Minimally Invasive Diagnostic and Therapeutic Management of … · 2016. 4. 6. · Endobronchial tumors can cause dyspnea, hemoptysis, cough, and post-obstructive pneumonia. Proximal

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Advances in Lung Cancer Advances in Lung Cancer

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AbstractMinimally invasive procedures allow for the diagno-

sis and treatment of lung cancer while reducing length of hospitalization and complications and palliating symp-toms. The procedures described in this chapter are key components of a thoracic oncology program.

IntroductionRapid advancements are being made in minimally

invasive diagnostic and therapeutic procedures for lung cancer patients.This chapter provides an overview of ad-vanced tools in interventional pulmonology that are cur-rently available as well as their indications, limitations, and risks.

Advanced Diagnostic TechniquesEndobronchial UltrasoundLinear or Convex probe endobronchial ultrasound

transbronchial needle aspiration (EBUS-TBNA) has be-come the premier modality for minimally invasive sam-pling of mediastinal and hilar lymph nodes and masses. EBUS (Olympus BF-UC160F-0L8, Olympus FV- UC180F, or Pentax EB-170BK) allows real-time visualization of transbronchial nodal aspiration [1] whereby the needle can be seen within the target lesion (Figure 1). It uses a 21- or 22-G cytology needle [2,3]. It is acclaimed for its high sensitivity and specificity, ability to simultaneously

Chapter 1

Minimally Invasive Diagnostic and Therapeutic Management of Lung CancerChristina Bellinger1*

1Department of Pulmonary/Critical Care, Medical Center Blvd, Wake Forest Baptist Health, USA

*Corresponding Author: Christina Bellinger, Depart-ment of Pulmonary/Critical Care, Medical Center Blvd, Wake Forest Baptist Health, Winston Salem, NC 27157, USA, Tel: 336-713-4649; Fax: 336-716-7277; Email: [email protected]

First Published February 16, 2016

Copyright: © 2016 Christina Bellinger.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source.



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diagnose and stage lung cancer even reaching hilar re-gions that mediastinoscopy cannot. It is cost effective compared with mediastinoscopy while maintaining a very low riskof complications [4,5,6]. Yields range from 85% to 96% which can be influenced by nodal size, type of cancer and bronchoscopist experience [1-3,5,7]. EBUS has been shown to have equivalent sensitivity and specificity to me-diastinoscopy for lung cancer staging [4,6]. In the current era of personalized medicine for NSCLS, it is important to note that EBUS-TBNA had demonstrated high yields for detecting driver mutations such as EGFR (epidermal growth factor receptor, 90-98 %) and ALK (anaplastic lymphoma kinase, 91-100%) [8-9]. Importantly, most of the studies involving EBUS-TBNA were performed at high volume centers, with experienced bronchoscopist and dedicated lung pathologists so there are likely to be local variations in yield.

Endoscopic ultrasound (EUS) offers additional nod-al station beyond that reached by mediastinoscopy and EBUS. It can access American Thoracic Society stations 4 L, 5, 6, 7, 8, and 9 with yields as high as 98% [10] and a combined EUS/EBUS approach established definitive nodal staging in 96% of cases [11]. Figure 2shows the lymph nodes accessible to EBUS, mediastinoscopy and EUS.

Radial EBUS (Olympus® UM-BS20-26R, 2.5mm di-ameter and Olympus UM-S20-20R, 1.4mm diameter) is a specialized ultrasound probe that fits down the channel of a bronchoscope. It enables visualization of lymph nodes

or peripheral lesions. As the probe must be removed for sampling to occur, it is not real-time. Yields in lymph node sampling with this modality are 85% [13]. Yields with the ultrathin probe for peripheral lesions range from 77% to 86% [14,15]. It can also be used in conjunction with navi-gational bronchoscopy (see below).

Figure 1: Endobronchial ultasound view of a lymph node (LN) with a transbronchial needle seen within the lymph

node.Navigational Bronchoscopy Electromagnetic navigation bronchoscopy (ENB)

enables bronchoscopists to sample peripheral lesions and lymph nodes, place gold fiducial markers to aid in stereo-tactic radiation, or perform pleural dye marking for surgi-



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cal resection of tumors. Adedicated computed tomogra-phy (CT) scan with thin cuts and high overlap is analyzed by the computer software enabling 3-dimensional (3D) reconstruction (Super Dimension; Medtronic/Covidienor Lung Point; Veran). Using the 3D reconstruction of the patient’s airway tree the bronchoscopist can map a course to the target lesion (Figure3).

Figure 2: Diagram of different nodes and which can be accessed by different diagnostic modalities. Mediastinoscopy=Green, EBUS=Green and Blue, EUS=Purple. A, Azygous vein, PA, Pulmonary artery, EO, Esophagus. Adapted from Yasufuku et al. Chest 2006 [12].

Figure 3: Navigational bronchoscopy three-dimensional airway tree created from reconstructed computed tomog-

raphy scan. The green sphere represents the targeted lesion.

During the procedure, the patient is placed on an electromagnetic location board on the surface of the en-doscopy bed or fluoroscopy table. A sensor probe (locat-able guide or LG) is inserted within an extended working channel (EWC) through the operating channel of a thera-peutic bronchoscope. The locatable board and the LG are connected to the computer tower. The software senses the LG in relationship to the patient’s reconstructed airway



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and guides the bronchoscopist to the predetermined tar-get. The LG is then retracted and biopsies are performed through the EWC with forceps, brushes, or needles [16,17]. The use of fluoroscopy or peripheral radial probe EBUS can provide additional confirmation of lesion prox-imity [17]. Yields for ENB range from 63% to 80% [16-18]. Combining ENB with radial probe EBUS, achieved 88% yield in one study [19]. Molecular genetic yields for EGFR driver mutations have been reported at 93% [20]. Figure 4 shows a fluoroscopic view of ENB in process and the corresponding radial probe imaging with the lesion visible in real time.

Figure 4: Navigational bronchoscopy with a)Fluorscopic visulization of the bronchoscope and biopsy tool through the external workin channel after navigation to a right middle lobe lesion, and b) Radial probe visulization of the

lesion after navigation.In addition to its role as a diagnostic tool, ENB can be

used to aid therapeutic procedures. Gold fiducial markers can be placed through the EWC and into or adjacent to tu-mors to facilitate stereotactic body radiosurgery [21,22].

Pleural dye marking can also be performed through the EWC to aid cardiothoracic surgeons in surgical resection of tumors [23]. The risks of EMN are similar to those in-curred with standard bronchoscopy except for a slightly higher pneumothorax rate (2% to 8%) [16-19], which is still an advantage over transthoracic fine needle aspiration with a pneumothorax rate as high as 23-44% [16].

Tumor DebulkingLung cancers are known to cause airway obstruc-

tion either from extrinsic compression from large masses or endoluminal tumor growth or a combination of both. Endobronchial tumors can cause dyspnea, hemoptysis, cough, and post-obstructive pneumonia. Proximal en-dobronchial tumors either 2cm from the main carina or within the trachea may render patients inoperable. Tu-mor destruction can relieve life-threatening obstruction until chemotherapy and/or radiation therapy is initiated. In cases were the patient has exhausted other treatment modalities, tumor destruction can offer symptom relief to improve dyspnea and cough and resolve hemoptysis. Mo-dalities for tumor debulking (Table 1) involve destruction though coagulation (argon plasma coagulation or APC), vaporization (laser therapy), and mechanical debulking (rigid scope debulking, microdebrider). Often coagula-tion or vaporization to reduce potential bleeding is per-formed followed by tumor debulking. This technique pro-vides immediate relief of airway obstruction [24]. Tumor debulking may be followed by stenting if the integrity of



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the airway wall is compromised (see the Stents section for further discussion). Figure 5 shows an airway tumor be-fore and after tumor debulking.

Table 1: Modalities to Treat Endobronchial Tumors [24,25,29].

UV, ultraviolet

Figure 5: Bronchoscopic images of an endobronchial tu-mor in the left mainstem a) before debulking, and b) af-ter debulking where the left upper and lower lobes can be

visualized.

Laser TherapyThe Nd:YAG laser (neodymium-yttrium-aluminum-

garnet light amplification by stimulated emission of ra-diation) therapy vaporizes and coagulates tissue by both contact and noncontact probes. It penetrates 3 to 4mm with a wavelength of 1064 nm to destroy tissue. Caution is exercised when treating lesions involving the poste-rior airway wall due to risk of perforation [25]. Inspired oxygen levels (FiO2) must be maintained at or <40% to avoid airway fire. Further mechanical tumor debulking can be performed after laser vaporization. Several studies have described high success rates with relief of hemopty-sis, high rate or recanulization and control of obstructive complications using laser therapy [26,27]. Contraindica-tions to laser therapy include high oxygen requirements, bronchoesophageal fistula, and coagulopathy. Procedural risks include airway fire, bleeding, perforation and fistula formation [24].

Argon Plasma CoagulationArgon plasma coagulationuses the release of an argon

gas jet (plasma) that is sparked to cause tissue coagula-tion. Argon flow can be adjusted from 0.3 to 2L/min and is sparked by an applied power of 10 to 80 Watts. APC is a superficial modality compared with Nd:YAG laser ther-apy which may be preferable if blood vessels are in close proximity. Also, APC can maneuver around airway bends suggesting an advantage in treating branching airway seg-ments compared with laser therapy which is a linear de-

Modality DescriptionLaser Light amplification is used to vaporize tissueArgon plasma Argon plasma is sparked to coagulate tissueCryotherapy Tissue is frozen with nitrous oxide causing

apoptosisPhotodynamic therapy Tissue sensitization followed by UV light

tumor destructionBrachytherapy Endoluminal radiation therapy



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livery system. Morice et al. [28] describe 57 patients with malignancy undergoing APC debulking and recanuliza-tion who had 100% resolution of their hemoptysis. They achieved 99% symptomatic improvement with no proce-dural complications. Similar to laser therapy, FiO2 must be maintained at <40% to avoid airway fire. Other rare risks include perforation, fistula formation, and gas em-boli. As with laser, tumor debulking can occur following coagulation and necrosis [24].

Rigid BronchoscopyThe rigid bronchoscope is a hollow, stainless steel cyl-

inder. Diameters for rigid barrels range from 9 to 14 mm and the bronchoscopist can chose the shorter tracheal barrel or longer bronchial barrel. One end is beveled for tumor debulking and the other contains connection ports for jet ventilation. This open ventilation system creates a lower risk of airway fire during APC or laser compared with the closed system of an endobronchial tube with flexible bronchoscopy, however it can increase the risk of barotrauma as minute ventilation cannot be accurately measured. Large forceps can be used for tumor debulk-ing or the bevel of the rigid scope itself can be used to core out tumor. The rigid bronchoscope can accommo-date large forceps, laser, argon plasma or cryoprobe. Si-multaneously a large suction catheter can fit into a sepa-rate port to manage any associated bleeding. Risks of rigid bronchoscopy include dental trauma, damage to the oro-pharynx, laryngeal edema, posterior wall perforation, and

pneumothorax. In addition, the anesthesiologist cannot obtain accurate end-tidal CO2 giving the additional risk of hypercarbia [29].

Therapeutic Modalities WithCurative IntentEarly stage endobronchial lesions without nodal in-

volvement (ie., carcinoma in situ and microinvasive squa-mous cell cancer) are targets for curative bronchoscopic modalities. Cryotherapy, APC, brachytherapy, and pho-todynamic therapy (PDT) (Table 1) can all be used with curative intent in the appropriate setting [24,30].

CryotherapyUnlike argon plasma and laser, cryotherapy does

not pose a threat when patients have high oxygen re-quirements. Cryotherapy uses nitrous oxide to freezeand crystallize cells to induce apoptosis. It can be performed through a flexible or rigid bronchoscope. For tumor de-struction, a freeze-thaw-freeze-thaw-freeze-thaw cycle (30 to 60 seconds of each freeze and each thaw) is per-formed as the tumor surface is coated. The induced ap-optosis results in necrotic tissue which will slough over the following week. Repeat bronchoscopy in 7 to 10 days can remove residual sloughing, necrotic tumor if needed. Cryotherapy can be used for curative intent in carcinoma in situ as well as palliation of tracheobronchial neoplasms [29,30]. Risks include fever, hemoptysis, fistulas and bron-chospasm [31].



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Photodynamic TherapyPhotodynamic therapy (PDT) provides slower tumor

destruction with a low risk of perforation or bleeding. It can be used for symptomatic relief or curative intent. It is most effective for small lesions of <10 mm in length and can be performed in conjunction with debulking mo-dalities, radiation and chemotherapy. If tumor debulking is also needed, this should occur before PDT to reduce necrotic debris from sloughing and causing obstruction [31,32].

PDT involves IV administration of a photosensi-tizer (most commonly Porfimer sodium [Photofrin; Sa-nofi Pharmaceuticals, New York, NY]) followed in two to three days by bronchoscopy and intraluminal ultraviolet light exposure at a wavelength of 630 nm. Tumor cells (as well as liver, spleen and skin) preferentially retain the photosensitizer. When exposed to UV light, it is excited and generates free radicals that destroy the tumor cells. Necrotic debris is removed in 24 to 48 hours via a repeat bronchoscopy. During this procedure, repeat laser expo-sure can be performed if there is residual tumor [31,32].

PDT effectiveness is reported as high as 85% [33]. It can cause transient liver dysfunction (1.9%), allergic reactions (7.7%) and other pulmonary complications (7.7%)-dyspnea, fever and obstructing pneumonitis. Due to the risk of sun burn following the photosensitizer, pa-tients should avoid sun exposure for 4 to 6 weeks [32].

Endobronchial BrachytherapyBrachytherapy for lung cancer can be for palliative or

curative intent. Palliative intent usually follows debulking of tumor in a mainstem that cannot be resected due to its proximity to the main carina or due to the patient’s perfor-mance status. Curative intent usually follows postsurgical resection with positive margins. Brachytherapy involves bronchoscopically placing a catheter into the airway seg-ment with infiltrative tumor (Figure 4). The catheter is se-cured in place (either taped to the nose if performed with moderate sedation or taped to the endotracheal tube if performed with general anesthesia). Radiation Oncology can then place radioactive seeds (Iridium-192) into the catheter and local radiation therapy is performed. It may take up to 3 weeks for the full effect for radiation-induced DNA alterations to result in apoptosis [31]. For this rea-son, obstructive tumors need to undergo debulking prior to consideration for brachytherapy.

Brachytherapy has been successful in up to 85% [31] of patients with improvements in dyspnea, cough, hemopty-sis, and post-obstructive pneumonia [34]. Complications include bleeding, fistulas, arrhythmias, bronchospasm, radiation pneumonitis and stenosis. Fatal hemoptysis oc-curs at a rate of 0% to 32% and has been attributed to radi-ation damage of airway integrity and/or tumor ingrowth into adjacent vascular structures [31].



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Airway StentsAirway stents have been employed for use in lung

cancer patients for many decades. They may be placed when endoluminal tumor compromises the structure of the airway wall especially following tumor debulking. Stents can be placed in the trachea, left mainstem, right mainstem, bronchus intermedius, and they come in vary-ing lengths and diameters to accommodate these different locations. The bronchoscopist must have training in stent placement, type and size determination and clinical deci-sion making to determine true benefit [25,29].

The main types of airway stents are silicone (Dumon; Novatech), polymer (Polyflex;Boston Scientific), metal stents (Ultraflex; Boston Scientific) and hybrid stents (Aero; Merit Medical Endotek). The Dumon stent is stud-ded to help prevent migration and comes in straight, L-shaped and Y-shaped designs that can be cut to accom-modate airway length. It requires placement and removal under rigid bronchoscopy with general anesthesia. The Polyflex stent is a polyester mesh covered in silicone. Sili-cone and polymer stents are prone to migration and may also cause granulation tissue accumulation or mucus ob-struction. The Dynamic Y-stent is a silicone-steel hybrid that extends from the trachea to the mainstems and is de-signed for obstructions proximal to or involving the ca-rina, especially tracheoesophageal fistulas [24,25,29].

Modern metal stents consist of self-expanding metal (nitinol) and are covered by a thin polymer membrane

(Ultraflex [covered and uncovered designs]; Boston Sci-entific, and Aero; Merit Medical Systems). They can be placed with flexible bronchoscopy under moderate seda-tion or general anesthesia. Complications include mucus obstruction, stent migration or fracture and granulation tissue accumulation causing airway stenosis or occlusion [25]. Figure 6 shows an Aero stent deployed in a mainstem bronchus.

Multiple studies have published the utility of stent placement, especially following tumor destruction. They have achieved resolution of the obstruction, improvement in dyspnea and improvement in quality of life [35,36].

Pleural DiseaseMalignant pleural effusions (MPEs) carry a poor

prognosis and lung cancer is one of the types of MPE with a shorter anticipated survival (ranges 3 to 12 months). Other predictors of truncated survival with MPE area poor performance status and with low pleural fluid glu-cose and pH [37].

PleuroscopyPleuroscopy allows forvisualization of the pleural cav-

ity using a semirigid endoscope (Olympus LFT-160) in-troduced inside the thoracic cavity through the intercos-tal space. The procedure can be performed under local or general anesthesia. The instrument has an outer diameter of 7 mm and a 2.8-mm working channel which can be used for introducing instruments to sample the parietal



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pleura. Pleuroscopy is usually indicated for undiagnosed pleural effusion with yields for malignancy as high as 90% [38]. During the procedure, the pleura may be visualized and biopsies can be taken from suspicious areas. Com-plications include empyema, persistent pneumothorax, pleurocutaneous fistula, subcutaneous emphysema, hem-orrhage, reexpansion pulmonary edema, and malignant invasion of scar [38-41]. After the procedure, a chest tube is placed to allow the lung to re-expand. In addition, pleu-roscopy may be used therapeutically to perform pleurode-sis for symptomatic, recurrent malignant effusions[41]. In a Cochrane Review, thorascopic talc pleurodesis was su-perior to chest tube-guided talc insufflation with relative risk of nonrecurrence of effusion being 1.68 (95% confi-dence interval, 1.35-2.10) [39].

Tunneled Pleural CathetersTunneled pleural catheters (TPCs) offer an alterna-

tive to surgical intervention in select patient cohorts. They canbe placed for recurrent, symptomatic effusion in a) pa-tients who need therapeutic relief until chemotherapy can be provided and hopefully help resolve the effusion, orb) patients who have had chemotherapy and the effusion persists and they cannot undergo talc pleurodesis due to trapped lungor poor performance status [42].

Two companies currently market the TPCs: Care Fusion (PleurX) and Bard Access Systems (Aspira). The fenestrated ends allow for drainage while the tunneled portion is designed to reduce risk of infection and dis-

lodgement. The one-way valve at the distal end seals the catheter when not in use. The procedure can be performed as an out patient with local anesthesia and under ultra-sound guidance [42].

Approximately 2 weeks after insertion, sutures are removed. Pleural catheters can be drained aggressively daily in hopes of autopleurodesis or sporadically based on patient symptoms. The choice should be based on patient preference. Aggressive daily drainage might be difficult depending upon the availability of caretakers and daily tape changes may cause local skin irritation. When the fluid is 50 mL or less for 3 consecutive drainages and chest x-ray (or ultrasound) confirms resolution of the pleural effusion, then the catheter can be removed [42].

TPCs are highly successful at symptomatic relief (96% on one systematic review, n=1370 patients) [43]. Sponta-neous pleurodesis may occur after which the catheter can be removed. Pleurodesis rate are variable: 12% to 58% [44]. The presence of trapped lung and absence of malignant cells on cytology make auto-pleurodesis less likely [4-46]. A randomized trial of 147 patients with malignant pleural effusion compared TPCs to talc pleurodesis. TPCs were as effective as talc pleurodesis in relieving symptoms while eliminating the need for hospitalization (TPC length of stay 0 days vs 4 days for talc pleurodesis) [45]. In addition, TPCscan achievesignificant quality of life improvement in patients with trapped lung [46].

More recently, a pilot study of 30 patients with MPE



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performed medical thoracoscopy with concurrent TPC placement and talc poudrage. Successful pleurodesis oc-curred in 92% with a median hospital stayof just 1.8 days. All patients had symptomatic improvement. Complica-tions occurred in 13% (2 fever, 1 TPC replacement need-ed, 1 empyema) [47]. This combined approach provides a high pleurodesis rate with rapid hospital discharge while eliminating the need for ongoing drainage and manage-ment of TPC. Further comparative studies are needed.

Infection can occur in the form of cellulitis or empy-ema (as high as 15%) [42]. The former can be treated with outpatient antibiotics where as the later may require in-patient monitoring. Empyema can be diagnosed through symptoms (fever and change in fluid appearance), labora-tory values (leukocytosis) and imaging as well as culturing fluid from the catheter [48]. The most likely organism is staphylococcus aureus and initial antibiotics should cov-erthis species according to local susceptibilities. If empy-ema occurs, the patient should be evaluated for possible pleurodesis as it is more likely in this setting (62% in one study) [48]. If this has occurred, the catheter should be removed near the end of the antibiotic course when the pleural space is likely sterile [48].

Other complications include tumor seeding, pneu-mothorax (1%), occluded catheters or loculated effusions (7%) and catheter fracture upon removal [42]. Tumor seeding along the catheter occurs around 2% of the time

and can be treated with local radiation [49]. There has been one case report ofbronchopleural fistula [50]. Oc-cluded catheters may require simple flushing or intracath-er dwell of tPA (tissue plasminogen activator) where as intrapleural fibrinolytics may be tried for loculated effu-sions. This requires a one hour dwell of tPA and DNAase (dornase alpha) in the pleural space followed by drainage and overnight observation [42]. Further studies are need-ed to discern the most effective treatment for loculations in the setting of TPCs.

ConclusionInterventional Pulmonology has become an integral

component in the diagnosis, staging and management of lung cancer. Minimally invasive techniques can offer low-er risk diagnostic approaches as well as palliative and even curative intent therapies for malignancies. Knowledge of the indications, technique and outcomes of these proce-dures can facilitate Oncologists, Radiation Oncologists, Thoracic Surgeons and Pulmonologists referral of patients for minimally invasive procedures.



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