578
`
`16. CUSHING'S DISEASE
`
`Severe Cushing's Disease Mimicking Classic
`Ectopic ACTH Syndrome
`The clinical presentation of genuine Cushing's
`disease may be severe enough to mimic the classic
`form of ectopic ACTH syndrome, with rapid onset,
`profound myopathy, severe hypokalemia and definite
`hyperpigmentation {174,719]. Although the dynamic
`exploration of the corticotroph function may be concor(cid:173)
`dant with Cushing's disease, in some cases the correct
`diagnosis is obscured by some unexpected responses,
`such as a lack of suppressibility on the classic high(cid:173)
`dose dexamethasone tests and sometimes lack of
`response to the CRH test (576). In most cases, however,
`pituitary imaging will point to the source of ACTH often
`showing a large macroadenoma on CT scan or MRI. If
`necessary, and if possible, bilateral inferior petrosal
`sinus sampling should ultimately provide the unequiv(cid:173)
`ocal solution.
`
`Mild Ectopic ACTH Syndrome Mimicking
`Classic Cushing's Disease
`It has become increasingly recognized that some non(cid:173)
`pituitary tumors provoke a Cushing's syndrome with
`both clinical and biochemical features similar to those
`of classic Cushing's disease [572). Mild and slowly
`progressive symptoms are found together with dynamic
`tests strictly compatible with a nonautonomous, gluco(cid:173)
`corticoid responsive, cortisol overproduction [372].
`In a minority of such cases a positive response to the
`CRH test is another pitfall for diagnosis [396,412,592].
`Because most of these patients have had small and
`rather indolent bronchial carcinoid tumors [720] that
`until recently had escaped the usual means of detection
`by standard X-ray, many have undergone unsuccessful
`pituitary surgery (721]. In some patients the correct
`diagnosis was made up to 10 years later [372).
`The rare but classic occult carcinoid tumor which can
`be suspected because of the detection of abnormal circu(cid:173)
`lating POMC fragments and successfully detected by
`chest CT scan or MRl should always be borne in mind.
`The clear evidence of a pituitary microadenoma on
`MRI helps to eliminate this possibility. If it is not detect(cid:173)
`able, the slight risk of an unwarranted pituitary surgery
`should be weighed against the mild risk and discomfort
`of bilateral inferior petrosal sinus sampling which, at
`this stage, offers the sole and highly efficient means to
`separate the two conditions.
`
`obtained by many different paths. Thus a general
`strategy is needed, the aim of which is to obtain a certain
`diagnosis with the minimum risk and discomfort for the
`patient at the maximum cost-benefit ratio. It should
`always be guided by the clinical features of the given
`patient and proceed in a stepwise fashion.
`
`A Clinically Driven Strategy
`Which Patients to Screen for Cushing's Syndrome?
`Classically, the diagnosis of Cushing's syndrome
`requires a clinical presentation compatible with that
`originally described by Harvey Cushing [106). Indeed,
`it may be wise to recall that in its absence no such inves(cid:173)
`tigation should be undertaken.
`Recently, however, some emphasis has been put on
`the frequent occurrence of "occult" or "subclinical"
`Cushing's syndrome, probably more often associated
`with adrenal cortical adenomas than with corticotroph
`adenomas. For these reasons an Endocrine Society
`Clinical Practice Guideline also suggests that " Patients
`with unusual features for age (e.g., osteoporosis, hyper(cid:173)
`tension) ... " be also screened for hypercortisolism [518].
`
`When to Screen for Cushing's Syndrome?
`In patients with severe stressful conditions or patho(cid:173)
`logical situations known to be accompanied by func(cid:173)
`tional hypercortisolism (anorexia nervosa, alcoholism),
`the fine exploration of glucocorticoid homeostasis
`should cautiously await the disappearance of the
`primary disorder. A patient with authentic Cushing's
`syndrome may have such severe complications of
`disease that some tests which could further compromise
`the condition may be contraindicated. Thus, the diag(cid:173)
`nostic approach may be modulated by some particular
`clinical presentations. There may be cases where it is
`important to delay testing, and others where it is urgent
`to treat and bypass tests. In the vast majority of cases,
`however, a defined and coordinated procedure can be
`applied.
`
`A Stepwise Strategy
`
`A two-step diagnostic approach should first establish
`the hypercortisolic state and subsequently its cause.
`
`The Hypercortisolic State
`Recent studies and consensus conferences have
`aimed at establishing a hierarchy between the various
`diagnostic approaches whereby one can distinguish
`the more usual and easy tests that are sufficient in the
`vast majority of cases ("first-line" tests), and those that
`can be necessary to confirm a difficult case ("second(cid:173)
`line" tests) [25,450,518].
`
`STRATEGY
`
`Because there are different causes of Cushing's
`syndrome and many different tests to distinguish
`between them, the final diagnosis can theoretically be
`
`ill. PITUITARY TIJMORS
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2015, Page 48
`
`

`

`TREATMENT
`
`579
`
`THE FIRST-UNE TESTS
`They are expected to be highly sensitive, simple to
`perform, possible in outpatients and not costly. Late
`night salivary cortisol, 24 h urine cortisol, 1 mg and
`2 mg 48 h dexamethasone suppression tests and
`combined strategies based on these tests have similar
`accuracies [517]. The use of one of the first-line tests is
`recommended: at least two measurements of 24 h urine
`cortisol [518]; two measurements of late night salivary
`cortisol (at bedtime or between 23:00-24:00 h) (518];
`1 mg overnight dexamethasone suppression test [518]
`or, in certain populations, 2 mg 48 h dexamethasone
`suppression test [518]. For some centers, the 2 mg 48 h
`dexamethasone suppression test is considered as
`a second-line test rather that a first-line test because it
`is not simple to carry out in an outpatient even if
`adequate written instructions are provided. In special
`populations, some tests are preferred: urine cortisol in
`pregnant women [518]; urine cortisol and late night
`salivary cortisol in patients receiving drugs that
`modify dexamethasone clearance [518]; 1 mg overnight
`dexamethasone suppression test in patients with severe
`renal failure (consensus); urine cortisol and late night
`salivary cortisol in suspected cyclic Cushing's syndrome
`[518]; 1 mg overnight dexamethasone suppression test
`or late night cortisol [518] in the case of an adrenal inci(cid:173)
`dentaloma. Intermittent Cushing's syndrome should be
`considered if the clinical impression contrasts with
`normal laboratory tests or even transient cortisol defi(cid:173)
`ciency [518].
`
`SECOND-LINE TESTS
`When the hypercortisolism is severe, the diagnosis is
`easily confinned by repeating first-line tests. The specific
`second-line tests are useful if doubts persist between
`Cushing's syndrome and a functional hypercortisolic
`state, the pseudo-Cushing state, as in patients suffering
`from depression and chronic alcoholism. The specific
`second-line tests are the following: midnight serum
`cortisol, serum and salivary cortisol cycle, dexametha(cid:173)
`sone-CRH test, desmopressin test, CRH test [518].
`
`The Cause of the Hypercortisolic State
`The first step to identify the cause of Cushing's
`syndrome is to measure plasma ACTH.
`An ACTH level that is less than 5-10 pg/ ml (1.1-
`2.2 pmol/L) on two separate occasions confirms that
`the Cushing's syndrome is ACTH-independent. If at
`least one of the two ACTH measurements is greater
`than 15-20 pg/ ml (3.3-4.4 pmol/L) during the hyper(cid:173)
`cortisolism phase, it is very likely that the Cushing's
`syndrome is ACTH-dependent. If there is any doubt, it
`is advisable to carry out a CRH test or even a high(cid:173)
`dose dexamethasone suppression test and a CT scan of
`the adrenal glands [25,450,518].
`
`The final diagnosis of Cushing's syndrome will
`invariably rely on the combination of several diagnostic
`procedures using both hormonal and imaging tests that
`are summarized in Figure 16.23.
`Diagnosis of Cushing's disease is based on a combina(cid:173)
`tion of several types of investigation including dynamic
`tests (high-dose dexamethasone suppression test; CRH;
`for some teams, desmopressin stimulation test), tumor
`markers, pituitary MRI, thoraco-abdomino-pelvic CT
`scan (if necessary, somatostatin receptor scintigraphy),
`and bilateral inferior petrosal sinus sampling for ACTH.
`Bilateral inferior petrosal sinus sampling is being
`increasingly performed with a high diagnostic accuracy
`to separate pituitary and nonpituitary sources of ACTH.
`It has led some groups to propose its systematic use as
`the main if not sole diagnostic procedure for the etio(cid:173)
`logic work-up. However, because it represents an inva(cid:173)
`sive technique, particularly considering the vascular
`fragility of these patients, and because its performance
`may rely above all on the skill of one particular investi(cid:173)
`gator, others are reluctant to consider this test as
`a primary, systematic and routine diagnostic procedure
`for etiology.
`A reasonable strategy therefore establishes the diag(cid:173)
`nosis of Cushing's disease on the basis of concordant
`dynamic testing of the pituitary corticotroph function
`and the simultaneous presence of a pituitary microade(cid:173)
`noma by MRI. In the case of a negative pituitary imaging
`a thorough and systematic search for a nonpituitary
`tumor should be undertaken. Bilateral inferior petrosal
`sinus sampling may be considered with the expectation
`that it will avoid unwarranted transsphenoidal surgery
`in the rare case of an occult ectopic ACTH syndrome
`mimicking Cushing's disease, and that it will provide
`useful information on the lateralization of the pituitary
`microadenoma for the surgeon in cases where the
`disease is confirmed [25,450].
`
`TREATMENT
`
`In identifying the goals of treatment for Cushing's
`disease, the morbidity and mortality of untreated
`chronic hypercortisolism dictate that the condition be
`treated rapidly and actively in most patients.
`Such goals are to correct adrenocortical oversecretion,
`ablate or destroy the primary tumoral lesion, respect
`anterior pituitary functions possibly restoring a normal
`pituitary-adrenal axis, and eventually reverse the
`peripheral manifestations of steroid excess.
`These ideal goals cannot always be achieved and in
`many cases the treatment will only permit a patient to
`be controlled but not cured. Correction of adrenocortical
`oversecretion may be accompanied by persistent
`abnormality of the circadian rhythm (on op'DDD),
`
`m. PITUITARY TIJMORS
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2015, Page 49
`
`

`

`580
`
`16. CUSHING'S DISEASE
`
`!clinical suspicion/patient at riskl
`t
`24-hour urinary cortisol excretion
`Late night serum/salivary cortisol
`Overnight 1mg dexamethasone suppression test
`Classic low-dose dexamethasone suppression test
`
`.----~--------, --------
`
`WITHOUT CUSHING'S
`SYNDROME
`
`I
`
`.
`
`~----~--------~~~ --------~~------~
`I HYPERCORTISOLIC STATE I
`I EUCORTISOLIC STATE I
`-------..------,
`I
`
`CUSHING'S SYNDROME
`
`.
`
`NO CUSHING'S
`SYNDROME
`
`ACTH
`-Baseline
`-CRH
`Hlghdondex
`
`Adrenal CT
`Pituitary MRI
`
`tumor
`
`Petrosal sinus
`sampling
`• CentraVperipheral gradient
`
`Nor 1
`1
`+
`
`bilateral
`+
`
`+
`
`bilateral
`
`Depression
`Anorexia
`Alcoholism
`
`ADRENo(cid:173)
`CORTICAL
`TUMOR
`
`ECTOPIC
`ACTH
`CUSHING'S
`~SEASE SYNDROME
`
`Pathways to the diagnosis of Cushing's syndrome. ACTH, adrenocorticotroptic hormone; CRH, corticotropin-releasing
`FIGURE 16.23
`hormone; cr, computed tomography; MRI, magnetic resonance imaging.
`
`a need for life-long (bilateral adrenal surgery) or tran(cid:173)
`sient
`(selective pituitary adenomectomy) steroid
`coverage, or progressive development of pituitary insuf(cid:173)
`ficiency (radiotherapy).
`Over the years various strategies have been devel(cid:173)
`oped directed at either the adrenals or the pituitary
`and using surgical, radiation and pharmacologic
`approaches either alone or in various combinations.
`Several recent reviews address the overall treatment
`options and strategies [450,722-724].
`Today, surgical removal of a pituitary microadenoma
`by the transsphenoidal route appears as the only thera(cid:173)
`peutic means capable of curing a patient. Yet, it is not
`always feasible nor always successful. And long-term
`follow-up of "cured" patients does not always restore
`a perfect quality of life [473,725].
`
`PITUITARY,DIRECTED THERAPIES
`
`Surgery
`
`Pituitary surgery emerged as a major therapeutic
`approach in the late 1970s. Two groups [127,128) who
`performed it systematically in patients who had no
`evidence of sellar enlargement on skull X-ray
`
`demonstrated that most patients harbored a microade(cid:173)
`noma in their pituitary and were cured by its selective
`removal. The rationale that guided this systematic
`approach was based on the prevalence of such micro(cid:173)
`adenomas at autopsy [3,106), the reported successes in
`occasional patients who had been operated on
`(726-728], and the convenience and safety of a novel
`neurosurgical procedure, namely the transsphenoidal
`route [727,729]. Over the last 10 years transsphenoidal
`pituitary exploration has become widespread in many
`centers and more than a thousand operated patients
`have been reported in published series.
`Prior to surgery, patients should be prepared so that
`severe hypertension and hyperglycemia are controlled
`and infected areas eradicated. Depending on the
`severity of the hypercortisolic state some patients may
`need a course of anticortisolic treatment for several
`months before surgery. In all cases patients should
`receive glucocorticoid coverage during surgery and the
`operation should be performed only by experienced
`neurosurgeons, preferably in referral centers. Under
`these strict conditions the transsphenoidal approach is
`considered a safe procedure [616]. Mortality is excep(cid:173)
`tionally reported as a consequence of meningitis [129],
`bleeding [730], or delayed myocardial infarction [651],
`accounting for five operation-related deaths in about
`
`m. PITUITARY TIJMORS
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2015, Page 50
`
`

`

`PITIJITARY-DIRECTED THERAPIES
`
`581
`
`550 published patients [731]. CSF leak occurs in 3-8% of
`cases. Mild and transient complications such as diabetes
`insipidus and facial and periorbital hematomas are more
`frequent.
`A successful surgical outcome of a selective adeno(cid:173)
`mectomy characteristically induces a state of usually
`transient, although sometimes lasting up to several
`years, corticotroph deficiency during which steroid
`coverage is necessary. In most patients a progressive
`return to a completely normal pituitary-adrenal axis
`is observed. All baseline measurements, all dynamic
`tests and the circadian rhythm of cortisol are normal
`(Figure 16.24) [129,134,158-160,163,188]. Late night
`salivary cortisol is also validated to assess the outcome
`of pituitary surgery [732]. Thus pituitary surgery has
`the potential to cure patients.
`Estimating the cure rate of pituitary surgery is diffi(cid:173)
`cult when comparing the results of different series.
`There are variable criteria for cure (733-737], variable
`durations of follow-up after surgery, and even variable
`surgical techniques and strategies. If an immediate
`success (or initial cure) is defined as the patient with
`a normal or a low cortisolic state in the first 1-3 months
`after surgery, there is a general agreement for a high
`early success rate. Screening the results of more than
`800 operated patients reported in 14 series from 14
`different centers published between 1979 and 1989
`shows that the early success rates varied between 66
`and 88% (738]. In the seven largest series which report
`
`between 60 and 216 cases, this number varies between
`70 and 92% [129-135]. These figures are confirmed by
`more recent series [739,740], and similar success rates
`are reported whether the patients were operated by
`the classical sub labial transseptal approach or the newer
`transnasal combined endoscopic microsurgery [741];
`with the latter approach, there was less blood loss, and
`both the time of anesthesia and the hospital stay were
`shorter.
`These encouraging figures must be tempered by the
`fact that some patients who were early successes by
`the best criteria [315] eventually relapse. The rate of
`recurrence is difficult to analyze in the various series
`for lack of uniformity and because the valid figure, i.e.,
`relapse rate (patients x years of follow-up) is only rarely
`reported. It has been estimated at about 8% [731],
`although it can be as high as 15% [129,738] in some
`series. With longer time of follow-up, recent series
`have reported recurrence rates of 25% at 5 years (742],
`or a final success rate at 10 years of only 56% [743].
`The postoperative work-up shows that, as a group,
`patients who ultimately recur have higher cortisol
`responses to CRH and higher baseline urinary cortisol
`excretion than other early cured patients who will not
`recur [129,738]. Also, the ACTH response to desmopres(cid:173)
`sin, in the postoperative period, has been more and more
`recognized as a good predictor of later recurrence in
`a number of series [744-749]; because, in contrast with
`CRH, desmopressin response is rather specific to the
`
`Long-term follow-up of pituitary(cid:173)
`FIGURE 16.24
`adrenal function after successful pituitary surgery (S).
`(A) Circadian variation of plasma cortisol. (B, C) Plasma
`cortiso[ and adrenocorticotropic hormone
`(ACTH)
`responses to the lysine vasopressin (LVP) test. From
`Guilhaume et a/. [129].
`
`200
`
`04 ~~l Lu...u..J L..u_uj
`
`8
`
`48
`
`48
`
`48
`Clock hours
`
`4 8
`
`4 8
`
`4
`
`-
`
`100
`
`~ ..s
`
`~
`
`~
`-~
`"' s "' 200
`100 /
`
`L___j
`08
`
`i t
`
`/
`
`~ 100
`~ so
`E
`E o L_j
`Preop.
`
`Q.
`
`~
`L__j L__j L_ j L_j L_ j L_ j
`0.75
`1.7
`2.6
`3.6
`4.8
`5.8
`Years after surgery
`
`ill. PITUITARY TUMORS
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2015, Page 51
`
`

`

`582
`
`16. CUSHING'S DISEASE
`
`tumoral cells in the excised tissue were more prevalent
`in early successes (72%) than in surgical failures (24%,
`p <0.01) [129). The fact that adenomatous cells were
`not identified in most surgical failures suggested that
`either a pituitary adenoma was present which had
`been missed, or that there was no adenoma in the pitu(cid:173)
`itary. The latter, which would favor a hypothalamic
`hypothesis for some Cushing's disease [152), actually
`is hardly tenable since no evidence of corticotroph cell
`hyperplasia was found histologically in this same study
`[129,752). A much more likely explanation is that most of
`the time surgical failure occurs because a microadenoma
`was indeed present but missed. The fact that pre- and
`postoperative urinary cortisol excretion and plasma
`ACTH remained absolutely unchanged in patients
`who failed surgery despite removal of a significant
`portion (ca. 50%) of their anterior pituitary can be taken
`as an indication that only suppressed corticotroph cells
`had been removed, leaving the adenoma in situ [129].
`Some patients have finally been cured when a microade(cid:173)
`noma was found at a second operation [135,317}. There
`is no theoretical reason why it should be easy to explore
`a solid organ and discover inconspicuous lesions a few
`millimeters in size under a microscopic view that is
`often blurred by hemorrhages, and at the same time
`ignore the lures of small microcystic structures lying
`close to the posterior lobe. Thus, technical difficulties
`should not be minimized as an evident cause of surgical
`failure.
`The surgical outcome does not always correlate with
`the histological data when some patients are cured after
`a mere exploration of the pituitary [130] or when no
`adenomatous cells were apparently removed [129,752],
`and others being surgical failures although such cells
`were found [129). In a large series reporting 216 cases
`the primary predictor of failure of surgery was the exis(cid:173)
`tence of lateral extrasellar extension of the tumor [130].
`Some groups have advocated that total hypophysec(cid:173)
`tomy be performed systematically in order to diminish
`the risk of failure [753]. Others find no improved early
`success with this strategy [731). Although total hypophy(cid:173)
`sectomy appears to lower the risk of relapses it certainly
`augments the risks of hypopituitarism, and many
`recommend it in particular patients - usually postmen(cid:173)
`opausal women - and only if the surgeon fails to iden(cid:173)
`tify the adenoma [130].
`In an attempt to improve the efficacy of pituitary
`surgery several groups have tried to develop new
`approaches to help the neurosurgeon find the microade(cid:173)
`noma, or at least locate the pituitary half which harbors
`the lesion. Perioperative histologic examinations and
`ACTH determinations in peripituitary blood [754]
`have been claimed to be of help. But the most popular
`approach has been bilateral inferior petrosal sinus
`sampling. A ratio of the ACTH level on one side to the
`
`FIGURE I6.Z5
`
`sole tumoral corticotroph cells, this test is both sensitive
`and specific. Since true recurrences may occur as late as
`10 years, or even more, postoperatively, it is recommen(cid:173)
`ded that all initially cured patients be regularly - and
`indefinitely - followed. The reason for relapses remains
`obscure. It has been interpreted by some as the manifes(cid:173)
`tation of a persistent hypothalamic drive that would
`have been primarily responsible for the development
`of a pituitary adenoma; alternatively a partial adeno(cid:173)
`mectomy could spare a small population of tumoral cells
`that subsequently regrow [316,317].
`A crucial question is to understand the reasons for the
`early surgical failures. Some circumstances provide an
`obvious explanation: (1) profuse local bleeding, often
`due to dural venous sinus, may prevent exposure of
`the gland [130}; (2) a pituitary adenoma may be located
`above the sella (Figure 16.25) or even in the sphenoid
`sinus [138,139]; or (3) a patient with an occult ectopic
`ACIH syndrome may have been misdiagnosed
`[572,721].
`Excluding these causes there are still patients who are
`unexpected surgical failures, either because the explora(cid:173)
`tion cannot detect the adenoma or because removal of an
`apparent adenoma does not control the hypercortiso(cid:173)
`lism. A thorough search for an indicator that would
`predict a favorable or unfavorable surgical outcome
`has not clearly distinguished a convincing predictive
`biochemical parameter [129]. It has been proposed that
`the cure rate was lower in patients with large macroade(cid:173)
`nomas [130] with paradoxical responses to TRH and/or
`LHRH [738], with circulating autoantibodies against
`pituitary ACTH-producing cells [750], and in those
`with evidence of intermediate lobe involvement [270].
`These suggestions remain controversial [731]. A positive
`pituitary MRI imaging is positively [740] - or not [751]
`- associated with a higher likelihood of surgical success.
`Better correlations have emerged
`from studies
`systematicaUy comparing the surgical outcome and
`histologic characteristics of the removed pituitary frag(cid:173)
`ments [129J30,731,752]. One study reported
`that
`
`ill. PITUITARY TUMORS
`
`-
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2015, Page 52
`
`

`

`PlnJITARY·DIRECfED THERAPIES
`
`583
`
`other greater than 1.5 indicates that the adenoma lies in
`that same half of the pituitary gland [611,621]. Because
`some patients have been cured by hemihypophysec(cid:173)
`tomy guided on the sole results of this test it may be
`indicated in the patients with no MRI evidence of micro(cid:173)
`adenoma. It might avoid the total hypophysectomy,
`with its life-long hormone replacement, proposed by
`some if the surgical exploration were negative. Yet this
`technique should probably be reserved for experienced
`teams and its real diagnostic accuracy is variably appre(cid:173)
`ciated [615,642].
`Pituitary surgery has re-emerged as a most fruitful
`treatment of Cushing's disease. It essentially provides
`a rapid and easily assessable result with a high rate of
`success in expert hands. It has been successfully per(cid:173)
`formed in a patient with an empty sella [755]. Its major
`causes of failure are anatomic due to the lateral exten(cid:173)
`sion, the small size, or the inaccessibility of the tumor.
`It is the sole treatment that results in a complete restitu(cid:173)
`tion ad integrum of the pituitary-adrenal axis. After
`successful pituitary surgery in 161 patients treated
`for Cushing's disease, long-term (mean of 8.7 years)
`survival was similar to that expected from an age- and
`sex-matched con trol population (461]. In the case of
`failure of a selective adenomectomy or partial hypophy(cid:173)
`sectomy all other therapeutic strategies remain open,
`including a second attempt at transsphenoidal explora(cid:173)
`tion, although usually with a lower success rate
`compared to first surgery [756-758]. It is ideally per(cid:173)
`formed and evaluated by an integrated team with an
`endocrinologist, a radiologist, a neurosurgeon and
`a histologist. Transsphenoidal pituitary surgery for
`ACTH~secreting pituitary tumors is associated with
`a higher complication rate than that observed after
`similar surgery for other pituitary tumor cell types.
`About 13% of patients undergoing tumor resection in
`an experienced center develop complications, especially
`deep vein thrombosis [616].
`
`Radiation
`Conventiotull RJuliotherapy
`Probably the first patient to receive pituitary irradia(cid:173)
`tion for Cushing's disease was patient E. G. F. (or case
`11 of Cushing's monograph) who was almost dying
`from his condition when:
`
`" ... he was given ... four X-ray treatments. During their
`course, he felt particularly miserable, but, his downward
`progression for the preceding month was unmistakably
`checked. The improvement in his general condition was so
`striking it must have been something more than coincidence ... "
`[106).
`
`Subsequently conventional megavoltage pituitary
`irradiation has been proposed as a first-line treatment
`
`of Cushing's disease. Success rates vary between groups
`depending on the proposed criteria to define cure.
`Because this treatment usually does not restore a normal
`circadian rhythm or a normal response to the classic
`low-dose dexamethasone suppression test, the criteria
`for "cured" or "improved " patients are most often set
`arbitrarily according to some plasma cortisol or urinary
`steroid values. In a series of 51 irradiated patients, out of
`44 who had been followed-up for more than 1 year, ten
`were judged cured (urinary 17-hydroxycorticosteroids
`<7 mg/g creatinine) for periods up to 14 years, and 13
`others were judged improved (urinary 17-hydroxycorti(cid:173)
`costeroids <10 mg/g creatinine) [759]. Subsequent re(cid:173)
`evaluation of this group showed that the success rate
`was especially high in the children ( <20 years old)
`with 80% being cured, and it was suggested that only
`about 15% of adults would be cured with an additional
`30% improved [760]. Other groups have reported
`success rates somewhat higher, in the 50% range
`(761,762]. Most groups have delivered between 35 and
`52 Gy with a daily fractional dose of ca. 200 cGy. Lower
`doses (20 Gy) have a high relapse rate [763].
`The response to radiotherapy is slow, taking months
`or years for a full effect. Significant complications of
`modem radiotherapy are rare provided that the total
`and fractional doses remain within established limits.
`The most frequent is the late occurrence of hypopituita(cid:173)
`rism [763,764]. Serious complications such as injury to
`optic nerve or chiasma, radiation-induced carcinogen(cid:173)
`esis and brain necrosis have also been reported in occa(cid:173)
`sional patients with Cushing's disease. However, they
`are truly exceptional for total doses of less than 50 Gy
`[765].
`Because of its limitations as the sole treatment of
`Cushing's disease, pituitary radiotherapy has been
`combined with various other therapeutic regimens
`[766]. Its combination with unilateral adrenalectomy
`does not seem justified in view of the poor success rate
`[767]. More logically and more efficiently, pituitary irra(cid:173)
`diation is associated with transient adrenocortical(cid:173)
`treatment such as metyrapone,
`directed medical
`op'DDD, or ketoconazole (768-771] until it has achieved
`its full effect. Twenty-five of 30 patients with persistent
`or recurrent Cushing's disease after pituitary surgery
`who underwent radiation were in remission for
`a median follow-up of 42 months under combined keto(cid:173)
`conazole treatment (768]. No recurrences occurred, and
`most patients were controlled within 2 years, especially
`when receiving concomitant ketoconazole
`therapy.
`Pituitary irradiation is probably undisputed in large
`macroadenomas that are either inoperable or only
`partially removed by surgery because of local extension
`[762]. Some controversy still exists on its prophylactic
`action for Nelson's syndrome in patients subjected to
`bilateral adrenalectomy.
`
`ill. PITUITARY TUMORS
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2015, Page 53
`
`

`

`584
`
`16. CUSHING'S DISEASE
`
`Stereotactic Radiosurgery with the r-Knife
`An original device called a y-knife has been developed
`and efficiently used for the last 20 years at the Karolinska
`Institute of Stockholm. A hemispheric instrument (colli(cid:173)
`mator helmet) allows a cerebral target to be placed at
`a constant and exact intersection of 201 beams of 60Co
`radiation that simultaneously crossfire to the lesion.
`This technique achieves high precision and can deliver
`a fixed dose of radiation to areas ranging in size from
`4 em to a few millimeters without major side effects.
`The complete treatment is achieved in a single painless
`session of 5-30 minutes. The y-knife has been widely
`used to destroy pituitary adenomas with a high success
`rate, reaching 76% in Cushing's disease with no relapses
`[771]. These impressive figures were not confirmed in
`more recent series from other centers where only
`44-54% of the patients were in remission, and with
`some recurrences [772,773]. It would be desirable that
`this radiation procedure be extended to several other
`centers, allowing a wider and more significant evaluation
`of what appears as a highly promising therapeutic means
`for its convenience and, hopefully, its high success rate.
`
`Heavy,particle Radiotherapy
`
`The use of heavy particles (a.-particle irradiation or
`proton-beam therapy) allows the delivery of a higher
`dose of radiation on a smaller-volume target. Reported
`success rates appear somewhat higher than with
`conventional radiotherapy, between 65 and 80%
`[774,775]. 1his gain in efficacy is offset by an increased
`incidence of side effects such as optic nerve alteration,
`oculomotor palsies and hypopituitarism. These methods
`are not applicable to large tumors with suprasellar or
`sinus extension, and they are only available in a limited
`number of specialized centers with a cyclotron.
`
`Radioactive Implants
`Direct implantation of radioactive seeds within the
`sella has been claimed a safe and efficient treatment in
`the limited centers that perform this specialized stereo(cid:173)
`tactic approach [776,777]. Local interstitial irradiation
`is delivered by 198 Au or 9oy. In the largest recently
`reported series of 86 patients, 77% had achieved remis(cid:173)
`sion after 1 year [778]. The authors emphasize the lack
`of recurrence of their cured patients as a major advan(cid:173)
`tage over pituitary surgery. Yet interstitial irradiation is
`associated with a 50% incidence of hypopituitarism
`which compares quite unfavorably with conventional
`radiotherapy, and especially with surgery.
`
`Medical Treatments
`
`Various drugs have been tentatively used to try to
`suppress oversecretion of ACTH in Cushing's disease.
`
`Whatever the promises of the initial studies it is fair to
`say that in the long range none has gained a level of
`credibility that could favorably compare with that of
`the other therapeutic means [779).
`
`Cyproheptadine
`In the mid-1970s the first cases of cyproheptadine(cid:173)
`induced remissions were reported in three patients
`with C