6. Pharmakologische Substanzen zur Verbesserung des Ernährungszustandes bei Personen mit fortgeschrittener Tumorerkrankung – Klinische Ernährung in der Onkologie

Reference

Level of Evidence

Trial design

Patients n

Patients characteristics

Intervention/methods

Outcome

Results

Chlebowski et al., 1986: Influence of nandrolone decanoate on weight loss in advanced non-small cell lung cancer. Cancer

Ib

RCT

37

patients with unresectable non-small cell lung cancer undergoing combination chemotherapy

Patients were treated with doxorubicin, cyclophosphamide, CCNU, and vincristine, with and without cisplatin, all given every 28 days. In addition, patients were randomized to receive either nandrolone decanoate 200 mg intramuscularly weekly for 4 weeks (n=17) or no additional therapy (n=20).

Effect of a 4 week treatment with nandrolone decanoate on body weight, performance score, antitumor response to chemotherapy and survival

Patient age, disease extent, performance score, and pretreatment weight loss were similar in the two treatment arms. Objective antitumor response frequency and survival were comparable on both treatment arms. There was no difference in weight loss.

Loprinzi et al., 1999: Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia

Ib

RCT

475

Patients suffering from cancer anorexia/ cachexia

Patients were randomized to receive either dexamethasone 0.75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid.

The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia.

Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P=0.03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P=0.06).

Burney et al.
2012: Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia

Ib

OBS

45

50

45

males with cancer-cachexia male cancer patients without cachexia male noncancer controls

cross-sectional study; enrolled were patients from a tertiary-care center. Total testosterone, bioavailable testosterone, C-reactive protein (CRP), and IL-6 were measured in plasma. Functional performance was assessed by the Eastern Cooperative Oncology Group (ECOG) and Karnofsky Performance Scales (KPS), and sexual function was assessed by the International Index of Erectile Function (IIEF)

inflammation, and symptom relationship between serum testosterone levels, burden.

Low testosterone levels were seen in more than 70% of patienst with cancer cachexia. Total testosterone was lower in cancer patients with cachexia compared to non-cachectic patients. Also, cachectic patients had lower bioavailable testosterone, grip strength, IIEF scores, appendicular lean body mass, and fat mass and higher IL-6 and CRP compared to controls. ECOG and KPS were lower in both cachectic and non-cachectic cancer patients compared to controls. On multiple regression analysis, total testosterone, albumin, and CRP predicted symptoms differentially in cancer patients.

Wright et al. 2018: A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women

LoE 2

RCT/Phase II

Double-blind

Prospective

Monocentric

n=24 (randomized)

http://clinicaltrials.gov number NCT00878995

Country: Texas (US)

Study period: discrepant reporting between protocol (3 months) and publication (7 weeks)

18–75 years (men & women)

Advanced or recurrent squamous cell carcinoma of the cervix (stages IIB, IIIA, and IIIB) or advanced or recurrent head and neck squamous cell carcinoma (stage III or IV)

Lost at least 5% of body mass over the past 12 months

ECOG: 0-1

A: Testosterone (T)

100 mg T testosterone enanthate injection (im) 1x/week for 7 weeks.

(n=9)

B: Placebo (P)

Sterile saline injection 1x/week for 7 weeks.

(n=12)

Study duration:

47,0 ± 7,7 days (testosterone)

47,8 ± 9,6 days

(placebo)

Prim. EP:

1. LBM (DEXA)

Sec. EP:

2.Muscle strength (peak leg extension torque and power)

P n=7; T n=8

3. Physical performance (SPPB)

P n=8; T n=5

4.mREE (indirect calorimetry) & nutrition (SDR)

P n=8; T n=7

5. Activity (accelerometry monitor on the waist)

P n=10; T n=6

6. QoL (FACT-G)

P n=8; T n=8

7. 1-year survival

8. Safety

9. Blood chemistry (not reported here, as no patient-oriented outcome)

After 7 weeks:

1. LBM decreased in the placebo group by 2.0 kg or 3.3% (95% CI, -7.3% to 0.7%, p=0.09), and increased in the testosterone group by 1.3 kg or 3.2% (95% CI, -0.5% to 6.7%, p = 0.06). à The per cent change in lean body mass was significantly different between groups (p=0.015).

2. Muscle strength

The average per cent change in peak power was not significantly different between the placebo and testosterone groups (p=0.83).

3. Physical performance

The testosterone group had a clinically meaningful increase in total SPPB score of 1.4 (95% CI, 2.6 to 5.4) points following treatment (not significant)

4. mREE & nutrition

The average energy balance was more positive in the testosterone group than placebo, the values were variable and not significantly (p=0.63).

5. Activity

Pre and post study or between placebo and testosterone group à no significant difference

6. QoL

The testosterone group showed clinically meaningful improvement in total score (+4.5, 95% CI, -10.7 to 19.6) with no meaningful change in the placebo group (-3.1, (95% CI, -14.3 to 8.1) (not significant).

Result of subtest: Social well-being improved meaningfully in the testosterone group (+3.6) and had no meaningful change in the placebo group (-0.4). (p=0.05) (just significant)

7. Survival

Survival was not different between the two groups (p=0.96)

No of patients experiencing any adverse event:

Placebo: 7 (58.3%)

Testosterone:6 (66.7 %). p=1.000.

à no significant difference between groups

Funding

National Cancer Institute grant & the Institute for Translational Sciences at the Univer- sity of Texas Medical Branch, supported in part by a Clinical and Translational Science Award from the National Center for Advancing Translational Sciences, National Institutes of Health.

COI:

All authors declare that they have no COI.

RoB assessment:

High risk of bias (lean body mass)

Domain 1: Low

Domain 2: High

Domain 3: Some concerns

Domain 4: Low

Domain 5: High

à Data quality very low

PRO:

Study approved by Institutional Review Board

Power analysis reported (indicating that a sample size of 12 patients per group would provide >0.99 power to detect changes in lean body mass, with as few as 6 patients per group providing power >0.87)

CONTRA: Monocentric; small study size; risk of multiple testing without adjustment, risk of selective reporting

Rhee et al. 2021: A Novel Liver-targeted Testosterone Therapy for Sarcopenia in Androgen Deprived Men With Prostate Cancer

Level 2

RCT/pilot study

Double-blind

Prospective

Monocentric

n=50 (randomized)

Clinical Trials Registry: ACTRN12616001166460 (registration occurred after first participant had been enrolled).

Country: Australia

Study period: not reported

18–80 years

Men with prostate cancer on androgen deprivation therapy (ADT)

A: Testosterone (T)

40 mg oral testosterone (via LTTT*) daily for 6 months (analyzed n=19)

B: Placebo

Matching placebo capsules taken in an identical manner (analyzed n=23)

Stratifications: Participants were recruited into acute or chronic groups in a ratio of 2:3.

Prim. EP:

1. LBM (DEXA)

2. bone mineral content (DEXA)

Sec. EP:

3. Fat mass (DEXA)

4. Safety (at 3 & 6 months), mainly PSA

After 6 months:

1. LBM

A trend toward an increase of 0.5 kg (95% CI, −0.2 to 1.3) of LBM during LTTT and toward a fall of −0.2 kg (95% CI, −0.8 to 0.3) during placebo treatment resulting in a gain of 0.8 kg (1.3%; 95% CI, −0.1 to 1.7, p=0.04), compared to placebo.” à slight increase in LBM, not significant with significant level p=0.025, due to two primary endpoints.

2. “Mean BMC also increased during LTTT and fell during placebo treatment resulting in a significant gain of 49 g (1.7%; 95% CI, 5 to 93) g (p=0.014) over placebo treatment.”

3. Fat mass increased by 0.7 kg (2.1%) in both groups. (at the border to significance)

During the treatment phase, 5 testosterone patients were withdrawn from the study because of rising PSA levels.

The PSA concen- trations in all 5 patients returned to baseline levels after withdrawal.

Funding

National Prostate Cancer Foundation of Australia & Princess Alexandra Hospital Re- search Support Scheme.

COI:

The authors declare that they have no COI.

RoB assessment:

High risk of bias (lean body mass)

Domain 1: Low

Domain 2: High

Domain 3: High

Domain 4: Low

Domain 5: Some concerns

à Data quality very low

PRO: Study approved by Research Ethics Committee

CONTRA: Two primary endpoints, significant level should be p<0.05/2= 0.025;

the power analysis differs between protocol and publication;

small study size; patients with rising PSA were excluded from efficacy analysis set (no ITT); monocentric; application method of LTTT not approved to be appropriate.

Reference

Level of Evidence

Trial design

Patients n

Patients characteristics

Intervention/methods

Outcome

Results

Lundholm et al., 1994: Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumors

Ib

RCT

135;

45 patients in each group

patients with insidious or overt malnutrition due to generalized malignancy (various kinds of solid tumors); expected survival of more than 6 months

Group 1: placebo;

Group 2: prednisolone (10 mg twice daily)

Group 3: indomethacin (50 mg twice daily) p.o. until death;

effect of anti-inflammatory treatment on tumor progression in clinical cancer. Endpoints: physiological variables, nutritional state variables, fatigue and pain sensation, use of analgetics, handgrip strength, Karnowsky index, blood chemistry, energy expenditure

indomethacin and prednisolone treatment maintained Karnowsky index, placebo-treated patients experienced a decreased index; indomethacin-treated patients suffered less pain and consumed less additional analgetics compared to the other groups; indomethacin prolonged mean survival compared to placebo-treated patients from 250±28 days to 510±28 days (P<0.05); significantly prolonged survival by antiinflammatory treatment compared to placebo treatment (log rank, P<0.03)

Loprinzi et al., 1999: Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia.

Ib

RCT

475

Patients suffering from cancer anorexia/ cachexia

Patients were randomized to receive either dexamethasone 0. 75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid.

The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia.

Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P=0.03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P=0.06).

Yavuzsen et
al., 2005: Systematic review of the treatment of cancer-associated anorexia and weight loss

SR

55

RCT of appetite stimulants in the treatment of cancer anorexia

systematic assessment of relevant trials. Studies were graded according to quality.

efficacy and safety of appetite stimulants in the management of cancer-related anorexia.

Only two drugs have evidence to support their use for anorexia: progestins and corticosteroids. There is strong evidence against the use of hydrazine sulfate. The outcomes of these trials have been mixed and patient population heterogeneous.

Paulsen et al., 2014: Efficacy of methylprednisolone on pain, fatigue, and appetite loss in patients with advanced cancer using opioids: a randomized, placebo-controlled, double-blind trial.

Ib

RCT

97

patients with advanced cancer receiving opioids with average pain intensity ≥ 4 (numeric rating scale [NRS], 0 to 10) in the last 24 hours

IG: methylprednisolone (MP) 16 mg twice daily;

CG: placebo (PL) for 7 days.

Primary outcome was average pain intensity measured at day 7 (NRS, 0 to 10); secondary outcomes were analgesic consumption (oral morphine equivalents), fatigue and appetite loss and patient satisfaction (NRS, 0 to 10).

A total of 592 patients were screened; 50 were randomly assigned, and 47 were analyzed. Baseline opioid level was 269.9 mg in the MP arm and 160.4 mg in the PL arm. At day-7 evaluation, there was no difference between the groups in pain intensity (MP, 3.60 v PL, 3.68; P=0.88) or relative analgesic consumption (MP, 1.19 v PL, 1.20; P=0.95). Clinically and statistically significant improvements were found in fatigue (-17 v 3 points; P=0.003), appetite loss (-24 v 2 points; P=0.003), and patient satisfaction (5.4 v 2.0 points; P=0.001) in favor of the MP compared with the PL group, respectively. There were no differences in adverse effects between the groups.

Miller et al.,
2014: Use of corticosteroids for anorexia in palliative medicine: a systematic review

SR

8

Studies in adult patients with life-limiting diagnoses prescribed corticosteroids for anorexia in any care setting.

A search of MEDLINE and CINAHL was carried out to identify original studies relevant to this question. Data was extracted and a narrative analysis was carried out. Quality of studies was assessed using the system used by the Scottish Intercollegiate Guidelines Network for grading evidence

Effectivity of corticosteroids, and the most safe and effective dosing regimen for management of anorexia in palliative care patients.

used were wide ranging, and a variety of tools The corticosteroid drugs and dosing regimens were used to assess appetite within these studies. Changes in appetite with the corticosteroids used did not always reach statistical significance. It was not possible to identify the most effective corticosteroid drug, dose, or duration of treatment from the identified studies: the best quality evidence was for an eight-week course of intravenous methylprednisolone; however the studies using this regimen had the highest attrition rates.

Currow et al., 2021: A randomised, double blind, placebo‐controlled trial of megestrol acetate or dexamethasone in treating symptomatic anorexia in people with advanced cancer

LoE 2

RCT/Phase III

Prospektiv

Multizentrisch

Verblindet

N = 190

Land: Australien

Rekrutierung: Jan 2009 bis Mar 2015

≥18 Jahre; Krebsdiagnose im fort-geschrittenen Stadium; einem Palliativteam bekannt; Appetitscore ≤4 (NRS von 0-10) für mind. 2 Wochen; ECOG 0-3 oder AKPS 30-100

Häufigste Krebsarten:

Lungenkrebs (29,5%), Kolorektalkrebs (13,2%), Prostatakrebs (12,1%), andere GI Krebsarten (10,5%);

A: Dexamethason (4 mg/Tag)

(N=67)

B: Megestrolacetat 480 mg/Tag (N=61)

C: Placebo (N=62)

Behandlung bis zu vier Wochen.

Prim EP:

1. Appetit (am Ende 1. Woche)

Sek. EP:

2. Gewicht

3.Leistungs-status (AKPS)

4. Appetit

(Item zur Appetitstörung aus dem MSAS & Abschnitt "Zusätzliche Bedenken" des FAACTs.

5. QoL (FACT-G)

T0: Baseline

T1-T4: Wöchentliches Assessment, ob Responder à Wenn keiner, dann geplanter Ausstieg aus der Studie.

Definition Responder: Verbesserung des NRS um ≥ 25 % gegenüber dem Ausgangswert

Nach 1. Woche:

1. Appetit (NRS)

Anteil Responder:

A: 65,5% (Dexa)

B: 79,3%

C: 58,5% (Placebo)

à Die Unterschiede zwischen den Gruppen sind nicht signifikant (p = 0,067)

2. Gewicht

Anteil Responder:

A: 74% (Dexa)

B: 87%

C: 85% (Placebo)

à „Es gab keine Unterschiede beim Gewicht zwischen den Gruppen (p=0,2417)“

3. AKPS:

A: 95% (Dexa)

B: 98%

C: 92% (Placebo)

à „Es wurden keine Unterschiede in Bezug auf den Leistungsstatus festgestellt (p=0,3367)“

4. Appetit:

MSAS

A: 38,3% (Dexa)

B: 68,2%

C 48,9% (Placebo)

(p = 0,3114).”

à „Es gab keinen Unterschied in der MSAS-Appetit-Ansprechrate“

FAACT

à „Es gab keinen Unterschied im Anteil der Responder auf der FAACT-Subskala für Anorexie.“

5. QoL: Total Score (SD)

FACT-G:

A: -4,8 (3,4) (Dexa)

B: -2,1 (3,4)

C: -0,8 (3,4) (Placebo)

CQOLC:

A: 79,8 (6,5) (Dexa)

B: 89,6 (7,1)

C: 81,2 (7,9) (Placebo)

à„Es wurden keine Unterschiede in Bezug auf die Lebensqualität festgestellt (p=0,576 & p=0,520)“

„Unerwünschte Ereignisse, die bei der Behandlung auftraten, gab es vergleich-bar in allen Gruppen.  Hyperglykämie und tiefe Venenthrombosen traten unter Dexamethason häufiger auf als in den beiden anderen Gruppen.“

Finanzierung:

Commonwealth of Australia

COI:

Die Autoren erklären, dass sie keine konkurrierenden Interessen haben.

RoB-Qualitäts-bewertung (bezügl. des primären Endpunkts Appetit nach einer Woche):

Some concerns (Some concerns in Domäne 2 & 3 des RoB2.0 Cochrane-Tools)

à Studienqualität moderat

PRO:

Ethikvotum

Power-Analyse

Multizentrisch

Reference

Level of Evidence

Trial design

Patients n

Patients characteristics

Intervention/methods

Outcome

Results

Loprinzi et al., 1999: Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia

Ib

RCT

475

Patients suffering from cancer anorexia/ cachexia

Patients were randomized to receive either dexamethasone 0.75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid.

The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia.

Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P=0.03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P=0.06).

Jatoi et al., 2002: Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study.

Ib

RCT

469

Adult patients with histologic evidence of an incurable malignancy other than brain, breast, ovarian, or endometrial cancer

Group 1: oral megestrol acetate 800 mg/d liquid suspension plus placebo, Group 2: oral dronabinol 2.5 mg twice a day plus placebo,

Group 3: both agents

To determine whether dronabinol administered alone or with megestrol acetate was more, less, or equal in efficacy to single-agent megestrol acetate for palliating cancer-associated anorexia.

Groups were comparable at baseline in age, sex, tumor type, weight loss, and performance status. A greater percentage of megestrol acetate-treated patients reported appetite improvement and weight gain compared with dronabinol-treated patients: 75% versus 49% (P=0.0001) for appetite and 11% versus 3% (P=0.02) for ≥10% baseline weight gain. Combination treatment resulted in no significant differences in appetite or weight compared with megestrol acetate alone. The Functional Assessment of Anorexia/Cachexia Therapy questionnaire, which emphasizes anorexia-related questions, demonstrated an improvement in quality of life (QOL) among megestrol acetate-treated and combination-treated patients. The single-item Uniscale, a global QOL instrument, found comparable scores. Toxicity was also comparable, with the exception of an increased incidence of impotence among men who received megestrol acetate.

Jatoi et al., 2004: An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: a North Central Cancer Treatment Group and National Cancer Institute of Canada collaborative effort

Ib

RCT

421;

IG 1: 141, IG 2: 140, IG 3: 140

advanced cancer patients who are suffering from cancer-associated wasting

IG 1: an EPA nutritional supplement 1.09 g administered bid plus placebo; IG 2: megestrol acetate (MA) liquid suspension 600 mg/d plus an isocaloric, isonitrogenous placebo

IG 3: both agents (Megestrol Acetate + EPA);

administered twice a day

effect of an EPA-containing nutritional supplement—either alone or in combination with MA—on weight, appetite, quality of life, and survival, compared with MA alone

a smaller percentage taking the EPA supplement gained ≥10% of baseline weight compared with those taking MA: 6% v 18%, respectively (P=0.004); combination therapy resulted in weight gain of ≥10% in 11% of patients (P=0.17 across all arms); the percentage of patients with appetite improvement was not statistically different (P=0.69); 4-week Functional Assessment of Anorexia/Cachexia Therapy scores suggested MA-containing arms experienced superior appetite stimulation compared with the EPA arm, with scores of 40, 55, and 55 in EPA-, MA-, and combination-treated arms, respectively (P=0.004); survival was not significantly different among arms; global quality of life was not significantly different

Yavuzsen et
al., 2005: Systematic review of the treatment of cancer-associated anorexia and weight loss

SR

55

RCT of appetite stimulants in the treatment of cancer anorexia

systematic assessment of relevant trials. Studies were graded according to quality.

efficacy and safety of appetite stimulants in the management of cancer-related anorexia.

Only two drugs have evidence to support their use for anorexia: progestins and corticosteroids. There is strong evidence against the use of hydrazine sulfate. The outcomes of these trials have been mixed and patient population heterogeneous.

Ruiz Garcia et al., 2013: Megestrol acetate for treatment of anorexia-cachexia syndrome

SR

35

RCT, including 3,963 patients with a clinical diagnosis of anorexia-cachexia syndrome related to cancer, AIDS or any other underlying pathology; studies were included if they assessed megestrol acetate (MA) compared to placebo or other drug treatments

search of electronic databases, journals, and other search strategies outlined in the We sought studies through an extensive reference lists, contact with investigators methods. The most recent search for this quality. We performed quantitative analyses independent review authors conducted data update was carried out in May 2012. Two extraction and evaluated methodological using appetite and quality of life as a dichotomous variable, and analyzed weight gain as continuous and dichotomous variables.

To evaluate the efficacy, effectiveness and safety of MA in palliating anorexia-cachexia syndrome in patients with cancer, AIDS and other underlying pathologies.

Sixteen trials compared MA at different doses with placebo, seven trials compared different doses of MA with other drug treatments and 10 trials compared different doses of MA. Meta-analysis showed a benefit of MA compared with placebo, particularly with regard to appetite improvement and weight gain in cancer, AIDS and other underlying patients when MA was compared to other conditions, and lack of benefit in the same drugs. There was insufficient information to define the optimal dose of MA, but higher doses were more related to weight improvement than lower doses. Quality of life improvement in patients was seen only when comparing MA versus placebo but not other drugs in both subcategories: cancer and AIDS. Edema, thromboembolic phenomena and deaths were more frequent in the patients treated with MA. More than 40 side effects were studied.

Y. L. Lim et al., 2022: A Systematic Review and Meta-Analysis of the Clinical Use of Megestrol Acetate for Cancer-Related Anorexia/Cachexia

LoE 1

SR & MA

SR: 23 RCTs mit 3790 TN

MA: 8 Studien (N=576) für Meta-Analyse (MA) (Endpunkt Gewichtszunahme)

Suche:

JAN 1988 -

MAY 2021

Onkologische Patienten mit Anorexie oder Kachexie

(jedes Alter)

Max. Studiendauer 8 Monate.

Studiengrößen: 6 - 475 TN (MA: 12-158 TN).

Zwei Studien mit pädiatrischen Patienten (nicht in MA)

Länder: Australien, Kanada, China, Italien, Taiwan, UK, USA

A: Megestrol-Azetat

Subgruppen: Hohe (>320mg/Tag) versus niedrige Dosierung (≤320mg/Tag)

B: Placebo/ andere Substanzen/ andere Dosierungen / Messung an unterschiedlichen Zeitpunkten).

Prim. EP

1. Gewicht (kg)

2. QoL

Zu 1. MA:

„8 Studien lieferten ausreichende Daten zur Gewichts-veränderung.“

Alle folgenden Ergebnisse sind statistisch nicht signifikant:

„Die Gewichts-veränderung bei Megestrol-Azetat betrug unabhängig von der Dosierung 0,75 kg [95% KI -1,64; 3,15]“.

„Die Gewichts-veränderung mit hochdosiertem Megestrol-Acetat betrug -0,5 kg [95% KI -2,71; 22,60].“

„Die Gewichts-veränderung mit niedrig dosiertem Megestrol-Azetat betrug 2,24 kg [95% KI -7,19; 11,67].“

Zu 2. „Die Lebensqualität scheint sich nicht zu verbessern. Dies wurde allerdings nur in wenigen Studien untersucht.“

„Megestroazetat wurde im Allgemeinen gut vertragen, mit Ausnahme eines eindeutigen Thrombo-embolierisikos, insbesondere bei höheren Dosen.“

SR:

Folgende CoI: Erst- und Letztautor sind Mitarbeiter der Holdinggesellschaft für Singapurs Gesundheitseinrichtungen (MOH Holdings Pte Ltd.). Laut Angabe war die Holding nicht an der Abfassung oder Vorbereitung des Manuskripts beteiligt.

Primärstudien:

Keine Angaben zu den CoI

SR-Bewertung: low quality

CONTRA:

Es liegt beträchtliche Heterogenität zwischen den Studien vor (I²>90%), sodass eine Auswertung als MA per se in Frage gestellt werden kann à Interpretation der Ergebnisse mit Vorsicht.

Autoren haben 2x gleiche Datenbank durchsucht (Pubmed & OVID Medline).

Funnel Plot (Publikationsbias) mit 8 Studien (für eine valide Aussage sind mind. 10 Studien notwendig)

PRO: RoB-Bewertung der Studien mit Cochrane Tool; Evidenztabelle zu Primärstudien.

Qualität

Primärstudien:

RoB: 18 Studien mit „high-risk“ & 5 Studien mit „unclear“ bewertet

Ruiz-Garcia et al., 2018: Megestrol acetate for chachexia-anorexia syndrome. A systematic review

LoE 1

SR & MA

38 RCTs (4304 TN)*

Nur Krebs:

25 RCTs (zwei neue seit Ruiz-Garcia 2013: Kanat, 2013 und Baker, 2014. Achtung Baker ist eine Kinderstudie

Suche:

MAI 2012 –

NOV 2016

Patienten mit definierter Kachexie, Anorexie oder Gewichtsverlust (jedes Alter)

A: Megestrolazetat

B: Placebo

C: Keine Behandlung

D: Aktive Substanz

1. Gewicht (kg)

2. QoL

3. Tod

Zu 1.

Versus Placebo:

à Gewichtszunahme (Ergebnis signifikant)

2,36 kg [95% KI 1,00; 3,71] à Achtung Kinderstudie, siehe MA unten.

(4 RCTs; N=250; Studienqualität niedrig)

Versus keine Behandlung:

à Gewichtszunahme (Ergebnis signifikant)

1,45 kg [95% KI 0,15; 2,75]

(2 RCTs; N=101, “we judged the quality of evidence for weight gain to be low”)

Zu 2.QoL gain:

Versus Placebo: à kein signifikanter Unterschied, siehe MA unten; (1 RCT; N=33)

Versus keine Behandlung:

à kein signifikanter Unterschied:

-3.89 [95% KI -14.07, 6.28] (2 RCTs; N=99)

Versus aktive Substanz:

à kein signifikanter Unterschied:

0.20 [95% KI 0.02; 0.43] (1 RCT; N=469)

Zu 3. Nicht spezifisch für Krebspatienten berichtet

AEs: “Unerwünschte Ereignisse”

als Risk Ratio (Referenz: 1,00):

Versus keine Behandlung:

à kein signifikanter Unterschied zwischen den Gruppen:

RR 0.90, 95% KI [0.39, 2.08]

(2 RCTs; N=99)

Daten aus anderen Armen sind nicht spezifisch für Krebspatienten berichtet. Alle Patienten: „Overall, participants treated with Megestrol-Azetat at any dose reported a higher number of adverse events (relative risk, RR 1.46, 95% CI [1.05, 2.04]; 8 studies, 638 participants).”

SR: Laut Angabe keine CoI

Primärstudien:

Keine Angaben zu den CoI

SR-Bewertung: moderate quality

PRO: RoB-Bewertung der Studien mit Cochrane Tool

CONTRA:

Keine Evidenztabelle zu den Primärstudien, außer den 2 neuen Krebsstudien sind aber alle im Cochrane-Review Ruiz-Garcia (2013) zu finden.

Qualität Endpunkte:

weight gain/ Placebo: moderate quality of evidence (alle Erkrankungen)

weight gain/ keine Behandlung: low quality of evidence

QoL/Placebo: very low quality of evidence (alle Erkrankungen)

QoL/keine Behandlung:

very low quality of evidence

QoL/aktive Substanz: low quality of evidence

Safety (AEs): very low quality of evidence

Safety (AEs): moderate quality of evidence (alle Erkrankungen)

Studienqualität (Figure 2):

Versus Placebo:

Baker 2014: High RoB

De Conno 1998: High RoB

Fietkau 1996: High RoB

Loprinzi 1990: Unclear RoB

Versus keine Behandlung:

Madeddu 2012: High RoB

Kanat 2013: High RoB

Versus aktive Substanz:

Jatoi 2002: Unclear RoB