|Year : 2022 | Volume
| Issue : 1 | Page : 1-7
The effect of prophylactic cranial irradiation on brain 18F-fluorodeoxyglucose uptake in small cell lung cancer in the metabolic imaging era
Sibel Goksel1, Sema Yilmaz Rakici2
1 Department of Nuclear Medicine, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
2 Department of Radiation Oncology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
|Date of Submission||27-Dec-2021|
|Date of Acceptance||21-Jan-2022|
|Date of Web Publication||28-Feb-2022|
Dr. Sibel Goksel
Department of Nuclear Medicine, Faculty of Medicine, Recep Tayyip Erdogan University, Rize
Source of Support: None, Conflict of Interest: None
Introduction: Prophylactic cranial irradiation (PCI) increases survival in patients with small-cell lung cancer. Although the underlying pathophysiology is not fully understood, it has been associated with posttreatment neurocognitive impairment. Our study aims to show the brain's glucose metabolism change after PCI with 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). Materials and Methods: A total of 17 patients who underwent PET/CT before and after PCI were evaluated retrospectively. 18F-FDG PET images of the brain before and after PCI were compared visually and semi-quantitatively using MI-Neurology Software. The brain was automatically segmented into eleven regions by this software. The mean standard uptake values (SUVmean) of all brain regions were measured within the automatically drawn region of interest area, and standard uptake value ratio (SUVR) values were found for each region by taking the brainstem SUVmean value as a reference. SUVR values were calculated from PET/CT scannings taken before and after PCI for each patient. The P < 0.05 value was considered statistically significant in comparisons. Results: We found a significant decrease in 18F-FDG uptake and glucose metabolism of the brain after PCI when compared with PET/CT before PCI in all brain regions identified according to the Combined-AAL atlas (all P < 0.001). Similarly, a significant decrease was found in brain 18F-FDG uptake on PET/CT taken after PCI in the brainstem used to calculate SUVR (P = 0.039). Conclusion: 18F-FDG PET/CT neuroimaging may be a new metabolic imaging technique for diagnosing radiation-induced cognitive impairment in the metabolic imaging era.
Keywords: Brain 18F-fluorodeoxyglucose uptake, metabolic imaging, prophylactic cranial irradiation, small cell lung cancer
|How to cite this article:|
Goksel S, Rakici SY. The effect of prophylactic cranial irradiation on brain 18F-fluorodeoxyglucose uptake in small cell lung cancer in the metabolic imaging era. J Radiat Cancer Res 2022;13:1-7
|How to cite this URL:|
Goksel S, Rakici SY. The effect of prophylactic cranial irradiation on brain 18F-fluorodeoxyglucose uptake in small cell lung cancer in the metabolic imaging era. J Radiat Cancer Res [serial online] 2022 [cited 2022 May 17];13:1-7. Available from: https://www.journalrcr.org/text.asp?2022/13/1/1/338797
| Introduction|| |
Small cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma subtype with a high potential to metastasize and only one-third of the patients have the limited-stage at initial staging.,,
While only 10% of SCLC patients have brain metastases initially, this rate is 50% in the 2-year follow-up. Prophylactic cranial irradiation (PCI) reduces the risk of brain metastasis and increases overall survival in patients with limited-stage who respond well to initial therapy and in patients with the extensive stage who respond well to systemic therapy.,,,
PCI is not performed in half of limited-stage patients because of neurocognitive toxicity., The severity of temporary or permanent neurocognitive impairment is affected by many factors and can range from mild to progressive dementia.,, In a study, patients who were still alive after PCI were evaluated, and it was stated that more than 50% of the patients had neurocognitive disorders. Some areas of the brain are more radiosensitive, and radiation damage changes accordingly. The standard dose for the whole brain for PCI is 25 Gray (Gy) in a 10-day fraction, although the dose can rarely be changed on a case-by-case basis. In a randomized controlled study, patients who received 36 Gy doses had higher mortality and increased neurotoxicity than those who received 25 Gy. The risk of developing neurotoxicity after PCI increases in proportion to the dose. In the literature, there are conflicting results regarding the changes in neurocognitive functions and brain 18F-Fluorodeoxyglucose (18F-FDG) uptake of PCI applications that avoid the hippocampus versus standard PCI.,
Although many neuroimaging studies evaluate PCIs effects on brain structures, there are limited studies on metabolic imaging.,,,,,, In this study, we aim to evaluate the effect of PCI on regional FDG brain glucose metabolism with positron emission tomography/computed tomography (PET/CT) imaging in SCLC patients.
| Materials and Methods|| |
Patients diagnosed with SCLC who underwent PET/CT scanning for staging and underwent PCI were evaluated retrospectively. Patients over 18 diagnosed with SCLC, who had a whole-body PET/CT scan at the initial staging before PCI and who had a restaging PET/CT scan at least 3 months after PCI were included in this study. Patients exclusion criteria are as follows: patients with receiving neoadjuvant or adjuvant treatment before initial PET/CT, no restaging PET/CT imaging after PCI, brain metastasis at initial staging according to magnetic resonance imaging, who moved during CT and PET imaging and had fusion shift at the time of scanning, fasting blood glucose level >200 before PET/CT imaging, history of second malignancy, had previous radiotherapy (RT) or surgery to the brain, a diagnosis of neurocognitive disease or epilepsy, and a history of the cerebrovascular accident.
Patient files and PET/CT images were obtained from the radiation oncology and nuclear medicine clinic and hospital electronic medical records. Staging of all patients was performed as an limited-stage and extensive-stage based on initial PET/CT images. The files and image archives were scanned retrospectively, and the age of the patients, the date of diagnosis, the date of PCI application, the radiation dose given in PCI, the elapsed time between PCI, and restaging PET/CT examination were recorded. The FDG dose and fasting blood glucose levels given to the patients before the initial and restaging PET/CT examination of all patients, the last control dates of the patients, and the survival times were noted.
The study was initiated after approval by the University Hospital Ethics Committee (Approval No. 2021/190) and adhered to the principles of the Declaration of Helsinki.
Positron emission tomography/computed tomography imaging and analysis
All patients were fasted for at least 6 h before PET/CT scan. Before the FDG injection, all patients had fasting blood glucose levels <200 mg/dL. According to the patients' weight, 18F-FDG was injected intravenously at an average dose of 3.7 MBq/kg. PET/CT scans of the patients were performed in three-dimensional (3D) mode on a PET/CT (Siemens Healthineers, Biograph mCT/20 slice) device. All patients rested in low-light and quiet restrooms for an average of 60–70 min after FDG injection until they were taken for PET/CT imaging. A whole-body scan was performed without intravenous contrast material from the vertex to the upper thigh, including the whole brain parenchyma. Low-dose CT data were obtained at a mean dose of 120 kV–50 mA, and PET scanning was performed at 2 min/bed position.
PET/CT scans of all patients before and after PCI were re-evaluated by an experienced nuclear medicine physician for initial staging and restaging. PET images were evaluated both visually and semi-quantitatively. Brain sections of 18F-FDG PET images from the whole body scanning of the patients were evaluated one by one by the program using MI-Neurology Software. The whole-brain parenchyma is automatically divided into 11 regions (frontal cortex, central regions, anterior cingulate cortex, lateral parietal cortex, precuneus/posterior cingulate cortex, medial temporal cortex, lateral temporal cortex, occipital cortex, basal ganglia, corpus striata, brainstem, and cerebellum) using the Combined-AAL Atlas from MI-Neurology Software (Syngo. Via, Siemens) as in similar literature [Figure 1].
|Figure 1: Axial (a), Coronal (b), and Sagittal (c) section of positron emission tomography images and (d) SUVmean, SUVmax and standard uptake value ratio values in the regions determined in both hemispheres according to AAL Atlas|
Click here to view
The mean standard uptake value (SUVmean) was calculated automatically from the region of interest (ROI) drawn in both hemispheres. In the current literature, it has been shown that it is appropriate to use the brainstem as a reference region in 18F-FDG PET brain metabolism studies. Our study used the brainstem SUVmean value as a reference for the normalization of SUVmean values, as suggested in the literature., The standard uptake value ratio (SUVR) was calculated with the following formula: SUVR = SUVmean/Brainstem SUVmean. There were no measurement or segmentation failures since the evaluation was performed with the automated Combined-AAL Atlas from MI-Neurology Software.
All radiation treatments were planned and administered in the same institution. Planning CT cranial area RT plans of the patients were simulated by 3D CT. The standard PCI dose was 25 Gy in a 10-day fraction. It was applied using mutually parallel areas with multi-leaf collimator protection of the eyes, lens, and oral cavity. Treatment planning was based on the Field in Field-intensity-modulated radiation therapy technique. All plans were designed using 6 MV photon rays with Trilogy (Varian Medical System, Palo, CA) EclipseTM treatment planning system version 13.6. According to institutional guidelines, the dose covering 95% (D95) of the planning target volume was at least 95% and not more than 107% of the prescribed dose.
IBM SPSS Statistics (for Windows. Version 22.0. Armonk, NY, IBM Corp.) was used for statistical analysis. The conformity of the variables to the normal distribution was evaluated with the Kolmogorov–Smirnov test. Independent Samples t-test was used for variables showing normal distribution. Mean ± standard deviation values were given for normally distributed variables. We compared the SUVR values with the related-samples wilcoxon signed-rank test. P < 0.05 was considered significant for statistical differences in all statistical methods.
| Results|| |
A total of 17 patients with SCLC who underwent PET/CT scanning before and after PCI were included in this study. The mean age was 63.24 ± 8.40 (range 52–74), and all of the patients were male. Majority of the patients (70.6%) were 60 years or older. Ten (58.8%) patients had the limited-stage, and 7 (41.2%) had the extensive-stage disease. All patients received chemotherapy (etoposide accompanied platinum-based chemotherapeutic agent) before PCI. The characteristics of patients are given in [Table 1].
Most patients (70.6%) died during the follow-up period. The mean follow-up time of all patients was 21.88 ± 10.83 months (range 10–50), and the mean follow-up time after PCI was 14.29 ± 10.37 months (range 4–45).
Although the PCI doses of the patients were at the level recommended by the guidelines, 30 Gy was given to only two patients and 25 Gy to all other patients. The mean planning PCI dose of all patients was 25.59 ± 1.66 Gy. The standard PCI-dose distribution of a patient is as in [Figure 2].
|Figure 2: Standard prophylactic cranial irradiation plans of three-dimensional radiotherapy dose distribution in axial (a), coronal (b), and sagittal (c) sections, and dose-volume histogram of target and normal tissue doses (d) in a patient|
Click here to view
All patients' initial PET/CT examination was taken when they did not receive any chemotherapy or RT. Between PCI and restaging PET/CT, the mean time elapsed after PCI is 145.41 days (range 54–287). It was noted that the time elapsed between PET/CT examination and PCI for restaging after PCI was longer than 3 months. Due to the small number of patients, this period was < 3 months in only two patients. In these two patients, the SUVmean values were partially high in all brain regions, including the brainstem, in restaging PET/CT without statistical difference. It was observed that SUVR values were not different from other patients because the SUVmean value of the brainstem, which was used for normalization in the calculation of the SUVR value, was also partially high.
The administered FDG dose, preextraction fasting glucose level, and the time to scan after FDG injection were similar in PET/CT examinations taken before and after PCI. There was no significant difference between these parameters in PET/CT scans taken before and after PCI. The mean fasting blood glucose level was 109.94 ± 27.82 mg/dL in the first and 108.82 ± 27.94 mg/dL in the second PET/CT (P = 0.705), the mean FDG doses given to the patients at 37 MBq/body weight were 293.82 ± 49.81 MBq in the first and 292.95 ± 49.99 MBq in the second PET/CT (P = 0.813), and the mean waiting time after FDG injection was 65.12 ± 2.83 min in the first and 65.76 ± 3.38 min in the second PET/CT scanning (P = 0.615).
In the semi-quantitative analysis of 11 brain regions determined according to the AAL atlas, the brainstem region, which is also used and recommended in the current literature, was found suitable for normalization. Although there was a significant difference between the mean values of SUV measured before and after PCI of the brainstem, it was used for the normalization region since it is the region least affected by radiation (SUVmean: 4.39 ± 0.68 vs. 4.37 ± 0.82, P = 0.039).
PET/CT examination performed after PCI revealed a decrease in 18F-FDG uptake and metabolism in 11 brain regions determined according to the AAL atlas. We found statistically significant differences between SUVR values of the all regions on PET/CT scanning before and after PCI (all P < 0.001). SUVR values obtained in the first PET/CT and second PET/CT examinations of regions are given in the box plots in [Figure 3].
|Figure 3: Box plots of standard uptake value ratio for basal ganglia, central regions, corpus striatum, frontal cortex, occipital cortex, lateral temporal cortex, cerebellum, medial temporal cortex of the combined-AAL Atlas before and after prophylactic cranial irradiation|
Click here to view
| Discussion|| |
Our study shows that PCI applied to prevent brain metastasis in SCLC patients diffusely reduces brain glucose metabolism.
Studies conducted since the 1920s on the use of substrates in the brain have shown that the brain's primary energy source is carbohydrates. The brain glucose metabolism can be affected by factors such as the time between PCI and PET/CT after PCI FDG dose, received chemotherapy, age, waiting for the time after FDG injection, visual or auditory stimuli during the waiting period in the rest-room, fasting blood glucose level. To make reliable comparisons with PET/CT scans taken before and after PCI, these parameters should be standardized, not patient-specific. Both examinations must be performed with similar characteristics. The parameters such as FDG dose, waiting time, fasting blood glucose level, and receiving chemotherapy were similar in our study's initial and restaging PET/CT scanning. Besides the publications stating that brain glucose metabolism decreases after PCI, a study also reported increasing. In the neurology software program used in this study, the brain was divided into five regions, and the regions in both hemispheres were evaluated separately. Unilateral increase or decrease, as well as bilateral changes, have been reported. Unlike this study, the whole brain is divided into 11 regions ın the neurology software program that we use. Since equal doses were given to both hemispheres, the SUVmean values measured in the ROIs drawn automatically in the regions of both hemispheres were averaged, rather than unilateral evaluation. Another difference between this study and ours is that we used the brainstem less affected by radiation as the normalization value to normalize the mean ROI values plotted in 11 regions and compared the SUVR values in both PET/CT examinations. In this study, it is seen that the measured values were not normalized. Our study found a diffuse decrease in brain glucose metabolism after PCI in all brain regions. Eshghi et al. reported an increase in brain FDG uptake after PCI in some patients in their study but, they did not explain the reason for this increase. There is no data on whether the parameters affecting brain FDG uptake are different in that study. The different results may depend on all these parameters.
The result we obtained in our study is similar to the results given in recent literature. They found a reduction in diffuse FDG uptake in all brain regions except the brainstem in patients who underwent standard PCI. The same MI neurology software program was used with the literature. Similar to our study, there was no difference in PET/CT parameters and patient characteristics before and after PCI. The only difference between our study and this study is that the time between PCI with restaging PET/CT is different. While we performed PET/CT imaging at the earliest 54 and the latest 287 days after PCI, the interval in this study is quite different from ours (min: 21, max: 1516 days). Time to PET/CT scan after PCI may affect brain FDG uptake. We can obtain higher values secondary to inflammation in the early period and lower values in the late period. This period was shorter than 3 months in our two patients. Although there was no statistical difference in these two patients, we observed relatively higher SUVmean values compared to other patients. Although the brainstem is recommended as the least affected region, this may vary patient-by-patient. Due to the limited number of patients, different results, even in one patient, may affect the mean SUVmean value in the brainstem.
All patients received chemotherapy before PCI in our study. Although it is known that chemotherapy reduces brain glucose metabolism, it is the standard treatment method and inevitable for these patients to receive chemotherapy before or after PCI treatment., Although radiation is the main reason for the diffuse 18F-FDG decrease in the brain, chemotherapy may affect this decrease. The decrease in diffuse FDG uptake of the brain in all of our patients may also be associated with the fact that most of our patients are over 60 years of age. A study reported that 83% of patients older than 60 years and 56% of patients younger than 60 years of age developed chronic neurotoxicity 12 months after PCI. In the relationship between neurocognitive function and RT, it can be said that advanced age and high radiation doses are the most determining risk factors for the development of chronic neurotoxicity.
In recent years, 18F-FDG PET/CT has been used in the differential diagnosis of various dementias and cognitive disorders. Since this metabolic imaging technique shows glucose metabolism in the brain, it can contribute to the effects of radiation-induced cognitive impairment and can be applied more frequently in clinical practice. A study showed that 18F-FDG PET/CT could detect regional differences in 18F-FDG uptake in patients who underwent PCI. Because PCI treats the whole brain, diffuse change in the brain parenchyma is likely to occur.
The most important limitation of our study is that it is retrospective, and the number of patients is small. We could not associate the widespread reduction in FDG uptake detected by PET/CT with any neuropsychological test that performs the cognitive assessment. There is a need for prospective studies involving many patients in which neurocognitive tests will be performed together with PET/CT before and after PCI for clinically significant cognitive impairment.
| Conclusion|| |
Our study suggests a diffuse decrease in brain FDG uptake and glucose metabolism after PCI. These changes can be detected with 18F-FDG PET/CT and may guide clinicians in diagnosing radiation-induced neurocognitive deficit. In the follow-up of patients after PCI, both whole-body tumor burden and glucose metabolism of the brain can be evaluated in the same session with whole-body PET/CT imaging and can be informed the clinician about the response of the patients to the treatment. Neurocognitive disorders associated with a decrease in FDG uptake corresponding to high doses in the dose schedule given in RT planning will guide future new PCI planning that will allow dose reduction to these regions.
The authors thank Siemens Healthineers for support for the MI neurology software program.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]