Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis

Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis Purpose To systematically review the effectiveness of medical treatment for Cushing’s syndrome in clinical practice, regard- ing cortisol secretion, clinical symptom improvement, and quality of life. To assess the occurrence of side effects of these medical therapies. Methods Eight electronic databases were searched in March 2017 to identify potentially relevant articles. Randomized controlled trials and cohort studies assessing the effectiveness of medical treatment in patients with Cushing’s syndrome, were eligible. Pooled proportions were reported including 95% confidence intervals. Results We included 35 articles with in total 1520 patients in this meta-analysis. Most included patients had Cushing’s dis- ease. Pooled reported percentage of patients with normalization of cortisol ranged from 35.7% for cabergoline to 81.8% for mitotane in Cushing’s disease. Patients using medication monotherapy showed a lower percentage of cortisol normalization compared to use of multiple medical agents (49.4 vs. 65.7%); this was even higher for patients with concurrent or previous radiotherapy (83.6%). Mild side effects were reported in 39.9%, and severe side effects were seen in 15.2% of patients after medical treatment. No meta-analyses were performed for clinical symptom improvement or quality of life due to lack of sufficient data. Conclusions This meta-analysis shows that medication induces cortisol normalization effectively in a large percentage of patients. Medical treatment for Cushing’s disease patients is thus a reasonable option in case of a contraindication for surgery, a recurrence, or in patients choosing not to have surgery. When experiencing side effects or no treatment effect, an alternate medical therapy or combination therapy can be considered. Keywords Cushing’s syndrome · Cushing’s disease · Medical treatment · Effectiveness · Side effects Introduction Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1110 2-018-0897-z) contains Cushing’s syndrome due to endogenous glucocorticoid supplementary material, which is available to authorized users. excess is either adrenocorticotropic hormone (ACTH)- dependent or ACTH-independent, both with a variety of * Leonie H. A. Broersen L.H.A.Broersen@lumc.nl underlying causes [1]. Cushing’s disease results from an ACTH-secreting pituitary adenoma and has a reported inci- Department of Medicine, Division of Endocrinology, Leiden dence of approximately 1.2–2.4 patients per million each University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, year [2]. Ectopic Cushing’s syndrome is a rare condition The Netherlands resulting from a non-pituitary ACTH-producing source. Center for Endocrine Tumors Leiden (CETL), Leiden ACTH-independent Cushing’s syndrome is caused by a cor- University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands tisol-producing adrenal adenoma or carcinoma [1]. Excess of glucocorticoids alters body composition and metabolic Department of Endocrinology, Diabetes and Nutrition, Charité Universitätsmedizin Berlin, Chariteplatz 1, profile, inducing fat maldistribution, muscle wasting, insulin 10117 Berlin, Germany resistance, dyslipidemia, hypercoagulability, and increasing Department of Clinical Epidemiology, Leiden University the risk of osteoporosis, hypertension, and neuropsychiatric Medical Center, Albinusdreef 2, 2333 ZA Leiden, disorders [3, 4]. The Netherlands Vol.:(0123456789) 1 3 Pituitary Transsphenoidal pituitary adenomectomy is a well-estab- analysis. Articles irretrievable online were requested by con- lished and effective treatment for Cushing’s disease [5 ]. tacting the authors. Only articles in the English language Cushing’s syndrome is generally approached by removing were considered. the ACTH-producing tumor in ectopic Cushing’s syndrome and by adrenalectomy in ACTH-independent Cushing’s syn- Search strategy drome [6]. However, there is increasing experience with first line medical treatment, both for patients with contraindica- To identify potentially relevant articles, PubMed, Embase, tions for surgery and for patients with recurrent disease [7]. Web of Science, COCHRANE Library, CENTRAL, Emcare, Furthermore, drugs can be used to control cortisol secretion LWW and ScienceDirect were systematically searched in preoperatively and to bridge the time period until control March 2017 in cooperation with a specialized librarian (see of hypercortisolism is achieved by radiotherapy [7]. Drugs Online Resource 1 for the complete search strategy). The used in medical practice vary per country and underlying search was repeated in PubMed in May 2017. Furthermore, cause of Cushing’s syndrome and include ketoconazole, references of included articles were searched to increase the metyrapone, mitotane, cabergoline, pasireotide, and mife- number of potentially eligible articles. pristone [7, 8]. A recent review described the percentage of patients achieving cortisol normalization after mono- Data extraction therapy with the steroidogenesis inhibitors ketoconazole and metyrapone [9]. However, until now no systematic review All identified articles were imported in EndNote 8 (Thomson and meta-analysis has been performed to summarize the Reuters, Philadelphia, PA, USA). Studies were screened by effectiveness of all medical agents used in clinical practice title and abstract and two independent reviewers reviewed (ketoconazole, metyrapone, mitotane, cabergoline, pasire- potentially relevant articles in detail. The Meta-analysis Of otide, and mifepristone). Observational Studies in Epidemiology (MOOSE) guide- lines were used for reporting [10]. Study aims From included articles we extracted the following data: number and type of Cushing’s syndrome patients included, The primary aim of the present systematic review and meta- type of medical agent used, treatment dose, treatment dura- analysis was to evaluate the effectiveness of medical treat- tion, duration of follow-up, number of patients pre-treated ment for Cushing’s syndrome in clinical practice. Effective- with medication before surgery, number of patients with ness of medical treatment was evaluated regarding cortisol normalization of cortisol, clinical improvement, well-being, secretion, clinical symptom improvement, and quality of quality of life, and side effects. Where available, separate life. The secondary study aim was to compare these medi- outcomes were extracted for patients with primary treat- cal therapies according to occurrence of side effects. ment (before any other treatment for Cushing’s syndrome) and patients with secondary treatment (after recurrence or failure of surgery and/or radiotherapy). For clinical improve- Methods ment, all reported symptoms as well as general statements (e.g. “Clinical signs regressed in full responders”, without Eligibility criteria specifying which clinical signs) were extracted. However, only hypertension and diabetes mellitus were considered Randomized controlled trials and cohort studies assessing for analysis, because these symptoms were expected to be the effectiveness of FDA/EMA approved medical treatment reported homogeneously by multiple articles. For quality of for treatment of Cushing’s syndrome, either de novo or with life, all general and Cushing’s disease specific questionnaires persistent or recurrent disease, were eligible for inclusion, were considered. All reported side effects were extracted. as well as cabergoline, which has been used for Cushing’s syndrome in multiple investigator initiated clinical trials. Risk of bias assessment Medical agents considered were ketoconazole, metyrapone, mitotane, cabergoline, pasireotide, and mifepristone. Arti- We used a component approach to assess risk of bias for all cles were excluded if reporting broad inclusion categories included studies. The following components were included, without separating the subgroup of Cushing’s patients, or which could potentially bias a reported association between if the study included children (age < 18 years) only. For eli- medical treatment for Cushing’s syndrome and outcome: gibility, at least ten patients had to be included per treat- ment group to minimize risk of selection bias. For multiple 1. Inclusion of patients (consecutive inclusion from all articles describing (partially) overlapping populations, the patients eligible or a random sample is considered low article with the largest study population was included in the risk of bias) 1 3 Pituitary 2. Loss to follow-up (< 5% is considered low risk of bias) mentioned medical agents at the same time or consecutively 3. Criteria for diagnosis of Cushing’s syndrome adequately were assessed separately. reported (see below) For normalization of cortisol, all measurements of corti- 4. Outcome measurement for cortisol normalization: uri- sol were considered. However, measurement of urinary free nary free cortisol, midnight salivary cortisol or a low cortisol, midnight salivary cortisol or morning cortisol after a dose dexamethasone test is considered low risk of bias low dose dexamethasone test was considered low risk of bias 5. Reporting of outcome definition (see below) (see above). Data on reduction of cortisol as a percentage of 6. Description of protocol for laboratory measurements baseline were not considered for analysis. (see below) Secondary outcomes were the pooled percentages of 7. Description of dose and duration of intervention (see patients with mild or severe side effects stratified by medical below) agent. Severe side effects were considered those that required therapy adjustment or withdrawal, as well as all side effects As criteria for diagnosis of Cushing’s syndrome vary categorized as severe by the authors. Mild side effects were all widely over time and even by study center, and per under- not categorized as severe. For articles reporting only specific lying etiology, adequately reporting the criteria used for side effects, the side effect that affected the most patients was diagnosis is considered a low risk of bias. Reporting of out- included in the analysis. come definition is considered adequate if the article at least Subgroup analyses were performed according to indication mentioned which outcome was studied, which test was used (primary therapy, including pre-treatment before surgery, and to determine the outcome, and if applicable, which corti- therapy for recurrence) if described separately. As few stud- sol level had to be measured. Description of protocol for ies provided separate data for primary/secondary analysis, a laboratory measurements is considered adequate if the assay separate subgroup analysis was performed, in which studies used for measuring cortisol is reported, or the assay for the were categorized as low (≤ 20%) or high (≥ 80%) percentage main outcome if this was not cortisol. Description of dose of patients using medical agents as pre-treatment before sur- and duration of intervention is considered adequate if dose gery. A separate analysis was performed for normalization of (per day or per week) and duration of medical treatment are cortisol according to the presence of multiple medical treat- reported (average and range, or exact dose and duration if ments and concurrent or previous radiotherapy. this is equal for all patients). Also considered adequate is reporting of exact treatment protocol for trials with dose Statistical analysis increase based on cortisol levels. Referring to another pub- lished article in which the information is reported is also A random-effects logistic regression model was used to pool considered adequate. percentages for analyses including ≥ 5 articles, whereas a Risk of bias assessment was conducted to explore poten- fixed-effects logistic regression model was used for analyses tial heterogeneity. As there were no studies that compared including < 5 articles. All pooled percentages are accompa- two different medical agents directly, confounding was not nied by 95% confidence intervals. The Freeman-Tukey arc- judged at the study level, but was assessed by comparing sine transformation was used to stabilize variances, in order baseline characteristics for all included studies. to prevent exclusion of studies with 0 or 100% as outcome. All analyses were performed using Stata 11.2 (Stata Corp., Study endpoints College Station, TX, USA). Sensitivity analyses were performed for normalization of Primary outcome of this study was the effectiveness of medical cortisol for low risk of bias studies, and for the combination treatment for Cushing’s syndrome, represented by the pooled of low and intermediate risk of bias studies. Articles were con- percentage of patients reaching normalization of cortisol sidered low risk of bias if they adhered to at least six (out of secretion (definition according to the authors) after medical seven) of the above mentioned criteria for risk of bias. Only treatment, patients showing symptom improvement, improved one article adhered to all seven criteria [11]. Articles were well-being and improved quality of life. Main analyses were considered intermediate risk of bias if they adhered to five of performed in studies reporting on pituitary Cushing patients. the above mentioned criteria for risk of bias. Separate analyses were performed for publications reporting on (1) mixed etiologies other than adrenocortical carcinomas, (2) mixed etiologies including adrenocortical carcinomas, and (3) ectopic Cushing only, if sufficient data were available. Studies were categorized according to type of medical agent (ketoconazole, metyrapone, mitotane, cabergoline, pasireotide, and mifepristone). Studies using more than one of the above 1 3 Pituitary as an outcome). There were 25 studies reporting on clini- Results cal improvement, and three studies reporting on quality of life. Study selection Baseline characteristics of included studies show clear differences between studies. Reported average age varied The initial search identified 960 potentially relevant arti- between 32.2 and 60.0  years. Percentage female varied cles. Searching through references of included articles between 21.7 and 95.0%. Average duration of follow-up identified one additional article, thereby yielding a total was 2 weeks to 11.5 years. Seven articles reported that at of 961 articles. By screening these articles by title and least part of their study population received radiotherapy in abstract, 874 articles were excluded. The remaining 87 addition to medical treatment (two with mitotane, one with articles were reviewed in detail. Reasons for exclusion are ketoconazole, and four with metyrapone). Pasireotide and summarized in Fig. 1. In total, 35 articles were included, cabergoline were used only for pituitary Cushing’s disease, reporting on six different drugs. whereas all other medical agents were used for various eti- ologies of Cushing’s syndrome. Study characteristics (Online Resource 2) Risk of bias assessment (Online Resource 3) We included five studies on mitotane [12– 16], two on Loss to follow-up [reported in twelve studies (34%)] ranged pasireotide [17, 18], three on cabergoline [19–21], eight from 0 to 60%. Inclusion of consecutive patients or a random on ketoconazole [22–29], five on metyrapone,[30– 34] sample was explicitly stated in seventeen articles (49%). Cri- two on mifepristone [35, 36], and ten on multiple medi- teria for diagnosis of Cushing’s syndrome were adequately cal agents [11, 37–45]. Studies were published between reported in 31 articles (89%). Reporting of outcome defini- 1971 and 2017. There were eleven single-arm trials, two tion was adequate in 25 articles (71%). Description of proto- randomized trials with two treatment arms (pasireotide col for laboratory measurements was adequate in 23 articles 600 µg vs. pasireotide 900 µg; first cabergoline, then add (66%). Description of dose and duration of intervention was ketoconazole vs. first ketoconazole, then add cabergoline), adequate in 23 articles (66%). A total of nine articles were and 22 cohort studies. We included eighteen studies on with low risk of bias (adherent to at least six out of seven pituitary Cushing’s disease only, two on ectopic Cush- criteria) and another nine articles with intermediate risk of ing’s syndrome only, and fifteen on Cushing’s syndrome bias (adherent to five out of seven criteria). patients due to various underlying etiologies. In total, 1520 patients were included. There were 28 articles measuring Study outcomes normalization of cortisol by at least urinary free cortisol, midnight salivary cortisol or a low dose dexamethasone For 26 articles (1000 patients) normalization of cortisol test (88% of 32 articles reporting normalization of cortisol was reported as outcome measure. There were 25 articles reporting on clinical improvement. One article reported no improvement in any of the measured clinical symptoms (weight, blood pressure, glucose and HbA1c) [19]. All other Potenally relevant published arcles idenfied (n=961), Arcles excluded (n=874) articles reported improvement in one or more clinical symp- screened by tle and abstract -No original data: 276 toms. Well-being was not reported by any of the included -No Cushing’s syndrome: 64 -No medical treatment: 88 articles. Three articles (228 patients) reported on quality -Wrong medical agent: 7 -N<10: 254 of life. These reported an improvement in CushingQoL -Language other than English: 148 score, SF-36 score, and emotional reaction on the Not- -No human subjects: 35 -Children only: 2 tingham Health Profile (NHP), and on the other hand more Arcles reviewed in detail pain measured by the RAND-36 [18, 36, 44]. There were (n=87) Arcles excluded (n=52) 30 articles (86%) reporting at least one side effect. Two of -Same populaon: 13 these articles, using mifepristone, described an increase in -No relevant outcome: 19 -No separate analysis for Cushing’s cortisol levels during the study period in a total of 47 out of syndrome: 1 -N<10: 12 70 included patients (67%) [35, 36]. No meta-analysis was -Selecon on outcome: 3 performed for clinical improvement, as results were consid- -Wrong medical agent: 1 -No medical treatment: 2 ered too heterogeneous. Hypertension and diabetes mellitus Arcles included (n=35) -Only abstract available: 1 were described by heterogeneous articles (type of medical agent, etiology of Cushing’s syndrome) and the type of out- come was heterogeneous (difference in blood pressure and Fig. 1 Flow-chart of inclusion of articles in this systematic review 1 3 Pituitary glucose vs. number of patients with improved values, only more often showed mild side effects compared to the total patients with disturbed values at start of the study vs. all population (68.5 and 58.3%). patients analysed). Detailed study outcomes at the individual For pituitary Cushing’s disease, severe side effects were study level are reported in Online Resource 4. seen in 15.2% (95% CI 9.1–22.4%). In the group of mixed etiologies including adrenocortical carcinoma, patients using mifepristone showed severe side effects relatively Meta‑analyses of normalization of cortisol (Table 1; often (42.0%; 95% CI 30.4–54.0%). Due to the severe side Fig. 2: normalization of cortisol per medical agent effects, 23.9% (95% CI 15.9–32.8%) of patients adjusted in pituitary Cushing) their medical therapy, and 8.5% (95% CI 2.8–16.3%) of patients stopped their medical therapy. For Cushing’s disease, pooled reported treatment effect ranged from 32.3% if a large percentage of patients used medication as pre-treatment before surgery, to 83.6% if med- Discussion ication was combined with radiotherapy. When comparing medical agents, a relatively high percentage of patients using We performed a systematic review and meta-analysis to mitotane showed normalization of cortisol (81.8%), whereas evaluate effectiveness of medical treatment in routine clini- treatment with cabergoline and pasireotide less often nor- cal practice in Cushing’s syndrome. Medical treatment malized cortisol secretion (35.7 and 41.1%). For detailed was effective in normalizing cortisol levels in Cushing’s results, including data on different etiologies (mixed etiolo- syndrome in 35.7% (cabergoline) to 81.8% (mitotane) of gies other than adrenocortical carcinomas, mixed etiologies patients. Furthermore, the combined use of medical agents including adrenocortical carcinomas, and ectopic Cushing), at the same time or consecutively increased the percent- see Table 1. age of patients with normalized cortisol secretion (65.7%). Seven studies reported data separately for medication Importantly, medical agents for hypercortisolism can cause as primary (n = 4) and/or secondary therapy (n = 5). For severe side effects, leading to therapy adjustment or with- patients with pituitary Cushing’s disease, medication as drawal in 4.8% (cabergoline) to 28.4% (mitotane) of patients. primary therapy normalized cortisol in 58.1% (95% CI These results suggest that medical therapy can be considered 49.7–66.2%), similar to the effect of medication as sec- a reasonable treatment alternative to the first choice surgical ondary therapy, 57.8% (95% CI 41.3–73.6%). Articles in treatment when regarding treatment effectiveness and side which ≤ 20% of patients were medically pre-treated before effects. surgery showed normalization of cortisol in 59.7% of This study is the first systematic review and meta-analysis patients (95% CI 49.4–69.6%). Articles in which ≥ 80% of of all medical agents currently used in clinical practice for patients were pre-treated with medication before surgery Cushing’s syndrome. Only one previous study performed showed a preoperative normalization of cortisol in 32.3% a systematic review and meta-analysis of two medical (95% CI 20.0–45.8%) for patients with pituitary Cushing’s agents in Cushing’s syndrome. Daniel et al. studied nor- disease. Patients with medical monotherapy showed a rela- malization of cortisol after monotherapy with ketocona- tively low percentage of cortisol normalization. This per- zole or metyrapone, and found that urinary free cortisol centage was higher for patients using multiple agents, and normalized in 60% (ketoconazole) and that normalization highest for patients with concurrent or previous radiotherapy. of hypercortisolism as defined by the authors occurred in The sensitivity analyses, both excluding articles with high 75% of patients using metyrapone [9]. This is in line with risk of bias (n = 18 included), as well as excluding articles the results obtained in the current study (49.0–71.1% for with high and intermediate risk of bias (n = 9 included), ketoconazole and 60.0–75.9% for metyrapone depending showed similar results as the main analysis. The most on patient categories). Since our last search in May 2017, remarkable difference is that lower percentages of patients one more research article on medical treatment in Cush- with normalization of cortisol were seen for multiple medi- ing’s syndrome was published. Lacroix et al. described a cal agents in both sensitivity analyses than for multiple 12 month clinical trial using pasireotide in various dosages medical agents in the main analysis. in 150 patients. Urinary free cortisol normalized in 41.3% of patients. This is in line with our own results for corti- Meta‑analyses of side effects (Table 1; Fig. 3: side sol excretion normalization for patients using pasireotide effects per medical agent in pituitary Cushing) (41.1%). Adverse events grade 1–2 were described in up to 48% of patients, and adverse events grade 3–4 in up to 16% For pituitary Cushing’s disease, mild side effects were of patients. This is in line with our own results for mild side reported in 39.3% (95% CI 25.0–55.8%) of patients after effects (58.3%) and severe side effects (15.7%) for patients medical treatment. Patients using mitotane and pasireotide using pasireotide [46]. 1 3 Pituitary Table 1 Results of meta-analyses according to etiology of Cushing’s syndrome Pituitary Cushing’s disease All etiologies (pituitary, All etiologies (pituitary, Ectopic Cushing’s syn- adrenal, ectopic) other than adrenal, ectopic) including drome adrenal carcinoma adrenal carcinoma Estimated 95% confi- Estimated 95% confi- Estimated 95% confi- Estimated 95% confi- percent- dence interval percent- dence interval percent- dence interval percent- dence interval age (N) age (N) age (N) age (N) Normalization of cortisol 59.5 48.4–70.1 (18) 61.6 51.8–71.0 (22) 64.7 55.6–73.3 (26) 83.3 64.9–96.8 (3)  Per medical agent   Mitotane 81.8 75.4–87.6 (4) 81.8 75.4–87.6 (4) 79.8 73.3–85.7 (4) – –   Pasireotide 41.1 32.7–49.8 (2) 41.1 32.7–49.8 (2) 41.1 32.7–49.8 (2) – –   Cabergoline 35.7 24.6–47.6 (3) 35.7 24.6–47.6 (3) 35.7 24.6–47.6 (3) – –   Ketoconazole 49.0 42.0–56.0 (3) 49.3 42.6–56.0 (4) 71.1 51.6–87.5 (7) – – a a   Metyrapone 60.0 31.3–83.2 75.9 57.5–90.9 (2) 75.9 57.5–90.9 (2) – –   Mifepristone – – – – – – – –   Multiple medical agents 65.7 46.9–82.4 (5) 67.8 51.9–81.9 (7) 67.6 53.6–80.3 (8) – –  Primary treatment 58.1 49.7–66.2 (4) 49.4 41.3–57.5 (4) 49.4 41.3–57.5 (4) – –  Secondary treatment 57.8 41.3–73.6 (5) 48.6 41.2–56.1 (4) 48.6 41.2–56.1 (4) – –  Per percentage pretreatment   ≤20% 59.7 49.4–69.6 (8) 59.7 49.4–69.6 (8) 59.7 49.4–69.6 (8) – –   ≥80% 32.3 20.0–45.8 (2) 42.6 33.5–51.9 (3) 53.6 45.0–62.0 (4) – –  Adjuvant treatment   No other treatment 49.4 36.0–62.9 (10) 52.7 40.1–65.1 (12) 57.2 44.4–69.6 (14) – –   Multiple medical agents 65.7 46.9–82.4 (5) 67.8 51.9–81.9 (7) 67.6 53.6–80.3 (8) – –   Radiotherapy 83.6 75.5–90.4 (3) 83.6 75.5–90.4 (3) 84.8 78.0–90.6 (4) – –  Sensitivity analysis (low risk of bias) a a a a a a   Mitotane 71.6 59.9–81.0 71.6 59.9–81.0 71.6 59.9–81.0 – a a a a a a   Pasireotide 17.2 7.6–34.5 17.2 7.6–34.5 17.2 7.6–34.5 – –   Cabergoline 35.0 20.6–50.9 (2) 35.0 20.6–50.9 (2) 35.0 20.6–50.9 (2) – –   Ketoconazole – – – – – – – –   Metyrapone – – – – – – – –   Mifepristone – – – – – – – –   Multiple medical agents 50.6 40.9–60.2 (3) 50.6 40.9–60.2 (3) 50.6 40.9–60.2 (3) – –  Sensitivity analysis (low and intermediate risk of bias)   Mitotane a a a a a a   Pasireotide 71.6 59.9–81.0 71.6 59.9–81.0 71.6 59.9–81.0 – – a a a a a a   Cabergoline 17.2 7.6–34.5 17.2 7.6–34.5 17.2 7.6–34.5 – –   Ketoconazole 35.7 24.6–47.6 (3) 35.7 24.6–47.6 (3) 35.7 24.6–47.6 (3) – a a   Metyrapone 48.5 41.7–55.4 48.3 41.5–55.2 (2) 59.8 54.1–65.4 (4) a a a a   Mifepristone – – 83.3 60.8–94.2 83.3 60.8–94.2 –   Multiple medical agents 53.1 43.8–62.3 (4) 67.5 46.5–85.7 (5) 67.4 50.0–82.8 (6) Mild side effects 39.9 25.0–55.8 (13) 40.2 27.4–53.8 (15) 35.3 25.6–45.7 (23) – –  Per medical agent   Mitotane 68.5 59.1–77.2 (3) 68.5 59.1–77.2 (3) 69.1 60.0–77.6 (3) – –   Pasireotide 58.3 51.4–65.1 (2) 58.3 51.4–65.1 (2) 58.3 51.4–65.1 (2) – –   Cabergoline 24.0 14.4–35.1 (3) 24.0 14.4–35.1 (3) 24.0 14.4–35.1 (3) – –   Ketoconazole – – – – 22.6 15.1–31.0 (3) – – a a   Metyrapone 30.8 12.7–57.6 32.2 16.3–50.3 (2) 19.7 12.2–28.2 (3) – –   Mifepristone – – – – 35.6 24.5–47.4 (2) – –   Multiple medical agents 18.0 10.6–26.7 (4) 25.5 7.6–48.5 (5) 26.7 12.8–43.2 (7) – – Severe side effects 15.2 9.1–22.4 (12) 16.2 10.1–23.3 (14) 15.3 10.1–21.3 (21) – – 1 3 Pituitary Table 1 (continued) Pituitary Cushing’s disease All etiologies (pituitary, All etiologies (pituitary, Ectopic Cushing’s syn- adrenal, ectopic) other than adrenal, ectopic) including drome adrenal carcinoma adrenal carcinoma Estimated 95% confi- Estimated 95% confi- Estimated 95% confi- Estimated 95% confi- percent- dence interval percent- dence interval percent- dence interval percent- dence interval age (N) age (N) age (N) age (N)  Per medical agent   Mitotane a a a a a a 28.4 19.0–40.1 28.4 19.0–40.1 28.4 19.0–40.1 – –   Pasireotide 15.7 10.9–21.2 (2) 15.7 10.9–21.2 (2) 15.7 10.9–21.2 (2) – –   Cabergoline 4.8 0.5–11.9 (3) 4.8 0.5–11.9 (3) 4.8 0.5–11.9 (3) – – a a   Ketoconazole 20.5 15.5–26.6 18.8 13.5–24.6 (2) 14.2 10.3–18.7 (4) – – a a   Metyrapone 7.7 1.4–33.3 27.1 12.2–44.7 (2) 16.2 9.4–24.3 (3) – –   Mifepristone – – – – 42.0 30.4–54.0 (2) – –   Multiple medical agents 20.9 13.6–29.2 (4) 20.9 13.6–29.2 (4) 14.6 4.2–28.8 (6) – –  Result of severe side effect   Adjust therapy 23.9 15.9–32.8 (4) 23.6 10.0–40.4 (6) 20.4 8.6–35.2 (9) – –   Stop therapy 8.5 2.8–16.3 (9) 8.5 2.8–16.3 (9) 8.5 4.6–13.4 (15) – – N number of articles included in meta-analysis No meta-analysis was performed, as the total number of studies equaled 1 (results only shown for analyses per medical agent if other medical agents were reported in multiple articles) Fig. 2 Meta-analysis of normalization of cortisol after medical treatment in Cushing disease In interpreting the results, the following study limitations heterogeneity regarding outcome measurement for clini- need to be taken into account. There was a large amount cal symptoms (difference in blood pressure and glucose vs. of heterogeneity in included studies, regarding medical number of patients with improved values, only patients with agent, etiology of Cushing’s syndrome, indication for use disturbed values at start of the study vs. all patients ana- of medical therapy for Cushing (presurgical cortisol con- lysed), we were unable to perform a quantified analysis of trol, contra-indication for surgery, post-surgical therapy clinical improvement after medical therapy. Included articles failure or recurrence), outcome measurement (definition of showed various levels of risk of bias. However, sensitivity cortisol normalization), and concurrent or previous use of analyses excluding articles with high risk of bias or with radiotherapy. Heterogeneity concerning medical agent and high and intermediate risk of bias showed similar results to etiology was handled by performing separate analyses per the main analysis. medical agent and per etiology, although this substantially For patients with pituitary Cushing’s disease, first line reduced the number of articles in some categories. Due to transsphenoidal surgery yields better results than medical 1 3 Pituitary Fig. 3 Meta-analysis of side effects after medical treatment in Cushing disease therapy (80% remission). However, remission after a repeat increases the likelihood of successful treatment, i.e. in nor- surgery was shown to be only 42.6–55.7% in a recent meta- malizing cortisol levels. This suggests that sensitivity for analysis. Various complications occurred in up to 18.5% of different medical agents may vary per patient. patients [47]. This underlines that medical treatment is a No difference was shown in normalization of cortisol reasonable alternative to repeat surgical procedure. between patients using medical agents as primary treat- Differences in effectiveness and side effects between the ment vs. secondary treatment, suggesting that effectiveness various etiological groups were small. In ectopic Cushing’s of medical agents is independent of other treatment modal- syndrome only, a higher percentage of patients reached ities. A higher percentage of patients reaches normaliza- normalization of cortisol levels than in the other etiological tion of cortisol in studies where a small part of included categories. As there were only three articles with separate patients received medication preoperatively (including data on patients with ectopic Cushing’s syndrome (of which patients with contraindications to surgery and patients one article only reported on one patient with ectopic Cush- after previous surgery) than in studies where a large part of ing’s syndrome, besides reporting on Cushing patients with included patients received medication before elective sur- other etiologies), no further subanalyses were possible, and gery. The most likely explanation is that in patients with reliability of this result is uncertain. However, we found no planned surgery, medication is given to control cortisol explanation for this high percentage of cortisol normaliza- excess, and surgery is performed before complete normali- tion in ectopic Cushing’s syndrome when considering risk of zation of cortisol occurs. Unfortunately, we don’t know bias, type of medical agent, or additional treatment. the average time until cortisol normalization, as this was When comparing different medical agents, it seems that a not reported by most articles. Total follow-up time was high percentage of patients with cortisol normalization cor- not different for studies with a high percentage of medical responds to a high percentage of patients with side effects pre-treatment before surgery (average 0.1–11.5 years) than and vice versa. However, all dosages used and studied were for all included studies. It would be interesting to know if within the boundaries advised by the European Medicines the effectiveness of surgery is dependent upon the normali- Agency (EMA) and the food and drug administration (FDA). zation of cortisol with medical treatment before surgery It might mean that advised and commonly used dosages are compared to presurgical medical treatment without corti- in fact not the optimal dosages for treatment of Cushing’s sol normalization and compared to no presurgical medical syndrome considering the balance between treatment effect treatment at all. Especially in pituitary Cushing’s disease, and side effects. Furthermore, medical agents with a high the percentage of patients with preoperative medical treat- percentage of patients with normalized cortisol secretion ment that reaches cortisol normalization is low. This might (mitotane and metyrapone) are relatively often combined be due to the higher expectations of surgery in pituitary with radiotherapy, which may lead to overestimating the Cushing’s disease compared to other etiologies, which effect and side effects of the drug per se. The use of com- may be why surgery is performed before patients reach bined medical therapy, in combination or consecutively, normalization of cortisol levels. However, these results 1 3 Pituitary pseudo-Cushing’s states. Endocr Rev 19(5):647–672. https://doi. should be interpreted with caution, as a small number of org/10.1210/edrv.19.5.0346 articles were included in these analyses, and in the articles 2. Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt- with a mixed etiologies population, a large proportion of Rasmussen U, Hagen C, Jorgensen J, Kosteljanetz M, Kristensen included patients had pituitary Cushing’s disease [23, 43]. L, Laurberg P, Schmidt K, Weeke J (2001) Incidence and late prognosis of cushing’s syndrome: a population-based study. J Based on the current study, medication can be regarded Clin Endocrinol Metab 86(1):117–123. https ://doi.org/10.1210/ a valuable alternative to pituitary surgery for Cushing’s jcem.86.1.7093 disease patients with contraindications to surgery, patients 3. Fernandez-Rodriguez E, Stewart PM, Cooper MS (2009) The pitu- with a recurrence considering repeat surgery, and patients itary-adrenal axis and body composition. Pituitary 12(2):105–115. https ://doi.org/10.1007/s1110 2-008-0098-2 that choose not to undergo surgery. For all other Cushing’s 4. Pereira AM, Tiemensma J, Romijn JA (2010) Neuropsychi- disease patients, pituitary surgery remains the first-choice atric disorders in Cushing’s syndrome. Neuroendocrinology treatment. For other etiologies of Cushing’s syndrome, at 92(Suppl1):65–70. https ://doi.org/10.1159/00031 4317 present, there is insufficient evidence to recommend when 5. Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Muller OA, Fahlbusch R (2008) Long-term results after microsurgery to use medical treatment to lower cortisol levels. However, for Cushing disease: experience with 426 primary operations from the total group of patients, it suggests that medical over 35 years. J Neurosurg 108(1):9–18. https ://doi.org/10.3171/ agents have similar effectiveness in normalizing cortisol jns/2008/108/01/0009 levels for all etiologies of Cushing’s syndrome. For a higher 6. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A (2015) Treatment of Cushing’s syndrome: chance of treatment success, a different medical agent could an endocrine society clinical practice guideline. J Clin Endocrinol be tried if there is no treatment effect or if the patient expe- Metab 100(8):2807–2831. https ://doi.org/10.1210/jc.2015-1818 riences side effects. There is no evidence for which drug 7. Ciato D, Mumbach AG, Paez-Pereda M, Stalla GK (2017) Cur- should be used first. Based on the current study, mitotane or rently used and investigational drugs for Cushing s disease. Expert Opin Investig Drugs 26(1):75–84. https ://doi.org/10.1080/13543 metyrapone seem to be most effective in normalizing corti- 784.2017.12663 38 sol levels, but also cause the highest percentage of patients 8. Molitch ME (2017) Diagnosis and treatment of pituitary adeno- with side effects. mas: a review. JAMA 317(5):516–524. https ://doi.org/10.1001/ In conclusion, we consider medical treatment for Cush- jama.2016.19699 9. Daniel E, Newell-Price JD (2015) Therapy of endocrine disease: ing’s disease a reasonable option in patients with contrain- steroidogenesis enzyme inhibitors in Cushing’s syndrome. Eur J dication to surgery, with a recurrence, or that choose not Endocrinol 172(6):R263-280. https://doi.or g/10.1530/eje-14-1014 to have surgery. Patients that experience side effects or no 10. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Ren- treatment effect should be advised to start treatment with a nie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta- analysis of observational studies in epidemiology: a proposal for different medical agent to increase the chance of treatment reporting. Meta-analysis of observational studies in epidemiology success. (MOOSE) group. JAMA 283(15):2008–2012 11. van den Bosch OF, Stades AM, Zelissen PM (2014) Increased Funding This research did not receive any specific grant from any long-term remission after adequate medical cortisol suppression funding agency in the public, commercial or not-for-profit sector. therapy as presurgical treatment in Cushing’s disease. Clin Endo- crinol 80(2):184–190. https ://doi.org/10.1111/cen.12286 12. Baudry C, Coste J, Bou KR, Silvera S, Guignat L, Guibourdenche Compliance with ethical standards J, Abbas H, Legmann P, Bertagna X, Bertherat J (2012) Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from Conflict of interest The authors declare that they have no conflict of a single center. Eur J Endocrinol 167(4):473–481. https ://doi. interest. org/10.1530/EJE-12-0358 13. Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Hautecou- Ethical approval This article does not contain any studies with human verture M, Simon D, Laudat MH, Touitou Y, Bricaire H (1979) participants or animals performed by any of the authors. Treatment of Cushing’s disease by o,p’DDD. Survey of 62 cases. N Engl J Med 300(9):459–464. https ://doi.org/10.1056/NEJM1 97903 01300 0903 Open Access This article is distributed under the terms of the Crea- 14. 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Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis

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Medicine & Public Health; Diabetes; Human Physiology
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Abstract

Purpose To systematically review the effectiveness of medical treatment for Cushing’s syndrome in clinical practice, regard- ing cortisol secretion, clinical symptom improvement, and quality of life. To assess the occurrence of side effects of these medical therapies. Methods Eight electronic databases were searched in March 2017 to identify potentially relevant articles. Randomized controlled trials and cohort studies assessing the effectiveness of medical treatment in patients with Cushing’s syndrome, were eligible. Pooled proportions were reported including 95% confidence intervals. Results We included 35 articles with in total 1520 patients in this meta-analysis. Most included patients had Cushing’s dis- ease. Pooled reported percentage of patients with normalization of cortisol ranged from 35.7% for cabergoline to 81.8% for mitotane in Cushing’s disease. Patients using medication monotherapy showed a lower percentage of cortisol normalization compared to use of multiple medical agents (49.4 vs. 65.7%); this was even higher for patients with concurrent or previous radiotherapy (83.6%). Mild side effects were reported in 39.9%, and severe side effects were seen in 15.2% of patients after medical treatment. No meta-analyses were performed for clinical symptom improvement or quality of life due to lack of sufficient data. Conclusions This meta-analysis shows that medication induces cortisol normalization effectively in a large percentage of patients. Medical treatment for Cushing’s disease patients is thus a reasonable option in case of a contraindication for surgery, a recurrence, or in patients choosing not to have surgery. When experiencing side effects or no treatment effect, an alternate medical therapy or combination therapy can be considered. Keywords Cushing’s syndrome · Cushing’s disease · Medical treatment · Effectiveness · Side effects Introduction Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1110 2-018-0897-z) contains Cushing’s syndrome due to endogenous glucocorticoid supplementary material, which is available to authorized users. excess is either adrenocorticotropic hormone (ACTH)- dependent or ACTH-independent, both with a variety of * Leonie H. A. Broersen L.H.A.Broersen@lumc.nl underlying causes [1]. Cushing’s disease results from an ACTH-secreting pituitary adenoma and has a reported inci- Department of Medicine, Division of Endocrinology, Leiden dence of approximately 1.2–2.4 patients per million each University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, year [2]. Ectopic Cushing’s syndrome is a rare condition The Netherlands resulting from a non-pituitary ACTH-producing source. Center for Endocrine Tumors Leiden (CETL), Leiden ACTH-independent Cushing’s syndrome is caused by a cor- University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands tisol-producing adrenal adenoma or carcinoma [1]. Excess of glucocorticoids alters body composition and metabolic Department of Endocrinology, Diabetes and Nutrition, Charité Universitätsmedizin Berlin, Chariteplatz 1, profile, inducing fat maldistribution, muscle wasting, insulin 10117 Berlin, Germany resistance, dyslipidemia, hypercoagulability, and increasing Department of Clinical Epidemiology, Leiden University the risk of osteoporosis, hypertension, and neuropsychiatric Medical Center, Albinusdreef 2, 2333 ZA Leiden, disorders [3, 4]. The Netherlands Vol.:(0123456789) 1 3 Pituitary Transsphenoidal pituitary adenomectomy is a well-estab- analysis. Articles irretrievable online were requested by con- lished and effective treatment for Cushing’s disease [5 ]. tacting the authors. Only articles in the English language Cushing’s syndrome is generally approached by removing were considered. the ACTH-producing tumor in ectopic Cushing’s syndrome and by adrenalectomy in ACTH-independent Cushing’s syn- Search strategy drome [6]. However, there is increasing experience with first line medical treatment, both for patients with contraindica- To identify potentially relevant articles, PubMed, Embase, tions for surgery and for patients with recurrent disease [7]. Web of Science, COCHRANE Library, CENTRAL, Emcare, Furthermore, drugs can be used to control cortisol secretion LWW and ScienceDirect were systematically searched in preoperatively and to bridge the time period until control March 2017 in cooperation with a specialized librarian (see of hypercortisolism is achieved by radiotherapy [7]. Drugs Online Resource 1 for the complete search strategy). The used in medical practice vary per country and underlying search was repeated in PubMed in May 2017. Furthermore, cause of Cushing’s syndrome and include ketoconazole, references of included articles were searched to increase the metyrapone, mitotane, cabergoline, pasireotide, and mife- number of potentially eligible articles. pristone [7, 8]. A recent review described the percentage of patients achieving cortisol normalization after mono- Data extraction therapy with the steroidogenesis inhibitors ketoconazole and metyrapone [9]. However, until now no systematic review All identified articles were imported in EndNote 8 (Thomson and meta-analysis has been performed to summarize the Reuters, Philadelphia, PA, USA). Studies were screened by effectiveness of all medical agents used in clinical practice title and abstract and two independent reviewers reviewed (ketoconazole, metyrapone, mitotane, cabergoline, pasire- potentially relevant articles in detail. The Meta-analysis Of otide, and mifepristone). Observational Studies in Epidemiology (MOOSE) guide- lines were used for reporting [10]. Study aims From included articles we extracted the following data: number and type of Cushing’s syndrome patients included, The primary aim of the present systematic review and meta- type of medical agent used, treatment dose, treatment dura- analysis was to evaluate the effectiveness of medical treat- tion, duration of follow-up, number of patients pre-treated ment for Cushing’s syndrome in clinical practice. Effective- with medication before surgery, number of patients with ness of medical treatment was evaluated regarding cortisol normalization of cortisol, clinical improvement, well-being, secretion, clinical symptom improvement, and quality of quality of life, and side effects. Where available, separate life. The secondary study aim was to compare these medi- outcomes were extracted for patients with primary treat- cal therapies according to occurrence of side effects. ment (before any other treatment for Cushing’s syndrome) and patients with secondary treatment (after recurrence or failure of surgery and/or radiotherapy). For clinical improve- Methods ment, all reported symptoms as well as general statements (e.g. “Clinical signs regressed in full responders”, without Eligibility criteria specifying which clinical signs) were extracted. However, only hypertension and diabetes mellitus were considered Randomized controlled trials and cohort studies assessing for analysis, because these symptoms were expected to be the effectiveness of FDA/EMA approved medical treatment reported homogeneously by multiple articles. For quality of for treatment of Cushing’s syndrome, either de novo or with life, all general and Cushing’s disease specific questionnaires persistent or recurrent disease, were eligible for inclusion, were considered. All reported side effects were extracted. as well as cabergoline, which has been used for Cushing’s syndrome in multiple investigator initiated clinical trials. Risk of bias assessment Medical agents considered were ketoconazole, metyrapone, mitotane, cabergoline, pasireotide, and mifepristone. Arti- We used a component approach to assess risk of bias for all cles were excluded if reporting broad inclusion categories included studies. The following components were included, without separating the subgroup of Cushing’s patients, or which could potentially bias a reported association between if the study included children (age < 18 years) only. For eli- medical treatment for Cushing’s syndrome and outcome: gibility, at least ten patients had to be included per treat- ment group to minimize risk of selection bias. For multiple 1. Inclusion of patients (consecutive inclusion from all articles describing (partially) overlapping populations, the patients eligible or a random sample is considered low article with the largest study population was included in the risk of bias) 1 3 Pituitary 2. Loss to follow-up (< 5% is considered low risk of bias) mentioned medical agents at the same time or consecutively 3. Criteria for diagnosis of Cushing’s syndrome adequately were assessed separately. reported (see below) For normalization of cortisol, all measurements of corti- 4. Outcome measurement for cortisol normalization: uri- sol were considered. However, measurement of urinary free nary free cortisol, midnight salivary cortisol or a low cortisol, midnight salivary cortisol or morning cortisol after a dose dexamethasone test is considered low risk of bias low dose dexamethasone test was considered low risk of bias 5. Reporting of outcome definition (see below) (see above). Data on reduction of cortisol as a percentage of 6. Description of protocol for laboratory measurements baseline were not considered for analysis. (see below) Secondary outcomes were the pooled percentages of 7. Description of dose and duration of intervention (see patients with mild or severe side effects stratified by medical below) agent. Severe side effects were considered those that required therapy adjustment or withdrawal, as well as all side effects As criteria for diagnosis of Cushing’s syndrome vary categorized as severe by the authors. Mild side effects were all widely over time and even by study center, and per under- not categorized as severe. For articles reporting only specific lying etiology, adequately reporting the criteria used for side effects, the side effect that affected the most patients was diagnosis is considered a low risk of bias. Reporting of out- included in the analysis. come definition is considered adequate if the article at least Subgroup analyses were performed according to indication mentioned which outcome was studied, which test was used (primary therapy, including pre-treatment before surgery, and to determine the outcome, and if applicable, which corti- therapy for recurrence) if described separately. As few stud- sol level had to be measured. Description of protocol for ies provided separate data for primary/secondary analysis, a laboratory measurements is considered adequate if the assay separate subgroup analysis was performed, in which studies used for measuring cortisol is reported, or the assay for the were categorized as low (≤ 20%) or high (≥ 80%) percentage main outcome if this was not cortisol. Description of dose of patients using medical agents as pre-treatment before sur- and duration of intervention is considered adequate if dose gery. A separate analysis was performed for normalization of (per day or per week) and duration of medical treatment are cortisol according to the presence of multiple medical treat- reported (average and range, or exact dose and duration if ments and concurrent or previous radiotherapy. this is equal for all patients). Also considered adequate is reporting of exact treatment protocol for trials with dose Statistical analysis increase based on cortisol levels. Referring to another pub- lished article in which the information is reported is also A random-effects logistic regression model was used to pool considered adequate. percentages for analyses including ≥ 5 articles, whereas a Risk of bias assessment was conducted to explore poten- fixed-effects logistic regression model was used for analyses tial heterogeneity. As there were no studies that compared including < 5 articles. All pooled percentages are accompa- two different medical agents directly, confounding was not nied by 95% confidence intervals. The Freeman-Tukey arc- judged at the study level, but was assessed by comparing sine transformation was used to stabilize variances, in order baseline characteristics for all included studies. to prevent exclusion of studies with 0 or 100% as outcome. All analyses were performed using Stata 11.2 (Stata Corp., Study endpoints College Station, TX, USA). Sensitivity analyses were performed for normalization of Primary outcome of this study was the effectiveness of medical cortisol for low risk of bias studies, and for the combination treatment for Cushing’s syndrome, represented by the pooled of low and intermediate risk of bias studies. Articles were con- percentage of patients reaching normalization of cortisol sidered low risk of bias if they adhered to at least six (out of secretion (definition according to the authors) after medical seven) of the above mentioned criteria for risk of bias. Only treatment, patients showing symptom improvement, improved one article adhered to all seven criteria [11]. Articles were well-being and improved quality of life. Main analyses were considered intermediate risk of bias if they adhered to five of performed in studies reporting on pituitary Cushing patients. the above mentioned criteria for risk of bias. Separate analyses were performed for publications reporting on (1) mixed etiologies other than adrenocortical carcinomas, (2) mixed etiologies including adrenocortical carcinomas, and (3) ectopic Cushing only, if sufficient data were available. Studies were categorized according to type of medical agent (ketoconazole, metyrapone, mitotane, cabergoline, pasireotide, and mifepristone). Studies using more than one of the above 1 3 Pituitary as an outcome). There were 25 studies reporting on clini- Results cal improvement, and three studies reporting on quality of life. Study selection Baseline characteristics of included studies show clear differences between studies. Reported average age varied The initial search identified 960 potentially relevant arti- between 32.2 and 60.0  years. Percentage female varied cles. Searching through references of included articles between 21.7 and 95.0%. Average duration of follow-up identified one additional article, thereby yielding a total was 2 weeks to 11.5 years. Seven articles reported that at of 961 articles. By screening these articles by title and least part of their study population received radiotherapy in abstract, 874 articles were excluded. The remaining 87 addition to medical treatment (two with mitotane, one with articles were reviewed in detail. Reasons for exclusion are ketoconazole, and four with metyrapone). Pasireotide and summarized in Fig. 1. In total, 35 articles were included, cabergoline were used only for pituitary Cushing’s disease, reporting on six different drugs. whereas all other medical agents were used for various eti- ologies of Cushing’s syndrome. Study characteristics (Online Resource 2) Risk of bias assessment (Online Resource 3) We included five studies on mitotane [12– 16], two on Loss to follow-up [reported in twelve studies (34%)] ranged pasireotide [17, 18], three on cabergoline [19–21], eight from 0 to 60%. Inclusion of consecutive patients or a random on ketoconazole [22–29], five on metyrapone,[30– 34] sample was explicitly stated in seventeen articles (49%). Cri- two on mifepristone [35, 36], and ten on multiple medi- teria for diagnosis of Cushing’s syndrome were adequately cal agents [11, 37–45]. Studies were published between reported in 31 articles (89%). Reporting of outcome defini- 1971 and 2017. There were eleven single-arm trials, two tion was adequate in 25 articles (71%). Description of proto- randomized trials with two treatment arms (pasireotide col for laboratory measurements was adequate in 23 articles 600 µg vs. pasireotide 900 µg; first cabergoline, then add (66%). Description of dose and duration of intervention was ketoconazole vs. first ketoconazole, then add cabergoline), adequate in 23 articles (66%). A total of nine articles were and 22 cohort studies. We included eighteen studies on with low risk of bias (adherent to at least six out of seven pituitary Cushing’s disease only, two on ectopic Cush- criteria) and another nine articles with intermediate risk of ing’s syndrome only, and fifteen on Cushing’s syndrome bias (adherent to five out of seven criteria). patients due to various underlying etiologies. In total, 1520 patients were included. There were 28 articles measuring Study outcomes normalization of cortisol by at least urinary free cortisol, midnight salivary cortisol or a low dose dexamethasone For 26 articles (1000 patients) normalization of cortisol test (88% of 32 articles reporting normalization of cortisol was reported as outcome measure. There were 25 articles reporting on clinical improvement. One article reported no improvement in any of the measured clinical symptoms (weight, blood pressure, glucose and HbA1c) [19]. All other Potenally relevant published arcles idenfied (n=961), Arcles excluded (n=874) articles reported improvement in one or more clinical symp- screened by tle and abstract -No original data: 276 toms. Well-being was not reported by any of the included -No Cushing’s syndrome: 64 -No medical treatment: 88 articles. Three articles (228 patients) reported on quality -Wrong medical agent: 7 -N<10: 254 of life. These reported an improvement in CushingQoL -Language other than English: 148 score, SF-36 score, and emotional reaction on the Not- -No human subjects: 35 -Children only: 2 tingham Health Profile (NHP), and on the other hand more Arcles reviewed in detail pain measured by the RAND-36 [18, 36, 44]. There were (n=87) Arcles excluded (n=52) 30 articles (86%) reporting at least one side effect. Two of -Same populaon: 13 these articles, using mifepristone, described an increase in -No relevant outcome: 19 -No separate analysis for Cushing’s cortisol levels during the study period in a total of 47 out of syndrome: 1 -N<10: 12 70 included patients (67%) [35, 36]. No meta-analysis was -Selecon on outcome: 3 performed for clinical improvement, as results were consid- -Wrong medical agent: 1 -No medical treatment: 2 ered too heterogeneous. Hypertension and diabetes mellitus Arcles included (n=35) -Only abstract available: 1 were described by heterogeneous articles (type of medical agent, etiology of Cushing’s syndrome) and the type of out- come was heterogeneous (difference in blood pressure and Fig. 1 Flow-chart of inclusion of articles in this systematic review 1 3 Pituitary glucose vs. number of patients with improved values, only more often showed mild side effects compared to the total patients with disturbed values at start of the study vs. all population (68.5 and 58.3%). patients analysed). Detailed study outcomes at the individual For pituitary Cushing’s disease, severe side effects were study level are reported in Online Resource 4. seen in 15.2% (95% CI 9.1–22.4%). In the group of mixed etiologies including adrenocortical carcinoma, patients using mifepristone showed severe side effects relatively Meta‑analyses of normalization of cortisol (Table 1; often (42.0%; 95% CI 30.4–54.0%). Due to the severe side Fig. 2: normalization of cortisol per medical agent effects, 23.9% (95% CI 15.9–32.8%) of patients adjusted in pituitary Cushing) their medical therapy, and 8.5% (95% CI 2.8–16.3%) of patients stopped their medical therapy. For Cushing’s disease, pooled reported treatment effect ranged from 32.3% if a large percentage of patients used medication as pre-treatment before surgery, to 83.6% if med- Discussion ication was combined with radiotherapy. When comparing medical agents, a relatively high percentage of patients using We performed a systematic review and meta-analysis to mitotane showed normalization of cortisol (81.8%), whereas evaluate effectiveness of medical treatment in routine clini- treatment with cabergoline and pasireotide less often nor- cal practice in Cushing’s syndrome. Medical treatment malized cortisol secretion (35.7 and 41.1%). For detailed was effective in normalizing cortisol levels in Cushing’s results, including data on different etiologies (mixed etiolo- syndrome in 35.7% (cabergoline) to 81.8% (mitotane) of gies other than adrenocortical carcinomas, mixed etiologies patients. Furthermore, the combined use of medical agents including adrenocortical carcinomas, and ectopic Cushing), at the same time or consecutively increased the percent- see Table 1. age of patients with normalized cortisol secretion (65.7%). Seven studies reported data separately for medication Importantly, medical agents for hypercortisolism can cause as primary (n = 4) and/or secondary therapy (n = 5). For severe side effects, leading to therapy adjustment or with- patients with pituitary Cushing’s disease, medication as drawal in 4.8% (cabergoline) to 28.4% (mitotane) of patients. primary therapy normalized cortisol in 58.1% (95% CI These results suggest that medical therapy can be considered 49.7–66.2%), similar to the effect of medication as sec- a reasonable treatment alternative to the first choice surgical ondary therapy, 57.8% (95% CI 41.3–73.6%). Articles in treatment when regarding treatment effectiveness and side which ≤ 20% of patients were medically pre-treated before effects. surgery showed normalization of cortisol in 59.7% of This study is the first systematic review and meta-analysis patients (95% CI 49.4–69.6%). Articles in which ≥ 80% of of all medical agents currently used in clinical practice for patients were pre-treated with medication before surgery Cushing’s syndrome. Only one previous study performed showed a preoperative normalization of cortisol in 32.3% a systematic review and meta-analysis of two medical (95% CI 20.0–45.8%) for patients with pituitary Cushing’s agents in Cushing’s syndrome. Daniel et al. studied nor- disease. Patients with medical monotherapy showed a rela- malization of cortisol after monotherapy with ketocona- tively low percentage of cortisol normalization. This per- zole or metyrapone, and found that urinary free cortisol centage was higher for patients using multiple agents, and normalized in 60% (ketoconazole) and that normalization highest for patients with concurrent or previous radiotherapy. of hypercortisolism as defined by the authors occurred in The sensitivity analyses, both excluding articles with high 75% of patients using metyrapone [9]. This is in line with risk of bias (n = 18 included), as well as excluding articles the results obtained in the current study (49.0–71.1% for with high and intermediate risk of bias (n = 9 included), ketoconazole and 60.0–75.9% for metyrapone depending showed similar results as the main analysis. The most on patient categories). Since our last search in May 2017, remarkable difference is that lower percentages of patients one more research article on medical treatment in Cush- with normalization of cortisol were seen for multiple medi- ing’s syndrome was published. Lacroix et al. described a cal agents in both sensitivity analyses than for multiple 12 month clinical trial using pasireotide in various dosages medical agents in the main analysis. in 150 patients. Urinary free cortisol normalized in 41.3% of patients. This is in line with our own results for corti- Meta‑analyses of side effects (Table 1; Fig. 3: side sol excretion normalization for patients using pasireotide effects per medical agent in pituitary Cushing) (41.1%). Adverse events grade 1–2 were described in up to 48% of patients, and adverse events grade 3–4 in up to 16% For pituitary Cushing’s disease, mild side effects were of patients. This is in line with our own results for mild side reported in 39.3% (95% CI 25.0–55.8%) of patients after effects (58.3%) and severe side effects (15.7%) for patients medical treatment. Patients using mitotane and pasireotide using pasireotide [46]. 1 3 Pituitary Table 1 Results of meta-analyses according to etiology of Cushing’s syndrome Pituitary Cushing’s disease All etiologies (pituitary, All etiologies (pituitary, Ectopic Cushing’s syn- adrenal, ectopic) other than adrenal, ectopic) including drome adrenal carcinoma adrenal carcinoma Estimated 95% confi- Estimated 95% confi- Estimated 95% confi- Estimated 95% confi- percent- dence interval percent- dence interval percent- dence interval percent- dence interval age (N) age (N) age (N) age (N) Normalization of cortisol 59.5 48.4–70.1 (18) 61.6 51.8–71.0 (22) 64.7 55.6–73.3 (26) 83.3 64.9–96.8 (3)  Per medical agent   Mitotane 81.8 75.4–87.6 (4) 81.8 75.4–87.6 (4) 79.8 73.3–85.7 (4) – –   Pasireotide 41.1 32.7–49.8 (2) 41.1 32.7–49.8 (2) 41.1 32.7–49.8 (2) – –   Cabergoline 35.7 24.6–47.6 (3) 35.7 24.6–47.6 (3) 35.7 24.6–47.6 (3) – –   Ketoconazole 49.0 42.0–56.0 (3) 49.3 42.6–56.0 (4) 71.1 51.6–87.5 (7) – – a a   Metyrapone 60.0 31.3–83.2 75.9 57.5–90.9 (2) 75.9 57.5–90.9 (2) – –   Mifepristone – – – – – – – –   Multiple medical agents 65.7 46.9–82.4 (5) 67.8 51.9–81.9 (7) 67.6 53.6–80.3 (8) – –  Primary treatment 58.1 49.7–66.2 (4) 49.4 41.3–57.5 (4) 49.4 41.3–57.5 (4) – –  Secondary treatment 57.8 41.3–73.6 (5) 48.6 41.2–56.1 (4) 48.6 41.2–56.1 (4) – –  Per percentage pretreatment   ≤20% 59.7 49.4–69.6 (8) 59.7 49.4–69.6 (8) 59.7 49.4–69.6 (8) – –   ≥80% 32.3 20.0–45.8 (2) 42.6 33.5–51.9 (3) 53.6 45.0–62.0 (4) – –  Adjuvant treatment   No other treatment 49.4 36.0–62.9 (10) 52.7 40.1–65.1 (12) 57.2 44.4–69.6 (14) – –   Multiple medical agents 65.7 46.9–82.4 (5) 67.8 51.9–81.9 (7) 67.6 53.6–80.3 (8) – –   Radiotherapy 83.6 75.5–90.4 (3) 83.6 75.5–90.4 (3) 84.8 78.0–90.6 (4) – –  Sensitivity analysis (low risk of bias) a a a a a a   Mitotane 71.6 59.9–81.0 71.6 59.9–81.0 71.6 59.9–81.0 – a a a a a a   Pasireotide 17.2 7.6–34.5 17.2 7.6–34.5 17.2 7.6–34.5 – –   Cabergoline 35.0 20.6–50.9 (2) 35.0 20.6–50.9 (2) 35.0 20.6–50.9 (2) – –   Ketoconazole – – – – – – – –   Metyrapone – – – – – – – –   Mifepristone – – – – – – – –   Multiple medical agents 50.6 40.9–60.2 (3) 50.6 40.9–60.2 (3) 50.6 40.9–60.2 (3) – –  Sensitivity analysis (low and intermediate risk of bias)   Mitotane a a a a a a   Pasireotide 71.6 59.9–81.0 71.6 59.9–81.0 71.6 59.9–81.0 – – a a a a a a   Cabergoline 17.2 7.6–34.5 17.2 7.6–34.5 17.2 7.6–34.5 – –   Ketoconazole 35.7 24.6–47.6 (3) 35.7 24.6–47.6 (3) 35.7 24.6–47.6 (3) – a a   Metyrapone 48.5 41.7–55.4 48.3 41.5–55.2 (2) 59.8 54.1–65.4 (4) a a a a   Mifepristone – – 83.3 60.8–94.2 83.3 60.8–94.2 –   Multiple medical agents 53.1 43.8–62.3 (4) 67.5 46.5–85.7 (5) 67.4 50.0–82.8 (6) Mild side effects 39.9 25.0–55.8 (13) 40.2 27.4–53.8 (15) 35.3 25.6–45.7 (23) – –  Per medical agent   Mitotane 68.5 59.1–77.2 (3) 68.5 59.1–77.2 (3) 69.1 60.0–77.6 (3) – –   Pasireotide 58.3 51.4–65.1 (2) 58.3 51.4–65.1 (2) 58.3 51.4–65.1 (2) – –   Cabergoline 24.0 14.4–35.1 (3) 24.0 14.4–35.1 (3) 24.0 14.4–35.1 (3) – –   Ketoconazole – – – – 22.6 15.1–31.0 (3) – – a a   Metyrapone 30.8 12.7–57.6 32.2 16.3–50.3 (2) 19.7 12.2–28.2 (3) – –   Mifepristone – – – – 35.6 24.5–47.4 (2) – –   Multiple medical agents 18.0 10.6–26.7 (4) 25.5 7.6–48.5 (5) 26.7 12.8–43.2 (7) – – Severe side effects 15.2 9.1–22.4 (12) 16.2 10.1–23.3 (14) 15.3 10.1–21.3 (21) – – 1 3 Pituitary Table 1 (continued) Pituitary Cushing’s disease All etiologies (pituitary, All etiologies (pituitary, Ectopic Cushing’s syn- adrenal, ectopic) other than adrenal, ectopic) including drome adrenal carcinoma adrenal carcinoma Estimated 95% confi- Estimated 95% confi- Estimated 95% confi- Estimated 95% confi- percent- dence interval percent- dence interval percent- dence interval percent- dence interval age (N) age (N) age (N) age (N)  Per medical agent   Mitotane a a a a a a 28.4 19.0–40.1 28.4 19.0–40.1 28.4 19.0–40.1 – –   Pasireotide 15.7 10.9–21.2 (2) 15.7 10.9–21.2 (2) 15.7 10.9–21.2 (2) – –   Cabergoline 4.8 0.5–11.9 (3) 4.8 0.5–11.9 (3) 4.8 0.5–11.9 (3) – – a a   Ketoconazole 20.5 15.5–26.6 18.8 13.5–24.6 (2) 14.2 10.3–18.7 (4) – – a a   Metyrapone 7.7 1.4–33.3 27.1 12.2–44.7 (2) 16.2 9.4–24.3 (3) – –   Mifepristone – – – – 42.0 30.4–54.0 (2) – –   Multiple medical agents 20.9 13.6–29.2 (4) 20.9 13.6–29.2 (4) 14.6 4.2–28.8 (6) – –  Result of severe side effect   Adjust therapy 23.9 15.9–32.8 (4) 23.6 10.0–40.4 (6) 20.4 8.6–35.2 (9) – –   Stop therapy 8.5 2.8–16.3 (9) 8.5 2.8–16.3 (9) 8.5 4.6–13.4 (15) – – N number of articles included in meta-analysis No meta-analysis was performed, as the total number of studies equaled 1 (results only shown for analyses per medical agent if other medical agents were reported in multiple articles) Fig. 2 Meta-analysis of normalization of cortisol after medical treatment in Cushing disease In interpreting the results, the following study limitations heterogeneity regarding outcome measurement for clini- need to be taken into account. There was a large amount cal symptoms (difference in blood pressure and glucose vs. of heterogeneity in included studies, regarding medical number of patients with improved values, only patients with agent, etiology of Cushing’s syndrome, indication for use disturbed values at start of the study vs. all patients ana- of medical therapy for Cushing (presurgical cortisol con- lysed), we were unable to perform a quantified analysis of trol, contra-indication for surgery, post-surgical therapy clinical improvement after medical therapy. Included articles failure or recurrence), outcome measurement (definition of showed various levels of risk of bias. However, sensitivity cortisol normalization), and concurrent or previous use of analyses excluding articles with high risk of bias or with radiotherapy. Heterogeneity concerning medical agent and high and intermediate risk of bias showed similar results to etiology was handled by performing separate analyses per the main analysis. medical agent and per etiology, although this substantially For patients with pituitary Cushing’s disease, first line reduced the number of articles in some categories. Due to transsphenoidal surgery yields better results than medical 1 3 Pituitary Fig. 3 Meta-analysis of side effects after medical treatment in Cushing disease therapy (80% remission). However, remission after a repeat increases the likelihood of successful treatment, i.e. in nor- surgery was shown to be only 42.6–55.7% in a recent meta- malizing cortisol levels. This suggests that sensitivity for analysis. Various complications occurred in up to 18.5% of different medical agents may vary per patient. patients [47]. This underlines that medical treatment is a No difference was shown in normalization of cortisol reasonable alternative to repeat surgical procedure. between patients using medical agents as primary treat- Differences in effectiveness and side effects between the ment vs. secondary treatment, suggesting that effectiveness various etiological groups were small. In ectopic Cushing’s of medical agents is independent of other treatment modal- syndrome only, a higher percentage of patients reached ities. A higher percentage of patients reaches normaliza- normalization of cortisol levels than in the other etiological tion of cortisol in studies where a small part of included categories. As there were only three articles with separate patients received medication preoperatively (including data on patients with ectopic Cushing’s syndrome (of which patients with contraindications to surgery and patients one article only reported on one patient with ectopic Cush- after previous surgery) than in studies where a large part of ing’s syndrome, besides reporting on Cushing patients with included patients received medication before elective sur- other etiologies), no further subanalyses were possible, and gery. The most likely explanation is that in patients with reliability of this result is uncertain. However, we found no planned surgery, medication is given to control cortisol explanation for this high percentage of cortisol normaliza- excess, and surgery is performed before complete normali- tion in ectopic Cushing’s syndrome when considering risk of zation of cortisol occurs. Unfortunately, we don’t know bias, type of medical agent, or additional treatment. the average time until cortisol normalization, as this was When comparing different medical agents, it seems that a not reported by most articles. Total follow-up time was high percentage of patients with cortisol normalization cor- not different for studies with a high percentage of medical responds to a high percentage of patients with side effects pre-treatment before surgery (average 0.1–11.5 years) than and vice versa. However, all dosages used and studied were for all included studies. It would be interesting to know if within the boundaries advised by the European Medicines the effectiveness of surgery is dependent upon the normali- Agency (EMA) and the food and drug administration (FDA). zation of cortisol with medical treatment before surgery It might mean that advised and commonly used dosages are compared to presurgical medical treatment without corti- in fact not the optimal dosages for treatment of Cushing’s sol normalization and compared to no presurgical medical syndrome considering the balance between treatment effect treatment at all. Especially in pituitary Cushing’s disease, and side effects. Furthermore, medical agents with a high the percentage of patients with preoperative medical treat- percentage of patients with normalized cortisol secretion ment that reaches cortisol normalization is low. This might (mitotane and metyrapone) are relatively often combined be due to the higher expectations of surgery in pituitary with radiotherapy, which may lead to overestimating the Cushing’s disease compared to other etiologies, which effect and side effects of the drug per se. The use of com- may be why surgery is performed before patients reach bined medical therapy, in combination or consecutively, normalization of cortisol levels. However, these results 1 3 Pituitary pseudo-Cushing’s states. Endocr Rev 19(5):647–672. https://doi. should be interpreted with caution, as a small number of org/10.1210/edrv.19.5.0346 articles were included in these analyses, and in the articles 2. Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt- with a mixed etiologies population, a large proportion of Rasmussen U, Hagen C, Jorgensen J, Kosteljanetz M, Kristensen included patients had pituitary Cushing’s disease [23, 43]. L, Laurberg P, Schmidt K, Weeke J (2001) Incidence and late prognosis of cushing’s syndrome: a population-based study. J Based on the current study, medication can be regarded Clin Endocrinol Metab 86(1):117–123. https ://doi.org/10.1210/ a valuable alternative to pituitary surgery for Cushing’s jcem.86.1.7093 disease patients with contraindications to surgery, patients 3. Fernandez-Rodriguez E, Stewart PM, Cooper MS (2009) The pitu- with a recurrence considering repeat surgery, and patients itary-adrenal axis and body composition. Pituitary 12(2):105–115. https ://doi.org/10.1007/s1110 2-008-0098-2 that choose not to undergo surgery. For all other Cushing’s 4. Pereira AM, Tiemensma J, Romijn JA (2010) Neuropsychi- disease patients, pituitary surgery remains the first-choice atric disorders in Cushing’s syndrome. Neuroendocrinology treatment. For other etiologies of Cushing’s syndrome, at 92(Suppl1):65–70. https ://doi.org/10.1159/00031 4317 present, there is insufficient evidence to recommend when 5. Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Muller OA, Fahlbusch R (2008) Long-term results after microsurgery to use medical treatment to lower cortisol levels. However, for Cushing disease: experience with 426 primary operations from the total group of patients, it suggests that medical over 35 years. J Neurosurg 108(1):9–18. https ://doi.org/10.3171/ agents have similar effectiveness in normalizing cortisol jns/2008/108/01/0009 levels for all etiologies of Cushing’s syndrome. For a higher 6. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A (2015) Treatment of Cushing’s syndrome: chance of treatment success, a different medical agent could an endocrine society clinical practice guideline. J Clin Endocrinol be tried if there is no treatment effect or if the patient expe- Metab 100(8):2807–2831. https ://doi.org/10.1210/jc.2015-1818 riences side effects. There is no evidence for which drug 7. Ciato D, Mumbach AG, Paez-Pereda M, Stalla GK (2017) Cur- should be used first. Based on the current study, mitotane or rently used and investigational drugs for Cushing s disease. Expert Opin Investig Drugs 26(1):75–84. https ://doi.org/10.1080/13543 metyrapone seem to be most effective in normalizing corti- 784.2017.12663 38 sol levels, but also cause the highest percentage of patients 8. Molitch ME (2017) Diagnosis and treatment of pituitary adeno- with side effects. mas: a review. JAMA 317(5):516–524. https ://doi.org/10.1001/ In conclusion, we consider medical treatment for Cush- jama.2016.19699 9. Daniel E, Newell-Price JD (2015) Therapy of endocrine disease: ing’s disease a reasonable option in patients with contrain- steroidogenesis enzyme inhibitors in Cushing’s syndrome. Eur J dication to surgery, with a recurrence, or that choose not Endocrinol 172(6):R263-280. https://doi.or g/10.1530/eje-14-1014 to have surgery. Patients that experience side effects or no 10. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Ren- treatment effect should be advised to start treatment with a nie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta- analysis of observational studies in epidemiology: a proposal for different medical agent to increase the chance of treatment reporting. Meta-analysis of observational studies in epidemiology success. (MOOSE) group. JAMA 283(15):2008–2012 11. van den Bosch OF, Stades AM, Zelissen PM (2014) Increased Funding This research did not receive any specific grant from any long-term remission after adequate medical cortisol suppression funding agency in the public, commercial or not-for-profit sector. therapy as presurgical treatment in Cushing’s disease. 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PituitarySpringer Journals

Published: May 31, 2018

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