Key Results
The aim of the present study was to compare long-term clinical outcomes of the treatment of patients with pulmonary metastases to determine whether or not VATS is of disadvantage to the patient from an oncological standpoint. Our results show a 5-year overall survival rate of 70% in VATS patients. Open thoracotomy was taken as a reference treatment, with an expected survival of 50% since prior studies have demonstrated a 5-year survival ranging from 30–50% for the resection of pulmonary metastases. This study showed improved long-term survival in this group of patients treated with thoracotomy relative to previous studies [6–12], thereby supporting its consistent efficacy in the treatment of pulmonary metastases [17]. The Kaplan Meier analysis demonstrates that survival in this group of patients is comparable to the survival expected for lung cancer operations by thoracotomy [21].
Non-inferiority analysis suggests that the newer treatment (VATS) is not inferior to the standard treatment (thoracotomy). The 10% difference in overall survival was in favor of VATS, although this was not significantly different from those metastasectomies done using thoracotomy. However, since the estimated 5-year survival difference in our study of 0.108 was less than the non-inferiority margin set at 0.20, the findings support the conclusion that the 5-year overall survival rate using VATS is equivalent to thoracotomy for the treatment of pulmonary metastases. There were also no major differences in morbidity and mortality between both groups.
Selection of patients with the same prognosis is mandatory to accurately compare two therapeutic strategies. We took this into consideration to address the possibility that our analysis of non-inferiority is not valid given that the 36 patients in the VATS group had lesions associated with a more favorable prognosis. The two groups of this study were believed to be comparable in the majority of baseline patient and tumor characteristics with a few exceptions. Univariate and multivariate analyses demonstrated that age and primary tumor type were the only predictors of survival; however, from the adjusted analysis, we can infer that the imbalances in age and magnitude were not important and the groups are comparable in these features, and are unrelated to response to treatment. The only predictor which may influence the response to treatment is the primary tumor type.
Limitations
We recognize that our sample size calculation (using α of 0.01 and Δ of 0.20) was more appropriately indicative in a per-protocol (PP) analysis, which requires fewer patients than an intention-to-treat (ITT) analysis. Despite the marginal difference between the computed size and the evaluable patients, PP analysis is preferable since ITT tends to bias towards making two treatments look similar [14]. For future investigations, the risk of Type I error can be minimized by setting α below the standard 0.05, or choosing a smaller non-inferiority margin [17].
This study is also a retrospective investigation. A prospective randomized controlled trial on a large scale is necessary to reach definitive conclusions regarding the efficacy of VATS for the treatment of pulmonary metastases relative to other techniques. However, the possibility of designing a three arm non-inferiority trial is limited by the controversy of using surgical placebos. We feel that non-inferiority of VATS over thoracotomy was effectively demonstrated without the use of a placebo. In this study, VATS was compared to an efficacious therapy [6, 7, 11], and VATS was believed to be comparable to thoracotomy. This permits basing efficacy conclusions of VATS in this study [22]. We also recognize the possibility of bio-creep and recommend that future trials exercise caution in the selection of an appropriate comparator therapy and non-inferiority margin.
The present study may be subject to pretreatment selection bias given that group assignment was determined through a shared decision made between physician and patient. This can produce misleading estimates of the size and direction of treatment effects [23]. For example, most of the patients selected for open thoracotomy were those with sarcoma and multiple lesions; these are associated with higher risk, suggesting that surgeon was selecting. Furthermore, the smaller number of patients available who had VATS may further exaggerate the better outcomes. Despite these possibilities, multivariate methods were used to reduce confounding and both groups were believed to be comparable. The increasing use of VATS will yield more cases to evaluate in future comparative studies over a considerable length of time.
Interpretation
The present study demonstrates a favorable outcome in 5-year and possibly 10-year survival rates that will hopefully contribute to VATS gaining popularity in becoming a standard procedure. This is an interim evaluation until further follow-up can be obtained and reported. Although there is a difference in median follow-up, survivorship analysis allows for estimated survival rates to be more reliable, even when lengths of follow-up are not equal at any given date. The 10-year survival must be interpreted with caution since the number of subjects at risk at this time is small; however, the study adequately accounts for survivorship in both groups for at least 6 years after the start date.
The improved long-term survival seen in the present study relative to previous studies could be explained by a number of factors. The study includes patients from a single institution with extensive experience in treating pulmonary metastases, as well as a high volume of cases. Improvements in our ability to detect the progression of this disease may have occurred, as well as refinements in surgical techniques. The 5-year survival being better for VATS than thoracotomy could also be explained by the possibility of completer node clearance as a result of a clearer view and superior spread with VATS.
Altogether, among the prognostic variables tested in univariate analysis age, magnitude and primary tumor type were poor predictors of overall or recurrence free survival. After comparing the unadjusted and adjusted survival curves, primary tumor type remained as the only predictor that may influence the response to treatment. Furthermore, cancers known to be associated with poorer survival, such as testicular and melanoma, were all grouped into sarcoma. Most thoracotomy patients had sarcoma, which could explain the relatively lower overall and recurrence free survival compared to VATS. Patients with carcinoma had better overall and recurrence free survival, except for VATS patients with sarcoma who had the highest overall survival.
Although age does not seem to have a prognostic influence on overall survival in previously published reports [6, 8, 10, 12, 13, 15], this study demonstrates that age > 53 had a negative influence on overall survival. This could be explained by the fact that these patients altogether are closer to death in the timeline of their cancer, and they will die sooner. On the other hand, Welter and associates found a survival advantage for elderly patients [24]. The difference in median age at the time of initial metastasectomy might be explained by the fact that younger patients can tolerate an open procedure better-better respiratory reserve and better health condition overall. Also, older patients are not offered open thoracotomy simply because they will not live long enough to benefit from the procedure. In the cases of younger patients, surgeon might offer open approach to ensure extra exploration (given the patient can tolerate it).
Overall survival might be expected to be better in the younger thoracotomy patients, especially since most VATS patients were older than the median age. The survival analysis adjusted for age showed that overall survival remained higher in VATS patients aged > 53, although this was not significantly different compared to the thoracotomy subgroup. We have not found an explanation for this in the literature. The favorable survival in this subgroup of VATS patients might also be explained by having more patients with unilateral and single nodular disease.
Longer DFI seems to be a favorable prognostic factor [7, 15, 24], although this study did not demonstrates DFI as a predictor of survival. The most favorable time interval cannot be clearly established since patients with a DFI-1 > 5 years had a better 1-, 3- and 5-year overall survival, yet a poorer 10-year overall survival rate. We found that the length of DFI-1 is associated with the length of DFI-2 in only one study [7]. This study does not demonstrate this association, and the use of VATS did not negatively impact DFI-2. Median DFI-2 was slightly shorter in VATS, although not statistically significant. There was no major difference in median recurrence free survival, although recurrences were seen less often with VATS patients, and the recurrence free survival at 5-years was much better than in the open thoracotomy group.
We did not take into account to location or tumor size, but our experience leads us to believe that metastases located in the hilar region should be treated with thoracotomy and larger tumors should be treated with resection that optimizes complete removal. We did consider magnitude of resection. Wedge resection was associated with a poor RFS in univariate analysis, which was also the case in multivariate analysis. This information may have skewed in favor of the other procedures because this included patients with segmentectomy, lobectomy and pneumonectomy. Furthermore, the single patient with pneumonectomy also had 100% OS and RFS. Lastly, since most patients with recurrence in both groups were treated with wedge resection, this may not have been the most ideal resection for the patient regardless of the type of surgery done.
One of the general goals of surgical oncology is complete removal of all metastatic deposits. In the International Registry of Lung Metastases, complete removal of all metastatic deposits was associated with long-term survival [15]. The results of this study are in agreement with published reports. Complete removal was associated with a 5-year overall survival of 70% in VATS and 59% in thoracotomy. In the thoracotomy group, there was one case where the pathology report showed some positivity at the margin, and one case with gross residual disease. Both occurred at the time of second occurrence, and neither had a third metastatic occurrence.
Some issues exist concerning the safety of VATS. Prior studies have reported conversion of VATS to thoracotomy due to incomplete fissures [25]. In this study, patients were not converted for this reason. Other issues include incomplete resection, and port site and pleural cavity seeding [3]. Incomplete resection was seen in only 1 VATS patient and this patient did not meet inclusion criteria. There were no cases of pleural cavity seeding in this study. There was only a single case where 1 of 2 nodules was not shown on preoperative CT, subsequently detected intraoperatively by digital exploration. Overall, the use of VATS did not appear to compromise the safety of the patients in this study.