[F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: Clinical outcomes and patterns of failure

doi:10.1016/j.ijrobp.2005.08.013

International Journal of Radiation OncologyBiologyPhysics

Volume 64, Issue 3, 1 March 2006, Pages 886-891

https://doi.org/10.1016/j.ijrobp.2005.08.013 Get rights and content

Purpose: [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for brain tumors has been shown to identify areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme may lead to improved disease control. Based on these premises, we initiated a prospective study of FDG-PET for the treatment planning of radiation dose escalation for the treatment of glioblastoma multiforme.

Methods and Materials: Forty patients were enrolled. Patients were treated with standard conformal fractionated radiotherapy with volumes defined by MRI imaging. When patients reached a dose of 45–50.4 Gy, they underwent FDG-PET imaging for boost target delineation, for an additional 20 Gy (2 Gy per fraction) to a total dose of 79.4 Gy (n = 30).

Results: The estimated 1-year and 2-year overall survival (OS) for the entire group was 70% and 17%, respectively, with a median overall survival of 70 weeks. The estimated 1-year and 2-year progression-free survival (PFS) was 18% and 3%, respectively, with a median of 24 weeks. No significant improvements in OS or PFS were observed for the study group in comparison to institutional historical controls.

Conclusions: Radiation dose escalation to 79.4 Gy based on FDG-PET imaging demonstrated no improvement in OS or PFS. This study establishes the feasibility of integrating PET metabolic imaging into radiotherapy treatment planning.

Introduction

The treatment of glioblastoma multiforme (GBM) remains one of the most challenging endeavors in oncology. Radiotherapy is the most effective treatment to date, but overall survival (OS) is poor. Of the estimated 17,000 new primary central nervous system tumors diagnosed per year in the United States, GBM accounts for almost one-third of new diagnoses and a majority of the anticipated 13,000 deaths per year. Sequential studies over the past few decades have attempted to define the optimal radiation dose and treatment volume. Past studies compared whole-brain radiotherapy vs. more limited field radiation and demonstrated no benefit to whole-brain treatment. A four-arm randomized intergroup trial showed no advantage to the use of whole brain vs. limited fields, and no advantage to a dose of 70 Gy vs. 60 Gy (1). Attempts at combining chemotherapy with radiotherapy have generally been disappointing, although a recent randomized trial demonstrated that temozolomide concurrent with and after radiotherapy modestly improved survival and disease-free survival (2, 3). The majority of failures, regardless of the treatment approach, are within irradiated volumes.

Recently, local radiation dose escalation using three-dimensional treatment planning techniques has been employed in an attempt to improve local control. Chan et al. (4) reported the results of dose escalation to 90 Gy using magnetic resonance imaging (MRI)-defined volumes and found no improvement in outcomes. Preliminary data from Radiation Therapy Oncology Group (RTOG) 98–03 indicated that dose escalation using three-dimensional conformal radiotherapy up to a dose of 84 Gy was feasible (5). No additional toxicity was noted from the use of highly conformal fields at this dose level compared with historical controls in either study. Shaw et al. (6) have recently reported preliminary results of a dose escalation trial using intensity-modulated radiotherapy techniques. At dose levels of 70 and 75 Gy, no dose-limiting toxicities were noted. These studies have used MRI to determine the initial radiation treatment volumes, as well as the boost volumes. Despite dose escalation, local failure in the high-dose region continues to be the primary mode of failure.

An improvement in survival by radiation dose escalation, if possible, will require an expansion of the therapeutic window by targeting the volume at greatest risk for first recurrence while minimizing radiation exposure to normal, functional brain tissue. The use of newer functional imaging modalities such as [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) to guide the radiation treatment of malignancies has been postulated to be more accurate for determining target volumes. Imaging with FDG-PET has been used for brain tumors to differentiate areas of active disease from regions of treatment-related necrosis. FDG uptake correlates with tumor grade and aggressiveness, and the level of FDG uptake in primary brain tumors is predictive of survival (7, 8, 9, 10, 11). Based on these experiences with FDG-PET imaging, along with the tolerability of escalated radiation dose reported with MRI-guided three-dimensional conformal therapy for GBM, we initiated a prospective phase II trial using FDG-PET to guide high-dose radiation boost volumes. A preliminary report from this trial demonstrated that FDG-PET–defined volumes differed from those defined by MRI T1 gadolinium enhancement and T2 signal abnormality, and that the volumes defined by FDG-PET were more predictive of survival and time to progression than were MRI volumes (12). We now report the clinical outcomes for all patients treated on this trial.

Section snippets

Subjects

Forty patients were enrolled in this prospective trial between March 1977 and August 2000, after institutional review board approval. Eligibility criteria were pathologic diagnosis of GBM or gliosarcoma, age at least 18 years, life expectancy greater than 3 months, Karnofsky performance status at least 70, no prior radiation or chemotherapy for a brain tumor, and no medical or psychiatric condition that would compromise the patient’s ability to tolerate radiotherapy or PET scanning.

A historical

Patient characteristics

Table 1 shows the characteristics of patients enrolled on the PET boost protocol in comparison with the historical controls. As expected, patients on the PET boost protocol received significantly higher radiation dose than historical controls. The only other significant difference between the two groups was mean age (younger subjects in the PET boost group). No significant differences were observed with respect to Karnofsky performance status, proportion of patients younger than 50 years,

Discussion

Treatment outcomes for patients with GBM remain suboptimal despite the improvement in surgical resection, addition of chemotherapy, and radiotherapy dose escalation. The median survival of these patients has changed little in the past 20 years, with most patients suffering from local recurrences occurring in the initial tumor bed. The most promising recent results were reported by the European Organization for Research and Treatment of Cancer using concurrent temozolomide and radiotherapy with

Conclusion

Radiation dose escalation to 79.4 Gy based on FDG-PET imaging in GBM patients did not improve OS or PFS compared with conventional radiation doses at our institution or on previously published RTOG trials. Local in-field failure remains the predominant pattern, and further local treatment strategies need to be developed to improve survival.

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Dose Escalated Radiation Therapy for Glioblastoma Multiforme: An International Systematic Review and Meta-Analysis of 22 Prospective Trials
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Citation Excerpt :
Lower-risk areas were generally defined more conventionally as peritumoral edema defined on magnetic resonance imaging (MRI) fluid-attenuated inversion recovery imaging. With respect to the use of PET, a single arm prospective trial by Douglas et al, of 40 patients used a PET-directed boost to a total cumulative dose of 79.4 Gy with no incidences of grade 3 or greater toxicities and a median OS of 70 weeks.29 A more recent study by Piroth et al, among 22 patients with GBM used PET-FET (fluoroethyl-L-tyrosine) to escalate dose to 72 Gy/30 fractions to residual disease with FET-avidity similarly with a median OS of 14.8 months without incidences of grade 3 or greater toxicities and no incidences of radionecrosis.34
Limited evidence is available on the utility of dose-escalated radiation therapy (DE-RT) with or without temozolomide (TMZ) versus standard-of-care radiation therapy (SoC-RT) for patients with newly diagnosed glioblastoma multiforme. We performed a systematic review/meta-analysis to compare overall survival (OS) and progression-free survival (PFS) between DE-RT and SoC-RT.
We used a Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses/Meta-analysis of Observational Studies in Epidemiology selection criterion to identify studies. The primary and secondary outcomes were 1-year OS and 1-year PFS, respectively. Outcomes and comparisons were subdivided based on receipt of TMZ and MGMT status. DE-RT was defined based on equivalent dose calculations. Random effects meta-analyses using the Knapp-Hartung correction, arcsine transformation, and restricted maximum likelihood method were conducted. Meta-regression was used to compare therapeutic (eg, DE-RT or TMZ) and pathologic characteristics (eg, MGMT methylation status) using the Wald-type test.
Across 22 published studies, 2198 patients with glioblastoma multiforme were included; 507 received DE-RT. One-year OS after DE-RT alone was higher than SoC-RT alone (46.3% vs 23.4%; P = .02) as was 1-year PFS (17.9% vs 5.3%; P = .02). No significant difference in 1-year OS (73.2% vs 64.4%; P = .23) or 1-year PFS (44.5% vs 44.3%; P = .33) between DE-RT + TMZ and SoC-RT + TMZ was noted. No difference in 1-year OS was noted between DE-RT + TMZ and SoC-RT + TMZ in either MGMT methylated (83.2% vs 73.2%; P = .23) or MGMT unmethylated (72.6% vs 50.6%; P = .16) patients.
DE-RT alone resulted in superior PFS and OS versus SoC-RT alone. DE-RT + TMZ did not lead to improved outcomes versus SoC-RT + TMZ. No differential benefit based on MGMT status was found. Future studies are warranted to define which subgroups benefit most from DE-RT.
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Gliomas amount to about 45% of all primary CNS tumors and 77% of all malignant primary CNS tumors. It is now generally accepted that the modulation of gene expression may be the most effective modality to control specific gene functions correlated to the development and progression of gliomas. The efficacy of current multimodal therapeutic strategies in gliomas is limited by the lack of specific therapies against malignant cells, and the prognosis in patients affected by primary brain tumors is still very unfavorable. Current pharmacological treatments for brain tumors are also limited by the presence of the blood–brain barrier as a natural obstacle to overcome. Thus, therapies for brain tumors are still limited to date. Nanotechnology offers a way to bypass, in a noninvasive manner, the barrier delivering specific therapeutic compounds. Moreover, nanoparticles drug delivery systems can improve bioavailability and sustain release of drugs for systemic delivery. Interestingly, multifunctional nanoplatforms provide multiple functions in a single compound. These innovative compounds are able to deliver drugs in the optimal dose range, which results in augmented therapeutic efficacy and minimal side effects. In this chapter we will focus on the different types of nanoparticle compounds studied for the treatment of brain tumors. Finally, we will report various preclinical and/or clinical studies in brain tumor treatment.
Success and Failures of Combined Modalities in Glioblastoma Multiforme: Old Problems and New Directions
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Glioblastoma multiforme (GBM) is an aggressive intracranial tumor characterized by local and distant brain relapse despite aggressive therapy. Current standard treatment includes surgical resection followed by radiation with concurrent and adjuvant temozolomide as part of a combined modality approach. In this review, the historical basis for the current standard treatment is discussed as well as other recent combined modality successes and failures. An overview of emerging combined modality therapies for GBM is presented including immunotherapy, and rationally designed radiosensitizers. Unanswered questions facing the oncology community regarding the treatment of GBM are also discussed.
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Preliminary data in 27 patients with glioma WHO IV, suggested additional radiotherapy, 20 Gy, to patients whose tumours showed positive [18F]FDG uptake improved median survival and time to tumour progression.68 Conversely, however, Douglas et al. found no evidence that dose escalation based on [18F]FDG-PET improved patient prognosis in a study of 40 patients.69 PET is capable of non-invasively detecting incorporation of nucleosides into DNA in proliferating cells using labelled thymidine.
The field of neuro-oncology is concerned with some of the most challenging and difficult to treat conditions in medicine. Despite modern therapies patients diagnosed with primary brain tumours often have a poor prognosis. Imaging can play an important role in evaluating the disease status of such patients. In addition to the structural information derived from MRI and CT scans, positron emission tomography (PET) provides important quantitative metabolic assessment of brain tumours. This review describes the use of PET with radiolabelled glucose and amino acid analogues to aid in the diagnosis of tumours, differentiate between recurrent tumour and radiation necrosis and guide biopsy or treatment. [¹⁸F]Fluorodeoxyglucose (FDG) is the tracer that has been used most widely because it has a 2 h half life and can be transported to imaging centres remote from the cyclotron and radiochemistry facilities which synthesise the tracers. The high uptake of FDG in normal grey matter however limits its use in some low grade tumours which may not be visualised. [¹¹C] methionine (MET) is an amino acid tracer with low accumulation in normal brain which can detect low grade gliomas, but its short 20 min half life has limited its use to imaging sites with their own cyclotron. The emergence of new fluorinated amino acid tracers like [¹⁸F]Fluoroethyl-l-tyrosine (FET) will likely increase the availability and utility of PET for patients with primary brain tumours. PET can, further, characterise brain tumours by investigating other metabolic processes such as DNA synthesis or thymidine kinase activity, phospholipid membrane biosynthesis, hypoxia, receptor binding and oxygen metabolism and blood flow, which will be important in the future assessment of targeted therapy.
A phase i dose escalation study of hypofractionated IMRT field-in-field boost for newly diagnosed glioblastoma multiforme
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Citation Excerpt :
Other RTOG trials investigating hyperfractionation (18) or stereotactic radiosurgical boost (19) also found no benefit to dose escalation. More recent studies have likewise shown no added benefit to dose escalation (9–11). The University of Michigan reported 35/36 recurrences within the high-dose central region in patients with malignant astrocytoma who were treated with computed tomography–guided radiotherapy to a dose of 70–80 Gy (9).
To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost.
Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4–5 acute neurotoxicity attributable to radiotherapy.
All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy.
Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

View all citing articles on Scopus

: Supported in part by Grant P01-CA42045 from the National Institutes of Health.

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Clinical investigationBrain[F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: Clinical outcomes and patterns of failure

Introduction

Section snippets

Subjects

Patient characteristics

Discussion

Conclusion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Neuroimaging Clin N Am

Int J Radiat Oncol Biol Phys

FEBS Lett

Combined modality approach to treatment of malignant gliomasRe-evaluation of RTOG7401/ECOG 1374 with long-term follow-up. A joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group

Natl Cancer Inst Monogr

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide

J Clin Oncol

Concomitant and adjuvant temozolomide and radiotherapy for newly diagnosed glioblastoma multiformeConclusive results of a randomized phase III trial by the EORTC Brain and RT Groups and NCIC Clinical Trials Group [Abstract]

Proc Am Soc Clin Oncol

Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy

J Clin Oncol

A phase I dose escalating study of intensity modulated radiation therapy for the treatment of glioblastoma multiforme [Abstract]

Int J Radiat Oncol Biol Phys

Prediction of survival in glioma patients by means of positron emission tomography

J Neurosurg

18-fluorodeoxyglucose uptake and survival of patients with suspected recurrent malignant gliomas

Cancer

Regional glucose metabolism and histopathology of gliomasA study on positron emission tomotherapy-guided stereotactic biopsy

Cancer

Clinical investigation
Brain
[F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: Clinical outcomes and patterns of failure