Endobronchial Ultrasound to Evaluate Downstaging of Lung Cancer After Combined Chemotherapy and Radiation Treatment

While previous studies did indeed advance novel treatment methods for NSCLC, the team in Bangkok Hospital found it curious that even in a recent study published in April 2012, the most advanced staging evaluation methods used were mediastinoscopy or mediastinotomy (following bronchoscopy, bone scan, computed tomography (CT) scan of the chest) to acquire biopsy samples from lymph nodes. A randomized trial in 2010 of two-hundred and forty one patients revealed that a staging strategy combining endosonography and surgical staging showed a higher sensitivity rate for mediastinal nodal metastases when compared to surgical staging alone among patients with (suspected) NSCLC. A minimallyinvasive procedure, endobronchial ultrasonography is currently considered the gold standard in the evaluation of mediastinal lymph nodes and lung lesions along with its other usage in the clinical set-up.


Saenghirunvattana S, MD
Endobronchial Ultrasound to Evaluate Downstaging of Lung Cancer After Combined Chemotherapy and Radiation Treatment C hemotherapy and radiotherapy, separately or sequentially, are established protocols in the management of lung malignancy.However, as early as 1999 a study in Osaka, increased response rate and enhanced median survival duration when compared with the sequential approach [as applied to selected patients with unresectable stage III non-small cell lung cancer (NSCLC)]. 1veral other studies and clinical trials that were subsequently radiotherapy in the management of NSCLC. 2 While previous studies did indeed advance novel treatment methods for NSCLC, the team in Bangkok Hospital found it curious that even in a recent study published in April 2012, 3 the most advanced staging evaluation methods used were mediastinoscopy or mediastinotomy (following bronchoscopy, bone scan, computed tomography (CT) scan of the chest) to acquire biopsy samples from lymph nodes.A randomized trial in 2010 of two-hundred and forty one patients revealed that a staging strategy combining endosonography and surgical staging showed a higher sensitivity rate for mediastinal nodal metastases when compared to surgical staging alone among patients with (suspected) NSCLC. 4A minimallyinvasive procedure, endobronchial ultrasonography is currently considered the gold standard in the evaluation of mediastinal lymph nodes and lung lesions along with its other usage in the clinical set-up.use of chemotherapy and radiotherapy by using endobronchial ultrasound (a low-risk method), as an evaluation tool for downstaging of lung cancer patients not limited to NSCLC.

Eligibility Criteria
The patients who were selected for this study were histologically lung cancer.They were aged 18 and above, without intake of aspirin or any blood thinners 7 days prior to procedure and signed a written consent for treatment in the hospital and for receiving the EBUS procedure in the operating room.

Exclusion Criteria
Patients who were excluded were pregnant or nursing, or fertile patients who aren't using effective contraception; had previous thoracic radiotherapy, chemotherapy, immunotherapy or biologic therapy for lung cancer; or blood thinner intake 7 days prior to procedure.

Endosonography
A combination of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endobronchial ultrasound with guide sheath (EBUS-GS) was used to obtain sample specimens for biopsy.During endobronchial ultrasound (EBUS) procedures, the lungs and mediastinum were visualized for possible pathology enabled the operator to see structures through the wall of the airway.Samples of the lymph nodes and any masses were taken as necessary.Biopsy specimens underwent On-site pathology/Rapid on-site evaluation (ROSE).The remaining tissue samples were sent to the laboratory for further cytological and immunohistochemistry testing.
via Anaplastic lymphoma kinase (ALK) and the epidermal growth factor receptor (EGFR) tests.

Chemotherapy and Radiotherapy
chemotherapy and radiotherapy drug combination.

Case Report #1
A 72-year-old male patient was previously being treated for chronic obstructive pulmonary disease (COPD) when chest x-ray revealed left lower lung mass.Carcinoembryonic antigen (CEA) was 108.90ng/ml and positron emission tomography and computed tomography (PET/CT) Scan showed there was a 3.5x4.0cmspeculated mass in the superior segment of the left lower lobe with radiating nodule was present at the posterior gutter of the left lower lobe.There are a few 0.6-0.9cmnodes at the interlobar station of the left hilum.There was another 1.0cm pleural based nodule at the posterior segment of the right upper was seen.There are a few 0.5-0.7cmnodes in the lower emission tomography (PET) scan in the thorax was a left lower lobe lung mass showing markedly increased the foundations of digital Games (FDG) uptake with maximum standardized uptake value (SUV) of 6.1.Hypermetabolic hilar node was also noted with SUV of Faint metabolic activity of nodule in right upper lobe and right hilar region was noted with SUV of 0.8 and 1.1 respectively.Bronchoscopy and biopsy were done which revealed small sheets of tumor cells found with highly pleomorphic enlarged hyperchromatic nuclei, occasional small nucleoli and abundant vacuolated cytoplasm.He was then diagnosed of non-small cell carcinoma.
The patient underwent sessions of radiation and chemotherapy treatment.He was able to tolerate the medications and therapy until 6 months later, when he developed left lung atelectasis.His chest x-ray showed retrocardiac left lower lobe atelectasis appearing slightly increased.Small amounts of bilateral pleural effusion, more on the left side were noted.The CT scan of chest revealed right pneumothorax, measuring about 0.7 cm in segment of left lower lobe, where atelectasis was increased.Fluid in left bronchi was observed.
Fiberoptic bronchoscopy was done and revealed endobronchial obstruction of the medial and lateral segment of left lower lobe.A tumor at the medial segment was completely removed but the lateral segment tumor was hard as stone.Biopsy was done instead and bleeding was managed by electrocautery.Cytopathology report was acute and chronic bronchitis with mild squamous metaplasia.found.Microscopic investigation showed that two pieces of bronchial mucosa showing mild acute and chronic epithelioid granuloma or malignancies were observed.
He was then treated for atelectasis and bronchitis.The recurrence of lung cancer.

Case Report # 2
A 60-year-old male, was diagnosed with limited small cell lung cancer post chemo, thoracic radiation therapy and prophylactic whole brain radiation therapy (WBRT).His last dose was given 3 months prior to consultation.
Three months prior to consult, the patient complained of dysphagia, body weight loss of 8 kilograms (kg) for the past 2 months, chest discomfort that radiates to the abdomen and voice hoarseness.
Physical examination revealed that he appeared thin, had diminished breath sounds upon auscultation, no coughing, no sputum, and had no fever episodes.PET/ CT scan revealed there is a 3.0x3.5cmspeculated mass segment of the right upper lobe with extension to the the right hemithorax (Figure 1).There are scattered foci of reticulonodular opacities in the upper lobe, superior segment right lower lobe and the right middle lobe, possibly representing underlying or superimposed infection.A few lungs.There was no pleural effusion.A 0.7cm right hilar node and 0.6cm subcarinal and right lower paratracheal nodes were observed.PET scan revealed speculated mass in the posterior segment of right upper lung and showed faint uptake of the FDG with SUV of 1.3.Opacities in right upper and right lower lung also showed minimally increased  FDG uptake with SUV of 1.6.The metabolic activity of each hilum or mediastinum was not increased.EBUS-GS and EBUS-TBNA were done to investigate if there was evidence of recurrence of lung cancer.
Brushing slide specimen revealed therapy-induced atypia and mediastinal lymph node was negative for granuloma and malignancy.Fluid and brush showed benign reactive bronchial cells along with some foamy macrophages, lymphocytes and neutrophils.Some atypical cells were seen with enlarged cells, vacuolated cytoplasm, multinucleated nuclei and prominent nucleoli.There was no evidence of granuloma or malignancy.Smears contain mature lymphocytes which have small dark nuclei and scanty cytoplasm.The polymorphous population of lymphocytes was also seen.The background shows numerous red cells and benign bronchial epithelial cells.There was no evidence of tumor or granuloma.Bronchial loma or malignancy.
With the provided results, the tumor panel concluded at that moment, there was no evidence of recurrence of small cell lung cancer.

Case Report # 3
A 50-year-old male caucasian patient was diagnosed with adenocarcinoma stage II.He was a former smoker for 6 years and has family history of lung cancer.
Three months prior to consultation, he developed fever, cough, anorexia, body weight loss of 13kg and pain in with his bones.He was then diagnosed with giardiasis and gastritis but was subsequently treated.He regained his appetite but his cough still persisted.One month prior to consultation, he had had several episodes of febrile (temperature 39.8 o C), sweating, and cough.He went for a medical consultation in Chiang Mai, Thailand where he was tested for tuberculosis which came back negative.CT scan of chest revealed mass at the right upper lobe with mediastinal node enlargement.Initial assessment revealed diminished lung breath sounds at right upper lobe lung.PET/CT scan was done and revealed an irregularly outlined soft tissue mass at the posterior segment of the right upper lobe with a broad cm.There was central necrosis at the main component of the mass and cavitation at the peripheral aspect, and at the medial extension behind the right main bronchus.There was no abnormality in the rest of the lungs or pleural effusion.A 0.9cm node was seen at the precarinal space and a few 0.5-0.7cmnodes in the right lower paratracheal showed increased FDG uptake with SUV max of 5.3.The cavitating postbronchial component showed a hypermetabolic activity with SUV of 1.8.CEA was 1.70ng/mL and Quantiferon TB result was negative.
EBUS-GS and EBUS-TBNA were advised for further assessment and evaluation.The onsite pathologist revealed that the specimen obtained from the upper lobe mass revealed adenocarcinoma.However, the two slides from right paratracheal nodes were negative for malignancy.Post operatively, the patient did not manifest pneumothorax, bleeding, and infection.smear contained mature lymphocytes which have small dark nuclei and scanty cytoplasm.The polymorphous population of lymphocytes was also seen.The background showed numerous benign bronchial epithelial cells.The second, showed more bloody background.There is no evidence of tumor or granuloma.The second smear contains some clusters of atypical cells which have enlarged vesicular nuclei, prominent nucleoli and foamy cytoplasm.The background showed benign bronchial epithelium and numerous neutrophils.Bronchial biopsy revealed a section of a small piece infiltrated of malignant glandular epithelium with nuclear enlargement, hyperchromicity, small nucleoli and moderate amount of pink foamy cytoplasm.The larger piece showed only benign bronchial mucosa with numerous neutrophils and results were both negative.
In cooperation with Dr. Lodi, the patient was treated under two protocols.First, was the combination of Taxotere 10mg and Carboplatin 50mg alternating every other week with the second protocol was Cisplatin 10mg, Eteposide 10mg and Vinorelbine 10mg.
After the treatment, the patient decided to go back to his home country, underwent lobectomy which revealed no presence of malignancy in lung tissue.

Discussion
(EUS-FNA) is a mediastinal staging modality that has been developed in the last decade.High sensitivities and speci-4 The procedure is well tolerated, safe and has a high diagnostic accuracy (89-95%) for the analysis of mediastinal lymph node (LN).So far, no complications of EUS-FNA in the analysis of mediastinal LN have been reported.The advantages of this technique are multiple: tissue samples are obtained (in contrast to the imaging technique of CT) and the procedure itself is minimally invasive, is performed in an out-patient setting and can be (in contrast to mediastinoscopy). 5 A similar study published in 2008 investigated the accuracy and sensitivity of EBUS-TBNA for restaging the mediastinum after induction chemotherapy in patients with NSCLC.The team from the University of Heidelberg concluded that despite EBUS-TBNA being a sensitive, mediastinal restaging of patients with NSCLC, tumorstaging before thoracotomy. 6study in Japan, on the other hand, stated that for mediastinal staging in lung cancer, the diagnostic yield of EBUS-TBNA is comparable to surgical staging in patients with enlarged lymph nodes.7 Saenghirunvattana S, et al.
The above studies are important contributions to the development of EBUS.However, their research does not include analysis and evaluation of the downstaging of lung cancer after combined chemotherapy and radiation treatment.To our knowledge, this study in Bangkok Hospital is the pioneering report with which combined EBUS-TBNA and EBUS-GS has been used as an evaluation tool to measure downstaging of lung cancer after combined chemotherapy and radiation treatment.

Conclusion
Endobronchial Ultrasonography (EBUS) is an effective tool in evaluating downstaging in patients with lung cancer after combined chemotherapy and radiotherapy.
EBUS-GS provides a pathway to peripheral pulmonary lesions, enabling the operator to obtain short-axis bronchial views.It is a useful method for collecting samples from peripheral pulmonary lesions, including those which are EBUS-TBNA is known for increasing diagnostic yield in obtaining a specimen for biopsy.It can be used for collecting both cellular and tissue specimen collection.With this capability, administering these procedures in tandem can effectively diagnose lung cancer as well as other diseases such as sarcoidosis and malignant lymphoma.The two procedures, complementing each other in many ways, are both safe for the patient: minimally invasive, relatively low risk and avoiding possible unnecessary thoracotomies. 8

Figure 1 :
Figure 1: A picture of the CT scan result as described in case study # 2