European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas
Pituitary tumours are common and easily treated by surgery or medical treatment in most cases. However, a small subset of pituitary tumours does not respond to standard medical treatment and presents with multiple local recurrences (aggressive pituitary tumours) and in rare occasion with metastases (pituitary carcinoma). The present European Society of Endocrinology (ESE) guideline aims to provide clinical guidance on diagnosis, treatment and follow-up in aggressive pituitary tumours and carcinomas.
We decided upfront, while acknowledging that literature on aggressive pituitary tumours and carcinomas is scarce, to systematically review the literature according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The review focused primarily on first- and second-line treatment in aggressive pituitary tumours and carcinomas. We included 14 single-arm cohort studies (total number of patients = 116) most on temozolomide treatment (n = 11 studies, total number of patients = 106). A positive treatment effect was seen in 47% (95% CI: 36–58%) of temozolomide treated. Data from the recently performed ESE survey on aggressive pituitary tumours and carcinomas (165 patients) were also used as backbone for the guideline.
(i) Patients with aggressive pituitary tumours should be managed by a multidisciplinary expert team. (ii) Histopathological analyses including pituitary hormones and proliferative markers are needed for correct tumour classification. (iii) Temozolomide monotherapy is the first-line chemotherapy for aggressive pituitary tumours and pituitary carcinomas after failure of standard therapies; treatment evaluation after 3 cycles allows identification of responder and non-responder patients. (iv) In patients responding to first-line temozolomide, we suggest continuing treatment for at least 6 months in total. Furthermore, the guideline offers recommendations for patients who recurred after temozolomide treatment, for those who did not respond to temozolomide and for patients with systemic metastasis.
Summary of the recommendations
The recommendations (R) are worded as recommend (strong recommendation) and suggested (weak recommendation). We formally graded only the evidence underlying recommendations for therapeutic choices. The quality of evidence behind the recommendations is classified as very low (+ooo), low (++oo), moderate (+++o) and strong (++++). See section ‘Summary of methods used for guideline development’.
1. General remarks
R 1.1.1 We recommend that these patients should be discussed in a multidisciplinary expert team meeting (endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist, medical oncologist).
2. Assessment of aggressiveness
2.1 Diagnosis of an aggressive pituitary tumour
R 2.1.1 We recommend the diagnosis of an aggressive pituitary tumour be considered in patients with a radiologically invasive tumour and unusually rapid tumour growth rate, or clinically relevant tumour growth despite optimal standard therapies (surgery, radiotherapy and conventional medical treatments).
R 2.1.2 We recommend that imaging (MRI in most instances) should be used for quantification of tumour dimensions, invasion and growth.
R 2.1.3 We recommend full endocrine laboratory evaluation in patients with aggressive pituitary tumours.
R 2.1.4 In patients with aggressive pituitary tumours, and either site-specific symptoms or discordant biochemical and radiological findings, we recommend screening for metastatic disease.
2.2 Potential predictors of aggressiveness in pituitary tumours
R 2.2.1 We recommend that all pituitary tumours should undergo histopathological analysis, which should include a minimum immunodetection of pituitary hormones and Ki-67 proliferative index evaluation. The p53 immunodetection and the mitotic count should be evaluated at least, when the Ki-67 index is ≥3% (+000).
R 2.2.2 We suggest interpretation of histopathological results in the clinical context of the individual patient (+000).
R 2.2.3 In patients with aggressive pituitary tumours, we suggest germline genetic testing based on young age at presentation or family history of pituitary or endocrine neoplasia, as recommended for patients with non-aggressive pituitary tumours (+000).
3. Therapeutic options
3.1 Role of surgery
R 3.1.1 We recommend that surgery should be performed by a neurosurgeon with extensive experience in pituitary surgery (++00).
R 3.1.2 We recommend discussion with an expert neurosurgeon regarding repeat surgery prior to consideration of other treatment options (++00).
3.2 Role of radiotherapy
R 3.2.1 We recommend radiotherapy in patients with clinically relevant tumour growth despite surgery in non-functioning tumours or surgery and standard medical treatment in functioning tumours (++00).
R 3.2.2 We suggest that adjuvant radiotherapy should be considered in the setting of a clinically relevant invasive tumour remnant with pathological markers (Ki-67 index, mitotic count, p53 immunodetection) strongly indicating aggressive behaviour (+000).
R 3.2.3 We suggest discussion with an expert radiation oncologist regarding the different radiotherapeutic options taking into consideration tumour size and location, as well as pathology, prior RT and dose.
3.3 Standard medical therapies
R 3.3.1 We recommend standard medical treatment with maximally tolerated doses in order to control tumour growth, as per current guidelines.
3.4 Medical therapies in aggressive pituitary tumours
R 3.4.1 We recommend use of temozolomide monotherapy as first-line chemotherapy for aggressive pituitary tumours and pituitary carcinomas, following documented tumour growth (++00).
R 3.4.2 We recommend first evaluation of treatment response after 3 cycles. If radiological progression is demonstrated, temozolomide treatment should be ceased (++00).
R 3.4.3 We recommend use of the standard dosing regimen: 150–200 mg/m2 for 5 consecutive days every 28 days (+000).
R 3.4.4 We recommend monitoring of haematological parameters, liver function tests and careful clinical observation for potential adverse effects during treatment (+++0).
R 3.4.5 We suggest, in patients with rapid tumour growth in whom maximal doses of radiotherapy have not been reached, combining temozolomide with radiotherapy (Stupp protocol) (+000).
R 3.4.6 We suggest that evaluation of MGMT status by immunohistochemistry by an expert neuropathologist should be performed. High MGMT expression is suggestive of a lack of response; however, there may be exceptions (++00).
R 3.4.7 In patients responding to first-line temozolomide, as assessed after 3 cycles, we suggest treatment to be continued for at least 6 months in total, with consideration for longer duration if continued therapeutic benefit is observed (+000).
R 3.4.8 In patients with rapid tumour progression on temozolomide treatment, we suggest a trial with other systemic cytotoxic therapy. Given the variety of chemotherapeutic agents that have been reported, we cannot suggest a particular regimen (+000).
R 3.4.9 In patients who develop a recurrence following response to temozolomide treatment, we suggest a second trial of 3 cycles of temozolomide (+000).
3.5 Local treatment of metastatic disease
R 3.5.1 In patients with isolated metastases, we suggest consideration of loco-regional therapies, independent of decisions regarding the need for systemic treatment (+000).
4. Follow-up of an aggressive pituitary tumour
R 4.1 We recommend that imaging (MRI in most instances) is performed every 3–12 months as guided by prior tumour growth rate and/or location of tumour (proximity to vital structures) (+000).
R 4.2 We recommend that full endocrine evaluation should be performed every 3–12 months as guided by the clinical context (+000).
R 4.3 We recommend lifelong follow-up of patients with aggressive pituitary tumours (++00).