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Surgery after multimodality treatment for non-small-cell lung cancer
Lung Cancer 45 Suppl. 2 (2004) S107–S112
www.elsevier.com/locate/lungcan
Surgery after multimodality treatment for non-small-cell lung cancer Georgios Stamatis a, *, Wilfried Eberhard b , Christoph P¨ ottgen c a
Department of Thoracic Surgery and Endoscopy, Ruhrlandklinik, T¨ uschener Weg 40, D-45239 Essen, Germany b Department of Internal Medicine, West German Cancer Centre, University of Essen Medical School, Hufelandstraße 55, D-45122 Essen, Germany c Department of Radiotherapy and Radio-Oncology, West German Cancer Centre, University of Essen Medical School, Hufelandstraße 55, D-45122 Essen, Germany
KEYWORDS Advanced NSCLC; Induction chemo– radiotherapy; Perioperative course; Long-term survival
Summary Neoadjuvant treatment for locally advanced non-small-cell lung cancer (NSCLC) stage IIIA and IIIB promises higher resection rates because of a reduction of the primary tumour and sterilisation of mediastinal nodes (“downstaging”). In this study we analyse the perioperative course and the long-term survival of patients with trimodality treatment. Between 03/1991 and 12/2002, 392 patients with NSCLC underwent resection after induction treatment. Included were 266 males and 126 females, age 55.8±9 (28–74), of whom 218 were stage–IIIA patients, 174 were stage–IIIB patients. Induction treatment included 3 courses of chemotherapy with cisplatin/etoposide or cisplatin/paclitaxel, followed by one course of chemotherapy with cisplatin/ etoposide as well as hyperfractionated accelerated radiotherapy of the primary tumour and the mediastinal nodes with 45 Gy, followed by surgery. Before induction treatment all patients underwent mediastinoscopy. In patients with N3 disease mediastinoscopy was repeated before surgery. Resections included 133 pneumonectomies (34%), 15 bilobectomies (4%), 55 sleeve lobectomies (14%), 168 lobectomies (42.5%), 6 segmentectomies (1,5%), and 15 explorative thoracotomies (4%). In-hospital mortality rates amounted to 4.6% (18 patients) while postoperative morbidity ran up to 46% (180 patients). Morbidity and mortality rates were significantly higher in patients with Karnofsky status lower than 80% and patients older than 65 years. Bronchopleural fistulas occurred in 16 patients (3.2%). The protection of the bronchial stump or anastomosis with viable tissue, like pericardial fat, proves to be a significant factor for the reduction of septic complications. For NSCLC, the 5- and 7-year survival rates were 36% and 31%, respectively, for stage IIIA, and 26% for stage IIIB. This intensive trimodality treatment proves to be feasible. Treatment-related toxicities
* Correspondence to: Georgios Stamatis MD. Department of Thoracic Surgery and Endoscopy, Ruhrlandklinik, T¨ uschenerweg 40, 45239 Essen, Germany. Tel.: +49-(201)-433-4011; fax: +49-(201)-433-1716. E-mail: [email protected] 0169-5002/$ – see front matter © 2004 Published by Elsevier Ireland Ltd. doi:10.1016/j.lungcan.2004.07.000
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G. Stamatis et al. are overall moderate and acceptable. Accurate cardiopulmonary evaluation before surgery and reinforcement of bronchial stump or anastomosis can contribute to reducing complications. Induction treatment demonstrated a “downstaging effect”, so that a clear trend for organ-sparing resection was observed. Long-term survival rates for selected groups look very promising when compared to historical controls. © 2004 Elsevier Science Ltd.
1. Introduction Today, only a few patients with non-small-cell lung cancer (NSCLC) in stage III show a primary indication for surgery alone [1–3]. This includes for stage IIIA a small subset of patients with T3N1 tumours or minimal disease in mediastinal nodes – so called “minimal N2 disease” – with only one nodal station, microscopically involved. Standard treatment for stage-IIIB non-small-cell lung cancer has been radiotherapy alone, but it is also widely accepted that some subgroups of T4 disease can be potential candidates for surgical approaches (T4 carina, T4 vena cava, T4 satellite nodes), while others are generally not considered for any inclusion of surgery [4,5]. In the vast majority of stage-III patients, upfront surgery is no longer considered appropriate, due to early locoregional and/or systemic relapse. Therefore, treatment including a combination of local and systemic therapy has became a popular approach, and several investigators have meanwhile tested the value of different induction strategies in extended phase-II trials and a small number of randomised trials [6,7]. Chemotherapy or chemo–radiotherapy are used to downstage tumours and render them completely resectable [8,9]. Even if response rates between 60% and 80% have been reported, the randomised trials were based on too small numbers of patients so that patients’ heterogeneity of the staged groups complicates the interpretation of published data of phase-II and phase-III trials. Additionally, certain studies suggest postoperative risks with an increase of morbidity and mortality after induction therapy compared to historical groups. The aim of the present study was firstly to evaluate the postoperative cardiopulmonary and bronchial complications and secondly to identify stage-III subgroups with improved long-term prognosis in patients after induction chemo–radiotherapy and final surgery.
2. Methods and material Between March 1991 and December 2002, 392 patients with NSCLC, who underwent elective thoracotomy after induction chemo–radiotherapy at
the Ruhrlandklinik Essen, were retrospectively reviewed. In the course of two phase-II studies and one phase-III study, 266 men and 126 women were treated with preoperative chemotherapy consisting of three courses of split cisplatin 60 mg/m2 d1,7 and etoposide 150 mg/m2 d3,4,5 (260 patients) and cisplatin 50 mg/m2 d1,8 and paclitaxel 125 mg/m2 d1 (132 patients), followed in all 392 patients by concurrent chemoradiotherapy (one course of cisplatin 50 mg/m2 d2,9 and etoposide 100 mg/m2 d4,5,6 combined with 45 Gy hyperfractionated accelerated radiotherapy to the primary tumour and mediastinal nodes). Furthermore, from 1993 to 1998 all patients were routinely offered a prophylactic cranial irradiation (PCI) of 30 Gy in 2-Gy fractions, administered over three weeks. Median age was 55.8±9.0 (range 28–74 years), Karnofsky index [10] was 79.3±9.9% (range 60–100%). 218 patients (55.6%) had IIIA disease, 174 (44.4%) had IIIB disease. All 392 patients underwent a cervical mediastinoscopy before induction treatment. For those with initially proven positive contralateral mediastinal nodes (N3 disease), mediastinoscopy was repeated before surgery. Patients still showing contralateral involvement after repeated mediastinoscopy, were excluded from surgery. In addition to staging investigations to rule out metastases, patients underwent a preoperative cardiovascular risk assessment, including cardiopulmonary function testing. Excluding criteria were a predicted postoperative forced expiratory volume at 1 second of less than one litre (quantitative ventilation–perfusion lung scanning), cardiac infarction, unstable angina pectoris in the 6 months before study entry, or cardiac disability of class III or greater (NYHA criteria). If re–evaluation showed continuing medical/functional operability, patients were taken to thoracotomy 3–5 weeks after the end of radiation treatment. 227 patients (58%) had a right-side, 165 patients (42%) a left-side thoracotomy. The operation time was 157.6±64.3 min (range 28–342 min). 15 patients (4%) had an exploration only. The causes were infiltration of oesophagus (n=2), trachea (n=1) and heart (n=1) on the right and aortic arch (n=4), pulmonary truncus (n=5) and heart (n=2) on the left side. Resections included 133 pneumonectomies (34%), 15 bilobectomies (4%), 55 sleeve
Surgery after multimodality treatment for non-small-cell lung cancer Table 1 Additional operations to pulmonary resections n
%
Pericard
94
24.0
Parietal pleura
88
22.5
Chest wall
36
9.1
Diaphragm
14
3.4
Main carina
5
1.3
Aorta/adventicia
4
1.0
Esophageal muscle
4
1.0
Superior vena cava
3
0.7
Vertebral body
3
0.7
Subclavia artery
2
0.5
Operation
lobectomies (14%), 168 lobectomies (42.5%), 6 segmentectomies (1,5%), and 15 explorative thoracotomies (4%). Additionally, operations to pulmonary resection are listed in Table 1. Lymphadenectomy included interlobar, hilar and ipsilateral mediastinal nodes. Contralateral nodes were not resected. Bronchial stump was closed hand-sutured in all patients. We applied the “Overholt” technique after lobectomy/bilobectomy as well as after pneumonectomy. From 1996 onwards, the bronchial stump after pneumonectomy was routinely sutured with 2–0 monofilament, non-absorbal continuous horizontal mattress sutures, running at the length of the stump. After water testing with a pressure of 40 cm H2 O, a second layer with 4 or 5 single sutures followed. In 1993, we started to reinforce the bronchial stump individually and from 1996 obligatory with viable tissue. In patients after pneumonectomy, a reinforcement was performed with intercostal muscle flap (n=8), diaphragmatic muscle (n=6), and thymus/mediastinal fat (n=119). To reduce tissue oedema, prednisolone 1 mg/ kg body weight was administered for 3 days, already starting in the operating room. The overall blood loss was 360 ml (110–1720 ml); 121 patients had intraoperatively (n=24) or postoperatively (n=97) at least one blood transfusion (median 2.4 U, range 2–9 U). For the statistical analysis, data are presented as the mean ± standard deviation. The primary endpoints of analysis were length of hospital stay, occurrence of complications and mortality. The effects of risk factors on these endpoints are evaluated with univariate analysis first. Categorical variables were analysed by c2 test. Continuous variables were assessed by means of t-test, or by Mann–Whitney rank sum test, if the data did not follow a gaussian distribution. Variables were selected for multivariate analysis, if their P values were below 0.10 by univariate analysis.
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Multiple logistic regression was performed for multivariate analysis of risk factors. Correlation between variables and the length of hospital stay were analysed by using Pearson’s correlation coefficient. All tests were two-tailed and were performed by Statview version 5.0 statistical software (SAS Institute Inc., SAS Campus Drive, Cary, NC 27513, USA). Differences were considered significant with p<0.05.
3. Results The overall hospital mortality rate was 4.6% (n=18). 7.1% of the patients died after pneumonectomy, 3.6% after lobectomy/bilobectomy. The causes of death were sepsis (n=5), pneumonia and respiratory failure (n=4), ARDS (n=3), cardiac failure (n=3), and lung embolism (n=3). Univariate analysis demonstrated that higher age (p=0.0312) and lower Karnofsky index (p<0.0001) adversely affected incidence of mortality. Multivariate analysis extracted lower Karnofsky index (p=0.0008) to be a significant risk factor for mortality. There was neither a significant difference (c2 test) with regard to the side (p=0.3483) or to the type of resection (pneumonectomies versus lobectomies p=0.6572), nor to the amount of blood transfusion (p=0.2457). 180 patients (46%) developed one or more early or late complications (Table 2). The most common complications were arrhythmia (41 patients, 10.6%), air leakage longer than 7 days (34 patients, 8.5%), pneumonia (19 patients, 4.8%), atelectasis with more than one bronchoscopic suction (19 patients, 4.8%), septic complications as bronchopleural fistula (BPF) (16 patients, 3.2%), and empyema without BPF (6 patients, 1.6%). Arrhythmia occurred in all patients within the Table 2 Postoperative complications in 180 patients (46%) n
%
Arrhythmia
41
10.6
Pneumonia
19
4.8
Atelectasis
17
4.5
BPF
16
3.2
6
1.6
Complication
Empyema without BPF Air leakage>7d
34
8.7
Persistent pleural space
11
2.8
Pulmonary embolism
6
1.5
Postoperative bleeding
10
2.5
ICU syndrome
11
2.8
Chylothorax
6
1.5
Recurrens nerve palsy
3
0.8
S110 first 72 hours and was treated with digitoxin and verapamil. Abnormal findings in echocardiography before surgery were risk factors for postoperative arrhythmia with statistical significance (p<0.0001). Air leakage from lung parenchyma was more common than in historical groups without induction therapy and resulted in a longer hospital stay of 15.9±10.5 days (range, 7–163 days). Postoperative bleeding, requiring re-thoracotomy, occurred in 10 patients (6 after lobectomy and 4 after pneumonectomy). The cause was found only in 4 cases (1 bronchial, 2 intercostal and 1 oesophageal artery, respectively); in the other 6 patients haematothorax was concerned to diffused bleeding after extended adhesiolysis. Bronchopleural fistulas occurred between days 6 and 28: in 16 patients after resection, in 12 after pneumonectomy, in 10 on the right side, in 2 on the left side, in 4 after lower lobectomy, and in 2 in each side. Statistical analysis (c2 test) showed that only the stumpcovering technique at the operation with viable tissue effected a prevention of BPF with statistical significance (p=0.0321). BPF resulted in sepsis and death of 5 patients (4 after pneumonectomy, 1 after lobectomy). Our attempt to close the fistula with diaphragmatic muscle (n=2) or intercostal muscle (n=3) was of short duration, so that open thoracostomy in all cases was necessary. 11 patients who survived these complications were treated by partial thoracoplasty in combination with muscle latissimus dorsi transposition. Empyema without BPF was observed in 6 patients (4 after lobectomy, 1 after bilobectomy and 1 after pneumonectomy). Thoracoscopic debridement was done and chest tube was placed, followed by daily irrigation with 1000 ml saline solution. The actuarial survival rate for stage IIIA was 36% at five years, 31% at seven years, with a median survival of 22 months. For stage IIIB, both fiveand seven-year survival was 26%, with a median survival of 18 months. The corresponding rates were 45% and 42% for R0-resected patients in stage IIIA and 38% and 33% in stage IIIB. No difference was observed between patients with R0 resection and those with pathological complete response (pCR).
4. Discussion Recent experiences in two small randomised trials, reported for stage IIIA, have shown that an early inclusion of systemic treatment into the management of locally advanced NSCLC is feasible and effective, and leads to a significant increase of survival. Other investigators have focussed on
G. Stamatis et al. an early intensification of preoperative downstaging by so-called “bimodality induction”, including chemotherapy as well as radiation therapy prior to surgery [11–14]. This approach seems to be especially attractive for more locally advanced selected IIIB subgroups, where a maximum of preoperative downstaging is mandatory in order to enable a complete resection of any vital tumour, left after induction – mostly at areas of bulky disease in the primary tumour or the mediastinum. In spite of all these promising reports, some groups observed an increased morbidity and mortality, especially in patients after pneumonectomy, suggesting a higher risk after induction treatment [15–17]. Fowler et al. [15] in a small series with 13 patients reported an overall perioperative mortality of 23% (43% occurring after pneumonectomy). They used an aggressive protocol with high-dose concomitant thoracic irradiation of 60 Gy. Abolhoda et al. [16] found that right pneumonectomy was the only predictor of postoperative mortality in a large series of 471 patients. Doddoli et al. [17] reported an in-hospital mortality of 9% for all patients and 14% for right pneumonectomy, from respiratory origin in all cases. Contrary to these reports, other groups observed lower mortality rates of 5.7% (only after lobectomy) [18] and 5.3% (mainly after pneumonectomy) [19]. In our series, overall in-hospital mortality rate was 4.6%. Since patients who require pulmonary resection for lung cancer often have a pre-existent chronic obstructive and/or cardiopulmonary disease, pulmonary and cardiovascular complications were most frequent in our series, amounting to 90% of all complications [20]. Even if smokers and patients with chronic obstructive disease participated in an intensive training and inhalative treatment with bronchodilatators before surgery, complications such as pneumonia and atelectasis, requiring bronchoscopy, were common. Despite a meticulous preparation of interlobar fissure or adhesiolysis, the incidence of air leakage after lobectomy or bilobectomy was higher than in historical collectives without induction, probably due to the tissue damage caused by radiotherapy. Also, changes in the structure of interlobar and hilar nodes after chemo–radiotherapy, especially in patients with SCLC, resulted in lung parenchyma injury during their removal with prolonged postoperative air leakage. The hospital stay of 15.9 days compares with other reports [21]. Arrhythmia occurred in 10.6% of all patients, in 26.7% after pneumonectomy. Because of the generally known toxicity of chemotherapeutic drugs to myocardium, all patients were investigated before surgery with echocardiography, and with
Surgery after multimodality treatment for non-small-cell lung cancer stress electrocardiogram. We found that pathological echocardiography was a risk factor for postoperative arrhythmia with statistical significance. Even if our induction protocol included for all patients a preoperative radiotherapy, the incidence of BPF of 3.2% compares favourably to that reported by others [15,17,22,23]. We suppose that aggressive lymph-node resection with removal of the surrounding fat tissue and de-vitalisation of peribronchial tissue, in addition to high-dose radiotherapy of more than 45 Gy, are important factors for the development of bronchial fistulas. Therefore, we decided in our protocols to give all patients a standard dose of radiation of 45 Gy and to preserve as much peribronchial and peritracheal tissue as possible. Lymphadenectomy was performed only ipsilateral. Patients who still suffered from N3 disease in the repeated mediastinoscopy were excluded from surgery. Finally, the analysis of our data showed that bronchial stump covering technique is an effective BPF-preventing procedure with statistical significance. In order to reinforce bronchial stump after pneumonectomy, we favour the use of a flap of mediastinal fat/thymus tissue. The blood supply from the pericardiophrenic artery is excellent and the tissue volume sufficient. In a prospective study with 50 patients after preoperative chemoradiotherapy and pneumonectomy, a normal bronchial healing was observed – in all cases without BPF. Re-intervention, caused by postoperative bleeding, was observed in 2.5% of the cases. We tend to re-operate the patients as early as possible so as to reduce further complications. Statistical analysis showed that postoperative bleeding rates did not affect the morbidity and mortality. Long-term survival at 5 and 7 years of 36% and 31% for stage IIIA and 26% for stage IIIB looks very promising for these advanced-stage subgroups. So far, prognosis of our patients with T4, N2 and N3 disease are comparable. Long-term survival became possible in T4N0/1, T2–4N2 or T1/2N3. The only group with more unfavourable prognosis seems to be that with a combination of higher T and N stages (T3–4N2 and T3–4N3). These were also the groups with the lowest rate of complete resection after induction (35%). It is still not clear whether – following such an intensive preoperative downstaging – the extent of resection can be confined to the primary tumour and the ipsilateral mediastinal nodes, or whether one has to include the contralateral mediastinum in order to achieve an anatomically complete resection of initially involved tissue. Our relapse pattern in patients with N2 and N3 nodes proves that local or locoregional relapse in the
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succession of negative re-biopsies of contralateral nodes is rarely observed. Induction treatment turned out to be much more effective in the mediastinum (69% initially involved N2/N3 nodes free of cancer) than at the primary tumour site (21% pathological complete responses). However, the SWOG database did concisely show that N2 or N3 disease at thoracotomy was the most significant negative prognostic factor for postoperative survival duration and prognosis in their patients. Different to our results, SWOG did find significantly better survival results for the stage subgroup T4N0/1. Other investigators, Choi from Boston and Grunenwald from Paris, have also included IIIB patients into tri-modality protocols (T4 as well as N3), comparable to our trial and that of SWOG [8,9,14]. However, in the Boston study the induction chemoradiotherapy was more intensive with a complex irradiation scheme of combining once- with twice-daily irradiation up to 60 Gy. The Paris trial had comparable radiation doses preoperatively (45 Gy), but included a more complex and more extensive surgical approach (sternotomy). They reported a complete resection rate of 57% among 30 patients and a three-year actuarial survival rate of 25% [14]. Choi found among 26 IIIB patients (T4 or N3) a complete resection rate of 52% and an actuarial three-year survival of 52% [9].
5. Conclusion Our analysis demonstrates that in patients with locally advanced lung cancer and induction chemo– radiotherapy, surgery can be feasible with acceptable mortality but increased morbidity. Patient selection for surgery after accurate cardiopulmonary evaluation and standard operative technique with reinforcement of bronchial stump or anastomosis with sufficient tissue can contribute to reduce complications. Long-term survival rates, now achievable with multimodality treatment and surgery for selected groups, look very promising when compared to historical controls.
References 1. Ginsberg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In: DeVita Jr VT, Hellmann S, Rosenberg SA (editors), Cancer: Principles and Practice of Oncology, 5th edition. Philadelphia, PA: Lipincott; 1997, pp. 858–911. 2. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710–23. 3. Fabrice A, Grunenwald D, Pignon JP, Dujon A, Brouchet L, Depierre A, Pujol JL, Le Chevalier T. Survival of patients with resected N2 non small cell lung cancer (NSCLC): Heterogeneity of prognosis and evidence for a subclassification. Proc Am Soc Clin Oncol 1999;18: abstract 1802.
S112 4. Van Raemdonck DE, Schneider A, Ginsberg RJ. Surgical treatment for higher stage non-small cell lung cancer. Ann Thorac Surg 1992;54:999–1013. 5. Mathisen DJ, Grillo HC. Carinal resection for bronchogenic carcinoma. J Thorac Cardiovasc Surg 1988;102:16–23. 6. Roth, JA, Fossella FV, Komaki R, et al. A randomized trial comparing preoperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small cell lung cancer. J Natl Cancer Inst 1994;86:673–80. 7. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small cell lung cancer. N Engl J Med 1994;330:153–8. 8. Choi NC, Carey RW, Daly W, et al. Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer. J Clin Oncol 1997;15:712–22. 9. Albain KS, Pass HI. Induction therapy for locally advanced non-small cell lung cancer. In: Lung cancer – Principles and Practice, 6th edition. Philadelphia, PA: Lippincott; 2000, pp. 798–820; Cardiovasc Surg 1988;102:16–23. 10. Karnofsky DA, Abalmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the palliative treatment of carcinoma. Cancer 1948;1:834–56. 11. Green MR, Cox JD, Ardizzoni A, et al. Endpoints for multimodal clinical trials in stage III non-small cell lung cancer (NSCLC): A consensus report. Lung Cancer 1994;11:11–3. 12. Johnson DH, Turrisi AT, Pass HJ. Combined modality treatment for locally advanced non-small cell lung cancer. In: Pass HJ, Mitchell J, Johnson DH, Turrisi AT (editors), Lung Cancer: Principles and Practice. Philadelphia, PA: LippincottRaven; 1996, pp. 863–73. 13. Eberhardt W, Wilke H, Stamatis G, et al. Preoperative chemotherapy followed by concurrent chemoradiation therapy based upon hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer: Mature results of a phase II trial. J Clin Oncol 1998;16:622–34. 14. Grunenwald D, Le Chevalier T, Arriagada R, et al. Results of surgical resection in stage IIIB non-small cell lung cancer
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(NSCLC) after concomitant induction chemoradiotherapy. Lung Cancer 1997;18:73. Fowler WC, Langer CJ, Curran WJ, et al. Postoperative complications after combined neoadjuvant treatment of lung cancer. Ann Thorac Surg 1997;55:986–9. Abolhoda A, Martin J, Rusch V, Bains MS, Downey RJ, Korst RJ, Weigel TL, Kris MG, Ginsberg RJ. Morbidity and mortality after neoadjuvant treatment of non-small cell lung cancer: the dangers of right pneumonectomy, 37th Annual Meeting, STS, 2001:232. Abstract. Doddoli C, Thomas P, Thirion X, Ser´ ee Y, Giudicelli R, Fuentes P. Postoperative complications in relation with induction therapy for lung cancer. Eur J Cardiothorac Surg 2001;20:385–90. Mathisen DJ, Wain JC, Wright C, Choi N, Carey R, Hilgenberg A, Grossbard M, Lynch T, Grillo H. Assessment of preoperative accelerated radiotherapy and chemotherapy in stage IIIA(N2) non-small-cell lung cancer. J Thorac Cardiovasc Surg 1996;111:123–33. Rusch VW, Albain KS, Crowley JJ, Rice TW, Lonchyna V, McKenna R, Livingston RB, Griffin BR, Benfield JR. Surgical resection of stage IIIa and stage IIIb non-small-cell lung cancer after concurrent induction chemoradiotherapy. J Thorac Cardiovasc Surg 1993;105:97–106. Bernard A, Deschamps C, Allen MS, Miller DL, Trastek VF, Jenkins GD, Pairolero PC. Pneumonectomy for malignant disease: Factors affecting early morbidity and mortality. J Thorac Cardiovasc Surg 2001;121:1076–82. Macchiarini P, Chapelier AR, Monnet I, Vannetzel JM, Rebischung JL, Cerrina J, Parquin F, Le Roy Ladurie F, Lenot B, Dartavelle PG. Extended operations after induction therapy for stage IIIb (T4) non-small cell lung cancer. Ann Thorac Surg 1994;57:966–73. Deschamps C, Bernard A, Nichols FC, Allen MS, Miller DL, Trastek VF, Jenkins GD, Pairolero PC. Empyema and bronchopleural fistula after pneumonectomy: factors affecting incidence. Ann Thorac Surg 2001;72:243–8. Rice TW, Adelstein DJ, Koka A, Tefft M, Kirby TJ, van Kirk MA, Taylor ME, Olencki TE, Perreboom D, Budd GT. Accelerated induction therapy and resection for poor prognosis stage III non-small cell lung cancer. Ann Thorac Surg 1995;60:586–92.
www.elsevier.com/locate/lungcan
Surgery after multimodality treatment for non-small-cell lung cancer Georgios Stamatis a, *, Wilfried Eberhard b , Christoph P¨ ottgen c a
Department of Thoracic Surgery and Endoscopy, Ruhrlandklinik, T¨ uschener Weg 40, D-45239 Essen, Germany b Department of Internal Medicine, West German Cancer Centre, University of Essen Medical School, Hufelandstraße 55, D-45122 Essen, Germany c Department of Radiotherapy and Radio-Oncology, West German Cancer Centre, University of Essen Medical School, Hufelandstraße 55, D-45122 Essen, Germany
KEYWORDS Advanced NSCLC; Induction chemo– radiotherapy; Perioperative course; Long-term survival
Summary Neoadjuvant treatment for locally advanced non-small-cell lung cancer (NSCLC) stage IIIA and IIIB promises higher resection rates because of a reduction of the primary tumour and sterilisation of mediastinal nodes (“downstaging”). In this study we analyse the perioperative course and the long-term survival of patients with trimodality treatment. Between 03/1991 and 12/2002, 392 patients with NSCLC underwent resection after induction treatment. Included were 266 males and 126 females, age 55.8±9 (28–74), of whom 218 were stage–IIIA patients, 174 were stage–IIIB patients. Induction treatment included 3 courses of chemotherapy with cisplatin/etoposide or cisplatin/paclitaxel, followed by one course of chemotherapy with cisplatin/ etoposide as well as hyperfractionated accelerated radiotherapy of the primary tumour and the mediastinal nodes with 45 Gy, followed by surgery. Before induction treatment all patients underwent mediastinoscopy. In patients with N3 disease mediastinoscopy was repeated before surgery. Resections included 133 pneumonectomies (34%), 15 bilobectomies (4%), 55 sleeve lobectomies (14%), 168 lobectomies (42.5%), 6 segmentectomies (1,5%), and 15 explorative thoracotomies (4%). In-hospital mortality rates amounted to 4.6% (18 patients) while postoperative morbidity ran up to 46% (180 patients). Morbidity and mortality rates were significantly higher in patients with Karnofsky status lower than 80% and patients older than 65 years. Bronchopleural fistulas occurred in 16 patients (3.2%). The protection of the bronchial stump or anastomosis with viable tissue, like pericardial fat, proves to be a significant factor for the reduction of septic complications. For NSCLC, the 5- and 7-year survival rates were 36% and 31%, respectively, for stage IIIA, and 26% for stage IIIB. This intensive trimodality treatment proves to be feasible. Treatment-related toxicities
* Correspondence to: Georgios Stamatis MD. Department of Thoracic Surgery and Endoscopy, Ruhrlandklinik, T¨ uschenerweg 40, 45239 Essen, Germany. Tel.: +49-(201)-433-4011; fax: +49-(201)-433-1716. E-mail: [email protected] 0169-5002/$ – see front matter © 2004 Published by Elsevier Ireland Ltd. doi:10.1016/j.lungcan.2004.07.000
S108
G. Stamatis et al. are overall moderate and acceptable. Accurate cardiopulmonary evaluation before surgery and reinforcement of bronchial stump or anastomosis can contribute to reducing complications. Induction treatment demonstrated a “downstaging effect”, so that a clear trend for organ-sparing resection was observed. Long-term survival rates for selected groups look very promising when compared to historical controls. © 2004 Elsevier Science Ltd.
1. Introduction Today, only a few patients with non-small-cell lung cancer (NSCLC) in stage III show a primary indication for surgery alone [1–3]. This includes for stage IIIA a small subset of patients with T3N1 tumours or minimal disease in mediastinal nodes – so called “minimal N2 disease” – with only one nodal station, microscopically involved. Standard treatment for stage-IIIB non-small-cell lung cancer has been radiotherapy alone, but it is also widely accepted that some subgroups of T4 disease can be potential candidates for surgical approaches (T4 carina, T4 vena cava, T4 satellite nodes), while others are generally not considered for any inclusion of surgery [4,5]. In the vast majority of stage-III patients, upfront surgery is no longer considered appropriate, due to early locoregional and/or systemic relapse. Therefore, treatment including a combination of local and systemic therapy has became a popular approach, and several investigators have meanwhile tested the value of different induction strategies in extended phase-II trials and a small number of randomised trials [6,7]. Chemotherapy or chemo–radiotherapy are used to downstage tumours and render them completely resectable [8,9]. Even if response rates between 60% and 80% have been reported, the randomised trials were based on too small numbers of patients so that patients’ heterogeneity of the staged groups complicates the interpretation of published data of phase-II and phase-III trials. Additionally, certain studies suggest postoperative risks with an increase of morbidity and mortality after induction therapy compared to historical groups. The aim of the present study was firstly to evaluate the postoperative cardiopulmonary and bronchial complications and secondly to identify stage-III subgroups with improved long-term prognosis in patients after induction chemo–radiotherapy and final surgery.
2. Methods and material Between March 1991 and December 2002, 392 patients with NSCLC, who underwent elective thoracotomy after induction chemo–radiotherapy at
the Ruhrlandklinik Essen, were retrospectively reviewed. In the course of two phase-II studies and one phase-III study, 266 men and 126 women were treated with preoperative chemotherapy consisting of three courses of split cisplatin 60 mg/m2 d1,7 and etoposide 150 mg/m2 d3,4,5 (260 patients) and cisplatin 50 mg/m2 d1,8 and paclitaxel 125 mg/m2 d1 (132 patients), followed in all 392 patients by concurrent chemoradiotherapy (one course of cisplatin 50 mg/m2 d2,9 and etoposide 100 mg/m2 d4,5,6 combined with 45 Gy hyperfractionated accelerated radiotherapy to the primary tumour and mediastinal nodes). Furthermore, from 1993 to 1998 all patients were routinely offered a prophylactic cranial irradiation (PCI) of 30 Gy in 2-Gy fractions, administered over three weeks. Median age was 55.8±9.0 (range 28–74 years), Karnofsky index [10] was 79.3±9.9% (range 60–100%). 218 patients (55.6%) had IIIA disease, 174 (44.4%) had IIIB disease. All 392 patients underwent a cervical mediastinoscopy before induction treatment. For those with initially proven positive contralateral mediastinal nodes (N3 disease), mediastinoscopy was repeated before surgery. Patients still showing contralateral involvement after repeated mediastinoscopy, were excluded from surgery. In addition to staging investigations to rule out metastases, patients underwent a preoperative cardiovascular risk assessment, including cardiopulmonary function testing. Excluding criteria were a predicted postoperative forced expiratory volume at 1 second of less than one litre (quantitative ventilation–perfusion lung scanning), cardiac infarction, unstable angina pectoris in the 6 months before study entry, or cardiac disability of class III or greater (NYHA criteria). If re–evaluation showed continuing medical/functional operability, patients were taken to thoracotomy 3–5 weeks after the end of radiation treatment. 227 patients (58%) had a right-side, 165 patients (42%) a left-side thoracotomy. The operation time was 157.6±64.3 min (range 28–342 min). 15 patients (4%) had an exploration only. The causes were infiltration of oesophagus (n=2), trachea (n=1) and heart (n=1) on the right and aortic arch (n=4), pulmonary truncus (n=5) and heart (n=2) on the left side. Resections included 133 pneumonectomies (34%), 15 bilobectomies (4%), 55 sleeve
Surgery after multimodality treatment for non-small-cell lung cancer Table 1 Additional operations to pulmonary resections n
%
Pericard
94
24.0
Parietal pleura
88
22.5
Chest wall
36
9.1
Diaphragm
14
3.4
Main carina
5
1.3
Aorta/adventicia
4
1.0
Esophageal muscle
4
1.0
Superior vena cava
3
0.7
Vertebral body
3
0.7
Subclavia artery
2
0.5
Operation
lobectomies (14%), 168 lobectomies (42.5%), 6 segmentectomies (1,5%), and 15 explorative thoracotomies (4%). Additionally, operations to pulmonary resection are listed in Table 1. Lymphadenectomy included interlobar, hilar and ipsilateral mediastinal nodes. Contralateral nodes were not resected. Bronchial stump was closed hand-sutured in all patients. We applied the “Overholt” technique after lobectomy/bilobectomy as well as after pneumonectomy. From 1996 onwards, the bronchial stump after pneumonectomy was routinely sutured with 2–0 monofilament, non-absorbal continuous horizontal mattress sutures, running at the length of the stump. After water testing with a pressure of 40 cm H2 O, a second layer with 4 or 5 single sutures followed. In 1993, we started to reinforce the bronchial stump individually and from 1996 obligatory with viable tissue. In patients after pneumonectomy, a reinforcement was performed with intercostal muscle flap (n=8), diaphragmatic muscle (n=6), and thymus/mediastinal fat (n=119). To reduce tissue oedema, prednisolone 1 mg/ kg body weight was administered for 3 days, already starting in the operating room. The overall blood loss was 360 ml (110–1720 ml); 121 patients had intraoperatively (n=24) or postoperatively (n=97) at least one blood transfusion (median 2.4 U, range 2–9 U). For the statistical analysis, data are presented as the mean ± standard deviation. The primary endpoints of analysis were length of hospital stay, occurrence of complications and mortality. The effects of risk factors on these endpoints are evaluated with univariate analysis first. Categorical variables were analysed by c2 test. Continuous variables were assessed by means of t-test, or by Mann–Whitney rank sum test, if the data did not follow a gaussian distribution. Variables were selected for multivariate analysis, if their P values were below 0.10 by univariate analysis.
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Multiple logistic regression was performed for multivariate analysis of risk factors. Correlation between variables and the length of hospital stay were analysed by using Pearson’s correlation coefficient. All tests were two-tailed and were performed by Statview version 5.0 statistical software (SAS Institute Inc., SAS Campus Drive, Cary, NC 27513, USA). Differences were considered significant with p<0.05.
3. Results The overall hospital mortality rate was 4.6% (n=18). 7.1% of the patients died after pneumonectomy, 3.6% after lobectomy/bilobectomy. The causes of death were sepsis (n=5), pneumonia and respiratory failure (n=4), ARDS (n=3), cardiac failure (n=3), and lung embolism (n=3). Univariate analysis demonstrated that higher age (p=0.0312) and lower Karnofsky index (p<0.0001) adversely affected incidence of mortality. Multivariate analysis extracted lower Karnofsky index (p=0.0008) to be a significant risk factor for mortality. There was neither a significant difference (c2 test) with regard to the side (p=0.3483) or to the type of resection (pneumonectomies versus lobectomies p=0.6572), nor to the amount of blood transfusion (p=0.2457). 180 patients (46%) developed one or more early or late complications (Table 2). The most common complications were arrhythmia (41 patients, 10.6%), air leakage longer than 7 days (34 patients, 8.5%), pneumonia (19 patients, 4.8%), atelectasis with more than one bronchoscopic suction (19 patients, 4.8%), septic complications as bronchopleural fistula (BPF) (16 patients, 3.2%), and empyema without BPF (6 patients, 1.6%). Arrhythmia occurred in all patients within the Table 2 Postoperative complications in 180 patients (46%) n
%
Arrhythmia
41
10.6
Pneumonia
19
4.8
Atelectasis
17
4.5
BPF
16
3.2
6
1.6
Complication
Empyema without BPF Air leakage>7d
34
8.7
Persistent pleural space
11
2.8
Pulmonary embolism
6
1.5
Postoperative bleeding
10
2.5
ICU syndrome
11
2.8
Chylothorax
6
1.5
Recurrens nerve palsy
3
0.8
S110 first 72 hours and was treated with digitoxin and verapamil. Abnormal findings in echocardiography before surgery were risk factors for postoperative arrhythmia with statistical significance (p<0.0001). Air leakage from lung parenchyma was more common than in historical groups without induction therapy and resulted in a longer hospital stay of 15.9±10.5 days (range, 7–163 days). Postoperative bleeding, requiring re-thoracotomy, occurred in 10 patients (6 after lobectomy and 4 after pneumonectomy). The cause was found only in 4 cases (1 bronchial, 2 intercostal and 1 oesophageal artery, respectively); in the other 6 patients haematothorax was concerned to diffused bleeding after extended adhesiolysis. Bronchopleural fistulas occurred between days 6 and 28: in 16 patients after resection, in 12 after pneumonectomy, in 10 on the right side, in 2 on the left side, in 4 after lower lobectomy, and in 2 in each side. Statistical analysis (c2 test) showed that only the stumpcovering technique at the operation with viable tissue effected a prevention of BPF with statistical significance (p=0.0321). BPF resulted in sepsis and death of 5 patients (4 after pneumonectomy, 1 after lobectomy). Our attempt to close the fistula with diaphragmatic muscle (n=2) or intercostal muscle (n=3) was of short duration, so that open thoracostomy in all cases was necessary. 11 patients who survived these complications were treated by partial thoracoplasty in combination with muscle latissimus dorsi transposition. Empyema without BPF was observed in 6 patients (4 after lobectomy, 1 after bilobectomy and 1 after pneumonectomy). Thoracoscopic debridement was done and chest tube was placed, followed by daily irrigation with 1000 ml saline solution. The actuarial survival rate for stage IIIA was 36% at five years, 31% at seven years, with a median survival of 22 months. For stage IIIB, both fiveand seven-year survival was 26%, with a median survival of 18 months. The corresponding rates were 45% and 42% for R0-resected patients in stage IIIA and 38% and 33% in stage IIIB. No difference was observed between patients with R0 resection and those with pathological complete response (pCR).
4. Discussion Recent experiences in two small randomised trials, reported for stage IIIA, have shown that an early inclusion of systemic treatment into the management of locally advanced NSCLC is feasible and effective, and leads to a significant increase of survival. Other investigators have focussed on
G. Stamatis et al. an early intensification of preoperative downstaging by so-called “bimodality induction”, including chemotherapy as well as radiation therapy prior to surgery [11–14]. This approach seems to be especially attractive for more locally advanced selected IIIB subgroups, where a maximum of preoperative downstaging is mandatory in order to enable a complete resection of any vital tumour, left after induction – mostly at areas of bulky disease in the primary tumour or the mediastinum. In spite of all these promising reports, some groups observed an increased morbidity and mortality, especially in patients after pneumonectomy, suggesting a higher risk after induction treatment [15–17]. Fowler et al. [15] in a small series with 13 patients reported an overall perioperative mortality of 23% (43% occurring after pneumonectomy). They used an aggressive protocol with high-dose concomitant thoracic irradiation of 60 Gy. Abolhoda et al. [16] found that right pneumonectomy was the only predictor of postoperative mortality in a large series of 471 patients. Doddoli et al. [17] reported an in-hospital mortality of 9% for all patients and 14% for right pneumonectomy, from respiratory origin in all cases. Contrary to these reports, other groups observed lower mortality rates of 5.7% (only after lobectomy) [18] and 5.3% (mainly after pneumonectomy) [19]. In our series, overall in-hospital mortality rate was 4.6%. Since patients who require pulmonary resection for lung cancer often have a pre-existent chronic obstructive and/or cardiopulmonary disease, pulmonary and cardiovascular complications were most frequent in our series, amounting to 90% of all complications [20]. Even if smokers and patients with chronic obstructive disease participated in an intensive training and inhalative treatment with bronchodilatators before surgery, complications such as pneumonia and atelectasis, requiring bronchoscopy, were common. Despite a meticulous preparation of interlobar fissure or adhesiolysis, the incidence of air leakage after lobectomy or bilobectomy was higher than in historical collectives without induction, probably due to the tissue damage caused by radiotherapy. Also, changes in the structure of interlobar and hilar nodes after chemo–radiotherapy, especially in patients with SCLC, resulted in lung parenchyma injury during their removal with prolonged postoperative air leakage. The hospital stay of 15.9 days compares with other reports [21]. Arrhythmia occurred in 10.6% of all patients, in 26.7% after pneumonectomy. Because of the generally known toxicity of chemotherapeutic drugs to myocardium, all patients were investigated before surgery with echocardiography, and with
Surgery after multimodality treatment for non-small-cell lung cancer stress electrocardiogram. We found that pathological echocardiography was a risk factor for postoperative arrhythmia with statistical significance. Even if our induction protocol included for all patients a preoperative radiotherapy, the incidence of BPF of 3.2% compares favourably to that reported by others [15,17,22,23]. We suppose that aggressive lymph-node resection with removal of the surrounding fat tissue and de-vitalisation of peribronchial tissue, in addition to high-dose radiotherapy of more than 45 Gy, are important factors for the development of bronchial fistulas. Therefore, we decided in our protocols to give all patients a standard dose of radiation of 45 Gy and to preserve as much peribronchial and peritracheal tissue as possible. Lymphadenectomy was performed only ipsilateral. Patients who still suffered from N3 disease in the repeated mediastinoscopy were excluded from surgery. Finally, the analysis of our data showed that bronchial stump covering technique is an effective BPF-preventing procedure with statistical significance. In order to reinforce bronchial stump after pneumonectomy, we favour the use of a flap of mediastinal fat/thymus tissue. The blood supply from the pericardiophrenic artery is excellent and the tissue volume sufficient. In a prospective study with 50 patients after preoperative chemoradiotherapy and pneumonectomy, a normal bronchial healing was observed – in all cases without BPF. Re-intervention, caused by postoperative bleeding, was observed in 2.5% of the cases. We tend to re-operate the patients as early as possible so as to reduce further complications. Statistical analysis showed that postoperative bleeding rates did not affect the morbidity and mortality. Long-term survival at 5 and 7 years of 36% and 31% for stage IIIA and 26% for stage IIIB looks very promising for these advanced-stage subgroups. So far, prognosis of our patients with T4, N2 and N3 disease are comparable. Long-term survival became possible in T4N0/1, T2–4N2 or T1/2N3. The only group with more unfavourable prognosis seems to be that with a combination of higher T and N stages (T3–4N2 and T3–4N3). These were also the groups with the lowest rate of complete resection after induction (35%). It is still not clear whether – following such an intensive preoperative downstaging – the extent of resection can be confined to the primary tumour and the ipsilateral mediastinal nodes, or whether one has to include the contralateral mediastinum in order to achieve an anatomically complete resection of initially involved tissue. Our relapse pattern in patients with N2 and N3 nodes proves that local or locoregional relapse in the
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succession of negative re-biopsies of contralateral nodes is rarely observed. Induction treatment turned out to be much more effective in the mediastinum (69% initially involved N2/N3 nodes free of cancer) than at the primary tumour site (21% pathological complete responses). However, the SWOG database did concisely show that N2 or N3 disease at thoracotomy was the most significant negative prognostic factor for postoperative survival duration and prognosis in their patients. Different to our results, SWOG did find significantly better survival results for the stage subgroup T4N0/1. Other investigators, Choi from Boston and Grunenwald from Paris, have also included IIIB patients into tri-modality protocols (T4 as well as N3), comparable to our trial and that of SWOG [8,9,14]. However, in the Boston study the induction chemoradiotherapy was more intensive with a complex irradiation scheme of combining once- with twice-daily irradiation up to 60 Gy. The Paris trial had comparable radiation doses preoperatively (45 Gy), but included a more complex and more extensive surgical approach (sternotomy). They reported a complete resection rate of 57% among 30 patients and a three-year actuarial survival rate of 25% [14]. Choi found among 26 IIIB patients (T4 or N3) a complete resection rate of 52% and an actuarial three-year survival of 52% [9].
5. Conclusion Our analysis demonstrates that in patients with locally advanced lung cancer and induction chemo– radiotherapy, surgery can be feasible with acceptable mortality but increased morbidity. Patient selection for surgery after accurate cardiopulmonary evaluation and standard operative technique with reinforcement of bronchial stump or anastomosis with sufficient tissue can contribute to reduce complications. Long-term survival rates, now achievable with multimodality treatment and surgery for selected groups, look very promising when compared to historical controls.
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