12. Qualitätsindikatoren – 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 

RCT

Gesamtüberleben

-

-

+¹

-

-

⊕⊕⊕⊝ moderate

Progressionsfreies Überleben

-

-

+¹

-

-

⊕⊕⊕⊝ moderate

Behandlungsbedingte Mortalität

-

-

-

++²

-

⊕⊕⊝⊝ low 

Langzeitnebenwirkungen (Sekundärneoplasien)

-

-

-

++²

-

⊕⊕⊝⊝ low 

Lebensqualität

Not reported 

(Borchmann, Goergen et al. 2018)

Randomised, open-label, multicentre phase 3 trial (HD18 trial)

n = 1964 (2101 enrolled)

Inclusion Criteria:

• newly diagnosed advanced stage HL patients with Ann-Arbor stage IIB (+ large mediastinal mass or extranodal lesions), III or IV
• ECOG performance status of 2 or lower
• age 18–60 years
• HIV negativity
• freedom from concurrent disease

Exclusion Criteria:

not reported

Arm A:

n = 217

PET-positive pts., 8 cycles of R-eBEACOPP (8×R-Besc group) and PET-guided radiotherapy

Baseline characteristics:

• Age: median: 29
• Stage: (Ann Arbor) IIA: 1, IIB: 54, IIIA: 29, IIIB: 51, IVA: 26, IVB: 56
• Recurrence status: not reported

Arm B:
n = 501
PET-negative pts., 4 cycles of eBEACOPP (4×Besc group) and PET-guided radiotherapy

Baseline characteristics:

• Age: median: 33
• Stage: (Ann Arbor IIB: 42, IIIA: 156, IIIB: 122, IVA: 60, IVB: 121

Recurrence status: not reported

Arm C:

n = 723
PET-positive pts., 8 cycles of eBEACOPP (8× Besc+ group, n = 217), 6 cycles of eBEACOPP after amendment in 2011 (6x Besc+ group, n = 506), and PET-guided radiotherapy

Baseline characteristics:

8x Besc+

• Age: median. 30
• Stage: (Ann Arbor) IIB: 49, IIIA: 41, IIIB: 58, IVA: 20, IVB: 49
• Recurrence status: not reported

Baseline characteristics:

6x Besc+

• Age: median. 31
• Stage: (Ann Arbor) IIB: 96, IIIA: 93, IIIB: 118, IVA: 63, IVB: 136
• Recurrence status: not reported

Arm D:

n = 504

PET-negative pts., 8 cycles of eBEACOPP (8× Besc- group), 6 cycles of eBEACOPP (6x Besc- group) after amendment in 2011, and PET-guided radiotherapy

Baseline characteristics:

• Age: median: 32
• Stage: (Ann Arbor) IIB: 40, IIIA: 156, IIIB: 131, IVA: 59, IVB: 118

Recurrence status: not reported

• OS
• PFS
• Superiority or non-inferiority of treatment

• OS: 5-year OS

Arm A: 93.9%
Arm B: 97.7%
Arm C: 96.4%
Arm D: 95.4%

• PFS: 5-year PFS

Arm A: 88.1%
Arm B: 92.2%
Arm C: 89.7%
Arm D: 90.8%

• Second malignancies
• Acute myeloid leukaemia or myelodysplastic syndrome: Arm A: 4/217 

Arm B: 2/501
Arm C: 5/217
Arm D: 8/504

• Non-Hodgkin lymphoma: 

Arm A: 2/217
Arm B: 8/501
Arm C: 3/217
Arm D: 5/504

• Solid tumour: 

Arm A: 8/217
Arm B: 3/501
Arm C: 2/217
Arm D: 5/504

• Any event: 

Arm A: 8/217
Arm B: 13/501
Arm C: 10/217
Arm D: 18/504

• 5-year cumulative incidence estimate:

Arm A: 3.5%
Arm B: 3.3%
Arm C: 4.0%
Arm D: 3.8% 

• AE: Toxicity
• Anaemia: 

Arm B: 195/501,
Arm D 8xBesc: 164/288,
Arm D 6xBesc: 110/216

• Thrombopenia: 

Arm B: 286/501,
Arm D 8xBesc: 212/288,
Arm D 6xBesc: 150/216

• Leukopenia: 

Arm B: 438/501,
Arm D 8xBesc: 268/288,
Arm D 6xBesc: 199/216

• Anaemia, thromobopenia or leukopenia: 

Arm B: 447/501,
Arm D 8xBesc: 274/288,
Arm D 6xBesc: 202/216

• Infection: 

Arm B: 40/501,
Arm D 8xBesc: 50/288,
Arm D 6xBesc: 25/216

• Nausea or vomiting: 

Arm B: 32/501,
Arm D 8xBesc: 31/288,
Arm D 6xBesc: 18/216

• Mucositis: 

Arm B: 28/501,
Arm D 8xBesc: 26/288,
Arm D 6xBesc: 13/216

• Gastrointestinal tract disorders: 

Arm B: 11/501,
Arm D 8xBesc: 15/288,
Arm D 6xBesc: 14/216

• Respiratory tract disorders: 

Arm B: 10/501,
Arm D 8xBesc: 16/288,
Arm D 6xBesc: 4/216

• Nervous system disorders: 

Arm B: 17/501,
Arm D 8xBesc: 37/288,
Arm D 6xBesc: 15/216

• Any organ toxicity: 

Arm B: 38/501,
Arm D 8xBesc: 62/288,
Arm D 6xBesc: 29/216

• Any toxicity: 

Arm B: 455/501,
Arm D 8xBesc: 280/288,
Arm D 6xBesc: 205/216

• Anaemia, thrombopenia or infection of CTCAE grade IV: 

Arm B: 187/501,
Arm D 8xBesc: 169/288,
Arm D 6xBesc: 115/216

• Treatment-related morbidity: Arm B: 204/501, Arm D 8xBesc: 189/288, Arm D 6xBesc: 132/216
• Occurrence of febrile neutropenia: 

Arm B: 109/501,
Arm D 8xBesc: 96/288,
Arm D 6xBesc: 49/216

• QoL: not reported

• Study Duration: 6 years
• Follow-up: median follow up 52 months for disease, 53 months for survival
• ITT: yes
• Randomisation: yes
• Blinding: no
• Funding: Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG
• Other limitations: none identified

(Engert, Goergen et al. 2017)

http://dx.doi.org/10.1097/HS9.0000000000000005

HD15

Follow-up von Engert 2012, HD15

updated follow-up information was available for 89%

• Survival: Median follow-up: 112 months
• Disease Status: Median follow-up:102 months

• OS (10-year OS):

8xeBEACOPP: 88% (97.5% CI 85%–91%)
6x eBEACOPP: 90% (88%–93%) 8xBEACOPP-14: 92% (89%–94%)
significant superiority of 6xeBEACOPP over 8xeBEACOPP (HR 0.7, 97.5% CI 0.5–0.999, P=0.0245); trend toward superiority of 8xBEACOPP-14 over 8xeBEACOPP (HR 0.7, 97.5% CI 0.5 to 1.04, P=0.05)

• PFS (10-year PFS):

8xeBEACOPP: 81% (97.5% CI 77%–85%),
6xeBEACOPP: 84% (80%–87%)
8xBEACOPP-14: 84% (80%–87%)
longer follow-up: HR (97.5% CI):
6xeBEACOPP: 0.7 (0.5–1.01) 
8xBEACOPP-14: 0.9 (0.7–1.2), versus 8xeBEACOPP, and both excluded the noninferiority margin of 1.51
per-protocol analysis (n= 1741): 6xeBEACOPP proved to be significantly superior to 8xeBEACOPP: HR of 0.7 (97.5% CI 0.5–0.9)

• AE: not reported
• QoL: not reported

• Other:
• second malignancy within the observed follow-up period (n= 142): therapy-related acute myeloid leukemia or myelodysplastic syndrome (MDS) (n= 40), acute lymphoblastic leukemia (ALL) (n= 3), non-Hodgkin lymphoma (NHL) (n= 29), solid tumors (n= 71)
• SIR:2.5 (6xeBEACOPP) to 4.3 (8xeBEACOPP), significantly elevated with respect to age- and sex-specific German reference data in all 3 groups
• 59/142 died from their malignancy
• Cumulative incidences of second malignancies after 10 years: 10% (97.5% CI 7%–13%) (8xeBEACOPP), 7% (4%–9%) (6xeBEACOPP), 7% (4%–10%) (8xBEACOPP-14), possible trend toward higher incidence in the standard arm
• significantly more cases of secondary leukemia or MDS after treatment with 8xeBEACOPP, 10year cumulative incidences: 5% (97.5% CI3%–7%),1%(0%– 1%), and 2% (1%–4%)

• Follow up: 102 months

(Engert, Haverkamp et al. 2012)

Randomised, open-label, multicenter, phase 3 non-inferiority trial (HD15 trial)

n = 2182

Inclusion Criteria:

• Newly diagnosed advanced stage HL in Ann-Arbor stage IIB (+ large mediastinal mass or extranodal lesions) and all patients in stages III and IV
• ECOG performance status of 2 or lower
• age 18–60 years
• HIV negativity
• freedom from concurrent disease

Exclusion Criteria:

• not reported

Arm A:

n = 705

8 cycles of BEACOPP_escalated (8×Besc group) and PET-guided radiotherapy

Baseline characteristics:

• Age: median: 33
• Stage: (Ann Arbor) II B: 118, III A: 153, III B: 192, IV A: 65, IV B: 176
• Recurrence status: not reported

Arm B:

n = 711
6 cycles of BEACOPP_escalated (6×Besc group) and PET-guided radiotherapy

Baseline characteristics:

• Age: median: 34
• Stage: (Ann Arbor) II B: 104, III A: 178, III B: 179, IV A: 78, IV B: 170
• Recurrence status: not reported

Arm C:

n = 728

8 cycles of BEACOPP₁₄ (8×B14 group) and PET-guided radiotherapy

Baseline characteristics:

• Age: median: 33
• Stage: (Ann Arbor) II B: 109, III A: 159, III B: 204, IV A: 57, IV B: 171
• Recurrence status: not reported

• Non-inferiority of two less intensive regimens
• freedom from treatment failure

• OS (5-year OS)

Arm A: 91·9 (89·4 to 94·4)
Arm B: 95·3 (93·4 to 97·2)
Arm C: 94·5 (92·5 to 96·6)

• PFS (5-year PFS)

Arm A.85·6 (82·3 to 88·9)
Arm B: 90·3 (87·6 to 93·0)
Arm C: 85·8 (82·4 to 89·2)

• AE:
• Leucopenia: 

Arm A: 613/684 (89·6%)
Arm B: 619/696 (88·9%)
Arm C: 504/693 (72·7%)

• Anaemia: 

Arm A: 425/684 (62·1%)
Arm B: 370/696 (53·2%)
Arm C: 385/693 (55·6%)

• Thrombocytopenia:

Arm A: 429/684 (62·7%)
Arm B: 372/696 (53·4%)
Arm C: 133/693 (19·2%)

• Any haematological: 

Arm A: 632/684 (92·4%)
Arm B; 638/696 (91·7%)
Arm C: 552/693 (79·7%)

• Alopecia: 

Arm A: 374/684 (54·7%)
Arm B: 368/696 (52·9%)
Arm C: 369/693 (53·2%)

• Infection: 

Arm A: 169/684 (24·7%)
Arm B: 155/696 (22·3%)
Arm C: 143/693 (20·6%)

• Nausea or vomiting: 

Arm A: 88/684 (12·9%)
Arm B: 77/696 (11·1%)
Arm C: 74/693 (10·7%)

• Mucositis: 

Arm A: 83/684 (12·1%)
Arm B: 73/696 (10·5%)
Arm C: 55/693 (7·9%)

• Pain:

Arm A: 90/684 (13·2%)
Arm B: 64/696 (9·2%)
Arm C: 56/693 (8·1%)

• Nervous system:

Arm A: 52/684 (7·6%)
Arm B: 35/696 (5·0%)
Arm C: 88/693 (12·7%)

• Respiratory tract: 

Arm A: 44/684 (6·4%)
Arm B: 26/696 (3·7%)
Arm C: 64/693 (9·2%)

• Gastrointestinal tract:

Arm A: 47/684 (6·9%)
Arm B: 44/696 (6·3%)
Arm C: 41/693 (5·9%)

• Drug fever: 

Arm A: 30/684 (4·4%)
Arm B: 28/696 (4·0%)
Arm C: 31/693 (4·5%)

• Treatment with 6 cycles of BEACOP_Pescalated followed by PET-guided radiotherapy was less toxic than eight cycles of the same chemotherapy regimen

• QoL: not reported

• Other:
• 5 year FFTF:

Arm A: 84·4 (81·0 to 87·7), Arm B: 89·3 (86·5 to 92·1), Arm C: 85·4 (82·1 to 88·7)
Treatment with 6 cycles of BEACOPPescalated followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure than eight cycles of the same chemotherapy regimen

• Study Duration: 5 years
• Follow-up: median follow up of 48 months
• ITT: yes
• Randomisation: yes
• Blinding: no
• Funding: Deutsche Krebshilfe and the Swiss Federal Government
• Other limitations: not reported

(von Tresckow, Kreissl et al. 2018)

RCT
Update zu HD9

http://dx.doi.org/10.1016/S2352-3026%2818%2930140-6

n=1282

Inclusion Criteria:

• newly diagnosed, histology-proven, advanced-stage Hodgkin’s lymphoma

Exclusion Criteria:

• not reported

Baseline characteristics:

• Age: median 32
• Stage: IIA: 0, IIB: 161, IIIA: 290, IIIB: 347, IVA: 113, IVB: 285
• Recurrence status: not reported

Arm B
n = 498
8 cycles of bBEACOPP + RT

Arm C
n = 496
8 cycles of eBEACOPP + RT

Arm A

n = 288

8 cycles of COPP/ABVD + RT

• PFS
• OS
• cumulative incidence of second primary malignant neoplasms

• OS (15-year OS, 95% CI)

Arm A: 72·3% (66·5–78·1)
Arm B: 74·5% (70·1–78·9)
Arm C: 80·9% (76·7–85·0)
eBEACOPP remained significantly better than COPP/ABVD with differences of 8·6% (1·4–15·7) (HR 0·68 [0·50–0·93], p=0·015) 

• PFS (15-year PFS)

Arm A: 57·0% (95% CI 50·0–64·0)
Arm B: 66·8% (61·9–71·8)
Arm C: 74·0% (69·0–79·0)
eBEACOPP remained significantly better than COPP/ABVD with differences of 17·0% (95% CI 8·3–25·6) (HR 0·53 [95% CI 0·41–0·69], p<0·0001)
second progression-free survival after 5 years: 39·1% (95% CI 32·4–45·7) 

• AE: not reported

• QoL: not reported

• Second primary malignant neoplasm: A/B/C
• Acute leukaemia or MDS: n= 1/8//15
• Non-Hodgkin lymphoma or myeloma: n= 8/12/8
• Solid tumour: n= 10/28/27
• Total: n= 19/48/50
• 10-year cumulative incidence (95% CI): 5·2% (2·4–8·0)/ 7·6% (5·0–10·2)/ 6·5% (4·1–8·9)
• 15-year cumulative incidence (95% CI): 7·2% (3·7–10·7)/ 13·0% (9·1–16·9)/ 11·4% (7·6–15·1)
• Standardised incidence ratio (95% CI): 2·0 (1·2–3·2)/ 2·6 (1·9–3·4)/ 2·6 (1·9–3·4)
• 15-year estimates: 7·2% (95% CI 3·7–10·7)/13·0% (9·1–16·9)/11·4% (7·6–15·1) (p=0·41 for COPP/ABVD vs bBEACOPP, p=0·53 for COPP/ABVD vs eBEACOPP)

• Study Duration: Feb 1, 1993 - Jan 13, 2003
• Follow-up: including follow-up of up to 22 years in individual patients
• ITT: yes
• Randomisation: yes
• Blinding:
• Funding: Deutsche Krebshilfe e.V.
• Other limitations: final analysis

(von Tresckow, Kreissl et al. 2018)
Follow-up-analysis, Update zu HD12

NCT00265031

n=1670

Recruitment: 1993-2003

Inclusion Criteria:

• newly diagnosed, histology-proven, advanced-stage Hodgkin’s lymphoma

Exclusion Criteria:

• not reported

Baseline characteristics:

• Age: not reported
• Stage: IIA: 1, IIB: 255, IIIA: 346, IIIB: 422, IVA: 149, IVB: 400
• 964 male, 610 female
• Recurrence status: not applicable, first-line treatment

Arm A

n = 415
8 cycles of eBEACOPP + radiotherapy to regions of initial bulk (>5 cm) or residual disease (≥1·5 cm by CT)

median follow-up for OS: 97 (69-141) months

Arm B
n = 414
8 cycles of eBEACOPP, no radiotherapy

median follow-up for OS: 97 (67-143) months

Arm C
n = 407
4 cycles of eBEACOPP plus 4 cycles of bBEACOPP + radiotherapy to regions of initial bulk (>5 cm) or residual disease (≥1·5 cm by CT)

median follow-up for OS: 95 (69-143) months

Arm D

n = 407
4 cycles of eBEACOPP plus 4 cycles of bBEACOPP, no radiotherapy

median follow-up for OS: 100 (70-146) months

• PFS
• OS
• cumulative incidence of second primary malignant neoplasms

• OS (10-year OS, 95% CI):

Arm A+B: 87·3% (84·7–89·9)% Arm C+D: 86·8% (84·2–89·4)% HR 1·02 (95% CI 0·77–1·36)
Arm A+C: 88·7% (86·0–91·3)%
Arm B+D: 91·5% (89·3–93·7)% HR 1·21 (0·87–1·70)
Subgroup = bulk/residual disease (10-year OS, 95% CI):
Arm A+C: 93·7% (91·2–96·2)% Arm B+D: 90·4% (87·4–93·4)% HR 1·44 (0·88–2·37)

• PFS (10-year PFS, 95%-CI):

Arm A+B: 82·6% (79·6–85·6)%
Arm C+D: 80·6% (77·4–83·7)%
HR of 1·13 (0·89–1·43), non-inferiority of reduced intensity chemotherapy; within the calculated non-inferiority margin of 1·50

Arm A+C: 86·8% (84·1–89·6)
Arm B+D: 82·2% (79·0–85·4) HR 1·34 (1·02–1·75)

Subgroup = bulk/residual disease (10-year PFS, 95% CI): Arm A+C: 89·8% (86·5–93·0)
Arm B+D: 83·3% (79·5–87·2) HR of 1·64 (1·12–2·41)
Among 141 patients with progression or relapse, second progression-free survival after 5 years: 46·6% (95% CI 37·6–55·5)

• AE: not reported 

• QoL: not reported

• Second primary malignant neoplasm: A/B/C/D
• Acute leukaemia or MDS: n= 10/5/4/7
• Non-Hodgkin lymphoma or myeloma: n= 8/6/5/3
• Solid tumour: n= 18/14/14/14
• Total: n= 36/25/23/24
• 10-year cumulative incidence (95% CI): 9·7% (6·2–13·3)/ 8·8% (5·2–12·4)/ 6·4% (3·8–9·1)/ 6·4% (3·3–9·5)
• 15-year cumulative incidence (95% CI): ND
• Standardised incidence ratio (95% CI): 3·2 (2·2–4·4)/ 2·4 (1·5–3·5)/ 2·5 (1·6–3·7)/ 2·3 (1·5–3·4)

• Study Duration: Feb 1, 1993 - Jan 13, 2003
• Follow-up: including follow-up of up to 22 years in individual patients
• ITT: yes
• Randomisation: yes
• Blinding: no
• Funding: Deutsche Krebshilfe e.V.
• Other limitations:  updated information beyond the previous analysis was not available for all patients (availale for more than half of the patients). However, no relevant differences in baseline characteristics or treatment group allocation between patients with or without new information; possible bias due to loss of follow-up, due to the long follow-up time (10 and 15 years); however, the differenct follow-up intervals was  accounted for through Kaplan-Meier-based analysis methods. Time-to-event endpoints allowed to include all patients in the analyses, censored at the last date of follow-up.

(Skoetz, Trelle et al. 2013)

SR

1a

RCTs searched in

• Cochrane Library, including the Cochrane Central Register of Controlled Trials (CENTRAL; issue 5, 2013)
• Medline (Ovid; January, 1980, to June, 2013)
• conference proceedings of annual meetings of the American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, and
• International Symposium on Hodgkin Lymphoma from 2000 to 2012, if not included in CENTRAL

N= 9993

Inclusion criteria:

• Adult pts
• newly diagnosed Hodgkin´s lymphoma
• advanced stage
• randomised controlled trials

Exclusion criteria:

• not reported

A. Comparator:

ABVD

B. Interventions:

1.MOPP      2.MOPP/ABV    3.C(M)OPP/ABVD 4.8*BEACOPP (baseline)
5. 8*BEACOPP (escalated)
6. Stanford V
7.C(M)OPP/EBV/CAD
8. 4*BEACOPP (escalated)+2-4*BEACOPP (baseline)
9. 8*BEACOPP-14   10. 6* BEACOPP (escalated)

• OS
• Secondary neoplasia
• Secondary leukaemia
• FFTF

14 trials incldued in review

Results:

• OS
• „OS was highest in patients who received B.10. (HR 0,38, 95% CI: 0,20–0,75)
• Compared with a 5 year survival of 88% for A., the survival benefit for B.10. is 7% (95% CrI 3–10)—ie, a 5 year survival of 95%“ 

• PFS
• statistically significantly longer for BEACOPPescalated than for ABVD (HR 0·53, 95% CI 0·44–0·64)

• Safety/AEs
• BEACOPP-14 induces more severe toxicity associated with the nervous system and respiratory tract than does BEACOPPescalated
• Data were too sparse to assess other safety outcomes

• QoL: not reported

• Other relevant outcomes
• 327 secondary malignancies and 109 cases of leukaemia occurred

Descriptive statistics:

patient characteristics

• Median age: 30-70

Overall quality of included studies: high

Follow-Up: Median follow-up: 5,9 years (IQR 4,9-6,7)

Randomisation: yes

ITT: not reported

Blinding: no

Funding: „No specific funding was provided for this project“

Heterogeneity:

-Random effects model

- τ²=0·01 [95% Crl 0·00–0·08] for the Bayesian analysis and τ²=0·00 for the analysis of reconstructed individual patient data

Diehl 2003-GHSG HD9

Vivani 2011-GITIL/IIL

Gordon 2013 -ECOG2496

Ballova 2005-GHSG HD9

Chisesi - HD9601

Frederico 2009-GISL HD2000

Hoskin 2009-BNLI

Canellos 1992 -CALGB

Connors 1997 -NCIC

Duggan 2003- CALGB 8952

Borchmann 2011-GHSG HD12

Engert 2012(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert, Haverkamp et al. 2012)(Engert 2012)-GHSG HD15

Carde 2012-EORTC 20012

SR, RCTs

Gesamtüberleben

-

-

-

-

-

⊕⊕⊕⊕ high

Progressionsfreies Überleben

-

-

-

-

-

⊕⊕⊕⊝ moderate

Behandlungsbedingte Mortalität

-

-

-

++¹

-

⊕⊕⊝⊝ low 

Langzeitnebenwirkungen (Sekundärneoplasien)

-

-

-

++¹

-

⊕⊕⊝⊝ low 

Lebensqualität

Not reported 

RCT

Gesamtüberleben

-

-

-

-

-

⊕⊕⊕⊕ high

Progressionsfreies Überleben

-

-

-

-

-

⊕⊕⊕⊕ high

Behandlungsbedingte Mortalität

-

-

-

++¹

-

⊕⊕⊕⊝ moderate

Langzeitnebenwirkungen (Sekundärneoplasien)

-

-

-

++¹

-

⊕⊕⊕⊝ moderate

Lebensqualität

Not reported 

Referenz/ Studientyp

Untersuchte Population

Intervention

Kontrolle

untersuchte Endpunkte

Hauptergebnisse

methodische Bemerkungen

(Kobe, Dietlein et al. 2008)

RCT, HD15

Hier für die Fragestellung, wan nein PET/CT durchgeführt werden soll (d.h. als Kohorte) 

ISRCTN32443041

AS2 – a subsample of AS1 with available PET as reviewed by the PET panel, and available follow-up of at least 12 months or with event within 12 months

n = 275 in AS2

Interim PET ([18F]-fluorodeoxyglucose technique) at median 21 days after last administration of chemotherapy after 4 cycles (incl. CT of all initially involved regions)

RT (30 Gy) was restricted to PET-positive patients after chemotherapy and partial response measuring ≥ 2.5 cm

Inclusion Criteria:

• newly diagnosed, histology-proven HL
• clinical stages IIB with extranodal disease and/or large mediastinal mass, III and IV
• 18 to 60 years
• free of other concurrent disease precluding protocol treatment
• PR after chemotherapy (6-8 cycles of BEACOPP), at least one involved nodal site ≥ 2.5 cm in the transversal/longitudinal diameter as measured by computed tomography (Falorio, Biasoli et al.)

Exclusion Criteria:

• HL as part of a composite lymphoma
• previous malignancy, chemotherapy or radiotherapy
• pregnancy or lactation
• diabetes mellitus, elevated fasting blood sugar level more than 130 mg/dL
• skeletal involvement with risk of instability

Baseline characteristics:

• Age: 18-20: 59, 20-30: 267, 30-40: 229, 40-50: 154, 50-60: 102
• Stage: II B: 136, III A: 192, III B: 210, IV A: 77, IV B: 202
• Recurrence status: not applicable

N=275

Secondary analysis: Progression and relapse and PET results: analysis set 3

Patients were distributed into three arms for this study:

Arm A:

8 cycles of BEACOPP escalated

Arm B:

6 cycles of BEACOPP escalated

Arm C:

8 cycles of time-condensed BEACOPP14

• Siehe Engert 2017, HD15

Siehe Engert 2012, Engert 2017 für:

• OS
• PFS
• AE
• QoL: not reported

Negative residues (%)

No progression: 96% (95% CI: 94%-99%

Progression: 4% 

Positive residues (%)

No progression: 85% (95% CI: 78%-95%)

Progression: 9%

The median observation time for patients included was 18 months.

• Study Duration: not reported
• Follow-up: 12 months
• ITT: not reported
• Randomisation: yes
• Blinding: yes
• Funding: not reported
• Other limitations: The original analysis kept the randomisation. However, here, the predictive value of PET for events within 12 months was evaluated, this is not treated as randomised trial, but rather as prognostic study

Diagnostic test accuracy single study (part of RCT)

Sensitivität¹

-

-

+¹

-

-

⊕⊕⊕⊝
moderate 

Spezifität¹

-

-

+¹

-

-

⊕⊕⊕⊝
moderate 

RCT

Gesamtüberleben

-

-

+¹

-

-

⊕⊕⊕⊝ moderate

Progressionsfreies Überleben

-

-

+¹

-

-

⊕⊕⊕⊝ moderate

Behandlungsbedingte Mortalität

-

-

+¹

++²

-

⊕⊝⊝⊝ very low 

Langzeitnebenwirkungen (Tod durch Sekundärneoplasien)

-

-

+¹

++²

-

⊕⊝⊝⊝ very low 

Lebensqualität

Not reported 

(Brincker and Bentzen 1994)

and

(Vijayakumar and Myrianthopoulos 1992)

Dose-response analysis;

Brincker is the re-analysis of Vijayakumar

n = not reported

Inclusion Criteria:

• Not reported

Exclusion Criteria:

•  Not reported

Baseline characteristics:

• Age:
• Stage:
• Recurrence status:

Dose-response relationship of radiotherapy – collection of literature

Baseline characteristics:

• Age: not overall reported
• Stage: all stages

Dose-response relationship – radiation and disease control

• the dose required for 95% in-field control was:
• 26.5 Gy for subclinical disease,
• 32.7 Gy for nodes < 6 cm,
• and 36.8 Gy for nodes > 6 cm.

• Above 32 Gy, no dose-response relationship is apparent for the observed control rates

• For all other outcomes, see individual studies.

• Study Duration: various
• Follow-up: various
• ITT: no
• Randomisation: no
• Blinding: not reported
• Funding: not reported
• Other limitations:
• differences of patient selection
• clinical staging
• of histological classification
• of radiotherapy
• techniques and of duration of follow-up.
• Staging

Analyse

Dose-response Analyse

-

-

+¹

-

-

⊕⊕⊕⊝ moderate

(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