Radiotherapy and temozolomide for anaplastic astrocytic gliomas

Abstract

We previously reported results of a phase II non-comparative trial that randomized patients with glioblastoma following radiotherapy to one of two different temozolomide schedules, followed by 13-cis-retinoic acid (RA) maintenance. Here we report the results of an exploratory cohort of patients accrued with anaplastic astrocytic tumors. Patients with newly diagnosed anaplastic astrocytoma (AA) or anaplastic oligo-astrocytoma (AOA) were treated with concurrent radiotherapy (60 Gy over 6 weeks) and temozolomide (75 mg/m²), and six adjuvant 28-day cycles of either dose-dense (150 mg/m², days 1–7, 15–21) or metronomic (50 mg/m², days 1–28) temozolomide. Subsequently, maintenance RA (100 mg/m², days 1–21/28) was administered until disease progression. All outcome measures were descriptive without intention to compare between treatment arms. Survival was measured by the Kaplan–Meier method. There were 31 patients (21 men, 10 women) with median age 48 years (range 28–74), median KPS 90 (range 60–100). Extent of resection was gross-total in 35 %, subtotal 23 %, and biopsy 42 %. Histology was AA in 90 %, and AOA in 10 %. MGMT promoter methylation was methylated in 20 %, unmethylated in 50 %, and uninformative in 30 % of 30 tested. Median progression-free survival was 2.1 years (95 % CI 0.95–Not Reached), and overall survival 2.9 years (95 % CI 2.0–Not Reached). We report outcomes among a homogeneously treated population with anaplastic astrocytic tumors. Survival was unexpectedly short compared to other reports. These data may be useful as a contemporary historic control for other ongoing or future randomized trials.

Introduction

The standard treatment for newly diagnosed glioblastoma (GBM) is radiotherapy (RT) with concurrent temozolomide followed by adjuvant temozolomide [1]. However, the optimal treatment for anaplastic (WHO grade III) gliomas is not as well established.

Adjuvant (post-RT) temozolomide is conventionally dosed at 150–200 mg/m² for a 5/28-day cycle [2]. Temozolomide has demonstrated schedule-dependent anti-tumor activity and there has been significant interest in testing other dosing schedules to enhance cytotoxicity. O⁶-methylguanine-DNA methyltransferase (MGMT) is a DNA-repair enzyme encoded by the methylguanine methyltransferase (MGMT) gene. Protracted exposure of temozolomide, which targets the O⁶ position of guanine, may lead to cumulative and sustained MGMT depletion, thereby reducing temozolomide resistance [3]. More recent phase III trials have demonstrated no benefit of different schedules of temozolomide in recurrent high grade gliomas or newly diagnosed GBM [4, 5]. The trial described in the current report was designed before the results of those studies were available, and in patients with newly diagnosed anaplastic astrocytic tumors rather than GBM or recurrent tumors.

Separately, retinoids induce differentiation and apoptosis of glioma cells, as well inhibit cell proliferation and migration [6–8]. Accordingly, 13-cis-retinoic acid (RA) may help maintain disease control in treated patients with malignant glioma, as well as in those with recurrent disease [9].

In 2009, Clarke et al. published the results of a single-institution randomized non-comparative phase II trial of chemoradiation followed by 6-cycles of either “metronomic” or “dose-dense” temozolomide and then maintenance RA for newly diagnosed GBM [10]. Patients with anaplastic tumors were accrued to a separate arm to explore efficacy of these regimens in patients with other glioma subtypes. Here, we present the results from this exploratory cohort, specifically those with anaplastic astrocytic tumors (anaplastic astrocytoma, AA; or anaplastic oligo-astrocytoma, AOA).

Patients and methods

The eligibility criteria were published previously [10]. In brief, participation required age ≥18 years, diagnosis of treatment naïve (except surgery) newly diagnosed anaplastic (WHO grade III) glioma, normal bone marrow and end organ function, and Karnofsky Performance Status (KPS) ≥60. Following maximal safe surgical resection, protocol treatment started within 6 weeks which included concurrent RT (60 Gy ± 5 % without stereotactic boost) and temozolomide (75 mg/m² daily) followed by randomized (1:1) treatment to adjuvant temozolomide using either a “dose-dense” schedule (150 mg/m2 days 1–7 and 15–21 of 28) or metronomic (50 mg/m2 days 1–28 of 28) schedule. Patients who withdrew consent prior to randomized therapy were excluded. Following six adjuvant temozolomide 28-day cycles of either regimen, patients then received oral RA (100 mg/m2, days 1–21 of 28) until disease progression (MRI every other cycle using Macdonald criteria [11]), unacceptable toxicity (CTCAE 3.0), or withdrawal of consent. Supportive therapy including anti-emetics and growth factors were permitted per standard of care. Median progression-free and overall survival were was estimated by the Kaplan–Meier method; however, the study was not powered to compare treatment arms against each other or historic controls, and all statistical analyses were entirely exploratory in nature. When available, tumor tissue was analyzed for MGMT promoter methylation status by Oncomethylome Sciences (Amsterdam, the Netherlands). Informed consent was obtained from all individual participants included in the study (or appropriate surrogates) which was approved by the institutional review board of Memorial Sloan Kettering Cancer Center.

Results

Patient characteristics

Results among patients with GBM were published previously. Those with AA/AOA are reported here. Patients were enrolled from July 2005 through February 2011. There were 31 patients with a median age 48 years (range 20–74) and median KPS 90 (range 60–100). There were 21 men (68 %). Extent of resection, assessed by the treating investigator using the post-operative MRI, was gross-total in 11 (35 %), subtotal in 7 (23 %), and biopsy in 13 (42 %). Histology was AA in 28 (90 %). Chromosome 1p19q deletion status was assessed in 2 of 3 AOAs, and one had co-deletion. MGMT promoter methylation was assessed in 30 tumors (27 AAs, 3 AOAs), and was methylated in 6 (20 %), unmethylated in 15 (50 %), and uninformative in 9 (30 %).

Treatment

There were 14 randomized to dose-dense and 17 to metronomic adjuvant temozolomide. However, 6/31 did not proceed to adjuvant therapy because of either refusal (2) or early progression (4). Therefore, 25 received either dose-dense (11) or metronomic (14) adjuvant therapy, and 18 completed the proscribed 6 adjuvant temozolomide cycles without disease progression or unacceptable toxicity. However, 7/18 did not proceed to RA maintenance because of either refusal (5) or insurance denial coverage (2). One patient remained on adjuvant temozolomide at the time of the analysis.

Toxicity

The toxicity of concurrent RT and temozolomide has been well described and was not collected in this exploratory cohort. Adjuvant metronomic and dose-dense temozolomide was well-tolerated, with the grade 3 lymphopenia as most common serious treated related adverse event (10 events) (Table 1). Adverse events were more common in the metronomic temozolomide group. One patient discontinued treatment because of toxicity (grade 3 fatigue and GI intolerance) from dose-dense temozolomide. One patient developed a second malignancy (invasive squamous cell carcinoma), but this was considered unrelated to protocol therapy.

Table 1.

Adverse events attributable to temozolomide

Adverse events	Metronomic temozolomide (n = 17)		Dose-dense temozolomide (n = 14)
	Grade 3	Grade 4	Grade 3	Grade 4
Elevated liver enzymes	1	–	–	–
Constipation	1	–	–	–
Abdominal pain	–	–	1	–
Fatigue	2	–	2	–
Lymphopenia	6	1	4	2
Neutropenia	–	1	–	–
Thrombocytopenia	1	1	–	–

Survival

After a median follow up of 2.4 years (range, 0.4–5.4 years) and 18 deaths, the median overall survival (OS) was 2.9 years (95 % CI 2.0–Not Reached) and 1-year OS rate was 87 % (95 % CI 75–99 %) (Fig. 1, n = 31). Median progression-free survival (PFS) was 2.1 years (95 % CI 0.95–Not Reached) and 1-year PFS rate was 64 % (95 % CI 47–81 %). Outcome per arm is shown in Table 2 and Supplemental Fig. 1. The arms were not powered for comparison.

Fig. 1.

Overall survival (OS) and Progression-free survival (PFS) for all patients

Table 2.

Survival by arm

Cohort	Metronomic Temozolomide (n = 17)	Dose-dense temozolomide (n = 14)
Median OS	2.1 years (95 % CI, 1.5–4.6)	Not Reached
1-year OS	88 % (95 % CI, 73–100)	85 % (95 % CI, 66–100)
Median PFS	1.5 years (95 % CI, 0.7–3.4)	3.8 y (95 % CI, 0.3–No Upper Limit)
1-year PFS	59 % (95 % CI, 35–82)	71 % (95 % CI, 47–95)

Discussion

Following maximal surgical resection, chemoradiotherapy with temozolomide is the standard of care for newly diagnosed GBM [1]. We explored this approach in a prospective clinical trial for patients with anaplastic astrocytic tumors. An ongoing phase III study (CATNON—Concurrent and adjuvant temozolomide for 1p19q non-codeleted anaplastic gliomas) will definitively address the benefit of this approach in a similar population of patients, but results will not mature for several years.

Comparison with prior studies (Table 3) [12–19] is difficult because of heterogeneity of histology and treatment approaches. For example, a German phase III study (NOA-04) of anaplastic gliomas included patients with pure oligodendrogliomas, and also used sequential rather than concurrent radiotherapy and chemotherapy [14]; it was also published when results were relatively immature [20]. Moreover, in NOA-04, although the median PFS for patients with all histologies receiving either RT or chemotherapy was ≥2.5 years, median PFS for those with AA was <1 year in patients receiving RT alone and 1.5 years in those receiving chemotherapy alone. By contrast, our data represent a reasonably homogenous population with mature survival data.

Table 3.

Prior studies in WHO grade III gliomas

Design	Histology	N	Treatment	PFS (y)	OS (y)	Reference/Authors
Phase III	AG	190	RT + PCV	–	4.08	Prados et al. (RTOG 9404) [13]
			RT/BUdR +PCV		4.50
Retrospective	AA	109	RT → PCV	2.87	NR	Brandes et al. [15]
			RT → TMZ	3.01	NR
Phase III	AA	193	RT	1.03	1.99	Hildebrand et al. (EORTC 26882) [16]
			RT + DBD/BCNU	1.23	2.28
Retrospective	AA, AOA	60	RT	0.58	1.08	Combs et al. [17]
			RT/TMZ	0.50	1.25
Phase III	AA, AO, AOA	274	RT	2.55	6.01	Wick et al. (NAO-04) [14]
			PCV/TMZ	2.66	6.88
Phase II	AA, AO	33	RT/TMZ → TMZ	4.06	5.50	Kim et al. [18]
Phase II	AA, AO, AOA	32	TMZ, 13-cRA	3.15	NR	Grauer et al. (RNOP-05) [12]
Retrospective	AA	97	RT/TMZ → TMZ	3.0	4.2	Minniti et al. [19]

N number of patients; AG anaplastic glioma; AA anaplastic astrocytoma; AOA anaplastic oligoastrocytoma; AO anaplastic oligodendroglioma; RT radiation therapy; PCV procarbazine, lomustine, vincristine; BUdR bromodeoxyuridine; DBD dibromodulcitol; BCNU bichloroethylni-trosourea/carmustine; TMZ temozolomide; 13-cRA 13-cis-retinoic acid

The most striking finding may be the relatively low proportion of patients who actually completed the entire planned course of treatment. For example, 12 (39 %) did not complete all 6 cycles of adjuvant temozolomide because of either early confirmed (3) or suspected (2) disease progression, tumor (2) or treatment (1) related side effects, non-compliance (1), refusal (2), or loss to follow up (1) These findings highlight the high degree of variability in biologic function of the anaplastic glioma group. While grade III histology is often expected to confer a better prognosis than GBM, these data emphasize that only a subgroup of patients with WHO grade III tumors actually have a better outcome and many have or behave as if they have a WHO grade IV (GBM) tumor. The relatively low frequency of MGMT promoter methylation (20 %) may partially explain the poor outcome. In addition, 42 % of our patients had only a biopsy for diagnosis and those patients may have harbored WHO grade IV disease in the unsampled tissue—an important issue in studies that do not require at least subtotal resection for eligibility. However, we reviewed the images for all patients that underwent biopsy only. Among 13 patients, all had unresectable tumors because of involvement of deep structures or motor or language cortex, thus limiting the sample available for diagnostic and molecular evaluations. Regarding radiographic features, only 3 patients had heterogeneously enhancing lesions typical for GBM. Three others had non-enhancing tumors. The remainder had largely non-enhancing tumors with faint or punctate areas of enhancement consistent with anaplastic astrocytoma, one of whom underwent re-operation after chemoradiation which re-confirmed anaplastic histology.

Our sample size was too small to delineate the different effects of the extent of surgical resection, varying histology (astrocytoma vs mixed), MGMT methylation, 1p19q deletion, and the typical prognostic factors such as age and KPS. However, our patients were relatively young and had an excellent performance status, making it less likely those factors confounded results. While GBM has four (at least) well-described molecular profile categories, such an analysis has not yet separated the almost certain subgroups of anaplastic glioma [21]. Recent studies have indicated that isocitrate dehydrogenase 1 (IDH1) mutation may confer a favorable prognosis in patients with anaplastic gliomas, but its definitive role remains to be seen [19, 22]. A limitation of our study is missing IDH mutational information. IDH mutational testing was not performed routinely at the time this study was conducted. In addition, finite tissue was available from those who underwent biopsy, and molecular analysis was focused on MGMT promoter methylation, the biomarker of interest at the time. Accordingly, the challenges in obtaining archival tissue from external sites, and the costs associated with analysis, proved impractical for a post hoc analysis of a small exploratory cohort of a larger trial. Moreover, we also did not analyze tissue for other potentially prognostic biomarkers, such as Glioma CpG island methylator phenotype [23, 24] or myriad others. Varying representation of different subgroups within large and small cohort studies may well explain the highly variable PFS and OS reported for this group of patients.