mass, three or more involved lymph node areas, high erythrocyte sedimentation rate (ESR), extranodal lesion, and advanced age, and may slightly vary between different study groups. Additionally, the definition of bulky disease (largest tumour diameter greater than 10 cm), often referred to as the Cotswold modification (Lister 1989), is taken into consideration.

Generally, Hodgkin lymphoma is classified into early favourable, early unfavourable and advanced stage (Engert 2007; Klimm 2005). In Europe, the early favourable stage group usually comprises Ann Arbor stages I and II without risk factors. Early unfavourable stage includes those patients in stages I and II with risk factors, as well as selected patients with stage IIIA disease. Most stage III and IV patients are classified in the advanced-stage risk group (Diehl 2001; Engert 2003). Patients with Ann Arbor stage IIB and some specific risk factors, or stage II with bulky disease, may be included in trials for advanced stages.

With cure rates of 80 to 90%, HL is one of the most curable cancers worldwide (Engert 2010; Engert 2012; von Tresckow 2012). A combination of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) has been widely accepted as the gold-standard chemotherapy regimen in HL (Canellos 1992; Engert 2010). For treatment of limited stage disease, a combination of chemotherapy and involved field radiation (IF-RT) is performed (Engert 2010; von Tresckow 2012) whereas advanced stage disease is treated with an intensified regime such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (Bauer 2011; Borchmann 2011; Engert 2012) or ABVD. Recently, a large randomised trial showed that two cycles of ABVD followed by 20 Gy of IF-RT is sufficient for the treatment of early favourable HL (Engert 2010), whereas patients with early unfavourable HL are usually treated with four cycles of chemotherapy followed by 30Gy IF-RT. Of late, two cycles of BEACOPPescalated (esc) followed by two cycles of ABVD have been shown to improve the progression-free survival (PFS) in comparison to four cycles of ABVD in early unfavourable patients (von Tresckow 2012).

In case of relapse or refraction to initial treatment, high dose chemotherapy followed by autologous hemapoietic stem cell transplantation is the therapy of choice (Josting 2010; Linch 1993; Schmitz 2002).

Description of the intervention

Computer tomography is an imaging tool for interim tumour staging, associated with a high radiation exposure. Another imaging tool to make a statement about the progression or non-progression of a tumour during therapy is [F-18]-fluorodeoxy-D-glucose (FDG)-positron emission tomography (PET, also called PETscan). It has become a standard procedure for numerous oncological situations. The principle of FDG-PET is based on FDG being a labelled glucose analogue and therefore being a good representative of the glucose metabolism of the tissue. More precisely 18F-FDG consists of two parts: a vector part (2-deoxy-D-glucose) and the 18F part which is a positron emitting nuclide. When FDG is taken up by cells, preferably by those with a high basis metabolic rate, it is not metabolised but is 'trapped' within the cell and can then be detected by scintigraphy. This process is used to give evidence about FDG-avid tumours like HL, their state and progression (Boellaard 2010).

FDG-PET is not only used for tumour staging, but also for response evaluation in lymphoma patients, and has been widely accepted (Kobe 2010b; Markova 2009; Specht 2007). Recent data demonstrate that early interim FDG-PET is a good predictor of prognosis and therefore could help to distinguish between good and poor responders at an early time point of therapy (Gallamini 2007; Kobe 2010a; Markova 2012). The differentiation of responding and non-responding patients could lead to response adapted therapeutic strategies such as de-escalation in responding patients or escalation in non-responding patients. A potential therapy adaptation is a fairly new method which was introduced with the exploration of FDG-PET (Engert 2012; Kobe 2008). However, the question to be answered is whether patients could benefit from such an aligned therapy in terms of response and overall survival.

How the intervention might work

PET-based treatment modifications are broadly used in numerous trials. As FDG-PET imaging gives us a good insight into the tumour's metabolic activity, treatment modification will include escalation in PET-positive as well as de-escalation in PET-negative patients. More precisely this means chemotherapy intensification (e.g. number of cycles or number of chemotherapeutic agents or additional immunotherapy) on the one hand, and chemotherapy reduction (e.g. number of cycles or number of chemotherapeutic agents, or no further treatment/no radiotherapy) on the other. The idea behind this method is to achieve maximum efficacy in terms of overall and progression-free survival, and to reduce long-term adverse events.

Why it is important to do this review

To our knowledge, no systematic review on the effectiveness of interim PET-based treatment modification in Hodgkin lymphoma patients has been performed to date. As the question of PET-guided therapy adaptation is very important, and pivotal for decision-making, it has been evaluated in several randomised controlled trials. At least two published randomised controlled trials and nine ongoing trials are assessing the potential advantages and disadvantages of interim PET-based treatment adaptation. The available data from these randomised studies will be summarised in our review, and we will be provided with more precise and reliable evaluation of intervention effects by meta-analysing single trials. Thereby we will overcome the limitations of individual studies due to small sample sizes and lack of statistical power. Summing up all results will help to identify the best available therapeutic strategy, as well as drawing conclusions on the treatment modification in question.

Objectives

To assess the effects of interim [18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging for treatment modification in patients with Hodgkin lymphoma by critical, systematic and statistical analysis of randomised controlled trials, regarding overall survival, progression-free survival, response rate, adverse events and quality of life.

Methods

Criteria for considering studies for this review

Types of studies

We will include only randomised controlled trials. We will include both full text and abstract publications if sufficient information is available on study design, characteristics of participants, interventions and outcomes. We will exclude quasi-randomised trials, e.g. treatment allocation alternate or by date of birth, and cross-over trials.

Types of participants

We will include all patients with a newly-confirmed diagnosis of Hodgkin lymphoma, without age, gender or ethnicity restriction. We will consider all stages and subtypes of newly-diagnosed Hodgkin lymphoma patients. In trials consisting of mixed populations with varying haematological malignancies we will use only data from the Hodgkin lymphoma patients. We will exclude trials which have fewer than 80% of HL patients, if subgroup data for these patients are not provided after contacting the trial authors.

Types of interventions

The main experimental intervention will be positron emission tomography (PET)-adapted treatment modification compared to the control intervention of up to date standard therapy without modification.

If PET-adapted treatment modification is evaluated in a randomised design, we will consider the following interventions:

  • For patients in early stages, PET-negative

    • Experimental: treatment modification: no further treatment/ no radiotherapy

    • Control: standard approach: additional radiotherapy

  • For patients in early stages, PET-positive

    • Experimental: treatment modification: chemotherapy intensification (e.g. shift to BEACOPP) plus radiotherapy

    • Control: radiotherapy

  • For patients in advanced stages, PET-negative

    • Experimental: treatment modification: chemotherapy reduction (e.g. number of cycles or chemotherapeutic agents)

    • Control: standard chemotherapy (e.g. BEACOPP or ABVD)

  • For patients in advanced stages, PET-positive

    • Experimental: treatment modification: chemotherapy intensification (e.g. number of cycles or number of chemotherapeutic agents or plus additional immunotherapy)

    • Control: standard chemotherapy (e.g. BEACOPP or ABVD)

Types of outcome measures

Primary outcomes

The specific aim of this systematic review will be to meta-analyse overall survival (OS) as the primary endpoint as it is of greatest clinical relevance and utmost importance to patients.

Secondary outcomes
  • Progression-free survival (PFS)

    • The time interval from random treatment assignment onto the study to first confirmed progression, relapse, death from any cause, or the last follow-up.

  • Response rate

    • Measured as overall response (OR), complete response (CR), and partial response (PR).

  • Adverse events (AE)

  • Treatment-related mortality (TRM)

  • Quality of life (QoL) if measured with reliable and valid instruments.

We will not evaluate the diagnostic value of PET.

Search methods for identification of studies

We will adapt search strategies from the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). We will seek studies in all languages to limit language bias.

Electronic searches

We will search the following databases and sources:

  • Databases of medical literature:

    • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), (for search strategy see Appendix 1).

    • MEDLINE (Ovid) (1990 to present), (for search strategy see Appendix 2).

  • Conference proceedings of annual meetings of the following societies for abstracts (2000 to present, if they are not included in CENTRAL):

    • American Society of Hematology;

    • American Society of Clinical Oncology;

    • European Hematology Association;

    • International Symposium on Hodgkin Lymphoma.

  • Electronic search in databases of ongoing trials:

Searching other resources

  • Handsearching:

    • We will check references of all identified trials, relevant review articles and current treatment guidelines for further literature.

  • Personal contacts:

    • We will contact experts in the field in order to retrieve unpublished trials.

Data collection and analysis

Selection of studies

Two review authors will independently screen the results of the search strategies for eligibility for this review by reading the abstracts. In the case of disagreement we will obtain the full text publication. If no consensus can be reached, we will ask a third review author for final decision (Higgins 2011b).

We will document the study selection process in a flow chart as recommended in the PRISMA statement (Moher 2009) showing the total numbers of retrieved references and the numbers of included and excluded studies.

Data extraction and management

Two review authors will extract data as specified in the guidelines of the Cochrane Collaboration. If required, we will contact authors of particular studies for auxiliary information (Higgins 2011a).

For the data extraction we will use a standardised form containing the following items:

  • General information: author, title, source, publication date, country, language, duplicate publications

  • Quality assessment: (as specified at Assessment of risk of bias in included studies)

  • Study characteristics: trial design, aims, setting and dates, source of participants, inclusion/exclusion criteria, comparability of groups, subgroup analysis, statistical methods, power calculations, treatment cross-overs, compliance with assigned treatment, length of follow-up, time point of randomisation

  • Participant characteristics: age, gender, ethnicity, number of participants recruited / allocated / evaluated, participants lost to follow-up, additional diagnoses, stage of disease

  • Interventions: setting, PET technique, PET assessment, type of (multi-agent) chemotherapy (intensity of regimen, number of cycles), field and dose of radiotherapy, duration of follow-up

  • Outcomes: overall survival, progression-free survival, response rate, adverse events, quality of life

Assessment of risk of bias in included studies

Two review authors (NS and SF) will independently assess the risk of bias for each study using the following criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a):

  • Sequence generation;

  • Allocation concealment;

  • Blinding (participants, personnel, outcome assessors);

  • Incomplete outcome data;

  • Selective outcome reporting;

  • Other sources of bias.

For every criterion we will make a judgement using one of three categories.

  1. 'Low risk': if the criterion is adequately fulfilled in the study, i.e. the study is at a low risk of bias for the given criterion.

  2. 'High risk': if the criterion is not fulfilled in the study, i.e. the study is at high risk of bias for the given criterion.

  3. 'Unclear': if the study report does not provide sufficient information to allow for a judgement of 'low risk' or 'high risk' or if the risk of bias is unknown for one of the criteria listed above.

Measures of treatment effect

For binary outcomes, we will calculate risk ratios (RR) with 95% confidence intervals (CI) for each trial. For time-to-event outcomes, we will extract hazard ratios (HR) from published data according to Parmar and Tierney (Parmar 1998; Tierney 2007). We will calculate continuous outcomes (e.g. quality of life) as mean differences.

Dealing with missing data

As described in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b) there are a number of potential sources for missing data which have to be considered: at study level, at outcome level, and at summary data level. First of all, it is of the utmost importance to differentiate between data 'missing at random' and 'not missing at random'. In the next step, we will contact original investigators to request missing data. If data are still missing, we will make explicit assumptions of any methods used; for example that the data are assumed to be missing at random or that missing values are assumed to have a particular value, such as a poor outcome. We will perform sensitivity analysis to estimate how sensitive results are to reasonable changes in the assumptions that are made. Furthermore the potential impact of missing data on the findings of the review will be addressed in the Discussion section.

Assessment of heterogeneity

We will evaluate heterogeneity of treatment effects using a Chi2 test with a significance level at P < 0.1. We will use the I² statistic to quantify possible heterogeneity (I² > 30% moderate heterogeneity, I² > 75% considerable heterogeneity) (Deeks 2011). We will explore potential causes of heterogeneity by sensitivity and subgroup analysis.

Assessment of reporting biases

In meta-analyses with at least 10 trials, we will explore potential publication bias by generating a funnel plot and statistically test using a linear regression test (Sterne 2011). We will consider a P value of less than 0.1 as being significant for this test.

Data synthesis

We will perform analyses according to the recommendations of the Cochrane Collaboration (Deeks 2011). We will use the Cochrane statistical software RevMan 5 for analysis. Should the data be considered sufficiently similar to be combined, we will pool results using the fixed-effect model, while we will use the random-effects model in a sensitivity analysis.

We will use the GRADE profiler to create 'Summary of findings' tables as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). We will prioritise outcomes according to patient relevance. The most important outcome is overall survival, followed by progression-free survival, adverse events and quality of life. We will calculate numbers needed to treat to benefit (NNTB) and numbers needed to treat to harm (NNTH) with corresponding 95% CI for clinical interpretation.

Subgroup analysis and investigation of heterogeneity

We will perform subgroup analyses of the following characteristics:

  • Age

  • Stage (early favourable/early unfavourable/advanced)

  • Type

  • Intensity of chemotherapeutic regimen, (e.g. aggressive therapy like BEACOPP or less aggressive therapy like ABVD)

  • Duration of follow-up

We will use the tests for interaction to test for differences between subgroup results.

Sensitivity analysis

We will perform sensitivity analyses of the following characteristics:

  • Quality components, including full text publications/abstracts

  • Preliminary results versus mature results

Acknowledgements

We thank the following members of the Cochrane Haematological Malignancies Group (CHMG) for their comments and improving the protocol: Ambuj Kumar and Lena Specht (Editors), Céline Fournier (Consumer Editor), and Michaela Rancea (Editorial base).

Appendices

Appendix 1. CENTRAL search strategy

#1MeSH descriptor Lymphoma explode all trees
#2MeSH descriptor Hodgkin Disease explode all trees
#3Germinoblastom*
#4Reticulolymphosarcom*
#5(hodgkin* or hogkin* or hodkin* or hodgin*):ti,ab,kw
#6(malignan* NEAR/2 (lymphogranulom* or granulom*))
#7(#1 OR #2 OR #3 OR #4 OR #5 OR #6)
#8MeSH descriptor Positron-Emission Tomography explode all trees
#9MeSH descriptor Tomography, Emission-Computed explode all trees
#10(pet* or petscan* or (Positron* and emission*) or (Positron* and tomography*))
#11(pet* and (deoxy* or fluor* or 18fluor* or fdg* or 18fdg* or fludeoxy*))
#12(pet* or petscan*)
#13(tomograph* or tomographs* or tomographic* or tomography* or tomographies*)
#14emission*
#15(#13 AND #14)
#16(#8 OR #9 OR #10 OR #11 OR #12 OR #15)
#17(#7 AND #16)
#18"accession number" near pubmed
#19(#17 AND NOT #18)

Appendix 2. MEDLINE search strategy

1Lymphoma/
2exp Hodgkin Disease/
3Germinoblastom$.tw,kf,ot.
4Reticulolymphosarcom$.tw,kf,ot.
5Hodgkin$.tw,kf,ot.
6(malignan$ adj2 (lymphogranulom$ or granulom$)).tw,kf,ot.
7or/1-6
8exp Positron-Emission Tomography/
9(pet$ or petscan$ or (Positron$ and emission$) or (Positron$ and tomography$)).tw,kf,ot.
10(pet$ and (deoxy$ or fluor$ or 18fluor$ or fdg$ or 18fdg$ or fludeoxy$)).tw,kf,ot.
11exp Tomography, Emission-Computed/
12(pet$ or petscan$).tw,kf,ot.
13(tomograph$ or tomographs$ or tomographic$ or tomography$ or tomographies$).tw,kf,ot.
14emission$.tw,kf,ot.
1513 and 14
168 or 9 or 10 or 11 or 12 or 15
177 and 16
18randomized controlled trial.pt.
19controlled clinical trial.pt.
20randomi?ed.ab.
21placebo.ab.
22clinical trials as topic.sh.
23randomly.ab.
24trial.ti.
25or/18-24
26humans.sh.
2725 and 26
2817 and 27

Contributions of authors

  • Marie-Therese Sickinger: development and writing of protocol

  • Bastian von Tresckow: clinical expertise

  • Carsten Kobe: clinical expertise

  • Andreas Engert: clinical expertise, content input

  • Nicole Skoetz: search strategy, proofreading of the protocol, statistical and methodological advice, content input

Declarations of interest

None known

Sources of support

Internal sources

  • Cochrane Haematological Malignancies Group, Department of Internal Medicine, University Hospital of Cologne, Germany.

External sources

  • No sources of support supplied

Ancillary