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Radiation Therapy and High-Dose Tamoxifen in the Treatment of Patients With Diffuse Brainstem Gliomas: Results of a Brazilian Cooperative Study

From the Pediatric Oncology Division, Instituto da Criança, and Department of Radiology, Hospital das Clínicas, São Paulo University Medical School; and Laboratory of Toxicology, School of Pharmaceutical Sciences, São Paulo University, Ribeirão Preto, São Paulo, Brazil.

Address reprint requests to Alberto Broniscer, MD, 221 Middle Neck Rd L-3, Great Neck, NY 11021; email vbroniscer{at}aol.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: The efficacy of radiation therapy (RT) combined with tamoxifen (TX) was tested in patients diagnosed with diffuse brainstem gliomas in a multicenter trial.

PATIENTS AND METHODS: TX was administered orally (maintenance dose: 200 mg/m² per day) along with conventional local RT and then continued for 52 additional weeks. Survival, tumoral radiologic response, and toxicity were evaluated. Compliance was assessed using pharmacokinetic measurements.

RESULTS: Of 29 patients, 27 completed RT (median dose, 54 Gy). Of 22 assessable patients, 11 (50%) had an objective radiologic response. The mean TX steady-state serum level was 2.44 µmol/L ± 1.02 µmol/L. Only three patients completed the entire course of treatment without tumoral progression or significant toxicity. Common side effects included nausea and vomiting. Hepatotoxicity (five patients), neurotoxicity (two patients), venous thrombosis (one patient), bilateral ovarian cysts (two patients), and transient neutropenia (one patient) were also observed. Median survival was 10.3 months. Only four patients remain alive without tumoral progression. The 1-year survival rate (mean ± SD) was 37.0% ± 9.5%.

CONCLUSION: This treatment combination produced no significant change in the overall poor prognosis of these patients. Most tumors responded initially to treatment but recurred as the study progressed. A minority of patients seemed to benefit from the extended use of TX. Generally, treatment was well tolerated, with good patient compliance, but we recommend continuous close monitoring for side effects. Based on our poor results, we recommend that alternative treatments be tested in patients with this type of tumor.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
THE MANAGEMENT OF children with CNS neoplasias has evolved significantly in the past three decades, improving treatment results.¹ This improved outcome, however, has not been as significant as the advances seen in other pediatric malignancies such as acute lymphoblastic leukemia.² Moreover, few improvements in prognosis have occurred in some subgroups of patients despite advances in radiologic diagnostic methods, surgical techniques, radiation therapy (RT), and oncologic treatment.

The 3-year survival rate of children diagnosed with diffuse brainstem gliomas and treated with RT and/or chemotherapy is still only 5% to 15%.^3-7 Several experimental studies aimed at delivering more intensive and, presumably, more effective therapy have been tested. Hyperfractionated RT and brachytherapy used for this purpose have produced no meaningful change in results.^3,5,7,8 Several chemotherapeutic studies, some using myeloablative doses of chemotherapy, have not been able to demonstrate a better outcome.^4,9-11

To obtain either additive or synergistic effects, recent studies have explored treating these patients concomitantly with RT and chemotherapy or biologic agents.^12,13 Tamoxifen (TX), an antiestrogenic drug used in the treatment of estrogen receptor–positive breast carcinoma, has been shown to have an inhibitory activity against glial-derived cell lines in several in vitro studies.^14,15 This antiglial effect is independent of the antiestrogenic activity and is mediated via the inhibition of the intracellular enzyme protein kinase C.¹⁶

Clinical experience using TX in the treatment of glial neoplasms is limited. A few case reports and clinical studies have described some success in treating adult patients with recurrent high-grade gliomas, either with TX alone or in combination with other drugs.^17-26 In one of the most promising studies, Couldwell et al²⁰ treated 32 adult patients with recurrent high-grade gliomas with TX. The authors reported an objective radiologic partial response of 25% and a significant improvement in survival. Only two studies to date have tested the activity of TX in children diagnosed with glial neoplasms.^27,28 We report our results in the treatment of children newly diagnosed with diffuse brainstem gliomas using the combination of local conventionally fractionated RT and TX.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Participants in this study were enrolled from seven pediatric oncology centers in Brazil from December 1996 to December 1998. All were less than 16 years old with clinically and radiologically diagnosed diffuse brainstem gliomas.

Each patient was required to meet the following clinical and radiologic criteria: (1) duration of signs and symptoms for less than 6 months; (2) the presence of at least two of the following: pyramidal tract involvement, cerebellar signs and symptoms, and/or cranial nerve deficits attributable to the tumor; (3) no previous RT or chemotherapy; and (4) cranial magnetic resonance imaging (MRI) at diagnosis showing diffuse involvement of the brainstem, ie, either tumoral involvement of more than 50% of one segment of the brainstem or the involvement of more than two of these segments.²⁹ Patients ineligible for this study included those with the diagnosis of neurofibromatosis type 1 and those with focal tumors or tumors with an exophytic component that exceeded 50% of the overall tumor volume. Histologic diagnosis was not mandatory if the clinical and radiologic characteristics were typical of diffuse brainstem glioma.

Informed consent was obtained from the patients’ parents or legal guardians. This protocol was approved by the ethics committees of three of the participating hospitals (Hospital das Clínicas, Instituto de Oncologia Pediátrica, and Hospital A.C. Camargo, São Paulo, Brazil). Eight patients treated in the four remaining centers had their treatment approved and monitored by the ethics committee at Hospital das Clínicas according to Brazilian law.

Study Design
RT. All patients received megavoltage photon-beam RT through parallel opposed lateral fields. The target volume encompassed the entire tumor as determined by the T2-weighted hyperintense signal on MRI, plus a 2-cm margin. Patients were treated with conventional fractions of RT, ranging between 1.5 to 1.8 Gy once a day, 5 days a week, for a total dose of between 54 to 60 Gy. Field reductions to protect the pituitary gland were permissible. No central review of RT techniques or fields was performed.

TX treatment. TX was started as soon as possible after diagnosis. TX was supplied by Zodiac-Tecnofarma (São Paulo, Brazil). Preferably, treatment began before the initiation of RT, but patients who started TX within 2 weeks of the start of RT were still eligible for this study. The loading dose of TX on the first day was 300 mg/m² orally divided into three doses (10 and 20 mg tablets of TX citrate). From the second day on, the maintenance dose was 200 mg/m² per day divided into two doses. The maximal loading dose for the first day was 450 mg, and the maximal maintenance dose was 300 mg per day. We intended to administer TX for the entire duration of RT and for an additional 52 weeks after RT. TX treatment would be interrupted if tumoral progression was documented clinically and/or radiologically, if severe toxicity (grade 4) occurred as a result of the drug, or if directed by the patient and/or his/her family.

Toxicity was evaluated based on National Cancer Institute common toxicity criteria. If grade 3 toxicity occurred as a result of the medication, we followed the TX treatment guidelines, which recommended discontinuing the drug for a week and reducing subsequent doses by 25%. If toxicity persisted or recurred, the drug was to be discontinued for a week and subsequent doses decreased to 50% of the original dose. If toxicity persisted or recurred at this decreased dosage, the drug was to be discontinued.

Patient Evaluation
A complete medical history and physical examination were obtained from all patients at diagnosis. Laboratory evaluations included a complete blood cell count, coagulation tests, liver tests (AST, ALT, and albumin), and renal function tests (blood urea nitrogen and creatinine). Complete blood cell count measurements and renal and liver function tests were repeated monthly during TX treatment.

A cranial MRI was performed at the time of diagnosis and again between 4 to 8 weeks after the end of RT to evaluate the objective tumoral response. A spinal MRI and a lumbar puncture to collect cerebrospinal fluid were performed only if meningeal dissemination was suspected. Tumoral reassessment was carried out at intervals varying from 3 to 6 months during treatment or whenever there was any indication of progressive disease.

One of the authors (C.C.L.), who was unaware of the patients’ clinical status, reviewed all of the MRIs. Using this central radiologic review, we ascertained the number of brainstem segments affected, the T1- and T2-weighted signal abnormalities (including evaluation of the presence of cystic/necrotic areas and hemorrhage), gadolinium-diethylenetriamine pentaacetic acid contrast enhancement, and tumor volume measurements. Tumor volume was determined through the product of the three largest perpendicular diameters of all lesions (longitudinal, lateral, and anteroposterior).

The best radiologic response documented 4 to 8 weeks subsequent to the completion of RT was used as the patient’s objective radiologic response. These responses were assigned to one of the following categories: (1) complete response, marking the complete disappearance of all measurable tumor with simultaneous neurologic improvement; (2) partial response, defined as a shrinkage of 50% or more in volume of all measurable lesions with simultaneous neurologic improvement; (3) minimal response, indicating a tumor shrinkage between 25% and 50% without neurologic deterioration; (4) stable disease, designating a less than 25% change in tumor volume with no neurologic deterioration; and (4) progressive disease, defined as a 25% or more increase in tumor volume or the presence of new tumoral lesions with simultaneous neurologic deterioration. The use and dose of corticosteroids were documented simultaneously with all MRIs to ensure consistency of results.

Ophthalmologic evaluation was performed at treatment entry and at 6-month intervals until the end of treatment. Evaluation consisted of ophthalmoscopy and slit-lamp examination to rule out both retinal and corneal damage secondary to treatment.³⁰ A pelvic ultrasound for evaluation of the internal female genitalia was recommended at intervals of 6 months for all girls receiving TX for prolonged periods of time.

One week after the start of TX, blood samples for pharmacokinetic studies were collected to measure TX and its metabolite, N-desmethyltamoxifen. After collection, samples were centrifuged, and the serum was stored at temperatures between -20°C to -70°C. Serum levels were measured using a gas chromatograph (Shimadzu CG-17A, Kyoto, Japan) equipped with a flame thermionic detector.

TX, N-desmethyltamoxifen, and the internal standard flurazepam were extracted from serum samples (500 µL) and dissolved in a mixture of hexane-isoamyl alcohol (98.5:1.5, volume per volume). After evaporation and redissolution in methanol, the compounds were separated and determined by gas chromatography-mass spectometry. A 1-µL splitless injection of the samples was made into an SPB-608 fused-silica capillary column (30 x 0.53–mm internal diameter with a 0.25 µm-film thickness; Supelco, Belleforte, PA) with helium as a carrier gas. A three-stage temperature program was used (180°C for 1 minute, an increase from 180°C to 280°C at a rate of 10°C/min for 10 minutes, and 280°C for 10 minutes). The resulting assessable data were analyzed using mass-selective detection in electron impact mode. Selected-ion monitoring was performed for TX (mass-to-charge ratio [m/z], 371.20 target ion), N-desmethyltamoxifen (m/z, 358.00 target ion and 300.00 qualifier ion), and the internal standard (m/z, 387.00 target ion and 315.00 qualifier ion).

Calibration curves were linear in the concentration range of 250 to 2,500 ng/mL. The coefficients of variation obtained in the study of intra- and interassay precision were less than 10%. All other drugs used during treatment did not interfere with measurements. All measurements were based on previously determined standards for TX and N-desmethyltamoxifen (gift from J.M. Sanders, National Institute of Environmental Health Sciences, Research Triangle Park, NC).

Statistical Analysis
Survival distribution was estimated using the method of Kaplan and Meier.³¹ Survival was defined as the time interval from diagnosis to death from any cause or to the date of the last follow-up evaluation. The diagnosis date was considered the date when the clinical picture was unequivocally correlated to radiologic findings obtained by either computerized tomography or MRI.

Mean TX and N-desmethyltamoxifen steady-state serum levels were calculated for each individual patient. The number of TX and N-desmethyltamoxifen measured samples varied from one to 10 and from one to eight for each patient, respectively. Mean serum levels and SDs were calculated for the entire cohort based on the mean serum levels obtained for each patient.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Clinical Characteristics
Twenty-nine patients were enrolled onto this study. One patient with an atypical MRI at diagnosis was later found to have a primitive neuroectodermal tumor originating from the meninges and extending toward the brainstem. This patient was not included in the analysis of our results but is still available for toxicity and pharmacokinetic analysis.

The children eligible for enrollment onto this study included 11 boys and 18 girls. The median age was 6.4 years (range, 1.1 to 13.8 years). Mean duration of symptoms before diagnosis was 60 days (range, 9 days to 7 months); 12 patients had symptoms for less than 1 month. One patient had symptoms for more than 6 months, but she was diagnosed only after experiencing a significant deterioration 23 days before referral. This patient, whose disease was considered to be aggressive both clinically and radiologically, was included in this report.

Tumor histology was available in three patients, and all three were diagnosed with astrocytomas (one with grade 2 and two with grade 3/4). Three months after completing RT, the tumor of another patient showed mostly necrotic tissue on biopsy.

Radiologic Characteristics
The cranial MRIs obtained from 28 of 29 patients at diagnosis showed that all 28 had typical tumoral characteristics. All tumor images showed a hypointense signal on T1-weighted and a hyperintense signal on T2-weighted MRI. The images of 16 (64%) of 25 patients showed some degree of gadolinium-diethylenetriamine pentaacetic acid contrast enhancement that, generally, was very localized. Twenty (71%) out of 28 patients had involvement of all three brainstem segments at diagnosis, whereas only one patient (3%) had a tumor restricted to and involving more than 50% of the pons. None of the 28 patients had any radiologic evidence of meningeal dissemination at diagnosis. Median tumor volume at diagnosis of 27 assessable patients was 75 cm³ (mean volume, 87 cm³; range, 10 to 290 cm³).

Treatment
Twenty-seven patients received the prescribed RT dose (median dose, 54 Gy; range, 45 to 60 Gy). Two patients died before the end of RT, one of progressive disease and the other of probable obstructive hydrocephalus. One patient, contrary to protocol recommendations, received only 45 Gy, and one very young child (age 1.1 years) received a reduced RT dose (50.4 Gy). Median RT duration was 53 days (range, 37 to 71 days).

Among the 29 assessable patients, 28 received TX at the doses described previously; one patient received a maintenance dose of 160 mg/m² per day for 85 days until progressive disease was documented. The duration of TX treatment ranged from 33 to 594 days. One patient, who maintained a minor response radiologically, had the treatment electively continued for 17 months after the end of RT. Twelve patients received the medication for a period longer than 6 months, and three patients finished the entire course of treatment without experiencing any significant toxicity or progressive disease (Table 1).

Two patients have maintained a partial response, one of them with more than a 90% decrease in tumor volume for 29 months and the other for 16 months. One patient maintained a minimal response with a 33% decrease in tumor volume for the entire duration of treatment (19 months) but developed tumor recurrence 1 month after treatment discontinuation.

Toxicity
Nausea and vomiting were commonly observed, usually at the beginning of both RT and TX treatment or by the time of disease progression. Generally, these symptoms were mild to moderate and improved with oral antiemetics. Only two patients had persistent severe vomiting during treatment. In both cases, vomiting was one of the main symptoms at presentation before any therapy had been started. One patient, who required nutritional support, did not improve with TX interruption and/or dose reduction but did improve after CSF diversion. Interestingly, this patient’s TX serum levels were almost always well below 1.0 µmol/L, lower than the serum levels found in other patients. In the second patient with severe vomiting, symptoms eventually subsided after outpatient parenteral antiemetics were administered.

Despite the prophylactic use of a platelet antiaggregant agent, one patient had an iliac-femoral thrombosis diagnosed 30 days after the start of TX. This patient was admitted to the intensive care unit for a prolonged period of time because of central respiratory failure secondary to the brainstem involvement.

Three patients showed a significant increase in liver function tests (AST and/or ALT 70 times normal values) together with nausea and vomiting. All three were receiving low doses of corticosteroids at the time of these episodes. One of the patients also presented with somnolence and worsened cerebellar signs and symptoms; the TX serum level obtained during this episode was high in this patient, making it impossible at the time to distinguish between hepatic encephalopathy and TX-related neurotoxicity. In all three cases, other causes of liver dysfunction were ruled out, and they had a complete clinical recovery, with hepatic function returning to normal after TX discontinuation. Two patients had an asymptomatic increase in liver function tests concomitant with the need for high doses of corticosteroids.

Four patients had seizures during TX treatment. In one case, the seizure was considered to be related to hypoxemia and acidosis caused by an aspirative pneumonia. In two other cases, the seizures were probably secondary to obstructive hydrocephalus. One of these patients achieved seizure control after CSF diversion. The second patient died soon after the seizure episode and did not undergo a postmortem study. The fourth patient developed seizures along with signs of liver dysfunction secondary to hepatitis A infection. This child had a normal electroencephalogram and experienced no further seizures after treatment interruption.

TX ophthalmologic toxicity was not systematically investigated at all institutions. Nine patients received both retina and cornea evaluations 56 to 540 days after treatment start, which ruled out any toxicity.

Evaluation of the internal female genital tract was not uniformly conducted. Among the four prepubertal girls who received treatment for more than 6 months, three had a pelvic ultrasound, as recommended by the protocol. One of the girls had normal findings at the 6-month evaluation, and two patients, 6 and 13 years old, had multiple bilateral ovarian cysts at treatment interruption. The massive size of the cysts in one of these patients necessitated surgical resection; histologic examination ruled out neoplastic etiology. No significant endometrial changes were documented in any of the girls who underwent evaluation.

Four patients developed a mild increase in the mammary bud without any other signs of precocious puberty. Of two patients with mild vertigo, one case resolved spontaneously. One patient had a grade 3 transitory neutropenia during treatment. Eleven patients received treatment without experiencing any side effects.

Survival
Twenty-one of 29 assessable patients have died. The median survival time is 10.3 months; the 1-year survival rate is 37.0% ± 9.5% (Fig 1). Sixteen patients died of progressive disease; one patient died of CNS bleeding while receiving oral anticoagulants; one patient died of an aspirative pneumonia with stable disease; two patients died of intracranial hypertension with stable disease; and one patient died of probable intracranial hypertension without postmortem confirmation.

View larger version (10K): [in this window] [in a new window]   Fig 1. Survival curve of all patients.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The combination of local conventionally fractionated RT and high-dose TX therapy produced poor results in the treatment of newly diagnosed patients with diffuse brainstem gliomas. Our results are similar to the vast majority of trials worldwide using RT and/or chemotherapy.^3-13

Tumors in children with high-grade gliomas arising in the brainstem are extremely radio- and chemoresistant, similar to tumors with the same histology found in adults. The poor prognosis of patients harboring high-grade gliomas has stimulated investigators to explore the antitumoral activity of new agents. The inhibitors of the intracellular enzyme protein kinase C have emerged as a potentially promising class of agents to be tested in these patients. Although TX is only a modest inhibitor of this intracellular enzyme, it is currently the best known drug among this group. Furthermore, TX is available throughout the world and, most important, has a long record of reasonable safety and patient tolerance.

This study is the largest experience to date using TX in high doses to treat children with high-grade glial neoplasms. In the two previous pediatric studies, 19 patients were treated.^27,28 Freeman et al²⁷ reported anecdotal results obtained using lower doses of TX to treat five patients with brainstem gliomas, one of whom had a low-grade neoplasm. The authors documented objective radiologic responses in four patients (80%) and stable disease in one patient. Four patients received the medication shortly after local RT. The four patients with objective tumoral response remained well for a follow-up period that varied between 2 to 26 months. No significant side effects were reported.

In the second study, Pollack et al²⁸ described 14 heavily pretreated children with recurrent high-grade gliomas who were enrolled onto a phase I study that tested two levels of TX dosages (120 and 200 mg/m² per day). No patient had tumoral regression with the medication, and four patients experienced tumor stabilization that lasted from 3 to 11 months. Side effects were mild, including asymptomatic prolongation of the QT interval in ECG. Pharmacokinetic studies demonstrated a rapid achievement of high serum levels of TX and its metabolites in the range of those concentrations demonstrated to produce a cytostatic effect against glioma-derived cell lines in vitro. All patients had advanced disease. TX treatment lasted from 3 weeks to 11 months. Ten of 14 patients had rapid tumoral progression; treatment in these patients lasted 8 weeks or less.

Our study differs from the Pollack et al²⁸ study in several ways. Even though patient diagnoses and drug dosages were similar, we studied only newly diagnosed patients who had not been treated previously. Additionally, our patients received TX for a considerably longer duration than the patients in the Pollack study. This allowed us to better assess the drug toxicity profile. We also evaluated the efficacy of the combination of RT and high doses of TX as opposed to assessing TX activity alone. Consequently, it is impossible to compare the differences in objective tumoral response and survival rates between the two studies. However, similar to the Pollack study, we showed that high TX serum levels can be obtained with this drug dosage. Furthermore, our pharmacokinetic results are in the same range as those obtained in adult patients receiving similar doses of TX.³²

Unexpectedly, we have shown that hepatotoxicity occurs in a significant percentage of children receiving high doses of TX for a prolonged period of time. Hepatotoxicity was seen in five of our patients (17%). In the three who were symptomatic, we were able to rule out other common infectious etiologies that cause liver damage. At the time of presentation, these three patients were receiving only corticosteroids in significantly low doses in addition to TX. The clinical course of the liver damage was short after TX was discontinued, and no sequelae were documented. Only one of the three patients was administered the medication again at lower doses, and toxicity recurred. In at least one case, the patient’s presenting symptoms were considered ominous enough to require hospital admission. However, none of the three patients required liver biopsy because their signs, symptoms, and liver function tests improved with cessation of the drug.

In two patients with asymptomatic hepatotoxicity, liver dysfunction was detected at the final stages of tumoral progression concomitant with the use of high doses of corticosteroids. Consequently, the etiology of liver dysfunction in these two patients was not determined.

Liver damage attributable to TX has been previously described. Although the most commonly found histologic abnormality is hepatic steatosis, in rare cases the medication causes clinically and histologically proven acute hepatitis or massive liver damage.^33,34 We could not find any predicting factor that would determine which patients were prone to developing hepatotoxicity. Regardless, the lack of a histologic relationship precludes any further conclusions about the pathophysiology of this process.

We have also shown that neurotoxicity, which is described as the dose-limiting toxicity in adult patients receiving high doses of TX, was not a common problem in children.³⁵ In two of our patients, we were unable to exclude neurotoxicity secondary to TX therapy. Both patients improved clinically with drug discontinuation and experienced no recurrence of symptoms, thus strengthening the association of neurotoxicity with TX. For three other patients, in whom neurotoxicity secondary to TX therapy was suspected, an alternative plausible cause for the seizure episodes was evident. It is important to emphasize that some of the symptoms of TX neurotoxicity resemble those of tumoral involvement of the brainstem. Every time one of our patients presented with worsened clinical features, we recommended a thorough investigation to rule out drug toxicity. In all such cases, the clinical follow-up and imaging studies linked the neurologic deterioration to tumoral progression. In addition, pharmacokinetic measurements corroborated exclusion of TX-related neurotoxicity. No conclusions can be drawn about an estrogen-mediated effect in the female internal organs based on the occurrence of ovarian cysts in two of our patients. We believe that close radiologic follow-up is mandatory in female patients receiving prolonged treatment.

Treatment was well tolerated by the majority of our patients. As seen in studies with adult patients, the other main side effects were nausea, vomiting, and thrombotic episodes. Although our study protocol recommended prophylaxis for deep venous thrombosis in bedridden patients, our experience showed that this strategy was not always effective.

TX activity in glial neoplasms is that of a biologic agent. Biologic agents may induce cellular differentiation, cytostatic and cytotoxic effects, and apoptosis. Additionally, they may cause a delayed tumoral response.²² Frequently, tumoral progression will occur shortly after RT in children with diffuse brainstem gliomas, giving the appearance that the biologic agents are of limited immediate effect. The poor results obtained in this study using TX in the treatment of diffuse brainstem gliomas can not be extrapolated to either high-grade gliomas arising in different sites in the CNS or to low-grade tumors.

This is the first multicenter trial in Brazil (and probably the first in any developing country) to report clinical and radiologic characteristics as well as treatment outcomes in patients with diffuse brainstem gliomas. The characteristics of our patients seem to confer a worse prognosis compared with patients in other previously published studies; a higher percentage of those patients experienced longer symptom duration and/or involvement of a single brainstem segment.^5,6

In conclusion, the addition of high-dose TX to RT did not have a significant impact in treatment outcome of newly diagnosed children with diffuse brainstem gliomas. This study increased our knowledge of the spectrum of side effects caused by the prolonged use of high-dose TX in children. New alternative treatments need to be tested for this deadly tumor.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following hospitals and physicians participated in this study: Grupo de Pediatria Oncológica, São José dos Campos (C.P. Melo, MD; E. Pontes, MD; G. Plens, MD; and M.M. Silva, MD); Hospital A.C. Camargo (A.M. Fürrer, MD, and C.A.M. Osório, MD); Hospital Darcy Vargas (M.L. D’Andrea, MD); Hospital Sara Rolim Caracante, Sorocaba (A.L. Cornacchioni, MD); Instituto da Criança, Hospital das Clínicas, São Paulo University Medical School (A.J. Diament, MD; E. Weltman, MD; H. Matsushita, MD; M.T. de Almeida, MD; U. Reed, MD; V. Odone Filho, MD; and W. Nadalin, MD); Instituto de Oncologia Pediátrica, the Federal University of São Paulo (N.S. da Silva, MD; A.S. Petrilli, MD; and W. Rodrigues, MD); and Santa Casa de São Paulo, São Paulo, Brazil (P. Bruniera, MD, and S. Rosemberg, MD).

	ACKNOWLEDGMENTS

 
Supported, in part, by the Ação Solidária Contra o Câncer Infantil, São Paulo, Brazil.

We thank Dr Q. Shi, PhD, for performing the statistical analysis and Victoria Frigo for her help in editing this manuscript. We also thank the physicians in the participating institutions who enrolled their patients onto this study and, most of all, our patients and their families for their willingness to participate in this trial.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted July 28, 1999; accepted November 16, 1999.

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