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CODEL

Year of Publication: 2021

Journal: Neuro-Oncology

Link: https://doi.org/10.1093/neuonc/noaa168

PDF: https://academic.oup.com/neuro-oncology/...180/noaa168.pdf

Clinical Question

Is temozolomide monotherapy as effective as RT-based regimens for newly diagnosed 1p/19q codeleted anaplastic oligodendroglioma?

Bottom Line

In 36 patients with newly diagnosed 1p/19q codeleted anaplastic oligodendroglioma randomly assigned to RT alone, RT+TMZ, or TMZ alone (before trial redesign), TMZ-alone patients had significantly shorter progression-free survival than the pooled RT arms (HR 3.12; 95% CI 1.26-7.69; p=0.014). OS comparison was underpowered but trended worse. Trial dropped TMZ-alone arm and was redesigned to compare RT+PCV vs RT+TMZ. Confirmed that radiation should remain part of first-line therapy even for codeleted oligodendroglioma.

        Major Points
        International phase 3 intergroup RCT (CODEL, Jaeckle 2021; NCCTG/Alliance N0577, EORTC 26081-22086, NRG 1071, CCTG CEC.6)
Initial 3-arm design (RT alone vs RT+TMZ vs TMZ alone) enrolled N=36 before TMZ-alone arm was dropped
Newly diagnosed 1p/19q codeleted WHO grade III oligodendroglial tumor, ≤3 months from surgery, ECOG 0-2
1:1:1 randomization stratified by age, registering group, ECOG status; median follow-up 7.5 years
TMZ monotherapy: 10/12 (83%) progressed vs 9/24 (37.5%) on RT-containing arms
PFS TMZ alone vs pooled RT arms: HR 3.12 (95% CI 1.26-7.69); p=0.014
IDH-adjusted PFS: HR 3.33 (95% CI 1.31-8.45); p=0.011 confirming TMZ-alone inferiority
OS trended worse with TMZ alone but underpowered (HR 2.78; 95% CI 0.58-13.22; p=0.20)
Grade ≥3 AEs: 25% (RT), 42% (RT+TMZ), 33% (TMZ alone)
No between-arm differences in 3-month neurocognitive change
Confirmed radiation should remain part of first-line therapy for codeleted oligodendroglioma
Trial redesigned to compare RT+PCV vs RT+TMZ; initial 36 patients excluded from redesigned primary analysis

      

Design

Study Type: International phase 3 intergroup randomized trial (initial 3-arm design before redesign)

Randomization: 1

Blinding: Open-label

Follow-up Duration: Median 7.5 years

Sample Size: 36

Analyzed: 36

Analysis: Kaplan-Meier PFS/OS; Cox regression adjusted for IDH status

Baseline Characteristics

Characteristic	Control	Active
N	24	12
Age median	Likely similar	Likely similar
1p/19q codeleted	100% (eligibility)	100% (eligibility)
IDH mutated	Majority	Majority
ECOG 0-1	Majority	Majority

Arms

Field	Control	RT + TMZ (arm B)	TMZ alone (arm C)
N	12	12	12
Intervention	RT 5940 cGy in 33 fractions (control arm; later replaced by RT+PCV)	RT 5940 cGy + concomitant TMZ 75 mg/m²/day + adjuvant TMZ 150-200 mg/m² days 1-5 q28d x up to 12 cycles	TMZ 150-200 mg/m² days 1-5 q28d x up to 12 cycles, no RT
Duration	6-7 weeks RT	~12-18 months	~12 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Overall survival (arm A vs B); secondary: OS and PFS pooled RT arms vs TMZ alone (arm C)	Primary	Underpowered for original primary	Trial redesigned before primary accrual complete		N/A (redesigned)
PFS TMZ alone vs pooled RT arms	Secondary	Pooled RT arms reference	TMZ alone worse	HR 3.12 (95% CI 1.26-7.69)	p=0.014
IDH-adjusted PFS TMZ vs RT pooled	Secondary	Pooled RT reference	TMZ alone worse	HR 3.33 (95% CI 1.31-8.45)	p=0.011
OS TMZ alone vs RT pooled (IDH-adjusted)	Secondary	Reference	Trend worse	HR 2.78 (95% CI 0.58-13.22)	p=0.20 (underpowered)
Progression events	Secondary	9/24 (37.5%) pooled RT arms	10/12 (83.3%) TMZ alone		Consistent with HR
Death from disease progression	Secondary	4/24 (17%) RT arms	3/12 (25%) TMZ alone		Small numbers
Neurocognitive change (3 months post-randomization)	Secondary	Similar	Similar		No between-arm differences
Grade ≥3 any AE	Adverse	25% (RT alone)	42% (RT+TMZ); 33% (TMZ alone)		Higher with combination
Myelosuppression (TMZ-related)	Adverse	Low (RT only)	Higher in TMZ-containing arms		TMZ class effect
Lymphopenia	Adverse	Moderate (RT)	Higher with concurrent RT+TMZ		Expected
Fatigue	Adverse	Common	Common		Similar
Hepatic dysfunction	Adverse	Rare	Rare		No signal
Nausea/vomiting (TMZ)	Adverse	Low	Modest		TMZ-related
Infections	Adverse	Rare	Rare		No signal
Second malignancy	Adverse	None	None at this follow-up		Long-term AEs require longer follow-up

Subgroup Analysis

Small N precludes meaningful subgroup analysis. IDH status available in 35/36 (97%), with most patients IDH-mutant as expected for 1p/19q codeleted tumors. The TMZ-alone inferiority signal was consistent across IDH subgroups. The redesigned CODEL (ongoing) compares RT+PCV with RT+TMZ in a larger sample (data from the initial 36 patients will not contribute to redesigned primary analysis).

Criticisms

Very small N=36 before redesign — underpowered for OS; analysis primarily descriptive
TMZ-alone arm was exploratory at inception — chosen on clinical practice patterns of the era, not rigorous equipoise
Study redesigned mid-trial after RTOG 9402 and EORTC 26951 published, complicating interpretation; initial patients not used in redesigned primary analysis
Comparison of TMZ alone to pooled RT arms (A+B) is not the planned comparison — post-hoc analytic choice
Neurocognitive outcomes at 3 months are too early to capture late RT-related effects
No head-to-head PCV vs TMZ data here — redesigned CODEL will address this gap

Funding

NCI intergroup consortium (NCCTG/Alliance, EORTC, NRG, CCTG); Schering-Plough and Merck provided temozolomide

Based on: CODEL (Neuro-Oncology, 2021)

Content summarized and formatted by NeuroTrials.ai.

CODEL

(2021)

Objective

RT alone vs RT+TMZ vs TMZ alone — initial CODEL design analysis in newly diagnosed 1p/19q codeleted anaplastic oligodendroglioma, to evaluate whether temozolomide monotherapy was comparable to radiation-based strategies.

Study Summary

• Initial 3-arm CODEL design abandoned the TMZ-alone arm after early evidence of inferior PFS.
• At median follow-up 7.5 years: 10/12 (83%) TMZ-alone patients progressed vs 9/24 (37.5%) on RT arms.
• PFS significantly shorter with TMZ alone: HR 3.12 (95% CI 1.26-7.69; p=0.014) vs pooled RT arms.
• IDH-adjusted Cox PFS: HR 3.33 (95% CI 1.31-8.45; p=0.011) confirmed robust inferiority of TMZ-alone.
• OS comparison underpowered (36 patients total across 3 arms) — trended worse but not significant.
• Grade ≥3 AEs: 25% (RT), 42% (RT+TMZ), 33% (TMZ) — no difference in neurocognitive decline at 3 months; trial redesigned to compare RT+PCV vs RT+TMZ.

Intervention

RT alone (5940 cGy in 33 fractions) vs RT + concomitant and adjuvant TMZ (75 mg/m²/day during RT, then 150-200 mg/m² days 1-5 every 28 days x up to 12 cycles) vs TMZ alone (150-200 mg/m² days 1-5 every 28 days x up to 12 cycles). 1:1:1 randomization stratified by age, registering group, ECOG status.

Inclusion Criteria

Adults ≥18 years with newly diagnosed 1p/19q codeleted WHO grade III oligodendroglial tumor, ≤3 months from surgery, ECOG 0-2, adequate organ function, central pathology confirmation.

Study Design

Arms: RT alone vs RT+TMZ vs TMZ alone

Patients per Arm: RT 12; RT+TMZ 12; TMZ alone 12 (N=36 before redesign)

Outcome

• PFS: TMZ-alone vs pooled RT arms — HR 3.12 (95% CI 1.26-7.69); p=0.014
• Progression events: 10/12 (83%) TMZ-alone vs 9/24 (37.5%) RT arms
• Death from disease progression: 3/12 (25%) TMZ-alone vs 4/24 (17%) RT arms
• IDH-adjusted PFS HR (Cox model): 3.33 (95% CI 1.31-8.45); p=0.011 for TMZ alone vs RT arms
• OS not significantly different (underpowered); Grade ≥3 AEs 25%, 42%, 33% across RT, RT+TMZ, TMZ arms

Bottom Line

Major Points

International phase 3 intergroup RCT (CODEL, Jaeckle 2021; NCCTG/Alliance N0577, EORTC 26081-22086, NRG 1071, CCTG CEC.6)
Initial 3-arm design (RT alone vs RT+TMZ vs TMZ alone) enrolled N=36 before TMZ-alone arm was dropped
Newly diagnosed 1p/19q codeleted WHO grade III oligodendroglial tumor, ≤3 months from surgery, ECOG 0-2
1:1:1 randomization stratified by age, registering group, ECOG status; median follow-up 7.5 years
TMZ monotherapy: 10/12 (83%) progressed vs 9/24 (37.5%) on RT-containing arms
PFS TMZ alone vs pooled RT arms: HR 3.12 (95% CI 1.26-7.69); p=0.014
IDH-adjusted PFS: HR 3.33 (95% CI 1.31-8.45); p=0.011 confirming TMZ-alone inferiority
OS trended worse with TMZ alone but underpowered (HR 2.78; 95% CI 0.58-13.22; p=0.20)
Grade ≥3 AEs: 25% (RT), 42% (RT+TMZ), 33% (TMZ alone)
No between-arm differences in 3-month neurocognitive change
Confirmed radiation should remain part of first-line therapy for codeleted oligodendroglioma
Trial redesigned to compare RT+PCV vs RT+TMZ; initial 36 patients excluded from redesigned primary analysis

Study Design

Study Type: International phase 3 intergroup randomized trial (initial 3-arm design before redesign)
Randomization: Yes
Blinding: Open-label
Sample Size: 36
Follow-up: Median 7.5 years

Primary Outcome

Definition: Overall survival (arm A vs B); secondary: OS and PFS pooled RT arms vs TMZ alone (arm C)

Control	Intervention	HR/OR	P-value
Underpowered for original primary	Trial redesigned before primary accrual complete	- (N/A)	N/A (redesigned)

Limitations & Criticisms

Very small N=36 before redesign — underpowered for OS; analysis primarily descriptive
TMZ-alone arm was exploratory at inception — chosen on clinical practice patterns of the era, not rigorous equipoise
Study redesigned mid-trial after RTOG 9402 and EORTC 26951 published, complicating interpretation; initial patients not used in redesigned primary analysis
Comparison of TMZ alone to pooled RT arms (A+B) is not the planned comparison — post-hoc analytic choice
Neurocognitive outcomes at 3 months are too early to capture late RT-related effects
No head-to-head PCV vs TMZ data here — redesigned CODEL will address this gap

Citation

View Original Publication →

CODEL

Clinical Question

Bottom Line

Major Points

Design

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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