Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas

Abstract

Objectives Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival. Design Multicenter retrospective study by members of the French Society of Endocrinology. Methods Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment. Results The median treatment duration was 6.5 cycles (range 2–24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0–72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0–57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success. Discussion Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

“…Methylguanine methyltransferase (MGMT) levels were measured in 3 of the 4 patients, and were low in these three patients, which possibly contributed to the outcome (see 'Predictors of response to temozolomide' section). Others have added capecitabine to TMZ after TMZ failure, or at progression after an initial response to TMZ alone, but had not observed an enhanced effect (11,12,25,107).…”

“…Supplementary Table 7 outlines dose reduction and discontinuation thresholds for adverse effects as recommended by the manufacturer. Out of a total of 190 patients, across 3 large published pituitary cohorts and the ESE survey, 29 (15%) patients discontinued TMZ as a result of side effects (15 with pervasive fatigue, nausea in 6, haematological abnormalities in 3, 1 each due to headache/oedema/ hypotension, adrenal crisis, fungal septicaemia, abnormal liver function tests (LFTs) and hearing loss) (11,12,25,111). A further case of hearing loss has been described (102), as has been reported in patients with non-pituitary tumours (113).…”

“…The response rate was 76%, i.e., higher than that reported with TMZ alone. However, some of the patients had not received prior RT (11,125,126,127).…”

“…The value of MGMT status as a predictor of TMZ response in aggressive pituitary tumours is less clear. Promotor methylation of the gene occurs less frequently in pituitary tumours, and MGMT measured by PCR-based methods has not been associated with response to TMZ (11,102,107,111,130). The reasons are not understood and may involve mechanisms regulating MGMT expression independent of promotor methylation.…”

“…Early identification of aggressive pituitary tumours is challenging, but is of major clinical importance as they are associated with an increased morbidity and mortality even in the absence of metastases (11,12). Despite numerous studies and advances in prognostic classification, no pathological marker has been shown as yet to reliably predict pituitary tumour behaviour (6,13,14,15).…”