Recurrent Cushing's Disease Research Articles

Case Report: Opposite Tumoral and Hormonal Responses to Low-dose Pasireotide in Cushing’s Disease

Background:: Pasireotide is a multireceptor somatostatin analogue approved for the treatment of patients with Cushing's disease (CD) who are ineligible or poor candidates for pituitary surgery. Here we present a patient with severe recurrent CD who was treated with pasiretide and showed opposite results between hormonal levels and pituitary tumour size. Case Presentation:: A 54-year-old woman was diagnosed with CD, a first surgical transsphenoidal procedure was performed at the time of diagnosis, and the disease recurred seven years later. She underwent a second transsphenoidal surgery, but despite apparent complete removal of the adenoma, the hypercortisolism worsened. Magnetic resonance imaging showed a tiny remnant of the adenoma adjacent to the cavernous sinus, and ketoconazole was started at a dose of 800 mg/day. Due to the persistence of pathological urinary free cortisol levels, 600 μg bid pasireotide was added. The combination therapy induced first normalisation of urinary free cortisol and later hypoadrenalism, so that ketoconazole was discontinued and pasireotide was maintained. A marked clinical improvement was achieved with pasireotide. Adrenal insufficiency persisted despite progressive tapering of the pasireotide dose to 150 mg once daily. Pituitary magnetic resonance imaging performed at 12 and 24 months during low-dose pasireotide treatment showed a few millimetres increase of the remnant. Conclusions:: This report suggests that CD Pas induces an opposite effect between hormonal profile and increase of pituitary tumor size. This peculiar phenomenon may be a consequence of the unusually low doses of pasireotide needed to control hormonal hypersecretion.

Clinical decision-making based on 11C-methionine PET in recurrent Cushing's disease with equivocal MRI findings.

Diagnosis and accurate localization of recurrent tumors in Cushing's disease (CD) are challenging, especially after multiple transsphenoidal surgeries (TSSs) or radiosurgery. Even experts face difficulties in detecting these recurrent tumors, and a favorable surgical outcome is not guaranteed. In this report, the authors aimed to determine the usefulness of 11C-methionine positron emission tomography (MET-PET) for evaluating patients with recurrent CD with inconclusive magnetic resonance imaging (MRI) lesions and to develop a treatment protocol for these cases. In this retrospective study of patients with recurrent CD in the period between April 2018 and December 2022, the authors assessed the usefulness of MET-PET in determining whether equivocal MRI findings were recurrent tumors or postsurgical cavities and deciding further treatment options. All patients had undergone at least one TSS, and most had undergone multiple TSSs and had pathologically confirmed corticotroph tumors with hypercortisolemia. Overall, 15 patients with recurrent CD (10 females and 5 males) were included, all of whom had undergone MET-PET. All patients had been subjected to multiple treatments, including TSSs or radiosurgeries. Their MRI scans demonstrated less-enhanced lesions that were not confirmed as recurrences even with cutting-edge MRI because they could not be distinguished from postsurgical changes with confidence. MET uptake was positive in 8 patients (9 examinations) and negative in 7. Following MET-PET, repeat TSS was performed in 5 patients. Corticotroph tumors were identified in all 5 patients, even though one of them had negative MET uptake. The MET uptake precisely identified a tumor location on the opposite side of the MRI-suspected lesion in 2 patients. Meanwhile, patients with negative uptake and mild hypercortisolism were only observed. Nonsurgical options were also used in other patients: temozolomide (TMZ) was administered in 2 patients owing to a prior history of multiple TSSs and radiosurgery and the drug-resistant nature of the disease. TMZ was highly effective in these patients; their Cushing's symptoms ameliorated, and their adrenocorticotropic hormone and cortisol levels continued to decline. Interestingly, MET uptake disappeared following TMZ treatment. MET-PET is extremely useful for confirming equivocal lesions on MRI in patients with recurrent CD and for deciding further treatment options. The authors propose a novel protocol based on MET-PET results for treating patients with relapsing CD in whom the recurrent tumors cannot be confirmed with MRI.

Recurrent Cushing's Disease in Adults: Predictors and Long-Term Follow-Up.

Cushing's disease (CD) is characterized by endogenous hypercortisolism that is associated with increased mortality and morbidity. Due to high recurrence rates in CD, the determination of high-risk patients is of paramount importance. In this study, we aimed to determine recurrence rates and clinical, laboratory, and histological predictors of recurrence in a high volume single-center. This retrospective study included 273 CD patients operated in a single pituitary center between 1997 and 2020. The patients with early postoperative remission were further grouped according to recurrence status (recurrent and sustained remission groups). Demographic, radiologic, laboratory, pathologic, and follow-up clinical data of the patients were analyzed and compared between groups. The recurrence rate was 9.6% in the first 5 years; however, the overall recurrence rate was 14.2% in this study. Higher preoperative basal ACTH levels were significantly correlated with CD recurrence even with ACTH levels adjusted for tumor size, Ki-67 levels, and tumoral invasion. Recurrence rates were significantly higher in patients with ACTH levels higher than 55 pg/ml, tumor diameter>9.5 mm, and if adrenal axis recovery was before 6 months. The severity of hypercortisolism, morbidities, and demographic factors except age were not predictive factors of recurrence. Based on our study data, younger age at diagnosis, a diagnosis of osteoporosis, higher preoperative ACTH levels, larger tumor size, invasive behavior, higher Ki 67 index, and early recovery of the adrenal axis during the postoperative period attracted attention as potential predictors of recurrent disease.

Recurrent Cushing Disease: An Extensive Review on Pros and Cons of Different Therapeutic Approaches.

Recurrent Cushing disease (CD) is characterized by the reappearance of clinical and hormonal aspects of hypercortisolism that occur more than 6 months after an initial post-treatment remission. We performed a systematic review and meta-analysis to synthesize the evidence about remission and complication rates after transsphenoidal surgery (TSS) radiotherapy (RT) and medical therapy (MT) in recurrent CD patients. A quantitative systematic review was performed. Article selection was performed by searching MEDLINE (using PubMed), and Cochrane electronic bibliographic databases through2020. We noted 61 articles described therapeutic management of recurrent CD patients with representative outcome. A total of 723 patients received different therapeutic modality for their recurrent CD. The remission rates were 0.65 (95% confidence interval [CI] 0.60-0.70), 0.57 (95% CI 0.51-0.63), and 0.75 (95% CI 0.60-0.86) in the TSS, RT, and MT subgroups, respectively. The total remission rate after therapeutic approaches on recurrent CD patients was 0.64 (95% CI 0.60-0.68). A test for subgroup differences revealed there was a statistically significant difference between different subgroups (P= 0.01). The post hoc test showed that in comparison with RT, TSS (P=0.0344) and MT (P= 0.0149) had a higher rate of remission. However, there was no statistically significant difference between separate therapeutic modalities in terms of complications including diabetes insipidus (P=1.0) and hypopituitarism (P=0.28). Compared MT and TSS, RT has a statistically lower rate of remission. Although there is robust superiority of surgery over RT, interpretation of MT data must considered with caution due to the small number of included cases and wide CI range.

Clinical Utility of Osilodrostat in Cushing's Disease: Review of Currently Available Literature.

Cushing's disease (CD) is caused by endogenous hypercortisolism as a result of adrenocorticotropin (ACTH) secretion from a pituitary tumor. The condition is associated with multiple comorbidities and increased mortality. First-line therapy for CD is pituitary surgery, performed by an experienced pituitary neurosurgeon. Hypercortisolism may often persist or recur after initial surgery. Patients with persistent or recurrent CD will generally benefit from medical therapy, often administered to patients who underwent radiation therapy to the sella and are awaiting its salutary effects. There are three groups of medications directed against CD, including pituitary-targeted medications that inhibit ACTH secretion from tumorous corticotroph cells, adrenally-directed medications that inhibit adrenal steroidogenesis and a glucocorticoid receptor (GR) antagonist. The focus of this review is osilodrostat, a steroidogenesis inhibitor. Osilodrostat (LCI699) was initially developed to lower serum aldosterone levels and control hypertension. However, it was soon realized that osilodrostat also inhibits 11-beta hydroxylase (CYP11B1), leading to a reduction in serum cortisol levels. The focus of drug development then shifted from treatment of hypertension to treatment of hypercortisolism in CD. In a series of studies (LINC 1 through 4), osilodrostat was shown to be effective in normalizing 24-h urinary free cortisol (UFC) in the majority of treated patients and was approved for patients with CD who have failed surgery or are not surgical candidates. Further study is needed to examine the role of combination therapy as well as long-term outcomes of treated patients. Osilodrostat was shown to have an overall good safety profile. Most common adverse effects include nausea, headache, fatigue, arthralgias, dizziness, prolonged QTc interval, hypokalemia. In females, the drug can cause hirsutism and acne. Osilodrostat is administered twice daily, making it a good choice for patients with difficulty adhering to more complex regimens. Osilodrostat has an important, albeit adjunctive, role in the management of patients with CD.

Role of radiosurgery in the treatment of Cushing's disease.

Radiotherapy is a useful adjuvant treatment for patients with Cushing's disease that is not cured by surgery. In particular, Gamma Knife radiosurgery (GKRS) has been increasingly used worldwide as the preferred radiation technique in patients with persistent or recurrent Cushing's disease. The most widely accepted criterion for hormonal remission after GKRS is normalization of urinary free cortisol (UFC) levels. When a clear biological target is not identified, irradiation of the whole pituitary gland can be considered. The 5-year probability of remission is 65%-75%. Normalization of hypercortisolism usually occurs within 3 years from GKRS treatment and control of tumor growth is optimal, approaching more than 90%. No clear predictor of a favorable outcome has emerged up to now, except for the experience of the treating team. In the largest series, development of partial or complete hypopituitarism occurred between 15% and 36%. Severe side effects of GKRS, such as optic neuropathy and oculomotor palsy, are uncommon but have been documented in patients previously exposed to radiation. Recurrence of disease has been reported in as high as 16%-18% of the patients who achieved normalization of UFC levels in the two largest series, whereas smaller series did not describe late failure of GKRS. The reason for this discrepancy is unclear, as is the relationship between hormonal and tumoral recurrence. Another unresolved issue is whether treatment with adrenal blocking drugs can jeopardize the results of GKRS. GKRS is an effective second-line treatment in patients with Cushing's disease not cured by surgery. Hypopituitarism is the most frequent side effect of GKRS, whereas severe neurologic complications are uncommon in radiation-naïve patients.

Role of Radiation in the treatment of Cushing Disease.

In Cushing disease (CD), radiation therapy (RT) is mostly used in the adjuvant setting in patients who have failed transsphenoidal surgery or have recurrent CD. Stereotactic radiotherapy (SRT) is administered as either single or several sessions, and the most commonly used modalities include photon source (Gamma Knife, CyberKnife, and LINAC) or heavy particles (protons). In multicenter studies, Gamma Knife SRT can lead to biochemical control in 80%, with medial time to remission approximately 15 mos, and 70% recurrence free at 10 years. Conventional RT (CRT) consists of administration of small daily fractions over six weeks, with cumulative dose of 45-50Gy. Biochemical control is achieved in up to 64% of patients with CRT. Choice of radiation modality includes convenience for patients (SRT is more convenient) and proximity to critical structures. Both forms of RT can result in hypopituitarism. RT remains an important modality for the treatment of patients with CD.

Evolution from recurrent cushing's disease to pituitary carcinoma

Evolution from recurrent cushing's disease to pituitary carcinoma

Outcome in repeat transsphenoidal surgery in patients with persistent and recurrent Cushing's disease

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Treatment of recurrent and persistent Cushing's disease after first transsphenoidal surgery: lessons learned from an international meta-analysis.

Transsphenoidal surgery (TSS) is the first-line treatment for patients with Cushing's Disease (CD). Recurrence rates after a first TSS range between 3 and 22% within 3years. Management of recurrent or persistent CD may include repeat TSS or stereotactic radiosurgery (SRS). We performed a meta-analysis to explore the overall efficacy of TSS and SRS for patients with CD after an initial surgical intervention. EMBASE, PubMed, SCOPUS, and Cochrane databases were searched from their dates-of-inception up to December 2021. Inclusion criteria were comprised of patients with an established diagnosis of CD who presented with persistent or biochemically recurrent disease after a first TSS for tumor resection and were treated with a second TSS or SRS. Search criteria yielded 2,116 studies of which 37 articles from 15 countries were included for analysis. Mean age ranged between 29.9 and 47.9years, and mean follow-up was 11-104months. TSS was used in 669 (67.7%) patients, while SRS was used in 320 (32.4%) patients, and remission rates for CD were 59% (95%CI 0.49-0.68) and 74% (95%CI 0.54-0.88), respectively. There was no statistically significant difference in the remission rate between TSS and SRS (P = 0.15). The remission rate of patients with recurrent CD undergoing TSS was 53% (95%CI 0.32-0.73), and for persistent CD was 41% (95%CI 0.28-0.56) (P = 0.36). Both TSS and SRS are possible approaches for the treatment of recurrent or persistent CD after a first TSS. Our data show that either TSS or SRS represent viable treatment options to achieve remission for this subset of patients.

Abstract #1183320: Cushing's Disease due to Recurrent Cystic Macroadenoma

Crooke's tumor is a rare histological type of ACTH-producing adenomas. The most frequent clinical presentation is as Cushing's syndrome in middle-aged women and on other occasions as silent corticotropic adenomas. We present the case of a patient with recurrent Cushing's disease due to cystic Crooke's tumor.

Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase

Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11β-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease. LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete. Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0-49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7-53·4]; p<0·0001). At week 24, 72 (53%; 95% CI 43·9-61·1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase. Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease. Novartis Pharma AG.

Radiosurgical Management of Patients With Persistent or Recurrent Cushing Disease After Prior Transsphenoidal Surgery: A Management Algorithm Based on a 25-Year Experience.

Patients with persistent or recurrent Cushing disease (CD) after prior transsphenoidal surgery require further treatment to reduce the disease's metabolic consequences. To assess patient outcomes after stereotactic radiosurgery (SRS) for persistent or recurrent CD from adrenocorticotropin hormone (ACTH)-secreting pituitary adenomas and propose a management algorithm. Retrospective review of 38 patients without prior radiation treatment having SRS for ACTH-secreting pituitary adenomas from 1990 to 2015. Favorable outcome was defined as biochemical remission and tumor growth control. Patients were evaluated separately if they underwent bilateral adrenalectomy (Adx). Twenty patients (53%) were treated with Adx and SRS (median margin dose, 25 Gy) and 18 patients (47%) received SRS alone (median margin dose, 22.5 Gy). Median follow-up after SRS was 76 mo. Of patients undergoing Adx, 18/20 (90%) had a favorable outcome. Two patients (10%) had tumor growth requiring additional treatment. A favorable outcome was achieved in 13/18 patients (72%) having SRS alone (median, 14 mo; interquartile range, 8-23). Five patients (28%) required additional treatment due to persistent hypercortisolemia (n=4) or hypercortisolemia and tumor growth (n=1). Favorable outcomes were more frequent in the Adx and SRS group at 1 yr (100% vs 33%; P<.001) and 3 yr (100% vs 62%; P<.01), but no different at 5 yr (88% vs 77%; P=.63). SRS was effective for patients with persistent or recurrent CD. Patients with mild to moderate CD can be safely managed with SRS alone; patients with severe CD should be considered for Adx with either concurrent SRS or SRS performed at a later date if tumor growth occurs.

The Novel Use of Stereotactic Radiotherapy for Remnant Adrenal Tissue in Nelson Syndrome

Recurrent Cushing disease (CD) is a rare complication that occurs in patients who have undergone bilateral adrenalectomy (BLA). We report a case of recurrent CD in a patient with Nelson syndrome and adrenalectomy due to remnant adrenal tissue, and a novel treatment strategy using stereotactic body radiation therapy (SBRT) to the adrenal glands. We report a case of recurrent CD in a woman with Nelson syndrome and adrenalectomy and describe her clinical course and management. We also include a literature review of CD management and adrenal radiation. The patient had persistent pituitary CD despite pituitary surgery and radiosurgery and underwent BLA. She developed recurrent CD due to a remnant adrenal gland post adrenalectomy. She then underwent SBRT to both adrenal beds to treat the remnant adrenal tissue. Her serum cortisol dropped rapidly after adrenal radiation and she experienced minimal side effects. She has been in remission for over 2 years. This is the first reported case of recurrent CD in a patient post adrenalectomy that was successfully treated with SBRT to the remnant adrenal tissue.

Outcomes After Repeat Transsphenoidal Surgery for Recurrent Cushing Disease: Updated.

Transspheniodal surgery (TSS) for Cushing disease (CD) is considered the first-line treatment; however, reported recurrence rates are high. To systemically review indications and outcomes for repeat TSS in recurrent CD. Retrospective review of patients undergoing TSS from 2008 to 2018 was performed. Patients undergoing repeat TSS for clinical and/or biochemically recurrent CD with follow-up at least 12 mo postoperatively were included. These data were analyzed in our "current cohort" and combined with our previously published data in a "combined cohort." The current cohort of patients undergoing operations from 2008 to 2018 with repeat surgery following a prior operation included 15 patients. Pathology at the time of first operation was positive for adrenocortiotrophic hormone (ACTH) adenoma in 13/15 (86.7%) and 9/15 (60%) had evidence of recurrence after a previous surgical procedure on preoperative magnetic resonance imaging (MRI). Remission was achieved immediately postoperatively in 13/15 (86.7%). Over an average follow-up of 34.7 mo (range: 12-116), 11/15 (68.8%) achieved persistent remission. When combined with the historical cohort that underwent an operation during 1992-2006, 44/51 (86.3%) patients had a prior operation demonstrating ACTH adenoma and 35/51 (68.6%) had evidence of recurrent disease on preoperative MRI. Thirty-five (68.6%) patients went into remission immediately postoperatively. Thirty one (60.8%) had continued remission at most recent reported follow-up. Recurrent CD can be a therapeutic challenge; however, these data demonstrate that in many patients repeat surgery can be an effective and safe next step prior to radiation or medical therapy.

Cabergoline may act as a radioprotective agent in Cushing's disease.

Conventional fractionated radiotherapy (CRT) achieves control of pathological hypercortisolism in 75%-80% of patients with persistent or recurrent Cushing's disease (CD), over a mean period of 18-24months. Medical therapy is recommended as bridge therapy while awaiting RT effect. To determine long-term outcome of CRT and its predictors in CD patients. This is a retrospective case record analysis of 42 patients with CD who received CRT as a treatment modality and had at least 12months post-RT follow-up. The dose delivered was 45Gy in 25 fractions over 5weeks. Demographic details, hormonal evaluation and radiological data were extracted from case records. Dexamethasone suppressed cortisol at cut-off of 1.8µg/dL was used to define remission or recurrence. Possible predictors for remission and recurrence were analysed. The mean age at the time of CRT administration was 23.7±10.7 (range: 12-48) years. A total of 29 (69%) patients achieved remission 26.5±28.5 (median: 18, range: 3-120) months after RT, while 13 (31%) patients had persistent disease at last follow-up. There were no significant predictors of disease remission after CRT. Six (20.7%) patients had recurrence after a documented initial remission. Recurrence occurred 66.6±25.9 (median: 74; range: 18 to 90) months after documented remission. Recurrence of the disease was exclusively seen in patients who received peri-RT cabergoline. Peri-CRT use of cabergoline was significantly associated with increased recurrence rates (P=.016). Use of cabergoline in the peri-CRT period did not affect initial remission after CRT but was associated with increased recurrence after initial remission in CD.

Recovery of Adrenal Function after Pituitary Surgery in Patients with Cushing Disease: Persistent Remission or Recurrence?

Background: Cushing disease (CD) represents the principal cause of endogenous hypercortisolism. The first-line therapy of CD is surgical removal of the ACTH-secreting pituitary adenoma, which is generally followed by adrenal insufficiency (AI). Objective: To analyze the recovery of AI in patients with CD after pituitary surgery in relation with recurrence and persistent remission of CD. Patients and Methods: We performed a retrospective analysis of patients with CD who met the following inclusion criteria: adult age, presence of AI 2 months after the surgical intervention, and a minimum follow-up of 3 years after the surgical intervention. Results: Sixty-one patients were followed for a median of 6 years. Ten (16.4%) patients recurred during follow-up. The patients who restored adrenal function did so after a median time of 19 months, with a significantly shorter time in the recurrence group (12.5 vs. 25 months, p = 0.008). All 10 patients who recurred recovered their adrenal function within 22 months. The recovery rate of AI in the persistent remission group was 37.3% (19/51) at 3 years and 55.8% (24/43) at 5 years. In all patients the duration of AI was negatively associated with disease recurrence. Conclusion: The duration of postsurgical AI in patients with recurrent CD is significantly shorter than that in patients with persistently remitted CD, and this parameter may be a useful predictor of recurrence. Patients showing a normal pituitary-adrenal axis within 2 years after surgery should be strictly monitored as they are at higher risk of disease relapse.

Effect of cabergoline monotherapy in Cushing's disease: an individual participant data meta-analysis.

The primary treatment of choice for Cushing's disease (CD) is the removal of the pituitary adenoma by transsphenoidal surgery (TSS). The surgical failure is seen in up to 75% of cases depending on the experience of the surgeon in different studies. Medical therapy is one of the options for the treatment of recurrent or persistent CD. The primary outcome of this meta-analysis was to find the proportion of patients achieving normalisation of 24-h urinary free cortisol (remission of CD) following cabergoline monotherapy. Literature search was conducted in January 2018 in PubMed/MEDLINE database from its date of inception to 31st December 2017. The search strategy used was "[(cushing) OR Cushing's] AND cabergoline". Individual participant data were extracted from the included studies and risk of bias was analysed by review checklist proposed by MOOSE. The individual participant data of 124 patients from six observational studies were included in this meta-analysis. 92 patients (74.2%) had past pituitary surgery. The proportion of patients achieving remission of Cushing’s disease (CD) with cabergoline monotherapy was 34% (95% confidence interval 0.26–0.43; P = 0.001) [corrected]. The previous surgery [odds ratio (OR) 28.4], duration of cabergoline monotherapy (OR 1.31) and maximum cabergoline dose (OR 0.19) were predictors for remission of CD. Mild and severe side effects were reported in 37.3% and 5.6% of patients, respectively, during cabergoline monotherapy. This meta-analysis shows that cabergoline monotherapy is a reasonable alternative for subjects with persistent or recurrent CD after TSS. It can also be used in CD patients either as a bridge therapy while waiting for surgery or in those unwilling for surgery or have contraindication to it.

Repeat stereotactic radiosurgery for Cushing’s disease: outcomes of an international, multicenter study

Stereotactic radiosurgery (SRS) is frequently used for Cushing's disease (CD) after failed pituitary surgery. Management of patients with persistent CD after failed SRS is complex, as the alternative therapeutic options harbor significant risks. The outcomes of repeat pituitary radiosurgery, however, have not been described. We sought to determine the outcomes of repeat SRS in patients with CD. We pooled data from five institutions participating in the International Gamma Knife Research Foundation for patients with recurrent or persistent CD ≥ 12months after initial SRS. Patients were included in the study if they had ≥ 6months endocrine follow-up after repeat SRS. Twenty patients were included in the study. Repeat single-session SRS was performed 1.3-9.7years after initial SRS. Median endocrine follow-up was 6.6years (1.4-19.1years). Median margin dose was 20Gy (range 10.8-35Gy). Endocrine remission after second SRS was noted in 12 patients (60%), with a median time to remission of 6months (range 2-64months). Biochemical recurrence occurred in two patients (17%) after initial remission. Overall, the cumulative rates of durable endocrine remission at 5 and 10years were 47 and 53%, respectively. Two patients (10%) experienced adverse radiation effects, including transient visual loss and permanent diplopia. Repeat SRS achieves lasting biochemical remission in approximately half of patients with CD refractory to both prior microsurgery and SRS. Because of the morbidity of refractory or recurrent CD, repeat SRS should be considered for carefully selected patients with hypercortisolism confirmed one or more years after initial SRS.

The Value of Perioperative Levels of ACTH, DHEA, and DHEA-S and Tumor Size in Predicting Recurrence of Cushing Disease.

Despite the development of hypocortisolemia after corticotroph surgical adenomectomy, 15% to 20% patients have recurrence of Cushing disease (CD). In this study, we investigated the effect of tumor size and the value of perioperative assessment of corticotropin (ACTH) and adrenal steroid levels in predicting recurrence. Perioperatively, no glucocorticoids were administered until the serum cortisol was ≤3 μg/dL. Blood samples were obtained before and repeatedly after adenomectomy in 79 patients with CD. Of these, 66 had a nadir serum cortisol of ≤3.0 μg/dL and clinical and biochemical remissions. During a median follow-up of 131 months, 11 of 66 had disease recurrence (REC), whereas 55 of 66 did not (NO-REC). Preoperative hormone levels in the REC and NO-REC groups were similar. After adenomectomy, a brief and similar increase in ACTH, cortisol, and dehydroepiandrosterone (DHEA) levels was observed in both groups followed by gradual decline in those levels. Although REC and NO-REC patients had similar cortisol levels (3.4 ± 1.7 μg/dL vs 2.9 ± 2.2 μg/dL) at the 36th postoperative hour, their respective ACTH (33 ± 7.1 ng/L vs 12.1 ± 5.4 ng/L; P < 0.0001), DHEA (3.8 ± 1.7 ng/mL vs 1.2 ± 1.1 ng/mL; P = 0.005), and dehydroepiandrosterone sulphate (DHEA-S) (143.9 ± 45.2 μg/dL vs 48.9 ± 38.2 μg/dL; P < 0.0001) were higher. At nadir hypocortisolemia, perioperative ACTH levels were >20 in all REC patients and <20 ng/L in the NO-REC group. Patients with REC had larger tumors than those with NO-REC. Recurrent CD is characterized by persistent perioperative ACTH secretion after adenomectomy. Higher perioperative levels of ACTH, DHEA, and DHEA-S are highly predictive of future disease recurrence, particularly in those with profound hypocortisolemia.