16   Chemotherapy Options for Sellar and Parasellar Tumors

Pituitary Carcinomas

Pituitary carcinomas are extremely rare and aggressive tumors, accounting for only 0.1 to 0.2% of all pituitary tumors.1–3 The hallmark of these tumors is concomitant metastasis, either outside the CNS or in noncontiguous foci within the CNS.

The mainstay of the treatment of pituitary carcinoma remains surgery, with either conventional or focused adjuvant radiation therapy modalities that have been well discussed in other chapters of this book. However, when the tumor is a carcinoma, disease generally progresses despite these interventions. Cytotoxic chemotherapy is usually employed as a last resort, and several single case reports and small series of pituitary carcinomas treated with chemotherapy have been published^2,4–18 (Table 16.1).

Temozolomide

Temozolomide (TMZ) is an imidazotetrazine derivative that acts as a DNA-methylating agent. It is absorbed rapidly after oral administration and crosses the blood-brain barrier.20 TMZ in addition to radiation therapy is the standard treatment for glioblastoma (GBM).^21,22 The effect of TMZ depends on methylation of a specific guanine in DNA. MGMT (O-6-methylguanine-DNA methyltransferase) is a DNA repair enzyme removing the alkyl group from the guanine.^23,24 A high level of expression of MGMT in gliomas implicates a poor response to TMZ.²³ McCormack et al, analyzing MGMT expression in 88 pituitary tumor samples, found low MGMT expression in only 13% of the cases and did not find a significant difference between MGMT expression in invasive and noninvasive tumors, or in recurrent and nonrecurrent tumors.²⁵

TMZ is usually administered at a dose of 200 mg/m² per day for 5 days in cycles of 28 days, as for high-grade gliomas. Recently, a multicenter Phase II study by the Spanish Neuro-Oncology Group using extended-schedule dose-dense TMZ in refractory gliomas (85 mg/m² per day for 21 consecutive days in 28-day cycles until disease progression or unacceptable toxicity) showed activity deserving further evaluation in larger cohorts.²⁶ The rationale for the protracted schedule is the continuous depletion of MGMT, enhancing the cytotoxicity of TMZ.^27,28

Fadul et al in 2004 reported in abstract form two cases of pituitary carcinoma that responded partially to TMZ. The first patient, who had a prolactin-secreting tumor, received 10 cycles of TMZ with reduction of prolactin levels and control of pain caused by metastasis to the cervical and thoracic spine; treatment was stopped secondary to persistent fatigue. The second patient, who had a nonsecreting pituitary carcinoma and local invasion plus multiple drop metastases to the cervical and thoracic spinal cord, received 12 cycles of TMZ with improvement of visual fields and magnetic resonance imaging (MRI) showing reduction of the metastasis volume until treatment was discontinued secondary to lymphopenia.²⁹ Also in 2004, Zhu et al reported the successful use of TMZ in a patient with refractory malignant prolactinoma.³⁰

Another reported case summarized the course of a 72-year-old man who had a prolactin-secreting pituitary carcinoma treated with TMZ during 24 months, with stabilization of his prolactin levels, marked reduction of the size of the cerebellopontine angle and cervical metastatic deposits, and a remarkable functional recovery.³¹ Kovacs et al reported a case of a prolactin-secreting pituitary carcinoma treated with TMZ with decrease of serum prolactin levels and clinical improvement.³² Kovacs et al also demonstrated hemorrhage, necrosis, fibrosis, and shrinkage in the tumor after TMZ treatment. Neuronal transformation was also seen, a process described in various tumor types including pituitary adenomas, mainly growth hormone (GH)–producing tumors.^33,34 The cause of the neuronal transformation is unknown, and the authors believe that TMZ may act similarly to nerve growth factor, causing neuronal metaplasia, which is the transformation of pituitary tumor cells to nerve cells.

Hagen et al reported two patients with invasive pituitary macroadenoma and one patient with pituitary carcinoma treated with TMZ who experienced a significant decrease in tumor volume, hormone hypersecretion, and symptoms. All three patients were tested for MGMT expression; this was negative in two patients, and only a few nuclei stained positive in the third patient, potentially explaining the favorable treatment response.24

Neffet al reported a patient who had an invasive prolactinoma treated with TMZ, with marked decrease and stabilization of the prolactin levels and continuous tumor bulk reduction on follow-up imaging over 26 cycles of TMZ.³⁵

Moyes et al reported a case of a patient with Nelson syndrome, an aggressive ACTH-secreting macroadenoma, in addition to high levels of ACTH and skin hyperpigmentation, treated successfully with TMZ. The ACTH levels fell from 2472 to 389 pmol/L, and follow-up imaging confirmed marked shrinkage of the tumor after 4 cycles of TMZ.³⁶ Immunostaining was negative for MGMT, again perhaps explaining the favorable tumor response.

Mohammed et al published three cases of aggressive pituitary macroadenomas treated with TMZ. The first two patients had ACTH-secreting macroadenomas of the Crooke’s cell variant, and the third patient harbored GBM with an incidental pituitary tumor. The first two patients had radiologic evidence of tumor shrinkage and clinical improvement during treatment. One of these patients had a diagnosis of Nelson syndrome. The third patient underwent radiation therapy and TMZ for GBM, and pituitary tumor reduction was also noticed on follow-up scans, with collapse of the suprasellar component into the sella despite the sellar area not having been included in the radiation treatment field.³⁷

Recently, Thearle et al reported a patient with an invasive ACTH-secreting macroadenoma who failed conventional treatment and developed rapid tumor growth leading to the compromise of multiple cranial nerves. This patient was treated with a combination of TMZ and capecitabine (Xeloda), with a marked tumor burden reduction and a decrease in ACTH levels of more than 90%. The tumor recurred after 5 months with a hypermetabolic positron emission tomography (PET) scan, suggesting transformation into a more aggressive histology.³⁸ Capecitabine is an oral chemotherapeutic agent that is converted to 5-fluorouracil (5-FU) in vivo by the enzyme thymidine phosphorylase.³⁹ 5-FU is metabolized to 5-dUMP, which produces a deficiency of thymidylate by inhibiting thymidylate synthase (TS). This leads to a decrease in DNA synthesis and inhibition of cell division by reducing the conversion of UMP to dTMP by TS, leading to thymidylate deficiency. TMZ causes DNA damage at any point in the cell cycle through base pair mismatch of O-6-methylguanine with thymidine in the sister chromatid instead of cytosine, which arises because the mismatch repair enzymes misread the methylated guanine as an adenosine and place thymidine in the sister chromatid. The basis of the use of capecitabine for 10 days before the addition of TMZ is that decreased thymidine levels intracellularly accentuate the mismatch repair process leading to a break in DNA, which is a potent stimulus for apoptosis.^38,39

Bush et al reported a retrospective series of seven patients with aggressive pituitary tumors treated with TMZ.⁴⁰ MGMT promoter methylation and MGMT expression in 14 surgical specimens from these seven patients were compared and correlated with the clinical response to TMZ. Clinically significant tumor reduction was observed in two patients, a 20% tumor reduction in one, stable disease in three, and progressive metastatic disease in one patient. The DNA promoter site for MGMT was unmethylated, and variable amounts of MGMT expression were seen in all 14 specimens. The authors could not find any correlation between MGMT expression and clinical outcomes but concluded that TMZ is a valuable alternative in the management of aggressive pituitary tumors.

Laws et al in 2003 published the results of a Phase I study of transsphenoidal post-resection implantation of Gliadel wafers in nine patients with aggressive pituitary adenomas.⁴¹ Gliadel is a polymer wafer impregnated with BCNU (bis-chloroethyl-nitrosurea), an alkylating agent, designed to capitalize on the concept of delivering local treatment to brain tumors, avoiding the toxic effects of systemic treatment and bypassing the blood-brain barrier.^42,43 Three patients were disease-free after a mean follow-up of 19 months, two had stable residual disease, one had disease progression, two patients died secondary to disease progression, and one died because of a stroke. The study concluded that Gliadel implantation into the sella turcica for aggressive pituitary tumors is safe.⁴¹ No further studies of this agent in pituitary adenomas have been reported.

With respect to ongoing studies, presently there is one Phase II study evaluating the safety and efficacy of TMZ in the treatment of invasive pituitary tumors (NCT00601289). In addition, there is one study investigating the use of lapatinib in slowing the growth rate of pituitary tumors. Lapatinib is an FDA-approved drug used to treat breast cancer and has been shown to inhibit both epidermal growth factor receptor (EGFR) and erbB2 tyrosine kinases, which are overexpressed in pituitary adenomas.

Craniopharyngiomas

Craniopharyngiomas are benign tumors of the sellar and parasellar region that may be solid, cystic, or a combination of the two. Their treatment poses a challenge because the tumors are difficult to completely resect, and recurrence, even in instances of presumed gross total resection, is common. Craniopharyngiomas are the most common suprasellar tumor in the pediatric age group and the most common nonglial primary intracranial tumor in children.44,45

The treatment of craniopharyngiomas is multidisciplinary, involving surgical resection by craniotomy or the transsphenoidal route, fractionated radiation therapy, and radiosurgery for residual tumor.⁴⁴ In patients with primarily cystic tumors, recurrent tumors, and/or tumors with a difficult surgical approach, and in young patients, for whom postponing more aggressive treatment such as radiation therapy or surgery is desirable, the use of intracavitary bleomycin has a role.⁴⁶ Bleomycin, an antibiotic produced from the fungus Streptomyces verticillus, inducessingle-strand and double-strand DNA breaks.46–48 The double-strand breaks and resulting loss of chromosome fragments probably account for bleomycin cytotoxicity.^46,49

Takahashi et al in 1985 reported the first seven cases of craniopharyngiomas treated with intracavitary bleomycin administered through an Ommaya reservoir inserted into the cyst.⁵⁰ Among these patients, those with cystic tumors had a better outcome than the ones with solid or combination lesions.⁵⁰ This initial publication was supported by several others.^51–60

Hargrave in 2006, analyzing the data of those publications, found that stable disease (stable cyst volume reduction) was achieved in 57% of the patients, with an obviously better response seen in cystic craniopharyngiomas. The median dose of bleomycin was 5 mg (2–15 mg). Seventyone percent of the patients received 3 doses per week (1–7 doses); the median number of doses was 8 (1–30). The median cumulative dose was 53 mg (5–150 mg).⁶¹ The major side effects directly attributed to bleomycin were headaches (42%), fever (36%), nausea and vomiting (21%), endocrine manifestations (16%), somnolence (15%), infarct/hemorrhage (10%), personality changes, vision changes (7%), and hearing problems, seizures, and death related to bleomycin therapy (1%).⁶¹

Hukin et al recently reported the Canadian experience with intracystic bleomycin.⁶² Seventeen patients were reported, of whom 12 were treated at the time of diagnosis and five at recurrence. Five patients achieved a complete response and six a partial response, and five had a minor response to intracystic bleomycin. The treatment protocol varied between centers, with most following a thriceweekly regimen. The course of treatment averaged 4 weeks (range, 2–15 weeks), and the median dose per course was 36 mg (range, 15–75 mg). The median dose per instillation was 3 mg (range, 2–5 mg), and the median dose per week was 9 mg (range, 4–20 mg). In a single injection, the median drug concentration within the cyst was 0.09 mg/ mL per dose (range, 0.01–2 mg/mL per dose). The median follow-up was 4 years (range, 0.5–10.2 years), and the median progression-free survival (PFS) was 1.8 years (range, 0.3–6.1 years). Observed complications included transient symptomatic peritumoral edema in two patients, precocious puberty in one patient, and panhypopituitarism in two patients.

Bleomycin is a neurotoxic drug; if leakage occurs, severe complications may develop, such as hypothalamic toxicity causing hypersomnia, personality changes, memory impairment, and thermal dysfunction,⁶⁰ and even death.⁵⁷

Lactate dehydrogenase (LDH) activity in craniopharyngioma fluid is elevated typically to ~3000 units, and the LDH isoenzyme pattern shows elevation of L4 and L5 fractions. Repeated injection of bleomycin causes a gradual clearing of the motor oil–colored cystic fluid, with a decrease in LDH activity (<1000 units), and the L4 and L5 fractions show a flat pattern.^50,63

Laws et al treated one patient who had craniopharyngioma with Gliadel placement after transsphenoidal tumor resection. This patient had previously undergone three transsphenoidal resections, one craniotomy, and one gamma knife radiosurgery; at recurrence, the patient was treated with a new transsphenoidal tumor resection and placement of three Gliadel wafers. After 6 months of follow-up, no tumor recurrence was seen.⁴¹

Jakacki et al reported a Phase II evaluation of systemic interferon alfa-2a (IFN-α-2a) in patients with progressive and/or recurrent craniopharyngiomas.⁶⁴ The rationale for using IFN-α-2a is that the drug shows activity against squamous cell skin carcinoma, which is believed to have the same embryologic origin as craniopharyngioma.^65,66 IFNs exert antitumor activity through direct antiproliferative, cytotoxic, and maturational effects, and they also modulate the immune response.^64,67,68 IFN-α-2a was administered in a dose of 8 million units (MU) per square meter daily for 16 weeks (induction phase), followed by the same dose three times per week for 32 weeks (maintenance phase). Fifteen patients received the drug, but only 12 could be followed with imaging. Radiologic response was seen in three patients with predominantly cystic tumors.

Intratumoral IFN-α was used in nine patients, with complete disappearance of the tumor in seven and partial reduction in two. Mean follow-up was 1 year and 8 months (range, 1–3.5 years), and the doses ranged from 18 to 36 MU. The most frequent side effects of IFN-α are fatigue, fever, weight loss, loss of appetite, and behavioral changes.⁵⁹

IFN-α also seems to reduce the size of cystic craniopharyngiomas by activating the Fas apoptotic pathway. Twenty-one patients with cystic craniopharyngiomas received intracystic IFN-α; the tumor size of all patients and the apoptotic factor soluble FasL (sFasL) concentration in eight patients were monitored. A complete response (tumor reduction) was observed in 11 patients (52.4%), a partial response in seven (33.3%), and a minor response in three (14.3%). The concentration of sFasL was increased in all eight patients, and it was examined concomitantly with tumor reduction. The mean follow-up was 27 months (range, 6 months to 4 years). Two patients underwent surgical resection, and tumor removal was easier than in the ones who had received chemotherapy preoperatively⁶⁹

Pituitary Lymphomas

Although particularly rare, primary central nervous system lymphomas (PCNSLs) arising from the sellar and parasellar region are one of the causes of hypothalamic-pituitary dysfunction.70 In a series of 1120 patients with pituitary tumors resected via the transsphenoidal route, only one case (0.1%) was diagnosed as a pituitary lymphoma.⁷¹ In another series of 353 patients with pituitary masses, pituitary lymphoma was found in one case (0.3%).⁷² The majority of PCNSLs are B-cell lymphomas, and besides acquired immunodeficiency syndrome (AIDS) and other immunodeficiency conditions, lymphocytic hypophysitis and pituitary adenomas have been implicated as risk factors for pituitary lymphomas.⁷³

The treatment of PCNSL traditionally combines whole-brain radiation therapy (WBRT) and chemotherapy with methotrexate (MTX) alone or in combination with other agents. MTX is a folate antagonist and has limited penetration in the CNS because of its high degree of ionization at a physiologic pH; high doses (≥3.5 g/m²) are used to achieve cytotoxic intratumoral concentrations.⁷⁴ We extrapolate the treatment of PCNSL anywhere in the CNS to lesions arising in the sellar and parasellar areas.

Several combination regimens of WBRT and MTX are associated with reasonable response rates.75–80 The combination of MTX, procarbazine, and vincristine (MPV) followed by WBRT and cytarabine after radiation is associated with an overall response rate of 91%, a PFS of 24 months, and an overall survival of 36.9 months.⁸¹ In another important study, rituximab, a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells, was tested with MPV followed by a lower dose of WBRT (23.4 Gy for patients who had complete response to chemotherapy or 45 Gy for patients who did not have a complete response).⁷⁷ The overall response rate was 93%, and the 2-year median PFS rate was 57%. No treatmentrelated neurotoxicity was observed. The authors concluded that the addition of rituximab to MPV (R-MPV) increased the risk for significant neutropenia requiring routine growth factor support, that additional cycles of R-MPV nearly doubled the complete response rate, and that reduced-dose WBRT was not associated with neurocognitive decline.

Chemotherapy protocols without WBRT were designed to avoid the delayed cognitive effects associated with radiation therapy, particularly in patients older than 60 years of age and in those with underlying vascular risk factors, with radiation therapy reserved for an eventual relapse.⁷⁴ Intravenous MTX alone, 8 g/m², was used in 25 patients, with a complete response achieved in 52% of the patients, a median PFS of 12.8 months, and a median overall survival of 55.4 months.^82,83 Interestingly, 5 of 25 patients in this trial treated with MTX alone achieved a complete response and, after a median follow-up of 6.8 years, had not had a relapse. Several other drugs, including rituximab, have been added to MTX therapy in regimens that do not include WBRT,^84,85 with the intent to achieve a more durable response.

The blood-brain barrier can limit the diffusion of MTX into brain and tumor. The blood-brain barrier can be disrupted with the use of osmotic agents (ie, mannitol), enhancing drug delivery to the tumor. A multicenter analysis of 149 patients treated with blood-brain barrier disruption and intra-arterial MTX over 23 years showed an overall response rate of 81.9% (57.8% complete response), a median overall survival of 3.1 years (25% estimated survival at 8.5 years), a median PFS of 1.8 years, a 5-year PFS rate of 31%, and a 7-year PFS rate of 25%.⁸⁶ Focal seizures (9.2%) were the most frequent side effect, and no long-term sequelae were reported. The study concluded that tumor control and outcomes were comparable or superior to those achieved with other PCNSL treatment regimens.

Intrathecal chemotherapy is reserved for patients with concomitant leptomeningeal lymphoma, although prospective^87–89 and retrospective^90,91 studies indicate that intrathecal chemotherapy does not improve outcomes in patients who received MTX-based therapy.⁷⁵ Additionally, some studies indicate that systemic MTX eradicates neoplastic cells from the cerebrospinal fluid (CSF).^92,93 Other aspects should be taken into consideration before intrathecal chemotherapy is started, including the risks for complications of Ommaya reservoir placement, chemical meningitis, drug leakage outside the CNS, and infection. Several clinical trials have included intrathecal chemotherapy.^78,79,84,85

Patients with relapse of PCNSL after an initial response to therapy have a median survival of ~4.5 months, posing a challenge to the clinician. WBRT alone is associated with a radiographic response in 74 to 79% of patients, with a median survival after radiation of 10.9 to 16 months; patients younger than 60 years of age tend to perform better.⁷⁴ Several chemotherapeutic agents have been used for relapsed PCNSL. Intraventricular rituximab is an alternative for patients who did not receive it as an initial therapy⁹⁴ A trial comparing intraventricular rituximab and intraventricular MTX in patients with relapsed PCNSL is ongoing.

Germ Cell Tumors

Primary intracranial germ cell tumors account for 1% of all primary brain tumors in adults and are divided into five types: germinomas (65%), teratomas (18%), embryonic carcinomas (5%), choriocarcinomas (5%), and endodermal sinus tumors (7%).95,96 Germinomas are more often located in the suprasellar region than in the pineal region.⁹⁷

Germinomas are extremely radiosensitive tumors; patients have 5-year survival rates of more than 90% with radiation therapy alone.^98–101 In contrast, tumors containing nongerminomatous malignant elements are less radiosensitive; studies including radiation therapy with or without chemotherapy show a 5-year survival rate of 20 to 76%.^102–104

Results of the Third International CNS Germ Cell Tumor Study, designed to demonstrate the efficacy of a chemotherapy-only protocol in avoiding the additional morbidity caused by radiation therapy of germ cell tumors, were recently published.¹⁰⁵ Twenty-five patients with newly diagnosed germ cell tumors were treated with one of two risk-tailored chemotherapy regimens. Regimen A consisted of 4 to 6 cycles of carboplatin/etoposide alternating with cyclophosphamide/etoposide for patients who had low-risk localized germinoma with normal CSF and serum tumor markers. Regimen B consisted of 4 to 6 cycles of carboplatin/cyclophosphamide/etoposide for patients who had intermediate-risk germinoma, positivity for human chorionic gonadotropin β(HCG-β) and/or CSF HCG-β below 50 mIU/mL, and high-risk biopsy-proven nonger minomatous malignant elements or elevated serum/CSF α-fetoprotein and/or serum/CSF HCG-β above 50 mIU/mL. The 6-year event-free and overall survival rates were 45.6% and 75.3%, respectively. The study concluded that chemotherapy-alone regimens are less effective than regimens including radiation therapy. The authors recommended radiation therapy, either alone or with chemotherapy, as the standard treatment for pure germinomas and radiation plus chemotherapy for tumors with nongerminomatous malignant elements.

Chordomas

Chordomas are very rare tumors that arise from the remnants of the embryonic notochord; they are characterized by slow growth, a long natural history, frequent local recurrences, and an axial skeleton location (sacrum, skull base, and spine). They are considered low-grade malignancies, but they have the capacity to metastasize to distant organs. Chordomas were diagnosed in 10 patients in a series of 1120 sellar masses treated with transsphenoidal surgery.71

Classically, the treatment of skull base chordomas consists of surgery to reduce tumor volume and, if possible, establish a safety margin for irradiation between the tumor and neurovascular structures. This is followed by some form of radiation therapy or stereotactic radiosurgery.^106,107

Historically, chemotherapy has not played a role in the treatment of chordomas, and reports of tumor responses to anthracyclines, cisplatin, and alkylating agents have been anecdotal. In rare instances, chordomas can transform into high-grade sarcomas, becoming a potential target for chemotherapy.⁷⁶

Recently, a strong expression of EGFR and C-met (mesenchymal-epithelial transition factor) was reported in a series of 12 chordomas.¹⁰⁸ In addition, platelet-derived growth factor receptor β (PDGFR-β) was overexpressed in a series of 31 chordomas.¹⁰⁹ Because chordomas seem to express EGFR and PDGFR, these tumors may be amenable to treatment with currently available targeted therapy. Several cases of the successful use of imatinib and erlotinib, tyrosine kinase inhibitors, have reported.^110–112

Meningiomas

Meningiomas are one of the more common brain tumors in adults. About 90% of them are World Health Organization (WHO) grade 1 (benign), 5 to 7% are WHO grade 2 (atypical), and only 3% are WHO grade 3 (malignant or anaplastic).113

Historically, the gold standard treatment for meningiomas has been complete surgical resection. Chemotherapy is reserved for more aggressive tumors, recurrent tumors, or those localized in areas of difficult surgical approach; it is also used after radiation therapy when other options have been exhausted. Although chemotherapy is sometimes useful, reliable, effective agents are lacking and remain an area of investigation.

Chamberlain reported a series of 14 patients who had malignant meningiomas treated with adjuvant chemotherapy that included cyclophosphamide, Adriamycin, and vincristine (CAV); the patients showed a modest improvement in survival when compared with patients treated with surgery alone.¹¹⁴ In a prospective Phase II study of TMZ in 16 patients with refractory meningiomas, no patient demonstrated PFS at 6 months; therefore, the study was terminated, and the conclusion was that TMZ is ineffective in meningiomas.¹¹⁵ In a study investigating the MGMT promoter methylation status in 36 meningiomas, none of the specimens showed MGMT gene promoter methylation, providing a rationale for TMZ ineffectiveness.¹¹⁶

Twelve patients with recurrent postoperative residual masses or inoperable meningiomas were treated with INF-α and followed with PET. In five patients treated from 9 months to 8 years, INF-α seemed to be an effective oncostatic drug, deserving of further studies.¹¹⁷

Irinotecan (CPT-11), a topoisomerase I inhibitor, demonstrated growth-inhibiting effects in primary meningioma cultures and in malignant cell lines in vitro and in vivo, but the drug proved ineffective in a Phase II study.^118,119

Several successful reports of hydroxyurea, an oral ribonucleotide reductase inhibitor against meningiomas, have been published.^120–125 Schrell at al, after demonstrating that hydroxyurea inhibits growth of cultured human meningioma cells and meningioma transplants in nude mice by inducing apoptosis,¹²⁴ reported a successful outcome in four patients who had recurrent and/or unresectable meningiomas treated with hydroxyurea.¹²⁵ In another study, of 21 patients with recurrent and progressive meningiomas treated with fractionated three-dimensional conformal radiation therapy and concurrent hydroxyurea, disease stabilization was achieved in 14 patients (66%). Progression-free survival rates at 1 and 2 years were 84% and 77% respectively.¹²¹ A Phase II study to further evaluate the role of hydroxyurea in meningiomas (SWOG-S9811) has been completed, but the results have not yet been reported.

PDGF and its receptor PDGFR are frequently co-expressed in meningiomas. A Phase II study of imatinib mesylate (a PDGFR inhibitor) for recurrent meningiomas accrued 23 patients (13 with benign, five with atypical, and five with malignant meningiomas), of whom 22 were eligible. Overall median PFS was 2 months (0.7–34 months), and the 6-month PFS rate was 29.4%. For benign meningiomas, median PFS was 3 months (1.1–34 months), and the 6-month PFS rate was 45%. For atypical and malignant meningiomas, median PFS was 2 months (0.7–3.7 months), and the 6-month PFS rate was zero. Imatinib was well tolerated but did not show any significant activity against recurrent meningiomas.¹²⁶

Meningiomas also overexpress EGFR. Based on this observation, a Phase II study with the EGFR inhibitors gefitinib and erlotinib for recurrent meningiomas was conducted. The study accrued 25 patients. Sixteen patients (64%) received gefitinib, and nine patients (36%) received erlotinib. Eight patients (32%) had benign tumors, nine (36%) atypical meningiomas, and eight (32%) malignant meningiomas. No objective imaging responses were seen, but eight patients (32%) maintained stable disease. The study concluded that although well tolerated, neither gefitinib nor erlotinib appears to be effective against recurrent meningiomas.¹²⁷

Clinical trials of treatments for recurrent meningiomas, including target therapies with bevacizumab (a monocloncal antibody against vascular endothelial growth factor [VEGF]), sorafenib, sunitinib, and vatalanib (targets VEGFR and PDGFR), are under way.

Plasmacytomas

Intrasellar plasmacytomas are rare and can mimic nonfunctional pituitary adenomas clinically and radiologically. Plasmacytomas can progress to multiple myeloma, or multiple myeloma can be diagnosed simultaneously.128

Traditionally, plasmacytomas have been treated with surgery and radiation therapy for local or residual disease. Chemotherapy is added for systemic myeloma treatment. Sinnott et al, in a review of 22 cases of intrasellar plasmacytomas reported in the literature, found that radiation therapy was administered to the sellar lesion in 71% of the patients after surgery and systemic chemotherapy was administered to 29% of the patients following the diagnosis of multiple myeloma.128

Patients undergoing chemotherapy for multiple myeloma comprise two groups: those who are candidates for autologous hematopoietic cell transplantation (HCT) and those who are not candidates for HCT.

In patients who were not candidates for HCT, three randomized trials demonstrated superior PFS in those treated with melphalan, prednisone, and thalidomide (MPT) versus patients treated with melphalan and prednisone.^129–132 Bortezomib, melphalan, and prednisone (VMP) are an alternative to MPT.^133,134

In patients who are candidates for HCT, induction chemotherapy with thalidomide and dexamethasone is the standard treatment.^135,136 Lenalidomide (a thalidomide analogue) combined with dexamethasone seems to be an alternative and is highly effective and well tolerated.¹³⁷ Bortezomib with dexamethasone is also a well-tolerated and effective alternative.¹³⁸

The term hematopoietic cell transplantation indicates transplantation of progenitor (stem) cells from any source (eg, bone marrow, peripheral blood, cord blood), and HCT may be the only treatment with a chance of producing cure.

Conclusion

1. Ragel BT, Couldwell WT. Pituitary carcinoma: a review of the literature. Neurosurg Focus 2004;16(4):E7
   
2. Pernicone PJ, Scheithauer BW, Sebo TJ, et al. Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 1997;79(4):804–812
   
3. Kaltsas GA, Nomikos P, Kontogeorgos G, Buchfelder M, Grossman AB. Clinical review: Diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab 2005;90(5):3089–3099
   
4. Asai A, Matsutani M, Funada N, Takakura K. Malignant growth hormone-secreting pituitary adenoma with hematogenous dural metastasis: case report. Neurosurgery 1988;22(6 Pt 1): 1091–1094
   
5. Harris PE, Bouloux PM, Wass JA, Besser GM. Successful treatment by chemotherapy for acromegaly associated with ectopic growth hormone releasing hormone secretion from a carcinoid tumour. Clin Endocrinol (Oxf) 1990;32(3):315–321
   
6. Walker JD, Grossman A, Anderson JV, et al. Malignant prolactinoma with extracranial metastases: a report of three cases. Clin Endocrinol (Oxf) 1993;38(4):411–419
   
7. Kaiser FE, Orth DN, Mukai K, Oppenheimer JH. A pituitary parasellar tumor with extracranial metastases and high, partially suppressible levels of adrenocorticotropin and related peptides. J Clin Endocrinol Metab 1983;57(3):649–653
   
8. Vaughan NJ, Laroche CM, Goodman I, Davies MJ, Jenkins JS. Pituitary Cushing’s disease arising from a previously non-functional corticotrophic chromophobe adenoma. Clin Endocrinol (Oxf) 1985;22(2):147–153
   
9. Hashimoto N, Handa H, Nishi S. Intracranial and intraspinal dissemination from a growth hormone-secreting pituitary tumor. Case report. J Neurosurg 1986;64(1):140–144
   
10. Kasperlik-Zaluska AA, Wislawski J, Kaniewska J, Zborzil J, Frankiewicz E, Zgliczyński S. Cytostatics for acromegaly. Marked improvement in a patient with an invasive pituitary tumour. Acta Endocrinol (Copenh) 1987;116(3):347–349
    
11. Nawata H, Higuchi K, Ikuyama S, et al. Corticotropin-releasing hormone- and adrenocorticotropin-producing pituitary carcinoma with metastases to the liver and lung in a patient with Cushing’s disease. J Clin Endocrinol Metab 1990;71(4):1068–1073
    
12. Petterson T, MacFarlane IA, MacKenzie JM, Shaw MD. Prolactin secreting pituitary carcinoma. J Neurol Neurosurg Psychiatry 1992;55(12):1205–1206
    
13. Mixson AJ, Friedman TC, Katz DA, et al. Thyrotropin-secreting pituitary carcinoma. J Clin Endocrinol Metab 1993;76(2):529–533
    
14. Beauchesne P, Trouillas J, Barral F, Brunon J. Gonadotropic pituitary carcinoma: case report. Neurosurgery 1995;37(4):810–815, discussion 815–816
    
15. Kaltsas GA, Mukherjee JJ, Plowman PN, Monson JP, Grossman AB, Besser GM. The role of cytotoxic chemotherapy in the management of aggressive and malignant pituitary tumors. J Clin Endocrinol Metab 1998;83(12):4233–4238
    
16. Gollard R, Kosty M, Cheney C, Copeland B, Bordin G. Prolactin-secreting pituitary carcinoma with implants in the cheek pouch and metastases to the ovaries. A case report and literature review. Cancer 1995;76(10):1814–1820
    
17. McCutcheon IE, Pieper DR, Fuller GN, Benjamin RS, Friend KE, Gagel RF. Pituitary carcinoma containing gonadotropins: treatment by radical excision and cytotoxic chemotherapy: case report. Neurosurgery 2000;46(5):1233–1239, discussion 1239–1240
    
18. Lopes MB, Scheithauer BW, Schiff D. Pituitary carcinoma: diagnosis and treatment. Endocrine 2005;28(1):115–121
    
19. Kaltsas GA, Grossman AB. Malignant pituitary tumours. Pituitary 1998;1(1):69–81
    
20. Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 1997;23(1):35–61
    
21. Stupp R, Mason WP, van den Bent MJ, et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10): 987–996
    
22. MirimanoffRO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 2006;24(16):2563–2569
    
23. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352(10):997–1003
    
24. Hagen C, Schroeder HD, Hansen S, Hagen C, Andersen M. Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy. Eur J Endocrinol 2009;161(4):631–637
    
25. McCormack AI, McDonald KL, Gill AJ, et al. Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours. Clin Endocrinol (Oxf) 2009;71(2):226–233
    
26. Berrocal A, Perez Segura P, Gil M, et al; GENOM Cooperative Group. Extended-schedule dose-dense temozolomide in refractory gliomas. J Neurooncol 2010;96(3):417–422
    
27. Tolcher AW, Gerson SL, Denis L, et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 2003;88(7):1004–1011
    
28. Baer JC, Freeman AA, Newlands ES, Watson AJ, Rafferty JA, Margison GP. Depletion of O6-alkylguanine-DNA alkyltransferase correlates with potentiation of temozolomide and CCNU toxicity in human tumour cells. Br J Cancer 1993;67(6):1299–1302
    
29. Fadul CE, Kominsky AL, Meyer LP, et al. Pituitary carcinomas respond to temozolomide. Neuro-oncol 2004;6:374
    
30. Zhu Y, Shahinian H, Maya MM, Bonert V, Lim S, Heaney A. Temodar: novel treatment for pituitary carcinoma. The Endocrine Society Annual Meeting 2004(138):43–45
    
31. Lim S, Shahinian H, Maya MM, Yong W, Heaney AP. Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncol 2006;7(6):518–520
    
32. Kovacs K, Horvath E, Syro LV, et al. Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings. Hum Pathol 2007;38(1):185–189
    
33. Horvath E, Kovacs K, Scheithauer BW, Lloyd RV, Smyth HS. Pituitary adenoma with neuronal choristoma (PANCH): composite lesion or lineage infidelity? Ultrastruct Pathol 1994;18(6):565–574
    
34. Thodou E, Kontogeorgos G, Theodossiou D, Pateraki M. Mapping of somatostatin receptor types in GH or/and PRL producing pituitary adenomas. J Clin Pathol 2006;59(3):274–279
    
35. NeffLM, Weil M, Cole A, et al. Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists. Pituitary 2007;10(1):81–86
    
36. Moyes VJ, Alusi G, Sabin HI, et al. Treatment of Nelson’s syndrome with temozolomide. Eur J Endocrinol 2009;160(1):115–119
    
37. Mohammed S, Kovacs K, Mason W, Smyth H, Cusimano MD. Use of temozolomide in aggressive pituitary tumors: case report. Neurosurgery 2009;64(4):E773–E774; discussion E774
    
38. Thearle MS, Freda PU, Bruce JN, Isaacson SR, Lee Y, Fine RL. Temozolomide (Temodar(R)) and capecitabine (Xeloda(R)) treatment of an aggressive corticotroph pituitary tumor. Pituitary 2009 Dec 4 [Epub ahead of print]
    
39. Amatori F, Di Paolo A, Del Tacca M, et al. Thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer and normal mucosa in patients. Pharmacogenet Genomics 2006;16(11):809–816
    
40. Bush ZM, Longtine JA, Cunningham T, et al. Temozolomide as an adjuvant treatment for aggressive pituitary tumors: correlations of clinical outcomes with DNA methylation and MGMT expression. J Clin Endo Metab 2010;95:280–290
    
41. Laws ER Jr, Morris AM, Maartens N. Gliadel for pituitary adenomas and craniopharyngiomas. Neurosurgery 2003;53(2):255–269, discussion 259–260
    
42. Brem H, Ewend MG, Piantadosi S, Greenhoot J, Burger PC, Sisti M. The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. J Neurooncol 1995;26(2):111–123
    
43. Brem H, Mahaley MS Jr, Vick NA, et al. Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 1991;74(3):441–446
    
44. Jane JA Jr, Laws ER. Craniopharyngioma. Pituitary 2006;9(4):323–326
    
45. Laws ER Jr, Jane JA Jr. Craniopharyngioma. J Neurosurg Pediatr 2010;5(1):27–28, discussion 28–29
    
46. Linnert M, Gehl J. Bleomycin treatment of brain tumors: an evaluation. Anticancer Drugs 2009;20(3):157–164
    
47. Umezawa H, Ishizuka M, Maeda K, Takeuchi T. Studies on bleomycin. Cancer 1967;20(5):891–895
    
48. Umezawa H, Maeda K, Takeuchi T, Okami Y. New antibiotics, bleomycin A and B. J Antibiot (Tokyo) 1966;19(5):200–209
    
49. Mir LM, Tounekti O, Orlowski S. Bleomycin: revival of an old drug. Gen Pharmacol 1996;27(5):745–748
    
50. Takahashi H, Nakazawa S, Shimura T. Evaluation of postoperative intratumoral injection of bleomycin for craniopharyngioma in children. J Neurosurg 1985;62(1):120–127
    
51. Alén JF, Boto GR, Lagares A, de la Lama A, Gómez PA, Lobato RD. Intratumoural bleomycin as a treatment for recurrent cystic craniopharyngioma. Case report and review of the literature. Neurocirugia (Astur) 2002;13(6):479–485, discussion 485
    
52. Park DH, Park JY, Kim JH, et al. Outcome of postoperative intratumoral bleomycin injection for cystic craniopharyngioma. J Korean Med Sci 2002;17(2):254–259
    
53. Jiang R, Liu Z, Zhu C. Preliminary exploration of the clinical effect of bleomycin on craniopharyngiomas. Stereotact Funct Neurosurg 2002;78(2):84–94
    
54. Mottolese C, Stan H, Hermier M, et al. Intracystic chemotherapy with bleomycin in the treatment of craniopharyngiomas. Childs Nerv Syst 2001;17(12):724–730
    
55. Hader WJ, Steinbok P, Hukin J, Fryer C. Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children. Pediatr Neurosurg 2000;33(4):211–218
    
56. Savas A, Arasil E, Batay F, Selcuki M, Kanpolat Y. Intracavitary chemotherapy of polycystic craniopharyngioma with bleomycin. Acta Neurochir (Wien) 1999;141(5):547–548, discussion 549
    
57. Savas A, Erdem A, Tun K, Kanpolat Y. Fatal toxic effect of bleomycin on brain tissue after intracystic chemotherapy for a craniopharyngioma: case report. Neurosurgery 2000;46(1):213–216, discussion 216–217
    
58. Sagoh M, Murakami H, Hirose Y, Mayanagi K. Occlusive cerebrovasculopathy after internal radiation and bleomycin therapy for craniopharyngioma—case report. Neurol Med Chir (Tokyo) 1997;37(12):920–923
    
59. Cavalheiro S, Sparapani FV, Franco JO, da Silva MC, Braga FM. Use of bleomycin in intratumoral chemotherapy for cystic craniopharyngioma. Case report. J Neurosurg 1996;84(1):124–126
    
60. Haisa T, Ueki K, Yoshida S. Toxic effects of bleomycin on the hypothalamus following its administration into a cystic craniopharyngioma. Br J Neurosurg 1994;8(6):747–750
    
61. Hargrave DR. Does chemotherapy have a role in the management of craniopharyngioma? J Pediatr Endocrinol Metab 2006;19(Suppl 1):407–412
    
62. Hukin J, Steinbok P, Lafay-Cousin L, et al. Intracystic bleomycin therapy for craniopharyngioma in children: the Canadian experience. Cancer 2007;109(10):2124–2131
    
63. Buckell M, Crompton MR, Robertson MC, Barnes GK. Lactate dehydrogenase in cerebral cyst fluids; total activity and isoenzyme distributions as an index of malignancy. J Neurosurg 1970;32(5):545–552
    
64. Jakacki RI, Cohen BH, Jamison C, et al. Phase II evaluation of interferon-alpha-2a for progressive or recurrent craniopharyngiomas. J Neurosurg 2000;92(2):255–260
    
65. Ikić D, Padovan I, Pipić N, et al. Treatment of squamous cell carcinoma with interferon. Int J Dermatol 1991;30(1):58–61
    
66. Ikić D, Padovan I, Pipić N, et al. Interferon therapy for basal cell carcinoma and squamous cell carcinoma. Int J Clin Pharmacol Ther Toxicol 1991;29(9):342–346
    
67. Yates AJ, Stephens RE, Elder PJ, Markowitz DL, Rice JM. Effects of interferon and gangliosides on growth of cultured human glioma and fetal brain cells. Cancer Res 1985;45(3):1033–1039
    
68. Sen GC, Lengyel P. The interferon system. A bird’s eye view of its biochemistry. J Biol Chem 1992;267(8):5017–5020
    
69. Ierardi DF, Fernandes MJ, Silva IR, et al. Apoptosis in alpha interferon (IFN-alpha) intratumoral chemotherapy for cystic craniopharyngiomas. Childs Nerv Syst 2007;23(9):1041–1046
    
70. Yasuda M, Akiyama N, Miyamoto S, et al. Primary sellar lymphoma: intravascular large B-cell lymphoma diagnosed as a double cancer and improved with chemotherapy, and literature review of primary parasellar lymphoma. Pituitary 2010;13(1): 39–47
    
71. Freda PU, Post KD. Differential diagnosis of sellar masses. Endocrinol Metab Clin North Am 1999;28(1):81–117
    
72. Gsponer J, De Tribolet N, Déruaz JP, et al. Diagnosis, treatment, and outcome of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients. Medicine (Baltimore) 1999;78(4):236–269
    
73. Da Silva AN, Lopes MB, SchiffD. Rare pathological variants and presentations of primary central nervous system lymphomas. Neurosurg Focus 2006;21(5):E7
    
74. Gerstner ER, Batchelor TT. Primary central nervous system lymphoma. Arch Neurol 2010;67(3):291–297
    
75. Ferreri AJ, Abrey LE, Blay JY, et al. Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol 2003;21(12):2407–2414
    
76. Ferreri AJ, Reni M, Foppoli M, et al; International Extranodal Lymphoma Study Group (IELSG). High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 2009;374(9700):1512–1520
    
77. Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 2007;25(30):4730–4735
    
78. Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, et al; European Organization for Research and Treatment of Cancer Lymphoma Group. High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962. J Clin Oncol 2003;21(24):4483–4488
    
79. Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol 2006;24(28):4570–4574
    
80. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol 2000;18(17):3144–3150
    
81. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 2002;20(24):4643–4648
    
82. Batchelor T, Carson K, O’Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol 2003;21(6):1044–1049
    
83. Gerstner ER, Carson KA, Grossman SA, Batchelor TT. Long-term outcome in PCNSL patients treated with high-dose methotrexate and deferred radiation. Neurology 2008;70(5):401–402
    
84. Pels H, Schmidt-Wolf IG, Glasmacher A, et al. Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 2003;21(24):4489–4495
    
85. Hoang-Xuan K, Taillandier L, Chinot O, et al; European Organization for Research and Treatment of Cancer Brain Tumor Group. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol 2003;21(14):2726–2731
    
86. Angelov L, Doolittle ND, Kraemer DF, et al. Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clin Oncol 2009;27(21):3503–3509
    
87. Glass J, Gruber ML, Cher L, Hochberg FH. Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg 1994;81(2):188–195
    
88. Cher L, Glass J, Harsh GR, Hochberg FH. Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results. Neurology 1996;46(6):1757–1759
    
89. Glass J, Shustik C, Hochberg FH, Cher L, Gruber ML. Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD). J Neurooncol 1996;30(3):257–265
    
90. Ferreri AJ, Reni M, Pasini F, et al. A multicenter study of treatment of primary CNS lymphoma. Neurology 2002;58(10):1513–1520
    
91. Khan RB, Shi W, Thaler HT, DeAngelis LM, Abrey LE. Is intrathecal methotrexate necessary in the treatment of primary CNS lymphoma? J Neurooncol 2002;58(2):175–178
    
92. Ferreri AJ, Reni M, Dell’Oro S, et al. Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients. Oncology 2001;60(2):134–140
    
93. Guha-Thakurta N, Damek D, Pollack C, Hochberg FH. Intravenous methotrexate as initial treatment for primary central nervous system lymphoma: response to therapy and quality of life of patients. J Neurooncol 1999;43(3):259–268
    
94. Rubenstein JL, Fridlyand J, Abrey L, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 2007;25(11):1350–1356
    
95. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985;63(2):155–167
    
96. Kyritsis AP. Management of primary intracranial germ cell tumors. J Neurooncol 2010;96(2):143–149
    
97. Liang L, Korogi Y, Sugahara T, et al. MRI of intracranial germ-cell tumours. Neuroradiology 2002;44(5):382–388
    
98. Ogawa K, Shikama N, Toita T, et al. Long-term results of radiotherapy for intracranial germinoma: a multi-institutional retrospective review of 126 patients. Int J Radiat Oncol Biol Phys 2004;58(3):705–713
    
99. Maity A, Shu HK, Janss A, et al. Craniospinal radiation in the treatment of biopsy-proven intracranial germinomas: twenty-five years’ experience in a single center. Int J Radiat Oncol Biol Phys 2004;58(4):1165–1170
    
100. Merchant TE, Sherwood SH, Mulhern RK, et al. CNS germinoma: disease control and long-term functional outcome for 12 children treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys 2000;46(5):1171–1176
     
101. Rogers SJ, Mosleh-Shirazi MA, Saran FH. Radiotherapy of localised intracranial germinoma: time to sever historical ties? Lancet Oncol 2005;6(7):509–519
     
102. Ogawa K, Toita T, Nakamura K, et al. Treatment and prognosis of patients with intracranial nongerminomatous malignant germ cell tumors: a multiinstitutional retrospective analysis of 41 patients. Cancer 2003;98(2):369–376
     
103. Matsutani M; Japanese Pediatric Brain Tumor Study Group. Combined chemotherapy and radiation therapy for CNS germ cell tumors—the Japanese experience. J Neurooncol 2001;54(3):311–316
     
104. Aoyama H, Shirato H, Ikeda J, Fujieda K, Miyasaka K, Sawamura Y. Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 2002;20(3):857–865
     
105. da Silva NS, Cappellano AM, Diez B, et al. Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study. Pediatr Blood Cancer 2010;54(3):377–383
     
106. Casali PG, Stacchiotti S, Sangalli C, Olmi P, Gronchi A. Chordoma. Curr Opin Oncol 2007;19(4):367–370
     
107. Yoneoka Y, Tsumanuma I, Fukuda M, et al. Cranial base chordoma—long term outcome and review of the literature. Acta Neurochir (Wien) 2008;150(8):773–778, discussion 778
     
108. Weinberger PM, Yu Z, Kowalski D, et al. Differential expression of epidermal growth factor receptor, c-Met, and HER2/neu in chordoma compared with 17 other malignancies. Arch Otolaryngol Head Neck Surg 2005;131(8):707–711
     
109. Tamborini E, Miselli F, Negri T, et al. Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas. Clin Cancer Res 2006;12(23):6920–6928
     
110. Singhal N, Kotasek D, Parnis FX. Response to erlotinib in a patient with treatment refractory chordoma. Anticancer Drugs 2009;20(10):953–955
     
111. Casali PG, Messina A, Stacchiotti S, et al. Imatinib mesylate in chordoma. Cancer 2004;101(9):2086–2097
     
112. Casali PG, Stacchiotti S, Messina A, et al. Imatinib mesylate in 18 advanced chordoma patients. J Clin Oncol 2005;23(suppl):9012
     
113. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114(2):97–109
     
114. Chamberlain MC. Adjuvant combined modality therapy for malignant meningiomas. J Neurosurg 1996;84(5):733–736
     
115. Chamberlain MC, Tsao-Wei DD, Groshen S. Temozolomide for treatment-resistant recurrent meningioma. Neurology 2004;62(7):1210–1212
     
116. de Robles P, McIntyre J, Kalra S, et al. Methylation status of MGMT gene promoter in meningiomas. Cancer Genet Cytogenet 2008;187(1):25–27
     
117. Muhr C, Gudjonsson O, Lilja A, Hartman M, Zhang ZJ, Långström B. Meningioma treated with interferon-alpha, evaluated with [(11)C]-L-methionine positron emission tomography. Clin Cancer Res 2001;7(8):2269–2276
     
118. Gupta V, Su YS, Samuelson CG, et al. Irinotecan: a potential new chemotherapeutic agent for atypical or malignant meningiomas. J Neurosurg 2007;106(3):455–462
     
119. Chamberlain MC, Tsao-Wei DD, Groshen S. Salvage chemotherapy with CPT-11 for recurrent meningioma. J Neurooncol 2006;78(3):271–276
     
120. Fuentes S, Chinot O, Dufour H, et al. Hydroxyurea treatment for unresectable meningioma. Neurochirurgie 2004;50(4): 461–467
     
121. Hahn BM, Schrell UM, Sauer R, Fahlbusch R, Ganslandt O, Grabenbauer GG. Prolonged oral hydroxyurea and concurrent 3D-conformal radiation in patients with progressive or recurrent meningioma: results of a pilot study. J Neurooncol 2005;74(2):157–165
     
122. Newton HB, Scott SR, Volpi C. Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up. Br J Neurosurg 2004;18(5):495–499
     
123. Mason WP, Gentili F, Macdonald DR, Hariharan S, Cruz CR, Abrey LE. Stabilization of disease progression by hydroxyurea in patients with recurrent or unresectable meningioma. J Neurosurg 2002;97(2):341–346
     
124. Schrell UM, Rittig MG, Anders M, et al. Hydroxyurea for treatment of unresectable and recurrent meningiomas. I. Inhibition of primary human meningioma cells in culture and in meningioma transplants by induction of the apoptotic pathway. J Neurosurg 1997;86(5):845–852
     
125. Schrell UM, Rittig MG, Anders M, et al. Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. Decrease in the size of meningiomas in patients treated with hydroxyurea. J Neurosurg 1997;86(5):840–844
     
126. Wen PY, Yung WK, Lamborn KR, et al. Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08). Neuro-oncol 2009;11(6):853–860
     
127. Norden AD, Raizer JJ, Abrey LE, et al. Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma. J Neurooncol 2010;96(2):211–217
     
128. Sinnott BP, Hatipoglu B, Sarne DH. Intrasellar plasmacytoma presenting as a non-functional invasive pituitary macroadenoma: case report & literature review. Pituitary 2006;9(1):65–72
     
129. Palumbo A, Bertola A, Musto P, et al. Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma. Cancer 2005;104(7):1428–1433
     
130. Palumbo A, Bringhen S, Caravita T, et al; Italian Multiple Myeloma Network, GIMEMA. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006;367(9513): 825–831
     
131. Facon T, Mary JY, Hulin C, et al; Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 2007;370(9594): 1209–1218
     
132. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27(22):3664–3670
     
133. Mateos MV, Hernández JM, Hernández MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood 2006;108(7):2165–2172
     
134. Mateos MV, Hernández JM, Hernández MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica 2008;93(4):560–565
     
135. Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002;20(21):4319–4323
     
136. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24(3):431–436
     
137. Gay F, Hayman SR, Lacy MQ, et al. Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients. Blood 2010;115(7):1343–1350
     
138. Jagannath S, Durie BG, Wolf JL, et al. Extended follow-up of a phase 2 trial of bortezomib alone and in combination with dexamethasone for the frontline treatment of multiple myeloma. Br J Haematol 2009;146(6):619–626

Related posts:

Medical Evaluation and Management Introduction and Historical Perspective Transsphenoidal Approaches to the Sellar and Parasellar Area Radiation Therapy Transcranial Approaches to the Sellar and Parasellar Area Anatomy of the Sellar and Parasellar Region

Stay updated, free articles. Join our Telegram channel

Join