Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the benefits and harms of nivolumab in adult individuals with Hodgkin lymphoma (HL).
Background
Description of the condition
Hodgkin lymphoma (HL) is a cancer of the lymphatic system, and involves the lymph nodes, spleen and other organs such as the liver, lung, bone or bone marrow, depending on the tumour stage (Lister 1989). HL typically shows a bimodal age distribution with a first peak around the age of 30 years and a second peak after the age of 60 years. It accounts for 10% to 15% of all lymphoma in industrialised countries, with an incidence of 2 to 3 per 100,000 inhabitants. It can therefore be regarded as a relatively rare disease, but is nevertheless one of the most common malignancies in young adults. (Thomas 2002).
The disease usually develops in lymph nodes in the upper part of the body, mostly the latero‐cervical lymph nodes, and results in painless swelling of the lymphatic tissue involved. Normally HL appears within these parts of the body, with peripheral extranodal involvement being rare. As a sign of large tumour size or spreading, 25% of individuals present with B‐symptoms such as fever, drenching night sweats and a loss of more than 10% body weight (Connors 2009; Pileri 2002).
The World Health Organiztion (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues distinguishes between two types of HL: classic HL (cHL), which represents about 95% of all HL, and lymphocyte predominant HL, which represents about 5% of all HL (Mathas 2016). Both types differ in morphology, phenotype and molecular features, and therefore in clinical behaviour and presentation (Re 2005).
The Ann Arbor Classification is used for staging and distinguishes between four different tumour stages (Rosenberg 1971). Stages I to III indicate the degree of lymph node and localised extranodal organ involvement or both, and stage four includes disseminated organ involvement, which can be found in 20% of cases. Factors associated with a poor prognosis include a large mediastinal mass, three or more involved lymph node areas, a high erythrocyte sedimentation rate, extranodal lesions, B‐symptoms (weight loss of greater than 10%, fever, drenching night sweats) and advanced age, but the factors considered significant vary slightly between different study groups (German Hodgkin Study Group (GHSG), European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC)). HL is classified into early favourable, early unfavourable and advanced stage (Engert 2007). In Europe, the early favourable‐stage group usually comprises Ann Arbor stages I and II without risk factors. The early unfavourable‐stage group includes individuals with Ann Arbor stages I or II and one or more risk factors. Most individuals with stages IIB, III or IV disease are included in the advanced‐stage risk group (Engert 2003).
With cure rates of up 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) is widely accepted as the gold‐standard chemotherapy regimen in people with HL (Canellos 1992; Engert 2010). Individuals with limited‐stage disease usually receive a combination of chemotherapy and involved‐field radiation (IF‐RT) (Engert 2010; von Tresckow 2012), whereas those with advanced‐stage disease usually receive an intensified regimen, such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) (Borchmann 2011; Engert 2012; Skoetz 2013) or ABVD. 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). Two cycles of escalated BEACOPP (BEACOPPesc) followed by two cycles of ABVD can improve progression‐free survival (PFS) in comparison to four cycles of ABVD in individuals with early unfavourable HL (von Tresckow 2012).
Approximately 10% of people with HL will be refractory to initial treatment or will relapse; this is more common in those people with advanced stage or bulky disease. Standard of care for these individuals is high‐dose chemotherapy and autologous stem cell transplantation (ASCT), but only 55% of patients treated with high‐dose chemotherapy and ASCT have been shown to be free from treatment failure at three years (Rancea 2013). For patients progressing after ASCT, brentuximab vedotin can improve PFS and is the preferred treatment (Younes 2012). However, most patients eventually become refractory to brentuximab vedotin, with limited treatment options.
Description of the intervention
The European Commission has approved nivolumab for the treatment of patients with relapsed/refractory classical HL after autologous stem cell transplant and treatment with brentuximab vedotin. The approval was based on an objective response rate (ORR) of 66% in a combined analysis of 95 patients with relapsed or refractory classic HL who received nivolumab either in the phase II CheckMate‐205 trial or the phase I CheckMate‐039 trial (Ansell 2015; Younes 2016). A recent data report for CheckMate‐205 stated that the median duration of response was prolonged to 13.1 months. The 12‐month PFS was 54.6% and 12‐month overall survival (OS) was 94.9% (Timmermann 2016).
The most common drug‐related adverse events (AEs) included fatigue, infusion‐related reaction, arthralgia and rash. The most common drug‐related grade 3 or 4 AEs were neutropenia and increased lipase concentrations. The most common serious adverse events (SAEs) include fever, pneumonia, tumour progression, arrhythmia, infusion reaction and meningitis (≤ 4% each) (Timmermann 2016; Younes 2016).
Recent data show that nivolumab is now also used in combination with other drugs to treat patients with relapsed or refractory HL (Ansell 2016).
How the intervention might work
Checkpoint inhibitors that target the interaction of the programmed death (PD)‐1 immune checkpoint receptor, and its ligands PD‐L1 and PD‐L2, have shown remarkable activity in a wide range of malignancies. Development started in solid tumours and is most advanced in malignant melanoma and lung cancer (Brahmer 2015; Hamid 2013). In classical HL, malignant Hodgkin Reed‐Sternberg (HRS) cells are dispersed within an extensive inflammatory/immune cell infiltrate (Küppers 2009; Mathas 2016). HRS cells frequently overexpress PD‐L1 and PD‐L2 due to alterations in chromosome 9p24.1 and HL tumours may thus be genetically susceptible to blockade of the PD‐1 pathway (Green 2012; Roemer 2016). Nivolumab is an anti‐(PD)‐1 monoclonal antibody and currently approved by the US Food and Drug Administration (FDA) for the treatment of melanoma, non‐small cell lung cancer, renal cell carcinoma (Matsuki 2016), and, since 2016, for classical HL after treatment with ASCT and brentuximab vedotin.
Why it is important to do this review
To our knowledge, no systematic review on the effectiveness of nivolumab in individuals with HL has been performed to date. As nivolumab is now approved by the European Commission and the FDA based on non‐randomised data, we will critically appraise all published trials and conduct a rapid review on nivolumab. If we identify controlled clinical trials, we will meta‐analyse these data, which will lead to a more precise and reliable evaluation of the benefits and harms of nivolumab. In this way we aim to overcome the limitations of individual studies, such as small sample sizes and a lack of statistical power.
For this review we will use the software RobotReviewer (Marshall 2016; RobotReviewer 2015) to extract study data and assess risk of bias. As this software has not been not validated yet, one review author will extract manually all these data and a second review author will compare the results from the software tool and the first review author. Any discrepancies between the software results and the manually extracted data will be resolved by discussion between both review authors.
Objectives
To assess the benefits and harms of nivolumab in adult individuals with Hodgkin lymphoma (HL).
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs). In case we do not identify any RCTs, we will include quasi‐RCTs (e.g. assignment to treatment by alternation or by date of birth) and cross‐over trials. In case we do not identify any published RCT, quasi‐RCT or cross‐over trial, we will include published reports of prospectively planned studies.
We will include both full‐text and abstract publications if sufficient information is available on study design, characteristics of participants, interventions and outcomes.
Types of participants
We will include studies that evaluate adult individuals with a confirmed diagnosis of HL, with no gender or ethnicity restrictions. We will consider individuals with all stages, first‐line and relapsed and refractory people and all subtypes of HL. In trials that include mixed populations of individuals with haematological malignancies we will use only data from participants with HL. We will exclude trials in which fewer than 80% of participants had HL, unless the trial authors provide the subgroup data for these individuals in the publication or after we contact the trial authors.
Types of interventions
The main experimental intervention is nivolumab treatment (with or without other drugs). In case we identify RCTs that meet the inclusion criteria of the review, the comparison of interest will be nivolumab (with or without other drugs) versus control treatment. We will conduct separate analyses for trials that evaluate nivolumab and nivolumab combined with other drugs.
Types of outcome measures
Primary outcomes
Overall survival (OS)
Quality of life (QoL), if measured using reliable and valid instruments
Secondary outcomes
-
Progression‐free survival (PFS)
The time interval from random treatment assignment onto the study to first confirmed progression, relapse or death from any cause, or to the last follow‐up
-
Response rate
Measured as overall response, complete response and partial response
Treatment‐related mortality (TRM)
Overall rate of grade 3 and grade 4 adverse events (AEs), including potential relationship between intervention and adverse reaction
Overall rate of serious adverse events (SAEs)
Search methods for identification of studies
We will adapt search strategies from the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). We will search for studies in all languages in order to limit language bias.
Electronic searches
We will search the following databases and sources. We will start the search in 2000 as PD‐L1 blockade for tumour control, the underlying mechanism of nivolumab, has been first mentioned in 2002 (Iwai 2002)
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Databases of medical literature
Cochrane Central Register of Controlled Trials (CENTRAL; latest issue) (Appendix 1)
MEDLINE (Ovid) (2000 to present) (Appendix 2)
Embase (2000 to present) (Appendix 3)
International Pharmaceutical Abstracts (Appendix 4)
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Conference proceedings of the annual meetings of the following societies for abstracts (2000 to present, if not included in CENTRAL)
American Society of Hematology
American Society of Clinical Oncology
European Hematology Association
International Symposium on Hodgkin Lymphoma
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Databases of ongoing trials
Register of controlled trials: www.controlled‐trials.com
EU clinical trials register: www.clinicaltrialsregister.eu/ctr‐search/search (Appendix 5)
ClinicalTrials.gov: https://clinicaltrials.gov/ (Appendix 6)
European Organisation for Research and Treatment of Cancer www.eortc.be
German Hodgkin Study Group: www.ghsg.org
Databases and websites of relevant institutions, such as pharmaceutical organisations, agencies and societies.
Searching other resources
-
Handsearching
We will check the reference lists of all identified trials, relevant review articles and current treatment guidelines for further literature.
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Personal contacts
We will contact experts in the field, drug manufacturers and regulatory agencies in order to retrieve information on 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 using Covidence software (Covidence 2016). We will code the abstracts as either 'retrieve' or 'do not retrieve'. In the case of disagreement or if it unclear whether we should retrieve the abstract or not, we will obtain the full‐text publication for further discussion. Two review authors will assess the full‐text articles of selected studies. If the two review authors are unable to reach a consensus, we will consult a third review author to reach final decision (Higgins 2011b).
We will document the study selection process in a flow chart, as recommended in the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement (Moher 2009), and will show the total numbers of retrieved references and the numbers of included and excluded studies. We will list all articles we exclude after full‐text assessment and their reasons for exclusion in a 'Characteristics of excluded studies' table.
Data extraction and management
One review authors will extracted data on the characteristics of included studies and a second review author will compare with the results from the software RobotReviewer (Marshall 2016; RobotReviewer 2015). The two review authors will resolve any discrepancies between the results from the first review author and the software by discussion.
Two review authors will extract data using a standardised data extraction form developed in Covidence (Covidence 2016). If the authors are unable to reach a consensus, we will consult a third review author. If required, we will contact the authors of specific studies for supplementary information (Higgins 2011a).
We will extract the following information.
General information: author, title, source, publication date, country, language, duplicate publications
Quality assessment: (as specified in the 'Assessment of risk of bias in included studies' section)
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
Participant characteristics: age, gender, ethnicity, number of participants recruited/allocated/evaluated, participants lost to follow‐up, additional diagnoses, stage of disease, previous treatment (type of (multi‐agent) chemotherapy (intensity of regimen, number of cycles), field and dose of radiotherapy, autologous stem cell transplantation (ASCT), brentuximab vedotin dosage and duration)
Interventions: nivolumab dosage, duration of treatment, duration of follow‐up, for RCTs: comparator (type, dosage)
Outcomes: overall survival (OS), QoL, PFS, response rate, TRM, AEs (including assessment of causality, how it was determined, relation between intervention and adverse drug reaction, method of AEs ascertainment (passive or active methods), method of measurement, how severity or seriousness was measured)
Assessment of risk of bias in included studies
Randomised controlled trials
One review author will assess the risk of bias for each RCT. Therafter, we will use the RobotReviewer software to assess risk of bias (RobotReviewer 2015) and a second review author will compare these results with the results from the first review author. Both review authors will resolve any discrepancies between the results from the first review author and the software by discussion. We will use 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.
'Low risk': if the criterion was adequately fulfilled in the study (i.e. the study was at a low risk of bias for the given criterion)
'High risk': if the criterion was not fulfilled in the study (i.e. the study was at high risk of bias for the given criterion)
'Unclear risk': if the study report did not provide sufficient information to allow for a judgement of 'low risk' or 'high risk', or if the risk of bias was unknown for one of the criteria listed above
Non‐randomised prospectively planned trials
As reported in the 'Types of studies' section, we will include non‐randomised studies only if we do not identify any RCTs.
Two review authors will independently assess eligible studies for methodological quality and risk of bias (using the Risk Of Bias in Non‐randomised Studies ‐ of Interventions (ROBIN‐I) tool) (Sterne 2016). The quality assessment strongly depends upon information on the design, conduct and analysis of the trial. The two review authors will resolve any disagreements regarding the quality assessments by consulting a third review author until they reach a consensus.
We will assess the following domains of bias.
Bias due to confounding
Bias in selection of participants into the study
Bias in classification of interventions
Bias due to deviations from intended interventions
Bias due to missing data
Bias in measurement of outcomes
Bias in selection of the reported result
For every criterion we will make a judgement using one of five response options.
Yes
Probably yes
Probably no
No
No information
Measures of treatment effect
We will estimate the dichotomous outcomes of individual studies as rates by extracting the number of events and the total number of participants (overall and complete response rate, TRM, AEs). For RCTs, we will extract dichotomous outcomes from both study arms and will report them as risk ratios (RRs) with 95% confidence intervals (CIs) (Deeks 2011).
We will estimate survival data (OS, PFS) using Kaplan–Meier methods. From RCTs we will extract and report hazard ratios (HRs). If HRs are unavailable, we will estimate the HR by using the available data as described by Parmar 1998 and Tierney 2007.
We will measure continuous outcomes (e.g. QoL) as mean difference (MD) values. For RCTs we will extract and report the mean or mean change from baseline, standard deviation and total number of participants in both the experimental and control arms. If the same scale is used to measure effect, we will perform analyses using the MD with 95% CIs. If the included studies used different scales to measure effect, we will use standardised mean difference values with 95% CIs.
Unit of analysis issues
Studies with multiple treatment groups
As recommended in Chapter 16.5.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b), for studies with multiple treatment groups we will combine arms as long as they can be regarded as subtypes of the same intervention.
When arms can not be pooled this way we will compare each arm with the common comparator separately. For pair wise meta‐analysis, we will split the ‘shared’ group into two or more groups with smaller sample size, and include two or more (reasonably independent) comparisons. For this purpose, for dichotomous outcomes, both the number of events and the total number of patients will be divided up, and for continuous outcomes, the total number of participants will be divided up with unchanged means and standard deviations.
Dealing with missing data
Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions suggests a number of potential sources for missing data are suggested (Higgins 2011b), which we will need to taken into account: at study level, at outcome level and at summary data level. In the first instance it is of the utmost importance to differentiate between data 'missing at random' and 'not missing at random'.
If data are missing, we will request these data from the original investigators. If, after this, data are still missing, we will have to make explicit assumptions of any methods the included studies used: for example, we will assume that the data were missing at random or we will assume that missing values had a particular value, such as a poor outcome.
Assessment of heterogeneity
We will assess heterogeneity of treatment effects between trials using a Chi2 test with a significance level at P value < 0.1. We will use the I2 statistic to quantify possible heterogeneity (I2 statistic value > 30% to signify moderate heterogeneity, I2 statistic > 75% to signify considerable heterogeneity) (Deeks 2011). If heterogeneity is above 80%, and we identify a cause for the heterogeneity, we will explore potential causes through sensitivity and subgroup analyses. If we cannot find a reason for heterogeneity, we will not perform a meta‐analysis, but will comment on results from all studies and presented these in tables.
Assessment of reporting biases
In meta‐analyses involving at least 10 trials, we intend to explore potential publication bias by generating a funnel plot and statistically testing this by conducting a linear regression test (Sterne 2011). We will consider a P value of < 0.1 as significant for this test.
Data synthesis
If the clinical and methodological characteristics of individual studies are sufficiently homogeneous, we will pool the data in a meta‐analysis. We will perform analyses according to the recommendations of theCochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). We will use the Review Manager 5 (RevMan 5) software for analyses (Review Manager 2014). One review author will enter the data into the software, and a second review author will check the data for accuracy. As we expect there will be some heterogeneity in trial design, we will use a random‐effects model.
We will not conduct meta‐analyses by including both RCTs and non‐RCTs. We will not meta‐analyse data from uncontrolled trials, as there might be no additional benefit in meta‐analysing data without a control group. In the case of uncontrolled trials, we will report results of each included trial.
In case meta‐analysis is feasible for non‐randomised but controlled trials, we will only analyse outcomes with adjusted effect estimates if these are adjusted for as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Reeves 2011).
If data do not allow quantitative assessment, we will present outcome data individually per study.
'Summary of findings' table
We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of the evidence. We will use GRADEpro Guideline Development Tool (GDT) software to create a 'Summary of findings' table (GRADEpro GDT 2014), as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). In addition, we will provide an interactive 'Summary of findings' table for a better user‐experience and for improved dissemination of the findings of this Cochrane Review (Schünemann 2016). We will avoid use of lengthy text.
We prioritise outcomes according to their relevance to patients.
OS
QoL
PFS
Response rates
TRM
AEs
Subgroup analysis and investigation of heterogeneity
We will perform subgroup analyses of the following characteristics.
Age
Stage of disease (first‐line treatment versus relapsed and refractory disease, early versus advanced stage)
Type of previous therapy (ASCT, brentuximab vedotin)
Duration of follow‐up.
We will use the tests for interaction to test for differences between subgroup results.
Sensitivity analysis
We will perform only one sensitivity analysis for the following.
Quality components
Preliminary results versus mature results
Acknowledgements
We thank the following members of Cochrane Haematological Malignancies Group (CHMG) for their comments, which improved the protocol: Nicola Köhler (Editorial Base), Professor Benjamin Djulbegovic and Professor Robert Killeen (Editors), and Celine Fournier (Consumer Editor). Also we thank Dr Karla Soares‐Weiser and Dr David Tovey of the Cochrane Editorial Unit.
Appendices
Appendix 1. CENTRAL search strategy
ID Search
#1 MeSH descriptor: [Lymphoma] this term only
#2 MeSH descriptor: [Hodgkin Disease] explode all trees
#3 Germinoblastom*
#4 Reticulolymphosarcom*
#5 Hodgkin*
#6 (malignan* near/2 lymphogranulom*) or (malignan* near/2 granulom*)
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 nivolumab*
#9 opdivo*
#10 nivo*
#11 (BMS‐936558 or MDX‐1106 or ONO‐4538 or BMS936558 or MDX1106 or ONO4538)
#12 (Anti‐PD‐1 or Anti‐PD1)
#13 ("death 1 (PD‐1)" near/3 checkpoint‐inhibitor*)
#14 #8 or #9 or #10 or #11 or #12 or #13
#15 #7 and #14
Appendix 2. MEDLINE search strategy
| # | Searches |
| 1 | *LYMPHOMA/ |
| 2 | exp HODGKIN DISEASE/ |
| 3 | Germinoblastom$.tw,kf,ot. |
| 4 | Reticulolymphosarcom$.tw,kf,ot. |
| 5 | Hodgkin$.tw,kf,ot. |
| 6 | (malignan$ adj2 (lymphogranulom$ or granulom$)).tw,kf,ot. |
| 7 | or/1‐6 |
| 8 | nivolumab*.tw,kf,ot,nm. |
| 9 | Opdivo*.tw,kf,ot. |
| 10 | nivo*.tw,kf,ot. |
| 11 | (BMS‐936558 or MDX‐1106 or ONO‐4538 or BMS936558 or MDX1106 or ONO4538).tw,kf,ot. |
| 12 | (Anti‐PD‐1 or Anti‐PD1).tw,kf,ot. |
| 13 | ("death 1 (PD‐1)" adj3 checkpoint‐inhibitor*).tw,kf,ot. |
| 14 | or/8‐13 |
| 15 | 7 and 14 |
Appendix 3. Embase search strategy
| No. | Query |
| #1 | 'lymphoma'/mj |
| #2 | 'hodgkin disease'/exp |
| #3 | germinoblastom* |
| #4 | reticulolymphosarcom* |
| #5 | hodgkin*:ti,ab,de |
| #6 | hodgkin*:tt |
| #7 | (malignan* NEAR/2 (lymphogranulom* OR granulom*)):ti,ab,de |
| #8 | (malignan* NEAR/2 (lymphogranulom* OR granulom*)):tt |
| #9 | #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 |
| #11 | nivolumab* |
| #12 | opdivo* |
| #13 | nivo* |
| #14 | 'bms 936558' OR 'mdx 1106' OR 'ono 4538' OR bms936558 OR mdx1106 OR ono4538 |
| #15 | 'anti pd 1' OR 'anti pd1' |
| #16 | 'death 1 (pd‐1)' NEAR/3 'checkpoint inhibitor*' |
| #17 | #11 OR #12 OR #13 OR #14 OR #15 OR #16 |
| #18 | #9 AND #17 |
Appendix 4. International Pharmaceutical Abstracts search strategy
| # | Query |
| S1 | Germinoblastom* |
| S2 | Reticulolymphosarcom* |
| S3 | Hodgkin* OR (SU Lymphoma) |
| S4 | (malignan* N2 (lymphogranulom* or granulom*)) |
| S5 | S1 OR S2 OR S3 OR S4 |
| S6 | nivolumab* |
| S7 | opdivo* |
| S8 | nivo* |
| S9 | BMS‐936558 OR MDX‐1106 OR ONO‐4538 OR BMS936558 OR MDX1106 OR ONO4538 |
| S10 | Anti‐PD‐1 OR Anti‐PD1 |
| S11 | "death 1 (PD‐1)" N3 checkpoint‐inhibitor* |
| S12 | S6 OR S7 OR S8 OR S9 OR S10 OR S11 |
| S13 | S5 AND S12 |
Appendix 5. EU clinical trials register search strategy
hodgkin in the condition
AND nivolumab in the intervention
Appendix 6. ClinicalTrials.gov search strategy
Conditions: Hodgkin OR Lymphom
Interventions: nivolumab OR BMS‐936558 OR MDX‐1106 OR ONO‐4538 OR Opdivo
Contributions of authors
Nicole Skoetz developed and wrote the protocol, and provided methodological expertise
Marius Goldkuhle proofread the protocol and provided content input
Gerald Gartlehner provided: methodological expertise
Ina Monsef designed the search strategy
Philipp Dahm provided methodological expertise
Jan‐Peter Glossmann provided content expertise
Andreas Engert provided clinical expertise and, content input
Bastian von Tresckow provided clinical expertise
Sources of support
Internal sources
Cochrane Haematological Malignancies, Department of Internal Medicine, University Hospital of Cologne, Germany.
External sources
No sources of support supplied
Declarations of interest
Nicole Skoetz: none known
Marius Goldkuhle: none known
Ina Monsef: none known
Andreas Engert: none known
Gerald Gartlehner: none known
Philipp Dahm: none known
Jan‐Peter Glossmann: none known
Bastian von Tresckow received: travel grants, scientific grants, personal fees and non‐financial support from Novartis; travel grants, scientific grants, personal fees and non‐financial support from Takeda; personal fees from Amgen; personal fees from Celgene; scientific grants and personal fees from MSD; and a travel grant from Bristol‐Myers Squibb.
Notes
Some passages in this protocol, especially in the Methods part, are from the standard template of the CHMG.
New
References
Additional references
- Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD‐1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. New England Journal of Medicine 2015;372(4):311‐9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ansell S, Gutierrez ME, Shipp MA, Gladstone D, Moskowitz A, Borello I, et al. A phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039). Blood. 2016. [Google Scholar]
- Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD, et al. Eight cycles of escalated‐dose BEACOPP compared with four cycles of escalated‐dose BEACOPP followed by four cycles of baseline‐dose BEACOPP with or without radiotherapy in patients with advanced‐stage Hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. Journal of Clinical Oncology 2011;29(32):4234‐42. [PUBMED: 21990399] [DOI] [PubMed] [Google Scholar]
- Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous‐cell non‐small‐cell lung cancer. New England Journal of Medicine 2015;373(2):123‐35. [PUBMED: 26028407] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. New England Journal of Medicine 1992;327(21):1478‐84. [PUBMED: 1383821] [DOI] [PubMed] [Google Scholar]
- Connors JM. Clinical manifestations and natural history of Hodgkin's lymphoma. Cancer Journal 2009;15(2):124‐8. [DOI] [PubMed] [Google Scholar]
- Veritas Health Innovation. Covidence systematic review software. Melbourne, Australia: Veritas Health Innovation, Available at www.covidence.org.
- Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta‐analyses. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
- Engert A, Schiller P, Josting A, Herrmann R, Koch P, Sieber M, et al. Involved‐field radiotherapy is equally effective and less toxic compared with extended‐field radiotherapy after four cycles of chemotherapy in patients with early‐stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. Journal of Clinical Oncology 2003;21(19):3601‐8. [DOI] [PubMed] [Google Scholar]
- Engert A, Franklin J, Eich HT, Brillant C, Sehlen S, Cartoni C, et al. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended‐field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial. Journal of Clinical Oncology 2007;25(23):3495‐502. [DOI] [PubMed] [Google Scholar]
- Engert A, Plütschow A, Eich HT, Lohri A, Dörken B, Borchmann P, et al. Reduced treatment intensity in patients with early‐stage Hodgkin's lymphoma. New England Journal of Medicine 2010;363(7):640‐52. [PUBMED: 20818855] [DOI] [PubMed] [Google Scholar]
- Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A, et al. Reduced‐intensity chemotherapy and PET‐guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open‐label, phase 3 non‐inferiority trial. Lancet 2012;379(9828):1791‐9. [PUBMED: 22480758] [DOI] [PubMed] [Google Scholar]
- GRADE Working Group, McMaster University. GRADEpro Guideline Development Tool (GDT). Version accessed 02.2017. Hamilton (ON): GRADE Working Group, McMaster University, 2014.
- Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O'Donnell E, et al. Constitutive AP‐1 activity and EBV infection induce PD‐L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clinical Cancer Research 2012;18(6):1611‐8. [PUBMED: 22271878] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti‐PD‐1) in melanoma. New England Journal of Medicine 2013;369(2):134‐44. [PUBMED: 23724846] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Higgins JPT, Altman DG. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
- Higgins JPT, Deeks JJ, Altman DG. Chapter 16: Special topics in statistics. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
- Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD‐L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD‐L1 blockade. Proceedings of the National Academy of Sciences of the United States of America 2002;99(19):12293‐7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Küppers R. The biology of Hodgkin's lymphoma. Nature Reviews. Cancer 2009;9(1):15‐27. [PUBMED: 19078975] [DOI] [PubMed] [Google Scholar]
- Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
- Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. Journal of Clinical Oncology 1989;7(11):1630‐6. [DOI] [PubMed] [Google Scholar]
- Marshall IJ, Kuiper J, Wallace B C. RobotReviewer: evaluation of a system for automatically assessing bias in clinical trials. Journal of the American Medical Informatics Association 2016;23(1):193‐201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mathas S, Hartmann S, Küppers R. Hodgkin lymphoma: Pathology and biology. Seminars in Hematology 2016;53(3):139‐47. [PUBMED: 27496304] [DOI] [PubMed] [Google Scholar]
- Matsuki E, Younes A. Checkpoint inhibitors and other immune therapies for Hodgkin and non‐Hodgkin lymphoma. Current Treatment Options in Oncology 2016;17(6):31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. Journal of Clinical Epidemiology 2009;62(10):1006‐12. [PUBMED: 19631508] [DOI] [PubMed] [Google Scholar]
- Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta‐analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17(24):2815‐34. [PUBMED: 9921604] [DOI] [PubMed] [Google Scholar]
- Pileri SA, Ascani S, Leoncini L, Sabattini E, Zinzani PL, Piccaluga PP, et al. Hodgkin's lymphoma: the pathologist's viewpoint. Journal of Clinical Pathology 2002;55(3):162‐76. [PUBMED: 11896065] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rancea M, Monsef I, Tresckow B, Engert A, Skoetz N. High‐dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 10.1002/14651858.CD009411.pub2; PUBMED: 23784872] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Re D, Thomas RK, Behringer K, Diehl V. From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential. Blood 2005;105(12):4553‐60. [PUBMED: 15728122] [DOI] [PubMed] [Google Scholar]
- Reeves BC, Deeks JJ, Higgins JPT, Wells GA. Chapter 13: Including non‐randomized studies. In: Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
- Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
- Marshall IJ, Kuiper J, Wallace BC. RobotReviewer. Version accessed 02.2017 2015. Available at www.robotreviewer.net.
- Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD‐L1 and PD‐L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. Journal of Clinical Oncology 2016;34(23):2690‐7. [PUBMED: 27069084] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rosenberg SA, Boiron M, DeVita VT Jr, Johnson RE, Lee BJ, Ultmann JE, et al. Report of the Committee on Hodgkin's Disease Staging Procedures. Cancer Research 1971;31(11):1862‐3. [PUBMED: 5121695] [PubMed] [Google Scholar]
- Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and 'Summary of findings tables'. In: Higgins JPT, Green S, editor(s). Cochrane Handbook of Systematic Reviews of Intervention. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
- Schünemann HJ, Mustafa R, Brozek J, Santesso N, Alonso‐Coello P, Guyatt G, et al. GRADE Guidelines: 16. GRADE evidence to decision frameworks for tests in clinical practice and public health. Journal of Clinical Epidemiology 2016;76:89‐98. [DOI] [PubMed] [Google Scholar]
- Skoetz N, Trelle S, Rancea M, Haverkamp H, Diehl V, Engert A, et al. Effect of initial treatment strategy on survival of patients with advanced‐stage Hodgkin's lymphoma: a systematic review and network meta‐analysis. Lancet Oncology 2013;14(10):943‐52. [PUBMED: 23948348] [DOI] [PubMed] [Google Scholar]
- Sterne JAC, Egger M, Moher D. Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S, editor(s). Cochrane Handbook of Systematic Reviews of Intervention. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
- Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS‐I: a tool for assessing risk of bias in non‐randomised studies of interventions. BMJ 2016;355:i4919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thomas RK, Re D, Zander T, Wolf J, Diehl V. Epidemiology and etiology of Hodgkin's lymphoma. Annals of Oncology 2002;13 Suppl 4:147‐52. [PUBMED: 12401681] [DOI] [PubMed] [Google Scholar]
- Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time‐to‐event data into meta‐analysis. Trials 2007;8:16. [PUBMED: 17555582] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Timmerman J, Engert A, Younes A, Santoro A, Armand P, Fanale MA, et al. Checkmate 205 update with minimum 12‐month follow up: A phase 2 study of nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma. Blood. 2016. [Google Scholar]
- Tresckow B, Plütschow A, Fuchs M, Klimm B, Markova J, Lohri A, et al. Dose‐intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin study group HD14 trial. Journal of Clinical Oncology 2012;30(9):907‐13. [PUBMED: 22271480] [DOI] [PubMed] [Google Scholar]
- Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. Journal of Clinical Oncology 2012;30(18):2183‐9. [PUBMED: 22454421] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem‐cell transplantation and brentuximab vedotin: a multicentre, multicohort, single‐arm phase 2 trial. Lancet Oncology 2016;17(9):1283‐94. [DOI] [PMC free article] [PubMed] [Google Scholar]