10. Verhalten vor, während und nach der Erkrankung und Fertilitätsprotektion – Hodgkin Lymphom

(Knips, Bergenthal et al. 2019)

SR

RCTs searched in

• Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2018, Issue 7)
• MEDLINE (1950 to January 30, 2018)
• Conference proceedings of annual meetings (1990 to 2018) of the following societies: American Society of Hematology (ASH) (2011 to 2017); American Society of Clinical Oncology (ASCO) (2011 to 2018); European Hematology Association (2011 to 2018)
• Databases of ongoing trials: meta-register of controlled trials (original SR); ISRCTN, EU clinical trials register, clinicaltrials.gov (up to July 01, 2018, update only)
• Handsearching of references: We checked references of all identified trials and relevant review articles for further literature

Inclusion criteria:

• ≥ 18 years
• confirmed diagnoses of haematological malignancies
• studies that evaluated the response of the participant to aerobic exercise
• studies with exercise interventions such as moderate cycling, walking, Nordic walking, running, swimming and other related forms of sport
• studies that analysed further physical exercise programmes, such as moderate strength training in addition to the aerobic exercise programme

• < 80% of participants with haematological malignancies
• yoga, tai chi chuan, qigong and similar types of exercise
• studies solely exploring the influence of strength training
• studies assessing outcomes without any clinical impact

Intervention:

aerobic physical exercise in addition to

standard care

Comparator:

standard care alone

Primary outcome

• Overall survival (OS) or mortality

Secondary outcomes

• QoL
• Fatigue
• Physical performance (e.g. aerobic capacity, cardiovascular fitness)
• Anthropometric measurements (e.g. weight, body mass
• index)
• SAEs

18 studies (38 publications) included in the review, n = 1892

Results:

• OS: 1 study

RR 0.67 (P = 0.112)
no difference
Mortality: 6 studies, n = 1172
RR 1.10 (0.79 – 1.52; P = 0.59)
no difference

• QoL: 8 studies, n = 1259

SMD 0.11 (-0.03 – 0.24)
no difference

• SAEs: 6 studies, n = 435

RR 1.39 (0.94 – 2.06; P = 0.10)
no difference

• Other relevant outcomes

QoL subscale physical functioning:
8 studies, n = 1329, SMD 0.15 (-0.01 – 0.32, I2 = 48%)
no difference

• QoL subscale depression: 

6 studies, n = 445, SMD 0.19 (0.0 – 0.38, I2 = 0%)
small effect favouring exercise

• QoL subscale anxiety: 

6 studies, n = 445, SMD 0.03
(-0.30 – 0.36, I2 = 63%)
no difference

• Fatigue: 

9 studies, n = 826, SMD 0.31 (0.13 – 0.48, I2 = 31%)
effect favouring exercise

• Physical performance: 

13 studies, different outcome definitions did not allow for pooling data, results of each trial reported in SR

• Anthropometric measurements: body weight in

3 studies, n = 964, MD 0.44 kg (-1.94 – 2.82, P = 0.72, I2 = 0%)
no difference
lean body mass in 3 studies,
n = 290, MD 1.26 kg (-1.22 – 3.74, P = 0.69, I2 = 0%)
no difference

• Descriptive statistics: 

Country of origin:

• USA (6)
• Canada (2)
• Germany (3)
• Taiwan (1)
• Switzerland (1)
• Australia (1)
• Denmark (1)
• the Netherlands (1)
• Brazil (1)
• South Korea (1)

Overall quality of included studies: unclear

Follow-Up: no (4), 12 weeks (1), 3 months (1), 100 days (1), 6 months (1), 36 weeks (1)

Randomisation: yes (3)

ITT: yes (6)

Blinding: no

Funding: Lance Armstrong Foundation (1), National Heart, Lung, and Blood Institute and the National Cancer Institute (1), SolarisCare foundation (1), The Center for Integrated Rehabilitation of Cancer Patients, The Novo Nordic Foundation, The University Hospitals’ Centre for Health Research (UCSF), The Lundbeck Foundation, The Novo Nordic Foundation for Clinical Nursing Research and the Danish Cancer Society (1), Zruich cnacer league and the Federal Authorities of the Swiss Confederation, Federal Department of Defence, Civil Protection and Sport (1), AMGEN (1)

Heterogeneity:

• Random-effects model
• I² = 29% (mortality)
• I² = 26% (QoL)
• I² = 0% (SAEs)

Alibhai 2014

Baumann 2010

Bryant 2018

Chang 2008

Coleman 2003

Coleman 2012

Courneya 2009

Cunningham 1986

DeFor 2007

Furzer 2016

Jacobsen 2014

Jarden 2016

Kim 2006

Knols 2011

Mello 2003

Persoon 2017

Streckmann 2014

Wiskemann 2015

Aktualisierte Meta-analyse

Mortalität

-

-

-

+¹

-

⊕⊕⊕⊝
moderate

Lebensqualität

+²

-

-

+¹

-

⊕⊕⊝⊝
low 

Körperliche Funmktion

+²

-

-

+¹

-

⊕⊕⊝⊝
low 

Depression

+²

-

-

+¹

-

⊕⊕⊝⊝
low 

Angst

+²

+³

-

+¹

-

⊕⊝⊝⊝
very low 

Fatigue

+²

-

-

+¹

-

⊕⊕⊝⊝
low 

Nebenwirkungen (SAE)

+²

-

-

++⁴

+⁵

⊕⊝⊝⊝
very low 

Referenz/
Studientyp

Untersuchte Studien

(verglichene) Interventionen

untersuchte Endpunkte

Hauptergebnisse

methodische Bemerkungen

Literaturbelege/
eingeschlossene Publikationen

(Gafter-Gvili, Fraser et al. 2012)

SR

1a

RCTs and quasi-RCTs searched from 1966 to 2005, update: November 2005 to March 2011 in

• Cochrane Cancer Network Register of Trials
• Cochrane Central Register of Controlled Trials (CENTRAL)
• (The Cochrane Library Issue 2, 2011)
• MEDLINE
• EMBASE
• the following conference proceedings (2005 to 2010):
• Abstracts of the Interscience Conference on Antimicrobial Agentsand Chemotherapy (ICAAC)
• Annual Meetings of the Infectious Diseases
• Society of America (IDSA)
• European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
• the American Society of Hematology (ASH)
• the European Society of Hematology (EHA)
• the European Society for Bone Marrow and Transplantation (EBMT)

Inclusion criteria:

• Pts. with cancer and neutropenia
• chemotherapy or following bone marrow transplantation

Exclusion criteria:

• not reported

Arm A: (different types of) antibiotic prophylaxis

Arm B: placebo/ no intervention

Primary outcomes:

• All-cause mortality

Secondary outcomes:

• Indicators of infection
• Adverse events

109 studies included in review

Results:

• OS: not reported
• PFS: not reported
• Safety/AEs
• Infection related death (5777 participants; 43 trials)
• Favoring A: RR 0.61 (95% CI: 0.48-0.77)
• Febrile pts. and episodes (6658 participants; 54 studies)
• Favoring A: RR 0.80 (95% CI: 0.74-0.87)
• Bacteremia (6390 participants; 53 trials):
• Favoring A: RR 0.5 (95% CI: 0.43-0.60)
• “Prophylaxis also significantly reduced the occurrence of fever (54 trials, 6658 participants; RR 0.80, 95% CI: 0.74-0.87), clinically documented infection (48 trials, 5758 participants; RR 0.65, 95% CI: 0.56-0.76), microbiologically documented infection (53 trials, 6383 participants; RR 0.51, 95% CI: 0.42-0.62) and other indicators of infection”
• QoL: not reported
• Other relevant outcomes
• All-cause mortality (5635 participants; 46 trials):
• Favoring A: RR 0.66 (95% CI: 0.55-0.79)
•  
• Descriptive statistics:
• patient characteristics
• Adults only: 76 studies
• Children <=16 years: 10 studies
• Both: 26 studies
• “Most pts had hematological malignancies, mostly ALL, AML or acute lymphoblastic leukemia but also lymphoma, CML in blast crisis and multiple myeloma.”

Overall quality of included studies: not reported

Follow-Up: “All-cause mortality (at 30 day follow-up or at the end of the follow-up in each study)“

Randomisation: yes

ITT: yes

Blinding: yes

Funding: Internal source of support: Rabin Medical Center, Israel

External source of support: European Commission

Heterogeneity:

-Random and fixed effects model

- I2 = 7% (All-cause mortality, quinolone vs. placebo/no intervention), I2 = 31% (All-cause mortality, TMP-SMZ vs. placebo/ no intervention), I2 = 0.0% (All-cause mortality, other systemic vs. placebo/ no intervention), I2 = 39% (All-cause mortality, nonabsorbable vs. placebo/ no intervention), I2 = 24% (All-cause mortality, ciprofloxacin vs. TMP-SMZ), I2 = 30% (All-cause mortality, ofloxacin vs. TMP-SMZ), I2 = 0.0% (All-cause mortality, norfloxacin vs. TMP-SMZ), I2 =0.0% (All-cause mortality, nalidixic acid vs. TMP-SMZ)

109 trials (involving 13,579 patients) that were conducted between the years 1973 to 2010 were included.

SR

Mortalität

-

-

-

-

-

⊕⊕⊕⊕
high 

Febrile Patienten

-

+¹

-

-

-

⊕⊕⊕⊝
moderate 

Bakteriämie

-

-

-

-

-

⊕⊕⊕⊕
high 

(Aapro, Bohlius et al. 2011)

2010 Update of EORTC guidelines

Several trials of different design searched from

MEDLINE, PreMEDLINE, EMBASE and The Cochrane Library. The search used to support the 2006 guidelines (31st December 1994 to 16th September 2005). The search was extended to cover the period to 21st July 2009.

Studies involving children <18 years of age or patients with leukaemia were excluded, as were cost analyses.

Different between trials.

Different between trials

• Other relevant outcomes
• Patient-related adverse risk factors and neutrophil count should be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy
• Prophylactic G-CSF recommended for patients receiving a chemotherapy regimen with high risk of FN
• Prophylactic G-CSF support is recommended for dose-dense/ intense chemotherapy strategies connected with survival benefits or if reductions in dose intensity/ density are associated with poor prognosis,
• G-CSF have clinical efficacy and are recommended to prevent FN and FN-related complications where indicated

Follow-Up: Different  between trials

Randomisation: Different between trials

ITT: Different between trials

Blinding: Different between trials

Funding: Funding was by means of an unrestricted grant from Amgen,

Comments on early drafts of the manuscript were received from Nicole Kuderer and on the final draft of the manuscript from Amgen GmbH, Chugai Sanofi Aventis, Ratiopharm GmbH, Sandoz International GmbH,Teva Generics GmbH and Hoffmann LaRoche

In total, 58 pieces of evidence were included, of which 51 were identified by the electronic database or meta-analysis review (ms = 48) or congress searches (abstracts = 3). In addition, six manuscripts and four abstracts were highlighted by members of the working party as being of relevance.

• Phase I to III trials
• Prospective observational studies
• Retrospective observational study or Audit data
• SRs and MAs

(Bohlius, Herbst et al. 2008)

SR

1a

RCTs searched from

January 1980

toApril 21 2008 in

• Cochrane Central Register of Controlled Trials (CENTRAL)
• MEDLINE
• EMBASE
• CancerLit
• Medikat
• Russmed Articles
• SOMED
• Toxline
• BIOSIS Previews
• LILACS
• internet databases of grey literature (SIGLE)

Inclusion criteria:

• Pts ≥16 years
• NHL or HL confirmed by biopsy
• randomised controlled trials comparing G-CSF or GM-CSF prophylaxis with placebo/no prophylaxis
• Studies on long lasting G-CSF preparations such as filgrastim

Exclusion criteria:

• acute and chronic leukaemias, including chronic lymphatic leukaemia, multiple myeloma and human immunodeficiency virus (HIV) associated lymphoma
• Crossover studies, quasi-randomised, non-randomised comparative studies
• Studies with less than ten lymphoma patients per study arm

Arm A: G-CSF orGM-CSF prophylaxis

Arm B: placebo/no prophylaxis

• OS
• FFTF
• QoL
• Risk and duration of neutropenia/ febrile neutropenia
• Infection
• Mortality during chemotherapy
• Received dose intensity of chemotherapy
• Tumour response
• Adverse effects
• Risk and duration of parenteral antibiotic treatment
• Hospitalisation
• Risk and duration of thrombo-cytopenia and anaemia

13 studies included in review

Results:

• OS (11 trials, n=2221):
• No improvement by prophylaxis (HR 0.97; 95% CI 0.87 to 1.09)
• PFS: not reported
• Safety/AEs
• Relative risk (RR) for severe neutropenia (8 trials, n=1013):

Reduced by prophylaxis (RR 0.67; 95% CI 0.60 to 0.73)

• RR for febrile neutropenia (4 trials, n=360):

Reduced by prophylaxis (RR 0.74; 95% CI 0.62 to 0.89)

RR for infection (9 trials, n=1292):

Reduced by prophylaxis (RR 0.74; 95% CI 0.64 to 0.85)

• No of pts requiring intravenous antibiotics (4 trials, n=395):

No evidence for improvement by prophylaxis (RR 0.82; 95%CI 0.57 to 1.18)

• Infection related mortality (10 trials, n=1170):

no evidence for improvement by prophylaxis (RR 0.93; 95% CI 0.51 to 1.71)

• QoL (1 trial, n=132):

no differences between treatment groups

• Other relevant outcomes
• FFTF (5 trials, n=718) :

No improvement by prophylaxis (HR 1.11; 95% CI 0.91 to 1.35).

• Tumour response (11 trials, n=2368):

no evidence for improvement by prophylaxis (RR 1.03; 95% CI 0.95 to 1.10)

Relevant subgroup analysis:

• Safety/AEs: Neutropenia: A stronger treatment effect was observed in trials with antibiotic prophylaxis (RR 0.43; 95% CI 0.31 to 0.60, 2 trials with N = 229) compared to trials without antibiotic prophylaxis (RR 0.72; 95% CI 0.65 to 0.79, 5 trials with N =784)
• Bone pain:  Significantly (P = 0.026) smaller risk of bone pain for patients treated with GM‐CSF (RR 1.37; 95% CI 0.54 to 3.47, 2 studies of N = 232), compared to patients receiving G‐CSF (RR 5.33; 95% CI 2.66 to 10.68, 6 studies of N = 972).

Descriptive statistics:

• patient characteristics
• Age: 15-90
• Gender: male > female

Overall quality of included studies: not reported 

Follow-Up: not applicable

Randomisation: yes

ITT: yes

Blinding: not applicable

Funding: Internal sources: Department I of Internal Medicine, University of Cologne, Germany; Köln Fortune, Germany

External sources: BMBF, Germany; Cochrane Incentive Scheme, UK

Heterogeneity:

-Random and fixed effects model

-I2 tests

Withdrawal:

-  113 of 531 (G-/GM-CSF group), 122 of 518 (control group)

Publication bias:

-  imbalance of positive

and negative results, indicating that studies with negative findings

might be under-represented

Cunningham

Pettengell 1992

Bastion

1993

Gerhartz 1993

Avilés 1994

Fridrik 1997

Gisselbrecht

1997

Zinzani 1997

Dunlop 1998

Aglietta 2000

Doorduijn

2003

Ösby 2003

Burton 2006

(Engert, Diehl et al. 2009)

RCT

1b

n = 1196

Inclusion Criteria:

• Newly diagnosed pts. with histology-proven HL
• Karnovsky performance status >70%
• 16 - 65 years old

Exclusion Criteria:

• Not reported

Arm A:

n = 261

8xCOPP/ABVD

Baseline characteristics:

• Age: median 32
• Stage: II B: 9, III: 60, IV: 32, bulky disease: 58
• Recurrence status: not reported

Arm B:

n = 469

8xBEACOPP baseline

• Age: median 33
• Stage: II B: 14, III: 52, IV: 35, bulky disease: 68

Recurrence status: not reported

Arm C:

n = 466

8xBEACOPP escalated

• Age: median 32
• Stage: II B: 16, III: 52, IV: 33, bulky disease: 67
• Recurrence status: not reported

• CR
• FFTF
• OS

• OS: 10 yrs
• Arm A: 75%
• Arm B: 80%
• Arm C: 86%, P < 0.0005
• A vs B, P = 0.19
• B vs C, P = 0.0053
• A vs C, P < 0.0001
• PFS: not reported
• AE:
• Acute toxicity:
• Arm A:71%
• Arm B:73%
• Arm C: 98%
• QoL: not reported
• Other:
• CR
• Arm A:85%
• Arm B: 88%
• Arm C:96%; (P <0 .0001)
• FFTF: 10 yrs
• Arm A: 64%
• Arm B: 70%
• Arm C: 82%, P < 0.0001
• A vs B, P = 0.04
• B vs C, P < 0.0001
• A vs C, P < 0.0001
• Deaths: N=205
• Arm A. 62
• Arm B: 88
• Arm C: 55
• Secondary malignancies:
• Arm A: 0.4%
• Arm B: 2.2%
• Arm C: 3.2%, (P = .82)
• Increase from 43 (3.6%) of 1.196 at 5 years to 74 (6.2%) or 1.196 at 10 years

• Study Duration: 1993 to 1998
• Follow-up: Median: 111 months (range: 3 to 167 months)
• ITT: yes
• Randomisation: yes
• Blinding: not reported
• Funding: Supported by a grant from the Deutsche Krebshilfe and by the Swiss Group for Clinical Cancer Research
• Other limitations: none

SR, RCTs

Gesamtübnerleben

-

-

-

-

-

⊕⊕⊕⊕
high 

Febrile Neutropenie

-

-

-

-

-

⊕⊕⊕⊕
high 

Infektionen

-

-

-

-

-

⊕⊕⊕⊕
high 

Infektionsbedingte Mortalität

-

-

-

++¹

-

⊕⊕⊝⊝
low 

Lebensqualität

-

-

-

++¹

-

⊕⊕⊝⊝
low 

Nebenwirkungen (Unterbrechung der Therapie)

-

-

-

++¹

-

⊕⊕⊝⊝
low 

Referenz/
Studientyp

Untersuchte Studien

(verglichene) Interventionen

untersuchte Endpunkte

Hauptergebnisse

methodische Bemerkungen

Literaturbelege/
eingeschlossene Publikationen

(Tonia, Mettler et al. 2012)

SR

1a

RCTs searched from

2004 to September 2009, Update: January 2011 and November 2011 in

• EMBASE
• MEDLINE
• CENTRAL

Inclusion criteria:

• Pts. diagnosed with malignant disease (using clinical and histological/cytological criteria)
• Anemic or risk for anemia from chemo-, radio-, or combination therapy, or the underlying malignant disease
• randomised controlled trials using recombinant human erythropoietin or darbepoetin
• trials with more than 10 documented participants in each study arm or relevant stratum
• studies that were stopped or suspended prematurely

Exclusion criteria:

• trials in which patients were allocated by a quasi-random method, for example date of birth or day of month, as we considered this study design to be of poor quality leading to unreliable results
• interim analyses of ongoing studies
• Other causes of anaemia, such as haemolysis, iron deficiency and occult bleeding
• more than 80% of participants were diagnosed with an acute leukaemia

A: Control

B: Erythropoietin or Darbepoetin

Primary outcomes:

• Hematological response
• Pts. receiving RBC transfusions
• Nb. Of RBC transfusions per patient
• OS
• On-study mortality

Secondary Outcomes:

• Tumor response (CR)
• Changing of QoL
• AEs

91 studies included in review

Results:

• OS: Favoring B: : HR 1.05 (95% CI: 1 – 1.11) (19003 pts.; 78 studies)
• PFS: not reported
• Safety/AEs
• Thromboembolic events

increased by 52% for patients receiving ESAs (RR 1.52; 95% CI 1.34 to 1.74)

• Hypertension

increased by 30% (fixed-effect model RR 1.30; 95%CI 1.08 to 1.56), reaching statistical significance (P = 0.006)

Thrombocytopenia
increased for erythropoietin-treated participants (RR 1.21; 95% CI 1.04 to 1.42), reaching statistical significance (P = 0.01)

• skin rash, irritation or pruritus

53 events in the erythropoietin group (N = 1,359) and 27 cases in the control group (N = 1,126) , resulting in a risk ratio of 1.49 (95%CI 0.99 to 2.24)

• seizures

19 events in the erythropoietin group (N=1,583) and 21 events in the control group (N = 1,307), resulting in a risk ratio of 0.77 (95% CI 0.42 to 1.41)

• QoL
• FACT-F 13 sub-scale

MD was 2.08 (95% CI 1.43 to 2.72)
The beneficial effect of ESAs on QoL measured with FACT-F 13 was significantly larger in patients receiving chemotherapy than in those receiving radiotherapy or no anticancer therapy (P < 0.0001)

• FACT-An 20

MD is 6.14 (95% CI 4.55 to 7.73, N = 1,085)

• FACT-An Total 47

MD is 6.92 (95% CI 4.59 to 9.25)

• Other relevant outcomes
• Hematologic response: Favoring B: RR 3.93 (95% CI 3.10-3.71) (6413 pts.; 31 trials)
• Risk of RBC: Favoring B: RR 0.65 (95% CI: 0.62 – 0.68)
• “On average, participants in the ESAs group received one unit of blood less than the control group (mean difference -0.98; 95% CI: -1.17 - 0.78) (4715 pts.; 19 trials)”
• On study mortality: Favoring B (=higher no. of deaths in B): HR 1.17 (95% CI: 1.06 – 1.29) (15935 pts.; 70 studies)

Relevant subgroup analysis:

• OS: statistically significant differences for the analyses of baseline Hb levels (P = 0.02), iron supplementation (P = 0.005) and intention-to-treat analysis (P = 0.02)
• PFS: not reported
• Safety/AEs
• Thromboembolic events

Subgroup analyses did not show robust evidence for

statistically significant differences in magnitude or direction of the ESA effect between any of the subgroups tested

• QoL
• FACT-F 13 sub-scale

The observed effect was larger in unblinded trials (MD 3.76, 955CI 2.60 to 4.92) compared with double-blind trials(MD 1.33, 95% CI 0.56 to 2.10, P = 0.0006), significant differences observed for age group (adults versus >70% non-elderly adults, P = 0.008)

• FACT-An 20

Subgroup analyses did not identify any significant differences in the magnitude of effect between the different subgroups

• FACT-An Total 47

significantly different magnitudes of ESA effect

between each other: imputed versus non-imputed data (P = 0.005), baseline Hb level (P < 0.0001), type of anti-cancer therapy (P <0.0001), duration of ESA treatment (P < 0.0001) and ITT analysis (P = 0.01)

• Other
• Haematological response

Univariate analyses identified significant differences (P < 0.05) between subgroups for baseline Hb level, age, type of anti-cancer therapy, iron supplementation, duration of treatment, placebo control and type of publication

• Change in haemoglobin level

Univariate analyses identified significant differences between

subgroups for baseline Hb level, different malignancies, age, type of anti-cancer therapy, short-lasting versus long-lasting ESA, duration of ESA treatment, iron supplementation, masking, intention-to-treat and type of publication

• Patients receiving RBC transfusions

Univariate analyses identified significant differences (P <

0.05) between subgroups for baseline Hb level, different malignancies, age, type of anti-cancer therapy, iron supplementation, concealment

of allocation, placebo control, intention-to-treat analysis and type of publication

• Number of red blood cell units transfused

statistically significant for different age groups (test between subgroups P = 0.02), duration of ESA therapy (test between subgroups P = 0.03) and type of publication (test between subgroups P = 0.04)

• On-study mortality

Univariate analysis identified statistically significant differences only for intention-to-treat analyses (P = 0.04)

Overall quality of included studies: not reported

Follow-Up: not reported

Randomisation: yes

ITT: No restriction criteria, but included in RoB assessment

Blinding: No restriction criteria, but included in RoB assessment

Funding: Internal sources of support: Department of Internal Medicine I, University of Cologne, Germany; Cochrane Haematological Malignancies Group (CHMG), Germany; Institute of Social and Preventive Medicine, University of Bern, Switzerland

External sources of support: Department of Health, UK

Heterogeneity:

-Random effects model

-I2 = 53% (Hematologic response), I2 = 87% (change in haemoglobin level), I2 = 60% (patients receiving RBC transfusions), I2 = 30% (Number of red blood cell units transfused), I2 = 21% (OS), I2 = 0% on-study mortality), I2 = 0% (CR), I2 = 53% (FACT-F 13), I2 = 0% (FACT-An 20), I2 = 85% (FACT-An Total 47), I2 = 0% (thromboembolic events), I2 = 0% (hypertension), I2 = 0% (thrombocytopenia) I2 = 0% (skin rash, irritation or pruritus), I2 = 3% (seizure s)

In the current update a total of 91 trials with 20,102 participants were included.  

Referenz/ Studientyp

Untersuchte Population

Intervention

Kontrolle

untersuchte Endpunkte

Hauptergebnisse

methodische Bemerkungen

(Chen, Gopal et al. 2010)

Phase 2, single-arm, multicenter study.

Abstract only.

n = 102

Inclusion Criteria:

• relapsed or refractory HL post autologous stem cell transplant (ASCT)

Exclusion Criteria:

n = 102

Brentuximab vedotn 1.8 mg/k, every 3 weeks,as a 30-minute outpatient IV infusion, ≤ 16 cycles 

Baseline characteristics:

Age:

• Median:  31 years (range: 15-77)
• ECOG performance status at baseline: 0: 41%, 1: 59%
• Recurrence status:
• Gender: 53% were famle

none

• Efficacy and safety of brentuximab vedotin

• OS: not reported
• PFS: not reported
• AE: Any grade:
• peripheral sensory neuropathy (43%)
• fatigue (40%)
• nausea (35%)
• neutropenia (19%)
• diarrhea (18%)
• pyrexia (16%)
• most events were Grade 1 or 2
• Grade 3 treatment-related AEs in n >1
• neutropenia (14%)
• peripheral sensory neuropathy (5%)
• thrombocytopenia 83%)
• hyperglycemia (3%)
• fatigue (2%)
• Grade 4 treatment-related events
• neutropenia (4%)
• thrombocytopenia (1%)
• abdominal pain (1%)
• pulmonary embolism (1%)
• Related Grade 5 events
• none observed
• discontinued treatment due to an AE: n= 18
• QoL:
• Other:
• Reduction of tumor size per investigator assessment: n= 97 (95%)

• Study Duration: not reported
• Follow-up: not reported
• ITT: not reported
• Randomisation: no
• Blinding: no
• Funding: not reported
• Other limitations: NA

SR, RCT

Gesamtüberleben

-

-

-

-

-

⊕⊕⊕⊕
high 

Sterblichkeit während der Studie

-

-

-

-

-

⊕⊕⊕⊕
high 

Thrombotische Ereignisse

-

-

-

-

+¹

⊕⊕⊕⊝
moderate 

Lebensqualität

-

-

-

+²

+¹

⊕⊕⊝⊝
low 

Anzahl Patienten, die Erythrozyten-konzentrate erhieten

-

-

-

-

+¹

⊕⊕⊕⊝
moderate 

(Chen, Xiao et al. 2019)

SR

Update von (Chen, Li et al. 2011)

RCTs searched in

• Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11)
• MEDLINE via Ovid (up to November 2018)
• Embase via OVID (up to November 2018)
• Chinese Biomedicine Database (up to November 2018)
• Handsearching of references for related articles

Inclusion criteria:

• Premenopausal women (confirmed by age, menstrual history, ovarian sonography and/or hormone levels, such as FSH and estradiol)
• malignant or non-malignant conditions
• receiving GnRH analogues supplementation before or in parallel to chemotherapy

Exclusion criteria:

• Premenopausal women who had taken oral contraceptive pills or hormone replacement therapy after chemotherapy

1. GnRH agonists or antagonists or both vs. placebo or other interventions, before or in parallel to chemotherapy 

2. Combination of GnRH agonists and antagonists vs.GnRH agonists or antagonists alone, before or in parallel to

chemotherapy

3. GnRH agonists or antagonists or both plus other

interventions vs. GnRH agonists or antagonists or both, or

other methods alone, before or in parallel to chemotherapy (other interventions being alternative treatments to preserve ovarian function, e.g. oral contraceptive pills)

• Menstruation recovery or maintenance
• Premature ovarian failure
• Pregnancy
• Ovulation
• Ovarian sonography
• Hormone levels
• Survival
• Safety/AEs

12 studies (13 publications) included in the review, n = 1369

Results:

1. GnRH agonist + CT vs. CT alone

• Menstruation recovery or maintenance: for 5 studies with ≤ 12 months follow-up: 178/239 vs. 110/221, RR 1.60 (1.14 – 2.24, P = 0.006, I2 = 79%)

for 8 studies with > 12 months follow-up: 326/447 vs. 276/422, RR 1.08 (0.95 – 1.22, P = 0.24, I2 = 56%)

• Premature ovarian failure: 4 studies, n = 780, 43/401 vs. 96/379, RR 0.44 (0.31 – 0.61, P < 0.00001, I2 = 0%)
• Pregnancy: 7 studies, n = 703, 32/356 vs. 22/347, RR 1.59 (0.93 – 2.70, P = 0.09, I2 = 0%)
• Survival: 5-year disease-free survival in 1 study (Lambertini 2015):

80.5% (77.2 – 90.5) vs.
83.7% (76.1 – 89.1)
4-year disease-free survival in 1 study (Moore 2015): 89% vs. 78% (P = 0.04)
4-year overall survival in 1 study (Moore 2015): 92% vs. 82% (P = 0.05)

• Safety/AEs: varying numbers of studies included
• hot flush: 172/369 (46.6%) vs. 141/362 (39.0%), RR 1.49 (0.16 – 13.6, P = 0.73, I2 = 99%)
• vaginal dryness: 26/250 (10.4%) vs. 21/238 (8.8%), RR 1.18 (0.68 – 2.04, P = 0.55, I2 = 0%)
• urogenital symptoms: 95/119 (79.8%) vs. 95/124 (76.6%), RR 2.37 (0.01 – 448.16, P = 0.75, I2 = 96%)
• sweating: 31/250 (12.4%) vs. 18/238 (7.6%), RR 1.65 (0.93 – 2.80, P = 0.09, I2 = 0%)
• headache: 40/250 (16.0%) vs. 20/238 (8.4%), RR 2.54 (0.54 – 11.92, P = 0.24, I2 = 75%)
• mood swings: 107/266 (40.2%) vs. 111/251 (44.2%), RR 1.00 (0.98 – 1.02, P = 0.99, I2 = 0%)
• QoL: not reported

2. GnRH agonist-antagonist cotreatment + CT vs. CT alone

• Menstruation recovery or maintenance: 1 study (Elgindy 2013), n = 50, 20/25 in both groups, RR 1.00 (0.76 – 1.32, P = 1.00) during 12 months follow-up;

13/25 vs. 14/25, RR 0.93 (0.56 – 1.55, P = 0.78) during > 12 months follow-up

• Pregnancy: 1 study (Elgindy 2013), n = 50, 1/25 vs. 0/25, RR 3.00 (0.13 – 70.30, P = 0.49)
• Survival: not reported
• Safety/AEs: not reported
• QoL: not reported

3. GnRH agonists/antagonists/both + other interventions vs. GnRH agonists/antagonists/both/other methods alone, before/in parallel to CT

Not reported

Descriptive statistics:

country of origin:

• Egypt (2)
• Iran (2)
• Italy (2)
• UK (2)
• Germany (1)
• China (1)
• USA (1)
• Australia, Switzerland, Peru and USA (1)

Overall quality of included studies: very low

Follow-up: > 12 months in 9/12 studies

Randomisation: unclear

ITT: not reported

Blinding: unclear

Funding: by the university (Elgindy 2013),

research centres (Lambertini 2015a; Leonard 2017; Moore

2015; Munster 2012), a pharmaceutical company (Gerber 2011), not reported (Badawy 2009; Gilani 2007; Giuseppe 2007; Karimi-Zarchi 2014; Song 2013; Waxman 1987)

Heterogeneity:

• Random effects model
• See: Results

Badawy 2009

Elgindy 2013

Gerber 2011

Gilani 2007

Giuseppe 2007

Karimi-Zarchi 2014

Lambertini 2015a

Leonard 2017

Moore 2015

Munster 2012

Song 2013

Waxman 1987

(Behringer, Thielen et al. 2012)

RCT

1b

n = 31

Inclusion Criteria:

• Women diagnosed with HL
• 18 - 40 years
• at time of fertility assessment
• being in remission for at least 12 months after therapy
• “Core set” consisted of patients without contraception and sexual intercours

Exclusion Criteria:

• Patients with stage IIB disease and bulky mediastinal mass and/or extranodal involvement 
• Patients with impaired heart, lung, liver, or kidney function; previous malignant disease, or HIV-positive status
• were pregnant or lactating

Arm A:

n = 157

4 cycles of ABVD

Baseline characteristics:

• Age: mean 32
• Stage (Ann Arbor): I A: 3, I B: 3, II A: 105, II B: 26
• Recurrence status: not reported

Arm B:

n = 174

2 cycles of BEACOPP esc. followed by 2 cycles of ABVD

Baseline characteristics:

• Age: mean 32
• Stage (Ann Arbor): I A: 1, I B: 2, II A: 101, II B: 22
• Recurrence status: not reported

• Pregnancies after therapy
• Cycle
• Hormonal parameters (LH, FSH, AMH, estradiol)
• Menopausal symptoms
• Factors predicting pregnancy

• Pregnancies

A: 15%

B: 26%

P=0.043, significant difference

• Regular cycle

A: 87%

B: 83%

• Hormonal parameters

FSH

Statistically significant higher FSH levels in arm A compared to arm B

AMH

Statistically significant higher AMH levels in older patients in arm B compared to arm A. No evidence for a difference in young patients.

Menopausal symptoms (on Menopausal Rating Scale)

No statistical significant difference in MRS score between arm A and B.

• Factors predicting pregnancy

Motherhood before therapy

OR: 0.82

P=0.76

• Chemotherapy regimen

OR: 0.5

P=0.18

Pill consumption

OR: 1.64

P=0.43

• GnRH concomitantly administered to chemotherapy

OR: 12.87

P= 0.001

• Months since chemotherapy

OR: 1.07

P= 0.0008

• Study Duration: not reported
• Follow-up: Mean observation time:
• A: 42 months
• B: 43 months
• ITT: not reported
• Randomisation: yes
• Blinding: not reported
• Funding: Funding by Deutsche Krebshilfe, Bundesministerium für Bildung und Forschung and Kompetenznetz maligne Lymphome.

(Blumenfeld, Zur et al. 2014)

Abstract only

n = 380

Women who were exposed to gonadotoxic chemotherapy and GnRHa  vs. women without agonists.

n = 250

Monthly depot IM injection of GnRH analogue in parallel to, and until the end of chemotherapy.

Baseline characteristics:

• Age: range 14-40 ears
• Stage: not reported
• Recurrence status: not reported

n = 130

Women, with similar diagnoses and treatment.

Baseline characteristics:

• Age: range 14-40 years
• Stage: not reported
• Recurrence status: not reported

Premature ovarian failure (POF)

• Spontaneously conceived:
• GnRHa+chemotherapy group: N= 56 spontaneously conceived 86 times, and were delivered of 70 healthy neonates
• Control group: n= 18, 28 pregnancies [p<0.05]
• age of the patients who spontaneously conceived: GnRHa group: 16-34, control group: 16-28 years
• GnRHa group: n= 1, spontaneously conceived three times and was delivered  of three healthy neonates despite two stem cell transplantations [SCT], 11 years apart; n= 1 spontaneously conceived four times and was successfully delivered of four healthy neonates

• Study Duration: not reported
• Follow-up: not reported
• ITT: not reported
• Randomisation: not reported
• Blinding: not reported 
• Funding: not reported
• Other limitations:  not reported

(Del Mastro, Boni et al. 2011) PROMISE-GIM6

Randomized trial (parallel, randomized, open-label,phase 3 superiority trial)

Included in (Chen, Li et al. 2011)

n = 281

Inclusion Criteria:

• Premenopausal women
• Age: 18-45
• Histologically proven stage I, II or III breast cancer
• Be candidates for adjuvant or neoadjuvant chemotherapy

Exclusion Criteria:

• Previous chemotherapy, radiotherapy, or for both cancer or nonneoplastic diseases
• Evidence of distant metastases
• Other malignancies in the previous 5 years, except basal or squamous cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix
• Pregnancy or lactation

n = 148

Chemotherapy combined with triptorelin

Addministered intramuscularly at a dose of 3.75 mg at least 1 week before start of chemotherapy, then every 4 weeks for the duration of chemotherapy)

Baseline characteristics:

• Age: median: 39 (range: 24-45)
• Stage: I - III
• Recurrence status: not reported

n = 133

Chemotherapy only

 Baseline characteristics:

• Age: median: 39 (range: 25-45)
• Stage: I-III
• Recurrence status: not reported

Incidence of chemotherapy induced early menopause

• Menstrual activity 

• FSH levels

• E2 levels

• Intervention group:

Rate of early menopause: 8.9%

• Control group:
• Rate of early menopause: 25.9%
• Absolute difference: -17% (95% confidence interval,     -26% to -7.9%; P<.001>
• Odds ratio (for treatment related early menopause): 0.28 (95% confidence interval, 0.14 to 0.59; P<.001>

• Intervention group:
• Resumption of menses: observed in 88 pts (63.3%;)
• Control group:
• Resumption of menses: observed in 60 pts (49.6%)
• Absolute difference: 13.7% (95% CI, 1.0% to 26.5%; P=.03)

• Intervention group:
• FSH evaluation: 104 of 139 pts (75%) underwent at least 1 FSH evaluation
• E2 evaluation: 98 pts (70%) underwent at least 1 E2 evaluation
• Control group:
• FSH evaluation: 83 of 121 pts (68%) underwent at least 1 FSH evaluation
• E2 evaluation: 80 pts (66%) underwent at least 1 E2 evaluation 

• Triptorelin induced temporary ovarian suppression during chemotherapy in premenopausal patients with early stage breast cancer reduced the occurrence of chemotherapy induced early menopause

• Study Duration: October 2003 to January 2008
• Follow-up: 12 months after last cycle of chemotherapy
• ITT: yes (all randomized patients included; missing values imputed using multiple imputation method)
• Randomisation: yes
• Blinding: no (open-label)
• Funding: sponsored by the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy, and partly supported by a grant from the Associazione

• Other limitations:
• Secondary analysis
• Post hoc subgroup analysis performed to evaluate the effect of the treatment in the presence and absence of tamoxifen

(Demeestere, Brice et al. 2016)

RCT

NCT01160315

n = 129 initally randomized

n = 67 with available data for analysis

HL and non-HL patients!

Inclusion Criteria:

• Women between 18 and 45 years old with lymphoma.
• Menarche >2 year
• Subject treated by chemotherapy-induced ovarian failure including alkylant agents (except less than 8 ABVD)
• Presence of both ovaries (ovarian biopsy or hemiovariectomy for cryopreservation before treatment is accepted).
• Ability to give written informed consent

Exclusion Criteria:

Main exclusion criteria:

• pelvic irradiation
• history ofamenorrhea (. 3 months)
• thromboembolic processes
• severe hypertension
• severe obesity
• hepatic or renal insufficiency
• contraindication of intramuscular injection
• prior chemotherapy treatment
• presence of ovarian abnormalities (other than functional cysts)
• ovarian insufficiency defined as FSH . 15 IU/L at the time of diagnosis
• receipt of fewer than eight cycles of ABVD

n = 32

Baseline characteristics:

• Age: mean 25 (range 18-38)
• Stage: not reported: HL patients = 19, non-HL = 13
• Recurrence status: unclear

n = 35

Baseline characteristics:

• Age: mean 26 (range 18-38)
• Stage: not reported: HL patients = 23, non-HL = 12
• Recurrence status: unclear

• Overall survival
• Disease-free survival
• Premature ovarian failure (POF)
• Ovarian reserve
• Pregnancy outcomes

• OS: 4 deaths in GnRHa group and 2 deaths in control group
• DFS: 82% (intervention) and 87.5% (control)
• POF: A total of 6 out of 31 patients (19.4%) in the GnRHa group and 8 out of 32 patients (25%) in the control group experienced POF (P = .763). An increased risk of POF was also observed according to age (P = .047), but not according to the type of disease (P = .281), nor to the coadministration of GnRHa during chemotherapy (P = .651;
• Other:
• Ovarin reserve: Mean AMH values decreased significantly after treatment (3.14 6 0.80 ng/mL at inclusion v 1.26 6 0.3 ng/mL after 2 to 4 years, P = .039) and remained at a similar level after 5 to 7 years (1.58 6 0.38 ng/mL, P = .520; individual values: Fig 3). A higher rate of low AMH (AMH, 0.5 ng/mL) was observed in both groups after 2 to 4 years of follow up.
• Pregnancy: 17 of 32 patients (53.1%) and 15 of 35 patients (42.8%) achieved pregnancy in the GnRHa and control groups, respectively (P = .467).

• Study Duration: July 2002 – October 2015
• Follow-up: median 5.33 years
• ITT: no
• Randomisation:  yes
• Blinding: no (open-label)
• Funding: Celgene, Janssen Pharmaceuticals, Gilead Sciences
• Other limitations: high drop out rate (50%) of which 25% were due to loss of follow-up or unavailability of data

(Donnez and Dolmans 2011)

State of the art review

• Adolescents and young women requiring chemotherapy with alkylating agents
• Cryobanking of ovarian tissueAge: <35

N/A

none

• Strategies for preserving fertility:
• Embryo cryopreservation
• Oocyte cryopreservation
• Ovarian tissue cryopreservation

• Other:
• Embryo cryopreservation is effective for pts with mature oocytes.
• Oocyte cryopreservation for pts with or without partner. Mature oocyte banking is limited b< low success rate

• Ovarian tissue cryopreservation for pts who need immediate CHT.

• Ovarian cortex banking should be offered before chemotherapy in all cases where emergency IVF is not possible

• 15 live births obtained after autotransplantation of frozen-thawed ovarian tissue in human.

N/A

(Donnez, Dolmans et al. 2013)

Fertility and Sterility    Review

n = 60

• Hematologic diseases (35%)
• Malignant pathology (other than hematologic diseases) (45%)
• Benign pathology (Turner syndrome, family history of POF, endometriosis, recurrent ovarian cysts, etc.) (20%)

• Orthotopic reimplantation of cryopreserved ovarian tissue
• Girls and young women

NA

none

Restoration of ovarian activity and pregnancy

• Other:
• Cryopreservation of ovarian tissue is the only option for prepubertal girls and women who cannot delay the start of chemotherapy

• Restoration of ovarian activity observed in at least 52 cases among the 56 (93%)

• Donnez’s series (Belgium):
• Restoration of ovarian activity observed in 10 out of 13 cases

• Pellicers’s series (Spain):
• Restoration of ovarian activity observed in 17 out of 18 cases (four patients are still to follow up)

• Andersen’s series (Denmark):
• Restoration of ovarian activity observed in all 25 cases

• 11 out of 60 pts conceived (6 of them already delivered 12 healthy babies)

• Worldwide 24 live births obtained after orthotopic reimplantation

NA

(Karimi Zarchi, Forat-Yazdi et al. 2012)

Double blind randomized controlled trial (conference abstract only)

n = 42

Inclusion Criteria:

• Young women diagnosed with breast cancer

Exclusion Criteria:

Not reported

n = not reported

GnRH agonists during chemotherapy with cyclophosphamide

Baseline characteristics:

• Age: average: 36.5 (range: 30-45)
• Stage: not reported
• Recurrence status: not reported

n = not reported 

not reported

Baseline characteristics:

• Age: not reported
• Stage: not reported
• Recurrence status: not reported

• Ovarian function
• Menstrual conditions (examined with vaginal sonography)
• Hormonal parameters (LH, FSH)

• OS: not reported
• PFS: not reported
• AE: not reported
• QoL: not reported
• Other:
• Intervention group:
• After 3 months: 84% maintained ovarian function

After 6 months: 90.5% maintained ovarian function

• Control group:
• After 3 months: 14.3% maintained ovarian function
• After 6 months: 33.3% maintained ovarian function (menopause symptoms: flashes, night sweats, fatigue, vaginal dryness)
• GnRH analogue can significantly preserve ovarian function (p<0.001)

• Study Duration: 6 months?
• Follow-up: not reported
• ITT: not reported
• Randomisation: yes
• Blinding: double blind
• Funding:
• Other limitations: N/A

(Sverrisdottir, Nystedt et al. 2009)

Four randomized multi-center trials (ZIPP study)

n = 260

Goserelin

n = 63

Goserelin + Tam

N = 74

Tamoxifen

N = 60 

Baseline characteristics:

• Age: mean 45 (range 29-54)
• Stage: I- II
• Recurrence status:  women at high risk of recurrence

n = 63

Baseline characteristics:

• Age: mean 46 (range 36-55)
• Stage: I - II
• Recurrence status: women at high risk of recurrence

Premature ovarian failure (POF) / amenorrhea

• Amenorrhea in MF chemotherapy treated patients:
• At 3 months, 50% (13/26) of the women in the control group reported amenorrhea. For women receiving tamoxifen (T), the figure was 73% (19/26). Women treated with goserelin (G) or goserelin plus tamoxifen (GT), reported amenorrhea in 93–94% (26/28 and 34/36 respectively) of cases.
• At 24 months, i.e. after 2 years of endocrine treatment, 85% (17/20) of the controls, 95% (19/20) of the T group, 97% (29/30) of the GT and 92% (22/24) of the G group were amenorrheic.
• At 36 months, i.e. 1 year after stopped endocrine treatment, the proportion of amenorrheic women in the control group was 90% (18/20), 87% (20/23) for the T group, 93% (27/29) for the GT group but had decreased to 64% (14/22) for the G group.
• Amenorrhea in nottreated patients:
• At 3 months, 9% (3/34) of the controls, 21% (6/29) of the T group, 86% (31/36) of the GT group and 97% (32/33) of the G group were amenorrheic.
• At 2 years after randomization, 13% (4/31) of the controls, 21% (5/24) of the T-group, 69% (22/32) of GT-group and 82% (23/28) of the G-group reported amenorrhea.
• Six months after completed endocrine treatment, 17% (5/29) of the controls, 12% (3/24) of the T group, 28% (8/29) of the GT group and 37% (10/27) of the G group were amenorrheic.
• At 36 months, i.e. 1 year after completed endocrine treatment, 20% (6/30 and 5/25 respectively) of the controls and T group, 32% (10/31) of the GT group and 41% (12/29) of the G group were amenorrheic.

Study Duration: August 1987 and March 1999

• Follow-up: not reported
• ITT: not reported
• Randomisation: yes
• Blinding: no
• Funding: Free drug was supplied by ICI (now AstraZeneca) for the CRUK BCTG and GIVIO trials. Payment towards the cost of IHC estimation of ERs in UK patients was also given. In the UK the trial was supported by a grant from the CRUK (formally Cancer Research Campaign). In Italy the coordination of the trial was supported by an educational grant from AstraZeneca. The Stockholm trial received funding from the King Gustaf V Jubilee Fund and an unrestricted research grant from AstraZeneca.
• Other limitations: none

(Wilson, Gossiel et al. 2016)

Secondary endpoint-analysis of OPTION trial (RCT)

n = 227

Inclusion Criteria:

• Not reported

Exclusion Criteria:

• No follow up time point sample

n = 54

CT alone

Baseline characteristics:

• Age: median: 41.5 (range: 30-51)
• Stage: not reported
• Recurrence status: not reported

n = 54

CT + Goserelin

Baseline characteristics:

• Age: median: 41.0 (range: 26-49)
• Stage: not reported
• Recurrence status: not reported

Not reported

• Other:
• Baseline BALP and NTX:
• Similar between CT and CT+G groups
• Median [IQR] BALP (μg/l):6.1 [4.9–7.9] and 6.3 [4.7–7.5]
• Median [IQR] NTX (nmol/mmol creatinine): 33.9 [23.3–43.2] and 34.9 [28.8–47.2] 

• Adjuvant tamoxifen use:
• Similar between both groups (CT: n=20, CT+G: n=22)

• Acute/on treatment median [IQR] NTX:
• significantly increased at 6 months (6/12) in patients treated with CT+G (6/12=57.8 [39.4–72.9] p=0.0030); CT (37.07 [27.5–59.1]), significantly higher NTX level at 6 months in the CT+G group (p=0.0032)

• Acute/on treatment median [IQR] BALP:
• Significantly increased at 6/12 compared to baseline in patients treated with CT+G (baseline=6.3 [4.7–7.5], 6/12=8.2 [6.3–10.4] p=0.0174)

• patients >40 yrs.:
• significant increase in median [IQR] NTX in the CT+G group at 6/12 compared to baseline (baseline:37.6 [30.4–50.7], 6/12:59.1 [41.0–81.9], p= 0.0128)
• significant difference in NTX  at 6/12 (CT+G; 59.1[41.0–81.9], CT;37.7 [28.0–61.6] (p=0.0451))
• significant increase in median [IQR] BALP at 12/12 in CT+G (baseline: 5.7 [4.6–7.5],12/12: 7.7 [6.3–10.5] p=0.0472)
• CTgroup: persistently significantly elevated BALP compared to baseline at 12/12 (p=0.0039) and 36/12 (p=0.013), significantly higher BALP at 36/12 in the CT group compared to CT+G (p=0.017)

• Changes in bone markers over time:
• patients for whom the primary endpoint data of POI at 12 months was known
• median BALP levels were higher in amenorrhoeic women compared to menstruating women at 6/12 and 12/12, median NTX was higher at 12/12 and 18/12 in amenorrheic women
• in women who were amenorrheic median [IQR] BALP was significantly higher than baseline at 6/12 (baseline:5.6 [4.7–7.6], 6/12:7.8 [6.0–9.4] p=0.0063), 12months (9.4[7.6–11.5] p=0.0001) and 18 months (7.6 [6.3–9.7] p=0.03)

• Study Duration: not reported
• Follow-up: not reported
• ITT: not reported
• Randomisation: yes
• Blinding: not reported
• Funding: Anglo Celtic Cooperative Oncology Group, Cancer Research UK, Experimental Cancer Medicine Centre, the National Institute of Health Research UK
• Other limitations: secondary endpoint analysis

Aktualisierte Meta-Analyse

Wiederauftreten der Menstruation

+¹

+²

-

-

-

⊕⊕⊝⊝
low 

Ovulation

+¹

-

-

++³

-

⊕⊝⊝⊝
very low 

Schwangerschaft

-

-

-

+⁴

-

⊕⊕⊕⊝
moderate 

Ovarialinsuffizienz

-

-

-

+⁴

-

⊕⊕⊕⊝
moderate 

Hitzewallungen

+¹

-

-

++³

-

⊕⊝⊝⊝
very low 

Vaginale Trockenheit

-

-

-

+⁴

-

⊕⊕⊕⊝
moderate 

(Holoch and Wald 2011)

Report

n = n/a

Inclusion Criteria:

• male survivors of childhood cancer

Exclusion Criteria:

• not reported

Fertility preservation in male cancer pts

none

• Options for preservation of fertility in the male

• OS: not reported
• PFS: not reported
• AE: not reported
• QoL: not reported

• Other:
• Male:
• Cryopreservation of sperm from semen samples is the most reliable option.
• Conception is possible with ICSI.
• Prepubertal male:
• Cyropreservation in adolescent oncology pts ( 13.5 years old) can be performed with similar success

• Study Duration: not reported
• Follow-up: not reported
• ITT: n/a
• Randomisation: n/a
• Blinding: n/a
• Funding: not reported

(Hsiao, Stahl et al. 2011)

Review

n = 73 (HL: n= 27)

Inclusion Criteria:

• persistent postchemotherapy azoospermia

• not reported

n = 73

testicular sperm extraction (TESE)

Baseline characteristics:

• Age: mean: 34.5 years
• Stage: not reported
• Recurrence status: not reported

none

• successfully retrieved spermatozoa
• fertilization rate
• clinical pregnancy rate
• live birth rate

• OS: not reported
• PFS: not reported
• AE: not reported
• QoL: not reported
• Other:
• Sperm Retrieval and Reproductive Outcomes
• Sperm successfully retrieved: n= 27 (37%) on initial TESE
• overall sperm retrieval rate: 42.9% (36 of 84)
• fertilization rate: 57.1% per injected oocyte (198 of 347)
• clinical pregnancy rate: 50% (18 of 36)
• live birth rate: 42% (15 of 36) for the overall series
• 15 deliveries with five twin births, total of 20 healthy children
• first attempt TESE (per patient basis)
• clinical pregnancy rate: 48.1% (13 of 27)
• live birth rate: 48.1% (13 of 27), 18 healthy children (five twin births and eight singleton births)
• Factors Associated With Successful Sperm Retrieval
• no differences in age at TESE, FSH, luteinizing hormone, testosterone, time since chemotherapy, and average testis volume
• The presence of hypospermatogenesis seen on preoperative biopsy: associated with successful sperm retrieval (100%; six of six)
• Sertoli-cell only seen on preoperative biopsy: significantly lower sperm retrieval rate (38.2%; 21 of 55; P=.004)
• lower sperm retrieval in the group exposed to alkylating agents (21.4%; six of 28) versus those not exposed to alkylating agents (45.7%; 16 of 35; P=.048) or with unknown chemotherapy regimen (50%; five of 10; P = .11)
• Use of Medical Therapy
• 40% (26 of 65) were on medical therapy:

• testosterone significantly increased on therapy from a mean pretreatment value of 214 ng/dL (SD, ± 71) to 454 ng/dL (SD, ± 185; P= .001, paired t-test)
• sperm retrieval rates: similar for men who initially had a low testosterone and then received medical therapy (38.5%; 10 of 26) compared to men not on medical therapy (35.9%; 14 of 39; P=.83)

• Study Duration: June 1995 to December 2009
• Follow-up: no
• ITT: no
• Randomisation: no
• Blinding: no
• Funding: no
• Other limitations: retrospective

Beobachtungsstudien

Schwangerschaft

-

-

-

++¹

-

⊕⊝⊝⊝
very low 

Anzahl Spermatozyten

-

-

-

++¹

-

⊕⊝⊝⊝
very low