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RTOG 9402

Year of Publication: 2013

Journal: Journal of Clinical Oncology

Link: https://doi.org/10.1200/JCO.2012.43.2674

PDF: https://ascopubs.org/doi/pdf/10.1200/JCO.2012.43.2674

Clinical Question

Does adding intensive PCV chemotherapy to radiotherapy prolong overall survival in newly diagnosed anaplastic oligodendroglioma/oligoastrocytoma, particularly in 1p/19q codeleted tumors?

Bottom Line

In 291 patients with newly diagnosed anaplastic oligodendroglioma/oligoastrocytoma, intensive PCV before RT did NOT prolong overall survival in the unadjusted cohort (4.6 vs 4.7 years; HR 0.79; p=0.1). HOWEVER, in 1p/19q codeleted tumors (n=126), median OS doubled with PCV+RT (14.7 vs 7.3 years; HR 0.59; 95% CI 0.37-0.95; p=0.03). Established 1p/19q codeletion as both prognostic and predictive biomarker and made PCV+RT (or analogous chemoradiation) standard of care for codeleted anaplastic gliomas.

        Major Points
        Phase 3 multicenter randomized intergroup trial RTOG 9402 (Cairncross JCO 2013); enrolled 1994-2002 at 76 centers
N=291 adults ≥18 with newly diagnosed anaplastic oligodendroglioma or anaplastic oligoastrocytoma, KPS ≥60
1:1 randomization to 4 cycles intensive PCV before 59.4 Gy RT vs RT alone; stratified by age, KPS, degree of anaplasia
Median follow-up 11.3 years — long-term results essential to reveal benefit in codeleted tumors
Primary outcome: median OS in entire cohort — 4.6 (PCV+RT) vs 4.7 y (RT); HR 0.79 (95% CI 0.60-1.04); p=0.1
1p/19q codeleted subset (n=126): median OS 14.7 vs 7.3 years; HR 0.59 (95% CI 0.37-0.95); p=0.03
Noncodeleted subset (n=136): median OS 2.6 vs 2.7 y; HR 0.85; no benefit from PCV
PFS in codeleted subset: 8.4 vs 2.9 years; HR 0.47; p<0.001
Cox-adjusted OS (codeletion, clinical factors) HR 0.67 (95% CI 0.50-0.91); p=0.01
PCV toxicity substantial: 20% discontinuation, 2 neutropenic deaths
Established 1p/19q codeletion as predictive and prognostic biomarker
Made chemoradiation standard of care for codeleted anaplastic oligodendroglioma

      

Design

Study Type: Phase 3 multicenter randomized intergroup trial (RTOG/Alliance)

Randomization: 1

Blinding: Open-label (surgical/oncology)

Follow-up Duration: Median 11.3 years (range 0.5-16.8)

Sample Size: 291

Analyzed: 291

Analysis: Kaplan-Meier and Cox proportional hazards; 1p/19q retrospectively assessed by FISH in 91%

Baseline Characteristics

Characteristic	Control	Active
N	143	148
Age median	43	43
KPS ≥80	90%	90%
1p/19q codeleted	52% (67/128)	44% (59/135)
AO (vs AOA)	51%	52%

Arms

Field	Control	Intensive PCV + RT
N	143	148
Intervention	Involved-field RT 59.4 Gy in 33 fractions (50.4 Gy initial + 9 Gy boost)	4 cycles intensive PCV (lomustine 130 mg/m², procarbazine 75 mg/m² ×14 days, vincristine 1.4 mg/m² no cap) every 6 weeks, then RT 59.4 Gy within 6 weeks
Duration	6-7 weeks RT	~5-6 months chemo + 6-7 wk RT

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Overall survival (entire cohort)	Primary	Median 4.7 years	Median 4.6 years		p=0.1 (not significant in unadjusted analysis)
OS in 1p/19q codeleted subset	Secondary	Median 7.3 years	Median 14.7 years	HR 0.59 (95% CI 0.37-0.95)	p=0.03
OS in noncodeleted subset	Secondary	Median 2.7 years	Median 2.6 years	HR 0.85 (95% CI 0.58-1.23)	p=0.39 (no benefit)
PFS in codeleted subset	Secondary	Median 2.9 years	Median 8.4 years	HR 0.47 (95% CI 0.30-0.72)	p<0.001
PFS in noncodeleted subset	Secondary	Median 1.0 year	Median 1.2 years	HR 0.81 (95% CI 0.56-1.16)	p=0.24
OS adjusted for codeletion status (Cox)	Secondary	Reference	Prolonged	Adjusted HR 0.67 (95% CI 0.50-0.91)	p=0.01
OS in codeleted Cox-adjusted (steroids, lesions, surgery, neuro function)	Secondary	Reference	Prolonged	Adjusted HR 0.51 (95% CI 0.31-0.83)	p=0.007
Codeleted vs noncodeleted (PCV+RT arm)	Secondary	Noncodeleted 2.6 y	Codeleted 14.7 y	HR 0.36 (95% CI 0.23-0.57)	p<0.001 (prognostic biomarker)
Acute myelosuppression (PCV)	Adverse	Low (RT only)	Common; dose-limiting		PCV-specific
Peripheral/autonomic neuropathy (vincristine)	Adverse	Low	Common		PCV-specific
Vomiting (procarbazine)	Adverse	Low	Common		PCV-specific
Hepatic dysfunction	Adverse	Rare	Reported		PCV-specific
Allergic rash (procarbazine)	Adverse	Rare	Reported		PCV-specific
Cognitive/mood change (acute)	Adverse	Reported	More frequent during PCV		PCV-related
PCV-related neutropenic death	Adverse	N/A	2 patients		Rare fatal toxicity
PCV discontinuation for toxicity	Adverse	N/A	20%		Substantial
Late RT toxicity (leukoencephalopathy, necrosis)	Adverse	Low	Low, comparable		No late RT excess
Late second malignancy (leukemia)	Adverse	None	None reported		None at mature follow-up

Subgroup Analysis

1p/19q codeletion emerged as both prognostic (better outcome regardless of therapy) and predictive (PCV benefit specifically) biomarker. Median OS for codeleted PCV+RT (14.7 y) vs noncodeleted PCV+RT (2.6 y) highlights the biomarker's power. Sister trial EORTC 26951 (van den Bent 2013) used post-RT standard-dose PCV and reached similar conclusions. NOA-04 (Wick 2009) suggested PCV and temozolomide are approximately equivalent. CODEL (Jaeckle 2021) confirmed TMZ alone is inferior to RT-based regimens in codeleted tumors. Together these established chemoradiation as standard for codeleted anaplastic oligodendroglioma.

Criticisms

Unplanned codeletion subgroup analysis — though biologically driven, increases risk of type I error; small subgroup numbers
1p/19q codeletion assessment was retrospective (tissue retrieval improved from 70% at original report to 91% here) — not intention-to-treat at randomization
PCV toxicity substantial (20% discontinuation for toxicity, 2 fatal); temozolomide generally preferred in modern practice despite no head-to-head RCT showing TMZ superiority
Used pre-RT intensive PCV rather than post-RT standard-dose (EORTC 26951) — optimal sequencing and dose intensity unclear
IDH mutation status not considered at trial design — now known to be a key molecular marker in gliomas; CIC mutations also relevant
Dose intensity (4 cycles pre-RT) may exceed what most community practices accept — dose-intense regimens rarely used today

Funding

NCI (RTOG, NCCTG, SWOG, ECOG grants); Canadian Cancer Society

Based on: RTOG 9402 (Journal of Clinical Oncology, 2013)

Content summarized and formatted by NeuroTrials.ai.

RTOG 9402

(2013)

Objective

Intensive PCV (procarbazine + lomustine + vincristine) before radiotherapy vs RT alone — long-term results of RTOG 9402 in newly diagnosed anaplastic oligodendroglioma and oligoastrocytoma to determine survival benefit.

Study Summary

• In entire 291-patient cohort, PCV+RT did not significantly prolong median OS vs RT alone (4.6 vs 4.7 years; HR 0.79; p=0.1).
• In 1p/19q codeleted subgroup (n=126), median OS doubled: 14.7 years (PCV+RT) vs 7.3 years (RT); HR 0.59 (95% CI 0.37-0.95); p=0.03.
• Noncodeleted tumors (n=136): median OS 2.6 vs 2.7 years; no benefit from PCV (HR 0.85; p=0.39).
• PFS markedly prolonged in codeleted tumors: 8.4 vs 2.9 years (HR 0.47; p<0.001).
• Adjusted for codeletion status, PCV+RT improved OS in Cox model (HR 0.67; 95% CI 0.50-0.91; p=0.01).
• PCV+RT had more acute toxicities (myelosuppression, neuropathy, cognitive/mood change); 2 PCV-related deaths.

Intervention

4 cycles of intensive PCV (lomustine 130 mg/m² day 1, procarbazine 75 mg/m² days 8-21, vincristine 1.4 mg/m² days 8 and 29, no 2-mg cap, every 6 weeks) before 59.4 Gy involved-field radiotherapy, vs RT alone. Randomization stratified by age, KPS, degree of anaplasia.

Inclusion Criteria

Adults ≥18 years with newly diagnosed anaplastic oligodendroglioma or anaplastic oligoastrocytoma; postoperative KPS ≥60; adequate organ function; central pathology review.

Study Design

Arms: PCV intensive pre-RT + RT (59.4 Gy) vs RT alone (59.4 Gy)

Patients per Arm: PCV+RT 148; RT alone 143 (N=291 eligible; median follow-up 11.3 years)

Outcome

• Primary: Overall survival (all patients) — PCV+RT 4.6 y vs RT 4.7 y; HR 0.79 (95% CI 0.60-1.04); p=0.1 (NS)
• 1p/19q codeleted subset OS: PCV+RT 14.7 y vs RT 7.3 y; HR 0.59 (95% CI 0.37-0.95); p=0.03
• Noncodeleted subset OS: 2.6 vs 2.7 y; HR 0.85; p=0.39 (no benefit)
• Codeleted PFS: 8.4 vs 2.9 y; HR 0.47; p<0.001
• Adjusted (codeletion, clinical factors) OS HR 0.67 (95% CI 0.50-0.91); p=0.01

Bottom Line

Major Points

Phase 3 multicenter randomized intergroup trial RTOG 9402 (Cairncross JCO 2013); enrolled 1994-2002 at 76 centers
N=291 adults ≥18 with newly diagnosed anaplastic oligodendroglioma or anaplastic oligoastrocytoma, KPS ≥60
1:1 randomization to 4 cycles intensive PCV before 59.4 Gy RT vs RT alone; stratified by age, KPS, degree of anaplasia
Median follow-up 11.3 years — long-term results essential to reveal benefit in codeleted tumors
Primary outcome: median OS in entire cohort — 4.6 (PCV+RT) vs 4.7 y (RT); HR 0.79 (95% CI 0.60-1.04); p=0.1
1p/19q codeleted subset (n=126): median OS 14.7 vs 7.3 years; HR 0.59 (95% CI 0.37-0.95); p=0.03
Noncodeleted subset (n=136): median OS 2.6 vs 2.7 y; HR 0.85; no benefit from PCV
PFS in codeleted subset: 8.4 vs 2.9 years; HR 0.47; p<0.001
Cox-adjusted OS (codeletion, clinical factors) HR 0.67 (95% CI 0.50-0.91); p=0.01
PCV toxicity substantial: 20% discontinuation, 2 neutropenic deaths
Established 1p/19q codeletion as predictive and prognostic biomarker
Made chemoradiation standard of care for codeleted anaplastic oligodendroglioma

Study Design

Study Type: Phase 3 multicenter randomized intergroup trial (RTOG/Alliance)
Randomization: Yes
Blinding: Open-label (surgical/oncology)
Sample Size: 291
Follow-up: Median 11.3 years (range 0.5-16.8)

Primary Outcome

Definition: Overall survival (entire cohort)

Control	Intervention	HR/OR	P-value
Median 4.7 years	Median 4.6 years	- (0.60 to 1.04)	p=0.1 (not significant in unadjusted analysis)

Limitations & Criticisms

Unplanned codeletion subgroup analysis — though biologically driven, increases risk of type I error; small subgroup numbers
1p/19q codeletion assessment was retrospective (tissue retrieval improved from 70% at original report to 91% here) — not intention-to-treat at randomization
PCV toxicity substantial (20% discontinuation for toxicity, 2 fatal); temozolomide generally preferred in modern practice despite no head-to-head RCT showing TMZ superiority
Used pre-RT intensive PCV rather than post-RT standard-dose (EORTC 26951) — optimal sequencing and dose intensity unclear
IDH mutation status not considered at trial design — now known to be a key molecular marker in gliomas; CIC mutations also relevant
Dose intensity (4 cycles pre-RT) may exceed what most community practices accept — dose-intense regimens rarely used today

Citation

View Original Publication →

RTOG 9402

Clinical Question

Bottom Line

Major Points

Design

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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