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Evidence-Based Surgery:
Positron-Emission Tomography (PET)
for diagnosis of recurrence in gliomas

                Johnny Wong
               14th April, 2011




                                         1
Case: LB
• 45 year old woman
• Presented with
  dysphasia
• Craniotomy and
  excision of tumour
  (09/10)
• Histology: Anaplastic
  Astrocytoma (WHO III)




                          2
• Post-op dysphasia &
  dysarthria gradually
  resolved
• CATNON trial – XRT
  only
• Significantly
  worsening dysphasia
• MRI & FDG-PET in
  01/11
• Tumour recurrence
  or radiation
  necrosis?


                         3
Clinical Questions:


• What is the sensitivity and specificity of PET in
  diagnosing tumour recurrence in high-grade
  astrocytomas ?

• What is the best imaging modality to differentiate
  tumour recurrence from radionecrosis in
  astrocytomas ?




                                                       4
Search strategy
•   P = Patients with high-grade astrocytoma
•   I = Positron-emission tomography
•   C = Magnetic resonance imaging
•   O = Sensitivity and specificity of diagnosing recurrence
    and radiation necrosis

• Search terms (exp MESH and keywords): Astrocytoma,
  GBM, Positron-emission tomography, recurrence,
  radiation necrosis, “sensitivity and specificity”
          – Limit to English and Humans


                                                               5
Results of
search:

• 17 articles
• 10 useful
articles
• 1 related
• 3 not
accessible
• 3 not
relevant
Results of search: 65 articles, 3 additional articles
3 more
articles
Effects of XRT and chemotherapy
• Radiotherapy
  – Pseudo-progression (Enhancement within 2 months XRT)
  – Radiation necrosis (Enhancement after 3 – 12 months XRT)
  – BBB breakdown / ↑ VEGF expression - ↑ permeability
• Chemotherapy
  – Concommitant XRT and chemo – 3x more likely for
    pseudoprogression
  – Temozolamide sensitivity (MGMT –ve status) – increases
    likelihood of pseudo-progression
  – Avastin – anti-VEGF: increases sensitivity to XRT, decreased
    permeability (less enhancement; increased FLAIR)



                                                                   10
Positron-emission tomography (PET):
• Glucose                       • Amino-acids
  – F18-FDG                       – AA transport and protein
  – Correlation between             synthesis; also in
    grade and glucose               inflammatory cells
    metabolism
  – Difficulty with low-grade     – MET: Methionine (Short
    lesions                         half-life)
  – High baseline in normal       – FET: tyrosine
    cerebral cortex               – FLT: thymidine
  – Sensitivity: 40-86%           – N-NH3: Ammonia
  – Specificity: 22-100%          – FFCho: Choline
                                    (membrane synthesis)
                                  – IMT-SPECT

                                                               11
“Sensitivity and specificity of PET”
• FDG vs MET-PET (Van Laere 2005)
  –   30 patients; both scans on same day.
  –   Gliomas (Grades II-IV astrocytomas, oligos and mixed)
  –   Radiology: recurrence 18/30, necrosis 4/30, unsure 5/30
  –   MET: Increased uptake: 28/30;
       Inter-observer 100%; Sensitivity: 75%; Specificity: 70%; Accuracy: 73%
  – FDG: Increased uptake: 17/30;
       Inter-observer 73% ; Sensitivity: 95%, Specificity: 50%; Accuracy: 80%




                                                                                12
“Sensitivity and specificity of PET”
• FDG vs MET-PET: (Potzi et al.)
   – 28 patients; Histologically confirmed GBM
   – MRI evidence of progression as “recurrence”
      • MET-PET: Sens 89%, Spec 29%, Accuracy: 72%
      • FDG: Sens 11%, Spec 100%, Accuracy: 36%
   – Survival analysis for >12 months:
      • MET-PET: Spec 8%, Accuracy 48%
• Other studies (Tsuyuguchi):
   – Sens: 100%; Spec: 60%
   – Accuracy:82%




                                                     13
“Sensitivity and specificity of PET”
• FET vs MRI (Rachinger et al 2005)
   – 45 patients (32 tissue diagnosis of recurrence; 13 transient
     symptoms)
   – FET: half life 110 mins (vs MET 20 mins)
   – FET-PET: Sensitivity 100%, specificity 92.9%
   – MRI : Sensitivity 93.5%; specificity 50% (p<0.05)




                                                                    14
“Sensitivity and specificity of PET”

• FDG vs 13N-NH3 (Zhang et al, 2007)
   – 8 patients, Gd enhanced lesions
   – FDG and NH3
      • NH3: 100% accuracy (6 recurrences, 2 necrosis)
      • FDG: 75% accuracy (1 FP, 1 FN)




                                                         15
Other modalities – MRS and DWI
• MRI + Gad: Not suitable for diagnosis of
  recurrence, especially after anti-VEGF (Sens and
  spec < 60%).
• DWI: ADC coefficient 1.82 vs 1.43 (P-P vs
  recurrence, p<0.001)
• DTI: Radiation necrosis damages WM tracts vs
  recurrences which displace them.
• MRS: 3-D multi-voxel MRS: 94% sensitivity; 100%
  specificity (28 patients)




                                                     16
Multi-voxel MRS




                  17
The “gold standard” for diagnosis of
recurrence:
• MRI
   – Progression of enhancing lesion
   – Heterogeneity of lesion grades
• Stereotactic biopsy
   – Sampling error
• Survival
   – Confounding from different tumour grades and treatment
     regimens
               Larger studies required


                                                              18
Implications from PET

• MET-PET vs Gad-enhancement (Galldiks et al. 2009)
   –   12 patients; Histologically confirmed GBM
   –   Volumetric study
   –   MET uptake indices: >1.3 vs >1.5 and Gd-enhancement
   –   Active tumour volume: 30.17 vs 13.68 vs 13.7 cm3
   –   MET-PET detects larger tumour volume than the contrast
       enhancement
        • Implication for larger surgical resection margins.

   – ? Higher reoperation rates because of higher
     sensitivity and low specificity.



                                                                19
20
Latest follow-up

                   • Commenced on
                     Avastin
                     (Bevacizumab) and
                     Temodal
                     (Temozolomide)
                   • Good improvement
                     clincially and
                     radiologically




                                         21
References
1.   Yang I, Aghi M. New advances that enable identification of glioblastoma
     recurrence. Nat. Rev. Clin Oncol 6:648-657, 2009.
2.   Potzi C, Becherer A, Marosi C et al. 11C Methionine and 18F
     Fluorodeoxyglucose PET in the follow up of glioblastoma mutliforme. J.
     Neurooncol 84:305-314, 2007
3.   Galldiks N et al. Volumetry of 11C-Methionine PET uptake and MRI contrast
     enhancement in patients with recurrent glioblastoma multiforme. Eur J Nucl
     Med mol Imaging 37:84-92, 2010
4.   Zhang XS, Chen W. Differentiation of recurrent astrocytoma from radiation
     necrosis: a pilot study with 13N-NH3 Pet. J. Neurooncol 82:305-311, 2007
5.   Rachinger W et al. Positron Emission tomography with O218F Fluroethyl L
     tyrosine versus magnetic resonance imaging in the diagnosis of recurrent
     gliomas. Neurosurg 57:505-511, 2005.




                                                                                  22
6.   Van Laere et al. Direct comparison of 18F-FDG and 11C-Methionine PET in
     suspected recurrence of glioma: sensitivity, interobserver variability and
     prognostic value. Eur J. Nucl Med Mol Imaging 32:39-51, 2005
7.   Tsuyuguchi et al. Methionine positron emission tomography for differentiation
     of recurrent brain tumour and radiation necrosis after stereotactic radiosurgery
     in malignant glioma. Annals Nucl Med 18:291-296, 2004
8.   Mertens et al. PET with 18F-labelled choline based tracers for tumour imaging:
     a review of the literature. Eur J. Nucl. Med Mol Imaging 37:2188-2193, 2010.




                                                                                        23

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Pet and gbm

  • 1. Evidence-Based Surgery: Positron-Emission Tomography (PET) for diagnosis of recurrence in gliomas Johnny Wong 14th April, 2011 1
  • 2. Case: LB • 45 year old woman • Presented with dysphasia • Craniotomy and excision of tumour (09/10) • Histology: Anaplastic Astrocytoma (WHO III) 2
  • 3. • Post-op dysphasia & dysarthria gradually resolved • CATNON trial – XRT only • Significantly worsening dysphasia • MRI & FDG-PET in 01/11 • Tumour recurrence or radiation necrosis? 3
  • 4. Clinical Questions: • What is the sensitivity and specificity of PET in diagnosing tumour recurrence in high-grade astrocytomas ? • What is the best imaging modality to differentiate tumour recurrence from radionecrosis in astrocytomas ? 4
  • 5. Search strategy • P = Patients with high-grade astrocytoma • I = Positron-emission tomography • C = Magnetic resonance imaging • O = Sensitivity and specificity of diagnosing recurrence and radiation necrosis • Search terms (exp MESH and keywords): Astrocytoma, GBM, Positron-emission tomography, recurrence, radiation necrosis, “sensitivity and specificity” – Limit to English and Humans 5
  • 6. Results of search: • 17 articles • 10 useful articles • 1 related • 3 not accessible • 3 not relevant
  • 7. Results of search: 65 articles, 3 additional articles
  • 9. Effects of XRT and chemotherapy • Radiotherapy – Pseudo-progression (Enhancement within 2 months XRT) – Radiation necrosis (Enhancement after 3 – 12 months XRT) – BBB breakdown / ↑ VEGF expression - ↑ permeability • Chemotherapy – Concommitant XRT and chemo – 3x more likely for pseudoprogression – Temozolamide sensitivity (MGMT –ve status) – increases likelihood of pseudo-progression – Avastin – anti-VEGF: increases sensitivity to XRT, decreased permeability (less enhancement; increased FLAIR) 10
  • 10. Positron-emission tomography (PET): • Glucose • Amino-acids – F18-FDG – AA transport and protein – Correlation between synthesis; also in grade and glucose inflammatory cells metabolism – Difficulty with low-grade – MET: Methionine (Short lesions half-life) – High baseline in normal – FET: tyrosine cerebral cortex – FLT: thymidine – Sensitivity: 40-86% – N-NH3: Ammonia – Specificity: 22-100% – FFCho: Choline (membrane synthesis) – IMT-SPECT 11
  • 11. “Sensitivity and specificity of PET” • FDG vs MET-PET (Van Laere 2005) – 30 patients; both scans on same day. – Gliomas (Grades II-IV astrocytomas, oligos and mixed) – Radiology: recurrence 18/30, necrosis 4/30, unsure 5/30 – MET: Increased uptake: 28/30; Inter-observer 100%; Sensitivity: 75%; Specificity: 70%; Accuracy: 73% – FDG: Increased uptake: 17/30; Inter-observer 73% ; Sensitivity: 95%, Specificity: 50%; Accuracy: 80% 12
  • 12. “Sensitivity and specificity of PET” • FDG vs MET-PET: (Potzi et al.) – 28 patients; Histologically confirmed GBM – MRI evidence of progression as “recurrence” • MET-PET: Sens 89%, Spec 29%, Accuracy: 72% • FDG: Sens 11%, Spec 100%, Accuracy: 36% – Survival analysis for >12 months: • MET-PET: Spec 8%, Accuracy 48% • Other studies (Tsuyuguchi): – Sens: 100%; Spec: 60% – Accuracy:82% 13
  • 13. “Sensitivity and specificity of PET” • FET vs MRI (Rachinger et al 2005) – 45 patients (32 tissue diagnosis of recurrence; 13 transient symptoms) – FET: half life 110 mins (vs MET 20 mins) – FET-PET: Sensitivity 100%, specificity 92.9% – MRI : Sensitivity 93.5%; specificity 50% (p<0.05) 14
  • 14. “Sensitivity and specificity of PET” • FDG vs 13N-NH3 (Zhang et al, 2007) – 8 patients, Gd enhanced lesions – FDG and NH3 • NH3: 100% accuracy (6 recurrences, 2 necrosis) • FDG: 75% accuracy (1 FP, 1 FN) 15
  • 15. Other modalities – MRS and DWI • MRI + Gad: Not suitable for diagnosis of recurrence, especially after anti-VEGF (Sens and spec < 60%). • DWI: ADC coefficient 1.82 vs 1.43 (P-P vs recurrence, p<0.001) • DTI: Radiation necrosis damages WM tracts vs recurrences which displace them. • MRS: 3-D multi-voxel MRS: 94% sensitivity; 100% specificity (28 patients) 16
  • 17. The “gold standard” for diagnosis of recurrence: • MRI – Progression of enhancing lesion – Heterogeneity of lesion grades • Stereotactic biopsy – Sampling error • Survival – Confounding from different tumour grades and treatment regimens Larger studies required 18
  • 18. Implications from PET • MET-PET vs Gad-enhancement (Galldiks et al. 2009) – 12 patients; Histologically confirmed GBM – Volumetric study – MET uptake indices: >1.3 vs >1.5 and Gd-enhancement – Active tumour volume: 30.17 vs 13.68 vs 13.7 cm3 – MET-PET detects larger tumour volume than the contrast enhancement • Implication for larger surgical resection margins. – ? Higher reoperation rates because of higher sensitivity and low specificity. 19
  • 19. 20
  • 20. Latest follow-up • Commenced on Avastin (Bevacizumab) and Temodal (Temozolomide) • Good improvement clincially and radiologically 21
  • 21. References 1. Yang I, Aghi M. New advances that enable identification of glioblastoma recurrence. Nat. Rev. Clin Oncol 6:648-657, 2009. 2. Potzi C, Becherer A, Marosi C et al. 11C Methionine and 18F Fluorodeoxyglucose PET in the follow up of glioblastoma mutliforme. J. Neurooncol 84:305-314, 2007 3. Galldiks N et al. Volumetry of 11C-Methionine PET uptake and MRI contrast enhancement in patients with recurrent glioblastoma multiforme. Eur J Nucl Med mol Imaging 37:84-92, 2010 4. Zhang XS, Chen W. Differentiation of recurrent astrocytoma from radiation necrosis: a pilot study with 13N-NH3 Pet. J. Neurooncol 82:305-311, 2007 5. Rachinger W et al. Positron Emission tomography with O218F Fluroethyl L tyrosine versus magnetic resonance imaging in the diagnosis of recurrent gliomas. Neurosurg 57:505-511, 2005. 22
  • 22. 6. Van Laere et al. Direct comparison of 18F-FDG and 11C-Methionine PET in suspected recurrence of glioma: sensitivity, interobserver variability and prognostic value. Eur J. Nucl Med Mol Imaging 32:39-51, 2005 7. Tsuyuguchi et al. Methionine positron emission tomography for differentiation of recurrent brain tumour and radiation necrosis after stereotactic radiosurgery in malignant glioma. Annals Nucl Med 18:291-296, 2004 8. Mertens et al. PET with 18F-labelled choline based tracers for tumour imaging: a review of the literature. Eur J. Nucl. Med Mol Imaging 37:2188-2193, 2010. 23

Editor's Notes

  1. Pseudo:Within 2 months of XRTMinimal abnormal histologySpontaneous resolutionRadiation nec3 – 12 months after XRT; Oedema and mass effect on MRINot always resolveEndothelial apoptosis, gliosis and White Matter necrosis
  2. Highest tumour to background uptake: Fchol &gt; FET &gt; FDG. But all have increased uptake in inflammatory cells around necrosis.