This research paper presents clinical outcomes of hypofractionated high-dose irradiation by intensity-modulated radiation therapy (Hypo-IMRT) with 11C-methionine positron emission tomography (MET-PET) data for the treatment of glioblastoma multiforme (GBM). A total of 45 patients with GBM were treated with Hypo-IMRT after surgery. Gross tumor volume (GTV) was defined as the area of enhanced lesion on MRI, including MET-PET avid region; clinical target volume (CTV) was the area with 5 mm margin surrounding the GTV; planning target volume (PTV) was the area with 15 mm margin surrounding the CTV, including MET-PET moderate region. Hypo-IMRT was performed in 8 fractions; planning the dose for GTV was escalated to 68 Gy and that for CTV was escalated to 56 Gy, while keeping the dose delivered to the PTV at 40 Gy. Concomitant and adjuvant TMZ chemotherapy was administered. At a median follow-up of 18.7 months, median overall survival (OS) was 20.0 months, and median progression-free survival was 13.0 months. The 1- and 2-year OS rates were 71.2% and 26.3%, respectively. Adjuvant TMZ chemotherapy was significantly predictive of OS on multivariate analysis. Late toxicity included 7 cases of Grade 3-4 radiation necrosis. Hypo-IMRT with MET-PET data appeared to result in favorable survival outcomes for patients with GBM.
Glioblastoma multiforme (GBM) is the most common primary malignancy of the adult central nervous system (CNS) and is associated with an exceptionally poor prognosis. Although radiation therapy (RT) has been shown to prolong overall survival (OS) compared to surgery alone [
Recently, new methods have been developed that enable elucidation of the biologic pathways of tumors, yielding additional information about the metabolism of the tumor tissue. Functional imaging studies, such as 11C-methionine positron emission tomography (MET-PET), have demonstrated increased metabolic activity due to increased amino acid transport in glioma cells compared to normal brain tissue [
Herein, we review our preliminary experience of planning and delivery of hypofractionated high-dose irradiation by intensity-modulated radiation therapy (Hypo-IMRT) with complementary use of MET-PET data. This study was designed to measure the acute and late toxicity of patients treated with our regimen, response of GBM to this treatment, OS, and the time to disease progression after treatment.
From April 2006 to July 2011, 45 patients with newly diagnosed GBM were enrolled. Eligibility criteria included histologically confirmed GBM, age ≥18 years, and adequate bone marrow, liver, and renal function. The extent of surgery was evaluated by three observers by viewing postoperative contrast-enhanced T1-weighted MRI images. Gross total resection of the tumor was defined as resection with no residual enhancing tumor. Exclusion criteria included multifocal or recurrent gliomas, involvement of the brainstem or posterior fossa, cerebrospinal fluid dissemination, severe concurrent disease, or prior history of RT or chemotherapy. Patients were grouped according to radiation therapy oncology group (RTOG) recursive partitioning analysis (RPA) class [
Patient's characteristics.
Parameter |
|
---|---|
Age, years | |
≥50 | 37 (82.2) |
<50 | 8 (17.8) |
Gender | |
Male | 28 (62.2) |
Female | 17 (37.8) |
KPS score | |
≥70 | 31 (68.9) |
<70 | 14 (31.1) |
RPA class | |
III | 5 (11.1) |
IV | 23 (51.1) |
V | 5 (11.1) |
VI | 12 (26.7) |
Resection | |
GTR | 17 (37.8) |
Others | 28 (62.2) |
Adjuvant TMZ chemotherapy | |
Yes | 33 (73.3) |
No | 12 (26.7) |
KPS: Karnofsky performance status, RPA: recursive partitioning analysis, GTR: gross total removal, and TMZ: temozolomide.
CT (matrix size:
MRI (matrix size:
The MET-PET study was performed using a standardized procedure. All patients fasted for at least 5 h before MET-PET and were advised to eat only a light breakfast in the morning of the examination day to ensure standardized metabolic conditions. The PET scanner was an ADVANCE NXi Imaging System (General Electric Yokokawa Medical System, Hino-shi, Tokyo), which provides 35 transaxial images at 4.25 mm intervals. The crystal width is 4.0 mm (transaxial). The in-plane spatial resolution (full width at half-maximum) was 4.8 mm, and scans were performed in standard two-dimensional mode. Before emission scans were performed, a 3-minute transmission scan was performed to correct photon attenuation using a ring source containing 68 Ge. A dose of 7.0 MBq/kg of MET was injected intravenously, depending on the exam. Emission scans were acquired for 30 min, beginning 5 min after MET injection. During MET-PET data acquisition, head motion was continuously monitored using laser beams projected onto ink markers drawn over the forehead skin and corrected as necessary. Image registrations were performed with Syntegra software (Philips Medical System, Fitchburg, WI) using a combination of automatic and manual methods. Automatic registration was performed, and three observers evaluated by consensus the fusion accuracy using landmarks such as the eyeball, lacrimal glands, and lateral ventricles.
Postoperative MRI and MET-PET were used along with the treatment-planning CT to define the radiation treatment volume. First, a simulation PET/MRI image fusion was performed for contouring. Secondly, the fusion image was positioned properly by CT scans equipped with tomotherapy (Helical TomoTherapy Hi-Art System, TomoTherapy Inc., Madison, WI). Three layered target volumes were contoured. Gross tumor volume (GTV) was the area of enhanced lesion on MRI, including MET-PET avid region; clinical target volume (CTV) was the area with 5 mm margin surrounding the GTV; planning target volume (PTV) was the area with 15 mm margin surrounding the CTV, including MET-PET moderate region (Figure
An example of the targets planned for a Hypo-IMRT procedure. (a) 11C-Methionine positron emission tomography (MET-PET). (b) Contrast-enhanced T1-weighted magnetic resonance imaging (MRI). Gross tumor volume (GTV) was the area of enhanced lesion on MRI, including MET-PET avid region. Clinical target volume (CTV) was the area with 5 mm margin surrounding the GTV. Both MET-PET moderate region (red line) and the area with 15 mm margin surrounding the CTV (green line) were included in planning target volume. The final determination of target delineation was obtained by consensus among three observers.
Dose map and dose-volume histogram of a representative case. Prescribed doses for gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) were demonstrated.
Patients received concomitant TMZ at a dose of 75 mg/m2 per day during Hypo-IMRT, followed by adjuvant TMZ at a dose of 150–200 mg/m2 per day for 5 days every 28 days, according to the European Organization for Research and Treatment of Cancer-National Cancer Institute of Canada regimen [
Patients were assessed weekly during RT by clinical examination, complete blood count, blood chemistry, and liver enzyme tests. Regular follow-up was performed with serial neurological and radiological examinations at 1 month after completion of treatment and then every 3 months thereafter. Follow-up MRI and MET-PET were routinely conducted every 3 months or in the event of unexpected neurological worsening. When enlargement of the local lesion was observed, corticosteroid therapy was initiated and MRI was performed once a month thereafter to evaluate the efficacy of corticosteroid treatment. If the follow-up MRI revealed further enlargement of the enhanced mass, the lesion was diagnosed as “local progression,” and the day on which MRI first revealed lesion enlargement was defined as the date of progression. However, in cases in which a second surgery revealed no viable tumor cells in the enhanced lesion, the diagnosis was changed to “radiation necrosis.” Lesions that decreased in size during corticosteroid treatment were also defined as “radiation necrosis.” “Distant failure” was defined as the appearance of a new intraparenchymal enhanced lesion distant from the original tumor site. If the new lesion arose distant from the original tumor site and was exposed to the cerebrospinal fluid (CSF) space, the lesion was defined as “CSF dissemination.” Acute and late toxicities were scored according to RTOG criteria.
Survival events were defined as death from any cause for OS and as disease progression for progression-free survival (PFS). OS and PFS were analyzed from the date of pathologic diagnosis to the date of the documented event using the Kaplan-Meier method. Tumor- and therapy-related variables were tested for a possible correlation with survival, using the log-rank test. Variables included Karnofsky performance status (KPS) (≥70 versus <70), RPA class (III, IV versus V, VI), surgery extent (gross total removal versus others), and adjuvant TMZ chemotherapy (yes versus no). The survival benefit was also evaluated by multivariate analysis using Cox’s proportional hazards model.
Patient characteristics are listed in Table
Hematologic toxicity.
Adverse event | Acute phase | Late phase | ||||||
---|---|---|---|---|---|---|---|---|
G 1 | G 2 | G 3 | G 4 | G 1 | G 2 | G 3 | G 4 | |
Neutropenia | 1 (2.2) | 3 (6.7) | 0 (0) | 0 (0) | 0 (0) | 3 (6.7) | 1 (2.2) | 0 (0) |
Thrombocytopenia | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2.2) |
G: grade.
Data presented as number of patients, with percentages in parentheses.
Nonhematologic toxicity.
Adverse event | Acute phase | Late phase | ||||||
---|---|---|---|---|---|---|---|---|
G 1 | G 2 | G 3 | G 4 | G 1 | G 2 | G 3 | G 4 | |
Headache | 3 (6.7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
Nausea/vomiting | 2 (4.4) | 2 (4.4) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
Radiation necrosis | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 5 (11.1) | 2 (4.4) |
Cerebropathy | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2.2) | 0 (0) |
Hemorrhage | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2.2) | 1 (2.2) |
G: grade.
Data presented as number of patients, with percentages in parentheses.
Analysis of prognostic variables for overall survival.
Variables | Median survival (months) | Univariate analysis* |
Multivariate |
---|---|---|---|
KPS | |||
≥70 | 23 | 0.0297 | 0.5994 |
<70 | 15 | ||
RPA-class | |||
III, IV | 23 | 0.1385 | |
V, VI | 13 | ||
Extent of resection | |||
GTR | 25 | 0.0422 | 0.131 |
Others | 13 | ||
Adjuvant TMZ chemotherapy | |||
Yes | 23 | 0.0004 | 0.0124 |
No | 10 |
Abbreviations as in Table
Statistical analyses were performed with
Overall survival (a) and progression-free survival (b) for all patients. Median OS was 20.0 months, and the 1- and 2-year OS rates were 71.2% and 26.3%, respectively. Median PFS was 13.0 months, and the 1- and 2-year PFS rates were 52.6% and 20.6%, respectively.
Overall survival
Progression-free survival
Overall survival rates among different subgroups by (a) Karnofsky performance status (KPS), (b) recursive partitioning analysis (RPA) subclass, (c) extent of surgical resection, and (d) adjuvant temozolomide (TMZ) chemotherapy.
A 56-year-old man of GBM with symptomatic radiation necrosis. Before Hypo-IMRT, enhanced lesions were demonstrated in the right frontal lobe on T1-weighted magnetic resonance imaging (MRI) (a). 11C-Methionine positron emission tomography (MET-PET) demonstrated a MET high-uptake on the region (b). 12 months after Hypo-IMRT, the enhanced lesion with perifocal edema was increased in size (c), although MET uptake decreased in the irradiated region (d). Second surgery was performed, and pathological diagnosis was defined as necrotic tissue without viable tumor cells.
Analysis of prognostic variables for progression-free survival.
Variables | Median survival (months) | Univariate analysis* |
Multivariate |
---|---|---|---|
KPS | |||
≥70 | 20 | 0.0282 | 0.1279 |
<70 | 8 | ||
RPA-class | |||
III, IV | 16 | 0.5895 | |
V, VI | 11 | ||
Extent of resection | |||
GTR | 22 | 0.2004 | |
Others | 11 | ||
Adjuvant TMZ chemotherapy | |||
Yes | 16 | 0.0548 | |
No | 8 |
Abbreviations as in Table
Statistical analyses were performed with
Representative cases of cerebrospinal fluid dissemination: 55-year-old man with GBM. Before Hypo-IMRT, an enhanced tumor was demonstrated in the left temporal lobe on T1-weighted magnetic resonance imaging (MRI) (a). 11C-Methionine positron emission tomography (MET-PET) demonstrated a MET high-uptake region in the left temporal lobe (b). 20 months after Hypo-IMRT, the enhanced tumor was decreased in size (c), and the MET high-uptake region could not be detected distinctly (d), although disseminated lesion was observed around the left lateral ventricle (e).
Lately, much work has been performed on various hypofractionation regimens and dose escalation with Hypo-IMRT for GBM which revealed relatively favorable survival results [
PET is a newer method that can improve the visualization of molecular processes. In one study, several amino acids were radio-labeled to evaluate their potential imaging characteristics in primary brain tumors; such an analysis might be expected to elucidate mechanisms related to either amino acid metabolism or breakdown of the BBB [
Considering the informative results of these recent trials, MET-PET might have substantial reliability as a marker of tumor biological characteristics, as well as a valuable impact on visualizing the tumor-invasive area of malignant glioma. Previously, we reported three preliminary cases of GBM treated by Hypo-IMRT with complementary use of MET-PET [
In the special feature of this study, local tumor progression occurred at a lower incidence (25.0%), suggesting that selectively increasing the radiation dose to MET-PET uptake area contributed to better local control of original tumors. Meanwhile, the most common type of failure was CSF dissemination (60.7% of all failures). It still remains difficult to prevent CSF dissemination for extended periods with our regimen, although the original lesion might be well controlled (Figure
Both univariate analysis and multivariate analysis revealed a significant difference in OS between patients who did and did not receive adjuvant TMZ (Table
Late toxicity was more common with this treatment regimen than early toxicity; specifically, the most severe adverse event associated with our regimen was radiation necrosis. Overall, 5 and 2 patients experienced Grade 3 and Grade 4 radiation necrosis, respectively, and necrotomy was required in 2 patients (Figure
Our preliminary study demonstrated that Hypo-IMRT with complementary use of MET-PET data appeared to result in favorable survival outcomes for patients with GBM, although a properly designed randomized trial could firmly establish whether the present regimen is superior to the standard treatment.
The authors report no conflict of interests concerning the materials or methods used in this study or the findings specified in this paper.