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EPCOG

Early palliative care for patients with glioblastoma: A randomized phase III clinical trial (EPCOG)

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Year of Publication: 2026

Authors: Golla H et al.

Journal: Neuro-Oncology

Citation: Neuro Oncol. 2026 Jan 1;28(1):226-240

Link: https://doi.org/10.1093/neuonc/noaf230

Bottom Line

Monthly early palliative care did not significantly improve the primary FACT-Br Trial Outcome Index at 6 months, but produced consistent benefits in emotional well-being, palliative-care symptom burden, anxiety and depression; unexpectedly, median overall survival was 7 months shorter in the intervention arm (HR 1.56, P=.018).

Major Points

  • First adequately powered phase III RCT of early palliative care specifically in glioblastoma — a setting where data from oncology in general were extrapolated.
  • Primary endpoint (TOI at 6 months) was negative (EMM diff 4.1, P=.34), but multiple secondary QoL and symptom domains improved persistently, particularly after the intervention ended.
  • Statistically significant survival decrement in the intervention arm (median 14 vs 21 months; HR 1.56, P=.018), most pronounced for newly diagnosed patients (P=.035) — raises critical question whether informed earlier acceptance of palliative goals reduced uptake of life-prolonging therapy.
  • Caregivers (ZBI-12) showed no improvement, challenging the 'unit of care' premise of EIPC.
  • Intervention significantly increased palliative-care utilization (outpatient/inpatient PC, physiotherapy) but did not change place of death.

Design

Study Type: Randomized Controlled Trial

Phase: III

Randomization: 1

Blinding: Rater-blinded (open-label; 85.4% of assessments preserved blinding)

Enrollment Period: May 2019 - Apr 2021

Follow-up Duration: Up to 24 months (12 months intervention + 12 months follow-up)

Centers: 6

Countries: Germany

Sample Size: 217

Analysis: Modified intention-to-treat (mITT); mixed model for repeated measures with pre-specified, time-of-death-adjusted, and survivors-only sensitivity analyses

Inclusion Criteria

  • Adults ≥18 years with newly diagnosed glioblastoma (histologically confirmed by biopsy or resection) within 4 weeks of diagnosis
  • OR recurrent glioblastoma within 4 weeks after diagnosis of recurrence (RANO criteria and/or radiological deterioration leading to change in oncological treatment)
  • ECOG performance status 0-2
  • Ability to understand, read and respond in German
  • Ability to give informed consent
  • Caregivers were eligible if relatives or close persons living with the patient or in face-to-face contact at least twice weekly (patients without such a caregiver could still be enrolled)

Exclusion Criteria

  • Unwillingness to abide by the protocol
  • Legally incapacitated
  • Ongoing drug or alcohol abuse, or psychiatric condition making participation unsuitable per investigator
  • Dependency on the investigator or employed by the sponsor/investigator
  • Held in an institution by legal or official order

Baseline Characteristics

CharacteristicControlActive
Arm LabelOptimized Standard CareEarly Integration of Palliative Care (EIPC) + Optimized Standard Care
N (patients)8998
N (caregivers)7991
Median Age (years)59 (IQR 55-67)61 (IQR 56-70)
Sex - Male56.2%55.1%
Newly Diagnosed79.8%78.6%
Recurrent20.2%21.4%
MGMT Methylated50.6%46.9%
IDH Wild-type96.6%92.9%
Tumor - Temporal53.9%42.9%
Tumor - Frontal29.2%33.7%
Married78.7%77.6%
Advance Directive in Place51.7%60.2%
Comorbidities ≥322.5%27.6%
Caregiver Available88.8%92.9%

Arms

FieldEarly Integration of Palliative Care (EIPC)Control
InterventionMonthly structured palliative care contacts delivered by a PC physician + PC social worker for 12 months. Quarterly face-to-face visits aligned with neuro-oncology clinic visits, with monthly telephone contacts in between (face-to-face or with caregivers if patient unable). PC manual covered pain/symptom management, psychosocial and spiritual support, treatment-decision support, advance care planning and care planning. 95.5% completion of scheduled visits. Layered on top of optimized standard neuro-oncology care.Standard guideline-based neuro-oncologic management with neurosurgery/neuro-oncology outpatient visits every 3 months, regular FACT-Br QoL assessment at clinic visits enabling timely needs detection, and palliative care available on-demand at any point. 27.0% of control patients eventually received specialized palliative care outside the protocol.
Duration12 months active intervention, 12 months follow-up12 months, with 12 months follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change in FACT-Br Trial Outcome Index (TOI: brain-specific + physical + functional well-being subscales; range 0-148, higher = better QoL) from baseline to 6 monthsPrimaryEMM TOI at 6 mo (mITT analysis)EMM TOI at 6 mo (mITT analysis)0.34 (not significant)
FACT-Br Emotional Well-Being subscale (group effect)Secondary0.0093 (pre-specified); 0.011 (adjusted for time of death) — favors EIPC, significant at months 15 and 24
FACT-Br Brain-Specific subscale (BRCS) group effectSecondary0.018 (adjusted for time of death) — favors EIPC at months 12, 18
FACT-Br Social Well-Being (survivors only)Secondary0.038 — favors EIPC
IPOS total burden (group effect)Secondary0.0024 (pre-specified); 0.0009 (adjusted); 0.0014 (survivors only) — lower (better) at months 6, 9, 18, 24 in EIPC
IPOS psychological/practical issues subscoreSecondary<0.0001 in all three analyses — lower (better) at months 6, 9, 15, 18, 21 in EIPC
HADS-Anxiety (group effect)Secondary0.045 (pre-specified); 0.012 (adjusted); 0.045 (survivors) — lower at months 15, 24 in EIPC
HADS-Depression (group effect)Secondary0.019 (adjusted) — lower at months 12, 15, 24 in EIPC
HADS-Total (group effect)Secondary0.0051 (adjusted); 0.031 (survivors) — lower in EIPC
Overall survival — medianSecondary21 months14 months1.560.018 — significant survival disadvantage with EIPC
Overall survival — newly diagnosed subgroupSecondary0.035 — significant survival disadvantage with EIPC
Overall survival — recurrent subgroupSecondary0.28 — not significant
Caregiver burden (ZBI-12)SecondaryNot significant — both groups showed slight increase in burden
Cognitive function (MoCA)SecondaryGroup effect not significant overall; at month 12 favored control in adjusted analysis (P<.05)
Health-care utilization — PC outpatient visitsSecondary0.013 — higher in EIPC
Health-care utilization — inpatient PC admissionSecondary0.023 — higher in EIPC
Place of death (hospital/home/hospice/other)Secondary0.72 — no difference
Formal AE assessmentAdverseNot performed — non-AMG/non-MPG trial; deterioration and death anticipated as natural history of glioblastoma
Safety monitoringAdverseInternal trial steering committee analyzed a study-specific distress score every 6 months; no signal to halt the trial
Survival decrementAdverseMedian OS 14 mo (EIPC) vs 21 mo (control); HR 1.56, P=.018 — counted as a critical safety/efficacy signal rather than a discrete AE

Subgroup Analysis

Forest plot for primary endpoint (TOI at 6 mo): significant benefit of EIPC in patients with ≥3 comorbidities (P=.029); numerically pronounced benefit in women and in patients without caregivers (NS). No interaction by MGMT, IDH, age, surgery, or tumor location. Survival decrement strongest in newly diagnosed subgroup.

Criticisms

  • Primary endpoint (TOI focused on physical/functional QoL) may have been mismatched to the more emotional/psychological domains where EIPC actually helps
  • Unblinding by month 6 (25.6% of intervention vs 10.1% of control) introduced bias — when removed, TOI difference dropped by 13.2 points (P<.001)
  • Unexpected 7-month median OS decrement in the intervention arm requires explanation: possible earlier acceptance of palliative goals leading to reduced uptake of life-prolonging therapy, but not directly measured
  • Optimized standard care (regular QoL assessment + on-demand PC) may have raised the comparator's effectiveness and diluted the between-group effect
  • Tumor characteristics linked to survival (size, location, extent of resection) were not controlled for
  • COVID-19 pandemic overlapped enrollment (May 2019 - April 2021), with potential differential impact on in-person assessments and isolation
  • Caregiver outcomes did not improve, undermining the family-centered premise of EIPC
  • Single-country (Germany) study with mature palliative-care infrastructure — limits generalizability
  • 27% of control patients accessed specialized PC outside the protocol, blurring contrast between arms

Funding

Federal Ministry of Education and Research (BMBF), Germany — grant FKZ 01GY1703. No industry funding.

Based on: EPCOG (Neuro-Oncology, 2026)

Authors: Golla H et al.

Citation: Neuro Oncol. 2026 Jan 1;28(1):226-240

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