American Society of Clinical Oncology 2010: report of selected studies from the CNS tumors section

Abstract

A number of important studies were presented at the CNS tumors section of the 2010 American Society of Oncology (ASCO) Annual Meeting. There was particular interest in a Phase II study showing that the mTOR inhibitor everolimus had significant activity in tuberous patients with subependymal giant cell astrocytomas. Two Phase III studies reported on the relative benefits of radiotherapy and chemotherapy in elderly patients with glioblastomas. Other studies focused on promising new agents such as XL184 and ANG1005.

The CNS tumors section of the 2010 American Society of Clinical Oncology Annual Meeting was notable for a major advance in treating subependymal giant cell astrocytomas (SEGAs) in tuberous sclerosis patients [1], as well as progress in therapies for several other types of brain tumors, including medulloblastomas and glioblastomas, especially in elderly patients.

Tuberous sclerosis is an autosomal dominant condition characterized by mutations in TSC1 or TSC2, leading to increased signaling through the mTOR pathway. Up to 15% of tuberous sclerosis patients have SEGAs. These slow growing tumors are often located near the foramen of Monro and can lead to hydrocephalus and even sudden death. Franz and colleagues conducted a Phase II study of the mTOR inhibitor, everolimus, in 28 patients with enlarging SEGAs [1]. The everolimus dose (3 mg/m2 daily orally) was titrated according to tolerability to achieve target trough concentrations of 5–15 ng/ml. The results were striking. Virtually all the patients showed some reduction in tumor size, with 78% of patients achieving the prespecified 30% or greater reduction at 6 months. Nine out of 16 patients who had video EEG experienced seizure reduction. The drug was well tolerated and offers a viable alternative to surgical resection. This study provided an excellent example of the successful use of a targeted molecular agent inhibiting a pathway known to be critical in driving the growth of a particular tumor.

Brandes reported the results of a Phase II trial involving 95 adults with medulloblastoma, another rare brain tumor [2]. Low-risk patients treated only with craniospinal radiation had a progression-free survival (PFS) at 5 and 10 years (PFS-5y and PFS-10y) of 78 and 46%, while high-risk patients treated with two cycles of ‘up-front chemotherapy’ (cisplatin 25 mg/m2/day for 4 days, etoposide 40 mg/m2/day for 4 days and cyclophosphamide 1000 mg/m2 on day 4; every 4 weeks) before craniospinal radiation followed by maintenance chemotherapy had a PFS-5y and PFS-10y of 58 and 36%, respectively. Given the paucity of studies in adult medulloblastomas, this trial provided useful data for comparison with future studies. However, issues regarding the value of adjuvant chemotherapy in low-risk patients, as well as the relative benefits of preirradiation chemotherapy compared with postirradiation chemotherapy in adult medulloblastoma patients, remains unresolved.

There were a number of abstracts focused on advances in antiangiogenic therapies. Wen et al. presented the interim data on a Phase II study of XL184 [3]. There is increasing evidence that a subset of patients treated with anti-VEGF agents have an invasive, nonenhancing phenotype [4]. XL184, a VEGF receptor 2 (VEGFR2) and MET inhibitor, potentially targets both angiogenesis and tumor invasion. Two cohorts of patients, one receiving XL184 175 mg daily and a second cohort receiving XL184 125 mg daily, were examined. Both groups showed a high response rate in patients not treated with prior antiangiogenic agents; 21% for the 175?mg group and 30% for the 125?mg group. The 6-month PFS (PFS6) was at least 25% in the 125?mg group. The 125?mg dose appeared to be better tolerated than the 175?mg dose without a reduction in efficacy. XL184 also appeared to have modest activity in patients treated with prior antiangiogenic therapies. In addition, a relatively small number of patients developed distant or diffuse disease at progression, suggesting that XL184 may have anti-invasive effects.

Cloughesy et al. presented the updated results of the BRAIN study, the randomized Phase II study of bevacizumab versus bevacizumab and irinotecan in recurrent glioblastomas that contributed to the accelerated approval of bevacizumab in 2009 [5]. The median overall survival (OS) was 9.3 months (95% CI: 8.2–11.8) in the bevacizumab arm and 8.9 months (95% CI: 7.9–11.9) in the combination arm. Up to 16% of patients remained alive at 30 months. The incidence of selected adverse events was consistent with that previously reported, and no new safety signals were identified.

A number of previous studies suggested that a subset of patients treated with anti-VEGF agents developed an invasive, nonenhancing tumor at the time of recurrence [4]. Some studies at this meeting confirmed these findings [6], but others did not [7]. It is possible that differences in the methodology used to define distant and diffuse recurrence may have contributed to some of these discrepancies.

The incidence of elderly patients with high-grade gliomas is increasing. The optimal treatment for this group of patients is unknown as they tend to respond less well to standard therapies and have a worse prognosis. Previous studies suggest that radiotherapy is beneficial [8], but that an abbreviated course of treatment (45 Gy in 3 weeks) may be equivalent to the standard 6 weeks of therapy [9]. Several small Phase II studies also suggested that temozolomide alone may be as effective as radiotherapy [10]. The Neuro-oncology Working Group (NOA)-08 trial of the German Cancer Society (Frankfurt, Germany) compared standard postsurgical involved-field radiotherapy to a dose of 54–60 Gy in patients with anaplastic astrocytoma or glioblastoma aged over 65 years with a Karnofsky performance score of 60 or higher, with temozolomide using a 1 week on/1 week off schedule at 100 mg/m2 [11]. The trial involved 373 patients and sought to demonstrate the noninferiority of temozolomide compared with radiotherapy. Instead, they found that patients in the temozolomide arm had an increased risk of death (HR: 1.24; 95% CI: 0.94–1.63) compared with patients in the radiotherapy arm, as well as an increased incidence of adverse events, suggesting that radiotherapy is preferable in this population.

Malmstrom et al. presented another Phase III study evaluating the optimal therapy in elderly patients with newly diagnosed glioblastomas [12]. A total of 342 patients aged 60 years or older were randomized to either standard radiotherapy (60 Gy in 2-Gy fractions over 6 weeks), hypofractionated radiotherapy (34 Gy in 3.4-Gy fractions over 2 weeks) or six cycles of chemotherapy with temozolomide (200 mg/m2 day 1–5 every 28 days). There was no significant difference in OS between the three treatment arms, with median survival being 8 months for temozolomide, 7.5 months for hypofractionated radiotherapy and 6 months for 6 weeks radiotherapy (p = 0.14). The authors concluded that hypofractionated radiotherapy is preferable to standard 6-week radiotherapy in elderly patients, consistent with the prior study by Roa et al.[9]. In contrast to the NOA-8 study, temozolomide monotherapy was not inferior to radiotherapy and appeared to be an option for elderly patients with glioblastomas. As a result, the relative value of temozolomide compared with radiotherapy in this group of patients remains unresolved.

Results of a number of novel agents were also presented. Drappatz et al. conducted a Phase I study of ANG1005 in patients with recurrent glioblastomas. ANG1005 consists of three paclitaxel molecules linked to a novel peptide, angiopep, that allows it to be transported across the blood–brain barrier via the low-density lipoprotein receptor-related protein 1 receptor [13]. The drug was fairly well tolerated and appeared to display good activity. Intratumoral drug concentrations were significantly higher than plasma concentrations, providing evidence that it was able to penetrate across the blood–brain barrier. In a Phase II study of CT322, an adnectin targeting VEGFR2, alone or with irinotecan, there appeared to be activity with a PFS6 of 32.1% with fairly good tolerability [14].

NovoTTF® (NovoCure, Israel) is a portable medical device delivering low-intensity, intermediate frequency alternating electric fields using disposable scalp electrodes. These tumor treatment fields potentially physically interfere with cell division and the assembly of organelles. Stupp et al. conducted a Phase III trial of 237 patients comparing NovoTTF with best standard chemotherapy in patients with recurrent glioblastomas [15]. The study failed to reach its primary end point. Median OS was 6.6 months for NovoTTF compared with 6.0 months for best standard care, although the NovoTTF group had a slightly higher response rate and a nonsignificantly longer time to treatment failure. These results suggest that this device does not display activity in recurrent glioblastomas alone; whether it shows activity in combination with other agents remains to be determined.

Financial & competing interests disclosure

Patrick Y Wen has received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, Novartis, Angiochem and Merck. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.