RESTAGING AFTER RESTAGING AFTER NEOADJUVANT THERAPY NEOADJUVANT THERAPY

Prof. Dr. Nezih ÖzdemirProf. Dr. Nezih ÖzdemirAnkara Ankara University School of University School of

Medicine Medicine Department of Thoracic Surgery Department of Thoracic Surgery

20062006

STAGESTAGE

The most important factor The most important factor affecting treatment plan and affecting treatment plan and

prognosis prognosis

Importance of restaging after Importance of restaging after induction treatmentinduction treatment

N2N2 The most important prognostic factor The most important prognostic factor

5 year survival pN0 %35.8 5 year survival pN0 %35.8 pN1-2 %9pN1-2 %9 3 year survival pN0 %59 3 year survival pN0 %59 pN2 %0pN2 %0

P. Van Schil “The restaging issue” Lung Cancer 2003;42:39-45

Induction Treatment Induction Treatment

to improve survival by controlling to improve survival by controlling subclinical metastasessubclinical metastases

other:other:

• to increase resectabilityto increase resectability

• to reduce the extent of resectionto reduce the extent of resection

objectives

GGood prognostic factors after induction ood prognostic factors after induction therapy:therapy:

• downstagingdownstaging• complete pathological responsecomplete pathological response• pN0pN0• complete resection complete resection

Staging patterns c – clinical p – pathologic y – restaging after first treatment r – staging at the time of

recurrence a – autopsy

cTNM

yTNM

pTNM

staging methods

induction therapy

restagingmethods

assessment ofobjective response

surgeryChT - RT

OObjective bjective RResponseesponse complete response: disappearance of all complete response: disappearance of all

known diseaseknown disease

partial response: partial response: 5050% or > decrease% or > decrease

progressive disease: progressive disease: 2525% or > increase% or > increase, or , or newly appearing lesionsnewly appearing lesions

stable disease: stable disease: no changeno change

progressive after responseprogressive after response

EORTC, A practical guide to EORTC studies, 1994.

Objective responseObjective response ‘‘It is also clear from these studiesIt is also clear from these studies (trials (trials

on induction therapy) on induction therapy) that radiographic that radiographic assessment of response is relatively assessment of response is relatively inaccurate’inaccurate’..

• complete resection rates similar for stable complete resection rates similar for stable disease and objective responsesdisease and objective responses

• stable disease may have complete stable disease may have complete responseresponse

Bunn Jr PA. 1994.

TNM classification and stagingTNM classification and staging

based on the evidence acquired based on the evidence acquired before treatment, arising from:before treatment, arising from:

• physical examinationphysical examination

• imagingimaging

• endoscopyendoscopy

• biopsybiopsy

• surgical explorationsurgical exploration

cTNM / yTNM

TNM classification and stagingTNM classification and staging

it can be done by clinical, radiological, it can be done by clinical, radiological, and invasive techniquesand invasive techniques

the C-Factor (Certainty Factor) reflects the C-Factor (Certainty Factor) reflects the validity of the classification the validity of the classification according to the methods usedaccording to the methods used

Certainty factorCertainty factor

aTNMevidence from autopsyC5

pTNMdefinitive surgery and pathological examination

C4

invasive staging (biopsy and cytology)

C3

special diagnostic means (CT, MRI, PET, scintigraphy)

C2

cTNM,

rTNM,

and

yTNM

standard diag. meansC1

ApplicabilityDescription of staging

methodsFactor

Sobin LH, Wittekind Ch. TNM classification, 1997.

Methods for mediastinal Methods for mediastinal restagingrestaging

non-invasive meansnon-invasive means• computed tomographycomputed tomography• magnetic resonance imagingmagnetic resonance imaging• positron emission tomographypositron emission tomography

invasive meansinvasive means• remediastinoscopyremediastinoscopy• video-assisted thoracic surgeryvideo-assisted thoracic surgery

alternativealternative approachesapproaches• transbronchial biopsytransbronchial biopsy• ultrasound-guided biopsiesultrasound-guided biopsies

lowsensitivity

higher sensitivity,100% specificity,highest certainty -C3-

little experience to date

P. Van Schil The restaging issue Lung Cancer 2003;42:39-45

Computed Tomography Computed Tomography

SensitivitSensitivityy 41 – 6941 – 69 % % SpeSpecifitycifity 44 – 8444 – 84 % %

*** No superiority of MRI on CT !

CTCT Clinical and pathologic TNM Clinical and pathologic TNM

adaptation adaptation

46.6% (46.6% (GoldstrawGoldstraw))

35.1% (35.1% (Van SchillVan Schill))

For N2-3 disease, FP rate 45%For N2-3 disease, FP rate 45%

((Detterbeck) FN rate 13% FN rate 13%

After induction treatment, reasons After induction treatment, reasons are nonneoplasic in 40% of patients are nonneoplasic in 40% of patients in whom lymph node progression is in whom lymph node progression is seen on CT seen on CT

CT sensitivity 41 % specifity 75 % accuracy 58 %

Rami-Porta et al. Ann Thorac Surg 2000;70:391–5

CTCT

Atelectasis, radiation pneumonia and

fibrosis T? LAP inflammatory ?, micrometastases ?

Because of cell viability decreases more rapidly than tumor volume, CT may show insufficient response to treatment

Evaluation with CT: decrease = partial or complete remission ?

CTCT Mistakes Mistakes

Positron Emission Positron Emission TomographyTomography

SPN SPN Restaging ? Restaging ? >>CTCT Can establish the residual disease better in Can establish the residual disease better in

primary tumor than mediastinal lymph nodes primary tumor than mediastinal lymph nodes High sens. limited spec. in SUV based High sens. limited spec. in SUV based

analysis analysis Lower sens. higher spec. for nodal status Lower sens. higher spec. for nodal status Can not distinguish biological alive and Can not distinguish biological alive and

methabolic active but still dying cells methabolic active but still dying cells Insufficient in determining residual Insufficient in determining residual

microscopic focussmicroscopic focuss

Ryu et all. 26 patients / stage III disease sensitivity and specifity (SUV cut-off 3) 88 ve 67%After pathological examination sensitivity 67, specifity 63% Qualitative analysis of LN sensitivity and specifity 58 & 93, diagnostic accuracy 85%

Memorial Sloan–Kettering 56 LASLC patients retrospective sensitivity and specifity 90 & 67% for residual N disease, sensitivity and specifity 67 & 61%

FDG-PET is more successful for determining recurrences after curative treatment (after high dose RT specifity decreases)

Ryu JS. et al. FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology. Lung Cancer 35(2):179-187, 2002

Akhurst T, Downey RJ, Ginsberg MS. An initial experience with FDG-PET in the imaging of residual disease after induction therapy for lung cancer. Ann Thorac Surg 73:259-266, 2002

47 NSCLC patients 1998/2003 16 cases mediastinoscopy / all patients ChT + 16 cases mediastinoscopy / all patients ChT +

33 cases RT33 cases RT yTNM (CT) 3 CR, 35 PR, 9 stable disease FDG-PET 5 weeks after the ending of induction

treatment 37 patients resection and systematic LND FDG-PET found 9 cases of unsuspected M1

disease 1 FN brain metastasis fixed on CT later Sensitivity 81% specifity 64%

diagnostic accuracy 76% PPV 84% NPV 58% Hellwig D. et al. Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma J Thorac Cardiovasc Surg 2004;128:892-9

FP results after RT FN results related to small tumors and BAC

The role of PET is not clear for restaging Especially for N status, more studies are

needed An important feature of PET is exposing the

newly developed or old but, couldn’t be determined by conventional methods before, distant metastases

FDG uptake can be used as a prognostic indicator in initial application, early period after chemotheraphy, during RT or after curative treatment

Hellwig D. et al. Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma J Thorac Cardiovasc Surg 2004;128:892-9

Hellwig D. et al. Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma J Thorac Cardiovasc Surg 2004;128:892-9

25 patients, 2 different phase II study groups 19 patients staged with mediastinoscopy PET performed to all patients before and after induction therapy

+ surgical resection

PPV and NPV 43 & 100% whom major pathologic response observed in primary tumor

Could not show nodal status correctly 52% of cases For LN (+) cases PPV and NPV 73 & 64% For N2 disease PPV ‹%20

For pN2 sens. and spec. 20 & 70%, PPV-NPV-diag. accuracy 14-77-60%

Accuracy of CT for nodal disease after treatment 56% PET is insufficient in restaging after induction, for both T and N

Port JL. et al. Positron Emission Tomography Scanning Poorly Predicts Response to Preoperative Chemotherapy in Non-Small Cell Lung Cancer Ann Thorac Surg 2004;77:254 –9

Comparison of PET and pathologic stages for nodal disease

PET stage Pathologic stagesN0 N1 N2

N0 (14) 9 3 2 N1 (4) 0 2 2 N2 (6) 3 2 1 N3 (1) 0 1 0 25 12 8 5

Port JL. et al. Positron Emission Tomography Scanning Poorly Predicts Response to Preoperative Chemotherapy in Non-Small Cell Lung Cancer Ann Thorac Surg 2004;77:254 –9

3 studies investigating the value of PET after induction therapy

For restaging of T, PET sensitivity 90, 88, ve 97 %

For residual nodal disease sensitivity 71% and specifity 88%

Although overall sensitivity for residual nodal disease 50%, for paratracheal LN 100% but hilar LN 15%

Specifity is better when the induction includes only ChT / FP results are more frequent for the reason of induced inflamation due to RT

Today; invasive techniques like EUS-NAB or remediastinoscopy should continue for mediastinal restaging and, role of PET should be guidance as well as in the initial staging

Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Positron-emission tomography in prognostic and therapeutic assessment of lung cancer:systematic review Lancet Oncol 2004; 5: 531–40

Candidates for surgical Candidates for surgical resection resection

INVASIVE STAGING

IInvanvasivesive staging staging

Does not totally Does not totally elimineliminatate e nodal disease but,nodal disease but, Prevent unnecessary thoracotomies Prevent unnecessary thoracotomies Obtain high complete resection rates Obtain high complete resection rates Select Select neoadjuvanneoadjuvantt chemotherapy indicated chemotherapy indicated

cases (extracapsular spread, N3 disease)cases (extracapsular spread, N3 disease) Seperate downstaged or showing progression Seperate downstaged or showing progression

cases after induction treatmentcases after induction treatment

Invasive methods

Method Sensitivity% Specifity% FP% FN% Patient population

Mediastinoscopy 81 100 0 9 clinical N0–2

Mediastinostomy 87 100 0 15 clinical N0–2

TTNA 91 100 0 22 clinical N2

EUS-FNAB 88 91 2 23 clinical N2

TBNAB 76 96 0 29 clinical N2

Detterbeck et al. CHEST 2003; 123:167S–175

BronBronchoscopy/TBNABchoscopy/TBNAB T descriptionT description -Lobe bronchus-Lobe bronchus

-Carina-Carina-Trachea-Trachea

TBNABTBNAB -mediastinal LAP on CT (Subcarinal)-mediastinal LAP on CT (Subcarinal)-Sensitivity-Sensitivity %%7676 -Specifity-Specifity %96 %96 -FN %30-FN %30

If CT/flouroscopy assisted, sensitivity arises to 86-If CT/flouroscopy assisted, sensitivity arises to 86-100% and specifity 100%100% and specifity 100%

(Toloza EM et al. Chest 2003;123:157S-166S)

RemediastinoscopyRemediastinoscopy

incomplete first mediastinoscopyincomplete first mediastinoscopy delayed treatmentdelayed treatment second primary tumourssecond primary tumours recurrent tumoursrecurrent tumours assessment of response after assessment of response after

induction treatmentinduction treatment

indications

First report: Palva T et al. Arch Otolaryngol 1975; 101:748-50.

Restaging Restaging & & treatment treatment protoprotocolcolmediastinoscopy: N2-N3? disease

induction chemoradiotherapy

response/stable disease

remediastinoscopy

No mediastinal involvement

thoracotomy

persistent N2 or N3 disease

radiotherapy

Rami Porta 2004Rami Porta 2004 JanJan 1994 1994 -- April April 2002 2002 43 43 NSCLC patientsNSCLC patients

• 41 N2 41 N2

• 2 N3 2 N3 IIndnduction therapy uction therapy

• ChTChT: 37: 37

• ChT&RTChT&RT: 6: 6

RRemediastinosemediastinoscopy results copy results

persistpersistentent N2 N2 diseasedisease: 20 : 20 New New N3 N3 diseasedisease: 1 : 1

No No nodal nodal diseasedisease: : 22 22

RT

thoracotomy

True (+)

ThThoraoracotomy resultscotomy results

reresseectionction: 21/22 (: 21/22 (%%95.4)95.4) ssyystematistematicc nodal di nodal dissssectionection

• N0: 13 N0: 13

• N1: 3 N1: 3

• N2: 6N2: 6

True (-)

False (-)

RemediastinosRemediastinoscopycopyStaging value

SensitivitSensitivityy 0.780.78

SpeSpecifitycifity 11

Diagnostic accuracy Diagnostic accuracy 0.860.86

PoPositive predictive value sitive predictive value 11

NegatiNegative predictive value ve predictive value 0.730.73

CT sensitivity-specifity-accuracy 41-75-58 %CT sensitivity-specifity-accuracy 41-75-58 %

RemediastinosRemediastinoscopycopyStaging value

ValueValue Van Schil Van Schil

20022002

Rami-PortaRami-Porta

20020044

SensitivitSensitivityy 0.730.73 0.780.78

SpeSpecifitycifity 11 11

Diag. Accuracy Diag. Accuracy 0.850.85 0.860.86

PPVPPV 11 11

NPVNPV 0.750.75 0.730.73

# # patients patients 2727 4343

ConclusionConclusion

Usually done by CT and PET Usually done by CT and PET important to assess objective responseimportant to assess objective response should be aimed to identify patients who should be aimed to identify patients who

will benefit from lung resectionwill benefit from lung resection to rule out persistent N2-N3 diseaseto rule out persistent N2-N3 disease invasive techniques offer the highest invasive techniques offer the highest

classification certaintyclassification certainty

Restaging

ConclusionConclusion

technically feasibletechnically feasible has low morbidityhas low morbidity has high accuracyhas high accuracy best method to identify patients who will best method to identify patients who will

benefit from lung resectionbenefit from lung resection should be performed routinely when should be performed routinely when

there is no evidence of progressive there is no evidence of progressive diseasedisease

Remediastinoscopy

Stamatis et all. Stamatis et all. 279 lung cancer cases --- remediastinoscopy279 lung cancer cases --- remediastinoscopy Incomplete first procedure, recurrence, second Incomplete first procedure, recurrence, second

primary tumor primary tumor 165 cases after induction ChT/RT (116 N2–49 165 cases after induction ChT/RT (116 N2–49

N3)N3) Interval between two mediastinoscopies 132 Interval between two mediastinoscopies 132

days days No mortality, 7 minor complications, 5 patients No mortality, 7 minor complications, 5 patients

unsuccessful unsuccessful 126 N0, 20 N2, 14 N3 126 N0, 20 N2, 14 N3 Persistent N2 + surgery ---- 5 year survival 5%Persistent N2 + surgery ---- 5 year survival 5% FP rate related to PET 18.8%FP rate related to PET 18.8%Ann Thorac Surg 1999;68:1144-9 / Pneumologie 2005 59(12):862-6

After induction therapy, remediast. 32 patients After induction therapy, remediast. 32 patients 26 ChT, 6 ChT/RT ---- complication (-)26 ChT, 6 ChT/RT ---- complication (-) 12 (+) and RT, 20 (-) and thoracotomy12 (+) and RT, 20 (-) and thoracotomy RM --- sens, spec ve accuracy 71, 100 and 84%RM --- sens, spec ve accuracy 71, 100 and 84% Median survival Median survival + RM 7 months+ RM 7 months

- RM 41 months- RM 41 months FN RM 24 monthsFN RM 24 months

Only nodal disease significant prognostic factor Only nodal disease significant prognostic factor Diagnostic accuracy is lower compared with Diagnostic accuracy is lower compared with

initial mediastinoscopy but, for persistent N2 initial mediastinoscopy but, for persistent N2 most valuable method most valuable method

Van Schil P. Nodal status at repeat mediastinoscopy determines survival in non-small cell lung cancer with mediastinal nodal involvement, treated by induction therapy Eur J Card Thorac Surg 2006; 29:240-3

1988-1996, 103 stage IIIA (N2) NSCLC patients, all invasive 1988-1996, 103 stage IIIA (N2) NSCLC patients, all invasive staged and received induction therapy staged and received induction therapy

76 ChT, 18 RT, 9 ChT76 ChT, 18 RT, 9 ChT&&RTRT All restaged with CT All restaged with CT Anatomic resection + radical lymphadenectomy performed to Anatomic resection + radical lymphadenectomy performed to

all all

Complete pathologic response (T0N0) 4 casesComplete pathologic response (T0N0) 4 cases29 N0, 25 N1 (downstaging) --- 49 persistent N2 29 N0, 25 N1 (downstaging) --- 49 persistent N2

74 adjuvant treatment (RT - 58)74 adjuvant treatment (RT - 58)

5 year survival for all patients 17.5%, 5 year survival for all patients 17.5%, N0 35.8%, N1-2 9%N0 35.8%, N1-2 9%(No statistical difference between N1 and N2)(No statistical difference between N1 and N2)

To identify patients downstaged and will benefit from surgery, To identify patients downstaged and will benefit from surgery, re-invasive staging (VATS, remediastinoscopy, TBNAB or re-invasive staging (VATS, remediastinoscopy, TBNAB or endoscopic USG-NAB) is neededendoscopic USG-NAB) is needed

Bueno R, Sugarbaker DJ. et al. Ann Thorac Surg 2000;70:1826 –31

1996-1999, 36 NSCLC patients, N2 (+) with 1996-1999, 36 NSCLC patients, N2 (+) with mediastinoscopymediastinoscopy

* * restaging with restaging with CTCT

** nonsurgical group medium survival nonsurgical group medium survival 8 months8 months

** surgical group surgical group 3 year survival 3 year survival

“downstaged” group 59 % “downstaged” group 59 % persistent N2 0 % persistent N2 0 %

Voltolini L. et al. Results of induction chemotherapy followed by surgical resection in patients with stage IIIA (N2) non-small celllung cancer: the importance of the nodal down-staging after chemotherapy European Journal of Cardio-thoracic Surgery 2001; 20:1106–12

EUS-FNAB 89-95% accuracy Multiple advantages: tissue samples

taken, minimally invasive and multiple repetitions if wanted

19 invasively staged N2 patients Not taken into consideration for firstly

positive lymph nodes were which stations

Taken biopsies from accessible all lymph nodes with guidance of “real time USG” by 22G fine needles

All materials “on-site” determined Jouke T. Annema et al. Mediastinal restaging: EUS-FNA offers a new perspective Lung Cancer (2003) 42, 311-18

Procedure lasted on average 20 mins and no complications occured

8 cases persistent N2, sonography suspected but could not be biopsied one case confirmed by mediastinotomy (4R)

PPV, NPV, sensitivity, specifity and diag. accuracy 100, 67, 75, 100 83

Because of air in the trachea and main bronchi obscuring visualisation, procedure has limitations at paratracheal stations (2L, 2R & 4R)

But 4L, 5, 7, 8 and 9 can be reached (not accessible with mdstcopy)

Only contraindication esophageal stricture A major advantage is the real-time controlled biopsy where the tip

of the needle is visible during the complete biopsy procedure. With the current technique it has not been possible to perform EBUS guided TBNA

Diagnostic accuracy of this study is near remediastinoscopy Jouke T. Annema et al. Mediastinal restaging: EUS-FNA offers a new perspective Lung Cancer (2003) 42, 311-18

EUS-FNAB results Final stage pN2 pN0 TotalpN2 9 3 12pN0 0 6 6Total 9 9 18

Jouke T. Annema et al. Mediastinal restaging: EUS-FNA offers a new perspective Lung Cancer (2003) 42, 311-18

RESULTRESULT

Progress RTProgress RT

Partial response/stable disease Partial response/stable disease

Invasive staging (-)Invasive staging (-)

PET ±

Resection