The Effects of Chemotherapy on the Pediatric Brain

Christine Kim MD1,2, Michael Iv MD2, Kristen W. Yeom MD1

1 Department of Radiology, Pediatric Neuroradiology Section, Lucile Packard

Children’s Hospital, Stanford University, Palo Alto, CA2 Department of Radiology, Stanford University and Stanford University

Medical Center, Stanford, CA

CONTROL # 1791 POSTER # EP-122

DISCLOSURES

No disclosures

BACKGROUND Neurotoxic effects after chemotherapy for malignancies,

such as breast cancer, lymphoma, and acute lymphoblastic leukemia, have been previously described1-14

Management and treatment of cancer may require aggressive chemotherapy regimens, which can produce adverse effects. For example, methotrexate is associated with neurocognitive

deficits and/or leukoencephalopathy.

BACKGROUND The radiologic signs of leukoencephalopathy have been

well established, including increased T2/FLAIR signal intensity in the supratentorial white matter. Diffusion restriction can be seen with acute toxicity.

Studies have shown that the incidence of leukoencephalopathy increases with methotrexate dose, and the risk of developing this adverse effect decreases upon treatment completion15-16.

Leukoencephalopathy After Methotrexate Chemotherapy

BACKGROUND Major depressive disorder and depressive symptoms are of

high prevalence in patients with malignancy.

Post traumatic stress disorder is found with variable prevalence in this population.

BACKGROUND Previous studies in patients with Hodgkin’s disease who

received Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) demonstrated17-18 Significant but transient hypometabolism in the prefrontal

cortex (Brodmann area 10)Early significant reduction of glucose metabolism in the

prefrontal cortex, orbitofrontal cortex (Brodmann area 11), and anterior cingulate cortex (Brodmann area 32)

PURPOSE The purpose of this study was to identify the effects of

chemotherapy on cerebral perfusion in pediatric oncology patients treated with chemotherapy.

Based on prior studies of adult lymphoma patients with altered brain metabolism on PET imaging, we hypothesized that children treated with chemotherapy have abnormal perfusion in the frontal and cingulate cortices.

MATERIALS AND METHODS: SUBJECTS

All pediatric patients presenting to Lucile Packard Children’s Hospital presenting for therapy of acute lymphoblastic leukemia (ALL) or Langerhans cell histiocytosis (LCH) were included in this retrospective study.Patients with ALL received chemotherapy regimens that

included methotrexate.Patients with LCH received chemotherapy regimens that

included prednisone, vinblastine, cytosine arabinoside, 2-chlorodeoxyadenosine, and/or 6 mercaptopurine

Inclusion criteria:Children aged 0-18 years old at the time of ALL or LCH

diagnosisHistory of current or prior chemotherapy treatmentPatients who underwent imaging [MRI with arterial spin

labeling (ASL) imaging at 3 Tesla] for neurologic symptoms or surveillance of underlying pathology

MATERIALS AND METHODS: SUBJECTS

Exclusion criteriaHistory of radiation therapy Patients presenting with other unrelated pathology, such

as infection, stroke, or seizures Normal controls: age-matched controls with no known

pathology were provided from our database

MATERIALS AND METHODS: SUBJECTS

MATERIALS AND METHODS: IMAGING TECHNIQUE

All patients were imaged at 3 Tesla MRI (Discovery 750; GE Medical Systems, Milwaukee, WI) using an eight-channel head coil.  

Imaging included ASL imaging using following parameters19-20:Whole-brain images obtained with 3D background-suppressed

fast-spin-echo (FSE) stack-of-spirals methodTR/TE 4632/10.5, FOV 24cm x 24cm, 512 x 8 matrix, NEX of 3.Pseudocontinous labeling period of 1500 ms, followed by a 1500

ms post-label delay

MATERIALS AND METHODS: IMAGING ANALYSIS

Region of interest method was used to evaluate ASL cerebral blood flow (ml/100 g/min) and performed over the brain regions in the following areas17-

18:

Angular gyrus (Brodmann area 39)

Anterior prefrontal cortex (Brodmann area 10)

Orbitofrontal cortex (Brodmann area 11)

Dorsal anterior cingulate cortex (Brodmann area 32)

Hippocampi (included due to known cognitive deficits associated with chemotherapy)

Quantile (median) regressions were run for each ROI location.

REGIONS OF INTEREST ON ASL CEREBRAL BLOOD FLOW IMAGING

Anterior Prefrontal Cortex Bilateral Angular Gyri Bilateral Dorsal Anterior Cingulate Cortex

Bilateral Hippocampi Bilateral Orbitofrontal Cortex

REGIONS OF INTEREST ON ASL CEREBRAL BLOOD FLOW IMAGING

RESULTS The following number of patients met the inclusion criteria

and were included in the analysis:21 patients with ALL

12 patients had negative conventional MRI findings 9 patients had positive conventional MRI findings,

which included acute or evolving leukoencephalopathy19 patients with LCH33 age-matched control patients

CEREBRAL BLOOD FLOW IN PATIENTS WITH ALL AND LCH COMPARED TO AGE MATCHED CONTROLS

Region of the Brain

Overall CBF Difference in CBF of ALL patients

versus Age Matched Controls

Difference in CBF of LCH patients

versus Age Matched Controls

Difference in CBF of Regions on the

Left Versus the Right

Angular Gyrus 61.3 -5.7 (p=0.144) -9.8 (p=0.018) 1.1 (p=0.737)

Anterior Prefrontal Cortex

70.0 -7.0 (p=0.058) -8.6 (p=0.027) 8.9 (p=0.005)

Dorsal Anterior Cingulate Cortex

62.1 -6.8 (p=0.054) -8.1 (p=0.030) 7.2 (p=0.016)

Hippocampus 51.5 -1.3 (p=0.667) -1.7 (p=0.594) 0.0 (p=1.000)

Orbitofrontal Cortex 69.8 -6.4 (p=0.202) -5.2 (p=0.325) 5.2 (p=0.219)

CBF = cerebral blood flow (mL blood/100g tissue/minute)

COMPARISON OF CEREBRAL BLOOD FLOW FOR LCH, ALL, AND AGE MATCHED

CONTROLS PATIENTS

N = Age matched controls

Orb = Orbitofrontal cortex

Ant = Anterior prefrontal cortex

Dors = Dorsal anterior cingulate cortex

Hipp = Hippocampus

RESULTS SUMMARY

Significantly abnormal perfusion was seen in children treated for chemotherapy in LCH compared to age matched controls in the angular gyrus, anterior prefrontal cortex, and dorsal anterior cingulate cortex.

While no significant perfusion abnormality was detected in children treated for ALL in specific brain regions, wide variability in perfusion was observed in both patients with and without abnormality on conventional MRI compared to age matched controls.

CONCLUSION Our findings suggest altered cerebral perfusion in children

treated with chemotherapy.   This might reflect altered underlying metabolism or

chemotherapy-associated impact on cerebral hemodynamics.  

Future studies that combine cognitive assessment and perfusion changes may further provide insight into role of ASL perfusion in assessing neurotoxic effects in children treated by chemotherapy.

REFERENCES 1. Wefel JS, Lenzi R, Theriault RL, et al.: The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast

carcinoma: results of a prospective, randomized, longitudinal trial. Cancer 100:2292-2299, 2004

2. Tannock IF, Ahles TA, Ganz PA, et al.: Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J Clin Oncol 22:2233-2239, 2004

3. Nolan CP, DeAngelis LM: Neurologic complications of chemotherapy and radiation therapy. Continuum (Minneap Minn) 21:429-451, 2015

4. Scherling CS, Smith A: Opening up the window into "chemobrain": a neuroimaging review. Sensors (Basel) 13:3169-3203, 2013

5. Koppelmans V, Breteler MM, Boogerd W, et al.: Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol 30:1080-1086, 2012

6. Mahoney DH, Jr., Shuster JJ, Nitschke R, et al.: Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy--a Pediatric Oncology Group study. J Clin Oncol 16:1712-1722, 1998

7. Parasole R, Petruzziello F, Menna G, et al.: Central nervous system complications during treatment of acute lymphoblastic leukemia in a single pediatric institution. Leukemia & Lymphoma 51:1063-1071, 2010

8. Langer T, Martus P, Ottensmeier H, et al.: CNS late-effects after ALL therapy in childhood. Part III: neuropsychological performance in long-term survivors of childhood ALL: impairments of concentration, attention, and memory. Medical & Pediatric Oncology 38:320-328, 2002

9. Pui CH, Howard SC: Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol 9:257-268, 2008

REFERENCES 10. Buizer AI, de Sonneville LM, Veerman AJ: Effects of chemotherapy on neurocognitive function in children with acute

lymphoblastic leukemia: a critical review of the literature. Pediatr Blood Cancer 52:447-454, 2009

11. Duffner PK, Armstrong FD, Chen L, et al.: Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group. J Pediatr Hematol Oncol 36:8-15, 2014

12. Gross-King M, Booth-Jones M, Couluris M: Neurocognitive impairment in children treated for cancer: how do we measure cognitive outcomes? J Pediatr Oncol Nurs 25:227-232, 2008

13. Anderson FS, Kunin-Batson AS: Neurocognitive late effects of chemotherapy in children: the past 10 years of research on brain structure and function. Pediatr Blood Cancer 52:159-164, 2009

14. Robinson KE, Livesay KL, Campbell LK, et al.: Working memory in survivors of childhood acute lymphocytic leukemia: functional neuroimaging analyses. Pediatr Blood Cancer 54:585-590, 2010

15. Reddick WE, Glass JO, Helton KJ, et al.: Prevalence of leukoencephalopathy in children treated for acute lymphoblastic leukemia with high-dose methotrexate. AJNR Am J Neuroradiol 26:1263-1269, 2005

16. Bhojwani D, Sabin ND, Pei D, et al.: Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 32:949-959, 2014

17. Chiaravalloti A, Pagani M, Cantonetti M, et al.: Brain metabolic changes in Hodgkin disease patients following diagnosis and during the disease course: An F-FDG PET/CT study. Oncol Lett 9:685-690, 2015

18. Chiaravalloti A, Pagani M, Di Pietro B, et al.: Is cerebral glucose metabolism affected by chemotherapy in patients with Hodgkin's lymphoma? Nucl Med Commun 34:57-63, 2013

REFERENCES 19. Dai W, Garcia D, de Bazelaire C, et al.: Continuous flow-driven inversion for arterial spin labeling using pulsed radio frequency

and gradient fields. Magn Reson Med 60:1488-1497, 2008

20. Buxton RB, Frank LR, Wong EC, et al.: A general kinetic model for quantitative perfusion imaging with arterial spin labeling. Magn Reson Med 40:383-396, 1998