65 YEARS OF THE DOUBLE HELIX: Treatment of pituitary tumors with temozolomide: an update

in Endocrine-Related Cancer
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  • 1 Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia
  • 2 Division of Pathology, Department of Laboratory Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
  • 3 Division of Neuro-Oncology, Instituto de Cancerologia, Clinica Las Americas. Medellin, Colombia

Temozolomide is an alkylating chemotherapeutic agent used in malignant neuroendocrine neoplasia, melanoma, brain metastases and an essential component of adjuvant therapy in the treatment of glioblastoma multiforme and anaplastic astrocytoma. Since 2006, it has been used for the treatment of pituitary carcinomas and aggressive pituitary adenomas. Here, we discuss the current indications and results of temozolomide therapy in pituitary tumors, as well as frequently asked questions regarding temozolomide treatment, duration of therapy, dosage, tumor recurrence and resistance.

Abstract

Temozolomide is an alkylating chemotherapeutic agent used in malignant neuroendocrine neoplasia, melanoma, brain metastases and an essential component of adjuvant therapy in the treatment of glioblastoma multiforme and anaplastic astrocytoma. Since 2006, it has been used for the treatment of pituitary carcinomas and aggressive pituitary adenomas. Here, we discuss the current indications and results of temozolomide therapy in pituitary tumors, as well as frequently asked questions regarding temozolomide treatment, duration of therapy, dosage, tumor recurrence and resistance.

Introduction

Pituitary adenomas (PAs) arise in different adenohypophyseal cells and represent 15% of intracranial tumors (Melmed 2011, Osamura 2017a). The majority are slow-growing, noninvasive and benign neoplasms; however, several others are more rapidly growing and invade surrounding areas. Very rarely, PAs do metastasize, and these adenomas are called pituitary carcinomas. Mode of treatment of PAs includes drug therapy, surgery and, in some cases, irradiation. In prolactin (PRL)-producing PAs, dopamine agonists are effective and the preferred first line of treatment (Melmed et al. 2011). Long-acting somatostatin analogs are useful in growth hormone (GH)- and thyroid-stimulating hormone (TSH)-producing PAs. No primary medical treatment is currently available for adrenocorticotropic hormone (ACTH)-producing PAs and for nonfunctional PAs, so that surgery is the first option. In several cases the tumor is not completely resected, resulting in returning symptoms and the patient requiring further surgical intervention and additional treatment. Irradiation – conformal external beam radiation therapy or stereotactic radiosurgery – a third option, may not always be successful and could cause side effects. Two issues must be considered. The first is the mass effect; in this case surgery, or cabergoline in PRL-producing PAs, offer a chance to reduce quickly mass-related symptoms. The second is the hormonal secretion. Here, effective drugs directed to the tumor function can be used (i.e., somatostatin analogs in acromegaly), or in case of severe symptoms of endocrine excess, medical treatment that does not impact the tumor can be chosen (i.e., pegvisomant in acromegaly or steroidogenesis inhibitors in Cushing’s disease). Currently, the quest of many researchers, clinical endocrinologists and neurosurgeons is to find other options of treatment, especially in cases of large, invasive and recurrent tumors and pituitary carcinomas.

Temozolomide (TMZ) is an alkylating chemotherapeutic agent used as an essential component of adjuvant therapy in the treatment of glioblastoma multiforme (GBM) and anaplastic astrocytoma (Stupp et al. 2005, van den Bent et al. 2017). Since 2006, TMZ has been found to be an effective treatment of pituitary carcinomas (Fadul et al. 2006, Lim et al. 2006) and aggressive PAs (Syro et al. 2006). The present study discusses the current indications and results of TMZ therapy in PAs, examines the pathways involved in its action and attempts to answer frequently asked questions about TMZ treatment, duration of therapy, dosage, tumor recurrence and resistance (Bruno et al. 2015).

Aggressive adenomas and pituitary carcinomas

PAs are a heterogenous group of lesions with different clinical manifestations and a wide range of proliferative and invasive behaviors. Most PAs are controlled by current treatment protocols which, according to their functional activity, include surgery, radiotherapy and/or drug therapy. Some PAs invade bone, dura or adjacent structures, precluding their resection. They may also recur during follow-up despite repeated surgeries, radiotherapy, and pharmacologic treatments. From a pragmatic and clinical perspective, they have been called aggressive PAs and their exact prevalence is not known (Buchfelder 2009, Di Ieva et al. 2014, Raverot et al. 2018).

In an attempt to differentiate tumors with clinical aggressive behavior, the previous World Health Organization (WHO) classification (2004) of PAs, characterized a subtype of adenomas as ‘atypical adenomas’ if they presented an elevated mitotic index, a Ki-67 labeling index greater than 3%, and extensive nuclear staining for p53 immunoreactivity (Lloyd 2004). It was assumed that these atypical adenomas may have an uncertain clinical and biological behavior. This assumption has not been proven and, to date, it also has not been able to accurately predict tumor recurrence or resistance to therapy (Miermeister et al. 2015). In the recent WHO classification of PAs (2017) (Osamura 2017b), the term ‘atypical adenomas’ is no longer recommended. To identify adenomas that may behave in a clinically aggressive manner, assessment of tumor proliferation markers and invasion – evaluated by MRI, surgical and/or morphological findings – is now suggested. This classification also recognizes some subtypes of PAs as ‘high-risk’ PAs due to their previously reported clinical aggressive behavior (Gomez-Hernandez et al. 2015, Lopes 2017, Osamura 2017a). These include sparsely granulated somatotroph adenomas, lactotroph adenomas in men, Crooke’s cell adenomas, silent corticotroph adenomas and plurihormonal Pit-1-positive adenomas (formerly classified as silent subtype III adenomas) (Mete & Lopes 2017).

As in the previous classification, the current WHO classification (2017) characterizes pituitary carcinomas only when craniospinal or systemic metastases are found, independent of their histological appearance (Roncaroli 2017). Pituitary carcinomas are rare and account for approximately 0.12% of PAs in the German Pituitary Tumor Registry (Saeger et al. 2007). Its etiology is not clear and two possible mechanisms have been proposed: (i) step-wise transformation from an adenoma to an invasive adenoma and to a carcinoma, or alternatively, (ii) de novo development of carcinoma from either a normal gland or from a slow growing adenoma (Melmed 2011, Roncaroli 2017).

The term adenoma is applied to benign epithelial neoplasms that produce gland-like structures. It is considered benign because its macroscopic and microscopic features suggest that it will remain localized and amenable to be surgically resected. Conversely, the term malignant is applied to a neoplasm that can invade and destroy adjacent structures, and spread to distant sites. PAs are considered benign tumors, even if some of them behave in a clinically aggressive manner, whereas pituitary carcinoma – malignant – is only applied when metastases are found. In this context, the so-called aggressive adenomas would be a group of benign lesions with malignant potential. Different designations have been used to describe them: premetastatic lesions in the sellar phase (Scheithauer et al. 2006), carcinoma in situ (Heaney 2011), localized pituitary carcinomas (Syro 2015), and invasive/proliferative tumors with high risk of recurrence and suspect of malignancy (Trouillas et al. 2013).

The terms atypical, invasive and aggressive have been used synonymously when evaluating PAs. This has led to different interpretations and it has become clear that standardized definitions are required. PAs can then be classified according to their pathologic features, radiological findings or clinical behavior such as typical or atypical, invasive or noninvasive, and aggressive or non-aggressive. Thus, the terms typical and atypical adenoma should refer only to pathologic features, invasive and noninvasive to radiological, surgical and/or morphological findings of invasion, and, aggressive and non-aggressive to their clinical behavior (Sav et al. 2015). The classification of pituitary tumors must include not only morphologic characteristics, but also radiologic and clinical features. The focus must be on early diagnosis and treatment of these aggressive adenomas (Ceccato et al. 2018).

Temozolomide

TMZ was synthesized in 1987 (Stevens et al. 1987). It is a pro-drug that, after administration, is pharmacologically inactive until it is hydrolyzed within the body. It has important features such as low molecular weight, hydrophobicity and the ability to undergo rapid conversion to its active form, methyl-triazeno-imidazole-carboxamide (MTIC), after it is absorbed (Neidle & Thurston 2005). Its cytotoxic effect is exerted through methylation of deoxyribonucleic acid (DNA) at the O6 position of guanine, which mispairs with thymine during the next cycle of DNA replication. If it is not repaired, the sequence of mismatch-repair events leads to apoptosis (Sabharwal & Middleton 2006).

The action of TMZ depends on its accumulation in the tumor and the capacity for O6-methylguanine-DNA methyltransferase (MGMT), present in the cells, to repair its effects (Kaina et al. 2007, Sharma et al. 2009). MGMT is an enzyme that removes the methylated base, transferring the methyl group, from the methylated DNA to an internal cysteine residue thereby restoring guanine. It can only catalyze a single turnover, and for this reason, it is called a ‘suicide enzyme’ (Kaina et al. 2007). MGMT is therefore an important DNA repair system, which influences the mechanism of action of TMZ. Common, non-hematologic adverse effects, mild to moderate in severity, can occur in more than 30% of the patients taking TMZ. These include nausea, vomiting, fatigue, headache and constipation. Not every patient experiences all the side effects, they are reversible and will go away after treatment is complete. The hematologic toxicities of TMZ are managed with dose reduction or temporary suspension. Severe, TMZ-related myelodysplastic syndrome and aplastic anemia have been reported in GBM cases, but to date, not in pituitary tumor patients (Scaringi et al. 2013).

To our knowledge, approximately 160 cases of PAs and pituitary carcinomas have been treated with TMZ. Recent publications describing case reports, retrospective patient studies, clinical practice guidelines, and an international survey also review the effect of TMZ treatment on pituitary tumors (Bengtsson et al. 2015, Ji et al. 2016, Losa et al. 2016, Almalki et al. 2017, Halevy & Whitelaw 2017, Lasolle et al. 2017, McCormack et al. 2018, Raverot et al. 2018).

MGMT expression and MGMT promoter methylation

Effectiveness or resistance to TMZ treatment may be the result of the presence of MGMT. Many studies have shown an inverse relationship between MGMT immunoexpression and innate sensitivity to TMZ (Kovacs et al. 2008, Wiewrodt et al. 2008, Salehi et al. 2010). Low-level expression of MGMT may be due to epigenetic silencing, by hypermethylation of the MGMT gene promoter in a wide spectrum of human tumors (Esteller et al. 2000, Jacinto & Esteller 2007, Sharma et al. 2009, Gusyatiner & Hegi 2017). It has been shown that low-level MGMT expression is a prognostic marker of favorable outcome in patients with TMZ treated GBM (Esteller et al. 2000). MGMT expression may be analyzed using immunohistochemistry (IHC), methylation-specific PCR (MSP), pyrosequencing (PSQ) and by high-resolution melting (HRM) analysis (Switzeny et al. 2016). Although MGMT status in GBM has been evaluated by identification of MGMT promoter methylation, in pituitary tumors, IHC has proven to be reliable, inexpensive, and accessible to most laboratories (Salehi et al. 2011).

The inverse relationship between MGMT immunoexpression and TMZ response was first reported in two patients with aggressive PAs (Kovacs et al. 2008). Other studies have not shown a conclusive relationship between the MGMT expression and response to treatment, but this may be attributed to the technical differences in tissue fixation, processing, immunostaining and the fact that published studies are retrospectively conducted. Nevertheless, it appears that low MGMT immunoexpression is mostly associated with a better response to TMZ treatment, and it may be used as predictive marker of TMZ response (Bengtsson et al. 2015, Raverot et al. 2018). MGMT expression may also be used as a prognostic marker in pituitary tumors. Two recent studies (Dai et al. 2017, Micko et al. 2017) have shown that progression and recurrence of PAs are associated with loss of MGMT immunoexpression. This is in concordance with earlier publications that suggested the same association between progression, recurrence, and MGMT immunoexpression (Widhalm et al. 2009, Lau et al. 2010). Thus, low MGMT immunoexpression could be both a predictive marker for TMZ response, and a prognostic marker of tumor recurrence and poor prognosis in PAs.

How can TMZ response be defined?

Clinical and radiographic changes

Studies have shown that in TMZ-responsive cases, the clinical response has been rapid with decreased chiasmic compression and mass effects. In patients with functional tumors, an important reduction of plasma hormone values became apparent after commencement of therapy (Ji et al. 2016, Losa et al. 2016, Halevy & Whitelaw 2017, Lasolle et al. 2017). Response can be seen after 3–6 months of therapy; therefore, the first evaluation of treatment response can be performed after 3 cycles (Raverot et al. 2018).

In patients who respond to TMZ treatment, several patterns of radiographic changes have been seen on MRI: tumor necrosis and hemorrhage, cystic change, and shrinkage of the tumor (Syro et al. 2011). These changes can be seen as early as two months after the onset of treatment. To evaluate the response to treatment, Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), MacDonald criteria of response for supratentorial glioma, and Response Assessment in Neuro-Oncology Criteria (RANO) may be used (Macdonald et al. 1990, Eisenhauer et al. 2009, Wen et al. 2010) (Table 1). It is advisable to standardize the reports for future prospective studies, and RANO criteria are recommended for its feasibility. According to these, the response is classified as complete response, partial response, stable disease and progressive disease. Comparison of these criteria is presented in Table 1. The effectiveness of TMZ in aggressive PAs and pituitary carcinomas according to tumor pathological subtype is presented in Table 2.

Table 1

Criteria for response to treatment.

ResponseMacDonaldRECIST (version 1.1)RANO
Complete response (CR)Imaging features: Disappearance of all enhancing disease

Sustained for at least 4 weeks

No new lesions

Clinical features: Clinically stable or improved
Disappearance of all target lesions

Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm
Disappearance of the lesion for at least 4 weeks

Stable or improved clinically
Partial response (PR)Imaging features: 50% or more decrease of all measurable enhancing lesions

Sustained for at least 4 weeks

No new lesions

Clinical features: Clinically stable or improved
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diametersA decrease of more than 50% compared with baselineStable or improved clinically
Stable disease (SD)Imaging features: Does not qualify for complete response, partial response or progression

Clinical features: Clinically stable
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on studyDoes not qualify for complete response, partial response or progression

A decrease of less than 50%, stabilization of the lesion or increase less than 25%

Stable clinically
Progressive disease (PD)Imaging features: 25% of more increase in enhancing lesions

Any new lesions

Clinical features: Clinical deterioration
At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study)

In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (note: the appearance of one or more new lesions is also considered progression)
Increased more than 25% of the lesion

Appearance of new lesions

Clinical deterioration

Data from Macdonald et al. (1990), Eisenhauer et al. (2009), Wen et al. (2010).

RANO, Response Assessment in Neuro-Oncology Criteria; RECIST, Response Evaluation Criteria in Solid Tumors.

Table 2

Aggressive adenomas and pituitary carcinomas. Response to temozolomide treatment according to tumor pathological subtype.

TumorComplete response (CR) (%)Partial response (PR) (%)Stable disease (SD) (%)Progressive disease (PD) (%)Total (%)
PRL2 (7)17 (45)10 (26)9 (22)38 (100)
ACTH6 (8)22 (30)20 (27)25 (35)73 (100)
NPPA0 (0)4 (14)15 (54)9 (32)28 (100)
GH + TSH1 (6)6 (33)7 (39)4 (22)18 (100)
Total9 (6)49 (31)52 (33)47 (30)157 (100)

Data from McCormack et al. (2018).

ACTH, adrenocorticotropic hormone; GH, growth hormone; NPPA, nonfunctioning pituitary adenoma; PRL, prolactin; TSH, thyroid-stimulating hormone.

Morphologic changes

Although only few cases studied have compared their pathology before and after TMZ treatment, it has been shown that TMZ produces edema, necrosis, hemorrhage, accumulation of connective tissue, inflammatory infiltrates, larger and more differentiated tumor cells, and neuronal transformation (Kovacs et al. 2007, Bush et al. 2010). Analysis of tissue following TMZ treatment shows a decrease in Ki67 labeling index with a corresponding reduction in mitotic activity (Kovacs et al. 2007). Operative findings include tumor softening and friability, both of which may facilitate resection at re-intervention post TMZ treatment (Syro et al. 2011). In a single study, tissue obtained after TMZ therapy showed heterogenous response, with areas of tumor cell destruction as well as viable, non-damaged, MGMT immunopositive cells, which probably were resistant to TMZ (Ersen et al. 2012).

When to start TMZ treatment?

Based on published literature and reported response rates, there is no doubt that patients with pituitary carcinomas are the first indication for TMZ treatment. Unfortunately, there are differences among studies regarding TMZ response rates because there is overlapping information, since some patients are included in more than one study. Not all the studies differentiate response rates between carcinomas and aggressive PAs. Lack of standardization regarding the criteria to evaluate response rate is another issue, since some studies consider only complete and partial response as successful TMZ treatment (Table 1). Nevertheless, the overall survival (OS) at 5 years in pituitary carcinomas after TMZ therapy is approximately 56.2% (Ji et al. 2016). Comparing this with OS in patients with pituitary carcinomas treated before TMZ – when almost all the patients died within one year and had a mean survival rate of 1.9 years (Pernicone et al. 1997, Kaltsas et al. 2005, Scheithauer et al. 2006) – TMZ represents an enormous advancement in therapeutic options. In this context, facing the ominous evolution of pituitary carcinomas, one can conclude that a stable disease response is a good response as well (Tables 1 and 2). Whether stable disease is included or not, the response rate of pituitary carcinomas with TMZ varies from 50 to 87.6% (Hirohata et al. 2013, Bengtsson et al. 2015, Ji et al. 2016, Almalki et al. 2017, Lasolle et al. 2017, McCormack et al. 2018).

In cases of aggressive PAs, the decision to start TMZ treatment is not as easy and some considerations must be contemplated. Comparing demographic characteristics, age, sex, time of duration of disease, previous radiotherapy, number of surgeries, functional status of the tumors and Ki67, there are no statistically significant differences between aggressive PAs and pituitary carcinomas, except for the presence of metastases (Bengtsson et al. 2015, Ji et al. 2016, McCormack et al. 2018, Raverot et al. 2018). Perhaps aggressive PAs and pituitary carcinomas are two faces on the same coin? Due to the lack of morphologic, biochemical or molecular biomarkers that can indicate in advance which tumors will behave in an aggressive manner, the decision to start TMZ will always be a difficult task (Lin et al. 2016, Halevy & Whitelaw 2017). Age, previous medical therapy, radiotherapy, number of previous surgical interventions, invasion, proliferation markers, and histologic subtype of the tumor must be considered (Ceccato et al. 2018). The benefits of starting TMZ must outweigh the risks of repeated surgeries, re-irradiation and potential complications with standard treatments (Lin et al. 2016). The decision must be considered from an interdisciplinary perspective (Raverot et al. 2018).

In a recent meta-analysis, the 5-year OS for aggressive PAs treated with TMZ was 57.4% (Ji et al. 2016). The lack of standardization regarding tumor response criteria gave a response rate from 50% to 80.6% whether stable disease is included or not (Ji et al. 2016, Raverot et al. 2018). In aggressive PAs, TMZ is often used as a last resort after standard medical therapies, repeated surgeries and radiotherapy have been unsuccessful. Therefore, it should be taken into consideration that a stable disease response after TMZ therapy, may be considered a good response as well. Interestingly, no statistically significant differences in OS and progression-free survival (PFS) were found between patients with aggressive PAs and those with pituitary carcinomas. The 5-year PFS was 21.9% for patients with aggressive PAs and 36.1% for patients with pituitary carcinomas. This suggests that aggressive PAs and pituitary carcinomas are closer in identity than previously perceived.

It is advisable to perform MGMT immunoexpression before starting TMZ therapy. A low MGMT immunoexpression has been correlated with a positive response to TMZ. If it is not possible to perform MGMT IHC, or if MGMT immunoexpression is high, then, TMZ can be started for 3–6 cycles to determine the response of the tumor to therapy (Raverot et al. 2018).

What should the starting and maintenance doses be?

The standard therapeutic dose of TMZ is 150–200 mg/m2/day for 5 of every 28 days (5/28). TMZ response is schedule dependent and alternative dosing regimens may enhance its efficacy (Mrugala & Chamberlain 2008). TMZ can be administered on a continuous daily metronomic schedule as well, thus achieving MGMT depletion and improving response. In this case, the dose is 50 mg/m2/day without interruption (28/28). Other TMZ schedules include its administration every other week (7/14) and on a 21-consecutive-day regimen administered every 28 days (21/28). Both are considered dose-dense regimens: they increase the dose intensity of the regimen by delivering standard-dose chemotherapy with shorter intervals between the treatment cycles. This improves the efficacy by minimizing the opportunity for cellular regrowth between cycles (Liu & Gerson 2006). In these dose-dense regimens, TMZ is administered at 150 mg/m2/day for 7 days every other week (7/14) or at 85–100 mg/m2/day for 21 consecutive days (21/28).

In most pituitary cases (87.8%), TMZ has been used according to the standard regimen (5/28) (Ji et al. 2016). If external beam radiation therapy is needed, TMZ may be used concomitantly as in the Stupp protocol for GBM at 75 mg/m2/day for 6 weeks. This could not be applicable for stereotactic radiosurgery. TMZ absorption is minimally affected by food. No serious side effects have been reported with its use in pituitary tumors. In cases of dose-dense regimens, the secondary effects can be more severe.

A small number of patients in different series have received a combination of TMZ with another medication: capecitabine (Zacharia et al. 2014), pasireotide (Bode et al. 2010, Ceccato et al. 2015), octreotide (Bush et al. 2010, Vieira Neto et al. 2013), bevacizumab (Touma et al. 2017) and thalidomide (Raverot et al. 2018). In patients with functional tumors, the addition of a second medication can be useful. The small number of patients does not allow proper analysis of the effects of these combinations and their use must be decided according to each patient.

How long should the treatment be given?

In patients with GBM, the duration of treatment is 6–12 months and, in some cases, it may be extended for several years (Mannas et al. 2014). In pituitary tumors, 73% of patients have received short-term therapy (1–12 months). On average, they received 13 cycles of TMZ (range, 1–45 cycles). In patients with short-term treatment, the median number of TMZ cycles was 8 (range, 1–12 cycles) and 26 (range, 14–45 cycles) for those in long-term therapy (more than 12 cycles) (Ji et al. 2016). In patients who responded to TMZ, there was a trend toward benefit from long-term therapy. The 5-year OS rate was 91.7% and the 5-year PFS rate 61.3% in patients with long-term treatment vs 54.1% and 16.3% respectively, in patients with short-term treatment (Ji et al. 2016). Although not statistically significant, it seems that patients can benefit from extended TMZ therapy. It was shown that patients receiving long-term treatment, stayed free of disease progression up to 120 months (Ji et al. 2016).

In patients with pituitary carcinomas, TMZ treatment can be extended according to their tolerance, clinical and radiological response. In aggressive Pas, the benefits to extended therapy must outweigh the risks of secondary effects and may be continued if therapeutic benefit is observed. Relapse after TMZ suspension has been observed in some patients and a second attempt of TMZ usually has not been successful (Raverot et al. 2018). Based on these findings, and in the fact that there are no alternative drugs, an extended or lifelong treatment may be justified, especially in pituitary carcinomas.

What to do with TMZ resistant tumors?

Tumors that were initially sensitive to chemotherapeutic agents can develop resistance. This condition is known as acquired resistance and may be caused by genetic or epigenetic alterations in particular genes, that provide tumor cells with a survival advantage to continue to replicate (Alvino et al. 2006). In this scenario, if a heterogenous tumor is treated using chemotherapy, only the sensitive tumor cells would be killed, thereby leaving behind the resistant tumor cells to continue to grow and replicate. Studies have shown that acquired resistance is conferred by a variety of mechanisms that result in TMZ treatment having little or no effect on the specific tumors (Longley & Johnston 2005, Bradshaw et al. 2008). Moreover, certain glioma cases may contain various multi-drug resistant proteins that are able to diminish or tolerate the effects of TMZ (Calatozzolo et al. 2005).

In pituitary tumors non-responsive to TMZ, progressive disease under treatment, or relapse after discontinuation of therapy, a second-line option has been used with limited success. Anti-angiogenic therapy with bevacizumab has been successful in one case (Ortiz et al. 2012) and the patient is still alive after 7 years of continuous therapy. Everolimus, lapatinib, sunitinib and erlotinib have also been tried without success (Jouanneau et al. 2012, Donovan et al. 2016, Raverot et al. 2018). Re-irradiation can be another option, but the risk of secondary effects must be balanced against the possible benefits.

Suggested indications for TMZ treatment

Based on current data, TMZ continues to be used as the last resort and as a salvage treatment in many cases. The suggested indications are:

Future directions

TMZ has documented to be of value in the treatment of aggressive PAs and pituitary carcinomas. After twelve years of its use, prospective, clinical trials are needed. With the advancement in research and clinical techniques, future studies involving TMZ can be expanded on many levels. First and foremost, research should focus on establishing novel reliable markers, beyond MGMT methylation and IHC analysis, in order to improve accuracy in predicting TMZ response rate in individual cases. This is an ongoing issue with current TMZ treatment. Another possibility is to study whether TMZ response increases if used alone or concurrently with radiotherapy. Studies should focus whether TMZ response improves when different radiation therapy methods are used.

Researchers studying genetic mutations in PAs and pituitary carcinomas should collaborate with clinicians to correlate whether TMZ therapy response varies with the existence of other genetic mutations, present in various pituitary tumors. It may be that certain genetic mutations may make some tumors resistant or less responsive to TMZ therapy. There is also a crucial need to further explicate the mechanisms that confer tumor resistance to TMZ in PAs and pituitary carcinomas, as well as in all other tumor types. Increased knowledge of the molecular mechanisms and processes present within these tumors may reveal novel targets that would increase the effectiveness of TMZ therapy especially in cases of TMZ resistant cases. Perhaps the secret to increasing TMZ effectiveness lies in the simple fact that novel mechanisms or agents are needed to deplete MGMT levels within the tumor cells in order to heighten the effect of TMZ.

While the identification of genetic mutations in pituitary tumors is a step in the right direction, future research should seek to determine why certain tumors are drug resistant. Here, studies should include whether prolonged TMZ dosing regimens will overcome TMZ resistance in both recurring tumors, and tumors where MGMT immunoexpression is strong. They can also look at whether TMZ therapy applied earlier in the treatment process (i.e. after initial diagnosis) is more effective in these types of tumors as opposed to using TMZ therapy as a ‘last resort’ (Lin et al. 2016).

Along with using genetic information to determine effect of TMZ treatment, future studies should look at whether response rates improve if TMZ is used in combination with drugs/antibodies that are known enzyme/protein blockers in tumor cell growth. Capecitabine may augment the effects of TMZ if it is administered some days before, but more studies are needed. Studies should focus on VEGF and rapamycin effects when used along with TMZ to treat tumors. Along with this, emphasis should be given to whether immunotherapy can be combined with TMZ therapy to treat recurrent aggressive PAs and pituitary carcinomas.

Although TMZ may be the ‘best’ therapy as a last resort in many cases of aggressive PAs and pituitary carcinomas, more work on a greater number of cases should be of the utmost importance to establish the true capabilities of this agent. The lack of clinical trial data for TMZ effectiveness, and the establishment of the indications, doses and duration of TMZ administration needed in tumors, necessitates multidisciplinary approaches to provide patients with the most informed and best treatment options. The use of TMZ as neoadjuvant therapy in cases of recurrent PAs should be explored.

To conclude, the fact that TMZ treatment, a chemotherapeutic agent, has been effective in both aggressive PAs (considered benign) and pituitary carcinomas (considered malignant), and that the studies have shown clinical similarities in both groups, a new paradigm of benignity, aggressiveness and malignancy in pituitary tumors emerges. Perhaps their boundaries are not so clear. This can lead us to find the missing link between them and help us to clarify their pathogenesis and their management.

Declaration of interest

The authors have no personal financial or institutional interest in any pharmaceutical agents or testing devices described herein.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgment

Authors are grateful to the Jarislowsky and Lloyd Carr-Harris Foundations for their continuous support.

References

  • Almalki MH, Aljoaib NN, Alotaibi MJ, Aldabas BS, Wahedi TS, Ahmad MH & Alshahrani F 2017 Temozolomide therapy for resistant prolactin-secreting pituitary adenomas and carcinomas: a systematic review. Hormones 16 139149. (https://doi.org/10.1002/ijc.23219)

    • Search Google Scholar
    • Export Citation
  • Alvino E, Castiglia D, Caporali S, Pepponi R, Caporaso P, Lacal PM, Marra G, Fischer F, Zambruno G, Bonmassar E, et al. 2006 A single cycle of treatment with temozolomide, alone or combined with O(6)-benzylguanine, induces strong chemoresistance in melanoma cell clones in vitro: role of O(6)-methylguanine-DNA methyltransferase and the mismatch repair system. International Journal of Oncology 29 785797. (https://doi.org/10.3892/ijo.29.4.785)

    • Search Google Scholar
    • Export Citation
  • Bengtsson D, Schroder HD, Andersen M, Maiter D, Berinder K, Feldt Rasmussen U, Rasmussen AK, Johannsson G, Hoybye C, van der Lely AJ, et al. 2015 Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide. Journal of Clinical Endocrinology and Metabolism 100 16891698. (https://doi.org/10.1210/jc.2014-4350)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bode H, Seiz M, Lammert A, Brockmann MA, Back W, Hammes HP & Thome C 2010 SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Experimental and Clinical Endocrinology and Diabetes 118 760763. (https://doi.org/10.1055/s-0030-1253419)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bradshaw TD, Stone EL, Trapani V, Leong CO, Matthews CS, te Poele R & Stevens MF 2008 Mechanisms of acquired resistance to 2-(4-amino-3-methylphenyl)benzothiazole in breast cancer cell lines. Breast Cancer Research and Treatment 110 5768. (https://doi.org/10.1007/s10549-007-9690-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bruno OD, Juarez-Allen L, Christiansen SB, Manavela M, Danilowicz K, Vigovich C & Gomez RM 2015 Temozolomide therapy for aggressive pituitary tumors: results in a small series of patients from Argentina. International Journal of Endocrinology 2015 587893. (https://doi.org/10.1155/2015/587893)

    • Search Google Scholar
    • Export Citation
  • Buchfelder M 2009 Management of aggressive pituitary adenomas: current treatment strategies. Pituitary 12 256260. (https://doi.org/10.1007/s11102-008-0153-z)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bush ZM, Longtine JA, Cunningham T, Schiff D, Jane JA Jr, Vance ML, Thorner MO, Laws ER Jr & Lopes MB 2010 Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression. Journal of Clinical Endocrinology and Metabolism 95 E280E290. (https://doi.org/10.1210/jc.2010-0441)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Calatozzolo C, Gelati M, Ciusani E, Sciacca FL, Pollo B, Cajola L, Marras C, Silvani A, Vitellaro-Zuccarello L, Croci D, et al. 2005 Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma. Journal of Neuro-Oncology 74 113121. (https://doi.org/10.1007/s11060-004-6152-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ceccato F, Lombardi G, Manara R, Emanuelli E, Denaro L, Milanese L, Gardiman MP, Bertorelle R, Scanarini M, D’Avella D, et al. 2015 Temozolomide and pasireotide treatment for aggressive pituitary adenoma: expertise at a tertiary care center. Journal of Neuro-Oncology 122 189196. (https://doi.org/10.1007/s11060-014-1702-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ceccato F, Regazzo D, Barbot M, Denaro L, Emanuelli E, Borsetto D, Rolma G, Alessio L, Gardiman MP, Lombardi G, et al. 2018 Early recognition of aggressive pituitary adenomas: a single-centre experience. Acta Neurochirurgica 160 4955. (https://doi.org/10.1007/s00701-017-3396-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dai C, Sun B, Liu X, Bao X, Feng M, Yao Y, Wei J, Deng K, Yang C, Li X, et al. 2017 O-6-methylguanine-DNA methyltransferase expression is associated with pituitary adenoma tumor recurrence: a systematic meta-analysis. Oncotarget 8 1967419683. (https://doi.org/10.18632/oncotarget.14936)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Di Ieva A, Rotondo F, Syro LV, Cusimano MD & Kovacs K 2014 Aggressive pituitary adenomas – diagnosis and emerging treatments. Nature Reviews Endocrinology 10 423435. (https://doi.org/10.1038/nrendo.2014.64)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Donovan LE, Arnal AV, Wang SH & Odia Y 2016 Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy. CNS Oncology 5 203209. (https://doi.org/10.2217/cns-2016-0011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. 2009 New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer 45 228247. (https://doi.org/10.1016/j.ejca.2008.10.026)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ersen A, Syro LV, Penagos L, Uribe H, Scheithauer BW, Ortiz LD, Rotondo F, Horvath E & Kovacs K 2012 Non-uniform response to temozolomide therapy in a pituitary gonadotroph adenoma. Canadian Journal of Neurological Sciences 39 683685. (https://doi.org/10.1017/S0317167100018242)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB & Herman JG 2000 Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. New England Journal of Medicine 343 13501354. (https://doi.org/10.1056/NEJM200011093431901)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fadul CE, Kominsky AL, Meyer LP, Kingman LS, Kinlaw WB, Rhodes CH, Eskey CJ & Simmons NE 2006 Long-term response of pituitary carcinoma to temozolomide. Report of two cases. Journal of Neurosurgery 105 621626. (https://doi.org/10.3171/jns.2006.105.4.621)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gomez-Hernandez K, Ezzat S, Asa SL & Mete O 2015 Clinical implications of accurate subtyping of pituitary adenomas: perspectives from the treating physician. Turkish Journal of Pathology 31 (Supplement 1) 417. (https://doi.org/10.5146/tjpath.2015.01311)

    • Search Google Scholar
    • Export Citation
  • Gusyatiner O & Hegi ME 2017 Glioma epigenetics: from subclassification to novel treatment options. Seminars in Cancer Biology [epub]. (https://doi.org/10.1016/j.semcancer.2017.11.010)

    • Search Google Scholar
    • Export Citation
  • Hagen C, Schroeder HD, Hansen S, Hagen C & Andersen M 2009 Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy. European Journal of Endocrinology 161 631637. (https://doi.org/10.1530/EJE-09-0389)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Halevy C & Whitelaw BC 2017 How effective is temozolomide for treating pituitary tumours and when should it be used? Pituitary 20 261266. (https://doi.org/10.1007/s11102-016-0745-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Heaney AP 2011 Pituitary carcinoma: difficult diagnosis and treatment. Journal of Clinical Endocrinology and Metabolism 96 36493660. (https://doi.org/10.1210/jc.2011-2031)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hirohata T, Asano K, Ogawa Y, Takano S, Amano K, Isozaki O, Iwai Y, Sakata K, Fukuhara N, Nishioka H, et al. 2013 DNA mismatch repair protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the national cooperative study by the Japan Society for Hypothalamic and Pituitary Tumors. Journal of Clinical Endocrinology and Metabolism 98 11301136. (https://doi.org/10.1210/jc.2012-2924)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jacinto FV & Esteller M 2007 Mutator pathways unleashed by epigenetic silencing in human cancer. Mutagenesis 22 247253. (https://doi.org/10.1093/mutage/gem009)

  • Ji Y, Vogel RI & Lou E 2016 Temozolomide treatment of pituitary carcinomas and atypical adenomas: systematic review of case reports. Neuro-Oncology Practice 3 188195. (https://doi.org/10.1093/nop/npv059)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jouanneau E, Wierinckx A, Ducray F, Favrel V, Borson-Chazot F, Honnorat J, Trouillas J & Raverot G 2012 New targeted therapies in pituitary carcinoma resistant to temozolomide. Pituitary 15 3743. (https://doi.org/10.1007/s11102-011-0341-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kaina B, Christmann M, Naumann S & Roos WP 2007 MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair 6 10791099. (https://doi.org/10.1016/j.dnarep.2007.03.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M & Grossman AB 2005 Clinical review: diagnosis and management of pituitary carcinomas. Journal of Clinical Endocrinology and Metabolism 90 30893099. (https://doi.org/10.1210/jc.2004-2231)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kovacs K, Horvath E, Syro LV, Uribe H, Penagos LC, Ortiz LD & Fadul CE 2007 Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: morphological findings. Human Pathology 38 185189. (https://doi.org/10.1016/j.humpath.2006.07.014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kovacs K, Scheithauer BW, Lombardero M, McLendon RE, Syro LV, Uribe H, Ortiz LD & Penagos LC 2008 MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy. Acta Neuropathologica 115 261262. (https://doi.org/10.1007/s00401-007-0279-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lasolle H, Cortet C, Castinetti F, Cloix L, Caron P, Delemer B, Desailloud R, Jublanc C, Lebrun-Frenay C, Sadoul JL, et al. 2017 Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. European Journal of Endocrinology 176 769777. (https://doi.org/10.1530/EJE-16-0979)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lau Q, Scheithauer B, Kovacs K, Horvath E, Syro LV & Lloyd R 2010 MGMT immunoexpression in aggressive pituitary adenoma and carcinoma. Pituitary 13 367379. (https://doi.org/10.1007/s11102-010-0249-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lim DS & Fleseriu M 2017 The role of combination medical therapy in the treatment of acromegaly. Pituitary 20 136148. (https://doi.org/10.1007/s11102-016-0737-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lim S, Shahinian H, Maya MM, Yong W & Heaney AP 2006 Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncology 7 518520. (https://doi.org/10.1016/S1470-2045(06)70728-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lin AL, Sum MW & DeAngelis LM 2016 Is there a role for early chemotherapy in the management of pituitary adenomas? Neuro-Oncology 18 13501356. (https://doi.org/10.1093/neuonc/now059)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Liu L & Gerson SL 2006 Targeted modulation of MGMT: clinical implications. Clinical Cancer Research 12 328331. (https://doi.org/10.1158/1078-0432.CCR-05-2543)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Longley DB & Johnston PG 2005 Molecular mechanisms of drug resistance. Journal of Pathology 205 275292. (https://doi.org/10.1002/path.1706)

  • Lopes MBS 2017 The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathologica 134 521535. (https://doi.org/10.1007/s00401-017-1769-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Losa M, Bogazzi F, Cannavo S, Ceccato F, Curto L, De Marinis L, Iacovazzo D, Lombardi G, Mantovani G, Mazza E, et al. 2016 Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas. Journal of Neuro-Oncology 126 519525. (https://doi.org/10.1007/s11060-015-1991-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lloyd RV, Kovacs K, Young WF Jr, Farrell W, Asa SL, Trouillas J, Kontogeorgos G, Sano T, Scheithauer BW & Hern E 2004 Pituitary tumors: introduction. In Pathology and Genetics of Tumours of Endocrine Organs, pp 1013. Eds DeLellis RA, Lloyd RV, Heitz PU & Eng C. Lyon, France: IARC Press.

    • Search Google Scholar
    • Export Citation
  • Macdonald DR, Cascino TL, Schold SC Jr & Cairncross JG 1990 Response criteria for phase II studies of supratentorial malignant glioma. Journal of Clinical Oncology 8 12771280. (https://doi.org/10.1200/JCO.1990.8.7.1277)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mannas JP, Lightner DD, Defrates SR, Pittman T & Villano JL 2014 Long-term treatment with temozolomide in malignant glioma. Journal of Clinical Neuroscience 21 121123. (https://doi.org/10.1016/j.jocn.2013.03.039)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • McCormack AI, Dekkers O, Petersenn S, Popovic V, Trouillas J, Raverot G & Burman P 2018 Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. European Journal of Endocrinology 178 265276. (https://doi.org/10.1530/EJE-17-0933)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Melmed S 2011 Pathogenesis of pituitary tumors. Nature Reviews Endocrinology 7 257266. (https://doi.org/10.1038/nrendo.2011.40)

  • Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA & Wass JAH 2011 Diagnosis and treatment of hyperprolactinemia: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 96 273288. (https://doi.org/10.1210/jc.2010-1692)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mete O & Lopes MB 2017 Overview of the 2017 WHO classification of pituitary tumors. Endocrine Pathology 28 228243. (https://doi.org/10.1007/s12022-017-9498-z)

  • Micko ASG, Wohrer A, Hoftberger R, Vila G, Marosi C, Knosp E & Wolfsberger S 2017 MGMT and MSH6 immunoexpression for functioning pituitary macroadenomas. Pituitary 20 643653. (https://doi.org/10.1007/s11102-017-0829-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miermeister CP, Petersenn S, Buchfelder M, Fahlbusch R, Ludecke DK, Holsken A, Bergmann M, Knappe HU, Hans VH, Flitsch J, et al. 2015 Histological criteria for atypical pituitary adenomas – data from the German pituitary adenoma registry suggests modifications. Acta Neuropathologica Communications 3 50. (https://doi.org/10.1186/s40478-015-0229-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mrugala MM & Chamberlain MC 2008 Mechanisms of disease: temozolomide and glioblastoma – look to the future. Nature Clinical Practice Oncology 5 476486. (https://doi.org/10.1038/ncponc1155)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Neidle S & Thurston DE 2005 Chemical approaches to the discovery and development of cancer therapies. Nature Reviews Cancer 5 285296. (https://doi.org/10.1038/nrc1587)

  • Ortiz LD, Syro LV, Scheithauer BW, Ersen A, Uribe H, Fadul CE, Rotondo F, Horvath E & Kovacs K 2012 Anti-VEGF therapy in pituitary carcinoma. Pituitary 15 445449. (https://doi.org/10.1007/s11102-011-0346-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Osamura RY, Grossman A, Korbonits M, Kovacs K, Lopes MBS, Matsuno A & Trouillas J 2017a Pituitary adenoma. In WHO Classification of Tumours of Endocrine Organs, 4th ed., pp 1418. Eds Lloyd RV, Osamura RY, Klöppel G & Rosai J. Lyon, France: IARC Press.

    • Search Google Scholar
    • Export Citation
  • Osamura RY, Lopes MBS, Grossman A, Kontogeorgos G & Trouillas J 2017b Tumours of the pituitary gland. Introduction. In WHO Classification of Tumours of Endocrine Organs, 4th ed., p 13. Eds Lloyd RV, Osamura RY, Klöppel G & Rosai J. Lyon, France: IARC Press.

    • Search Google Scholar
    • Export Citation
  • Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WF Jr, Lloyd RV, Davis DH, Guthrie BL & Schoene WC 1997 Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79 804812. (https://doi.org/10.1002/(SICI)1097-0142(19970215)79:4<804::AID-CNCR18>3.0.CO;2-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J & Dekkers OM 2018 European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. European Journal of Endocrinology 178 G1G24. (https://doi.org/10.1530/EJE-17-0796)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Roncaroli F, Kovacs K, Lloys RV, Matsuno A & Righi A 2017 Pituitary carcinoma. In WHO Classification of Tumours of Endocrine Organs, 4th ed., pp 4144. Eds Lloyd RV, Osamura RY, Klöppel G & Rosai J. Lyon, France: IARC Press.

    • Search Google Scholar
    • Export Citation
  • Sabharwal A & Middleton MR 2006 Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy. Current Opinion in Pharmacology 6 355363. (https://doi.org/10.1016/j.coph.2006.03.011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ & Petersenn S 2007 Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. European Journal of Endocrinology 156 203216. (https://doi.org/10.1530/eje.1.02326)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Salehi F, Scheithauer BW, Moyes VJ, Drake WM, Syro LV, Manoranjan B, Sharma S, Horvath E & Kovacs K 2010 Low immunohistochemical expression of MGMT in ACTH secreting pituitary tumors of patients with Nelson syndrome. Endocrine Pathology 21 227229. (https://doi.org/10.1007/s12022-010-9138-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Salehi F, Scheithauer BW, Kros JM, Lau Q, Fealey M, Erickson D, Kovacs K, Horvath E & Lloyd RV 2011 MGMT promoter methylation and immunoexpression in aggressive pituitary adenomas and carcinomas. Journal of Neuro-Oncology 104 647657. (https://doi.org/10.1007/s11060-011-0532-6)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sav A, Rotondo F, Syro LV, Di Ieva A, Cusimano MD & Kovacs K 2015 Invasive, atypical and aggressive pituitary adenomas and carcinomas. Endocrinology Metabolism Clinics of North America 44 99104. (https://doi.org/10.1016/j.ecl.2014.10.008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Scaringi C, De Sanctis V, Minniti G & Enrici RM 2013 Temozolomide-related hematologic toxicity. Onkologie 36 444449. (https://doi.org/10.1159/000353752)

  • Scheithauer BW, Gaffey TA, Lloyd RV, Sebo TJ, Kovacs KT, Horvath E, Yapicier O, Young WF Jr, Meyer FB, Kuroki T, et al. 2006 Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59 341353; discussion 341353. (https://doi.org/10.1227/01.NEU.0000223437.51435.6E)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sharma S, Salehi F, Scheithauer BW, Rotondo F, Syro LV & Kovacs K 2009 Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis. Anticancer Research 29 37593768.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stevens MF, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R, Baig G, Goddard C, Gibson NW, Slack JA, et al. 1987 Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Research 47 58465852.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. 2005 Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine 352 987996. (https://doi.org/10.1056/NEJMoa043330)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Switzeny OJ, Christmann M, Renovanz M, Giese A, Sommer C & Kaina B 2016 MGMT promoter methylation determined by HRM in comparison to MSP and pyrosequencing for predicting high-grade glioma response. Clinical Epigenetics 8 49. (https://doi.org/10.1186/s13148-016-0204-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Syro LV, Uribe H, Penagos LC, Ortiz LD, Fadul CE, Horvath E & Kovacs K 2006 Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm. Clinical Endocrinology 65 552553. (https://doi.org/10.1111/j.1365-2265.2006.02653.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Syro LV, Ortiz LD, Scheithauer BW, Lloyd R, Lau Q, Gonzalez R, Uribe H, Cusimano M, Kovacs K & Horvath E 2011 Treatment of pituitary neoplasms with temozolomide: a review. Cancer 117 454462. (https://doi.org/10.1002/cncr.25413)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Syro LV, Rotondo F, Cusimano MD & Kovacs K 2015 Aggressive pituitary tumors or localized pituitary carcinomas. In 14th International Pituitary Congress, 2015. San Diego, CA, USA: The Pituitary Society.

    • Search Google Scholar
    • Export Citation
  • Touma W, Hoostal S, Peterson RA, Wiernik A, SantaCruz KS & Lou E 2017 Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after resection. Journal of Clinical Neuroscience 41 7577. (https://doi.org/10.1016/j.jocn.2017.02.052)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Trouillas J, Roy P, Sturm N, Dantony E, Cortet-Rudelli C, Viennet G, Bonneville JF, Assaker R, Auger C, Brue T, et al. 2013 A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathologica 126 123135. (https://doi.org/10.1007/s00401-013-1084-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, et al. 2017 Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390 16451653. (https://doi.org/10.1016/S0140-6736(17)31442-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vieira, Neto L, Chimelli L, Pereira PJ, Gasparetto EL, Bines J, Wildemberg LE & Gadelha MR 2013 The role of temozolomide in the treatment of a patient with a pure silent pituitary somatotroph carcinoma. Endocrine Practices 19 e145e149. (https://doi.org/10.4158/EP12400.CR)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, et al. 2010 Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. Journal of Clinical Oncology 28 19631972. (https://doi.org/10.1200/JCO.2009.26.3541)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Whitelaw BC, Dworakowska D, Thomas NW, Barazi S, Riordan-Eva P, King AP, Hampton T, Landau DB, Lipscomb D, Buchanan CR, et al. 2012 Temozolomide in the management of dopamine agonist-resistant prolactinomas. Clinical Endocrinology 76 877886. (https://doi.org/10.1111/j.1365-2265.2012.04373.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Widhalm G, Wolfsberger S, Preusser M, Woehrer A, Kotter MR, Czech T, Marosi C & Knosp E 2009 O(6)-methylguanine DNA methyltransferase immunoexpression in nonfunctioning pituitary adenomas: are progressive tumors potential candidates for temozolomide treatment? Cancer 115 10701080. (https://doi.org/10.1002/cncr.24053)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wiewrodt D, Nagel G, Dreimuller N, Hundsberger T, Perneczky A & Kaina B 2008 MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome. International Journal of Cancer 122 13911399. (https://doi.org/10.1002/ijc.23219)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zacharia BE, Gulati AP, Bruce JN, Carminucci AS, Wardlaw SL, Siegelin M, Remotti H, Lignelli A & Fine RL 2014 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 74 E447E455; discussion E455. (https://doi.org/10.1227/NEU.0000000000000251)

    • Crossref
    • Search Google Scholar
    • Export Citation

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  • Almalki MH, Aljoaib NN, Alotaibi MJ, Aldabas BS, Wahedi TS, Ahmad MH & Alshahrani F 2017 Temozolomide therapy for resistant prolactin-secreting pituitary adenomas and carcinomas: a systematic review. Hormones 16 139149. (https://doi.org/10.1002/ijc.23219)

    • Search Google Scholar
    • Export Citation
  • Alvino E, Castiglia D, Caporali S, Pepponi R, Caporaso P, Lacal PM, Marra G, Fischer F, Zambruno G, Bonmassar E, et al. 2006 A single cycle of treatment with temozolomide, alone or combined with O(6)-benzylguanine, induces strong chemoresistance in melanoma cell clones in vitro: role of O(6)-methylguanine-DNA methyltransferase and the mismatch repair system. International Journal of Oncology 29 785797. (https://doi.org/10.3892/ijo.29.4.785)

    • Search Google Scholar
    • Export Citation
  • Bengtsson D, Schroder HD, Andersen M, Maiter D, Berinder K, Feldt Rasmussen U, Rasmussen AK, Johannsson G, Hoybye C, van der Lely AJ, et al. 2015 Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide. Journal of Clinical Endocrinology and Metabolism 100 16891698. (https://doi.org/10.1210/jc.2014-4350)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bode H, Seiz M, Lammert A, Brockmann MA, Back W, Hammes HP & Thome C 2010 SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Experimental and Clinical Endocrinology and Diabetes 118 760763. (https://doi.org/10.1055/s-0030-1253419)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bradshaw TD, Stone EL, Trapani V, Leong CO, Matthews CS, te Poele R & Stevens MF 2008 Mechanisms of acquired resistance to 2-(4-amino-3-methylphenyl)benzothiazole in breast cancer cell lines. Breast Cancer Research and Treatment 110 5768. (https://doi.org/10.1007/s10549-007-9690-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bruno OD, Juarez-Allen L, Christiansen SB, Manavela M, Danilowicz K, Vigovich C & Gomez RM 2015 Temozolomide therapy for aggressive pituitary tumors: results in a small series of patients from Argentina. International Journal of Endocrinology 2015 587893. (https://doi.org/10.1155/2015/587893)

    • Search Google Scholar
    • Export Citation
  • Buchfelder M 2009 Management of aggressive pituitary adenomas: current treatment strategies. Pituitary 12 256260. (https://doi.org/10.1007/s11102-008-0153-z)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bush ZM, Longtine JA, Cunningham T, Schiff D, Jane JA Jr, Vance ML, Thorner MO, Laws ER Jr & Lopes MB 2010 Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression. Journal of Clinical Endocrinology and Metabolism 95 E280E290. (https://doi.org/10.1210/jc.2010-0441)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Calatozzolo C, Gelati M, Ciusani E, Sciacca FL, Pollo B, Cajola L, Marras C, Silvani A, Vitellaro-Zuccarello L, Croci D, et al. 2005 Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma. Journal of Neuro-Oncology 74 113121. (https://doi.org/10.1007/s11060-004-6152-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ceccato F, Lombardi G, Manara R, Emanuelli E, Denaro L, Milanese L, Gardiman MP, Bertorelle R, Scanarini M, D’Avella D, et al. 2015 Temozolomide and pasireotide treatment for aggressive pituitary adenoma: expertise at a tertiary care center. Journal of Neuro-Oncology 122 189196. (https://doi.org/10.1007/s11060-014-1702-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ceccato F, Regazzo D, Barbot M, Denaro L, Emanuelli E, Borsetto D, Rolma G, Alessio L, Gardiman MP, Lombardi G, et al. 2018 Early recognition of aggressive pituitary adenomas: a single-centre experience. Acta Neurochirurgica 160 4955. (https://doi.org/10.1007/s00701-017-3396-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dai C, Sun B, Liu X, Bao X, Feng M, Yao Y, Wei J, Deng K, Yang C, Li X, et al. 2017 O-6-methylguanine-DNA methyltransferase expression is associated with pituitary adenoma tumor recurrence: a systematic meta-analysis. Oncotarget 8 1967419683. (https://doi.org/10.18632/oncotarget.14936)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Di Ieva A, Rotondo F, Syro LV, Cusimano MD & Kovacs K 2014 Aggressive pituitary adenomas – diagnosis and emerging treatments. Nature Reviews Endocrinology 10 423435. (https://doi.org/10.1038/nrendo.2014.64)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Donovan LE, Arnal AV, Wang SH & Odia Y 2016 Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy. CNS Oncology 5 203209. (https://doi.org/10.2217/cns-2016-0011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. 2009 New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer 45 228247. (https://doi.org/10.1016/j.ejca.2008.10.026)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ersen A, Syro LV, Penagos L, Uribe H, Scheithauer BW, Ortiz LD, Rotondo F, Horvath E & Kovacs K 2012 Non-uniform response to temozolomide therapy in a pituitary gonadotroph adenoma. Canadian Journal of Neurological Sciences 39 683685. (https://doi.org/10.1017/S0317167100018242)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB & Herman JG 2000 Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. New England Journal of Medicine 343 13501354. (https://doi.org/10.1056/NEJM200011093431901)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fadul CE, Kominsky AL, Meyer LP, Kingman LS, Kinlaw WB, Rhodes CH, Eskey CJ & Simmons NE 2006 Long-term response of pituitary carcinoma to temozolomide. Report of two cases. Journal of Neurosurgery 105 621626. (https://doi.org/10.3171/jns.2006.105.4.621)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gomez-Hernandez K, Ezzat S, Asa SL & Mete O 2015 Clinical implications of accurate subtyping of pituitary adenomas: perspectives from the treating physician. Turkish Journal of Pathology 31 (Supplement 1) 417. (https://doi.org/10.5146/tjpath.2015.01311)

    • Search Google Scholar
    • Export Citation
  • Gusyatiner O & Hegi ME 2017 Glioma epigenetics: from subclassification to novel treatment options. Seminars in Cancer Biology [epub]. (https://doi.org/10.1016/j.semcancer.2017.11.010)

    • Search Google Scholar
    • Export Citation
  • Hagen C, Schroeder HD, Hansen S, Hagen C & Andersen M 2009 Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy. European Journal of Endocrinology 161 631637. (https://doi.org/10.1530/EJE-09-0389)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Halevy C & Whitelaw BC 2017 How effective is temozolomide for treating pituitary tumours and when should it be used? Pituitary 20 261266. (https://doi.org/10.1007/s11102-016-0745-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Heaney AP 2011 Pituitary carcinoma: difficult diagnosis and treatment. Journal of Clinical Endocrinology and Metabolism 96 36493660. (https://doi.org/10.1210/jc.2011-2031)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hirohata T, Asano K, Ogawa Y, Takano S, Amano K, Isozaki O, Iwai Y, Sakata K, Fukuhara N, Nishioka H, et al. 2013 DNA mismatch repair protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the national cooperative study by the Japan Society for Hypothalamic and Pituitary Tumors. Journal of Clinical Endocrinology and Metabolism 98 11301136. (https://doi.org/10.1210/jc.2012-2924)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jacinto FV & Esteller M 2007 Mutator pathways unleashed by epigenetic silencing in human cancer. Mutagenesis 22 247253. (https://doi.org/10.1093/mutage/gem009)

  • Ji Y, Vogel RI & Lou E 2016 Temozolomide treatment of pituitary carcinomas and atypical adenomas: systematic review of case reports. Neuro-Oncology Practice 3 188195. (https://doi.org/10.1093/nop/npv059)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jouanneau E, Wierinckx A, Ducray F, Favrel V, Borson-Chazot F, Honnorat J, Trouillas J & Raverot G 2012 New targeted therapies in pituitary carcinoma resistant to temozolomide. Pituitary 15 3743. (https://doi.org/10.1007/s11102-011-0341-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kaina B, Christmann M, Naumann S & Roos WP 2007 MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair 6 10791099. (https://doi.org/10.1016/j.dnarep.2007.03.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M & Grossman AB 2005 Clinical review: diagnosis and management of pituitary carcinomas. Journal of Clinical Endocrinology and Metabolism 90 30893099. (https://doi.org/10.1210/jc.2004-2231)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kovacs K, Horvath E, Syro LV, Uribe H, Penagos LC, Ortiz LD & Fadul CE 2007 Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: morphological findings. Human Pathology 38 185189. (https://doi.org/10.1016/j.humpath.2006.07.014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kovacs K, Scheithauer BW, Lombardero M, McLendon RE, Syro LV, Uribe H, Ortiz LD & Penagos LC 2008 MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy. Acta Neuropathologica 115 261262. (https://doi.org/10.1007/s00401-007-0279-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lasolle H, Cortet C, Castinetti F, Cloix L, Caron P, Delemer B, Desailloud R, Jublanc C, Lebrun-Frenay C, Sadoul JL, et al. 2017 Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. European Journal of Endocrinology 176 769777. (https://doi.org/10.1530/EJE-16-0979)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lau Q, Scheithauer B, Kovacs K, Horvath E, Syro LV & Lloyd R 2010 MGMT immunoexpression in aggressive pituitary adenoma and carcinoma. Pituitary 13 367379. (https://doi.org/10.1007/s11102-010-0249-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lim DS & Fleseriu M 2017 The role of combination medical therapy in the treatment of acromegaly. Pituitary 20 136148. (https://doi.org/10.1007/s11102-016-0737-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lim S, Shahinian H, Maya MM, Yong W & Heaney AP 2006 Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncology 7 518520. (https://doi.org/10.1016/S1470-2045(06)70728-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lin AL, Sum MW & DeAngelis LM 2016 Is there a role for early chemotherapy in the management of pituitary adenomas? Neuro-Oncology 18 13501356. (https://doi.org/10.1093/neuonc/now059)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Liu L & Gerson SL 2006 Targeted modulation of MGMT: clinical implications. Clinical Cancer Research 12 328331. (https://doi.org/10.1158/1078-0432.CCR-05-2543)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Longley DB & Johnston PG 2005 Molecular mechanisms of drug resistance. Journal of Pathology 205 275292. (https://doi.org/10.1002/path.1706)

  • Lopes MBS 2017 The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathologica 134 521535. (https://doi.org/10.1007/s00401-017-1769-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Losa M, Bogazzi F, Cannavo S, Ceccato F, Curto L, De Marinis L, Iacovazzo D, Lombardi G, Mantovani G, Mazza E, et al. 2016 Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas. Journal of Neuro-Oncology 126 519525. (https://doi.org/10.1007/s11060-015-1991-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lloyd RV, Kovacs K, Young WF Jr, Farrell W, Asa SL, Trouillas J, Kontogeorgos G, Sano T, Scheithauer BW & Hern E 2004 Pituitary tumors: introduction. In Pathology and Genetics of Tumours of Endocrine Organs, pp 1013. Eds DeLellis RA, Lloyd RV, Heitz PU & Eng C. Lyon, France: IARC Press.

    • Search Google Scholar
    • Export Citation
  • Macdonald DR, Cascino TL, Schold SC Jr & Cairncross JG 1990 Response criteria for phase II studies of supratentorial malignant glioma. Journal of Clinical Oncology 8 12771280. (https://doi.org/10.1200/JCO.1990.8.7.1277)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mannas JP, Lightner DD, Defrates SR, Pittman T & Villano JL 2014 Long-term treatment with temozolomide in malignant glioma. Journal of Clinical Neuroscience 21 121123. (https://doi.org/10.1016/j.jocn.2013.03.039)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • McCormack AI, Dekkers O, Petersenn S, Popovic V, Trouillas J, Raverot G & Burman P 2018 Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. European Journal of Endocrinology 178 265276. (https://doi.org/10.1530/EJE-17-0933)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Melmed S 2011 Pathogenesis of pituitary tumors. Nature Reviews Endocrinology 7 257266. (https://doi.org/10.1038/nrendo.2011.40)

  • Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA & Wass JAH 2011 Diagnosis and treatment of hyperprolactinemia: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 96 273288. (https://doi.org/10.1210/jc.2010-1692)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mete O & Lopes MB 2017 Overview of the 2017 WHO classification of pituitary tumors. Endocrine Pathology 28 228243. (https://doi.org/10.1007/s12022-017-9498-z)

  • Micko ASG, Wohrer A, Hoftberger R, Vila G, Marosi C, Knosp E & Wolfsberger S 2017 MGMT and MSH6 immunoexpression for functioning pituitary macroadenomas. Pituitary 20 643653. (https://doi.org/10.1007/s11102-017-0829-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miermeister CP, Petersenn S, Buchfelder M, Fahlbusch R, Ludecke DK, Holsken A, Bergmann M, Knappe HU, Hans VH, Flitsch J, et al. 2015 Histological criteria for atypical pituitary adenomas – data from the German pituitary adenoma registry suggests modifications. Acta Neuropathologica Communications 3 50. (https://doi.org/10.1186/s40478-015-0229-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mrugala MM & Chamberlain MC 2008 Mechanisms of disease: temozolomide and glioblastoma – look to the future. Nature Clinical Practice Oncology 5 476486. (https://doi.org/10.1038/ncponc1155)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Neidle S & Thurston DE 2005 Chemical approaches to the discovery and development of cancer therapies. Nature Reviews Cancer 5 285296. (https://doi.org/10.1038/nrc1587)

  • Ortiz LD, Syro LV, Scheithauer BW, Ersen A, Uribe H, Fadul CE, Rotondo F, Horvath E & Kovacs K 2012 Anti-VEGF therapy in pituitary carcinoma. Pituitary 15 445449. (https://doi.org/10.1007/s11102-011-0346-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Osamura RY, Grossman A, Korbonits M, Kovacs K, Lopes MBS, Matsuno A & Trouillas J 2017a Pituitary adenoma. In WHO Classification of Tumours of Endocrine Organs, 4th ed., pp 1418. Eds Lloyd RV, Osamura RY, Klöppel G & Rosai J. Lyon, France: IARC Press.

    • Search Google Scholar
    • Export Citation
  • Osamura RY, Lopes MBS, Grossman A, Kontogeorgos G & Trouillas J 2017b Tumours of the pituitary gland. Introduction. In WHO Classification of Tumours of Endocrine Organs, 4th ed., p 13. Eds Lloyd RV, Osamura RY, Klöppel G & Rosai J. Lyon, France: IARC Press.

    • Search Google Scholar
    • Export Citation
  • Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WF Jr, Lloyd RV, Davis DH, Guthrie BL & Schoene WC 1997 Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79 804812. (https://doi.org/10.1002/(SICI)1097-0142(19970215)79:4<804::AID-CNCR18>3.0.CO;2-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J & Dekkers OM 2018 European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. European Journal of Endocrinology 178 G1G24. (https://doi.org/10.1530/EJE-17-0796)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Roncaroli F, Kovacs K, Lloys RV, Matsuno A & Righi A 2017 Pituitary carcinoma. In WHO Classification of Tumours of Endocrine Organs, 4th ed., pp 4144. Eds Lloyd RV, Osamura RY, Klöppel G & Rosai J. Lyon, France: IARC Press.

    • Search Google Scholar
    • Export Citation
  • Sabharwal A & Middleton MR 2006 Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy. Current Opinion in Pharmacology 6 355363. (https://doi.org/10.1016/j.coph.2006.03.011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ & Petersenn S 2007 Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. European Journal of Endocrinology 156 203216. (https://doi.org/10.1530/eje.1.02326)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Salehi F, Scheithauer BW, Moyes VJ, Drake WM, Syro LV, Manoranjan B, Sharma S, Horvath E & Kovacs K 2010 Low immunohistochemical expression of MGMT in ACTH secreting pituitary tumors of patients with Nelson syndrome. Endocrine Pathology 21 227229. (https://doi.org/10.1007/s12022-010-9138-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Salehi F, Scheithauer BW, Kros JM, Lau Q, Fealey M, Erickson D, Kovacs K, Horvath E & Lloyd RV 2011 MGMT promoter methylation and immunoexpression in aggressive pituitary adenomas and carcinomas. Journal of Neuro-Oncology 104 647657. (https://doi.org/10.1007/s11060-011-0532-6)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sav A, Rotondo F, Syro LV, Di Ieva A, Cusimano MD & Kovacs K 2015 Invasive, atypical and aggressive pituitary adenomas and carcinomas. Endocrinology Metabolism Clinics of North America 44 99104. (https://doi.org/10.1016/j.ecl.2014.10.008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Scaringi C, De Sanctis V, Minniti G & Enrici RM 2013 Temozolomide-related hematologic toxicity. Onkologie 36 444449. (https://doi.org/10.1159/000353752)

  • Scheithauer BW, Gaffey TA, Lloyd RV, Sebo TJ, Kovacs KT, Horvath E, Yapicier O, Young WF Jr, Meyer FB, Kuroki T, et al. 2006 Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59 341353; discussion 341353. (https://doi.org/10.1227/01.NEU.0000223437.51435.6E)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sharma S, Salehi F, Scheithauer BW, Rotondo F, Syro LV & Kovacs K 2009 Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis. Anticancer Research 29 37593768.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stevens MF, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R, Baig G, Goddard C, Gibson NW, Slack JA, et al. 1987 Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Research 47 58465852.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. 2005 Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine 352 987996. (https://doi.org/10.1056/NEJMoa043330)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Switzeny OJ, Christmann M, Renovanz M, Giese A, Sommer C & Kaina B 2016 MGMT promoter methylation determined by HRM in comparison to MSP and pyrosequencing for predicting high-grade glioma response. Clinical Epigenetics 8 49. (https://doi.org/10.1186/s13148-016-0204-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Syro LV, Uribe H, Penagos LC, Ortiz LD, Fadul CE, Horvath E & Kovacs K 2006 Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm. Clinical Endocrinology 65 552553. (https://doi.org/10.1111/j.1365-2265.2006.02653.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Syro LV, Ortiz LD, Scheithauer BW, Lloyd R, Lau Q, Gonzalez R, Uribe H, Cusimano M, Kovacs K & Horvath E 2011 Treatment of pituitary neoplasms with temozolomide: a review. Cancer 117 454462. (https://doi.org/10.1002/cncr.25413)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Syro LV, Rotondo F, Cusimano MD & Kovacs K 2015 Aggressive pituitary tumors or localized pituitary carcinomas. In 14th International Pituitary Congress, 2015. San Diego, CA, USA: The Pituitary Society.

    • Search Google Scholar
    • Export Citation
  • Touma W, Hoostal S, Peterson RA, Wiernik A, SantaCruz KS & Lou E 2017 Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after resection. Journal of Clinical Neuroscience 41 7577. (https://doi.org/10.1016/j.jocn.2017.02.052)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Trouillas J, Roy P, Sturm N, Dantony E, Cortet-Rudelli C, Viennet G, Bonneville JF, Assaker R, Auger C, Brue T, et al. 2013 A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathologica 126 123135. (https://doi.org/10.1007/s00401-013-1084-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, et al. 2017 Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390 16451653. (https://doi.org/10.1016/S0140-6736(17)31442-3)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vieira, Neto L, Chimelli L, Pereira PJ, Gasparetto EL, Bines J, Wildemberg LE & Gadelha MR 2013 The role of temozolomide in the treatment of a patient with a pure silent pituitary somatotroph carcinoma. Endocrine Practices 19 e145e149. (https://doi.org/10.4158/EP12400.CR)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, et al. 2010 Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. Journal of Clinical Oncology 28 19631972. (https://doi.org/10.1200/JCO.2009.26.3541)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Whitelaw BC, Dworakowska D, Thomas NW, Barazi S, Riordan-Eva P, King AP, Hampton T, Landau DB, Lipscomb D, Buchanan CR, et al. 2012 Temozolomide in the management of dopamine agonist-resistant prolactinomas. Clinical Endocrinology 76 877886. (https://doi.org/10.1111/j.1365-2265.2012.04373.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Widhalm G, Wolfsberger S, Preusser M, Woehrer A, Kotter MR, Czech T, Marosi C & Knosp E 2009 O(6)-methylguanine DNA methyltransferase immunoexpression in nonfunctioning pituitary adenomas: are progressive tumors potential candidates for temozolomide treatment? Cancer 115 10701080. (https://doi.org/10.1002/cncr.24053)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wiewrodt D, Nagel G, Dreimuller N, Hundsberger T, Perneczky A & Kaina B 2008 MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome. International Journal of Cancer 122 13911399. (https://doi.org/10.1002/ijc.23219)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zacharia BE, Gulati AP, Bruce JN, Carminucci AS, Wardlaw SL, Siegelin M, Remotti H, Lignelli A & Fine RL 2014 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 74 E447E455; discussion E455. (https://doi.org/10.1227/NEU.0000000000000251)

    • Crossref
    • Search Google Scholar
    • Export Citation