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International Journal of Endocrinology logoLink to International Journal of Endocrinology
. 2015 May 27;2015:587893. doi: 10.1155/2015/587893

Temozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina

Oscar D Bruno 1,*, Lea Juárez-Allen 1, Silvia B Christiansen 2, Marcos Manavela 3, Karina Danilowicz 3, Carlos Vigovich 3, Reynaldo M Gómez 3
PMCID: PMC4461777  PMID: 26106414

Abstract

We evaluated results of temozolomide (TMZ) therapy in six patients, aged 34–78 years, presenting aggressive pituitary tumors. In all the patients tested O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression in surgical specimens was absent. Patients received temozolomide 140–320 mg/day for 5 days monthly for at least 3 months. In two patients minimum time for evaluation could not be reached because of death in a 76-year-old man with a malignant prolactinoma and of severe neutro-thrombopenia in a 47-year-old woman with nonfunctioning pituitary adenoma. In two patients (a 34-year-old acromegalic woman and a 39-year-old woman with Nelson's syndrome) no response was observed after 4 and 6 months, respectively, and the treatment was stopped. Conversely, two 52- and 42-year-old women with Cushing's disease had long-term total clinical and radiological remissions which persisted after stopping temozolomide. We conclude that TMZ therapy may be of variable efficacy depending on—until now—incompletely understood factors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be crucial to establish the indications, doses, and duration of temozolomide administration.

1. Introduction

Aggressive pituitary tumors are invasive macroadenomas refractory to surgical and medical treatments, showing tendency to continuous growth and implicating a bad vital prognosis [1]. Until some years ago, no therapies were efficacious in treating that kind of tumors. First publications of treatment with the alkylating agent temozolomide (TMZ) appeared in 2006 [2, 3] and since then, variable responses to this drug have been reported in a limited number of cases with tumor volume reduction and control of the disease in some of them. We present here our experience with the use of temozolomide in six patients with different variants of aggressive pituitary tumors.

2. Patients and Methods

Six patients with intention-to-treat with TMZ, presenting different types of aggressive pituitary tumors, were evaluated. They were 5 women aged 34–52 and one 78-year-old man. They all presented macroadenomas (more than 10 mm) with cavernous sinus invasion, two of them with third par palsies and one with bitemporal hemianopsia. The only male patient had pituitary carcinoma (malignant prolactinoma) with an isolated parietal metastasis which was first biopsied and then surgically excised. All patients had had unsuccessful previous pituitary surgery (from 1 to 5 times), radiotherapy in 3, and conventional drug treatment in 4 of them, aimed at controlling hyperfunction and/or tumor volume (Table 1). The definition of aggressive pituitary tumor was based on clinical grounds (invasive macroadenomas refractory to surgical and medical treatments, showing tendency to continuous growth) as previously stated. We use the denomination pituitary carcinoma when extrapituitary presence of tumor (metastasis) is found. Temozolomide was administered as oral pills in variable doses, from 140 to 320 mg/day for 5 days every month, for at least 3 months before evaluating results. TMZ administration was preceded by the oral intake of ondansetron, as antiemetic prevention. Hematologic and liver function tests were performed before each cycle of therapy. Results of treatment were evaluated by monthly clinical examination and pituitary MRI after at least 3 months of therapy; computerized visual field examination and routine hormone tests were also made, when indicated.

Table 1.

Main clinical traits of 6 patients with intention-to-treat with temozolomide.

Patient Sex Age Tumor type Number of previous surgeries RxT Previous drug therapy
JB M 78 PRL Ca 1 Yes CAB
SA F 47 CNFPA 3 No CAB
LC F 34 GH-oma 2 No CAB, SSAs
DDO F 39 NS 2 Yes None
CM F 42 CD 1 No None
GM F 52 CD 5 Yes KNZ
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PRLCa: prolactin carcinoma; GH-oma: somatotropinoma; CNFPA: clinically nonfunctioning pituitary adenoma; NS: Nelson' syndrome; CD: Cushing's disease; RxT: radiotherapy; CAB: cabergoline; SSAs: somatostatin analogs; KNZ: ketoconazole.

For determinations of MGMT and marker of cell proliferation Ki67 on pathological specimens, all blocks were formalin buffer fixed and paraffin embedded. Cuts of 3-4 microns were made and stained with hematoxylin and eosin. Immunohistochemical determinations for adenohypophyseal hormones GH, FSH, LH, and TSH were made by using rabbit polyclonal Cell Marque (http://www.cellmarque.com/) antibodies whereas for PRL and ACTH, rabbit polyclonal DAKO (http://www.dako.com/) antibodies were employed. Ki67 and O6-methylguanine-DNA methyltransferase Ab-1 (MGMT) were measured by using mouse monoclonal antibodies from Thermo Scientific (http://www.thermoscientific.com/) in a 1 : 20 dilution. Immunostaining for MGMT was considered negative when lower than 10%.

3. Results

Figure 1 shows a MGMT-negative macrocorticotropinoma study of patient GM as compared to a MGMT-positive glioblastoma. Table 2 shows the results of MGMT and Ki67 immunohistochemistry, individual doses administered, length of therapy, and clinical outcome in the six patients.

Figure 1.

Figure 1

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The upper panel (a) shows a diffuse positive MGMT control (glioblastoma). The lower panel (b) corresponds to a negative MGMT immunostaining of macrocorticotropinoma in patient GM.

Table 2.

Results of MGMT and Ki67 immunohistochemistry, doses, length of therapy, and clinical outcome in 6 patients with intention-to-treat with TMZ.

Patient Tumor type MGMT Ki67 TMZ mg/d Months Outcome
JB PRL Ca (−) 10% 140 1 Death
SA CNFPA ND 2% 150 1 Failure
LC GH-oma (−) 3% 320 4 Failure
DDO Nelson's (−) 1% 240 6 Failure
CM CD (−) 6% 250 13 Remission
GM CD (−) 4% 180 29 Remission
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Drug therapy effect could not be evaluated in patients JB and SA because they failed to complete a 3-month treatment. JB had a malignant prolactinoma with brain metastases which deceased after the first administration of TMZ and SA developed severe thrombocytopenia and neutropenia after the first cycle of therapy. In two more patients TMZ was stopped after 4 (LC) and 6 (DDO) months of treatment, because it was considered ineffective in reducing tumor size. The two last patients having macrocorticotropinoma and Cushing's disease have been reported in detail elsewhere [4]. They showed clinical response after just 3-4 cycles of administration of TMZ with remission of ocular signs, normalization of cortisol alterations, and significant shrinkage (more than 50%) of the tumors, which completely disappeared one year later and, most interestingly, long time (19–30 months) after stopping therapy the patients remained well with no signs of tumor relapse [4].

4. Discussion

Frequency of pituitary tumors appears to be higher than previously suspected, as high as 1 in 1000 of the general population [5, 6]. They are usually benign and in most cases controlled by surgery, radiation, or medical treatments. In 2004 the World Health Organization defined as “atypical” those tumors exhibiting a MIB-1 (Ki-67) proliferative index >3%, strong p53 immunoreactivity, and increased mitotic activity [7]. They make up 15% of resected pituitary tumors [8]. Up to 45% of macroadenomas show signs of invasion of the sphenoid or cavernous sinus [9]. The concept of  “aggressive” pituitary tumors represents a clinical appreciation to designate tumors that may recur quickly after surgery, grow into the cavernous sinus or skull base, and show resistance to the usual therapeutic means. The name pituitary carcinoma is reserved for those tumors with neural or extraneural metastases which make up less than 1% of the totality of pituitary tumors. It has to be emphasized that they do not show histological differences with other aggressive tumors save for the existence of metastases [10].

So called silent pituitary adenomas are tumors, mainly gonadotrope, corticotrope, and somatotrope, having an aggressive behavior, with frequent recurrences which made up 9% in 100 samples studied retrospectively [11]. They can be classified as “silent,” with immunohistochemical evidence but no biochemical or clinical evidence of hormone excess, or “clinically silent” with immunohistochemical and biochemical evidence but no clinical evidence of hormone excess.

Temozolomide is an alkylating drug which has been used mainly in the treatment of glioblastoma multiforme but also for colorectal cancer and melanoma [12–14]. This drug has been used for the treatment of pituitary carcinoma and aggressive adenoma from the year 2006 onwards [2, 3]. Its mechanism of action is through sticking an alkyl group to DNA bases, principally guanine, which induces methylation. Subsequently, it provokes the fragmentation of DNA by repairing enzymes in its attempt to replace the alkylated bases [15]. Up to now, around 105 pituitary tumors treated with TMZ have been reported in the literature with variable results (Table 3) [4, 16–53]. More than half (~60%) were aggressive adenomas, the remaining being pituitary carcinomas. Most were functioning tumors, especially corticotropinomas and prolactinomas (~80%). Global efficacy of TMZ therapy oscillated between 55% for aggressive adenomas and 58% for pituitary carcinomas, but it has to be underlined that criteria for efficacy were quite diverse, going from variable reduction to “stabilization” in tumoral size. It has to be remarked that in none of the reported cases a sustained disappearance of tumor after stopping TMZ was described. As far as aggressive macrocorticotropinomas are concerned, we were able to find 37 published cases silent or with overt hypercortisolism. Once again, criteria employed to evaluate response were quite diverse. In just one of those cases [20], the tumor disappeared under treatment but if the patient was treated with a CAPTEM schema (capecitabine plus temozolomide) we cannot know which one of the two drugs was more effective.

Table 3.

Literature update on aggressive pituitary adenomas and carcinomas.

Author, year 
[reference]		 Sex/age Tumor type Ki67 (%) MGMT TMZ (mg/m2) & schedule (no. cycles) MRI (% shrinkage) Clinical outcome
Thearle et al., 2011 [16] M/50 ACTH SA Ad → Ca → NS 31 NA 200 × 5/28 + CAP (4) Reduced (75) Death
Dillard et al., 2011 [17] M/56 ACTH Ad 5-6 NA 150–200 × 5/28 (4) Reduced (60) CR
Annamalai et al., 2012 [18] M/65 ACTH Ca 5–15 Low 200 × 5/28 (15) PR of METS “Remained well”
Moshkin et al., 2011 [19] M/46 ACTH SA Ad → Ca 1–5 (+) 200 × 5/28 (16) No change Progression
Zacharia et al., 2014 [20] M/50 ACTH Ad <5 (−) 150, 5/28 + CAP (30) SD PR
F/46 ACTH Ad 15–20 (−) 150, 5/28 + CAP (32) CR CR
M/44 ACTH Ad <5 (−) 150, 5/28 (45) + CAP + A-SST CR CR
Raverot et al., 2010 [21] M/31 ACTH Ca → NS 20 50 (+) 150–200 × 5/28 No change NA
M/49 ACTH Ad 20 <1 150–200 × 5/28 No change NA
M/38 ACTH Ca 10 30 (+) 150–200 × 5/28 SR “Significant response”
F/42 ACTH Ad 0.5 0 150–200 × 5/28 SR “Significant response”
M/32 PRL Ca NA NA 150–200 × 5/28 (24) Reduced (60), disappearance of METS NA
M/52 PRL Ad 0.5 30 150–200 × 5/28 (8) No change NA
M/54 PRL Ca 1 0 150–200 × 5/28 (5) No change NA
F/30 PRL Ca 10 100 150–200 × 5/28 (3) No change NA
Bush et al., 2010 [22] NA Null cell Ad <3 — 75 × 21/7 (10) Reduced (20) Stable
NA ACTH Ad 18 <10 75 × 21/28 (11) Reduced (80) “Improved”
NA NF Ad <3 10–50 75 × 21/(13) SD SD
NA Null cell Ad 6 >50 75 × 21/7 (10) SD SD
NA PRL Ad NA <10 75 × 21/7 (11) Reduced (80) “Improved”
NA Null cell Ca >20 >50 75 × 21/7 (2) SD × 2 months NA
NA Null cell Ca >20 <10 75 × 21/7 (7) Progression Death
Hirohata et al., 2013 [23] M/59 NF Ca 74.6 (+) 150–200 × 5/28 (5) PR NA
F/42 ACTH Ca 3.4 (−) 150–200 × 5/28 (7) PR NA
F/60 PRL Ca 18.7 (−) 150–200 × 5/28 (13) CR NA
M/23 NF Ca 2.5 (+) 150–200 × 5/28 (7) SD NA
F/53 ACTH Ca (Crooke cell) 2.0 (+) 150–200 × 5/28 (20) CR NA
F/60 PRL Ca 27.8 (+) 150–200 × 5/28 (12) PR NA
M/57 ACTH Ca 10 (+) 150–200 × 5/28 (8) SD NA
F/73 NF Ca 5.6 (−) 150–200 × 5/28 (22) PR NA
M/60 PRL Ca 40.2 (−) 150–200 × 5/28 (24) PR NA
F/61 NF Ca 12.2 (+) 75 × 6 weeks + RT Progression NA
F/66 PRL Ad 9.4 (−) 75 × 6 weeks + RT CR NA
F/49 PRL Ad 3.9 (−) NA (3) Progression NA
F/45 ACTH Ad (Crooke cell) 46.8 (+) 150–200 × 5/28 (11) PR NA
Losa et al., 2010 [24] M/64 ACTH Ad NA NA 150–200 × 5/28 Progression Death
M/52 ACTH Cd 1 (−) 150–200 × 5/28 “Response” Required GC therapy
F/55 ACTH Ad → NS 5 (−) 150–200 × 5/28 SD NA
F/53 ACTH Ad 2.5 (+) 150–200 × 5/28 Progression No change
M/62 PRL Ad 9 (−) 150–200 × 5/28 SD NA
F/57 PRL Ad NA Noninformative 150–200 × 5/28 “Response” “Improved”
Moyes et al., 2009 [25] F/64 ACTH Ad → NS “High” (−) 200 × 5/28 (6) “Marked shrinkage” “Improved”
Takeshita et al., 2009 [26] F/46 ACTH Ca → NS ~3 <5 (−) 150–200 × 5/28 (23) CR tumor + METS Required GC therapy
Curtò et al., 2010 [27] M/42 ACTH Ca 2–18 <5 (−) 150–200 × 5/28 (17) Reduced (>90) “Improved”
Mohammed et al., 2009 [28] F/43 ACTH Ad NA (−) 150–200 × 5/28 (12) PR “Improved”
M/60 ACTH Ca → NS NA (+) 150–200 × 5/28 (12) PR “Improved”
Bode et al., 2010 [29] NA ACTH Ca → NS NA NA 150 × 5/28 PR NA
Jouanneau et al., 2012 [30] NA SA → Ca NA NA 200 × 5/28 NR NA
Asimakopoulou et al., 2014 [31] F/55 ACTH Ad (Crooke cell) 1 NA 150–200 × 5/28 CR CR
Bengtsson et al., 2015 [32] F/71 ACTH Ad 50 90 150–200 × 5/28 SD NA
F/31 GH Ad 7 9–100 150–200 × 5/28 (6) Reduced (50) Regrowth after TMZ stop
F/13 GH Ad 5 95 150–200 × 5/28 NA NA
M/33 PRL-GH Ad 23 10 150–200 × 5/28 (3) Reduced (35) SD 25 months after TMZ
M/22 PRL Ad 8 90 150–200 × 5/28 (15) Reduced (25) Death
M/34 PRL Ad 6 9–100 150–200 × 5/28 (4) Stable 40 m after TMZ PR
M/45 PRL Ad 2 100 150–200 × 5/28 (5) Progression PR
M/55 PRL Ad 10 20 150–200 × 5/28 (11) Reduced (66) Death
M/60 PRL Ad 2 9 150–200 + CAB (21) Reduced (80) Death
M/68 PRL Ad NA   150–200 × 5/28 Progression Death
M/23 PRL Ad 41 100 150–200 × 5/28 (4) Progression Death
M/22 NF Ad 2 9 150–200 × 5/28 (12) Reduced (55) SD 69 m after TMZ
M/45 NF Ad 2 100 150–200 × 5/28 (18) Reduced (28) NA
F/52 NF Ad 10 90 150–200 × 5/28 (5) Progression Death
M/59 NF Ad 10 90 150–200 × 5/28 (6) Progression Death
M/57 NF Ad 3.3 95 150–200 × 5/28 Progression Death
M/51 ACTH Ca 80 0–60 150–200 × 5/28 NA Death
M/62 ACTH Ca (NS) 10 95 150–200 × 5/28 NA Lost to follow-up
M/70 ACTH Ca 70 9 150–200 × 5/28 NA NA
M/46 GH Ca 60 90 150–200 × 5/28 NA Death
F/40 GH Ca 20 9 150–200 × 5/28 CR CR after 48 months
F/49 PRL-GH Ca 5 9 150–200 × 5/28 CR CR after 91 months
F/32 PRL Ca 20 50 150–200 × 5/28 NA Death
F/59 PRL Ca 10 NA 150–200 × 5/28 NA PR
Vieira Neto et al., 2013 [33] F/54 GH S Ca 2.6 68 150–200 × 5/28 SD NA
Morokuma et al., 2012 [34] M/58 NF Ca/NEM-1 7.6 (−) 75/d × 42 days; then 192 × 5/28 + RT (20) “Visibly declined” “Improved”
Zhong et al., 2014 [35] F/30 NF Ad 20 NA 200/d × 5/4 consecutive weeks/2 months + RT (4) CR NA
Syro et al., 2009 [36] M/70 Gn Ad 2–6 30–>50 200 × 5/28 (6) “Minor reduction” and intratumoral necrosis Death
Hagen et al., 2009 [37] F/48 PRL Ad to mixed PRL-GH Ad to Ca 5 (−) 150–200 + CAB/STT-A Reduced (62) “Improved”
M/60 PRL Ad ~2 (−) 150–200 + CAB Reduced (80) “Improved”
M/20 NF Ad ~2 Few (+) 150–200 Reduced (55) “Improved”
Mendola et al., 2014 [38] M/58 NS Ca 10 NA 160 × 5/28 (1) No No change
Strowd et al., 2015 [39] F/44 PRL Ad NA NA 150–200 × 5/28 (3 months) “Reduction in tumor size” PR
Ceccato et al., 2015 [40] F/67 NF Ad <3 NA 150–200 × 5/28 Progression No change
F/39 GH Ad <3 NA 150–200 × 5/28 Progression No change
M/40 NF Ad <3 NA 150–200 × 5/28 Decreased (49) NA
M/32 ACTH Ad <3 NA 150–200 × 5/28 Decreased (63) No change
M/47 NF Ad → ACTH <3 NA 150–200 × 5/28 + pasireotide Decreased (21) No change
Philippon et al., 2012 [41] M/41 PRL Ca/MEN-1 NA NA 200 × 5/28 (24) Decreased (62) “Improved”
Fadul et al., 2006 [42] M/38 NF Ca 1 NA 200 × 5/23 (12) PR PR
M/26 PRL Ca 10   200 × 5/23 (10) PR PR
Kovacs et al., 2007 [43] M/46 PRL Ca 40–60 NA 200 × 5/28 (7) “Shrinkage” “Improved”
Cornell et al., 2013 [44] M/40 ACTH Ad 5–7 NA 200 × 5/28 (3) Progression No change
Phillips et al., 2012 [45] M/25 PRL Ad 23 NA 350 × 5 (1) No change Death
Rotondo et al., 2012 [46] F/49 Crooke cell Ad 5–8 (−) 85 p.o daily + SRT NA NA
Arnold et al., 2012 [47] F/61 ACTH Ca NA NA NA (12) “Resolved” PR
Morin et al., 2012 [48] M/22 GH Ad 3-4 NA 200 × 5/28 (5) No change Increased signs
Whitelaw et al., 2012 [49] M/34 PRL Ad 15 (−) 200 × 5/28 (6) “Dramatic reduction” “Significant improvement”
M/32 PRL Ad 8 (−) 200 × 5/28 (6) “Substantial reduction” “Significant improvement”
M/13 PRL Ad 4 (−) 200 × 5/28 (12) PR PR
Ersen et al., 2012 [50] NA Gn Ad NA Two zones: (−) and (+), 60% 200 × 5/28 (14) SD “Clinical improvement”
Scheithauer et al., 2012 [51] F/13 months Pituitary blastoma NA Varied from 40 to 60% 100 × 5/28 (12 + 6) Progression NA
Ortiz et al., 2012 [52] M/38 ACTH Ad → Ca NA High 200 × 5/28 (8) No change Progression
Batisse et al., 2013 [53] M/47 GH Ad (−) High 200 × 5/28 (3) Progression No significant response
Bruno et al., 2015 [4] F/52 ACTH Ad 6 (−) 150–200 × 5/28 (29) CR CR
F/42 ACTH Ad 4 (−) 150–200 × 5/28 (12) CR CR
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Ad: adenoma; Ca: carcinoma; SA: silent adenoma; NS: Nelson's syndrome; NF: nonfunctioning; PRL: lactotrope; ACTH: corticotrope; GH: somatotrope; Gn: gonadotrope; MRI: magnetic resonance imaging; NA: not available; RT: radiotherapy; CR: complete response; PR: partial response; SR: “significant” reduction; METS: metastases; SD: stable disease; CAB: cabergoline; STT-A: somatostatin agonist; CAP: capecitabine; →: change; (og): ongoing.

Doses of temozolomide usually recommended in neurology are adapted to body surface and oscillate from 150 to 200 mg/m2 [54]. Doses employed in our patients were variable, but generally lower than recommended. It has to be underlined that dose amount was mostly determined by availability following individual medical coverage. Interestingly, patients MC and GM who had total remission received fixed doses of 250 mg/d and 180 mg/d, respectively, while, if adapted to body surface area, those figures should have been 291–388 mg/d for MC and 273–364 mg/d for GM. The role that the DNA repairing systems may play in the effectiveness of temozolomide is controversial, especially concerning MGMT. This enzyme can reverse methylation of the guanine residues, thus antagonizing the effect of the drug. It has been reported that a low expression or the absence of this enzyme strongly correlates with the response to TMZ [15]. This has been challenged by other authors, who failed to find such a correlation [21, 23]. It has been proposed that the preservation of another enzyme system, MSH6 (DNA mismatch repair protein), correlated better with the response to TMZ than the absence of MGMT [23, 54].

In our series, the five patients in whom we were able to measure MGMT failed to show a significant expression (less than 5%); two of them having aggressive corticotropinoma had excellent clinical responses to temozolomide. Nevertheless, this does not enable us to extrapolate any conclusions at this respect, since two other MGMT-negative patients who completed the minimum period of treatment failed to show a response.

For a more rational use of TMZ several points deserve clarification: What should be the starting and maintenance doses? How can efficacy be defined? How long should the treatment be given? How big is the mutagenic risk? What is the recurrence risk after stopping TMZ? What is the probability of relapse with resistance to TMZ after stopping a successful therapy?

In conclusion, although less common, clinically aggressive pituitary tumors are not at all exceptional and pose special therapeutic challenges because surgery and radiotherapy are frequently useless and usual drug therapy is of variable and unpredictable efficacy. So called “silent” tumors appear to be particularly aggressive and, although less frequent, invasive corticotropinomas may present a difficult challenge as well, since besides local complications, they put life at risk because of the metabolic consequences of excess cortisol secretion. Temozolomide may be a salvage drug in selected cases, mainly in prolactinoma and corticotrope tumors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be of the outmost importance to establish the indications, doses, and duration of temozolomide administration.

Acknowledgments

The authors are deeply indebted to Drs. Mariano Volpacchio and Santiago Rossi, from the Centro de Diagnóstico Dr. Enrique Rossi, Buenos Aires, who generously provided gratuitous control MRI in patient MC.

Disclosure

This paper was presented in part at The Endocrine Society Annual Meeting, Phoenix, AZ, 2013.

Conflict of Interests

The authors declare that they have no conflict of interests.

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