MEDULLOBLASTOMA IN CHILDREN 0–3 YEARS OLD: Forty Years' Experience in Slovenia

Abstract

Twenty-one children 0–3 years with MB were admitted 1960–1996, of 14 before treated 1984, 3 had no treatment, 5 had postoperative RT, one had radioactive gold IT. Seven treated 1986–1996 had preradiation Cht, 5 with HDCy. Of the 14 treated before 1984, 12 died within 1 year, one after 42 years in hypopharynx cancer, one is alive, of normal height and working. Of the 7 treated 1986–1996, 3 with disseminated disease died. Four are longtime survivors, 2 treated with reduced doses of RT of normal development. Preradiation Cht with HDCy and reduced doses of RT seems to be a reasonable approach.

Keywords:

• children
• medulloblastoma
• preradiation chemotherapy

Surgery followed by postoperative radiation therapy (RT) of the central nervous axis (CNA) used to be the only succesful treatment in medulloblastoma (MB). The aim of preradiation chemotherapy (Cht) in very young children with MB is to reduce the severe sequelae of radiation therapy. Combination Cht with lower than conventional doses (24 cGy) RT has been fairly successful. With Cht alone the results are still poor, allthough salvage of some of its failures might still be possible [1–3]. A promising combination of mechlorethamine, oncovine, procarbazine, and prednisone (MOPP), curative alone in few cases, has been very toxic [4]. Other combinations have been also effective in delaying radiation therapy. In patients with recurrence, however, the outcome is poor and survivors after intensive salvage treatment are likely to experience severe sequelae [5]. Thus, the primary intention to reduce sequelae failed. The timing of RT after preradiation Cht and the choice of Cht to be used are not yet defined. Cht should be effective in preventing recurrence and only moderately toxic. The experience with our small series of children less than 3 years old with MB, although few, might be useful when future studies be planned.

PATIENTS AND METHODS

Between 1960 and 1996, 21 children 0–3 years of age (median 2.14), 3 girls and 18 boys, with MB were registered at the Cancer Registry of Slovenia. In most of the 14 children registered before 1984, neither the work-up, nor the treatment have been satisfactory, 3 below 1 year had no treatment, none had Cht, and postoperative mortality was high. Three patients had total tumor resection, after which one was treated with RT to the posterior fossa (30 Gy) and postoperative application of 5 mC radioactive gold, 4 had CNA irradiation (30–36 Gy) and 50–55 Gy to the posterior fossa.

Seven children were treated between 1986 and 1996 (Table 1), 3 with disseminated disease at diagnosis, 3 had total tumor resection. All had preradiation Cht, 5 with high-dose Cytoxan (HDCy), 40 mg/kg on 2 consecutive days. In one preradiation HDCy was abandoned after the first cycle, because of liver damage from birth (his mother was alcoholic) and he had postoperative RT with conventional doses when 3 years old. Four patients received 3 cycles of HDCy. One patient had preradiation Cht with cis-platinum and VP 16, one had also vincristine.

Children with Medulloblastoma Treated 1985–1996

		Age	Diagn.				Treatment		Follow-up
Patient	Sex	years	year	Stage	Surgery	RT doses (Gy)		Cht	Years
15 SS	M	3,0	1985	T2M0	+	36	51	HDCy	NED	18
16 ES	M	1,4	1986	T1M3	+	12	34	HDCy	DOD	2.8
17 DB	M	1,8	1986	T2M1	+	24	44	HDCy	DOD	4.2
18 SŽ	M	1,5	1989	T1M0	+	24	46	HDCy	NED	13
19 JR	M	1,8	1990	T1M0	+	24	50	HDCy	NED	12
20 BB	M	3,0	1991	T2M0	+	36	50	PT VP16	LFU	4
21 NA	M	3,0	1996	T3M3	+	36	48	VCR PT VP16	DOD	2.3
22 PT	M	2,9	2000	T1M0	−			VCR PT VP16	DOD	2
								MTX, Carbo
								MTX I.T.

DOD = Dead of disease, NED = Alive without sign of disease, HDCy = High-dose cytoxan, LFU = Lost from follow-up after 4 years.

No patients 0–3 years old with MB were registered between 1997 and 1999. The last patient treated during 2000 had, after total resection of a PNET of the IV ventricle, only postoperative Cht, including vincristine, carboplatinum, VP16, methotrexate IV and methotrexate intrathecally (HIT protocol) [6] during 1 year.

RESULTS

Of the 14 children treated before 1984, 12 died within 1 year from diagnosis (Figure 1). Of the remaining 2, one who had RT to the posterior fossa (30 Gy) and intrathecal application of radioactive gold, died 42 years later in hypopharynx cancer. No neurological complications were noted during his lifetime. The second survivor, who had total tumor resection and postoperative RT (30 cGy to the CNA and 55 Gy to the posterior fossa) when 2.5 years old, is of normal height, euthyroid, and working as a metal worker.

1 Survival of medulloblastoma in children 0–3 years old.

Of the 7 children treated between 1986 and 1996, all 3 with disseminated diseased died. In the patient ES, complete remission was achieved after 3 cycles of HDCy, treatment continued with RT, after 3 months malignant cells were found in the spinal fluid and multiple supratentorial tumors. Several applications of HDCy and local RT to new recurrences were combined with intrathecal methotrexate, Ara-C and hydrocortisone. The disease progressed after several intermittent remissions and the boy died 3 years and 3 months from diagnosis. He developed rather normally, was walking, talking, and as far as we can judge had a “good quality” of his short life. Patient DB experienced recurrence at the cribriform plate 2 months after completed first treatment, had more local RT in combination with HDCy, later with carboplatinum and VP 16, died 4 years after diagnosis. Of the 4 who had localized disease at diagnosis, 3 are long-term survivors, one was lost from follow-up after 4 years without recurrence. Late sequelae in the 2 who had RT with conventional doses are severe in one, now 20 years old (dwarphism, endocrinological and intellectual deficit) and moderate in the second, 15 years old (hypothyroidismus). The 2 patients (SŽ and JR) treated with reduced doses of RT are 15 and 16 years old, attending normal school, and so far in normal development.

The patient treated in the year 2000 experienced recurrence locally and in the spinal canal 2 months after completed Cht and 16 month after diagnosis. After a partial remission of 4 months with RT to the CNA, he died of tumor 2 years after diagnosis.

DISCUSSION AND CONCLUSIONS

In our opinon and based on very few patients, postoperative Cht alone for treatment of MB is not satisfactory. In view of the severe sequelae after irradiation, it is the only means so far for very young children; however, whenever possible and if the child after Cht has reached the age of 3 years and in remission, it would seem appropriate to continue treatment with moderate doses of RT. The question arises what kind of Cht can be used for such a long time that may be necessary, without risk of recurrence. In case of recurrence, the chances for the child to survive are poor, and that only after very intensive treatment. Preradiation Cht with HDCy and reduced doses of RT during remission seems, according our experience, to be a reasonable approach. Unfortunately, it was not successful in patients with disseminated tumor. However, even in those, it has proven to be rather effective in producing remissions and prolonging life. Several current protocols include Cytoxan in combination with other drugs in somewhat lower doses. As originally used, it might be more successful and less toxic, thus could be used for a prolonged time. Postoperative application of radioactive sources (with rather high doses) has been abandoned for treatment of MB because of severe complications [7]. We have not observed any complications during more than 40 years after one intrathecal application of 5 mC radioactive gold. How much the late secondary tumor in our patient was related to such treatment is impossible to tell. Treatment with radioactive sources is controversial and has been in general discouraged [7], although used for treatment in leukemias with little or no toxicity [8]. Maybe it could be reconsidered in moderate doses for postoperative treatment in very young children with MB, stage M0 in a trial comparing intrathecal applications of chemotherapeutic agents. Survival of children with “high risk” medulloblastoma is still very poor. Hopefully newly developed treatment modalities and Cht combinations will show improvement [9–11].