In terms of overall survival (OS), limited data are available for the very long-term outcomes of children treated for optic pathway glioma (OPG) with up-front chemotherapy. Therefore, we undertook ...this study with the aim of clarifying long-term OS and causes of death in these patients.
We initiated and analyzed a historical cohort study of 180 children with OPG treated in France with BB-SFOP chemotherapy between 1990 and 2004. The survival distributions were estimated using Kaplan-Meier method. The effect of potential risk factors on the risk of death was described using Cox regression analysis.
The OS was 95% 95% CI: 90.6-97.3 5 years after diagnosis and significantly decreased over time without ever stabilizing: 91.6% at 10 years 95% CI: 86.5-94.8, 80.7% at 15 years 95% CI: 72.7-86.8 and 75.5% 95% CI: 65.6-83 at 18 years. Tumor progression was the most common cause of death (65%). Age and intracranial hypertension at diagnosis were significantly associated with a worse prognosis. Risk of death was increased by 3.195% CI: 1.5-6.2 (p=0.002) for patients less than 1 year old at diagnosis and by 5.295% CI: 1.5-17.6 (p=0.007) for patients with initial intracranial hypertension. Boys without diencephalic syndrome had a better prognosis (HR: 0.3 95% CI: 0.1-0.8, p=0.007).
This study shows that i) in children with OPG, OS is not as favorable as previously described and ii) patients can be classified into 2 groups depending on risk factors (age, intracranial hypertension, sex and diencephalic syndrome) with an OS rate of 50.4% at 18 years 95% CI: 31.4-66.6 in children with the worst prognosis. These findings could justify, depending on the initial risk, a different therapeutic approach to this tumor with more aggressive treatment (especially chemotherapy) in patients with high risk factors.
Malignant brain tumors are not uncommon in infants as their occurrence before the age of three represents 20-25% of all malignant brain tumors in childhood 1. Genetic predisposition to infantile ...malignant brain tumors are known in Gorlin syndrome for example who present with desmoplastic medulloblastoma in about 5% of the affected patients. In addition, sequelae from tumor and its treatment are more severe at this age 2. Thus, malignant brain tumors represent a true therapeutic challenge in neuro-oncology. Before the era of modern imaging and modern neurosurgery these malignant brain tumors were misdiagnosed or could not benefit of the surgical procedures as well as older children because of increased risks in this age group. Since the end of the 80s, noninvasive imaging procedures produce accurate diagnosis of brain tumors and improvement in neurosurgery, neuroanesthesia and perioperative intensive care permit safe tumor resections or at least biopsies. Consequently, the pediatric oncologists are more often confronted with very young children who need a complementary treatment. Before the development of specific approaches for this age group, these children received the same kind of treatment than the older children did, but their survival and quality of life were significantly worse. The reasons of these poor results were probably due in part to the fear of late effects induced by radiation therapy, leading to decrease the necessary doses of irradiation which increased treatment failures without avoiding treatment related complications 3. At the end of the 80s, pilot studies were performed using postoperative chemotherapy in young medulloblastoma patients. Van Eys treated 12 selected children with medulloblastoma with MOPP regimen and without irradiation; 8 of them were reported to be long term survivors 4. Subsequently, the pediatric oncology cooperative groups studies have designed therapeutic trials for very young children with malignant brain tumors. Different approaches have been explored: * Prolonged postoperative chemotherapy and delayed irradiation as designed in the POG (Pediatric Oncology Group). * Postoperative chemotherapy without irradiation in the SFOP (Société Française d'Oncologie Pédiatrique) and in the GPO (German Pediatric Oncology) studies. * The role of high-dose chemotherapy with autologous stem cells transplantation was explored in different ways: High-dose chemotherapy given in all patients as proposed in the Head Start protocol. High-dose chemotherapy given in relapsing patients as salvage treatment in the French strategy. In the earliest trials, the same therapy was applied to all histological types of malignant brain tumors and whatever the initial extension of the disease. This attitude was justified by the complexity of the classification of all brain tumors that has evolved over the past few decades leading to discrepancy between the diagnosis of different pathologists for a same tumor specimen. Furthermore, it has become increasingly obvious that the biology of brain tumors in very young children is different from that seen in older children. However, in the analysis of these trials an effort was made to give the results for each histological groups, according to the WHO classification and after a central review of the tumor specimens. All these collected data have brought to an increased knowledge of infantile malignant brain tumors in terms of diagnosis, prognostic factors and response to chemotherapy. Furthermore a large effort was made to study long term side effects as endocrinopathies, cognitive deficits, cosmetic alterations and finally quality of life in long term survivors. Prospective study of sequelae can bring information on the impact of the different factors as hydrocephalus, location of the tumor, surgical complications, chemotherapy toxicity and irradiation modalities. With these informations it is now possible to design therapeutic trials devoted to each histological types, adapted to pronostic factors and more accurate treatment to decrease long term sequelae.
We report herein our institutional experience in the treatment of diffuse intrinsic pontine glioma (DIPG) with a hypofractionated external-beam radiotherapy schedule. Between April 1996 and January ...2004, 22 patients (age 2.9–12.5 years) with newly diagnosed DIPG were treated by hypofractionated radiation therapy delivering a total dose of 45 Gy in daily fractions of 3 Gy, given over 3 weeks. No other treatment was applied concomitantly. Fourteen of the 22 patients received the prescribed dose of 45 Gy in 15 fractions of 3 Gy, and 2 patients received a total dose of 60 and 45 Gy with a combination of two different beams (photons and neutrons). In five cases the daily fraction was modified to 2 Gy due to intolerance, and one patient died due to serious intracranial hypertension after two fractions of 3 Gy and one of 2 Gy. Among 22 children, 14 patients showed clinical improvement, usually starting in the second week of treatment. No grade 3 or 4 acute toxicity from radiotherapy was observed. No treatment interruption was needed. In six patients, steroids could be discontinued within 1 month after the end of radiotherapy. Median time to progression and median overall survival were 5.7 months and 7.6 months, respectively. External radiotherapy with a radical hypofractionated regimen is feasible and well tolerated in children with newly diagnosed DIPG. However, this regimen does not seem to change overall survival in this setting. It could represent a short-duration alternative to more protracted regimens.
To evaluate a strategy aimed at avoiding radiotherapy during first-line treatment of children with progressive optic pathway tumors (OPT), by exclusively administering multiagent chemotherapy during ...16 months.
Between 1990 and 1998, 85 children with progressive OPT were enrolled onto this multicenter nationwide trial. Chemotherapy alternating procarbazine plus carboplatin, etoposide plus cisplatin, and vincristine plus cyclophosphamide was given every 3 weeks. At the time of relapse or progression, second-line chemotherapy was authorized before recourse to radiotherapy.
Objective response rate (partial response PR + complete response CR) to chemotherapy was 42%. Five-year progression-free survival (PFS) and overall survival rates were 34% and 89%, respectively. The 5-year radiotherapy-free survival rate was 61%. In the multivariate analysis of the 85 patients that entered onto the study, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.047) and absence of neurofibromatosis type 1 (P =.035). In the multivariate analysis of the 74 patients that remained on study after the first cycle of chemotherapy, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.0053) and no objective response to chemotherapy (P =.0029). Three-year PFS was 44% in infants < or = 1 year versus 66% in children older than 1 year. Three-year PFS was 53% in the absence of an objective response to chemotherapy versus 68% after a PR or CR.
A significant proportion of children with OPT can avoid radiotherapy after prolonged chemotherapy. Deferring irradiation with chemotherapy protocols did not compromise overall survival of the entire population or visual function.
To evaluate a strategy that avoids radiotherapy in first-line treatment in children under 5 years of age with brain or posterior fossa ependymoma, by exclusively administering 16 months of adjuvant ...multiagent chemotherapy after surgery.
Between June 1990 and October 1998, 73 children with ependymoma (82% with high-grade tumors) were enrolled onto this multicenter trial. Children received adjuvant conventional chemotherapy after surgery consisting of seven cycles of three courses alternating two drugs at each course (procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) over a year and a half. Systematic irradiation was not envisaged at the end of chemotherapy. In the event of relapse or progression, salvage treatment consisted of a second surgical procedure followed by local irradiation with or without second-line chemotherapy.
Conventional chemotherapy was well tolerated and could be administered in outpatient clinics. No radiologically documented response to chemotherapy more than 50% was observed. With a median follow-up of 4.7 years (range, 5 months to 8 years), the 4-year progression-free survival rate in this series was 22% (95% confidence interval CI, 13% to 43%) and the overall survival rate was 59% (95% CI, 47% to 71%). Overall, 40% (95% CI, 29% to 51%) of the patients were alive having never received radiotherapy 2 years after the initiation of chemotherapy and 23% (95% CI, 14% to 35%) were still alive at 4 years without recourse to this modality. In the multivariate analysis, the two factors associated with a favorable outcome were a supratentorial tumor location (P =.0004) and complete surgery (P =.0009). Overall survival at 4 years was 74% (95% CI, 59% to 86%) for the patients in whom resection was radiologically complete and 35% (95% CI, 18% to 56%) for the patients with incomplete resection.
A significant proportion of children with ependymoma can avoid radiotherapy with prolonged adjuvant chemotherapy. Deferring irradiation at the time of relapse did not compromise overall survival of the entire patient population.
To investigate the neuropsychological outcome of children treated with surgery and posterior fossa irradiation for localized infratentorial ependymoma.
23 patients (age 0.3 - 14 years at diagnosis) ...who were treated with local posterior fossa irradiation (54 Gy) underwent one (4 patients) or sequential (19 patients) neuropsychologic evaluation. The last evaluation was performed at a median of 4.5 (1 to 15.5) years after RT.
Mean last full scale IQ (FSIQ), verbal IQ (VIQ) and PIQ were 89.1, 94.0, and 86.2 respectively. All patients had difficulties with reading, and individual patients showed deficits in visuospatial, memory and attentional tasks. There was no trend for deterioration of intellectual outcome over time. All 5 children with IQ scores < or = 75 were under the age of four at diagnosis. There was a significant association between the presence of cerebellar deficits and impaired IQ (72.0 vs 95.2, p < 0,001). The absence of hydrocephalus was an indicator of better neuropsychologic outcome (mean FSIQ of 102.6 vs 83.9, p = 0.025).
Within the evaluated cohort, intellectual functions were moderately impaired. Markedly reduced IQ scores were only seen with early disease manifestation and treatment, and postoperative neurological deficits had a strong impact on intellectual outcome.
Purpose. To correlate the radiological aspects of metastases, the response to chemotherapy, and patient outcome in disseminated childhood medulloblastoma. Patients and Methods. This population-based ...study concerned 117 newly diagnosed children with disseminated medulloblastoma treated at the Institute Gustave Roussy between 1988 and 2008. Metastatic disease was assessed using the Chang staging system, their form (positive cerebrospinal fluid (CSF), nodular or laminar), and their extension (positive cerebrospinal fluid, local, extensive). All patients received preirradiation chemotherapy. Results. The overall survival did not differ according to Chang M-stage. The 5-year overall survival was 59% in patients with nodular metastases compared to 35% in those with laminar metastases. The 5-year overall survival was 76% in patients without disease at the end of pre-irradiation chemotherapy compared to 34% in those without a complete response (P=0.0008). Conclusions. Radiological characteristics of metastases correlated with survival in patients with medulloblastoma. Complete response to sandwich chemotherapy was a strong predictor of survival.
Choroid plexus carcinomas are rare tumors with dismal prognosis. The role of surgery has been well established, but the benefit of either chemotherapy or radiotherapy remains controversial. To ...determine prognostic factors and effects of different therapeutic modalities on the outcome, we have reviewed the French experience of choroid plexus carcinoma.
Twenty-two children were registered in the Société Française d'Oncologie Pédiatrique between 1984 and 1995. All these children underwent surgical resection of the primary tumor. The intent of postoperative treatment was to delay or to avoid radiation therapy. Nineteen children received postoperative treatment, with chemotherapy in 17 and radiation therapy in 2. Two responding patients underwent high-dose chemotherapy with stem cell rescue.
The 5-year survival rate was 26%. The sole relevant prognostic factor was the extent of surgery. Patients with total or gross total resection had a 86% survival rate. Survival did not correlate with age, sex, delay between first appearance of symptoms and diagnosis, location of the primary tumor, tumor volume, or response to postoperative treatment. All but one patient with incomplete surgery had tumor recurrence within 2 to 23 months.
Choroid plexus carcinoma has a very poor prognosis when surgery is incomplete. Aggressive surgical resection of the tumor is necessary for survival. Although chemotherapy gives promising responses, local control remains the main challenge, and "second look" surgery has to be considered for patients with incomplete resection.
Purpose: To review the outcome and quality of life at 5 years and more of 37 children treated with radiation therapy combined or not with surgical resection for a craniopharyngioma in a single ...institution.
Methods and Materials: From January 1969 through December 1992, 37 children received external therapy at the Institut Gustave Roussy (Villejuif, France). Age ranged between 1 and 15 years (mean 7.4), M/F sex ratio was 0.76. In approximately one-half of the cases (18/37), radiation therapy was applied in conjunction with a surgical resection, and in almost one-half of the cases (18/37) as part of a salvage program following local failure. Total dose ranged between 45 and 56 Gy (median 50) given with a conventional fractionation in most children. Survival (S), event-free survival (EFS) were computerized according to the Kaplan-Meier method and prognostic factors for local failure and functional status analyzed. Functional outcome was evaluated according to the Wen score in 4 grades (gr 1: normal with/without hormonal replacement, gr 4: totally dependent, gr 2 and 3: intermediate disabilities).
Results: At the time of analysis, 24 children (65%) were alive with NED, 4 (11%) alive after failure, and 9 (24%) dead of various causes. Following therapy, S and EFS regularly degraded and didn’t seem to reach a plateau before 9 years (5 and 10 year S and EFS, respectively, 91, 65, and 78 and 56.5%). This was due to the occurrence of late failures (5 and 8.5 years) and late lethal complications (1 in-field glioblastoma multiforme at 9 years). A significant gain on EFS followed the introduction of modern imaging (
p = 0.03), the association of surgical resection with RT (
p = 0.01) and of higher doses of radiation superior or equal to 55 Gy (
p = 0.05); a similar gain on S was observed in patients with a good initial performance status (
p = 0.05). It is remarkable that surgical salvage of local failures following RT could induce prolonged remission in 4 children. Functional outcome was impaired in all but 5 children out of 35 fully evaluable (86%) and related with the initial symptomatology and/or therapy. Endocrinological, visual, neurological functions were affected in 97, 34, and 40%, respectively. It appeared correlated with the initial performance status (
p = 0.02) and possibly with a younger age at treatment (
p = 0.07).
Conclusions: Long-term follow-up beyond 5 years is warranted in craniopharyngioma to assess tumor control and functional outcome after radiation therapy. Although this therapeutical modality provides a high cure rate alone or in combination with surgery and even though at the time of failure, further strategies should aim to limit the severe toxicity (
i.e., Wen gr 3 + 4) that was observed in more than one-third of our patients.
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