Results

Patient characteristics and demographics

Fifty clinical records were screened, of which 32 (64%) patients met the inclusion criteria. The remaining 18 patients were excluded because of poor baseline performance status precluding treatment (n = 7), rapid clinical progression before protocol initiation (n = 5), or protocol completion outside our unit (n = 6).

Among the 32 patients analyzed, mean age at diagnosis was 50.7 ± 15.3 years (range: 19-75 years), and 62.5% (n = 20) were male. The most frequent comorbidities were arterial hypertension (37.5%), and tobacco use (25%). Clinical presentation was dominated by motor deficits (50%) and tonic-clonic seizures (50%). Baseline characteristics are detailed in Table 1.

Characteristic | Frequency (n) | Percentage (%) / mean ± SD
Sex: male | 20 | 62.5%
Sex: female | 12 | 37.5%
Age at diagnosis, years | - | 50.7 ± 15.3
Arterial hypertension* | 12 | 37.5%
Tobacco use (smoking)* | 8 | 25%
Heart failure* | 3 | 9.4%
Myocardial infarction* | 2 | 6.3%
Arrhythmia/dyslipidemia/allergies* | 3 | 9.3%
No comorbidities recorded | 8 | 25%
Motor deficit† | 16 | 50%
Tonic-clonic seizures† | 16 | 50%
Headache† | 9 | 28.1%
Intracranial hypertension syndrome† | 3 | 9.4%
Other focal neurological deficits† | 6 | 18.8%
Parietal lobe‡ | 13 | 40.7%
Frontal lobe‡ | 10 | 31.2%
Temporal lobe‡ | 9 | 28.1%
Occipital lobe‡ | 3 | 9.4%
Basal ganglia‡ | 3 | 9.4%
Left hemisphere | 17 | 53.1%
Right hemisphere | 14 | 43.8%
Bilateral | 1 | 3.1%

Therapeutic interventions and survival metrics

Maximal safe neurosurgical cytoreduction achieved GTR in 56.3% (n = 18) of patients. The full planned radiotherapy dose (60 Gy) was completed by 90.6% (n = 29) of the cohort, and 68.8% (n = 22) completed all six planned cycles of adjuvant TMZ.

Over a maximum follow-up of 107 months, 26 deaths were recorded. Median OS for the entire cohort was 17 months (95% CI: 7.0-26.9). Patients who completed the full Stupp regimen achieved a significantly longer median OS than those with incomplete maintenance therapy (24 vs. 11 months; log-rank p = 0.023). Long-term survival analysis showed that 15.6% (n = 5) of patients survived to three years and 3.1% (n = 1) survived to five years. Clinical characteristics of the five long-term survivors are summarized in Table 2.

Clinical factor | Patient 3 | Patient 13 | Patient 18 | Patient 19 | Patient 24
Sex | Female | Female | Male | Male | Male
Age at diagnosis, years | 47 | 27 | 34 | 37 | 19
Relevant comorbidities | Hypertension | Tobacco use | Other | Tobacco use | None
Anatomical location | Parietal | Frontal | Parietal | Frontal | Basal ganglia
Tumor lateralization | Left | Bilateral | Left | Right | Right
Extent of surgery | GTR (R0) | STR (R1) | GTR (R0) | STR (R1) | STR (R1)
MGMT/IDH status | Unknown | Unknown | Unknown | Unknown | Unknown
Stupp regimen compliance | Complete | Complete | Complete | Complete | Complete
5-year survival confirmed | No | No | Yes | No | No

Prognostic determinants (Cox regression)

In the multivariate model, protocol compliance was the only independent predictor of OS: patients who completed the full regimen had a 65% reduction in the risk of death (HR = 0.35; 95% CI: 0.14-0.86; p = 0.021). Extent of resection showed a trend toward improved survival but did not reach statistical significance (Table 3).

Variable | Univariate HR (95% CI) | p-Value | Multivariate HR (95% CI) | p-Value
Age at diagnosis (per year) | 1.02 (0.98–1.07) | 0.240 | 1.01 (0.96–1.06) | 0.530
Age at diagnosis (≥70 vs. <70 years) | 0.68 (0.39–1.15) | 0.110 | 0.74 (0.41–1.32) | 0.280
Extent of resection (GTR vs. STR) | 0.76 (0.32–1.81) | 0.597 | 0.81 (0.34–1.95) | 0.640
Protocol adherence (complete vs. incomplete) | 0.38 (0.16–0.89) | 0.025 | 0.35 (0.14–0.86) | 0.021

Safety and toxicity profile

During the concurrent phase, grade 1-2 non-hematological toxicities occurred in 69.5% of evaluable patients, most often asthenia and nausea. Severe (grade 3) hematological toxicities were limited to isolated cases of anemia and thrombocytopenia (3.12% each); adverse events during the concurrent phase are presented in Table 4. During the adjuvant phase, non-hematological toxicities were recorded in 53.1% of patients; hematological toxicity led to dose reduction in one (3.12%) patient and permanent discontinuation in two (6.24%) patients.

Adverse event | n | %
Grade 2 asthenia | 10 | 31.25%
Grade 2 nausea | 6 | 18.75%
Grade 1 nausea | 4 | 12.50%
Grade 1 asthenia | 3 | 9.38%
Grade 2 vomiting | 2 | 6.25%
Grade 1 vomiting / diarrhea / dermatologic rash | 3 | 9.38%
Grade 2 diarrhea | 1 | 3.12%
Urinary tract infection / headache (ungraded) | 2 | 6.25%
Not recorded (non-hematological) | 9 | 28.13%
Grade 2 neutropenia | 8 | 25%
Grade 2 thrombocytopenia | 6 | 18.75%
Grade 1 thrombocytopenia | 3 | 9.38%
Grade 1 neutropenia / grade 1 anemia | 4 | 12.50%
Grade 3 thrombocytopenia (severe) | 1 | 3.12%
Grade 3 anemia (severe) | 1 | 3.12%
Grade 2 lymphopenia | 1 | 3.12%
Grade 2 anemia | 1 | 3.12%
Not recorded (hematological) | 9 | 28.13%

In the adjuvant maintenance phase, non-hematological toxicities were recorded in 53.1% of patients, most often grade 2 asthenia (28.1%) and grade 2 nausea (21.8%). Grade 4 thrombocytopenia occurred in a single patient (3.12%), and grade 3 lymphopenia was recorded in another patient (3.12%). Hematological toxicity led to a dose reduction in one (3.12%) patient and permanent discontinuation in two (6.24%) patients during the standard 150-200 mg/m² maintenance cycles; adjuvant-phase toxicities are summarized in Table 5.

Adverse event | n | %
Grade 2 asthenia | 9 | 28.10%
Grade 2 nausea | 7 | 21.84%
Grade 2 vomiting | 5 | 15.60%
Grade 2 diarrhea | 4 | 12.50%
Grade 1 nausea | 2 | 6.24%
Grade 1 asthenia / grade 1 diarrhea / seizures | 3 | 9.36%
Not recorded (non-hematological) | 5 | 15.60%
Grade 2 thrombocytopenia | 5 | 15.60%
Grade 1 thrombocytopenia | 3 | 9.36%
Grade 2 neutropenia | 3 | 9.36%
Grade 1 neutropenia / grade 2 anemia | 4 | 12.48%
Grade 1 anemia | 1 | 3.12%
Grade 3 lymphopenia | 1 | 3.12%
Grade 4 thrombocytopenia (life-threatening) | 1 | 3.12%

Second- and third-line treatment

Following confirmed tumor progression or local recurrence, second-line treatment was offered to 43.8% (n = 14) of the cohort. Twelve (37.5%) patients underwent a second surgical intervention (all subtotal re-resections), and nine received additional tumor-directed treatment. Five (15.6%) patients received second-line salvage chemotherapy with biodegradable carmustine wafers for an average of two cycles. Other second-line modalities included fractionated re-irradiation (n = 1), irinotecan plus bevacizumab (n = 1), TMZ plus bevacizumab (n = 1), carboplatin monotherapy (n = 1), and carboplatin plus etoposide (n = 2).

A third line of treatment, consisting of a third subtotal neurosurgical cytoreduction, was accessible for 9.4% (n = 3) of patients; postoperative third-line systemic chemotherapy consisted of carmustine (n = 1) or carboplatin monotherapy (n = 1). At the study’s administrative census date, 21.9% (n = 7) of patients remained alive.