early diagnosis and treatment of lung cancer€¦ · objectives: epidemiology of lung cancer...

Eric L. Grogan, MD, MPH

Assistant Professor of Thoracic SurgeryAssistant Professor of Medicine –

Institute for Medicine and

Public Health

Thoracic Surgeon, Veterans Hospital

October 16, 2009

Early Diagnosis and Treatment of Lung Cancer

Objectives:

Epidemiology of Lung cancer

Diagnostic strategies for suspected Lung CACase presentationRisk factorsImaging

Diagnostic and surgical treatment optionsCases PresentationsVATS Lobectomies (video)Minimally invasive staging

EBUS / EUSMarginal operative candidate

RFA & SRTAdvances in biomarker based diagnostic strategies

http://www.cancer.org/statistics

Cancer Statistics 2007 ‐

United States

http://www.cancer.org/statistics

U.S. Age Adjusted Death Rates for Lung Cancer

National Vital National Vital Statistics SystemStatistics System

Rates calculated by Rates calculated by NCI using SEER data NCI using SEER data

US Death Rates ‐

Females

Objectives:


Diagnostic strategies for suspected Lung CA (workup)Case presentationRisk factorsImaging



RFA & SRT

Advances in biomarker based diagnostic strategies

Case Presentation

Case Presentation

Options ?Probability lesion is malignant

http://www.chestxray.com/SPN/SPNProb.html


Case Presentation

Options ?Probability lesion is malignant


ORAxillary thoracotomy – NSCLCLobectomy, MLNDT1N0M0 ‐ Stage 1a disease


Diagnosis of NSCLC Solitary Pulmonary Nodule(SPN)

> 150,000 cases / yr by CT and CXRChance of malignancy is multifactorial

Patient risk factorsCharacteristics of the lesion

Biopsy is the only way to make a definitive diagnosis

Swensen. Mayo Clin Proc 1999;74:319

SPN Management: Estimating Risk ‐ Clinician

Low Intermediate High

Age (years) < 40 40-60 > 60

Smoking history

Never smoked < 20 pack-yrs ≥

20 pack-

yrs

Lesion size < 1.0 1.1-2.0 > 2.0

Lesion margins Smooth Scalloped Spiculated

Probability of Cancer

Cummings. Am Rev Respir Dis 1986;134:449Henschke. Radiology 2000;215:s607

SPN Management: ’Mayo Model’

Multivariate logistic regression analysis629 patients

65% benign, 23% malignant, 12% indeterminate

Swensen. Arch Intern Med 1997;157:849

SPN Management: Estimating Risk with Bayesian Analysis

Statistical procedure which

estimates parameters of an underlying distribution

based on the observed distribution

Cummings. Am Rev Respir

Dis

1986;134:449


SPN: Management Goals

Cure all curable lung cancersResect appropriate metastatic lesionsACCP guidelines SPN Growth = Tissue

Avoid unnecessary surgery

Optimize quality of life

SPN: Evaluation & Workup

Clinical risk assessmentImaging

CXR CT ScanFDG‐PET

BronchoscopyFine needle aspirationExcisional biopsy

VATSThoracotomy

SPN: Clinical Risk Factors for NSCLC

Smoking historyAge

Rare below age 40Incidence increases until age 80

Occupational / environmental riskAsbestos, radon, heavy metals, radioactivity

Extrathoracic malignancyType and stage dependent≈ 40% of SPN are metastatic

Geography

# 1 Risk Factor

SPN Imaging ‐ CXR:

The “2 year rule” – search for old films9/26 nodules with no growth on CXR in 2 years were malignant> 95% accurate if stable by CT

Limits of detectable changes3.0 to 5.0 mm by CXR0.3 mm by high‐resolution CTBE CAREFUL USING CXR FOR DOUBLING TIME!

All suspicious nodules should be evaluated and followed with high resolution CT scan

Yankelevitz. AJR 1997;168:325

SPN Imaging ‐ CT scan

High ResolutionStandard of careAccurate to

High degree of accuracy – published literatureFalse positives:

Infection ‐ HistoplasmosisInflammatory processes

False negatives:small size

Gould. JAMA 2001;285:914

SPN Imaging – FDG‐PET:

Meta‐analysis40 studies, 1474 patients with nodules

Sensitivity 96.8 %Specificity 77.8 %Conclusions

FDG‐PET is very accurateThe utility of FDG‐PET depends on the pretest probability for malignancy“For low‐risk patients, FDG‐PET has a high negative predictive value and observation is probably safe”

Objectives:





Wedge / Brachytherapy, SRT & RFA


Diagnostic and Therapeutic options

Excisional Biopsy: VATS & Thoracotomy

Definitive diagnostic technique

Risk/Benefit ratio Malignancy vs M&M

Radiotracer guided surgery for small nodules 1cmTolerate single lung ventilation

ThoracotomyCentral lesionsIncreased morbidity and mortality

Radiotracer‐guided VATS Resection

CT CT -- fluoroscopy fluoroscopy 22 gauge needle22 gauge needle

Tc99m MAATc99m MAA–– 0.3 millicuries 0.3 millicuries

–– (0.3 ml volume )(0.3 ml volume )–– 0.3 ml saline flush0.3 ml saline flush

1

Grogan et. al. Ann Thorac

Surg

2008

Radiotracer‐guided VATS Resection

CT localization procedureCT localization procedureNuclear scintigraphy Nuclear scintigraphy –– to ensure to ensure ““hot spothot spot””Gamma probe guided excisionGamma probe guided excision

30-degreeprobe

Port for stapler & probe

Case Presentation69 y/o nonsmokerURI – CXR ‐ RUL SPN CT scan – Spiculated lesion RULFDG PET positive lesion, mediastinum negativeFNA ‐ nondiagnostic – pneumothoraxOptions?

Surgical options

VATS wedgePeripheral nodules > 1cmMarginal Pulmonary function

VATS LobectomySmall access incisionNo rib spreading

Axillary thoracotomy Muscle sparing – rib spreadingNo division of ribs

Posterior‐lateral thoracotomySacrifice or spare latissimus muscleDivide rib

Least invasive

Most invasive

Case Presentation69 y/o nonsmokerURI – CXR ‐ RUL SPN CT scan – Spiculated lesion RULFDG PET positive lesion, mediastinum negativeFNA ‐ nondiagnostic – pneumothoraxOR VATS wedge

NSCLCVATS lobe

Home POD 4T1N0M0 – Stage 1

VATS Lobectomy

VATS Lobectomy: Advantages

Less Pain – all incisions same at 3‐6 moShorter Length of Stay / Reduced Cost Faster return to full activityFewer complications (less pneumonia)Improved compliance with adjuvant ChemotherapyEquivalent oncologic results for Stage I Lung Ca

Grogan & Jones. VATS Lobectomy is better than Open Thoracotomy:What is the evidence for Short‐Term Outcomes, Thoracic Clinics, Aug

2008

Case presentation58 y/o smoker presented with hemoptysis

Self employed brick layer

CT scan 2.5 cm spiculated noduleRisk calculator ?

Case presentation58 y/o smoker presented with hemoptysis

Self employed as a brick layer

CT scan 2.5 cm spiculated noduleRisk calculator – 100% chance of malignancyOR – VATS wedge

Mass in fissure along Pulmonary ArteryOpen thoracotomy – lobectomyBenign granulomatous diseaseHome 5 days doing wellOut of work 6 weeks

Surgical StagingSurgical StagingMediastinoscopyMediastinoscopyEBUSEBUSEUSEUS

Thoracoscopy or

thoracotomy

Chamberlain’s procedureCervical mediastinoscopy

Invasive diagnosis and staging

Less invasive Diagnostic & Staging TechniquesFDGFDG‐‐PET (requires tissue)PET (requires tissue)Endobronchial ultrasonography (EBUS) Endobronchial ultrasonography (EBUS) Esophageal UltrasoundEsophageal Ultrasound

Endobronchial Ultrasonography (EBUS)Endobronchial Ultrasonography (EBUS)

Esophageal ultrasound (EUS)

•

Esophagus•

Lymph node

•

Vascular structure

Enlarged lymph node by EUS

EBUS vs MediastinoscopyEBUS vs Mediastinoscopy

•• CT and PET directed EBUS & EUSCT and PET directed EBUS & EUS•• Excellent Excellent --

minimally invasive toolsminimally invasive tools

•• MediastinoscopyMediastinoscopy•• Standard of care for mediastinal stagingStandard of care for mediastinal staging•• Necessary if EBUS negative with suspicious nodesNecessary if EBUS negative with suspicious nodes

Therapeutic options for high risk

surgical candidates

Chemo / XRTLimited Resections

SegmentalWedgeWedge with local brachytherapy

Stereotactic radiation therapy (SRT)Radiofrequency ablation (RFA)

Limited Resection vs. Lobectomy (T1N0)

Event N Rate N Rate p

Recurrence NOT 2nd

primary38 .101 23 .057 .02

Recurrence 2nd

primary 42 .112 32 .079 .079Recurrence local-regional 21 .06 8 .02 .008Recurrence Distant 17 .048 15 .037 .672Death w/ Ca 30 .073 21 .049 .094Death (all causes) 48 .117 38 .089 .088

Limited Lobectomy

Ginsberg RJ et al, Lung Cancer Study Group, "Randomized Trial of Lobectomy Versus Limited Resection for T1N0 Non-Small Cell Lung Cancer". Ann Thorac Surg 60:615-23 (1995).

Author #pts LR 5 yr. Survival

Santos, Surgery, 2003

1012% vs 18.6%

*

Lee, Ann Thor Surg, 2003

33 6% T1N0 77% (5 yr)

T2N0 53% (5 yr)

Birdas,Ann Thor Surg, 2006

41 (Ib) 4.8% 43% (4 yr)

Sublobar

Resection and Brachytherapy

* Without Brachytherapy

Brachytherapy‐ ACOSOG Z4032

Solitary pulmonary nodule in a patient at high risk of morbidity/mortality from lobectomy

Lambright -

VUMC PI


Creation ofbrachytherapy mesh


Placement ofbrachytherapy mesh

Stereotactic radiation therapy (SRT)

•• 3D Radiotherapy3D Radiotherapy

•• Use in U.S. increasingUse in U.S. increasing

••

Sustained local control rates as Sustained local control rates as high as 90% in early lesionshigh as 90% in early lesions

TimmermanTimmerman

et al et al ChestChest 2003;124:19642003;124:1964--1955. 1955.

•• < 3cm lesions< 3cm lesions

••

RTOG 0236: prospective study RTOG 0236: prospective study ongoing using modified dosing ongoing using modified dosing scheduleschedule

Stereotactic radiation therapy (SRT)Stereotactic radiation therapy (SRT)

Local Ablative TherapiesLocal Ablative Therapies

RFARFAMicrowave TxMicrowave Tx

ACOSOG Z4033ACOSOG Z4033

A Pilot Study of Radiofrequency A Pilot Study of Radiofrequency Ablation in HighAblation in High--Risk Patients Risk Patients Stage 1A NSCLCStage 1A NSCLC

Author # lesions Local

Recurrence

Survival(Overall)

Lanuti

et al, J Thor Card Surg, 2009

31 ptsSt 1 NSCLC

11% 47% (4 yr)

Pennathur

et al,J Thor Card Surg, 2007

19 ptsSt I NSCLC

42% 95% (1 yr)

Ambrogi

et al,Eur

J Cardiothor

Surg, 200664 lesions 39% n/a

Simon et al,Radiology, 2007

116 ptslesions

43% T1 (3 yr)75% T2 (3 yr)

27% (5 yr)

Local Ablative Therapies Local Ablative Therapies --

RFARFA

RFA – pre and post

Baseline 1 month 3 months 6 months 12 months

(35.9 HU) (0.0 HU) (4.0 HU) (26.0 HU) (15.0 HU)

Limitations of non surgical local control therapy

Cannot obtain a pathological stage

Cannot assess completeness of treatmentNo pathological marginsFollow‐up is essential

Long‐term follow‐up unavailableClinical trials ongoingLocal recurrence and survival as objectives

Objectives:





RFA & SRT


Eric L. Grogan, MD, MPHStephen Deppen, MA, MS (PhD Epi student)

Pierre Massion, MD (Mentor)

Dept

of Thoracic SurgeryInstitute for Medicine and Public Health

VPSD program

• Many new lung nodules• Accurate diagnosis essential (95%)

• Low threshold for resection• 20‐30% benign diagnosis rate• “Appendectomy”

• Need noninvasive tests to exclude benign nodules• Biomarkers• New imaging techniques

Surgically Evaluated Pulmonary Nodules

Malignancy Rates in VUMC Thoracic Surgery Population 2005 -

2009

Number of Pts

Malignancy Rate

Compared to All Cases

All Cases 191 72% ref.Age>50 Smoker

PET Positive 87 90%

Predicting cancer with current models (Mayo)

ROC curvesDifferent malignancy ratesSimilar curves

Isbell et al –

Accepted STS Jan 2010

How good is FDG PET to diagnose NSCLC?

All CasesSize ≤

3cm & No Diagnosis

Number of Patients 217 87Malignant Cases 171 (79%) 56 (63%)

Accuracy (PET) 78% 72%Sensitivity 89% 89%Specificity 37% 42%Positive Predictive Value 84% 72%Negative Predictive Value 49% 70%

Grogan et al –

Submitted AATS

Diagnostic testing 2X2

Prevalence = a+c

/ NAccuracy = (prevalence)(Sensitivity) + (1-prevalence)(Specificity)

DISEASE

TEST Yes No

Positive a b

Negative c d

Positive Predictive value = a / a+b

Negative Predictive Value = d / c+d

Sensitivity = a / a+c Specificity = d / b+ d

What do we need?

Test to exclude lung cancerHighly specificHigh negative predictive value

Better predictive modelsBiomarker based

Improved imaging techniques

http://www.vicc.org/jimayersinstitute/devt/pipeline.php, accessed 7/2009

http://www.vicc.org/jimayersinstitute/devt/pipeline.php

3 phases of our work

Identify who will benefit from additional testingSerum MALDI‐MS biomarker profile

Establish performance characteristicsClinically relevant patient population (nodules

Biomarker Test Population

50% Benign Disease12% Benign Disease

VUMC SPORE DATABASE –

Massion

Nodule Cohort

Prevalence = 64%Sensitivity = 26%Specificity = 100%Pos Pred Value = 100%Neg Pred Value = 47%

Cancer

MALDI Yes No

Positive 5 0

Negative 9 8

Small numbers: Pilot study

VUMC SPORE DATABASE –

Massion

Nodule Cohort

Conclusions

•

More accurate diagnosis of NSCLC in patients with SPN is needed

•

Sub‐populations of patients exist with “intermediate probability for disease”

who will

benefit from an additional tests•

New diagnostic strategies with high specificity

and high negative predictive value will reduce unnecessary operations for benign pulmonary nodules

Acknowledgements

MentorsPierre Massion, MDBill Putnam, MDBob Dittus, MD, MPH, Ted Speroff, PhD

Research TeamStephen Deppen (PhD Epidemiology student)Emphasis Students – Jodi Weinstein, Aaron Dawes, Gabriella Andrade

Dept of Thoracic SurgeryBill Putnam, Eric Lambright, Jon Nesbitt

PATZ model

Classification and regression tree analysisComplex algorithmCEA, RBP, SCC, AAT

ResultsSensitivity 77.8%Specificity 75.4%

In one of 3 “bins” 90% chance of cancerComplex – not practical for use

020406080

100

0 10 20 30 40 50 60Months

Potti

A et al: N Engl

J Med 355:570, 2006

Surv

ival

(%)

Surv

ival

(%)

ACOSOG Validation Cohort

CALGB Validation Cohort

020406080

100

0 25 50 75 100 125 150Months

Metagene models for prognosis in

NSCLC

Low risk

of recurrence

High risk

of recurrence

P

early diagnosis and treatment of lung cancer€¦ · objectives: epidemiology of lung cancer...

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