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Ann Thorac Surg 2004;77:431-437
© 2004 The Society of Thoracic Surgeons
a Center of Cardiothoracic Surgery, University Hospital of Coimbra, Coimbra, Portugal
Accepted for publication June 19, 2003.
* Address reprint requests to Dr Antunes, Centro de Cirurgia Cardiotorácica, Hospitais da Universidade de Coimbra, 3000 Coimbra, Portugal
e-mail: antunes.cct.huc{at}mail.telepac.pt
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Abstract |
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METHODS: We have reviewed retrospectively data for 78 patients who underwent 101 curative resections of epithelial pulmonary metastases between January 1988 and December 2000 at our department. Potential prognostic factors affecting late survival, namely histology of the primary tumor, disease-free interval, number and size of resected lung metastases, involvement of lymph nodes, use of nonsurgical adjuvant therapy, and relapse of pulmonary metastases, were investigated.
RESULTS: There was no operative mortality, and the postoperative course was uneventful in 91.1% of the procedures. The mean disease-free interval was 48.2 ± 59.8 months, and the mean follow-up after the first pulmonary metastasectomy was 40.8 ± 31.5 months. Mean overall survival was 81.0 ± 10.0 months, and 5-year and 10-year survival rates were 47.4% and 37.7%, respectively. By univariate and multivariate analyses, the disease-free interval and the prognostic grouping system proposed by the International Registry of Lung Metastases were found to significantly influence the long-term survival. Presence of symptoms also showed an important influence.
CONCLUSIONS: Resection of epithelial pulmonary metastases is safe and effective, and is associated with very low perioperative morbidity and mortality and a reasonable 5-year and 10-year survival. In the present study, the disease-free interval influenced significantly the long-term survival. Our results did not differ significantly from (and in many cases compared favorably with) those described in the literature.
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Introduction |
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The capability to disseminate, giving rise to local or distant metastases, is the main characteristic attributed to malignant tumors. This dissemination can be hematogenous, lymphatic, or through direct invasion of body cavities, and the specific structure and functional activity, with an extensive capillary network through which all the blood passes, determine that the lung works as a first filter [3].
In the past, pulmonary metastatic disease, which affects almost 30% of all oncology patients, was interpreted as an uncontrollable malignant illness without indication for surgical treatment [4]. Since the mid-1960s, surgical resection of lung deposits has been gradually accepted as a treatment of proven value, now being considered a standard therapeutic procedure in properly selected cases, and routinely performed with low morbidity and mortality.
Many publications refer to metastasectomy of sarcomas and of specific types of carcinomas. We have recently published our results of resection of pulmonary metastases from osteogenic sarcomas [5]. In the present study, we analyze our experience in the surgical management of pulmonary metastases from epithelial tumors (those generically arising from epithelial cells), to identify potential prognostic factors affecting survival, and review the literature to compare our results.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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Patients
Patients with nonepithelial metastases were excluded from this study. The patient characteristics are summarized in Table 1
. Two of the 64 patients (3.1%) whose lung was the first organ affected by metastatic disease had synchronous metastases, and all patients with the liver as the first site of secondary disease had metachronous metastases.
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Follow-up
The clinical decision about the use of neoadjuvant or adjuvant therapy was made by a medical oncologist, and all patients were followed in their original departments.
We have reviewed all clinical records and contacted all patients directly or by telephone. Data recorded included age, sex, location and histology of the primary tumor, disease-free interval, number of lung metastases, diameter of largest resected metastasis, type of pulmonary resection, presence of metastatic lymph nodes, use of adjuvant therapy, operative and postoperative complications, and immediate and follow-up survival.
Although other definitions have been used, in this manuscript, we have decided to use the classic definition of disease-free-interval as the time elapsed from the date of resection of the primary tumor to the date of diagnosis of lung metastases. Survival was calculated from the date of the first metastasectomy to the date of last follow-up or of death of the patient. All available survival data were updated in September 2002, for a minimum potential follow-up of 21 months for the last patients included in the study.
Statistical analysis
Actuarial survival after pulmonary resection was calculated according to the method of Kaplan and Meier [7]. The prognostic influence of variables on survival was analyzed using the log-rank test. Comparisons of percentages and mean values were performed using 
2 and Student's t tests, and multivariate analysis was performed by the Cox proportional hazards model [8]. A probability value of 0.05 or less was considered significant. Multivariate analysis for pulmonary relapse was carried out using the logistic regression model [9].
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Results |
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The primary tumor was a differentiated adenocarcinoma in 36 patients and undifferentiated in 5. Other histologic types were epidermoid carcinoma in 6 patients, invasive breast carcinoma in 10, melanoma in 3, transitional cell carcinoma in 2, embryonic carcinoma in 3, and other epithelial types (miscellaneous) in 13.
Mean disease-free interval was 48.2 months (standard deviation, 59.8) and ranged from 0 to 362 months. Fifty-one patients (65.4%) were asymptomatic. Signs and symptoms in the remaining 27 patients included cough in 13, pain in 10, dyspnea in 8, hemoptysis in 3, and asthenia in 1.
Table 3 summarizes data on the first pulmonary metastases. The right lung was more affected, and the mean number of metastases resected was 1.6 ± 1.3. Fifty-three patients had a single metastasis. In the group with multiple metastases, there were 16 patients with two metastases, 4 with three and 5 with four or more. Mediastinal or hilar lymph node involvement by metastatic disease was macroscopically found and histologically confirmed in 12 patients (15.4%).
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The operative procedure of choice was a wedge resection of pulmonary nodules in 69 cases. A lobectomy, when either a solitary metastasis was located deeply and centrally in the lobe or multiple nodules were confined to one lobe, was performed in 28 cases. In a single case a pneumonectomy was performed because there was no other way to achieve radical metastasectomy. A lobectomy combined with wedge resection on another lobe was performed in 3 patients.
Forty-five patients received some form of adjuvant or neoadjuvant therapy, postoperatively in 37 (47.4%). Chemotherapy alone was used in 35 patients, combined with radiation therapy in 1 patient, and with hormone therapy in another. Radiotherapy alone was used in 3 patients, and hormone therapy or iodine 131 were used in the remaining 5.
Mortality and morbidity
There were no operative deaths (to the postoperative 30th day or during the same hospital stay). Complications, occurring in 9 patients (11.5% of patients and 8.9% of procedures), included bronchopleural fistula in 3 (2 requiring chemical pleurodesis), and hyperthermia, hemorrhage, wound infection, atelectasis, transient ischemic attack, and renal insufficiency in 1 patient each.
Follow-up was complete in 68 patients (87.2%). The 10 patients (12.8%) lost to late follow-up were not included in the statistical analysis. Mean follow-up was 40.8 ± 31.5 months and ranged from 3 to 162 months.
After the first pulmonary resection, the disease recurred in 46 patients (67.6%) and the first site of recurrence was the lung in 26 (38.2%). Only 50% of these underwent reoperation, and a second recurrence occurred in 6 of the 13 patients (46.1%). Five of them again underwent metastasectomy and the metastatic disease relapsed a third time in 3. One patient underwent six operations and was alive, with extrapulmonary metastatic disease, 86 months after the first lung metastasectomy.
At the last follow-up, 20 patients (29.4%) were alive and well without evidence of recurrence, and 14 (20.6%) were alive but had relapse. Thirty-four patients died (50%) because of progressive metastatic disease in 32 and of unrelated causes in the other 2. Mean overall survival was 81.0 ± 10.0 months.
The actuarial survival after resection of pulmonary metastases was 47.4% at 5 years and 37.7% at 10 years (Fig 1). Five-year and 10-year disease free survival was 33.9% and 19.1%, respectively (Fig. 2). Mean disease-free survival was 61.0 ± 8.0 months.
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Risk factors for survival
The results of the univariate and multivariate analyses are shown in Table 4.
By univariate analysis, histology of the primary tumor, disease-free interval (considering both intervals previously described), and presence of symptoms were found to affect survival significantly. Also, patients with pulmonary metastases from melanoma and undifferentiated adenocarcinoma had a significantly worse survival when compared with patients who had other histologic types of primary tumor. Finally, asymptomatic patients had a better prognosis than those with symptoms before thoracotomy.
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By multivariate analysis, only disease-free interval of 0 to 35 months and 36 months or more remained as an independent prognostic factor (p = 0.019), and the presence of symptoms showed a borderline significance (p = 0.053).
In the univariate analysis, the only factor that significantly increased the probability of lung metastases to recur (p = 0.027) was the presence of more than one lesion, and this influence was confirmed by multivariate analysis (p = 0.016), reinforcing its prognostic value.
Prognostic groups
Patients were then divided into prognostic groups, as described by the Writing Committee of the International Registry of Lung Metastases [10], according to the presence or absence of three main risk factors: resectability, disease-free interval, and number of metastases. Group 1 included patients with all lung disease resected, with a single metastasis and with a disease-free interval of 36 months or more; group 2 included patients with all disease resected, and with either a single metastasis or a disease-free interval of 36 months or more; group 3 included patients with more than one metastasis completely resected and with a disease-free interval of less than 36 months. Group 4 of the International Registry of Lung Metastases, which included patients who underwent incomplete metastasectomy, had no representation in this study.
Figure 5 shows the respective Kaplan-Meier cumulative survival curves. We found highly significant differences (p = 0.0097) among these three groups. Five-year survival was 66.7% in group 1 and 42.8% in group 2, whereas group 3 patients had a survival of only 21.8% at 56 months.
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Comment |
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One of the selection criteria for metastasectomy is the absence of metastases elsewhere, but several authors consider that the presence of extrapulmonary metastatic disease is not a contraindication for pulmonary resection, as long as both are completely resectable [13]. Kobayashi and associates [13] found no significant difference in survival between a group of patients who underwent resection of both pulmonary and hepatic metastases and another group with resection of pulmonary metastases only. However, patients who had simultaneous pulmonary and hepatic resection (synchronous) had significantly lower survival than patients in whom hepatic metastases were resected before the diagnosis and resection of pulmonary metastases (metachronous).
Most pulmonary metastases do not cause symptoms and are detected incidentally on radiographic studies. In the literature, the incidence of symptoms ranged between 13% and 28% [14, 15], but 34.6% of our patients were symptomatic and they had a poorer survival. We found only one other study in which the presence of symptomatic disease seemed to have a significant influence in long-term survival [16].
All patients of this series underwent conventional surgery: video-assisted thoracoscopic surgery was not used. When video-assisted thoracoscopic surgery was introduced a few years ago, it rapidly won many followers and was adapted to metastasectomy. Being a minimally invasive technique, it is alleged to have numerous advantages, but currently most defenders concede that its use should be limited to the solitary, small (<3 cm), and peripherally located metastasis. Video-assisted thoracoscopic surgery depends on the accuracy of the preoperative examinations in identifying the exact number of pulmonary lesions, and there is a strong possibility of incomplete resection because of the inability to palpate the lung during the operation. It is almost unanimous that complete resection is the major prognostic factor for satisfactory long-term results, and this is not guaranteed with the thoracoscopic approach. In a prospective study, McCormack and colleagues [17] report a success rate of only 22% in detecting all lung nodules with video-assisted thoracoscopic surgery. They concluded that thoracotomy and manual palpation must remain the gold standard, even for solitary pulmonary metastases.
Resection of lung metastases is usually safe, with low morbidity and mortality rates. In the present series, there was no mortality, and morbidity was only 8.9% for all surgical procedures (11.5% for all patients). In the literature we found morbidity rates between 0% and 31.6% [17, 18] and operative and postoperative mortality ranged between 0% and 7.6% [16, 17].
Several factors that significantly influenced long-term survival have been described (Table 5). It is almost unanimous that complete resection is the major prognostic factor for long-term survival. This hypothesis was tested not only in retrospective studies of patients who underwent nonsurgical treatment some decades ago, but also in recent studies comparing patients who underwent complete and incomplete resection of metastases [10].
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In some studies, the histologic type of primary tumor was a determinant of long-term survival [10, 14, 21, 22], but the grade of differentiation of the primary growth was only found to be significant in one publication [23]. We could not confirm the prognostic value of either the histologic type or the grade of differentiation of the primary tumor. On the other hand, our experience confirms the good long-term survival in patients with pulmonary relapse who still fulfill the selection criteria for resection, in spite of recurrence.
The 5-year and 10-year survival rate of our patients was 47.4% and 37.7% respectively, and disease-free survival was 33.9% and 19.1% for the same periods. Other authors have reported 5-year survival between 10% and 63.7% [2, 3, 10, 13–16, 18–25], and the 10-year survival varied between 8.1% and 33% [2, 10, 16, 19, 25]. The 5-year disease-free survival ranged from 25% to 34% [15, 20].
The International Registry of Lung Metastases classification system [10], combining anatomic and biologic factors, was proven very useful in selecting patients for surgery on the basis of their likely prognosis. The predictive power of this system for survival [2, 10] is reinforced by the present study.
In conclusion, resection of epithelial pulmonary metastases is safe and effective, and is associated with very low perioperative morbidity and mortality and a reasonable 5-year and 10-year survival. In the present study, the disease-free interval and the prognostic grouping system proposed by the International Registry of Lung Metastases influenced significantly the long-term survival. The presence of symptoms showed a borderline predictable value in survival. Our results did not differ significantly from (and in many aspects compared favorably with) those described in the literature.
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References |
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