# Presentation: 659292

## F-18 FDG PET in Oncology: Safety and Effectiveness Review

- Florence Houn MD MPH
- February 18, 1999

## F-18 FDG Team

- Maboob Sabhan- Stat
- Rubynell Jordan- PM
- Flo Houn- Medical
- David Hussong- Micro

- Ravi Kasliwal- Chem
- Adebayo Laniyonu-Pharm/Tox
- Alfredo Sancho- Biopharm

## F-18 FDG Oncology S&E Preliminary Review Conclusions

- Effectiveness
**To evaluate malignancy in patients with either abnormalities found by other testing modalities or in patients with an existing diagnosis of cancer**
- Safety
- IV doses from 200-740 MBq
- fasting at least 4 hrs

## F-18 FDG Oncology S&E Review

- Guidances on Clinical Effectiveness/Medical Imaging
- Intended Use of F-18 FDG Oncology
- Pathology Standard
- Search Methodology
- Selection Criteria
- Review of  Findings
- Conclusions

## F-18 FDG Oncology ReviewGuidance on Clinical Effectiveness-Use of Published Literature Alone

- Multiple studies/adequate design/consistent findings
- Detailed protocol
- Objective and appropriate endpoints

- Consistent conclusions of efficacy
- Conduct of studies with documented operating procedures
- Examples: secretin, bleomycin and talc, doxycyline

## F-18 FDG Oncology ReviewAdequate/Well-Controlled (Med. Imaging Guidance)

- Selection of subjects=Target population
- Readers: independent, masked, randomized, separate
- Standards of truth
- Endpoints
- Analysis plans
- Safety: toxicity and radiation assessment

## F-18 FDG Oncology ReviewIntended Use: evaluating malignancy (diagnostic population)

- Preliminary review for major uses
- “Developing Medical Imaging Drugs and Biologics” draft guidance
- “Functional, Physiological, or Biochemical Assessment”
- Validated to a standard of truth
- Spectrum of disease and normality tested
- Pharmacological basis of “functional claim”

## F-18 FDG Oncology PETPathology Standard

- All studies compared to pathology
- Sensitivity and Specificity

## F-18 FDG Oncology ReviewLiterature Search Methodology

- Criteria for Search
- January 1, 1990 to July 1, 1998
- Human clinical trials
- English
- On-line databases: Medline, Cancerlit, Derwent Drug File, Biosis Preview, International Pharmacology Abstracts, and Embase
- PET community suggested articles
- References cited in above articles

## F-18 FDG Oncology ReviewLiterature Search Methodology

- Selection Criteria
- Prospective
- F-18 FDG PET results compared to pathology
- Clinical performance hypothesis
- Well-described study population
- More than 50 evaluable patients
- Larger data set reviewed when multiple papers were produced from same data set

## F-18 FDG OncologyPublished Literature

- Adequate/Well-Controlled Clinical Trials (2)
- Prospective enrollment
- Study population similar to target population for clinical use
- Pathology
- Multicentered studies or with at least 50 evaluable patients
- Details about intrepretive criteria and masking
- Other Supportive  Studies (14)
- Prospective
- Study population similar to target population for clinical use
- Pathology
- Ancillary hypotheses (retrospectively determined SUV)/no masking

## F-18 FDG OncologyAdequate/Well-Controlled Studies

- Lowe, J Clin Oncol 1998;16:1075-84.
- Carr R.  Blood 1998;91:3340-46.

## F-18 FDG Oncology Supportive Studies

- Avril N.  J Clin Oncol 1996;14:1848-57.
- Bury T.  Eur Respir J 1997;10:2529-34.
- Delbeke, Arch Surg 1998;133:510-16
- Dietlein M.  Eur J Nucl Med 1997;24:1342-48.
- Friess H.  Gut 1995;36:771-777.
- Gupta N. J Nucl Med 1996;37:943-48.
- Holder Jr. W. Annals of Surg 1998;227:764-771.

## F-18 FDG Oncology  Supportive Studies

- Lowe VJ.  J Nucl Med 1994;35:1771-76.
- Moog F.  J Cliln Oncol 1998;16:603-9.
- Schiepers C. Curo J of Surgical Oncol 1995;21:517-22.
- Utech C.  Eur J Nucl Med 1996;23:1588-93.
- Valk PE.  Ann Thorac Surg 1995;60:1573-82.
- Vansteenkiste JF.  J Clin Oncol 1998;16:2124-49.

## F-18 FDG Oncology ReviewAdequate /Well-Controlled: Carr (1998)

- _Objective_: F-18 FDG diff. benign vs malignant marrow lesions identified by routine staging after dx
- _Sample size_: 50 pts.
- _Design_: Prospective; compared pathology /PET; routine lymphoma staging: thor/ab CT, unilat iliac crest asp/trephine bx

-  _Image Protocol_: Masked, visual interpretation by 3 indep. masked nucl meds; Kappa=0.64; masked path.
- _Dose_: >6hrs fasting; 350 MBq IV, emission scan after 35-45 minutes
- _Sensitivity_ 13/16 (81%) _Specificity_  26/34 (76%) using unilat Bone Marrow

## F-18 FDG Oncology ReviewAdequate /Well-Controlled: Carr (1998)

- Strengths
- Combined HD and  non-HD patients
- 3 independent readers
- Criteria given for PET reading
- Kappa statistic
- Histology protocol given

- Weaknesses
- 50 patients only
- unilateral iliac crest aspirates
- Need to develop non-biased method for discrepancy resolution

## F-18 FDG Oncology ReviewAdequate/Well-Controlled: Lowe (1998)

- _Objective_: Sens/Spec of PET with SPN seen of CT or CXR
- _Sample Size_: 89 pts. Multicentered trial

- _Inclusion Criteria_: Lesion <4cm>0.7cm and consider indeterminant
- _Design_: Compare PET vs. pathology and SUV

## F-18 FDG Oncology :Adequate and Well-Controlled: Lowe (1998)

- _Image Protocol_: masked, independent, 2 readers, film copies, disagreement resolved by consensus, Kappa= 0.95.
- Prospectively determined SUV >2.5 for malignancy

- CXR and CT scans read by non-site radiologists, masked;
- SUV performed on ROI by masked reader
- _Dose_: Fast >4hrs; 370 MBq IV; emission scans after 55 -65 min.

## F-18 FDG Oncology Review:Lowe (1998) Con’t.

- _Results_
- 60/89 SPN malignant; 29 benign
- 50/60=NSCLC; melanoma, HD, small cell, carcinoid, neural, colon metastasis
- 7/29=granuloma; fungal, debris, inflammation, fibrosis, hemangioma, metaplasia
- Visual sens 98% (59/60); spec 69%(20/29)
- SUV sens 92% (55/60); spec 90% (26/29)

## F-18 FDG Oncology ReviewLowe (1998)

- Strengths
- Inclusion criteria
- Pathology standard
- Images read by 2 readers, independently, masked to CT/CXR
- Interobserver differences in PET tracked/analyzed
- Sensitivity and specificity

## F-18 FDG ReviewLowe (1998) Con’t.

- Strengths Continued
- Dispute resolution described
- Kappa for readers’ performances
- Information on CXR/CT readings controlled
- Multicentered trial
- Number of patients
- Detailed patient information

## F-18 FDG Oncology ReviewLowe (1998) Con’t.

- Weaknesses
- Twice as many malignant lesions as benign
- No information on pathology reading protocol
- Sampling variations for TTNA vs. open-lung biopsy

## F-18 FDG PET Oncology:Supportive Studies

## F-18 FDG OncologySupportive Studies

## F-18 FDG OncologySupportive Studies

## F-18 FDG OncologySupportive Studies

## F-18 FDG Oncology Supportive Studies

## F-18 FDG Oncology ReviewWeaknesses of Literature

- Absence of statistical criteria for significance and power
- Less information protocols for imaging handling and reading criteria
- Absence of source data
- Bias (publication bias, subjectivity of readers scoring, patient selection)

## F-18 FDG Oncology ReviewWeaknesses of Literature cont’d

- No control of prior imaging interpretations
- Use of furosemide and serum glucose
- Variations in pathological sampling

## F-18 FDG Oncology PET Preliminary Review Conclusions

- Efficacy
- Intended Use: To evaluate malignancy in patients with either an abnormality found by other testing modalities or with existing diagnosis of cancer (not for screening)
- Consistent findings, diverse malignancies-generalized mechanisms for    glc utilization
- Sensitivity and specificity calculated

## F-18 FDG Oncology S&E Preliminary Review Conclusions

- Safety (FDG/Radiation)
- Small amount of FDG/glucose introduced
- Know metabolism and excretion
- Short physical half-life (110 minutes)
- Acceptable radiation dosimetry
- Acceptable risk of radiation
- Unknown performance with hyperglycemia

## F-18 FDG Oncology Review Preliminary Conclusions

- Effectiveness
-  **To evaluate malignancy in patients with abnormalities found by other testing modalities or in patients with existing diagnosis of cancer**
- Safety:
** ****fasting at least 4 hours before  injection**
**IV doses of 200-740 MBq  studied**