9. Rezidivtherapie – Hodgkin Lymphom

(Bednaruk-Mlynski, Pienkowska et al. 2015)

Diagnostic test accuracy single studies

Diagnostic PET/CT

n = 96

Recruitment: 2008-2011

Inclusion Criteria:

• Patients with newly diagnosed HL

Exclusion Criteria:

• Not reported

Baseline characteristics:

• Age: Median age: 36 years (range: 19-78 years)
• Stage: not reported
• 51 males and 45 females
• Recurrence status: not reported

n = 96

CT imaging

n = 96

PET/CT imaging

Baseline characteristics:

• Age: Median age = 36 years (19-78 years old patients)
• Stage: not reported
• Recurrence status: not reported

• Disease stage evaluation
• Detection of lesions

• Diagnostic accuracy
• Sensitivity: not reported
• Specificity: not reported

• Disease stage evaluation:
• Concordance: 63%
• Upstaging by PET/CT: 28%
• Downstaging by PET/CT: 6%

• Other:
• Detection of nodal areas PET/CT: 907 CT: 807

• Detection of extranodal areas PET/CT: 73 in 52 pts CT: 25 in 21 pts

• Detection of spleen involvement PET/CT: 27 CT: 9

• Detection of liver involvement PET/CT: 2 CT: 2

• Detection of BM involvement, foci PET/CT: 23 pts CT: 4 pts

• Detection of lung involvement: PET/CT: 12 pts CT: 10 pts

• The study indicated that PET/CT should be mandatory in the initial staging of HL

• Study Duration: not reported
• Follow-up: not reported
• ITT: no
• Randomisation: not reported
• Blinding: The radiologist and nuclear medicine specialist were blinded to the original local-center assessment and were not aware of their mutual staging
• Funding: not reported
• Other limitations: no reference standard to be able to calculate sensitivity, specificity, PPV and NPV

(Hutchings, Loft et al. 2006)

Diagnostic PET/CT

n = 99

All patients were given oral and intravenous contrast agents

Inclusion Criteria:

• newly diagnosed HL

Exclusion Criteria:

• Diabetes mellitus
• Pregnancy 

staging PET/CT

n = 61

whole-body scans (mid-brain to upper thigh), 45-90 minutes after i.v. injection of approximately 400 MBq 18

F-FDG

GE LS Discovery PET/CT scanner (General Electric Medical Systems, Milwaukee, Wisconsin, USA), emission scans of 3 minutes per bed position

Baseline characteristics:

• Age: median: 37.3 (range: 18.6-79.2)
• Stage: I: 11(18%), II: 24 (39%), III: 18 (30%), IV: 8 (13%)
• Recurrence status: not reported

Staging PET

n = 99

whole-body scans (mid-brain to upper thigh), 45-90 minutes after i.v. injection of approximately 400 MBq 18

F-FDG 

Baseline characteristics:

• Age: median: 36.2 (range: 18.6-79.2)
• Stage: I: 22 (22%), II: 42 (42%), III: 27 (27%), IV: 8 (8%)

Recurrence status: not reported

Reference standard

n = 99

A standard of reference for each nodal region and organ was determined using all available information including scan results, histology and a minimum of one year's clinical follow-up data.

Region/organ with involvement seen on both PET and CT: true positive focus, site with no suspicious signs on PET and CT: true negative

In eight cases, there was histological evidence to prove or disprove the presence of disease (three lymph node, three bone marrow, and two liver biopsies; all other discrepant findings: status of the region/organ determined using information from treatment monitoring and follow-up examinations

Diagnostic accuracy:

• Sensitivity
• Specificity
• Positive predictive value (PPV)
• Negative predictive value (NPV)
• SUVmax (analyses of 60 patients who underwent staging PET/CT)

• Diagnostic accuracy

All nodal regions (CT: n= 980, PET: n= 990, PET/CT:n= 610, SUVmax: n= 600)

• Sensitivity

CT: 82,6% (78.0-86.4)
PET: 92,3% (89.5-94.4)
PET/CT: 92,2% (87.7-95.1)

• Specificity

CT: 98,9% (97.8-99.5)
PET: 97,6% (96.4-98.4)
PET/CT: 99,3% (97.8-99.7)

• Positive predictive value

CT: 97,4% (94.7-98.7)
PET: 94,9% (92.5-96.6)
PET/CT: 98,4% (95.5-99.5)

• Negative predictive value

CT: 92,3% (90.1-94.0)
PET: 96,3% (94.9-97.3)
PET/CT: 96,2% (93.9-97.6)

Organ staging (CT: n= 392, PET: n= 396, PET/CT: n= 244, SUVmax: n= 180)

•  Sensitivity

CT: 37,0% (26.3-49.1)
PET: 86,0% (76.0-92.2)
PET/CT: 72,7% (58.6-83.4)

• Specificity

CT: 99,7% (98.7-99.9)
PET: 96,5% (94.5-97.8)
PET/CT: 94.6-98.5)

• Positive predictive value 

CT: 94,4% (78.5-98.8)
PET: 78,2% (67.8-85.9)
PET/CT: 80,0% (65.7-89.3)

• Negative predictive value

CT: 92.2% (89.6-94.2)
PET: 97,9% (96.2-98.9)
PET/CT: 95,8% (92.9-97.5)

• Study Duration: November 2001- June 2004
• Follow-up: mean: A:24.4, B:22.7; median: A:23.8, B:20.8; range: A: 2.0-40.8, B: 2.0-40.8
• ITT: not applicable
• Randomisation: not applicable
• Blinding: nuclear medicine physicians: blind to the CT results and all other clinical information except the diagnosis, radiologists: blind to the results of PET
• Funding: not reported
• Other limitations: none

Diagnostic test accuracy single studies

Sensitivität¹

-

-

-

+²

-

⊕⊕⊕⊝
moderate 

Spezifität¹

-

-

-

+²

-

⊕⊕⊕⊝
moderate 

Referenz/ Studientyp

Untersuchte Population

Intervention

Kontrolle

untersuchte Endpunkte

Hauptergebnisse

methodische Bemerkungen

(Mocikova, Obrtlikova et al. 2010)

Cohort study, retrospective

2b

n = 113

327 PET scans were evaluated in 113 pts (237 PET and 90 PET/CT studies)

Recruitment: 1999-2008

Inclusion Criteria:

• HL pts at the end of therapy after first-line treatment

Exclusion Criteria:

• Not reported

Baseline characteristics:

• Age: median: 32 (17-78)
• Stage (Ann Arbor): I: 7, II: 52, III: 27, IV: 27
• Recurrence status: not reported

Arm A:

n = 57

CT (complete remission, complete remission unconfirmed)

Arm B:

n = 56
CT (partial remission, stable disease)

• Relapse/ progression of disease during follow-up in relation to PET results

Diagnostic accuracy:

• For routine surveillance (calculated from information below)

Sensitivity: 100%
Specificity: 80.3%
PPV: 33.3%
NPV: 100%
Efficacy: Regular: 6 of 155 PET scans, 3.9%

• For suspected cases:

Sensitivity: 100%
Specificity: 72.7%
PPV: 45.5%
NPV: 100%
Efficacy: 5 of 27 PET scans, 18,5%

• All patients

PET/CT: 35.7% (nachberechnet)
Specificity:
PET/CT: 85,8% (nachberechnet)
NPV at the end of therapy:
CT: 91.2%
PET/CT: 90.4%,
statistically not significant
PPV at the end of therapy:
CT: 16%
PET/CT: 26%,
statistically not significant

• Other outcomes
• End of treatment PET scan

9 pts subsequently relapsed
2 pts second tumor
PET positive: n= 19 (16.8%)
5 pts progressed
PET inconclusive: n=19
5 pts relapsed 

• Follow-up PET scans in PET-negative patients at the end of therapy (n= 94):

regular follow-up PET scans (n= 67):
PET negative: 49 pts (none relapsed)
PET positive:  n= 18, of these n= 6 were true positives
PET in suspected relapse: n= 27
PET-negative:16
PET positive: n= 11 (of these true PET positivity: n= 5 PET Inconclusive positivity: n= 6
Efficacy RR between susp. And routine:

RR = 0.21 (95% CI 7% to 64%)

• Study Duration: 1999-2008
• Follow-up: median: 34 months (range: 3-109)
• ITT: not applicable
• Randomisation: not applicable
• Blinding: not reported
• Funding: Ministry of Public Health, Czech Republic
• Other limitations: retrospective cohort

Diagnostic test accuracy single studies

Sensitivität¹

-

-

-

+²

-

⊕⊕⊕⊝
moderate 

Spezifität¹

-

-

-

+²

-

⊕⊕⊕⊝
moderate 

(Jerusalem, Beguin et al. 2003)

Cohort study

2b

n = 36

Recruitment: 1994-1999

Inclusion Criteria:

• histological verified HL

Exclusion Criteria:

• not reported

Baseline characteristics:

• Age: Median: 28 (range 13–71)
• Stage (Ann Arbor clinical stage): I: n= 6, II: n= 19, III: n= 6, IV: n= 5
• Recurrence status: Initial presentation: n= 26, First relapse: n= 8, Second relapse: n= 2
• Gender: male: n= 13, female: n= 23

n = 19
residual mass on CT

n = 17
no residual mass on CT

• value of whole-body 18 F-FDG PET for the detection of preclinical relapse in the follow-up of patients with HD

• Diagnostic test accuracy
• On patient-level:
• PET+: n=11, of these, 5 relapsed
• PET-: n= 25, none relapsed

• Calculated based on information above (patient-level, all time-points included):
• Sensitivity: 100%
• Specificity: 80.6%
• PPV: 45.5%
• NPV: 100%

• Divided into groups based on end-of-treatment CT-result
• Residual mass on CT:
• positive PET: n= 5 (relapse: n= 2, no relapse: n= 3),
• negative PET: n= 14 (no relapse: n= 14)

• No residual mass on CT:
• positive PET: n= 6 (relapse: n= 3, no relapse: n= 3),
• negative PET: n= 11 (no relapse: n= 11)

• Study Duration: not reported
• Follow-up: 2–3 years after the end of polychemo-therapy and/or radio-therapy
• 1 month after treatment CT and F-FDG PET
• Thereafter F-FDG PET studies every 4–6 months
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: not reported
• Other limitations: cohort study

(Lee, Zuckerman et al. 2010)

Outcome research

2c

Surveillance PET/CT scan

n = 192 

Recruitment: 2003-2006

Inclusion Criteria:

• treatment and surveillance at our institutions
• age ≥ 18 years
• histologic diagnosis of classic HL
• no history of other active malignancy
• CR1

Exclusion Criteria:

• consultation cases
• positive end-of-treatment imaging
• nodular lymphocyte predominant HL
• pediatric cases
• incomplete data
• treatment with noncurative intent
• concurrent malignancy
• death during induction treatment
• incorrect histologic diagnosis
• Epstein-Barr virus+ posttransplant lymphoproliferative disease
• incorrect year
• unacceptable imaging modalities

Baseline characteristics:

• Age: median: 33 (18-81)
• Stage: early (IA-IIA): 92 (48%), advanced (IIB-IV): 100 (52%)
• 96 male, 96 female

Recurrence status: not reported

Arm A:

n = 83

PET/CT scans

Arm B:

n = 27

CT scans

Arm C:

n = 82

CT & PET/CT scans

• Positive predictive value (PPV)
• Cumulative survival probabilities

• Diagnostic accuracy
• Sensitivity: not reported
• Specificity: not reported
• False positive 
• PET/CT: 7.8% (37 of474 scans)
• CT: 3.1% (10 of321)

• Positive predictive value
• Detecting Recurrent HL or Secondary Malignancy

• Abnormality at previously involved site: 

• Radiologic abnormality at ≤12 months: 

• Radiologic abnormality at >12 month: 

• Mediastinal abnormality: PET/CT: 33,3%, 

Other

• OS (4-year OS): 98.4%
• PFS (4 year PFS): 93,8%
• Event free survival: 91,7%

• Study Duration: not reported
• Follow-up: median: 31 months (range: 6-66)
• ITT: not applicable
• Randomisation: not applicable
• Blinding: not reported
• Funding: not reported
• Other limitations: retrospective cohort

(Zinzani, Tani et al. 2007)

Cohort study

2b

n = 151 (57 Hodgkin Lymphoma)

Recruitment: 2002-2005

Inclusion Criteria:

• Mediastinal lymphoma
• complete response (PET negativity) after frontline treatment

Exclusion Criteria:

• not reported

Baseline characteristics: (HD)

• Age (median):26
• Stage: I-II: 52, III-IV: 5

Recurrence status: not reported

PET followed by CT scan

no control group

• Suspicion of lymphoma relapse based on positive mediastinal PET scanning and histological confir-mation
• Diagnostic accuracy of SUVmax values

Diagnostic accuracy

• Sensitivity: not reported
• Specificity: not reported
• PPV: 0.57%
• NPV: not reported

• PET-positive: 30 pts (27 PET+CT+, 3PET+CT-; 21 HL, 9 NHL), of these, 17 had indeed recurrence
• PET-negative: 104 pts

• Study Duration: not reported
• Follow-up: January 2002 to July 2005
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: not reported
• Other limitations: retrospective cohort

Diagnostic test accuracy single studies

Sensitivität

-

-

-

+¹

-

⊕⊕⊕⊝
moderate 

Spezifität

-

-

-

+¹

-

⊕⊕⊕⊝
moderate 

(Petrausch, Samaras et al. 2010)

Retrospective analysis of hospital records

3

n = 134

Recruitment: 2002-2008

All included patients underwent FDG–PET/CT 1 month after the end of first-line treatment, groups a based on symptoms

Inclusion Criteria:

• HL in complete remission after first-line treatment
• at least one FDG–PET/CT during follow-up

Exclusion Criteria:

not reported

Arm A:

n= 83

asymptomatic patients

Baseline characteristics:

• Age: <45 years: n= 64, >45 years: n= 19
• Gender: male: n= 47, female: n= 36
• Stage: early (IA-IIB): n= 51, advanced (IIIA-IVB): n= 32

Recurrence status: yes: n= 10, no: n= 73

Arm B:

n= 51
symptomatic patients

Baseline characteristics:

• Age: <45 years: n= 42, >45 years: n= 9
• Gender: male: n= 34, female: n= 17
• Stage: early (IA-IIB): n= 29, advanced (IIIA-IVB): n= 22

Recurrence status: yes: n= 32, no: n= 19

• PPV of FDG-PET/CT
• Relapse during follow-up
• Recurrence determined by FDG-PET/CT

Significant risk factors for relapse

• Diagnostic accuracy
• Sensitivity: not reported
• Specificity: not reported
• Positive predictive value: 98%
• Negative predictive value: not reported

• Other outcomes
• Recurrence (as determined by FDG–PET/CT):
• Overall: n= 42/134 (31.3%)
• asymptomatic: n= 10/134 (7.5%),
• symptomatic group: n= 32/134 (23.9%)
• Relapse-free survival
• Mean RFS in patient group with recurrence (n = 42): 26.9 months (4.6–191.5 months)
• Relapse

negative follow-up FDG–PET/CT scan: n= 0

• Study Duration: not reported
• Follow-up: Mean follow-up time of patients without recurrence from the end of first-line treatment until last negative FDG–PET/CT scan (n= 92): 38.72 months (4.8 to 203 months)
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: not reported

Other limitations: retrospective cohort study, not all patients had end-of-treatment PET and a lower than usual coverage. This may indicate referreal based on suspected recurrence

(Zinzani, Stefoni et al. 2009)

Prospective Cohort study

2b

n= 421

n= 160 HL

n= 183 NHL

n= 78 IFNHL

Recruitment: 2002-2007

Inclusion Criteria:

• malignant lymphoma
• complete remission (clinical, laboratory, and diagnostic procedures, including PET and CT scan; therefore, all patients were required to have a baseline negative FDG-PET)

Exclusion Criteria:

• Patients who missed any of the scans were excluded from further considerations
• every time a patient experienced relapse, that patient was excluded from further analysis

NA

NA

• Value of serial FDG-PET in patients with CR

• Diagnostic accuracy:
• Sensitivity: not reported
• Specificity: not reported
• PPV: not reported
• NPV: not reported

• Other outcomes
• Comparison of Clinical, CT Scan, and PET-identified Relapses (HL: n= 160)

• PET Results
• 6 Months: n= 160

true negative: n= 139 (87%)
true positive: n= 14 (9%)
inconclusive PET but negative at follow-up: n= 5 (3%)
inconclusive PET but positive at follow-up: n= 2 (1%)

• 12 Months: n= 144

true negative: n= 124 (86%)
true positive: n= 14 (10%)
inconclusive PET but negative at follow-up: n= 3 (2%)
inconclusive PET but positive at follow-up: n= 3 (2%)

• 18 Months: n= 129

true negative: n= 118 (91%)
true positive: n= 5 (4%)
inconclusive PET but negative at follow-up: n= 3 (2%)
inconclusive PET but positive at follow-up: n= 3 (2%)

• 24 Months: n= 119

true negative: n= 112 (94%)
true positive: n= 3 (3%)
inconclusive PET but negative at follow-up: n= 2 (2%)
inconclusive PET but positive at follow-up: n= 2 (2%)

• 36 Months: n= 115

true negative: n= 111 (97%)
true positive: n= 3 (3%)
inconclusive PET but negative at follow-up: n= 0 (0%)
inconclusive PET but positive at follow-up: n= 1 (1%)

• 48 Months: n= 111

true negative: n= 110 (99%)
true positive: n= 1 (1%)
inconclusive PET but negative at follow-up: n= 0 (0%)
inconclusive PET but positive at follow-up: n= 0 (0%)

• Major decrease in relapse frequency: between 12 and 18 months: 10% to 4%

• Study Duration: October 2002 to September 2007
• Follow-up: HL, mean: 41 months (range: 15 to 60)
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: Partly by BolognAIL
• Other limitations: lack of a valid reference test for PET-

Diagnostic test accuracy single studies

Sensitivität

-

-

+¹

++²

-

⊕⊝⊝⊝
very low 

Spezifität

-

-

+¹

++²

-

⊕⊝⊝⊝
very low 

(Adams and Kwee 2016)

SR

1a

Studies searched from

start date to 12 July 2015 in

Medline

Inclusion criteria:

• Original studies reporting on the value of pretransplant FDG-PET in predicting patient outcome in refractory/relapsed Hodgkin lymphoma treated with salvage therapy, HDT, and autologous SCT

Exclusion criteria:

• not written in English, Spanish, French, German, Italian, or Dutch
• Articles without original patient data, such as reviews, editorials, letters, and conferences abstracts
• Articles with less than 10 patients
• Articles from which the same patient data were used in a more recent article
• Articles in which patients with Hodgkin lymphoma could not be separated from patients with other lymphoma subtypes
• Articles in which patients receiving allogeneic SCT could not be separated from patients receiving autologous SCT
• Articles in which patients undergoing FDG-PET could not be separated from patients who were examined with other imaging techniques
• Articles in which therapy was modified on the basis of the pretransplant FDG-PET result

Main experimental intervention

Prognostic value of pretransplant FDG-PET

Main comparison

Effect of pretansplant FDG-PET adapted therapy

• Prediction of treatment failure by pretransplant FDG-PET
• Effect of FDG-PET adapted therapy

14 studies included in review

Results:

• Prognostic test accuracy:
• Death 2 studies
• Sensitivity: 74.4% (95%CI: 58.8-86.5)
• Specifity: 58% (95%CI: 49.3-66.3)

• Treatment failure (5 studies, progressive, residual, or relapsed disease):
• Sensitivity: 67.2% (95%CI: 58.2-75.3)
• Specifity: 70.7% (95%CI: 64.2-76.5)
• P=0.285, no threshold effect

• Other outcomes:
• 5-year PFS:
• FDG-PET+: ranged between 0 and 52% FDG-PET-: ranged between 55 and 85%

• Effect of FDG-PET adapted therapy:
• FDG-PET negative status after extend lines of salvage therapy: 91% and ±80%
• FDG-PET negative status after standard therapy: 92% and ±80%
• Patients who did not acquire FDG-PET negative status: 46% and ±30%

Descriptive statistics:

patient characteristics

• Age: 11-77
• Gender: male > female
• Stage at relapse: I - IV

Country of origin:

• USA
• Multinational
• Saudi Arabia
• Turkey
• Czech Republic
• Netherlands
• Italy

Overall quality of included studies: moderate

Follow-Up: Range of median follow-up: 20.1-45 months

Randomisation: unclear

ITT: unclear

Blinding: unclear

Funding: “This work was financially supported by an Alpe d’HuZes/

Dutch Cancer Society Bas Mulder Award for T.C.K.”

Heterogeneity:

-Random or fixed effects model: not reported

-no heterogeneity in DORs among these five studies (I2 = 0.0 %)

Gentzler et al. (2014)

(Nieto, Popat et al. 2013)

Cocorocchio et al. [23] (2013)

Akhtar et al. [24] (2013)

(Sucak, Ozkurt et al. 2011)

Smeltzer et al. [26] (2011)

(Mocikova, Pytlik et al. 2011)

Arai et al. [28] (2010)

(Castagna, Bramanti et al. 2009)

(Jabbour, Hosing et al. 2007)

(Schot, Zijlstra et al. 2007)

(Moskowitz, Schoder et al. 2015)

(Devillier, Coso et al. 2012)

(Moskowitz, Matasar et al. 2012)

Referenz/ Studientyp

Untersuchte Population

Intervention

Kontrolle

untersuchte Endpunkte

Hauptergebnisse

methodische Bemerkungen

(Brockelmann, Muller et al. 2017)multinational prognostic multivariable modeling study

n = 656 (remained for the score development)

Recruitment: 1993-2013

Inclusion Criteria:

• relapsed/refractory HL undergoing an ASCT
• patients treated in the trials HD10-12, HD13-HD15, HL HDR1 arm B, HDR2, LYSA H96
• validation sample US at MSKCC (n=318)
• validation sample Denmark (n=71)

Exclusion Criteria:

• not reported

n = 656 dev.

n = 389 val.

Baseline characteristics:

• Age: <45: 1036, >=45: 276
• Stage: stage I-2 at relapse: 662, III/IV at relapse:680
• 494 female, 818 male
• Recurrence status:

Not applicable

• Identification of prognostic factors to predict PFS
• prognostic score for PFS after ASCT

 PFS reported per significant risk factor

• OS: score developed for PFS

0: -

1: 1.81 (1.03, 3.18)

2: 2.70 (1.55-4.72)

3-5: 4.63 (2.67-8.02)

• PFS (at 5 years) per RF:
• Stage IV

Risk-neg: 66.9%

Risk-pos: 48.1%

• TTR <=3 months

Risk-neg: 63.7%

Risk-pos: 45.6%

• ECOG >=1

Risk-neg: 65.8%

Risk-pos: 55.4%

• Bulk >=5cm

Risk-neg: 66.9%

Risk-pos: 50.2%

• Non-response to salvage

Risk-neg: 65.9%

Risk-pos: 46.8%

• Per risk score (5-y PFS, HR compared to group 0, 95% CI):

0: 76.8%

1: 67.9% (HR 1.76; 1.10-2.82)

2: 56.7% (HR 2.67; 1.67-4.28)

3-5: 34.8% (HR 4.80; 2.98-7.72)

• TRM: not reported

• AE: not reported

• QoL: not reported
• Other:

• Study Duration: 1993-2013
• Follow-up: median follow-up after ASCT 60 months for development and 59 months for validation
• ITT: no
• Randomisation: no
• Blinding: depends on RCT data, not blinded for aim of this analysis (prognostic, preferred design prospective cohort)
• Funding: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA
• Other limitations: retrospective use of RCT data

Diagnostic test accuracy meta-analysis

Sensitivität

-

-

-

+¹

-

⊕⊕⊕⊝
moderate 

Spezifität

-

-

-

+¹

-

⊕⊕⊕⊝
moderate 

(Devillier, Coso et al. 2012)

Retrospective analysis

3b

n = 111

Recruitment: 2002-2010

Reinduction: DHAP, IVA or ICE (Viviani , Zinzani  et al.) or IGEV (Italy)

Conditioning regimen: BEAM or BEAM+NCBV (Viviani , Zinzani  et al.) or BEAM or HD melphalan for single ASCT vs. HD melphalan+BEAM for double ASCT (Italy)

Inclusion Criteria:

• classical HL histology proven by biopsy
• treatment sensitive relapsed and/or treatment refractory classical HL
• underwent high-dose therapy followed by ASCT
• complete or partial response before ASCT
• serologically negative for human immunodeficiency virus

Exclusion Criteria:

• Patients who did not achieve at least a partial response after salvage therapy and before ASCT

Baseline characteristics:

• Age: median age at ASCT: 33 (17-71)
• Stage (Ann Arbor): I-II: 50 (46%), III-IV: 58 (54%), unknown: 3
• Recurrence status: refractory: 32%, relapse: 68%

Gender: male: 65 (59%)

Tandem ASCT

Arm D:

n = 64
tandem ASCT

Baseline characteristics:

• Age: median age at ASCT: 33 (20-65)
• Recurrence status: refractory 25%, relapse 75%
• Gender: male:41 (64%), female: 23 (36%)

Single ASCT

Arm C:

n = 47
Single ASCT

Baseline characteristics:

• Age: median age at ASCT: 34 (17-71)
• Recurrence status: refractory 40%, relapse 60%
• Gender: male: 24 (51%), female: 23 (49%)

• OS
• PFS

Comparison single vs. tandem ASCT:

• OS (at 5 years):

Overall: 81%

Single: 75%

Tandem: 84% (p=.144)

Pre-ASCT-PET-neg. (5y.)

Single: 84%

Tandem: 93%, p=.046

Pre-ASCT-PET-pos. (5y.)

Single: 47%

Tandem: 58%, p=.838

• PFS (at 5 years):

Overall: 64%

Single:48%

Tandem: 74% p=.002

Pre-ASCT-PET-neg.

Single: 75%

Tandem: 84%, p=.0.05

Pre-ASCT-PET-pos.

Single: 0%

Tandem: 43%, p=.034

• TRM: not reported

• AE: not reported

• QoL: not reported

• Study Duration: not reported
• Follow-up: Median follow-up after first ASCT: 36 months
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: not reported

Other limitations: retrospective analysis, choice for single or tandem ASCT was made based on risk factors (SFGM, interval from end of first-line therapy to relapse < 12 months; Ann-Arbor stage III or IV at relapse; and relapse in a previously irradiated field)

(Moskowitz, Matasar et al. 2012)intent-to-treat clinical

trial

NCT00255723

n = 97

Recruitment: 2004-2012

Inclusion Criteria:

• transplant-eligible patients with relapsed or refractory HL
• diagnosis of classic HL confirmed by the Department of Hematopathology at MSKCC
• either a doxorubicin- or nitrogen mustard–containing front-line regimen
• FDG-PET–positive disease
• cardiac ejection fraction of greater than 45%
• adjusted diffusing capacity > 50% on pulmonary function testing
• serum creatinine ≤ 1.5 mg/dL or, if > 1.5 mg/dL, then the measured 12- or 24-hour creatinine clearance must be more than 60 mL/minute
• neutrophil count >1000/µL, platelets >50000/µL, total bilirubin ≤ 2.0 mg/dL in the absence of a history of Gilbert disease
• hepatitis C virus, hepatitis B virus, and HIV I and II negative

Exclusion Criteria:

• Patients with all 3 risk factors (remission duration < 1 year, B symptoms, and extranodal sites of disease [ENS])

Baseline characteristics:

• Age: median: 35.3 (18.7-71.5)
• Stage: not reported
• Recurrence status: R|R

Gender: female: 56, male: 41

Arm A:
n = 56

0 or 1 risk factor

Standard ICE x1, augmented ICE x1

Baseline characteristics:

• Age: median: 36.2 (18.7-64.3)
• Stage: not reported
• Recurrence status: not reported

Gender: female: 35, male: 21

Arm B:
n = 41

2 risk factors

Augmented ICE x2

Baseline characteristics:

• Age: median: 33.1 (21.3-71.5)
• Stage: not reported
• Recurrence status: not reported

Gender: female: 21, male: 20

• Not reported

• OS (at median follow-up time):

Overall: 80%

Transplanted pts: 88%

• EFS (at median follow-up time):

Overall: 70%

Transplanted patients: 79%

There were no differences in outcome based on transplant conditioning regimen (P = .141)

• AE: Grade 3 or 4 toxicity
• Febrile neutropenia:

ICE (56 courses): 3
aICE (138 courses): 22
GVD (132 courses): 0
TLI (56 patients): 0
CBV (29 patients): 0

• Catheter-related infection/thrombosis:

ICE (56 courses): 1
aICE (138 courses): 8
GVD (132 courses): 0
TLI (56 patients): 0
CBV (29 patients): 0

• The following had a maximum of 2 cases per treatment, see table 2
• Acute renal failure
• Clostridium difficile
• Viral meningitis
• Pneumonia
• Pulmonary embolism
• Cellulitis
• Anaphylaxis
• Radiation esophagitis
• Depression
• Radiation pneumonitis
• Disseminated zoster
• Autologous graft vs host
• Pericardial tamponade
• Multisystem organ failure
• Myelodysplasia:

• QoL: not reported

• Other outcomes:
• FDG-PET- scan after ICE/aICE: n= 58 (60%)

• Study Duration: 2004-2012
• Follow-up: median: 51 months (range: 16-86 months)
• ITT: yes
• Randomisation: no
• Blinding: no
• Funding: Memorial Sloan Kettering Cancer Center
• National Cancer Institute (Moore, Unger et al.)
• Other limitations: "treatment adaptation" based on risk factors, therefore no direct comparison of groups

Retrospective Studien, Bröckelmann prognostisch

Gesamtüberleben

-

-

-

-

-

⊕⊕⊝⊝
low 

Progressionsfreies Überleben

⊕⊕⊝⊝
low

Behandlungsbedingte Mortalität

Langzeitnebenwirkungen

⊕⊕⊝⊝
low

Lebensqualität

(Palmer, Goggins et al. 2011)

Retrospective analysis

3

n = 90

HL: n = 30
NHL: n= 60

Recruitment: 1996-2007

Inclusion Criteria:

• Pts who underwent either auto-SCT for relapsed or refractory HL or aggressive NHL (including all NHL except grade I–II follicular lymphoma)
• Patients who had either a PET scan following salvage chemotherapy within 14 weeks of transplantation (prePET), and/or a PET scan 6–14 weeks following transplantation (post-PET)

Exclusion Criteria:

• Not reported

Baseline characteristics:

• Age: mean: 46.7 (18-78)
• Stage: not reported
• Recurrence status: not reported

PET before and after ASCT

Predictive value of pre-PET and post-PET scans

• Diagnostic test accuracy
• Sensitivity: not reported
• Specificity: not reported

• Other related:

Pre-PET+: n=26/65

Post-PET+: n=20/68

Disease relapse: n= 34 (37%)

Died from disease progression: n= 25 (27%) 

Pre-PET scan negativity did correlate with prolonged PFS 2.91 (1.25– 6.77) P=0.013, but not with OS.

Post-PET scan negativity did not correlate with prolonged PFS or OS.

• Other outcomes:
• OS: median: 5.1 years
• PFS: median: 4.6 years
• AE: not reported
• QoL: not reported

• Study Duration: not reported
• Follow-up: Median: 3.3 years (range: 0.13–12.0)
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: not reported
• Other limitations: retrospective cohort, patients with missing information excluded from the analysis, small sample size for HL

(Sucak, Ozkurt et al. 2011)

Retrospective analysis

3

n = 43

Recruitment: 2003-2010

Inclusion Criteria:

• relapsed/ refractory HL

Exclusion Criteria:

• not reported

Baseline characteristics:

• Age: median: 30 (16-61)
• Stage: II: 13 (30,2%), III: 11 ( 25,6%), IV: 19 (44,2%)
• Recurrence status: not reported
• Gender: male: n= 34, female: n= 9

A: negative PET/CT before and after ASCT

n= 17

B: positive PET/CT before and negative after ASCT
n= 13

C: positive PET/CT before and after ASCT

n= 13

• Predictive value of FDG-PET/CT following salvage ChT within 6 weeks of ASCT and at first month after ASCT
• OS
• PFS

• Diagnostic test accuracy
• Sensitivity: not reported
• Specificity: not reported
• FDG-PET positivity :

before ASCT: n= 26

after ASCT: n= 13  

• Other outcomes
• OS (at time of last follow-up):

Overall: 82.1%

PET- prior ASCT: 94.1%

PET+ prior ASCT: 74.5%, p>0.05)

• PET- after ASCT: 95.8%
• PET+ after ASCT: 49.8%
• (p=0.0002)

• Group combinations:

Arm A: 100%,

Arm B: 91.6% (median values not reached), not statistically significant,

Arm C: 54% (median values not reached) (p=0.002) 

• PFS (at last time of follow-up):

Overall: 50.9%

PET- prior ASCT: 70.6%,

PET- prior ASCT: (37.6%, p=0.008)

PET- after ASCT: 72.9%

PET- after ASCT: 0%
(p<0.0001)

• Group combinations:

Arm A: 75%,

Arm B: 69.8% (median values not reached), not statistically significant,

Arm C: 0% (median 4 months) (p<0.001)

• no transplantation-related mortality

• last follow-up:
• alive: n= 36 (83.7%)
• death: n= 7 (16.3%) due to progressive disease
• Disease progression or relapse: n= 19 (44.2%), median: 6 (0–34.5) months after ASCT

• Study Duration: November 2003-January 2010
• Follow-up: median: 21.5 months (range: 6–64.5)
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: not reported 
• Other limitations: retrospective data collection

Diagnostic test accuracy studies

Sensitivität

-

++¹

-

+²

-

⊕⊝⊝⊝
very low 

Spezifität

-

++¹

-

+²

-

⊕⊝⊝⊝
very low

(Rancea, Monsef et al. 2013)

SR

1a

RCTs searched in

• CENTRAL (2013, Issue 1)
• MEDLINE (1946 to January 2013)
• conference proceedings of annual meeting: ASH;  ASCO; (EHA)
• electronic databases of ongoing trials: metaRegister of controlled trials; Register of the US National Institutes of Health; International Conference on Malignant Lymphoma (ICML); International Symposium on Hodgkin Lymphoma

publications: n=14, pts: n=398

Inclusion criteria:

• Pts. With primary refractory or first relapse histologically confirmed HL without restrictions on age, gender or ethnicity
• full-text publications 

Exclusion criteria:

• less than 80% of patients were relapsed or had refractory HL

A: Any HDCT followed by ASCT

B: Different chemotherapy regimens without ASCT 

C: Different HDCT regimens (sequential or conventional; SHDCT) before ASCT

Primary:

• OS

• PFS
• ORR, CRR, PRR
• TRM
• AEs

3 studies with 398 patients included in review

• OS (3-year OS)
• HDCT + ASCT vs. other chemotherapy:

HR 0.67 (95% CI: 0.41-1.07; p=0.1; 157 pts.), favouring HDCT + ASCT

• HDCT + ASCT vs. SHDCT + ASCT:

no difference: HR 0.93 (95% CI: 0.5-1.74; p=0.816; 241 pts.)

HDCT+ASCT: 87%

SHDCT+ASCT:  80%

• PFS (3-year PFS)
• HDCT + ASCT vs. other chemotherapy:

HR 0.55 (95% CI: 0.35-0.86; p=0.009; 157 pts.), favouring HDCT + ASCT

• HDCT + ASCT vs. SHDCT + ASCT:

HDCT+ASCT: 72%

SHDCT+ASCT:  67%

• TRM
• HDCT + ASCT vs. other chemotherapy:

RR 0.61; 95% CI 0.16 to 2.22; P value = 0.45, 157 patients, moderate quality of evidence)

• HDCT + ASCT vs. SHDCT + ASCT:

SHDCT: 7 deaths (after prephase), 2 after additional salvage,41due to infection

HDCT: 1 death (after prephase), 3 after additional salvage, 1due to infection

• Safety/AEs:
• HDCT + ASCT vs. other chemotherapy reported in one trial only, did not differ statistically significant between the treatment arms
• HDCT + ASCT vs. SHDCT + ASCT:

The SHDCT arm resulted in higher toxicity compared with the HDCT arm

• QoL: not reported

• Descriptive statistics: patient characteristics
• Age: 18-57
• Gender: male > female
• Stage of disease: I – IV B

Country of origin:

• Czech Republic
• Norway
• Sweden
• Finland,
• Germany
• Switzerland
• Italy
• UK
• Belgium
• Croatia
• Denmark
• Poland
• Portugal

Overall quality of included studies: moderate

Follow-Up: Median follow-up: BNLI trial: 34 months, HDR1: 83 months, HDR2: 42 months

Randomisation: yes

ITT: Partly, “Two of the three trials […] stated that they had performed analyses according to the ITT principle”

Blinding: no

Funding: Internal sources of support: Dept. I of Internal Medicine, University Hospital of Cologne, Cologne, Germany

Heterogeneity:

-Fixed effects model

-I² =0.0% (OS),I² =0.0% (ORR), I² =48% (CRR), I² =68% (TRM), I² =0.0% (PFS)

(Linch, Winfield et al. 1993)-BNLI

(Schmitz, Pfistner et al. 2002)-HDR1

(Josting, Muller et al. 2010)-HDR2

Abbreviations: HDCT  = high-dose chemotherapy; ASCT = autologous stem cell transplantation

Systematic review

Gesamtüberleben

-

-

-

+¹

-

⊕⊕⊕⊝
moderate 

Progressionsfreies Überleben

-

-

-

+¹

-

⊕⊕⊕⊝
moderate 

Behandlungsbedingte Mortalität

-

-

-

+²

-

⊕⊕⊝⊝
low 

Langzeitnebenwirkungen

Not reported

Lebensqualität

Not reported

RCT, prognostic factor analysis and score

Gesamtüberleben

-

-

-

+¹

-

⊕⊕⊝⊝
low 

Progressionsfreies Überleben

-

-

-

+¹

-

⊕⊕⊝⊝
low 

Behandlungsbedingte Mortalität

-

-

-

+¹

-

⊕⊕⊝⊝
low 

Langzeitnebenwirkungen

Not reported

Lebensqualität

Not reported

(Josting, Rudolph et al. 2002)Data from multicenter

phase II study

n = 102

Inclusion Criteria:

• 18-65 years
• biopsy-proven relapsed or refractory HD
• adequate organ function (creatinine clearance >60 ml/min, serum transaminases < three times the normal value and bilirubin <2 mg/dl), left ventricular ejection fraction >0.45, forced expiratory volume in the first second or diffusion capacity of carbon monoxide >60% of predicted, ECOG performance status ≤2, and white blood cell count ≤3500/μl, haemoglobin level ≥8 g/dl, platelets ≥100 000/μl
• test negative for antibody against human immunodeficiency virus and free of active infection

Exclusion Criteria:

• not reported

n = 102 

two cycles of DHAP (dexamethasone

40 mg i.v. day 1–4, cisplatin 100 mg/m2 i.v. as 24-h continuous infusion

day 1, and cytarabine 2 g/m2 i.v. over 3 h 12q day 2) as salvage treatment in order to

reduce tumor volume before HDCT

Baseline characteristics:

• Age: median: 34 (range: 18-64)
• Stage (at relapse):

I: n= 12 (12%), II: n= 27 (26%), III: n= 25 (25%), IV: n= 38 (37%)

• Recurrence status: Late relapse: n= 44 (42%), Early relapse: n= 29 (29%), Progressive disease: n= 17 (16%), Multiple relapse: n= 12 (13%)
• Gender: male: n= 57 (56%), female: n= 45 (44%)

No control group

• efficacy and toxicity of DHAP

• OS: not reported

• PFS: not reported

• TRM: not reported

• AE - Toxicity:
• Leukocytopenia: grade 3: n= 50 (25%) grade 4: n= 86 (43%)
• Thrombocytopenia: grade 3: n= 42 (21%) grade 4: n= 97 (48%)
• Anemia: grade 3: n= 33 (16%) grade 4: n= 1 (0.5%)
• Mucositis: grade 3: n= 0 (0%) grade 4: n= 0 (0%)
• Infection: grade 3: n= 2 (1%) grade 4: n= 0 (0%)
• Nausea/vomiting: grade 3: n= 49 (24%) grade 4: n= 3 (2%)
• Renal: grade 3: n= 0 (0%) grade 4: n= 0 (0%)
• Neurotoxicity: grade 3: n= 1 (0.5%) grade 4: n= 0 (0%)
• Ototoxicity: grade 3: n= 2 (1%) grade 4: n= 0 (0%)

 QoL: not reported

• Other outcomes:
• Complete response:

All patients: n= 21 (21%)
Late relapse: n= 11 (26%)
early relapse: n= 5 (17%)
multiple relapse: n= 3 (23%)
progressive disease: n= 2 (12%)

• Partial response:

All patients: n= 68 (67%)
late relapse: n= 28 (65%)
early relapse: n= 22 (76%)
multiple relapse: n= 9 (69%)
progressive disease: n= 9 (53%)

• Failure:

all patients: n= 13 (12%)
late relapse: n= 4 (9%)
early relapse: n= 2 (7)
multiple relapse: n= 1 (8%)
progressive disease: n= 6 (35%)

Study Duration: not reported

Follow-up: median: 18 months

ITT: no

Randomisation: no

Blinding: no

Funding: not reported

Other limitations: retrospective data, no control group

Prospektive Studie

Gesamtüberleben

Not reported

Progressionsfreies Überleben

-

-

+¹

-

-

⊕⊝⊝⊝
very low 

Behandlungsbedingte Mortalität²

-

-

-

-

-

⊕⊕⊝⊝
low 

Nebenwirkungen

-

-

-

-

-

⊕⊕⊝⊝
low 

Lebensqualität

Not reported

(Crump, Kuruvilla et al. 2014)

RCT

NCIC-CTG LY.12

n = 619

Recruitment: 2003-2011

Inclusion Criteria:

• >18 years old
• aggressive-histology lymphoma according to the WHO classification
• measurable disease by CT scan or physical examination
• ECOG 0-3
• acceptable hematologic and biochemical parameters 

Exclusion Criteria:

• previously treated with cisplatin, cytarabine, or gemcitabine
• CNS involvement with lymphoma
• history of HIV infection
• or a medical condition that would interfere with the safe delivery of the protocol chemotherapy.

Baseline characteristics:

• Age: median 55 years
• Stage: III or IV
• Recurrence status:R&R
• DLBCL: 71, 15% with lymphoma transformed from indolent B-cell histology, 8% T-cell or anaplastic large-cell lymphoma

n= 310

gemcitabine, dexamethasone, and cisplatin (GDP)

n = 309 

dexamethasone, highdose

cytarabine, and cisplatin (DHAP)

• Response to treatment
• Transplantation rate
• Stem cell mobilisation
• Event-free survival
• Overall survival
• QoL (FACT-Total scores)
• Hospitalisation
• Platelet infusions

• Overall survival (at 4 years)

HR 1.03 (95% CI 0.83 to 1.28, p = .78)

• Event-free survival (at 4 years)

HR 0.99 (95% CI 0.82 to 1.21, p=0.95) 

• Adverse events
• Any G3|4 during cycle 1&2:

GDP: 47%

DHAP: 61%, P<.001>

• Febrile neutropenia

GDP: 9%

DHAP: 23%, P<.001>

• Thrombosis

GDP: 6%

DHAP: 6%, P >.05

• Fatigue

GDP: 10%

DHAP: 9%

P >.05

• Nausea

GDP: 4%

DHAP: 8%, P=.04

• Vomiting

GDP: 7%

DHAP: 7%, P >.05

• Infection

GDP: 7%

DHAP: 7%, P >.05

• Syncope

GDP: 2%

DHAP: 5%, P<.001>

• Quality of Life (FACT-Total scores) At midpoint of C2
• Improved clinically meaningful change score

GDP: 18%

DHAP: 11%

• Worse clinically meaningful change score

DGP: 33%

DHAP: 41%

• Other outcomes:
• Response rate (CR)

GDP: 45.1%

DHAP: 44.1%

P=.84, noninferiority of GDP compared with DHAP

• Transplantation rate

GDP: 51.0%

DHAP: 48.9%

• Stem cell mobilisation

GDP: 87.9.1%

DHAP: 82.2%, P = .14

• Study Duration: 2003-2011
• Follow-up: median follow-up 53 months
• ITT: yes
• Randomisation: yes
• Blinding: not reported
• Funding: Supported by Grants No. 015469 and 021039 from the Canadian Cancer Society Research Institute, and by Roche Canada and Eli Lilly Canada.
• Other limitations: non-HL patients

(Moccia, Hitz et al. 2017)

Retrospective

n = 235, 152 DLBCL, 83 HL

Recruitment: 2002-2010

Inclusion Criteria:

• >16 years old
• all sequential adult patients (_16 years of age) treated with GDP for relapsed/refractory DLBCL or HL
• confirmed diagnosis of DLBCL or HL based on central review of a biopsy performed at diagnosis or upon relapse

Exclusion Criteria:

• not reported

gemcitabine, dexamethasone, and cisplatin (GDP)

Baseline characteristics:

• median age: 30 (14–72)
• Stage: I/II: 41%, III/IV: 59%
• Recurrence status:R&R

No comparator

• Overall survival
• Progression-free survival
• Overall respone rate
• transplantation

• Overall survival (at 2 years)

85% (95% CI 76.2%–93.8%) 

• Progression-free survival (at 2 years)

58% (95% CI 46.0%–70.0%)

• Adverse events

Not retrievable, retrospective study

• QoL: not reported 

• Other outcomes
• Overall response rate: 71%

• Cumulative hospitalisation rate: 7%

• Transplantation rate: 96%

• Study Duration: 
• Follow-up: median follow-up 30 months (range 0-86 months)
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: not reported.
• Other limitations: retrospective study, database retrieval, limited information available

(Santoro, Magagnoli et al. 2007)Cohort study

2b

n = 91

Inclusion Criteria:

• Pts with relapsed/ refractory HL after chemotherapy with or without radiotherapy
• WHO performance status ≤2
• adequate pulmonary, cardiac, renal, and liver function

Exclusion Criteria:

• Human immunodeficiency virus-positive

Baseline characteristics:

• Age: median: 30 (range: 17-59)
•  Stage:
• Recurrence status:
• Gender: male: n= 52, female: n= 39

Salvage regime: IGEV (ifosfamide 2000 mg/m2 on days 1 to 4 as a 2-hour infusion/day with 2,000 mL saline solution hyperhydration, MESNA 2600 mg/m2 on days 1 to 4, gemcitabine 800 mg/m2 on

days 1 and 4, vinorelbine 20 mg/m2 on day 1, and prednisolone

100 mg on days 1 to 4, of each 3-week course)

• Response
• Toxicity
• Stem cell mobilization

• OS (at 3 years): 70.03%,

• PFS (at 3-years): 52.98%

• TRM: none documented

• AE:

Toxicity (Number of cycles: 313 (100%)), of these:

• delayed cycles: 13 (4.2 %)
• reduced cycles: 27 (8.6%)
• Infection (documented): n= 11 (3.5%)
• Treatment-related death: n= 0 (0%)
• Neutropenia (grade 3/4): n= 71/18 (22.7/5.7%)
• Thrombocytopenia (grade 3/4): n= 48/15 (15.3/4.8%)
• Anemia (grade 3/4): n= 52/5 (16.6/1.6%)
• Platelet transfusion: n= 15 (4.8%)
• Red blood cell transfusion: n= 25 (8.0%)
• Mucositis (grade 3/4): n= 6/1 (1.9/0.3%)
• Nausea/vomiting (grade 3/4): n= 10/0 (3.2/0%)
• Cystitis (grade 3/4): n= 1 (0.3/0%)
• Neurological (grade 3/4): n= 0 (0%)
• Hepatic (grade 3/4): n= 0 (0%)
• Cardiac (grade 3/4): n= 0 (0%)
• Renal (grade 3/4): n= 0 (0%)

• QoL: not reported

• Other outcomes:
• Response to IGEV
• CR: n= 49 (53.8%)
• PR: n= 25 (27.5%)
• ORR: n= 74 (81.3%)
• proceeded to:

single high-dose chemotherapy with PBSC Support: n= 29

tandem high-dose chemotherapy with PBSC Support: n= 35

non-myeloablative allogeneic transplants: n= 5

refused high-dose therapy: n= 5

• Study Duration: November 1997 to September 2005
• Follow-up: not reported
• ITT: yes
• Randomisation: no
• Blinding: no
• Funding: Yes, supported, but not reported
• Other limitations: no control group

IGEV

Prospektive Studie

Gesamtüberleben

-

-

-

-

-

⊕⊕⊝⊝
low 

Progressionsfreies Überleben

-

-

+¹

-

-

⊕⊝⊝⊝
very low 

Behandlungsbedingte Mortalität²

-

-

+³

-

-

⊕⊝⊝⊝
very low 

Nebenwirkungen

-

-

-

-

-

⊕⊕⊝⊝
low 

Lebensqualität

Not reported

GDP,

RCT³ & retrospective Studie

Gesamtüberleben

-

-

++³

⊕⊕⊝⊝
low 

Progressionsfreies Überleben

-⁴

-

++³

-

-

⊕⊝⊝⊝
very low 

Behandlungsbedingte Mortalität²

Not reported 

Nebenwirkungen

-⁴

-

++³

-

-

⊕⊝⊝⊝
very low 

Lebensqualität

-⁴

-

++³

-

-

⊕⊝⊝⊝
very low 

Referenz/ Studientyp

Untersuchte Population

Intervention

Kontrolle

untersuchte Endpunkte

Hauptergebnisse

methodische Bemerkungen

(Josting, Muller et al. 2010)

RCT

1b

n = 241

Inclusion Criteria:

• histological confirmed relapsed HL
• patients with multiple relapses and no prior HDCT
• 18 to 60 years
• Eastern Cooperative Oncology Group performance status ≤ 2
• primary multiagent chemotherapy

Exclusion Criteria:

• concurrent malignancy other than basal-cell carcinoma of the skin or cervical intraepithelial neoplasia
• unstable angina, congestive heart failure), poorly controlled diabetes, chronic pulmonary disease, cerebral disorders, coronary angioplasty or myocardial infarction within the past 6 month
• active infection, HIV positivity, creatinine clearance lower than 60 mL/min
• pregnant or lactating women
• concurrent treatment with investigational drugs

Arm 1:

n = 119

BEAM

Baseline characteristics:

• Age: mean 35,3
• Stage: (Ann Arbor) I A: 17, I B: 3, II A: 29, II B: 8, III A: 21, III B: 11, IV A: 17, IV B: 13
• Recurrence status: Early: 27, Late: 74, Mult: 18

Arm 2:

n = 122

sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM

Baseline characteristics:

• Age: mean 35,4
• Stage: (Ann Arbor) I A: 17, I B: 2, II A: 38, II B: 5, III A: 15, III B: 14, IV A: 17, IV B: 13
• Recurrence status: Early: 34, Late: 68, Mult: 19

• FFTF
• CR
• PFS
• OS
• TOT grade 3/4

• OS: 87% vs. 80% (P=0.816)
• PFS: 72% vs. 67% (P=0.505)
• AE: (Arm 1, Arm 2)
• Anemia: 59, 77
• Thrombopenia: 100, 102
• Leukopenia: 98, 98
• Infection: 37, 53
• Nausea: 40, 50
• Mucositis: 64, 74
• Respiratory: 7, 11
• QoL: not reported
• Other:
• FFTF
• 71% vs. 65% (P=0.557)
• CR:
• 83% vs 84%
• TOT
• 86% vs 98%
• anemia: 52% vs. 70%
• thrombopenia: 89% vs. 93%
• leukopenia: 87% vs. 89%