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Keywords:

  • low grade glioma;
  • pediatric;
  • intensity modulated radiotherapy;
  • dose painting

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

The objective of this study was to evaluate local control and patterns of failure in pediatric patients with low-grade glioma (LGG) who received treatment with intensity-modulated radiation therapy (IMRT).

METHODS

In total, 39 children received IMRT after incomplete resection or disease progression. Three methods of target delineation were used. The first was to delineate the gross tumor volume (GTV) and add a 1-cm margin to create the clinical target volume (CTV) (Method 1; n = 19). The second was to add a 0.5-cm margin around the GTV to create the CTV (Method 2; n = 6). The prescribed dose to the GTV was the same as dose to the CTV for both Methods 1 and 2 (median, 50.4 grays [Gy]). The final method was dose painting, in which a GTV was delineated with a second target volume (2TV) created by adding 1 cm to the GTV (Method 3; n = 14). Different doses were prescribed to the GTV (median, 50.4 Gy) and the 2TV (median, 41.4 Gy).

RESULTS

The 8-year progression-free and overall survival rates were 78.2% and 93.7%, respectively. Seven failures occurred, all of which were local in the high-dose (≥95%) region of the IMRT field. On multivariate analysis, age ≤5 years at time of IMRT had a detrimental impact on progression-free survival.

CONCLUSIONS

IMRT provided local control rates comparable to those provided by 2-dimensional and 3-dimensional radiotherapy. Margins ≥1 cm added to the GTV may not be necessary, because excellent local control was achieved by adding a 0.5-cm margin (Method 2) and by dose painting (Method 3). Cancer 2013;119:2654–2659. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Neoplasms arising in the brain account for approximately 20% of all pediatric tumors. Low-grade glioma (LGG) is the most common, with pilocytic astrocytoma comprising more than half of the cases. Other childhood LGGs also include fibrillary astrocytoma, ganglioglioma, oligodendroglioma, pilomyxoid astrocytoma, and pleomorphic xanthoastrocytoma. Despite the heterogeneity of LGG, the standard treatment approach is the same, with maximal safe resection as first-line treatment; chemotherapy and radiotherapy (RT) are reserved for patients with incompletely resected tumors and/or disease progression.

Intensity-modulated radiation therapy (IMRT) is currently used to treat many children with pediatric brain tumors. The advantage of this technique includes limitation of high doses of radiation to the tumor and tumor bed while sparing the surrounding normal tissue. Although there have been previous reports on IMRT for other pediatric brain tumors, to our knowledge, there have been no reports using IMRT solely for LGG.[1-3] Most reports in the last decade have used 3-dimensional conformal RT (3DCRT) with or without a stereotactic approach.[4, 5]

With the advent of IMRT and other 3DCRT techniques, there has been controversy regarding what margins to use for the clinical target volume (CTV). In different institutions, a margin ranging from 0 to 1 cm has been added to the gross tumor volume (GTV) to create the CTV.[4-6] The planning target volume (PTV) varied from 0.3 m to 1.0 cm in addition to the CTV. In our institution, we have used 3 different target volumes for LGG secondary to physicians' preference. The most common method used was a 1-cm margin around the GTV to create the CTV. In some patients, a margin of 0.5 cm was used instead of 1 cm to create the CTV. In both situations, the GTV, CTV, and PTV were prescribed the same RT dose. Finally, in another subset of patients, a dose-painting approach was used. A 1-cm margin was added to the GTV; however, the dose prescribed was different for the GTV and for the 1-cm margin around the GTV. The volume encompassing 1 cm around the GTV received a dose lower than the GTV. A PTV was not used for this final approach, unlike the 2 other methods of target delineation.

The main objective of this study was to determine the 5-year and 8-year progression-free survival (PFS) and overall survival (OS) of children with LGG who received treatment with IMRT. A secondary goal was to investigate the patterns of local failure to determine whether the margin used for treatment had an impact on PFS. Finally, we wanted to determine which treatment parameters had an impact on PFS and OS.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

From 1996 to 2012, 39 children with LGG received IMRT in 1 radiotherapy department. There were 24 boys and 15 girls, and the median patient age was 10 years (range, 1-17 years) at the time of IMRT. None of the patients had neurofibromatosis. The location of LGG was central (optic pathway, thalamus, hypothalamus) in 19 patients (48.7%), posterior fossa (cerebellum, brainstem) in 15 patients (38.5%), and hemispheric in 5 patients (12.8%). Tumors were graded according to the World Health Organization as grade 1 in 32 patients (82%) and grade 2 in 7 patients (18%). The types of LGG included pilocytic astrocytoma in 26 patients (66.7%), ganglioglioma in 6 patients (15.4%), fibrillary astrocytoma in 4 patients (10.3%), pilomyxoid astrocytoma in 1 patient (2.6%), oligodendroglioma in 1 patient (2.6%), and mixed oligoastrocytoma in 1 patient (2.6%). The median GTV was 21.7 mL (range, 4.3-195.6 mL).

IMRT was delivered within 4 to 6 weeks after subtotal resection in 19 patients (48.7%). In 20 patients, IMRT was received at the time of progression after resection alone in 10 patients (25.6%) and after chemotherapy in 10 patients (25.6%). Only children aged <10 years received chemotherapy, and the objective was to delay RT and minimize neurocognitive impairment. The most common chemotherapy regimen was carboplatin and vincristine in 9 of 10 patients. Two patients received a second chemotherapy regimen before IMRT. The median time to progression after chemotherapy was 2.1 years (range, 0.3-8 years). IMRT was delivered using serial tomotherapy in 19 patients (48.7%) and step-and-shoot or dynamic IMRT in 20 patients (51.3%). The technique for IMRT delivery has been described previously in other reports from our institution for children with medulloblastoma and ependymoma.[1, 3]

Target delineation was performed using fused magnetic resonance images. For pilocytic astrocytomas, the GTV was the entire tumor volume, including the cyst observed on a gadolinium-enhanced T1 sequence and any nonenhancing abnormality observed on a T2 or fluid-attenuated inversion recovery (FLAIR) sequence. For children with diffuse gliomas, the GTV was delineated using the T2 or FLAIR sequence. Three methods of target delineation were used during the study period (Fig. 1). The method of target delineation was determined by physician preference. During the era studied, 3 radiation oncologists treated children with pediatric brain tumors. The most common method in 19 patients (48.7%) was to delineate the GTV and add a 1-cm margin to create the CTV (Method 1). Another method used in 6 children (15.4%) was to delineate the GTV and add a 0.5-cm margin to create the CTV (Method 2). In both Methods 1 and 2, a 0.3-cm margin was added to the CTV to create the PTV. The prescribed dose to the GTV was the same as the prescribed dose to the CTV and the PTV. The median prescribed dose to the GTV, CTV, and PTV was 50.4 grays (Gy) (range, 45-60 Gy). One patient who had a fibrillary astrocytoma with a high proliferation index received a dose of 60 Gy. The other method, which was used in 14 patients (35.9%), was dose painting (Method 3). In this method, a GTV was delineated. A second target volume (2TV) was defined by adding 1 cm to the GTV. A PTV was not contoured, because the daily set-up error was built into the 2TV. Two different doses were prescribed to the GTV and the 2TV. The median prescribed dose was 50.4 Gy (range, 45-54 Gy) to the GTV and 41.4 Gy (range, 40-45 Gy) to the 2TV. Patient, tumor, and treatment characteristics according to the method of target delineation are listed in Table 1. The Fisher exact test was used to determine differences in patient, tumor, and treatment characteristics according to the target delineation method. More grade 2 tumors were treated using Method 3 (P = .017), whereas step-and-shoot or dynamic IMRT was the only technique used for children who were treated using Method 2 (P = .034).

image

Figure 1. Three methods of target delineation are illustrated for pediatric low-grade glioma. GTV indicates gross tumor volume; CTV, clinical target volume; PTV, planning target volume; 2TV, secondary target volume used for dose painting.

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Table 1. Patient, Tumor, and Treatment Characteristics According to the Method of Target Delineation
 No. of Patients 
ParameterMethod 1Method 2Method 3P
  1. Abbreviations: cGy, centigrays; IMRT, intensity-modulated radiotherapy.

Sex   .16
Boys1356 
Girls618 
Age at IMRT, y   .60
≤5714 
>512510 
Tumor grade   .017
11868 
2106 
Tumor location   .29
Central1054 
Hemispheric203 
Posterior fossa717 
Gross tumor volume, mL   .32
<5013612 
50602 
Use of chemotherapy before IMRT   .12
Yes711 
No12513 
Type of IMRT   .034
Serial tomotherapy1009 
Step-and-shoot or dynamic965 
Total dose, cGy   .70
≤504015410 
>5040424 
Treatment era   .52
1996-2001848 
2002-20121126 
Follow-up, mo    
Median737294 
Range7-17724-14025-148 

The patterns of failure were documented as local, marginal, or distant.[7] Local recurrence was defined as >95% of the recurrence volume receiving >95% of the prescribed dose. Marginal recurrence was defined as 20% to 95% of the recurrence volume receiving >95% of the prescribed dose. Distant recurrence was defined as <20% of the recurrence volume receiving >95% of the prescribed dose.

The following parameters were evaluated with respect to their impact on OS and PFS: sex, age at time of IMRT (≤5 years vs >5 years), tumor grade, tumor location (central, hemispheric, or posterior fossa), GTV (<50 mL vs ≥50 mL), receipt of chemotherapy before IMRT, target delineation method, type of IMRT delivery, total dose (≤5040 cGy vs >5040 cGy), and treatment era (1996-2001 vs 2002-2012). Both OS and PFS were calculated from the time of IMRT completion. Kaplan-Meier analysis was performed for estimates of survival. The log-rank test was used to compare survival according to different host, tumor, and treatment characteristics. Finally, a Cox regression analysis was performed to determine which parameters were significant on multivariate analysis. The median follow-up for all patients was 81 months (range, 7-177 months).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Progression-Free Survival

The 5-year and 8-year PFS rate was 78.2% (Fig. 2a). On univariate analysis, the only parameters that were significant for PFS were age at the time of IMRT, receipt of chemotherapy before IMRT, and method of target delineation (Table 2). The 5-year and 8-year PFS rate for children aged ≤5 years and >5 years at the time of IMRT was 55% and 90.6%, respectively (P = .02). The 5-year and 8-year PFS rate for children who did and did not receive prior chemotherapy was 50% and 88.4%, respectively (P = .03). The 5-year and 8-year PFS rate for children who received treatment using Methods 1, 2, and 3 for target delineation was 57.4%, 100%, and 92.3%, respectively (P = .05). On multivariate analysis, only age at time of RT was significant for PFS, with more disease progression observed among patients who were aged ≤5 years at the time of IMRT (P = .024).

image

Figure 2. (a) Progression-free survival and (b) Overall survival are illustrated for 39 children who received intensity-modulated radiation therapy for low-grade glioma.

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Table 2. Univariate Analysis of Patient, Tumor, and Treatment Parameters and Influence on Progression-Free and Overall Survival
ParameterFrequency: No. of Patients5-Year and 8-Year PFS, %P5-Year and 8-Year OS, %P
  1. Abbreviations: cGy, centigrays; IMRT, intensity-modulated radiotherapy; OS, overall survival; PFS, progression-free survival.

Sex  .12 .79
Boys2466.8 93.8 
Girls1593.3 93.3 
Age at radiotherapy, y  .02 .62
≤51255 90 
>52790.6 96.2 
Tumor grade  .71 .26
13275.7 95.5 
2785.7 85.7 
Tumor location  .09 .36
Central1963.3 87.4 
Hemispheric5100 100 
Posterior fossa1590.9 100.0 
Gross tumor volume, mL  .09 .48
<503185 92.2 
≥50850 100 
Chemotherapy before IMRT  .03 .41
Yes950 100 
No3088.4 91.6 
Margins  .05 .30
Method 1: 1 cm1957.4 86.3 
Method 2: 0.5 cm6100 100 
Method 3: Dose painting1492.3 100 
Type of IMRT  .34 .88
Serial tomotherapy1971.1 93.8 
Step-and-shoot or dynamic2088.2 94.4 
Total dose, cGy  .45 .37
≤50402973.8 95.2 
>50401090.9 88.9 
Treatment era  .29 .89
1996-20012070.8 93.3 
2002-20121986.8 94.1 

Patterns of Failure

Seven patients (17.9%) progressed at a median of 37 months (range, 4-60 months) after IMRT. All failures were in-field failures, and there were no marginal or distant failures. A girl aged 9 years who had a grade 2 fibrillary astrocytoma of the thalamus on biopsy received 60 Gy in 30 fractions secondary to a high proliferation index. Her tumor progressed 4 months after IMRT and, on rebiopsy, was identified as a malignant glioma.

Overall Survival and Late Effects

The 5-year and 10-year OS rate was 93.7% (Fig. 2b). None of the parameters examined were prognostic for OS (Table 2). One patient who was aged 4.5 years at the time of IMRT for a suprasellar pilocytic astrocytoma developed Moyamoya disease. Twenty-one children had endocrine follow-up, including 12 children with had centrally located tumors, 3 with hemispheric tumors, and 6 with posterior fossa tumors. Ten of 21 patients who had endocrine follow-up had hormone abnormalities, including 3 children with panhypopituitarism, 3 with 1 hormone deficiency, and 4 with 2 hormone deficiencies. Children who had centrally located tumors were more likely to have endocrine abnormalities compared with those who had hemispheric and posterior fossa tumors (P = .008). Nine of the 10 patients who had documented hormone deficiencies had tumors located either in the suprasellar, optic pathway, or hypothalamic region. There was no blindness secondary to IMRT. At last follow-up, 4 of the 15 patients who were aged ≥18 years were in college. Of the 39 patients who received IMRT, only 1 was receiving special education. None of the patients developed a radiation-induced tumor.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

The 5-year and 8-year PFS rate for pediatric patients with LGG who received IMRT in this study was 78.2%. This compares favorably with previous published reports. In the Hirntumorstudien LGG 1996 protocol, the 10-year PFS rate was 62% for patients who received RT.[8] In the current study, safety margins of 1 cm and 2 cm were added when magnetic resonance imaging and computed tomography scans were used, respectively. At St. Jude Children's Research Hospital, the 5-year and 10-year PFS rates were 87.4% and 74.3%, respectively, with the use of conformal RT using a 1-cm margin for the CTV.[4] At the Dana Farber Cancer Institute, the 5-year and 8-year PFS rates were 82.5% and 65%, respectively, using stereotactic RT. In the Boston study, the GTV and CTV were the same; a 2-mm margin was added to the CTV to create the PTV. In all of those reports, the OS rates at 8 to 10 years range from 82% to 96%, similar to the 8-year OS rate in the current report of 93.7%.

The question regarding the size of margins around the GTV to create the CTV is controversial and varies in different studies, as discussed above. In the recently completed Children's Oncology Group protocol ACNS0221, a margin of 0.5 cm was added to the GTV to create the CTV, and another 3 to 5 mm can be added to the CTV to create the PTV, depending on institutional experience. The results from that multi-institutional, prospective trial have not been reported. Although the univariate analysis in our current study suggests that the method of target delineation possibly contributed to disease progression, a further review of failures indicated that 5 of the 7 relapses occurred in children who received IMRT at age ≤5 years. This suggests that younger age rather than the method of target delineation was the primary predictor of disease progression. Our multivariate analysis indeed revealed no difference in progression according to the method of target delineation, and only age <5 years at the time of irradiation was associated with worse PFS, consistent with findings reported from other studies.[9, 10] Our findings suggest that ≥1-cm margins around the GTV may not be necessary for CTV delineation in pediatric LGG.

In this report, 14 patients were treated using Method 3, which involved dose painting. Dose painting has been used in other pediatric tumors, such as ependymoma and rhabdomyosarcoma.[3, 11] The main advantage of this approach compared with a sequential boost approach is the lower fractional dose to surrounding normal tissue.[11] This method of using a lower fraction size to surrounding normal tissue around the GTV may reduce late toxicity and allow for the possibility of dose escalation in selected tumors. We observed only 1 local failure among 14 patients who received treatment using this approach in our institution.

This report of 39 children who received IMRT for LGG compares favorably with previous published reports that used 2-dimensional and 3-dimensional, conformal techniques.[4-6, 8, 9] Although our report indicates that the efficacy of treatment is not compromised by using IMRT, the main reason for using IMRT in children is to reduce the high-dose RT volume to the surrounding normal tissues, which is expected to translate into a reduction in late effects. Although this was not a prospective study, the late toxicities described in our report appear to be comparable to those in other reports using conformal techniques. Of 21 patients who had endocrine data available, 10 (47.6%) developed endocrine deficiency. Endocrine data were available for 12 of 19 patients (63.2%) with centrally located tumors, for 3 of 5 patients (60%) with hemispheric tumors, and for 6 of 14 patients (42.9%) with posterior fossa tumors. It is possible that some patients who did not have endocrine follow-up did not have symptoms related to hormone loss, which usually would prompt endocrine testing and consultation. It is important to note that most of the endocrine abnormalities were observed in the patients who had centrally located tumors. It is possible that some of these patients had endocrine abnormalities before IMRT. In the study by Merchant et al, 24% and 12% of patients before conformal RT had growth hormone and precocious puberty, respectively.[12] In the same report, 48.9%, 64%, 19.2%, and 34.2% required growth, thyroid, glucocorticoid, and gonadotropin-releasing hormone analog therapy, respectively. Other reports of endocrine deficiency in the 2-dimensional era have demonstrated that 79% to 100% of long-term survivors have hormone deficits.[13, 14] Vasculopathy was observed in only 1 patient aged <5 years who received treatment for a suprasellar pilocytic astrocytoma. This is consistent with a recent literature review in which Moyamoya disease was identified as most common in young patients (<5 years) who received treatment for a hypothalamic or suprasellar tumor.[15]

One of the main concerns about using IMRT in children is the amount of radiation leakage to the rest of the body secondary to the number of monitor units necessary to deliver the treatment. Some have speculated that there may be an increase in radiation-induced cancers from 1% to 1.75% at 10 years because of IMRT.[16] This requires long-term follow-up in a large number of patients to determine the difference. We did not observe any radiation-induced secondary tumors in our study; and, to our knowledge, there have been no published reports to date with clinical experience demonstrating that IMRT is associated with a higher risk of radiation-induced secondary tumors.

This study had limitations secondary to its retrospective nature. The choice of target delineation method was secondary to the treating radiation oncologist at a specified period. Not all data were available for the study of late complications. Despite this limitation, our study indicates that IMRT is an excellent treatment for incompletely resected and recurrent pediatric LGG, and the PFS and OS outcomes are comparable to what is reported in the available literature. Young age at time of IMRT was identified as a detrimental factor for PFS. The current report also suggests that margins ≥1 cm may not be necessary when designing the CTV for these patients. IMRT with dose painting is a reasonable RT option for these patients to reduce the fractional dose to surrounding normal tissues. We await the results of the Children's Oncology Group protocol ACNS0221 to validate our results.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
  • 1
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  • 3
    Schroeder TM, Chintagumpala M, Okcu MF, et al. Intensity-modulated radiation therapy in childhood ependymoma. Int J Radiat Oncol Biol Phys. 2008;71:987-993.
  • 4
    Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol. 2009;27:3598-3604.
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    Gnekow AK, Falkenstein F, von Hornstein S, et al. Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German speaking Society of Pediatric Oncology and Hematology. Neuro Oncol. 2012;14:1265-1284.
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    Oh KS, Hung J, Robertson PL, et al. Outcomes of multidisciplinary management in pediatric low-grade gliomas [serial online]. Int J Radiat Oncol Biol Phys. 2011;81:e481-e488.
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    Qaddoumi I, Sultan I, Gajjar A. Outcome and prognostic features in pediatric gliomas: a review of 6212 cases from the Surveillance, Epidemiology, and End Results database. Cancer. 2009;115:5761-5770.
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    Yang JC, Dharmarajan KV, Wexler LH, et al. Intensity modulated radiation therapy with dose painting to treat rhabdomyosarcoma [serial online]. Int J Radiat Oncol Biol Phys. 2012;84:e371-e377.
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    Merchant TE, Conklin HM, Wu S, et al. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine and hearing deficits. J Clin Oncol. 2009;27:3691-3697.
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    Benesch M, Lackner H, Sovinz P, et al. Late sequelae after treatment of childhood low-grade gliomas: a retrospective analysis of 69 long-term survivors treated between 1983 and 2003. J Neurooncol. 2006;78:199-205.
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    Collet-Solberg PF, Sernyak H, Satin-Smith M, et al. Endocrine outcome in long-term survivors of low-grade hypothalamic/chiasmatic glioma. Clin Endocrinol (Oxf). 1997;47:79-85.
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    Desai SS, Paulino AC, Mai WY, et al. Radiation-induced Moyamoya syndrome. Int J Radiat Oncol Biol Phys. 2006;65:1222-1227.
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    Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys. 2003; 56:83-88.