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Eur J Cardiothorac Surg 2002;21:514-519
© 2002 Elsevier Science NL
Department of Thoracic Surgery, University of Torino, San Giovanni Battista Hospital, v. Genova 3, 10126 Turin, Italy
Received 17 September 2001; received in revised form 5 December 2001; accepted 10 December 2001.
* Corresponding author. Tel.: +39-011-633-6775; fax: +39-011-696-0170
e-mail: ottavio.rena{at}tiscalinet.it
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Abstract |
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 Top Abstract 1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Conference...References |
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3 cm vs >3 cm), histologic vascular invasion, visceral pleura involvement, positive bronchial resection margin, general T status. Results: Overall 5-year survival was 63%. In both univariate and multivariate survival analysis, significant prognostic factors were histology (adenocarcinoma 65% vs squamous cell carcinoma 51%), tumour size (3 cm 67% vs >3 cm 46%), and the presence of negative resection margin. Five-year survival by general T status was 66% in T1N0 vs 55% in T2N0 disease (P=0.19). Conclusions: Despite advances in early diagnosis and surgical technique, 5-year survival of stage I non-small cell lung carcinoma remains low as compared to survival of other solid organ neoplasm. Tumour size 3 cm, adenocarcinoma histologic type and negative bronchial resection margins were associated with a more favourable outcome in our patient population. More effective multimodality treatments are needed to increase survival rates.
Key Words: Early-stage non-small cell lung cancer • Stage I non-small cell lung cancer • Surgery
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1. Introduction |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Conference...References |
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Lung cancer is a significant disease, with approximately 170,000 new cases diagnosed annually in the United States. Of these, 45% are limited to the thorax, where surgery is not only an important therapeutic modality, but in many cases, the most effective method of controlling the disease. Of all resectable tumours, 28% are T1N0 lesions, which have a high cure rate and 37% are T1N1, T2N0 and T2N1 lesions, which have a somewhat lower cure rate.
According to the TNM staging system, stage I tumours of the lung are defined as those without lymph node metastasis (N0) [1]. In the revised stage grouping of TNM, stage I patients have been sub-classified into two subsets (Ia and Ib) because consistently better outcomes for patients with pT1N0M0 disease (stage Ia) have been referred. Stage Ia patients are affected by tumours less than 3 cm in diameter, surrounded by lung without bronchoscopic evidence of invasion more proximal than the lobar bronchus; stage Ib patients are affected by tumours involving the main bronchus >2 cm distant to the carina, or involving the visceral pleura or associated with atelectasis or obstructive pneumonitis that extends to the hilum but does not involve the entire lung.
We report a retrospective analysis of our experience in managing stage I non-small cell lung cancer (NSCLC) in order to evaluate the prognostic significance of some surgical and pathological variables on patients survival and disease control.
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2. Material and methods |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Conference...References |
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All patients were preoperatively submitted to radiological evaluation (chest X-rays, computed tomography of the thorax, upper abdomen and brain), pulmonary function testing (spirometry, blood gases analysis and pulmonary perfusion scintigraphy when predicted postoperative forced expiratory volume in 1 s was less that 1 l), bronchoscopy with endoscopic biopsy when centrally located lesions and computed tomography guided needle-biopsy in the case of peripherally located lesions. Preoperative histological diagnosis was obtained in 375 patients (86%). In the other cases, intraoperative histological confirmation by frozen sections was carried out before attempting the surgical excision.
Forty-eight patients out of 436 (11%) were submitted to sublobar resection because they were affected by neoplastic lesions associated with poor preoperative cardiopulmonary function which did not allow more extended resections such as the lobar one.
Three hundred and eighteen (73%) lobectomies were carried out because of tumours located distally than the lobar bronchus origin: eight of them were submitted to completion lobectomy for cancer recurrence after previous limited resection. Fifty-eight (13%) patients underwent pneumonectomy and 12 (3%) bilobectomy: ten of them received pneumonectomy or bilobectomy for neoplasms located at the left main stem bronchus or at the intermediate bronchus on the right.
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3. Results |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Conference...References |
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The histological diagnosis confirmed the preoperative carcinoma in 352 cases out of 375 (93%): in the remaining 23 cases the definitive diagnosis revealed various subtypes of NSCLC whereas the preoperative bioptic sampling had resulted in negative or ‘not specific’ carcinomas. Finally, the definitive diagnosis were as follows: 209 squamous-cell carcinoma (48%), 164 adenocarcinoma (37.6%), 42 bronchoalveolar carcinoma (9.6%), 21 large-cell carcinoma (4.8%).
All specimens were accurately analysed in order to evaluate the clearance or not at vascular or bronchial resection margins, visceral pleura involvement, vascular or lymphatic invasion within lung parenchyma, carcinoma in situ associated with the macroscopic lesion. One-hundred and seventy-nine patients had tumours 3 cm diameter or less and 257 larger than 3 cm. The visceral pleura was observed in 99 patients, 32 of whom (32.3%) had tumours of 3 cm or smaller. The tumours involved the bronchial tree proximally to the lobar bronchus in 10 cases and the main bronchus >2 cm distant to the carina in four cases. The median follow-up (complete for all 428 patients who survived surgery) was 52 months (range 18–84) and 5-years overall survival rate was 63% (Fig. 1 ). We defined the local recurrence as evidence of tumour within the same lung, at the bronchial stump or disease in the mediastinum or in the supraclavicular nodes and distant recurrence as disease in the contralateral lung or outside the thorax. During the course of follow-up, local or distant recurrence developed in 173 patients out of 428 (40%). Of these, 155 (89.5%) died of their disease, seven were alive with disease (4%) and 11 (6.5%) had had successful control of their recurrence. In 65% of patients with recurrent disease, the recurrence developed within the first 2 years after surgery.
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3 cm vs >3 cm), the presence or absence of visceral pleural involvement, general T1 vs T2 status, the presence of intra-parenchymal vascular or lymphatic invasion, the presence or absence of carcinoma in situ associated with the macroscopic tumour, the clearance or not at vascular or bronchial resection margins. Prognostic significance of the variables was tested using univariate (log-rank) (Table 2) and multivariate (Cox proportional-hazards) (Table 3) analyses.
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4. Discussion |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Conference...References |
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We reported a lower rate of survival after early lung cancer resection than those previously reported by other authors, and some variables were detected as significant negative prognostic factors.
Tumour size does make a significant difference in the survival of patients. Patients affected by tumours of 3 cm or less in size have better prognosis than those affected by larger ones. These data agree with those reported in the international literature, but the survival of patients with both T1N0 and T2N0 tumours is lower than that generally reported by other authors [4,6–11]. Recently Patz et al. reported a study about outcomes of 510 patients with stage Ia cancer: they did not note statistical relationship when tumour size and long-term survival were compared [12].
Visceral pleural involvement, even if related with lower survival rate at 5-years follow-up, seems not to be a significant prognostic factor, such as also reported by Martini et al. [4]; although Ichinose et al. were able to document by univariate analysis of survival curves that pleural invasion was a significant prognostic factor in their series [10].
General ‘T’ status, T1 vs T2, seemed not to be associated with significant difference in patients survival. In our series, the ‘T’ descriptor of the TNM staging system of early lung cancer could not be related with the long-term survival, which is highly influenced by the tumour size and the presence of intra-parenchymal invasion of blood and lymphatic vessels.
Histological type of the tumour is a fairly consistent determinant of survival in patients with resected stage I carcinoma. In the Lung Cancer Study Group (LCSG) analysis, cancer recurrences and cancer-related death were more frequent and recurrence rates were higher in patients with tumour of non-squamous histology; however, this advantage disappeared after 5 years [13]. Martini et al. reported that no difference in overall survival was identified in patients who had squamous cell tumours compared with those who had non-squamous cancers; however, they reported a survival advantage in patients affected by non-squamous cancer of smaller size (T1 vs T2) [4]. In their series, this survival difference was not apparent in patients with squamous cancer.
Unexpectedly in our series, 5-years survival rates were 65% for adenocarcinoma patients and 51% for squamous cell ones, respectively, which is contrary to those reported by other investigators. Bronchoalveolar carcinoma seems to be the more favourable histological subtype in predicting patients' survival (88% survival rate in our series) as reported by other authors [6].
Another factor which significantly affects long-term survival is the presence of vascular or lymphatic invasion in the lung parenchyma and Macchiarini et al. and Kessler et al. demonstrated that blood vessel invasion was a predictor of poor survival in limited subgroup of NSCLC patients [14,15]. This is probably one of the most important variables influencing the stage I NSCLC survival: a subgroup of patients who had probably entered the metastatic phase of the disease before diagnosis and surgery.
The extent of surgical resection did not appear as a prognostic factor, such as the presence of carcinoma in situ associated with the macroscopic tumour.
In our series, 40% of patients experienced cancer recurrences, despite early detection and resection of the disease. Nearly 65% of all recurrences occurred within the first 2 years of follow-up. Other authors reported overall-recurrence rates of about 20–27% and 60% occurred within the second postoperative year [4,5,13].
Eighty-nine percent of our patients died by their disease such as those reported by other authors [4]. The most frequent localizations of recurrent disease are distant from the primary cancer site (nearly 70% in our and other series) [4,5]. The local recurrences are mostly localized at the bronchial stump or within the same lung and rarely they involve the mediastinum or supraclavicular nodes [4]. These data are of high importance in order to define the clinical behaviour of the so called ‘early lung cancer’. One patient out of three in our series died from the disease after distant recurrence in two-thirds of the cases. One-third of the patients with recurrent disease demonstrated recurrence within the same lung or at the bronchial stump in two-thirds of the cases.
During the last decades, many authors expressed and supported their opinion that limited resection could be the gold standard in managing stage I bronchial carcinoma [2,16–19]. Some authors reported no statistically significant difference in the local/systemic recurrence rate between wedge resection or segmentectomy group and lobectomy group. However, other authors demonstrated that lesser resection than lobectomy could not afford similar chance of cancer free survival and no greater chance of local recurrence [5,20]. Lesser resection than lobectomy demonstrated significant local recurrence rate than anatomic excision. We think that lobectomy remains as gold standard in the surgical management of stage I lung cancer and is the only procedure that diminishes the risk of recurrence of local cancer.
On the other hand, we have reported 37% 5-years mortality in patients with stage I disease and the majority of patients died by distant metastases. The only way for us to induce improvements in the overall survival for stage I patients is to try to reduce the incidence of the local recurrences and distant metastases.
Several trials have evaluated postoperative radiation therapy, the majority of which suggest that overall survival may be only minimally improved with this adjuvant therapy, but local failure is probably reduced. Trials evaluating the role of adjuvant chemotherapy have been few, often enrolling small number of patients [21].
Wada et al. reported significant 5-year survival rate improvement in stage I patients submitted to postoperative chemotherapy which includes long-term oral administration of uracil and tegaful [22]. Recently, Mineo et al. have reported the results of a randomized trial confirming that postoperative adjuvant therapy is able to assess significant reduction in stage Ib local and distant recurrence rates and 5-years disease-free survival [23].
Results on adjuvant chemotherapy administration after surgical excision of an early stage lung cancer are actually not very consistent, although some adjuvant regimens may have biological activity, and further study is warranted for regimens that include newer chemotherapy agents.
In conclusion, early stage lung cancer, apart from other early stage cancers that can affect humans, is characterised by high local and distant recurrence-rate which significantly affects overall survival. The surgical management alone (even if performed by anatomic resections such as lobectomy), which was considered the treatment of choice during the last decades, seems not to be able to secure high percentages of short-term and long-term control of the disease. Postoperative radiation therapy has been indicated in some cases to be able to reduce local-recurrence rates but did not affect overall mortality, which is principally due to distant recurrences of the disease.
During the last years, some authors reported decreased distant recurrence rates and increased overall-survival rates in patients affected by stage I lung cancer treated by surgery associated with postoperative chemotherapy. More effective multimodality treatments are needed to increase survival rates.
In conclusion, stage I NSCLC revealed a 5-year overall survival rate of 63% and the overall incidence of recurrence was 40%. The high rate of recurrence, in the majority of patients distant from the primary tumour site, and the intermediate long-term prognosis suggest to consider these patients for multimodality treatments in order to reduce recurrence and long-term mortality rates.
Surgical and pathological variables were analysed to evaluate their importance in predicting patients' outcome: significant prognostic factors (P<0.05) were histology, tumour size less than 3 cm and the absence of intraparenchymal vascular or lymphatic invasion.
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Footnotes |
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Appendix A. Conference discussion |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Conference...References |
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Dr Ruffini: This was not a conclusion. It was kind of a suggestion and advice. You know that there are ongoing trials in the United States and in Italy evaluating the role of neo-adjuvant chemotherapy in early stage lung cancer. That is not only stage I, of course, but only stage II, IIb, for example. And our suggestion was supported by the fact that most recurrences were distant, and so probably these patients had micrometastases at the time of surgery. And so this could be the reason, the rationale, to use chemotherapy before.
Dr I. Poliakov (Krasnyk, Russia): Were there differences between the group with sublobar resection and other resection? That means recurrences.
Dr Ruffini: No, we didn't find any. Probably there was a higher local recurrence rate, yes, but it was not so significant. I speculate that most sublobar resections were, for example, adenocarcinoma patients in which we had a suspicion of metastases, so we did a wedge resection, and then the definite histology was adenocarcinoma of the lung. This could be the reason, because we usually performed lobectomy for primary nonsmall cell lung cancer. This is, of course, the operation of choice.
Dr Poliakov: Basically you perform lymph node dissection even with wedge resection?
Dr Ruffini: Yes, even with wedge resection, because it is important, of course, the amount of parenchyma resected, but it is important the mediastinal dissection. We did the mediastinal dissection always in wedge resection.
Dr Poliakov: So it means you leave some lymph nodes inside the lung parenchyma, which means N1?
Dr Ruffini: Yes, we did the hilar lymph nodes and mediastinal lymph nodes in that case.
Dr Poliakov: What about intrapulmonary lymph nodes?
Dr Ruffini: No, we didn't.
Dr H. Jessen Hansen (Copenhagen, Denmark): Are all your procedures an open operation or VATS procedures?
Dr Ruffini: Wedge procedures, sublobar.
Dr Jessen Hansen: Open?
Dr Ruffini: Open.
Dr Jessen Hansen: Then I would like to make a comment. If you ever would put forward a paper with VATS lobectomies and one-third of the recurrence will be local, that will be turned down that the wedge operation is an inadequate operation for lung cancer.
Mr G. Ladas (London, UK): A question and a comment. First of all, I think it is quite impressive, and rather worrying that you had a 30% local recurrence in stage I disease within 2 years of the operation. My question would be what kind of nodal dissection do you perform? Do you perform systematic nodal dissection, because a lot of people say mediastinal dissection does not change prognosis or survival, but they fail to appreciate that if you are doing a systematic nodal dissection you are systematically dissecting also station 10, 11,and,if necessary, station 12, that is segmental level lymph glands.
And if you are getting so many local recurrences so shortly after the operation, that might indicate that you are not dissecting properly the intrapulmonary, if you like, lymph glands, i.e. levels 11 or 12. Because if you had done a wedge resection, and I assume it is an anatomical segmentectomy, you should have established that station 12 and 11 and 10 are clear from disease. Otherwise you are doing an incomplete resection.
So my question to you is exactly what kind of nodal dissection you perform, and if you could tell us what is the average number of nodal stations you normally dissect?
And my comment is that it is well recognized that recurrence following resection for early stage disease can be a problem. There are studies from France as well as the MRC LU22 trial in the UK, which is ongoing, and the early results have already been reported, on induction chemotherapy in early stage cancer.
Dr Ruffini: The rate of local recurrence is not so high because it is in 30% of the recurrence patients, of course. It is in the range of hundreds; usually one-third is local than two-thirds. It is not so different from the literature, first. Second, the local regional recurrence usually is in the mediastinum, not in the hilum, and we did a systematic lymphadenectomy in the mediastinum, so 2, 4, 7 and 8 and 9, and 10 of course, and usually we do not dissect probably so carefully the interlobar. That means 11. This is our routine mediastinal lymphadenectomy.
Mr Ladas: It would be strange if your local recurrences were in the mediastinum, which you had previously dissected, but not in the hilum or fissure where you had not performed a nodal clearance. It doesn't make sense.
Dr Ruffini: I only noticed that most of our local recurrences are in the mediastinum. This is our experience.
Dr O. Kshivets (Siauliai, Lithuania): I agree with you that stage I, more than stage I generated more questions than answers, and in the future I think it needs to be updated.
My question is, did you analyze data from your survival rate according to tumor diameter without lymph node metastases?
Dr Ruffini: You mean prelevel?
Dr Kshivets: Yes.
Dr Ruffini: No, only two, less than three and more than three. Probably there are studies investigating less than one and one three and more than three, I know this, but we only did 3 cm.
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References |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionAppendix A. Conference...References |
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