Trends in Survival for Patients With Metastatic Soft-Tissue Sarcoma

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1 Trends in Survival for Patients With Metastatic Soft-Tissue Sarcoma Antoine Italiano, MD, PhD 1 ; Simone Mathoulin-Pelissier, MD, PhD 2,3 ; Axel Le Cesne, MD 4 ; Philippe Terrier, MD 5 ; Sylvie Bonvalot, MD 6 ; Françoise Collin, MD 7 ; Jean-Jacques Michels, MD 8 ; Jean-Yves Blay, MD, PhD 9 ; Jean-Michel Coindre, MD 10 ; and Binh Bui, MD 1 BACKGROUND: The objective of this study was to determine whether the overall survival of patients with metastatic soft tissue sarcoma (STS) has improved over the last 20 years. METHODS: In total, 1024 patients who had synchronous metastatic (SM) STS or metachronous metastatic (MM) STS diagnosed between 1987 and 2006 were included prospectively in the French Sarcoma Group database after central histologic review. Four periods of diagnosis of metastatic disease were defined: P1, from 1987 to 1991 (n ¼ 208); P2, from 1992 to 1996 (n ¼ 287); P3, from 1997 to 2001 (n ¼ 285); and P4, from 2002 to 2006 (n ¼ 244). Patient characteristics were analyzed as prognostic factors by using a Cox model. RESULTS: The proportion of patients with SM, the interval between diagnosis and MM, and the clinical characteristics of the patients were similar across the 4 periods. Although there was no significant difference in the median overall survival (OS) from P1 through P2 (P1, 12.3 months; 95% confidence interval [CI], months; P2, 11.4 months; 95% CI, months), significant improvements were observed in the later periods (P3, 15 months; 95% CI, months; P4, 18 months; 95% CI, months; P ¼.029; log-rank test). The 2-year OS rate also increased throughout the study period from 28.1% during P1 to 38.7% during P4. On multivariate analysis, period of diagnosis, age, histologic subtype, time to metastatic recurrence, French Federation of Cancer Centers Sarcoma Group grade, and the number of metastatic sites were independent prognostic factors for OS. CONCLUSIONS: The current analysis revealed that the median OS of patients with metastatic STS had improved by 50% during the last 20 years. These data should be considered in the interpretation of results from ongoing and future STS trials. Cancer 2011;117: VC 2010 American Cancer Society. KEYWORDS: sarcoma, metastatic, advanced, survival, prognosis. Forty percent to 50% of patients with soft-tissue sarcoma (STS) will develop metastatic disease. 1,2 Several prognostic factors have been associated with the risk of metastatic recurrence, and the most important is histologic grade. 1,2 Once metastases are detected, the treatment is based mainly on palliative chemotherapy, and past studies have indicated that the median survival is approximately 12 months in this setting. 3,4 The main objective of the current study was to evaluate whether there has been a significant improvement in the survival of patients with STS after a diagnosis of metastatic disease. Therefore, we analyzed the French Sarcoma Group (GSF) database over a 20-year period. MATERIALS AND METHODS Patients From 1980 to 2006, 3482 nonpediatric patients (aged 15 years) with STS (excluding gastrointestinal stromal tumors) were admitted in 1 of the 17 tertiary cancer centers of the GSF for the management of a first tumor event. Metastatic Corresponding author: Antoine Italiano, MD, PhD, Institut Bergonié, Department of Medical Oncology, 229 cours de l Argonne, Bordeaux Cedex; Fax: (011) ; italiano@bergonie.org 1 Department of Medical Oncology, Bergonie Institute, Bordeaux, France; 2 Centre d Investigation Clinique et d Épidémiologie Clinique 7, Institut National de al Santé et de la Recherche Médicale, Bordeaux, France; 3 Clinical Research Unit, Bergonie Institute, Bordeaux, France; 4 Department of Medicine, Gustave Roussy Institute, Villejuif, France; 5 Department of Pathology, Gustave Roussy Institute, Villejuif, France; 6 Department of Surgery, Gustave Roussy Institute, Villejuif, France; 7 Department of Pathology, Georges-Francois Leclerc Center, Dijon, France; 8 Department of Pathology, Francois Baclesse Center, Caen, France; 9 Department of Medicine, Lyon Berard Center, Lyon, France; 10 Department of Pathology, Bergonie Institute, Bordeaux, France The following centers participated in this study: Paul Papin Center, Angers; Bergonie; Institute, Bordeaux; Gustave Roussy Institute, Villejuif; Francois Baclesse Center, Caen; Jean Perrin Center, Clermont-Ferrand; Albert Chenevier-Henry Group Hospital, Mondor; Georges-Francois Leclerc Center, Dijon; University Hospital Center (CHU) Vaudois, Lausanne; Oscard Lambret Center, Lille; Lyon-Berard Center, Lyon; CHU Marseille, Marseille; Paoli-Calmette Institute, Marseille; Val d Aurelle Center, Montpellier; Alexis Vautrin Center, Nancy; Rene Gauducheau Center, Nantes; Antoine Lacassagne Center, Nice; Curie Institute, Paris; Cochin-St. Vincent de Paul Group Hospital, Paris; St. Louis Hospital, Paris; Rene Huguenin Center, St.-Cloud; Paul Strauss Center, Strasbourg; and Claudius Regaud Institute, Toulouse. DOI: /cncr.25538, Received: May 3, 2010; Revised: June 5, 2010; Accepted: June 16, 2010, Published online October 13, 2010 in Wiley Online Library (wileyonlinelibrary.com) Cancer March 1,

2 workup included a chest computed tomography scan at diagnosis. The follow-up of patients with localized disease who underwent surgery included clinical assessment of the primary site and regular chest x-rays. Among the 3482 patients, 1024 were diagnosed with synchronous or metachronous metastatic disease between 1987 and For all patients, a histologic review was performed by members of the Pathological Subcommittee of the GSF before inclusion into the GSF database. The histologic diagnosis was established according to the World Health Organization classification of tumors. 2 The histologic grade was determined after central review, as described previously, according to the French grading system 5 The data used in this study were provided by the GSF database as part of ConticaBase, the Connective Tissue Cancer Network (ConticaNet) database ( accessed July 30, 2009). These databases are supported by Contica- Net and the French National Cancer Institute. Statistical Analysis Statistical analyses of baseline demographics and clinical outcomes were based on all data available up to the cutoff date of July 30, Patients were categorized into the following four 5-year periods according to when they were diagnosed with metastatic disease: 1987 to 1991 (P1), 1992 to 1996 (P2), 1997 to 2001 (P3), and 2002 to 2006 (P4). Descriptive statistics were used to illustrate the distribution of variables in the population. Overall survival (OS) was defined as the interval between the diagnosis of metastatic disease and the time of death or last follow-up. Data on patients were censored at 2 years from the date of diagnosis of metastatic disease to avoid bias caused by differences in the length of follow-up between comparison groups. Follow-up was described as the median using an inverse Kaplan-Meier estimator. 6 Survival rates were estimated according to the Kaplan-Meier method and were compared using the log-rank test. Multivariate analyses were carried out with a Cox regression model in a backward, stepwise procedure. Univariate and multivariate analyses included the following variables: age, sex, histologic subtype, French Federation of Cancer Centers Sarcoma Group (FNCLCC) grade, time between diagnosis of the primary tumor and metastatic disease, and the number of metastatic sites. Variables that were associated with survival with a P value <.20 in the univariate analysis were included in the multivariate regression. Analyses were carried out using SAS 9.1 statistical software (SAS Institute, Inc., Cary, NC). All statistical tests were 2- sided, and P<.05 indicated statistical significance. RESULTS Patients The study population included 1024 patients. Their characteristics are described in Table 1. Characteristics did not differ significantly across the 4 periods of diagnosis except histologic subtype, with a significant reduction noted in the number of patients diagnosed with malignant fibrous histiocytoma (MFH). It is noteworthy that the proportion of patients diagnosed with synchronous metastatic disease and the time to diagnosis of metachronous metastases were similar across the 4 periods. Survival The median follow-up was 106 months (95% confidence interval [CI], months) for the overall population (Fig. 1). At the time of analysis (July 30, 2009), by censoring data at 2 years from the diagnosis of metastatic disease, 657 patients (64%) had died, and 357 patients (36%) remained alive. Six hundred thirtyfour deaths (96.5%) were related to disease. The median OS for the overall study period from 1987 to 2006 was 14 months (95% CI, months). The 6-month, 1-year, and 2-year OS rates were 73.9% (95% CI, 71%-76%), 54.9% (95% CI, 52%-58%), and 33.2% (95% CI, 30%-36%), respectively. Although there was no significant difference in the median OS from P1 (12.3 months; 95% CI, months) through P2 (11.4 months; 95% CI, months), significant improvements were observed in the later periods (P3: 15 months; 95% CI, months; P4: 18 months; 95% CI, months; log-rank test, P ¼.029). The 2-year OS rate also increased over the entire study period (P1: 28.1%; 95% CI, 22%-34.5%; P2: 32%; 95% CI, 26.6%-37.5%; P3: 33.3%; 95% CI, 27.8%-39%; P4: 38.7%; 95% CI, 32.3%-45%). Prognostic Factors for Survival On multivariate analysis, the period of diagnosis, patient age, histologic subtype, time to metastatic recurrence, FNCLCC grade, and the number of metastatic sites were identified as independent prognostic factors for OS (Table 2). A diagnosis of metastatic disease during the period P4 was associated with a significant 30% reduction in the risk of death with an overall HR of 0.7 (95% CI, ; P ¼.02). No interactions between prognostic 1050 Cancer March 1, 2011

3 Metastatic Sarcoma Survival/Italiano et al Table 1. Patient Characteristic No. of Patients (%) Characteristic Total Median age, y Sex Men 112 (54) 160 (56) 141 (49.5) 132 (54) 545 (53) Women 96 (46) 127 (44) 144 (50.5) 112 (46) 479 (47) Primary location Extremities 131 (63) 158 (55) 169 (59.5) 141 (57.8) 599 (58.5) Head and neck 6 (2.9) 19 (6.6) 14 (4.9) 9 (3.7) 48 (4.7) Trunk wall 43 (20.7) 60 (20.9) 59 (20.7) 61 (25) 223 (21.8) Internal trunk 26 (12.5) 46 (16) 41 (14.4) 33 (13.5) 146 (14.3) Unknown 2 (1) 4 (1.4) 2 (0.7) 0 (0) 8 (0.8) Histologic subtype Liposarcoma 21 (10) 33 (11.5) 37 (13) 37 (15) 128 (12) Leiomyosarcoma 26 (12.5) 51 (10) 55 (19) 60 (24.5) 192 (19) MFH 44 (21) 51 (18) 34 (12) 22 (9) 151 (15) Synovial sarcoma 22 (10.5) 37 (13) 35 (12.5) 24 (10) 118 (11.5) MPNST 19 (9) 17 (6) 13 (4.5) 8 (3.5) 57 (5.5) Rhabdomyosarcoma 13 (6.5) 22 (8) 18 (6.5) 8 (3.5) 61 (6) Unclassified 30 (14.5) 33 (11.5) 29 (10) 33 (13.5) 125 (12) Other 33 (16) 43 (15) 54 (19) 43 (17.5) 173 (17) Unknown 0 (0) 0 (0) 10 (3.5) 9 (3.5) 19 (2) Grade 1 6 (3) 8 (3) 9 (3) 10 (4) 33 (3) 2 56 (27) 67 (23.5) 82 (29) 71 (29) 276 (27) (61) 165 (57.5) 152 (53.5) 143 (58.5) 587(57.5) Synchronous metastasis 47 (22.5) 42 (14.5) 75 (26.5) 54 (22) 218 (21.5) Median time to metachronous metastasis, mo No. of metastatic sites (79.5) 229 (80) 197 (69) 184 (75.5) 775 (75.5) 2 38 (18.5) 56 (19.5) 80 (28) 51 (21) 225 (22) Unknown MFH, malignant fibrous histiocytoma MPNST, malignant peripheral nerve sheath tumor. factors, such as grade and period of diagnosis, were observed. DISCUSSION In this study, we investigated whether the survival of patients with metastatic STS has improved over the last 20 years. The comparison of clinical and pathologic factors between the 4 time periods allowed us to exclude any lead time bias, because the proportion of patients diagnosed with synchronous metastases and the median time to diagnosis of metachronous metastases were similar across the 4 periods. Moreover, because the metastatic workup included a chest computed tomography scan at diagnosis, improvements in OS for the successive cohorts probably was not related to better staging. The sole significant change in clinicopathologic characteristics over time was the decrease in the proportion of patients diagnosed with MFH. This is in accordance with recent clinicopathologic, ultrastructural, and immunohistochemical studies, which have demonstrated that MFHs are pleomorphic subtypes of other sarcomas, such as dedifferentiated liposarcomas or leiomyosarcomas. 7,8 Our multivariate analysis of prognostic factors for OS confirmed previously published data on prognostic factors in patients with metastatic STS. 3,4 Age, time since initial diagnosis of sarcoma, high tumor grade, certain histologic subtypes, and the number of metastatic sites are important adverse prognostic factors for patients with metastatic disease. However, contrary to what was observed in 1 previous study, 3 the absence of liver metastases was not associated with improved outcome. Our Cancer March 1,

4 Figure 1. Kaplan-Meier overall survival curves are illustrated according to the period of treatment. results indicated that the period of treatment also was a significant independent prognostic factor in OS. Indeed, the median OS of patients with metastatic STS has improved by 50% during the last 20 years. These results are in accordance with those presented recently in abstract by Berselli et al, who demonstrated a significant improvement in the survival of patients with metastatic STS who were treated at the Italian National Tumor Institute (Milan, Italy) between 2003 and 2007 compared with patients who were treated between 1987 and Our study has at least 2 main limitations. First, we cannot exclude the possibility of a selection bias, because the population of patients treated in the tertiary centers for the GSF represents only a small proportion of the patients in France who are diagnosed with sarcoma. Moreover, the GSF database does not contain information regarding treatment delivered in the metastatic setting. However, because the major prognostic factors associated with OS have not changed over time, the significant improvement in outcome of patients with metastatic STS probably is related to treatment. With the exceptions of rhabdomyosarcomas and soft part Ewing sarcomas, systemic chemotherapy for the different STS subtypes is based on doxorubicin and ifosfamide, which remain the cornerstone first-line treatment in ,11 In recent years, however, the insight has emerged that systemic therapy should become more tailored, and particularly for STS, according to histologic subtype. This approach is 1052 Cancer March 1, 2011

5 Metastatic Sarcoma Survival/Italiano et al Table 2. Univariate and Multivariate Analyses of Prognostic Factors for Overall Survival Univariate Analysis (n51024) Prognostic Factor Median OS, mo 95% CI P Whole population Age, y < Sex Men Women Grade 1 NR < Histologic subtype MFH <.0001 Liposarcoma Leiomyosarcoma Synovial sarcoma 22.1 MPNST Rhabdomyosarcoma Unclassified Other Time to metastasis Synchronous <.0001 <12 mo From 12 to <36 mo mo 23.2 Metastatic sites Lung only <.0001 Liver only Other site only Sites Multivariate Analysis (n5983) Independent Prognostic Factor HR 95% CI P Age 55 y <.0001 Period of diagnosis (reference: ) Metastatic sites (reference: lung only) <.0001 Histologic subtype (reference: leiomyosarcoma) MFH <.0001 Liposarcoma MPNST Rhabdomyosarcoma Unclassified Other Time to metastasis (reference: 36 mo) Synchronous <.0001 <12 mo to <36 mo FNCLCC grade 3 (reference: grade 1 or 2) <.0001 OS indicates overall survival; CI, confidence interval; NR, not reached; MFH, malignant fibrous histiocytoma MPNST, malignant peripheral nerve sheath tumor; FNCLCC French Federation of Cancer Centers Sarcoma Group. Cancer March 1,

6 illustrated clearly by the relevant activity of imatinib in advanced dermatofibrosarcoma protuberans, 12,13 paclitaxel in angiosarcoma, 14,15 gemcitabine in leiomyosarcomas, 16,17 trabectedin in patients with myxoid/round cell liposarcomas, 18 and of mammalian target of rapamycin inhibitors in perivascular epithelioid cell tumors. 19 This evolution has been associated over the last 2 decades with the widespread use of additional lines of chemotherapy along with first-line anthracycline-based regimens; the increasing participation of patients with STS in investigational agents trials; the increased used of locoregional treatments for metastatic disease (surgery, radiofrequency ablation); and the general improvement in oncology supportive care. In conclusion, the current results suggest that the survival of patients with metastatic STS has improved over time, and this improvement should be considered when interpreting the results from ongoing and future STS trials. Although supportive care strategies improved over the study period, this progress also is likely because of improved knowledge regarding the clinical and biologic characteristics of STS histologic subtypes, which form the basis for new, effective therapeutic strategies. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. REFERENCES 1. Coindre JM, Terrier P, Guillou L, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91: Fletcher C, Unni K, Mertens F, eds. World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; Van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al. 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