Radiation Oncology/CNS/Germinoma

CNS Germinoma Overview Rare primary CNS tumor, 3-5% of childhood brain tumors Typical age at presentation is early teens Mainly located in midline structures, suprasellar region or pineal gland, also basal ganglia and hypothalamus Can be M+ in as much as 24% histologically verified cases; Disease outside of CSF is very rare Bifocal germinomas (synchronous suprasellar and pineal tumors) regarded as M+ in USA but M0 in Europe Natural spread believed to be along subependymal lining of 3rd and 4th ventricles, leading to intraventricular relapse before spinal dissemination Very sensitive to both radiation and chemotherapy Location Treatment Treatment of M0 disease is somewhat controversial. Historically craniospinal RT was the gold standard, but with local control >99% and 10-year survival rates >90%, limiting side-effects is essential. There is now a movement toward WBRT, and further to tumor + ventricles only. Isolated spinal relapse appears comparable between CSI and whole-brain RT or whole-ventricular RT with neoadjuvant chemo Focal RT of primary tumor alone appears associated with significantly higher overall and isolated spinal relapse M+ disease continues to be treated with CSI Attempts at treatment with chemotherapy alone have resulted in ~50% relapses and ~10% treatment-related mortality; which is much worse than RT alone. This is currently not recommended Current RT approach (1/11, 20452141): Whole ventricular volume: 3rd, 4th, lateral, prepontine cistern Involved field volume: pre-chemotherapy volume + clinical margin 1-1.5 cm Dose to primary disease is typically 40-45 Gy, and to subclinical disease 20-24 Gy Review 15992700 -- "Radiotherapy of localised intracranial germinoma: time to sever historical ties?" (Rogers SJ, Lancet Oncol. 2005 Jul;6(7):509-19.) Reviewed 20 studies since 1988. 788 patients. 66% cases histologically confirmed, 12/20 series 100% confirmation. Median F/U 6.4 years CSI: local control 99.7%; relapses 3.8% but half of them outside CS axis; isolated spinal relapse 1% WBRT or Whole-ventricular RT+boost: both comparable. local control 97%; relapses 8%; isolated spinal relapse 3% Focal: local control 93%; relapses 23%; isolated spinal relapses 11% Conclusion: Whole-ventricular RT + boost should replace craniospinal RT in completely staged localized intracranial germinomas Treatment of relapses: Chemotherapy. Studies Seoul; 2008 (1981-2003) 18514777 -- "Upfront chemotherapy and involved-field radiotherapy results in more relapses than extended radiotherapy for intracranial germinomas: modification in radiotherapy volume might be needed." (Eom KY, Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):667-71.) Retrospective. 81 patients with tissue-confirmed intracranial germinoma. 39 RT only (all CSI), 42 chemo-RT (size depended on tumor extent, ranging from tumor only to CSI). Median F/U 5.7 years Outcome: 5-year OS RT 100% vs. chemo-RT 93%; 5-year RFS RT 100% vs. 88% (SS). 4 relapses in chemo-RT group (3 in brain and 1 in spine) Toxicity: same proportion return to school (NS), hormonal therapy RT 69% vs. chemo-RT 38% Conclusion: Better quality of life in chemo-RT but worse relapse compared with RT alone. Primary tumor RT not sufficient, suggest at least inclusion of ventricles POG 9530 (1997-1999) -- response-based RT Phase II. 12 germinoma patients (and 14 NGGCT patients and/or elevated AFP/bHCG - not further discussed here). Age >3 years. 5 resected, 7 bx. Germinoma treated with cisplatin/etoposide and vincristine/cyclophosphamide x4 cycles. If CR, primary site RT 30.6 Gy; if PR primary site RT 50.4 Gy with 2cm margin (3D-CRT) or 0.5cm margin (SRT). If disseminated disease and CR, CSI 30.6 Gy; if PR CSI 36 Gy 2007 16598761 -- "Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the Children's Oncology Group." (Kretschmar C, Pediatr Blood Cancer. 2007 Mar;48(3):285-91.) Outcome: 11/12 progression-free at median 5.5 years, 1/12 refused RT, failed at 10 months, RT salvage, progression-free at 4.8 years Conclusion: Response (91%) and survival encouraging Toronto; 2006 (1995-2004) 16530340 -- "Limited-field radiation for bifocal germinoma." (Lafay-Cousin L, Int J Radiat Oncol Biol Phys. 2006 Jun 1;65(2):486-92.) Retrospective. 6 patients with bifocal germinoma (pineal + suprasellar). All with diabetes insipidus at presentation. Treated with chemo followed by limited-field RT (whole ventricle 24-40 Gy +/- boost). Median F/U 4 years Outcome: 100% complete remission Conclusion: Bifocal germinoma can be considered locoregional rather than metastatic disease MAKEI 83/86/89, 1983-93 (German) - MAKEI = Maligue Keimzelltümoren (malignant germ cell tumors) Prospective, non-randomized. Goal: dose reduction. 60 pts. Germinomas. Three trials: 83(pilot) and two successive trials. Biopsy only (no resection) In MAKEI 83/86 (11 pts), RT to 36 Gy to craniospinal axis + 14 Gy boost to tumor (total 50 Gy, at 1.8-2 Gy/fx). In MAKEI 89 (49 pts), 30 Gy (CSI) + 15 Gy (total 34 Gy at 1.5 Gy/fx). 10561326, 1999 — "Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89." Bamberg M et al. J Clin Oncol. 1999 Aug;17(8):2585-92. Mean f/u 59 mos. CR in all pts. 5-yr RFS 91%, OS 93% Conclusion: dose reduction is feasible. SIOP CNS GCT 96 CSI 24 Gy MSKCC; 1996 8918487 -- "Chemotherapy without irradiation--a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study." (Balmaceda C, J Clin Oncol. 1996 Nov;14(11):2908-15.) Prospective. 68/71 patients (45 germinoma, 26 NGGCTs). Chemo carboplatin, etoposide, bleomycin x4 cycles. If CR, 2 more cycles. If PR, 2 more cycles intensified by cyclophosphamide. Outcome: CR rate germinomas 86%, NGGCT 78%. 2-year OS germinoma 84%, NGGCT 62% Toxicity: 7/71 patients (10%) Conclusion: Chemo-only regimens should be used only in setting of clinical trials Seoul; 1996 (Korea)(1980-1996) 8850422 -- "Radiotherapy of intracranial germinomas." (Huh SJ, Radiother Oncol. 1996 Jan;38(1):19-23.) Retrospective. 32 patients, confirmed intracranial germinomas (14 suprasellar, 12 basal/thalamus, 4 pineal, 2 multiple). CSI in 29 patients. RT tumor bed 54 Gy, whole-brain 36 Gy, spinal axis 24 Gy Outcome: 5-year OS 97%, 10-year OS 97%; 1 death with persistent tumor 2 months after RT; no intracranial or spinal recurrence Toxicity: 1 severe intellectual deterioration, 3 vertebral growth impairment Conclusion: Excellent result with RT alone Proton Therapy Harvard; 2010 (1998-2007) 20452141 -- "Proton Radiotherapy for Pediatric Central Nervous System Germ Cell Tumors: Early Clinical Outcomes." (Macdonald SM, Int J Radiat Oncol Biol Phys. 2010 May 6. [Epub ahead of print]) Retrospective. 22 patients, CNS germ cell tumors, treated with 3D PT. Patients also replanned with IMRT and IMPT. Median F/U 2.3 years Outcome: Local control 100%, no CNS recurrences, PFS 95%, OS 100% Treatment planning: Comparable CTV coverage with IMRT, 3D-CPT, and IMPT. Substantial normal tissue sparing with either PT over IMRT. IMPT may yield additional brain and temporal lobe sparing Conclusion: Preliminary disease control favorable; superior dose-distribution compared to IMRT