Advanced therapy in thoracic surgery - part 2 doc

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

there was no significant difference in the length of the

hospital stay.64A 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,

random-ized, controlled trial of patients undergoing pulmonary

resection, comparing conventional closure with

conven-tional closure plus treatment of all surgical sites at risk

for air leak with FocalSeal-L.62Each surgeon was trained

in the proper application of FocalSeal, and each

individ-ual 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 3

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

dura-tion and hospital stay, ultimately resulting in decreased

morbidity and cost However, this has not beensupported by any of the studies currently in the litera-ture FocalSeal appears to be safe, but its efficacy depends

on the proper application, which can be tedious as well asdifficult, especially in poorly exposed areas of the lung

Biologic Glue

The natural history of acute type A aortic dissectioncarries an extremely grim prognosis without surgery,with mortality rates of 38% in the first day and up to

Tissue Adhesives in Thoracic and Cardiovascular Surgery / 55

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.

0 20 40 60 80 100 120

Control (n = 55) FocalSeal (n = 177)

Intraoperative From Wound Closure

to Hospital Discharge

p = < 001

p = < 001

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.

0 2 4 6 8 10 12

Control (n = 55) FocalSeal (n = 117)

T T

p = 006

p = NS

p = NS

T T

T

T

From Skin Closure to Last Observed Air Leak

From Skin Closure to Chest Tube Removal

From Skin Closure to Hospital discharge

90% after 2 weeks from the onset of symptoms The best

chance of survival in patients with this disease depends

on immediate diagnosis and emergent surgical

interven-tion, 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

advo-cated, including the use of pledgeted sutures or

sand-wiching 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

dissec-tions.66Since 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

simplifi-cation 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

compo-nent.70Although 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

requir-ing reoperation in patients who had the aortic root

rein-forced with GRF glue with resuspension of the aortic

valve.71 Late aortic insufficiency occurred in 7 of 18

patients (39%), and 6 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 necrosiscould be attributed to either an improper glue application

56 / Advanced Therapy in Thoracic Surgery

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.

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

tissue-engineered 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

3 Harvey SC The use of fibrin papers and forms in surgery.

Boston Med Surg J 1916;174:658–9.

4 Cronkite EP, Lozner EL, Deaver JM Use of thrombin and

fibrinogen in skin grafting JAMA 1944;124:976–8.

5 Blomback B, Blomback M Purification of human and

bovine fibrinogen Arkiv Kemi 1956;10:415–43.

6 Trott AT Cyanoacrylate tissue adhesives: an advance in

wound care JAMA 1997;277:1559–60.

7 Hino M, Ishiko O, Honda KI, et al Transmission of

symp-tomatic parvovirus B19 infection by fibrin sealant used

during surgery Br J Haematol 2000;108:194–5.

8 Reece TB, Maxey TS, Kron IL A prospectus on tissue

adhe-sives Am J Surg 2001;182:40–4.

9 Matras H, Dinges HP, Lassmann H, Mamoli B Suture-free

interfascicular nerve transplantation in animal

experi-ments Wien Med Wochenschr 1972;122:517–23.

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

Human-Fibrinogen Z Kinderchir 1981;32:341.

12 Spangler HP, Holle J, Braun F, et al Die Verklebung

experi-menteller 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.

16 Borst HB, Haverich A, Walterbusch G, Maatz W Fibrin adhesive: an important hemostatic adjunct in cardiovascu- lar 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 rester- notomy or reoperation after cardiac operations: a multicen- ter 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’ rience with fibrin sealant in thoracic and cardiovascular surgery Ann Thorac Surg 1990;50:40–4.

expe-22 Burgos R Experience with fibrin sealant spray in cular reoperations Conference proceedings Update and future trends in fibrin sealing in surgical and nonsurgical fields Vienna: LBI Trauma; 1992 Abstract 193.

cardiovas-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 medi- cine: thoracic surgery—cardiovascular surgery Berlin: Springer; 1986 p 164–5.

24 Morikawa T Tissue sealing Am J Surg 2001;182:29–35S.

25 Berruyer M, Amiral J, Ffrench P, et al Immunization by bovine thrombin used with fibrin glue during cardiovascu- lar operations: development of thrombin and factor V inhibitors J Thorac Cardiovasc Surg 1993;105:892–7.

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 genic effects of fibrin sealant on microvascular anastomoses

thrombo-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.

58 / Advanced Therapy in Thoracic Surgery

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.

32 The CoStasis Multi-center Collaborative Writing

Committee A novel collagen-based composite offers

effec-tive hemostasis for multiple surgical indications: results of a

randomized controlled trial Surgery 2001;129:445–50.

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

autolo-gous 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

clini-cal 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

multivari-ate 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.

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.

47 El-Gamel A, Tsang GMK, Watson DCT The threshold for air leak: stapled versus sutured human bronchi, an experi- mental study Eur J Cardiothorac Surg 1999;15:7–10.

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 cal use in thoracic surgery Eur J Cardiothorac Surg 1992;6:52–4.

clini-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.

Tissue Adhesives in Thoracic and Cardiovascular Surgery / 59

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.

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.

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

complica-tions 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

redis-section 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.

75 Raanani E, Latter DA, Errett LE, et al Use of “BioGlue” in

aortic surgical repair Ann Thorac Surg 2001;72:638–40.

76 Passage J, Jalali H, Tam RK, et al BioGlue surgical

adhe-sive—an appraisal of its indications in cardiac surgery Ann

Thorac Surg 2002;74:432–7.

77 Kucukaksu DS, Akgul A, Cagil K, Tasdemir O Beneficial effect of BioGlue surgical adhesive Tex Heart Inst J 2000;27:307–8.

78 Kazui T, Washiyama N, Bashar AH, et al Role of biologic glue repair of proximal aortic dissection in the develop- ment of early and midterm redissection of the aortic root Ann Thorac Surg 2001;72:509–14.

79 LeMaire SA, Schmittling ZC, Coselli JS, et al BioGlue cal adhesive impairs aortic growth and causes anastomotic strictures Ann Thorac Surg 2002;73:1500–5.

surgi-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 gelatin- resorcin-formol biological glue Ann Thorac Surg 1996;62:486–8.

85 Robicsek F, Rielly JP, Marroum MC The use of late adhesive (Krazy Glue) in cardiac surgery J Card Surg 1994;9:353–6.

cyanoacry-86 Lachapelle K, DeVarennes B, Ergina PL, Cecere R Sutureless patch technique for postinfarction left ventricu- lar 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.

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.

89 Sierra DH Fibrin sealant adhesive systems: a review of their chemistry, material properties and clinical applica- tions J Biomater Appl 1993;7:309–51.

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 do 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.1The 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

postop-erative (adjuvant) or preoppostop-erative (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

benefit and will be reviewed in this chapter therapy administered prior to surgery or definitive irra-diation has improved survival for patients with stage IIINSCLC.2 – 5 The role of induction chemotherapy inpatients with early-stage (stage I and II) NSCLC iscurrently under investigation

Chemo-Part I: Adjuvant Therapy

Radiation

Although postoperative radiation has been associatedwith improved local control in patients with mediastinalnodal involvement,6no trials have found an improve-ment in overall survival Many of the trials of postopera-tive radiotherapy have not involved adequate numbers ofpatients to detect small but clinically relevant survivaldifferences A meta-analysis examining the effect of post-operative radiotherapy was published in 1998.7Thisanalysis found a detrimental effect of postoperativeradiotherapy for patients with completely resectedNSCLC A 21% relative increase in the risk of death asso-ciated with radiotherapy (absolute reduction in survivalfrom 55 to 48% at 2 yr) was found This effect was great-est for patients with earlier-stage disease or minimalnodal involvement No patient subgroup defined by stage

or nodal status showed evidence of a clear benefit frompostoperative radiotherapy.7Although a decrease in localrecurrence was seen, the authors cautioned that thiseffect was small and was outweighed by the adverse effect

of postoperative radiotherapy on survival This analysis must be interpreted with caution as many of thetrials included used outdated radiotherapy techniques

meta-At present, the use of postoperative radiotherapyshould 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 5-Year Survival (%)

Adapted from Mountain CF 1

NSCLC = nonsmall cell lung cancer; TNM = tumor, node, metastasis.

local recurrence (positive surgical margins, residual local

disease, or selected patients with multiple lymph node

involvement) Further research employing modern

radio-therapy techniques, such as conformal radioradio-therapy or

hyperfractionated radiotherapy, is warranted

Chemotherapy

Initial trials exploring the use of postoperative

chemother-apy were conducted in the 1960s and 1970s.8–12No survival

benefit was found; however, these early trials were flawed

as factors such as histology, nodal involvement,

perfor-mance status, age, and intraoperative staging were not

considered in their design Moreover, the

chemotherapeu-tic agents studied had minimal activity in NSCLC

Platin-based Regimens

Many NSCLC adjuvant chemotherapy trials have

exam-ined 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])

chemo-therapy or immunochemo-therapy (intrapleural bacille

Calmette-Guérin and 18 mo of oral levamisole).1 3

Disease-free survival was significantly prolonged in the

CAP arm (p = 018); however, the overall survival

differ-ence, although increased by 7 to 8 months (median), was

not statistically significant The second LCSG trial

enrolled patients with completely resected T2N1 and

T2N0 NSCLC.14This trial randomized patients to four

courses of postoperative CAP chemotherapy or no

post-operative treatment No difference in time to recurrence

or overall survival was found

CAP chemotherapy was also evaluated in a trial

conducted in Finland.1 5 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 withsurgery alone were reviewed as part of a meta-analysisexamining the role of chemotherapy in the treatment ofNSCLC.17 The results showed considerable diversity andevidence of a difference in direction of effect between thepredefined categories of chemotherapy (Table 4-2) Theresults 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 absolutedetriment of chemotherapy of 5% at 5 years For regi-mens containing cisplatin, the pattern of results wasconsistent 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 fromcisplatin-based chemotherapy was 5% at 5 years Thetrials that were classified as using other regimens werefound 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 tional studies has become available which has clarified therole of postoperative adjuvant platin-based chemotherapy

addi-A small trial from Japan randomized 119 patients withcompletely resected stage IIIA/N2 disease and randomizedpatients to postoperative vindesine and cisplatinchemotherapy for 3 cycles versus no further treatment Nosignificant differences in overall survival were seen.18Investigators in Italy and the EORTC (EuropeanOrganisation for Research and Treatment of Cancer)conducted a trial enrolling 1209 eligible patients withcompletely resected stage I to III NSCLC and randomizedpatients to postoperative mitomycin, vindesine andcisplatin chemotherapy for 3 cycles versus no postopera-tive chemotherapy.19Forty-three percent of patientsreceived postoperative radiotherapy In the ALPI(Adjuvant Lung Project Italy) trial, no significant differ-ence in overall survival was seen with a hazard risk ofdeath of 0.96, 95% confidence intervals (CI) 0.81–1.13,

p = 589.

The IALT (International Adjuvant Lung Trial) resultswere recently published and has been the largest trial ofpostoperative adjuvant chemotherapy in NSCLCconducted to date.20 This trial randomized 1867 eligiblepatients with completely resected stage I, II, and III

62 / Advanced Therapy in Thoracic Surgery

TABLE 4-2 Meta-analysis: Postoperative Chemotherapy Category Hazard Ratio (95% CI) p Value 5-Year Survival

(%) Alkylating agents 1.15 (1.04–1.27) 005
5

Adapted from Non-small Cell Lung Cancer Collaborative Group 17

NSCLC to postoperative cisplatin-based chemotherapy

for 3 or 4 cycles versus no postoperative chemotherapy

In addition to cisplatin, patients received either

etopo-side, 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 3 cycles of postoperative

cisplatin-based chemotherapy.21In 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) 2004.22This trial found a 15%

improvement in the overall 5-year survival rate for those

patients randomized to received 4 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 4

cycles versus no further therapy in 344 patients with

completely resected stage IB (T2N0) NSCLC.23Like the

NCIC study, this trial found a marked benefit in favor of

postoperative chemotherapy with a 12% improvement in

survival at 4 years and a hazard rate of 0.62 (95% CI

0.41–0.95, p = 028).

These recent trial results have now changed the

stan-dard of care for patients with completely resected

NSCLC Consistent reductions in the risk of death have

been obser ved in recent platin-based adjuvant

chemotherapy trials Postoperative platin-based

chemotherapy should be recommended to completely

resected NSCLC patients with good performance status

UFT RegimensStudies 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 6

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 Nstage, with more advanced cases assigned to the

combined modality arm (p = 018) On an

intention-to-treat analysis, the overall 5-year survival rate was 62% forsurgery and chemotherapy versus 58% for surgery alone(not significant) A reanalysis of the data incorporatingprognostic factors using the Cox proportional hazardsmodel was performed, and a significant difference inoverall 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 inthe postoperative setting.2 5 This trial enrolled 310patients with completely resected NSCLC (stages I–III).After surgery patients were randomly assigned to receiveone cycle of cisplatin and vindesine followed by oral UFTfor 1 year (CVUFT), 1 year of oral UFT, or no postopera-tive therapy The 5-year survival rates were 61% forCVUFT, 64% for UFT, and 49% for the control group

(differences among the three groups: p = 053 by rank test, and p = 044 by Wilcoxon rank sum test).

log-Adverse effects were generally mild

The UFT administered in these studies was well ated and appeared to inhibit recurrence and prolongsurvival when administered over 6 to 12 months follow-ing surgery

toler-The single largest trial studying the effects of erative UFT therapy in resected NSCLC was conducted inJapan.2 6 This study randomized 999 patients withcompletely resected stage I adenocarcinoma to either oralUFT for 2 years or no postoperative treatment There was

postop-a survivpostop-al benefit fpostop-avoring the use of UFT, p = 04.

Toxicity was minimal in this group of patients

The results of a meta-analysis examining the ness of postoperative UFT were presented at ASCO

effective-2004.27This meta-analysis included results from 2003patients and was restricted to studies where patientsreceived postoperative UFT only In this meta-analysis,95% of patients had stage I disease, 84% had adenocarci-noma, 45% were women, and the median age was 62years An overall benefit favoring the use of postoperativeUFT 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 ofUFT in the postoperative NSCLC setting outside ofJapan In addition, UFT is not available for use in theUnited States

Future trials of chemotherapy and surger y inresectable NSCLC will likely focus on the incorporation

of targeted therapies and sequencing of modalities

Multimodality Management of Early-Stage Lung Cancer / 63

Part II: Preoperative Therapy

Chemotherapy

Numerous phase II trials of induction chemotherapy

followed by surgery for stage III NSCLC have been

conducted.28–31These trials will be discussed more

exten-sively 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

postopera-tive chemotherapy and radiation Major objecpostopera-tive

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

resec-tion specimen) have been found in approximately 5 to

15% of patients treated Those patients who have been

found to have pathologic complete responses have been

noteworthy for significantly prolonged survival.32The

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

sur-gery alone with induction chemotherapy and sursur-gery

have been conducted in stage IIIA NSCLC.2,3 One study

was conducted by Rosell and colleagues from the

Uni-versity 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, 3 h infusion) and

carboplatin (area under the curve [AUC] = 6) The initial

cohort of 94 patients received two preoperative

chemo-therapy cycles and three cycles after surgery and has been

previously reported.33The BLOT trial had a second

cohort of 40 patients treated with three induction and

two postoperative chemotherapy cycles.34There were no

differences in age, gender, race, stage, or performancestatus between the cohorts The number of patients,major radiographic response rate and 95% confidenceintervals 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 thisapproach with encouraging survival rates compared withhistorical controls.1,33,34

Based on the phase II BLOT experience, a phase IIItrial, (Southwest Oncology Group [SWOG] 9900), wasinitiated to compare the bimodality approach (inductionpaclitaxel and carboplatin plus surgery) to surgical resec-tion alone in patients with early-stage NSCLC(Figure 4–1) The primary objective of this trial was toassess whether preoperative chemotherapy with pacli-taxel and carboplatin for three cycles improved survivalcompared with surgery alone in previously untreatedpatients with clinical stage IB, II, and selected IIIANSCLC Secondary objectives include a comparison oftime to progression, sites of relapse, operative mortality,and toxicity between the two study arms The responserates and toxicities associated with the combination ofpaclitaxel and carboplatin will also be evaluated Thestudy planned to enroll 600 patients (300 in each arm) todetect an improvement of 33% in median survival, orincrease in 5-year survival from 28 to 38% Patients werestratified by clinical stage IB/IIA versus IIB/IIIA andrandomized to induction chemotherapy followed bysurgery versus immediate surgery All patients enteredinto the trial are to be followed for survival, recurrence,and toxicity data Accrual to this trial was suspended inJuly 2004 after the results of the NCIC and CALGB adju-vant trials were presented Total accrual reached 354 out

of a planned 600 patients No data regarding outcome isavailable at this time

Depierre and colleagues have reported the Frenchexperience of a phase III randomized trial of inductionchemotherapy in early-stage NSCLC (stages IB, II, andIIIA).35The aim of the study was to assess the impact ofinduction chemotherapy prior to surgery on survival.Three hundred fifty-five eligible patients were random-

64 / Advanced Therapy in Thoracic Surgery

TABLE 4–3 Results of Phase II Bimodality Lung Oncology Team Trial

Induction N Major Response Operative Survival

5 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.

6 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.

7 PORT Meta-analysis Trialists Group Postoperative

radio-therapy 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.

8 Slack N Bronchogenic carcinoma: nitrogen mustard as a

surgical adjuvant and factor influencing survival Cancer

1970;25:987–1002.

9 Higgins GA, Shields TW Experience of the veterans

admin-istration 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

(NSC-2627,2) for radically resected bronchogenic carcinoma.

Cancer Chemother Rep 1973;4:125–32.

11 Girling DJ, Stott H, Stephens RJ, et al Fifteen-year

follow-up 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

undifferenti-ated carcinoma J Clin Oncol 1986;4:710–5.

14 Feld R, Rubinstein L, Thomas PA, and the Lung Cancer

Study Group Adjuvant chemotherapy with

cyclophos-phamide, 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-analy-sis 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 chemother- apy 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 apy after complete resection in non-small cell lung cancer J Clin Oncol 1996;14:1048–54.

chemother-26 Kato H, Ichinose Y, Ohta M, et al A randomized trial of adjuvant chemothearpy with uracil-tegafur for adenocarci- noma 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.

66 / Advanced Therapy in Thoracic Surgery

32 Pisters KMW, Kris MG, Gralla RJ, et al Pathologic

complete response in advanced non-small cell lung cancer

following preoperative chemotherapy: implications for the

design of future non-small cell lung cancer combined

modality trials J Clin Oncol 1993;11:1757–62.

33 Pisters KMW, Ginsberg RJ, Giroux DJ, et al Induction

chemotherapy before surgery for early-stage lung cancer: a

novel approach J Thorac Cardiovasc Surg 2000;119:429–39.

34 Pisters K, Ginsberg R, Giroux D, et al Phase II Bimodality

Lung Oncology Team trial of induction

paclitaxel/carbo-platin in early stage non-small cell lung cancer: effect of

number of induction cycles, sites of relapse and survival

[abstract] Proc Am Soc Clin Oncol 2001;20:323a.

35 Depierre A, Milleron B, Moro-Sibilot D, et al Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIA NSCLC J Clin Oncol 2002;20:247–53.

36 Siegenthaler MP, Pisters KMW, Merriman KW, et al Preoperative chemotherapy for lung cancer does not increase surgical morbidity Ann Thorac Surg 2001;71:1105–12.

37 Martin J, Abolhoda A, Bains MS, et al Long-term results of combined modality therapy in resectable non-small cell lung cancer [abstract] Proc Am Soc Clin Oncol 2001;20:311a Multimodality Management of Early-Stage Lung Cancer / 67

Video-assisted thoracic surgery (VATS) has developed to

the point at which standard thoracic procedures are

being performed on a regular basis with minimally

inva-sive surgery Anatomic pulmonary resections by VATS

have been developed in the hope of reducing morbidity,

mortality, and hospital stay lengths, while allowing a

quicker return to regular activities for patients after

procedures that formerly required major incisions There

is mounting evidence that VATS procedures do have

benefits over open procedures This chapter describes the

techniques and results of VATS pulmonary resections

Indications and Contraindications

Tables 5–1 and 5–2 show the indications and

contraindi-cations for a VATS lobectomy.1If a tumor is > 6 cm, then

it cannot be removed through the utility incision without

the ribs being spread Any process that produces

inflam-mation or fibrosis, such as benign or malignant nodal

disease or preoperative chemotherapy or radiation, may

make an open procedure safer than a VATS approach Asleeve resection is challenging but can be performed withVATS.2

General Approach for VATS Procedures

The general technique used is similar for all major VATSpulmonary resections Under one-lung general anesthe-sia, the patient is placed in a full lateral, decubitus posi-tion, as for a posterolateral thoracotomy Good collapse

of the lung is imperative to give the surgeon adequateexposure and enough room to operate in the closedchest A double-lumen tube usually provides better lungcollapse than does a bronchial blocker The anesthesiolo-gist stops ventilating the lung to be operated as soon asthe patient is positioned and the surgeon goes to scrub Ifthe lung is not adequately collapsed when the surgeonlooks into the chest, then suction with a catheter or bron-choscope in the main stem bronchus helps

Incisions

The procedures are usually performed with either three

or four incisions The surgeon stands on the anterior side

of the patient The procedure starts with a 2 cm incision

in the midclavicular line in the sixth intercostal space.Palpation through this incision confirms that there are

no significant adhesions in the lower part of the chest.Either a finger or a ring forceps through this incisionpushes the diaphragm away from the chest wall to makeplacement of the trocar safer by minimizing the chance

of injuring the liver on the right or the spleen on the left

A trocar and thoracoscope are placed through theeighth intercostal space to obtain the optimal panoramicview of the thoracic cavity This is in the midaxillary line

TABLE 5-1 Relative Contraindications for Video-Assisted

Thoracic Surgical Lobectomy

Nodal disease (benign or malignant)

Chest wall or mediastinal invasion (T3 or T4 stage)

on the right side and slightly more posteriorly on the left

to avoid the pericardium and pericardial fat pad

Preferred are the 5 mm thoracoscope because it causes

less trauma than the larger scopes, and the 30
lens

because it allows the surgeon to look around structures

better than a 0
lens

The utility incision through which the surgeon

performs the operation is in the midaxillary line It starts

at the anterior border of the latissimus dorsi muscle and

proceeds anteriorly for 4 to 6 cm This location avoids

the long thoracic nerve that is located on the serratus

anterior muscle 1 cm posterior to the anterior border of

the latissimus Precise placement of the location of this

incision is important for the ease of performing a VATS

resection Through the midaxillary incision, a ring

forceps retracts the lung posteriorly so that the superior

pulmonary vein can be visualized For an upper

lobec-tomy, the utility incision is placed directly up from the

vein For a middle or lower lobectomy, the utility incision

is made one interspace lower The ribs are not spread for

the procedure A Weitlaner retractor holds the soft tissues

of the chest wall open to facilitate passage of instruments

into the chest, and so that suctioning in the chest does

not create negative pressure that causes the lung to

expand A fourth incision is sometimes made in the

auscultatory triangle This allows retraction of the lung

and provides a good angle for stapling some structures

(Table 5-3)

Localization of Lung Nodules by VATS

Through an understanding anatomy and computed

tomography (CT) scans, an experienced thoracic surgeon

should be able to find almost all lung nodules The lung

is mobile and can be brought to a finger passed through

the utility incision Occasionally, preoperative

localiza-tion of a lung nodule with a wire is helpful when a lungmass is small (≤ 5 mm) or ≥ 2 cm below the pleura.3Preoperatively, the radiologist places a hooked wire in thenodule Complications from this procedure are rare.Wire localization has been performed more recently withthe increasing use of screening CT scans that find tinynodules that may be difficult to palpate

General Technique for VATS Lobectomy

A lobectomy should follow the same procedures whether

it is performed with a thoracotomy or VATS, that is, ananatomic resection with individual ligation of vessels andthe bronchus for the lobectomy and a lymph nodedissection or sampling.1

Hilar Dissection

Vessels in the hilum are dissected sharply through theutility incision with standard thoracotomy instrumentssuch as Metzenbaum scissors and DeBakey forceps.Removal of hilar lymph nodes facilitates pathologic stag-ing and enhances mobilization of vessels for transectionwith a nonarticulating endoscopic stapler (EZ 35,Ethicon, or Endo-GIA; US Surgical, Norwalk, CT).Spreading a right-angled clamp widely behind the vesselfacilitates the passage of the stapler (Figure 5-1).Alternatively, the surgeon can place a tie around a vessel

A properly placed utility incision allows the surgeon totie extracorporeal knots and follow the tie with a finger

in the same fashion as for an open procedure

Stapling Devices

The fissure, bronchus, and pulmonary vessels > 5 mm aretransected with an endoscopic stapler (Figures 5-2–5-4).The vascular (20 mm) staples are used for the vessels, andthe green cartridge (48 mm) staples are used on the

Anatomic Pulmonary Resections by Video-Assisted Thoracic Surgery / 69

TABLE 5-3 Incisions through Which the Stapler Is Passed*

RUL bronchus Inferior pulmonary vein Midclavicular incision Major fissure

Minor fissure Lower lobe artery Inferior pulmonary vein Lower lobe bronchus Auscultatory triangle incision Superior pulmonary vein

Anterior trunk artery RML artery RML vein LUL bronchus LUL = left upper lobe; RML = right middle lobe; RUL = right upper lobe.

*To transect the various structures that need to be stapled for a VATS

lobtomy or pneumonectomy.

FIGURE 5-1 Right-angled clamp mobilizing the middle lobe vein The

clamp is widely spread to allow easy passage of the stapler.

Anatomic Pulmonary Resections by Video-Assisted Thoracic Surgery / 71

Simultaneous Stapling Lobectomy

VATS lobectomy without individual stapling of the

vessels and bronchus has been reported,6rather than

individual ligation, as described Most surgeons believe

that a lobectomy should be performed with anatomic

dissection whether the procedure is performed as an

open or a VATS procedure

Techniques for Specific Lobectomies

Right Upper Lobectomy

A right upper lobectomy begins with the dissection of

the superior pulmonary vein Removal of hilar nodes

defines the middle and the upper lobe veins, which aids

definition of the anatomy for completion of the minor

fissure with the stapler The completed minor fissure

creates a pathway for a vascular stapler from the

auscul-tatory triangle incision to the upper lobe vein Removal

of lobar nodes along the artery provides exposure of the

arterial branches to the upper lobe A vascular stapler

from the auscultatory triangle transects the anterior

trunk Any additional, smaller arterial branches are tied

or clipped A stapler from the midclavicular incision

further completes the minor fissure This exposes the

posterior ascending artery A lymph node between the

upper and intermediate lobe bronchi is removed A

stapler from the midclavicular incision is placed on the

upper lobe bronchus Finally, the remainder of the fissure

is completed with the stapler through the midclavicular

incision

Middle Lobectomy

Middle lobectomy begins with hilar dissection to remove

hilar lymph nodes and mobilize the middle lobe vein

The vein is small, so it can be tied, clipped, or stapled A

stapler from the midclavicular incision then completesthe fissure between the middle and lower lobes Themiddle lobe is retracted superiorly If there is a secondartery, this manuever exposes the artery so that it can betied The bronchus is thus exposed for a stapler from theauscultatory traingle This exposes the middle lobeartery, which can be tied or clipped The final maneuver

is stapling the minor fissure through the utility tomy incision

thoraco-Lower Lobectomy with Complete Fissure

The approach for a lower lobectomy depends on thecompleteness of the fissure The operation is simplerwhen the fissure is well developed After opening thepleura, the artery is mobilized in the fissure and tran-sected with a stapler through the midclavicular incision.Through the same incision, a stapler completes the majorfissure to the level of the transected artery The surgeontakes down the pulmonary ligament and harvests level 7and 9 lymph nodes Removal of the lymph node on thesuperior edge of the inferior pulmonary vein and inci-sion of the pleura on the anterior aspect of the inferiorpulmonary vein expose the vein for transection with avascular stapler Lobar nodes are removed, the bronchus

is stapled, and the fissure is completed

Lower Lobectomy with Incomplete Fissure

The operation for a lower lobectomy is different whenthe fissure is poorly developed First, the pulmonary liga-ment is taken down and the inferior pulmonary vein ismobilized and transected as noted above The fissure iscompleted between the middle and lower lobes Superiorretraction of the lobe exposes the bronchus Dissectionalong the bronchus exposes the artery Along the surface

of the artery, a plane is created for the placement of astapler to complete the fissure Thus, the artery isexposed and transected The lobar nodes are removed;the bronchus and the fissure are stapled

Left Upper Lobectomy

The technique for a left upper lobectomy is similar tothat for a right upper lobectomy The approach beginsanteriorly with a hilar dissection, stapling of the superiorpulmonary vein, and stapling of the anterior trunk of theartery A stapler through the midclavicular incisioncompletes the major fissure between the lingula and thelower lobe to expose the lingular artery, which can be tiedfrom an anterior position or stapled from a posteriorposition The lobe is retracted superiorly to expose thebronchus The most dangerous part of a left upper lobec-tomy is mobilization of the bronchus as a right-angledclamp is passed between the bronchus and the artery.After mobilization, the bronchus is stapled from a poste-

FIGURE 5-5 Level 10 nodes after the pleura has been incised along

the superior vena cava, azygos vein, and hilum.

72 / Advanced Therapy in Thoracic Surgery

rior position The remaining branches of the artery are

thus exposed Dissection through the utility thoracotomy

incision mobilizes these arteries to be tied or clipped

Finally, the fissure is closed with multiple firings of the

stapler through the midclavicular incision

Left Lower Lobectomy

A left lower lobectomy is performed with the same

tech-nique as is used for a right lower lobectomy

Pneumonectomy

A pneumonectomy on either side is simpler than a

lobec-tomy The superior pulmonary vein is mobilized through

the utility incision and stapled through the midclavicular

or ascultatory incision Lymph nodes are removed to

expose the artery Concern about the endoscopic stapler

cutting without applying the staples on the vessel has led

surgeons to use either an endoscopic stapler with the

knife removed or a noncutting stapler The inferior

pulmonary ligament is taken down so that the vein can

be exposed and stapled Subcarinal nodes and

peri-cardium are separated from the main stem bronchus to

the level of the carina Through the utility incision, a

30 mm TA stapler is then fired on the bronchus If the

apex of the lung is passed first through the incision, an

entire lung can usually be removed through the same size

incision as is used to remove a lobe

Results of VATS Lobectomy

Although there is no contemporary, randomized trial

comparing VATS and open lobectomies, there is

mount-ing evidence that a VATS approach offers the same

opera-tion with less morbidity and mortality The literature

suggests that concerns regarding the safety of the

proce-dure appear to be unfounded The acceptance of VATS

lobectomy has been slow because of a lack of knowledge

regarding the literature, the difficulty of performing VATS

resections, and not enough training for the procedure

Results of VATS lobectomies and pneumonectomies

published in several larger, published series compare

favor-ably with those expected with thoracotomies (Table 5-4).5–12Seven (0.7%) deaths in 1,232 patients werecaused by venous mesenteric infarct, myocardial infarc-tion, respiratory failure, or unknown reasons The inci-dence of complications in these series varied from 10.0 to21.9% for patients after VATS lobectomy Complicationsincluded the following: prolonged air leak (5–10%),arrhythmias, pneumonia, respiratory failure, the need for atransfusion (0–3%), and bronchial stump leak (0.36%).There is no contemporar y randomized trial tocompare VATS and open approaches for lobectomy.Clinical trials groups have discussed conducting such atrial, but investigators feel that it would not be feasable.Comparisons of series suggest that the VATS approachmay have advantages In the series shown in Table 5-4,5–12complication rates are lower for the VATS proceduresthan in reported series for thoracotomy One small,randomized trial showed a significant benefit thatfavored VATS.1 3 Compared with patients who haveundergone a thoracotomy, patients who have undergoneVATS have better shoulder function,14a better 6-minutewalk, and less impairment of vital capacity.15A VATSapproach may be easier for older patients.16

Conversion to Thoracotomy

Overall, conversion from VATS to a thoracotomy wasnecessary in 119 of 1,232 operations (9.7%).5–12The inci-dence for the individual series was 0 to 19.5% In 70% ofthe cases, the conversion to thoracotomy was promptedfor oncologic reasons, such as centrally located tumorsrequiring vascular control, a sleeve resection, or unsus-pected T3 tumors attached to the chest wall, diaphragm,

or superior vena cava There were also nononcologicreasons for conversion, such as abnormal, benign hilarnodes and pleural symphysis

Intraoperative Hemorrhage

A major concern for VATS procedures is that trying todissect a pulmonary vessel during a VATS procedure canlead to bleeding that is difficult to control with limited

TABLE 5-4 VATS Lobectomies and Pneumonectomies

Study No of Procedures Incidences of Cancer Incidences of Mortality (%) Length of Hospital Stay (d)

Anatomic Pulmonary Resections by Video-Assisted Thoracic Surgery / 73

access However, it appears that the risk is low when the

operation is performed by surgeons experienced in VATS

At our institution, we keep a sponge stick available to

immediately apply pressure to control hemorrhage if

bleeding occurs With the bleeding thus controlled, a

decision is made as to whether a thoracotomy is needed

In these series, bleeding led to conversion to a

thora-cotomy in 10 cases (0.9%) No deaths resulted from the

bleeding episodes, and not all patients required

transfu-sion A multi-institutional survey of 1,560 VATS

lobec-tomies reported by Mackinlay found that the only

intraoperative death was related to an intraoperative

myocardial infarction, not bleeding.17

Postoperative Pain

Several studies now suggest that patients experience less

pain after a VATS lobectomy than after a lobectomy by

thoracotomy.18–20 In patients who had a lobectomy done

by VATS (n = 83) or by thoracotomy (n = 110), the VATS

group averaged less morphine use than did the

thoraco-tomy group (57 vs 83 mg of morphine, p < 001).18In a

randomized, prospective trial of lobectomy in 67 patients

(47 by VATS and 23 by muscle-sparing thoracotomies),

Giudicelli and colleagues reported that postoperative

pain was significantly less (p < 02) after a VATS

proce-dure.1 9 The incidence of post-thoracotomy pain

syndrome after VATS lobectomy (2.2%) is lower than

expected after thoracotomy.1A randomized trial showed

that patients experienced less pain and greater shoulder

strength in the first 6 months after VATS than after a

thoracotomy, but there was no difference after 1 year.20

Tumor Seeding of the Incision

In these series, seeding of the VATS incisions has

occurred in 3 of 1,033 (0.3%) lobectomies performed for

cancer The risk of tumor recurrence in a VATS incision

therefore appears to be low and can perhaps be even

lower with the use of proper bags to protect the incisions

during the removal of specimens.21

Adequacy of Cancer Operation

Long-term disease-free survival is the ultimate measure

for the adequacy of any cancer operation After VATS

lobectomy for cancer, 5-year survival has been reported

as 76 to 94%.5–13The cure rate for lung cancer does not

seem to be compromised when a complete cancer

opera-tion is performed by VATS The immunologic impact of

a VATS lobectomy may be less than the immunologic

impact of an open procedure.17

Robotics in Cardiothoracic Surgery

In cardiothoracic surgery, robotics have been used

primar-ily for cardiac procedures The robot has been successfully

used for esophagectomy A lobectomy is a complicatedprocedure that involves firing the stapler multiple times, sothe addition of robotics technology would simply makethe current procedure more complicated

Summary

In experienced hands, a VATS lobectomy appears to be asafe procedure with low morbidity and mortality ratesthat may be lower than those for a thoracotomy A VATS

is a complete cancer operation that offers patients at leastthe same survival as a lobectomy via a thoracotomy Theprocedure is not for all tumors or all thoracic surgeons

References

1 McKenna RJ Jr VATS lobectomy with mediastinal lymph node sampling or dissection Chest Surg Clin N Am 1995;4:223–32.

2 Santambrogio L, Cioffi U, De Simone M, et al assisted sleeve lobectomy for mucoepidermoid carcinoma

Video-of the left lower lobar bronchus: a case report [comment] Chest 2002;121:635–6.

3 Mack MJ, Gordon MJ, Postma TW, et al Techniques for localization of pulmonary nodules for thoracoscopic resec- tion J Thorac Cardiovasc Surg 1993;106;550.

4 Nomori H, Ohtsuka T, Horio H, et al Thoracoscopic tomy for lung cancer with a largely fused fissure Chest 2003;123:619–22.

lobec-5 Kaseda S, Aoki T, Hangai N Video-assisted thoracic surgery (VATS) lobectomy: the Japanese experience Semin Thorac Cardiovasc Surg 1998;10:300.

6 Lewis RJ, Caccavale RJ Video-assisted thoracic surgical non-rib spreading simultaneously stapled lobectomy (VATS(n)SSL) Semin Thorac Cardiovasc Surg 1998;10:332.

7 Yim APC, Izzat MB, Lui HP, et al Thoracoscopic major lung resections: an Asian perspective Semin Thorac Cardiovasc Surg 1998;10:326.

8 Hermansson U, Konstantinov IE, Aren C Video-assisted thoracic surgery (VATS) lobectomy: the initial Swedish experience Semin Thorac Cardiovasc Surg 1998;10:285.

9 Walker WS Video-assisted thoracic surgery (VATS) tomy: the Edinburgh experience Semin Thorac Cardiovasc Surg 1998;10:291.

lobec-10 Roviaro G, Varoli F, Vergani C, Maciocco M Video-assisted thoracoscopic surgery (VATS) major pulmonary resections: the Italian experience Semin Thorac Cardiovasc Surg 1998;10:313.

11 Solaini L, Prusciano F, Bagioni P, et al Video-assisted thoracic surgery major pulmonary resections Present expe- rience Eur J Cardiothoracic Surgery 2001;20:437–42.

12 McKenna RJ Jr, et al VATS lobectomy: the Los Angeles experience Semin Thorac Cardiovasc Surg 1998;10:321.

74 / Advanced Therapy in Thoracic Surgery

13 Hoksch B, Ablassmaier B, Walter M, Muller JM.

Complication rate after thoracoscopic and conventional

lobectomy Zentralblatt fur Chirurgie 2003;128:106–10.

14 Li WW, Lee RL, Lee TW, et al Impact of thoracic surgical

access on early shoulder function: video-assisted thoracic

surger y versus posterolateral thoracotomy Eur J

Cardiothoracic Surgery 2003;23:390–6.

15 Nomori H, Ohtsuka T, Horio H, et al Difference in the

impairment of vital capacity and 6-minute walking after a

lobectomy performed by thoracoscopic surgery, an anterior

limited thoracotomy, an anteroaxillary thoracotomy, and a

posterolateral thoracotomy Surg Today 2003;33:7–12.

16 McKenna RJ Jr, Fischel RJ VATS lobectomy and lymph

node dissection or sampling in eighty-year-old patients.

Chest 1994;106:1902.

17 Mackinlay TA VATS lobectomy: an international survey.

Presented at the IVth International Symposium on

Thoracoscopy and Video-Assisted Thoracic Surgery; May 1997; Sao Paulo, Brazil.

18 Leaver HA, et al Phagocyte activation after minimally sive and conventional pulmonary lobectomy Eur J Clin Invest 1996;26 Suppl 1:210.

inva-19 Giudicelli R, Thomas P, Lonjon T, et al Video-assisted minithoracotomy versus muscle-sparing thoracotomy for performing lobectomy Ann Thorac Surg 1994;8:712.

20 Landreneau RJ, Mack MJ, Hazelrigg SR, et al Prevalence of chronic pain following pulmonary resection by thoraco- tomy or video-assisted thoracic surger y J Thorac Cardiovasc Surg 1994;107:1079.

21 Downey RJ, McCormack P, LoCicero J III Dissemination of malignant tumors after video-assisted thoracic surgery: a report of twenty-one cases J Thorac Cardiovasc Surg 1996;111:954.

Heat treatment of human disease with cautery of open

wounds and ulcerating tumors has been reported and

observed among many societies since prehistoric times.1,2

Currently, electrocautery, fulguration, and hot wire

resec-tion are popular methods used to treat superficial

tumors, small cancers, and scar tissue adhesions found

among various organ mucosal lumens and mesothelial

surfaces The advent and frequent use of endoscopic and

laparoscopic techniques allow clinicians to explore the far

recesses of the body to attack superficial lesions with

minimally invasive procedures In the past, thermal

treat-ments of deep-seated lesions in solid organs have

centered on total body or regional hyperthermia, in

which tissue temperatures are raised to 42
C for hours,

theoretically to kill heat-sensitive cancer cells while

spar-ing the more heat-tolerant normal cells.3

Recent technologic advances in producing and

controlling heat generation by different energy sources

have sparked a new interest in using various delivery

methods to produce sufficient heat in deep-seated tissues

to thermally coagulate and lethally injure cells and

tissues, including cancers This treatment approach is

called interstitial thermal therapy (ITT), and it uses

energy sources such as lasers, radio frequency and

microwave generators, and focused ultrasound

transduc-ers Equally important to ITT are the exciting advances in

diagnostic imaging, including ultrasonography,

computed tomography (CT), magnetic resonance

imag-ing (MRI), and positron emission tomography (PET),

and the development of other feedback systems based on

tissue temperature and electric-conductivity changes

These technologies allow real-time, high-resolution

monitoring of thermal lesion formation to control lesion

size and extent during treatment.4–9

The general therapeutic concerns of ITT regardless ofthe energy source include (1) distribution and extent oflethal thermal injury in the cancer and the surroundingtissues, (2) the delayed effects of the treatment on thecancer and the patient, and (3) noninvasive methods ofdetermining therapeutic efficacy over time The diagnos-tic imaging technologies described above have beenfound to be useful to monitor the post-treatment tissueeffects, responses, and lesion resolution and to detecttumor eradication or recurrence over time

The successes and limitations of ITT are related toseveral engineering, physical, biologic, and medicalfactors The energies of nonionizing radiations, such aslight, microwave radiation, radio frequency radiation,and focused ultrasound, are transformed into heat by theinteractions of the radiation or acoustic waves with thetissues.10–13Therefore, the ultimate generation of heatenergy in the tissue depends on the following: (1) thetype of radiant or acoustic energy produced by thesource instrument, (2) the physical mechanisms thattransfer the energy from the source to the tissues, (3) thedelivered energy power or current, (4) the geometry ofthe energy-delivery system, (5) the physical properties ofthe tissues limiting the deposition of the energy, (6) themechanisms that transform the delivered energy to heatenergy within the tissues, (7) the physical and physiologicproperties of tissues that limit heat transfer within them,(8) the tissue and organ anatomy, and (9) the acute,intermediate, and delayed responses of the patient tothermal injury.1,14–17

Over the past 20 years, radio frequency interstitialthermal therapies (RF-ITTs) for treatment of primaryand metastatic cancers in the liver or lung have beentested and reported in preclinical phantom and animal

experiments, clinical case reports, and phase I clinical

trials.4–6 The driving force for these new treatments has

been the need to find new, relatively less invasive

meth-ods by which either cure or palliation of local pulmonary

cancer growth could be accomplished in those patients

who cannot tolerate the rigors of surgery or systemic

chemotherapy In these cases the therapeutic ideal is to

destroy the tumor and a small margin of surrounding

liver or lung tissue, while saving as much normal tissue

and function as possible, thus not compromising the

patient’s general health

Monopolar RF-ITT of a lung lesion was first reported

in 1983.18 A conducting wire, 120 cm long, was woven

into an unresectable 5 cm lung cancer, and radio

frequency power at 5 MHz was applied for 1 hour

However, the tissue temperatures did not go above 42
C

The nature and extent of tumor necrosis were not

reported at autopsy after the patient’s death of aspiration

pneumonia 2 months after placement of the wire

However, it was noted that the surrounding

noncancer-ous lung tissue appeared normal

Since that time, RF-ITT using needle monopolar

elec-trodes has been used with reasonable success in the

treat-ment of solid tumors in solid organs The most

experience and success has been in the interstitial

ther-mal coagulation of primary and metastatic liver tumors

(over 3,000 cases).19–21 It is with these tumors that the

quirks of RF-ITT instrumentation, probe design, energy

and heat distribution, and feedback mechanisms have

been tested, modified, and validated as demonstrated in

the excellent reviews of Goldberg and Dupuy.4,5 The

results of the liver applications have led to the

produc-tion of reasonably reliable machines and delivery and

feedback systems that are now being applied to other

organs and tissues including the lung

RF-ITT: Mechanisms of Tissue Heating

and Electrode Design

Radio frequency electromagnetic fields (usually ranging

from 500 kHz to 500 MHz) are delivered into tissues by

conductive electrodes (antennas) to form electric fields

in the tissues In monopolar applications an applicator

electrode formed in some variation of needle arrays is

inserted into the target tissue The electric current

disperses from the tips and sides of the exposed portions

of the applicator electrodes to flow through the body

tissues to the reference electrode, which is a relatively

large sheet of conductive material electrically coupled to

the skin surface (thighs or back) of the patient The field

strength at any distance around a single-volume-point

electrode drops off proportional to 1/r2, and the power

delivered is proportional to 1/r4 Therefore, the applicator

electrodes are configured to different geometries thatgovern the size and shape of the electric field and thusthe heated treatment volume (Figure 6-1).7,11,22–24

Heat is generated by resistive dissipation (joule heat)owing to movement of charged molecules such as ionsmoving within the electric fields.4,10,11,25 The heated treat-ment volume is not determined only by the geometry ofthe electrodes but also by the electric and thermal proper-ties of the tissue that limit the distribution of these ener-gies within the tissues.7,8,18It is to be remembered that thetissue electric and thermal properties change as the heatedtissue desiccates (increasing impedance, decreasing elec-tric conductivity, and decreasing heat transfer) during theinterstitial treatment.11,15Therefore, several modifications

of the electrodes have been implemented to better controlthe creation of the electric field in the tissues, the thermallesion size, and the uniformity of the heating process.4,26,27The tissue effects of ITT including RF-ITT are due toheat production sufficient to raise tissue temperatures to

a range of 60
to 90
C and maintain those temperaturesfor some time interval that results in lethal thermaldamage to cells and tissues in the treatment volume.Lethal thermal damage is the thermal denaturation ofproteins including enzymes, disruption of cellularmembranes and organelles, and loss of vital functions,which lead to cell and tissue death.1,28

Effective tissue heating in ITT usually takes severalseconds (for lasers) to several minutes (for radio frequency,microwaves, and focused ultrasound) These time intervalsare characterized by the creation of heat gradients extend-ing from the hot heat source volume to the cooler periph-ery The extent of the gradients depends on the powerdelivered at the heat source, the thermal properties of thenative and heated tissues, and the blood flow in livingtissues leading to convective heat loss.14If the volume heat

76 / Advanced Therapy in Thoracic Surgery

FIGURE 6-1 General configuration of radio frequency electrode

probes being used in radio frequency interstitial thermal therapy The applicator electrode probe diameters are usually about 17- or 18- gauge trochars.

source is flat, parallel layers of damage zones develop along

the heat gradient that extends perpendicularly from the hot

surface to the cooler periphery of the underlying tissues If

the volume heat source is a point, then the zones of thermal

damage form as concentric spherical bands extending from

the hot center along the heat gradients that radiate from the

hot center to form generally spherical, targetoid lesions

Cylindrical volume heat sources behave as a series of point

sources along the long axis of the cylinders, thus producing

elliptical thermal lesions (Figure 6-2).1,2,17,29–31

Distinct zones of pathologic thermal damage occur

along these thermal gradients The thermal damage zones

and the mechanisms of their production have been

described pathologically and are useful to map and

measure thermal injury produced by various energy

sources and delivery instruments.31 Some markers of

biologic thermal damage can be produced both in vitro

and in vivo, but others can only form in living tissues

with an intact blood flow and in animals and humans

that survive (Table 6-1)

In the past, the patient and cancer responses to ITT

have been hard to detect and measure clinically without

some kind of destructive diagnostic intervention such as

biopsy or excision.30 Practically, the most important

histopathologic treatment marker to determine efficacy

at the time of treatment is the detection of the outer

boundary of the red thermal damage zone in the thermal

lesion This boundary has been demonstrated to coincide

with the boundary of tissue necrosis, the “gold standard”

of tissue death, 2 to 4 days after heating This coincidence

has been demonstrated in several different tissues in

numerous vertebrate species, including humans.2,32

Other histopathologic methods of determining lethal

thermal damage have included using vital dyes to indicate

tissue viability and immunohistochemistry to detect

proteins associated with the cell cycle But, these

proce-dures have their limitations, including the need to extract

tissue by biopsy or excision to map tissue death and

some-what cumbersome, multistep techniques.33–35Vital dyes thatdepend on the oxidation-reduction reactions of certainmitochondrial enzymes are useful to delineate relativelethal thermal damage However, besides requiring tissue,the dyes have to be applied to fresh tissue immediatelyafter removal from the body False-positive reactions canoccur because some moribund cells still contain activemitochondrial membrane fragments at the time of stain-ing but die later False-negative reactions can result fromallowing the tissues to sit at room temperature for ≥ 1hour prior to staining, the “magic time” during which themitochondrial enzymes remain active after severing of theblood supply.2,31,33,34,36–38Immunohistochemistry is based onthe use of specific antibodies that bind with specific cellu-lar or tissue antigens Thermal coagulation of a proteinmay not destroy its antibody-binding site; therefore, therecan be an immunologic localization of the antigen in deadtissues I have observed that immunologic localization ofcell cycle proteins in thermally coagulated tissues does notimply viability

Radio Frequency Ablation of Thoracic Malignancies / 77

TABLE 6-1 Thermal Damage Zones

Ablation: removal of tissue solids Red thermal damage: thrombosis, Tissue lytic necrosis: outer boundary

hemostasis, hemorrhage, hyperhemia established at 2–3 d Carbonization of tissue: carbon formation at Tissue lytic necrosis: enzymatic Wound healing: organization begins at 3–5 d, vascular tissue/electrode interface degradation of tissues and fibrous granulation tissue formation begins at 4–6 d,

fibrous scar tissue formation begins at 5–7 d Tissue water vaporization; steam vacuole formation,

tissue desiccation

Structural protein denaturation: cell shrinkage,

cell hyperchromasia, collagen hyalinization,

collagen birefringence loss

Vital enzyme protein denaturization: loss of

vital enzyme function

FIGURE 6-2 Heat gradient vectors and zones of heat damage from

different volume heat sources.