Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I).

Two hundred and eighty-six patients with medulloblastoma from 46 centres in 15 countries were treated in a prospective randomized trial designed to assess the value of adjuvant chemotherapy. All patients were treated by craniospinal irradiation. Those randomly allocated to receive adjuvant chemotherapy were given vincristine during irradiation and maintenance CCNU and vincristine, given in 6-weekly cycles, for 1 year. The overall survival was 53% at 5 years and 45% at 10 years. At the close of the trial in 1979, the difference between the disease-free survival rate for the chemotherapy and control groups was statistically significant (P = 0.005). Since then, late relapses have occurred in the chemotherapy arm and the statistically significant difference between the two groups has been lost. Although there is now no statistical difference between the two arms of the trial, a benefit for chemotherapy persists in a number of sub-groups; partial or sub-total surgery (P = 0.007), brainstem involvement (P = 0.001), and stage T3 and T4 disease (P = 0.002). A number of prognostic factors for medulloblastoma have emerged; sub-total resection, extent of disease and being male sex carry a poor prognosis.

Long-term psychological effects in children treated for intracranial tumors.

The results are reported of the psychological assessment of 62 children who presented with primary intracranial tumors and who received radiotherapy at the Royal Marsden Hospital between 1963 and 1973. Evaluations were carried out 3-20 years after treatment. All patients were free from progressive tumor at testing. The average IQ of the total series was within the normal range (Full-Scale IQ 92) but 23% of the patients were functioning at an educationally subnormal level of intelligence (IQ less than 80). Sex, tumor type, tumor location and the radiotherapy volume and site of maximum dose were not found to have a significant effect on intellectual outcome. A significant correlation was found between intelligence and age at the time of treatment. Children who received treatment under the age of 5 years were more adversely affected (average IQ 72) than those who were aged 6-10 (average IQ 93) and those aged 11-15 years (average IQ 107). The incidence of neurological abnormalities and physical disability was significantly greater among patients with supratentorial tumors (72% of cases), compared with patients with infratentorial lesions (44% of cases). The results were discussed in terms of the management of young patients with intracranial tumors.

Medulloblastoma in adults: a review of 47 patients treated between 1952 and 1981.

The results of treatment of 47 adults with medulloblastoma are reviewed. For those treated with ortho-voltage radiotherapy between 1952 and 1963 the actuarial 5- and 10-year survival rates were 38% and 23%, respectively. Of those treated with megavoltage radiotherapy between 1964 and 1981, the corresponding 5- and 10-year survival rates were 59% and 53%, respectively. Of patients treated with megavoltage radiotherapy and adjuvant chemotherapy between 1971 and 1981, 76% were alive at 5 years and also at 10 years. Treatment factors associated with an increased survival were complete or subtotal resection of the primary tumor, as opposed to partial removal, a radiation dose to the posterior fossa of 55 Gy or more and the administration of adjuvant chemotherapy. Neither the quality of life, nor the fertility of the surviving patients, have been impaired by the treatment. Six patients (13%) developed metastatic disease outside the central nervous system.

Low grade glioma of the cerebral hemispheres in adults: a retrospective analysis of 88 cases.

Eighty-eight adult patients with histologically verified cerebral low grade gliomas (grades 1 and 2) treated with post-operative radiotherapy at the Royal Marsden Hospital between 1960 and 1985 were reviewed. Survival of oligodendroglioma patients was greater than those with astrocytoma (64% vs 36% at 5 years) but the difference was less marked in the long term (35% vs 26% at 10 years). Previous studies have identified prognostic factors important in these tumors: age, extent of surgery, grade, performance status, and duration of symptoms. In this study of low grade astrocytomas and oligodendrogliomas, age (highly significant in the former and significant in the latter), extent of surgery (oligodendrogliomas), and performance status have been demonstrated as factors influencing outcome. The precise role of radiotherapy including the optimal radiation dose and timing of treatment remains unclear. The information, given by a retrospective analysis such as this, helps in the design of prospective, randomized studies looking at radiation dose and time of surgical and radiotherapeutic interventions, always with careful assessment needed of quality of life and treatment morbidity.

Optic gliomas: radiation therapy and prognosis.

A retrospective study was performed of 30 patients with optic gliomas referred to the Royal Marsden Hospital between 1951 and 1981. Twenty-nine of these had progressive disease, and were treated with radiotherapy. At presentation 12 (41%) had visual deficit to the extent of at least one blind eye. Visual acuity improved following treatment in 10 (43%) of 23 evaluable patients, was stable in 11 (48%) and deteriorated in 2 (9%). There was increase in visual fields in 4 (18%) of 22 evaluable patients, and no change in the remaining 18 (82%). Overall 26/29 (90%) of irradiated patients remained free from disease progression at a median follow-up period of 10 years. The probability of survival was 100% at five years following radiotherapy, and 93% at 10 years and also at 15 years. In view of the substantial morbidity and mortality in reported series, and the tendency for referral of more serious cases to a radiotherapy center, we conclude from our results that radiotherapy is effective in preventing progression of optic glioma, and that treatment early in the course of the disease is indicated to minimize the associated visual deficit.

The role of radiotherapy in the management of intracranial meningiomas: the Royal Marsden Hospital experience with 186 patients.

One hundred and eighty-six patients with intracranial meningiomas were treated at the Royal Marsden Hospital between 1963 and 1983 with megavoltage photon irradiation (60Co gamma rays and 6-8 Mv. X rays). Survival parameters were measured from the time of referral for radiotherapy. The 10-year actuarial cause-specific survival was 67% for all cases and the actuarial disease-free survival was 61%. Both malignant and also "aggressive benign" histologies were associated with poor long-term survival. Benign angioblastic meningioma was associated with lower actuarial cause specific and disease-free survival compared with other benign histological sub-groups. Prognosis was related to the extent of initial surgical resection. Of those who underwent subtotal or partial tumor resection with post-operative radiotherapy the 10-year actuarial cause-specific survival was 77%, and in inoperable patients treated by radiotherapy alone it was 46%. Radiotherapy alone resulted in improvement of neurological performance (Karnofsky) in 12 out of the 32 (38%) patients with inoperable disease. The 10-year survival of patients referred for irradiation following "complete" surgical resection was only 34% owing to the high incidence of adverse histological sub-types in this treatment sub-group. Based upon univariate analysis, performance status of less than 60 (Karnofsky) and also age greater than 50 years at the time of referral for radiotherapy were adverse prognostic factors. Multivariate analysis revealed that histological type, extent of surgical resection and performance status at the time of presentation for radiotherapy were independent prognostic variables. However age at the time of referral lost significance as an independent variable when analyzed using this method. Patients undergoing complete surgical resection for the typical benign non-aggressive meningioma do not require adjuvant irradiation. The results of this study support the role of radiotherapy for treatment of incompletely resected and inoperable meningioma of all 3 histological types (benign, "aggressive benign", malignant).

Management of primary cerebral lymphoma with initial chemotherapy: preliminary results and comparison with patients treated with radiotherapy alone.

Between 1986 and 1988 10 patients with primary cerebral lymphoma (PCL) were treated with initial MACOP-B chemotherapy followed by radiotherapy. All demonstrated radiological response to chemotherapy but this did not predict final clinical outcome. The overall median survival was 14 months. Patients with poor MRC neurological performance status (NPS) 2-4 had a median survival of 5 months. Three of 7 patients with NPS 0-1 died and the median survival is 18 months with a median follow-up of 13 months (10-35 months). The results were compared to 25 patients with primary cerebral lymphoma treated between 1963 and 1986 with radiotherapy as the main treatment modality. The overall median survival was 16 months. Patients presenting with poor NPS (2 and 3) had worse survival (median survival 8 months) compared to patients with good NPS (median survival 22 months; p less than 0.025). Patients diagnosed and treated from 1982 to 1986 also had significantly worse prognosis when compared to earlier treated patients. The preliminary results of combined modality therapy are so far not significantly different when compared to historical series and we have to await long-term outcome before recommending combined modality therapy as the treatment of choice.

Intracranial ependymoma: long-term results of a policy of surgery and radiotherapy.

Ninety-three patients with primary intracranial ependymoma were treated at the Royal Marsden Hospital, between 1952 and 1988, with postoperative radiotherapy. The survival probability at 5, 10, and 15 years was 51%, 42% and 31%, respectively, and the corresponding progression free survival (PFS) probability, 41%, 38%, and 30%. Tumor grade was the single most important prognostic factor for survival and PFS with gender of lesser prognostic significance. Treatment parameters were stratified for grade. In patients with low grade tumors survival and PFS were better following complete macroscopic excision compared to incomplete surgery. The extent of resection had no significant influence on survival or PFS in patients with high grade tumors. Extent of irradiation did not influence PFS, irrespective of tumor grade, while patients with high grade tumors had marginally better survival following extensive irradiation compared to more limited radiotherapy. The main problem in the treatment of ependymoma remains local progression which was the cause of death in all but two patients. New treatment strategies should focus on improvement of local control, especially in incompletely resected low grade tumors and all high grade tumors. The use of spinal irradiation is unlikely to significantly improve treatment results.

The treatment and long-term prognosis of children with intracranial tumors: a study of 610 cases, 1950-1981.

Six hundred and ten children aged under 16 years with intracranial tumors were referred for radiotherapy between 1950 and 1981: 579 were new cases and 31 had recurrent disease after primary treatment elsewhere. Radiotherapy was completed in 93% of all cases. The actuarial survival rate for all new cases was 53% at 5 years, 46% at 10 years, 40% at 20 years, and 39% at 30 years. The oldest children (10-15 years) had the best survival and the youngest (0-2 years) had the worst survival. Children treated with megavoltage x-ray equipment (1970 to 1981) had a significantly greater survival than those treated with orthovoltage X rays (1950-1969). Overall, a direct correlation was found between survival and maximum radiotherapy dose. Children having a total excision of the tumor prior to radiotherapy showed a greater survival than those treated by a subtotal or partial tumor removal. Children treated by radiotherapy alone had a survival comparable to those treated by sub-total excision and radiotherapy. There is a striking difference in survival expectation depending on initial functional category (I to III). The overall survival rates of 428 children completing treatment for glioma were 49% at 5 years, 43% at 10 years, and 40% at 15 years. The results according to certain specific tumor sites within the cerebral hemispheres are reported. Age is an important prognostic factor in low grade and also high grade astrocytomas, children having longer survivals than adults. Sub-total or partial excision of craniopharyngiomas combined with radical radiotherapy appears to give the best long-term results. Of 73 new cases, the 5-, 10-, and and 15-year survival rates were 92%, 84%, and 79%. Recurrent craniopharyngiomas treated by surgery alone can be salvaged by further conservative surgery and radical radiotherapy. Optic gliomas are slow growing low grade astrocytomas. Survival rates at 5, 10, and 15 years for 20 children with mostly chiasmal lesions were 89%, 89%, and 78%, respectively. In 73 children with brain stem tumors, 17% remained alive for up to 15 years. The risk of CNS seeding from intracranial ependymomas depends on site of origin and grade of malignancy, with 50% incidence occurring in cases with high grade lesions situated in the posterior fossa. Survivals at 5, 10, and 15 years in 51 children were 51%, 40%, and 31%. Adjuvant chemotherapy improves survival.(ABSTRACT TRUNCATED AT 400 WORDS)

Pineal and CNS germ cell tumors: Royal Marsden Hospital experience 1962-1987.

A retrospective analysis has been made of all patients with pineal and CNS germ cell tumors who were treated at The Royal Marsden Hospital between 1962-1987. A total of 67 new cases were seen: 17 had initial histological verification of tumor type and the remainder were tested for radiosensitivity with a dose of 20 Gy following a shunting procedure. Patients with germ cell or radiosensitive tumors were treated with a uniform policy of whole neuraxis radiotherapy giving 50 Gy to the local tumor and 30 Gy to the remaining brain and spinal cord. Nonresponding lesions continued with local fields to a dose of 50 Gy. Patients were divided into three groups (a) germinoma and radiosensitive tumours, 34 cases; (b) malignant teratoma, 12 cases; (c) non-germ cell, 21 cases. Median follow-up is 83 months (range 2-246 months). Overall and cause specific actuarial 5/10 year survival were for group 1, 81.7%/69.4% and 86.5%;/86.5%; group 2, 18.2%/18.2% and 18.2%/18.2%, and group 3, 64.3%/46.8% and 64.3%/52.6%, respectively. No patient in group 1 treated during the last 12 years has recurred. Univariate analysis of factors at presentation, showed that neurological performance status (p less than .001) as well as tumor type (p less than .001) correlated with outcome. Recurrence was confined to the primary site in only 1 of 4 patients in group 1 compared to 6 of 9 patients in group 2 and 9 of 10 patients in group 3. No isolated spinal recurrence occurred in group 1 patients. A total of eight patients have received platinum containing chemotherapy for recurrence (6 cases) or adjuvant therapy (4 cases). Germinomas appear to respond better than teratomas, all of which have recurred rapidly following initial partial response. Shunting and radiosensitivity testing remains the treatment of choice for tumors compatible with germinoma. Craniospinal irradiation is associated with low morbidity providing spinal growth is complete and is recommended in older patients as salvage following spinal recurrence is unsatisfactory. Aggressive combined modality approaches with surgery, radiotherapy and chemotherapy need to be investigated to improve results in CNS teratoma.

Craniopharyngioma--a long-term results following limited surgery and radiotherapy.

Between 1950 and 1986 173 patients with craniopharyngioma were treated at the Royal Marsden Hospital with external beam radiotherapy either alone or following surgery. Four patients had complete tumour excision, 21 subtotal and 78 partial resection, 14 had biopsy alone, 34 aspiration alone and 22 had no surgery directed at tumour eradication. Seventy-seven (45%) were children (aged < 16 years). The 10 and 20 year progression-free survival (PFS) rates were 83% and 79%. There were no independent prognostic factors for PFS. The 10 and 20 year survival rates were 77% and 66% at a median follow-up of 12 years. After adjustment for mortality in the normal population, age and technique of radiotherapy (which corresponded with era of treatment) were significant independent prognostic factors for survival. The risk of death (corrected for mortality from natural causes and controlling for radiotherapy technique) for age groups 16-39 and > or = 40 was 0.58 and 0.40 respectively, relative to a risk of 1.0 for the age group < 16 years. Survival and PFS were not influenced by the extent of surgical excision. Visual field defect improved after radiotherapy in 36% of patients (38/106) and visual acuity in 30% (27/91). No patient developed radiation optic neuropathy. We conclude that limited surgery and radiotherapy achieve excellent long-term tumour control and survival with low morbidity.

Renal impairment following the combined use of high-dose methotrexate and procarbazine.

A major side-effect of high-dose methotrexate is renal toxicity, which may develop unexpectedly despite adequate standard precautions such as hydration and alkalinisation of the urine. The pathogenesis is unclear. Recent reports suggest that the combination of high-dose methotrexate with non-chemotherapeutic agents may cause such renal impairment. Three cases of unexpected renal impairment following the combined use of high-dose methotrexate and another cytotoxic agent, procarbazine, are reported. Possible mechanisms of this interaction are discussed, as are recommendations for future combined administration.

Postoperative radiotherapy in the management of spinal cord ependymoma.

Fifty-eight patients with histologically verified spinal cord ependymomas were treated at the Royal Marsden Hospital and Atkinson Morley's Hospital between 1950 and 1987. The median age in this series was 40 years (range 1 to 79 years) and the male:female ratio was 1.8:1. Ten patients had tumors in the cervical cord and 10 in the thoracic cord; 14 tumors involved the conus medullaris and 24 the cauda equina. Forty ependymomas were grade I and 13 were grades II to IV (in five patients there was insufficient material for grading). Eleven patients underwent biopsy only, 33 had partial or subtotal resection, and 14 had complete resection. Forty-three patients received postoperative radiotherapy. The median follow-up period was 70 months (range 3 to 408 months). Cause-specific survival rates were 74% and 68% at 5 and 10 years, respectively. On univariate analysis, age, histological grade, postoperative neurological function, and era of treatment were significant prognostic factors for survival. The histological grade was the only significant independent prognostic factor. The relative risk of death from ependymoma was 9.0 for patients with tumor grades II to IV compared to grade I (p less than 0.005, 95% confidence interval 2.7 to 30). The survival rates of patients following complete excision were significantly better compared to those after incomplete surgery (p less than 0.025). The majority of completely resected neoplasms were low-grade cauda equina tumors. Despite incomplete surgery, 5- and 10-year progression-free survival rates following radical radiotherapy were both 59%, and cause-specific survival rates were 69% at 5 years and 62% at 10 years. This suggests that radiotherapy may achieve long-term tumor control in over half of those patients with residual spinal ependymoma.