Evidence Based Questions Flashcards
In MB, how are NTR, STR, and “Bx only” defined?
NTR: <1.5 cm2 residual on postop MRI
STR: ≥1.5 cm2 residual on postop MRI
Bx only: No attempt at definitive resection
In MB, is there a difference b/t NTR vs. GTR in terms of EFS? How about STR and GTR?
Retrospective studies suggest that pts who obtain an NTR and GTR have similar outcomes. (Gajjar A et al., Ped Neurosurg 1996) However, 5-yr EFS is worse in STR pts (54%) compared to GTR/NTR pts (78%). (Zeltzer PM et al., JCO 1999)
What chemo agent improved DFS and OS according to MB studies in the 1990s?
Cisplatin. Prior to the introduction of cisplatin, several studies (SIOP I and CCG 942) failed to show improved OS with the addition of adj chemo.
What 2 studies demonstrated the need for chemo with reduced-dose CSI (23.4 Gy) for standard-risk MB?
There has been no RCT comparing reduced-dose CSI +/– cisplatin-based chemo. The need for cisplatin-based chemo is inferred from the following 2 studies:
- POG 8631/CCG 923: randomized standard-risk MB to 36 Gy vs. 23.4 Gy CSI alone (no chemo). There was a trend toward ↓ EFS and OS in the 23.4-Gy arm. (Thomas PR et al., JCO 2000)
- CCG 9892 (phase II): standard-risk MB treated with 23.4 CSI with concurrent weekly vincristine → 55.8-Gy boost to PF → adj cisplatin/CCNU/vincristine. 5-yr PFS was 79%, which was similar to historical controls treated with 36 Gy CSI and similar chemo. (Packer R et al., JCO 1999) Basis for POG A9961 reduced dose CSI.
Can RT be delayed for MB pts <3 yo by using chemo alone? What studies support this?
Yes. Given the toxicity of RT in pts <3 yo, it is reasonable to delay RT until 3 yo, especially with desmoplastic histology.
Baby POG (Duffner PK et al., Neurooncol 1999, NEJM 1993): <3 yo, 206 pts, high-/low-risk MB + other PNET, chemo alone (Cytoxan + Vincristine (VCR) × 2→ cisplatin + etoposide) × 2 yrs if <2 yo, × 1 yr if 2–3 yo. 5-yr OS was 40%, and PFS was 32%.
German BTSG data (Rutkowski S et al., NEJM 2005): <3 yo, 43 pts, high-/low-risk MB, chemo (Cytoxan, vincristine, Mtx, carboplatin, VP-16, intrathecal Mtx). 5-yr PFS was 58%, and OS was 66%. The majority of pts had a desmoplastic variant histology. The benefit was best in M0 pts (5-yr PFS of 68% and OS of 77%)
SFOP data (Grill J et al., Lancet Oncol 2005): <5 yo, 79 pts. 5-yr OS was best in R0M0 (73%) vs. 13% with M+.
What was the Tx regimen on COG A9934 for MB pts <3 yo?
Initial Sg → induction chemo × 4 mos with Cytoxan, vincristine, cisplatin, etoposide → 2nd Sg for identifiable or residual Dz → age/risk group/response-adapted conformal RT to PF + primary site (no CSI) → maintenance chemo × 8 mos. Enrolled children were older than 8 mos but younger than 3 yrs, all M0 MB.
Age/risk/response-adapted RT:
(Ashlet DM et al., JCO 2012)
If <24 mos and CR: 18 Gy to PF → tumor bed boost to 50.4 Gy, or 54 Gy if PR/Stable disease/+ residual
If >24 mos and CR or PR: 23.4 Gy to PF → tumor bed boost to 54 Gy
What evidence supports the use of >50 Gy total doses in MB?
Retrospective data suggest that LC in the PF varies with dose above and below 50 Gy. In 60 MB cases, if the PF dose was >50 Gy, the LC was 79%. However, if the PF dose was <50 Gy, the LC was 33%. (Hughes EN et al., Cancer 1988)
In MB pts, does the entire PF need to be boosted to >50 Gy?
Retrospective evidence suggests that few failures occur in the PF outside the tumor bed (<5%).
Fukunaga-Johnson et al. reviewed 114 pts treated with CSI → boost to the entire PF. The solitary site of the 1st failure within the PF but outside the tumor bed occurred in 1 of 27 failures. (IJROBP 1998)
Wolden et al. reviewed 32 pts treated with tumor bed boost only. There were 6 total failures: 5 outside the PF and 1 within the PF but outside the boost volume. (JCO 2003)
Merchant et al. conducted a prospective phase II trial of 23.4 Gy CSI + PF boost to 36 Gy and primary site to 55.8 Gy with dose-intensive chemo. 5-yr EFS was 83%, and PF failure was 5%. Reduced doses to temporal lobes, cochlea, hypothalamus. (IJROBP 2008)
What are the RT technique questions being addressed in COG ACNS0331?
In ACNS0331, standard-risk pts 3–7 yo are randomized to CSI to 18 Gy vs. 23.4 Gy. For the 18 Gy arm, all pts got a PF boost to 23.4 Gy. All standard-risk pts 3–7 yo underwent a 2nd randomization: CD to 54 Gy to whole PF vs. tumor bed only. Standard-risk pts 8–22 yo: 23.4 Gy CSI → randomization to CD to 54 Gy to PF vs. tumor bed only.
What was the rationale for 18-Gy CSI in ACNS0331?
CSI doses in excess of 20 Gy still pose a significant risk for cognitive and growth outcomes, particularly in young children. Pilot study in 10 children with PNET of the PF showed comparable outcomes to higher doses. (Goldwein J et al., IJROBP 1996)
What do the preliminary results of ACNS0331 show?
For pts with standard-risk MB, boosting the tumor bed alone is sufficient, but decreasing the CSI dose to 18 Gy is associated with higher risk of recurrence and is not recommended. (Michalski JM et al., IJROBP 2016)
What question does ACNS0334 attempt to address?
Phase III trial in children <3 yrs with high-risk MB or PNET. Trial addresses the addition of high-dose Mtx to the 4-drug induction chemo regimen of VCR, etoposide, Cytoxan, cisplatin → 2nd Sg, consolidation, and peripheral blood stem cell rescue. RT is at the discretion of the institution.
What study is examining molecular risk-adapted Tx?
SJMB12 is a St. Jude trial examining risk-adapted escalation and de-escalation of radiotherapy and chemo based on molecular subtype (WNT, SHH, and Non-WNT/SHH [Group 3/4]), cytogenetics, histology, and extent of resection.
Is there a role for pre-RT chemo in MB pts >3 yo?
No. In MB pts >3 yo, intensive chemo prior to RT (vs. RT then chemo) is associated with ↑ RT toxicity, RT Tx delays, and worsened RFS. (German HIT 91: Kortmann RD et al., IJROBP 2000)
What benefit does proton therapy have in the Tx of MB?
Retrospective data suggest that proton plans have ↓ dose to the cochlea/temporal lobe compared to IMRT (0.1%–2% vs. 20%–30%), and virtually no exit dose to the abdomen, chest, heart, and pelvis. Recent study suggests less morbidity, including GI and heme toxicity (although this is in adults). (Brown AP et al., IJROBP 2013)