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Anthracycline-containing regimens for treatment of follicular lymphoma in adults

  1. Gilad Itchaki1,*,
  2. Anat Gafter-Gvili2,
  3. Meir Lahav3,
  4. Liat Vidal2,
  5. Pia Raanani1,
  6. Ofer Shpilberg1,
  7. Mical Paul4

Editorial Group: Cochrane Haematological Malignancies Group

Published Online: 7 JUL 2013

Assessed as up-to-date: 17 APR 2013

DOI: 10.1002/14651858.CD008909.pub2


How to Cite

Itchaki G, Gafter-Gvili A, Lahav M, Vidal L, Raanani P, Shpilberg O, Paul M. Anthracycline-containing regimens for treatment of follicular lymphoma in adults. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD008909. DOI: 10.1002/14651858.CD008909.pub2.

Author Information

  1. 1

    Beilinson Hospital, Rabin Medical Center, Institute of Hematology, Davidoff Center, Petah Tikva, Israel

  2. 2

    Beilinson Hospital, Rabin Medical Center, Department of Medicine E, Petah Tikva, Israel

  3. 3

    Beilinson Hospital, Rabin Medical Center, Department of Medicine A, Petah Tikva, Israel

  4. 4

    Rambam Health Care Center. Haifa, Israel and Sackler Faculty of Medicine, Unit of Infectious Diseases, Tel Aviv, Israel

*Gilad Itchaki, Institute of Hematology, Davidoff Center, Beilinson Hospital, Rabin Medical Center, 39 Jabotinski Street, Petah Tikva, 49100, Israel. giladi@clalit.org.il. gilad14@gmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 7 JUL 2013

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Characteristics of included studies [ordered by study ID]
Federico 2013

MethodsRCT

Location: Italy, multicenter

Years: recruited 2006 to 2010

Follow-up: median 34 months

Pharmaceutical sponsorship: no

Classification system: WHO

Central pathology: only for grade 3 FL


ParticipantsNumber of patients randomized: 534

Number of patients analyzed: 504

Numbers of patients with FL: 504

Number of patients included in our analysis: 333

Lymphoma: previously untreated stage II to IV FL, grade 1 to 3a, age 18 to 75 years, ECOG 0 to 2

Line of treatment: first

Patients: median age (range) 56 years (30 to 75 years)


InterventionsSame: R-CHOP x 6 + R x 2 versus R-CVP x 8

Note number of courses in each arm


OutcomesTime to treatment failure

Response rate

Progression-free survival

Overall survival

Toxicity


NotesUnpublished data from authors

This was a triple arm study: R-CVP versus R-CHOP versus R-FM. We extracted data for the first comparison, according to protocol


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization arm was assigned automatically by the EDC system upon verification of eligibility criteria. Arm was communicated on screen and confirmed by email to the investigator. Randomization was based on prepopulated tables that were prepared and uploaded by the IT staff on the EDC system at study start

Allocation concealment (selection bias)Low riskRandomization tables could not be accessed or modified, or both, by any investigator or study co-ordinator

Blinding (performance bias and detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data

Selective reporting (reporting bias)Low riskNo change from protocol

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen study; review authors did not believe this will introduce bias

Jones 1983

MethodsRCT

Location: US, multicenter, SWOG study

Years: 1974 to 1977

Follow-up: maximum 6 years

Pharmaceutical sponsorship: no

Classification system: Rappaport

Central pathology: yes


ParticipantsNumber of patients randomized: 652

Number of patients analyzed: 497 (after central pathology)

Numbers of patients with FL: 226 (nodular lymphoma)

Lymphoma: advanced-stage NHL

Line of treatment: first or recurrence after RTx

Patients: of 226 patients with nodular lymphoma, grade classification was as follows: NLPD (nodular lymphocytic poorly differentiated or follicular small cleaved cell lymphoma), 160 patients; NM (nodular mixed or follicular small cleaved and large cell lymphoma), 42 patients; NH (nodular 'histiocytic' or follicular large cell lymphoma), 24 patients


InterventionsSame: CHOP-Bleo x 8 versus CVP-Bleo x 8

Control arm: d 1-14 cyclophosphamide 125 mg/m2 PO, d 1, 8 vincristine 1.4 mg/m2 IV (max 2 mg/dose), d 1-5 prednisone 100 mg/d PO, d 1,8 bleomycin 4 mg/m2 IV. 8 cycles, every 21 d

Experimental arm: d 1 cyclophosphamide 750 mg/m2 IV, d 1 doxorubicin 50 mg/m2 IV, d 1 vincristine 1.4 mg/m2 (max 2 mg) IV, d 1-5 prednisone 100 mg/d PO, d 1 bleomycin 4 mg/m2 IV. 8 cycles, every 28 d


OutcomesOverall survival

Response rate

Relapse-free survival

Toxicity


NotesPublished: journal article

Double publication of preliminary data: Jones 1979

Triple-arm design: CHOP-BCG versus CHOP-Bleo versus CVP-Bleo. Second randomization in patients achieving partial response was: no treatment versus BCG maintenance

CVP-Bleo arm terminated early


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "patients were assigned at random by the SWOG Statistical Office"

Comment: assumed proper sequence generation

Allocation concealment (selection bias)Low riskQuote: "patients were assigned at random by the SWOG Statistical Office"

Comment: assumed concealment of allocation

Blinding (performance bias and detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: 652 patients were randomized; 636 were evaluable (Quote: "16 were not evaluable - insufficient data submitted or major protocol violation"); only 497 had central pathology, according to which analysis was made. Data were reported only for 468 patients with chosen diagnoses

Data were reported for 226 FL patients. The number of patients with FL at randomization could not be inferred

Selective reporting (reporting bias)Unclear riskProtocol unavailable

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen study; review authors do not believe this will introduce bias

Kimby 1994

MethodsRCT

Location: Sweden, multicenter, LGCS study

Years: 1982 to 1988

Follow-up: minimum 57 months

Pharmaceutical sponsorship: NR

Classification system: Kiel

Central pathology: yes


ParticipantsNumber of patients randomized: 259

Number of patients analyzed: 259

Numbers of patients with FL: 76

Lymphoma: advanced-stage, symptomatic, low-grade NHL (CLL, immunocytoma, centrocytic lymphoma, centroblastic/centrocytic lymphoma)

Line of treatment: first

Patients: mean age 64 years


InterventionsDifferent: CHOP x 4-8 cycles versus CD x 4-8 cycles


OutcomesOverall survival

Response rate

Freedom from progression defined as survival without progression, measured from randomization

Response duration - time from CR or PR to relapse or progression

Toxicity


NotesPublished: journal article


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomization was centralized"

Comment: assumed proper sequence generation, since done by the LGCS

Allocation concealment (selection bias)Low riskQuote: "randomization was centralized"

Comment: assumed proper allocation concealment, since done by the LGCS

Blinding (performance bias and detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data

Selective reporting (reporting bias)Unclear riskProtocol unavailable

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen study; review authors do not believe this will introduce bias

Lepage 1990

MethodsRCT

Location: France, single center

Years: 1981 to 1984

Follow-up: median 59 months

Pharmaceutical sponsorship: NR

Classification system: working-formulation

Central pathology: yes


ParticipantsNumber of patients randomized: 113

Number of patients analyzed: 113

Numbers of patients with FL: 101

Lymphoma: stage II/IV and stage II bulky, low-grade NHL

Line of treatment: first

Patients: median age (range) 51 years (26 to 70 years), over 90% were advanced stage, 40% with bulky disease, and 65% with bone-marrow involvement


InterventionsSame: PCOP x 6 cycles versus PACOP x 6 cycles


OutcomesOverall survival

Response rate

Freedom from progression defined as survival without progression

Freedom from relapse defined as time from CR to relapse

Toxicity


NotesPublished: journal article

Double publication: Gisselbrecht 1987

Second randomization in responding patients to maintenance with chlorambucil versus CVP for 12 months


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNone reported

Allocation concealment (selection bias)Low riskComment: assumed proper since done as central randomization in a multicenter trial

Blinding (performance bias and detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data

Selective reporting (reporting bias)Unclear riskProtocol unavailable

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen study; review authors do not believe this will introduce bias

Peterson 2003

MethodsRCT

Location: USA, multicenter, CALGB study

Years: 1980 to1985

Follow-up: maximum 18 years

Pharmaceutical sponsorship: NR

Classification system: REAL

Central pathology: yes


ParticipantsNumber of patients randomized: 228

Number of patients analyzed: 228

Numbers of patients with FL: 189 after reclassification

Lymphoma: advanced FL grade 1 (follicular small cell lymphoma) and grade 2 (follicular mixed-cell lymphoma)

Line of treatment: first

Patients: median age 55 years, 36% of patients were over 60 years, 60% had bone marrow involvement, 50% were asymptomatic at initiation of treatment


InterventionsDifferent: CHOP-Bleo for a median of 26 months (Bleo only 6 cycles) versus daily cyclophosphamide PO for a median of 28 months


OutcomesOverall survival

Response rate

TTTP - time to first progression, relapse or recurrence, death from any cause, or discontinuation of treatment for non-responders

CR duration - from first CR to relapse or death by any cause

Toxicity


NotesPublished: journal article

Subgroup analysis of FSCL and FML patients, after reclassification, indicated better outcomes in FML patients treated with CHOP regimen, including overall survival, TTTF and complete remission duration


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported. No statement regarding where randomization actually took place

Allocation concealment (selection bias)Unclear riskNot reported. No statement regarding where randomization actually took place

Blinding (performance bias and detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Low risk6 of 234 randomized patients were cancelled, 3 in each arm (reasons not stated). Data were reported for 228 patients. Another analysis was made to compare between grades of FL (FSCL versus FML), and included 189 patients with after central pathology review

Selective reporting (reporting bias)Unclear riskProtocol unavailable

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen study; review authors do not believe this will introduce bias

Taylor 2006

MethodsRCT

Location: UK, multicenter, SNLG study

Years: 1993 to 2000

Follow-up: median 58 months

Pharmaceutical sponsorship: no

Classification system: Kiel/REAL

Central pathology: yes


ParticipantsNumber of patients randomized: 200

Number of patients analyzed: 183

Numbers of patients with FL: 155

Lymphoma: low-grade NHL

Line of treatment: first, but previous radiotherapy for localized low-grade NHL was allowed

Patients: age was matched across study arms, 34% of patients were over age 60 years; 83% and 94% of patients were stage III/IV, in CID and CD arms, respectively; 15% and 32% had a high FLIPI score


InterventionsSame: CD (Chlorambucil + dexamethasone) x 6 cycles versus CID (same + idarubicin) x 6. Radiotherapy to bulky disease allowed


OutcomesOverall survival

Response rate

Time to treatment failure - time from entry to the start of subsequent treatment or relapse

Toxicity


NotesPublished: journal article

Second randomization in responding patients: no treatment versus IFNα

Protocol violation in CID arm with access radiotherapy might have introduced bias


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Low risk17 patients were not analyzed: 2 withdrew consent (1 in each arm); 15 were ineligible on pathology review (9 in CID arm, 6 in CD arm)

Selective reporting (reporting bias)Unclear riskProtocol unavailable

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen study; review authors do not believe this will introduce bias

Unterhalt 1996

MethodsRCT

Location: Europe, multicenter, GLGLSG study

Years: 1989 to 1995

Follow-up: NR

Pharmaceutical sponsorship: NR

Classification system: Kiel/REAL

Central pathology: yes


ParticipantsNumber of patients randomized: 442

Number of patients analyzed: 246

Numbers of patients with FL: 200

Lymphoma: advanced-stage FL grade 1-2 and MCL

Line of treatment: first

Patients: median (range) age 54 years (28 to 77 years), 67% had bone marrow involvement


InterventionsDifferent: PmM x 4-6 cycles versus CVP x 4-6 cycles


OutcomesResponse rate

Event-free interval measured from response to the recurrence of lymphoma or death

Toxicity


NotesPublished: journal article

Triple publication: Hiddemann 1994; Hiddemann 1998


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "eligible patients underwent a central randomization procedure"

Comment: assumed proper sequence generation, since done by the GLGLSG

Allocation concealment (selection bias)Low riskQuote: "eligible patients underwent a central randomization procedure"

Comment: assumed proper allocation concealment, since done by the GLGLSG

Blinding (performance bias and detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
High riskOut of 344 randomized FL patients, only 200 were fully evaluable for central pathology, 33 of whom withdrew early from study (reasons stated in study), leaving only 167 FL patients for analysis

Selective reporting (reporting bias)Unclear riskProtocol unavailable

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen study; review authors do not believe this will introduce bias

Zinzani 2000

MethodsRCT

Location: Italy, multicenter

Years: 1995 to 1998

Follow-up: median 19 months (range 6 to 38 months) after end of chemotherapy

Pharmaceutical sponsorship: NR

Classification system: REAL

Central pathology: yes


ParticipantsNumber of patients randomized: 208

Number of patients analyzed: 199

Numbers of patients with FL: 102

Lymphoma: stage II-IV, indolent lymphoma (including FL, immunocytoma, and small lymphocytic lymphoma) or MCL

Line of treatment: first

Patients: median (range) age 54 years (25 to 65 years), 86% were stage III/IV, 12% had bulky disease, all had an IPI of 3 or less, 62% had IPI 0 or 1


InterventionsSame: FI x 6 cycles versus fludarabine x 6 cycles

Fludarabine was given for 5 days in the control arm versus 3 days in the experimental arm


OutcomesOverall survival

Response rate

Progression-free survival measured from date of any response until relapse or progression

Relapse-free survival measured from CR to relapse or death

Toxicity


NotesPublished: journal article


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
High riskOpen study

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "the nine patients who were excluded were so because of incorrect diagnosis (three patients), loss to follow-up (three patients), and protocol violations (three patients)"

Comment: data were reported for all other 199 patients

Selective reporting (reporting bias)Unclear riskProtocol unavailable

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen study

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen study; review authors do not believe this will introduce bias

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Acker 1983No anthracyclines in study arms

Al-Ismail 1987Did not state the number of FL patients out of low-grade lymphomas

Andersen 1990Not FL

Ben-Shahar 1998Did not report relevant outcomes (see Methods)

Bonadonna 1975Cross-over trial

Cabanillas 1978Anthracyclines in both study arms

Coiffier 1999Immunotherapy only in 1 study arm

Engelhard 1986Not FL

Flinn 2012No randomization between ACR and non-ACR arms

Gad 1976No anthracyclines in study arms

Gams 1985Not low-grade lymphoma

Gisselbrecht 1987Double publication

Ha 2005No chemotherapy on control arm (irradiation only)

Hainsworth 2005Non-randomized trial

Hiddemann 1994Double publication

Hiddemann 1998Comparison between FL and MCL, not between therapeutic study arms

Inoue 1993Non-randomized trial, few patients with low-grade lymphoma

Jones 1979Double publication

Junmin 2005Non-randomized trial

Meerwaldt 1991No chemotherapy on control arm (irradiation only)

Meusers 1989Not FL

Mukherji 2009Review article

Niitsu 1997Non-randomized trial

Parlier 1981Non-randomized trial

Parlier 1982Non-randomized trial

Peterson 1985Double publication

Pettengell 2009Not FL

Pott 1994Data could not be retrieved

Prentice 1996Did not state the number of FL patients out of low-grade lymphomas

Robak 2000Non-randomized trial

Rummel 2008Review article

Rummel 2009Different chemotherapeutic regimens in conjunction with immunotherapy (rituximab)

Rummel 2013Different chemotherapeutic regimens in conjunction with immunotherapy (rituximab)

Santini 2001Non-randomized trial

Santoro 2006Did not state the number of FL patients out of low-grade lymphomas

Somers 1987Report of a number of studies. No anthracyclines in study arms or anthracyclines in both study arms

Unterhalt 1994Double publication

Yahalom 1993No chemotherapy on control arm (irradiation only)

Young 1977No anthracyclines in study arms

 
Characteristics of ongoing studies [ordered by study ID]
NCT00551239

Trial name or titleFludarabine and rituximab with or without pixantrone in treating patients with relapsed or refractory indolent non-Hodgkin lymphoma

MethodsRCT, single blind (outcomes assessor)

ParticipantsPatients with relapsed or refractory indolent non-Hodgkin lymphoma

InterventionsCombination BBR 2778, fludarabine, and rituximab with the combination fludarabine and rituximab

OutcomesPrimary: progression-free survival

Starting dateAugust 2007

Contact informationCell Therapeutics, Inc (Igor Gorbatchevsky, Medical Director)

NotesOngoing but not recruiting

NCT00801281

Trial name or titleFirst-line R-CVP vs R-CHOP induction immunochemotherapy for indolent lymphoma and R maintenance (PLRG4)

MethodsMulticenter, Phase III randomized study

ParticipantsFirst-line indolent NHL

InterventionsR-CVP versus R-CHOP and R maintenance

OutcomesPrimary: event-free survival

Starting dateFebruary 2007

Contact informationPolish Lymphoma Research Group

NotesRecruiting

 
Comparison 1. Anthracycline versus no anthracycline same chemotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival3464Hazard Ratio (95% CI)0.99 [0.77, 1.29]

 2 Overall survival with Zinzani4663Hazard Ratio (95% CI)0.97 [0.76, 1.23]

 3 Mortality at 3 years3465Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.67, 1.26]

 4 Mortality at 5 years3465Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.77, 1.18]

 5 Complete response5881Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.94, 1.18]

 6 Overall response3616Risk Ratio (M-H, Fixed, 95% CI)1.06 [1.00, 1.12]

 7 Disease control4759Hazard Ratio (95% CI)0.65 [0.52, 0.81]

    7.1 Progression-free survival
2514Hazard Ratio (95% CI)0.65 [0.50, 0.84]

    7.2 Response duration
2245Hazard Ratio (95% CI)0.63 [0.40, 0.98]

 8 Progression/relapse at 3 years4724Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.63, 0.85]

 9 Neutropenia grade 3-42533Risk Ratio (M-H, Fixed, 95% CI)1.94 [1.46, 2.56]

 10 Infection31185Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.75, 1.80]

 
Comparison 2. Sensitivity analysis for allocation concealment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival3Hazard Ratio (95% CI)Subtotals only

    1.1 Adequate allocation concealment
2265Hazard Ratio (95% CI)0.92 [0.63, 1.34]

    1.2 Unclear allocation concealment
1199Hazard Ratio (95% CI)0.97 [0.67, 1.41]

 2 Disease control4Hazard Ratio (95% CI)Subtotals only

    2.1 Adequate allocation concealment
2476Hazard Ratio (95% CI)0.70 [0.52, 0.95]

    2.2 Unclear allocation concealment
2283Hazard Ratio (95% CI)0.58 [0.41, 0.81]

 
Comparison 3. Sensitivity analysis for second randomization

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Disease control4Hazard Ratio (95% CI)Subtotals only

    1.1 Second randomization
2324Hazard Ratio (95% CI)0.72 [0.54, 0.98]

    1.2 No second randomization
2435Hazard Ratio (95% CI)0.56 [0.40, 0.78]

 
Comparison 4. Comparison of different anthracyclines

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival3Hazard Ratio (95% CI)Subtotals only

    1.1 Doxorubicin
2265Hazard Ratio (95% CI)0.92 [0.63, 1.34]

    1.2 Idarubicin
1199Hazard Ratio (95% CI)0.97 [0.67, 1.41]

 2 Disease control4Hazard Ratio (95% CI)Subtotals only

    2.1 Doxorubicin
2476Hazard Ratio (95% CI)0.70 [0.52, 0.95]

    2.2 Idarubicin
2283Hazard Ratio (95% CI)0.58 [0.41, 0.81]

 
Comparison 5. Anthracycline versus no anthracycline different chemotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Overall survival2Hazard Ratio (95% CI)Subtotals only

 2 Mortality at 3 years2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 3 Complete response3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 4 Disease control3Hazard Ratio (95% CI)Subtotals only

 
Comparison 6. Cardiotoxicity for all studies

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Cardiotoxicity41412Risk Ratio (M-H, Fixed, 95% CI)4.55 [0.92, 22.49]

    1.1 Same chemotherapy regimen
31184Risk Ratio (M-H, Fixed, 95% CI)4.30 [0.66, 28.03]

    1.2 Different chemotherapy regimen
1228Risk Ratio (M-H, Fixed, 95% CI)5.45 [0.26, 112.37]

 
Summary of findings for the main comparison. ACR compared to non-ACR for treatment of follicular lymphoma in adults

ACR compared to non-ACR for treatment of follicular lymphoma in adults

Patient or population: adults receiving treatment for follicular lymphoma
Settings:
Intervention: Aanthracycline
Comparison: no anthracycline same chemotherapy

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

No anthracycline same chemotherapyAnthracycline

Overall survival
number of dead patients
Follow-up: median 50 months
538 per 1000535 per 1000
(449 to 631)
HR 0.99
(0.77 to 1.29)
464
(3 studies)
⊕⊕⊕⊝
moderate1

Mortality at 3 years260 per 1000239 per 1000
(174 to 327)
RR 0.92
(0.67 to 1.26)
465
(3 studies)
⊕⊕⊕⊝
moderate1

Overall response839 per 1000889 per 1000
(839 to 940)
RR 1.06
(1 to 1.12)
622
(3 studies)
⊕⊕⊕⊝
moderate2

Disease control
number of patients with progression
Follow-up: median 30 months
492 per 1000356 per 1000
(297 to 423)
HR 0.65
(0.52 to 0.81)
759
(4 studies)
⊕⊕⊕⊕
high

Progression/relapse at 3 years544 per 1000397 per 1000
(343 to 463)
RR 0.73
(0.63 to 0.85)
724
(4 studies)
⊕⊕⊕⊕
high

Neutropenia grade 3-4190 per 1000368 per 1000
(277 to 485)
RR 1.94
(1.46 to 2.56)
533
(2 studies)
⊕⊝⊝⊝
very low1,2,3

Cardiotoxicity**2 per 10008 per 1000
(2 to 40)
RR 4.55
(0.92 to 22.49)
1412
(3 studies)
⊕⊝⊝⊝
very low4,5

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

**Includes all trials, irrespectively of the comparison ("same chemotherapy"; "different chemotherapy").
CI: confidence interval; RR: risk ratio; HR: hazard ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Small number of events
2 Moderate heterogeneity
3 Different reporting methods
4 Not consistently reported
5 Wide confidence interval
 
Table 1. Studies included in meta-analysis

AuthorRandomizedAnalyzedFL analyzedFL gradeData specific for FL

Federico 2013534504504 (333)*1, 2, 3aFor all outcomes

Jones 1983652497226 (146)*1, 2, 3For all outcomes

Lepage 19901131131011, 2For some outcomes

Taylor 2006200183155Low gradeNo

Zinzani 2000208199102IndolentFor some outcomes

Kimby 1994259259761, 2For some outcomes

Peterson 20032282281891, 2For all outcomes

Unterhalt 19964422061671, 2For some outcomes

Total263621891520

 * number of FL patients analyzed in 2 (of 3) arms compared
FL: follicular lymphoma
 
Table 2. Baseline characteristics of interventions

AuthorPublication statusSame/different interventionAnthracyclineControl armExperimental arm

Federico 2013Full textSameDoxorubicinR-CVPR-CHOP

Jones 1983Full textSame*DoxorubicinCVP-BCHOP-B

Lepage 1990Full textSameDoxorubicinPCOPPACOP

Taylor 2006Full textSameIdarubicinChDChID

Zinzani 2000Full textSame*IdarubicinFFI

Kimby 1994Full textDifferentDoxorubicinCh-DCHOP

Peterson 2003Full textDifferentDoxorubicinCCHOP

Unterhalt 1996Full textDifferentMitoxantroneCVPPmM

 * trials with higher non-anthracycline dose in control-arm
 
Table 3. Detailed therapeutic regimens in included studies

AuthorControl armExperimental arm

Federico 2013d 1 rituximab 375 mg/m2, d 1 cyclophosphamide 750 mg/m2 IV, d 1 vincristine 1.4 mg/m2 (max 2 mg) IV, d 1-5 prednisone 40 mg/m2 PO, 8 cycles, every 21 d

[Note: more treatment cycles]
d 1 rituximab 375 mg/m2, d 1 cyclophosphamide 750 mg/m2 IV, d 1 doxorubicin 50 mg/m2 IV, d 1 vincristine 1.4 mg/m2 (max 2 mg) IV, d 1-5 prednisone 100 mg/d PO 6 cycles, every 21 d. Added 2 cycles of rituximab every 21 d

Jones 1983d 1-14 cyclophosphamide 125 mg/m2 PO, d 1, 8 vincristine 1.4 mg/m2 IV (max 2 mg/dose), d 1-5 prednisone 100 mg/d PO, d 1, 8 bleomycin 4 mg/m2 IV. 8 cycles, every 21 d

[Note: different route of administration for cyclophosphamide; total doses differ for all drugs; cycles are more frequent]
d 1 cyclophosphamide 750 mg/m2 IV, d 1 doxorubicin 50 mg/m2 IV, d 1 vincristine 1.4 mg/m2 (max 2 mg) IV, d 1-5 prednisone 100 mg/d PO, d 1 bleomycin 4 mg/m2 IV. 8 cycles, every 28 d

Lepage 1990d 1, 8 cyclophosphamide 400 mg/m2 IV, d 1, 8 vincristine 1.4 mg/m2 , d 1, 14 procarbazine 80 mg/m2 PO, d 1-5 prednisone 60 mg/m2 PO. 6 cycles, every 28 dsame + d 1, 8 doxorubicin 20 mg/m2 IV

Taylor 2006d 1-3 chlorambucil 20 mg/m2/d, d 1-5 dexamethasone 4 mg bd. 6 cycles, every 21 dsame + d 1-3 idarubicin 10 mg/m2/d

Zinzani 2000d 1-5 fludarabine 25 mg/m2/d IV. 6 cycles, every 28 d
[Note: total fludarabine dose is higher by 66%]
d 1-3 fludarabine 25 mg/m2/d IV, d 1-3, d 1 idarubicin 12 mg/m2 6 cycles, every 28 d

Kimby 1994d 1 chlorambucil 0.4 mg/kg PO, d 1-3 prednisone 75 mg PO every 14 d, for 4-8 monthsd 1 cyclophosphamide 750 mg/m2 IV, d 1 doxorubicin 50 mg/m2 IV, d 1 vincristine 2 mg/m2 IV, d 1-5 prednisone 50 mg/m2 PO 4-8 cycles every 28 d

Peterson 2003d 1 cyclophosphamide 750 mg/m2 IV, d 1 doxorubicin 50 mg/m2 IV, d 1 vincristine 1.4 mg/m2 (max 2 mg) IV, d 1-5 prednisone 60 mg/m2 PO, d 1 bleomycin 10 u/m2 IM every 21 d until complete response and then every 28 d up to 2 years, bleomycin up to 6 cycles100 mg/m2/d PO until 2 years from maximal response

Unterhalt 1996d 1-5 cyclophosphamide 400 mg/m2/d IV, d 1 vincristine 1.4 mg/m2 (max 2 mg) IV, d 1-5 prednisone 100 mg/m2/d PO 4-6 induction cycles every 21 dd 1-5 prednimustine 100 mg/m2/d PO, d 1-2 mitoxantrone 8 mg/m2/d IV. 4-6 induction cycles every 28 d

 d: day; IM: intramuscular; IV: intravenous; PO: oral
 
Table 4. Outcome measures in trials with different chemotherapeutic regimens

OSMortality at 3 yearsMortality at 10 yearsCRORRDisease controlProgression or relapse

Kimby 19940.89

(0.67 to 1.18)
0.87

(0.63 to 1.18)
NR3.42

(1.52 to 7.68)
1.70

(1.30 to 2.23)
0.66

(0.41 to 1.05)
0.90

(0.67 to 1.20)

Peterson 20030.96

(0.70 to 1.31)
1.15

(0.66 to 2.00)
0.95

(0.74to 1.23)
0.90

(0.74 to 1.10)
1.04

(0.96 to 1.13)
0.84

(0.63 to 1.11)
1.03

(0.82 to 1.28)

Unterhalt 1996NRNRNR1.82

(1.10 to 3.01)
1.02

(0.89 to 1.17)
0.59

(0.36 to 0.98)
NR

 CR: complete response; NR: not reported; ORR: overall response rate; OS: overall survival