Case Study Illustrates Need for More Effective Treatment Options for Aggressive Pituitary Adenomas

Share

By Eliza B. Geer, MD Andrew Lin, MD on behalf of the MSK research team

Endocrinologist Dr Eliza Geer

Endocrinologist Dr Eliza Geer

Pituitary adenomas continue to grow in a small subset of patients despite treatment with standard surgery and radiotherapy.

Further treatments may provide symptom relief but are rarely definitive for disease management in this cohort.

Recognizing the significant unmet needs in this patient population, we recently published a review of the latest treatment options in The Journal of Clinical Endocrinology & Metabolism. We discuss reresection, reirradiation, temozolomide, and off-label investigational approaches, including targeted therapies and checkpoint inhibitors. (1)

The case of a female patient who was diagnosed at the age of 46 with an invasive pituitary macroadenoma clearly illustrates the need for better treatment options. After receiving standard treatments at another cancer center and participating in two clinical trials, she was referred to Memorial Sloan Kettering Cancer Center (MSK) for further evaluation at the age of 58. (1)

The case study also underscores the need to refer patients with rare, complex tumors to cancer centers with multidisciplinary expertise. At MSK, doctors with the Multidisciplinary Pituitary and Skull Base Tumor Center collaborate to provide world-class, comprehensive care to patients diagnosed with pituitary, parasellar, paranasal sinus, and other skull base tumors. Our team of neurosurgeons, head and neck surgeons, endocrinologists, neuro-ophthalmologists, radiation oncologists, medical oncologists, and neuro-radiologists ensure each patient receives coordinated care. MSK is one of few centers in the world offering interoperative MRI for every pituitary and skull base tumor surgery.

Case: 46-year-old patient
Diagnosis, Standard Surgery and Chemotherapy, First Clinical Trial, Emergent Radiotherapy

A 46-year-old woman presented with amenorrhea, weight gain, and myopathy. She had an elevated urine free cortisol value (UFC) of 689 μg/24 hours (normal is < 45 μg/24 hours) with an elevated plasma adrenocorticotrophic hormone (ACTH) of 99 pg/mL. Magnetic resonance imaging (MRI) revealed a large pituitary adenoma that had invaded the clivus, body of the sphenoid bone, tuberculum sellae, and sphenoid sinus.

She underwent subtotal resection of the sellar tumor, and pathology confirmed a corticotroph pituitary adenoma with a Ki-67 of 5 percent and p53 immunoreactivity. Post-operative MRI showed residual tumor, and UFC was 90 μg/24 hours.

The patient declined radiotherapy and instead enrolled in a clinical trial investigating pasireotide, a somatostatin pan-receptor ligand. However, after four weeks of treatment, she required intubation and a tracheostomy as her cancer progressed rapidly and compromised respiration via involvement of cranial nerves IX and XII.

The patient received emergent radiotherapy with 1,000 centigray (cGy) in five fractions through parallel opposed conventional radiotherapy, followed by a 3D conformal plan for an additional 3,200 cGy in 16 fractions, with a final 3D conformal cone down plan of 800 cGy in four fractions.

The patient had a biochemical and radiographic response, as well as a dramatic clinical response. Her cortisol levels normalized, and cranial neuropathies nearly resolved, which permitted decannulation.

Unfortunately, the patient’s disease progressed 2.5 years later, as confirmed by an elevated UFC of 754 μg/24 hours, plasma ACTH of 88 μg/24 hours, and recurrent tumor growth.

Aggressive Pituitary Adenomas

Aggressive pituitary adenomas that are resistant to standard surgery and radiotherapy fall into two general categories:

  1. Remain confined to the skull base: These tumors can cause significant local destruction that manifests with severe headaches and cranial neuropathies, vision loss through suprasellar extension and compression of optic structures and nerve compression, diplopia, and pupillary dilation and ptosis, which can progress to complete eyelid closure and loss of vision. Cranial nerve compression can cause numbness and paresthesia in the upper two-thirds of the face. Frontotemporal lobe destruction due to locally aggressive tumors can cause somnolence, hyperphagia, obstructive hydrocephalus, seizures, diabetes insipidus, and death. (2) Hormonal control becomes increasingly challenging when functional tumors progress, sometimes with life-limiting consequences, as seen in patients with ACTH-secreting tumors. (3), (4), (5), (6), (7), (8) Bilateral adrenalectomy is often required to treat hypercortisolemia , which can lead to Nelson syndrome, and possibly more aggressive tumor growth. (9) A recent series found a 10-year progression-free survival (PFS) of 62 percent for patients diagnosed with Nelson syndrome. Among the subset of patients who failed initial management of Nelson syndrome with surgery, radiotherapy, pasireotide, or observation, 28 percent (five of 18) had aggressive tumors, and 11 percent (2 of 18) developed metastases. (10)
  2. Metastasize and become pituitary carcinomas: These tumors spread either through the spinal fluid, resulting in leptomeningeal metastases on the surface of the brain, brainstem, or spinal cord, or through the bloodstream, resulting in distant metastases anywhere in the body.

Aggressive pituitary adenomas and pituitary carcinomas have not been well defined to date. Many registries, such as the Central Brain Tumor Registry of the United States (CBTRUS) and the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program, (11) do not adequately capture the incidence and prevalence of aggressive pituitary tumors. While rare, pituitary carcinomas may be underdiagnosed since identifying distant metastases requires high suspicion.

Small case series have reported a median survival of less than a year, (12) with a definite subset of patients who experience a relatively indolent disease course. Spread through the spinal fluid may be more advantageous than through the blood. (11) For example, there is a report in the literature of a patient with leptomeningeal metastases who remained recurrence-free for at least 21 years after a complete radiographic response to surgery and whole-brain radiotherapy. (13)

The best imaging modality for identifying distant metastases has not been defined. Neuroendocrine tumors, including pituitary adenomas and especially those that are more differentiated, may not exhibit hypermetabolism and therefore, not show well with 18-fluorodeoxyglucose (18F-FDG) PET, the most common method for staging malignancies. (14) Further, leptomeningeal metastases, especially micrometastases, may be challenging to find due to the high background uptake of neural tissue and low spatial resolution.

Radiolabeled octreotide derivatives such as Gallium-68 (68Ga) DOTATATE may be useful for tumor management and for identifying distant metastases, (15), (16) which binds to somatostatin 2 (SSTR2), (17) a receptor expressed in a majority of pituitary tumors expressing thyroid-stimulating hormone and growth hormone. Tracers that bind to SSTR5 and SSTR3 may be more sensitive for non-functioning tumors and tumors secreting ACTH and prolactin. (17)

Total spine MRI with and without gadolinium and lumbar puncture is often required to rule out leptomeningeal spread. Clear indications for testing include back pain, radicular pain, signs and symptoms of cord compression, or the identification of leptomeningeal deposits in the MRI field of view during surveillance of the pituitary tumor.

Back to top

Standard of Care Treatments

Reresection

Aggressive pituitary adenomas are most often macroadenomas at the time of diagnosis, (12), (18) following a failure to cure surgically due to invasion into unresectable structures such as the cavernous sinus. The tumor becomes even less operable with transsphenoidal and even transcranial approaches as it grows. Moreover, each additional surgery places the patient at a higher risk of stroke, diabetes insipidus, and spinal fluid leak. Accordingly, the primary indication for repeat surgery is decompression of the optic chiasm. Subtotal resection in other locations has limited benefit.

Reirradiation

Locally aggressive pituitary adenomas often cannot be treated with stereotactic radiosurgery due to their large size and proximity to sensitive structures. The total dose is typically fractionated over 25 to 30 fractions over five or six weeks, (19), (20) which results in more than 90 percent local control at five years for most patients. (20)

Fractionation is less destructive to normal tissue, and there are established tolerances for the optic chiasm, optic nerve, and other nearby structures. Surpassing these tolerances can lead to complications, including blindness and brain tissue necrosis. It is critical to establish the cumulative dose of radiation administered to every structure before beginning treatment and counseling individual patients on their expected risk of developing complications. There are no treatments for radiation-induced neuropathy, which usually causes permanent vision loss over days to weeks. (21)

Proton radiation can partially mitigate the risks of reirradiation with conventional photon radiation. Protons deliver the majority of their energy at tissue depth, (22) whereas photon radiation deposits energy further away from the target. Proton radiotherapy can reduce the dose delivered to nearby normal tissue, such as temporal lobes, the orbit, and the brainstem, but cannot spare directly adjacent structures.

Temozolomide

The alkylating agent temozolomide is the only chemotherapy with documented evidence of effectiveness in treating pituitary tumors. The Endocrine Society and European Society of Endocrinology include its use in their guidelines. (18), (23) Still, it remains an off-label treatment for pituitary tumors in the United States (US). Without US Food and Drug Administration approval or addition to the National Cancer Center Network Guidelines, (24) insurance denials for this indication are not uncommon.

The alkylating agent temozolomide is the only chemotherapy with documented evidence of effectiveness in treating pituitary tumors. The Endocrine Society and European Society of Endocrinology include its use in their guidelines. Still, it remains an off-label treatment for pituitary tumors in the United States.
Eliza B. Geer Medical Director, Pituitary & Skull Base Tumor Center

Though a prospective trial has not been conducted, several large case series have reported favorable response rates. The largest study by the European Society of Endocrinology captured 166 patients treated with temozolomide via electronic survey. (25) The observed objective response rate (ORR) was 37 percent, including a complete response in six percent and a partial response in 31 percent. A partial response was defined as a 30 percent regression without no measurement parameters specified. Unfortunately, the result is not reproducible as the survey did not use validated response criteria, such as RECIST (26) or RANO. (27) However, among patients who had an objective response, tumor shrinkage was typically identifiable after three or four months and radiographic response of functional tumors typically correlated with biochemical response. (18) Other case series have found response rates closer to 50 percent, (28) suggesting that an ORR of 37 percent may be a conservative estimate.

As a single agent, temozolomide is dosed based on body surface area at 150 to 200 mg/m2/day for five consecutive days every 28 days. Usually well tolerated, common side effects include fatigue, rash, transaminitis, constipation, nausea and vomiting that are well-controlled by anti-emetic premedication, and thrombocytopenia that rarely requires transfusion. Temozolomide works by induced DNA damage. In a cancer cell with a functional mismatch repair system, the DNA damage results in cell apoptosis. One mechanism of resistance to temozolomide is expression of the gene MGMT.

As it is teratogenic, contraception during treatment and for a period after drug cessation is essential, and patients receive counseling on fertility preservation options. There is also a small risk that temozolomide can cause myelodysplastic syndrome or leukemia.

Two major controversies about the optimal use of temozolomide in patients with aggressive pituitary adenomas are the optimal duration of treatment and whether it should be used in combination with other therapies.

In the European Society of Endocrinology survey, the median time to first progression after treatment cessation was only 12 months, but durable responses have been reported. (25), (28) The response rate to a second course of temozolomide was low among 18 patients with outcome data who progressed on observation after completing a first course of treatment and a rechallenge: two of 18 patients had another partial response, and five of 18 were stable for an unreported duration. (25) Some have suggested that longer courses of temozolomide may lengthen the time to first progression. However, the evidence supporting this approach is limited. (29), (30)

Interestingly, in the trial that led to the FDA approval of temozolomide for the treatment of glioblastoma, patients only received six monthly cycles of the drug. (31) It is common practice to continue it for 12 cycles and beyond for this indication. However, retrospective studies have not demonstrated a survival benefit with protracted courses of therapy in primary brain tumors. (32) Longer treatment courses may be beneficial, or they may provide no additional benefit while exposing patients to unnecessary toxicities and creating resistance to future alkylating chemotherapy. (33)

Two main combination approaches have been described in the literature:

  • Concurrent capecitabine and temozolomide: Capecitabine is an oral agent that interferes with DNA synthesis, replication, and repair, and also has a cytotoxic effect via inclusion in replicating RNA. (34) Common side effects include bone marrow suppression, diarrhea, hand-foot syndrome, nausea, vomiting, and fatigue. It has been used in combination with temozolomide in the treatment of non-pituitary, neuroendocrine tumors. A small case series of four patients reported a high response rate: two patients had a complete response, one had a partial response, and one had stable disease. (35) The prospective trial NCT03930771 is evaluating the response rate for this combination, known as CAPTEM, which will hopefully reveal whether adding capecitabine increases the response rate or adds toxicity.
  • Concurrent temozolomide and radiotherapy. There is major interest in combining temozolomide with radiotherapy after the European Society of Endocrinology’s survey reported an ORR of 71 percent over an indefinite observation period. (25) The finding was consistent with previous preclinical evidence that showed temozolomide is a radiosensitizer. (36) Since there is a high rate of control with radiation alone for the average patient with a pituitary adenoma, it remains unclear which patients might benefit from the addition of temozolomide, even if the two therapies are synergistic. Select patients with aggressive tumors that demonstrate rapid growth before radiotherapy and tumors that did not respond adequately to the initial course of radiotherapy might derive the most benefit.

Case: Patient at age 50 years
Reresection, Dopamine Agonist Therapy, Second Clinical Trial, Progression after Eight Years

The patient progressed clinically (with worsening hormonal hypersecretion and recurrent cranial neuropathies) and also radiographically.

She underwent a second surgery to decompress her optic chiasm, which revealed a corticotroph adenoma with five mitoses per 10 high powered fields, a Ki-67 labeling index of 15 to 20 percent, and MGMT expression in less than 15 percent of tumor cells by immunohistochemistry.

At the time she was referred to radiotherapy, only photon radiotherapy was available. However, the risk of a second course was prohibitive, given the need to overlap fields in the brainstem.

Treatment with ketoconazole (an anti-fungal with cortisol inhibiting activity) an cabergoline (a dopamine receptor agonist which can inhibit growth in some corticotroph tumors) did not achieve biological control (UFC stayed elevated at 1,028 μg/24 hours with a plasma ACTH of 88 pg/ml.

The patient enrolled in a clinical trial investigating the combination of temozolomide and capecitabine (CAPTEM). The regimen was capecitabine 1,500 mg/m2/day up to a maximum daily dose of 2,500 mg) divided into two doses on days one to 14, and temozolomide 150 to 200 mg/m2/day through divided into two doses on days 10 through 14 of a 28-day cycle.

Bilateral adrenalectomy was planned but obviated as the patient’s plasma ACTH decreased from 68 to 15 pg/ml, and serum cortisol fell from 20.5 to 1.3 μg/ml, rendering her adrenally insufficient and requiring hydrocortisone replacement. After five cycles, her ACTH and cortisol decreased to 5 pg/ml and 0.5 μg/ml, respectively. The tumor shrank by 50 percent, and her recurrent cranial neuropathies had mostly resolved. After ten cycles, the combination achieved a complete radiographic response, and plasma ACTH was undetectable. (1)

The patient continued on the CAPTEM combination for eight years on the assumption that it would have a suppressive impact on minimal residual disease. Over time, cycles were extended from 28 to 42 days and then every three months. Many of the patient’s Cushing comorbidities resolved during this period, including diabetes and hypertension, but she required continued treatment for depression, anxiety, and hyperlipidemia.

Case: Patient at age 58, Referred to MSK
Imaging, Proton Radiotherapy, MSK-IMPACT Genomic Profiling

The patient eventually progressed while being maintained on CAPTEM. Her plasma ACTH rose to 27 pg/ml with a serum cortisol of 2.3 mcg/dL. Her proopiomelanocortin (POMC) level was elevated at 179 fmol/ml (normal is < 50 fmol/ml), suggesting the development of an undifferentiated tumor. She was referred to MSK for further evaluation.

18F-FDG PET identified the site of progression in the left jugular foramen, and CAPTEM was discontinued. 68Ga-DOTATATE PET found no further disease sites.

The patient did well with reirradiation with proton radiotherapy, which allowed us to administer under 1,750 cGy to the brainstem. By contrast, a photon radiotherapy plan for 1.750 cGY would have placed the patient at high risk for radiation necrosis of the brainstem. The patient developed vocal cord paralysis, left-sided hearing loss, and vestibular dysfunction, which were expected complications with the proton radiotherapy plan. Vestibular issues resolved, but hearing loss persisted. Vocal cord paralysis required no intervention and did not impact her ability to breathe or swallow.

One year later, at the age of 59, liver metastases were found and confirmed by biopsy. Due to insufficient tissue from the liver biopsy, we performed whole-exome sequencing of the temozolomide-naïve recurrent sellar tumor and a matched normal tissue sample. MSK-IMPACT revealed her tumor was hypermutated with an exceptionally high burden of subclonal mutations in the absence of microsatellite instability/mismatch repair deficiency.

Back to top

Investigational Second-Line Treatments

All second-line treatments following temozolomide are investigational and should be considered of unproven benefit. Available data is mostly limited to case reports and small series. Limited experience using cytotoxic chemotherapy for managing aggressive pituitary tumors has been disappointing, with isolated ORRs reported for cisplatin/etoposide, (37) lomustine/5-fluorouracil (5-FU), (38) and 5FU/cyclophosphamide/doxorubicin. (39)

With the advent of molecular profiling, biomarker-driven targeted therapies are increasingly being considered. We reviewed five targeted therapies, including four with reported single-agent activity and checkpoint inhibitors, as follows:

  1. Lapatinib: The tyrosine kinase inhibitor lapatinib inhibits epidermal growth factor receptor (EGFR) and ErbB2 (HER2) signal transduction. Recurrent ubiquitin specific peptidase 8 USP8 mutations have been found with a prevalence of 31 to 36 percent. (40), (41) These mutations led to an increased in POMC transcription and ACTH secretion. EGFR-targeted therapy may be less relevant for aggressive tumors, but this remains unknown. The trial NCT02484755 is currently investigating the use of gefitinib, another EGFR inhibitor, in a small series of ACTH-secreting tumors. Case: Interrogation of the USP8 gene on whole-exome sequencing of the tumor and a matched normal revealed two subclonal mutations: a silent mutation in exon 14 and a S755T missense mutation in exon 15, outside the 14-3-3 binding motif. These mutations were present in a minority of cells, and we believed they were clinically insignificant.
  2. Everolimus: The mammalian target of rapamycin (mTOR) pathway, which plays a role in metabolism, cell growth, and proliferation, is another potential treatment target for aggressive pituitary tumors as it may be upregulated in tumors compared to normal tissue, (42) and is associated with cavernous sinus invasion. (43) In vitro studies with everolimus have been promising, but clinical data is sparse with use in at least seven cases to date with partial response in one patient and stable disease in another patient who received concomitant palliative radiotherapy. (44) The remaining five patients showed no radiographic response. (45), (25), (46) Case: Most genetic alterations in the sequenced resection were subclonal and unlikely to be genetic drivers. Sequencing did not provide compelling evidence supporting activation of the mTOR pathway. However, it may have developed as the tumor transformed over time. Thus, everolimus is a treatment consideration.
  3. VEGF Inhibition: Bevacizumab is a monoclonal antibody that binds VEGF and prevents it from interacting with receptors on endothelial cells. It is the primary anti-VEGF therapy that has been tried in pituitary tumors. Because it can be safely combined with radiotherapy and chemotherapy, it is often used with other agents. Case reports in pituitary tumors suggest single-agent activity. (25) There are negative case reports, (47) however prolonged stabilization of a pituitary tumor has also been reported. (48) This treatment requires further exploration.
  4. Peptide receptor radionuclide therapy (PRRT): Subtypes of pituitary tumors express SSTR. (49) SSTR receptors can be targeted with different SSTR ligands, some of which can be radiolabeled. Treatment with an SSTR ligand that delivers a cytotoxic dose of radiation, called PRRT, is the next logical step after visualization with radiolabeled diagnostic tracers, such as 68Ga-DOTATATE, but only when the tracer establishes that the tumor sufficiently over-expresses SSTR receptors. (50) The FDA approved 177Lu-DOTATATE for the treatment of advanced gastro-entero-pancreatic neuroendocrine tumors, (51) however data supporting the use of PRRT for treating pituitary tumors is limited. A recent review of 20 patients with aggressive tumors treated with PRRT using several different radiolabeled therapies found three cases of partial response and three cases of stable disease — and all six patients were temozolomide-naïve. Clinical trials are needed to determine response rates for this approach. Case: Liver metastases were undetectable on 68Ga-DOTATATE PET due to low receptor density. Therefore, 177Lu-DOTATATE was not considered worth pursuing.
  5. Checkpoint inhibitors: Since temozolomide is an alkylator, it can cause hypermutation. When a tumor cell acquires mismatch repair deficiency under the selective pressure of temozolomide, the drug can induce mutations without causing the tumor cells to undergo apoptosis, resulting in a tumor with a heavy mutational burden, including oncogenic mutations that cause malignant transformation. (33) This phenomenon was reported recently in a pituitary tumor that transformed from a locally aggressive tumor to a pituitary carcinoma. (52), (53) Mutational burden is associated with response to checkpoint inhibitors, as seen with melanoma and non-small cell lung cancer. (54), (55)

The FDA approved the checkpoint inhibitor pembrolizumab for the treatment of any tumor, including pituitary tumors, that have microsatellite instability as a marker of high mutational burden. A dramatic response has been reported for the treatment of a pituitary tumor with checkpoint inhibitors ipilimumab and nivolumab: After initial response with plasma ACTH decreasing from 45,550 to 59 pg/ml, the dominant liver metastasis decreased by 92 percent and the intracranial tumor regressed by 59 percent over six months on volumetric assessment. Preclinical research and human data support the hypothesis that the response was mediated by hypermutation. (56), (57)

MSK is leading the Phase II clinical trial NCT04042753 to investigate further the role of ipilimumab and nivolumab in patients with aggressive pituitary tumors. Note that while the combination may prove advantageous, it has greater toxicity than monotherapy, with one study reporting a rate of severe/life-threatening events at 59 percent compared with 21 percent for patients who received nivolumab alone. (58)

Case: Hypermutation occurred in this patient’s temozolomide-naïve tumor in the absence of mismatch repair deficiency. It may have been amplified by eight years of exposure to temozolomide, providing a compelling argument for considering a checkpoint inhibitor.

Back to top

Advancing Pituitary Cancer Treatment

Since aggressive pituitary tumors are relatively uncommon, even major cancer centers cannot support a clinical trial. A clinical trial consortium is needed to develop multicenter trials to advance evidence in the field. Patients who cannot be treated with temozolomide, do not respond, or progress on the agent should be preferentially enrolled into clinical trials to gain access to novel treatments.

This research was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support grants P30 CA008748 and R25CA020449.

Dr. Andrew L. Lin has received research funding from Bristol-Myers Squibb for a phase II trial investigating nivolumab plus ipilimumab in the treatment of aggressive pituitary tumors and from NantOmics to investigate MGMT quantification via mass spectrometry and its relationship with treatment response to temozolomide. Dr. Eliza B. Geer is an investigator for research grants to MSKCC from Ionis, Novartis, Corcept, Strongbridge Biopharma, and Bristol-Myers Squibb. For disclosures from other study authors, please refer to the paper.

Refer a Patient
Call our dedicated clinician access number at 646-677-7440 or click the link below, and one of our care advisors will assist you with your referral needs.
Refer Online
Back to top
  1. Lin AL, Donoghue MTA, Wardlaw SL, Yang TJ, Bodei L, Tabar V, Geer EB. Approach to the Treatment of a Patient with an Aggressive Pituitary Tumor. J Clin Endocrinol Metab. 2020 Sep 15:dgaa649. doi: 10.1210/clinem/dgaa649. Epub ahead of print.
  2. Kaltsas GA, Nomikos P, Kontogeorgos G, et al. Clinical review: Diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab. 2005;90(5):3089-3099.
  3. Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004;89(2):667-674.
  4. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454-2462.
  5. Katznelson L, Laws ER, Jr., Melmed S, et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951.
  6. Bates AS, Van’t Hoff W, et al. An audit of outcome of treatment in acromegaly. Q J Med. 1993;86(5):293-299.
  7. Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 1998;83(8):2730-2734.
  8. Plotz CM, Knowlton AI, Ragan C. Natural course of Cushing’s syndrome as compared with the course of rheumatoid arthritis treated by hormones. Ann Rheum Dis. 1952;11(4):308-309.
  9. Patel J, Eloy JA, Liu JK. Nelson’s syndrome: a review of the clinical manifestations, pathophysiology, and treatment strategies. Neurosurg Focus. 2015;38(2):E14.
  10. Fountas A, Lim ES, Drake WM, et al. Outcomes of Patients with Nelson’s Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers. J Clin Endocrinol Metab. 2020;105(5).
  11. Hansen TM, Batra S, Lim M, et al. Invasive adenoma and pituitary carcinoma: a SEER database analysis. Neurosurg Rev. 2014;37(2):279-285; discussion 285-276.
  12. Pernicone PJ, Scheithauer BW, Sebo TJ, et al. Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer. 1997;79(4):804-812.
  13. Landman RE, Horwith M, Peterson RE, et al. Long-term survival with ACTH-secreting carcinoma of the pituitary: a case report and review of the literature. J Clin Endocrinol Metab. 2002;87(7):3084-3089.
  14. Chittiboina P, Montgomery BK, Millo C, et al. High-resolution(18)F- fluorodeoxyglucose positron emission tomography and magnetic resonance imaging for pituitary adenoma detection in Cushing disease. J Neurosurg. 2015;122(4):791-797.
  15. Sharma P, Mukherjee A, Bal C, et al. Somatostatin receptor-based PET/CT of intracranial tumors: a potential area of application for 68 Ga-DOTA peptides? AJR Am J Roentgenol. 2013;201(6):1340-1347.
  16. Xiao J, Zhu Z, Zhong D, et al. Improvement in diagnosis of metastatic pituitary carcinoma by 68Ga DOTATATE PET/CT. Clin Nucl Med. 2015;40(2):e129-131.
  17. Reubi JC, Schar JC, Waser B, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27(3):273-282.
  18. Raverot G, Burman P, McCormack A, et al. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol. 2018;178(1):G1-G24.
  19. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing’s Disease. Endocr Rev. 2015;36(4):385-486.
  20. Loeffler JS, Shih HA. Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab. 2011;96(7):1992-2003.
  21. Roden D, Bosley TM, Fowble B, et al. Delayed radiation injury to the retrobulbar optic nerves and chiasm. Clinical syndrome and treatment with hyperbaric oxygen and corticosteroids. Ophthalmology. 1990;97(3):346-351.
  22. Newhauser WD, Zhang R. The physics of proton therapy. Phys Med Biol. 2015;60(8):R155- 209.
  23. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyperprolactinemia: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273-288.
  24. McGivney W. NCCN Guidelines and Their Impact on Coverage Policy. Journal of the National Comprehensive Cancer Network. 2010;8(6).
  25. McCormack A, Dekkers OM, Petersenn S, et al. Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. Eur J Endocrinol. 2018;178(3):265-276.
  26. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205-216.
  27. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high- grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963-1972.
  28. Bengtsson D, Schroder HD, Andersen M, et al. Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide. J Clin Endocrinol Metab. 2015;100(4):1689-1698.
  29. Elbelt U, Schlaffer SM, Buchfelder M, et al. Efficacy of temozolomide therapy in patients with aggressive pituitary adenomas and carcinomas - a German survey. J Clin Endocrinol Metab. 2019.
  30. Lasolle H, Cortet C, Castinetti F, et al. Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. Eur J Endocrinol. 2017;176(6):769- 777.
  31. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.
  32. Blumenthal DT, Gorlia T, Gilbert MR, et al. Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG. Neuro Oncol. 2017;19(8):1119-1126.
  33. Johnson BE, Mazor T, Hong C, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343(6167):189-193.
  34. Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005;27(1):23-44.
  35. Zacharia BE, Gulati AP, Bruce JN, et al. High response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory Cushing disease from capecitabine and temozolomide (CAPTEM): a case series. Neurosurgery. 2014;74(4):E447-455; discussion E455.
  36. Chakravarti A, Erkkinen MG, Nestler U, et al. Temozolomide-mediated radiation enhancement in glioblastoma: a report on underlying mechanisms. Clin Cancer Res. 2006;12(15):4738-4746.
  37. Cornell RF, Kelly DF, Bordo G, et al. Chemotherapy-induced regression of an adrenocorticotropin-secreting pituitary carcinoma accompanied by secondary adrenal insufficiency. Case Rep Endocrinol. 2013;2013:675298.
  38. Kaltsas GA, Mukherjee JJ, Plowman PN, Monson JP, Grossman AB, Besser GM. The role of cytotoxic chemotherapy in the management of aggressive and malignant pituitary tumors. J Clin Endocrinol Metab. 1998;83(12):4233-4238.
  39. Mixson AJ, Friedman TC, Katz DA, et al. Thyrotropin-secreting pituitary carcinoma. J Clin Endocrinol Metab. 1993;76(2):529-533.
  40. Reincke M, Sbiera S, Hayakawa A, et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat Genet. 2015;47(1):31-38.
  41. Ma ZY, Song ZJ, Chen JH, et al. Recurrent gain-of-function USP8 mutations in Cushing’s disease. Cell Res. 2015;25(3):306-317.
  42. Monsalves E, Juraschka K, Tateno T, et al. The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas. Endocr Relat Cancer. 2014;21(4):R331-344.
  43. Jia W, Sanders AJ, Jia G, Liu X, Lu R, Jiang WG. Expression of the mTOR pathway regulators in human pituitary adenomas indicates the clinical course. Anticancer Res. 2013;33(8):3123- 3131.
  44. Donovan LE, Arnal AV, Wang SH, Odia Y. Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy. CNS Oncol. 2016;5(4):203-209.
  45. Alshaikh OM, Asa SL, Mete O, Ezzat S. An Institutional Experience of Tumor Progression to Pituitary Carcinoma in a 15-Year Cohort of 1055 Consecutive Pituitary Neuroendocrine Tumors. Endocr Pathol. 2019;30(2):118-127.
  46. Jouanneau E, Wierinckx A, Ducray F, et al. New targeted therapies in pituitary carcinoma resistant to temozolomide. Pituitary. 2012;15(1):37-43.
  47. Xu L, Khaddour K, Chen J, Rich KM, Perrin RJ, Campian JL. Pituitary carcinoma: Two case reports and review of literature. World J Clin Oncol. 2020;11(2):91-102.
  48. Ortiz LD, Syro LV, Scheithauer BW, et al. Anti-VEGF therapy in pituitary carcinoma. Pituitary. 2012;15(3):445-449.
  49. Chinezu L, Vasiljevic A, Jouanneau E, et al. Expression of somatostatin receptors, SSTR2A and SSTR5, in 108 endocrine pituitary tumors using immunohistochemical detection with new specific monoclonal antibodies. Hum Pathol. 2014;45(1):71-77.
  50. Hope TA, Calais J, Zhang L, et al. (111)In-Pentetreotide Scintigraphy Versus (68)Ga-DOTATATE PET: Impact on Krenning Scores and Effect of Tumor Burden. J Nucl Med. 2019;60(9):1266-1269.
  51. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376(2):125-135.
  52. Lin AL, Jonsson P, Tabar V, et al. Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab. J Clin Endocrinol Metab. 2018;103(10):3925-3930.
  53. Hunter C, Smith R, Cahill DP, et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 2006;66(8):3987-3991.
  54. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189-2199.
  55. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128.
  56. Kemeny HR, Elsamadicy AA, Farber SH, et al. Targeting PD-L1 Initiates Effective Antitumor Immunity in a Murine Model of Cushing Disease. Clin Cancer Res. 2020;26(5):1141-1151.
  57. Albarel F, Gaudy C, Castinetti F, et al. Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur J Endocrinol. 2015;172(2):195-204.
  58. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377(14):1345-1356.