Clinical investigation: Brain
Radiotherapy treatment planning and long-term follow-up with [11C]methionine PET in patients with low-grade astrocytoma

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Abstract

Purpose: To evaluate the feasibility of [11C]-methionine positron emission tomography (MET PET) in radiotherapy (RT) treatment planning and long-term follow-up in patients with low-grade glioma.

Patients: Thirteen patients with low-grade astrocytoma and 1 with anaplastic astrocytoma underwent sequential MET PET and magnetic resonance imaging (MRI) before and 3, 6, 12, and 21–39 months after RT, respectively. Ten patients were studied after initial debulking surgery or biopsy and 4 in the recurrence phase.

Methods: A total of 58 PET scans were performed. After transmission scanning, a median dose of 425 MBq of MET was injected intravenously and emission data was acquired 20 min after injection for 20 min. The uptake of MET in tumor area was measured as standardized uptake value (SUV) and tumor-to-contralateral brain SUV ratios were generated to assess irradiation effects on tumor metabolism. Functional imaging with PET was compared with concurrent MRI in designing the RT planning volumes and in assessment of response to RT during a median follow-up time of 33 months.

Results: In 12 patients (86%), tumor area was clearly discernible in the baseline PET study. In the remaining 2 patients with a suspected residual tumor in MRI, PET showed only a diffuse uptake of MET interpreted as negative in the original tumor area. In the dose planning of RT, MET PET was helpful in outlining the gross tumor volume in 3 of 11 cases (27%), whereas PET findings either coincided with MRI (46%) or were less distinctive (27%) in other cases. In quantitative evaluation, patients with a low tumor SUV initially had significantly better prognosis than those with a high SUV. Tumor-to-contralateral brain uptake ratios of MET discriminated well patients remaining clinically stable from those who have since relapsed or died of disease.

Conclusion: Quantitative MET PET has prognostic value at the time of initial treatment planning of low-grade glioma. Some patients may benefit of RT volume definition with MET PET, which seems to disclose residual tumor better than MRI in selected cases. Stable or decreasing uptake of MET in tumor area after RT during follow-up seems to be a favorable sign.

Introduction

Low-grade gliomas often affect relatively young and otherwise healthy people. The onset of symptoms is often slow and inconspicuous and diagnosis can be delayed over several months or even years. Reported 5-year survival rates varies between 35% and 60%, but some patients may live considerably longer (1). Usually these tumors show intact blood–brain barrier and they typically lack contrast enhancement on computed tomography (CT) and less commonly on magnetic resonance imaging (MRI). Histopathological diagnosis is established through stereoguided biopsies or histology of resected tissue after open surgery, but sometimes it is difficult to obtain representative sample of viable tumor cells. Clearly, these tumors may demarcate poorly and local treatment design is problematic (2) because both astrocytomas and oligodendrogliomas tend to infiltrate diffusely into the surrounding and seemingly normal or edematous brain tissue.

Standard treatment of low-grade astrocytomas consists of surgical debulking whenever possible (3). The complete resection of Grade II gliomas is more easily achieved in small tumors, and this may reduce the probability of recurrence and malignant transformation (4). The use of immediate postoperative radiotherapy (RT) is highly controversial because sometimes tumors have a very slow progression and problems related to late toxicity to normal brain tissue may be substantial. Limited-field radiation is always preferred, because most recurrences are local. From a survival viewpoint, RT seems to be of value and, given early, may postpone development of recurrence 5, 6. The studies conducted by the European Organization for Research and Treatment of Cancer (EORTC) and other investigators, however, have raised questions on the appropriate dose and timing of radiation, because no survival difference could be demonstrated among those irradiated early and those who received RT once the tumor started to progress 7, 8. As results from the ongoing quality-of-life evaluation of the EORTC study mature, these questions may ultimately find an answer.

Early detection of recurrent glioma is difficult with morphological imaging techniques, especially in irradiated patients. MRI and CT cannot easily differentiate between tumor and postoperative or radiotherapy changes, which may persist over several months after initial treatment. The distinction is important because recurrent tumors may sometimes be reoperated succesfully or receive further irradiation by conformal radiotherapy techniques or with radioactive implants. Moreover, chemotherapy has been advocated as a treatment of choice for recurrent oligodendrogliomas and should be considered also for patients whose tumors have progressed to anaplastic astrocytomas 9, 10.

Positron emission tomography (PET) has been used now for 2 decades to assess cerebral metabolism of patients with gliomas. Di Chiro et al. (11) concluded in their classical study that glioma metabolism, as measured with 18F-2-fluoro-2-deoxy-D-glucose (FDG) and PET reflected survival better than histological classification. The same authors showed the usefulness of FDG PET for detection of recurrent glioma after radiation or chemotherapy (12). FDG has not, however, gained uniform acceptance as a tracer of choice for PET studies of patients with brain tumors. The major drawback is the high physiological uptake of FDG in normal gray matter, which may compromise recognition of the pattern of growth of slowly progressing tumors, as is often the case with low-grade gliomas.

The sensitivity of L-methyl-[11C]methionine (MET) PET for detection of gliomas tumors appears to be very high (13), although there have been occasional false-negative findings in low-grade tumors 14, 15. Mosskin et al. (16) demonstrated that MET accumulation was high in all of 9 contrast-enhancing high-grade tumors and in 22 of 25 low-grade tumors that had a low attenuation in CT. Other studies have indicated that the use of MET could improve diagnosis especially in low-grade gliomas, even if their glucose consumption as measured by FDG would be low (17). Analogously to FDG, MET PET appears to have potential in detection of recurrence (18), and later studies have suggested that MET indeed improves the accuracy of PET, as compared with FDG, in the differential diagnosis of recurrent brain tumors (19). Because MET uptake by the normal brain parenchyma is relatively low, MET PET shows promise in assessment of cerebral tumor dimensions (20). It has been suggested that MET PET may outline more precisely the true extent of viable tumor tissue than MRI, whereas MRI has the capability to delineate better the total extent of associated pathologic changes, such as edema, in the adjacent brain (21).

Knowledge of the presence of residual viable tumor would be potentially advantageous both in the planning of postsurgical treatment and during the follow-up phase for demonstration of progressive disease. Bearing this in mind, we evaluated the clinical usefulness of MET PET vs. MRI in follow-up of patients with low-grade astrocytoma. First, we studied whether MET PET provides any additional information to MRI in volume definition for radiation treatment planning, and, second, we assessed long-term effects of irradiation on MET metabolism to study the sensitivity of MET PET for detection of glioma progression.

Section snippets

Patients and tumor characteristics

Fourteen patients, of which 13 had low-grade astrocytomas and one anaplastic astrocytoma, were admitted to the Department of Oncology and Radiotherapy at Turku University Central Hospital between June 1995 and March 1997 and agreed to participate in this study. All patients gave a written informed consent, and the study protocol was approved by the joint Ethical Committee of the University of Turku and Turku University Central Hospital.

The median age of 10 men and 4 women patients was 33 years

Results

The results of individual PET and MRI studies are also presented in detail in Table 2. Comparison of results from analyses using SUV were equal to those using SUVlean and we use, therefore, only SUV in the following account.

Discussion

This study was designed to investigate the potential role of MET PET in planning of RT and follow-up in patients with newly diagnosed or recurrent low-grade astrocytoma. We found increased uptake of MET consistent with residual or recurrent tumor in 12 of 14 patients in the baseline PET study. In the remaining 2 patients with a suspected residual tumor in MRI, PET showed only a diffuse uptake interpreted as negative in the original tumor area. In the dose planning of RT, MET PET was helpful in

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