J Clin Oncol 26: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 26 NUMBER 31 NOVEMBER JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Outcome After Surgical Resections of Chest Wall Sarcomas Michael W. Wouters, Albert N. van Geel, Lotte Nieuwenhuis, Harm van Tinteren, Cees Verhoef, Frits van Coevorden, and Houke M. Klomp From the Departments of Surgical Oncology and Medical Statistics, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam; and the Department of Surgical Oncology, Erasmus Medical Center, Daniel den Hoed kliniek, Rotterdam, the Netherlands. Submitted March 31, 2008; accepted June 10, 2008; published online ahead of print at on September 15, Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Michael W. Wouters, MD, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; m.wouters@nki.nl by American Society of Clinical Oncology X/08/ /$20.00 DOI: /JCO A B S T R A C T Purpose Sarcomas of the chest wall are rare, and wide surgical resection is generally the cornerstone of treatment. The objective of our study was to evaluate outcome of full-thickness resections of recurrent and primary chest wall sarcomas. Patients and Methods To evaluate morbidity, mortality, and overall and disease-free survival after surgical resection of primary and recurrent chest wall sarcomas, we performed a retrospective review of all patients with sarcomas of the chest wall surgically treated at two tertiary oncologic referral centers between January 1980 and December Patient, tumor, and treatment characteristics, as well as the follow-up of these patients, were retrieved from the patients original records. Results One hundred twenty-seven patients were included in this study, 83 patients with a primary sarcoma and 44 patients with a. Age, sex, tumor size, histologic type, grade and localization on the chest wall were similar for both groups. Fewer neoadjuvant and adjuvant therapies were used in the treatment of s. Chest wall resection was more extensive in the recurrent group, which did not result in more complications (23%) or more reinterventions (5%). Microscopically radical resection was achieved in 80% of the primary sarcomas and 64% of the s. With a median follow-up of 73 months, disease-free survival after surgery for s was 18 months versus 36 months for primary sarcomas, with 5-year survival rates of 50% and 63%, respectively. Conclusion Although chances for local control are lower after surgical treatment of recurrent chest wall sarcoma, chest wall resection is a safe and effective procedure, with an acceptable survival. J Clin Oncol 26: by American Society of Clinical Oncology INTRODUCTION Sarcomas account for approximately one percent of all malignancies in adults. Only 10% to 15% arise in the chest wall. Generally, surgical resection is the treatment of choice, with a wide full-thickness chest wall resection, a skeletal reconstruction, and soft tissue coverage. may be preceded or followed by radiotherapy or chemotherapy. Parallel to the extent of the resection, the rigidity of the chest wall is affected, which can lead to significant morbidity and even mortality. This could especially be true for resections of s after previous chest wall resection. In the literature, few data are available regarding the appropriate management of patients with recurrent sarcomas of the chest wall. 1 Most series are heterogeneous, describing resections for sarcoma as well as carcinoma, without distinguishing primary, recurrent, and metastatic disease. To our knowledge, the largest series of recurrent chest wall sarcomas described 17 patients. 2 To analyze the safety and effectiveness of chest wall resections for primary and recurrent sarcoma, we evaluated morbidity, mortality, and oncologic outcome of a consecutive series of chest wall resections from two tertiary referral centers in the Netherlands. PATIENTS AND METHODS From the histopathologic results in file of the department of Pathology of the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital and the Erasmus Medical Center/Daniel den Hoed Clinic, 133 consecutive full-thickness chest wall resections for sarcoma were identified. Both hospitals are referral centers for the treatment of soft tissue 2008 by American Society of Clinical Oncology 5113

2 Wouters et al tumors in the Netherlands. Resections were performed between January 1980 and December Pretreatment patient evaluation included medical history and physical examination, baseline assessment of pulmonary function, chest x-ray, and magnetic resonance imaging or computed tomography of the chest wall tumor site. Patients were seen by oncologic surgeons (mainly F.v.C. and A.N.v.G.) for assessment of feasibility of primary resection or reexcision surgery. The appropriateness of neoadjuvant and adjuvant radiation or chemotherapy treatment was discussed in multidisciplinary teams. Resection of either primary or recurrent sarcoma was performed with an intentional 1- to 2-cm margin of normal soft tissue surrounding the mass, wherever feasible. In cases in which the tumor was in proximity to functionally significant but not directly involved neurovascular structures, the margin could be less than 1 cm. For this study, we defined chest wall sarcoma as any sarcoma involving ribs, sternum, costovertebral junction, or vertebral body. Tumors of the clavicle or scapula, without expansion into the ribs or sternum, were excluded. Retrospectively, patient, tumor, and treatment characteristics of Table 1. Patient, Tumor, and Treatment Characteristics of Chest Wall Resections for Sarcoma (n 83) (n 44) Characteristic No. of Patients % No. of Patients % Age, years Median Range Sex Male Female Histology Chondro/osteosarcoma Liposarcoma Fibrosarcoma Pleiomorphic sarcoma Leiomyosarcoma Angiosarcoma Sarcoma NOS Other Tumor grade Low Intermediate High Unknown Location Ventral Lateral Dorsal Sulcus superior Neoadjuvant treatment None Chemotherapy Radiotherapy Intention of surgery Curative Salvage Skeletal resection Ribs Median Range Sternum Other (vertebra, scapula, clavicle, four quarter) Reconstruction None Mesh alone Omentum Myocutaneous flap Unknown Adjuvant treatment Radiotherapy Chemotherapy Total No. of patients Abbreviation: NOS, not otherwise specified by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

3 Outcome After Resection of Chest Wall Sarcomas Table 2. Outcome After Chest Wall Resections for Sarcoma Outcome No. of Patients % No. of Patients % Complications None Bleeding Infectious Reconstructive failure Pulmonary Cardiac Other Reoperations Hospital stay, days Median 9 12 Maximum In-hospital mortality Margins R R R Unknown Recurrence None Local Distant Median disease-free survival, months Median survival, months Median follow-up, months Total No. of patients patients were retrieved from the patients original records, completed with detailed information about postoperative morbidity and mortality. Patients were classified to the primary sarcoma group when a fullthickness chest wall resection for a primary sarcoma was performed in the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital or the Erasmus Medical Center/Daniel den Hoed Clinic. Patients belonged to the recurrent sarcoma group when they presented with a recurrent sarcoma or had only a superficial chest wall resection for the primary tumor. Two independent investigators reviewed the pathology reports (L.N. and M.W.W.). A macroscopically irradical (R2) resection was defined as gross irresectable tumor or spill, and a microscopically positive (R1) margin was defined as tumor extension to the inked margin on permanent histopathologic Chest wall sarcomas (N = 127) sarcomas (n = 83; 65%) sarcomas (n = 44; 35%) Recurrence (n = 41; 49%) Disease free (n = 42; 51%) Disease free (n = 11; 25%) 2nd (n = 33; 75%) Fig 1. Recurrence patterns after chest wall resection for primary and recurrent sarcoma. Local (n = 17; 41%) Local and distant (n = 3; 7%) Distant (n = 21; 51%) Local (n = 20; 61%) Local and Distant (n = 1; 3%) Distant (n = 12; 36%) (n = 5; 29%) (n = 12; 60%) by American Society of Clinical Oncology 5115

4 Wouters et al sections. Cases in which tumors did not extend to the inked margin were considered to have microscopically negative (R0) margins. Follow-up information was retrieved from the patients original records. Incidence, type, and time of, as well as localization and treatment of s, were entered into the database. Kaplan and Meier analysis was used to estimate overall survival (OS) and disease-free survival (DFS). Survival times were calculated from the date of operation. Differences in survival were estimated by log-rank analysis. All statistical analyses were performed using the statistical software package SPSS, version 15.0 (SPSS, Chicago, IL). during follow-up. These distant metastases mainly occurred in the lungs (14 of 21 patients and nine of 12 patients, respectively). Other locations were bone, liver, and brain. The treatment of metastases with combinations of chemotherapy, surgery, or radiotherapy was similar in both groups. In the absence of distant metastases, second local s were often treated surgically, but reresections were performed more often in the group (60%) than in the primary group (29%), as shown in Figure 2. RESULTS Of the 133 patients in our series, 83 patients underwent chest wall resection for primary sarcoma, 44 patients underwent chest wall resection for recurrent sarcoma, and six patients underwent chest wall resection for a distant metastasis in the chest wall. These six patients were excluded. In the recurrent sarcoma group, 35 patients had a previous full-thickness chest wall resection. Nine patients underwent a superficial resection for their primary sarcoma (primary resection regarded to be radical). Patient and tumor characteristics are listed in Table 1. There were only minor differences in age, sex, comorbidities, histologic type, localization, and grade between patients in the primary sarcoma group and in the group. Neoadjuvant and adjuvant therapies were used more often in the primary than in the group. Especially chemotherapy was delivered more often in the primary sarcoma group as a part of a multimodality treatment. Two patients in the primary sarcoma group and one patient in the recurrent group underwent salvage surgery. In all other patients, a chest wall resection was performed with a curative intent. Additional to earlier resections, a median number of 2.4 ribs were resected in the group, which is similar to the number of resected ribs in the primary sarcoma group. In patients in whom no additional ribs were resected, another part of the bony thorax was excised, for example, part of the sternum. The skeletal reconstructions to cover the defect in the chest wall are listed in Table 1. Postoperative morbidity was similar in the two groups. Operative reintervention for complications was performed in three patients in the primary sarcoma group and in two patients in the group. Median hospital stay was 3 days longer for patients in the group (Table 2). R0 resection was achieved in 80% of patients with a primary chest wall sarcoma and in 61% of the patients with a recurrent sarcoma. With a median follow-up time of 73 months, almost half of the patients with recurrent sarcomas had a second on the chest wall (48% as compared with 24% in the primary group). Only 25% of patients with a resection for recurrent sarcoma remained tumor free, as compared with 51% of the patients after a primary resection. In the group of patients who underwent surgery for, considerably more local than distant s were seen. Of all patients with irradical resections, 86% developed recurrent disease (94% in the group and 63% in the primary group). Figure 1A shows the DFS curves: median DFS was 36 months after resection for primary sarcoma and 18 months after resection of recurrent sarcoma. OS is shown in Figure 1B. In both groups, approximately one of four patients (25% v 27%) developed distant metastases DISCUSSION We analyzed the results of 127 full-thickness resections for chest wall sarcoma, of which 44 were performed for. Analysis A B Disease-Free Survival (probability) Overall Survival (probability) Time From (months) Time From (months) Fig 2. (A) Disease-free survival and (B) overall survival of patients after chest wall resections for primary and recurrent sarcomas by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

5 Outcome After Resection of Chest Wall Sarcomas showed that a full-thickness surgical resection is a safe and effective procedure, with a limited number of complications, and is associated with adequate long-term survival, even for recurrent chest wall sarcoma. Sarcomas of the chest wall are uncommon. The available literature consists of a number of series, often with mixed differentiation (sarcoma/carcinoma), histologic subtype, and presentation as a primary or recurrent sarcoma. Reviewing the literature, we found 16 articles reporting outcome after full-thickness chest wall resections for malignancies (Table 3). Seven of these series included not only sarcomas, but also resections for carcinoma, like locally advanced breast or lung cancer. 5,9,15,16 Gordon et al 13 described the results of 149 cases of chest wall sarcomas surgically treated in the Memorial Sloan- Kettering Cancer Center between 1948 and Only nine resections for recurrent sarcoma were included in this series, and these were not separately analyzed. Gross et al 2 described the largest series of recurrent chest wall sarcomas, concerning 17 patients surgically treated for a in a series of 55 chest wall resections. This group of patients had a 5-year DFS rate of 66%. In our series, 44 chest wall resections for recurrent sarcoma were identified; 43 patients had a resection with curative intent. In comparison to the primary sarcoma group, localization, size, grade, and the number of ribs resected were not different (Table 1). sarcomas were less often treated with neoadjuvant or adjuvant chemotherapy, because an isolated local mainly needs local therapy. Morbidity of resections for was similar to that of resections for primary sarcoma (Table 2). With a complication rate of 21% and only 5% of patients needing operative reintervention, full-thickness chest wall resection can be considered a safe procedure for primary sarcomas as well as recurrent disease. Our study has several limitations. Although this is one of the largest series in the literature, patient groups are still relatively small and heterogeneous. Combination of data from different tertiary referral centers may solve part of this problem. Centralized and multidisciplinary treatment of these rare tumors and prospective evaluation of interventions may improve our understanding of factors leading to successful treatment. This retrospective study covers 26 years of chest wall resections for sarcoma in two different tertiary referral centers. In this period, imaging techniques have improved (eg, computed tomography and magnetic resonance imaging) and different treatment protocols have been used, although wide local excision of the tumor has always been the cornerstone of treatment. Selection bias can be part of encouraging survival rates in recurrent sarcomas, because only locally recurrent sarcomas, with a favorable course of the disease (no distant metastases), were selected for surgery. Obviously there were differences in oncologic outcome between the group of patients with a primary sarcoma and those with a. Along with the number of microscopically irradical resections, DFS was significantly less for patients who underwent surgery for recurrent sarcoma. With a similar rate of distant metastases occurring during follow-up, the incidence of local was two-fold higher in the recurrent sarcoma group (48% v 24%). In surgical procedures for recurrent disease, it may be more difficult to obtain tumor-free margins as a result of fibrosis caused by earlier resections and restrictions of the respiratory function in relation to the rigidity of the chest wall. However, tumor-free margins are critical, because 86% of irradical resections result in. This is especially true in the recurrent group: 93% of irradical resections were followed by a re, often presenting as an isolated local on the chest wall without distant metastases. Surgical treatment of these second s is performed in 60% of these patients (Fig 2). Favorable OS supports these repeated attempts to obtain local control. In this series, 5-year survival after resections for recurrent chest wall sarcoma was 50%, as compared with 63% for primary chest wall sarcomas. These survival rates support surgical resection or reresection of any sarcoma of the chest wall, if technically possible. Because local is the main problem in these resections, radiotherapy may improve local control rates in some cases. The decision to offer patients a combination of radiotherapy and surgery Table 3. Studies on Chest Wall Resections for Sarcoma First Author Year of Study Study Period (years) Chest Wall Malignancy Sarcoma Sarcomas Wouters (current study) Pfannschmidt Gross Chapelier Chang Unknown Walsh Warzelhan Unknown Sabanathan Incarbone Martini Chapelier Burt Gordon Perry King Unknown Pairolero Graeber Unknown by American Society of Clinical Oncology 5117

6 Wouters et al requires careful patient selection and planning. Although radiation carries clinically significant risks of wound complications, fibrosis, and pulmonary toxicity, patients, especially those who are at high risk of local or compromised margins, may benefit from intensified local treatment. Unfortunately, only some sarcomas of the chest wall are radiosensitive. In conclusion, surgical resection of chest wall sarcoma is a safe and effective procedure, with acceptable long-term survival, even for recurrent sarcomas. Local control rates need attention and may be improved by intensified multimodality treatment. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Michael W. Wouters, Albert N. van Geel Provision of study materials or patients: Michael W. Wouters, Albert N. van Geel, Cees Verhoef, Frits van Coevorden, Houke M. Klomp Collection and assembly of data: Michael W. Wouters, Lotte Nieuwenhuis Data analysis and interpretation: Michael W. Wouters, Albert N. van Geel, Lotte Nieuwenhuis, Harm van Tinteren, Cees Verhoef, Frits van Coevorden, Houke M. Klomp Manuscript writing: Michael W. Wouters, Albert N. van Geel, Lotte Nieuwenhuis, Harm van Tinteren, Cees Verhoef, Frits van Coevorden, Houke M. Klomp Final approval of manuscript: Michael W. Wouters, Albert N. van Geel, Lotte Nieuwenhuis, Harm van Tinteren, Cees Verhoef, Frits van Coevorden, Houke M. Klomp REFERENCES 1. Perry RR, Venzon D, Roth JA, et al: Survival after surgical resection for high-grade chest wall sarcomas. Ann Thorac Surg 49: , Gross JL, Younes RN, Haddad FJ, et al: Soft-tissue sarcomas of the chest wall: Prognostic factors. Chest 127: , Pfannschmidt J, Geisbusch P, Muley T, et al: Surgical treatment of primary soft tissue sarcomas involving the chest: Experiences in 25 patients. Thorac Cardiovasc Surg 54: , Chapelier AR, Missana MC, Couturaud B, et al: Sternal resection and reconstruction for primary malignant tumors. Ann Thorac Surg 77: , Chang RR, Mehrara BJ, Hu QY, et al: Reconstruction of complex oncologic chest wall defects: A 10-year experience. Ann Plast Surg 52: , Walsh GL, Davis BM, Swisher SG, et al: A single-institutional, multidisciplinary approach to primary sarcomas involving the chest wall requiring full-thickness resections. J Thorac Cardiovasc Surg 121:48-60, Warzelhan J, Stoelben E, Imdahl A, et al: Results in surgery for primary and metastatic chest wall tumors. Eur J Cardiothorac Surg 19: , Sabanathan S, Shah R, Mearns AJ: Surgical treatment of primary malignant chest wall tumours. Eur J Cardiothorac Surg 11: , Incarbone M, Nava M, Lequaglie C, et al: Sternal resection for primary or secondary tumors. J Thorac Cardiovasc Surg 114:93-99, Martini N, Huvos AG, Burt ME, et al: Predictors of survival in malignant tumors of the sternum. J Thorac Cardiovasc Surg 111:96-105, Chapelier A, Macchiarini P, Rietjens M, et al: Chest wall reconstruction following resection of large primary malignant tumors. Eur J Cardiothorac Surg 8: , Burt M, Fulton M, Wessner-Dunlap S, et al: bony and cartilaginous sarcomas of chest wall: Results of therapy. Ann Thorac Surg 54: , Gordon MS, Hajdu SI, Bains MS, et al: Soft tissue sarcomas of the chest wall: Results of surgical resection. J Thorac Cardiovasc Surg 101: , King RM, Pairolero PC, Trastek VF, et al: chest wall tumors: Factors affecting survival. Ann Thorac Surg 41: , Pairolero PC, Arnold PG: Chest wall tumors: Experience with 100 consecutive patients. J Thorac Cardiovasc Surg 90: , Graeber GM, Snyder RJ, Fleming AW, et al: Initial and long-term results in the management of primary chest wall neoplasms. Ann Thorac Surg 34: , by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY