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Revisiting bronchoscopic intratumoral chemotherapy in malignant central airway obstruction via EUS-B approach and its review of literature

Critical central airway obstruction has always been a dreaded complication to which interventional pulmonologist commonly encounters. There have been various modalities which are used for the management and palliation, which includes mechanical coring, laser, cryoextraction, electrocautery and airway stenting. Rigid bronchoscopy with or without jet ventilation has been corner stone of therapeutics and palliation of central airway obstruction. There are only a few conditions where it is not possible to use rigid bronchoscopy. Here we report a case of metastatic tracheal tumour which presented with critical airway obstruction in a patient who had atlantoaxial instability (AAI) due to rheumatoid arthritis. Here we used endobronchial ultrasound scope (EBUS) via esophageal route, i.e. EUS-B guided approach for sampling of the tracheal tumour, and intratumoral chemotherapy was instilled in multiple sessions, which resulted in shrinking of tumour, thus relieving the critical airway obstruction. This is the first report of using EUS-B approach for intratumoral chemotherapy for tracheal tumors. Bronchoscopic intratumoral chemotherapy therapy (BITC) in tracheal tumors is also one of the options but has not been explored much and there has been a dearth of literature for it.


Introduction
Malignant central airway obstruction is usually managed by multidisciplinary approach involving tumour debulking, stent placement and palliative radiotherapy (RT). Rigid bronchoscopy has been main stay for this procedure [1]. There are few conditions where rigid bronchoscopy is contraindicated or may prove counterproductive. Atlantoaxial instability is one of such cases where any manipulation of cervical spine could result in spinal cord compression [2]. In such cases BITC may be attempted via flexible bronchoscope, EBUS or EUS-B approach. EUS-B approach i.e. using endobronchial ultrasound scope (EBUS) for oesophageal ultrasound which has been used time and again, has proven to be effective and with less side effects [3]. We used this approach in our case of malignant central airway obstruction thus not comprising the airway. Later this approach was improvised for first time in available literature for intratumoral chemotherapy.

Case Report
A 53-year-old female farmer, non-smoker but with history of biomass exposure presented with cough for 4 weeks. She was diagnosed 3 years back with atlantoaxial Instability (AAI) due to rheumatoid arthritis for which she was using a semi-rigid cervical collar and was taking mycophenolate mofetil. She had cough which used to get worsened on exertion and was accompanied by noisy breathing. Patient had breathlessness which progressed from grade II to grade III in the last 3 months. Spirometry showed fixed airway obstruction with flattening of inspiratory and expiratory limb of the flow volume curve on spirometry. Chest radiology showed possibility of tracheal mass which was later confirmed on computerized tomographic scan (CT scan). CT showed soft tissue endotracheal lesion of size 15 bifurcation. Mass had a broad base and was arising from the right lateral and posterior wall encroaching 75% lumen resulting in critical airway obstruction. Lung window showed centrilobular and peri-bronchial nodules in bilateral lower lobes with tree in bud appearance with ground glass opacity suggestive of pneumonia ( Figure 1). Bronchoscopy revealed fleshy globular mass which had tortuous vessels over it and Karl Storz scope (C-MAC® FIVE S) with outer diameter 3.5 mm could just be negotiated. Biopsy was deferred due to anticipated haemorrhage as tumour appeared very vascular. As in cases of critical airway obstruction even mild haemorrhage can asphyxiate patient as airway is already being compromised. In addition, tracheal washings were positive for acid fast bacilli. Rigid bronchoscopy is the procedure of choice for managing central airway obstruction (CAO). However, in our case it was not possible due to AAI [3]. So, TBNA was planned via EUS-B approach. EBUS scope (EVIS EXERA II, Olympus Inc., Tokyo, Japan) was introduced via oesophagus [3,4]. Sonography showed heterogenous mass with a coursing vessel and had well defined margins. It was obliterating almost 75% of lumen and was extending almost 2 cm longitudinally. EUS-B guided FNAC was done and three passes were taken. FNAC was suggestive of squamous cell carcinoma. PET CT showed FDG avid very small subcarinal nodes (SUV 4.2) and mesenteric nodes (SUV 4.9) along with endotracheal mass (SUV 9.6) rendering it non-operable.
In non-operable critical airway obstruction, only options are related to palliation of symptoms. Palliation of symptoms can be achieved by debulking procedures via rigid bronchoscopy (RB) or by using radiotherapy. RB was not an option as the patient was having AAI. Radiotherapy primarily was deferred as acute oedema post RT would have resulted in a catastrophe in form of asphyxia.
Systemic chemotherapy alone would have taken long time to act and patient had tuberculosis which would have become fulminant. Thus, there was need of modality that could palliate symptoms and be acceptable. Hence, intratumoral chemotherapy therapy (ITC) for palliation of CAO was considered. After informed consent, she underwent novel EUS-B guided intratumoral cisplatin instillation. Using EUS-B had advantages as critically obstructed airway was not compromised further. ITC required multiple sessions and with this approach complications such as hypoxia, aspiration pneumonia, haemorrhage and fever, which have all been seen in previous studies (Table 1), were avoided. Patient needed systemic chemotherapy as it was a metastatic disease which was started after 4 weeks of initiation of antitubercular treatment.
For EUS-B guided ITC, EBUS scope was introduced in oesophagus. After visualizing endotracheal mass via EUS-B, EBUS needle was used to puncture it and in first session 10 ml of cisplatin in aqueous solution (4 mg/ml) was instilled into the mass in three different sites. Dose was according to previous study where they have used cisplatin intratumorally [3]. Minimal increase in size was visualised sonographically while instillation. Patient had no peri procedural and post procedural complication and check bronchoscopy after 1 week showed around 10% decrease in size. Sessions of ITC were repeated at week 2, 3 and 4. In the 3 rd and 4 th week we used cisplatin 40 mg (4 mg/ml) in combination with gemcitabine 500 mg (100 mg/ml) as mass had shrunken in size and there was scope of instilling more volume of drug. After 4 weeks of anti-tubercular treatment patient was started on systemic chemotherapy. There was almost 50% reduction at 4 th week. Check FOB after 6 months showed that CAO reduced to almost 25 % ( Figure 2). Follow-up CT scan was planned but could not be done as patient expired due to sudden cardiac arrest, a year after the initial procedure.  where it was used in breast carcinoma with 66% improvement rate. It has been used over the years for lid carcinoma, head and neck carcinoma, skin carcinoma and deep seated intra-abdominal tumour with variable success [4].

Case Report
BITC has been used in past in lung cancer but has not gain much popularity. Following Jabbardarjani et al. [10] 100 patients with unresectable 20 ml cisplatin with the The lumen was considerably Bleeding (9), hypoxia (12), of chemotherapeutic agent in the tumour without or with very minimal systemic side effects. Conventional treatment using systemic chemotherapy and/or radiotherapy has proven unsatisfactory in yielding rapid restoration of airway patency in patients with malignant airway obstruction. Various successful palliative modalities use systemic treatment with combined local interventional modalities. In our case presence of tuberculosis delayed systemic chemotherapy but BITC can be used in such cases. After BITC, the concentration of anti-neoplastic agent decreases exponentially when it traverses through tumour vessels, and the drug concentration becomes half in 40 micrometres [15]. Intralymphnodal instillation of chemotherapy has been also shown useful in reducing tumour mass but it was not used as nodes were very small.
Our is the first case where EUS-B approach was used to instil chemotherapy. It had many advantages like patient's airway which was already compromised was not shared and throughout the procedure patient had no episode of hypoxia. As it was a vascular tumour there was anticipated danger of bleeding in airway leading to asphyxia. This danger was averted as tumour was approached via oesophagus. Few studies showed post procedural pneumonia after BITC because of aspiration of chemotherapeutic agent. It too was taken care of as puncture was made through oesophageal wall so any spill of chemotherapeutic agent in lungs was averted.
There are few limitations which are responsible for BITC not gaining much popularity, first there are no larger trials to determine its efficacy and safety profile. BITC takes longer time to palliate CAO when compared to rigid bronchoscopic coring and thermal endobronchial ablative measures. Expertise and evidence have remained the major issue. Most interventional pulmonologist are not comfortable with multiple sessions and theoretical complications, though practically only few developed pneumonias and rarely one required hospitalization.

Conclusions
BITC can be considered as an alternative neoadjuvant therapy to mechanical or thermal debulking for palliative management of centrally obstructing tumours, where tumour mass is easily accessible by bronchoscope with opportunity for direct intralesional injection of chemotherapeutic agent. Mechanical debulking and thermal modalities often unreachable in distal tumours or may have contraindications; bronchoscopic intralesional chemotherapy could provide an advantage over these modalities in such cases. It is safe, simple, cost-effective procedure which exhibited neither systemic toxicity nor any significant complications in expert hands. It can be done via regular flexible bronchoscopy or EBUS scope. Though further studies are needed to confirm these findings.