PET-CT in Lung Cancer:Positron emission tomography – computed tomography

to whom, when ?

Jann Mortensen, MD, DMSci

Department of Clinical Physiology, Nuclear Medicine & PET,

Rigshospitalet University Hospital of Copenhagen,Denmark

Jann.Mortensen@rh.regionh.dkAntalya, 26 april 2008

Fused PET + CTCT PET

Anato-metabolic imaging2

PET - CT

Investigates functional changes in the body tissues and anatomy

simultaneusly

FDG signal in tumor is dependent on 1) delivery (blood flow),2) transport into the cells (glut), and 3) phosporylation (hexokinase)

Physiology of FDG tumor uptake

FDG tumor uptake ~ number of viable cancer cells

R.Wahl. Priciples and practice of positron emission tomography, 2002

BrainSalivary glands

LarynxThyroidHeart

GI tract incl liverGenito-urinary tract

Bone marrowLymphoid tissue

Brown fat

Physiological uptake of FDG

Main indications for PET in lung cancer

• Characterising pulmonary nodules which are borderline for malignancy on CT

• And cannot be easily biopsied

• Staging in NSCLC– Preoperative evaluation

• N and M (nodes and metastasis)

55 studies with > 2000 patients with histologic or long-term follow-up

Fischer BM, Mortensen J, et al.

Lancet Oncol 2001;2:659-66

Publications of PET & PET/CT in Lung cancer

PETPETCT

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SCLC

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PubMed April 2008

– Indeterminate single pulmonary nodule/mass on CT

• Malignant or benign ?

– N=16 studies

– Sensitivity 0.96 (0,90-1,00)

– Specificity 0.78 (0,69-0.95)

• Size: 1-4 cm• 1474 nodules (JAMA 2001; 285: 914-24)• Only few nodules <1 cm:

FDG-PET in solitary pulmonary nodules

FDG-PET can discriminate between malignant / benign ≥ 10 mm solid pulmonary nodules !!!

•FDG-PET has a high negative predictive value, can correctly exclude malignancy in the vast majority of nodules seen in daily practice. • ~ changes management in > 26 % of patients

•A surgical procedure can be avoided, and a repeat CT after 3 (6, 12 and 24) months can be used to confirm the absence of growth.Lancet Oncol 2001; 2: 659-66 Lung Cancer 2004; 45: 29-30.

FDG PET in >1 cm nodules

What is the diagnostic value in < 1 cm small nodules ?

9 mm nodule found on high-resolution CT

18F-FDG PET

57 yr male with COPD

transaxial coronal saggital

attenuation corrected RH - PET / jm (ap)

Diagnosis and staging(PET suggests T1 N0 M0)

57 yr male with COPD

Fischer BM, Mortensen J, et. al. Nucl Med Commun 2004; 25: 3-9.

On going screening study in Copenhagen: • Included 4000• Yearly CT vs. Control in 5 yrs• now 3 year

Value of PET in characterising indeterminate SPN 6-15 mm detected with low-dose CT

- all SPNs followed-up with re-CT at 3 months to assess growth

PET in ”The Danish randomisedlow-dose CT screening study of lung cancer”

Initial 9x12x9 mm solid nodule in R3, PET positive + 2 N2

PETpos + CT growth -> Biopsi/Mediastinoscopy: T1N2M0 (->Chemotherapy)

PET positive case

PET in Danish randomised low dose CT screeningPET in Danish randomised low dose CT screening

CT + PET axial

10 mm solid nodule in L3 PET negative CT stationary

a PET negative case

PET in Danish randomised low dose CT screeningPET in Danish randomised low dose CT screening

Jann Mortensen, klinisk fysiologi, nuklearmedicin og PET, Rigshospitalet

20

PET data from CT- screening in Milano

With PET : complete diagnostic workup < 4 months at baseline and < 2 months at 2-5 yrs

PET in 68 SPN >7 mm ~ 1,4% of 1.035 participants

Danish study:Accurracy.

89%

FDG PET in small nodules (<10 mm)

• PET is promising as a tool in lung cancer screening with low-dose CT

[Lung Cancer 2004; 45:19—27] [Nucl Med Commun 2004; 25: 3-9]

[Am J Respir Crit Care Med 2005; 171:1378-83][Lancet 2003;362:593-79]

• The interpretation of FDG-PET findings in subcentimetric nodules is at present unsolved

• [Vansteenkiste JF. Lung Cancer 2004; 45: 29-30].

Staging T N M status (in one exam)

•Conventional staging is inaccurate [Lancet 1996;347:649–653].

Oturai, Mortensen, Eigtved et al. J Nucl Med 2004;45:1351-7

Preoperative staging with FDG-PET

PET for staging:•Staging the MediastinumPET more accurate than CT for detection of locoregional metastases PET sensitivity >84%, specificity >89% (18 prospective studies)

• Detecting distant metastases:PET sensitivity >90%, specificity >90%and better than CT (17 prospective studies)

•Change in management• >25% of patients (15 prospective studies)

Pieterman et al. N Engl J Med 2000;343:254-61

102 patients with resectable NSCLC, 6 months follow-up,

histopathological reference.  (N) metastasis Sensitivity Specificity PET 91 % 86 %CT 75 % 66 %

(M) metastasis: PET identified distant metastases not foundby standard methods in 11 of 102 patients:

PET identified a different stage in 62 patients:stage was lowered in 20 and raised in 42

Prospective study of Preoperative staging with PET vs. standard staging (CT, ultrasound, bone scanning/ biopsy)

Randomised study of PET staging

• Effect parameter: no. unneccesary thoracotomy´s• 188 ptt. usual work-up +/- PET, 1 yr follow-up• 9 Deutch hospitals (1 dedicated PET center)

• PET reduced the no. unneccesary thoracotomy´s:– PET 32 (41%) , + PET 18 ptt (21%)

• For each 5 PET scans one unneccesary thoracotomy was avoided– reduced cost per patient with PET: > 1.000 EURO

(PLUS study. Lancet 2002; 359: 1388-92)

Mediastinoscopy, EUS, EBUS and PET/CT

Mediastinal staging with CT, PET, and endoscopic esophageal ultrasound (EUS)

EUS+FNA better ? for locoregional staging (N)• PET was superior (higher sensitivity and specificity), to CT but also to EUS.PET was superior (higher sensitivity and specificity), to CT but also to EUS.

•[Chest 2003;123(suppl 1):137S–146S]. [Chest 2003;123(suppl 1):137S–146S].

• PET and EUS with fine-needle aspiration had similar sensitivities (79%) for advanced cancer, but PET and EUS with fine-needle aspiration had similar sensitivities (79%) for advanced cancer, but EUS with FNA had a superior specificity (100% vs. 72%).EUS with FNA had a superior specificity (100% vs. 72%).

• [Am J Respir Crit Care Med 2003;168:1293–1297][Am J Respir Crit Care Med 2003;168:1293–1297]

• EUS with fine-needle aspiration had higher sensitivity (87% vs. 61%), specificity (100% vs. 91) and EUS with fine-needle aspiration had higher sensitivity (87% vs. 61%), specificity (100% vs. 91) and accuracy (94% vs. 77%) than PET. accuracy (94% vs. 77%) than PET.

•[Clin Gastroenterol Hepatol 2006;4:846-51].[Clin Gastroenterol Hepatol 2006;4:846-51].

• In 5 papers on > 300 patients with PET positive N (N1-3): EUS+FNA had high accuracy and in ~50% detected malignancy obviating the need for further surgical procedures •[Chest 2005;128:3004-9 & 2005;127:130-7][Ann Thorac Surg 2005;80:1231-40][Thorax 2004;59:596-601][Lung Cancer 2004;44:59-60].

Mediastinal staging with CT, PET, and endobronchial ultrasound (EBUS) with TBNA

• 102 patients with potentially operable suspected lung cancer.

Gold standard: histology-cytology [Chest 2006;130:710-718].

EBUS with TBNA vs. PET vs. CT:

• Sensitivity (92% vs. 80% vs. 77%),

• Specificity (100% vs. 70% vs. 55%),

• Accuracy (98% vs. 73% vs. 61%).

EBUS + TBNA better ? for locoregional staging (N)

In the majority of 33 patients with PET positive N (N1-3): EBUS-TBNA could detect malignancy obviating the need for futher surgical procedures [Eur Respir J 2006;27:276-281].

Publications of PET & PET/CT in Lung cancer

PETPETCT

NSCLC

SCLC

0

50

100

150

200

250

300

350

400

Ref

eren

ces

PubMed April 2008

”PET/CT improves staging in 20-40% of lung cancer patients compared to PET and CT” (T and N status)

Lardinois D et al. N Engl J Med 2003;348:2500-7

PET/CT improves staging in lung cancer

“Compared to PET, PET/CT better predicts stage I and II, as well as T and N status”Cerfolio RJ et al. Ann Thorac Surg 2004; 78: 1017–23

”PET/CT is significantly better than CT in NSCLC staging and provides enhanced accuracy and specificity in nodal staging” (10 FN Nodes with CT and 5 with PET/CT)

Shim SS et al. Radiology 2005; 236:1011-9

”PET-CT is more accurate, sensitive and specific compared to CT alone in nodal staging. Nael Al-Sarraf et al. Lung Cancer 2008;60:62-8

PET/CT 10-15% more accurate than PET

Extrathoracic metastasis• 40% with NSCLC have distant metastases at presentation, most often in the

adrenal glands, bones, liver, or brain [Ann Thorac Surg 1996;62:246–250].

• Adrenal glands: 10% of NSCLC have enlarged adrenal glands on CT, 2/3 being benign.

PET has high sensitivity (100%) and specificity (80%–100%) -> reduces number of unnecessary adrenal biopsies.

• Bone: Bone scintigraphy good sensitivity (90%), low specificity (±60%), PET similar or higher sensitivity (90%), similar or higher specificity ( 98%), and higher accuracy (96%).

• Liver: US and/or CT and /or MR remain the standard imaging techniques for the liver. No good comparisons studies. Additional diagnostic information by PET combined with CT, in the differentiation of hepatic lesions that are indeterminate on conventional imaging.

• Brain: FDG-PET low sensitivity (60%) not suited for the detection of brain metastases.

The Oncologist 2004; 9 (6): 633-43; (Lung Cancer 2004;44,317-25)

True positive FDG-PET in spine, false negative bone scan at presentation, but true positive 3 months later

Lung Cancer (2004) 44, 317—325

Adrenal lesion

Diagnostic value of PET in lung cancer

• Sensitivity ~ 97 % (SPN); ~ 73% (N staging)

• Specificity ~ 78 % (SPN), ~ 93% (N staging)

• Reasons for false negative ?

• Reasons for false positive ?

Solitary pulmonary nodules (SPN) Mediastinal staging (N)

Value of PET in lung cancer

• Reasons for false negative– Small size (resolution 4-6 mm,

respiratory movement)

– Well-differentiated tumors: • Some bronchioalveolar carcinoma (GGO)• Some carcinoids (Neuroendocrine tumors)• E.g. Adenocarcinoma• E.g. Renal cell carcinoma

False positive• Inflammation

– Granulomas: – Tuberculosis– Sarcoidosis– Histoplasmosis– Silicosis– BOOP, etc.

• Iatrogenic causes– Invasive procedures– Talc pleurodesis– Radiation sequelae

• Focal physiological FDG uptake– Gastrointestinal tract– Striated muscles– Brown fat– Artheroschlerotic plaques

Pitfalls of FDG-PET in lung cancer

TB in a 58-year-old man. (A) chest radiograph shows two nodules (b) coronal FDG PET scan shows increased uptake (solid arrow) in the left upper lobe nodules (SUV 4). Radiology 2000 6:117-21

Fischer BM, Mortensen J.

Respiration 2006;73:267-76

Sarcoidosis

Milman N, Mortensen J, Sloth C. Respiration. 2003;70:408-13.

Before treatment:

After inhaled steroid:

After prednisolone:

Localisation of activity in- and outside lungs:

Monitoring:

Indication for use of PET

Guidelines

• PET/CT is now implemented in guidelines

PET & PET/CT in guidelines for staging lung cancer to improve staging (Nodes+Metastases) & avoid unneccesary surgery

ESTS guidelines for preoperative lymph node staging in NSCLCEur J Cardio-thoracic Surgery 2007; 32:1-8

Noninvasive Staging of Non-small Cell Lung Cancer*

ACCP Evidenced-Based Clinical Practice Guidelines (2nd Edition) Silvestri, G. A. et al. Chest 2007;132:178S-201S

The Danish National Board of Health, 18 jan 2008:PET/CT in lung cancer staging for potentially curable patients

STAGING OF NSCLC

Invasive procedures can be omitted in patients with peripheral tumors and negative mediastinal PET (N0)

In case of central tumors, PET hilar N1 disease, low SUV of primary tumor and LNs 16mm on CT, invasive staging remains indicated.

ESTS-guidelines

PET positive mediastinal findings should always be confirmed cyto-histologically. so staging remains indicated.

De Leyn et al. Eur J Card-Thor Sur 2007;32:1-8

Newer indications for PET in lung cancer

• Prognostic information from SUV

• Evaluation of treatment effect ->

• PET/CT for planning of radiation field

• Staging and monitoring SCLC ->

• Staging Mesothelioma

PET predicts survival

SUV median survival < 10 2 yr > 10 1 yr + mass >3 cm ½ yr

• Ahuja et al. Cancer 1998; 83 ; 918-24

In multivariate analysis, the SUV was independently predictive of disease-free and overall survival

• Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Lancet Oncol 2004; 5: 531–40

Newer indications for PET in lung cancer

• Prognostic information from SUV

• Evaluation of treatment effect ->

• PET/CT for planning of radiation field

• Staging and monitoring SCLC ->

• Staging Mesothelioma

1. Re-staging after neoadjuvant therapy (invasive best)

2. Early assessment (Reduction in metabolism correletes closely to outcome)

3. Re-staging after completion of therapy (scar/residual tumor)

Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Lancet Oncol 2004;5:531-40

Newer indications for PET in lung cancer

• Prognostic information from SUV

• Evaluation of treatment effect ->

• PET/CT for planning of radiation field

• Staging and monitoring SCLC ->

• Staging Mesothelioma

PET/CT guided RT improves radiation dose to the tumorand metastases and reduce dose to adjacent normal tissueTarget volumes in NSCLC were changed by PET/CT:• Several studies show changes between 35-62 % (Increased and decreased)• No studies with patient outcome yet

Newer indications for PET in lung cancer

• Prognostic information from SUV

• Evaluation of treatment effect ->

• PET/CT for planning of radiation field

• Staging (and monitoring) SCLC

CT/Bone scint/bone marrow PET PET/CT Sensitivity 79% 93% 93%Specificity 100% 83% 100%PET/CT (n=32) changed stage in 17% of SCLC (LD->ED in 10%) “PET/CT can simplify and perhaps even improve the accuracy of the current staging procedure”. Fischer MBB, Mortensen J et al. Ann Oncol 2007;18(2):338-45

Brink et al (PET only, n=120) Significantly superior to CT in the detection of distant metastases: PET changed stage in 12% (upstaging 10, downstaging 3 of 120)

Newer indications for PET in lung cancer

• Prognostic information from SUV

• Evaluation of treatment effect ->

• PET/CT for planning of radiation field

• Staging and monitoring SCLC ->

• Staging Mesothelioma

PET/CT for:• Extent of tumour and invasion?• Preop. staging extrathoracic/contralat. metastasis (not N1,2)• Monitoring treatment• Prognosis (high metabolism -> bad prognosis)

J Nucl Med. 1999 Aug;40(8):1241-5.

Semin Oncol. 2002 Feb;29(1):26-35

Lung cancer 2005;49:s27-s32

J Thoracic Cardiovasl Surg 2005;129:1364-1370

Conclusion• Diagnosis of SPN

– Differentiate between benign/malignant SPN, unable to be biopsied• High negative predictive value

– the uptake (metabolism) is an independent prognostic factor (high->bad prognosis)– PET of value as adjunct to low-dose CT lung cancer screening

• Staging PET/CT improves conventional staging (CT+US+bone scintigraphy)

– PET/CT changes stage and treatment in 10-50 % of patients• Usually a higher stage is found• Avoids unneccesary thoracotomy (in 10-20%) due to N2-3 or M disease- Mediastinoscopy may be avoided if PET/CT is normal in the Mediastinum (non-central T), but

needs to be performed if PET/CT is positive

- Emerging indications:- restaging- treatment monitoring,- radiation field planning,- staging SCLC and Mesothelioma

Perspectives for PET/CT in lung cancer

• Simplify the staging procedure• one-stop procedure

– More often assign the correct stage• And correct treatment to the patient

• Better assesment of prognosis

– Therapy evaluation

– Other PET tracers eg. hypoxia tracers especially for RT

Thanks foryour attention!

Respiration gated PET (4-D PET)

4-D PET

Most relevant for peripheral basal nodules with much respiratory movement

12 mm solid nodule in R3; 89 d dobling time,PET positive, surgery T1N0M0

Randomised studies of PET in NSCLC stagingAuthor Patients Design End Point Conclusion

Van Tinteren et al. Lancet 2002; 359:1388-92(PLUS study)

188 (9 centers)Pot. operable. Diagnosis in 50%70% I+II

Conv. vs. Conv.+PET1 yr follow-upMed.scopy in 66% -PET, 73% + PET

No. of Futile thoracotomies #(Cost)

Rel. Reduction of 51%41% (-PET)21% (+PET)(Reduction in Cost)

Herder et al.J Clin Oncol 2006;24(12):1800-6 

465 (22 centers)12-19 % benign29-28 % I+II9-11 % IIIa33-32% IIIb+IV 

Conv. vs. PET up-front at first presentation.1 yr follow up

No. of non-invasive procedures for staging

Cost and No. of non-invasive procedures similar, Rel. reduction in invasive procedures incl Med.scopies

Viney et al.J Clin Oncol 2004; 22:2357-62

184 (4 centers)Pot. operable. Diagnosis in 100%92% I, 8% II

Conv. vs. Conv.+PETSurgeon decides to do (or not) med.scopy (in 10) and thoracotomy

No. of total thoracotomies

Slightly better staging with PET, No diff. in End Point.Management changed in 13% (+13%)

Lassen U, Mortensen J, BMB Fischer, &DLCG et al. (closed)PERALUST study

220 (4 centers)Potent. operable.

Conv. vs. Conv.+ PET/CTMed.scopy in 100%1 yr follow-up

No. of Futile thoracotomies #

?Data processing