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Persistent Cushing’s Disease A Dilemma of Treatment A Case Report

Explore expert insights on diagnosing, treating, and managing Cushing’s Disease, including remission criteria, medical treatments like ketoconazole, and considerations for reoperation and radiotherapy.

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Persistent Cushing’s Disease A Dilemma of Treatment A Case Report

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  1. Persistent Cushing’s DiseaseADilemma of TreatmentA Case Report Presented by: B.Rezvankhah MD May 2017

  2. Persistence or Recurrence? • Medical treatment post radiotherapy • Failure in medical treatment;what’s next step?

  3. !There is no consensus on the criteria for remission after resecting an ACTH-producing tumor. • Remission is generally defined as; • morning serum cortisol values<5 mcg/dL(138 nmol/L) or UFC 28–56 nmol/d (10–20 g/d) within 7 days of selective tumor resection. • Although clinicians have used glucocorticoid dependence to characterize surgical response, we advocate measuring serum cortisol levels as a preferable and quantifiable alternative. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline,JCEM,2015

  4. Criteria for disease remission vary significantly from study to study but include: • resolution of clinical symptoms related to hypercortisolism • need for corticosteroid replacement for >6 months after TSS • hypocortisolemia/eucortisolemia • the presence of clinical and laboratory signs of low serum cortisol and AI • Low serum cortisol in the immediate postoperative period and normal UFC and LNSC appear to have a higher sensitivity and specificity for determining remission compared to other biochemical markers . Diagnosing Recurrent Cushing Disease, EndocrPract. 2016

  5. !Patients with mild or cyclic CS and those rendered eucortisolemic • by medical treatment before surgery may not have suppressed corticotropes. • Their postoperative UFC and morning cortisol may be normal. • In these patients,cliniciansmust measure late-night serum or salivary cortisol. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline,JCEM,2015

  6. Resurgery _early (within 2months) _delayed • Advantages of early repeat TSS: • It allows a reapproach to the pituitary tumor with minimal additional trauma because it is undertaken before the formation of scar tissue and the modification of surgical anatomy . • The surgeon is often able to recall particular anatomical details of the earlier operation, which may be essential for reoperation . • Early repeat surgery has been suggested to have a relatively low morbidity, compared with delayed repeat surgery but this finding needs to be confirmed.

  7. Radiotherapy: • In cases where recurrent or residual tumor is in the cavernous sinus oraccompanying dural invasion , radiotherapy is another option that can be offered to control hypercortisolism. • Conventional RT results in remission in up to 83% of adult patients, from 6–60 months after treatment, but often within 2 years • Eucortisolemiahas been demonstrated in 43–63 % of patients at 12.1–22 months.

  8. !It’s recommended confirming that medical therapy is effective in normalizing cortisol before administering RT/radiosurgery

  9. Medical treatment • Adrenal-directed drugs (Steroidogenesis inhibitors) • Pituitary-directed drugs

  10. Ketoconazole • In clinical practice,administeredorally at dosages ranging from 200 to 1200 mg/d • Normalization of cortisol was most commonly observed between ketoconazole dosages of 600–800 mg/d • Some studies showed that compared to lower doses, 600–1,200 mg/day implies a greater risk for endocrine side-effects, such as gynecomastia, • impairement of testicular function, and adrenal Insufficiency.

  11. Endocrine Reviews 36: 385–486, 2015) Endocrine Reviews 36: 385–486, 2015)

  12. J Clin Endocrinol Metab , 2014

  13. Study method:200 patients followed in 14 French centers were included in this retrospective study. All patients were treated with ketoconazole as a single treatment for active CD between 1995 and 2012. • Urinary cortisol secretion was usually monitored at 1- to 4-month intervals, and if necessary, ketoconazole dosage was increased by 200 mg/d every 7 to 28 days. • Patients were considered controlled if they had normal 24-hour UFC at 2 consecutive evaluations. • When the dose of ketoconazole was finally established,biological evaluation of hypercortisolism was performed at 3- to 6-month intervals.

  14. !Of the 49 patients with lack of control, only 9 reached the final dose of 1200 mg/d. • ! Because most males (59%) had at least a 50% decrease of UFC (including 39% with normal UFC at the last visit), restricting the use of ketoconazole in males is not recommended. • ! It could not be identified any other predictive factor of control of hypercortisolism,including initial UFC. • !15% of the patients treated for more than 24 months had a final increase in UFC, despite initial control.

  15. Ketoconazole in Cushing’s disease: is it worth a try? J ClinEndocrinolMetab. 2014

  16. Adverse effects were observed with a frequency of 0.6–18.4%. • An increase in liver enzymes was observed in 35 of 190 patients (18.4%), among whom the increase was up to 5-fold the normal values in 30 patients (85.7%), 5- to 10-fold in 4 patients (11.4%), and 40-fold higher than normal values in 1 patient (2.9%) • No increase in liver enzyme levels was observed after the first month of treatment or dose increase performed after the first month of treatment. • The elevation of liver enzyme levels generally normalized within 1–3 months after ketoconazole withdrawal. Ketoconazole inCushing’s disease: is it worth a try? J ClinEndocrinolMetab. 2014

  17. !Ketoconazole induced normalization of cortisol secretion at the end of the treatment period in an average of 64% of patients. • !It is noteworthy that information related to the use of ketoconazole in CDis supported mainly by noncontrolled retrospective studies, which might have overestimated the efficacy and underestimated the safety of the drug.

  18. The other most frequent adverse effects were GI complaints (13.1%), adrenal insufficiency (5.3%), and pruritus (3.7%) • !Use of proton-pump inhibitors needs to be considered when choosing the dose of ketoconazole during treatment of CD.

  19. Cabergoline: D2 receptoris expressed by most corticotrophadenomas(nearly 80%). Tumor volume decreased or remained stable in the small number of reported patients with visible adenomas.

  20. J Clin Endocrinol Metab, 2009

  21. Study Method; • Twenty patients (15 females, five males, 24–60 yr) with persistent CD were entered study. • The diagnosis of the persistence of CD after surgery was based on: The persistence of the presurgicalclinical syndrome, hormonal pattern, and pituitary tumor &elevated daily urinary cortisol excretion. • At the beginning of the study all patients included in the study had baseline urinary cortisol levels more than 2.0 times higher than the upper limit of the normal range. • Mild hyperprolactinemia was present in nine of 20 patients (45%). • The patients included in the study had been operated 0.5–5 years before the study: those operated more than six months before, had been treated with ketoconazole since 3 months before the study.

  22. UFC normalization was found in 8 out of 20 patients • Tumor shrinkage was observed in four of the eight who were followed for 24 months, whereas a stable tumor volume was found in the remaining responsive patients. • Better response in comparison to other study might be perhaps attributed to the fact that 9of these patients had mild hyperprolactinemia.

  23. Combination therapy: • The rationale behind this approach would be that using drugs with complementary pharmacological mechanisms offers a higher chance of hypercortisolismbeing controlled in the long term, using lower doses of each drug and consequently with a lower incidence of side effects.

  24. Study method:The patients were randomly assigned to group A and given cabergoline alone (0.5–1 mg/week), or to group B and treated with ketoconazole (200 mg/daily) alone. The dosage of both drugs was gradually increased: the cabergoline dose rose by 1 mg every month until UFC levels normalized or up to a maximal dose of 3.0 mg/week; ketoconazole by 200 mg/day every month and titrated up until UFC normalization or to a maximal dose of 600 mg/day. A clinical assessment was performed once a month. After 6 months of monotherapy, if neither UFC nor LNSC were under control, ketoconazole was added in group A, and cabergolinein group B.

  25. Study method; • Twelve patients (eight women and four men; mean age, 42.8 ± 6.2; age range 34–52) with persistent CD after unsuccessful surgery were included in this prospective study. • The diagnosis of CD was mainly based on (1) the confirmation of the hypercortisolism by the demonstration of at least two of the following findings: elevation of daily UFC concentration and/or midnight salivary cortisol levels (two or more times the upper limit of normal range) and failure of cortisol suppression to less than 1.8 lg/dl after low-dose dexamethasone suppression tests, (2)plasma ACTH greater than 20 pg/ml, (3) serum cortisol suppression greater than 50% after high-dose oral dexamethasone suppression test and/or ACTH increase greater than 35% after CRH or desmopressin stimulation tests, (4) evidence of a pituitary tumor at magnetic resonance imaging (MRI) of the pituitary gland or at the bilateral inferior petrosal sinus sampling.

  26. !Maximal dose of 3 mg/week fully responsive patients(monotherapy) had an UFC increase of no more than 4.0 times higher than the upper limit of normal range. • !After 12–18 months of treatment,there were no escape in our patients that were given cabergoline alone or in combination.

  27. European Journal of Endocrinology (2017)

  28. There is no simple correlation between the cabergoline dosage and the decrease in UFC. • It’s reported for the first time that corticotropic insufficiency can occur on cabergoline(necessity for regular monitoring of morning plasma cortisol) • Time variability in control of UFC (<3 months in 52% of patients, <6 months in 86%)

  29. Escape phenomenon: • How could the possibility of transient fluctuations or poor treatment adherence be excluded?

  30. Conclusion: • Titration of Ketoconazole up to 600 mg/d • Adding Cabergoline up to 3 mg/weekly (starting dose: 1mg & increment every month) • Following for 6 month on maximal dose of both drugs. OR 1) Using ketoconazole up to maximal dose (1200mg/d) 2) Adding cabergoline in the case of non responsiveness.

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