Prognostic factors for medulloblastoma.

PURPOSE: To evaluate prognostic factors for medulloblastoma. METHODS AND MATERIALS: One hundred and seventy-three consecutive patients with medulloblastoma, treated at King Faisal Specialist Hospital (KFSH) from 1988-1997, were reviewed. Eighty-four percent were children less than 15 years old. From 1988-1994, treatment was at the discretion of the investigator. From 1994-1998, patients entered a single-arm best practice protocol in which, in staged patients, the surgical intent was total resection, standard radiation treatment was defined, and adjuvant chemotherapy was given to a "high-risk" subset. RESULTS: For 150 patients who completed surgical and radiation treatment, the 5-year survival rate was 58%, compared with 0% for 16 patients who were unable to start or complete radiation treatment. For staged patients, the 5-year survival was M0 + M1, 78% and M2 + M3, 21% (p < 0.0001). Other favorable significant prognostic factors were age >14 years and gross cystic/necrotic features in the primary tumor. The size of the primary tumor, the degree of hydrocephalus at diagnosis, the presence of residual tumor in the post-operative CT/MRI, and the functional status of the patient prior to radiation treatment were not significant factors. CONCLUSIONS: Stage M0 + M1 was the most powerful favorable prognostic factor. In Saudi Arabia more patients present with advanced disseminated disease, 41% M2 + M3, than in the West, and this impacts adversely on overall survival. Total resection and standard radiation treatment were not sensitive prognostic factors in a treatment environment in which 78% of patients underwent at least 90% tumor resection and 60% received standard radiation treatment. In order to improve the proportion of patients able to complete radiation treatment, consideration should be given to limiting resection when the attainment of total resection is likely to be morbid, and to delaying rather than omitting radiation treatment in the patient severely compromised postoperatively.

Subsequent quality of life for children irradiated for a brain tumor before age four years.

BACKGROUND: We wanted to evaluate survival and functional morbidity following radiation treatment of brain tumors in children less than 4 years old. PROCEDURE: Outcome was evaluated for 222 children who were less than 4 years old when they were irradiated at University of Toronto Centres, 1958-1995. The status of the survivors with regard to focal neurological defects, vision, hearing, and education at last follow-up was recorded. In 23 adult survivors older than 21 years at last follow-up, information was obtained with regard to higher education, occupation, and living arrangements. RESULTS: The overall 10-year survival rate was 40%, not significantly different than the 45% for 776 4-16-year-olds with irradiated brain tumors treated at the same institutions. Forty-five percent of the survivors had no major focal neurological, visual, or hearing defects. There were no major differences in the frequencies of these criteria or of schooling between 0-2- and 2-4-year-olds. Among adult survivors, older than 21 at last follow-up, 26% successfully completed higher education, 31% were in full-time employment, and 37% had never been employed. For medulloblastoma, the 5-year survival rate was 61% for 30 children less than 3 years old and treated from 1975-1995. This compared favorably with recent reports of survival following primary chemotherapy with delayed or omitted radiation treatment. SUMMARY: Radiation treatment of a young child with a brain tumor was associated with cure in 1 of every 3 patients. Unfortunately, quality of life for many survivors was not good. Only one of every 3 adult survivors was able to have a normal life-style. This shortfall was the result of focal neurological defects which were present from the time of first treatment, and of the long-term effects of radiation treatment. CONCLUSIONS: The search for less toxic treatment remains appropriate, but is experimental and researchers must recognize that there may be a trade-off between morbidity and mortality.

Craniopharyngioma in children.

PURPOSE: The treatment regimens at presentation and recurrence, the related morbidity, and survival rates were studied for children with craniopharyngioma who were treated at King Faisal Specialist Hospital & Research Center (KFSH&RC). METHODS & MATERIALS: From 1975 to 1996, a total of 56 children younger than 18-years-old at diagnosis underwent treatment with surgery and/or radiotherapy for craniopharyngiomas at KFSH&RC. There was evidence that these patients had advanced disease at diagnosis; 36% of 51 patients whose visual status pretreatment was known were either blind or had major bilateral visual defects prior to treatment, and 36% of the 56 patients had diabetes insipidus. This report concentrates on 44 patients who had first definitive resection at KFSH&RC. Treatment policy was total resection if possible (17 patients), if not, subtotal resection (17 patients) or lesser procedures (10 patients). Five patients received postoperative irradiation after first definitive resection. RESULTS: Ten-year-survival, and progression-free and event-free survival rates were 65%, 39%, and 29%, respectively. There were 9 postoperative deaths; 7 following the first procedure and 2 following resection for relapse, and 3 early deaths at home prior to relapse, following the first resection. None of the 22 patients who underwent less than total resection without postoperative radiation treatment were progression-free at 5 years, whereas the 5 patients who were irradiated remain progression-free. CONCLUSION: A more selective approach to total resection, and the routine use of postoperative irradiation following lesser surgical procedures requires evaluation.

The radiation treatment of medulloblastoma.

Following the introduction of CS-RT the survival rate for this malignant tumour rose from zero to approximately 50%. It appears that the major advances over the last twenty years associated with the introduction of CT/MRI, adequate staging, total resection, adjuvant therapy and improved radiation technique has only added 10-20% to the survival rate making it extremely difficult to evaluate the impact of these advances. While radiation treatment is currently omitted or delayed under the age of 36 months, due to enhanced neurocognitive toxicity, and replaced by maintained systemic therapy, the early encouraging results must stand the test of time in order to become standard practice. The treatment of a child with medulloblastoma with radiation treatment remains the corner stone of treatment while additional novel therapies are being developed.

Second malignant tumours in childhood Hodgkin's disease.

This study was undertaken to determine the treatment-specific incidence of second malignant tumours (SMT) in childhood Hodgkin's disease. The institutional databases at The Hospital for Sick Children, the Princess Margaret Hospital, and the Toronto-Bayview Regional Cancer Centre were reviewed for the years 1958-1993. Three hundred and forty-three consecutive newly diagnosed children were evaluated. The overall 30 year cumulative SMT incidence was 31%. The 20 year SMT incidence was greater for patients who relapsed (n = 129), 27%, compared with patients who remained relapse free (n=214), 13%. For patients with stage 1-3B disease who remained relapse free, the 10 year SMT rate was 7% for patients who were surgically staged and treated with extended field radiation treatment (EF RT) (35 G), compared with 3% in clinically staged patients treated with MOPP (six cycles) and EF RT (25-30 G). To date there is no significant difference in the oncogenicity of these treatment protocols. However, EF RT alone was less effective in disease control. For stages 1-3B, 62% of patients relapsed after EF RT alone compared with 18% after bimodal treatment. Therefore treatment intensification due to relapse was more frequent in the former group. The overall 10 year SMT incidence for patients treated with these protocols was 11% and 3%, respectively. The 20 year SMT incidence following EF RT alone was 24%. We conclude that SMTs were a common late complication in childhood Hodgkin's disease and are a limiting factor in the achievement of cure. The incidence of SMTs was increased in children who required retreatment and was minimal in children who remained in a first complete remission. Therefore the initial treatment strategy in childhood Hodgkin's disease must be to minimize the risk of relapse, in order to avoid the morbidity and mortality associated with both relapse and SMT induction, and to achieve this objective with a primary treatment protocol of low oncogenicity.

Long-term survival of children with brain tumors.

Outcome is described for 1,034 children who received radiation treatment in the management of a brain tumor at the University of Toronto Institutions from 1958 to 1995. The 5-, 10-, 20-, and 30-year relapse-free (or progression-free) survival rates were 47%, 45%, 44%, and 44%, respectively, whereas the corresponding overall survival rates were 52%, 44%, 38%, and 30%. Second malignant tumors became an important cause of death over time, with cumulative incidences of 2.5%, 13%, and 19% at 10, 20, and 30 years, respectively. The 5-year survival rate after the diagnosis of a second malignant tumor was 58%. In general, high-grade tumors, eg, high-grade astrocytomas or brainstem tumors, had a poor 20-year survival rate (18%), compared with low-grade tumors (39% to 47%). Despite improvements in imaging, neurosurgical technique, and radiation treatment, children treated during the last 20 years did not have a significantly improved outcome when compared to children treated earlier.

Brain tumors in children: long-term survival after radiation treatment.

PURPOSE: To determine the cause of death in children who survive more than 5 years after radiation treatment of a brain tumor. METHODS AND MATERIAL: Nine hundred and twelve consecutive children with a primary brain tumor irradiated at the Princess Margaret Hospital or Toronto-Bayview Regional Cancer Center from 1958 to 1991, were evaluated for long-term outcome. RESULTS: Overall 10- and 20-year survival rates were 44% and 37%. Subsequent survival of 377 5-year survivors was, at an additional 10 and 20 years, 78% and 67%. Most (83%) deaths that occurred more than 5 years from diagnosis were a result of relapse of the original tumor. The 10-year survival rate subsequent to relapse was 9% when the first relapse occurred less than one year from diagnosis, 17% for 1-2 years, and 31% when the time to relapse was 3 years or greater. The cumulative actuarial incidence of, and death from, second malignant tumors at 30 years from diagnosis was 18% and 13%, respectively. CONCLUSIONS: Death later than 5 years from diagnosis of a brain tumor in children is common and is usually due to progressive disease in slowly evolving low grade tumors. Death from a second malignant tumor becomes more frequent than death from the original tumor after 15 years from diagnosis.

Nasopharyngeal carcinoma in the young.

This study was carried out to determine whether locoregional control of nasopharyngeal carcinoma in the young by irradiation has improved since 1975. Fifty-seven consecutive, previously untreated, patients, less than 30 years old, were diagnosed and treated at University of Toronto Hospitals between 1958 and 1990; 21 patients were treated before and 36 after 1975. Staging was as follows: M0, n = 54; M1, n = 3; T1 + T2, n = 26; T3 + T4, n = 31; N0, n = 10; N1 + N2a, n = 10; N2b + N2c, n = 24; N3, n = 13. All patients were irradiated. The primary tumour dose was 3500-7000 cGy (median 5450). Adjuvant chemotherapy was introduced in 1977. Subsequently, 10/26 (38%) M0 patients received this treatment. For all 57 patients, 10-year survival was 56%. For 52 M0 patients with complete follow-up data, 10-year survival was 63%; 10-year relapse free survival (RFS) was 61%. Age, sex, race, and histology were not significant variables. Ten-year RFS results were: T1 + T2, M0 (n = 24) 70%, T3 + T4, M0 (n = 27) 52%, (P = 0.25); N0-N2c (n = 41) 64%, N3 (n = 11) 54% (P = 0.31). Relapse occurred in 20/52 (38%) patients. Survival from the date of first relapse was 10% at 10 years. No patient with systemic relapse survived. Only 1/32 (3%) patients treated after 1975 developed an isolated locoregional relapse, giving a 10-year isolated locoregional relapse free rate (LR RFS) of 96%, compared with 5/20 (25%) prior to 1975, which gave a 10-year LR RFS of 75% (P = 0.05). Two of the five patients who relapsed before 1975 were salvaged by re-irradiation. Systemic relapse, either alone or combined with locoregional relapse, accounted for 6/11 (55%) relapses before 1975 and 8/9 (89%) after 1975. Ten-year systemic RFS was 90% for patients who received adjuvant chemotherapy (n = 10) and 72% for patients treated since 1977 by irradiation alone (n = 16) (P = 0.41). Isolated local relapse was exceptional in patients treated after 1975 (1/32).(ABSTRACT TRUNCATED AT 250 WORDS)

Optic pathway/hypothalamic gliomas: a dilemma in management.

Optic pathway gliomas follow an unpredictable course. Some remain static for years; others increase rapidly in size and often lead to death. This unpredictability, along with the histological similarity of these tumors, has resulted in controversy about their management. We have reviewed the results of management of all 62 patients with a diagnosis of optic pathway/hypothalamic glioma treated at The Hospital for Sick Children during the years 1976-1990. Twelve patients received no direct treatment, and 3 only a biopsy. Six patients were treated with radiotherapy alone. Eight patients received radiotherapy following a biopsy. Seventeen patients were treated by resection alone and 16 had a resection followed by radiotherapy. Eight patients received chemotherapy in addition to other therapy, and in 5 of them the chemotherapy was given as an initial therapy. Forty-eight patients are well with their visual deficits but 7 of them are receiving hormone replacement therapy. Six patients have significant neurologic deficits and 8 have died.

Optic glioma in children: surveillance, resection, or irradiation?

Eighty-seven consecutive children with newly diagnosed optic glioma were managed at University of Toronto hospitals 1958-1990. Overall the 10-year survival, relapse-free survival and freedom from second relapse rates were 84%, 68% and 85%. Twenty-seven patients relapsed or progressed, of whom 40% were free of a second relapse 10 years after the first relapse. Fourteen patients had a second relapse. Thirteen are dead. None survived 5 years after second relapse. Patients with anteriorly located tumors (N = 35), which involved the optic nerve, or chiasm and optic nerves, fared better than those with posteriorly located tumors (N = 52) with spread beyond the chiasm, 10-year survival 95% versus 76%, (p = .02), 10-year relapse-free survival 80% versus 59% (p = .02), respectively. For posterior tumors primary irradiation was more effective than primary subtotal resection for prevention of subsequent relapse, 10-year relapse-free survival 75% versus 41% (p = .02), but salvage therapy was, in part, successful and multivariate analysis of prognostic factors influencing survival for posterior tumors indicated that neither primary resection nor primary irradiation were significant factors. For first relapse, primary irradiation and the presence of neurofibromatosis were the significant favorable factors. Since 1977 and for posterior optic glioma subtotal resection or surveillance were used in 21/29 (72%) patients compared with 4/23 (17%) previously. Ten-year survival rates before and after 1977 were 78% and 67% and 10-year relapse-free survival 64% and 56%, respectively.

Psychologic adaptation of survivors of childhood cancer.

When adult survivors of childhood cancer were compared with their peers, survivors were found to be at least as well adjusted. Indeed, some evidence was suggestive of survivors having adaptive advantages in everyday life. The survivors reported significantly more positive affect, less negative affect, higher intimacy motivation, more perceived personal control, and greater satisfaction with control in life situations. Despite these apparent strengths associated with surviving childhood cancer, several specific problems were documented. Survivors were more likely than peers to have repeated school grades, to be worried about issues of fertility, and to express dissatisfaction with important relationships. The latter finding was interpreted as reflecting the high expectations of survivors for relationships, based on their difficult yet interpersonally rewarding experiences during times of illness.

Preoperative chemotherapy for children with Wilms' tumor.

Five years ago, the use of preoperative chemotherapy for Wilms' tumor was adopted at this institution. Thirty children ranging in age from 5 months to 9 years had histologically confirmed Wilms' tumor (needle biopsy, n = 26; open biopsy, n = 4). Stage was determined by chest and abdominal computed tomography (CT) scan. Bilateral tumors were present in 6 children. All children received actinomycin D and vincristine from 3 weeks to 6 months before surgery. Seven children with bilateral tumors or stage IV disease also received adriamycin. CT-measured tumor masses shrunk in most cases. Subsequently, nephrectomy was performed in 23 patients and partial nephrectomy in 4, 2 of whom had bilateral disease. In 2 patients, residual bilateral well-differentiated epithelial tumor was not surgically resected. One child died before surgery. Reevaluation at delayed total or partial nephrectomy resulted in a downstaging of disease in 12 (41%). Further chemotherapy and radiation was based on the surgical stage. Postoperative chemotherapy (4 months to 2 years) was administered to all patients. The chest and/or abdomen were radiated in 12. Four patients (13%) died, 1 of radiation pneumonitis and 3 of the disease progression (2 with unfavorable histology, 1 of whom had bilateral disease). Two of 4 with unfavorable histology and 4 of 6 with stage IV disease have survived. It is concluded that this preoperative chemotherapy protocol is as effective as the National Wilms' Tumor Study (NWTS) protocol. The treated tumor is smaller, less friable, and easier to remove. Furthermore, because of downstaging, less radiation is necessary for cure.

Intracranial germ-cell tumors in children.

All patients with confirmed intracranial germ-cell tumors treated at the Hospital of Sick Children during the period January, 1952, to December, 1989, were reviewed. Of the 51 tumors reviewed, 16 were located in the suprasellar region, 32 in the pineal region, and three in both the pineal and the suprasellar regions. Forty-nine patients underwent surgical resection which was total in seven and partial in 20, and consisted of a biopsy in 22. Two patients were managed on the basis of serum and cerebrospinal fluid markers. Surgical tools such as the operating microscope, the ultrasonic surgical aspirator, and the laser beam allowed safe debulking and removal of the deep-seated tumors in the pineal region. There were no operative deaths in the 36 patients treated since 1972, who included 23 with pineal tumors. Twenty-five patients with germinomas received radiotherapy and had a 5-year survival rate of 85.1%. Thirteen patients with non-germinoma germ-cell tumors received radiotherapy and had a 5-year survival rate of 45.5%. On the basis of this review, the authors recommend resection of pineal and suprasellar germ-cell tumors in order to firmly establish an accurate histological diagnosis to guide the extent of adjuvant therapy. In the case of a pure germinoma without evidence of dissemination, adjuvant therapy consists only of local radiotherapy. On the other hand, for malignant non-germinoma germ-cell tumors, adjuvant therapy must include chemotherapy as well as craniospinal axis radiotherapy.

Neuroblastoma stage IV-S: a heterogeneous disease.

Eighteen patients were diagnosed and treated for Stage IV-S neuroblastoma at The Hospital for Sick Children, Toronto between January 1971 and December 1988. All patients were 6 months of age or younger at diagnosis. Nine patients (50%) have remained disease free with a mean follow-up of 9.3 years. Of the seven patients under 6 weeks of age at presentation, four presented in the early neonatal period and died, three due to mechanical complications related to progressive disease, and one due to late recurrence. The remaining three patients under 6 weeks of age, two of whom had skin involvement at diagnosis, are alive and disease free. Six of the 11 patients over 6 weeks of age at presentation survived, combined modality therapy (CMT) being more effective than single modality treatment. N-myc was studied from tumor tissue at diagnosis in four patients and was amplified in three (25x, 25x, 100x), all of whom had late disease progression and died. The patient with a single gene copy has no evidence of disease 24 months following diagnosis. Our study confirms the heterogeneity described in this clinically defined group of patients. Because of it, management of Stage IV-S neuroblastoma cannot be uniform and until further development of a subclassification, or a reclassification based on molecular biologic markers is developed, pediatric oncologists will regularly be confronted with a decision whether or not to treat a newly presenting patient that fits into the clinical classification IV-S.

Posterior fossa medulloblastoma in childhood: treatment results and a proposal for a new staging system.

Seventy-two children with posterior fossa medulloblastoma were diagnosed at the Hospital for Sick Children, Toronto, from 1977 to 1987 and treated by standard methods. The 5- and 10-year survival and disease-free survival rates were 71% and 63%, and 64% and 63%, respectively. Total tumor resection, as determined by the surgeon was the most significant favorable prognostic factor. Post-operative meningitis, a residual enhancing mass lesion on the post-operative, pre irradiation CT scan and dissemination to the brain or cord at diagnosis were unfavorable factors. These four easily definable factors were used to define a staging system with prognostic significance. Five-year disease-free survival rates were for Stage I (total resection, no adverse factor) 100%, Stage II (total resection with one or more adverse factor or less than total resection with no other adverse factor) 78%, and Stage III (less than total resection with one or more adverse factor) 18%. Evaluation of treatment results in medulloblastoma requires that these prognostic factors be known.

Pineal region germinomas in childhood treatment considerations.

From 1967-1986, 21 children were treated for pineal germinoma, including 16 biopsy-proven, 2 biopsy non-diagnostic, and 3 metastatic unbiopsied (marker negative) patients. Ten of 18 (56%) biopsied patients underwent partial or sub-total tumor resection. Twenty patients were irradiated, 19 of whom are alive. No irradiated patient died of progressive germinoma, but two patients relapsed in the spinal cord and required treatment intensification for salvage. Long-term survivors have significant morbidity. Determination of the minimum effective treatment remains the chief therapeutic challenge.

Infratentorial ependymomas in childhood: prognostic factors and treatment.

The prognostic factors and survival data were analyzed for 35 children (aged under 16 years at diagnosis) with childhood infatentorial ependymomas treated surgically at The Hospital for Sick Children in Toronto during the years 1970 to 1987. Tumor histology was reviewed individually and grouped into three categories (Categories I to III) for survival analysis. An overall 5-year survival rate of 44.6% was obtained after the exclusion of perioperative mortality. Factors associated with an improved 5-year survival rate were: total tumor removal, noninvasive tumors, Category I histology, age greater than 6 years, and absent physical signs of parenchymal invasion or lower cranial nerve involvement. The 5-year survival rate was lower when associated with Category III histology, brain-stem or cranial nerve signs, age less than 2 years, tumor invasion and/or cranial nerve involvement, and subtotal tumor removal. Clinical evidence of spinal metastases was found to be uncommon (3.1%). Surgical excision followed by radiation therapy was the primary mode of treatment for these tumors. Different approaches regarding the volume of radiotherapy to be delivered and the use of adjuvant chemotherapy are discussed.