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Surgical treatment of stage III non-small cell lung cancer
Lung Cancer 34 (2001) S137– S143
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Surgical treatment of stage III non-small cell lung cancer Tadeusz M. Orlowski *, Tomasz J. Szczesny Department of Surgery, Institute of Lung Diseases and Tuberculosis, Ptocka St. 26, 01 -138 Warsaw, Poland
Abstract The resectability of NSCLC is determined by its stage. The surgical treatment in stage I and II NSCLC remains a golden standard. Stage IIIA NSCLC constitutes a non-homogenous group, and many patients are potentially non-resectable. The patients in stage IIIA NSCLC also constitute a non-homogenous group. The patients in stage T3N1 usually undergo surgical resection, but many patients with N2 disease are disqualified from surgical treatment due to the negative prognostic factors. The negative prognostic factors comprise: (1) metastases to upper paratracheal (no 2), anterior paratracheal (no 3), and subcarinal (no 7) lymph nodes; (2) metastases to multiple mediastinal lymph nodes; (3) occurrence of the so called ‘bulky disease’; (4) capsular lymph node invasion. The occurrence of one of these negative prognostic factors disqualifies the patient with N2 disease from radical surgical treatment. In more advanced cases, i.e. stage IIIB, and stage IV NSCLC, patients are rarely operated. It regards the patients in stage T4 N1, and in M1 disease with a single metastasis (mainly to CNS) accompanied by the stage I, or II, of the primary focus. In these cases N2 disease always constitutes the contraindication to the surgical treatment. Multidisciplinary approach in the treatment of NSCLC is supposed to improve the results of the treatment of NSCLC. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lung cancer; Surgery; Staging; Prognosis
1. Introduction Since the first successful one-stage resection performed for a primary lung cancer by Graham and Singer [1], surgery remains the most effective and best tolerated treatment option in patients with non-small cell lung cancer (NSCLC). Today, our knowledge is enriched with the experience of three generations of thoracic surgeons. During the last 70 years much was learned about the criteria of susceptibility to different treatment options: surgery, radiotherapy and chemotherapy. Specialists involved in the treatment of lung cancer are also more conscious about the factors influencing development of serious complications of treatment as well as how to avoid them. For the entire population of lung cancer patients the early diagnosis remains the best method to improve the overall survival. However, a better assessment which patients are best candidates for surgery or other methods of treatment allows to improve results within the treated * Corresponding author. Tel.: + 48-22-6912266; fax: +48-226912455. E-mail address: [email protected] (T.M. Orlowski).
groups. This becomes especially important in patients with locally advanced disease for whom all pros and contras must be balanced in order to choose the optimal treatment option. Preoperative staging, with the use of TNM staging system [2] remains the best tool for preoperative assessment of the extent of disease. Contemporary criteria of the assessment of extent of disease are based mostly on data from imaging procedures, such as chest radiograms, computer tomography, MRI, bone scan and positron emission tomography (PET). These procedures enable to visualize major metastases to regional lymph nodes (N2, N3) as well as involvement of the adjacent organs (T3, T4) and hematogenous metastases (T4, if metastasis to the same lobe is present and M1 for other metastases). Surgical preoperative staging incorporates also invasive staging procedures, i.e. cervical mediastinoscopy, parasternal mediastinotomy, videothoracoscopy and peripheral lymph node biopsy. However, it must be emphasized that up to now no reliable procedures detecting micrometastases and occult metastases (not detectable by imaging procedures) are available. The search of such procedures remains an important goal for future investigations.
0169-5002/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 1 ) 0 0 3 5 8 - 0
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Table 2 Correlation between the diameter of lymph nodes in chest CT and the rate of malignant involvement [4]
Table 1 Classification of stage III lung cancer IA IB IIA IIB IIIA IIIB
IV
T1N0M0 T2N0M0 T1N1M0 T2N1M0 T3N1M0 T2N2M0 T4N0M0 T4N2M0 T2N3M0 T4N3M0 Every M1
T3N0M0 T1N2M0 T3N2M0 T4N1M0 T1N3M0 T3N3M0
Even in the developed countries, only less than 30% of patients with NSCLC are candidates for surgical curative resection. About 80% of them present a stage I or II disease at the time of diagnosis. The remaining 20% are patients with locally advanced (stage III) or disseminated (stage IV) lung cancer. Stage III disease is subdivided into stage IIIA (limited to one hemithorax and not involving vital organs) and IIIB (metastases to contralateral mediastinal lymph nodes and/ or direct involvement of the vital organs) (Table 1). Resectable cases can be found in both these subgroups. Treatment of patients with stage III disease is often a matter of choice between extended surgical resection and other methods of antineoplasmatic treatment i.e. radiotherapy and/or chemotherapy. Another dilemma is whether these patients should be treated with surgery alone or with a multidisciplinary approach incorporating pre- or postoperative treatment.
2. Mediastinal lymph node involvement
2.1. N2 disease Surgical treatment of patients with ipsilateral mediastinal lymph node involvement (N2) is still controversial. There is a general agreement that a 5-year survival rate does not exceed 5% in a group with bulky N2 disease, capsular infiltration, involvement of multiple lymph node stations and involvement of subcarinal lymph nodes [3]. There is a correlation between the diameter of mediastinal lymph nodes and a probability of their malignant involvement [4] (Table 2). An introduction of PET enabled more accurate diagnosis of mediastinal node involvement than does routine chest CT [5]. An American meta-analysis shows that the accuracy of PET is higher than that of chest CT in predicting metastases to mediastinal lymph nodes [6]. Cervical mediastinoscopy, originally described by Carlens [7] became in the 1970s a routinely performed surgical staging procedure in many leading centers.
Diameter of lymph node
% of malignant involvement
B10 mm 10–19 mm \20 mm Bulky\50 mm
2.7 31.8 69.6 100.0
Although routine mediastinoscopy did not result in longer overall survival of lung cancer patients, it decreased the rate of explorative thoracotomies [8] and allowed to define a group of patients with a better prognosis, who did not have metastases to lymph nodes confirmed in mediastinoscopy and eventually had only metastases found in a postoperative specimen. Subsequently it resulted in a higher 5-year survival rate of patients submitted to surgical resection (24 vs 9%) [9]. The use of cervical mediastinoscopy also enabled to distinguish new categories of patients, with the involvement of a single lymph node, termed ‘minimal N2 disease’, and with lymph nodes not enlarged in CT scans, termed ‘pathological N2 disease’. An analysis of these groups treated with surgery alone showed that a 20% 5-year survival rate was achieved [10], in contrast with patients with ‘clinical N2 disease’ who have enlarged mediastinal lymph nodes detected in chest CT and confirmed with mediastinoscopy, and have apparently a worse prognosis. Despite a relatively poor outcome of patients with ipsilateral lymph node involvement, most of experienced thoracic surgeons continue to operate these patients. They believe that a successful treatment is possible with the surgical removal of mediastinal lymph nodes. In most of thoracic surgical centers some methods of mediastinal lymph node dissection are performed. The most popular seems to be lymph node sampling, i.e. removal of all visible/enlarged lymph nodes from the ipsilateral mediastinum. The accuracy of nodal sampling is variable, highly depending upon the surgeon’s assessment. For the right upper mediastinum a technique of systematic mediastinal lymph node dissection (systematic-MLND) was introduced by Cahan [11,12]. This technique enables a complete removal of 25–40 lymph nodes from groups 1, 2R, 3, 4R and 7 [13]. However, this technique is easy to perform only through postero-lateral thoracotomy (recently less popular in most centers in Europe and North America) while muscle-sparing surgical incisions (anterolateral thoracotomy, vertical thoracotomy, VATS, etc.) make systematic-MLND much more challenging. SystematicMLND results in about 30% 5-year survival rate in patients with pathologically confirmed metastases to N2 nodes [3] and even 43% 5-year survival rate if only
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one mediastinal lymph node is involved [13]. Recent data comparing the efficacy of systematic MLND with mediastinal node sampling show a significant difference in median survival, 66.4 and 24.5 months, respectively [14].
2.2. N3 disease It must be emphasized that metastases to contralateral mediastinal lymph nodes (N3) are thought by most surgeons to be a contraindication to curative surgery. Although involvement of N3 lymph nodes was traditionally believed to be connected to 0% cure rate [15], some surgeons continue to operate these patients. Two rationales and two therapeutic approaches can be distinguished. First, assuming that preoperative treatment (chemoradiotherapy) is able to sterilize contralateral lymph nodes [16,17]; and second, based on anatomical considerations that in the superior mediastinum the lymphatic drainage, especially from the lower lobe of the left lung, is directed to contralateral lymph node stations [18–20]. The first approach resulted in several trials assessing the value of preoperative chemoradiotherapy. In a phase I study conducted by Southwest Oncology Group a 25% 2-year survival and a median survival of 13 months were achieved [16]. In another study 78% of patients were operated on after an initial treatment and among them a 72% rate of mediastinal complete response rate was noted [17]. Distant metastases were the most common pattern of failure. The second approach resulted in introducing bilateral mediastinal lymphadenectomy, either through median sternotomy or through left hemiclamshell incision. In a pilot study Hata et al. noted a 60% 2-year survival rate [21]. However, an elevated risk of bronchopleural fistula occurs, especially in patients who received preoperative radiotherapy [22,23].
3. Vital organs involvement: resectable T4 disease Even relatively small tumors arising from the lung can directly invade vital organs localized in the mediastinum. Most of these patients are not amenable to curative resection. For patients in a good performance status and without distant metastases radical chemoand/or radiotherapy is a valuable alternative. However, late results of radical non-surgical treatment of these cases remain unsatisfactory [24].
3.1. Heart When the tumor either directly involves the pericardium, forshortens the pulmonary veins, invades the proximal portion of superior vena cava or pulmonary
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artery, or invades the left atrium, it becomes necessary to open the pericardium and to complete the resection via an intrapericardial approach. Direct infiltration of ventricles occurs rarely and obviously is not amenable to resection. It can be diagnosed preoperatively by echocardiography, transesophageal ultrasonography (EUS) or chest MRI. In our experience, chest CT scans are of lesser value in detecting direct invasion of ventricles. Results of intrapericardial resection are good only for tumors invading pulmonary veins [25], while infiltration of atrium is usually connected with poor prognosis [26].
3.2. Great 6essels Direct invasion of the main stem of pulmonary artery is obviously a contraindication for surgical treatment. Intrapericardial involvement of right and left pulmonary arteries is considered to be T4 disease. If a left pulmonary artery is involved, it is relatively easy to clamp its origin and resect the involved portion with maintenance of a sufficient oncological margin. The introduction of staplers made this maneuver even more feasible. The right pulmonary artery is hidden behind the superior vena cava, and has a short extrapericardial part. Therefore, in case of its invasion it is usually impossible to dissect it safely. In few cases amenable to resection, a surgical approach can be best achieved through a midline sternotomy. Infiltration of an aortic arch and arteries originating from it is usually a contraindication for surgery. In some cases, when only vascular adventitia is involved, it is possible to ‘peel’ the tumor out from the aortic arch. However, these cases should be considered as T3 rather than T4 disease. A true involvement of the aortic arch can be operated on only in young and generally fit patients, with the use of extracorporeal circulation. Some long-term survivors after such treatment were observed [27]. Infiltration of descending aorta is usually believed to be a contraindication to surgical resection. Development of a spinal chord ischemia as a commonest complication makes late results of this treatment extremely poor. Tumors invading the superior vena cava can be successfully resected either by marginal clamping and partial resection of the vascular wall or circumferential resection with subsequent reconstruction with ring-reinforced polytetrafluoroethylene grafts. The main problem after this treatment remains a need for a persistent anticoagulation to maintain the patency of low-pressure grafts. However, late results are encouraging, even in patients with concomitant sleeve pulmonary resection [28], with an over 20% 5-year survival rate [29]. An obvious contraindication to all vascular resections is an invasion of large vessels by tumor extending from bulky N2 disease. This must be distinguished from a direct tumor infiltration.
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3.3. Trachea and carina Patients with tumors invading the tracheal bifurcation, especially the right tracheobronchial angle, can be considered candidates for sleeve pneumonectomy, with a primary end-to-end tracheobronchial anastomosis. Some authors believe that this operation should not be contraindicated in patients with metastases to adjacent (subcarinal and ipsilateral paratracheal) lymph nodes [30]. Because carinal resection in lung cancer patients is possible only through right thoracotomy, therefore left sleeve pneumonectomy requires bilateral approach and is rarely performed. A preoperative treatment, consisting of chemo- or chemoradiotherapy is recommended [31]. Either high frequency ventilation, a single-lumen endotracheal tube or a sterile second endotracheal tube intermittently passed over the operating field are necessary for this kind of resection. A frozen section of resection margins is obligatory. Complications after sleeve pneumonectomy are common and a high operative mortality is reported, ranging from 11 to 25% [32]. The largest reported series consists of 55 cases, with a 23% 5-year survival rate. Surprisingly, longer survivals were achieved in patients with subcarinal (MS =33 months) than paratracheal nodal metastases (MS =11 months) [33].
3.4. Esophagus Despite some exceptional reported acses [34], the direct invasion of esophagus present at the preoperative assessment is considered to be a definitive contraindication to surgery [23].
3.5. Vertebrae Recent advances in spinal surgery have greatly changed the prognosis for patients with vertebral bodies’ involvement. A novel, two-stage operative technique was established [35]. It consists of arteriografic visualization with eventual embolization and subsequent en bloc partial or total resection of vertebral body, together with anatomical resection of lung parenchyma. An overall estimated 3-year survival of 35% was achieved in a group of 12 patients treated in Institut Montsouris in France [36]
3.6. Malignant effusion Although malignant effusion, confirmed either cytologically or pathologically (in patients after diagnostic videothoracoscopy), is generally not amenable to surgical resection, attempts are continued to treat some of these patients operatively. Candidates for this kind of treatment usually have a small, peripheral adeno-
carcinoma producing a pleural effusion and pleural dissemination. Ichinose et al. reported a series of patients treated by anatomical resection plus pleurectomy. They report a 20% long-term survival in patients without lymph node involvement [37].
3.7. Superior sulcus tumor Direct invasion of the chest wall, especially superior sulcus tumor, was traditionally connected with poor outcome [38]. However, introduction of preoperative radiotherapy [39] and improvement of surgical techniques [40,41] resulted in better prognosis of patients with Pancoast tumors. Thus, infiltration of the chest wall, including superior sulcus tumors, is contemporarily classified as T3 disease, despite the extended operation needed for cure. Only patients with accompanying infiltration of the vertebral column are classified as T4 disease. Furthermore, because of better prognosis, in the last classification [42] T3N0 tumors became incorporated into a newly formed stage IIB. However, a need for extended resection and multimodality approach justifies the incorporation of these tumors into the present paper. Superior sulcus tumors were traditionally connected with squamous histology, but the latest data show that also in this localization adenocarcinoma becomes the most common histological pattern [43]. Although preoperative radiotherapy, introduced by Paulson, was a golden standard for a quarter of the century, today many surgeons prefer postoperative radiotherapy with equally good results [43,44]. Attempts to add brachytherapy to therapeutic regimen did not prolong survival nor improve the local control [45]. Data concerning preoperative chemotherapy or chemoradiotherapy are limited, but on the basis of small series it can be expected that induction chemoradiotherapy may improve the likelihood of pathologic complete response, local control, and overall survival [46]. Most surgeons agree that involvement of thoracic vertebrae (T4) is a frank contraindication to surgical resection, although early results of some novel approaches are encouraging [35,47]. The value of routinely performed mediastinoscopy is emphasized, due to extremely poor prognosis in T3N2 patients [43]. The role of a proper surgical approach is especially important because completeness of surgical resection remains one of three main prognostic factors (beside N2 disease and involvement of vertebral body) [39,43]. Most of Pancoast tumors arise in the posterior part of the thoracic outlet and in these cases a standard postero-lateral thoracotomy remains an incision of choice. For tumors localized in the anterior part a transcervical approach provides better visualization.
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4. Multidisciplinary approach in the treatment of stage III NSCLC A retrospective analysis of non-small cell lung cancer treated by surgery alone shows an unsatisfactory level of recurrences. The analysis of relapse patterns disclosed that most of patients died of distant metastases, despite an efficient local control of the disease [48,49]. Therefore several attempts were made to diminish the rate of local and distant recurrences. The most promising seemed the addition of radiotherapy and/or chemotherapy either pre- or postoperatively.
4.1. Adju6ant radiotherapy Data from clinical trials and meta-analyses show that the use of thoracic irradiation after a complete resection results in a significant decrease of local recurrences [50,51]. However, the influence of thoracic irradiation on the long-term survival of these patients remains a matter of controversy. One of the reasons is that in retrospective analyses which proved a positive influence of radiotherapy on survival, the analyzed groups of patients (surgery vs surgery+RTH) were not comparable. Also a prospective study performed in USA did not show any impact of addition of RTH on survival [50]. Similar conclusions were made by authors of a British meta-analysis [52]. Results of this meta-analysis showed that postoperative radiotherapy in N0 and N1 patients resulted in shorter median survival than surgery alone. For N2 patients postoperative radiotherapy does not prolong survival. However, many patients included in this meta-analysis were treated with regimens which are today believed to be suboptimal. Probably recent advances in radiotherapy (conformal 3D planning, hyperfractionated radiotherapy, etc.) would allow to achieve lower rates of complications and local recurrences, and a better survival.
4.2. Adju6ant chemotherapy Unsatisfactory late results of surgical treatment of NSCLC (caused predominantly by distant metastases) resulted in a number of trials incorporating a systemic therapy. Early prospective randomized trials using noncisplatin based regimens often resulted in a significantly shorter survival in chemotherapy arm [53,54]. Even after introduction of cisplatin-based regimens, data available from postoperative chemotherapy trials show that this treatment is still controversial, [55]. The metaanalysis performed by Non-Small Cell Lung Cancer Collaborative Group [56] showed only a moderate improvement (by 5%) of median survival in a group treated with adjuvant chemotherapy. This tendency was not confirmed in prospective trials. [57]. Also for postoperative concommitant chemo-radiation no advantage
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over postoperative radiation was noted. The late results of large international prospective trials (ALPI, IALT, ANITA1, ANITA2) are still not available.
4.3. Neoadju6ant chemotherapy Promising results of chemotherapy in inoperable and disseminated NSCLC resulted in several prospective randomized trials in less advanced disease. Preoperative chemotherapy was expected to shrink the tumor and enable its surgical resection, as well as eradication of micrometastases responsible for development of distant metastases. The first two trials, performed by Rosell et al. [58] and Roth et al. [59] were interrupted because of big differences in survival in favor of the chemotherapy arm. Several other studies were also performed on unacceptably low number of patients. In most of the studies a better survival in patients treated with preoperative chemotherapy is observed, especially in patients who responded on preoperative treatment [60–63]. In order to confirm these results on a large group of patients, and to assess the effectiveness of chemotherapy in less advenced disease (IB and IIA) an international study is designed by Depierre et al. [64]. Early results are moderately encouraging.
4.4. Neoadju6ant chemoradiotherapy Early results of trials on preoperative chemoradiotherapy show that a further progress in late results of treatment can be expected. [65–69].The median survival after induction chemoradiotherapy achieved in these trials ranged between 13 and 25 months, and the 5-year survival rate between 22 and 37%. These results are better than in groups treated with chemotherapy alone. However, this difference can be greatly explained by more rigorous accrual of patients (better performance status). Additionally, this more aggressive treatment is more likely to cause side effects. This can highly influence median survival, especially in elderly patients and patients with underlying disease. Therefore preoperative chemoradiotherapy is not recommended for a routine use outside clinical trials.
4.5. Adju6ant PCI in patients with completely resected NSCLC An analysis of the patterns of relapse of resected stage IIIA NSCLC patients shows that brain metastases are a common site of relapse. Brain metastases occur more often in stage IIIA N2 patients who were treated with preoperative chemotherapy than in patients treated with surgery alone (32 and 18%, respectively). This difference was even more astonishing for isolated brain metastases (22 and 11% respectively). Brain metastases also appear to be more common in patients
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with adenocarcinoma subtype [70]. The phenomenon of increased rate of brain metastases in cN2 patients treated with preoperative chemotherapy, comparing to metastases to other organs, can be explained by lower cisplatin concentrations in the normal brain comparing with other tissues. The brain is considered to be a sanctuary site for chemotherapy. Because of promising data from a recent meta-analysis concerning prophylactic cranial irradiation (PCI) in limited disease SCLC patients who achieved a complete response after chemotherapy and chest radiotherapy (approximately 4% survival improvement at 5 years) [71], PCI was used in 47 locally advanced NSCLC patients treated with a multidisciplinary approach [72]. In this study PCI reduced the rate of brain metastases as a first site of relapse from 30 to 8%, respectively at 4 years, and overall brain relapse from 54 to 13%. Neuropsychologic tests and imaging data performed in 18 long-term survivors showed that a regimen consisting of 30Gy administered in 15 fractions (2Gy per fraction) did not cause any serious malfunctioning of the central nervous system. References [1] Graham EA, Singer JJ. Successful removal of an entire lung for carcinoma of the bronchus. J Am Med Assoc 1933;101:1371. [2] Mountain CF. Prognostic implication of the international staging system for lung cancer. Sem Oncol 1988;15:236 –45. [3] Martini N. Mediastinal lymph node dissection for lung cancer — the memorial experience. Chest Surg Clin North Am 1995;5:189 – 202. [4] Whittlesey D. Prospective computed tomografic scanning in the staging of bronchogenic cancer. J Thorac Cardiovasc Surg 1988;95:876 – 82. [5] Schiepers C., Cameron R, Yap C, et al., Impact of metabolic imaging on staging of newly diagnosed and recurrent lung cancer. Proceedings of ASCO 2001, Abstract. [6] Al-Sugair A, Coleman RE. Applications of PET in lung cancer. Semin Nucl Med 1998;4:303 –19. [7] Carlens E. Mediastinoscopy: a method for inspection and tissue biopsy in the superior mediastinum. Dis Chest 1959;36:343. [8] Nohl-Oser HC. The long-term survival of patients with lung cancer treated surgically after selection by mediastinoscopy. J Thorac Cardiovasc Surg 1980;28(3):158 –61. [9] Pearson FG, Delarue NC, Ilves R, Todd TR, Cooper JD. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg 1982;83:1 – 11. [10] Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000;18:2981 – 9. [11] Cahan WG. Radical lobectomy. J Thorac Cardiovasc Surg 1960;39:555 – 72. [12] Cahan WG, Watson WL, Pool JL. Radical pneumonectomy. J Thorac Surg 1951;22:449 –73. [13] Martini N, Flehinger BJ. The role of surgery of N2 lung cancer. Surg Clin North Am 1987;67:1037 – 49. [14] Keller S, Adak S, Wagner H, Johnson D. Mediastinal lymph node dissection improves survival in patients with stages II and IIIA non-small cell lung cancer. Ann Thorac Surg 2000;70:358 – 66.
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[57] Keller SM, Adjak S, Wagner H, et al. Prospective randomized trial of postoperative adjuvant therapy in patients with completely resected stages II and IIIa, non-small cell lung cancer. An Intergroup trial (E3590). N Engl J Med 2000;243:1217 –22. [58] 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. [59] Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994;86:673 – 80. [60] 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. [61] Martini N, Kris MG, Flehinger BJ, et al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993;55:1365 – 74. [62] Mathisen DJ, et al. Assessment of preoperative accelerated radiotherapy and chemotherapy in stage IIIA (N2) non-small-cell lung cancer. J Thorac Cardiovasc Surg 1996;111:123 – 33. [63] Sugarbaker DJ, Herdon J, Kohman IJ, et al. Results of Cancer and Leukemia Group B Protocol 8935. A multiinstitutional phase II trimodality trial for stage IIIA (N2) non-small-cell lung cancer. J Thorac Cardiovasc Surg 1995;109:473 – 85. [64] Depierre A, Milleron B, Moro D. Phase III trial of neo-adjuvant chemotherapy in resectable stage I (except T1N0), II, IIIA non-small cell lung cancer: the French experience. Proc Am Soc Clin Oncol 1999;18:465a Abstr.1792. [65] Albain K, Rusch V, Crowley J, et al. Concurrent cisplatin/ etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB (N3) non-small-cell lung cancer; Mature results of SWOG 8805. J Clin Oncol 1995;13:1880 – 92. [66] Eberhardt W, Wilke H, Stusche M, et al. Preoperative chemotherapy and concurrent chemoradiotherapy based on hyperfractionated accelerated radiotherapy followed by surgery in locally advanced inoperable non-small-cell lung cancer stages IIIA and IIIB. Proc Am Soc Clin Oncol 1997;16:1650 abstr. [67] Rush VW, Albain KS, Crowley JJ, et al. Surgical resection of stage IIIA and IIIB non-small cell lung cancer after concurrent induction chemoradiotherapy: a Southwest Oncology Group trial. J Thorac Cardiovasc Surg 1993;105:97 – 106. [68] Strauss G, Herndon J, Sherman D, et al. Induction chemoradiation followed by surgery in stage IIIA non-small-cell lung cancer: long term results of CALGB 8634. Proc Am Soc Clin Oncol 1996;15:376 abstr. [69] Weiden P, Piantadosi S. Preoperative chemotherapy (cisplatin and fluorouracil) and radiation therapy in stage III non-smallcell lung cancer: a phase II study of the LCSG. J Natl Cancer Inst 1991;83:266 – 72. [70] Andre F, Grunenwald D, Pujol JL, et al. Patterns of relapse of N2 nonsmall-cell lung carcinoma patients treated with preoperative chemotherapy. Should prophylactic cranial irradiation be reconsidered? Cancer 2001;91:2394 – 400. [71] Arriagada R, Auperin A, Pignon JP, et al. Prophylactic cranial irradiation overview in patients with small cell lung cancer in complete remission. Proc Am Soc Clin Oncol 1998;17:457a. [72] Stuschke M, Eberhardt W, Poettgen C, et al. Prophylactic cranial irradiation in Locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects. J Clin Oncol 1999;17:2700 – 9.
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Surgical treatment of stage III non-small cell lung cancer Tadeusz M. Orlowski *, Tomasz J. Szczesny Department of Surgery, Institute of Lung Diseases and Tuberculosis, Ptocka St. 26, 01 -138 Warsaw, Poland
Abstract The resectability of NSCLC is determined by its stage. The surgical treatment in stage I and II NSCLC remains a golden standard. Stage IIIA NSCLC constitutes a non-homogenous group, and many patients are potentially non-resectable. The patients in stage IIIA NSCLC also constitute a non-homogenous group. The patients in stage T3N1 usually undergo surgical resection, but many patients with N2 disease are disqualified from surgical treatment due to the negative prognostic factors. The negative prognostic factors comprise: (1) metastases to upper paratracheal (no 2), anterior paratracheal (no 3), and subcarinal (no 7) lymph nodes; (2) metastases to multiple mediastinal lymph nodes; (3) occurrence of the so called ‘bulky disease’; (4) capsular lymph node invasion. The occurrence of one of these negative prognostic factors disqualifies the patient with N2 disease from radical surgical treatment. In more advanced cases, i.e. stage IIIB, and stage IV NSCLC, patients are rarely operated. It regards the patients in stage T4 N1, and in M1 disease with a single metastasis (mainly to CNS) accompanied by the stage I, or II, of the primary focus. In these cases N2 disease always constitutes the contraindication to the surgical treatment. Multidisciplinary approach in the treatment of NSCLC is supposed to improve the results of the treatment of NSCLC. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lung cancer; Surgery; Staging; Prognosis
1. Introduction Since the first successful one-stage resection performed for a primary lung cancer by Graham and Singer [1], surgery remains the most effective and best tolerated treatment option in patients with non-small cell lung cancer (NSCLC). Today, our knowledge is enriched with the experience of three generations of thoracic surgeons. During the last 70 years much was learned about the criteria of susceptibility to different treatment options: surgery, radiotherapy and chemotherapy. Specialists involved in the treatment of lung cancer are also more conscious about the factors influencing development of serious complications of treatment as well as how to avoid them. For the entire population of lung cancer patients the early diagnosis remains the best method to improve the overall survival. However, a better assessment which patients are best candidates for surgery or other methods of treatment allows to improve results within the treated * Corresponding author. Tel.: + 48-22-6912266; fax: +48-226912455. E-mail address: [email protected] (T.M. Orlowski).
groups. This becomes especially important in patients with locally advanced disease for whom all pros and contras must be balanced in order to choose the optimal treatment option. Preoperative staging, with the use of TNM staging system [2] remains the best tool for preoperative assessment of the extent of disease. Contemporary criteria of the assessment of extent of disease are based mostly on data from imaging procedures, such as chest radiograms, computer tomography, MRI, bone scan and positron emission tomography (PET). These procedures enable to visualize major metastases to regional lymph nodes (N2, N3) as well as involvement of the adjacent organs (T3, T4) and hematogenous metastases (T4, if metastasis to the same lobe is present and M1 for other metastases). Surgical preoperative staging incorporates also invasive staging procedures, i.e. cervical mediastinoscopy, parasternal mediastinotomy, videothoracoscopy and peripheral lymph node biopsy. However, it must be emphasized that up to now no reliable procedures detecting micrometastases and occult metastases (not detectable by imaging procedures) are available. The search of such procedures remains an important goal for future investigations.
0169-5002/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 1 ) 0 0 3 5 8 - 0
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Table 2 Correlation between the diameter of lymph nodes in chest CT and the rate of malignant involvement [4]
Table 1 Classification of stage III lung cancer IA IB IIA IIB IIIA IIIB
IV
T1N0M0 T2N0M0 T1N1M0 T2N1M0 T3N1M0 T2N2M0 T4N0M0 T4N2M0 T2N3M0 T4N3M0 Every M1
T3N0M0 T1N2M0 T3N2M0 T4N1M0 T1N3M0 T3N3M0
Even in the developed countries, only less than 30% of patients with NSCLC are candidates for surgical curative resection. About 80% of them present a stage I or II disease at the time of diagnosis. The remaining 20% are patients with locally advanced (stage III) or disseminated (stage IV) lung cancer. Stage III disease is subdivided into stage IIIA (limited to one hemithorax and not involving vital organs) and IIIB (metastases to contralateral mediastinal lymph nodes and/ or direct involvement of the vital organs) (Table 1). Resectable cases can be found in both these subgroups. Treatment of patients with stage III disease is often a matter of choice between extended surgical resection and other methods of antineoplasmatic treatment i.e. radiotherapy and/or chemotherapy. Another dilemma is whether these patients should be treated with surgery alone or with a multidisciplinary approach incorporating pre- or postoperative treatment.
2. Mediastinal lymph node involvement
2.1. N2 disease Surgical treatment of patients with ipsilateral mediastinal lymph node involvement (N2) is still controversial. There is a general agreement that a 5-year survival rate does not exceed 5% in a group with bulky N2 disease, capsular infiltration, involvement of multiple lymph node stations and involvement of subcarinal lymph nodes [3]. There is a correlation between the diameter of mediastinal lymph nodes and a probability of their malignant involvement [4] (Table 2). An introduction of PET enabled more accurate diagnosis of mediastinal node involvement than does routine chest CT [5]. An American meta-analysis shows that the accuracy of PET is higher than that of chest CT in predicting metastases to mediastinal lymph nodes [6]. Cervical mediastinoscopy, originally described by Carlens [7] became in the 1970s a routinely performed surgical staging procedure in many leading centers.
Diameter of lymph node
% of malignant involvement
B10 mm 10–19 mm \20 mm Bulky\50 mm
2.7 31.8 69.6 100.0
Although routine mediastinoscopy did not result in longer overall survival of lung cancer patients, it decreased the rate of explorative thoracotomies [8] and allowed to define a group of patients with a better prognosis, who did not have metastases to lymph nodes confirmed in mediastinoscopy and eventually had only metastases found in a postoperative specimen. Subsequently it resulted in a higher 5-year survival rate of patients submitted to surgical resection (24 vs 9%) [9]. The use of cervical mediastinoscopy also enabled to distinguish new categories of patients, with the involvement of a single lymph node, termed ‘minimal N2 disease’, and with lymph nodes not enlarged in CT scans, termed ‘pathological N2 disease’. An analysis of these groups treated with surgery alone showed that a 20% 5-year survival rate was achieved [10], in contrast with patients with ‘clinical N2 disease’ who have enlarged mediastinal lymph nodes detected in chest CT and confirmed with mediastinoscopy, and have apparently a worse prognosis. Despite a relatively poor outcome of patients with ipsilateral lymph node involvement, most of experienced thoracic surgeons continue to operate these patients. They believe that a successful treatment is possible with the surgical removal of mediastinal lymph nodes. In most of thoracic surgical centers some methods of mediastinal lymph node dissection are performed. The most popular seems to be lymph node sampling, i.e. removal of all visible/enlarged lymph nodes from the ipsilateral mediastinum. The accuracy of nodal sampling is variable, highly depending upon the surgeon’s assessment. For the right upper mediastinum a technique of systematic mediastinal lymph node dissection (systematic-MLND) was introduced by Cahan [11,12]. This technique enables a complete removal of 25–40 lymph nodes from groups 1, 2R, 3, 4R and 7 [13]. However, this technique is easy to perform only through postero-lateral thoracotomy (recently less popular in most centers in Europe and North America) while muscle-sparing surgical incisions (anterolateral thoracotomy, vertical thoracotomy, VATS, etc.) make systematic-MLND much more challenging. SystematicMLND results in about 30% 5-year survival rate in patients with pathologically confirmed metastases to N2 nodes [3] and even 43% 5-year survival rate if only
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one mediastinal lymph node is involved [13]. Recent data comparing the efficacy of systematic MLND with mediastinal node sampling show a significant difference in median survival, 66.4 and 24.5 months, respectively [14].
2.2. N3 disease It must be emphasized that metastases to contralateral mediastinal lymph nodes (N3) are thought by most surgeons to be a contraindication to curative surgery. Although involvement of N3 lymph nodes was traditionally believed to be connected to 0% cure rate [15], some surgeons continue to operate these patients. Two rationales and two therapeutic approaches can be distinguished. First, assuming that preoperative treatment (chemoradiotherapy) is able to sterilize contralateral lymph nodes [16,17]; and second, based on anatomical considerations that in the superior mediastinum the lymphatic drainage, especially from the lower lobe of the left lung, is directed to contralateral lymph node stations [18–20]. The first approach resulted in several trials assessing the value of preoperative chemoradiotherapy. In a phase I study conducted by Southwest Oncology Group a 25% 2-year survival and a median survival of 13 months were achieved [16]. In another study 78% of patients were operated on after an initial treatment and among them a 72% rate of mediastinal complete response rate was noted [17]. Distant metastases were the most common pattern of failure. The second approach resulted in introducing bilateral mediastinal lymphadenectomy, either through median sternotomy or through left hemiclamshell incision. In a pilot study Hata et al. noted a 60% 2-year survival rate [21]. However, an elevated risk of bronchopleural fistula occurs, especially in patients who received preoperative radiotherapy [22,23].
3. Vital organs involvement: resectable T4 disease Even relatively small tumors arising from the lung can directly invade vital organs localized in the mediastinum. Most of these patients are not amenable to curative resection. For patients in a good performance status and without distant metastases radical chemoand/or radiotherapy is a valuable alternative. However, late results of radical non-surgical treatment of these cases remain unsatisfactory [24].
3.1. Heart When the tumor either directly involves the pericardium, forshortens the pulmonary veins, invades the proximal portion of superior vena cava or pulmonary
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artery, or invades the left atrium, it becomes necessary to open the pericardium and to complete the resection via an intrapericardial approach. Direct infiltration of ventricles occurs rarely and obviously is not amenable to resection. It can be diagnosed preoperatively by echocardiography, transesophageal ultrasonography (EUS) or chest MRI. In our experience, chest CT scans are of lesser value in detecting direct invasion of ventricles. Results of intrapericardial resection are good only for tumors invading pulmonary veins [25], while infiltration of atrium is usually connected with poor prognosis [26].
3.2. Great 6essels Direct invasion of the main stem of pulmonary artery is obviously a contraindication for surgical treatment. Intrapericardial involvement of right and left pulmonary arteries is considered to be T4 disease. If a left pulmonary artery is involved, it is relatively easy to clamp its origin and resect the involved portion with maintenance of a sufficient oncological margin. The introduction of staplers made this maneuver even more feasible. The right pulmonary artery is hidden behind the superior vena cava, and has a short extrapericardial part. Therefore, in case of its invasion it is usually impossible to dissect it safely. In few cases amenable to resection, a surgical approach can be best achieved through a midline sternotomy. Infiltration of an aortic arch and arteries originating from it is usually a contraindication for surgery. In some cases, when only vascular adventitia is involved, it is possible to ‘peel’ the tumor out from the aortic arch. However, these cases should be considered as T3 rather than T4 disease. A true involvement of the aortic arch can be operated on only in young and generally fit patients, with the use of extracorporeal circulation. Some long-term survivors after such treatment were observed [27]. Infiltration of descending aorta is usually believed to be a contraindication to surgical resection. Development of a spinal chord ischemia as a commonest complication makes late results of this treatment extremely poor. Tumors invading the superior vena cava can be successfully resected either by marginal clamping and partial resection of the vascular wall or circumferential resection with subsequent reconstruction with ring-reinforced polytetrafluoroethylene grafts. The main problem after this treatment remains a need for a persistent anticoagulation to maintain the patency of low-pressure grafts. However, late results are encouraging, even in patients with concomitant sleeve pulmonary resection [28], with an over 20% 5-year survival rate [29]. An obvious contraindication to all vascular resections is an invasion of large vessels by tumor extending from bulky N2 disease. This must be distinguished from a direct tumor infiltration.
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3.3. Trachea and carina Patients with tumors invading the tracheal bifurcation, especially the right tracheobronchial angle, can be considered candidates for sleeve pneumonectomy, with a primary end-to-end tracheobronchial anastomosis. Some authors believe that this operation should not be contraindicated in patients with metastases to adjacent (subcarinal and ipsilateral paratracheal) lymph nodes [30]. Because carinal resection in lung cancer patients is possible only through right thoracotomy, therefore left sleeve pneumonectomy requires bilateral approach and is rarely performed. A preoperative treatment, consisting of chemo- or chemoradiotherapy is recommended [31]. Either high frequency ventilation, a single-lumen endotracheal tube or a sterile second endotracheal tube intermittently passed over the operating field are necessary for this kind of resection. A frozen section of resection margins is obligatory. Complications after sleeve pneumonectomy are common and a high operative mortality is reported, ranging from 11 to 25% [32]. The largest reported series consists of 55 cases, with a 23% 5-year survival rate. Surprisingly, longer survivals were achieved in patients with subcarinal (MS =33 months) than paratracheal nodal metastases (MS =11 months) [33].
3.4. Esophagus Despite some exceptional reported acses [34], the direct invasion of esophagus present at the preoperative assessment is considered to be a definitive contraindication to surgery [23].
3.5. Vertebrae Recent advances in spinal surgery have greatly changed the prognosis for patients with vertebral bodies’ involvement. A novel, two-stage operative technique was established [35]. It consists of arteriografic visualization with eventual embolization and subsequent en bloc partial or total resection of vertebral body, together with anatomical resection of lung parenchyma. An overall estimated 3-year survival of 35% was achieved in a group of 12 patients treated in Institut Montsouris in France [36]
3.6. Malignant effusion Although malignant effusion, confirmed either cytologically or pathologically (in patients after diagnostic videothoracoscopy), is generally not amenable to surgical resection, attempts are continued to treat some of these patients operatively. Candidates for this kind of treatment usually have a small, peripheral adeno-
carcinoma producing a pleural effusion and pleural dissemination. Ichinose et al. reported a series of patients treated by anatomical resection plus pleurectomy. They report a 20% long-term survival in patients without lymph node involvement [37].
3.7. Superior sulcus tumor Direct invasion of the chest wall, especially superior sulcus tumor, was traditionally connected with poor outcome [38]. However, introduction of preoperative radiotherapy [39] and improvement of surgical techniques [40,41] resulted in better prognosis of patients with Pancoast tumors. Thus, infiltration of the chest wall, including superior sulcus tumors, is contemporarily classified as T3 disease, despite the extended operation needed for cure. Only patients with accompanying infiltration of the vertebral column are classified as T4 disease. Furthermore, because of better prognosis, in the last classification [42] T3N0 tumors became incorporated into a newly formed stage IIB. However, a need for extended resection and multimodality approach justifies the incorporation of these tumors into the present paper. Superior sulcus tumors were traditionally connected with squamous histology, but the latest data show that also in this localization adenocarcinoma becomes the most common histological pattern [43]. Although preoperative radiotherapy, introduced by Paulson, was a golden standard for a quarter of the century, today many surgeons prefer postoperative radiotherapy with equally good results [43,44]. Attempts to add brachytherapy to therapeutic regimen did not prolong survival nor improve the local control [45]. Data concerning preoperative chemotherapy or chemoradiotherapy are limited, but on the basis of small series it can be expected that induction chemoradiotherapy may improve the likelihood of pathologic complete response, local control, and overall survival [46]. Most surgeons agree that involvement of thoracic vertebrae (T4) is a frank contraindication to surgical resection, although early results of some novel approaches are encouraging [35,47]. The value of routinely performed mediastinoscopy is emphasized, due to extremely poor prognosis in T3N2 patients [43]. The role of a proper surgical approach is especially important because completeness of surgical resection remains one of three main prognostic factors (beside N2 disease and involvement of vertebral body) [39,43]. Most of Pancoast tumors arise in the posterior part of the thoracic outlet and in these cases a standard postero-lateral thoracotomy remains an incision of choice. For tumors localized in the anterior part a transcervical approach provides better visualization.
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4. Multidisciplinary approach in the treatment of stage III NSCLC A retrospective analysis of non-small cell lung cancer treated by surgery alone shows an unsatisfactory level of recurrences. The analysis of relapse patterns disclosed that most of patients died of distant metastases, despite an efficient local control of the disease [48,49]. Therefore several attempts were made to diminish the rate of local and distant recurrences. The most promising seemed the addition of radiotherapy and/or chemotherapy either pre- or postoperatively.
4.1. Adju6ant radiotherapy Data from clinical trials and meta-analyses show that the use of thoracic irradiation after a complete resection results in a significant decrease of local recurrences [50,51]. However, the influence of thoracic irradiation on the long-term survival of these patients remains a matter of controversy. One of the reasons is that in retrospective analyses which proved a positive influence of radiotherapy on survival, the analyzed groups of patients (surgery vs surgery+RTH) were not comparable. Also a prospective study performed in USA did not show any impact of addition of RTH on survival [50]. Similar conclusions were made by authors of a British meta-analysis [52]. Results of this meta-analysis showed that postoperative radiotherapy in N0 and N1 patients resulted in shorter median survival than surgery alone. For N2 patients postoperative radiotherapy does not prolong survival. However, many patients included in this meta-analysis were treated with regimens which are today believed to be suboptimal. Probably recent advances in radiotherapy (conformal 3D planning, hyperfractionated radiotherapy, etc.) would allow to achieve lower rates of complications and local recurrences, and a better survival.
4.2. Adju6ant chemotherapy Unsatisfactory late results of surgical treatment of NSCLC (caused predominantly by distant metastases) resulted in a number of trials incorporating a systemic therapy. Early prospective randomized trials using noncisplatin based regimens often resulted in a significantly shorter survival in chemotherapy arm [53,54]. Even after introduction of cisplatin-based regimens, data available from postoperative chemotherapy trials show that this treatment is still controversial, [55]. The metaanalysis performed by Non-Small Cell Lung Cancer Collaborative Group [56] showed only a moderate improvement (by 5%) of median survival in a group treated with adjuvant chemotherapy. This tendency was not confirmed in prospective trials. [57]. Also for postoperative concommitant chemo-radiation no advantage
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over postoperative radiation was noted. The late results of large international prospective trials (ALPI, IALT, ANITA1, ANITA2) are still not available.
4.3. Neoadju6ant chemotherapy Promising results of chemotherapy in inoperable and disseminated NSCLC resulted in several prospective randomized trials in less advanced disease. Preoperative chemotherapy was expected to shrink the tumor and enable its surgical resection, as well as eradication of micrometastases responsible for development of distant metastases. The first two trials, performed by Rosell et al. [58] and Roth et al. [59] were interrupted because of big differences in survival in favor of the chemotherapy arm. Several other studies were also performed on unacceptably low number of patients. In most of the studies a better survival in patients treated with preoperative chemotherapy is observed, especially in patients who responded on preoperative treatment [60–63]. In order to confirm these results on a large group of patients, and to assess the effectiveness of chemotherapy in less advenced disease (IB and IIA) an international study is designed by Depierre et al. [64]. Early results are moderately encouraging.
4.4. Neoadju6ant chemoradiotherapy Early results of trials on preoperative chemoradiotherapy show that a further progress in late results of treatment can be expected. [65–69].The median survival after induction chemoradiotherapy achieved in these trials ranged between 13 and 25 months, and the 5-year survival rate between 22 and 37%. These results are better than in groups treated with chemotherapy alone. However, this difference can be greatly explained by more rigorous accrual of patients (better performance status). Additionally, this more aggressive treatment is more likely to cause side effects. This can highly influence median survival, especially in elderly patients and patients with underlying disease. Therefore preoperative chemoradiotherapy is not recommended for a routine use outside clinical trials.
4.5. Adju6ant PCI in patients with completely resected NSCLC An analysis of the patterns of relapse of resected stage IIIA NSCLC patients shows that brain metastases are a common site of relapse. Brain metastases occur more often in stage IIIA N2 patients who were treated with preoperative chemotherapy than in patients treated with surgery alone (32 and 18%, respectively). This difference was even more astonishing for isolated brain metastases (22 and 11% respectively). Brain metastases also appear to be more common in patients
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with adenocarcinoma subtype [70]. The phenomenon of increased rate of brain metastases in cN2 patients treated with preoperative chemotherapy, comparing to metastases to other organs, can be explained by lower cisplatin concentrations in the normal brain comparing with other tissues. The brain is considered to be a sanctuary site for chemotherapy. Because of promising data from a recent meta-analysis concerning prophylactic cranial irradiation (PCI) in limited disease SCLC patients who achieved a complete response after chemotherapy and chest radiotherapy (approximately 4% survival improvement at 5 years) [71], PCI was used in 47 locally advanced NSCLC patients treated with a multidisciplinary approach [72]. In this study PCI reduced the rate of brain metastases as a first site of relapse from 30 to 8%, respectively at 4 years, and overall brain relapse from 54 to 13%. Neuropsychologic tests and imaging data performed in 18 long-term survivors showed that a regimen consisting of 30Gy administered in 15 fractions (2Gy per fraction) did not cause any serious malfunctioning of the central nervous system. References [1] Graham EA, Singer JJ. Successful removal of an entire lung for carcinoma of the bronchus. J Am Med Assoc 1933;101:1371. [2] Mountain CF. Prognostic implication of the international staging system for lung cancer. Sem Oncol 1988;15:236 –45. [3] Martini N. Mediastinal lymph node dissection for lung cancer — the memorial experience. Chest Surg Clin North Am 1995;5:189 – 202. [4] Whittlesey D. Prospective computed tomografic scanning in the staging of bronchogenic cancer. J Thorac Cardiovasc Surg 1988;95:876 – 82. [5] Schiepers C., Cameron R, Yap C, et al., Impact of metabolic imaging on staging of newly diagnosed and recurrent lung cancer. Proceedings of ASCO 2001, Abstract. [6] Al-Sugair A, Coleman RE. Applications of PET in lung cancer. Semin Nucl Med 1998;4:303 –19. [7] Carlens E. Mediastinoscopy: a method for inspection and tissue biopsy in the superior mediastinum. Dis Chest 1959;36:343. [8] Nohl-Oser HC. The long-term survival of patients with lung cancer treated surgically after selection by mediastinoscopy. J Thorac Cardiovasc Surg 1980;28(3):158 –61. [9] Pearson FG, Delarue NC, Ilves R, Todd TR, Cooper JD. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg 1982;83:1 – 11. [10] Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000;18:2981 – 9. [11] Cahan WG. Radical lobectomy. J Thorac Cardiovasc Surg 1960;39:555 – 72. [12] Cahan WG, Watson WL, Pool JL. Radical pneumonectomy. J Thorac Surg 1951;22:449 –73. [13] Martini N, Flehinger BJ. The role of surgery of N2 lung cancer. Surg Clin North Am 1987;67:1037 – 49. [14] Keller S, Adak S, Wagner H, Johnson D. Mediastinal lymph node dissection improves survival in patients with stages II and IIIA non-small cell lung cancer. Ann Thorac Surg 2000;70:358 – 66.
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