12. Qualitätsindikatoren – Diffuses großzelligen B-Zell-Lymphom (DLBCL)

Gomez Leon 2018

Randomized controlled trial

N= 72 pts with DLBCL

·  Median Age: NR

·  Stage: NR

Inclusion criteria:

·  Adults (18+)

·  Histological diagnosis of DLBCL

·  Not previously treated for lymphoma

·  Without prior imaging of staging

Exclusion criteria:

·  Chronic renal failure

·  HIV infection

·  Granulomatous/ inflammatory disease

·  Life expectancy <3 months

·  Allergy to iodinated contrasts

·  Positive pregnancy test

·  Suspicion/confirmation of substance abuse

A: 18-Full-dose PET/CT contrast-enhanced

B: 64-Slice Multidetector contrast-enhanced CT

(Reference standard included clinical data, complementary tests and follow-up)

Sensitivity (agreement with reference standard in initial and end-of-treatment-staging)

·Initial staging: k=0.5 (95% CI: 0.2–0.9; p = 0.002) (A) vs k=0.6 (95% CI: 0.1–0.9; p = 0.009)

·End-of-treatment restaging: k=0.7 (95% CI: 0.4–0.9; p = 0.001) [91.67%] (A) vs k=0.4 (95% CI: 0.1-0.8; p = 0.01) [86.43%] (B); A superior to B

k indicates the agreement with the reference standard which is equal between A and B for initial staging, but superior for A vs. B for end-of-treatment staging

·  Study Duration: NA

·  Follow-up: median 14 months, range 1–36 months

·  ITT: NA

·  Randomisation: Randomly allocated pts

·  Blinding: Yes

·  Funding: NR

·  Other limitations: none

Metser 2019

Prospective register study

N = 520 pts with aggressive NHL (n=308 with DLBCL)

·  Median Age: men/women: 64/66 years

·  Stage: Presumed limited (I–II) based on clinical data and CT staging or with equivocal CT findings for advanced stage (III–IV)

Inclusion criteria:

·  Adults (18+)

·  Histological diagnosis of HL/ANHL

·  LS (stage I-II) based on clinical data/CT staging

·  Advanced stage (stage III-IV) based on CT findings

·  Consideration for front-line, curative-intent therapy

Exclusion criteria:

·  NR

A: PET/CT

B: CT (historic control)

·Mortality

·PET/CT-based upstaging

·PET/CT-based adaptation of treatment

·Mortality at 1 year: 6% (A) vs. 14.2% (B); HR 0.63 (95% CI: 0.40-1.0, p < .05)

“Participants with (aggressive NHL) whose first-line therapy was guided by PET/CT had significantly better survival compared with participants whose treatment was guided by CT”

·PET/CT-based upstaging:
advanced stage in pts with presumed limited stage: 28.2%
advanced stage in pts with equivocal limited stage for advanced stage: 55.7%

·PET/CT-based adaptation of treatment: 12.6%

·  Study Duration: NA

·  Follow-up: NA

·  ITT: NA

·  Randomisation: NA

·  Blinding: NA

·  Funding: Ontario Ministry of Health and Long-Term Care

·  Other limitations: none

Sabate-Llobera 2016

Retrospective study

N = 28 pts with DLBCL

·  Median Age (range): 59 year

·  Stage: I: 57%; II: 43%

Inclusion criteria:

·  Adults (18+)

·  Diagnosed with DLBCL

·  Localised stage according to PET/CT

Exclusion criteria:

·  NR

A: Low-dose PET/CT

B: Contrast-enhanced CT

·Detection of lesions

·Staging

·Adaptation of treatment

·Detection of lesions:
nodal: 41 (A) vs. 36 (B)
extranodal: 16 (A) vs. 15 (B)

·PET/CT-based upstaging: 4%

·PET/CT-based downstaging: 18%

·PET/CT-based adaptation of treatment: 11%

·  Study Duration: NA

·  Follow-up: NA

·  ITT: NA

·  Randomisation: NA

·  Blinding: NA

·  Funding: no external sources

·  Other limitations: none

High

1 observational study (prospective register study)

OS (1 year)

/ 

/

/

-1 (only few events (death): 122 in 520 pts; wide CI: HR 0.63 (95% CI: 0.40-1.0))

/

⊕⊕⊕⊝

Moderate

High

1 RCT, 2 observational studies (1 prospective register study, 1 retrospective study)

Staging (sensitivity/ specificity of staging/ detection of lesions) 

/

/

/

/

/

⊕⊕⊕⊕

High

Pfreundschuh 2008

Randomised controlled trial

N = 1242 elderly patients with B-cell NHL (80% DLBCL)

·  Median age (range): 68 years (61 – 80 years)

·  Stage III/IV: 50%

Inclusion criteria:

·  Previously untreated, biopsy-confirmed aggressive NHL of B-cell type

·  Aged 61-80 years

Exclusion criteria:

·  Previous lymphoma associated with acquired immunodeficiency syndrome

·  Diagnosis or history of indolent lymphoma or other malignancies

·  Marked impairment of cardiac, pulmonary, hepatic, renal function

·  WHO performance status > 2

·  Initial white-blood count <2.5*10³/L

·  Initial platelet count <100*10³/L

·  Inability to comply with study requirements

A1: 6 cycles CHOP-14

A2: 8 cycles of CHOP-14

B1: 6 cycles of R-CHOP-14

B2: 8 cycles of R-CHOP-14

· OS

· PFS

· EFS

· AEs

· response

“Additional sensitivity analyses of the primary and secondary endpoints restricted to 949 patients with DLBCL yielded findings almost identical with the entire population (data not shown). “

3-year OS:

A1: 67.7% (95% CI: 62.0 – 73.5%)
A2: 66.0% (95% CI: 60.1% - 71.9%), p = 0.8358

B1: 78.1% (95% CI: 73.2% - 83.0%), p = 0.0181

B2: 72.5% (95% CI: 67.1% - 77.9%), p = 0.2602

3-year PFS:

A1: 56.9% (95% CI: 50.8% - 63.0%)

A2: 56.9% (95% CI: 50.8% - 63.0%), p = 0.6155

B1: 73.4% (95% CI: 68.1% - 78.7%), p < 0.0001

B2: 68.8% (95% CI: 63.2% - 74.5%), p = 0.0012

3-year EFS:

A1: 47.2% (95% CI: 41.2% - 53.3%)

A2: 53.0% (95% CI: 47.0% - 59.1%), p = 0.037

B1: 66.5% (95% CI: 60.9% – 72.0%), p < 0.0001

B2: 63.1% (95% CI: 57.4% - 68.8%), p < 0.0001

AEs:

leukocytopenia:

A1: 48%, A2: 48%, B1: 52%, B2: 50%, p = 0.817

thrombocytopenia:

A1: 10%, A2: 17%, B1: 12%, B2: 16%, p = 0.1242

anaemia:

A1: 16%, A2: 23%, B1: 16%, B2: 16%, p = 0.0013

neuropathy:

A1: 7%, A2: 11%, B1: 7%, B2: 8%, p = 0.3946

Complete response:

A1: 68% (95% CI: 63% - 73%)

A2: 72% (95% CI: 66% - 77%), p = 0.315

B1: 78% (95% CI: 73% - 82%), p = 0.007

B2: 76% (95% CI: 70% - 80%), p = 0.037

Study Duration: 07/2000 – 06/2005

Median follow-up (range): 34.5 months (0.2 – 70.1 months)

ITT: Yes

Randomisation: Yes

Blinding: NR (probably not)

Funding: Deutsche Krebshilfe

Other limitations: none

High

1 RCT

OS

/

/

/

/

/

⊕⊕⊕⊕

High

High

1 RCT

PFS

-1 (no blinding)

/

/

/

/

⊕⊕⊕⊝
Moderate

High

1 RCT

EFS

-1 (no blinding)

/

/

/

/

⊕⊕⊕⊝
Moderate

High

1 RCT

AEs

-1 (no blinding)

/

/

/

/

⊕⊕⊕⊝
Moderate

High

1 RCT

response

-1 (no blinding)

/

/

/

/

⊕⊕⊕⊝
Moderate

High

3 RCTs

OS

/

-1 (small percentage of pts with subtype)

/

/

⊕⊕⊕⊝

Moderate

High

2 RCTs

PFS

-1 (no blinding)

/

-1 (small percentage of pts with subtype)

/

/

⊕⊕⊝⊝

Low

High

3 RCTs

EFS/FFS/DFS

-1 (no blinding)

-1 (small percentage of pts with subtype)

/

/

⊕⊕⊝⊝

Low

High

3 RCTs

safety

/

/

-1 (small percentage of pts with subtype)

/

/

⊕⊕⊕⊝

Moderate

High

1 RCT

OS

/

/

/

/

/

⊕⊕⊕⊕

High

High

1 RCT

PFS

-1 (no blinding of pts and investigators)

/

/

/

/

⊕⊕⊕⊝

Moderate

High

1 RCT

EFS

-1 (no blinding of pts and investigators)

/

/

/

/

⊕⊕⊕⊝

Moderate

High

1 RCT

Safety

-1 (no blinding of pts and investigators)

/

/

/

/

⊕⊕⊕⊝

Moderate

Pöschel 2019

Randomised controlled trial

N = 588 (A: n = 293, 86% DLBCL, B: n = 295, 84% DLBCL)

·  Median age (range):

A: 49 years (18 – 60 years)

B: 47 years (19 – 60 years)

·  Stage: I: A: 59%, B: 58%, II: A: 40%, B: 40%, III/IV: A: 1%, B: 1%

Inclusion criteria:

·  Aged 18 – 60

·  Previously untreated, biopsy-confirmed, aggressive, CD20-positive B-cell lymphoma

·  No risk factor according to age-adjusted IPI

·  No bulky disease

Exclusion criteria:

·  CNS involvement

·  Primary CNS lymphoma, marked impairment of cardiac, pulmonary, hepatic or renal function

·  White blood cell count <2,5*103 cells per µL

·  Initial platelet count <100+103 cellsper µL

·  Known hypersensitivity to the medication used

·  Known HIV positivity

·  Active hepatits infection

·  Previous chemotherapy or radiotherapy for past disorder

·  Pregnancy and lactation period

·  Simultaneous participation in other treatment studies

·  Previous immunosuppressive treatment with cytostatics

·  Other concomitant tumour disease or within past 5 years

·  MALT lymphoma

·  Planned radiotherapy of exxtranodal involvement

·  Inability to comply with study requirements

A: 4 cycles of R-CHOP + 2 cycles rituximab

B: 6 cycles of R-CHOP

· OS

· PFS

· EFS

· safety

3-year OS:

A: 99% (95% CI: 98% - 100%)

B: 98% (95% CI: 96% - 99%)

3-year PFS:

A: 96% (95% CI: 94% - 99%)

B: 94% (95% CI: 91% - 97%)

3-year EFS:

A: 89% ()5% CI: 86% - 93%)

B: 89% ()5% CI: 95% - 92%)

Safety:

Haematological AEs:

A: 294 events

B: 426 events

Non-haematological AEs:

A: 1036 events

B: 1280 events

SAEs:

A: 48

B: 45

Infections:

A: 116 infections, 22 grace ¾

B: 156 infections, 23 grade 3/4

Study Duration:12/2005 – 10/2016

Follow-up: Median 66 months (IQR 42 – 100)

ITT: Yes

Randomisation: Yes

Blinding: none

Funding: Deutsche Krebshilfe

Other limitations: none

Gomez Leon 2018

Randomized controlled trial

N= 72 pts with DLBCL

·  Median Age: NR

·  Stage: NR

Inclusion criteria:

·  Adults (18+)

·  Histological diagnosis of DLBCL

·  Not previously treated for lymphoma

·  Without prior imaging of staging

Exclusion criteria:

·  Chronic renal failure

·  HIV infection

·  Granulomatous/ inflammatory disease

·  Life expectancy <3 months

·  Allergy to iodinated contrasts

·  Positive pregnancy test

·  Suspicion/confirmation of substance abuse

A: 18-Full-dose PET/CT contrast-enhanced

B: 64-Slice Multidetector contrast-enhanced CT

(Reference standard included clinical data, complementary tests and follow-up)

· Sensitivity (agreement with reference standard in initial and end-of-treatment-staging)

· Initial staging: k=0.5 (95% CI: 0.2–0.9; p = 0.002) (A) vs k=0.6 (95% CI: 0.1–0.9; p = 0.009)

· End-of-treatment restaging: k=0.7 (95% CI: 0.4–0.9; p = 0.001) [91.67%] (A) vs k=0.4 (95% CI: 0.1-0.8; p = 0.01) [86.43%] (B); A superior to B

k indicates the agreement with the reference standard which is equal between A and B for initial staging, but superior for A vs. B for end-of-treatment staging

·  Study Duration: January 2012 – June 2015

·  Follow-up: median 14 months, range 1–36 months

·  ITT: NA

·  Randomisation: Randomly allocated pts

·  Blinding: Yes

·  Funding: NR

·  Other limitations: none

High

1 RCT

Sensitivity

/

/

/

-1 (small sample size)

/

⊕⊕⊕⊝

Moderate

Freeman 2021

Retrospective cohort study

N = 723 pts with advanced-stage DLBCL

·  Median age (range): 65 years (18 - 89 years)

·  Stage III/IV: 74%

Inclusion criteria: 

· advance-stage DLBCL

· treated with at least 6 cycles of R-CHOP

· underwent EOT PET

Exclusion criteria: 

· disease progression during therapy

· HIV-positive

· underlying indolent lymphoproliferative disorder

· CNS involvement at diagnosis

· primary-mediastinal B-cel lymphoma

· treated with <6 cycles of R-CHOP

· had RT

· had additional anti-neoplastic agents during initial R-CHOP

PET-negative pts:

A: observed

PET-positive pts, offered consolidative RT when feasible:

B1: observed, no RT

B2: consolidative RT

· OS

· TTP

3-year OS:

A: 87% (95% CI: 84% - 90%)

B1: 44% (95% CI: 34% - 54%)

B2: 80% (95% CI: 71% - 87%)

3-year TTP:

B1: 34% (95% CI: 25% - 44%)

B2: 76% (95% CI: 66% - 83%)

Study Duration: 01/2005 – 03/2017

Median follow-up: 4.3 years (0.9 - 14.2 years)

ITT: NR

Randomisation: NA

Blinding: NR

Funding: NR

Other limitations: none

Low

1 retrospective cohort study

Overall survival

/

/

/

/

/

⊕⊕⊝⊝

Low

Low

1 retrospective cohort study

Time-to-progression

/

/

/

/

/

⊕⊕⊝⊝

Low

Low

1 retrospective cohort study

Overall survival

/

/

-1 (small percentage of pts with subtype)

/

/

⊕⊝⊝⊝

Very low

Low

1 retrospective cohort study

Time-to-progression

/

/

-1 (small percentage of pts with subtype)

/

/

⊕⊝⊝⊝

Very low