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Keywords:

  • temozolomide;
  • pituitary carcinoma;
  • pituitary adenoma;
  • O6-methylguanine-DNA methyltransferase;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had high-level MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011. © 2010 American Cancer Society.

Clinically, aggressive pituitary adenomas are difficult to manage. A significant number of patients with these adenomas have invasion of bone, dura, and/or adjacent structures, thus complicating or precluding their resection.1 Patients with aggressive pituitary adenomas present with problems caused largely by incomplete resection, recurrence, and associated morbidity.2 Repeated surgeries, pharmacologic treatments, and radiotherapy are used, but many patients experience tumor regrowth.3, 4 Functional adenomas, particularly prolactin (PRL)-producing and growth hormone (GH)-producing tumors, may become resistant to medical therapy, thereby necessitating multiple surgical procedures. Radiotherapy and even conventional chemotherapy are used in an attempt to control tumor growth, but the results often are disappointing.5

Pituitary carcinomas are rare. Their large size, invasiveness, and craniospinal or systemic metastases represent particular diagnostic and therapeutic challenges.6-9 Progression of disease after a diagnosis of pituitary carcinoma is variable but often inexorable. Multiple treatment approaches, including surgery, external-beam radiotherapy, radiosurgery, adjuvant pharmacologic treatment, and various chemotherapeutic regimens, generally are palliative at best and achieve only temporary local control.8 Fully 75% of patients with systemic metastasis and 66% of all patients die of disease within 1 year of presenting with disease spread.9 Recent publications have reported the use of temozolomide in the treatment of aggressive pituitary adenomas and carcinomas2, 10-25 (unpublished results). These form the basis of our review.

Temozolomide

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

Temozolomide is a second-generation alkylating chemotherapeutic agent that is related to a series of imidazotetrazines that were synthesized in 1987.26, 27 Orally administered, it readily crosses the blood-brain barrier. At physiologic pH, it undergoes rapid chemical conversion to methyl-triazeno-imidazole-carboxamide, the active drug.28 This exerts its cytotoxic effect through methylation of deoxyribonucleic acid (DNA) at the O6 position of guanine,29 which then mispairs with thymine during the next cycle of DNA replication. The sequence of mismatch-repair events initiated leads to apoptosis. One advantage of temozolomide is that it is not cell cycle-specific; thus, it inhibits all phases of tumor cell growth. Consequently, the agent is ideal for the treatment of relatively slow-growing pituitary tumors.17

Temozolomide is accepted as an essential component of adjuvant therapy in the treatment of glioblastoma multiforme and other tumors of the central nervous system.30-32 Recent reports indicate its efficacy in advanced-stage, malignant neuroendocrine neoplasia33, 34 and in melanoma.35

The standard therapeutic dose of temozolomide is 150 to 200 mg/m2 daily for 5 of every 28 days. Temozolomide absorption is minimally affected by food. The most common nonhematologic adverse effects include nausea, vomiting, fatigue, headache, and constipation. Generally, these are mild to moderate in severity. Hematologic toxicities (ie, neutropenia and thrombocytopenia) are observed but occur in <10% of patients.30

MGMT is a DNA repair protein that reverses alkylation at the O6 position of guanine by transferring the alkyl group to a sulfur group of cysteine within its sequence.36 It plays the role of removing alkylating adducts induced by temozolomide treatment, thereby counteracting its antineoplastic action.37, 38 It appears that high tumor expression of MGMT confers resistance to temozolomide. It is widely believed that low-level expression in a wide spectrum of human tumors results from epigenetic silencing of the MGMT gene, largely because of hypermethylation of its promoter.39-41 Low-level MGMT expression results in the accumulation of guanine-to-adenosine transition mutations and also furthers genomic instability.42, 43 However, it is a predictive marker of a favorable outcome in patients with temozolomide-treated glioblastomas.44-47 Temozolomide also reportedly enhances radiation responsiveness in MGMT-negative human glioblastoma cell lines.48

Pituitary Carcinomas

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

Pituitary carcinomas are difficult to manage because of their relentless growth and metastatic spread despite multimodality therapy. The latter treatments include repeat surgery, pharmacologic manipulation, radiotherapy, and chemotherapy.49, 50 Various combinations, such as cis-platinum, etoposide, and/or paclitaxel, have not achieved sustained responses.8

Fadul et al12, 13 first reported the successful use of temozolomide in pituitary carcinomas in 2004. Their 2 patients, 1 patient who had systemic metastases of a luteinizing hormone (LH)-producing (gonadotropic) pituitary carcinoma and 1 patient who had a prolactin (PRL)-producing (lactotrophic) carcinoma with spinal dissemination, were treated, and both achieved a sustained response. Thereafter, Zhu et al25 and Lim et al17 administered temozolomide to a patient who had a PRL-producing pituitary carcinoma. In these first 3 patients, persistent, significant clinical and biochemical improvement as well as substantial radiographic tumor shrinkage were noted.

To date, 6 patients with pituitary carcinomas have received treatment with temozolomide10, 12-14, 17, 19, 23-25 (Table 1). These included 4 men and 2 women ages 26 to 77 years (mean, 49.8 years). The time between disease presentation and temozolomide administration was 7 to 23 years (mean, 11.8 years). The group included 4 PRL-producing carcinomas, 1 LH-producing carcinoma, and 1 adrenocorticotropic hormone (ACTH)-producing carcinoma of the Crooke cell type in the setting of Nelson syndrome. All patients exhibited clinical and radiologic responses to temozolomide. Assessment of MGMT immunoexpression was performed in only 3 patients, and all 3 had low expression levels.

Table 1. Pituitary Carcinomas Treated With Temozolomide
PatientReference(s)TumorAge, ySexTime From Disease Onset to TMZ Treatment, yPrevious RTNo. of Previous SurgeriesResponseTreatmentFollow-UpMGMT Expression
  1. TMZ indicates temozolomide; RT, radiotherapy; PRL, prolactin; LH, lutenizing hormone; CCA, Crooke cell adenoma; ACTH, adrenocorticotropic hormone.

1Lim 2006,17 Zhu 200425PRL carcinoma72Man12Yes3Yes18 Mo
2Fadul 200613LH carcinoma38Man8Yes2Yes12 Cycles16 Mo; free of disease
3Fadul 200613PRL carcinoma26Man7Yes2Yes10 Cycles15 Mo; free of disease
4Byrne 2009,10 McCormack 200919PRL carcinoma64Man23Yes; ×26Yes12 MoControlledLow
5Hagen 200914PRL carcinoma48Woman8.5Yes1Yes23 MoFree of disease ≥3 yLow
6Takeshita 200924CCA, ACTH carcinoma46Woman9Yes; gamma ×33YesMonthly for 1 y; bimonthly for 2 yGood at 2 y 3 moLow

Pituitary Adenomas

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

In 2006, the first patient with a temozolomide-treated pituitary adenoma was reported.15, 23 The patient was a man aged 42 years with a PRL-producing adenoma who had undergone 5 previous surgeries. He had received not only radiotherapy but also bromocriptine, pergolide, and cabergoline treatment, and none of those treatments had any effect on the growth of his tumor. When temozolomide treatment was administered, the PRL levels decreased immediately. After 8 cycles of treatment, a magnetic resonance imaging (MRI) scan disclosed tumor hemorrhage and necrosis. The patient underwent an additional surgery at which the tumor was resected easily given its friable and soft consistency. Histologic, immunohistochemical, and ultrastructural investigations revealed significant differences from the previously resected tumor that was not treated with temozolomide.

Neff et al21 reported a patient who had an invasive prolactinoma that was resistant to dopamine agonists but was quite responsive to temozolomide treatment. The PRL level dropped over the course of treatment, and an MRI scan revealed marked tumor shrinkage, precluding yet another surgery. Tumor size and PRL level in that patient continued to be stable after 26 months of treatment.

Kovacs et al16 reported a patient aged 41 years who had an aggressive, silent, subtype 2 corticotrophic adenoma with no morphologic changes after temozolomide treatment. MGMT immunoexpression was positive. Based on these results, those authors suggested that MGMT immunoexpression may predict responsiveness to temozolomide therapy.

Fully 10 more patients with pituitary adenomas have received treatment with temozolomide2, 10, 11, 14, 19, 20, 22 (unpublished results), bringing the current total to 13 patients, including 9 men and 4 women ages 20 to 61 years (mean, 47.9 years) (Table 2). Aside from 1 incidentally discovered tumor in a patient with concomitant glioblastoma multiforme, all tumors have been studied morphologically. The group includes 4 PRL-producing tumors (30%), 3 ACTH-producing tumors (23%), 2 nonfunctioning pituitary adenomas, 1 silent subtype 2 adenoma, 1 GH-producing adenoma, 1 gonadotroph adenoma with oncocytic features, and 1 null cell adenoma of the oncocytic type. The time elapsed from the clinical onset of disease to the beginning of temozolomide treatment ranged from 2 years to 23 years (mean, 11.8 years). Eleven of the 13 tumors (87%) had been irradiated previously, except for the incidentally discovered tumor. The latter tumor lay outside the radiation treatment field. All other patients underwent at least 1 surgery (range, 1-7 surgeries; mean, 3 surgeries).

Table 2. Pituitary Adenomas Treated With Temozolomide
PatientReference(s)TumorAge, ySexTime From Disease Onset to TMZ Treatment, yPrevious RTNo. of Previous SurgeriesResponseTreatmentFollow UpMGMT
  1. TMZ indicates temozolomide; RT, radiotherapy; PRL, prolactin; MI, myocardial infarction; ACTH, adrenocorticotropic hormone; NFPA, nonfunctioning pituitary adenoma; GH, growth hormone.

1Syro 200623PRL46Man15Yes5Yes8 Cycles, +surgery, +24 cyclesDead. 2 y; MILow
2Neff 200721PRL52Woman15Yes+gamma1Yes26 MoControlled
3Kovacs 200816Silent ACTH41Man20Yes4No8 Cycles, +surgery, +16 cycles, +surgery, +6 cycles, +surgeryCervical metastases, recurrenceHigh
4Moyes 200920Nelson syndrome, ACTH64Woman6Yes1Yes6 CyclesNo dataLow
5Mohammed 20092ACTH43Woman2Yes3Yes16 MoFree of diseaseLow
6Mohammed 20092ACTH, Nelson60Man2Yes2Yes; progression12 MoMetastasis 4 mo after stopping TMZIntermediate
7Mohammed 20092NFPA, incidental, glioma28Woman0No0Yes10 MoControlled
8McCormack 200919GH54Man6Yes4No3 CyclesDeadHigh
9Debono 200811PRL47Man23Yes+gamma1Yes11 CyclesRecurrence 1 y after treatment; TMZ restartedLow
10Syro 200922Oncocytoma61Man18Yes4Yes6 CyclesDead; pulmonary thromboembolismIntermediate
11Syro (unpublished results)Oncocytoma47Man23Yes4Yes4 CyclesImproved; in treatmentIntermediate
12Hagen 200914PRL60Man19No1Yes12 Cycles12 mo after treatmentLow
13Hagen 200914NFPA20Man5Yes6Yes15 CyclesIn treatmentIntermediate

MGMT immunoexpression was documented in 11 of the 13 patients and was high in 2 patients, intermediate in 4 patients, and low in 5 patients. The 2 patients with high MGMT expression had no response to temozolomide (1 patient with a silent corticotrophic adenoma subtype 2 and 1 patient with a GH-producing adenoma). One of the tumors with intermediate MGMT expression recurred when temozolomide therapy was stopped; whereas, in 5 patients who had low MGMT immunoexpression, the response was favorable.

Morphologic Changes

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

Syro et al23 and Kovacs et al15, 16 published the only morphologic comparisons of pathology before and after temozolomide treatment. In those studies, operative findings included tumor softening and friability, both of which facilitated resection at reintervention. The temozolomide-treated tumor had better differentiation and consisted of larger cells, exhibited fewer mitoses, and had a lower Ki-67 labeling index. Tumor hemorrhage, necrosis, focal fibrosis, and neuronal transformation also were observed,30 and MGMT immunoexpression was lacking entirely.

Post-treatment, the PRL-producing adenoma exhibited necrosis, edema, hemorrhage, accumulation of connective tissue, inflammatory infiltrates, larger/more differentiated tumor cells, and neuronal transformation. The Ki-67 labeling index had decreased (from 40%-60% pretreatment to 5% thereafter). There also was a corresponding reduction in mitotic activity (from 11 of 1000 nuclei to 2 of 1000 nuclei).15 Predictably, in the MGMT-positive, silent, subtype 2 corticotrophic adenoma, no such alterations were produced.16

Radiographic Changes

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

Three patterns of radiographic change have been observed on MRI images from patients who had a good response to temozolomide treatment. These included tumor necrosis and hemorrhage,15, 23 tumor degenerative and cystic changes,22 and tumor shrinkage.2, 10, 11, 14, 19-21, 24 These changes could be observed as early as 2 months after the onset of temozolomide treatment.

Clinical Response

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

In all reported temozolomide-responsive tumors, the clinical response has been rapid and has been associated with decreased chiasmatic compression and mass effects. In the patients with functional (PRL-producing and ACTH-producing) tumors, an almost immediate reduction in plasma hormone values became apparent after the commencement of therapy (Tables 1 and 2).

MGMT Immunoexpression

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

Kovacs et al were the first to report the inverse relation between MGMT immunoexpression and temozolomide response in 2 patients with aggressive adenomas.16 Their observations were confirmed subsequently by McCormack et al, who assessed MGMT reactivity in a PRL cell carcinoma and an aggressive growth hormone-producing adenoma.19 In both studies, tumors with low MGMT expression demonstrated a clinical and radiologic response to temozolomide therapy, whereas tumors with high MGMT expression were resistant. Two additional case reports of invasive, ACTH-producing adenomas with low-level MGMT expression also demonstrated the corresponding efficacy of temozolomide therapy.2, 20 Thus, determining the level of MGMT immunostaining appears to be useful for predicting the response of aggressive pituitary adenomas and carcinomas to temozolomide.2

The reports of Kovacs et al16 and McCormack et al19 underscored the inverse relation between MGMT immunoexpression and the efficacy of temozolomide therapy, a relation that also has been noted in high-grade gliomas.51, 52 Whereas the standard method of evaluating MGMT status is the identification of promoter methylation, the detection of MGMT expression by immunohistochemistry presents an attractive alternative. It represents inexpensive, readily accessible technology that is available to most laboratories.53 Most available data pertaining to gliomas and temozolomide therapy are based on an analysis of the methylation status of the MGMT promoter, whereas data pertaining to pituitary neoplasms are based simply on immunohistochemistry for MGMT expression.

To date, MGMT immunoexpression has been documented in 3 carcinomas and 11 adenomas (Table 3). In 8 tumors, including 3 carcinomas and 5 adenomas, MGMT expression was low and was correlated with a good therapeutic response to temozolomide. In 4 adenomas, MGMT staining was intermediate; 3 of those patients responded well, and the other patient had tumor progression when treatment was discontinued. High MGMT immunoexpression in 2 adenomas was not associated with a therapeutic response. Thus, patients who had tumors that featured low and intermediate MGMT immunoexpression (n=12), compared with those who had tumors with high MGMT immunoexpression (n=2), had a good response to temozolomide treatment (11 of 12 patients [91.6%] vs 0 of 2 patients [0%]; P = .03; 2-tailed Fisher exact test).

Table 3. O6-Methylguanine-DNA Methyltransferase Immunoexpression and Response to Treatment With Temozolomide in Pituitary Carcinomas and Adenomas
Reference(s)TumorResponseMGMT Expression
  1. MGMT indicates O6-methylguanine-DNA methyltransferase; PRL, prolactin; ACTH, adrenocorticotropic hormone; GH, growth hormone.

Byrne 2009,10 McCormack 200919PRL carcinomaYesLow
Hagen 200914PRL carcinomaYesLow
Takeshita 200924ACTH carcinomaYesLow
Syro 200623PRLYesLow
Moyes 200920ACTH, Nelson syndromeYesLow
Mohammed 20092ACTHYesLow
Debono 200911PRLYesLow
Hagen 200914PRLYesLow
Mohammed 20092ACTH, Nelson syndromeYes/progressionIntermediate
Syro 200922OncocytomaYesIntermediate
Syro 2009 (unpublished results)OncocytomaYesIntermediate
Hagen 200914Nonfunctional adenomaYesIntermediate
Kovacs 200816Silent ACTHNoHigh
McCormack 200919GHNoHigh

PRL-producing and ACTH-producing tumors most frequently had low MGMT expression (Table 3). McCormack et al also observed that prolactinomas accounted for >60% of tumors with low-level MGMT expression.19 Of the reported cases, 4 of 11 pituitary adenomas11, 14-16, 23 and 4 of 6 pituitary carcinomas10, 13, 14, 25 that were responsive to temozolomide were the PRL-producing type (Tables 1 and 2), in keeping with the finding by McCormack et al that prolactinomas had a propensity for low-level MGMT expression compared with other tumors.19 Also noteworthy is the study by Takeshita et al24 of 7 invasive Crooke cell adenomas, a morphologic variant of corticotrophic adenomas; of these, 5 had low MGMT expression compared with 1 of 17 conventional ACTH-producing adenomas.

Two studies focused on MGMT immunoexpression in both primary and recurrent tumors.19, 53 McCormack et al19 observed no significant differences between recurrent and nonrecurrent tumors. Widhalm et al53 assessed MGMT immunohistochemistry in 45 nonfunctioning pituitary adenomas, including 24 progressive/recurrent tumors and 21 control specimens from patients who were tumor free postoperatively, and reported that 12 of 24 progressive/recurrent tumors (50%) had low MGMT expression compared with 5 of 21 tumors in the control group (24%). A greater proportion of recurrent tumors in that study had <10% MGMT immunoreactivity, and a 25% reduction in MGMT expression was observed between the first and last surgeries. Although these differences were not statistically significant, they suggest that half of patients who have recurring, nonfunctioning pituitary adenomas are potential candidates for temozolomide treatment.

Reduced MGMT immunoexpression in recurrent tumors may correlate with a change in its behavior. During tumorigenesis, loss of MGMT expression and impaired capability of DNA repair have been observed.37, 38, 41 In contrast, MGMT overexpression has prevented carcinogenesis in mouse models.37 In low-grade astrocytomas, lack of MGMT expression has been considered a marker of malignant transformation.54 The issue of promoter methylation of the MGMT gene is important for diminished MGMT function. It has been demonstrated that, in pituitary tumors, promoter methylation is a frequent event.55, 56 Bello et al57 reported that MGMT was methylated at significant rates in both functional and nonfunctional adenomas. This epigenetic alteration may disrupt the key cellular functions of MGMT and contribute to pituitary adenoma development. In this vein, a change in MGMT expression in recurring tumors could affect adenoma progression, recurrence, and aggressive behavior.

Suggested Indications for Temozolomide Treatment

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

On the basis of published cases, suggested and possible indications for treating patients with temozolomide include the following:

  • 1
    Patients with aggressive, PRL-producing tumors that are resistant to bromocriptine or cabergoline and undergo continued growth after surgery and radiotherapy;
  • 2
    Aggressive, ACTH-producing tumors, especially the Crooke cell and Nelson syndrome variants, that are not cured by surgery and radiotherapy;
  • 3
    Recurrent, nonfunctional tumors that exhibit continued growth after repeated surgeries and radiotherapy;
  • 4
    Recurrent, regrowing tumors that have undergone repeat surgeries and radiotherapy with unsuccessful resection because of hard, fibrous consistency of the tumor (in such tumors, temozolomide could serve to soften the lesion before another attempt at resection); and
  • 5
    Pituitary carcinomas.

Future Directions

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

In recurrent, aggressive pituitary adenomas and carcinomas that are resistant to multimodality therapy, radiotherapy, pharmacologic manipulation, and multiple conventional chemotherapy, the assessment of MGMT immunoexpression may serve as a predictor of response to temozolomide. If MGMT expression is low, then a dramatic response can be anticipated. If MGMT expression is high, then therapeutic alternatives can be used in an effort to improve outcome.

For example, depletion of MGMT has been proposed as a means of improving tumor response to temozolomide. Experimental and clinical data have demonstrated that temozolomide response is schedule-dependent and that alternative dosing regimens may enhance its efficacy.58, 59 Temozolomide can be administered on a continuous, daily, metronomic schedule as well, thus producing more MGMT depletion and improving response to treatment: The dose is 50 mg/m2 daily without interruption.

Furthermore, it has been demonstrated that pseudosubstrates of MGMT, such as O6-benzylguanine or lomeguatrib (O6-[4-bromothenyl]guanine), can deplete MGMT levels in tumors with high MGMT expression, thus enhancing the therapeutic effect of alkylating agents.60, 61 At therapeutic levels, O6-benzylguanine renders the tumor cells more sensitive to the alkylating agent and establishes its potential therapeutic effect as an enhancer of drug effect. In gliomas, it has been used with negative results.62

Conclusion

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

Temozolomide has demonstrated value in the treatment of aggressive pituitary adenomas and carcinomas. The clinical and radiologic responses are encouraging. Clearly, there is an inverse correlation between MGMT immunoexpression and therapeutic response to temozolomide. In our literature review, a significant proportion of pituitary neoplasms that were responsive to temozolomide featured low MGMT immunoexpression, whereas the only 2 nonresponders had tumors with high-level MGMT expression. Immunohistochemistry for MGMT appears to be a promising method for guiding therapeutic decision-making and predicting the therapeutic response to temozolomide.19, 53 The molecular mechanisms that affect MGMT expression remain to be fully elucidated. Targeted modulation of MGMT may be useful in patients who otherwise may not respond to temozolomide therapy. Future therapies that change dosing regimens or that use pseudosubstrates may improve tumor responsiveness to temozolomide.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES

We are grateful to the Jarislowsky and Lloyd Carr Harris Foundations for their continuous support. We thank Mrs. Michelle Lemke and Mrs. Denise Chase of Mayo Clinic for their assistance and secretarial support. Dr. Syro thanks Mr. Jesus Rodriguez for his support.

REFERENCES

  1. Top of page
  2. Abstract
  3. Temozolomide
  4. Pituitary Carcinomas
  5. Pituitary Adenomas
  6. Morphologic Changes
  7. Radiographic Changes
  8. Clinical Response
  9. MGMT Immunoexpression
  10. Suggested Indications for Temozolomide Treatment
  11. Future Directions
  12. Conclusion
  13. Acknowledgements
  14. CONFLICT OF INTEREST DISCLOSURES
  15. REFERENCES