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Meta-Analysis
. 2015 Jan 9;1(1):CD010533.
doi: 10.1002/14651858.CD010533.pub2.

Positron emission tomography-adapted therapy for first-line treatment in individuals with Hodgkin lymphoma

Marie-Therese Sickinger  1 , Bastian von Tresckow, Carsten Kobe, Andreas Engert, Peter Borchmann, Nicole Skoetz
Affiliations
Meta-Analysis

Positron emission tomography-adapted therapy for first-line treatment in individuals with Hodgkin lymphoma

Marie-Therese Sickinger et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Hodgkin lymphoma (HL) is a B-cell lymphoma accounting for 10% to 15% of all lymphoma in industrialised countries. It has a bimodal age distribution with one peak around the age of 30 years and another after the age of 60 years. Although HL accounts for fewer than 1% of all neoplasms worldwide, it is considered to be one of the most common malignancies in young adults and, with cure rates of 90%, one of the most curable cancers worldwide. Current treatment options for HL comprise more- or less-intensified regimens of chemotherapy plus radiotherapy, depending on disease stage. [18F]-fluorodeoxy-D-glucose (FDG)-positron emission tomography (PET, also called PET scanning) is an imaging tool that can be used to illustrate a tumour's metabolic activity, stage and progression. Therefore, it could be used as a standard interim procedure during HL treatment, to help distinguish between individuals who are good or poor early responders to therapy. Subsequent therapy could then be de-escalated in PET-negative individuals (good responders) or escalated in those who are PET-positive (poor responders). It is currently unknown whether such response-adapted therapeutic strategies are of benefit to individuals in terms of overall and progression-free survival, and the incidence of long-term adverse events (AEs).

Objectives: To assess the effects of interim [18F]-FDG-PET imaging treatment modification in individuals with HL.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; latest issue) and MEDLINE (from 1990 to September 2014) as well as conference proceedings (American Society of Hematology; American Society of Clinical Oncology; European Hematology Association; and International Symposium on Hodgkin Lymphoma) for studies. Two review authors independently screened search results.

Selection criteria: We included randomised controlled trials (RCTs) comparing FDG-PET-adapted therapy with non-adapted treatment in individuals with previously untreated HL of all stages and ages.

Data collection and analysis: Two review authors independently extracted data and assessed the quality of trials. As none of the included studies provided HRs for OS, we described risk ratios (RRs) for this outcome and did not pool the data. As an effect measure we used hazard ratios (HRs) for progression-free survival (PFS). We described RRs for the dichotomous data on AEs. We also calculated 95% confidence intervals (CIs).

Main results: Our search strategies led to 308 potentially relevant references. From these, we included three studies involving 1999 participants. We judged the overall potential risk of bias as moderate. The studies were reported as RCTs; blinding was not reported, but given the study design it is likely that there was no blinding. One study was published in abstract form only; hence, detailed assessment of the risk of bias was not possible.Two trials compared standard treatment (chemotherapy plus radiotherapy) with PET-adapted therapy (chemotherapy only) in individuals with early-stage HL and negative PET scans. The study design of the third trial was more complex. Participants with early-stage HL were divided into those with a favourable or unfavourable prognosis. They were then randomised to receive PET-adapted or standard treatment. Following a PET scan, participants were further divided into PET-positive and PET-negative groups. To date, data have been published for the PET-negative arms only, making it possible to perform a meta-analysis including all three trials.Of the 1999 participants included in the three trials only 1480 were analysed. The 519 excluded participants were either PET-positive, or were excluded because they did not match the inclusion criteria.One study reported no deaths. The other two studies reported two deaths in participants receiving PET-adapted therapy and two in participants receiving standard therapy (very-low-quality evidence). Progression-free survival was shorter in participants with PET-adapted therapy (without radiotherapy) than in those receiving standard treatment with radiotherapy (HR 2.38; 95% CI 1.62 to 3.50; P value < 0.0001). This difference was also apparent in comparisons of participants receiving no additional radiotherapy (PET-adapted therapy) versus radiotherapy (standard therapy) (HR 1.86; 95% CI 1.07 to 3.23; P value = 0.03) and in those receiving chemotherapy but no radiotherapy (PET-adapted therapy) versus standard radiotherapy (HR 3.00; 95% CI 1.75 to 5.14; P value < 0.0001) (moderate-quality evidence). Short-term AEs only were assessed in one trial, which showed no evidence of a difference between the treatment arms (RR 0.91; 95% CI 0.54 to 1.53; P value = 0.72) (very-low-quality evidence). No data on long-term AEs were reported in any of the trials.

Authors' conclusions: To date, no robust data on OS, response rate, TRM, QoL, or short- and long-term AEs are available. However, this systematic review found moderate-quality evidence that PFS was shorter in individuals with early-stage HL and a negative PET scan receiving chemotherapy only (PET-adapted therapy) than in those receiving additional radiotherapy (standard therapy). More RCTs with longer follow ups may lead to more precise results for AEs, TRM and QoL, and could evaluate whether this PFS advantage will translate into an overall survival benefit.It is still uncertain whether PET-positive individuals benefit from PET-based treatment adaptation and the effect of such an approach in those with advanced HL.

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Conflict of interest statement

None

Figures

1
1
Study flow diagram.
2
2
Study design of the H10F/H10U trial
3
3
Flow diagram for included studies
4
4
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
5
5
Forest plot of comparison: 1 PET‐adapted therapy in individuals with HL, outcome: 1.3 Progression‐free survival (PFS) (subgroup analysis).
6
6
Forest plot of comparison: 1 PET‐adapted therapy in individuals with HL, outcome: 1.5 Adverse events.
1.1
1.1. Analysis
Comparison 1 PET‐adapted therapy in HL patients, Outcome 1 Overall survival (OS); per protocol.
1.2
1.2. Analysis
Comparison 1 PET‐adapted therapy in HL patients, Outcome 2 Progression‐free survival (PFS).
1.3
1.3. Analysis
Comparison 1 PET‐adapted therapy in HL patients, Outcome 3 Progression‐free survival (PFS) (subgroup analysis).
1.4
1.4. Analysis
Comparison 1 PET‐adapted therapy in HL patients, Outcome 4 Progression‐free survival (sensitivity analysis, random‐effects).
1.5
1.5. Analysis
Comparison 1 PET‐adapted therapy in HL patients, Outcome 5 Adverse events.
See this image and copyright information in PMC

References

References to studies included in this review

H10F {published data only}
    1. Andre MPE. An update on the EORTC/LYSA/FIL H10 trial. 9th International Symposium on Hodgkin Lymphoma Cologne, Germany 2013.
    1. Andre MPE, Reman O, Federico M, Girinski T, Brice P, Brusamolino E, et al. Interim analysis of the randomized EORTC/LYSA/FIl Intergroup H10 trial on early PET‐scan driven treatment adaptation in stage I/II Hodgkin lymphoma [abstract]. Blood. 2012; Vol. 120:549.
    1. Raemaekers JM, Andre MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, et al. Omitting radiotherapy in early positron emission tomography‐negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. Journal of Clinical Oncology 2014;32(12):1188‐94. [PUBMED: 24637998] - PubMed
H10U {published data only}
    1. Andre MPE. An update on the EORTC/LYSA/FIL H10 trial. 9th International Symposium on Hodgkin Lymphoma Cologne, Germany 2013.
    1. Andre MPE, Reman O, Federico M, Girinski T, Brice P, Brusamolino E, et al. Interim analysis of the randomized EORTC/LYSA/FIl Intergroup H10 trial on early PET‐scan driven treatment adaptation in stage I/II Hodgkin lymphoma [abstract]. Blood. 2012; Vol. 120:549.
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Picardi {published data only}
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UK NCRI RAPID {published data only}
    1. Radford J. Update on the NCRI RAPID trial. 9th International Symposium on Hodgkin Lymphoma, Cologne, Germany 2013.
    1. Radford J, Barrington S, Counsell N, Pettengell R, Johnson P, Wimperis J, et al. Involved field radiotherapy versus no further treatment in patients with clinical stages IA and IIA Hodgkin lymphoma and a 'negative' PET scan after 3 cycles ABVD. Results of the UK NCRI RAPID trial [abstract]. Blood. 2012; Vol. 120:547.
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References to studies excluded from this review

HD 0607 {published data only}
    1. Gallamini A, Rossi A, Patti C, Picardi M, Raimondo F, Cantonetti M, et al. Early treatment intensification in advanced‐stage high‐risk Hodgkin lymphoma (HL) patients, with a positive FDG‐PET scan after two ABVD courses ‐ first interim analysis of the GITIL/FIL HD0607 clinical trial [Abstract 550]. Blood (ASH Annual Meeting Abstracts) 2012;120:550.

References to ongoing studies

Casanovas PHRC N 2010 {published data only}
    1. Randomised phase III study of a treatment driven by early PET response compared with a treatment not monitored by early PET in individuals with Ann Arbor stage III‐IV or high‐risk IIB HL. Ongoing study May 2011.
CRUK‐07/146 {published data only}
    1. A randomised phase III trial to assess response‐adapted therapy using FDG‐PET imaging in individuals with newly diagnosed, advanced HL. Ongoing study August 2008.
EU‐20931 {published data only}
    1. A randomised phase III trial to determine the role of FDG‐PET imaging in clinical stages IA/IIA Hodgkin's disease. Ongoing study July 2003.
HD0607 {published data only}
    1. PET‐adapted chemotherapy in advanced HL. Ongoing study June 2008.
HD 18 {published data only}
    1. HD18 for advanced stages in HL. Ongoing study May 2008.

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