The Role of PET in Lung Cancer Screening Michael M. Graham, PhD, MD University of Iowa

October 3, 2015

Conflict of Interest None

FDA Statement No unapproved agents are discussed

The Role of PET in Lung Cancer • Diagnosis – Screening (with or without prior CT) – Evaluation of Solitary Lung Nodule

• Staging • Response to therapy • Surveillance

Kojima S, et al. Cancer screening of healthy volunteers using whole-body 18F-FDG-PET scans: The Nishidai clinic study. Eur J Cancer. 2007;43:1842.

Total N = 4881

Mean age = 54.7

50% current or former smoker

Kojima S, et al. Cancer screening of healthy volunteers using whole-body 18F-FDG-PET scans: The Nishidai clinic study. Eur J Cancer. 2007;43:1842. Total N = 4881 Positive

Yield

11.4%

0.7%

PPV = 38.7% PPV = 6.86%

NPV = 99.67%

Minamimoto R, et al. The current status of an FDG-PET cancer screening program in Japan, based on a 4-year (2006-2009) nationwide survey. Ann Nucl Med. 2013; 27:46.

233 facilities; N= 155,456; Positive = 16,955 (11%) PPV = 11%; Detection yield = 1.2%

National Lung Screening Trial Research Team, Aberle DR, et al.

Reduced lung-cancer mortality with low-dose CT screening. N Engl J Med. 2011; 365:395.

National Lung Screening Trial Research Team, Aberle DR, et al. Reduced lung-cancer mortality with low-dose CT screening. N Engl J Med. Aug 2011; 365:395.

American Cancer Society Initial Guideline Clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about screening with apparently healthy patients aged 55 years to 74 years who have at least a 30–pack-year smoking history and who currently smoke or have quit within the past 15 years.

March, 2013

Current Recommendation Release Date: December 2013 The USPSTF recommends annual screening for lung cancer with low-dose computed tomography in adults ages 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.

WWW.nature.com/nature/outlook/lungcancer

Hungary Serbia

North Korea

National Lung Screening Trial Research Team, Aberle DR, et al. Reduced lung-cancer mortality with low-dose CT screening. N Engl J Med. 2011; 365:395.

Number screened: 26722

68%

NLST Low-Dose CT Sens=93.1% Spec=76.5% PPV = 3.6% NPV = 99.9%

Practical Problems • • • •

How many subjects will be screened? Will there be reimbursement? How should follow-up studies be done? What is the role of FDG PET-CT in follow-up?

SOLID

GGO

No Role for PET

Multiple GGO

No Role for PET

129 Christensen JA, Nathan MA, Mullan BP, Hartman TE, Swensen SJ, Lowe VJ. Characterization of the solitary pulmonary nodule: 18F-FDG PET versus nodule-enhancement CT. AJR Am J Roentgenol. 2006 Nov;187(5):1361-7.

N= 42

Original dictated report

SUV > 2.5

132 Fletcher JW, et al with the VA SNAP Cooperative Studies Group. A comparison of the diagnostic accuracy of 18F-FDG PET and CT in the characterization of solitary pulmonary nodules. J Nucl Med. 2008; 49:179-85.

N = 344 Sensitivity = 92% (95% CI, 87%–95%) Specificity = 82% (95% CI, 75%–88%)

Veronesi, G et al. Difficulties encountered managing nodules detected during a computed tomography lung cancer screening program. J Thorac Cardiovasc Surg 2008;136:611

Positive PET definition: SUVmax > 1.5

Hypothetical Sequential Low-dose CT followed by FDG PET-CT Incidence = 2.4 %

Low-dose CT PPV = 3.6%

1000 +

680 PET - CT PPV = 32%

Low Dose CT Positive CT results (22 TP)

FDG PET - CT +

59 Note: assumes all positive LDCT nodules are solid and > 8mm

High risk subjects (24 TP)

+

Positive PET results (19 TP)

Biopsy/Surgery

Definitive PET-CT Guidelines are Needed

Emphasis on standardization of patient preparation, image acquisition, image reconstruction and quality control. Interpretation criteria: “FDG PET is generally assessed using visual criteria (in the context of oncology, looking for a focally increased uptake that may be compatible with malignancy in the clinical context.”

NCCN Suggestion

Conclusions • We are likely to see an increasing number of SPNs for FDG PET-CT imaging. • We need consistent methodology and consistent reading criteria. • Oncologists, pulmonologists, and radiologists need to work together to define the algorithm (including PET) for work-up of SPNs.

Practical Issues Related to Standardization • Standardized Uptake Value (SUV) measurements • Time of imaging • Partial volume effect • Pre-test probability

Standardized Uptake Value

SUV SUV =

=

The average SUV in the entire body is 1.0

Tissue activity (µCi/cc) Administered activity (µCi/g) Tissue activity (µCi/cc) Administered activity (mCi/kg)

Body weight or LBM (kg)

• Tissue activity is determined from attenuation corrected images • Administered activity is known from dose calibrator • Both activities are decay corrected to time of injection

Changing SUV with Time

Lowe VJ, DeLong DM, Hoffman JM, Coleman RE. Optimum scanning protocol for FDG-PET evaluation of pulmonary malignancy J Nucl Med 1995 36:883

Looking for the simple solution Patz EF Jr, et al. Focal pulmonary abnormalities: evaluation with FDG PET scanning. Radiology. 1993 Aug;188(2):487-90. 2.5 N=41

A somewhat more realistic view Benign 2.5

Malignant

Reality: Not very nice Solitary Pulmonary Nodules (Iowa) 217 FDG PET-CT studies for SPNs obtained from 2003 to 2008. 106 nodules were benign, 111 malignant.

Benign

Malignant

Solitary Pulmonary Nodules (Iowa) 1

At SUVmax=2.5

2 3 4 5

SUVmax = 2.5

Sensitivity = 71% Specificity = 71%

Solitary Pulmonary Nodules (Iowa)

Estimating the Risk of Malignancy in a Solitary Pulmonary Nodule

www.chestx-ray.com

Estimating the Risk of Malignancy in a Solitary Pulmonary Nodule

www.chestx-ray.com

www.chestx-ray.com

Estimating the Risk of Malignancy in a Solitary Pulmonary Nodule

www.chestx-ray.com

www.chestx-ray.com

Swensen SJ, et al. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med. 1997;157:849.

Probability of malignancy=ex/(1+ ex)

N=629

X = − 6.8272 + (0.0391×age) + (0.7917×smoke) + (1.3388×cancer) + (0.1274×diameter) + (1.0407×spiculation) + (0.7838×location) age = patient’s age in years smoke = 1 if the patient is a current or former smoker (otherwise, smoke = 0) cancer = 1 if the patient has a hx of extrathoracic cancer >5 years ago (otherwise =0) diameter = diameter of the nodule in millimeters spiculation = 1 if the edge of the nodule has spicules (otherwise, spiculation = 0) location = 1 if the nodule is located in an upper lobe (otherwise, location = 0)

55yo smoker, no hx ca, 10mm spiculated upper lobe nodule Probability of malignancy = 0.313

McWilliams A, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med. 2013; 369:910.

McWilliams A, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med. 2013; 369:910.

1%

0.1%

How big does a lung nodule have to be to see it on PET?

It depends .....

Partial Volume Effect (Iowa)

Assumptions: FWHM = 1.0 cm, Background SUV = 0.5

The Role of PET in Lung Cancer Diagnosis and Screening Conclusions • • • • •

SUV = 2.5 (or 1.5) is not a magic number High SUV increases probability of cancer Low SUV decreases probability of cancer Pre-test probability is important Histoplasmosis and Low-grade Adenocarcinoma are the problems • It makes sense in context of CT screening

National Lung Screening Trial Research Team, Aberle DR, et al. Reduced lung-cancer mortality with low-dose CT screening. N Engl J Med. 2011; 365:395.

Number screened: 26722

For ground-glass nodules and nodules < 8 mm

68%

Repeat f/u LDCT

For solid nodules > 8 mm FDG PET-CT