Clinical trialPhase 3Brain tumours

Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma

N Engl J Med · 2016251 eligible patients (enrolled 1998 to 2002)

Buckner JC, Shaw EG, Pugh SL, et al. N Engl J Med. 2016. 374:1344-1355

Study type: Clinical trial
Study name: RTOG 9802
Phase: Phase 3
Design: Multicentre randomised trial (US cooperative groups led by RTOG); report of long-term results
Sample size: 251 eligible patients (enrolled 1998 to 2002)
Source: N Engl J Med · 2016
Trial registration: NCT00003375

In plain words

Grade 2 gliomas are slow-growing brain tumours that are often seen in young people. This long study (about 12 years of follow-up) showed that in patients who need more treatment after surgery, adding 6 cycles of the three-drug PCV chemotherapy after radiotherapy increases average survival from about 8 years to about 13 years. PCV chemotherapy can lower white blood cells and platelets and needs regular blood tests.

Key results

13.3 vs 7.8 years

Median overall survival

HR for death 0.59; P=0.003; median follow-up 11.9 years

60% vs 40%

10-year overall survival

51% vs 21%

10-year progression-free survival

Oligodendroglioma and receipt of PCV were favourable prognostic factors in the Cox model

Dose and schedule cards

Radiotherapy followed by PCV (RTOG 9802)

High-risk grade 2 glioma (younger than 40 years with subtotal resection or biopsy, or 40 years or older); per the guidelines, the preferred regimen for grade 2 and 3 oligodendroglioma when treatment is neededCycle length: PCV every 8 weeksOn the page “Brain tumours” · IDH-mutant gliomas (astrocytoma and oligodendroglioma)

Drug	Dose	Route	Schedule
Radiotherapy
Radiotherapy	54 Gy in 30 fractions of 1.8 Gy	External beam radiotherapy	Over 6 weeks
Then 6 cycles of PCV
Lomustine (CCNU)	110 mg/m²	Oral	Day 1
Procarbazine	60 mg/m² per day	Oral	Days 8 to 21
Vincristine	1.4 mg/m² (maximum 2 mg)	IV	Days 8 and 29

Cycle length: PCV every 8 weeks
Duration: 6 weeks of radiotherapy, then 6 cycles of PCV (about 1 year)

Toxicity is mainly haematologic: grade 3 neutropenia in 44 and grade 4 in 11 of the 125 patients in the PCV group. Lomustine warnings (delayed myelosuppression, dispensing only one dose per cycle, pulmonary function testing) as in the lomustine “Common safety considerations” in the recurrent glioblastoma regimens. Temozolomide is a reasonable alternative for patients who do not tolerate PCV. Dose source: full text of the article.

On the page “Brain tumours” · IDH-mutant gliomas (astrocytoma and oligodendroglioma)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Radiotherapy + PCV

Radiotherapy 54 Gy in 30 fractions of 1.8 Gy over 6 weeks.

Then 6 cycles of 8 weeks of PCV: lomustine (CCNU) 110 mg/m² orally on day 1; procarbazine 60 mg/m² orally daily on days 8 to 21; vincristine 1.4 mg/m² (maximum 2 mg) IV on days 8 and 29.

2Radiotherapy alone

Radiotherapy 54 Gy in 30 fractions of 1.8 Gy over 6 weeks.

Source of the regimen details: Radiotherapy dose (54 Gy in 30 fractions) and PCV regimen from the "Treatment" section of the full text of the paper (author manuscript in PMC: PMC5170873).

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with grade 2 glioma (astrocytoma, oligoastrocytoma or oligodendroglioma) in the "high-risk" group: younger than 40 with subtotal resection or biopsy, or 40 and older with any extent of surgery (biopsy or resection). Stratified by age, histology, KPS and presence of contrast enhancement.

Endpoints

Primary outcome: overall survival (OS).

Secondary outcomes: progression-free survival, toxicity and cognitive status (MMSE).

Safety and side effects

Toxicity was mainly haematological and in the PCV group: grade 3 neutropenia in 44 and grade 4 in 11 of 125 patients in the PCV group (versus 1 grade 3 case in the radiotherapy-alone group). Grade 3 thrombocytopenia in 23 patients in the PCV group. Fatigue, anorexia, nausea and vomiting were mostly grade 1 or 2. One case of febrile neutropenia; no grade 5 events or cases of myelodysplasia/leukaemia were reported.

Clinical significance and place in guidelines

This trial made radiotherapy followed by PCV the standard treatment for high-risk grade 2 gliomas. The EANO 2021 guideline considers radiotherapy followed by maintenance PCV (citing RTOG 9802) the standard of care for grade 2 IDH-mutant astrocytoma requiring further treatment (C: II; L: B) and also recommends radiotherapy followed by PCV for grade 2 1p/19q-codeleted oligodendroglioma (C: III; L: B).

Limitations

Patients were enrolled on the basis of histology (older WHO classification) and before routine use of IDH and 1p/19q markers; later molecular analyses are retrospective. There was no comparator arm with temozolomide chemotherapy. The sample size was relatively small, and accrual was slow.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.