Chemotherapy for adult patients with spinal cord gliomas

Patients and Tumors

In accordance with approval from the appropriate Institutional Review Boards, the surgical specimens and clinical records were retrieved from 21 patients treated at the University Hospital Zurich, Zurich, Switzerland, or at one of the University Hospitals in Germany participating in the German Glioma Network (GGN). The GGN is a consortium involving eight University Hospitals in Germany and participating in multiple studies and projects including this retrospective study. The GGN was supported by the German Cancer Aid from 2004 to 2012. Patients included in this study were diagnosed with primary brain tumors in the years 1990 through 2017. All tumors were initially classified and graded according to the WHO classification of tumors of the central nervous system in the local pathology departments.⁸ The astrocytic tumors of WHO grades 2-4 were re-classified according to the 2016 WHO classification.³IDH mutation status was determined by immunohistochemistry using a mutation-specific antibody against IDH1-R132H.⁹ Mutational analyses of the IDH1 and IDH2 genes were carried out by Sanger sequencing or pyrosequencing.^10,11 The H3 K27M mutation status was assessed by immunohistochemistry with commercially available antibodies. The O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was determined by methylation-specific polymerase chain reaction (PCR).¹² Epidemiological and treatment data were taken from patient health records. Patient characteristics from patients included in the GGN were extracted from the GGN database, and also from appropriate medical records provided from the local medical institutions. Radiological response rates to chemotherapy were assessed in astrocytomas by applying response assessment in neuro-oncology (RANO) criteria^13,14 and were also used to assess response in ependymomas.

Statistics

Progression-free survival (PFS) was calculated from the neurosurgical intervention (or radiographic diagnosis in patient P1, who had surgery only later on during the course of the disease) or from the date of first chemotherapy dose to the date of progression. Overall survival (OS) was measured from the neurosurgical intervention (or radiographic diagnosis in patient [P] 1) or from the date of first chemotherapy dose to the date of death. Patients without documented progression after diagnosis or after start of chemotherapy were censored at the last follow-up visit for PFS. Patients without confirmed death were censored for OS at the last follow-up visit. Survival data were calculated with the Kaplan-Meier method. Cox proportional hazards regression models were used for univariate analyses to test the association of the MGMT promoter methylation status with outcome after start of chemotherapy. All statistical tests were two-tailed and a P value of .05 was set as statistically significant. All statistical analyses were performed using IBM Statistics, version 26 (SPSS).

Literature Review

An online literature search was conducted to summarize the data available on adult patients diagnosed with spinal cord glioma, who received chemotherapy alone at any time of their disease. We searched for relevant studies published through November 2020 using the following keywords: adult(s), glioma(s), ependymoma(s), astrocytoma(s), chemotherapy, spinal/spinal cord. Secondary tumor manifestation in the spinal cord or leptomeningeal disease, children, as well as combination therapies including chemotherapy plus radiotherapy were excluded.

Data Availability Statement

Anonymized data not provided in the article will be made available by request of other qualified investigators for purposes of replicating results.

Individual Patient Characteristics

A total of 21 patients diagnosed with spinal cord glioma were included in this study. Individual patient characteristics are summarized in Supplementary Table 1. Median follow-up of the whole patient cohort was 137.7 months (95% confidence interval [CI] 67.2-208.2) assessed from time of diagnosis (see Supplementary Table 2), and 92.0 months (95% CI 43.0-141.0) measured from start of first chemotherapy (Table 1).

Histology and Molecular Markers

Most patients were diagnosed with astrocytic gliomas of WHO grades 1-4 (N = 13), the remaining patients were diagnosed with ependymal tumors of WHO grades 1 or 3 (N = 8) (Table 1). In the subgroup of patients diagnosed with astrocytic gliomas, most patients had astrocytoma WHO grade 3 or 4, including glioblastoma (N = 1), diffuse midline glioma, H3 K27M mutant (N = 4), and anaplastic astrocytoma (N = 3). Two patients were diagnosed with diffuse astrocytoma WHO grade 2 and 3 patients were diagnosed with WHO grade 1 astrocytoma (pilocytic astrocytoma). The IDH mutation status was available in 4 patients (P4, P11, P12, P13), all patients had IDH wild-type tumors, and a H3 K27M mutation was found in one additional patient, assuming an IDH wild-type status (P10). Data on these molecular markers were not available in the remaining cases. In the subgroup of ependymoma patients, most patients had anaplastic ependymomas (N = 5), the remaining patients were diagnosed with WHO grade 1 myxopapillary ependymoma (N = 3). The MGMT promoter methylation status was available in 11 tumors (astrocytomas N = 7; ependymomas N = 4): 8 tumors (73%) had an unmethylated MGMT promoter (diffuse astrocytoma WHO grade 2 N = 1, anaplastic astrocytoma WHO grade 3 N = 1, diffuse midline glioma, H3 K27M mutant N = 3; myxopapillary ependymoma N = 2, anaplastic ependymoma N = 1). A methylated MGMT promoter (N = 3) was found in patients diagnosed with pilocytic astrocytoma (N = 1), anaplastic astrocytoma (N = 1), and anaplastic ependymoma (N = 1) (see Supplementary Table 1).

Clinical Presentation

At time of diagnosis, most patients had a cervical or thoracic tumor localization (58%), the remaining cases showed involvement of more than one spinal cord segment. Patients suffered from paresthesia in up to 70% of cases, followed by back pain (47%) or muscle weakness of the limbs (21%). At time of diagnosis, most patients had a Karnofsky performance status (KPS) of 70%-80% (56%) and a McCormick score of 1 or 2 (89%) (see Supplementary Table 2).

Neurosurgical Intervention and Adjuvant Treatment Strategies

Eleven patients (52%) had more than one neurosurgical intervention. One patient was diagnosed with a spinal cord glioma based on radiological criteria only (P1; see Supplementary Table 1); this patient had a neurosurgical intervention and neuropathological diagnosis 10 years afterwards (pilocytic astrocytoma), followed by the start of chemotherapy. Most patients had initially partial tumor resection (N = 12, 57%), followed by biopsy (N = 5, 24%) and gross total tumor resection (N = 4, 19%). Mainly because of histology (pilocytic astrocytoma, N = 2; myxopapillary ependymoma, N = 2; diffuse astrocytoma WHO grade 2, N = 1; anaplastic astrocytoma, N = 2; anaplastic ependymoma, N = 3), 10 patients (48%) did not have tumor-specific treatment after the first neurosurgical intervention, while all patients diagnosed with spinal cord glioblastoma or diffuse midline glioma, H3 K27M mutant received chemotherapy plus radiotherapy as first-line treatment (see Supplementary Table 1).

Patient Characteristics at Start of Chemotherapy

Patient characteristics at start of chemotherapy are summarized in Table 1. Seven patients had chemotherapy combined with radiotherapy as first-line treatment (P8-13, P21). Two patients had chemotherapy plus radiotherapy at recurrence (P6, P7), and 2 patients had chemotherapy alone at recurrence (P3, P20), without other prior tumor-specific treatment with the exception of surgery. Only one patient received chemotherapy alone as first-line treatment (P4). The remaining 9 patients had received radiotherapy before and chemotherapy was given at further progression (P1, P2, P5, P14-19).

Chemotherapy in Combination with Radiotherapy

Patients who received chemotherapy plus radiotherapy as first-line treatment were diagnosed mainly with spinal cord glioblastoma (N = 1), or diffuse midline glioma, H3 K27M mutant (N = 4), as well as with anaplastic astrocytoma (N = 1), or anaplastic ependymoma (N = 1). At further recurrence, this combined treatment was also applied to patients diagnosed with anaplastic astrocytoma (N = 2) without prior tumor-specific treatment beyond surgery (Tables 1 and 2). All patients receiving chemotherapy with radiotherapy (N = 9) had alkylating drugs, mainly TMZ (N = 6), TMZ plus CCNU (N = 1), CCNU (N = 1) or ACNU plus teniposide (N = 1). Median PFS from start of chemotherapy in this patient group was 6.1 months (95% CI 1.2-11.0) and median OS from start of chemotherapy was 29.4 months (23.4-35.4) (Table 1).

Chemotherapy Alone

Chemotherapy alone was administered in patients diagnosed with pilocytic astrocytoma (N = 3) or diffuse astrocytoma (N = 2). In this patient group, 1 patient had chemotherapy as first-line treatment, 1 at time of recurrence but without prior radiotherapy, and 3 at time of recurrence with prior radiotherapy. All these patients diagnosed with astrocytic glioma received TMZ.

The remaining patients diagnosed with myxopapillary ependymoma (N = 3) or anaplastic ependymoma (N = 4) had chemotherapy alone at further recurrences and with prior radiotherapy (N = 6) with the exception of patient 20 diagnosed with anaplastic ependymoma who received chemotherapy at recurrence but without prior tumor-specific treatment beyond surgery (N = 1). These patients diagnosed with ependymoma had TMZ (N = 2), CCNU (N = 1), hydroxyurea (N = 1), carboplatin/etoposide (N = 1), etoposide/ifosfamide/doxorubicin (N = 1), or carboplatin/etoposide/vincristine (N = 1) (Table 2).

In the group of patients diagnosed with astrocytoma or ependymoma, who had chemotherapy alone without or with prior radiotherapy (N = 12), median PFS from start of chemotherapy was 9.0 months (95% CI 0.0-37.6) and median OS from start of chemotherapy was 58.0 months (0.0-116.8) (Table 1).

Benefit From Chemotherapy

Radiological overall responses to chemotherapy were assessed in every patient by magnetic resonance imaging (MRI). Duration of best responses (defined from start of chemotherapy) are shown for every patient in Supplementary Table 1. In the patient cohort who had chemotherapy plus radiotherapy as first-line therapy (N = 7) or at recurrence without prior tumor-specific treatment (N = 2) responses were as follows: complete response (CR) (N = 1; glioblastoma), stable disease (SD) (N = 4; anaplastic astrocytoma (N = 2), diffuse midline glioma, H3 K27M mutant (N = 1), anaplastic ependymoma (N = 1)), and progressive disease (PD) (N = 4; anaplastic astrocytoma (N = 1), diffuse midline glioma, H3 K27M mutant (N = 3)) (Table 2). In the patient cohort who had chemotherapy alone as first-line therapy (N = 1) or at recurrence without prior tumor-specific treatment (N = 2) or at recurrence with radiotherapy at an earlier timepoint during the course of the disease (N = 9) responses were as follows: partial response (PR) (N = 1; anaplastic ependymoma), SD (N = 7; pilocytic astrocytoma (N = 1), diffuse astrocytoma (N = 1), myxopapillary ependymoma (N = 3), anaplastic ependymoma (N = 2)), and PD (N = 4; pilocytic astrocytoma (N = 2), diffuse astrocytoma (N = 1), anaplastic ependymoma (N = 1)) (Table 2).

Bevacizumab in Spinal Cord Gliomas at Recurrence

Beyond classical chemotherapy, four patients received bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor. These patients had pilocytic astrocytoma (P2), diffuse astrocytoma (P4), glioblastoma (P9), or diffuse midline glioma, H3 K27M mutant (P10). Detailed information on bevacizumab treatment are summarized in Supplementary Table 3. All patients had contrast enhancement in the MRI at start of bevacizumab. One patient (P10), diagnosed with diffuse midline glioma, H3 K27M mutant had PD, the other patients had SD or PR, as best response to bevacizumab. The median PFS from start of bevacizumab application was 14.6 months (95% CI 0.0-29.2), the median OS was 21.6 months (95% CI 10.6-32.7).

Survival Data

A univariate Cox regression analysis revealed MGMT promoter methylation status as a risk factor for death neither in the group of patients who had chemotherapy plus radiotherapy (N = 6), nor in the group of patients who had chemotherapy alone without or with prior radiotherapy (N = 5) (chemotherapy alone: P = .678; chemotherapy plus radiotherapy: P = 0.303), but patient numbers are low in these subgroups. In addition, Kaplan-Meier survival curves are summarized in Figure 1 for patients who had chemotherapy alone and in Supplementary Figure 1 for patients who had chemotherapy plus radiotherapy. Survival curves are shown in these patients stratified by histology. Group sizes were too small for comparisons, but no obvious signal of activity for one histologically defined disease became apparent.