Radiation Oncology/Medulloblastoma/Randomized

CSI RT Dose

• POG 8631/CCG 923 (1986-1990) -- CSI 36 Gy vs. CSI 23.4 Gy
  • 2000, PMID 10944134 -- "Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation." (Thomas PR, J Clin Oncol. 2000 Aug;18(16):3004-11.)
  • Randomized. 126 patients, low risk (>3 years, complete resection T1-T2, later also T3a, M0) standard CSI 36(20*1.8) vs. reduced CSI 23.4(13*1.8); both followed by posterior fossa boost to 54(30*1.8) Gy. Study closed prematurely due to high relapse in reduced arm
  • 5-year EFS: standard CSI 67% vs. reduced CSI 52% (p=0.080)
    8-year EFS: standard CSI 67% vs. reduced CSI 52% (p=0.141)
    These data confirm the original one-sided conclusions but suggest that differences are less marked with time
  • Conclusion: Reduced CSI 23.4 Gy alone is insufficient; may need concurrent chemo

• SIOP II (1984-1989) -- CSI 35 Gy vs. CSI 25 Gy; also +/- adjuvant chemo
  • 1995, PMID 7623725 "Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO)" Bailey et al. Med Pediatr Onc 25(3):166-78, 1995
  • Randomized. 364 patients. SIOP I low risk (total/subtotal resection, no brain stem invasion, M0) randomized to +/- adjuvant chemo (vincristine, methotrexate, procarbazine), and then randomized to standard CSI 35 Gy vs. reduced CSI 25 Gy. Boost posterior fossa to 55 Gy. High risk randomized to +/- adjuvant chemo, then standard CSI and additional post-RT chemo
  • Outcome: No advantage to pre-RT chemo. Standard CSI 35 Gy for low risk pts increased EFS (68% vs 55%). Low risk patients with adjuvant chemo and CSI 25 Gy did particularly badly
  • Conclusion: No benefit to adjuvant chemo. Standard dose of CSI is 35 Gy

CSI +/- Chemo

• CCG A9961 (1996-2000) -- CSI 23.4 Gy + CCNU-based vs. cyclophosphamide-based chemo
  • 2006, PMID 16943538 "Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma" Packer et al. JCO 24(25):4204-8, 2006.
  • Randomized. 421 patients, standard risk. Treated with reduced dose RT (23.4 Gy CSI + 55.8 Gy to posterior fossa) and concurrent vincristine, and randomized to either: 1) CCNU, cisplatin and vincristine or 2) cyclophosphamide, cisplatin, vincristine. Median F/U 5 years
  • 5-year outcome: EFS 81%, OS 86%. No difference by chemo arm
  • Prognostic factors: anaplasia OS 75% vs. 89% (SS)
  • Relapse: posterior fossa alone 32%, disseminated alone 40%, PF+disseminated 25%
  • Toxicity: 25% with delayed onset mutism, hypotonia, cerebellar deficits, supranuclear CN deficits, extreme irritability, and/or emotional lability. ~50% residual deficits at 1 year
  • Conclusion: Reduced dose CSI with chemo can be done safely to avoid toxicities of higher dose RT. No difference between chemo arms

• PNET 3 (1992-2000) -- CSI 35 Gy +/- neoadjuvant chemo
  • 2003, PMID 12697884 -- "Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study." (Taylor RE, J Clin Oncol. 2003 Apr 15;21(8):1581-91.)
  • Randomized. 179/217 standard risk patients (including M1). Treated with neoadjuvant chemo (vincristine/etoposide/carboplatin/cyclophosphamide) vs. RT alone (CSI 35 Gy + 20 Gy posterior fossa boost). Median F/U 5.4 years. Study closed early due to lack of accrual in RT alone arm
  • 5-year outcome: OS 70% (NS), EFS chemo-RT 74% vs. RT alone 60% (SS)
  • Conclusion: improved EFS with addition of chemo, no impact on survival

• SIOP II (1984-1989) -- CSI 35 Gy vs. CSI 25 Gy; also +/- adjuvant chemo
  • 1995, PMID 7623725 "Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO)" Bailey et al. Med Pediatr Onc 25(3):166-78, 1995
  • Randomized. 364 patients. SIOP I low risk (total/subtotal resection, no brain stem invasion, M0) randomized to +/- adjuvant chemo (vincristine, methotrexate, procarbazine), and then randomized to standard CSI 35 Gy vs. reduced CSI 25 Gy. Boost posterior fossa to 55 Gy. High risk randomized to +/- adjuvant chemo, then standard CSI and additional post-RT chemo
  • Outcome: No advantage to pre-RT chemo. Standard CSI 35 Gy for low risk pts increased EFS (68% vs 55%). Low risk patients with adjuvant chemo and CSI 25 Gy did particularly badly
  • Conclusion: No benefit to adjuvant chemo. Standard dose of CSI is 35 Gy

• SIOP I -- CSI +/- adjuvant chemo
  • 1990, PMID 2141512 -- "Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I)." (Tait DM, Eur J Cancer. 1990 Apr;26(4):464-9.)
  • Randomized. 286 patients, 15 countries. Treated with CSI, randomized to +/- chemo (concurrent vincristine, then CCNU/vincristine maintenance)
  • Survival: 5-year 53%, 10-year 45%. No difference between arms
  • Subgroup benefit: subtotal surgery, brainstem involvement, T3-T4 disease
  • Conclusion: No difference, but subgroup benefit

• CCG 942 -- CSI +/- adjuvant chemo
  • 1990, PMID 2319316 -- "The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone." (Evans AE, J Neurosurg. 1990 Apr;72(4):572-82.)
  • Randomized. 233 patients. CSI +/- chemo (CCNU, vincristine, prednisone)
  • 5-year outcomes: EFS chemo-RT 59% vs. RT alone 50% (NS); OS 65% for both (NS)
  • Subgroup benefit: large tumors (EFS chemo-RT 48% vs. RT alone 0%)
  • Conclusion: no benefit for chemo in low stage, subgroup benefit for advanced stage

CSI + adjuvant chemo alternatives

• CCG 921 (1986-1992) -- vincristine/lomustine/prednisone (VCP) vs. 8-in-1
  • 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
  • 1999 PMID 10071274 -- "Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study." (Zeltzer PM, J Clin Oncol. 1999 Mar;17(3):832-45.) Median F/U 7.0 years
    • Subset analysis. 203 patients with medulloblastoma. Median OS 8-in-1 55% vs. VCP 54% (NS); PFS 63% vs. 45% (SS)
    • Prognostic factors: age <3 (who received lower CSI dose); if >3 y/o then M stage (PFS M0 70% vs. M1 57% vs. M2+ 40%, SS); if M0 tumors, then residual (PFS <1.5 cm2 78% vs. >1.5 cm2 54%)
    • Conclusion: VCP + XRT superior; if <3 years (with reduced RT) had lowest survival

Pre-RT chemo vs. Post-RT chemo

• German HIT 91 (1991-97) -- Chemo x2 cycles ->RT vs. RT -> chemo x8 cycles
  • Trial enrolled pts with supratentorial PNET, medulloblastoma, and anaplastic ependymomas. All treated with extensive resection. In HIT 88/89, pts treated In HIT 91, randomized to 1) chemo x2 cycles (Ifosfamide, etoposide, MTX, cisplatin, cytarabine) -> RT (CSI 35.2 Gy + PF boost 20 Gy) or 2) immediate RT (35.2 + 20) followed by maintenance chemo x8 cycles (CCNU, cisplatin, vincristine).
  • Medullo subset, 2000 PMID 10661332 -- "Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91." (Kortmann RD, Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):269-79.)
    • Subset report of 158 medulloblastoma patients (137 randomized). Median F/U 2.5 years
    • 3-year outcome: RFS RT->chemo 78% vs. chemo->RT 65% (SS), but no difference if age 3-6 years
    • Negative prognosis: M2/3 disease, age <8 years. M1 not a bad prognostic factor
  • Conclusion: RT upfront with maintenance chemo more effective. Neoadjuvant chemo caused higher RT myelotoxicity, and more RT interruptions