Ahmet Tunceroğlu, MD, PhD
Sabin B. Motwani, MD
WORKUP
All Cases
H&P (make note of age, performance status, neuro deficits)
CT head and MRI brain w/ and w/o contrast (variable, but generally some enhancement on T1 + contrast, no frank central necrosis)
Considerations
1p19q codeletion (increases sensitivity to procarbazine, lomustine, vincristine [PCV] chemo)
Isocitrate dehydrogenase (IDH) mutation
TREATMENT RECOMMENDATIONS BY HISTOLOGIC SUBTYPE
1p19q codeleted or IDH1 mutated Anaplastic oligodendroglioma (AO) Anaplastic oligoastrocytoma (AOA) Anaplastic astrocytoma (AA) |
Maximum safe resection → chemo with PCV → standard fractionation RT OR maximum safe resection → standard fractionation RT → chemo (PCV) OR maximum safe resection → chemoRT with temozolomide (TMZ) → adjuvant chemo (TMZ) |
1p19q uni- or noncodeleted, and IDH1 wild type AO AOA AA |
Maximum safe resection → chemoRT with TMZ → chemo (TMZ) |
Poor performance status (KPS < 60) |
Standard fractionation RT OR hypofx (preferred) external beam radiation therapy OR palliative care |
TECHNICAL CONSIDERATIONS
Simulation
Simulate and treat with aquaplast mask. Obtain pre- and post-op T1 post contrast and T2 FLAIR MRI, fuse to CT if no MRI sim.
Dose Prescription
Definitive RT
59.4 Gy in 33 fx or 60 Gy in 30 fx
Hypofractionated RT
40 Gy in 15 fx
Post-Op ChemoRT
59.4 Gy in 33 fx (cone down after 50.4 Gy) followed by six cycles PCV q6 weeks
Or four cycles PCV q6 weeks followed by 59.4 Gy in 33 fx (cone down after 50.4 Gy)
Or 60 Gy in 30 fx (cone down after 46 Gy) with concurrent and adjuvant TMZ
TMZ Dose
Concurrent: 75 mg/m2/d × 7 d/wk
Adjuvant: 150 mg/m2/d × 5 d/month × 6 months (if tolerates 150 mg/m2 for first cycle, then raise to 200 mg/m2 for subsequent cycles)
Target Delineation
Treat initial PTV 50.4 (or PTV 46) then cone down to PTV 59.4 (or PTV 60)
Initial Fields
GTV 50.4 = T1 enhancement + T2 FLAIR signal + tumor bed
CTV 50.4 = GTV 50.4 + 2 cm, crop at natural barriers (dura, ventricles, falx, tentorium cerebelli)
PTV 50.4 = CTV 50.4 + 0.3 to 0.5 cm
Cone Down
GTV 59.4 = T1 enhancement + tumor bed
CTV 59.4 = GTV 59.4 + 1 to 1.5 cm
PTV 59.4 = CTV 59.4 + 0.3 to 0.5 cm
Hypofx RT Target Delineation
GTV 40 = T1 enhancement + tumor bed
CTV 40 = GTV 40 + 2 cm
PTV 40 = CTV 40 + 0.3 to 0.5 cm
Treatment Planning
Intensity-modulated radiation therapy with 6-MV photons
Multiple beams and/or arcs, consider some noncoplanar beams/arcs
Avoid beam entrance/exit through mouth, lenses
FOLLOW UP
If asymptomatic: MRI brain and H&P 2 to 6 weeks after RT, then q2 to 4 months for 2 to 3 years
Pseudoprogression: Radiation-induced necrosis. Can occur in 20% to 30% of patients and can be very difficult to differentiate from disease recurrence/progression on MRI.
RANO proposed criteria (Wen et al., J Clin Oncol 2010; DOI: 10.1200/JCO.2009.26.3541)
If <12 weeks post chemoRT: new enhancement must be out of high-dose RT field (80% isodose line) or must have histologic evidence of recurrence.
If >12 weeks post chemoRT: new enhancement out of RT field, ≥25% increase in sum of product of diameters, or clinical deterioration.
Consider obtaining magnetic resonance spectroscopy, especially if within 3 months of completing RT.
SELECTED STUDIES
RTOG 9402 (Cairncross, J Clin Oncol 2006; DOI: 10.1200/JCO.2005.04.3414)
289 patients (AOA and AO), 88% s/p resection, randomized to 59.4 Gy RT alone versus four cycles PCV followed by 59.4 Gy RT.
PCV improved progression-free survival (PFS) (2.6 vs. 1.7 years) but not 3-year overall survival (OS).
Patients with 1p19q codeletion had longer survival compared to noncodeleted (>7 years vs. 2.8 years).
Long-term update (Cairncross 2013) showed improved OS in codeleted patients with sequential PCV + RT (14.7 years) versus RT alone (7.3 years). No benefit of PCV for noncodeleted patients.
RTOG 9402 Subgroup Analysis (Cairncross J Clin Oncol 2014; DOI: 10.1200/JCO.2013.49.3726)
Retrospective analysis of patient population from RTOG 9402 to evaluate for potential survival advantage of IDH mutation in the context of PCV treatment.
OS improved with sequential PCV > RT versus RT alone in patients with IDH mutation both in the background of 1p19q codeletion (14.7 years vs. 6.8 years) and in noncodeleted patients (5.5 years vs. 3.3 years).
EORTC 26951 (Van Den Bent, J Clin Oncol 2013; DOI: 10.1200/JCO.2012.43.2229)
368 patients (AO) randomized to 59.4 Gy RT alone versus 59.4 Gy RT followed by six cycles PCV.
Median OS improved with sequential RT > PCV (42.3 months) versus RT (30.6 months).
Even greater benefit in 1p19q codeleted patients with sequential RT > PCV versus RT alone for PFS (150 months vs. 50 months) and OS (not reached vs. 112 months).
NOA-04 Trial (Wick, J Clin Oncol 2009; DOI: 10.1200/JCO.2009.23.6497)
318 patients (AO, AOA, and AA), 80% s/p resection, randomized to 60 Gy RT versus chemo (PCV or TMZ). Patients switched arms if unacceptable toxicity or disease progression.
Time to treatment failure, PFS, or OS did not differ based on whether initial treatment was RT or chemo.
CODEL Trial (Currently Ongoing)
Initially to evaluate role of TMZ in 1p19q codeleted patients.
Patients randomized to RT + PCV versus RT + TMZ versus TMZ alone (3-arm study).
As of 08/15, randomization is now … RT + PCV versus RT + TMZ concurrent/adjuvant TMZ (2-arm study). TMZ-alone arm closed due interim data revealing TMZ-alone treated patients would be unlikely to have equivalent or superior survival outcome to patients treated on the two RT containing arms. TMZ arm was also underpowered.
CATNON Trial (Reported ASCO 2016)
To evaluate role of TMZ in patients without 1p19q codeletion.
Patients randomized to RT alone versus RT + concurrent TMZ versus RT + adjuvant TMZ versus RT + concurrent + adjuvant TMZ (4-arm study).
Adjuvant TMZ improved PFS as well as OS compared to regimens without adjuvant TMZ (5 year OS 56% vs. 44%).
Concurrent TMZ (vs. RT alone) results still pending.