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Nuclear Medicine Communications:
doi: 10.1097/MNM.0b013e32835aa7de
Original Articles

Is cerebral glucose metabolism affected by chemotherapy in patients with Hodgkin’s lymphoma?

Chiaravalloti, Agostinoa; Pagani, Marcoc,e; Di Pietro, Barbaraa; Danieli, Robertaa; Tavolozza, Marioa; Travascio, Lauraa; Caracciolo, Cristiana R.a; Simonetti, Giovannia; Cantonetti, Mariab; Schillaci, Orazioa,d

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Author Information

Departments of aBiopathology and Diagnostic Imaging

bHematology, University Tor Vergata

cInstitute of Cognitive Sciences and Technologies, CNR, Rome

dIRCCS Neuromed, Pozzilli, Italy

eDepartment of Nuclear Medicine Karolinska Hospital Stockholm, Sweden

Correspondence to Agostino Chiaravalloti, MD, Department of Biopathology and Diagnostic Imaging, University Tor Vergata, Viale Oxford 81, 00173 Rome, Italy Tel: +39 062 090 2418; fax: +39 062 090 2469; e-mail: agostino.chiaravalloti@gmail.com

Received June 2, 2012

Accepted September 22, 2012

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Abstract

Objective: The aim of the study was to investigate the effect of chemotherapy treatment with ABVD on brain glucose metabolism in patients with Hodgkin’s disease (HD).

Methods: A total of 49 patients (23 men, 26 women; mean age 32±9 years) diagnosed with HD were included in the study. All of them underwent a baseline (PET0) and an interim (PET2) 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) PET/computed tomography (CT) brain scan. All patients were treated after PET0 with two cycles of ABVD consisting of doxorubicin (adriamycin), bleomycin, vinblastine, and dacarbazine for 2 months. Thirty-five patients were evaluated further 15±6 days after four additional cycles (PET6). Differences in brain 18F-FDG uptake were analyzed by statistical parametric mapping (SPM2).

Results: Compared with PET0, PET2 showed a significantly higher metabolic activity in the right angular gyrus (Brodmann area 39) and a significant metabolic reduction in Brodmann areas 10, 11, and 32 bilaterally. All these changes disappeared at PET6.

Conclusion: Our results support the conclusion of a very limited impact of ABVD chemotherapy on brain metabolism in patients with HD.

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Introduction

Hodgkin’s disease (HD) is a lymphoproliferative disorder that presents newly in over 8400 individuals annually in the USA, accounting for ∼8.7% of all lymphomas in the USA, and is diagnosed worldwide in ∼635 000 individuals every year 1.

In common clinical routine, adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy (CHT) 2,3 is a widely used treatment modality of which the most important mechanism of action is the induction of oxidative stress in cancer tissues by increasing reactive oxygen species and reactive nitrogen concentrations 4, which in turn are responsible for treatment response and injuries to nontargeted tissues, respectively 4. ABVD has been shown to be less toxic than mustargen, oncovin, procarbazine, and prednisone (MOPP) 5 and bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine (oncovin), procarbazine, and prednisone (BEACOPP) regimens 6. The integration of ABVD with radiation therapy increases efficacy and allows the radiation field and dose to be reduced, leading to widespread use of the combined approach in patients with early-stage HD and to a favorable prognosis 7,8. Moreover, prospective multicentric randomized controlled trials have shown that ABVD is superior to MOPP treatment, whereas the intensive escalated BEACOPP regimen has given results that indicate superiority over ABVD for control of HD 9.

Recent studies have shown that the principal short-term toxic effect of ABVD treatment is represented by neutropenia and hair loss 7,8, whereas skin and lung complications have been reported only in a few patients 7–10.

To the best of our knowledge, to date no study has been carried out to investigate the possible effect of ABVD on brain metabolism. Side effects such as nausea and vomiting have been described 7, but they can be considered a consequence of systemic effects even in the presence of reported neurotoxicity for these compounds 11,12; in addition, a recent study hypothesized that adriamycin could be toxic to cortical neurons at therapeutic concentrations as well 11.

While investigating brain functional alterations in cancer patients, especially in young patients, one should take into account the fact that cancer is often a severe and life-threatening disease for which treatment may be harmful and results may be uncertain 13 and that major depression or depressive symptoms have a high prevalence in these patients 13,14. It has been reported that 50% of patients will present day-to-day stress or response to crisis, whereas the remaining 50% will present adjustment disorders with symptoms of depression or anxiety, among whom 20% will have major depressive episodes 15. Together with a CHT neurotoxicity, these factors could affect cerebral glucose metabolism as well 4,16–18. The aim of the study was to investigate a possible impact of ABVD CHT on cerebral glucose metabolism, evaluating brain 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) uptake in 49 patients with HD at the moment of diagnosis and after two ABVD cycles. Moreover, 35 of them with a negative interim PET/computed tomography (CT) scan were evaluated after four additional ABVD cycles. Because of the exploratory nature of our study, the functional results of our data will be investigated in the light of the above disease and treatment issues.

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Materials and methods

Patients

From September 2008 to April 2010, 49 consecutive patients (23 men and 26 women, mean age 32.4±9.2 years) with biopsy-proven HD, included in a national protocol evaluating the early treatment response to ABVD CHT 19, underwent an 18F-FDG PET/CT brain scan using a three-dimensional (3D)-mode standard technique 20 contextually to a whole-body-staging PET/CT study. Data on educational level and occupation were also collected (Table 1). Twenty-seven patients were of HD stage II, seven were of stage III, and 15 were of stage IV according to the Ann Arbor criteria 21.

Table 1
Table 1
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All patients underwent the first PET/CT scan (PET0) within 1 week of the diagnosis of the disease. A second PET/CT scan was performed 15±5 days after the first two ABVD cycles 22–24 (PET2). Four CHT cycles were started a week after PET2 in 35 patients in whom a negative PET/CT scan for disease recurrence was found (18 women and 17 men, mean age 32±9.3). They were further evaluated 15±6 days after the four additional 1-month ABVD cycles for a total of six cycles (PET6) 22–24.

Patients with diabetes, other oncological or HIV histories, neurological, psychiatric, or mood disorders, or with a history of surgery, radiation, or trauma to the brain were excluded from the study. Moreover, we did not consider patients undergoing treatment with drugs that could interfere with 18F-FDG uptake and distribution in the brain 16. No patient was suffering from liver or renal diseases, nor was any patient pregnant or breastfeeding. Written informed consent was obtained from all patients in accordance with the Declaration of Helsinki.

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Treatment protocol

Cycles were repeated every 28 days. A cycle of treatment consisted of 25 mg/m2 doxorubicin intravenously for 1 day, 10 000 U/m2 bleomycin for 1 day, 6 mg/m2 vinblastine for 1 day, and 375 mg/m2 dacarbazine for 1 day (dose intensity 100%, regardless of blood count).

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PET/CT scanning

The PET/CT system Discovery ST16 (GE Medical Systems, Tennessee, USA) was used to assess 18F-FDG distribution in all patients by means of a 3D-mode standard technique in a 128×128 matrix. Filtered back projection was used for image reconstruction. The system combines a high-speed ultra 16-detector-row (912 detectors per row) CT unit and a PET scanner with 10 080 bismuth germanate crystals in 24 rings (axial full-width at half-maximum 1-cm radius, 5.2 mm in 3D mode, axial field of view 157 mm). All patients fasted for at least 5 h before intravenous injection of 18F-FDG; the serum glucose level was up to 120 mg/ml in all of them. Patients were injected intravenously with 3 MBq/kg (210–350 MBq) of 18F-FDG and hydrated with 500 ml of saline (0.9% sodium chloride).

18F-FDG was injected in a dedicated room for each patient with the light turned off. All patients were required to remain in a resting condition with their eyes closed before the PET/CT scan. A brain PET/CT scan was taken before the whole-body PET/CT scan 45 min after 18F-FDG injection by placing the patient’s head in a dedicated support. A low-amperage CT scan of the head for attenuation correction (40 mA; 120 kV) was taken before PET image acquisition. The duration of the brain PET image set acquisition was 15 min in all the patients.

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Statistical analysis

Differences in brain 18F-FDG uptake were analyzed using statistical parametric mapping (SPM2; Wellcome Department of Cognitive Neurology, London, UK) implemented in Matlab 6.5 (Mathworks, Natick, Massachusetts, USA). PET data were subjected to affine and nonlinear spatial normalization into the Montreal Neurological Institute space. The spatially normalized set of images were then smoothed with a 12 mm isotropic Gaussian filter to blur individual variations in the gyral anatomy and increase the signal-to-noise ratio. Images were globally normalized using proportional scaling to remove confounding effects on global cerebral glucose consumption changes, with a masking threshold of 0.8. The resulting statistical parametric maps (SPM{t}) were transformed into normal distribution (SPM{z}) units. SPM coordinates were corrected to match the Talairach coordinates by the subroutine implemented by Matthew Brett (http://www.mrc-cbu.cam.ac.uk/Imaging). Brodmann areas (BAs) were then identified at a range of 0–3 mm from the corrected Talairach coordinates of the SPM output isocenters, after importing the corrected coordinates, using a Talairach client (http://www.talairach.org/index.html). Following on the argument by Bennett et al. 25, SPM t-maps were thresholded at P-values less than 0.05, corrected for multiple comparisons with the false discovery rate option at the voxel level, and at P-values less than 0.01, corrected for multiple comparisons at the cluster level. Because of the explorative nature of the study, when statistically significant differences were not found at such conservative thresholds, a height threshold of P-value less than 0.001 uncorrected at the voxel level was set. Only those clusters containing more than 125 (5×5×5 voxels, i.e. 11×11×11 mm) contiguous voxels were accepted as significant on the basis of the calculation of the partial volume effect resulting from the spatial resolution of the PET camera (about the double of full-width at half-maximum). The voxel-based analyses were performed using a ‘two conditions: one scan/condition, paired t-test’ design model. The following comparisons were assessed: (i) PET0 versus PET2 and vice versa and (ii) PET0 versus PET6 and vice versa. Two-way analysis of variance was used to assess differences in sex and age. Differences in educational level and occupation were analyzed using Fisher’s exact test. A hypothesis was considered valid when the P-value was less than or equal to 0.05.

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Results

Table 1 summarizes the sociodemographic variables of the patients. Figure 1 shows an example of a brain 18F-FDG PET/CT scan at the three stages of the disease course. In all patients a negative PET/CT brain scan was found by visual examination at PET0 and after two ABVD treatment cycles (PET2), and all of them were found to be disease free for more than 12 months after the second scan (PET2).

Fig. 1
Fig. 1
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When PET2 data were subtracted from PET0 a highly significant hypometabolic area including a large portion of the prefrontal and orbitofrontal cortices (BAs 10, 11), bilaterally, and of the left anterior cingulate cortex (BA 32) was found. Compared with PET0 scans, PET2 scans showed a significantly higher 18F-FDG uptake distribution in the right angular gyrus (BA 39; Figs 2 and 3; Table 2).

Fig. 2
Fig. 2
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Fig. 3
Fig. 3
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Table 2
Table 2
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The 18F-FDG uptake distribution changes found during PET2 disappeared during PET6, in which no significant changes at any explored statistical threshold were found in either analysis.

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Discussion

The most noteworthy result of the study was significant hypometabolism in the prefrontal cortex after the first two CHT cycles that disappeared at the end of the therapy 6 months after diagnosis. Early significant reductions in brain glucose metabolism were found in BA 10 [the prefrontal cortex (PFC)], BA 11 [the orbitofrontal cortex (OFC)], and BA 32 [the anterior cingulate cortex (ACC)] whose functions were previously reported to be affected by CHT 26,27.

Studies evaluating PFC and OFC processing have reported an important role of these structures in mood disorders 18. Some functional imaging analyses of patients with major depressive disorders (MDDs) found either an increased or a decreased cerebral blood flow (CBF) or metabolism in BAs 10 and 32, even though increased CBF or metabolism at rest in these areas was the prevalent result 18. In particular, BA 32 is considered an integral part of the ventral ‘emotion’ circuit and together with BA 10 has been implicated in affective illness 18. Several functional imaging studies, with few exceptions, demonstrate hypometabolism in the PFC of patients with primary and secondary depression, with severity of depression often correlating with the degree of frontal inactivity 28. These studies imply that dysfunction of PFC, particularly with respect to its role in modulating limbic activity, could produce many of the symptoms seen in clinical depression 28. One of the most cited studies investigating the prevalence of mood disorders in patients with cancer diagnosis has been conducted by Harter et al. 14. In a population of 517 patients, mostly women with breast cancer, the prevalence rate of mental disorders was estimated at 56.5% over their lifetime. Notably, they found that the current prevalence rates of affective and anxiety disorders were ∼25–33% higher than the prevalence rates found in the general population 14.

In contrast, it has been reported that a variable percentage (from 34% to 80%) of patients are likely to encounter individual post-traumatic stress disorder (PTSD) symptoms following cancer diagnosis 29,30. Since its introduction in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 31, PTSD has been increasingly diagnosed as an additional morbidity in cancer patients 32. In oncologic patients, diverse potential traumatic experiences occur during the course of the illness, ranging from detection of symptoms, disclosure of diagnosis to palliative care. Moreover, treatment procedures involve constant interaction with potential trauma-related stressors 32. In their study conducted on 127 postsurgery patients for breast cancer and at 6-month follow-up, Mehnert and colleagues concluded that the diagnosis of breast cancer itself, as well as the overwhelming feelings of uncertainty about the future, was most frequently perceived as traumatic 32. In this paper 18.5% of women presented symptoms related to PTSD 1 week after diagnosis and considered the disease to be significantly less threatening 6 months later 32.

The possible presence of acute (lasting up to 3 months) PTSD in our patients could explain the findings of a temporarily reduced brain glucose metabolism in the PFC and ACC and an increased metabolism in the right parietal region.

A malfunction in the networks located in the medial PFC 16 and in the OFC 17 is associated with PTSD symptoms and the reports of PTSD-associated alterations within these regions have shown a decrease in blood flow, especially in comparison with controls without PTSD 17. A reduction in gray matter volume (GMV) has also been reported in anterior PFC and ACC of patients with PTSD 33. In particular, Hakamata and colleagues compared GMV in cancer survivors with PTSD, in those without PTSD, and in healthy individuals using voxel-based morphometry. The authors found that the GMV of the right OFC was significantly smaller in cancer survivors with PTSD in comparison with controls 33.

Moreover, by means of perfusional SPECT, regional CBF in right parietal regions was higher in PTSD patients than in healthy controls 33,34. In agreement with these previous findings we found a significantly higher 18F-FDG uptake distribution in the right inferior parietal lobule in PET2 as compared with PET0. The reported alterations in the inferior parietal lobule have been related to increased attention or fear response when under stress associated with PTSD 35. It has to be emphasized that our results were obtained on comparing a brain PET/CT scan soon after cancer diagnosis, which is considered to be a traumatic event 29,30, with the PET scan obtained 2 and 6 months after disease diagnosis, whereas most of the previously cited studies evaluated brain functions in patients with long-standing exposure to traumatic events 35.

These unexpected changes are in agreement with the findings of previous neuropsychological studies on cancer patients in which the impairment of brain function induced by CHT was considered to be transient and related to psychological involvement 36,37. This could be due to a diagnosis of cancer at a young age (mean age of 32 years in our cohort) 29,30, the beginning of CHT treatment, and the onset of symptoms because of its collateral effects 7,8. The normalization of neuronal activity in these areas after six CHT cycles represents a return to ‘basal’ conditions and is associated with a general improvement in the disease because of CHT (i.e. the disappearance of a massive lymph node swelling that is common in HD). All the patients examined by PET6 presented a negative PET2 scan that is related to a high disease-free survival rate in patients with HD 21–23. This observation has already been reported by some authors who concluded that there is a decrease in PTSD rates over time (6–12 months) 32.

In contrast, possible anxiety states related to PET/CT examinations should be taken into account and could have partially affected our results. During the ‘resting state’ and in clinical studies that do not imply brain activations, each individual is actually processing information and elaborating on concepts and sensations. This may impact brain metabolism and blood flow. In our study the different physical and psychological states at the time of PET/CT, related both to CHT treatment and to patients’ expectations and worries about the clinical outcome, could have been responsible for the different metabolic patterns. However, larger regional metabolic differences were found between PET0 and PET2, with a high level of anxiety expected in both cases: for the recent diagnosis along with the uncertainty related to the stage of the diseases during PET0 and for the anxiety related to therapeutic outcome during PET2.

Furthermore, before the PET6 examination, there could still be a state of anxiety related to the possibility of disease recurrence. These assumptions are for the time being speculative, as the present study was limited to functional findings and aimed at evaluating the possibility of any brain alterations in patients treated with the ABVD scheme. Hence, its main limitation is the lack of a neuropsychological evaluation after disease diagnosis and during treatment. It will be necessary for future studies to include longitudinal assessments of neuropsychological performance before the administration of systemic therapies, as well as an appropriate follow-up. In addition, a control group of healthy individuals could lend further support to the data.

The hypothesis of cellular damage in BAs 10, 11 and 32 should also be considered as this could have been responsible for the reduced brain glucose metabolism in these areas after the first two cycles of CHT. However, the comparison of PET0 (before chemotherapy administration) with PET6 (after six ABVD cycles) did not show any significant difference in 18F-FDG distribution, but in the case of a CHT brain-induced damage a diffuse and not limited reduced brain glucose metabolism at a cortical and subcortical level can be expected in this comparison. This finding contradicts the dose-dependent permanent brain damage induced by this CHT and demonstrates restoration of normal metabolism in PFC and OFC at the end of therapy.

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Conclusion

Brain glucose metabolism does not seem to be permanently affected in patients with HD treated with the ABVD scheme. Our findings suggest that a psychiatric condition (i.e. PTSD-like disorder) may affect these patients after disease diagnosis. Further studies with both functional and morphological data (i.e. MRI voxel-based analysis), along with a neuropsychological or psychiatric evaluation, are necessary to confirm this hypothesis.

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Acknowledgements

The authors thank Emanuela Enrico for editing the English used in this article.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

ABVD; chemotherapy; chemobrain; depression; Hodgkin’s disease; post-traumatic stress disorder

© 2013 Lippincott Williams & Wilkins, Inc.

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