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European guideline addresses treatment of aggressive pituitary tumors, carcinomas
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Patients with aggressive pituitary tumors and carcinomas should be treated by a multidisciplinary team and receive full endocrine laboratory evaluation and histopathologic analyses for tumor classification, according to recommendations included in new a clinical practice guideline released by the European Society of Endocrinology.
The guideline further identifies temozolomide monotherapy as first-line chemotherapy for these patients.
“Early identification of aggressive pituitary tumors is challenging, but is of major clinical importance as they are associated with an increased morbidity and mortality even in the absence of metastases,” the researchers wrote. “Despite numerous studies and advances in prognostic classification, no pathological marker has been shown as yet to reliably predict pituitary tumor behavior. This guideline proposes a definition of an aggressive pituitary tumor and provides recommendations for current management.”
The guideline recommends that, when necessary, surgery should be performed by a neurosurgeon with extensive experience following discussions between the patient and surgeon regarding repeat surgery before considering other treatment options.
Radiotherapy should be performed in patients with clinically relevant tumor growth despite surgery or surgery with standard medical treatment. Adjuvant radiotherapy should be used for clinically relevant invasive tumor remnant with pathologic markers, and discussions should take place between the patient and an expert radiation oncologist to address different radiotherapeutic options.
To control tumor growth, the guideline recommends standard medical treatment with maximally tolerated doses.
The guideline also recommends use of the oral chemotherapy drug temozolomide as first-line treatment and evaluation of treatment success after three cycles. Treatment with temozolomide should be continued for 6 months in patients who respond to the first three cycles.
Follow-up with an MRI, in most cases, and full endocrine evaluation should be performed every 3 to 12 months, according to the guideline.
“The publication of the [European Society of Endocrinology] clinical practice guidelines on aggressive pituitary tumors and carcinomas will hopefully improve identification and treatment of these rare tumors,” the researchers wrote. “Future efforts, similar to other European networks working on rare endocrine tumors, should combine the efforts of researchers and clinicians to establish an international register for this rare disorder. Our most recent experience in compiling the European survey on aggressive pituitary tumors highlights many clinicians who are interested in developing such an international clinical register.” – by Amber Cox
Disclosures: Some of the authors report financial ties with Ipsen, Pfizer and Novartis. Please see the guidelines for all other authors’ relevant financial disclosures.
Perspective
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Pituitary carcinomas considered rare, and the majority of publications addressing them are case reports. Although, I know of no U.S. guideline in the works, these recommendations from the European Society of Endocrinology are reasonable and in line with current U.S. practice.
This guideline includes functional aggressive pituitary tumors and references relatively recent treatment options, such as temozolomide. Fourteen studies were reviewed (of 811 publications considered), 11 of which used temozolomide treatment.
I agree with the recommendations for a multidisciplinary approach and histopathologic evaluation. The guideline recommends full (serial) endocrine evaluations, with which I agree. The question of hormone replacement (including growth hormone) is not addressed.
I agree with when to consider tumors aggressive. In addition, any discordance between size/symptoms/age can be considered for an “aggressive” protocol work-up. Of note, however, there is no clear differentiating presenting clinical or biochemical feature that has been found to differentiate benign from malignant pituitary tumors (Lenders N, et al. Pituitary. 2018;doi:10.1007/s11102-017-0857-z). The aggressive nature of a lesion is based on its growth (rate, invasiveness) and any metastases. Transformation (silent to hormone-producing) and the presence of proliferative markers may herald malignant behavior.
Earlier this year, the European Society of Endocrinology (ESE) published a guideline on management of aggressive pituitary adenomas and carcinomas. Though data in the literature are limited, and strong recommendations based on GRADE system are thus harder to construct, an attempt to systematically review the literature and guide clinicians in treating these relatively rare disorders is more than welcome. The authors included data from a survey of ESE members on their approach in managing these disorders. Data from a survey cannot change the grading recommendation per se (strong recommendations are based on prospective randomized studies), but can help the writers and the readers to assess a broad need for guidelines and to detect differences in management between countries.
The definition of what constitutes an aggressive tumor is still debated: clinical vs. pathology markers vs. extent of invasion on imaging; some tumors with intermediate features were considered atypical adenomas. In 2017, WHO appropriately changed the pituitary tumor classification, and one of the many modifications was elimination of the term “atypical adenoma,” which was confusing and irrelevant.
This guideline suggests, as iterated in another recent publication (Casanueva FF, et al. Pituitary. 2017;doi: 10.1007/s11102-017-0838-2), that patients with aggressive pituitary tumors should be managed by a multidisciplinary expert team. This is an important point, which can help improve outcomes for these and other rare pituitary diseases, as many patients, particularly in the United States, are not followed in specialized pituitary centers.
The guideline also emphasizes the importance of germline genetic testing in patients with aggressive tumors who are young at presentation or who have family history of pituitary or endocrine neoplasia. Based on data from many studies, temozolomide monotherapy is recommended as first-line chemotherapy for aggressive pituitary tumors and pituitary carcinomas after failure of standard therapies, but treatment evaluation after three cycles is suggested to allow identification of responder vs. non-responder patients. Continuing treatment for at least 6 months is suggested in responders.
While some proposals for management of aggressive pituitary tumors have been included in the Endocrine Society guidelines for acromegaly and Cushing’s, this is the first international guideline to compile all available data and discuss treatment in a more formal way for aggressive pituitary tumors.
Further studies are needed in this rare disease arena to improve our overall knowledge and increase awareness, timely diagnosis and, hopefully, our ability to predict earlier which tumors will be more aggressive and require initial multimodal regimen to prevent recurrences.
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