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Meta-Analysis
. 2017 Apr 27;4(4):CD007110.
doi: 10.1002/14651858.CD007110.pub3.

Chemotherapy alone versus chemotherapy plus radiotherapy for adults with early stage Hodgkin lymphoma

Oliver Blank  1 , Bastian von Tresckow  2 , Ina Monsef  1 , Lena Specht  3 , Andreas Engert  2 , Nicole Skoetz  1
Affiliations
Meta-Analysis

Chemotherapy alone versus chemotherapy plus radiotherapy for adults with early stage Hodgkin lymphoma

Oliver Blank et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Combined modality treatment consisting of chemotherapy followed by localised radiotherapy is the standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long- term adverse effects such as secondary malignancies the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication.

Objectives: To assess the effects of chemotherapy alone compared to chemotherapy plus radiotherapy in adults with early stage HL .

Search methods: For the or i ginal version of this review, we searched MEDLINE, Embase and CENTRAL as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology and International Symposium of Hodgkin Lymphoma) from January 1980 to November 2010 for randomised controlled trials (RCTs) comparing chemotherapy alone versus chemotherapy regimens plus radiotherapy. For the updated review we searched MEDLINE, CENTRAL and conference proceedings to December 2016.

Selection criteria: We included RCTs comparing chemotherapy alone with chemotherapy plus radiotherapy in patients with early stage HL. We excluded trials with more than 20% of patients in advanced stage. As the value of radiotherapy in addition to chemotherapy is still not clear, we also compared to more cycles of chemotherapy in the control arm. In this updated review, we also included a second comparison evaluating trials with varying numbers of cycles of chemotherapy between intervention and control arms, same chemotherapy regimen in both arms assumed. We excluded trials evaluating children only, therefore only trials involving adults are included in this updated review.

Data collection and analysis: Two review authors independently extracted data and assessed the quality of trials. We contacted study authors to obtain missing information. As effect measures we used hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RR) for response rates. Since not all trials reported PFS according to our definitions, we evaluated all similar outcomes (e.g. event-free survival) as PFS/tumour control.

Main results: Our search led to 5518 potentially relevant references. From these, we included seven RCTs in the analyses involving 2564 patients. In contrast to the first version of this review including five trials, we excluded trials randomising children. As a result, we excluded one trial from the former analyses and we identified three new trials.Five trials with 1388 patients compared the combination of chemotherapy alone and chemotherapy plus radiotherapy, with the same number of chemotherapy cycles in both arms. The addition of radiotherapy to chemotherapy has probably little or no difference on OS (HR 0.48; 95% confidence interval (CI) 0.22 to 1.06; P = 0.07, moderate- quality evidence), however two included trials had potential other high risk of bias due to a high number of patients not receiving planned radiotherapy. After excluding these trials in a sensitivity analysis, the results showed that the combination of chemotherapy and radiotherapy improved OS compared to chemotherapy alone (HR 0.31; 95% CI 0.19 to 0.52; P <0.00001, moderate- quality evidence). In contrast to chemotherapy alone the use of chemotherapy and radiotherapy improved PFS (HR 0.42; 95% CI 0.25 to 0.72; P = 0.001; moderate- quality evidence). Regarding infection- related mortality (RR 0.33; 95% CI 0.01 to 8.06; P = 0.5; low- quality evidence), second cancer- related mortality (RR 0.53; 95% CI 0.07 to 4.29; P = 0.55; low- quality evidence) and cardiac disease- related mortality (RR 2.94; 95% CI 0.31 to 27.55; P = 0.35;low- quality evidence), there is no evidence for a difference between the use of chemotherapy alone and chemotherapy plus radiotherapy. For complete response rate (CRR) (RR 1.08; 95% CI 0.93 to 1.25; P = 0.33; low- quality evidence), there is also no evidence for a difference between treatment groups.Two trials with 1176 patients compared the combination of chemotherapy alone and chemotherapy plus radiotherapy, with different numbers of chemotherapy cycles in both arms. OS is reported in one trial only, the use of chemotherapy alone (more chemotherapy cycles) may improve OS compared to chemotherapy plus radiotherapy (HR 2.12; 95% CI 1.03 to 4.37; P = 0.04; low- quality evidence). This trial also had a potential other high risk of bias due to a high number of patients not receiving planned therapy. There is no evidence for a difference between chemotherapy alone and chemotherapy plus radiotherapy regarding PFS (HR 0.42; 95% CI 0.14 to 1.24; P = 0.12; low- quality evidence). After excluding the trial with patients not receiving the planned therapy in a sensitivity analysis, the results showed that the combination of chemotherapy and radiotherapy improved PFS compared to chemotherapy alone (HR 0.24; 95% CI 0.070 to 0.88; P = 0.03, based on one trial). For infection- related mortality (RR 6.90; 95% CI 0.36 to 132.34; P = 0.2; low- quality evidence), second cancer- related mortality (RR 2.22; 95% CI 0.7 to 7.03; P = 0.18; low- quality evidence) and cardiac disease-related mortality (RR 0.99; 95% CI 0.14 to 6.90; P = 0.99; low-quality evidence), there is no evidence for a difference between the use of chemotherapy alone and chemotherapy plus radiotherapy. CRR rate was not reported.

Authors' conclusions: This systematic review compared the effects of chemotherapy alone and chemotherapy plus radiotherapy in adults with early stage HL .For the comparison with same numbers of chemotherapy cycles in both arms, we found moderate- quality evidence that PFS is superior in patients receiving chemotherapy plus radiotherapy than in those receiving chemotherapy alone. The addition of radiotherapy to chemotherapy has probably little or no difference on OS . The sensitivity analysis without the trials with potential other high risk of bias showed that chemotherapy plus radiotherapy improves OS compared to chemotherapy alone.For the comparison with different numbers of chemotherapy cycles between the arms there are no implications for OS and PFS possible, because of the low quality of evidence of the results.

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Conflict of interest statement

Blank O: no known conflict of interest.

Monsef I: no known conflict of interest.

Specht L: no known conflict of interest.

Engert A: no known conflict of interest.

Skoetz N: no known conflict of interest.

von Tresckow B: no known conflict of interest.

Figures

1
1
Study flow diagram.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Forest plot of comparison: 2 Overall survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44 , outcome: 2.1 Sensitivity analysis ‐ without UK NCRI Rapid and MSKCC trial #90‐44.
4
4
Forest plot of comparison: 2 Progression‐free survival, outcome: 2.1 All trials.
5
5
Forest plot of comparison: 3 Complete response rate, outcome: 3.1 All trials.
6
6
Forest plot of comparison: 4 Overall Response Rate, outcome: 4.1 All Trials.
1.1
1.1. Analysis
Comparison 1 Overall survival ‐‐ same number of chemotherapy cycles, Outcome 1 All trials.
1.2
1.2. Analysis
Comparison 1 Overall survival ‐‐ same number of chemotherapy cycles, Outcome 2 Proportion of patients early favourable.
1.3
1.3. Analysis
Comparison 1 Overall survival ‐‐ same number of chemotherapy cycles, Outcome 3 Bulky vs non‐bulky.
1.4
1.4. Analysis
Comparison 1 Overall survival ‐‐ same number of chemotherapy cycles, Outcome 4 Timing of radiotherapy.
1.5
1.5. Analysis
Comparison 1 Overall survival ‐‐ same number of chemotherapy cycles, Outcome 5 Type of radiotherapy.
1.6
1.6. Analysis
Comparison 1 Overall survival ‐‐ same number of chemotherapy cycles, Outcome 6 Type of chemotherapy.
1.7
1.7. Analysis
Comparison 1 Overall survival ‐‐ same number of chemotherapy cycles, Outcome 7 ITT‐analysis.
2.1
2.1. Analysis
Comparison 2 Overall survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 1 Sensitivity analysis ‐ without UK NCRI RAPID and MSKCC trial #90‐44.
2.2
2.2. Analysis
Comparison 2 Overall survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 2 Proportion of patients early favourable.
2.3
2.3. Analysis
Comparison 2 Overall survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 3 Bulky vs non‐bulky.
2.4
2.4. Analysis
Comparison 2 Overall survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 4 Timing of radiotherapy.
2.5
2.5. Analysis
Comparison 2 Overall survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 5 Type of radiotherapy.
2.6
2.6. Analysis
Comparison 2 Overall survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 6 Type of chemotherapy.
2.7
2.7. Analysis
Comparison 2 Overall survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 7 ITT‐analysis.
3.1
3.1. Analysis
Comparison 3 Progression‐free survival ‐‐ same number of chemotherapy cycles, Outcome 1 All trials.
3.2
3.2. Analysis
Comparison 3 Progression‐free survival ‐‐ same number of chemotherapy cycles, Outcome 2 Proportion of patients early favourable.
3.3
3.3. Analysis
Comparison 3 Progression‐free survival ‐‐ same number of chemotherapy cycles, Outcome 3 Bulky vs non‐bulky.
3.4
3.4. Analysis
Comparison 3 Progression‐free survival ‐‐ same number of chemotherapy cycles, Outcome 4 Timing of radiotherapy.
3.5
3.5. Analysis
Comparison 3 Progression‐free survival ‐‐ same number of chemotherapy cycles, Outcome 5 Type of radiotherapy.
3.6
3.6. Analysis
Comparison 3 Progression‐free survival ‐‐ same number of chemotherapy cycles, Outcome 6 Type of chemotherapy.
3.7
3.7. Analysis
Comparison 3 Progression‐free survival ‐‐ same number of chemotherapy cycles, Outcome 7 Sensitivity analysis (per protocol results of the UK NCRI RAPID, without MSKCC trial #90‐44).
4.1
4.1. Analysis
Comparison 4 Progression‐free survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 1 Sensitivity analysis ‐ without UK NCRI RAPID and MSKCC trial #90‐44.
4.2
4.2. Analysis
Comparison 4 Progression‐free survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 2 Proportion of patients early favourable.
4.3
4.3. Analysis
Comparison 4 Progression‐free survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 3 Bulky vs non‐bulky.
4.4
4.4. Analysis
Comparison 4 Progression‐free survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 4 Timing of radiotherapy.
4.5
4.5. Analysis
Comparison 4 Progression‐free survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 5 Type of radiotherapy.
4.6
4.6. Analysis
Comparison 4 Progression‐free survival ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 6 Type of chemotherapy.
5.1
5.1. Analysis
Comparison 5 Complete response rate ‐‐ same number of chemotherapy cycles, Outcome 1 All trials.
5.2
5.2. Analysis
Comparison 5 Complete response rate ‐‐ same number of chemotherapy cycles, Outcome 2 Proportion of patients early favourable.
5.3
5.3. Analysis
Comparison 5 Complete response rate ‐‐ same number of chemotherapy cycles, Outcome 3 Bulky vs non‐bulky.
5.4
5.4. Analysis
Comparison 5 Complete response rate ‐‐ same number of chemotherapy cycles, Outcome 4 Timing of radiotherapy.
5.5
5.5. Analysis
Comparison 5 Complete response rate ‐‐ same number of chemotherapy cycles, Outcome 5 Type of radiotherapy.
5.6
5.6. Analysis
Comparison 5 Complete response rate ‐‐ same number of chemotherapy cycles, Outcome 6 Type of chemotherapy.
5.7
5.7. Analysis
Comparison 5 Complete response rate ‐‐ same number of chemotherapy cycles, Outcome 7 ITT‐analysis.
6.1
6.1. Analysis
Comparison 6 Complete response rate ‐‐ same number of cycles without MSKCC trial #90‐44, Outcome 1 Sensitivity analysis ‐ without MSKCC trial #90‐44.
6.2
6.2. Analysis
Comparison 6 Complete response rate ‐‐ same number of cycles without MSKCC trial #90‐44, Outcome 2 Bulky vs non‐bulky.
6.3
6.3. Analysis
Comparison 6 Complete response rate ‐‐ same number of cycles without MSKCC trial #90‐44, Outcome 3 Timing of radiotherapy.
6.4
6.4. Analysis
Comparison 6 Complete response rate ‐‐ same number of cycles without MSKCC trial #90‐44, Outcome 4 Type of radiotherapy.
6.5
6.5. Analysis
Comparison 6 Complete response rate ‐‐ same number of cycles without MSKCC trial #90‐44, Outcome 5 Type of chemotherapy.
6.6
6.6. Analysis
Comparison 6 Complete response rate ‐‐ same number of cycles without MSKCC trial #90‐44, Outcome 6 ITT‐analysis.
7.1
7.1. Analysis
Comparison 7 Overall response rate ‐‐ same number of chemotherapy cycles, Outcome 1 All trials.
7.2
7.2. Analysis
Comparison 7 Overall response rate ‐‐ same number of chemotherapy cycles, Outcome 2 Proportion of patients early favourable.
7.3
7.3. Analysis
Comparison 7 Overall response rate ‐‐ same number of chemotherapy cycles, Outcome 3 Bulky vs non‐bulky.
7.4
7.4. Analysis
Comparison 7 Overall response rate ‐‐ same number of chemotherapy cycles, Outcome 4 Timing of radiotherapy.
7.5
7.5. Analysis
Comparison 7 Overall response rate ‐‐ same number of chemotherapy cycles, Outcome 5 Type of radiotherapy.
8.1
8.1. Analysis
Comparison 8 Overall response rate ‐‐ same number of chemotherapy cycles without MSKCC trial #90‐44, Outcome 1 Sensitivity analysis ‐ without MSKCC trial #90‐44.
9.1
9.1. Analysis
Comparison 9 Adverse events‐ related mortality ‐‐ same number of chemotherapy cycles, Outcome 1 Infection‐ related mortality.
9.2
9.2. Analysis
Comparison 9 Adverse events‐ related mortality ‐‐ same number of chemotherapy cycles, Outcome 2 Second cancer‐ related mortality.
9.3
9.3. Analysis
Comparison 9 Adverse events‐ related mortality ‐‐ same number of chemotherapy cycles, Outcome 3 Cardiac disease‐ related mortality.
10.1
10.1. Analysis
Comparison 10 Adverse events related mortality ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 1 Second cancer‐ related mortality.
10.2
10.2. Analysis
Comparison 10 Adverse events related mortality ‐‐ same number of chemotherapy cycles without UK NCRI Rapid and MSKCC trial #90‐44, Outcome 2 Cardiac disease‐ related mortality.
11.1
11.1. Analysis
Comparison 11 Overall survival ‐ different numbers of chemotherapy cycles, Outcome 1 All trials.
12.1
12.1. Analysis
Comparison 12 Progression‐free survival ‐‐ different numbers of chemotherapy cycles, Outcome 1 All trials.
12.2
12.2. Analysis
Comparison 12 Progression‐free survival ‐‐ different numbers of chemotherapy cycles, Outcome 2 Proportion of patients early favourable.
12.3
12.3. Analysis
Comparison 12 Progression‐free survival ‐‐ different numbers of chemotherapy cycles, Outcome 3 Bulky vs non‐bulky.
12.4
12.4. Analysis
Comparison 12 Progression‐free survival ‐‐ different numbers of chemotherapy cycles, Outcome 4 Type of radiotherapy.
13.1
13.1. Analysis
Comparison 13 Progression‐free survival ‐‐ different numbers of chemotherapy cycles without HD6, Outcome 1 Sensitivity analysis ‐ without HD6.
13.2
13.2. Analysis
Comparison 13 Progression‐free survival ‐‐ different numbers of chemotherapy cycles without HD6, Outcome 2 Proportion of patients early favourable.
13.3
13.3. Analysis
Comparison 13 Progression‐free survival ‐‐ different numbers of chemotherapy cycles without HD6, Outcome 3 Bulky vs non‐bulky.
14.1
14.1. Analysis
Comparison 14 Adverse events related mortality ‐‐ different numbers of chemotherapy cycles, Outcome 1 Infection‐ related mortality.
14.2
14.2. Analysis
Comparison 14 Adverse events related mortality ‐‐ different numbers of chemotherapy cycles, Outcome 2 Second cancer‐ related mortality.
14.3
14.3. Analysis
Comparison 14 Adverse events related mortality ‐‐ different numbers of chemotherapy cycles, Outcome 3 Cardiac disease‐ related mortality.
See this image and copyright information in PMC

Update of

References

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HD6 {published data only}
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References to studies excluded from this review

Andrieu 1999 {published data only}
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Dionet 1988 {published data only}
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Friedmann 2014 {published data only}
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Hirsch 1996 {published data only}
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Horning 1996 {published data only}
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Horning 2007 {published data only}
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Kim 2003 {published data only}
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Thistlethwaite 2007 {published data only}
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References to ongoing studies

GHSG HD16 {published data only}
    1. GHSG. HD16 for early stages ‐ treatment optimization trial in the first‐line treatment of early stage Hodgkin lymphoma; treatment stratification by means of FDG‐PET. www.clinicaltrials.gov NCT00736320.
GHSG HD17 {published data only}
    1. GHSG. HD17 for intermediate stages ­ treatment optimization trial in the first­line treatment of intermediate stage Hodgkin lymphoma. www.clinicaltrials.gov NCT01356680.
HD0801 {published data only}
    1. Fondazione Italiana Linfomi ONLUS. High‐dose chemotherapy and stem cell transplantation, in patients PET‐2 positive, after 2 courses of ABVD and comparison of RT versus no RT in PET‐2 negative patients (HD0801). www.clinicaltrials.gov NCT00784537.

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