Recent Technical Advances and Indications for Radiation Therapy in Low-Grade Glioma

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Recent technical Advances and Indications for radiation therapy in low grade glioma Michael D. Chan M.D.

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S1053-4296(15)00018-1 http://dx.doi.org/10.1016/j.semradonc.2015.02.001 YSRAO50496

To appear in: Semin Radiat Oncol

Cite this article as: Michael D. Chan M.D., Recent technical Advances and Indications for radiation therapy in low grade glioma, Semin Radiat Oncol , http://dx.doi.org/10.1016/j.semradonc.2015.02.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Recent Technical Advances and Indications for Radiation Therapy in Low Grade Glioma Michael D. Chan, M.D.1 1

Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157

Corresponding Author: Michael D. Chan, M.D. Medical Center Blvd Winston-Salem, NC 27157 Phone: (336) 713-3600 Fax: (336) 713-6515 e-mail: [email protected] Abstract The use of radiotherapy in low grade glioma has been a topic of controversy over the past two decades. While earlier studies showed no overall survival benefit and no dose response, recent studies demonstrate a possible synergism between radiotherapy and chemotherapy. However, many questions remained unanswered with regards to the proper management including the potential roles of biologic imaging in treatment planning, the role of re-irradiation after recurrence, the role of intensity modulated radiation therapy and proton beam radiotherapy, and the proper choice of chemotherapy agents. Further clinical trials are necessary in order to help integrate these new therapies and technologies into clinical practice.

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Introduction

The proper treatment of low grade glioma (LGG) continues to evolve. Several advances in radiation therapy modalities and imaging have recently been reported, though it remains a question as to how these advances will be integrated into the treatment of patients. Recently reported prospective trials have the potential to shape the evolving management paradigm. This review is intended as an overview of recent advances to incorporate modern technologies, with results reported from recent clinical studies. Current practice in radiation oncology for the management of LGG will be discussed.

Indications for Radiotherapy Radiation therapy has often been considered a controversial modality in the treatment of patients with LGG because of the prolonged natural history of the disease, and the potential for late toxicity from radiotherapy. Several prospective randomized trials have been performed in an attempt to define the populations that benefit from radiotherapy, and those that may be safely observed. It is notable that for the existing randomized trials for LGG, the populations included a diversity of patients including those who received biopsy alone, subtotal resection, and gross total resection. Furthermore, these studies also included patients presenting with astrocytoma, oligodendroglioma and mixed oligoastrocytoma. As such, the interpretation of these studies has traditionally been generalized for all types of resection as well as for multiple histologies. Unfortunately, prior studies were not powered to detect differences amongst these subgroups. However, as the data has evolved, it has become clear that some populations may be at higher risk of recurrence, and that risk stratification may ultimately be the paradigm by which it is decided which patients are treated in the upfront setting and which are observed.

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The EORTC 22845 trial was a study of the optimal timing of radiotherapy. Also known as the “non-believers study”, as it questioned the role of upfront radiotherapy, patients were randomized to upfront radiotherapy vs. radiotherapy at time of progression. While there was a statistically significant improvement in progression free survival (55 vs 35%, p<0.0001), overall survival was equivalent1. Seizures were more likely to be controlled at 1 year in the early radiotherapy group. What this study demonstrated was that radiotherapy could be safely withheld for the population of LGG as a whole without a detriment in overall survival. Limitations of the study were that it did not look at differences between risk groups, and did not assess quality of life differences between the arms. In spite of the EORTC 22845 results, it has been long known that LGG are a heterogeneous group of tumors, and that the presence of certain risk factors causes some tumors to act more aggressively2. These factors included large size, age greater than 40 years, astrocytoma histology, tumor crossing midline and presence of pre-surgical neurologic deficit. In the recent RTOG 9802 study, investigators included an observation arm of 111 patients with low-risk LGG that were prospectively observed3. Patients assigned to this observation arm must have been both younger than 40 years and have undergone a neurosurgeon-defined gross total resection. In spite of no upfront therapy, the 5-year survival for this cohort was 93%. However, even in the low risk cohort, patients with astrocytoma histology were found to have had increased rate of recurrence and death. The high-risk arm of the RTOG 9802 study randomized high risk patients with LGG to radiotherapy vs chemoradiotherapy4. Patients randomized to the chemoradiotherapy arm received 54 Gy followed by 6 cycles of PCV chemotherapy. The results of RTOG 9802 are potentially paradigmchanging as this study is the first prospective study to demonstrate an overall survival advantage for any treatment modality in patients with LGG. The initial analysis detected a trend in improved outcomes in the patients receiving chemoradiotherapy, particularly those who survived for longer than 2 years4. The update of the study was presented at the American Society of Clinical Oncology (ASCO) 2014 national

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meeting. With this update, there was a statistically significant benefit in both progression free survival and overall survival with the addition of PCV chemotherapy5. The RTOG 0424 study was a single arm phase II study in which patients with high risk LGG received concurrent and adjuvant temozolomide with radiotherapy. Patients were required to have at least 3 high risk factors, which could include age greater than 40, astrocytoma histology, tumor crossing midline, size greater than 6 cm or poor preoperative functional status. The preliminary results of this trial were presented at the ASCO 2013 national meeting and revealed a 3 year overall survival of 73% which was significantly higher than historical controls for this cohort (54%, p<0.0001)6. Because temozolomide tends to be more tolerable than PCV, the results of RTOG 0424 likely justifies the use of temozolomide in the upfront setting as an alternative to PCV.

Use of Imaging for Treatment Planning LGG commonly appear as non-enhancing masses on both CT and MRI. Prior studies have estimated the rate of contrast enhancement in LGG to be 15-40%7-9. On MRI, tumor extent is determined most easily on the T2 or Fluid Attenuated Inversion Recovery (FLAIR) sequences. The advantage of FLAIR over T2 for tumor delineation is that the FLAIR has subtracted the extracellular fluid and thus provides a better delineation between tumor and edema or tumor and CSF. Fusion of T2 or FLAIR imaging to the treatment planning CT is generally advised for tumor delineation during the radiation treatment planning process. Biologic imaging remains investigational for LGG. There have been several reports of different histologies of LGG having distinct appearances on diffusion or perfusion-weighted imaging. Grade II oligodendroglioma have been found to have a higher relative cerebral blood volume (rCBV) than grade II astrocytoma10. At this time, biologic imaging does not have a defined role in the radiation treatment planning process.

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A possible future utility for advanced imaging techniques may be for determination of the likelihood of malignant transformation in the pre-treatment setting. As much as one third of nonenhancing gliomas represent higher grade tumors. Unfortunately, these tumors can also be quite heterogeneous on pathologic sampling. As such, a potential role for biologic imaging as it evolves may be to determine higher grade tumors. This information could be used to adjust radiation dose or even boost volumes in the future, though further data is necessary to determine if this approach is of use.

Radiotherapy Dose Two prospective phase III dose escalation studies have previously been published demonstrating that there is no role for dose escalation for patients with LGG. The NCCTG 86-72-51 trial was a randomized trial of 203 patients with LGG, comparing doses of 50.4 Gy to 64.8 Gy. While there was no survival difference between the two arms (72% vs 64% at 5 years, respectively, p=), the likelihood of grade 3-5 toxicity was doubled in the higher dose arm (2.5% vs 5%, p=0.04)9. The EORTC 22844 randomized patients to low dose (45 Gy) vs. high dose (59.4 Gy) upfront radiotherapy. Similar to the RTOG study, there was no survival difference (58% vs 59% at 5 years, respectively, p=0.73) or progression free survival difference (47% vs 50%, p=0.94) between the two arms11. One limitation of these studies is that they were performed in the time period where CT scans were the standard imaging modality and modern conformal radiotherapy techniques were unavailable. Overall, the two aforementioned studies were unable to detect a dose response with regards to survival or progression-free survival from the dose range of 45 Gy to 64.8 Gy. Modern trials have adopted doses of either 50.4 Gy (EORTC 22033) or 54 Gy (RTOG 98-02). The advantage of these fractionation schemes is that they do not exceed either brainstem or optic tolerances and should be tolerable for even large volume tumors with respect to the endpoint of radiation necrosis. As recent data suggests that large treatment volumes and involvement of regions such as dominant temporal lobes may

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predispose to late cognitive sequelae, doses as low as 45 Gy remain defensible in clinical situations where late cognitive toxicity is a concern such as very large volume tumors12.

Radiotherapy Volumes The proper target volume for LGG in the 3D planning era is controversial. Gliomas are known to be infiltrative beyond the MRI abnormality13, 14. Proper radiotherapy volumes for high grade gliomas have been derived from three major sources: 1) biopsy studies, 2) patterns of failure studies, and 3) clinical trials comparing radiotherapy margins. Because of the relative rarity of LGG and the controversial role of radiotherapy, the data for LGG is scarce compared to glioblastoma. Clinical trials done in the 2D era of treatment planning used margins of 2cm from tumor margin to block edge, which translates to approximately 1 cm clinical target volume (CTV), 5 mm planning target volume (PTV), and 5 mm of dose buildup region to block edge. A biopsy study was performed by Kracht et al in which [11C]MET PET uptake was correlated to the degree of infiltration detected by biopsies14. This study demonstrated that tumor extended beyond the solid portion of the abnormality detected on MRI. For grade II astrocytomas, [11C]MET PET was able to detect significantly further extent of infiltration than MRI, though these tumors still represented the tumors with highest rate of false negative as compared to biopsy specimens. A pattern of failure analysis was performed on the NCCTG 86-72-51 study which revealed that the great majority (92%) of LGG failed within the highest dose region of the radiation field9. The proportion of marginal failures (within 2 cm of radiation field) and out of field failures was low (3% and 2% respectively). These patterns of failure are quite similar to those of high grade glioma after radiotherapy. As such, modern trends in management of high-grade glioma such as the use of sharper dose gradients associated with intensity modulated radiation therapy (IMRT), and smaller CTV margins may also be acceptable in LGG15.

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Integration of New Technologies Intensity Modulated Radiation Therapy (IMRT) The past two decades have brought about advanced technologies in radiation treatment planning and delivery. While these technologies started in large academic centers, they are becoming ubiquitous in private and community practices. IMRT allows for modulation of the radiation dose profile in order to spare critical structures such as the brain stem, optics, cochlea, retina and lacrimal glands without significantly compromising tumor coverage. Because the dose and fractionation of 54 Gy in 1.8 Gy fractions is generally quite tolerable for most critical structures, the clinical scenarios where IMRT is useful for LGG tends to be less common than for high grade gliomas. Larger or multifocal tumors that border upon multiple critical structures represent an example where IMRT can be beneficial. An example of a tumor for which IMRT was indicated is shown in Figure 1. A series of 39 pediatric LGG was reported by Paulino et al in which patients received IMRT using a dose painting method to deliver a median dose of 50.4 Gy to the high dose region16. At last follow-up, seven of the tumors had recurred, all within the high dose volume, suggesting that IMRT does not lead to marginal failures resulting from sharper dose gradients.

Stereotactic Techniques, Hypofractionated Stereotactic Radiotherapy (HfSRT) and Radiosurgery (SRS) Stereotactic radiotherapy is the use of improved immobilization and image guidance in order to deliver radiotherapy at higher precision than standard. Several options exist to accomplish stereotactic radiotherapy, including cone-beam CT and optical guidance with bite-block immobilization. Stereotactic techniques are commonly used in the treatment of brain tumors in order to minimize treatment margins in patients with benign tumors, and to assure accuracy in the treatment of small targets with larger fractions

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of radiation. In the setting of patients with LGG, the use of stereotactic radiotherapy techniques is generally limited because of the commonly large radiation margins used for LGG, and the fact that the standard dose of 54 Gy does not lead to significant risk to most critical structures. However, in children, where the incentive is to minimize the treatment volume because these doses of radiation can impede cognitive development, use of stereotactic techniques can help to decrease the treatment volumes by minimizing the planned treatment volume (PTV). Stereotactic techniques may also be useful in patients for which hypofractionation is planned as the use of large doses per fraction is generally optimized with the use of the smallest possible PTV margin. Few long-term results exist for the use of hypofractionated radiotherapy in the upfront setting for LGG, though data is emerging for hypofractionation in the salvage setting. Roberge et al reported a single institution series of 21 patients with LGG treated with upfront hypofractionated radiotherapy, with a 10-year actuarial overall survival of 71%17. While the early results are encouraging, such series are subject to selection bias of including only tumors sufficiently small to treat with hypofractionation. Stereotactic radiosurgery (SRS) is the use of stereotactic techniques to deliver a single large dose of radiotherapy. The major concern for the use of single fraction SRS for LGG is that the nature of the sharp dose falloff and targeting of only gross disease with SRS leads to the concern of untreated microscopic disease that is known to be infiltrative into normal brain parenchyma. As such, SRS has traditionally been reserved for small residual tumors after maximum safe resection, small unresectable tumors in the pediatric population, and recurrent tumors18. Several retrospective series have reported the use of SRS in the setting of recurrent disease after prior fractionated RT as well as in the setting of no prior RT19, 20. These series are difficult to interpret given small total numbers and the inherent bias in studies of SRS where tumors are limited to those with sufficiently small volume to be treated with SRS. In the setting of unresectable pediatric LGG, SRS represents a reasonable upfront treatment option because the integral dose to the normal brain parenchyma is significantly less with SRS than with conventionally fractionated RT. Lower integral dose has been implicated in improved cognition in

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pediatric brain tumor patients21, and the delay in delivering a high integral dose to pediatric patients can lead better cognition in the long term22. In a series of 50 patients from the University of Pittsburgh, patients with juvenile pilocytic astrocytomas were treated with SRS to a median margin dose of 14.5 Gy with progression free survival of 71% at 5 years23. In adults, the role for SRS likely remains as a salvage option for small unresectable tumors that have previously been treated with conventionally fractionated radiotherapy.

Proton Beam Radiotherapy Proton beam radiotherapy has the advantage of delivering no exit dose beyond the spread out Bragg Peak. The indications for proton beam radiotherapy in LGG are quite limited and rare, with the most obvious indication being leptomeningeal dissemination requiring craniospinal irradiation (CSI). While the likelihood of leptomeningeal dissemination in adult LGG is <1%, the likelihood in the pediatric LGG population has been reported to be as high as 15%24. With CSI, proton beam radiotherapy is able to avoid exit dose through the patient’s viscera including heart, lungs, and GI tract. Minimizing the dose to patient’s viscera will decrease the likelihood of late heart toxicity25 and secondary malignancy26. A recent statistical analysis from MD Anderson suggested that the use of proton beam radiotherapy over traditional photon CSI may decrease lifetime secondary malignancy risk from 54% to 5%26. Proton beam radiotherapy has also been utilized in the pediatric LGG population in an attempt to spare integral dose to the brain, which has been investigated in leading to worsened cognitive outcomes. The decrease of integral dose with proton beam radiotherapy is not meant to be as dramatic as with SRS because CTV margins and conventional fractionation is used with proton beam radiotherapy. At this time, tolerance thresholds and even the specific targets within the brain remain unclear. Moreover, there is a lack of concrete data demonstrating a benefit in this situation. Preliminary results of a prospective study of 19 patients with LGG treated with proton beam radiotherapy have been reported by Hauswald et

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al27. While neuropsychological endpoints have yet to be reported, acute toxicity was acceptable. An example of a proton radiotherapy plan is shown in Figure 2.

Response Assessment after Radiotherapy Response assessment continues to evolve for LGG as criteria now take into account such factors as tumor volumetric changes, tumor genetics, radiation changes to the normal brain tissue, tumor enhancement, tumor progression or transformation and tumor pseudoprogression. The slow growth pattern of LGG also makes these assessments more difficult. As the role and timing of radiotherapy has been controversial, the heterogeneity of management from observation, radiotherapy, chemotherapy and chemoradiotherapy complicates response assessment. It is possible that ultimate imaging response assessment criteria may need to be separate depending on the treatment modality. The Response Assessment in Neuro-Oncology (RANO) group has recently published expert opinion guidelines for response assessment for LGG taking into account several of the aforementioned factors. In these guidelines, the RANO group suggest that progression of tumor be defined as any of the following: 1) development of new lesions or increased in enhancement, 2) a 25% increase in T2 or FLAIR lesion from baseline or best response after therapy, 3) definite clinical deterioration not attributable to causes apart from the tumor or decrease in steroid dose28. Ducray and colleagues have reported rates and time courses of imaging responses of LGG after radiotherapy29. They found that 37 of 39 patients experienced a decrease in tumor diameter after radiotherapy and that the median duration of the decreasing tumor diameter was 1.9 years. The authors also described a two-phase decrease in tumor diameter after radiotherapy: an initial rapid phase, followed by a slower prolonged phase.

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Pseudoprogression is quite common for grade I tumors after radiotherapy, whether it is with conventionally fractionated radiotherapy or stereotactic radiosurgery30, or proton beam radiotherapy27. Pseudoprogression has also been reported for grade I tumors in both the pediatric27 and adult populations30 and for grade II tumors as well31. In a series of WHO grade II and III patients, 8 of 37 (22%) grade II patients experienced pseudoprogression after chemoradiotherapy32. Presence of 1p19q codeletion appeared to confer a lower probability of pseudoprogression in this population. An example of pseudoprogression in a grade I tumor is shown in Figure 3. Advanced imaging techniques such as diffusion and perfusion-weighted MRI, and PET are being integrated into response assessment for LGG33. After treatment, as many as 80% of LGG will transform to higher grade tumors34. In the follow-up setting, advanced imaging techniques may be used to determine whether changes on conventional MRI represent treatment-related enhancement or malignant transformation. In cases of transformation, perfusion changes may be detectable up to 12 months prior to increased contrast enhancement on conventional MRI35. An example of this phenomenon is depicted in Figure 4. It is generally helpful to have such advanced imaging in the pre-treatment setting to use as baseline studies so that changes can be documented longitudinally.

Recurrent Disease and the Role of Re-Irradiation Because of a modest heterogeneity in patterns of tumor progression, biopsy confirmation is generally advised prior to initiation of salvage therapy. A biopsy series from Mayo Clinic of 51 previously irradiated patients with LGG and suspected recurrence demonstrated a heterogeneity in pathologic results including tumor alone (59%), tumor plus necrosis (33%), radiation necrosis (6%) and radiation-induced sarcoma (3%)36. Furthermore, 63% of those found to be recurrent tumor were of a higher grade at time of biopsy.

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Chemotherapy is an important treatment option for patients with recurrent LGG, especially those who have had radiotherapy in the past. Several series have demonstrated tangible response rates with salvage chemotherapy. Patients with 1p19q co-deletion may have improved survival after salvage chemotherapy37. There is concern that a salvage chemotherapy regimen after primary chemotherapy does not work well, particularly in patients who have had either prior PCV or temozolomide and is treated with the other at failure38. Re-irradiation has a limited role in the treatment of recurrent LGG. Conventionally fractionated radiotherapy, hypofractionated radiotherapy and stereotactic radiosurgery have all been reported in the setting of recurrent disease. While re-irradiation may be a useful option in selected populations, its use should be judicious and based upon tumor volume, possible gains in life expectancy, and expectation of toxicity. The choice of radiation treatment modality in the setting of re-irradiation is often made based upon the volume of disease and the concern for tumor infiltration into surrounding brain. Use of bevacizumab in the concurrent or adjuvant setting with re-irradiation has been shown to decrease the likelihood of radiation necrosis39.

Re-irradiation with Stereotactic Radiosurgery SRS is generally only appropriate for patients with a discreet and focal recurrence. Larger recurrences are at higher risk of both radiation necrosis and for marginal failure after SRS. However, recurrent pilocytic astrocytomas are commonly good candidates for salvage SRS as these tumors are often distinct on imaging and without distant tumor infiltration. The Mayo clinic has recently published a series of SRS for recurrent or unresectable pilocytic astrocytoma using a median margin dose of 15 Gy40. Of note, patients receiving prior radiotherapy in this series had worsened overall survival, though this may be related to lead time bias.

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Prior series have suggested that oligodendroglioma treated with salvage radiosurgery may have better outcome than astrocytoma20, 41. In a series from the University of Pittsburgh in which patients were treated with median marginal dose of 14.5 Gy, progression free survival was 82% at 5 years for grade II oligodendrogliomas41. The same group reported its series of patients with grade II astrocytoma treated with a median marginal dose of 14 Gy, and progression-free survival was 54% at 5 years. It is notable that the median volume treated in both of these series for grade II oligodendroglioma and astrocytoma was 15.4 and 3.7 cc, respectively. Tumor progression after SRS for LGG generally occurs within the treatment volume20.

Re-irradiation with Hypofractionated RT Hypofractionated radiotherapy has also been reported by Fogh et al using a median dose of 35 Gy in 3.5 Gy fractions42. No CTV margin was used in this series as the only volume targeted was gross tumor. The median survival of the patient population was 8.5 months. A concern for hypofractionated re-irradiation is that unlike for single fraction radiosurgery, the volume constraints for these fractionation patterns have not been well described. In the reported series of high-grade glioma treated with hypofractionated re-irradiation, it appears that tumors on the order of 5 cm or smaller are likely safe to treat in this manner.

Re-irradiation with Conventionally Fractionated RT The advantage of conventionally fractionated radiotherapy for definitive re-irradiation is the ability to treat larger volumes and to minimize late radiation toxicity in a population that may still have a reasonable life expectancy. There is not a standard dose used for definitive re-irradiation, though the clinical scenario may help to dictate the dose. Tumors that have transformed to glioblastoma (GBM)

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represent secondary GBM, which are thought to have improved survival as compared to de novo GBM. As such, these tumors may deserve more aggressive dosing and concurrent chemotherapy should patients maintain a good performance status. There are other LGG which have undergone multiple recurrences and multiple salvage regimens. These patients often have compromised performance status due to recurrent tumor and cumulative effects of treatment. These patients may be best treated with lower doses to palliate symptoms. The largest series of conventionally fractionated re-irradiation for LGG was published by Combs et al. Using a median dose of 36 Gy in 2 Gy fractions, they treated 63 patients with stereotactic irradiation43. Patients achieved a median progression free survival of 12 months and overall survival of 24 months. References 1. van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, Malmstrom PO, Collette L, Pierart M, Mirimanoff R, Karim AB: Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366:985-990, 2005. 2. Pignatti F, van den Bent M, Curran D, Debruyne C, Sylvester R, Therasse P, Afra D, Cornu P, Bolla M, Vecht C, Karim AB: Prognostic factors for survival in adult patients with cerebral lowgrade glioma. J Clin Oncol 20:2076-2084, 2002. 3. Shaw EG, Berkey B, Coons SW, Bullard D, Brachman D, Buckner JC, Stelzer KJ, Barger GR, Brown PD, Gilbert MR, Mehta M: Recurrence following neurosurgeon-determined gross-total resection of adult supratentorial low-grade glioma: results of a prospective clinical trial. J Neurosurg 109:835-841, 2008. 4. Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer KJ, Barger GR, Brown PD, Gilbert MR, Mehta MP: Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol 30:3065-3070, 2012. 5. Buckner JC, Pugh SL, Shaw EG, Gilbert MR, Garger G, Coons S, Ricci P, Bullard D, Brown PD, Stetzer K, Brachman D, Suh JH, Schultz CJ, Bahary J, Fisher BJ, Kim H, Murtha AD, Curran WJ, Mehta MP: Phase III study of radiation therapy with or without PCV in low-grade glioma: RTOG 9802 with Alliance, ECOG, and SWOG. J Clin Oncol 32:abstr 2000, 2014. 6. Fisher BJ, Lui J, Macdonald DR, Lesser GJ, Coons S, Brachman D, Ryu S, Werner-Wasik M, Bahary J, Hu C, Mehta MP: A phase II study of a temozolomide-based chemoradiotherapy regimen for high-risk low-grade gliomas: Preliminary results of RTOG 0424 J Clin Oncol 31:abstr 2008, 2013.

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Figure Legend Figure 1A. T2 axial MRI slice demonstrating a left frontal WHO grade II astrocytoma. 2A. Intensity modulated radiation therapy (IMRT) plan showing isodose lines delivering 54 Gy to the planning treatment volume. IMRT was indicated in this patient because of the periorbital location and the goal of keeping the mean retinal dose to <45 Gy.

Figure 2. Proton therapy plan for a 5 year old with a WHO grade II diffuse oligoastrocytoma of the tectal plate. Proton therapy was offered to the patient as a means of sparing integral dose in a child. Image is courtesy of Dr. Tamara Vern-Gross.

Figure 3A. T1 with contrast axial MRI slice at time of diagnosis of a WHO grade I pilocytic astrocytoma. 3B. T1 axial with contrast MRI slice one month after completion of radiotherapy demonstrating pseudoprogression. The pseudoprogression resolved over the next 4 months and the patient remains free from progression 3 years post-radiotherapy. Figure 4A. Post-radiotherapy baseline T1 MRI with contrast of a WHO grade II astrocytoma. 2B. Postradiotherapy baseline T2 MRI. 4C. T1 MRI with contrast performed 6 years after completion of radiotherapy. 4D. Dynamic contrast enhanced MRI performed 6 years after completion of radiotherapy demonstrating increased perfusion in the periventricular region. The patient ultimately experienced transformation to glioblastoma within 6 months.

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Table 1: Contemporary Trials of Adjuvant Therapy for Low Grade Glioma Trial

Adjuvant Therapy

5 yr PFS

EORTC 22844

45 Gy

47%

58%

59.4 Gy

50%

59%

50.4 Gy

55%

72%

64.8 Gy

52%

64%

observation

35%

66%

54 Gy

55%

68%

observation (non-randomized low risk arm)

48%

93%

54 Gy

72%

63%

54 Gy + PCV

84%

72%

RTOG 0424

54 Gy/TMZ (non-randomized)

46%

60%

EORTC 22033

50.4 Gy

NCCTG 86-72-51

EORTC 22845

RTOG 9802

TMZ (12 cycles) RTOG 0925

observation (non-randomized low risk only)

a

PCV – procarbazine, CCNU, vincristine

b

TMZ – temozolomide delivered daily and concurrently with fractionated radiation therapy.

19

5 yr OS

Fig 1

Fig 2

20

Fig 3

Fig 4

21