1. Neuroblastoma Meg Browning 3/31/04

2. Epidemiology 6% of childhood malignancies Most common cancer in children < 1 y.o. 2/3 are in children < 5 y.o. 70% of all patients have mets at dx One of the small blue round cell tumors [leukemia, lymphoma, Ewing/PNET, RMS, Wilms, desmoplastic]

3. Clinical findings Originates in sympathetic NS: paraspinal ganglia or adrenal medulla Most common: mass effect sxs, bone pain, proptosis/periorbital ecchymoses from retrobulbar mets Can invade neural foramina,  paralysis Less commonly: fever, anemia, HTN Rarely: VIP secretion  diarrhea, cerebellar ataxia, opsoclonus/myoclonus

4. Prognostic factors Stage (males present later, but o/w male is not worse) Age (<1 y.o. better except maybe <6 wks with no skin nodules) Primary tumor site ONLY for stage 3- 4 (abd is worse) +/- Primary tumor size (> 100 cm3 is worse) Shimada criteria

5. Prognostic factors, cont. Biology, esp. myc-n but also: Good: hyperdiploidy, TRK-A (high-affinity nerve growth factor receptor, proto- oncogene), LNGFR, HA-ras p 21 Bad: 1p-, 17/17q-, B-myb oncogene, increased telomerase RNA (hTR), high ferritin, neuron-specific enolase, high LDH, low tumor CD44 NOT catecholamine levels

6. Shimada FavorableUnfavorable Age > 5y Age <1.5y Stroma rich Nodular pattern?yesno Stroma poor Age <1.5y yesno MKI < 200? Differentiated AND MKI < 200? yes no yes no

7. Staging (INSS) 1: localized, GTR, attached +LN’s okay 2A: as above but no GTR 2B: ipsilateral +LN’s: must Bx contralat LN’s 3: Unresectable tumor crossing midline (edge of vertebral body) +/- regional nodes OR bilateral extension/nodes (regional only) 4: Disseminated tumor, not 4S 4S: Stage 1, 2A, or 2B primary with mets ONLY to skin, liver, and/or < 10% of marrow; MIBG (-) if done

8. Work-up is therefore: MIBG or bone scan CT/MR to look for nodes and evaluate liver CXR Catecholamines Tumor biology, at least for myc-n and ploidy BMA and Bx Path on any relevant nodes (if not already stage 4)

9. Treatment and Prognosis 1: > 90%, still good even with local recurrence. Surgery only UNLESS: age > 2y, myc-n amplified, unfavorable histology, ? +LN 2: 75-90%. Bx/surg, chemo (4-6 mos of CTX/DOX), then definitive surg. 3, <1y: 80%. Surg +/- chemo 3, >1y: 50-70%. Surg + chemo, +/- XRT. May need SCT if myc-n amplified.

10. Rx and Px, cont. 4, <1y: 50-80%, avg. 60%; biology important (approaches 0 if myc-n; approaches 95% without) 4, >1y: 10-40%, avg. 15%*; SCT better than chemo alone 4S: 57-100%, better if no sxs Recurrent Dz: bad if disseminated; usually disseminated. CNS involvement common, UNLIKE at primary Dx. *this is pre- the new protocol, which we’ll take on next

11. COG A3973 Purged v. Unpurged PBSCT for NBL 6 3-week cycles of chemo 1, 2, 4, and 6 VCR/CTX/DOX (+MESNA & G) 3 & 5 VP/CISPL (+ GCSF) Harvest after cycle 2 (Goes to LA; rules are complex. HD-GCSF is used for that cycle, on a specific schedule. Purging is randomized and has a separate consent. Assessment of remission is also done at that time; + marrow, progressive dz, HIV+, and pregnant pt’s do not go on to SCT; there is a chemo maintenance arm. Surgery after cycle 5

12. COG A3973: more on SCT Pt’s in CR, VGPR, and PR with an adequate (5 x 10 6 CD34+ cells/kg) tumor-free harvest product go on to SCT. Pt’s with minimal response may come off or stay on. There is a biology study re tumor detection, and another biology research part (the latter requires initials!) Conditioning (“consolidation”) for SCT is with CARBO/MEL/VP (+ G). Dosing is based on nuc med GFR, which must be done before MIBG!

13. Further Rx QOL study requires separate initials +/- XRT 1 mo after SCT to primary site and any mets “w/o significant response to chemo.” cis-Retinoic acid: new randomization; new consent. 6 mos of r.a. +/- anti-GD2 & GM-CSF & IL-2. Starts 2 mo after SCT. Pt’s ineligible for SCT get 3 cycles of CYCLO/TOPO, and may still go on to XRT and/or r.a. Recommendations for supportive care during SCT are c/w what we do for an allo transplant.

14. Subject of debate: When to involve BMT? We as a group (Onc/BMT) need to develop a plan that is satisfactory to all and helps our solid tumor/autoBMT patients transition successfully back and forth between the two teams. For the foreseeable future, the BMT team is still going to handle the auto-transplants – it’s required for BMT program accreditation. Suggestions?

15. Summary Common as pediatric solid tumors go Excellent Px in infants without myc-n amplification Current Px on the new high-risk protocol is generally being quoted around 30-40% Incredibly variable clinical course, largely based on tumor biology, has made this an attractive tumor to study – look for a “vaccine” protocol to come down the pike in the next few years.