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Interact CardioVasc Thorac Surg 2009;9:649-653. doi:10.1510/icvts.2009.212498 © 2009 European Association of Cardio-Thoracic Surgery
Repeat resection of pulmonary metastasis is beneficial for patients with osteosarcoma of the extremities
a Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan Received 22 May 2009; received in revised form 8 July 2009; accepted 9 July 2009
*Corresponding author. Tel.: +81-75-751-3835; fax: +81-75-751-4647.
Pulmonary metastasectomy in osteosarcoma can lead to long-term survival, but the role for repeat pulmonary metastasectomy is undefined. To confirm the value of repeat pulmonary resection of recurrent pulmonary metastases, we herein reviewed our institutional experience. Between 1989 and 2007, 25 patients with pulmonary metastases from osteosarcomas of the extremities underwent pulmonary resection, and 14 patients underwent repeat pulmonary metastasectomy. Ten of 14 patients underwent complete resection. Various perioperative variables were investigated retrospectively in these patients to confirm a role for repeat metastasectomy and analyze prognostic factors for overall survival (OS) after repeat pulmonary metastasectomy. OS rate after repeat pulmonary metastasectomy was 43% at two years and 19% at five years. On multivariate analysis, patients with complete resection presented significantly favorable OS (P=0.02). Interestingly enough, survival curve of patients with complete resection after the first pulmonary metastasectomy was almost the same as that of patients with complete resection after the second pulmonary metastasectomy. In conclusion, patients with complete resection for recurrent pulmonary metastasis show a significantly better prognosis after repeat pulmonary metastasectomy. Our data imply that repeat pulmonary metastasectomy might be beneficial because it can salvage a subset of patients with osteosarcoma who retain favorable prognostic determinants.
Key Words: Lung; Metastasectomy; Osteosarcoma; Recurrence; Repeat resection
Surgical resection has been consistently shown to prolong survival among patients with pulmonary metastases [1], and similar results are obtained for lung metastases from osteosarcoma [2–7]. The unique characteristics of osteosarcoma, including metastatic affinity for the lung, make pulmonary metastasectomy a central component of therapy for this disease [1]. Approximately 50% of patients with osteosarcoma develop synchronous or metachronous metastatic lung diseases, and only 20–40% of those found to have pulmonary metastases will survive five years [2–7]. Although the prognosis for patients with osteosarcoma has recently improved dramatically, those who develop metastatic pulmonary disease still continue to pose a particularly difficult challenge. There are several reports about the survival and the prognostic factors for patients with pulmonary metastasectomy for osteosarcoma [2–7], but there are few data in the literature on patients who have undergone repeat pulmonary metastasectomy for osteosarcoma [8, 9]. Thus, we reviewed the clinical data of patients with osteosarcoma treated with pulmonary metastasectomy in our hospital to determine the long-term results and the prognostic predictors of survival in this subset of patients.
From December 1989 to November 2007, according to our medical records, 25 patients had received pulmonary resection for the first time due to metastases of osteosarcoma of the extremities. Twenty-three of them underwent complete resection. Furthermore, 17 patients presented recurrence after the first metastasectomy and 14 patients underwent repeat pulmonary metastasectomy (Fig. 1). The patients were 10 males and 4 females with a median age of 22 years (range, 10–54 years) at the time of repeat pulmonary metastasectomy. Multimodality treatment consisting of surgery and chemotherapy were conducted in all cases. Diagnosis of metastatic pulmonary nodules was made by X-rays and computed tomography that was routinely examined at several months interval after the first diagnosis of primary tumor. Further examinations were also performed to exclude extrapulmonary metastases.
All patients who underwent resection of their pulmonary metastases at any time met the following criteria: (1) pulmonary lesions were deemed resectable not only by radiological examinations but also by the patients' general conditions, (2) metastatic disease was limited to the lungs, and (3) locoregional control of their primary cancer was obtained or obtainable. Complete resection was defined as no tumor cell at the surgical margin of the resected lung that was examined macroscopically and histologically. All the visible and palpable nodules were resected during the surgery and subjected to histological examination for confirmation of the diagnosis of metastases. The surgical approach was chosen according to the location and number of pulmonary nodules. Therapeutic control for patients with lung metastases was based on the surgery in combination with pre- and/or postoperative multiagent chemotherapy. As to the treatment of osteosarcoma in the original site, all the patients undertook the surgery in combination with neoadjuvant and/or adjuvant chemotherapy consisting of multiagents. The detailed regimens of chemotherapy were different among patients; however, cisplatin, adriamycin, etoposide, methotrexate, and isofamide were used as antitumor drugs for chemotherapy pre- and postoperatively. All patients were retrospectively analyzed for age, gender, detection of the first pulmonary metastasis, recurrence of primary tumors before pulmonary metastases, disease-free interval (DFI), number of pulmonary metastases, location of metastases, complete resection, and number of metastasectomy for pulmonary recurrence, regarding long-term survival. The endpoint was overall survival (OS) after the repeat pulmonary metastasectomy. DFI-1 was defined as the duration from the resection of the primary tumor to the initial diagnosis of the metastatic pulmonary tumor. DFI-2 was defined as the duration from the first pulmonary metastasectomy to the diagnosis of the recurrent pulmonary metastasis. OS was defined as the time between the repeat resection of pulmonary metastasis and the date of the last follow-up or death. Statistical analysis was performed using the StatView (version 4.5) software package (Abacus Concepts, Berkeley, CA). The postoperative survival rate was analyzed by the Kaplan–Meier method. The prognostic influence of variables on survival was analyzed using the log-rank test for univariate analyses and the Cox's proportional hazards model for multivariate analyses. Differences were considered significant when P<0.05.
Fourteen patients with recurrent pulmonary metastases from osteosarcomas underwent a thoracotomy and resection. The sites of primary tumors were the femur in eight cases, the tibia in five cases, and the humerus in one case (Table 1). In all cases, the primary tumors were resected completely. DFI-1 varied from 0 month to 9 years, including one case (7%) with simultaneous detection of the first pulmonary metastasis and the primary tumor. DFI-2 varied from 3 months to 8 years. In four patients (29%), lung metastases were found to be bilateral, while 10 patients (71%) had a solitary pulmonary metastasis. Ten of 14 patients underwent complete surgical resection. As of four patients with incomplete resection, two patients had bilateral metastatic lesions and were planned to undergo a staged bilateral thoracotomy; however, in all cases the disease exacerbated after unilateral metastasectomy. The remaining two patients had unilateral metastatic lesions, but one of them found pleural dissemination at the time of thoracotomy, and the other presented a new extrathoracic metastatic lesion at the perioperative time. Ten patients with unilateral tumors underwent a unilateral thoracotomy for resection of their metastases. One of four patients with bilateral tumors underwent simultaneous bilateral thoracotomy, whereas three patients had planned a staged bilateral thoracotomy for bilateral lesions; however, two patients were forced to abandon the contralateral surgery as described before. As for the number of surgeries, staged bilateral thoracotomies were counted as one operation. An attempt was made to conserve as much lung tissue as possible. This was reflected by the fact that wedge resections were the most common procedures performed. No patients died directly of surgery.
The median time at follow-up examination was 16 months (range 1–208 months). Of 10 patients with complete resection, three patients (30%) remained free of disease after repeat pulmonary metastasectomy, and seven patients (70%) developed recurrences, the majority of which were located in the chest. Seven of eight recurrent patients (88%) underwent a third metastasectomy for the re-recurrent pulmonary metastases. Three and two patients underwent fourth and fifth metastasectomy, respectively. The OS rate was 42.9% at two years and 19.0% at five years after pulmonary resection (Fig. 1). Three (21%) patients are currently alive without evidence of disease and no patient is alive with disease. Eleven patients (79%) died of disease, and none died of other causes. Univariate analysis showed that a better OS was observed for patients without lung metastases identified during chemotherapy (P=0.0036), without recurrence of primary tumors ahead of lung metastases (P=0.017), with DFI-1 <1 year (P=0.029), and with complete resection (P=0.0058) (Table 2, and Fig. 2). However, on multivariate analysis, patients with complete resection presented significantly favorable OS (P=0.021) (Table 3). Interestingly enough, survival curve of patients with complete resection after the first pulmonary metastasectomy was almost the same as that of patients with complete resection after the second pulmonary metastasectomy (Fig. 3).
Pulmonary metastasectomy has become the standard therapy for various metastatic malignancies to the lungs and pulmonary metastasectomy in osteosarcoma is also thought to lead to long-term survival [1, 2]. Unlike epithelial cancers, around 50–60% of patients with osteosarcoma relapse only in the lung, making pulmonary metastasectomy a viable option for treatment [8]. Furthermore, 40% of patients who relapse after pulmonary resection again exhibit recurrence in the lung [10]. There are several encouraging studies about repeated surgical interventions for recurrent metastases from various primaries [11–13]; however, few data are available in the literature on patients who have undergone repeat pulmonary metastasectomy for osteosarcoma [8, 9]. Therefore, we decided to report our experience with repeat pulmonary metastasectomy in patients with osteosarcomas and to evaluate its role in their treatment focusing on OS. The 5-year OS rate for patients who underwent first pulmonary metastasectomy for osteosarcomas was up to 40% in several reports [3–7]. Since Fig. 3 showed that the 5-year OS rate for patients who underwent first pulmonary metastasectomy was 36%, our attitude toward the first pulmonary metastasectomy for osteosarcomas appeared to be acceptable. Biccoli et al. showed that patients who have a second metastasectomy have the same probability of disease-free survival as those operated upon the first time [8]. Bielack et al. stated in their most recent and largest series that five-year OS for the second recurrence was 16%, while it went up to 32% when a renewed surgical remission was achieved [9]. On the other hand, we demonstrated that patients who have a second metastasectomy with complete resection have the same probability of OS as those who have a first metastasectomy with complete resection. To date, various parameters, such as DFI, completeness of the resection, timing of metastases, number of metastases, tumor size, and laterality of metastases have been reported as prognostic factors for the first metastasectomy [2–7], but there are few reports about the repeat pulmonary metastasectomy for osteosarcoma [9]. Bielack et al. described several parameters, such as shorter interval for recurrence, multiple lesions, failure to achieve a macroscopically complete surgical remission, and no chemotherapy administered for recurrence, as adverse prognostic factors for OS after the second recurrence on multivariate analysis [9]. In this study, several prognostic factors for the repeat pulmonary metastasectomy were found on univariate analysis, but a better OS was observed for patients with complete resection on multivariate analysis. Complete resection has been reported to be a better prognostic factor for OS after the first pulmonary metastasectomy in many studies [3, 6, 14]. Furthermore, complete resection has also been shown as a favorable prognostic factor for reoperative pulmonary metastasectomy for osteosarcoma and sarcomatous pediatric histologies [9, 15]; however, we should keep in mind that our study consisted of a small number of patients, so the accumulation of cases is necessary to evaluate a prognostic factor properly and to determine the selection criteria for resection. It is interesting that whether complete resection is performed or not is only determined after the surgical intervention is done. In this sense, our results support the idea that survival benefit will be obtained if pulmonary metastasectomy is performed aggressively and repetitively [2, 4, 8, 9]. There are several limitations to our analysis. The retrospective design is the most practical way of addressing our question because of the incidence of osteosarcoma, but the results should be interpreted carefully. Chemotherapeutic regimens have evolved substantially and rapidly over the last three decades and continue to be highly individualized based on unique patient and tumor characteristics, but we could not analyze our patients in this study because of a lack of complete data. It could be hypothesized that long-term survivors have biologically different and less aggressive tumors. In addition, since our results were based on the small number of patients in one institution, we needed a long study period to increase the number of patients in our study; however, several factors related to this could affect the results, such as the fact that a diagnostic modality had been changed due to the introduction of PET scan. Therefore, a prospective, large-scale study with multiple institutions would be inevitable in the future to reconfirm the current results. In conclusion, patients with complete resection for recurrent pulmonary metastasis show a significantly better prognosis after repeat pulmonary metastasectomy. Our data imply that repeat pulmonary metastasectomy might be beneficial because it can salvage a subset of patients with osteosarcoma who retain favorable prognostic determinants.
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Abstract
1. Introduction
