1 Respiratory Oncology (Pulmonology), 2 Thoracic Surgery, 3 Radiotherapy and 4 Pathology, University Hospital Gasthuisberg, Catholic University, Leuven, Belgium
* Correspondence to: Dr J. Vansteenkiste, Respiratory Oncology Unit (Pulmonology), University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32-16-346802; Fax: +32-16-346803; Email: johan.vansteenkiste{at}uz.kuleuven.ac.be
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Abstract |
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Methods: Univariate and multivariate analyses were carried out on a prospective cohort of 131 mediastinoscopy-proven IIIA-N2 NSCLC patients. Three preoperative cycles of vindesineifosfamidecisplatin (VIP) were given. Patients with at least stable disease (SD) were considered for surgery, or radical radiotherapy in selected cases.
Results: The response rate after VIP was 54% (95% confidence interval 45% to 63%) and was important for the final outcome. The median and 5-year survival for the total group were 24 months and 21% (38 months and 30% in responders), respectively. Involvement of subcarinal nodes at diagnosis was the most important prognostic factor (P=0.022). Seventy-five patients were considered for surgery. Downstaging occurred in 34 of 70 resection specimens, with a pathological complete response in six. Median and 5-year survival in the surgical cohort were 45 months and 35%, respectively. Surgery was rewarding both in patients with a response and in those with SD, although the complete resection rate was significantly lower in the latter. On multivariate analysis, favourable prognostic factors were low pathological T-stage (P=0.001) and downstaging of mediastinal nodes in the resection specimen (P=0.008).
Conclusions: VIP induction chemotherapy followed by surgical exploration was rewarding in mediastinoscopy-proven stage IIIA-N2 NSCLC, both in cases of response and SD, despite a lower complete resection rate in the latter. Patients with subcarinal nodes at diagnosis (5-year survival 8.5%) or without nodal downstaging at post-induction surgery (13.7%) might preferably be treated with a non-surgical approach.
Key words: combined modality treatment, induction chemotherapy, long-term follow-up, lymphatic metastasis, non-small-cell lung cancer, surgical resection
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Introduction |
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This observation has led to attempts to improve survival by adopting combined modality approaches, such as for example neo-adjuvant chemotherapy followed by surgery and/or radiotherapy. The rationale for using induction chemotherapy for the treatment of locally advanced NSCLC was based on the finding that chemotherapy can reduce the tumour burden, which could facilitate surgery and improve resectability, and abolish micro-metastases to prevent systemic relapse. Several phase II trials [5] and three small randomised trials [6
8
] suggested a prolonged survival for neo-adjuvant chemotherapy followed by surgery compared with surgery alone. In a recent phase III trial in potentially operable NSCLC patients, preoperative chemotherapy improved the prognosis, although not significantly [9
]. Even though more data are required, many European centres now advocate induction chemotherapy followed by surgery and/or radical radiotherapy as a standard treatment for selected patients with IIIA-N2 NSCLC. Because of the demonstrated heterogeneity in this patient population [10
], it is not yet clear for which subset of these patients this therapeutic strategy will be most rewarding. The identification of prognostic factors could be useful for better selection of therapy and design of future randomised trials.
In this prospective study, we describe a homogeneously staged group of potentially resectable IIIA-N2 NSCLC patients, with mediastinoscopy-confirmed ipsilateral mediastinal LNs, treated with vindesineifosfamidecisplatin (VIP) induction chemotherapy followed by attempted surgical resection. The objectives were to estimate clinical and pathological response rates, complete resection rate, survival, prognostic factors and relapse patterns.
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Patients and methods |
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Eligibility criteria and pre-treatment assessment
Pre-treatment staging consisted of a clinical examination, blood tests, a chest radiograph and CT, and a bronchoscopy. The upper abdomen was examined by extending the CT of the chest to the adrenal glands, and/or by ultrasonography. A brain CT was performed in case of neurological signs and in all patients with non-squamous tumour histology. A bone scan was performed on indication only. From May 1998 onwards, patients also underwent [18F]fluorodeoxyglucose positron emission tomography (FDG PET). Based on large-scale previous institutional experience [11], a policy of mediastinoscopy in all potentially resectable NSCLC patients was adopted, except in those with a T1 or T2 squamous cell carcinoma without enlarged mediastinal adenopathy on CT. All patients in this analysis (except two, for technical reasons) had surgical staging of the mediastinum, consisting of a cervical mediastinoscopy, completed by a left anterior mediastinoscopy in appropriate cases.
Other inclusion criteria were WHO performance status of 0 or 1, bidimensionally measurable disease, no previous radio- or chemotherapy and no previous malignancies. Baseline organ functions had to be normal, and comorbidity incompatible with cisplatin-based chemotherapy had to be absent. At the weekly multidisciplinary round, patients had to be considered to have potentially resectable disease by the attending thoracic surgeon.
Induction treatment
Induction chemotherapy consisted of three 4-week cycles of cisplatin 40 mg/m2 intravenously (i.v.) on day 1 and 30 mg/m2 on days 2 and 3, ifosfamide 1200 mg/m2 i.v. on days 1, 2 and 3, and vindesine 3 mg/m2 (maximum 5 mg) i.v. weekly during the first cycle, and every 2 weeks in cycles 2 and 3. Mesna was given for uroprotection: 600 mg just before ifosfamide, and 400 mg 4 and 8 h thereafter. Sufficient diuresis was obtained by adequate parenteral hydration. Parenteral ondansetron and methylprednisolone were used for emesis reduction. Dose-reduction guidelines were as described previously [12]. Since the toxicity of this chemotherapy had already been analysed in detail [12
], and because of the multicentre administration of the chemotherapy, only severe toxic effects (WHO grade
3) were prospectively registered.
Response was assessed by clinicians and a staff member in thoracic radiology at the weekly tumour round, by comparing the bidimensionally measurable lesions on a thoracic CT scan before and 24 weeks after the last chemotherapy. Clinical LN downstaging was defined as disappearance of enlarged mediastinal LNs on CT.
Locoregional therapy
In the first part of the study, from April 1995 to April 1998, at least a partial response (PR) was required to proceed to locoregional therapy with curative intent. This was based on study of the contemporary literature, in which pathological response, which is important for long-term favourable outcome, proved to be rare in patients achieving mere disease stabilisation after induction treatment [13]. Because of growing evidence in favour of radical treatment in all patients with at least disease stabilisation [14
, 15
], this policy was subsequently adopted in our group from May 1998 onwards.
In most patients, radical locoregional treatment consisted of surgical resection with radical mediastinal LN dissection through standard posterolateral thoracotomy. Resection was defined as radical (or complete) in case of removal of all tumour at the primary site and LNs, with the resection margins and the most proximal resected LNs free of tumour at microscopy. Pathological complete response (pCR) was defined as absence of any viable tumour cells in the lung resection specimen and LNs. Downstaging was defined as absence of viable tumour cells in the resected mediastinal nodes. Adjuvant thoracic radiotherapy (a total dose of 56 Gy in 28 daily fractions) was given to patients with persistent N2 in the resection specimen, if permitted by the cardiopulmonary and general status.
When lung surgery was associated with an unacceptable risk because of cardiopulmonary limitations, or when the disease was considered irresectable post-induction by the attending thoracic surgeon or on patient's request, radical locoregional treatment consisting of radiotherapy (dose ranging from 51 Gy in 17 daily fractions of 3 Gy, to 66 Gy in 33 daily fractions of 2 Gy) was applied.
Patients not eligible for radical locoregional treatment usually had a lower dose of radiotherapy (range 20 Gy in five daily fractions of 4 Gy, to 39 Gy in 13 daily fractions of 3 Gy) to improve locoregional control.
Follow-up
After combined modality treatment, patients were followed every 3 months with a thorough clinical examination, biological tests, a chest radiograph and other imaging studies as clinically indicated or to assess the site of recurrence. The cause of death was determined in all but one case.
Statistics
Prospective observation was ended on 1 November 2002, when the status of all patients was determined. Overall survival time was defined as the time interval from the date of pathological diagnosis to the date of death from any cause or to the date of the last follow-up visit. Survival time was calculated according to the KaplanMeier method and log-rank statistic [16], and in a multivariate analysis with the Cox regression model [17
]. Postoperative death was defined as a death within 30 days after surgery.
Time to recurrence was defined as the time from the date of pathological diagnosis to the time of the first documentation of tumour reappearance. Patients with disease progression during induction chemotherapy were not taken into account for calculation of time to recurrence.
A tumour recurrence involving the original tumour site or mediastinal LNs was defined as local, all other involved sites were distant relapses.
Numerical values are expressed as a mean and standard deviation. Comparison of groups was done with the 2 statistic, or a Fisher's exact test in case of cells with low (less than five) numbers.
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Results |
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Patients
The characteristics of the total group (131 patients) and the surgical subset (i.e. the 70 patients who underwent resection) are shown in Table 1. Overall, the characteristics were quite similar in the two groups. The median age was 63 years (range 3377). Male/female ratio was 4:1. Performance status was 0 or 1 in all patients. Tumours were more often located on the right side and in the upper lobe. Histology was squamous cell carcinoma in 46%. At bronchoscopy, 38% of the tumours were centrally located in the total group, and 49% in the surgical group. At mediastinoscopy, multiple mediastinal LN involvement was present in 29% and subcarinal node metastasis in 43%.
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Except for four cases, all patients received three cycles of induction chemotherapy. In three patients chemotherapy was discontinued after two cycles because of early progression, and in one because of lack of response and haematological toxicity.
In the remaining 127, a delay of administration was needed in 17 patients (1 week in 14, 2 weeks in one, 3 weeks in two patients), because of haematological toxicity in 13, a low performance status in two, investigation-related in one and no specified reason in one. Dose intensity was 96% of the planned dose for cisplatin and ifosfamide, and 67% for vindesine, due to dose reduction or omission, mostly on day 15.
Grade 3 and 4 toxic effects of induction chemotherapy are summarised in Table 2. The most common toxicity was leukopenia, occurring in 113 patients. This led to severe infection requiring hospitalisation in 18 cases. Grade 3 and 4 nausea and vomiting occurred in 15 patients. No severe renal toxiciy was noted. There were no chemotherapy-related deaths.
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A complete resection was obtained in 62 patients (89% of the resected cohort). There were eight incomplete resections, four out of 57 patients responsive to chemotherapy and four out of 13 patients with SD after induction (P=0.034). Resection was considered incomplete in six patients with tumour deposits in the most proximal resected node station, in one with a positive resection margin of bulky nodes and in one with pleural involvement. Downstaging to pN0-1 occurred in 34 of 70 resection specimens (49%), six of whom had no downstaging on thoracic CT. A pCR was achieved in six patients (9%). Of the 36 patients with persistent N2 in the resection specimen, 19 were considered fit enough to receive their postoperative radiotherapy as planned.
Major postoperative complications were catheter-related sepsis (n=1), persistent air leak (n=4) and severe pneumonia (n=9), complicated by an acute respiratory distress syndrome (ARDS) in five patients and requiring mechanical ventilation in six. One patient died of ARDS following a pneumonia 14 days after a left upper lobectomy with bronchovascular sleeve procedure.
Radical radiotherapy as primary locoregional therapy was applied in 19 patients (13 CR/PR, six SD), because of the unacceptable high surgical risk due to cardiopulmonary limitations (n=7), technical reasons (mediastinal LNs not considered to be completely resectable by the thoracic surgeon) (n=5) or on patient's request (n=7).
Radiotherapy with palliative intent was applied in 32 cases, all of whom had either PD (n=21) or SD (n=11). An additional 10 patients had radiotherapy for locoregional control after either incomplete resection or exploratory thoracotomy.
Survival and pattern of relapse
The mean duration of follow-up in the entire group was 25 months (standard deviation 18, range 389). In the surviving patients, this was 34 months (standard deviation 22, range 389). At the time of analysis, 49 patients were alive, of whom 38 had no evidence of disease. Four out of 131 patients died without any evidence of disease recurrence (one postoperative death, two cardiac deaths and one death to a secondary non-lung primary tumour).
The median survival time (MST) of the total group was 24 months, with 2- and 5-year survival rates of 51% and 21%, respectively (Table 3). Patients responsive to induction chemotherapy had an MST of 38 months, with 2- and 5-year survival rates of 68% and 30%, respectively (Figure 2).
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The MST in the surgical subgroup was 45 months, with 2- and 5-year survival rates of 68% and 35%, respectively (Table 4). There was no significant difference between resected patients with either response or SD on postinduction CT scan (Figure 3). Of the 30 patients with subcarinal LN involvement at baseline, who were treated surgically, the MST was only 20 months and the 5-year survival rate 16%, compared with 58 months and 38%, respectively, in those patient with no subcarinal metastasis at diagnosis (P=0.031).
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Relapse occurred in 61 of the 106 patients with at least SD after induction chemotherapy. The primary site of relapse was distant in 31 patients, local in 20 and a combination of both in 10. Isolated brain metastases as first site of failure were present in 11 patients. No data about relapse were available for one patient. The median time to recurrence was 14 months (standard deviation 9, range 658).
There were 12 (eight distant, four locoregional) relapses in the 34 patients with pathological LN downstaging after induction chemotherapy, and 22 (20 distant, two locoregional) in the 36 patients without downstaging. The median time to recurrence was 23 months (standard deviation 14, range 958) in the pathologically downstaged cohort, and 14.8 months (standard deviation 6, range 826) in the non-downstaged cohort.
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Discussion |
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Before the advent of CT, the subset of clinical or bulky N2 (i.e. detectable on chest X-ray or bronchoscopy) was described. Authors at that time reported that surgical resection for N2 disease could be rewarding in some patients, but not in those with bulky N2 [3, 18
]. More recently, Andre et al. [10
] reviewed the experience in six French centres. In that analysis, patients with no mediastinal LN enlargement (<10 mm) on CT, and those with enlarged mediastinal LNs on CT whose mediastinoscopy was negative, were classified as minimal N2. Patients with mediastinal LN enlargement on CT scan and a positive mediastinoscopy or those in whom mediastinoscopy was not performed were considered clinical N2. In the multivariate analysis, clinical N2 patients had a significantly worse survival than minimal N2 patients (P < 0.0001). Although this excellent study included >700 patients, there were some limitations. Apart from institution-based differences, e.g. variable policies towards preoperative chemotherapy and postoperative radiotherapy, the main limitation (given the timeframe and setting of the analysis) was the lack of consistent mediastinoscopy proof of N2 disease. Distinction between minimal and clinical N2 was not always certified by mediastinoscopy.
Ever since, the importance of optimal mediastinal staging has been stressed further, and became an accepted standard for many. It is essential to remember that CT scan is a very rough tool with which to stage the mediastinum, with an accuracy of 60% and with an important risk of both over- and understaging [11, 19
, 20
]. Mediastinoscopy not only confirms N2 disease, but also determines the extent of N2 (e.g. single or multiple level), and excludes N3 disease in this setting.
Our long-term single-institution experience expands on the analysis of Andre et al. [10] in the group of patients they would consider to have clinical N2. We report on the outcome of a combined modality strategy, consisting of induction chemotherapy followed by surgical resection in a cohort with strictly homogenous surgical staging of IIIA-N2 disease.
The chemotherapy consisted of the VIP combination, based on our previous experience in advanced NSCLC [12] and early favourable results in locally advanced NSCLC [21
, 22
]. The response rate of 54%, with disease stabilisation in another 27%, is comparable to the 54% reported by Kirn et al. [23
], 60% by Rosell et al. [6
] and 64% by Burkes et al. [24
]. Slightly higher response rates were recently reported with newer combinations of cisplatin and gemcitabine (70% [25
]) or cisplatin and docetaxel (66% [26
]). Pathological downstaging of mediastinal LNs was achieved in 49% of the surgical specimens, comparable to the experience with more recent cisplatin doublets (53% [25
] and 60% [26
]). Remarkably, six out of 34 patients with pathological downstaging did not have clinical downstaging. The observation that clinical response to induction chemotherapy does not necessarily correlate with pathological response assessment has convinced some teams to consider not only responders for surgical exploration, but also patients with SD [14
, 27
, 28
]. However, being well aware that long-term survival can only be obtained after complete resection, we were initially reluctant to adopt this policy in our institution. Indeed, complete resection rates in early series with surgical exploration in responders and patients with SD varied from only 37% [14
] or 44% [28
] to 65% [27
]. As we adopted this policy in our institution from May 1998 onwards, our series gives a unique opportunity to compare these two strategies. While there were only four incomplete resections in 57 responders, there were also four in 13 patients with disease stabilisation (P=0.03). Of the 17 patients with clinically SD after induction, in whom a surgical resection was attempted, nine underwent a complete resection and had survival prospects similar to responding patients with complete resection (Figure 3). Four others had an incomplete resection and thoracotomy was exploratory in another four. Thus, in the second period of our study, we managed to salvage an extra nine patients, which we consider rewarding.
Survival data in phase II series are always difficult to compare owing to the many institution-based differences in non-controlled trials: selection of patients, unknown institution-related habits, different definitions of resectability, and different interpretation of radiology and histopathology. Nonetheless, our survival data with this treatment program are encouraging (overall MST of 24 months and 2- and 5-year survival rates of 51% and 21%, respectively), and in line with other trials: MSTs were between 17 and 21 months [24, 25
], and 2-year survival rates between 40% and 60% [7
, 23
, 24
]. Only scant data exist on long-term survival: a 5-year survival rate of 17% was reported by Martini et al. [27
] and 22% by Elias et al. [28
].
Compared with historical literature on mediastinoscopy-proven N2 disease treated with surgery alone [3, 29
, 30
], the results in this series are hopeful. In our historical experience, we were very restrictive towards surgery for N2 disease. We operated on only 19 highly selected mediastinoscopy-proven N2 patients (young age, no or minimally enlarged mediastinal LNs on CT, single node involvement) over a period of 11 years. MST in this highly selected group was 12 months, and 2- and 5-year survival rates were 21% and 15%, respectively [4
]. Despite all the limitations inherent to historical comparison, when looking at the survival of the non-selected cohort of mediastinoscopy-positive N2-NSCLC patients in this series, the approach of induction chemotherapy followed by radical surgery seems to have brought progress for these patients, and warrants further large-scale randomised studies.
The only independent baseline clinical factor related to outcome in this series was subcarinal node involvement. Rather surprisingly, the often reported prognostic significance of the number of involved metastatic LNs [10, 31
] was not confirmed in our study.
Many investigators have observed that response after neo-adjuvant chemotherapy remains the most powerful and independent prognostic factor [27, 32
]. We also noted a survival rate of 30% at 5 years in responders, compared with only 9% in non-responders (Figure 2) (P < 0.0001).
In the surgical cohort, outcome was better in case of a lower pathological T-stage (T0-1-2) (HR 0.308; 95% CI 0.1150.824; P=0.019) and mediastinal LN downstaging (pN0-1) (HR 0.337; 95% CI 0.1510.752; P=0.008), both well-known favourable prognostic factors [10, 31
, 33
, 34
]. The survival benefit seen after downstaging is consistent with the hypothesis that absence of lymphatic involvement after induction chemotherapy is an accurate marker for systemic eradication, while a low T-stage may well reflect the efficient local control.
Systemic relapse after induction chemotherapy continues to be a problem. In most studies, lung metastases are not considered as a distant failure; however, in our study they were, and this may account for the high percentage of distant recurrences (41 of 61 relapses; 67%). As noted by others, the frequency of isolated brain metastases raises the question on whether prophylactic cranial irradiation should be incorporated into future trials [35].
We conclude that VIP induction chemotherapy followed by attempted complete resection was a rewarding approach in our mediastinoscopy-positive stage IIIA-N2 patients, and that it seemed to improve their prospects compared with our historical control group with surgery alone. Furthermore, radical treatment after induction chemotherapy led to long-term survival in both responders and patients with SD, despite a lower, but still acceptable, complete resectability rate in case of disease stabilisation.
The question of whether surgery is superior to radiotherapy in mediastinoscopy-positive N2 disease cannot be resolved by our data, but requires a multicentre randomised trial. However, the results of the surgical arm in such a multicentre setting will need to be interpreted with caution, given the effect of hospital volume on outcome in thoracic surgery [36]. In our data, the 5-year survival rate of 30% confirms the potentially curative role of surgical multimodality treatment in selected N2-NSCLC patients. The subset of patients with subcarinal LN involvement at diagnosis (5-year survival 8.5%) and those without LN downstaging after induction (5-year survival 9.4%) might preferably be treated with non-surgical combined modality treatment.
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Acknowledgements |
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We thank the following contributing LLCG collaborators from other Belgian hospitals: K. Demuynck (Salvator Hospital, Hasselt); P. De Rudder (St-Rembert Hospital, Torhout); P. Bertrand (H. Hart Hospital, Roeselare); J. Bockaert (St-Jozef Hospital, Mechelen); L. Coolen (General Hospital, Diest); R. Deman (St-Maarten Hospital, Kortrijk); G. Desmet (H. Hart Hospital, Oostende); J. Haerden (H. Hart Hospital, Mol); A. Heremans, J. Roelandts (Imelda Hospital, Bonheiden); I. Malysse (Onze-Lieve-Vrouw Hospital, Ieper); H. Struyven (H. Hart Hospital, Tienen); G. Tits (St-Andries Hospital, Tielt); D. Verrezen (St-Augustinus Hospital, Antwerpen).
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Notes |
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Received for publication March 31, 2004. Revision received June 21, 2004. Accepted for publication June 25, 2004.
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References |
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---|
2. Cox JC, Azarnia N, Byhardt R et al. N2 (clinical) non-small cell carcinoma of the lung: prospective trials of radiation therapy with total doses 60 GY by the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 1991; 20: 712.[ISI][Medline]
3. Pearson F, DeLarue N, Ilves R et al. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg 1982; 83: 111.[ISI][Medline]
4. Vansteenkiste JF, De Leyn PR, Deneffe GJ et al. Survival and prognostic factors in resected N2 non-small cell lung cancer: A study of 140 cases. The Leuven Lung Cancer Group. Ann Thorac Surg 1997; 63: 14411450.
5. Vansteenkiste J, De Leyn P, Deneffe G et al. Present status of induction treatment for N2 non-small cell lung cancer: A review. Eur J Cardiothorac Surg 1998; 13: 112.[ISI][Medline]
6. 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: 153158.
7. Roth J, Fossella F, Komaki RP 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: 673680.[Abstract]
8. Pass HI, Pogrebniak HW, Steinberg SM et al. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 1992; 53: 992998.[Abstract]
9. Depierre A, Milleron B, Moro-Sibilot D et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small cell lung cancer. J Clin Oncol 2002; 20: 247253.
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: 29812989.
11. Dillemans B, Deneffe G, Verschakelen J, Decramer M. Value of computed tomography and mediastinoscopy in preoperative evaluation of mediastinal nodes in non-small cell lung cancer. Eur J Cardiothorac Surg 1994; 8: 3742.[Abstract]
12. Vansteenkiste J, Vandebroek J, Marien S et al. Combination chemotherapy with vindesine-ifosfamide-cisplatin (VIP) in locally advanced unresectable stage III and in stage IV non-small cell lung cancer: A phase II trial. Lung Cancer 1995; 13: 285293.[CrossRef][ISI][Medline]
13. Pisters KM, Kris MG, Gralla RJ et al. Pathologic complete response in advanced non-small-cell lung cancer following preoperative chemotherapy: implications for the design of future non-small-cell lung cancer combined modality trials. J Clin Oncol 1993; 11: 17571762.[Abstract]
14. Sugarbaker DJ, Herndon J, Kohman LJ 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. Cancer and Leukemia Group B Thoracic Surgery Group. J Thorac Cardiovasc Surg 1995; 109: 473483.
15. Albain KS, Rusch VW, Crowley JJ et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995; 13: 18801892.[Abstract]
16. Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958; 53: 457481.[ISI]
17. Cox DR. Regression models and life tables. J R Stat Soc Biol 1972; 34: 187198.
18. Martini N, Flehinger BJ, Zaman MB, Beattie EJ. Results of resection in non-oat cell carcinoma of the lung with mediastinal lymph node metastases. Ann Surg 1983; 198: 386397.[ISI][Medline]
19. De Leyn P, Vansteenkiste J, Cuypers P et al. Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan. Eur J Cardiothorac Surg 1997; 12: 706712.[Abstract]
20. Toloza EM, Harpole L, McCrory DC. Noninvasive staging of non-small cell lung cancer: A review of the current evidence. Chest 2003; 123 (Suppl 1): 137S146S.[CrossRef][ISI][Medline]
21. Vansteenkiste JF, De Leyn PR, Deneffe GJ et al. Vindesine-ifosfamide-platinum (VIP) induction chemotherapy in surgically staged IIIA-N2 non-small cell lung cancer: A prospective study. Ann Oncol 1998; 9: 261267.[Abstract]
22. Van den Brande P, De Ruysscher D, Vansteenkiste J et al. Sequential vindesine-ifosfamide-platinum (VIP) chemotherapy followed by cisplatin sensitized radiotherapy in stage III B non-small cell lung cancer: A phase II trial. Lung Cancer 1998; 22: 4553.[CrossRef][ISI][Medline]
23. Kirn DH, Lynch TJ, Mentzer SJ et al. Multimodality therapy of patients with stage IIIA, N2 non-small-cell lung cancer. Impact of preoperative chemotherapy on resectability and downstaging. J Thorac Cardiovasc Surg 1993; 106: 696702.[Abstract]
24. Burkes R, Ginsberg RJ, Shepherd FA et al. Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small-cell lung cancer: Results of the Toronto phase II trial. J Clin Oncol 1992; 10: 580586.[Abstract]
25. Van Zandwijk N, Smit EF, Kramer GW et al. Gemcitabine and cisplatin as induction regimen for patients with biopsy-proven stage IIIA-N2 non-small cell lung cancer: A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group (EORTC 08955). J Clin Oncol 2000; 18: 26582664.
26. Betticher DC, Hsu Schmitz SF, Totsch M et al. Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small cell lung cancer: a multicenter phase II trial. J Clin Oncol 2003; 21: 17521759.
27. Martini N, Kris MG, Flehinger B et al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: The Sloan-Kettering experience with 136 patients. Ann Thorac Surg 1993; 55: 13651374.[Abstract]
28. Elias AD, Skarin AT, Gonin R et al. Neoadjuvant treatment of stage IIIA non-small cell lung cancer. Long-term results. Am J Clin Oncol 1994; 17: 2636.[ISI][Medline]
29. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1988; 96: 440447.[Abstract]
30. Watanabe Y, Shimizu J, Oda M et al. Aggressive surgical intervention in N2 non-small cell lung cancer of the lung. Ann Thorac Surg 1991; 51: 253261.[Abstract]
31. Vansteenkiste JF, De Leyn PR, Deneffe GJ et al. Clinical prognostic factors in surgically treated stage IIIA-N2 non-small cell lung cancer: Analysis of the literature. Lung Cancer 1998; 19: 315.[CrossRef][ISI][Medline]
32. Strauss GM, Langer MP, Elias AD et al. Multimodality treatment of stage IIIA non-small-cell lung carcinoma: a critical review of the literature and strategies for future research. J Clin Oncol 1992; 10: 829838.[Abstract]
33. Bueno R, Richards WG, Swanson SJ et al. Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 2001; 70: s1826s1831.[CrossRef]
34. Voltolini L, Luzzi L, Ghiribelli C et al. Results of induction chemotherapy followed by surgical resection in patients with stage IIIA (N2) non-small cell lung cancer: the importance of the nodal down-staging after chemotherapy. Eur J Cardiothorac Surg 2001; 20: 11061112.
35. Stuschke M, Eberhardt W, Pottgen 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: 27002709.
36. Bach PB, Cramer LD, Schrag D et al. The influence of hospital volume on survival after resection for lung cancer. N Engl J Med 2001; 345: 181188.