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Eur J Cardiothorac Surg 2006;30:217-222
© 2006 Elsevier Science NL
a Thoracic Surgery Department, University "A. Avogadro", Novara, Italy
b Thoracic Surgery Department, University of Torino, Torino, Italy
Received 1 January 2006; received in revised form 15 April 2006; accepted 22 April 2006.
* Corresponding author. Tel.: +39 0321 3733076; fax: +39 0321 3733578. (Email: ottaviorena{at}libero.it).
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Key Words: Epithelial tumours • Lung metastases • Surgery • Prognosis
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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In the present paper, we analyse the results of surgical management of pulmonary metastases from primary extrapulmonary epithelial tumours, to evaluate those factors positively affecting survival.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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From these, we selected patients undergoing lung resection for metastases from extrapulmonary epithelial primary tumours: 202 patients are the focus of the present paper.
Patients are characterised in Table 1 . Selection criteria for metastasectomy were as follows: (1) primary tumour controlled or imminently controllable; (2) absence of extrapulmonary metastases (if they exist, they should be controlled before any surgical procedure in the lung); (3) preoperative assessment of complete resectability of all the pulmonary lesions; (4) ability to tolerate the degree of envisaged lung resection (evaluation of the predictive postoperative lung function, consideration of co-existing co-morbidities and performance status); (5) nonavailability of other effective therapy. Preoperative diagnostic assessment to exclude extrathoracic metastases and evaluate the tolerability of the surgical procedure included chest X-ray, total-body CT-scan, isotopic bone scan (total-body FDG-PET since 1999), fiberoptic bronchoscopy and cardiac and pulmonary function tests (spirometry, electrocardiogram and, if necessary, diffusion lung capacity evaluation, pulmonary perfusion scintigram, myocardial scintigram, echocardiogram).
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Neoadjuvant or adjuvant therapies were decided and all patients were followed by a medical oncologist. Clinical records of all patients were reviewed and all patients were directly contacted. Recorded data were age, sex, side, symptoms at presentation, grading and histological subtype of the primary epithelial tumour, disease-free interval, number of resected lung metastases, type of pulmonary resection, metastatic lymph nodes, use of adjuvant therapy, operative and postoperative complications, recurrences and follow-up survival. Disease-free interval was defined as the time between the resection of the primary tumour and the date of diagnosis of lung metastases. Disease-free survival was defined as the time between the first metastasectomy to the date of diagnosis of lung or systemic recurrence. Survival was defined as the time between the first metastasectomy to the date of last follow-up or death. All available survival data were updated in December 2005, for a minimum follow-up of 24 months.
2.1 Statistical analysis
Actuarial survival after pulmonary resection was calculated according to the method of Kaplan–Meier. The influence of variables on survival was analysed by the log-rank test. Chi-square and Student's t-test were used to compare mean values and percentages. Multivariate analysis was carried out by Cox-proportional hazard model. A p-value of 0.05 or less was considered significant.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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The pulmonary metastases were single in 147 cases (72.7%), 2 in 33, 3 in 11, 4 in 1, 5 in 2, 6 in 8, 8 in 2, and 13 in 1. The right lung resulted to be affected in 126 and the left one in 85 cases. Symptoms at presentation were recorded in 23 patients (12%) and included cough, haemoptysis, asthenia and dyspnoea.
Complete resection was carried out in 169 (83.6%) cases; in 33 cases the resection resulted not complete because of microscopic (resection margin involvement) or macroscopic residual disease (previous undetected pleural spread or intraoperative detection of not resectable multiple nodules not detected at preoperative evaluation). Metastases to hilar and mediastinal nodes were found in 24 patients (11.8%). Chemotherapy was administered at the time of occurrence of lung metastases in 87 (43%) patients: in 25% before metastasectomy and in the remaining 18% only after surgery. The proportion of patients receiving chemotherapy was higher in the group of incomplete resection (63%) and in patients with multiple metastases (69.5% vs 37% with single metastases).
Mean disease-free interval was 49 ± 48 months, median 38.5 (range 0–228). Twenty-nine patients (14.3%) had metastases synchronous to their primary tumour. Disease-free interval was comprised between 1 and 11 months in 21 cases (10.4%), between 12 and 23 months in 28 (13.8%), between 24 and 35 months in 17 cases (8.4%), and more than 36 months in 107 cases (52.9%).
Operative death (to the postoperative 30th day or during the same hospital stay) was 0.9% (two patients died, one for pulmonary embolism after lobectomy and one for ARDS after bilobectomy). Complication, occurring in 16 patients (7.9% of patients and 7.7% of procedures), included 7 supraventricular arrhythmias, 3 lobe atelectasis, 2 pulmonary infections, 2 persistent air-leaks, 1 ARDS and 1 pulmonary embolism.
Follow-up was complete in 194 patients. Eight patients (3.9%) lost to late follow-up were not included in the statistical analysis. Mean follow-up was 33 ± 31 months, median 25 (range 1–218). After the first pulmonary resection, 147 patients (72.7%) had recurrent disease and the first site of recurrence was the lung in 62 patients (30.6%). Of these, only 21 patients (33.8%) underwent re-operation and a second recurrence occurred in 16 patients. Twelve of them were submitted to third operation, followed by recurrent disease in the lung in six patients. Three patients were submitted to lung resection for the fourth time and one of them was alive without metastases 144 months after the first metastasectomy.
Disease-free survival was 28% at 5 years and 13% at 10 years. Mean disease-free survival was 38 ± 11 months. At the last follow-up, 58 patients (29.9%) were alive and well without any evidence of relapsing disease, and 38 patients (19.6%) were alive but had recurrent disease. Ninety-eight patients (50.5%) died because of progressive metastatic disease in 89 and because of other unrelated causes in 9 cases.
The actuarial survival of pulmonary metastasectomy was 37% at 5 years and 15.8% at 10 years. When only patients submitted to complete resection (169 cases) were considered, the actuarial survival was 43% at 5 years and 17% at 10 years. Actuarial survival considering complete versus not complete surgical resection is illustrated in Fig. 1 ; differences between the two curves were statistically significant (p = 0.00064), and patients submitted to complete resection had better prognosis.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Criteria have been proposed to identify and select patients who will benefit optimally from resection of their pulmonary metastases. Primary tumour site must be controlled or immediately controllable. Extrapulmonary metastases must be excluded; in case of extrapulmonary deposits, they should be controlled before the surgical procedure in the lung. All pulmonary lesions must be resectable to ensure complete control of the disease. Patient must be able to tolerate the degree of envisaged resection. Not as the last one, no other available effective therapy should be absolutely demonstrated. In past series, metastatic breast cancer was a frequent indication for pulmonary resection; in the present one, only 24 patients were submitted to lung resection for metastatic breast cancer [8]. Among these, 14 patients were operated on before 1990, and 10 received limited lung resection (wedge-resection or segmentectomy) during the last 13 years (each patient has single pulmonary nodule, high disease-free interval, and the preoperative diagnosis was not available with nonsurgical procedure). Actually, because of the elevate response rate of systemic therapies, patients with positive anamnesis for breast cancer affected by single or few pulmonary nodules, receive lung surgery at out institution only as diagnostic approach when all the other less-invasive procedures have failed. Rare cases of patients affected by proved metastases from breast cancer are submitted to lung surgery after the demonstrated inefficacy of systemic therapies and the exclusion of noncontrollable extrapulmonary nodules. Even today, other solid tumours of epithelial histololgy that metastasise to the lung are relatively insensitive to currently available chemotherapy. Pulmonary resection is still an important primary form of treatment for these malignancies, which include colorectal cancer, some gynaecologic cancers, renal cell cancer, and various types of head and neck cancer.
A great part of pulmonary metastases do not cause any symptoms and are detected incidentally on radiographic studies after a long disease-free interval period from primary epithelial tumour resection or are detected on routine follow-up chest X-ray. In previous studies, the incidence of symptoms has been reported between 13% and 34.6%, and usually reflect the proximity of the metastatic deposit to central airways [9–11]. Even if fever, chest-pain or discomfort and paraneoplastic syndromes are occasionally seen, cough and haemoptysis are the most frequent ones. Some authors have observed a poorer survival in symptomatic patients [11,12]; in our series, probably because the symptomatic cohort of patients was small, the presence of symptoms at disease presentation did not appear as a prognostic factor.
All patients of our series underwent resection of their disease by conventional surgery; we did not use video-assisted thoracoscopic surgery (VATS). VATS using high-resolution video imaging can be helpful for diagnosis, staging and resection of thoracic tumours, but the possibility of its utilization is highly limited as metastases can be found on the surface of the lung or the outer 10–20% (with high dependence on the size of the lesion). In a prospective study, McCormack and colleagues [13] reported a success rate of only 22% in detecting all lung nodules with VATS and they concluded that thoracotomy and manual palpation should remain the gold standard, even for solitary pulmonary metastases. Metastases within the lung parenchyma may be undetectable by VATS; when detected, there is a substantial risk of not complete resection, especially when nonanatomical resection are performed. Parson and colleagues [14] have recently demonstrated that intraoperative palpation for detection of pulmonary nodules is still necessary for complete resection of the metastatic disease even if the patient has been previously submitted to helical-CT of the chest. It is almost unanimous that complete resection is the major prognostic factor for good long-term results, and this is not guaranteed with the VATS procedure. Actually VATS should be advocated only for staging metastases extension or their diagnosis but cannot be considered the standard approach for resection.
Lung metastasectomy by conventional surgery is often a safe procedure with low perioperative morbidity and mortality rate. The international literature referred morbidity and mortality rates between 0% and 31.6% and between 0% and 7.6%, respectively [11–13,15]. In our series, morbidity and mortality rates were absolutely the same as the previously described.
Although limited lung resection such as wedge and segmentectomy (140 cases, 67.6%, in our experience) are advocated in order to respect the maximum residual functioning lung volume, each type of lung resection up to pneumonectomy has been demonstrated to be useful in very selected patients [16]. In our series, four patients received pneumonectomy for the treatment of their metastases: in each one the disease-free interval was very high (median 94, range 73–141 months); the disease was single and centrally located. Alternative therapies have been demonstrated to be not effective and preoperative evaluation warranted sufficient pulmonary reserve and anticipated the high probability of a complete resection.
Several factors have been referred in the past to significantly influence the long-term survival. It is widely accepted that a complete resection of the disease is the most important factor influencing long-term prognosis [4]. Incomplete resection occurred in 16.3% cases in our series, and was followed by poor results.
Another factor previously described as an important prognostic factor was the number of resected pulmonary deposits [4,9,10,12,17]. In our series, patients with solitary metastases had significantly better long-term survival than those affected by multiple ones.
Disease-free interval was another factor frequently reported to affect long-term prognosis [4,11,12]: in the present series, disease-free interval resulted to be a significant prognostic factor at univariate and multivariate analyses.
Some previous studies indicated histology subtype and differentiation grading as prognostic factors too [4,9,18,19]. We could not confirm the prognostic value of either histology or grading of the primary tumour. Patients affected by hilar and mediastinal lymph nodes metastases had poor long-term prognosis, but this factor did not reach a significant value. Other authors described in the past the prognostic value of lymph nodes metastases detected after complete mediastinal lymph node dissection and emphasised the value of this procedure in staging and guide adjuvant treatment [20,21].
Regardless the primary tumour histology, 5-year and 10-year survivals of our patients submitted to complete resection were 43% and 17%, and 5-year and 10-year disease-free survivals were 28% and 13%, respectively. Other authors have reported 5-year and 10-year survivals between 10% and 63.7% and between 8.1% and 33%, respectively [4,8,10,12,15,17–19]. Local recurrence after pulmonary metastasectomy is a crucial problem during follow-up and the indication for re-operation is sometimes controversial. In our series, 62 patients experienced local recurrence, but only 21 were eligible for a second operation. In our study, the 5-year and 10-year survival rates for the cohort of patients submitted to re-operation were 63% and 26%, respectively. This is probably related to a less aggressive disease.
When the criteria of the International Registry of Lung Metastases classification system have been applied to our series, they have been confirmed to be highly useful in selecting patients for lung metastasectomy [4].
In conclusion, resection of epithelial pulmonary metastases is safe and effective and is associated with very low perioperative morbidity and mortality rates. Even if the lung resection should be planned and carried out taking maximum care of the residual normal parenchyma, large resection such as pneumonectomy is indicated in highly selected cases. Re-operation, when feasible, is a safe procedure allowing satisfactory long-term results, probably related to a less aggressive disease.
Complete resection, single metastasis and disease-free interval higher than 36 months are factors usually defining patients who experience a better outcome after surgery, but do not constitute absolute criteria by which to select patients. The decision to proceed with surgical resection of pulmonary metastases should be made jointly by the thoracic surgeon and a medical oncologist considering the continuous advances in systemic treatments.
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Footnotes |
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The study was performed within the Research Fellowship Program ‘Dottorato di Ricerca in Tecnologie e Terapie Avanzate in Chirurgia’, appointed by ‘Tor Vergata’ University, Rome, Italy. |
References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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