42 Chemotherapy for Intracranial Meningiomas
Meningiomas are extraaxial central nervous system (CNS) tumors most often discovered in middle to late adult life. They have a female predominance. Ninety percent of meningiomas are benign, 6% are atypical, and 2% are malignant.1–4 The majority of patients diagnosed with a symptomatic meningioma undergo surgical resection to relieve neurological symptoms.1–4 Complete surgical resection is often curative. For the majority of incompletely resected or recurrent tumors not previously irradiated, radiotherapy is administered.1–4 Radiotherapy may be administered as either conventional external beam irradiation or stereotactically by linear accelerator (LINAC), Leksell Gamma Knife (Elekta, Inc., Norcross, GA) or Cyberknife (Accuray, Sunnyvale, CA) radiosurgery. Advocates of stereotactic radiotherapy have suggested this therapy in lieu of surgery, particularly in poor surgical risk patients, patients with meningiomas in eloquent or surgically inaccessible locations, and patients of advanced age. In the subpopulation of patients with an unresectable meningioma and in whom all other treatments (radiotherapy) have failed, hormonal-chemotherapy-targeted therapy may be considered.5–30 Notwithstanding limited data, hydroxyurea has been modestly successful in patients with recurrent meningiomas and is frequently the agent of first choice in patients with refractory and recurrent meningiomas of all grades. Emerging targeted therapies may prove useful in refractory meningiomas and are discussed in the context of relevant biology and ongoing clinical trials.
Hormonal therapy, chemotherapy, or targeted therapy in the context of treating patients with meningioma is confined to recurrent disease otherwise considered inoperable or refractory to radiotherapy. These various therapies in other cancer settings have been administered in four contexts (i.e., neoadjuvant, chemoradiation, adjuvant, and salvage). When administered before surgery to downstage cancer, such as breast or head and neck cancer, such therapy is termed neoadjuvant. When administered with concomitant radio-therapy, as in the upfront treatment of glioblastoma, it is referred to as chemoradiation. Adjuvant therapy is used with hormonal, chemo-, or targeted therapy and follows resection, as in breast or lung cancer. Lastly, salvage therapy is administered for recurrent disease after failure of up-front treatment usually including surgery, radiotherapy, and chemotherapy. As well, therapy may be conceptually considered as cytotoxic (resulting in net cell kill and radiographic shrinkage) or cytostatic (antiproliferative and radiographically disease stabilizing). At present and as is discussed here, there are no compelling data to suggest a role for hormonal, chemo-, or targeted therapy for meningiomas in the context of neoadjuvant or adjuvant therapy or as a component of chemoradiation. Consequently, these therapies are confined to patients with recurrent meningiomas refractory to radiotherapy and considered inoperable. In addition, contemporary medical therapy of recurrent meningiomas remains at best cytostatic and of relatively short durability (i.e., palliative) when compared with outcomes following surgical resection or radiotherapy. The management of recurrent meningioma has utilized reoperation, radio-therapy, or stereotactic radiosurgery. However, there exists a subset of patients with recurrent meningioma desirous of further treatment in whom both surgical and radiotherapy options have been exhausted. It is in these patients that chemo-hormonal-targeted therapy may be considered.
Both epidemiological (female predominance) and biochemical evidence (70% of meningiomas are progesterone receptor positive and 10 to 30% are estrogen receptor positive) suggest meningioma growth may be hormone dependent ( Table 42.1 ).1–9 Additionally, ~60% of meningiomas show staining of prolactin receptors.1–9 As a consequence, a variety of hormonal therapies have been utilized in the treatment of recurrent benign meningiomas not amenable to further surgery or radio-therapy. The oral progesterone agonist megestrol acetate (megace) was used in a small trial of nine patients with no observed response.7 Subsequently, in a trial of 14 patients, the progesterone antagonist mifepristone (RU-486) was utilized.6 Five objective minor responses were seen, though availability of mifepristone limited further study. The Southwest Oncology Group (SWOG) completed a study of mifepristone for unresectable meningiomas (198 total patients, of whom 160 were evaluable).6 The results did not support a role for RU-486 as compared with placebo (median progression-free survival was 10 months in the RU-486 arm and 12 months in the placebo arm). In addition, SWOG reported on a phase 2 trial of 21 meningioma patients treated with oral tamoxifen, an estrogen receptor antagonist.5 One patient achieved a partial response, two patients had a minor response, and six patients had stable disease for > 6 months.
There has been interest in the role of growth hormone (GH) on meningiomas since the initial observation that the incidence of meningiomas may be increased in patients with acromegaly.10 GH secreted by the pituitary gland stimulates the synthesis of insulin-like growth factor-1 (IGF-1) in the liver, and together GH and IGF-1 facilitate normal growth. Growth hormone receptors (GHRs) are ubiquitous in meningiomas, and inhibition of the GHR decreases tumor growth in vitro.1–4,10 Pegvisomant, a pegylated GH analogue that acts as a competitive antagonist of the GHR, significantly inhibited the growth of meningioma xenografts in nude mice.10 Tumor IGF-1 concentrations did not vary with pegvisomant treatment, and there was no autocrine IGF-1 production by the tumors. The antitumor effect was thought to be a consequence of decreased IGF-1 in the circulation and/or surrounding host tissues. Direct blockade of the GHR on meningioma cells may contribute to the antitumor effect as well. Whether pegvisomant can inhibit meningioma growth in patients remains to be established.
Recombinant interferon-α (IFN-α) has been found to inhibit the growth of cultured human meningioma cell lines in vitro.11,12 Four small reports, two in abstract, have been published.12 In the largest report, 35 patients with recurrent unresectable and previously irradiated meningiomas were treated. IFN-α was considered a reasonable alternative therapy for refractory recurrent meningioma based on the data already presented, in addition to evidence suggesting antiproliferative, immunomodulatory, and antiangiogenic properties.12 Toxicity was modest in this trial and consisted mainly of fatigue that resulted in dose reduction (seven patients), institution of psychostimulant medication (10 patients), and early discontinuance of therapy (three patients).12 Based on neuroradiographic response, it appears that IFN-α functions as a cytostatic antimeningioma agent because there was no evidence of either a complete or partial radiographic response; rather, the best response seen was stable disease. Nonetheless, meaningful palliation was achieved, as reflected by a 6-month progression-free survival (PFS) of 54%, surpassing the study primary objective of 40% PFS at 6 months. Although no radiographic responses were seen, 74% demonstrated stable disease with a median PFS of 7 months (6-month and 12-month PFS were 54% and 31%, respectively). Median overall survival was 8 months (range 3 to 28 months).
Hydroxyurea, an oral ribonucleotide reductase inhibitor, arrests meningioma cell growth in the S phase of the cell cycle and induces apoptosis.13–1 7 In a preliminary report by Schrell et al, hydroxyurea (1000 to 1500 mg/day; 20 mg/kg/day) decreased tumor size in three patients with recurrent benign meningiomas and prevented recurrent disease for 24 months in a patient with a completely resected malignant meningioma.13 Several more recent studies ( Table 42.2 ) suggest that hydroxyurea has modest activity; responses are uncommon but some patients appear to have disease stabilization.14–1 7 Additionally, hydroxyurea has been demonstrated to have modest and acceptable toxicity in patients with recurrent meningioma manifested primarily as fatigue and treatment-related anemia. SWOG conducted a phase 2 study to further evaluate the role of hydroxyurea in meningiomas (SWOG-S9811). This study is closed to accrual but the final results are not yet available. Problematic with the various hydroxyurea trials, however, is that many patients had not failed radiotherapy or that radiotherapy was administered concurrently.
Rengel has demonstrated that the calcium channel antagonists verapamil, nifedipine, and diltiazem can block in vitro and in vivo meningioma growth at clinically relevant doses.18 However, only modest growth inhibition was exhibited in the tumors in these studies with calcium channel antagonists alone. Additionally, many authors have shown augmented growth inhibition by adding calcium channel antagonists to traditional chemothera-pies in other tumor types.18 Calcium channel antagonists seem to exert the majority of their antitumor effects by inhibiting calcium-dependent secondary messenger systems.18 Recently, Jensen has demonstrated that the use of verapamil or diltiazem with hydroxyurea enhances the growth inhibition of meningiomas seen with these drugs in vitro and in vivo. A clinical trial combining hydroxyurea and verapamil testing the aforementioned hypothesis for recurrent meningioma has recently opened and is actively accruing patients ( Table 42.3 ).
In a recent prospective phase 2 study of temozolomide (a DNA-damaging agent that methylates the O6 position of guanine), an oral agent with modest toxicity and known activity in a variety of gliomas, no clear activity was seen in patients with refractory meningioma no longer considered operable or having progressed following radiotherapy.19 The schedule of temozolomide (TMZ) attempted to optimize tumor drug exposure by exploiting a chronic daily schedule (75 mg/m2/day for 42 days administered every 56 days) permitting a nearly 2.5-fold increase in TMZ dose intensity as compared with the standard 5-day schedule given every 28 days.19 Notwithstanding these presumed pharmacological benefits, no patients demonstrated PFS at 6 months, the primary study objective. As a consequence, the study was terminated following enrollment of the first 16 patients. Based on the results of this study, TMZ does not appear to have activity against recurrent meningiomas, suggesting a need for further phase 1/2 chemotherapy trials for this common primary brain tumor.
A recent prospective phase 2 study used CPT-11 (Camp-tosar [Pfizer, Inc., New York, NY]; irinotecan), an intravenous topoisomerase 1 inhibitor with modest toxicity and activity in intermediate-grade glial tumors, for refractory recurrent World Health Organization (WHO) grade I meningiomas progressing despite prior surgery and radiotherapy.20,21 The trial was based on significant activity seen in vitro, suggesting antimeningioma activity.20 In addition, this study differs from hydroxyurea-based chemotherapy trials of recurrent meningioma mentioned earlier in that all patients had evidence of progressive disease despite previous surgery (50% of patients underwent a second resection) and radiotherapy (all patients received prior external beam radiotherapy and 35% were treated in addition with stereotactic radiotherapy). Though only 50% of patients had reconfirmation of initial pathology, it seems reasonable to assume that the patients in this series are representative of patients with treatment-refractory recurrent meningiomas. The schedule of CPT-11 utilized (once every 3 weeks) is one of two commonly used; however, no differences with respect to tumor response between weekly versus every-3-weeks schedules of CPT-11 administration are seen.21 Toxicity was manageable using this CPT-11 schedule, as reflected by no patient requiring a CPT-11 dose reduction, no delays in therapy, and no treatment-related deaths. This suggests that this regimen may be used with moderate toxicity not otherwise affecting treatment. Nonetheless, only a single patient demonstrated PFS at 6 months, the primary study objective. As a consequence, the study was terminated following enrollment of the first 16 patients. Based on the results of this study, CPT-11 does not appear to have activity against recurrent WHO grade I meningiomas, suggesting a need for further trials with other agents for this common primary brain tumor. However, because no aggressive or malignant meningiomas were treated, these results should not be extrapolated to this patient population.
Multidrug chemotherapy trials for recurrent meningiomas, whether aggressive, malignant, or refractory to surgery and radiotherapy, are scant.8,9,22 The best-documented chemotherapy regimen (cyclophosphamide, adriamycin, and vincristine) has been used primarily in an adjuvant setting for the treatment of malignant meningiomas; however, without a control group, the results are difficult to interpret.22 Other published regimens do not report response rates, length of response, or toxicity data and therefore should be regarded as investigational.8,9,22 Unpublished data from a small number of patients from a phase 2 SWOG trial for aggressive meningeal tumors and malignant meningiomas with ifosfamide/mesna disulfide did not show initial promise.