# Radiation Oncology/Peds/CNS PNET

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Supratentorial PNETs
* Account for <5% of pediatric CNS tumors
* Patients typically present with symptoms related to increased ICP
* Embryonal tumor composed of undifferentiated/poorly differentiated neuroepithelial cells, which can differentiate along neuronal, astrocytic, ependymal, muscular, or melanotic lines
** Distinct neuronal differentiation = cerebral neuroblastoma
** Ganglion cells present = ganglioneuroblastoma
** Arising in pineal region = pineoblastoma
* Typically more aggressive nature compared to medulloblastoma (infratentorial PNET), with rapid progression
** German HIT trials: 3-year PFS ST-PNET PFS 49% vs standard-risk medulloblastoma 78% on same protocol
** CCG 921 trial: 5-year PFS ST-PNET M0 53% vs. medulloblastoma M0 71%; M+ 29% vs. 52% on same protocol
* Different genetic alterations in ST PNET vs. medulloblastoma
* May occur anywhere in the CNS
* Historically treated on same protocols as medulloblastoma; treatment strategy now comparable to high-risk medulloblastoma
** Historically, POG has viewed PNET and medulloblastoma as different entities, while CCG was reporting them together
* Based on German HIT 87/92 trials, RT cannot be eliminated in young (<3 years) patients, even with intense chemotherapy, and delay should be <6 months. Similarly, in CCG and POG protocols, infants treated with only chemotherapy tended to progress and die of the disease
Poor prognostic factors:
* Disseminated disease at diagnosis (M+)
* Young age <3
* Non-cerebellar (medulloblastoma), non-pineal (pineoblastoma) primary

## Studies

* CCG 99701 (Ongoing)
** Phase I/II. Feasibility of concurrent/maintenance chemotherapy. Central primitive embryonic tumors (PNET, ATRT, Medulloblastoma, Ependymoblastoma, Medullomyoblastoma, Spongioblastoma, Medulloepithelioma, Neuroblastoma, Pineoblastoma). No M4 disease. RT CSI 36/20 followed by tumor boost to 53-58.6 Gy in 1.8 Gy/fx, with concurrent carboplatin/ vincristine, followed by maintenance vincristine/ cyclophosphamide or cisplatin/ vincristine/ cyclophosphamide
* HIT-SKK87 and HIT-SKK92 (1987-1992, 1992-1997)
** HIT-SKK87: Low-risk (complete resection, M0) and age <2.5 received maintenance chemo only until RT at 3 years or progression. High-risk (subtotal resction, M+) and age 2.5-3 induction chemo / maintence chemo until RT at 3 years or progression
** HIT-SKK92: Post-op chemo x3 cycles first, then if CR no RT. If PR and <18 months, then more chemo, if PR and >18 months, then RT.
** RT given as CSI 35.2/22 Gy + 20/10 Gy boost; if no residual disease, reduced to CSI 24 Gy + PF boost to 55 Gy
** 2006 PMID 16575007 -- "Role of radiotherapy in supratentorial primitive neuroectodermal tumor in young children: results of the German HIT-SKK87 and HIT-SKK92 trials." (Timmermann B, J Clin Oncol. 2006 Apr 1;24(10):1554-60.)
*** Total 29 children enrolled on both. No RT given in 15 children.
*** 3-year outcomes: OS 17% and PFS 15%. RT only positive predictive factor
** Conclusion: Outcomes unsatisfactory. Omission of RT jeopardizes survival, even when intensive chemo given. Suggest limiting delay of RT to maximum 6 months
* German HIT 88/89 and HIT 91 (1991-97)
** Pilot (HIT 88/89) followed by randomized (HIT 91). Trial enrolled pts with supratentorial PNET, medulloblastoma, and anaplastic ependymomas. All treated with extensive resection. In HIT 88/89, pts treated postoperatively with chemo x2 cycles (Ifosfamide, etoposide, MTX, cisplatin, cytarabine) -> RT (CSI 35.2 Gy + PF boost 20 Gy). In HIT 91, randomized to 1) immediate RT (35.2 + 20) followed by maintenance chemo x8 cycles (CCNU, cisplatin, vincristine), or 2) chemo -> RT (same as HIT 88/89).
** ST PNET subset, 2002 PMID 11821469, 2002 — "Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91." (Timmermann M et al. J Clin Oncol. 2002 Feb 1;20(3):842-9.)
*** Subset analysis of 63 children with ST PNET. 67% incomplete resection. 7 children RT to tumor site only, 2 children no RT, 15 children major RT violations. Median F/U 2.6 years
*** 3-yr OS 48.4%. Progression in 38 pts, LR in 27 pts. 3-year PFS correct RT 49% vs. major protocol violation RT 7%
*** Conclusion: Preirradiation chemo increases risk of recurrence. Volume should encompass whole CNS to 35 Gy with boost to at least 54 Gy
** Pilot HIT 88/89 PMID 9743957 -- "Preradiation chemotherapy of children and young adults with malignant brain tumors: results of the German pilot trial HIT'88/'89." (Kuhl J, Klin Padiatr. 1998 Jul-Aug;210(4):227-33.)
*** RT delayed median 23 weeks
*** 5-year OS: medulloblastoma 57%, ependymoma 62%, malignant glioma 36%, ST PNET 30%
*** Conclusion: Well tolerated and efficacious. Based on this, HIT 91 developed
* CCG 921 (1986-1992)
** Randomized. 427 children <21 years, with medulloblastoma, pineoblastoma, ependymoblastoma, central neuroblastoma, PNET, or malignant ependymoma, with unfavorable features. For ST-PNET required M+ staging. Children age >1.5 years (n=328) received post-op CSI with Arm A) vincristine, lomustine, prednisone vs. Arm B) 8-in-1 (cisplatin, procarbazine, lomustine, vincristine, cyclophosphamide, methylprednisolone, hydroxyurea, cytarabine). RT: age >3 received CSI 36 Gy, boost to 50.4-54 Gy spine mets and 54 Gy primary brain site; age <3 received CSI 23.4 Gy with boost to 45 Gy. Children age <1.5 years (n=99) were not randomized and received only Arm B
** Infants failures; 2005 PMID 16007595 -- "Patterns of treatment failure in infants with primitive neuroectodermal tumors who were treated on CCG-921: a phase III combined modality study." (Hong TS, Pediatr Blood Cancer. 2005 Oct 15;45(5):676-82.)
*** Infant (<1.5 years) subset of 65 patients (19 supratentorial, 46 posterior fossa.)
*** Outcome: 5-year relapse rate M0 64% vs. M+ 71%. ST-PNET subset M0 64% vs. M+ 100%. Relapses within 2 years
*** Conclusion: despite aggresive chemo, infents have high rates of treatment failure
** Older kids failures; 2004 PMID 15337557 -- "Patterns of failure in supratentorial primitive neuroectodermal tumors treated in Children's Cancer Group Study 921, a phase III combined modality study." (Hong TS, Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):204-13.)
*** ST-PNET subset of 44 patients, age >1.5 years. Compared to medulloblastoma treated on same protocol
*** Outcome: 3-year PFS M0 53% vs. M+ 14% (SS); 5-year relapse rate 47% vs. 71%. Worse relapse rate compared to medulloblastoma: M0 47% vs. 29%, M+ 71% vs. 48%
*** Pattern of failure: M0 11% in spine; M+ 43% in spine
*** Time-course: 80% within 2 years
*** Conclusion: High rate of failure, M+ patients doing particularly poorly
** 3-years; 1995 PMID 7602359 -- "Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized trial." (Cohen BH, J Clin Oncol. 1995 Jul;13(7):1687-96.)
*** ST-PNET subset of 55 patients, age >1.5 years.
*** Outcome: 3-year OS 57%, PFS 45%; pineal PNET better at 73% and 61% (SS); stage M0 PFS 50% vs. M+ 0%. No difference between chemo arms
*** Toxicity: 8-in-1 arm worse
*** Conclusion: No difference between chemo arms; M0 and pineal site better outcome
** Infants; 1994 PMID 8040673 — "Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group." (Geyer JR et al. J Clin Oncol. 1994 Aug;12(8):1607-15.)
*** Infant (<1.5 year) subset of 82 children (46 posterior fossa, 15 ependymoma, 11 nonpineal ST-PNET, 8 pineoblastoma, 2 ATRT. Received Arm B only (8-in-1), RT omitted in most cases
*** 3-year PFS: ST PNET 55% vs. medullo 22% vs. ependymoma 22% vs. pineoblastoma 0%. Median time-to-progression 6 months
*** Conclusion: OS is poor, a subset remained disease-free with chemo only
*** Comment: Results inferior compared to Baby POG, probably due to less intensive chemo, but ~20% long-term survivors with chemo only
* Baby POG I (1986-90)
** Prospective. 198 children < 3 yrs (132 < 2 yrs, 66 age 2-3 yrs), bx proven malignant brain tumors (low-grade astro excluded), treated with maximal surgery, postop chemo (CTX/VCR followed by cis/etopo) for 2 yrs (if age < 2 at dx) or 1 yr (age 2-3) or until disease progression, followed by RT.
** Histologies: medulloblastoma 31%, ependymoma 24%, PNET 18%, malignant glioma 9%, brain-stem glioma 7%, other 9%. 27% M+. GTR in 38% of cases.
** RT for medullo, PNETs, anaplastic ependymoma, or subarachnoid seeding CSI 35.2 Gy + boost to primary to 54 Gy. RT for ependymoma, gliomas local to 54 Gy. If no residual disease after chemo, reduced RT to CSI 24 Gy and primary site 50 Gy. Infants <2 years 90% of dose
** 1993 PMID 8388548 -- "Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors." (Duffner et al., N Engl J Med. 1993; 328(24):1725-31)
*** Response rate: best in medulloblastoma, glioma, ependymoma. Poor/no response in brain-stem gliomas and embryonal tumors
*** CR to chemo PFS comparable those with GTR PFS
*** Conclusion: Chemo effective in infancy. If GTF, chemo alone provided excellent control. No clinically important neurotoxicity. However, cannot recommend for embryonal tumors
** 10-years, 1999 PMID 11554387 — "The treatment of malignant brain tumors in infants and very young children: an update of the Pediatric Oncology Group experience." (Duffner PK et al. Neuro-oncol. 1999 Apr;1(2):152-61.)
*** ST PNET (17 children): 5-year OS 27%. Failures early
*** 3-year survival: GTR 100% vs. STR 11%
*** Conclusion: Some children may have prolonged survival