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Impact of Margin Status and Local Recurrence on Soft-Tissue Sarcoma Outcomes Benjamin K. Potter, MD, Paul F. Hwang, MD, Jonathan A. Forsberg, MD, Chadwick B. Hampton, MD, John C. Graybill, MD, George E. Peoples, MD, and Alexander Stojadinovic, MD Investigation performed at the Walter Reed National Military Medical Center, Bethesda, Maryland, and the Uniformed Services University of the Health Sciences, Bethesda, Maryland
Background: The impact of local recurrence and surgical resection margin status on survival in extremity soft-tissue sarcomas remains to be clearly defined. Our aim was to conduct a retrospective analysis of prospectively collected data to determine the prognostic relavance of positive resection margins and local recurrence for extremity soft-tissue sarcomas for survival. Methods: Three hundred and sixty-three patients who underwent resection of localized primary extremity soft-tissue sarcomas with curative intent were selected from the United States Department of Defense Automated Central Tumor Registry. Outcomes for local recurrence, distant recurrence, disease-specific survival, and overall survival were analyzed according to clinical, pathological, and treatment variables with use of the Kaplan-Meier method (log-rank test) and the multivariate Cox regression model. Results: Positive margins (hazard ratio, 1.99 [95% confidence interval, 1.15 to 3.45]), local recurrence (hazard ratio, 2.93 [95% confidence interval, 1.38 to 6.23]), and distant recurrence (hazard ratio, 12.13 [95% confidence interval, 5.97 to 24.65]) were significantly associated with overall survival on multivariate Cox regression analysis. However, for disease-specific survival, local recurrence was not significant and tumor size of >10 cm (hazard ratio, 2.83 [95% confidence interval, 1.15 to 6.95]), positive margins (hazard ratio, 1.95 [95% confidence interval, 1.05 to 3.63]), and distant recurrence (hazard ratio, 9.46 [95% confidence interval, 4.37 to 20.47]) were independent adverse prognostic factors. The disease-specific survival rate for patients with localized soft-tissue sarcomas was 89% (95% confidence interval, 85% to 92%) for five years and 75% (95% confidence interval, 70% to 81%) for ten years.
Conclusions: Positive surgical margins are consistently associated with adverse survival-related outcomes in localized soft-tissue sarcomas of the extremity. Local recurrence had a significant impact on overall survival, but not on diseasespecific survival. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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pproximately 50% to 70% of all extremity malignant tumors are soft-tissue sarcomas1,2. Reported prognostic variables for localized soft-tissue sarcomas of the extremity vary, but generally include primary tumor histological grade, size, depth relative to superficial investing muscular fascia, and surgical resection margin3-8. The current
treatment of localized soft-tissue sarcomas generally consists of limb-sparing surgery supplemented with the judicious use of local radiation therapy and/or systemic chemotherapy in appropriately selected patients. With this approach, limb salvage is often achievable with functional preservation of the affected limb, with amputations being infrequent and
Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article. Disclaimer: The views expressed in this presentation are those of the authors and do not reflect the official policy of the Department of the Army, the Department of the Navy, the Department of Defense, or the United States Government.
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typically reserved for extensive tumors with major neurovascular involvement. Radiation therapy can decrease local recurrence in many cases, but has had little impact on overall survival3,9. Adverse effects of radiation therapy are well known and include impaired wound-healing, fibrosis, joint stiffness and reduced joint motion, fractures, and radiation-induced sarcomas10-12. Additionally, primary tumor radiation may limit subsequent treatment options if the patient does have local recurrence 9. Systemic chemotherapy has demonstrated a modest survival benefit in meta-analyses; current multidrug regimens create even greater uncertainty as to the utility of cytotoxic chemotherapy in the treatment of extremity soft-tissue sarcomas, limiting use largely to clinical trials9,13-34. The true impact of local recurrence on survival remains to be demonstrated in soft-tissue sarcomas. Although surgical resection margin status is thought to be of prognostic importance for local recurrence, its effect on distant recurrence and overall survival remains controversial3,6,22,35-37. Relatively large, retrospective studies exploring the impact of local recurrence on survival have produced widely varying findings, leaving the prognostic impact of local recurrence a contentious matter38-43. Prospective, randomized, controlled trials incorporating external beam radiation therapy or brachytherapy as part of primary tumor treatment have demonstrated equivalent or improved local control following treatment, but no apparent effect on survival3,9,17,44. Large, longitudinal cancer registries have often been relied upon to gain insights into the behavior of this rare and heterogeneous group of malignancies. The U.S. Department of Defense (DOD) Automated Central Tumor Registry (ACTUR) database was established in 1986 to meet the requirements of the American College of Surgeons for a comprehensive cancer data reporting system and became the cancer database and clinical tracking system for the DOD45. The population includes all active-duty military personnel and their family members, retirees, and any National Guard or Reserve components that are called to active service. The cohort represented by this database is considerably younger than the general U.S. population, is ethnically diverse, and has free access to care across the spectrum of diagnosis, treatment, and follow-up. This database has previously been effectively utilized to study various common epithelial malignancies45-47. We conducted a retrospective analysis of prospectively collected ACTUR data to determine prognostic importance of positive resection margins and local recurrence for localized soft-tissue sarcomas of the extremity with regard to diseasespecific survival and overall survival in a relatively large cohort of patients followed over time. Materials and Methods
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ollowing approval by the institutional review board, the ACTUR database was used to retrospectively identify adult patients with extremity soft-tissue sarcomas, followed from the time of presentation until death or the latest date of follow-up. Four hundred and two patients were
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identified who were diagnosed with and were treated for sarcoma of the pelvis or extremity between 1988 and 2007. Patients who either presented with metastatic disease (n = 16) or had intrapelvic soft-tissue sarcomas (n = 23) were excluded from analysis. Three hundred and sixty-three patients underwent complete (attempted wide) resection of a localized primary tumor of the extremity with curative intent and form the basis of this study. Relevant clinical, pathological, and treatment variables were recorded, but information on specific chemotherapy and radiation therapy (preoperative compared with postoperative and total dose) regimens were not available in the ACTUR database. Time to local recurrence and time to distant recurrence were obtained, but dates of subsequent surgical procedures (amputation or excision of local recurrence) were not available. Patients received preoperative or adjuvant chemotherapy and/or radiation at the discretion of the treating physician and the institutional tumor board. Diagnosis of soft-tissue sarcomas and histopathologic subtype determination were at the discretion of the local pathologists; however, all DOD pathologists have free access to second opinions from the Joint Pathology Center (the former Armed Forces Institute of Pathology). Follow-up was calculated from the date of diagnosis to the date of the latest follow-up visit or death. Clinical, pathological, and treatment variables (specifically sex, tumor site, tumor size, depth, grade, resection margins, radiation therapy, chemotherapy, local recurrence, and distant recurrence or metastasis, when applicable) were analyzed with respect to the clinical end points of local recurrence, distant recurrence, disease-specific survival, and overall survival. Local recurrence was not included when local recurrence was the outcome measure, and distant recurrence was excluded when distant recurrence was the outcome of interest. The time to local recurrence was defined as the time from diagnosis to local recurrence in months, and the time to distant recurrence was defined as the time from diagnosis to distant recurrence in months. Disease-specific survival was defined as patients who had not died from the soft-tissue sarcomas. The type of attempted wide surgical resection (limb sparing or amputation) was not included because this information was not consistently available within the ACTUR database. A tumor was defined as a primary localized tumor if it was previously untreated or if a biopsy was performed at an outside institution, and there was no evidence of metastasis on presentation after staging. Local recurrence was defined as tumor recurrence at the prior site of resection. A positive surgical resection margin, evaluated microscopically, was a tumor present within 1 mm of the inked surgical margin. The tumor site was defined as the location where the primary tumor was diagnosed. Tumors arising in the groin and buttock were included in the lower-extremity category and axillary tumors were included in the upper-extremity category. Tumors at or below the knee or elbow joints were classified as distal extremity tumors. Tumor histological grade was classified as high, intermediate, or low on the basis of previously published 48 morphological criteria . Tumor size was the maximum tumor diameter in centimeters based on macroscopic measurement following resection, and tumors were categorized as 10 cm. Depth of tumor (deep or superficial) was assessed in relation to the superficial investing fascia of the 49 extremity . All tumor staging was conducted according to the American Joint 50 Committee on Cancer (AJCC) staging criteria .
Statistical Analysis Statistical computations were performed with use of the software package SPSS version 16.0 (SPSS, Chicago, Illinois). Survival was estimated according to the Kaplan-Meier method with comparisons using the log-rank test. A multivariate Cox proportional hazards regression model was composed with use of all of the prognostic variables (sex, tumor site, tumor size, depth, grade, resection margins, radiation therapy, chemotherapy, local recurrence, and distant recurrence or metastasis, when applicable) so as not to overfit the 51 regression model and yield unrealistic results . That is, variables were not excluded from the Cox regression model on the basis of our univariate findings to avoid these potential statistical pitfalls. Significance was defined as a two-tailed a of £0.05.
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TABLE I Patient and Tumor Characteristics
Characteristics
No. of Patients (N = 363)
Patient age* Less than fifty years Fifty years or more
200 (55.1%) 163 (44.9%)
Patient sex Male Female
266 (73.3%) 97 (26.7%)
Tumor location Upper proximal Upper distal Lower proximal Lower distal
71 (19.6%) 29 (8.0%) 175 (48.2%) 88 (24.2%)
Size 10 cm
154 (42.4%) 134 (36.9%) 75 (20.7%)
Grade Low Intermediate High
118 (32.5%) 112 (30.9%) 133 (36.6%)
Depth Superficial Deep
82 (22.6%) 281 (77.4%)
Surgical margins (microscopic) Negative Positive
240 (66.1%) 123 (33.9%)
Chemotherapy Yes No
64 (17.6%) 299 (82.4%)
Radiation therapy Yes No
214 (59.0%) 149 (41.0%)
Local recurrence
63 (17.4%)
Distant metastasis
50 (13.8%)
Died of disease Alive or died of other causes
73 (20.1%) 290 (79.9%)
*The median patient age was forty-six years, with an interquartile range of thirty-two to sixty-two years.
Source of Funding This clinical research effort was supported, in part, by a grant from the United States Military Cancer Institute. Funds were used to pay for statistical support and the salary of the research assistant.
Results he median patient age was forty-six years (interquartile range, thirty-two to sixty-two years) (Table I). There were 266 male patients (73%) and ninety-seven female patients (27%), reflecting the sex distribution of military service
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members and retirees. The median follow-up for surviving patients was eighty-two months (interquartile range, sixtythree to 133 months). The most common primary tumor anatomic sites were the thigh in the lower extremity and the arm in the upper extremity (see Appendix). One hundred and fifty-four patients (42%) had a tumor size of 10 cm. In eighty-two patients (23%), the tumor was superficial, and in 281 patients (77%), the tumor was considered deep. Thirty-seven percent of the tumors were high grade, and 34% of patients had positive microscopic surgical resection margins. Histopathological examination revealed that the majority of extremity soft-tissue sarcomas were of the high-grade pleomorphic undifferentiated sarcoma, leiomyosarcoma, and synovial sarcoma types (see Appendix). Sixty-three patients (17%) developed local recurrence, including fifty-five (45%) of 123 patients with positive margins and only eight (3%) of 240 patients with negative margins. Fifty patients (14%) developed distant recurrence following resection of primary localized soft-tissue sarcomas. All underwent resection of the localized primary tumor. Radiation therapy without chemotherapy was administered to 171 patients (47%), chemotherapy without radiation therapy was administered to twenty-two patients (6%), and both radiation therapy and chemotherapy were administered to forty-three patients (12%); 127 patients (35%) received no adjuvant treatment. At the time of the latest follow-up, thirty-six patients (10%) were alive with disease, 254 patients (70%) were alive without evidence of disease or had died of other causes, and
TABLE II Cox Regression Analysis for Local Recurrence, Distant Recurrence, Disease-Specific Survival, and Overall Survival Variables
Hazard Ratio (95% CI)
P Value
Local recurrence Tumor size of >10 cm Positive margins Chemotherapy
3.01 (1.52 to 5.97) 6.88 (2.88 to 16.42) 4.09 (2.32 to 7.20)
0.002 10 cm and positive surgical resection margins are consistently significant indicators of adverse disease-related outcomes including local and distant disease failure, diseasespecific survival, and overall survival. Local recurrence had a
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significant impact on overall survival, but was not significantly associated with disease-specific survival on multivariate analysis. Systemic chemotherapy was a negative prognostic variable for both local and distant disease failure as well as diseasespecific survival and overall survival. This finding is supported by the work done by Cormier et al.66, which demonstrated that the clinical benefit associated with adjuvant chemotherapy was not sustainable beyond one year. However, care should be taken to ensure the appropriate selection of patients for radiation therapy to augment local control or chemotherapy to treat systemic disease in an attempt to minimize overtreatment of patients that are unlikely to recur. The results of this study underscore the continued uncertainty of local recurrence impact on disease-specific survival while highlighting the importance of attaining adequate surgical margins to improve local control and disease-specific and overall outcomes in the treatment of soft-tissue sarcomas of the extremity. Appendix Tables showing the locations of soft-tissue sarcomas of the extremity by anatomical site and soft-tissue sarcomas of the extremity by histopathological examination are available with the online version of this article as a data supplement at jbjs.org. n NOTE: The authors gratefully acknowledge Dr. Richard Shoemaker for his statistical expertise and Tiffany Felix for her invaluable assistance, supported in part by the Henry M. Jackson Foundation for the Advancement of Military Medicine. We further offer our appreciation to the members and staff of the United States Military Cancer Institute for their consistent support of this collaborative research effort.
Benjamin K. Potter, MD Paul F. Hwang, MD Chadwick B. Forsberg, MD Jonathan A. Forsberg, MD John C. Graybill, MD Departments of Orthopaedics (B.K.P., C.B.H., and J.A.F) and Surgery (P.F.H. and J.C.G.), Walter Reed National Military Medical Center, 8901 Rockville Pike, America Building (Building 19), 2nd Floor, Orthopaedics, Bethesda, MD 20889. E-mail address for B.K. Potter: [email protected] George E. Peoples, MD Alexander Stojadinovic, MD Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814
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55. R¨oo¨ ser B, Gustafson P, Rydholm A. Is there no influence of local control on the rate of metastases in high-grade soft tissue sarcoma? Cancer. 1990 Apr 15;65(8):1727-9. 56. Gustafson P, R¨oo¨ ser B, Rydholm A. Is local recurrence of minor importance for metastases in soft tissue sarcoma? Cancer. 1991 Apr 15;67(8):2083-6. 57. Costa J, Wesley RA, Glatstein E, Rosenberg SA. The grading of soft tissue sarcomas. Results of a clinicohistopathologic correlation in a series of 163 cases. Cancer. 1984 Feb 1;53(3):530-41. 58. Trojani M, Contesso G, Coindre JM, Rouesse J, Bui NB, de Mascarel A, Goussot JF, David M, Bonichon F, Lagarde C. Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer. 1984 Jan 15;33(1):37-42. 59. Canter RJ, Beal S, Borys D, Martinez SR, Bold RJ, Robbins AS. Interaction of histologic subtype and histologic grade in predicting survival for softtissue sarcomas. J Am Coll Surg. 2010 Feb;210(2):191: e2. Epub 2009 Dec 4. 60. Kattan MW, Leung DH, Brennan MF. Postoperative nomogram for 12-year sarcoma-specific death. J Clin Oncol. 2002 Feb 1;20(3):791-6. 61. Brennan MF. Local recurrence in soft tissue sarcoma: more about the tumor, less about the surgeon. Ann Surg Oncol. 2007 May;14(5):1528-9. Epub 2007 Feb 13.
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62. O’Sullivan B, Davis A, Turcotte R, Bell R, Wunder JC, Catton C, Kandel R, Sadura A, Tu D, Pater J. Five-year results of a randomized phase III trial of pre-operative vs postoperative radiotherapy in extremity soft tissue sarcoma [abstract]. J Clin Oncol. 2004;22(Suppl 14S):1. 63. Suit HD, Mankin HJ, Wood WC, Proppe KH. Preoperative, intraoperative, and postoperative radiation in the treatment of primary soft tissue sarcoma. Cancer. 1985 Jun 1;55(11):2659-67. 64. Davis AM, O’Sullivan B, Turcotte R, Bell R, Catton C, Chabot P, Wunder J, Hammond A, Benk V, Kandel R, Goddard K, Freeman C, Sadura A, Zee B, Day A, Tu D, Pater J; Canadian Sarcoma Group; NCI Canada Clinical Trial Group Randomized Trial. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol. 2005 Apr;75(1):48-53. 65. Harrison LB, Franzese F, Gaynor JJ, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in the management of completely resected soft tissue sarcomas of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):259-65. 66. Cormier JN, Huang X, Xing Y, Thall PF, Wang X, Benjamin RS, Pollock RE, Antonescu CR, Maki RG, Brennan MF, Pisters PW. Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: chemotherapy-associated outcomes. J Clin Oncol. 2004 Nov 15;22(22):4567-74.
BY
T HE J OURNAL
OF
B ONE
AND J OINT
S URGERY, I NCORPORATED
Impact of Margin Status and Local Recurrence on Soft-Tissue Sarcoma Outcomes Benjamin K. Potter, MD, Paul F. Hwang, MD, Jonathan A. Forsberg, MD, Chadwick B. Hampton, MD, John C. Graybill, MD, George E. Peoples, MD, and Alexander Stojadinovic, MD Investigation performed at the Walter Reed National Military Medical Center, Bethesda, Maryland, and the Uniformed Services University of the Health Sciences, Bethesda, Maryland
Background: The impact of local recurrence and surgical resection margin status on survival in extremity soft-tissue sarcomas remains to be clearly defined. Our aim was to conduct a retrospective analysis of prospectively collected data to determine the prognostic relavance of positive resection margins and local recurrence for extremity soft-tissue sarcomas for survival. Methods: Three hundred and sixty-three patients who underwent resection of localized primary extremity soft-tissue sarcomas with curative intent were selected from the United States Department of Defense Automated Central Tumor Registry. Outcomes for local recurrence, distant recurrence, disease-specific survival, and overall survival were analyzed according to clinical, pathological, and treatment variables with use of the Kaplan-Meier method (log-rank test) and the multivariate Cox regression model. Results: Positive margins (hazard ratio, 1.99 [95% confidence interval, 1.15 to 3.45]), local recurrence (hazard ratio, 2.93 [95% confidence interval, 1.38 to 6.23]), and distant recurrence (hazard ratio, 12.13 [95% confidence interval, 5.97 to 24.65]) were significantly associated with overall survival on multivariate Cox regression analysis. However, for disease-specific survival, local recurrence was not significant and tumor size of >10 cm (hazard ratio, 2.83 [95% confidence interval, 1.15 to 6.95]), positive margins (hazard ratio, 1.95 [95% confidence interval, 1.05 to 3.63]), and distant recurrence (hazard ratio, 9.46 [95% confidence interval, 4.37 to 20.47]) were independent adverse prognostic factors. The disease-specific survival rate for patients with localized soft-tissue sarcomas was 89% (95% confidence interval, 85% to 92%) for five years and 75% (95% confidence interval, 70% to 81%) for ten years.
Conclusions: Positive surgical margins are consistently associated with adverse survival-related outcomes in localized soft-tissue sarcomas of the extremity. Local recurrence had a significant impact on overall survival, but not on diseasespecific survival. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
A
pproximately 50% to 70% of all extremity malignant tumors are soft-tissue sarcomas1,2. Reported prognostic variables for localized soft-tissue sarcomas of the extremity vary, but generally include primary tumor histological grade, size, depth relative to superficial investing muscular fascia, and surgical resection margin3-8. The current
treatment of localized soft-tissue sarcomas generally consists of limb-sparing surgery supplemented with the judicious use of local radiation therapy and/or systemic chemotherapy in appropriately selected patients. With this approach, limb salvage is often achievable with functional preservation of the affected limb, with amputations being infrequent and
Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article. Disclaimer: The views expressed in this presentation are those of the authors and do not reflect the official policy of the Department of the Army, the Department of the Navy, the Department of Defense, or the United States Government.
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typically reserved for extensive tumors with major neurovascular involvement. Radiation therapy can decrease local recurrence in many cases, but has had little impact on overall survival3,9. Adverse effects of radiation therapy are well known and include impaired wound-healing, fibrosis, joint stiffness and reduced joint motion, fractures, and radiation-induced sarcomas10-12. Additionally, primary tumor radiation may limit subsequent treatment options if the patient does have local recurrence 9. Systemic chemotherapy has demonstrated a modest survival benefit in meta-analyses; current multidrug regimens create even greater uncertainty as to the utility of cytotoxic chemotherapy in the treatment of extremity soft-tissue sarcomas, limiting use largely to clinical trials9,13-34. The true impact of local recurrence on survival remains to be demonstrated in soft-tissue sarcomas. Although surgical resection margin status is thought to be of prognostic importance for local recurrence, its effect on distant recurrence and overall survival remains controversial3,6,22,35-37. Relatively large, retrospective studies exploring the impact of local recurrence on survival have produced widely varying findings, leaving the prognostic impact of local recurrence a contentious matter38-43. Prospective, randomized, controlled trials incorporating external beam radiation therapy or brachytherapy as part of primary tumor treatment have demonstrated equivalent or improved local control following treatment, but no apparent effect on survival3,9,17,44. Large, longitudinal cancer registries have often been relied upon to gain insights into the behavior of this rare and heterogeneous group of malignancies. The U.S. Department of Defense (DOD) Automated Central Tumor Registry (ACTUR) database was established in 1986 to meet the requirements of the American College of Surgeons for a comprehensive cancer data reporting system and became the cancer database and clinical tracking system for the DOD45. The population includes all active-duty military personnel and their family members, retirees, and any National Guard or Reserve components that are called to active service. The cohort represented by this database is considerably younger than the general U.S. population, is ethnically diverse, and has free access to care across the spectrum of diagnosis, treatment, and follow-up. This database has previously been effectively utilized to study various common epithelial malignancies45-47. We conducted a retrospective analysis of prospectively collected ACTUR data to determine prognostic importance of positive resection margins and local recurrence for localized soft-tissue sarcomas of the extremity with regard to diseasespecific survival and overall survival in a relatively large cohort of patients followed over time. Materials and Methods
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ollowing approval by the institutional review board, the ACTUR database was used to retrospectively identify adult patients with extremity soft-tissue sarcomas, followed from the time of presentation until death or the latest date of follow-up. Four hundred and two patients were
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identified who were diagnosed with and were treated for sarcoma of the pelvis or extremity between 1988 and 2007. Patients who either presented with metastatic disease (n = 16) or had intrapelvic soft-tissue sarcomas (n = 23) were excluded from analysis. Three hundred and sixty-three patients underwent complete (attempted wide) resection of a localized primary tumor of the extremity with curative intent and form the basis of this study. Relevant clinical, pathological, and treatment variables were recorded, but information on specific chemotherapy and radiation therapy (preoperative compared with postoperative and total dose) regimens were not available in the ACTUR database. Time to local recurrence and time to distant recurrence were obtained, but dates of subsequent surgical procedures (amputation or excision of local recurrence) were not available. Patients received preoperative or adjuvant chemotherapy and/or radiation at the discretion of the treating physician and the institutional tumor board. Diagnosis of soft-tissue sarcomas and histopathologic subtype determination were at the discretion of the local pathologists; however, all DOD pathologists have free access to second opinions from the Joint Pathology Center (the former Armed Forces Institute of Pathology). Follow-up was calculated from the date of diagnosis to the date of the latest follow-up visit or death. Clinical, pathological, and treatment variables (specifically sex, tumor site, tumor size, depth, grade, resection margins, radiation therapy, chemotherapy, local recurrence, and distant recurrence or metastasis, when applicable) were analyzed with respect to the clinical end points of local recurrence, distant recurrence, disease-specific survival, and overall survival. Local recurrence was not included when local recurrence was the outcome measure, and distant recurrence was excluded when distant recurrence was the outcome of interest. The time to local recurrence was defined as the time from diagnosis to local recurrence in months, and the time to distant recurrence was defined as the time from diagnosis to distant recurrence in months. Disease-specific survival was defined as patients who had not died from the soft-tissue sarcomas. The type of attempted wide surgical resection (limb sparing or amputation) was not included because this information was not consistently available within the ACTUR database. A tumor was defined as a primary localized tumor if it was previously untreated or if a biopsy was performed at an outside institution, and there was no evidence of metastasis on presentation after staging. Local recurrence was defined as tumor recurrence at the prior site of resection. A positive surgical resection margin, evaluated microscopically, was a tumor present within 1 mm of the inked surgical margin. The tumor site was defined as the location where the primary tumor was diagnosed. Tumors arising in the groin and buttock were included in the lower-extremity category and axillary tumors were included in the upper-extremity category. Tumors at or below the knee or elbow joints were classified as distal extremity tumors. Tumor histological grade was classified as high, intermediate, or low on the basis of previously published 48 morphological criteria . Tumor size was the maximum tumor diameter in centimeters based on macroscopic measurement following resection, and tumors were categorized as 10 cm. Depth of tumor (deep or superficial) was assessed in relation to the superficial investing fascia of the 49 extremity . All tumor staging was conducted according to the American Joint 50 Committee on Cancer (AJCC) staging criteria .
Statistical Analysis Statistical computations were performed with use of the software package SPSS version 16.0 (SPSS, Chicago, Illinois). Survival was estimated according to the Kaplan-Meier method with comparisons using the log-rank test. A multivariate Cox proportional hazards regression model was composed with use of all of the prognostic variables (sex, tumor site, tumor size, depth, grade, resection margins, radiation therapy, chemotherapy, local recurrence, and distant recurrence or metastasis, when applicable) so as not to overfit the 51 regression model and yield unrealistic results . That is, variables were not excluded from the Cox regression model on the basis of our univariate findings to avoid these potential statistical pitfalls. Significance was defined as a two-tailed a of £0.05.
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TABLE I Patient and Tumor Characteristics
Characteristics
No. of Patients (N = 363)
Patient age* Less than fifty years Fifty years or more
200 (55.1%) 163 (44.9%)
Patient sex Male Female
266 (73.3%) 97 (26.7%)
Tumor location Upper proximal Upper distal Lower proximal Lower distal
71 (19.6%) 29 (8.0%) 175 (48.2%) 88 (24.2%)
Size 10 cm
154 (42.4%) 134 (36.9%) 75 (20.7%)
Grade Low Intermediate High
118 (32.5%) 112 (30.9%) 133 (36.6%)
Depth Superficial Deep
82 (22.6%) 281 (77.4%)
Surgical margins (microscopic) Negative Positive
240 (66.1%) 123 (33.9%)
Chemotherapy Yes No
64 (17.6%) 299 (82.4%)
Radiation therapy Yes No
214 (59.0%) 149 (41.0%)
Local recurrence
63 (17.4%)
Distant metastasis
50 (13.8%)
Died of disease Alive or died of other causes
73 (20.1%) 290 (79.9%)
*The median patient age was forty-six years, with an interquartile range of thirty-two to sixty-two years.
Source of Funding This clinical research effort was supported, in part, by a grant from the United States Military Cancer Institute. Funds were used to pay for statistical support and the salary of the research assistant.
Results he median patient age was forty-six years (interquartile range, thirty-two to sixty-two years) (Table I). There were 266 male patients (73%) and ninety-seven female patients (27%), reflecting the sex distribution of military service
T
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members and retirees. The median follow-up for surviving patients was eighty-two months (interquartile range, sixtythree to 133 months). The most common primary tumor anatomic sites were the thigh in the lower extremity and the arm in the upper extremity (see Appendix). One hundred and fifty-four patients (42%) had a tumor size of 10 cm. In eighty-two patients (23%), the tumor was superficial, and in 281 patients (77%), the tumor was considered deep. Thirty-seven percent of the tumors were high grade, and 34% of patients had positive microscopic surgical resection margins. Histopathological examination revealed that the majority of extremity soft-tissue sarcomas were of the high-grade pleomorphic undifferentiated sarcoma, leiomyosarcoma, and synovial sarcoma types (see Appendix). Sixty-three patients (17%) developed local recurrence, including fifty-five (45%) of 123 patients with positive margins and only eight (3%) of 240 patients with negative margins. Fifty patients (14%) developed distant recurrence following resection of primary localized soft-tissue sarcomas. All underwent resection of the localized primary tumor. Radiation therapy without chemotherapy was administered to 171 patients (47%), chemotherapy without radiation therapy was administered to twenty-two patients (6%), and both radiation therapy and chemotherapy were administered to forty-three patients (12%); 127 patients (35%) received no adjuvant treatment. At the time of the latest follow-up, thirty-six patients (10%) were alive with disease, 254 patients (70%) were alive without evidence of disease or had died of other causes, and
TABLE II Cox Regression Analysis for Local Recurrence, Distant Recurrence, Disease-Specific Survival, and Overall Survival Variables
Hazard Ratio (95% CI)
P Value
Local recurrence Tumor size of >10 cm Positive margins Chemotherapy
3.01 (1.52 to 5.97) 6.88 (2.88 to 16.42) 4.09 (2.32 to 7.20)
0.002 10 cm and positive surgical resection margins are consistently significant indicators of adverse disease-related outcomes including local and distant disease failure, diseasespecific survival, and overall survival. Local recurrence had a
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significant impact on overall survival, but was not significantly associated with disease-specific survival on multivariate analysis. Systemic chemotherapy was a negative prognostic variable for both local and distant disease failure as well as diseasespecific survival and overall survival. This finding is supported by the work done by Cormier et al.66, which demonstrated that the clinical benefit associated with adjuvant chemotherapy was not sustainable beyond one year. However, care should be taken to ensure the appropriate selection of patients for radiation therapy to augment local control or chemotherapy to treat systemic disease in an attempt to minimize overtreatment of patients that are unlikely to recur. The results of this study underscore the continued uncertainty of local recurrence impact on disease-specific survival while highlighting the importance of attaining adequate surgical margins to improve local control and disease-specific and overall outcomes in the treatment of soft-tissue sarcomas of the extremity. Appendix Tables showing the locations of soft-tissue sarcomas of the extremity by anatomical site and soft-tissue sarcomas of the extremity by histopathological examination are available with the online version of this article as a data supplement at jbjs.org. n NOTE: The authors gratefully acknowledge Dr. Richard Shoemaker for his statistical expertise and Tiffany Felix for her invaluable assistance, supported in part by the Henry M. Jackson Foundation for the Advancement of Military Medicine. We further offer our appreciation to the members and staff of the United States Military Cancer Institute for their consistent support of this collaborative research effort.
Benjamin K. Potter, MD Paul F. Hwang, MD Chadwick B. Forsberg, MD Jonathan A. Forsberg, MD John C. Graybill, MD Departments of Orthopaedics (B.K.P., C.B.H., and J.A.F) and Surgery (P.F.H. and J.C.G.), Walter Reed National Military Medical Center, 8901 Rockville Pike, America Building (Building 19), 2nd Floor, Orthopaedics, Bethesda, MD 20889. E-mail address for B.K. Potter: [email protected] George E. Peoples, MD Alexander Stojadinovic, MD Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814
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