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Ann Thorac Surg 1998;66:908-913
© 1998 The Society of Thoracic Surgeons

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Original articles: General Thoracic

Reoperative pulmonary metastasectomy for sarcomatous pediatric histologies

^a Thoracic Oncology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
^b Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
^c Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Address reprint requests to Dr Pass, Dept of Surgery and Oncology, 3990 John R, Suite #2102, Detroit, MI 48201

Presented at the Forty-fourth Annual Meeting of the Southern Thoracic Surgical Association, Naples, FL, Nov 6–8, 1997.

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. The role for reoperative pulmonary metastasectomy in patients with "pediatric sarcomas" (osteosarcoma, nonrhabdomyosarcoma–soft tissue sarcoma, and Ewing’s sarcoma) is undefined.

Methods. We reviewed our results for patients with these histologic presentations (median age, 17.5 years; range, 6 to 32 years) having two (70), three (27), or four (10) metastasectomies between January 1965 and March 1995 to define postresection survival and potential prognostic factors. Simple wedges (88 thoracotomies, 84%) were performed more frequently than anatomic (17 thoracotomies, 16%) resections.

Results. With a median potential follow-up of 12.7 years, median survival was 2.25, 3.60, and 0.96 years from the second, third, and fourth explorations, respectively. Primary tumor site, sex, histology, age, maximal metastasis size, and systemic chemotherapy did not influence survival. Resectability was the most important prognostic factor (5.6 versus 0.7 years, 5.2 versus 2.5 years, 2.2 versus 0.2 years, resectable versus unresectable, median survival from second, third, and fourth thoracotomy, respectively). Unresectability, disease-free interval less than 6 months between initial (ie, first) pulmonary resection and the second thoracotomy, and two or more preoperative nodules noted on the right were simultaneously negatively associated with survival from the second thoracotomy. Unresectability or finding two or more metastases negatively affected survival from the third thoracotomy.

Conclusions. These data imply that repeat metastasectomy can salvage a subset of patients with sarcomatous pediatric histologic presentations who retain favorable prognostic determinants.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
A number of retrospective series have reported on the results of initial metastasectomy for sarcoma [1–16]. The outcome and prognostic indicators for success by performing repeat metastasectomy for recurrent disease was addressed by Pogrebniak and colleagues [17] in a series of patients with a median age of 41 years. Median survival from the second thoracotomy in resectable patients was 25 months versus 10 months for unresectable patients. An improved survival was predicted by a disease-free interval greater than 18 months between the first and second thoracotomies. We have reported on the results of a metastasectomy in a group of young (median age, 19 years) patients with sarcoma histologic presentations usually seen in a pediatric population. Resection of pulmonary metastases produced a median survival of 2.2 years from the initial thoracotomy with unfavorable prognostic factors related to the presence of 3 or more sarcoma nodules, histologic presentation other than osteosarcoma, and performance of an incomplete resection [16]. The current report examines the subset of patients from the original pediatric group [16] in whom subsequent pulmonary metastases developed for which reoperation were performed. Data were analyzed to define the surgical risk, survival, and associated prognostic indicators.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Patient population
From January 1, 1965, to March 1, 1995, 70 patients underwent at least 1 redo operation for the resection of pulmonary metastases by the Thoracic Oncology Section of the National Cancer Institute. There were 28 female and 42 male patients with an age range from 6 to 32 years and a median age of 17.5 years. The primary lesions were controlled in all cases and located in the extremity in 59 patients, trunk in 9, and head and neck in 2.

The histologic types were 36 osteosarcomas, 23 nonrhabdomyosarcomas, and 11 Ewing’s sarcomas. A third thoracotomy (second redo operation) was performed in 27 patients and a fourth thoracotomy (third redo) in 10. Preoperative symptoms were present in 13 patients and included cough (4), chest pain (4), dyspnea (2), fever (1), dysphasia (1), and hemoptysis (1).

Preoperative evaluation
All patients were under the auspices of protocols of the Pediatric Oncology Branch of the National Cancer Institute. Sixty-six received adjuvant chemotherapy under clinical protocols. After initial thoracotomy for pulmonary metastasectomy, patients were followed up at 3-month intervals with computed tomography (CT) or linear tomography (LT) of the chest. Full lung LT was accomplished as contiguous 1-cm increments in the coronal plane. Chest CT used a GE 8800 CT/C scanner (General Electric Company, Fairfield, CT) and generated transaxial slices at 10-mm-thick intervals of the entire thorax with image display in a 256 x 256 matrix. Nodules were identified as new discrete areas of increased density, which were spherical, nonlinear, and subpleural or intraparenchymal. Surveillance included radiologic evaluation of control of the primary site and yearly bone scan. When recurrence was confined to the chest, patients were considered to be surgical candidates based on their ability to tolerate the operation. Pulmonary function tests were performed only if an anatomic resection was contemplated or if a significant amount of lung parenchyma had already been resected.

Operative procedure
The approach to the operation has been previously reported [2]. The major technical details included the use of median sternotomy, single posterolateral thoracotomy, or staged thoracotomies for a thorough assessment of the lungs, lymph nodes, mediastinum, and chest wall. Deflation of the lungs by double-lumen endotracheal intubation facilitated palpation of nodules. With the exception of obvious granulomas and intrapulmonary lymph nodes, all abnormalities were resected if possible. Metastases were often subpleural, and wedge resections were performed with automatic stapling devices. In selected cases, to obtain a clear margin of resection, segmental resection was performed by lobectomy or pneumonectomy only if the patient could be rendered disease free. Moreover, procedures for lung resection might be combined, such as wedge and segmentectomy or wedge with lobectomy. All specimens were labeled as to anatomic location and submitted for histologic evaluation. For the purposes of the statistical analyses, patients who had incomplete resection (ie, residual disease left behind) and patients who were found to have too numerous to count nodules and only had a biopsy performed were classified as "unresectable."

Statistical analysis
Survival durations were calculated from the date of the second, third, or fourth thoracotomy until the date of last follow-up. The probability of survival was calculated using the Kaplan-Meier method [18], and the significance of the difference between pairs of Kaplan-Meier curves was calculated using the Mantel-Haenszel procedure [19]. A detailed list of factors was examined for association with survival including age, sex, histology and location of the primary tumor, chemotherapy before the second thoracotomy, right and left histologically proven nodule at the second and third operations, number of histologically proven sarcoma nodules at each redo operation, maximal nodule size at second and third thoracotomies, number of nodules scanned before the second, third, and fourth thoracotomies, number of right and left nodules scanned before the second and third thoracotomies, initial disease-free interval (DFI) defined as the time in months from primary operation to first pulmonary metastases operation, DFI between first thoracotomy until pulmonary metastases, DFI between first and second thoracotomy, DFI between second and third thoracotomies, and DFI between third and fourth thoracotomies.

The Cox proportional hazards model was used to identify which factors are jointly significant in their association with survival [20]. The resulting model parameters (b_i) were converted to relative risks by computing where [21]. The 95% confidence interval for the relative risk was computed as where and The relative risk indicates the risk associated with dying while being in a greater risk category compared with that of being in a lower risk category. Only those variables that had potential associations with survival as demonstrated by a p value of 0.10 or less in the univariate (Kaplan-Meier) analyses and for which information was available on all or most patients were included in the Cox models.

This analysis was exploratory in nature, and results obtained should ideally be confirmed independently. For parameters that could be considered as continuous variables, initial univariate survival analyses were performed by dividing the data into quartiles based on this variable, and then selecting for inclusion in a Cox model the dichotomy with the smallest p value after regrouping. Thus, with separation into quartiles, the best of three possible separations was selected for the Cox model. As a result, one could appropriately multiply the obtained p value by 3 to account for the implicit multiple comparison analyses being performed by this procedure.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
The data from 107 thoracic operations were analyzed.

Preoperative roentgenographic studies
There were 18 instances in which the number of nodules on preoperative CT or LT was characterized only as "multiple." Before the first redo operation 121 nodules were documented roentgenographically; 207 nodules were subsequently resected at this second thoracotomy of which 154 were histologically positive (121/207/154). The corresponding figures for the second and third redo operations were 34/55/54 and 20/25/23, respectively. The totals of these results (175/287/231) indicate that preoperative studies underestimated the total number of nodules by 39% and missed 24% of the histologically proven metastases.

Operative findings
Complete resection was accomplished in 73% of second thoracotomies, 87% of the third thoracotomies, and 70% of fourth thoracotomies. Overall complete resection rate was 77% of the 107 cases. In the 25 incomplete resections, 4 cases (16%) left only microscopic residual disease. The incisions used for these reoperative metastasectomies were as follows: first redo: 29 single thoracotomies, 36 median sternotomies, 5 staged thoracotomies; second redo: 18 single thoracotomies, 8 median sternotomies, 1 bilateral synchronous thoracotomy. Thoracotomy was more often performed when dense adhesions from previous procedures were anticipated or for nodules situated posteriorly or deeply intraparenchymal. Wedge resection was accomplished in 78% of the operations. The specific resections were 83 wedge, 6 wedge with lobectomy, 3 wedge with segmentectomy, 2 wedge with other procedure, 1 wedge with chest wall, 1 wedge with lymph node sampling, 4 lobectomies, 3 segmentectomies, 2 pneumonectomies, 1 segmentectomy, and 1 other.

Operative mortality and morbidity
Mortality was 1% in a patient who died on postoperative day 74 because of respiratory insufficiency from progressive unresectable disease after a third redo thoracotomy. There was a 5.6% total morbidity rate from air leak (3 patients), superficial wound infection (1 patient), and pneumonia (2 patients).

Median survival after resection
Median survival was 2.25 years (5.6 years resectable versus 0.7 years unresectable; p₂ < 0.0001) from the time of the first reoperative thoracotomy. The survival duration from the second redo was 3.6 years (5.2 years versus 0.25 years; p₂ < 0.0001) and from the third redo was 0.96 years (2.2 years versus 0.2 years; p₂ < 0.0008).

Survival results and prognostic indicators
Univariate analyses determined that there was no significant impact of sex, age, histology and location of the primary tumor, chemotherapy before the second thoracotomy, or maximal size of the nodules resected at the second and third thoracotomy on survival duration from the date of the second, third, or fourth thoracotomy. There were, however, many factors that were identified by univariate analysis to be potentially associated with survival. For survival from second thoracotomy the following factors were identified: resectability; number of right-sided, left-sided, and total number of histologically proven sarcoma nodules; number of right-sided and left-sided and total number of nodules scanned; and the interval from first to second thoracotomy.

For survival from third thoracotomy the following factors were identified: resectability; number of left-sided nodules and total number of histologically proven nodules; and number of left-sided nodules and total number of nodules scanned. For survival from a successful second thoracotomy (ie, complete resection) the following factors were identified: number of right-sided and left-sided and total number of histologically proven nodules; number of right-sided and left-sided and total number of nodules scanned; and the interval between the first and second thoracotomy.

Cox proportional hazard models were constructed using the parameters that were found to be at least marginally prognostic based on the univariate analysis, eg, those with Mantel-Haenszel p values of 0.10 or less. Separate models were constructed for survival from second thoracotomy, third thoracotomy, or second thoracotomy with a complete resection. Models developed are presented in Tables 1, 2, and 3. In Table 1 the result is parameterized to present those factors that are negatively associated with outcome, eg, being unresectable, having an interval of less than 6 months between first and second thoracotomy, and having two or more right nodules scanned are those factors that are simultaneously negatively associated with survival. Table 2 shows that being unresectable at the thrd thoracotomy and having two or more histologically proven nodules at the third thoracotomy are simultaneously associated with decreased survival. Table 3 indicates results similar to those obtained for all patients with a second thoracotomy, but with different relative risks. Figures 1 through 3 correspond to the parameters included in the Cox models developed in Table 1.

View larger version (14K): [in this window] [in a new window]   Fig 1. Influence of resectability on survival after reoperative metastasectomy. See Table 1 and text for details.

View larger version (14K): [in this window] [in a new window]   Fig 2. Influence of number of preoperative nodules (right) on survival after second metastasectomy. See Table 1 and text for details.

View larger version (14K): [in this window] [in a new window]   Fig 3. Influence of disease-free interval from the first to the second thoracotomy on survival. See Table 1 and text for details.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

The surgical approach used was in keeping with previous publications from our center [2]. Emphasis needs to be placed on careful palpation of the lung parenchyma to ensure complete resection of pulmonary metastases, which is the major surgical prognosticator for satisfactory outcome [1, 2, 4, 8, 10, 13, 15–17]. As has been reported by McCormack and associates [22], video-assisted thoracic surgery should only be used as a diagnostic tool. Bilateral lung exploration is permitted by median sternotomy or the "clamshell" incision as the initial surgical approaches until thoracotomy is favored because of anatomic location of the nodules or projected extensive adhesions. Examination of the lung as well as lysis of adhesions is facilitated by double-lumen endotracheal intubation. The low operative mortality and morbidity confirms the logic of this management and is consistent with the literature [2, 16, 17]. Conduct of the anesthesia can contribute to the immediate postoperative outcome, and careful monitoring of the oxygen saturation and fluid administration is essential because the patient’s pulmonary reserve may be affected by multiple previous surgical resections and chemotherapy. The 77.5% rate of wedge resection follows a principle of lung conservation combined with adequate margins to prevent local recurrence.

The goal of operative intervention is to significantly improve on the documented median survival of 7 to 12 months from progressive sarcoma [17, 23, 24]. A number of factors have been investigated in the literature as to possible association with survival. A consistent finding associated with improved survival is the resectability of all pulmonary metastatic disease [1, 2, 4, 8, 10, 13, 15–17]. In adult soft tissue sarcomas, Pogrebniak and coworkers [17] reported that patients having complete resection at a second operation for recurrent pulmonary metastases have a prolonged median survival to 25 months. Similar results were found in our pediatric series for patients who had reoperative metastasectomy and could be rendered disease free after the second, third, and fourth thoracotomy for pulmonary relapses. Because of the limitation of preoperative diagnostic methods the ultimate determination of resectability must be made in the operating room.

There have been conflicting data on the survival impact of DFI for osteogenic and soft tissue sarcoma as defined from primary resection to pulmonary metastases. Correlation can be found in several reports [2, 14, 15] but not in others [16, 17]. In the adult soft tissue sarcoma reoperation series reported by Pogrebniak and associates [17] and in this investigation a longer DFI between the first and second thoracotomies favorably influenced survival. However, the adult series [17] established a favorable DFI as more than 18 months compared with more than 6 months for pediatric histologies. It should be noted that in this study, as well as in the publication by Pogrebniak and colleagues [17], the DFI between resection of the primary tumor and the first thoracotomy was not a predictor of survival.

The present patient studies found that the number of nodules scanned as well as the number of documented nodules at thoracotomy will influence survival. It is difficult to attach a given number to survivorship; however, patients should not be excluded for operation if they have a low number of nodules scanned. In the initial analysis for metastasectomy for sarcomatous pediatric histologic presentations, having three or more metastases at operation was an adverse predictor for survival [16]. There is no consensus for these data in the literature, and results in other studies have indicated no impact on the number of nodules resected in patients rendered free of disease. Pogrebniak and coworkers [17] did state that there was a trend toward decreased survival if five or more nodules were seen in the studies before the second metastasectomy (p = 0.081) and other publications have shown a survival difference relative to nodule number [1, 3, 13]. The factors of age, sex, histology and location of the primary tumor, chemotherapy before the second thoracotomy, and maximal nodule size at the second and third thoracotomies made no difference to survival.

This study as well as the other reports in the literature support an aggressive surgical approach to pulmonary metastases in osteosarcomas, nonrhabdomyosarcomas, soft tissue sarcomas, and Ewing’s sarcomas. Because the majority of these patients received postoperative chemotherapy according to National Cancer Institute protocols, it is impossible to ascertain whether this influenced survival compared with patients who had only complete resection. The aim should be resection of all metastases with a minimal loss of functional lung tissue. With the exception of resectability, analysis of prognostic indicators has produced different results from individual publications. This reflects the limitations of retrospective investigations that incorporate heterogeneous data. Our data indicate that nodule number, DFI, and the ability to perform a complete resection are important prognostic indicators in this population, and these factors should at least help in the dissemination of prognostic information to the family [25].

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Barbara K. Temeck Harvey I. Pass Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Temeck, B. K. Articles by Pass, H. I. Search for Related Content PubMed PubMed Citation Articles by Temeck, B. K. Articles by Pass, H. I.