Neuro-oncology: a selected review of ASCO 2011 abstracts

Abstract

American Society of Clinical Oncology (ASCO), the largest clinical oncology meeting in the USA, meets annually and consistently provides an exciting forum to present new cancer clinical trials and research data. The ASCO 2011 neuro-oncology session, comprising of 3 days of presentations and over 100 abstracts, provided an overview of neuro-oncology, including both metastatic diseases of the CNS and primary brain tumors. This brief article attempts to highlight select abstracts presented at this years meeting in an organizational manner that will hopefully provide a portrait of the large and multifaceted meeting.

Keywords::

• ASCO 2011 neuro-oncology abstracts
• primary and secondary brain tumors

Metastatic disease of the CNS

Parenchymal brain metastases

Three abstracts were presented, two regarding the use of the biodegradable carmustine wafer, Gliadel^®, implanted at the time of brain metastases (BM) resection and one evaluating the combined use of erlotinib, a tyrosine kinase EGF receptor (EGFR) inhibitor, with whole-brain irradiation (WBI) for BM resulting from non-small-cell lung cancer [1–3]. A prospective single-arm Phase II trial of one to three BM treated with surgical resection, Gliadel implantation, stereotactic radiotherapy (RT) and deferred WBI evaluated neurocognitive outcome in 59 patients [1]. The results suggested improvement in all three cognitive domains (memory, executive function and fine motor) following treatment as compared with baseline. In a retrospective study of 49 patients with BM treated with surgical resection, Gliadel implantation and WBI, local control was improved compared with an institutional historical control cohort treated with surgery and WBI only [2].

A study of 40 patients with BM and non-small-cell lung cancer using erlotinib and WBI followed by erlotinib only suggested an improved overall survival (OS) relative to historical controls (10.9 vs 3.9 months) [3].

Leptomeningeal disease

Five abstracts of special note were presented, three concerned with diagnosis and two with treatment of leptomeningeal disease (LMD) [4–8]. In a study of 80 women with breast cancer and LMD, cerebrospinal fluid (CSF) CA15-3 was found diagnostically useful; however, the relationship to CSF cytology or MRI was not presented, making a determination of the utility of CSF CA15-3 difficult [4]. A retrospective study of 21 patients suggested that CSF lactate, assessed by ventricular magnetic resonance spectroscopy, may be both sensitive and specific for LMD. However, whether CSF lactate determinations are useful compared with magnetic resonance spectroscopy obtained lactate levels was not mentioned in the abstract [5]. Another retrospective study suggested that CSF cytology is most useful (as determined by the likelihood ratio) in patients with cancer (n = 81) and neurological findings compatible with LMD, as contrasted with patients without cancer (n = 403) or patients with cancer and no neurological symptoms (n = 41) [6]. A retrospective study of 120 patients with LMD treated with intra-CSF liposomal cytarabine (80 by intraventricular and 40 by intralumbar administration) demonstrated a 14% incidence of permanent treatment-related neurological deficits, probably reflecting the long half-life of the chemotherapy and suggesting caution when using this agent [7]. Last, a large retrospective study of 96 women with breast cancer-related LMD demonstrated that median survival was 3.5 months and survival was improved in women with good performance status, those who were HER2/neu negative or did not have triple negative breast cancer, and those who received timely LMD-directed therapy – that is, intra-CSF and systemic chemotherapy and RT [8].

Primary brain tumors

Meningioma

Two abstracts were presented regarding the treatment of surgery and radiation refractory recurrent meningioma with SOM230 (pasireotide; n = 26; 17 with high-grade meningiomas) or PTK787 (vatalanib; n = 21; all with high-grade meningiomas). Both studies utilized targeted therapies; SOM230 is a somatostatin receptor agonist and PTK787 is a multifunctional tyrosine kinase inhibitor with anti-VEGFR2 activity [9,10]. The overall radiographic response was meager (0% with SOM230; 5.8% with PTK787), although median progression-free survival (mPFS) was similar in both (˜4 months). PTK787 had a superior 6-month progression-free survival (PFS-6) of 37.5 versus 20% for SOM230. These studies represent an evolving trend in neuro-oncology for using novel molecular targeted therapies for primary brain tumors.

Medulloblastoma

All three articles presented related to treatment, two regarding upfront treatment and one at recurrence [11–13]. Head Start III, an adjuvant dose-intense chemotherapy regimen (vincristine, cisplatin, cyclophosphamide, etoposide and high-dose methotrexate) with high-dose conditioning chemotherapy (carboplatin, etoposide and thiotepa) and peripheral stem cell transplantation, was utilized in a multinational multi-institutional study of 92 children [11]. RT was deferred in all but patients over the age of 6 years with incomplete responses following adjuvant chemotherapy. Event-free survival at 3 years (47%) surpassed that seen in prior studies, including similar Head Start I and II trials, suggesting the feasibility of this approach for childhood medulloblastoma and the need for a randomized trial comparing it to standard infant/childhood adjuvant treatment regimens. Another small study evaluated an attenuated chemotherapy regimen for postcraniospinal irradiation treatment that utilized nine alternating cycles of three noncross resistant chemotherapies (vincristine, temozolomide and etoposide; vincristine and cyclophosphamide; and vincristine and carboplatin) [12]. The utility of this study is to be examined in a larger randomized trial. Last, a small study (n = 47) suggested that recurrent medulloblastoma in a contemporary series is frequently metastatic (86% of patients in this small series) and more common than historically appreciated, presents on average 18 months after initial surgery and diagnosis, has a median OS of 6.8 months and a 3-year survival of 19% [13].

Primary CNS lymphoma

Three articles were derived from the large (n = 411) German primary CNS lymphoma randomized trial of high-dose methotrexate (HD-MTX) with or without ifosfamide followed in patients with a complete response to observation or whole brain RT [14–17]. The trial demonstrated no advantage to upfront RT and was further analyzed with respect to prognostic variables affecting survival, as well as chemotherapy-related toxicity [18]. Prognosis was primarily a function of age (< or > 60 years) and Karnofsky performance status (< or > 70) and secondarily of gender (female OS > male OS) and BMI [14]. These results recapitulate prior published data that was derived from a retrospective review of a large database [15]. Similarly, chemotherapy-related toxicity was a function of low performance (<70), advanced age (>60 years), receipt of HD-MTX and ifosfamide (compared with HD-MTX only), elevated serum LDH and pre-existing pulmonary or cardiovascular disease [16]. The German primary CNS lymphoma study also analyzed whether evidence of CSF dissemination at diagnosis affected outcome as determined by CSF cytology, polymerase chain reaction (PCR) gene rearrangement or MRI [17]. Despite no intra-CSF chemotherapy being administered in this study, outcome in the 19% of patients with CSF dissemination was similar to that of patients without evidence of CSF dissemination. Two articles concerned recurrent disease and treatment [19,20]. In a single institution study (n = 38), re-challenge with HD-MTX in patients previously responding to HD-MTX re-responded with a mPFS of 12 months and an overall radiologic response of 84% [19]. In a small (n = 16) Adult Brain Tumor Consortium trial, the combination of temozolomide (TMZ) and rituximab proved ineffective with an mPFS of 7 weeks [20].

Gliomas

Low-grade gliomas

Two studies were notable, one evaluating the effect of RT treatment on seizure control and the other identifying a new low-grade glioma (LGG) entity, the so-called triple-negative LGG [21,22]. RT, administered to nearly all patients with LGG, has been suggested as having salutatory benefits with regard to control of tumor-related epilepsy. In a small study of 40 patients with pretreatment epilepsy, nearly 70% improved following the administration of RT, suggesting that seizure control (defined as a greater than 50% reduction in seizures) may indeed be achieved by RT [21]. Metellus et al. define triple negative LGG as gliomas without 1p19q codeletion and possessing wild-type p53 and IDH1/2, a molecular signature that predicts poor outcome and is more commonly seen in older patients with LGG and large infiltrative tumors of the insula [23]. Molecular stratification of LGG has not yet entered clinical trials, but will probably be relevant with future studies.

Anaplastic gliomas

A newly diagnosed trial, the Temozolomide and BCNU for Newly Diagnosed Anaplastic Oligodendroglioma (TEMOBIC) study by the French Association des Neuro-Oncologues d’Expression Française consortium evaluated 54 patients with anaplastic oligodendroglial tumors treated with the combination of TMZ and carmustine (BCNU) for six cycles followed by consolidative RT [24]. Overall radiologic response for chemotherapy was 38%, mPFS was 15.4 months and median OS (mOS) 25 months. Grade 3 or higher heme-related toxicity was 50 and 6% of patients sustained a treatment-related death. The utility of this approach is uncertain given the large randomized trials that have recently opened for newly diagnosed anaplastic gliomas (AG) – that is, the Uni- or Non-1p19q Deleted Trial for Newly Diagnosed Anaplastic Glioma (CATNON; RT with or without TMZ followed by observation or TMZ) for non- or uni-deleted AG and the 1p19q Codeletion Trial for Newly Diagnosed Anaplastic Gliomas (CODEL; randomization to TMZ vs RT vs TMZ plus RT) for codeleted AG. A retrospective review of 96 elderly (aged >65 years) patients with AG suggests poor survival in patients with anaplastic astrocytoma (mOS: 5.4 months), as well as in patients with compromised performance status (Karnofsky <70) [25].

Glioblastoma

Upfront trials

Table 1 outlines the 15 clinical trials presented regarding the treatment of newly diagnosed glioblastoma (GBM) (Table 1)[24–40]. The most anticipated trial, RTOG 0525, was a randomized trial of 833 patients comparing post-RT standard dose TMZ (sdTMZ; standard of care [SOC]) to dose-dense TMZ (ddTMZ) [24]. No statistical difference was seen between these arms with respect to mPFS (5.5 vs 6.6 months), mOS (18.9 vs 16.8 months) or in methylation status. In addition, there was increased toxicity in the ddTMZ arm (grade 3+: 27 vs 19%). The study did confirm in a prospective manner the predictive value of methylguanine methyltransferase (MGMT) methylation in newly diagnosed GBM. Two other randomized Phase III trials were presented, the nimotuzumb (an EGFR monoclonal antibody) trial and the Avastin for Newly Diagnosed Glioblastoma (AvaGlio) trial (upfront bevacizumab in conjunction with SOC), which recently completed accrual, but are without outcome results [25,26]. The nimotuzumab trial compared standard therapy (RT plus TMZ followed by TMZ) with or without nimotuzumb in 150 patients [25]. No survival advantage was seen, although in a subset analysis of tumors with amplified EGFR (˜20% of all GBM), a suggestion of improved outcome was reported (14.9 vs 19.4 months). Eight trials (nine including the AvaGlio trial) were presented; however, all represent work in progress and consequently had no outcome results [26–29,31,32,34–36]. The majority of these trials are single institution and single arm utilizing upfront bevacizumab or cilengitide (an integrin inhibitor) with SOC. A novel trial design treated 57 patients with unmethylated MGMT and utilized enzastaurin (a protein kinase C inhibitor) in conjunction with RT followed by enzastaurin [30]. This represents the first completed trial of newly diagnosed patients with GBM selected for MGMT status and deferring TMZ use based on prior studies, suggesting little benefit from TMZ in this patient cohort [41]. Using PFS-6 as the primary end point, the study failed to achieve the primary objective. Two other small trials addressed novel approaches to newly diagnosed GBM [37,38]. In one, a radiation sensitizer paclitaxel polyglutamate polymer was utilized during TMZ-based chemoradiotherapy (CRT) and judged to sensitize the tumor based upon the high incidence of apparent pseudoprogression [37]. In the second trial, a dendritic cell vaccine was used post-RT and generated by the use of six tumor-associated antigens. mPFS in this highly selected cohort was 16 months and as a result is being taken forward as a randomized Phase II study [38]. Three population-based studies were presented [42–44]. In a Canadian study of 433 patients, only 44% received the SOC (CRT) for newly diagnosed GBM [42]. An analysis of the Surveillance, Epidemiology and End Results database of 7022 patients revealed an improvement in mOS and 2-year OS over three epochs (2000–2001, 2002–2003 and 2005–2006) suggesting continued improvement in care over time with the introduction of CRT [43]. In an Austrian database, a similar improvement of OS was seen in the contemporary cohort treated with CRT (n = 375) compared with a historical control treated primarily with RT only [44].

Salvage trials

Table 2 outlines the 12 clinical trials presented regarding the treatment of recurrent GBM (Table 2)[45–56]. In the only randomized trial, afatinib, an irreversible tyrosine kinase EGFR inhibitor, was compared with ddTMZ and to the combination of ddTMZ and afatinib in 120 patients with first recurrent GBM [45]. Afatinib was found not to be active, whereas ddTMZ with or without afatinib demonstrated a PFS-6 of approximately 20%, a result not dissimilar to the Canadian TMZ re-challenge RESCUE trial [57]. In an analysis of patients with overexpressed variant 3 EGFR, a suggestion of afatinib response was observed. In a small study of 48 patients with recurrent GBM, ddTMZ was utilized and demonstrated similar efficacy to that seen in the afatinib trial (mPFS: 10 weeks; PFS-6: 23%) [49]. A Phase I study evaluated the novel nitrosourea, laromustine, given in combination with ddTMZ and determined a maximum tolerated dose of laromustine (100 mg/m² every 4 weeks) in combination with ddTMZ [56]. Five articles discussed the continuing use of bevacizumab for recurrent GBM [46,47,50,53,55]. In three trials of these articles, a novel partner (fotemustine, a nitrosourea; bortezomib, a proteasomal inhibitor; or panobinostat, a histone deacetylase inhibitor) was combined with bevacizumab [46,50,55]. Results appear not dissimilar to single agent bevacizumab; however, increased toxicity was observed. Another study combined bevacizumab with stereotactic RT, suggesting both feasibility and efficacy not dissimilar to a prior published article [53,58]. In a large study of 95 patients treated following failure on bevacizumab, outcome was compared in two subgroups. In one subgroup (53 patients), treatment entailed the continuation of bevacizumab with another agent, while in the comparator group (42 patients) treatment with bevacizumab was discontinued and another treatment administered. mOS was 6.1 months in the bevacizumab continuation group compared with 4.5 months in the bevacizumab discontinuation group, suggesting a marginal advantage to continuing bevacizumab. Four articles utilized novel agents to treat bevacizumab-naive patients with recurrent GBM [48,51,52,54]. A combination of sorafenib (a multifunctional tyrosine kinase inhibitor that has anti-VEGF receptor activity) and temsirolimus (an mTOR inhibitor) was found to be inactive (mPFS: 2.6 months; mOS 4.2 months) and toxic in 37 patients [48]. Similarly, a study of 36 patients with sorafenib and metronomic (low dose daily) TMZ demonstrated limited activity, similar to the aforementioned trial of sorafenib and temsirolimus [52]. A study of 31 patients with the novel mitotic spindle and vascular disrupting agent verubilin was found to be inactive (mPFS: 1.8 months). Last, an interesting trial of the novel nitrosourea fotemustine in 119 patients suggested similar activity to that of the Canadian TMZ RESCUE trial wherein three groups of patients were analyzed with respect to failure on sdTMZ (progression on sdTMZ and within 6 months of completion of CRT; progression on sdTMZ while on post-RT sdTMZ for >6 months and progression after completion of post-RT sdTMZ) [51,57]. These data confirm the nitrosourea to be a valid salvage therapy for GBM progression following sdTMZ similar to that reported in the enzastaurin and cediranib trials [28,59].

Molecular correlatives

Five articles were presented in relation to molecular correlatives, four concerning GBM and one AG [60–64]. In an analysis of the German Glioma Network database, 233 elderly patients (median age: 74 years) underwent MGMT promoter methylation determination by two methods: DNA pyrosequencing and methylation-specific polymerase chain reaction (MSP-PCR) [61]. Interestingly, MGMT promoter methylation was found to be more common in the elderly (58%) and, as seen in other adult cohorts, had improved survival when treated with TMZ only or CRT. No benefit was seen with the administration of TMZ to the unmethylated MGMT elderly patients. Last, MGMT methylation appeared predictive of response to TMZ in the elderly. In a study of 418 patients with GBM treated primarily with CRT, a combined analysis of MGMT was assessed using immunohistochemistry (IHC; <30%>), a measure of protein expression and promoter methylation by both MSP-PCR (9 CpG sites interrogated) and bisulfite sequencing (BiSeq; 24 CpG sites investigated) [63]. All three determinations were predictive individually; however, BiSeq was superior to MSP-PCR, which was superior to IHC. The combination was most predictive and outcome of patients with low IHC expression was a function of promoter methylation status. A small study of 15 patients with paired tumor samples obtained at initial surgery and at time of recurrence analyzed for MGMT methylation status demonstrated concordance for the majority of patients (>85%) [64]. In an analysis of the RTOG 0525 trial, four molecular biomarkers were defined in 82% of all submitted tumors: MSP-PCR, glioma CpG island methylation phenotype, a microarray mRNA-based panel of 19 genes and IDH1/2 mutational status [60]. Using this biomarker panel, four molecular classes were defined, each with a distinct mOS ranging from 12 to 26 months. This aggregate biomarker panel may prove useful for future stratification of newly diagnosed GBM. Last, in a small study of 43 anaplastic oligodendroglial tumors, isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations were found in 56% of tumors and were associated with improved PFS and OS relative to wild-type IDH1/2 tumors, suggesting that IDH1/2 mutational status is a prognostic molecular signature in AG [62].

Table 1. Up-front glioblastoma trials.

Study (year)	Treatment	Trial design	Enrollment	Outcome	Ref.
Gilbert et al. (2011)	CRT + sdTMZ vs ddTMZ	Randomized Phase III	833	No advantage to ddTMZ	[24]
Bach et al. (2011)	SOC ± nimotuzumab	Randomized Phase III	150	No survival advantage; survival advantage in EGFR amplified	[25]
Chinot et al. (2011)	SOC ± Bev	Randomized Phase III	800+	Completed, no data	[26]
Verschaeve et al. (2011)	SOC + cilengitide vs cetuximab	Randomized Phase II	108	In progress	[27]
Chauefert et al. (2011)	Neoadjuvant Bev + CPT-11	Randomized Phase II	134 unresectable	In progress	[28]
Hofland et al. (2011)	Neoadjuvant Bev + CPT-11 vs Bev + TMZ	Randomized Phase II	62	In progress	[29]
Wick et al. (2011)	Enzastaurin + RT	Phase II	57 unmethylated	Failed primary end point (PFS-6)	[30]
Khasraw et al. (2011)	Cilengitide + low-dose TMZ and PCB	Phase II	48 unmethylated	In progress	[31]
Omuro et al. (2011)	Hypofractionated SRT + Bev + TMZ	Phase II	40	In progress	[32]
Lou et al. (2011)	SOC + Bev ± CPT-11	Phase II	82 unresectable	No added benefit for CPT-11	[33]
Quant et al. (2011)	SOC ± vandetanib	Phase II	110	In progress	[34]
Beauchesnes et al. (2011)	Hyperfractionated RT + TMZ	Phase II	38 unresectable	In progress	[35]
Vredenburgh et al. (2011)	SOC + Bev + oral topotecan	Phase II	80 unresectable	In progress	[36]
Jeyapalan et al. (2011)	SOC + PPX	Phase II	25	Acceptable toxicity	[37]
Phuphanich et al. (2011)	DC vaccine + SOC	Phase II	25	mPFS: 16 months	[38]
deGroot et al. (2011)	VEGF trap + SOC	Phase I	48	MTD 4 mg/kg	[39]
Wen et al. (2011)	CRT + Vorinostat + TMZ	Phase I	59	MTD vorinostat	[40]

Bev: Bevacizumab; CPT-11: Camptosar (irinotecan); CRT: Concurrent radiotherapy and temozolomide; DC: Dendritic cell; ddTMZ: Dose-dense temozolomide; EGFR: EGF receptor; mPFS: Median progression-free survival; MTD; Maximum tolerated dose; PCB: Procarbazine; PFS-6: Progression-free survival at 6 months; RT: Radiotherapy; sdTMZ: Standard-dose temozolomide; SOC: Standard of care (chemoradiotherapy and postradiotherapy temozolomide); SRT: Stereotactic radiotherapy; TMZ: Temozolomide.

Table 2. Recurrent glioblastoma trials.

Study (year)	Treatment	Trial design	Enrollment	Outcome	Ref.
Eisenstat et al. (2011)	Afatinib vs TMZ vs combination	Randomized Phase II	120	Afatinib not active	[45]
Soffietti et al. (2011)	Fotemustine + Bev	Phase II	54	ORR: 48%; PFS-6: 44%; mOS: 9.1 mns	[46]
Reardon et al. (2011)	Bev continuation	Retrospective	172	mOS Bev vs non-Bev: 6.1 vs 4.5 mns, respectively	[47]
Jaeckle et al. (2011)	Sorafenib + temsirolimus	Phase II	37	ORR: 10%; mPFS: 2.6 mns; PFS-6: 13%; mOS: 4.2 mns	[48]
Hammond et al. (2011)	ddTMZ	Phase II	48	mPFS: 10 weeks; PFS-6: 23%	[49]
Bota et al. (2011)	Bortezomib + Bev	Phase II	61	PFS-6: 40.6%; mOS: 9.1 mns	[50]
Paccapelo et al. (2011)	Fotemustine	Phase II	119	PFS-6: 24.5–34.2%	[51]
Zustovich et al. (2011)	Sorafenib + mTMZ	Phase II	36	mPFS: 2.7 mns	[52]
Cuneo et al. (2011)	SRT + Bev	Phase II	15	In progress	[53]
Kim et al. (2011)	Verubilin	Phase II	31	ORR: 10%; mPFS: 1.8 mns	[54]
Drappatz et al. (2011)	Panobinostat + Bev	Phase I	12	MTD established	[55]
Raizer et al. (2011)	Laromustine (VNP40101M) + ddTMZ	Phase I	14	MTD established	[56]

Bev: Bevacizumab; ddTMZ: Dose dense temozolomide; mns: Months; mOS: Median overall survival; MTD: Maximum tolerated dose; mTMZ: Metronomic temozolomide; ORR: Objective radiographic response; PFS-6: Progression-free survival at 6 months; SRT: Stereotactic radiotherapy; TMZ: Temozolomide.

Financial & competing interests disclosure

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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