Advanced therapy in thoracic surgery - part 2 doc

Tissue Adhesives in Thoracic and Cardiovascular Surgery / 55 morbidity and cost However, this has not been supported by any of the studies currently in the literature FocalSeal appears to be safe, but its efficacy depends on the proper application, which can be tedious as well as difficult, especially in poorly exposed areas of the lung Biologic Glue The natural history of acute type A aortic dissection carries an extremely grim prognosis without surgery, with mortality rates of 38% in the first day and up to 120 Control (n = 55) FocalSeal (n = 177) Patients without air leaks (%) 100 p = < 001 80 60 p = < 001 40 20 Intraoperative From Wound Closure to Hospital Discharge FIGURE 3-8 Percentage of patients without air leaks intraoperatively and from wound closure to hospital discharge for patients treated with FocalSeal-L versus controls Adapted from Wain JC et al 62 p 1626 12 p = NS T Control (n = 55) 10 FocalSeal (n = 117) Mean Time (d) there was no significant difference in the length of the hospital stay.64 A major criticism of this study is the chest tube management, which may have contributed to the incidence of empyema and the extended hospital stay Wain and colleagues reported a multicenter, randomized, controlled trial of patients undergoing pulmonary resection, comparing conventional closure with conventional closure plus treatment of all surgical sites at risk for air leak with FocalSeal-L.62 Each surgeon was trained in the proper application of FocalSeal, and each individual surgeon or institution determined protocol for chest tube management Of the 117 patients in the FocalSeal group and the 55 patients in the control group, there was no statistically significant difference in the extent of prerandomization air leak The FocalSeal group had no air leak detectable prior to chest closure in 92% of patients compared with 29% in the control group (p < 001) In the time from operation to hospital discharge, 39% of the patients in the FocalSeal group had no air leak versus 11% in the control group (p < 001) (Figure 3-8) The mean time from skin closure to the last detectable air leak was less in the FocalSeal group than in controls (30.9 ± 4.8 h vs 52.3 ± 11.6 h, respectively; p = 006) However, as in the previous studies, there was not a statistical difference between the groups in time to chest tube removal or length of hospital stay, although the trend favored the FocalSeal group (Figure 3-9) FocalSeal has also been used to seal air leaks that develop during cardiac reoperations Fifteen patients that had air leaks recognized intraoperatively had the pulmonary injuries treated with FocalSeal All leaks were controlled intraoperatively, and 73% of patients had air leaks recognized postoperatively Three of four patients with a recurrent air leak had the air leak resolved in days, but seal was never accomplished in one patient who was immunosuppressed.65 Interestingly, in all of the clinical trials, several patients appeared to have no air leak intraoperatively as assessed by submersion and controlled positive pressure ventilation, and then developed air leaks postoperatively This may be due to improper application of the sealant or ineffective adhesion of the sealant to the pulmonary tissue Another possibility is that negative intrathoracic pressure from suction on chest tubes postoperatively impeded closure of small air leaks Some have therefore advocated the avoidance of suction on chest tubes unless there is both an air leak and a pneumothorax, with a goal of removing the chest tubes as soon as drainage is ≤ 20 mL/h (John C Wain, personal communication, January 2003) The ability to seal most of the air leaks at the time of chest closure along with avoidance of chest tube suction may decrease postoperative chest tube duration and hospital stay, ultimately resulting in decreased T p = NS T T p = 006 T T From Skin Closure to Last Observed Air Leak From Skin Closure to Chest Tube Removal From Skin Closure to Hospital discharge FIGURE 3-9 Mean time to last air leak in patients treated with FocalSeal-L versus controls NS = not significant Adapted from Wain JC et al.62 p 1627 56 / Advanced Therapy in Thoracic Surgery 90% after weeks from the onset of symptoms The best chance of survival in patients with this disease depends on immediate diagnosis and emergent surgical intervention, although reported mortality after surgery remains 10 to 20% The dissection is occasionally limited to the ascending aorta but often extends to the arch and descending aorta Proximal extension of the dissection can involve the aortic valve or coronary arteries The friability of the remaining proximal and distal aorta makes anastomosis extremely tenuous, and severe bleeding or re-dissection can complicate the repair Many techniques to reinforce the aortic tissues have been advocated, including the use of pledgeted sutures or sandwiching the separated layers of the aortic wall with polytef strips prior to sewing on the graft Several authors have attributed improvements in outcomes in their experiences to the use of biologic glues to adhere the separated aortic wall layers, thus reinforcing the tissues enough to hold sutures The most frequently used biologic glue for this indication has been GRF glue In 1977, frustrated by the poor prognosis of treatment for acute type A aortic dissection, Guilmet and colleagues began using GRF glue clinically to seal the layers of the aortic wall during the repair of acute type A aortic dissections.66 Since then many surgeons have used GRF glue in every case of acute type A aortic dissection Although randomized, controlled studies in this patient population are impractical, surgeons advocating the use of GRF glue report that significantly decreased bleeding and simplification of the repair leads to decreased cardiopulmonary bypass times and improved overall survival 67 Some continue to oversew and reinforce the native aorta with polytef strips in addition to using the sealant, whereas others have abandoned this technique and rely on the GRF glue to reinforce the aorta for suturing to the graft Great care must be taken to avoid contamination of the lumen with glue, especially near the coronary ostia (Figure 3-10).68 Reports of glue emboli are infrequent, but these emboli can occur.69 GRF glue is not approved by the FDA owing to concerns about the toxicity of the formaldehyde component.70 Although GRF glue has been used extensively in Europe and several studies have reported the benefits, safety, and reliability of this sealant, recent reports of reoperations owing to aortic medial necrosis of sites previously repaired using this product are refocusing attention on its potential toxicity Bingley and colleagues recently reported high rates of aortic regurgitation requiring reoperation in patients who had the aortic root reinforced with GRF glue with resuspension of the aortic valve 71 Late aortic insufficiency occurred in of 18 patients (39%), and of these had re-dissection at the site of the GRF glue reinforcement Histologic findings were consistent with tissue necrosis at the site of glue use (Figure 3-11) Their conclusion was that this necrosis could be attributed to either an improper glue application A FIGURE 3-10 A–C, Suggested technique to reconstruct the aortic root and proximal aortic arch using GRF glue Gauze sponges are used to prevent intraluminal glue Adapted from and B and C reproduced with permission from Laas J et al.68 p 227 58 / Advanced Therapy in Thoracic Surgery Other potential indications under investigation include the use of tissue adhesives to avoid postoperative adhesions, allow the local release of pharmacologic agents, carry gene or protein therapeutic agents, or enhance endothelialization of prosthetic or tissueengineered grafts The clinical utility of tissue adhesives has shown great promise over the past century As the technology and experience with tissue adhesives continue to grow, we must expand our comprehension of the proper use and limitations of these agents to take full advantage of the clinical benefits they offer our patients References Bergel S Uber Wirkungen des Fibrins Dtsch Med Wochenschr 1909;35:663–5 Grey EG Fibrin as a hemostatic in cerebral surgery Surg Gynecol Obstet 1915;21:452–4 Harvey SC The use of fibrin papers and forms in surgery Boston Med Surg J 1916;174:658–9 Cronkite EP, Lozner EL, Deaver JM Use of thrombin and fibrinogen in skin grafting JAMA 1944;124:976–8 Blomback B, Blomback M Purification of human and bovine fibrinogen Arkiv Kemi 1956;10:415–43 Trott AT Cyanoacrylate tissue adhesives: an advance in wound care JAMA 1997;277:1559–60 Hino M, Ishiko O, Honda KI, et al Transmission of symptomatic parvovirus B19 infection by fibrin sealant used during surgery Br J Haematol 2000;108:194–5 16 Borst HB, Haverich A, Walterbusch G, Maatz W Fibrin adhesive: an important hemostatic adjunct in cardiovascular operations J Thorac Cardiovasc Surg 1982;84:548–53 17 Rousou J, Gonzalez-Lavin L, Cosgrove D, et al Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations: a multicenter study J Thorac Cardiovasc Surg 1989;97:194–203 18 Kjaergard HK, Weis-Fogh US, Sorensen H, et al Autologous fibrin glue—preparation and clinical use in thoracic surgery Eur J Cardiothorac Surg 1992;6:52–4 19 Mintz PD, Mayers L, Avery N, et al Fibrin sealant: clinical use and the development of the University of Virginia Tissue Adhesive Center Ann Clin Lab Sci 2001;31:108–18 20 Spotnitz WD, Dalton MS, Baker JW, Nolan SP Reduction of perioperative hemorrhage by anterior mediastinal spray application of fibrin glue during cardiac operations Ann Thorac Surg 1987;44:529–31 21 Matthew TL, Spotnitz WD, Kron IL, et al Four years’ experience with fibrin sealant in thoracic and cardiovascular surgery Ann Thorac Surg 1990;50:40–4 22 Burgos R Experience with fibrin sealant spray in cardiovascular reoperations Conference proceedings Update and future trends in fibrin sealing in surgical and nonsurgical fields Vienna: LBI Trauma; 1992 Abstract 193 23 Huth C, Hoffmeister H-E Use of fibrin glue (Tissucol/Tisseel) to achieve hemostasis in patches and suture lines in surgical repair of congenital heart defects In: Schlag G, Redl H, editors Fibrin sealant in operative medicine: thoracic surgery—cardiovascular surgery Berlin: Springer; 1986 p 164–5 Reece TB, Maxey TS, Kron IL A prospectus on tissue adhesives Am J Surg 2001;182:40–4 24 Morikawa T Tissue sealing Am J Surg 2001;182:29–35S Matras H, Dinges HP, Lassmann H, Mamoli B Suture-free interfascicular nerve transplantation in animal experiments Wien Med Wochenschr 1972;122:517–23 25 Berruyer M, Amiral J, Ffrench P, et al Immunization by bovine thrombin used with fibrin glue during cardiovascular operations: development of thrombin and factor V inhibitors J Thorac Cardiovasc Surg 1993;105:892–7 10 Kuderna H, Matras H Die klinische Anwendung der Klebung von Nervenanastomosen bei der Rekonstruktion verletzter peripherer Nerven Wien Klin Wochenschr 1975;87:495–6 11 Brands W, Beck M, Raute-Kreinsen U Gewebeklebung der rupturierten Milz mit hochkonzentriertem HumanFibrinogen Z Kinderchir 1981;32:341 12 Spangler HP, Holle J, Braun F, et al Die Verklebung experimenteller Leberverletzungen mittels hochkonzentriertem Fibrin Acta Chir Austr 1975;7:89 13 Spangler HP Gewebeklebung und Iokale Blutstillung mit Fibrinogen: Thrombin und Blutgerinnungsfaktor XIII Wien Klin Wochenschr 1976;88:1–18 14 Akrami R, Kalmar P, Pokar H, Tilsner V Abdichtung von Kunststoffprothesen beim Ersatz der Aorta im thorakalen Bereich Thoraxchirurgie 1978;26:144–7 15 Koveker G, de Vivie ER, Hellberg KD Clinical experience with fibrin glue in cardiac surgery Thorac Cardiovasc Surg 1981;29:287–9 26 Zumberg MS, Waples JM, Kao KJ, Lottenberg R Management of a patient with a mechanical aortic valve and antibodies to both thrombin and factor V after repeat exposure to fibrin sealant Am J Hematol 2000;64:59–63 27 Scheule M, Beierlein W, Wendel HP, et al Aprotinin in fibrin tissue adhesives induces specific antibody response and increases antibody response of high-dose intravenous application J Thorac Cardiovas Surg 1999;118:348–53 28 Fastenau DR, McIntyre JA Immunochemical analysis of polyspecific antibodies in patients exposed to bovine fibrin sealant Ann Thorac Surg 2000;69:1867–72 29 Marek CA, Amiss LR, Morgan RF, et al Acute thrombogenic effects of fibrin sealant on microvascular anastomoses in a rat model Ann Plast Surg 1998;41:415–9 30 Turner AS, Parker D, Egbert B, et al Evaluation of a novel hemostatic device in an ovine parenchymal organ bleeding model of normal and impaired hemostasis J Biomed Mater Res 2002;63:37–47 Tissue Adhesives in Thoracic and Cardiovascular Surgery / 59 31 Prior JJ, Wallace DG, Harner A, Powers N A sprayable hemostat containing fibrillar collagen, bovine thrombin, and autologous plasma Ann Thorac Surg 1999;68:479–85 46 Venuta F, Rendina EA, De Giacomo T, et al Technique to reduce air leaks after pulmonar y lobectomy Eur J Cardiothorac Surg 1998;13:361–4 32 The CoStasis Multi-center Collaborative Writing Committee A novel collagen-based composite offers effective hemostasis for multiple surgical indications: results of a randomized controlled trial Surgery 2001;129:445–50 47 El-Gamel A, Tsang GMK, Watson DCT The threshold for air leak: stapled versus sutured human bronchi, an experimental study Eur J Cardiothorac Surg 1999;15:7–10 33 Sherman R, Chapman WC, Hannon G, Block JE Control of bone bleeding at the sternum and iliac crest donor sites using a collagen-based composite combined with autologous plasma: results of a randomized controlled trial Orthopedics 2001;24:137–41 34 Reuthebuch O, LaChat ML, Vogt P, et al FloSeal: a new hemostyptic agent in peripheral vascular surgery Vasa 2000;29:204–6 35 Oz MC, Cosgrove DM, Badduke BR, et al Controlled clinical trial of a novel hemostatic agent in cardiac surgery Ann Thorac Surg 2000;69:1376–82 36 Wallace DG, Cruise GM, Rhee WM, et al A tissue sealant based on reactive multifunctional polyethylene glycol J Biomed Mater Res 2001;58:545–55 37 Hill A, Estridge TD, Maroney M, et al Treatment of suture line bleeding with a novel synthetic surgical sealant in a canine iliac PTFE graft model J Biomed Mater Res 2001;58:308–12 38 Glickman M, Cheissari A, Money S, et al A polymeric sealant inhibits anastomotic suture hole bleeding more rapidly than Gelfoam/thrombin: results of a randomized controlled trial Arch Surg 2002;137:326–31 39 Hewitt CW, Marra SW, Kann BR, et al BioGlue surgical adhesive for thoracic aortic repair during coagulopathy: efficacy and histopathology Ann Thorac Surg 2001;71:1609–12 40 White JK, Titus JS, Tanabe H, et al The use of a novel tissue sealant as a hemostatic adjunct in cardiac surgery Heart Surg Forum 2000;3:56–61 41 Kirsh MM, Rotman H, Behrendt DM, et al Complications of pulmonary resection Ann Thorac Surg 1975;20:215–36 42 Miller JI, Landreneau RJ, Wright CE, et al A comparative study of buttressed versus nonbuttressed staple line in pulmonary resections Ann Thorac Surg 2001;71:319–23 43 Yano T, Yoloyama H, Fukuyama Y, et al The current status of post-operative complications and risk factors after a pulmonary resection for primary lung cancer: a multivariate analysis Eur J Cardiothorac Surg 1997;11:445–9 44 Lawrence GH, Ristroph R, Wood JA, Starr A Methods for avoiding a dire surgical complication: bronchopleural fistula after pulmonar y resection Am J Surg 1982;144:136–40 45 Weissberg D, Kaufman M Suture closure versus stapling of bronchial stump in 304 lung cancer operations Scand J Thorac Cardiovasc Surg 1992;26:125–7 48 Cerfolio RJ, Bass C, Katholi CR Prospective randomized trial compares suction versus water seal for air leaks Ann Thorac Surg 2001;71:1613–7 49 Rice TW, Kirby TJ Prolonged air leak Chest Surg Clin North Am 1992;2:803–11 50 Turk R, Weidringer JW, Hartel W, Blumel G Closure of lung leaks by fibrin gluing: experimental investigations and clinical experience Thorac Cardiovasc Surg 1983;31:185–6 51 McCarthy PM, Trastek VF, Bell DG, et al The effectiveness of fibrin glue sealant for reducing experimental pulmonary air leak Ann Thorac Surg 1988;45:203–5 52 Grunewald D Intraoperative use of fibrin sealant in pulmonary surgery: a prospective study on a series of 124 procedures Ann Chir 1989;43:147–50 53 Kjaergard H Autologous fibrin glue: preparation and clinical use in thoracic surgery Eur J Cardiothorac Surg 1992;6:52–4 54 Mouritzen C, Dromer M, Keinecke H-O The effect of fibrin gluing to seal bronchial and alveolar leakages after pulmonar y resections and decortications Eur J Cardiothorac Surg 1993;7:75–80 55 Wong K, Goldstraw P Effect of fibrin glue in the reduction of postthoracotomy alveolar air leak Ann Thorac Surg 1997;64:979–81 56 Thistlethwaite PA, Luketich JD, Ferson PF, et al Ablation of persistent air leaks after thoracic procedures with fibrin sealant Ann Thorac Surg 1999;67:575–7 57 Fleisher AG, Evans KG, Nelems B, Finley RJ Effect of routine fibrin glue use on the duration of air leaks after lobectomy Ann Thorac Surg 1990;49:133–4 58 Izbicki JR, Kreusser T, Meier M, et al Fibrin-glue-coated collagen fleece in lung surgery: experimental comparison with infrared coagulation and clinical experience Thorac Cardiovasc Surg 1994;42:306–9 59 Wertzel H, Wagner B, Stricken L, et al Experimental gluing of lung parenchyma in rats Thorac Cardiovasc Surg 1997;45:83–7 60 Herget GW, Kassa M, Riede UN, et al Experimental use of an albumin-glutaraldehyde tissue adhesive for sealing pulmonary parenchyma and bronchial anastomoses Eur J Cardiothorac Surg 2001;19:4–9 61 Macchiarini P, Wain J, Almy S, Dartevelle P Experimental and clinical evaluation of a new synthetic, absorbable sealant to reduce air leaks in thoracic operations J Thorac Cardiovasc Surg 1999;117:751–8 60 / Advanced Therapy in Thoracic Surgery 62 Wain JC, Kaiser LR, Johnstone DW, et al Trial of a novel synthetic sealant in preventing air leaks after lung resection Ann Thorac Surg 2001;71:1623–9 77 Kucukaksu DS, Akgul A, Cagil K, Tasdemir O Beneficial effect of BioGlue surgical adhesive Tex Heart Inst J 2000;27:307–8 63 Ranger WR, Halpin D, Sawhney AS, et al Pneumostasis of experimental air leaks with a new photopolymerized synthetic tissue sealant Am Surg 1997;63:788–95 78 Kazui T, Washiyama N, Bashar AH, et al Role of biologic glue repair of proximal aortic dissection in the development of early and midterm redissection of the aortic root Ann Thorac Surg 2001;72:509–14 64 Porte HL, Jany T, Akkad R, et al Randomized controlled trial of a synthetic sealant for preventing alveolar air leaks after lobectomy Ann Thorac Surg 2001;71:1618–22 65 Gillinov AM, Lytle BW A novel synthetic sealant to treat air leaks at cardiac reoperation J Card Surg 2001;16:255–7 66 Guilmet D, Bachet J, Goudot B, et al Use of biological glue in acute aortic dissection Preliminary clinical results with a new surgical technique J Thorac Cardiovasc Surg 1979;77:516–21 67 Bachet J, Goudot B, Dreyfus G, et al The proper use of glue: a 20-year experience with the GRF glue in acute aortic dissection J Card Surg 1997;12(2 Suppl):243–53 68 Laas J, Jurmann MJ, Heinemann M, Borst HG Advances in aortic arch surgery Ann Thorac Surg 1992;53:227–32 69 Carrel T, Maurer M, Tkebuchava T, et al Embolization of biologic glue during repair of aortic dissection Ann Thorac Surg 1995;60:1118–20 70 Fukunaga S, Karck M, Harringer W, et al The use of gelatin-resorcin-formalin glue in acute aortic dissection type A Eur J Cardiothoracic Surg 1999;15:564–70 71 Bingley JA, Gardner MA, Stafford G, et al Late complications of tissue glues in aortic surgery Ann Thorac Surg 2000;69:1764–8 72 Suehiro K, Hata T, Yoshitaka H, et al Late aortic root redissection following surgical treatment for acute type A aortic dissection using gelatin-resorcin-formalin glue Jpn J Thorac Cardiovasc Surg 2002;50:195–200 73 Kirsch M, Ginat M, Lecerf L, et al Aortic wall alterations after use of gelatin-resorcinol-formalin glue Ann Thorac Surg 2002;73:642–4 74 Katsumata T, Moorjani N, Vaccari G, Westaby S Mediastinal false aneurysm after thoracic aortic surgery Ann Thorac Surg 2000;70:547–52 79 LeMaire SA, Schmittling ZC, Coselli JS, et al BioGlue surgical adhesive impairs aortic growth and causes anastomotic strictures Ann Thorac Surg 2002;73:1500–5 80 Erasmi AW, Sievers HH, Wolschlager C Inflammatory response after BioGlue application Ann Thorac Surg 2002;73:1025–6 81 Zimmermann T, Muhrer KH, Padberg W, Schwemmle K Closure of acute bronchial stump insufficiency with a musculus latissimus dorsi flap Thorac Cardiovasc Surg 1993;41:196–8 82 Baumann WR, Ulmer JL, Ambrose PG, et al Closure of a bronchopleural fistula using decalcified human spongiosa and a fibrin sealant Ann Thorac Surg 1997;64:230–3 83 Yasuda Y, Mori A, Kato H, et al Intrathoracic fibrin glue for postoperative pleuropulmonary fistula Ann Thorac Surg 1991;51:242–4 84 Musumeci F, Shukla V, Mignosa C, et al Early repair of postinfarction ventricular septal defect with gelatinresorcin-formol biological glue Ann Thorac Surg 1996;62:486–8 85 Robicsek F, Rielly JP, Marroum MC The use of cyanoacrylate adhesive (Krazy Glue) in cardiac surgery J Card Surg 1994;9:353–6 86 Lachapelle K, DeVarennes B, Ergina PL, Cecere R Sutureless patch technique for postinfarction left ventricular rupture Ann Thorac Surg 2002;74:96–101 87 Padro JM, Mesa JM, Silvestre J, et al Subacute cardiac rupture: repair with a sutureless technique Ann Thorac Surg 1993;55:20–3 75 Raanani E, Latter DA, Errett LE, et al Use of “BioGlue” in aortic surgical repair Ann Thorac Surg 2001;72:638–40 88 Fekete F, Gayet B, Panis Y Apport de la colle de fibrine dans le renforcement des anastomoses oesophagiennes Presse Med 1992;21:157–9 76 Passage J, Jalali H, Tam RK, et al BioGlue surgical adhesive—an appraisal of its indications in cardiac surgery Ann Thorac Surg 2002;74:432–7 89 Sierra DH Fibrin sealant adhesive systems: a review of their chemistry, material properties and clinical applications J Biomater Appl 1993;7:309–51 CHAPTER MULTIMODALITY MANAGEMENT OF EARLY-STAGE LUNG CANCER KATHERINE M.W PISTERS, MD benefit and will be reviewed in this chapter Chemotherapy administered prior to surgery or definitive irradiation has improved survival for patients with stage III NSCLC – The role of induction chemotherapy in patients with early-stage (stage I and II) NSCLC is currently under investigation For patients with early-stage nonsmall cell lung cancer (NSCLC), surgery remains the best treatment modality for potential cure Unfortunately, at the time of initial presentation, the majority of patients with NSCLC have disease that is not amenable to resection For patients who undergo surgical resection with curative intent, the 5-year survival rates are disappointing, ranging from 67% for T1N0 disease to 23% for patients with T1–3N2 disease extent.1 The stage; tumor, node, and metastasis (TNM) subsets; and 5-year survival rates for clinical and pathologic staging are shown in Table 4-1 Efforts at improving survival for patients with resectable NSCLC have examined the use of combined modality therapy, employing chemotherapy and/or radiation in the postoperative (adjuvant) or preoperative (neoadjuvant or induction) settings Until recently, randomized trials of adjuvant therapy have been disappointing, with the majority of trials demonstrating no survival benefit However, recent data from randomized clinical trials has shown a survival Part I: Adjuvant Therapy Radiation Although postoperative radiation has been associated with improved local control in patients with mediastinal nodal involvement,6 no trials have found an improvement in overall survival Many of the trials of postoperative radiotherapy have not involved adequate numbers of patients to detect small but clinically relevant survival differences A meta-analysis examining the effect of postoperative radiotherapy was published in 1998 This analysis found a detrimental effect of postoperative radiotherapy for patients with completely resected NSCLC A 21% relative increase in the risk of death associated with radiotherapy (absolute reduction in survival from 55 to 48% at yr) was found This effect was greatest for patients with earlier-stage disease or minimal nodal involvement No patient subgroup defined by stage or nodal status showed evidence of a clear benefit from postoperative radiotherapy.7 Although a decrease in local recurrence was seen, the authors cautioned that this effect was small and was outweighed by the adverse effect of postoperative radiotherapy on survival This metaanalysis must be interpreted with caution as many of the trials included used outdated radiotherapy techniques At present, the use of postoperative radiotherapy should be restricted to those patients at highest risk for TABLE 4-1 Survival Rates for Early-Stage NSCLC Based on Clinical and Pathologic Staging Stage TNM Classification IA IB IIA IIB T1N0M0 T2N0M0 T1N1M0 T2N1M0 T3N0M0 T3N1M0 T1–3N2M0 5-Year Survival (%) Clinical IIIA Pathologic 61 38 34 24 22 13 67 57 55 39 38 25 23 Adapted from Mountain CF.1 NSCLC = nonsmall cell lung cancer; TNM = tumor, node, metastasis 61 62 / Advanced Therapy in Thoracic Surgery local recurrence (positive surgical margins, residual local disease, or selected patients with multiple lymph node involvement) Further research employing modern radiotherapy techniques, such as conformal radiotherapy or hyperfractionated radiotherapy, is warranted Chemotherapy Initial trials exploring the use of postoperative chemotherapy were conducted in the 1960s and 1970s.8–12 No survival benefit was found; however, these early trials were flawed as factors such as histology, nodal involvement, performance status, age, and intraoperative staging were not considered in their design Moreover, the chemotherapeutic agents studied had minimal activity in NSCLC Platin-based Regimens Many NSCLC adjuvant chemotherapy trials have examined the efficacy of cisplatin-based regimens Only those trials involving postoperative chemotherapy (and no radiation) are reviewed in this chapter The Lung Cancer Study Group (LCSG) has conducted two postoperative chemotherapy trials The first trial, LCSG trial 772, randomized patients with completely resected stage II and III adenocarcinoma and large cell cancer to receive postoperative CAP (cyclophosphamide, doxorubicin [Adriamycin], cisplatin [Platinol]) chemotherapy or immunotherapy (intrapleural bacille Calmette-Guérin and 18 mo of oral levamisole) Disease-free survival was significantly prolonged in the CAP arm (p = 018); however, the overall survival difference, although increased by to months (median), was not statistically significant The second LCSG trial enrolled patients with completely resected T2N1 and T2N0 NSCLC.14 This trial randomized patients to four courses of postoperative CAP chemotherapy or no postoperative treatment No difference in time to recurrence or overall survival was found CAP chemotherapy was also evaluated in a trial conducted in Finland This trial randomized 110 patients with completely resected T1–3N0 NSCLC to postoperative CAP chemotherapy for six cycles or no further therapy In contrast to the LCSG studies, survival at 10 years in the chemotherapy arm was significantly better than for the control arm (61% vs 48%, p = 050) Twice as many pneumonectomy patients were assigned to the surgery-only arm, which may have influenced the results of this study A trial conducted in Japan randomized patients with completely resected stage III NSCLC to postoperative vindesine and cisplatin chemotherapy versus control.16 There was no difference in disease-free survival or overall survival in this study Trials comparing postoperative chemotherapy with surgery alone were reviewed as part of a meta-analysis examining the role of chemotherapy in the treatment of NSCLC.17 The results showed considerable diversity and evidence of a difference in direction of effect between the predefined categories of chemotherapy (Table 4-2) The results for long-term alkylating agents were consistent The hazard ratio estimates all favored surgery alone with a combined hazard ratio of 1.15 (p = 005) This 15% increase in the risk of death translated to an absolute detriment of chemotherapy of 5% at years For regimens containing cisplatin, the pattern of results was consistent with most trials favoring chemotherapy An overall hazard ratio of 0.87 (p = 08), or a 13% reduction in the risk of death was found The absolute benefit from cisplatin-based chemotherapy was 5% at years The trials that were classified as using other regimens were found to have an estimated hazard ratio of 0.89 in favor of chemotherapy (p = 30), but there was insufficient information to draw reliable conclusions Since the time of the meta-analysis, data from six additional studies has become available which has clarified the role of postoperative adjuvant platin-based chemotherapy A small trial from Japan randomized 119 patients with completely resected stage IIIA/N2 disease and randomized patients to postoperative vindesine and cisplatin chemotherapy for cycles versus no further treatment No significant differences in overall survival were seen.18 Investigators in Italy and the EORTC (European Organisation for Research and Treatment of Cancer) conducted a trial enrolling 1209 eligible patients with completely resected stage I to III NSCLC and randomized patients to postoperative mitomycin, vindesine and cisplatin chemotherapy for cycles versus no postoperative chemotherapy 19 Forty-three percent of patients received postoperative radiotherapy In the ALPI (Adjuvant Lung Project Italy) trial, no significant difference in overall survival was seen with a hazard risk of death of 0.96, 95% confidence intervals (CI) 0.81–1.13, p = 589 The IALT (International Adjuvant Lung Trial) results were recently published and has been the largest trial of postoperative adjuvant chemotherapy in NSCLC conducted to date.20 This trial randomized 1867 eligible patients with completely resected stage I, II, and III TABLE 4-2 Meta-analysis: Postoperative Chemotherapy Category Alkylating agents Other drugs Cisplatin based Hazard Ratio (95% CI) p Value 1.15 (1.04–1.27) 0.89 (0.72–1.11) 0.87 (0.74–1.02) 5-Year Survival (%) 005 30 08 Adapted from Non-small Cell Lung Cancer Collaborative Group.17 Ϫ5 Multimodality Management of Early-Stage Lung Cancer / 63 NSCLC to postoperative cisplatin-based chemotherapy for or cycles versus no postoperative chemotherapy In addition to cisplatin, patients received either etoposide, vindesine, vinblastine or vinorelbine In this trial, 27% of patients also received postoperative radiation This study found a 4% improvement in 5-year survival favoring chemotherapy This corresponded to a hazard ratio of 0.86 (95% CI 0.76–0.98), with a statistically significant p value of < 03 The BLT (Big Lung Trial) was conducted in Great Britain and randomized 381 patients with completely resected stage I-III NSCLC to cycles of postoperative cisplatin-based chemotherapy.21 In this study, 14% of patients received postoperative radiation No significant differences in survival in the 1-year survival data presented The NCIC (National Cancer Institute of Canada) presented the results of their phase III randomized trial of postoperative vinorelbine/cisplatin chemotherapy in 482 patients with completely resected stage IB and II NSCLC at the annual meeting of the American Society of Clinical Oncology (ASCO) 2004.22 This trial found a 15% improvement in the overall 5-year survival rate for those patients randomized to received cycles of postoperative chemotherapy The hazard rate was 0.70 (95% CI 0.52–0.92, p = 012) Also presented at ASCO 2004 was the results of the Cancer and Leukemia Group B (CALGB) randomized study of postoperative paclitaxel and carboplatin for cycles versus no further therapy in 344 patients with completely resected stage IB (T2N0) NSCLC.23 Like the NCIC study, this trial found a marked benefit in favor of postoperative chemotherapy with a 12% improvement in survival at years and a hazard rate of 0.62 (95% CI 0.41–0.95, p = 028) These recent trial results have now changed the standard of care for patients with completely resected NSCLC Consistent reductions in the risk of death have been observed in recent platin-based adjuvant chemotherapy trials Postoperative platin-based chemotherapy should be recommended to completely resected NSCLC patients with good performance status UFT Regimens Studies examining the use of adjuvant oral fluorouracil derivatives have been conducted in Japan These trials have examined the use of tegafur (FT) and UFT (Taiho Pharmaceuticals, Japan) (a combination of tegafur and uracil at a molar ratio of 1:4) The Chuba Oncology group examined the effect of one cycle of postoperative cisplatin and doxorubicin followed by oral UFT for months on completely resected stage I to III NSCLC.24 This trial did not stratify for known prognostic factors, and there was an imbalance with respect to pathologic N stage, with more advanced cases assigned to the combined modality arm (p = 018) On an intention-totreat analysis, the overall 5-year survival rate was 62% for surgery and chemotherapy versus 58% for surgery alone (not significant) A reanalysis of the data incorporating prognostic factors using the Cox proportional hazards model was performed, and a significant difference in overall and disease-free survival rates favoring the use of adjuvant chemotherapy was found (p = 044 and p = 036, respectively) Wada and colleagues also evaluated the use of UFT in the postoperative setting This trial enrolled 310 patients with completely resected NSCLC (stages I–III) After surgery patients were randomly assigned to receive one cycle of cisplatin and vindesine followed by oral UFT for year (CVUFT), year of oral UFT, or no postoperative therapy The 5-year survival rates were 61% for CVUFT, 64% for UFT, and 49% for the control group (differences among the three groups: p = 053 by logrank test, and p = 044 by Wilcoxon rank sum test) Adverse effects were generally mild The UFT administered in these studies was well tolerated and appeared to inhibit recurrence and prolong survival when administered over to 12 months following surgery The single largest trial studying the effects of postoperative UFT therapy in resected NSCLC was conducted in Japan This study randomized 999 patients with completely resected stage I adenocarcinoma to either oral UFT for years or no postoperative treatment There was a survival benefit favoring the use of UFT, p = 04 Toxicity was minimal in this group of patients The results of a meta-analysis examining the effectiveness of postoperative UFT were presented at ASCO 2004.27 This meta-analysis included results from 2003 patients and was restricted to studies where patients received postoperative UFT only In this meta-analysis, 95% of patients had stage I disease, 84% had adenocarcinoma, 45% were women, and the median age was 62 years An overall benefit favoring the use of postoperative UFT was seen with a hazard rate of 0.74 (95% CI 0.61–0.88, p = 001) There is no confirmatory data concerning the use of UFT in the postoperative NSCLC setting outside of Japan In addition, UFT is not available for use in the United States Future trials of chemotherapy and surger y in resectable NSCLC will likely focus on the incorporation of targeted therapies and sequencing of modalities 64 / Advanced Therapy in Thoracic Surgery Part II: Preoperative Therapy Chemotherapy Numerous phase II trials of induction chemotherapy followed by surgery for stage III NSCLC have been conducted.28–31 These trials will be discussed more extensively in another chapter In general, preoperative cisplatin-based combination chemotherapy is feasible and has higher response rates than have been previously seen in the metastatic patient population Treatment has usually consisted of two to four induction chemotherapy cycles Some of the trials included attempted postoperative chemotherapy and radiation Major objective response rates following chemotherapy have been as high as 70 to 80%, with clinical complete responses occurring in approximately 10% of patients Complete resection rates have ranged from 50 to 75%, and pathologic complete responses (no viable tumor found in the resection specimen) have been found in approximately to 15% of patients treated Those patients who have been found to have pathologic complete responses have been noteworthy for significantly prolonged survival.32 The median survival rates in these trials were similar around 18 to 25 months, with 5-year survival rates in the range of 25% These figures compared favorably to historical controls Two prospective, randomized trials comparing surgery alone with induction chemotherapy and surgery have been conducted in stage IIIA NSCLC.2,3 One study was conducted by Rosell and colleagues from the University of Barcelona and the other by Roth and colleagues at M D Anderson Cancer Center Both studies enrolled a total of 60 patients (both trials were terminated early after interim analyses indicated a significant survival advantage in the chemotherapy arm) Cisplatin-based chemotherapy was administered in both studies, and both found a significant improvement in survival for patients treated with induction chemotherapy Given the survival statistics following surgery alone and the lack of evidence to support postoperative therapy at that time, a multicenter phase II trial of induction chemotherapy followed by surgery was undertaken (the Bimodality Lung Oncology Team [BLOT] trial) in patients with early stage NSCLC Patients with clinical stage IB (T2N0), II (T1–2N1, T3N0), and selected IIIA (T3N1) disease received perioperative chemotherapy consisting of paclitaxel (225 mg/m2, h infusion) and carboplatin (area under the curve [AUC] = 6) The initial cohort of 94 patients received two preoperative chemotherapy cycles and three cycles after surgery and has been previously reported 33 The BLOT trial had a second cohort of 40 patients treated with three induction and two postoperative chemotherapy cycles.34 There were no differences in age, gender, race, stage, or performance status between the cohorts The number of patients, major radiographic response rate and 95% confidence intervals to induction chemotherapy, operative mortality, and 1- and 3-year survival rates are listed in Table 4–3 This trial established the feasibility and safety of this approach with encouraging survival rates compared with historical controls.1,33,34 TABLE 4–3 Results of Phase II Bimodality Lung Oncology Team Trial Induction N Chemotherapy cycles cycles Total 94 40 134 Major Response (%) (95% CI) Operative Mortality (%) 56 (46–67) 38 (23–54) 51 Survival (%) Year Year 86 83 85 64 NA 63 Adapted from Pisters K et al.34 NA = not available Based on the phase II BLOT experience, a phase III trial, (Southwest Oncology Group [SWOG] 9900), was initiated to compare the bimodality approach (induction paclitaxel and carboplatin plus surgery) to surgical resection alone in patients with early-stage NSCLC (Figure 4–1) The primary objective of this trial was to assess whether preoperative chemotherapy with paclitaxel and carboplatin for three cycles improved survival compared with surgery alone in previously untreated patients with clinical stage IB, II, and selected IIIA NSCLC Secondary objectives include a comparison of time to progression, sites of relapse, operative mortality, and toxicity between the two study arms The response rates and toxicities associated with the combination of paclitaxel and carboplatin will also be evaluated The study planned to enroll 600 patients (300 in each arm) to detect an improvement of 33% in median survival, or increase in 5-year survival from 28 to 38% Patients were stratified by clinical stage IB/IIA versus IIB/IIIA and randomized to induction chemotherapy followed by surgery versus immediate surgery All patients entered into the trial are to be followed for survival, recurrence, and toxicity data Accrual to this trial was suspended in July 2004 after the results of the NCIC and CALGB adjuvant trials were presented Total accrual reached 354 out of a planned 600 patients No data regarding outcome is available at this time Depierre and colleagues have reported the French experience of a phase III randomized trial of induction chemotherapy in early-stage NSCLC (stages IB, II, and IIIA).35 The aim of the study was to assess the impact of induction chemotherapy prior to surgery on survival Three hundred fifty-five eligible patients were random- 66 / Advanced Therapy in Thoracic Surgery Sause WT, Scott C, Taylor S, et al Radiation Therapy Oncology Group 88–08 and Eastern Cooperative Oncology Group 4588: preliminary results of a phase III trial of regionally advanced, unresectable non-small cell lung cancer J Natl Cancer Inst 1995;87:198–205 The Lung Cancer Study Group Effects of postoperative mediastinal radiation on completely resected stage II and stage III squamous cell carcinoma of the lung N Engl J Med 1986;315:1377–81 PORT Meta-analysis Trialists Group Postoperative radiotherapy in non-small cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomized controlled trials Lancet 1998;352:257–63 Slack N Bronchogenic carcinoma: nitrogen mustard as a surgical adjuvant and factor influencing survival Cancer 1970;25:987–1002 Higgins GA, Shields TW Experience of the veterans administration surgical adjuvant group In: Muggia FM, Bozencweig M, editors Lung cancer: progress in therapeutic research 11th ed New York: Raven Press; 1979 p 433–42 10 Brunner KW, Marthaler T, Muller W Effects of long-term adjuvant chemotherapy with cyclophosphamide (NSC2627,2) for radically resected bronchogenic carcinoma Cancer Chemother Rep 1973;4:125–32 11 Girling DJ, Stott H, Stephens RJ, et al Fifteen-year followup of all patients in a study of postoperative chemotherapy for bronchial carcinoma Br J Cancer 1985;52:867–73 12 Shields TW, Higgins GA Jr, Humphrey EW, et al Prolonged intermittent adjuvant chemotherapy with CCNU and hydroxyurea after resection of carcinoma of the lung Cancer 1982;50:1713–21 13 Holmes EC, Gail M Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma J Clin Oncol 1986;4:710–5 14 Feld R, Rubinstein L, Thomas PA, and the Lung Cancer Study Group Adjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I NSCLC J Natl Cancer Inst 1993;85:299–306 15 Niiranen A, Niitamo-Korhonen S, Kouri M, et al Adjuvant chemotherapy after radical surgery for non-small cell lung cancer: a randomized study J Clin Oncol 1992;10:1927–32 16 Ohta M, Tsuchiya R, Shimoyama M, et al Adjuvant chemotherapy for completely resected stage III non-small cell lung cancer J Thorac Cardiovasc Surg 1993;106:703–8 17 Non-small Cell Lung Cancer Collaborative Group Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials BMJ 1995;311:899–909 18 Tada H, Tsuchiya R, Ichinose Y, et al A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pN2 non-small cell lung cancer (JCOG9304) Lung Cancer 2004; 43; 167–73 19 Scagliotti SV, Fossati R, Torri V, et al Randomized study of adjuvant chemotherapy for completely resected stage I, II or IIIA non-small cell lung cancer J Natl Cancer Inst 2003;95:1453–61 20 The International Adjuvant Lung Cancer Trial Collaborative Group Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer New Engl J Med 2004;350:3351–60 21 Waller D, Fairlamb DJ, Gower N, et al The Big Lung Trial (BLT): Determining the value of cispaltin-based chemotherapy for all patinets with non-small cell lung cancer Preliminary results in the surgical setting [abstract 2543] Proc Am Soc Clin Oncol 2003;22:632 22 Winton TL, Livingston R, Johnson D, et al A prospective randomised trial of adjuvant vinorelbine and cisplatin in completely resected stage IB and II non small cell lung cancer Intergroup [abstract 7018] JBR.10 J Clin Oncol 2004;22(14 Suppl):621S 23 Strauss, GM, Herndon J, Maddaus MA, et al Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633 [abstract 7019] J Clin Oncol 2004;22(14 Suppl):621S 24 Imaizumi M and The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chuba, Japan) A randomized trial of postoperative adjuvant chemotherapy in non-small cell lung cancer (the second cooperative study) Eur J Surg Oncol 1995;21:69–77 25 Wada H, Hitomi S, Teramatsu T, et al Adjuvant chemotherapy after complete resection in non-small cell lung cancer J Clin Oncol 1996;14:1048–54 26 Kato H, Ichinose Y, Ohta M, et al A randomized trial of adjuvant chemothearpy with uracil-tegafur for adenocarcinoma of the lung N Engl J Med 2004;350:1713–21 27 Hamada C, Ohta M, Wada H et al Survival benefit of oral UFT of adjuvant chemtoherapy after comletely resected non-small cell lung cancer [abstract 7002] J Clin Oncol 2004;22(14 Suppl):617S 28 Burkes RL, Ginsberg RJ, Shepherd FA, et al Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small cell lung cancer: results of the Toronto phase II trial J Clin Oncol 1992;10:580–6 29 Darwish S, Minotti V, Crino L, et al Neoadjuvant cisplatin and etoposide for stage IIIA (clinical N2) non-small cell lung cancer Am J Clin Oncol 1994;17:64–7 30 Martini N, Kris MG, Flehinger BJ, et al Preoperative chemotherapy for stage IIIA (N2) lung cancer: the Memorial Sloan-Kettering experience with 136 patients Ann Thorac Surg 1993;55:1365–74 31 Vokes EE, Bitran JD, Hoffman PC, et al Neoadjuvant vindesine, etoposide, and cisplatin for locally advanced non-small cell lung cancer Chest 1989;96:110–3 CHAPTER LASER BRONCHOSCOPY ROBERT JAMES CERFOLIO, MD, FACS, FCCP cially true for patients with endobronchial obstruction, is described Patient characteristics that are favorable or unfavorable for each treatment strategy are listed Patients who are best served by the different types of laser are compared and contrasted with patients who are better served by laser’s main alternatives—stents, chemotherapy, external beam radiotherapy, and brachytherapy Although many view these modalities as competitors, we believe that it is best to view them as allies When all of these treatments are properly used together they lead to excellent palliation of the blocked, bloody, or narrowed airway The true strength of these diverse treatment strategies is maximized when patients receive a combination of techniques Laser bronchoscopy is a relatively new procedure Although it was first described only three decades ago, its clinical use has become widespread worldwide Interestingly, it is often used with a relatively old procedure—rigid bronchoscopy, which has been around for over 100 years Laser bronchoscopy is a powerful and versatile cog in the armamentarium available to thoracic surgeons, general surgeons, and pulmonologists Several new lasers developed in industry have come to fruition in the medical arena Some have become powerful clinical tools for the practicing surgeon As further scientific discoveries are made, the advancements made in the field of lasers will probably continue to be applied to the field of medicine, thus ensuring laser bronchoscopy’s future as bright and dynamic In the 1970s and 1980s laser bronchoscopy really only meant carbon dioxide (CO2) lasers Now there is a vast array of instruments that guide and direct a whole host of different types of lasers The lasers that are used most often clinically, however, via the bronchoscope, include the CO2 laser, the yttrium-aluminum-garnet (YAG) laser, and lasers for photodynamic therapy The YAG laser can be a KTP laser or a neodymium (Nd) laser This chapter focuses on these In the following pages we briefly discuss the history of laser bronchoscopy, the different types of lasers that are currently available, and their basic mechanism of action We describe the advantages and disadvantages of each type of laser The technique of rigid bronchoscopy, which remains our preferred way to transfer any laser’s energy to tissue in the airway, is also described The most common complications and pitfalls of laser bronchoscopy are discussed along with their treatments Patient selection, which is a critical component for clinical success in any arena but which is espe- History of Rigid Bronchoscopy The art of rigid bronchoscopy, an important precursor for the development of laser bronchoscopy, was forged by an otolaryngologist and not by a general or thoracic surgeon In 1897, Gustav Killian reported the first case report of rigid bronchoscopy.1 In that report, Killian retrieved “a pork bone” from a patient’s airway using an esophagoscope With this report, the age of rigid bronchoscopy was born By the early 1900s, many more case reports were published concerning the use of rigid bronchoscopy Chevalier Jackson distinguished himself as a pioneer and leader in this art.2 He not only championed the clinical art of how to perform rigid bronchoscopy, but he also helped design and develop the scope itself Despite the fact that almost 100 years have passed since Jackson’s initial work, the rigid bronchoscope we use today is amazingly similar to the one he “perfected” in the early 1900s The only real advancements have been in the light source and in the 91 92 / Advanced Therapy in Thoracic Surgery optics of flexible bronchoscopy, but little has been done to improve the scope itself History of Laser Bronchoscopy The first reported case of laser bronchoscopy was by Strong in 1972 He used the only laser then clinically available, the CO2 laser Over the next decade CO2 laser emerged as a safe and effective tool to treat laryngeal narrowing or tumors in the upper airway Although the CO2 laser was, and still is, a very useful tool for these types of lesions, it is housed in a cumbersome device The laser was harnessed to the rigid scope via a long tube that housed a series of mirrors These mirrors deflected the beam of light, which finally emerged from this large, bulky machine The rigid scope allowed the surgeon to ventilate and oxygenate the patient through one arm of the scope while visualizing and lasering the intended lesion in the airway through another In 1973 Strong and colleagues reported results with 15 patients who had undergone over 70 CO2 laser bronchoscopies.3 Perhaps most important to this report is that he reported few complications This publication proved the safety of shining a powerful beam of light, through a narrow steel tube inserted in a patient’s airway, despite the presence of oxygen It proved that the laser was safe in the operating room in proximity to tanks that were filled with highly flammable gaseous anesthetics This landmark paper laid the groundwork and allowed others to adopt the use of laser bronchoscopy in the clinical setting and to help further refine this art After these initial endeavors, further research led to the development of flexible scopes With the development of these scopes came the realization that a more flexible laser system was needed in order to be able to treat more distal aspect of the tracheobronchial tree Lasers become more powerful, smaller, more compact, and portable The fibers used to introduce them into the airway become smaller and more bendable This allowed the surgeon to treat lesions past the main stem bronchi— into lobar and even into subsegmental bronchii Although the rigid bronchoscope with the CO2 laser is still extremely useful, it is limited by its bulky design It is limited to treating pathology in the larynx, upper airway, the trachea, main stem bronchi, or in the proximal lower lobe bronchi The CO2 laser is restricted by the rigid scope’s size and by its nonbendable nature The scope was too big to enter distal parts of the tracheobronchial tree in most patients Even when rigid scopes became smaller, the CO laser was still limited to the areas described above Lesions in the superior segment of the lower lobes and most of the left upper lobe were not accessible Types of Lasers The lasers that are clinically used today are introduced into the airway via the rigid or flexible bronchoscope These lasers are the CO2 and Nd-YAG lasers, described above, and lasers that are used for photodynamic therapy, which include an argon laser (Coherent), a KTP-YAG laser (Laserscope), and a diode laser (Diomed) (Figures 7-1–7-3) Obvious advantages and disadvantages are visible from the photographs Some machines, such as the Coherent, are larger than others and less portable Others, like the KTP laser, require a cooling system, so they are also more difficult to move Some, like the Diomed, not require any optics and are easy to move FIGURE 7-1 The Coherent Laser is not portable and is about feet high and feet long FIGURE 7-2 The Laserscope Laser is portable but requires a water line and is about feet high and feet wide 94 / Advanced Therapy in Thoracic Surgery removed, but often it requires one to withdraw the entire scope from the airway and hope the fragment did not fall into the back of the pharynx The final and perhaps most important advantage of rigid bronchoscopy is that the flexible scope can be and should be used through the rigid scope In this way all of the advantages and safety features of the rigid scope are maintained and all of the advantages of the flexible scope are kept as well The disadvantage of rigid bronchoscopy is that it usually requires the patient to receive a general anesthesia Although rigid bronchoscopy can be performed without muscle paralysis and without general anesthesia, it is most commonly performed in our institution with a shortacting depolarizing agent and a gas anesthetic Many of the patients who require laser bronchoscopy have stage IV lung cancer They are weak and debilitated from their metastatic cancer and by previous radiotherapy and chemotherapy The laser bronchoscopic procedure is usually only palliative However, with careful management, anesthetic complications are very rare We have had no serious anesthetic complications in more than 900 rigid bronchoscopies Another potential disadvantage is cost Most rigid bronchoscopy is done in the operating room with an anesthesiologist present, and thus it is more costly However, if it delivers an open airway quicker and safer than other modalities, these costs may be offset A common perception of rigid bronchoscopy is that it is more difficult to perform Although this is probably true, like any other procedure it becomes relatively straightforward with experience Some physicians, especially pulmonologists, may feel uncomfortable with rigid bronchoscopy because it was not a large part of their training But for those who try it and stick with it, after about 10 to 15 procedures they often begin to prefer it for its debridement of the airway Another potential problem, though rare, is that some patients simply cannot have a rigid scope placed The surgeon needs to know when to stop trying to place the rigid scope and abandon the technique Patient characteristics that make rigid bronchoscopy difficult include having a small mouth; large teeth (often with caps on the upper teeth); a short, fat neck; a history of radiation to the head and neck; and difficulty extending the neck In these situations, or when performing a procedure on the subglottic apparatus in any patient, laryngoscopy should be available and employed when needed In our opinion, the surgical team that is going to perform rigid bronchoscopy should always have a formal laryngoscope with the appropriate attachments available to secure the scope to a table Figures 7-4 demonstrates how a laryngoscope should be anchored to a Mayo table Since the art of rigid bronchoscopy is fading and since we believe it is the preferred way to laser bronchoscopy, we briefly review the technique Rigid Bronchoscopy Technique The patient should be brought to a suite where all the potentially needed and appropriate equipment is available Most bronchoscopy suites either on the floor or in the operating room area should have overhead monitors so that everyone can see what is happening inside the airway This allows the nurses to better assist; they know what the airway looks like and what the problem is It also enables the anesthesiologists to better understand the anatomy and to anticipate any potential problems Rooms that are in the operating room area may offer an advantage for the very rare patient who requires an emergency thoracotomy because of bleeding The patient’s head should be at the end of the table The table should have a separate head section that can be flexed, extended, or removed The neck should be extended, and the degree to which a patient can flex and extend the neck and open the mouth should be assessed FIGURE 7-4 Intraoperative pictures demonstrate how a laryngoscope is anchored to an overhanging table and how a flexible fiberoptic bronchoscope can be easily inserted through the laryngoscope Laser Bronchoscopy / 95 prior to induction If the patient has teeth in the upper palate a tooth guard should be placed over them to protect them from injury (as shown in Figure 7-5) In general, there are two ways to introduce the scope We describe the classic way, which is preferred, first This classic technique entails placing the rigid bronchoscope between the thumb and index finger of the nondominant hand The thumb acts as a fulcrum at all times so that the patient’s teeth and the upper palate are spared any undue pressure The scope is slowly introduced into the mouth The assistant can help by pulling the left cheek outward with his or her index finger so the lip is not pinched The bevel end of the scope should be anterior (pointing towards the ceiling) The key is to stay in the midline from this point on The median furrow of the tongue acts as a vector and leads one to the midline of the oropharynx Once the oropharynx is identified, the tip of the scope usually has to be gently rotated The scope is advanced— again using the left thumb and fingers as a fulcrum so that all pressure is exerted against them and not against the patient’s upper teeth The epiglottis should then come into view The hypopharynx should then be carefully inspected Once this is done the beveled part of the scope is used to lift up the epiglottis anteriorly The glottic opening and the vocal cords should then come into full view They too should be examined Many patients with bronchogenic malignancy, who usually are smokers, also have concomitant head and neck cancers The scope is then turned about 90° to 120° clockwise Once the upper airway is intubated by the rigid scope, the scope should again be rotated slowly so that the bevel part is anterior If jet ventilation is used as is our preference (allowing the end of the scope to stay open—instruments can be easily and quickly passed through it and carbon dioxide is ventilated), it should now be hooked up to the side of the scope The other way to place the rigid scope is using the anesthesiologist’s handheld laryngoscope (Figure 7-6) This instrument is used to suspend or expose the tip of FIGURE 7-5 A tooth guard is placed on the teeth in the upper palate the epiglottis; the rigid scope can then be inserted almost like an endotracheal tube Once the tip is under the epiglottis the surgeon removes the hand-held laryngoscope and looks through the rigid scope and introduces it as described above (Figures 7-7 and 7-8) This technique, FIGURE 7-6 A hand-held laryngoscope is used to expose the tip of the epiglottis that is suspended, and the rigid scope is easily introduced into the upper airway FIGURE 7-7 The surgeon then looks through the rigid scope to evaluate the vocal chords and the rest of the upper airway FIGURE 7-8 The scope is gently rotated and inserted into the proximal trachea The surgeon’s fingers should serve as a fulcrum so that there is no pressure on the upper teeth 96 / Advanced Therapy in Thoracic Surgery although technically easier, eliminates the ability to perform a full examine of the upper airway Once the scope is in place (Figure 7-9), the flexible scope can be placed down the rigid scope Lasering Tumors in the Airway Each laser imparts its energy differently to the tumor Some impale the tumor, others direct the powerful beam of light onto its surface, and some touch the tumor Most CO2 lasers have an aiming beam that shines a red light onto the desired target This targeting light tells the surgeon where the beam is going to go The surgeon is then able to deliver the laser to the tumor’s surface via a foot pedal The laser can be delivered in either short bursts or with a continuous firing The latter is more dangerous, but if the tumor is large and the visibility is good little energy should be imparted to surrounding tissue The goal is to minimize the amount of lasering to the surrounding normal tissue while maximizing the amount of energy directed onto or into the cancer The desired amount of power can be dialed into the machine The surgeon looks through the lens of the CO2 laser that is fastened onto the end of the rigid bronchoscope and he or she works usually while sitting A smoke evacuator should also be applied to the end of the scope The YAG laser is delivered via a malleable cable that is snaked through the working chamber of a flexible scope This allows one to laser while standing and the action can be viewed on an overhead monitor The YAG laser also has an aiming beam, but unlike the CO2 laser it has a cooling mechanism that forces air out of the end of the laser The blowing air can distort one’s vision at times because blood can be stirred up while lasering and it can smear the end of the scope Like the CO laser, the desired amount of power can be set on a YAG laser and a foot pedal is used to deliver it Photodynamic therapy, which can be delivered by various lasers, uses a nonthermal method of killing tumor cells CO2 and YAG deliver heat and hence the risk of an airway fire is real Patients who undergo photodynamic therapy are given an intravenous chemical (Photofrin, Birmingham, AL) This chemical is picked up by most cells in the body but over the course of 48 to 72 hours is leached out of these cells, except for those in the skin, those in the reticuloendothelial system, and all types of cancer cells The surgeon then brings the patient to the operating room and selects a diffuser to help impart the laser’s energy to the tumor These diffusers come in several lengths (1.0, 2.5, 5, and 10 cm) These diffusers are flexible and, like the YAG laser system, are placed down the working port of a flexible bronchoscope If the tumor is soft and large the diffuser can be impaled directly into the tumor If the tumor is sessile or hard it can be placed against the tumor We refer to the latter technique as the juxtaposing technique and the former as the impaling technique The laser is activated, activating the Photofrin that is in high concentration in the tumor and causing a nonthermal injury to the cancer The activation releases free oxygen radicals, which leads to ischemic necrosis and cellular death Dead tissue is debrided the next day to help open the airway Debridement bronchoscopy is usually unnecessary when tumors of the esophagus are treated Patient Selection FIGURE 7-9 The scope is in place and a flexible fiberoptic bronchoscope or other working instruments can be easily inserted through while jet ventilation is used through a side hole For our review of laser bronchoscopy to be clinically complete, we must discuss where it fits into the treatment algorithm of these patients Most have stage IV lung cancer or metastatic endobronchial metastases These patients have a very poor life expectancy, so the goal of the treatment is palliation and improvement of quality of life Most patients with malignant pathology in their airway are best served by a combination of treatments available to palliate their symptoms Few patients are best Laser Bronchoscopy / 97 served by laser bronchoscopy alone In this section we briefly describe some of the characteristics that may make one treatment better than another for the airway blocked with tumor In general surgical resection is the best way to palliate an airway; we focus on the patient who is not a surgical candidate Usually surgery is not advised for patients with stage IV lung cancer, as it affords little to no benefit A much less common scenario is that the patient has early lung cancer but has underlying comorbidities that make the risks of surgery greater than the benefit In general, direct endoscopic therapy is the preferred treatment when the patient has an occluded airway It is our treatment of choice when there is hemoptysis from a bleeding endobronchial lesion or when the patient is significantly short of breath and the lesion is blocking a lobe or greater and the distal airway is patent or recruitable Direct endoscopic therapy is hallmarked by laser bronchoscopy, but it also includes shavers and rotary blades Photodynamic therapy, which will be discussed below, has a special role for the patient who suffers from recurrent significant hemoptysis It offers immediate control of bleeding and usually allows one to core out and remove the lesion and open the distal airway Photodynamic Therapy We prefer photodynamic therapy for patients who have vascular tumors This is especially true of metastatic lesions to the airways, such as melanoma and renal cell carcinoma We also prefer photodynamic therapy when we are unable to visualize the distal tree behind the tumor, because photodynamic therapy almost eliminates the risk of perforation Although the perforation risk is also extremely low with CO2 and YAG lasers, when the distal area cannot be visualized, it is possible, since the view of the anatomy is often distorted We have found photodynamic therapy to be extremely helpful in opening up large parts of the airway that is occluded by large bloody lesions It has become our treatment of choice in patients who have occlusion of either main stem bronchi or of the bronchus intermedius However, CO2 or YAG laser with a core-out therapy can be just as effective The only other advantages of photodynamic therapy are deeper penetration of up to to 10 millimeters and, in our experience, a lower risk of significant bleeding during the procedure Some data show that photodynamic therapy may continue to work via an inflammatory response after the treatment, unlike CO2 or YAG laser treatment Of course, the disadvantage of photodynamic therapy is that it requires the use of a chemical (Photofrin) This chemical makes patients light sensitive; patients must avoid direct exposure to sunlight for up to month Radiation Therapy If the airway has extrinsic compression from metastatic N1 regional lymph nodes narrowing it, then a treatment aimed at shrinking those nodes should be chosen Direct endoscopic therapy does not offer this capability If the nodes actually erode into the airway, initial treatment should be laser bronchoscopy to open the narrowed airway and remove the tip of the invading node Then radiotherapy can be used to treat the rest of the N1 node Brachytherapy or external beam radiotherapy are options Brachytherapy is best applied, in our opinion, when the endoluminal component of the mass has been fully treated but there are recurrent or new multiple areas of metastatic N1 nodes compressing several areas of the airway and the patient has already had the maximum amount of external beam radiation allowed Brachytherapy is contraindicated when the patient has an edematous narrowed airway, when photodynamic therapy has been performed in the previous weeks, or if there is a perforated airway or a fistula between the airway and esophagus As alluded to above, external beam radiotherapy is a mainstay treatment for nonsmall cell lung cancer and can also be effective However, in most patients sent to us for laser surgery, it has already been maximized The usual maximum dosage to the chest is around 60 Gy, although in isolated cases dosages up to 72 Gy have been delivered This does not take into account some of the new hyperfractionated methods of delivering external beam radiation Most patients with tumor in their airway have stage IV bronchogenic cancer and have already had several rounds of chemotherapy and radiation completed several months prior However, if the patient has bulky primary tumor or metastatic lymph nodes that are compressing, narrowing, or occluding the airway then external radiotherapy is an ideal treatment if it has not yet been tried and the maximum allowable dose has not been achieved Often patients can receive more radiotherapy; old radiation records need to be reviewed along with a survey of the exact areas treated Chemotherapy Chemotherapy is another effective, commonly used palliative treatment strategy It is reserved for the patient with a good performance status who has stage IIIa, stage IIIb, or stage IV cancer There may also be a role for it in early lung cancer, and several randomized trials are currently studying this issue One prospective randomized trial, referred to as the S9900 trial, by the American College of Surgeons is evaluating the effectiveness of chemotherapeutics agents in stage Ib, IIa, and IIb disease prior to surgical resection This topic is outside of the realm of this chapter 98 / Advanced Therapy in Thoracic Surgery Chemotherapy is also used for the patient with small cell cancer Chemotherapy can be useful in patients with tumor in the airway, but it is slow to open the airway and is rarely useful by itself It may be useful in patients with endoluminal cancer either as a bridge to surgery, to theoretically eliminate micrometastases, or to downstage the tumor prior to resection In patients with stage IV disease, chemotherapy such as Taxol may be used as a radiosensitizing agent when concurrent radiotherapy is planned Overall, it is best employed in the patient with cancer in the airway who also has metastatic stage IV disease with disease outside the chest and who has a good performance status However, chemotherapy by itself rarely will open an airway Some other treatment plan is usually needed to help palliate the airway problem and often laser bronchoscopy is most efficient Patients with small cell cancer often have mediastinal or hilar lymph nodes that are engorged with cancer These nodes frequently impinge on and extrinsically compress the airway and chemotherapy can help relieve this problem Laser bronchoscopy has no role if the airway is only compressed and there is no endoluminal component to the narrowing Stents Stents are also an important part of the armamentarium for the physician treating these patients Stents come in many different sizes, shapes, and types In general stents are also best suited for the patient with malignancy who has an extrinsically narrowed airway and who has already completed radiotherapy or for the patient with a malignant fistulous connection to the esophagus Because most stents employed today are metal, and thus permanent and difficult to remove after several weeks, our preference is to reserve these types of stents for malignant disease and when other modalities have been exhausted Their role in the algorithm is almost always after radiotherapy, chemotherapy, and several types of endoluminal treatments have been given and to palliate a perforated airway or to help keep one open Both covered and noncovered stents are available We reserve the former usually for malignant tracheoesophageal fistula Although these stents may be superior because they prevent tumor ingrowth, they may also increase secretions or increase one’s inability to clear secretions The covered metal stents grow into the surrounding tissue and after several weeks cannot be extracted Granulation tissue can form at the distal or proximal ends of the stent and can therefore cause a problem of narrowing further down or higher up the airway If the problem is marched down the airway, past the carina, and into distal lobar or segmental branches or if it goes up to the vocal chords, it is usually more diffi- cult to treat than the original tumor For this reason we not prefer stents for benign disease Results As reported in several series, the results of laser bronchoscopy are excellent The goal of any endoluminal procedure is to open the airway and relieve the patient’s dyspnea or hemoptysis The clinical reality is that laser bronchoscopy achieves this goal quicker than external beam radiation, chemotherapy, and brachytherapy No current prospective randomized trial shows this, but a large amount of data already exists that show the efficacy, safety, and swift results of laser bronchoscopy The real benefit of a prospective randomized trail, though difficult to perform, would be to compare the different types of lasers, their costs, and long-term results Clinical Applicability The type of lasers selected by the surgeon or pulmonologist is dependent on several features: probably foremost is the comfort of the operating clinician Some clinicians are extremely comfortable with one form of laser over another and will use it almost exclusively Although there are benefits to becoming very proficient with one type of laser, it is best to have all the available lasers in one’s armamentarium, allowing one to select the one that is ideal for the patient Other factors that the operating technician has to decide on are the type of anesthetic to use (general or local), the type of bronchoscopy needed (rigid with flexible or flexible alone), and the power of the laser As described above, we prefer general anesthesia and rigid bronchoscopy Lasers in Benign Disease Lasers are also useful for certain benign diseases that narrow the airway Although tracheal resection remain the mainstay of treatment for benign short segment tracheal or main stem lesions, the laser can be useful in isolated cases Although the specifics are beyond the scope of this chapter, it has been shown that crosshatching an area of stenosis in the 3, 6, 9, or 12 o’clock position followed by dilation with the rigid bronchoscope or balloon can be very effective The real complication of this procedure, in our opinion, is that it may lead to worsening of the inflammatory response This can make a surgical resection more difficult later and sometimes leads to more exuberant stenosis The stenosis can recur quicker and tighter and it also can occur at the distal or proximal end of the original stricture The application of a variety of topical chemicals has been used to try to prevent restenosis after laser and dilation Laser Bronchoscopy / 99 Complications and Treatments The most common complications of laser bronchoscopy are bleeding, airway fire, airway perforation, and injury to operating room personnel In general, these complications are extremely uncommon; when an experienced team works together and has good communication between the surgeon, laser nurse, anesthesiologist, and person operating the jet ventilator, major intraoperative complications are almost non-existent Patient selection is also critical, and experienced selection helps eliminate some of these complications For example, some tumors in the airway, such as melanoma and renal cell carcinoma, which not infrequently metastasize to the airway, are associated with angiogeneis These tumors can be associated with significant bleeding when targeted with a CO2 or YAG laser Therefore, in our treatment protocol they are treated by photodynamic therapy first and cored out via rigid bronchoscopy second Airway fires, the most dreaded and dramatic complication usually occurs because the oxygen source is still on while firing the CO2 or YAG lasers If a fire in the airway does occur several steps should be taken immediately The source of oxygen should be extinguished and removed, cold saline should be instilled, systemic steroids and antibiotics should be administered, and the intended procedure terminated or quickly finished depending on the degree of the fire, the level of injury, and the patient’s clinical status The next most devastating and feared complication is perforation of the bronchus or trachea Although this rare complication can be disastrous, it may not be recognized or diagnosed until several days after the procedure is completed Perforation during laser bronchoscopy can occur because the laser inadvertently fired, usually against the membranous weakened wall of the posterior trachea or in the anterior cartilaginous part of the trachea that has tracheal malacia It probably is most common, however, during aggressive dilation The ideal treatment is contingent on early recognition and repair If the patient has malignant disease and the procedure was meant to be palliative, usually repair is most appropriately performed by the placement of a stent Perforation can occur with any laser, but it is very unlikely with photodynamic therapy unless aggressive debridement or dilating is being performed It is also rare with CO2 and YAG lasers, but the former is less powerful Perforations can occur with any laser, and the key is prevention Prevention requires excellent visibility, the use of settings of no greater than 20 watts for YAG laser, 10 to 20 watts for CO2 laser, and 0.6 to 1.0 watts for photodynamic therapy This complication is extremely unusual, but when it does occur, early recognition is crit- ical If the injury is not diagnosed immediately, the diagnosis should be suspected by the presence of a new pneumothorax or pneumomediastinum on the postoperative chest radiograph x-ray that should be performed all on patients in the recovery room after a laser procedure Another feared and devastating complication from laser or rigid bronchoscopy is bleeding The treatment for the bleeding is contingent on what the bleeding is from and the rate of bleeding Very brisk bleeding from the pulmonary artery can be fatal If the bleeding is from a bronchial artery, one possible treatment is to immediately block off that side of the airway, suck the blood out of the other side and control the bleeding either by urgent thoracotomy (rarely indicated) or urgent radiologic embolization Embolization is reserved for arterial bleeding usually from an intercostal artery Usually embolization is not needed because local measures performed in the operating room through the scope are successful When significant bleeding comes from the tumor or if there is excessive bleeding at the time of laser bronchoscopy, several steps can be done to help control this dangerous and scary problem Although massive bleeding is rare, an aggressive endoscopist will often have significant bleeding; in the awake patient and without a rigid bronchoscope this can lead to a fatal result This is another reason to favor general anesthesia and rigid bronchoscopy The management of this problem is described at length elsewhere and is only briefly summarized here Lavage with epinephrine or ice-cold saline is the first step and usually is all that is needed We usually start with epinephrine diluted to 100, flushing 10 cc down the flexible scope placed through the rigid scope This alone almost always stops the bleeding if it is from the tumor itself The key to managing this problem is to first remove the blood from the unaffected side or segment This allows one to adequately oxygenate the patient The scope must be suctioned clean prior to shooting epinephrine down it, and the scope’s suction channel must also be cleaned In this way the vasoconstrictive agent is applied directly to the bleeding site, and blood in the scope is not shot over it The epinephrine usually causes these small vessels to stop bleeding Another excellent way to prevent bleeding is to remove the entire tumor in total—another advantage to rigid bronchoscopy When one is performing flexible fiberoptic bronchoscopy, only small pieces of tumor can be removed and bleeding is more difficult to treat because large bore suckers cannot be used The final major potential complication of laser bronchoscopy is injury to hospital personnel or patient from the laser itself Laser fibers can break, or the laser may not 100 / Advanced Therapy in Thoracic Surgery be put on standby, or it may be accidentally fired A beam of light that accidentally travels into the back of one’s retina can cause severe permanent injury to one’s vision For this reason, all persons in the operating room should use protective eyewear It is the surgeon’s responsibility to ensure everyone is given the opportunity to wear protective eyewear if they so desire Conclusion Laser bronchoscopy is an extremely effective and safe procedure in properly selected patients and in experienced centers There are many different types of lasers and several different ways to deliver the powerful energy harnessed in this concentrated beam of light to pathology in the tracheobronchial tree Laser bronchoscopy quickly opens the airway in patients with endoluminal occlusion from cancer, and it also has a small but important role in patients with benign lesions In a patient who has cancer invading the airway that is blocking significant segments or lobes of healthy distal lung, it affords the surgeon the chance to quickly, safely, and efficiently recruit that lung It leads to immediate relief of dyspnea and hemoptysis and opens the otherwise narrowed, blocked, or bloody airway It is best used as an adjunct to radiation and chemotherapy It is least successful when the distal airway is extrinsically compressed by stricture or malignant peribronchial lymph nodes are compressing it With careful patient selection and intraoperative techniques, rigid bronchoscopy and laser therapy lead to excellent palliation of patients already weakened by stage IV malignancy Intraoperative complications, despite the potential hazards of laser use near flammable materials, are rare References Becker HD, Gustav Killian A biographical sketch J Bronchol 1995;2:77–83 Jackson C The life of Chevalier Jackson: an autobiography New York: Macmillan; 1938 Strong Ms, Jako GJ, Polayni T, et al Laser surgery in the aerodigestive tract Am J Surg 1973;126:529–33 Beamis JF History of the rigid bronchoscope In: Bollinger CT, Mathur PN, editors Interventional bronchoscopy Progress in respiratory research Basel: Karger; 2000 p 2–15 Beamis JF, Rebeiz EE, Vergos KV, et al Endoscopic laser therapy for obstructing tracheobronchial lesions Ann Otol Rhinol Laryngol 1991;100:413–9 Dumon JF Technique of safe laser surgery Lasers Med Sci 1990;5:171–80 Fisher JC The power density of a surgical laser beam: its meaning and measurement Lasers Surg Med 1983;2:301–15 Perrin G, Colt HG, Martin C, et al Safety of interventional rigid bronchoscopy using intravenous anesthesia and spontaneous assisted ventilation A prospective study Chest 1992;102:1526–30 Personne C, Colchen A, Leroy M, et al Indications and techniques for endoscopic laser resections in bronchology J Cardiovasc Surg 1986;91:710–5 10 Rontal M, Rontal E, Wenokur ME, et al Anesthetic management for tracheobronchial laser surgery Ann Otol Rhinol Laryngol 1986;95:556–60 11 Strong MS, Jako GJ Laser surgery in the larynx Early clinical experience with continuous CO laser Ann Otol 1972;81:791–8 12 Toty L, Personne C, Colchen A, et al Bronchoscopic management of tracheal lesions using the neodymium yttrium aluminum garnet laser Thorax 1981;36:175–8 13 Unger M Neodymium: YAG laser therapy for malignant and benign endobronchial obstructions Line Chest Med 1985;2:276–90 14 Duhamel, DR, Harrell JH II Laser bronchoscopy Chest Surg Clin N Am 2001;11:769–91 CHAPTER SURGICAL MANAGEMENT OF SMALL CELL LUNG CANCER FRANCES A SHEPHERD, MD, FRCPC Twenty to 25% of all primary bronchogenic carcinomas are of the small cell subtype However, since dissemination to regional lymph nodes and/or distant metastatic sites can be identified in ≥ 90% of patients at the time of initial presentation,1 these tumors represent ≤ 5% of cases in most surgical series Furthermore, extrathoracic micrometastases are likely present even in patients with apparently “limited”-stage or operable tumors, which explains why almost all surgical series from the prechemotherapy era reported 5-year survival rates approaching zero for patients with small cell carcinoma.2,3 One of the most important early studies of surgery for small cell lung cancer was the prospective randomized trial of surgery versus radiation conducted by the Medical Research Council of Great Britain.4,5 Seventy-one patients were randomized to have surgery and 73 to receive thoracic irradiation (30 Gy or more over 20–40 d) The median survivals for patients in the surgical and radiotherapy arms were 199 and 300 days, respectively (Figure 8-1) At years, only one surgical and three radiotherapy patients were still alive (p = 04), and at 10 years, only the three patients in the radiotherapy arm remained alive Although it was concluded from this study that radical radiotherapy was preferable to surgery, clearly, neither of the treatment policies was really effective The investigators stated that it would be improbable that any advance in therapy could exert a significant effect on the death rate from this disease in the absence of successful smoking-prevention programs How true these words are, even today! Following this study, trials of combined modality therapy with preoperative radiotherapy followed by surgery were undertaken for patients with small cell lung cancer, but few patients achieved long-term survival.6–8 The observation in the 1970s that patients with small cell lung cancer were dying from systemic metastases led to the hypothesis that the addition of chemotherapy to local radiotherapy might improve survival Bergsagel and colleagues from the Princess Margaret Hospital in Toronto, ON, were the first to demonstrate a modest survival advantage with the addition of low-dose cyclophosphamide.9 The British Medical Research Council Lung Cancer Working Party also showed that adding low-dose cyclophosphamide and CCNU (1-[2chloroethyl]-3 cyclohexyl-1-nitrosourea) to radiotherapy resulted in a significant prolongation of progression-free, but not overall, survival.10 FIGURE 8-1 Survival in the two treatment series (all patients) Adapted from Working Party on the Evaluation of Different Methods of Therapy in Carcinoma of the Bronchus.4 p 979 101 102 / Advanced Therapy in Thoracic Surgery At the same time, other investigators were applying the same adjuvant chemotherapy principles to surgical patients In 1982 Shields and colleagues reviewed the results of four Veterans Administration Surgical Adjuvant Group (VASOG) adjuvant chemotherapy studies and undertook a separate analysis of the 148 patients (4.7%) in those trials who had small cell lung cancer 11 No survival advantage was seen when single-agent nitrogen mustard or single-agent cyclophosphamide was administered after surgery However, a small survival advantage was seen for patients in the chemotherapy arm of a three-arm trial in which patients were randomized to receive prolonged intermittent courses of CCNU and hydroxyurea, or no further therapy (Figure 8-2) Shields and colleagues also showed the importance of the TNM (tumor, node, metastasis) staging system in small cell lung cancer patients that has long been recognized to have prognostic significance for nonsmall cell A HN2, Control, N = 28 N = 27 Cyloxan Trial 80 Cyloxan, N = 27 Control, N = 20 60 40 B 20 0 1/2 Completed Postoperative Years C 100 80 60 40 20 CCNU + Hydroxyurea Treated, N = 11 Control, N = 18 Patients Still Living (%) Treated (CTX), N=6 Treated (CTX, MTX), N = Control, N=3 100 Patients Still Living (%) Patients Still Living (%) 100 lung cancer.12 Sixty percent of patients with T1N0M0 tumors were alive at years, whereas there were almost no 5-year survivors among the patients who presented either with T2–3 tumors or with mediastinal lymph node involvement (Figure 8-3) Patients with small stage II tumors had an intermediate survival of approximately 30% These observations suggested that there might be a small subpopulation of patients with small cell lung cancer for whom it might be appropriate to consider a surgical approach In support of this, Shore and Paneth reported an overall 5-year survival rate of 25% in their retrospective review of 40 patients with small cell lung cancer who underwent potentially curative resection between 1959 and 1972 Four of 10 patients (40%) without nodal involvement achieved long-term survival compared with of 26 patients (35%) who had hilar or mediastinal nodal involvement.13 Small cell lung cancer usually presents with a central mass associated with hilar and mediastinal adenopathy Lennox and colleagues observed that patients who had large proximal tumors and required a pneumonectomy were less likely to achieve long-term survival Their 2and 5-year survival rates for patients who required only a lobectomy were 32% and 18%, compared with 14.4% 0 80 1/2 Completed Postrandomization Years 60 40 20 0 1/2 Completed Postrandomization Years FIGURE 8-2 A, Survival of treated and control patients with undifferentiated small cell carcinoma in the nitrogen mustard (HN2) and cyclophosphamide (Cytoxan) adjuvant chemotherapy Veterans Administration Surgical Adjuvant Group (VASOG) lung trials B, Survival of treated and control patients with undifferentiated small cell carcinoma in the prolonged intermittent cyclochemotherapy VASOG lung trials C, Survival of treated and control patients with undifferentiated small cell carcinoma in the CCNU and hydroxyurea adjuvant chemotherapy VASOG lung trials Adapted from Shields TW et al.12 p 481 104 / Advanced Therapy in Thoracic Surgery controlled by systemic treatment Thus, it may be appropriate to consider a combined modality treatment program for patients with mixed histology tumors if they meet standard surgical criteria and have no evidence of extrathoracic spread Late Recurrence after Successful Treatment Several reviews have now suggested that long-term survivors of small cell lung cancer are at high risk of developing second primary tumors, in particular, second primary lung cancers.26–30 Although the patient population at risk for these second tumors is low because of the low cure rate for small cell lung cancer, clinicians must be aware that a new lesion on chest radiograph may not represent a relapse but, rather, a new tumor of different histology Histologic or cytologic confirmation of the type of malignancy should be obtained, and if nonsmall cell lung cancer pathology is found, further work-up should be directed at determining operability since surgical resection has the potential to be curative for some patients Adjuvant Chemotherapy following Surgery The favorable results reported by Shields and colleagues in their review of the VASOG trials led several investigators to administer combination chemotherapy to all patients following complete resection of small cell lung cancer.11 A summary of 10 retrospective reviews of adjuvant chemotherapy after surgery is shown in Table 8-1.12,31–42 Frequently surgery was undertaken for patients in these series because a preoperative diagnosis of small cell lung cancer had not been made For some, it had not been possible to obtain adequate tissue for any malignant diagnosis, and for others a preoperative diagnosis of nonsmall cell lung cancer had been made Some of those latter patients were subsequently found to have mixed histology tumors, whereas others had pure small cell tumors that had been incorrectly diagnosed preoperatively Maassen and Greschuchna reported that only 18 of 24 patients had a correct histologic diagnosis of small cell lung cancer preoperatively.36 Similarly, the University of Toronto Group found that a correct preoperative diagnosis of small cell cancer had been reached in only 18 of 63 patients.37 Postoperatively, small cell lung cancer was found in 54 patients and mixed histology tumors in Most of the series in Table 8-1 included patients seen over ≥ 10 years, and, frequently, multiple chemotherapy protocols were employed However, with the exception of the early trials reported by Shields and Hayata and colleagues,12,31 all patients were treated with combinations of drugs that would be considered adequate even today The duration of chemotherapy treatment was also variable and ranged from a single course of postoperative therapy to multiple courses for up to 18 months Most groups administered approximately six cycles of treatment Some centers also administered thoracic radiotherapy as well as prophylactic cranial irradiation In view of the variability in radiation treatment and incomplete reporting in several series, no conclusions can be drawn concerning the advisability of trimodality therapy The patients in the reviews summarized in Table 10-1 differ from limited-stage small cell lung cancer patients overall in that they all underwent pretreatment surgical resection and, therefore, detailed pathologic staging is available The results clearly show that the TNM staging system is highly prognostic for patients with limited small cell lung cancer In every study the best survival was achieved by patients who had pathologic stage I tumors, and the poorest survival was seen for patients with pathologic stage III tumors (Figure 8-4).39 Survival for patients TABLE 8-1 Survival by Pathologic Stage for Patients Treated with Adjuvant Chemotherapy after Surgery Study Stage I Stage II No of Patients Survival (%) Hayata et al, 197831 Shields et al, 198212 Meyer et al, 1983,32 198433 Wada et al, 198534 Osterlind et al, 198635 Maassen and Greschuchna, 198636 Shepherd et al, 198837 Karrer et al, 1990,38 Ulsperger et al, 199139 Macchiarini et al, 199140 Hara et al, 199141 Davis et al, 199342 NA = not available *Stages I and II combined Stage III No of Patients Survival (%) Total No of Patients Survival (%) No of Patients Survival (%) 27 49 18 41 19 63 26 51 ≥ 50 37* 22 34 48 61 55 19 24 54 17 20 50 NA NA 21 24 35 39 28 10 10 64 20 40 33 NA 11 24 35 72 132 30 17 36 124 63 157 11 (5 yr) 28 (5 yr) NA (5 yr) 32 25 (3.5 yr) 20 (3 yr) 31 (5 yr) NA (4 yr) 26 13 11 52 64 50 NA 10 16 NA 42 35 15 (T3N0) 14 13 10.7 21 42 37 32 36 (5 yr) NA (5 yr) 36 (5 yr) 106 / Advanced Therapy in Thoracic Surgery the 201 patients in those studies (Table 8-2) It is still possible, however, that this high rate of local control was due only to the fact that the patients in these series had fewer locally advanced tumors and that the local control rate might have been equivalent with a combination of systemic chemotherapy and thoracic irradiation Prospective Trials of Induction Chemotherapy followed by Surgical Resection Phase II Trials The encouraging results achieved with initial surgery followed by adjuvant chemotherapy led several groups to undertake prospective studies of chemotherapy followed by surgery for limited small cell lung cancer 46–56 The results of nine prospective phase II trials are summarized in Table 8-3.46–54 In all studies, patients received multiple courses (range 2–6) of combination chemotherapy that included agents that are currently considered to be active against small cell lung cancer (cyclophosphamide, doxorubicin, vincristine, etoposide, and cisplatin) The overall TABLE 8-2 Pattern of Relapse for Patients Treated with Surgery followed by Adjuvant Chemotherapy Study No of Patients No of Patients with Relapse Local Only Meyer et al, 198332 Friess et al, 198543 Littlewood et al, 198744 Shepherd et al, 198837 Macchiarini et al, 199140 Hara et al, 199141 Davis et al, 199342 Total 10 15 63 42 37 32 201 1 2 Distant Local and Only Distant 26 24 NA 15 72 0 NA = not available response rate was ≥ 82% in all studies except that of Baker and colleagues,49 in which only two preoperative courses of chemotherapy were given This perhaps suggests that a longer course of induction chemotherapy is advisable, although in the small study reported by Benfield and colleagues, 88% of patients responded to treatment and 100% were able to undergo complete surgical resection after only two courses of chemotherapy.51 On average, approximately 60% of patients in these trials were considered to have responded adequately enough for surgical exploration, and of those ≥ 80% could be resected completely When calculated from the total number of patients who entered the studies, however, the overall complete surgical resection rate was only about 50% Not all studies reported surgical toxicity, but it does not appear that the postoperative death or complication rates were significantly increased by the preoperative chemotherapy Only three postoperative deaths were reported, , , all in patients who had required a complete pneumonectomy Other postoperative complications included infection, bronchopleural fistula formation, and reversible supraventricular tachycardias The complete pathologic response rate was considerably lower than the clinical response rate, ranging from to 37%,48,50 and on average was approximately 10% It is of interest that this complete pathologic response rate is similar to rates reported in studies of induction chemotherapy followed by surgery for patients with stage III nonsmall cell lung cancer.57 All investigators reported that survival was strongly dependant on TNM stage (Figure 8-5) Patients with stage I (T1–2N0) tumors had the best prognosis, with 5year survival rates that approached 70% for completely resected patients Patients with stage II and III tumors fared less well, but all series reported a small number of patients with stage IIIA tumors (N2) who achieved longterm survival and appeared to be cured by their TABLE 8-3 Prospective Phase II Trials of Induction Chemotherapy followed by Surgery* Study Prager et al, 198446 Williams et al, 198747 Johnson et al, 198748 Baker et al, 198749 Shepherd et al, 198750 Benfield et al, 198951 Zatopek et al, 199152 Hara et al, 199153 Eberhardt et al, 199754 No.of Patients 39 38 24 37 72 25 17 46 Clinical Stage Chemotherapy I II III NA NA 21 NA 10 12 NA NA 16 25 NA 14 NA 35 24 38 CR/PR (ORR%) Thoracotomies/CSR(%) CAOE ϫ 2–4 CAE ϫ 5/26 (82) CAO ϫ ± EP CAE ϫ 1/19 (54) CAO ϫ ± EP CAEO ϫ 5/2 (88) COPE ϫ 10/14 (96) Various 4/10 (82) EP 15/28 (93) 13/21 (87) 25/21 (55) NA (100) 20/20 (54) 27/30 (80) 8/8 (100) 14/10 (40) 17/17 (100) 32/23 (50) Complete Pathologic Response(%) 11/8 (21) (5) (11) 23/15 (63) (38) (5) 38/33 (46) (4) (0) (20) NA 11 (24) A = doxorubicin (Adriamycin); C = cyclophosphamide; CR = complete response; CSR = complete surgical resection; E = etoposide; NA = not available; O = vincristine (Oncovin); ORR = overall response rate; P = cisplatin (Platinol); PR = partial response *For limited small cell lung cancer 108 / Advanced Therapy in Thoracic Surgery rate to chemotherapy was 68% (28% complete response, 37% partial response), only 144 (42%) of patients were randomized: 68 to receive surgery and radiotherapy and 76 to receive radiotherapy alone Of the 68 patients who were randomized to receive surgery, did not undergo thoracotomy; however, patients in the nonsurgical arm received off-study surgery, so a total of 70 thoracotomies were performed Fifty-eight patients had some resection of tumor (83%), but only 54 had a pathologic complete resection (77%) Complete pathologic response was documented for 18% of patients who underwent surgery Nonsmall cell pathology was found in 11% of patients The median survival from enrolment for all patients was 14 months, and for the randomized patients was 18 months, with no difference seen between the groups in either median or long-term survival (Figure 8-6) Because only half of the randomized patients in this study underwent surgical resection, it is not possible to compare survival based on pathologic stage or TNM subgroup The Toronto Group were the first to draw attention to the discrepancy between clinical and pathologic staging for patients with small cell lung cancer25,50, they showed that clinical staging could not identify subgroups of patients with different prognoses (Figure 87) In the LCSG trial, in which patients were staged care- 100 Thoracotomy (n = 68) fully at the time of surgery, clinical and surgical TNM stages after chemotherapy were the same in only 20 patients (29%), and most frequently patients moved into a more advanced stage 58 For the surgical group, no difference in resectability was identified for patients in any T or N subgroup, although there seemed to be a trend toward unresectability for patients with T3 tumors (p = 08) All pathologic T and N subsets in the surgical patients had similar survival Why was survival not improved by surgery, and how should the results of this important LCSG trial be interpreted? The survival curves shown in Figure 8-6 were generated on an “intent to treat” basis, which is, of course, mandatory for any prospective randomized trial It should be noted, however, that 10% of the patients did not receive protocol-specified therapy Six patients randomized to surgery declined operation, and, of perhaps even greater significance, eight patients in the nonsurgical arm underwent thoracotomy and surgical resection In such a small study, a 10% protocol violation of this nature may have masked a small but significant survival advantage between the treatment arms Another question to be asked is why complete surgical resection was possible for only three-quarters of the patients subjected to thoracotomy Although the combination of cyclophosphamide, doxorubicin, and vincristine was considered standard therapy at the time, a disappointingly low response rate of only 65% was seen in this study With newer regimens that incorporate Radiation Alone (n = 78) 110 Stage I (n = 69) Stage II (n = 27) 100 Stage III (n = 23) 90 60 Likelihood of Survival (%) Patients Surviving (%) 80 40 20 80 70 60 50 40 30 20 10 12 18 24 30 36 0 Time (mo) FIGURE 8-6 A comparison of survival for patients randomized to thoractomy and radiation or radiation alone Adapted from Shields TW, editor General thoracic surgery 4th ed Baltimore: Williams & Wilkins; 1994 Time (yr) FIGURE 8-7 A comparison of survival by pretreatment clinical stage for 119 patients who underwent surgery for limited small cell lung cancer Adapted from Shepherd FA et al.25 p 385 Surgical Management of Small Cell Lung Cancer / 109 Salvage Surgery There are few treatment options for patients with small cell cancer who not respond to initial therapy or who relapse after a primary response Typically, only brief periods of palliation or prolongation of survival are achieved with second-line chemotherapy or radiation This has led some investigators to evaluate whether surgery might be useful as salvage therapy for certain patients with limited small cell lung cancer Yamada and colleagues operated on nine patients: two who had failed to respond to chemotherapy, six who had achieved partial response, and one complete responder.55 Four patients achieved long-term disease-free survival that ranged from to 11+ years The Toronto Group performed salvage operations on 28 patients, only 18 of whom were found on pathologic examinations to have pure small cell tumors.60 Overall median survival of the 28 patients was 105 weeks, but only two patients with pure small cell cancer survived beyond years (Figure 8-8) In view of these results, surgery cannot be recommended for patients with pure small cell tumors who fail to respond or who relapse after initial standard therapy Mixed histology tumors are reported more frequently in surgical series.25,61 In the series of salvage operations reported by the Toronto Group, 10 patients had mixed histology or nonsmall cell tumors, and their median survival was 108 weeks.60 Four of the 10 patients (three with stage I tumors) achieved long-term survival after operation Because a small number of patients with tumors with mixed histologic type cancers may be cured by surgical treatment, consideration should be given to a second biopsy for patients who have localized, resistant small cell lung cancer Several authors have now reported that long-term survivors of small cell lung cancer are at increased risk of developing second primary tumors.26–30 In fact, a long- 110 Survival from Date of Diagnosis (Median 105 wk) 100 Likelihood of Survival (%) etoposide and cisplatin and concurrent radiotherapy administered early in the course of the disease, response rates of 90% or more are standard.16,20 One might speculate, therefore, that a more complete response to chemotherapy might have resulted in a higher complete surgical resection rate Seventeen percent of patients underwent “open and closed” procedures with no attempt at surgical resection For some patients the residual tumor was clearly unresectable at the time of thoracotomy However, for other patients the decision not to proceed to resection was based on scar tissue formation at the area of the primary tumor and in the mediastinum Response to chemotherapy is often accompanied by an intense local scirrhous reaction that makes surgical resection more difficult Tumors that may initially appear to be unresectable because of fibrosis may, in fact, be resected safely with careful dissection of the tumor bed and mediastinum Because this was an international multi-institutional study, each individual surgeon operated on just a few patients Had this been a larger study, it is possible that the overall resectability rate might have been higher This is suggested by the observation that the resectability rate was higher for LCSG surgeons than it was in other centers who joined the trial at a later date This may have been due to their greater experience in operating on both patients with small cell and those with nonsmall cell cancer after induction chemotherapy Finally, patient selection undoubtedly played a large role in the ultimate results of this trial All patients with limited disease were eligible to enter this study, with the exception of those who had supraclavicular lymph node involvement and those with pleural or pericardial effusions Therefore, the majority of patients had stage III tumors It has long be recognized that surgery has very little role to play in the management of stage III patients with nonsmall cell lung cancer, and this trial suggests that the same is true for patients with small cell lung cancer since many, if not most, patients with limited small cell lung cancer have mediastinal node involvement (often bulky) at the time of initial diagnosis Nonetheless, it still remains possible that patients with early-stage disease (T1–2N0 and, perhaps, nonbulky stage II) may benefit from a combined modality approach that includes surgery Because so few patients fall into this subgroup (likely ≤ 10%), it will probably never be possible to undertake a prospective, randomized trial to prove or disprove that surgery is appropriate in this setting Survival from Date of Surgery 90 (Median 74 wk) 80 70 60 13 50 40 30 20 10 0 Time (yr) FIGURE 8-8 Survival of 28 patients who underwent operations for small cell lung cancer Adapted from Shepherd FA et al.60 p 196 ... al, 1998 12 Total No of Procedures 20 0 21 4 145 30 150 169 1 12 2 12 1 ,23 2 NA = not available; VATS = video-assisted thoracic surgery Incidences of Cancer 171 168 103 15 123 1 42 99 21 2 1,033 Incidences... 55 19 24 54 17 20 50 NA NA 21 24 35 39 28 10 10 64 20 40 33 NA 11 24 35 72 1 32 30 17 36 124 63 157 11 (5 yr) 28 (5 yr) NA (5 yr) 32 25 (3.5 yr) 20 (3 yr) 31 (5 yr) NA (4 yr) 26 13 11 52 64 50... [abstract 70 02] J Clin Oncol 20 04 ;22 (14 Suppl):617S 28 Burkes RL, Ginsberg RJ, Shepherd FA, et al Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small