'Comparison of EUS/EBUS-guided fine needle aspiration and PET-CT in the restaging after induction therapy of locally advanced non-small cell lung cancer'.

Restaging after induction therapy of advanced non small cell lung cancer
(NSCLC) has been shown to be very important to determinate prognosis1-4 .
The choice of local therapy (surgery or radiotherapy) might be influenced by
the persistence of N2 or N3 disease as is studied at the moment by the Dutch
NVALT 6 study. Superiority of local therapy in downstaged patients is under
investigation. An EORTC proposal with randomization between radiotherapy or
surgery after downstaging is prepared at the moment. Restaging procedures to be
considered are re-mediastinoscopy, PET-CT, endoscopic ultrasound guided fine
needle aspiration (EUS-FNA) and endobronchial ultrasound guided transbronchial
needle aspiration (EBUS-TBNA). Results of re-mediastinoscopy were disappointing
demonstrated by 40% incomplete procedures due to fibrosis in a study of 15
patients5. PET-CT is by far superior to re-mediastinoscopy 6. Endoscopic
ultrasound (EUS) is feasible in mediastinal restaging (7), but covers just a
part of the mediasinum. Endobronchial ultrasound (EBUS) is developed more
recently and also showed to be very useful in staging the mediastinum (8,9).
Restaging studies with EBUS have not been published untill now. Combining both
ultrasound modalities showed the complementarity of EUS and EBUS in staging the
mediastinum (10). The accuracy of a combined approach of EUS-FNA and EBUS-TBNA
was 100% for the diagnosis of mediastinal cancer in a group of 28 patients (11).
On theoretical grounds it seems reasonable to assume that the combination of
EUS and EBUS makes an exploration of all mediastinal lymph nodes possible to a
greater extend than mediastinoscopy. Superiority of EUS-FNA over
mediastinoscopy was demonstrated in a study of 60 patients having both
diagnostic investigations for mediastinal staging of NSCLC (12).
Since resolution of ultrasound techniques is high and fine needle aspirations
are real-time it is expected that a combination of EUS and EBUS has a higher
accuracy than PET-CT and could become the preferred restaging tool in near
future. To prove this hypothesis we have to compare both modes of restaging in
a prospectively designed study. Therefore all patients with stage III treated
by induction therapy(chemotherapy or chemoradiotherapy) will be analysed with
PET-CT and EUS/EBUS as restaging tools. False negative findings could be caused
by sampling errors or false interpretations by the cytopathologist of specimens
with tumour cell poverty. Especially pre-treated nodes with diminished tumour
burden could theoretically raise this false negative rate. Although sampling
errors will remain a problem, the question rises if the more sensitive immune
histochemical analysis could modify EUS-FNA and EBUS-TBNA results. In order to
answer this question, biopsies obtained by EUS-FNA and EBUS-TBNA and blocked in
Agar-agar to make them suitable for immune histochemical analysis, will
retrospectively be analysed for patients with false-negative restaging results
proven by thoracotomy and lymph node dissection.

1. This study aims to compare the accuracy of EUS/EBUS and PET-CT as restaging
tools in patients treated with induction therapy for stage IIIA or IIIB
NSCLC.

2. To study the additive value of immune histochemical staining of adequate
biopsies without obvious tumour cells at routine microscopy.

prospective, open, single-arm trial.

Hundred patients with an age between the18-85 years treated with induction
therapy (chemotherapy and / or radiotherapy) for stage IIIA or IIIB NSCLC will
be recruited at the outpatient clinic of the pulmonology department. All
patients will undergo PET-CT and EUS-FNA and / or EBUS-TBNA before and after
induction therapy. Both PET-CT scans will be compared and the decline in
standard uptake value will be quantified. This decline will be correlated with
the results of restaging by means of ultrasound guided aspirates (EUS and
EBUS). Verification of negative cytologic results will be done by surgical
procedures like mediastinoscopy or preoperative lymph node dissections.
Patients will be (preferably) re-staged with the same procedure as in initial
analysis before induction treatment. If the patient was staged initially by
mediastinoscopy, the re-staging ultrasound procedure will be determined by the
localisation of lymph node metastasis. The approach of right sided paratracheal
lymph nodes and pretracheal lymph nodes is generally by EBUS-TBNA whereas the
other localisations could be biopsied with EUS-FNA. The subcarinal nodes can be
reached by either mode of ultrasound guided biopsy. The next possibilities
could occur in the diagnostic approach:

1. PET-CT shows activity in the lymph nodes, but EUS-FNA detects no tumorous
cells; mediastinoscopy will follow.

2. PET-CT shows no activity in the lymph nodes and EUS-FNA detects no tumorous
cells, surgery (seldom radiotherapy) will be undertaken.

3. PET-CT shows activity in the lymph nodes and EUS-FNA detects tumorous
cells, surgery is excluded.

4. PET-CT shows no activity in the lymph nodes, but EUS-FNA detects tumorous
cells, surgery is excluded.

Besides routine cytological analysis on stained slides, the specimen obtained
with EUS-FNA or EBUS-TBNA will be caught in a diagnostic tube, fixed with
carbowax and centrifuged to a cellular cast. This pellet of cells will be
fixed in agar-agar, sliced and used for immunehistochemical analysis. The
slides will be analysed by an experienced cytopathologist in those cases where
standard cytological investigations showed adequate lymphogenic material but no
tumour cells and only in patients where the results showed to be false negative
after a *golden standard procedure* such as thoracotomy with mediastinal lymph
node dissection. The accuracy of EUS/EBUS and PET-CT separately and in
combination as restaging tools in stage IIIA or IIIB NSCLC patients after
induction therapy will be determinated. The additive value of immune
histochemical staining of adequate biopsies without obvious tumour cells at
routine microscopy will also be evaluated. Patients who seem to be downstaged
(EUS/EBUS and PET-CT negative) will proceed to thoracotomy. Resection of tumor
and mediastinal lymph node dissection is obligatory. PET-CT*s of patients who
are excluded from surgery, but who are candidates for adjuvant radiotherapy,
could be used by the radiotherapist to detect the exact radiotherapy field.

All patients will undergo PET-CT and dependent on these findings EUS-FNA
and / or EBUS-TBNA or mediastinoscopy will be performed. Immunehistochemical
analysis will be performed retrospectively by a cytopathologist in
cases of negative finding after surgical verification.

Patients are at risk for infection and bleeding. These investigations are,
however,
also part of the regular diagnostic work-up and biopsies are inevitable for the
definite diagnosis.