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.
OBJECTIVE
The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT '91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy.


METHODS
Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine ("Philadelphia protocol"). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose).


RESULTS
During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4-62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70+/-0.08; for patients with residual disease: 0.72+/-0.06; without residual disease: 0.68+/-0.09; M0: 0.72+/-0.04; M1: 0.65+/-0.12; and M2/3: 0.30+/-0.15. For all randomized patients without M2/3 disease: 0.65+/-0.05 (arm I) and 0.78+/-0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60+/-0.13 and 0.64+/-0.14, respectively, but patients between 6 and 18 years: 0.62+/-0.09 and 0.84+/-0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03).


CONCLUSIONS
Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.
Kortmann
R D
RD
Department of Radiotherapy, University of Tuebinen, Germany. RDKORTMA@MED.UNI-TUEBINGEN.DE
Kühl
J
J
Timmermann
B
B
Mittler
U
U
Urban
C
C
Budach
V
V
Richter
E
E
Willich
N
N
Flentje
M
M
Berthold
F
F
Slavc
I
I
Wolff
J
J
Meisner
C
C
Wiestler
O
O
Sörensen
N
N
Warmuth-Metz
M
M
Bamberg
M
M
D000293:Adolescent; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D011832:Radiation Injuries / Q000150:complications; D011879:Radiotherapy Dosage; D016019:Survival Analysis