restaging after neoadjuvant therapy
DESCRIPTION
RESTAGING AFTER NEOADJUVANT THERAPY. Prof. Dr. Nezih Özdemir Ankara University School of Medicine Department of Thoracic Surgery 2006. STAGE The most important factor affecting treatment plan and prognosis. Importance of restaging after induction treatment. N2 - PowerPoint PPT PresentationTRANSCRIPT
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