Guidelines for Doctors and their Patients who have Residual Cushing’s Disease
Lewis S. Blevins, Jr. MD and Gwen Stanhope, PA-C
California Center for Pituitary Disorders at University of California, San Francisco
Dr. Blevins is the Medical Director of the California Center for Pituitary Disorders at UCSF. He has extensive experience in the evaluation and management of patients with Cushing's disease and other pituitary disorders. Gwen Stanhope is the physician's assistant of the Center and works with Dr. Blevins in the evaluation and management of patients. They are currently accepting referrals. Inquiries regarding appointments are directed to 415-353-7500.
Remission is achieved in 70 to 90% of patients who undergo surgery for Cushing's disease at experienced medical centers. Lower rates of remission, on the order of 50-65%, are seen in those who have larger pituitary tumors known as macroadenomas. Those patients who do not enter remission often suffer a great deal of disappointment and frustration at having failed surgery. In this day of age, however, a significant proportion of patients can ultimately achieve remission following additional treatment. Fortunately, in a majority of patients, the disease can ultimately be controlled even when a true cure is impossible.
Patients who have residual Cushing's disease and their treating physicians must partner together in the process of defining further evaluation and management. This article is intended to be a resource or a guide that patients can refer to and use to work with their physicians to establish a plan. We recommend a logical stepwise approach that begins with confirmation that residual disease is present and is followed by a review of information to ensure that the original diagnosis was correct, and then finally, establishment of an individualized management plan.
Step 1. Confirmation that residual disease is present.
Several schemes have been proposed to identify those patients with persistent disease. Many physicians employ measurement of the serum cortisol level in the first couple of days after surgery in order to determine which patients have residual disease and to plan for immediate additional treatment. Normally, we would expect cortisol levels to be very low after successful surgery because the high cortisol levels driven by the offending tumor producing ACTH usually turn off the normal pituitary glands ability to produce ACTH. It takes an average of 10 to 12 months for the normal pituitary gland to resume its function to control the adrenal glands after successful surgery for Cushing's disease. With this in mind, it is clear that patients with elevated postoperative serum cortisol concentrations and elevated urine cortisol levels have failed surgery and require additional treatment. However, a low cortisol does not imply patients are free of disease as recurrences are seen in 5 to 12% of these patients. Furthermore, finding a “normal” cortisol level does not imply that patients are not disease free. In our opinion, it takes 6 to 12 weeks for cortisol levels to fall to as low as they will after surgery. Thus, we recommend measurement of the cortisol level at 6 weeks after surgery for most patients. There is no hurry. In fact, a decision regarding remission or cure is probably best made 6 to 12 months after surgery. Even then, one can never be certain for we have seen patients who have had recurrent Cushing's disease up to 14 years after an initially successful surgery. Evaluation of the cortisol level sooner than 6 weeks makes sense when the surgeon is fairly certain that complete tumor removal was not accomplished and in patients who have continued ongoing symptoms and signs of Cushing's syndrome in the early postoperative period. For patients who have low cortisol levels, we presume that they might enter remission and continue steroid replacement therapy. They undergo reassessment at 6 to 12 week intervals for the first year. For patients who have “normal" levels at 6 weeks we usually discontinue steroids and conduct additional assessments, sometimes including dexamethasone suppression tests, salivary cortisol profiles (in order to determine the pattern of secretion of cortisol throughout the day), CRH tests, and MRI studies of the pituitary gland. The responses to these tests can be employed to determine which patients have residual disease and those that are likely to be in remission.
Step 2. Confirmation of the original diagnosis and a search for why cure was not achieved.
It is not at all surprising, given that Cushing's is a rather complex and unusual disorder, that some patients who have undergone surgery did not have Cushing's in the first place. Furthermore, some patients thought to have pituitary disease actually have the syndrome of ectopic ACTH production meaning that ACTH is produced by a tumor located somewhere other than in the pituitary gland. Therefore, it is critical that patients and physicians review all of the data pertaining to the workup performed prior to the original surgical procedure. Did the patient actually have Cushing's syndrome? Is there data to strongly suggest or confirm that the pituitary was the source of ACTH production? Inferior petrosal sinus sampling may be useful to determine if and to confirm that the pituitary is indeed the source of ACTH production. Review of the histopathology report is a critical task. Demonstration of an ACTH-secreting pituitary tumor in a patient who has persistent hypercortisolism can be useful to confirm that the preoperative diagnosis was correct and might suggest that removal of the tumor was incomplete. It is important to understand that a significant portion of patients with Cushing's disease have microscopic evidence of tumor invading surrounding structures. The surgeon cannot see microscopic tumor remnants and many of these structures are best not violated by the surgeon in the first place. Sometimes, a tumor is not found at the time of the operation. In one study, the absence of a tumor was associated with a higher rate of surgical failure (47%) than when ACTH-producing pituitary tumors were confirmed at the time of examination of tissue removed at surgery (17%). Absence of tumor does not imply the tumor was not present in the first place. Inferior petrosal sinus sampling, if not performed prior to unsuccessful surgery, should be performed in those patients in whom pituitary tumors were not identified at the time of surgery. Another potential cause of surgical failure is the inexperienced neurosurgeon. Practice surveys have shown complication rates are higher and remission rates are lower following attempts at pituitary surgery by relatively inexperienced surgeons compared with more experienced pituitary surgeons. Most believe that surgeons with sufficient experience have done more than 500 pituitary cases. Surgeons with moderate experience have accomplished 200 to 500 cases.
Step 3. Establishment of an individualized management plan. Once a diagnosis of persistent Cushing’s disease has been confirmed patients and their doctor's must consider the different treatment alternatives. We believe that treatment should be individualized based on patient needs and not on any preconceived treatment algorithms. Patients should be educated about the various treatment options, expected outcomes, risks, inconveniences, and costs so they can make informed decisions on how best to proceed. Generally speaking, we prefer that treatment directed against the tumor will also control the cortisol levels. However, in some cases, it is important to recognize that treatment must be designed to deal with cortisol levels and the tumor independently. This is more so the case in patients who have tumors that are incurable or unresponsive to surgery and radiotherapy.
Repeat pituitary surgery should be considered for all patients with residual Cushing’s disease. In general, we advise repeat surgery when there is a reasonable chance that patients will achieve benefits without significant risks even when their tumors might not be completely resected. For example, surgery might be very beneficial if it will result in marked lowering in ACTH and cortisol levels even though it may not achieve complete removal of the pituitary tumor. Repeat surgery is probably most beneficial when the previous operation had been performed by an inexperienced neurosurgeon and especially when there is evidence of tumor within the pituitary area that would seem to be accessible to the operating neurosurgeon. Approximately one-half to three-quarters of patients with microadenomas can be expected to enter remission following repeat surgery. Remission in patients with macroadenomas is uncommon but, once again, a second procedure may be employed to control tumor mass effects and to reduce cortisol levels when other treatments have failed.
Conventional radiotherapy can induce remission in 50-80% of adult subjects and a majority of children with residual Cushing's disease. Unfortunately, the response to treatment is delayed and remission may not occur for several years. As many as two-thirds of patients develop one or more deficiencies of anterior pituitary hormones within 10 years so it is important that evaluation of pituitary function be performed at least annually for life. Stereotactic radiosurgery, most commonly in the form of “gamma knife” radiosurgery, can normalize cortisol levels in 50 to 75% of patients. The average time to normalization of cortisol levels is approximately 12 months. Radiation usually controls the tumor but we have seen some patients who have progressive tumor growth despite radiation. We only employ radiotherapy in the management of patients with persistent Cushing’s disease when we have confirmed the pituitary as the site of ACTH hypersecretion. Furthermore, radiotherapy is often recommended when patients are poor candidates for repeat surgery due to medical issues and in those who have residual tumor that is inaccessible to our surgeons.
A number of different medications can be employed in order to gain control of the high cortisol levels and improve the overall health of patients while waiting for the beneficial effects of repeat surgery or radiation. We prefer to use the drug known as Ketoconazole as first line therapy. Therapy is monitored by a measurement of the urine cortisol levels and drug doses are altered when necessary in attempt to normalize the urine cortisol rates. Previously, we have used aminoglutethimide and metyrapone as second line agents but these drugs are increasingly difficult to obtain. We resort to mitotane as a drug of last resort because of its side effect profile.
Bilateral adrenalectomy is usually reserved and employed as a last resort when all else has failed and the patient is in grave danger due to the consequences of high cortisol levels. However, the success and relatively low risk of complications of laparoscopic bilateral adrenalectomy prompts us to reconsider our attitudes towards adrenalectomy in patients with residual and recurrent Cushing's disease. Perhaps adrenalectomy should be employed earlier in the course of treatment of patients with refractory Cushing's disease.
Finally, regardless of the treatment selected, is essential to keep in mind that lifelong follow-up is required. Follow-up will ensure that treatment has been complete, to allow for early diagnosis of recurrences, permit assessment pituitary function on an ongoing basis, allow for the assessment of the adequacy of any hormone replacements, etc. Furthermore, as medical science does indeed advance, one must stay connected with physicians, other patients, and support groups as well as the medical literature in order to stay abreast of developments in diagnosis and treatment.