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The status quo of treatment and clinical outcomes for patients over 80 years of age with high-grade soft tissue sarcoma: report from the soft tissue tumor registry in Japan

The status quo of treatment and clinical outcomes for patients over 80 years of age with... Abstract Objective The purpose of this study is to clarify the status quo of management and clinical outcome of treatments for oldest-old (≥80 years) patients with high-grade soft tissue sarcomas in Japan. Method The present study was conducted using data from the Soft Tissue Tumor Registry in Japan. There were 956 oldest-old patients with soft tissue sarcoma who were registered from 2006 to 2012. Among them, cases with incomplete data, low-grade soft tissue sarcoma and those who underwent treatment at other institutions were excluded from analysis. Results We examined 451 cases of high-grade soft tissue sarcoma in oldest-old patients. Three-hundred fifty-one cases (77.8%) were surgically managed, while 100 cases were conservatively managed. In patients aged 85 years and older, 73.1% underwent surgical treatment. A significantly higher proportion of patients underwent conservative therapy in oldest-old patients aged 85 years or older (P = 0.036), patients with deep-seated tumors (P = 0.027) and patients with distant metastases at the first visit (P = 0.000). The median follow-up period was 18.9 months (range, 0.2–83.1). Risk factors for overall survival were extracompartmental tumor progression (P = 0.014) and presence of distant metastases at the first visit (P = 0.000). Conclusion We reported the status quo of treatment and clinical outcome for oldest-old patients with high-grade soft tissue sarcoma in Japan. Although surgery is the primary treatment for soft tissue sarcoma, a significantly higher proportion of patients underwent conservative therapy over surgical treatment in patients aged 85 years or older, patients with deep-seated tumors and patients with distant metastases. orthopedics/sarcoma, soft tissue, aged, 80 and over, surgery, conservative therapy, survival Introduction Soft tissues are non-epithelial, extra-skeletal tissues that exclude the reticuloendothelial system, glia and structural tissues of parenchymal organs. These tissues are distributed throughout the body and include various structures such as fibrous tissue, adipose tissue, muscle tissue, vascular tissue and synovial membrane. Soft-tissue sarcoma (STS) is a malignant tumor arising from these tissues, most of which originate from the mesoderm, with the exception of tumors which are peripheral neuroectodermal in origin (1). STS comprises <1.5% of all malignant tumors and is a rare tumor compared with other cancers and malignant neoplasms, and the annual incidence per 100 000 is approximately six cases (1). The population is currently aging all over the world, and the annual rate of increase for oldest-old persons over 80 years of age (3.8%) is approximately twice that of old persons over 60 years of age (1.9%) (2). Japan is regarded as a country with the highest rate of aging in the world, and by 2050, one in three persons over 60 years of age are expected to become a part of its oldest-old population (2). With its aging population, the number of cases involving malignant tumors in the geriatric population is on a rising trend every year, and the country faces problems such as determining the appropriate indication for surgical resection and increasing medical costs (3). Although the geriatric population suffering from STS is relatively small, the number of patients are likewise increasing. Surgical intervention is a major treatment for STS (4). However, less invasive and more conservative treatment strategies are increasingly elected for STS in the geriatric population (5). Even in the analysis of the SEER registry of the USA, it has been reported that the number of patients undergoing surgical treatment for sarcoma is significantly lower for the population over 85 of age (6). The purpose of this study is to clarify the status quo of treatment and clinical outcome of high-grade STS for patients over 80 years of age in Japan, which is faced with the highest rate of aging in the world. Patients and methods The data presented in this work were obtained from the Soft Tissue Tumor Registry in Japan, promoted by the Japanese Orthopaedic Association (JOA) and National Cancer Center, details of which have been described elsewhere (7). Initial registration was carried out within 2 years of the first visit, and the data on prognosis were registered at 2 and 5 years. This study was approved by the Institutional Review Board and Musculoskeletal Tumor Committee of the JOA. Informed consent was waived by the IRB of JOA due to the retrospective nature of this study. From 2006 to 2012, 956 cases of STS in oldest-old patients over 80 years of age were registered under the Soft Tissue Tumor Registry in Japan. Among them, we excluded 173 patients who underwent initial treatment at a different hospital from the hospital where they registered and 159 cases with incomplete data, leaving a study population of 624 cases with STS in oldest-old patients. In addition, low-grade sarcomas such as well-differentiated liposarcoma/atypical lipomatous tumors were excluded from our study, resulting in 451 subjects for inclusion. Based on the information from the registry, we examined the following: age at the first visit, sex, follow-up period, diagnosis, site of occurrence, size, depth, the presence or absence of metastasis at the first visit, treatment method, outcome and survival rate. The follow-up period was regarded as the time from presentation to last follow-up. Overall survival and disease-specific survival curves were obtained by the Kaplan–Meier method. Univariate analyses were performed, comparing patient-, tumor- and treatment-related factors according to two groups (surgical therapy and conservative therapy) using the Mann–Whitney U test for continuous variables and the chi-square test for categorical variables. The factors associated with therapy were analyzed using the multivariate logistic regression analysis, and factors associated with survival were analyzed using the univariate and multivariate Cox proportional hazards model. Statistical analyses were performed using SPSS software version 25 (SPSS, Chicago, IL, USA). In all analyses, P < 0.05 indicated statistical significance. Results The median age at the first visit was 84.0 (80–99) years old. Of 451 cases, 254 cases were under 85 years old and 197 cases were 85 years old or older. Three-hundred and fifty-one cases underwent surgical therapy, and 100 cases underwent conservative therapy other than surgery. Although 73.1% patients aged 85 years or older underwent surgical therapy, the proportion of patients who elected to undergo conservative therapy significantly increased (P = 0.022). Even in cases where no metastasis was observed at the first visit, 76.3% of patients aged 85 years and older underwent surgical therapy; however, the proportion of patients who elected to undergo conservative treatment also significantly increased (P = 0.001). The study population consisted of 231 males and 220 females, and there were no significant differences between genders in terms of their elected treatment (P = 0.475). The median follow-up period was 18.9 (range, 0.2–83.1) months, and the outcome at the last follow-up were 224 cases of tumor-free survival, 117 cases of survival with tumor, 82 cases of death caused by tumor and 28 cases of death by other causes. Ten patients underwent chemotherapy and 111 patients underwent radiation therapy. The proportion of patients who received radiation therapy was significantly higher in the conservative therapy group compared with the surgical treatment group (Table 1). Table 1. Characteristics of patients and therapy Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Age (metastasis free) 0.022* (0.001**)  80–84 years old (metastasis free) 254 (218) 207 (193) 47 (25)  ≥85 years old (metastasis free) 197 (173) 144 (132) 53 (41) Sex 0.475  Male 231 179 52  Female 220 172 48 Chemotherapy 0.160  (+) 10 6 4  (−) 441 345 96 Radiotherapy 0.021*  (+) 111 78 33  (−) 340 273 67 Median follow-up period (months) 18.9 18.9 19.0 0.155 Clinical outcome  Alive without disease 224 224 0  Alive with disease 117 44 73  Died of other disease 28 22 6  Died of disease 82 61 21 Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Age (metastasis free) 0.022* (0.001**)  80–84 years old (metastasis free) 254 (218) 207 (193) 47 (25)  ≥85 years old (metastasis free) 197 (173) 144 (132) 53 (41) Sex 0.475  Male 231 179 52  Female 220 172 48 Chemotherapy 0.160  (+) 10 6 4  (−) 441 345 96 Radiotherapy 0.021*  (+) 111 78 33  (−) 340 273 67 Median follow-up period (months) 18.9 18.9 19.0 0.155 Clinical outcome  Alive without disease 224 224 0  Alive with disease 117 44 73  Died of other disease 28 22 6  Died of disease 82 61 21 *P < 0.05, **P < 0.01, ***P < 0.001. Table 1. Characteristics of patients and therapy Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Age (metastasis free) 0.022* (0.001**)  80–84 years old (metastasis free) 254 (218) 207 (193) 47 (25)  ≥85 years old (metastasis free) 197 (173) 144 (132) 53 (41) Sex 0.475  Male 231 179 52  Female 220 172 48 Chemotherapy 0.160  (+) 10 6 4  (−) 441 345 96 Radiotherapy 0.021*  (+) 111 78 33  (−) 340 273 67 Median follow-up period (months) 18.9 18.9 19.0 0.155 Clinical outcome  Alive without disease 224 224 0  Alive with disease 117 44 73  Died of other disease 28 22 6  Died of disease 82 61 21 Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Age (metastasis free) 0.022* (0.001**)  80–84 years old (metastasis free) 254 (218) 207 (193) 47 (25)  ≥85 years old (metastasis free) 197 (173) 144 (132) 53 (41) Sex 0.475  Male 231 179 52  Female 220 172 48 Chemotherapy 0.160  (+) 10 6 4  (−) 441 345 96 Radiotherapy 0.021*  (+) 111 78 33  (−) 340 273 67 Median follow-up period (months) 18.9 18.9 19.0 0.155 Clinical outcome  Alive without disease 224 224 0  Alive with disease 117 44 73  Died of other disease 28 22 6  Died of disease 82 61 21 *P < 0.05, **P < 0.01, ***P < 0.001. Unlike normal survival curves, the Kaplan–Meier survival curve exhibited a stepped curve with two horizontal segments (Figs 1 and 2). Censoring was concentrated at up to 20 months, around 40 months and 80 months, and there were few events and censoring at the horizontal segments in between the three sections. These periods approximately coincided with the period from the first visit, at first registration, and until prognostic evaluation at 2 and 5 years. The 2-year cumulative overall survival rate was 84.4% and the 5-year cumulative overall survival rate was 41.6%. In addition, the 2-year cumulative disease-specific survival rate was 87.9%, and the 5-year cumulative disease-specific survival rate was 51.6%. Further diagnoses were as follows: undifferentiated pleomorphic sarcoma, 231; liposarcoma, 51; leiomyosarcoma, 46; and myxofibrosarcoma, 35. The site of occurrence were 270 cases in the lower extremities, 123 cases in the trunk of the body and 53 cases in the upper extremities, with the most frequent occurrence found in the lower extremities. There were 282 cases with a maximum tumor diameter of <10 cm and 157 cases with 10 cm or more. A total of 111 cases occurred in the superficial layer, and 335 cases occurred in a layer deeper than the fascia. There were 17 cases with regional lymph node metastasis at the first visit and 52 cases with distant metastasis (with some degree of overlap). The proportion of patients who underwent conservative therapy was significantly higher in cases with tumors >10 cm (P = 0.014), deep-seated tumors (P = 0.003), regional lymph node metastasis (P = 0.000) and distant metastasis (P = 0.000) (Table 2). Figure 1. View largeDownload slide Kaplan–Meier curves showing overall survival. The cumulative overall survival at 2 and 5 years after presentation were 84.4 and 41.6%, respectively. Figure 1. View largeDownload slide Kaplan–Meier curves showing overall survival. The cumulative overall survival at 2 and 5 years after presentation were 84.4 and 41.6%, respectively. Figure 2. View largeDownload slide Kaplan–Meier curves showing disease-specific survival. The cumulative overall survival at 2 and 5 years after presentation were 87.9 and 51.6%, respectively. Figure 2. View largeDownload slide Kaplan–Meier curves showing disease-specific survival. The cumulative overall survival at 2 and 5 years after presentation were 87.9 and 51.6%, respectively. Table 2. Overall tumor characteristics Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Histological type  UPS 231 185 46  Liposarcoma 51 42 9  Leiomyosarcoma 46 40 6  Myxofibrosarcoma 35 31 4  Others 88 53 35 Tumor site  Lower extremity 270 223 47  Upper extremity 53 42 11  Trunk 123 83 43 Tumor size 0.014*  <10 cm 282 230 52  ≥10 cm 157 113 44 Tumor depth 0.003**  Superficial 111 97 14  Deep 335 252 83 Compartment 0.033*  In the compartment 197 163 34  Beyond the compartment 237 176 61 Regional lymph node metastasis 0.000***  (+) 17 8 9  (−) 417 336 81 Distant metastasis 0.000***  (+) 52 22 30  (−) 387 328 59 Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Histological type  UPS 231 185 46  Liposarcoma 51 42 9  Leiomyosarcoma 46 40 6  Myxofibrosarcoma 35 31 4  Others 88 53 35 Tumor site  Lower extremity 270 223 47  Upper extremity 53 42 11  Trunk 123 83 43 Tumor size 0.014*  <10 cm 282 230 52  ≥10 cm 157 113 44 Tumor depth 0.003**  Superficial 111 97 14  Deep 335 252 83 Compartment 0.033*  In the compartment 197 163 34  Beyond the compartment 237 176 61 Regional lymph node metastasis 0.000***  (+) 17 8 9  (−) 417 336 81 Distant metastasis 0.000***  (+) 52 22 30  (−) 387 328 59 *P < 0.05, **P < 0.01, ***P < 0.001. UPS, undifferentiated pleomorphic sarcoma. View Large Table 2. Overall tumor characteristics Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Histological type  UPS 231 185 46  Liposarcoma 51 42 9  Leiomyosarcoma 46 40 6  Myxofibrosarcoma 35 31 4  Others 88 53 35 Tumor site  Lower extremity 270 223 47  Upper extremity 53 42 11  Trunk 123 83 43 Tumor size 0.014*  <10 cm 282 230 52  ≥10 cm 157 113 44 Tumor depth 0.003**  Superficial 111 97 14  Deep 335 252 83 Compartment 0.033*  In the compartment 197 163 34  Beyond the compartment 237 176 61 Regional lymph node metastasis 0.000***  (+) 17 8 9  (−) 417 336 81 Distant metastasis 0.000***  (+) 52 22 30  (−) 387 328 59 Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Histological type  UPS 231 185 46  Liposarcoma 51 42 9  Leiomyosarcoma 46 40 6  Myxofibrosarcoma 35 31 4  Others 88 53 35 Tumor site  Lower extremity 270 223 47  Upper extremity 53 42 11  Trunk 123 83 43 Tumor size 0.014*  <10 cm 282 230 52  ≥10 cm 157 113 44 Tumor depth 0.003**  Superficial 111 97 14  Deep 335 252 83 Compartment 0.033*  In the compartment 197 163 34  Beyond the compartment 237 176 61 Regional lymph node metastasis 0.000***  (+) 17 8 9  (−) 417 336 81 Distant metastasis 0.000***  (+) 52 22 30  (−) 387 328 59 *P < 0.05, **P < 0.01, ***P < 0.001. UPS, undifferentiated pleomorphic sarcoma. View Large In the multivariate analysis, the proportion of cases undergoing conservative therapy increased in patients aged 85 years old or older (P = 0.036), patients with deep-seated occurrences (P = 0.027) and patients with distant metastases (P = 0.000) (Table 3). Table 3. Multivariate logistic regression analysis for conservative therapy Odds ratio 95% Confidence interval P value Age ≥ 85 years old 1.815 1.040–3.169 0.036* Sex (Female) 1.122 0.664–1.955 0.684 Chemotherapy (+) 1.303 0.281–6.035 0.735 Radiotherapy (+) 1.631 0.896–2.968 0.109 Tumor size > 10 cm 1.262 0.711–2.240 0.427 Tumor depth (deep) 2.483 1.110–5.557 0.027* Beyond the compartment 1.059 0.596–1.882 0.845 Lymph node metastasis (+) 2.680 0.710–10.121 0.146 Distant metastasis (+) 6.621 3.156–13.890 0.000*** Odds ratio 95% Confidence interval P value Age ≥ 85 years old 1.815 1.040–3.169 0.036* Sex (Female) 1.122 0.664–1.955 0.684 Chemotherapy (+) 1.303 0.281–6.035 0.735 Radiotherapy (+) 1.631 0.896–2.968 0.109 Tumor size > 10 cm 1.262 0.711–2.240 0.427 Tumor depth (deep) 2.483 1.110–5.557 0.027* Beyond the compartment 1.059 0.596–1.882 0.845 Lymph node metastasis (+) 2.680 0.710–10.121 0.146 Distant metastasis (+) 6.621 3.156–13.890 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Table 3. Multivariate logistic regression analysis for conservative therapy Odds ratio 95% Confidence interval P value Age ≥ 85 years old 1.815 1.040–3.169 0.036* Sex (Female) 1.122 0.664–1.955 0.684 Chemotherapy (+) 1.303 0.281–6.035 0.735 Radiotherapy (+) 1.631 0.896–2.968 0.109 Tumor size > 10 cm 1.262 0.711–2.240 0.427 Tumor depth (deep) 2.483 1.110–5.557 0.027* Beyond the compartment 1.059 0.596–1.882 0.845 Lymph node metastasis (+) 2.680 0.710–10.121 0.146 Distant metastasis (+) 6.621 3.156–13.890 0.000*** Odds ratio 95% Confidence interval P value Age ≥ 85 years old 1.815 1.040–3.169 0.036* Sex (Female) 1.122 0.664–1.955 0.684 Chemotherapy (+) 1.303 0.281–6.035 0.735 Radiotherapy (+) 1.631 0.896–2.968 0.109 Tumor size > 10 cm 1.262 0.711–2.240 0.427 Tumor depth (deep) 2.483 1.110–5.557 0.027* Beyond the compartment 1.059 0.596–1.882 0.845 Lymph node metastasis (+) 2.680 0.710–10.121 0.146 Distant metastasis (+) 6.621 3.156–13.890 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Significant risk factors for overall survival, according to univariate analysis, were as follows: tumor diameter >10 cm (hazard ratio = 1.610, 95% confidence interval = 1.103–2.353, P = 0.014), extracompartmental tumor progression (hazard ratio = 1.337, 95% confidence interval = 1.094–1.631, P = 0.005) and the presence of distant metastasis (hazard ratio = 3.086, 95% confidence interval = 2.020–4.717, P = 0.000) (Table 4). Multivariate analysis showed that distant metastasis (hazard ratio = 3.289, 95% confidence interval = 1.869–5.814, P = 0.000) and progress outside of the compartment (hazard ratio = 1.773, 95% confidence interval = 0.252–1.828, P = 0.014) were significant risk factors (Table 5). Table 4. Univariate Cox proportional hazards models of overall survival Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.674 0.456–0.994 0.047* Sex (Female) 0.871 0.598–1.269 0.472 Surgery (+) 0.915 0.736–1.138 0.426 Chemotherapy (+) 1.658 1.056–2.604 0.028* Radiotherapy (+) 1.087 0.886–1.333 0.427 Tumor size > 10 cm 1.610 1.103–2.353 0.014* Tumor depth (deep) 1.416 0.878–2.283 0.153 Beyond the compartment 1.337 1.094–1.631 0.005** Lymph node metastasis (+) 1.176 0.478–2.890 0.723 Distant metastasis (+) 3.086 2.020–4.717 0.000*** Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.674 0.456–0.994 0.047* Sex (Female) 0.871 0.598–1.269 0.472 Surgery (+) 0.915 0.736–1.138 0.426 Chemotherapy (+) 1.658 1.056–2.604 0.028* Radiotherapy (+) 1.087 0.886–1.333 0.427 Tumor size > 10 cm 1.610 1.103–2.353 0.014* Tumor depth (deep) 1.416 0.878–2.283 0.153 Beyond the compartment 1.337 1.094–1.631 0.005** Lymph node metastasis (+) 1.176 0.478–2.890 0.723 Distant metastasis (+) 3.086 2.020–4.717 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Table 4. Univariate Cox proportional hazards models of overall survival Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.674 0.456–0.994 0.047* Sex (Female) 0.871 0.598–1.269 0.472 Surgery (+) 0.915 0.736–1.138 0.426 Chemotherapy (+) 1.658 1.056–2.604 0.028* Radiotherapy (+) 1.087 0.886–1.333 0.427 Tumor size > 10 cm 1.610 1.103–2.353 0.014* Tumor depth (deep) 1.416 0.878–2.283 0.153 Beyond the compartment 1.337 1.094–1.631 0.005** Lymph node metastasis (+) 1.176 0.478–2.890 0.723 Distant metastasis (+) 3.086 2.020–4.717 0.000*** Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.674 0.456–0.994 0.047* Sex (Female) 0.871 0.598–1.269 0.472 Surgery (+) 0.915 0.736–1.138 0.426 Chemotherapy (+) 1.658 1.056–2.604 0.028* Radiotherapy (+) 1.087 0.886–1.333 0.427 Tumor size > 10 cm 1.610 1.103–2.353 0.014* Tumor depth (deep) 1.416 0.878–2.283 0.153 Beyond the compartment 1.337 1.094–1.631 0.005** Lymph node metastasis (+) 1.176 0.478–2.890 0.723 Distant metastasis (+) 3.086 2.020–4.717 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Table 5. Multivariate Cox proportional hazards models of overall survival Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.725 0.476–1.104 0.133 Sex (Female) 0.931 0.612–1.418 0.740 Surgery (+) 1.582 0.864–2.899 0.137 Chemotherapy (+) 2.252 0.854–5.917 0.101 Radiotherapy (+) 0.776 0.472–1.276 0.317 Tumor size > 10 cm 1.190 0.765–1.852 0.440 Tumor depth (deep) 1.361 0.794–2.326 0.262 Beyond the compartment 1.773 1.122–2.801 0.014* Lymph node metastasis (+) 0.679 0.252–1.828 0.443 Distant metastasis (+) 3.289 1.869–5.814 0.000*** Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.725 0.476–1.104 0.133 Sex (Female) 0.931 0.612–1.418 0.740 Surgery (+) 1.582 0.864–2.899 0.137 Chemotherapy (+) 2.252 0.854–5.917 0.101 Radiotherapy (+) 0.776 0.472–1.276 0.317 Tumor size > 10 cm 1.190 0.765–1.852 0.440 Tumor depth (deep) 1.361 0.794–2.326 0.262 Beyond the compartment 1.773 1.122–2.801 0.014* Lymph node metastasis (+) 0.679 0.252–1.828 0.443 Distant metastasis (+) 3.289 1.869–5.814 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Table 5. Multivariate Cox proportional hazards models of overall survival Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.725 0.476–1.104 0.133 Sex (Female) 0.931 0.612–1.418 0.740 Surgery (+) 1.582 0.864–2.899 0.137 Chemotherapy (+) 2.252 0.854–5.917 0.101 Radiotherapy (+) 0.776 0.472–1.276 0.317 Tumor size > 10 cm 1.190 0.765–1.852 0.440 Tumor depth (deep) 1.361 0.794–2.326 0.262 Beyond the compartment 1.773 1.122–2.801 0.014* Lymph node metastasis (+) 0.679 0.252–1.828 0.443 Distant metastasis (+) 3.289 1.869–5.814 0.000*** Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.725 0.476–1.104 0.133 Sex (Female) 0.931 0.612–1.418 0.740 Surgery (+) 1.582 0.864–2.899 0.137 Chemotherapy (+) 2.252 0.854–5.917 0.101 Radiotherapy (+) 0.776 0.472–1.276 0.317 Tumor size > 10 cm 1.190 0.765–1.852 0.440 Tumor depth (deep) 1.361 0.794–2.326 0.262 Beyond the compartment 1.773 1.122–2.801 0.014* Lymph node metastasis (+) 0.679 0.252–1.828 0.443 Distant metastasis (+) 3.289 1.869–5.814 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Discussion Ogura et al. reported on STSs for all ages registered from 2006 to 2012 in the Bone and Soft Tissue Tumor Registry in Japan (8). According to the report, 8288 patients were registered for STSs in 7 years, and among them, geriatric patients over 60 years of age accounted for more than 50% of registered patients, and the percentage of patients have dramatically increased with the aging of the Japanese population. In our current study, we focused on oldest-old patients with STS in Japan who were over 80 years of age, as Japan faces the highest rate of aging in the world. In light of this problem, we examined the status quo of treatment and clinical outcome for high-grade STS. In this study, the survival curves of patients aged 80 years or older exhibited atypical, stepped curves. We believe that this is due to restricting our subjects to the elderly, since Ogura et al. reported normal survival curves in a study across all ages. Moreover, in this study, cases treated at a hospital different from the hospital where they were registered were excluded in order to prevent duplication of cases. As the time periods that showed a concentration of censored data had approximately coincided with the time at the first registration and prognostic evaluation at 2 and 5 years, reasons for our atypical results may have been due to active treatment halted early because of old age that resulted in a transfer from a specialized care facility to a local clinic, discontinuation of clinical consultation or subsequent events that were unreported. Since proportional hazards were not adequately preserved in our results, a statistical comparison with the log-rank test remains difficult, and the results of our Cox regression analysis also requires scrutiny. The Bone and Soft Tissue Tumor Registry in Japan is limited by the anonymity of its aggregated data, which could be a subject of future research. With aging, various functions of the body will deteriorate, including cardiovascular, respiratory, mental, immunologic and urological functions (9). For this reason, surgical treatment for the geriatric population has been reported to induce distinctive perioperative complications such as cardiovascular disease, pneumonia and delirium, and the incidence increases with age (10). Infectious diseases after surgery in the geriatric population is one of the leading causes of complications and increased mortality rate, and the sites with high post-operative infection rates include the urinary tract, respiratory tract and operative wound (11). Post-operative delirium is also a notable complication for the geriatric population (12). Age is a risk factor for delirium (13), and post-operative delirium can be a cause for poor clinical outcome that includes functional deterioration, extended hospital stay, institutionalization, increase in medical costs and increased mortality rate (14). Being older is an independent prognostic factor for STS, which has been reported to be a result of undertreatment for the geriatric population (15), but we believe that the increased incidence of complications is also a contributing factor for undertreatment. The results of this study have revealed that the proportion of patients undergoing conservative therapy in the older population demonstrates a greater level of increase than that of patients in the younger population who are <85 years old. For various types of carcinomas, surgical therapy on malignant tumors can be safely performed regardless of age, and numerous reports have suggested that surgical intervention should be presented as treatment options (5,16–23). However, to the best of our knowledge, there are no reports that compare surgical therapy and conservative therapy such as chemotherapy or radiotherapy, and reports that suggest improved life expectancy with surgical intervention for oldest-old patients are scarce in the literature. Although this is a retrospective study, it is one of the few studies to examine the treatment outcomes for both surgical and conservative therapy of highly malignant STSs in patients 80 years or older. From the results of this study, we were unable to show whether or not surgical intervention improved the long-term vital prognosis of oldest-old patients compared with the conservative therapy. Our results may suggest that the surgical indication for elderly patients in Japan could have been generally correct. However, considering the limited patient background information and characteristics previously mentioned in this paper, we believe that the results should be interpreted with caution, and the surgical indication for elderly patients should likewise receive a close examination. According to a report by Ogura et al., 19.4% of STS cases across all age groups had received radiation therapy (8). In elderly patients aged 80 years and older, 22.2% in the surgical treatment group and 33% in the conservative therapy group received radiation therapy, and the percentage of cases receiving radiation therapy significantly increased in the conservative therapy group. We believe that surgical treatment is not elected for the reasons described above that are particular to the elderly, and that palliative radiotherapy is performed as an alternative treatment option. Although palliative treatment included chemotherapy, chemotherapy was only performed in 2.2% of all patients aged 80 years or older and only 4% of the conservative therapy group. Considering that chemotherapy is performed in 26.1% of patients across all ages (8), the low percentage is likely due to difficulties in safely administering chemotherapy for the elderly. In this study, the 2-year cumulative disease-specific survival rate was 87.9% and the 5-year cumulative disease-specific survival rate was 51.6% in elderly STS patients aged 80 years or older. The 2 and 5-year disease-specific survival rates across all ages are reported to be 86.8 and 77.5%, respectively (8). Even if the aforementioned characteristics of the registry are considered, our results were not dissimilar to that of the past literature, which report that the old age is an independent and poor prognostic factor for STSs (15). There are several limitations in our research. First, because the Bone and Soft Tissue Tumor Registry in Japan is organized by the Japanese Orthopaedic Association, the registry may underestimate sarcomas that originate in the trunk of the body that include the retroperitoneal cavity, which is not only treated by orthopedic surgeons but also surgeons and urologists. Second, the registry does not contain a geriatric assessment that is essential for research on elderly people. Third, since this is a retrospective study using a registry, in addition to the registered data, there are many factors that remain unclear, such as patient lifestyle, family background and motivation for treatment; thus, there are many biases in comparing surgical treatment and conservative therapy. Fourth, since cases treated at other institutions are excluded from our study, there could be insufficient reporting of events. Conclusion Japan faces the highest rate of aging in the world, and in this study, the status quo of treatment and clinical outcome for oldest-old patients over 80 years of age with high-grade STS were examined. The proportion of patients undergoing conservative therapy significantly increased in patients aged 85 years or older, patients with deep-seated occurrences and patients with metastases at the first visit. Extracompartmental tumor progression and the presence of distant metastasis at the first visit were significant risk factors for overall survival. Acknowledgements The data presented in this work was obtained from the Bone and Soft Tissue Tumor Registry in Japan (The Japanese Orthopaedic Association/National Cancer Center). We thank all the hospitals and medical staff participating in this registry. Conflict of interest statement None declared. References 1 Goldblum JR , Folpe AL , Weiss SW , Enzinger FM . Enzinger and Weiss’s soft tissue tumors . 6th edn . Philadelphia, PA : Saunders/Elsevier , 2014 . 2 United Nations . Dept. of Economic and Social Affairs. Population Division. World population ageing: 1950–2050 . New York, NY : United Nations , 2002 . 3 Muss HB . Cancer in the elderly: a societal perspective from the United States . Clin Oncol (R Coll Radiol) 2009 ; 21 : 92 – 8 . Google Scholar Crossref Search ADS PubMed 4 Clark MA , Fisher C , Judson I , Thomas JM . Soft-tissue sarcomas in adults . N Engl J Med 2005 ; 353 : 701 – 11 . Google Scholar Crossref Search ADS PubMed 5 Yoneda Y , Kunisada T , Naka N , et al. . Favorable outcome after complete resection in elderly soft tissue sarcoma patients: Japanese Musculoskeletal Oncology Group study . Eur J Surg Oncol 2014 ; 40 : 49 – 54 . Google Scholar Crossref Search ADS PubMed 6 Al-Refaie WB , Habermann EB , Dudeja V , et al. . Extremity soft tissue sarcoma care in the elderly: insights into the generalizability of NCI Cancer Trials . Ann Surg Oncol 2010 ; 17 : 1732 – 8 . Google Scholar Crossref Search ADS PubMed 7 Ogura K , Higashi T , Kawai A . Statistics of bone sarcoma in Japan: report from the Bone and Soft Tissue Tumor Registry in Japan . J Orthop Sci 2017 ; 22 : 133 – 43 . Google Scholar Crossref Search ADS PubMed 8 Ogura K , Higashi T , Kawai A . Statistics of soft-tissue sarcoma in Japan: report from the Bone and Soft Tissue Tumor Registry in Japan . J Orthop Sci 2017 ; 22 : 755 – 64 . Google Scholar Crossref Search ADS PubMed 9 Rosenthal RA , Zenilman ME , Katlic MR . Principles and Practice of Geriatric Surgery . 2nd edn . New York, NY : Springer , 2011 . 10 Etzioni DA , Liu JH , Maggard MA , Ko CY . The aging population and its impact on the surgery workforce . Ann Surg 2003 ; 238 : 170 – 7 . Google Scholar PubMed 11 Beliveau MM , Multach M . Perioperative care for the elderly patient . Med Clin North Am 2003 ; 87 : 273 – 89 . Google Scholar Crossref Search ADS PubMed 12 Inouye SK , Studenski S , Tinetti ME , Kuchel GA . Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept . J Am Geriatr Soc 2007 ; 55 : 780 – 91 . Google Scholar Crossref Search ADS PubMed 13 Dasgupta M , Dumbrell AC . Preoperative risk assessment for delirium after noncardiac surgery: a systematic review . J Am Geriatr Soc 2006 ; 54 : 1578 – 89 . Google Scholar Crossref Search ADS PubMed 14 Robinson TN , Eiseman B . Postoperative delirium in the elderly: diagnosis and management . Clin Interv Aging 2008 ; 3 : 351 – 5 . Google Scholar Crossref Search ADS PubMed 15 Boden RA , Clark MA , Neuhaus SJ , A’hern JR , Thomas JM , Hayes AJ . Surgical management of soft tissue sarcoma in patients over 80 years . Eur J Surg Oncol 2006 ; 32 : 1154 – 8 . Google Scholar Crossref Search ADS PubMed 16 Giri SK , Nayak B . Management of ovarian cancer in elderly . Rev Recent Clin Trials 2015 ; 10 : 270 – 5 . Google Scholar Crossref Search ADS PubMed 17 Okamoto M , Yoshimura Y , Aoki K , et al. . Clinical outcomes of patients 80 years of age and older with soft tissue sarcoma . J Orthop Sci 2017 ; 22 : 951 – 7 . Google Scholar Crossref Search ADS PubMed 18 Srisomboon C , Koizumi K , Haraguchi S , Mikami I , Iijima Y , Shimizu K . Thoracoscopic surgery for non-small-cell lung cancer: elderly vs. octogenarians . Asian Cardiovasc Thorac Ann 2013 ; 21 : 56 – 60 . Google Scholar Crossref Search ADS PubMed 19 Reginelli A , Calvanese M , Ravo V , et al. . Management of breast cancer in elderly patients . Int J Surg 2014 ; 12 : S187 – S92 . Google Scholar Crossref Search ADS PubMed 20 Lim JH , Lee DH , Shin CM , et al. . Clinicopathological features and surgical safety of gastric cancer in elderly patients . J Korean Med Sci 2014 ; 29 : 1639 – 45 . Google Scholar Crossref Search ADS PubMed 21 Lahat G , Dhuka AR , Lahat S , et al. . Complete soft tissue sarcoma resection is a viable treatment option for select elderly patients . Ann Surg Oncol 2009 ; 16 : 2579 – 86 . Google Scholar Crossref Search ADS PubMed 22 Cosker T , Lechler P , Gulati A , et al. . Surgical outcome of malignant primary bone tumours in elderly and very elderly patients . Int Orthop 2014 ; 38 : 2149 – 54 . Google Scholar Crossref Search ADS PubMed 23 Lavoue V , Zeng X , Lau S , et al. . Impact of robotics on the outcome of elderly patients with endometrial cancer . Gynecol Oncol 2014 ; 133 : 556 – 62 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

The status quo of treatment and clinical outcomes for patients over 80 years of age with high-grade soft tissue sarcoma: report from the soft tissue tumor registry in Japan

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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0368-2811
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1465-3621
DOI
10.1093/jjco/hyy118
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30137471
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Abstract

Abstract Objective The purpose of this study is to clarify the status quo of management and clinical outcome of treatments for oldest-old (≥80 years) patients with high-grade soft tissue sarcomas in Japan. Method The present study was conducted using data from the Soft Tissue Tumor Registry in Japan. There were 956 oldest-old patients with soft tissue sarcoma who were registered from 2006 to 2012. Among them, cases with incomplete data, low-grade soft tissue sarcoma and those who underwent treatment at other institutions were excluded from analysis. Results We examined 451 cases of high-grade soft tissue sarcoma in oldest-old patients. Three-hundred fifty-one cases (77.8%) were surgically managed, while 100 cases were conservatively managed. In patients aged 85 years and older, 73.1% underwent surgical treatment. A significantly higher proportion of patients underwent conservative therapy in oldest-old patients aged 85 years or older (P = 0.036), patients with deep-seated tumors (P = 0.027) and patients with distant metastases at the first visit (P = 0.000). The median follow-up period was 18.9 months (range, 0.2–83.1). Risk factors for overall survival were extracompartmental tumor progression (P = 0.014) and presence of distant metastases at the first visit (P = 0.000). Conclusion We reported the status quo of treatment and clinical outcome for oldest-old patients with high-grade soft tissue sarcoma in Japan. Although surgery is the primary treatment for soft tissue sarcoma, a significantly higher proportion of patients underwent conservative therapy over surgical treatment in patients aged 85 years or older, patients with deep-seated tumors and patients with distant metastases. orthopedics/sarcoma, soft tissue, aged, 80 and over, surgery, conservative therapy, survival Introduction Soft tissues are non-epithelial, extra-skeletal tissues that exclude the reticuloendothelial system, glia and structural tissues of parenchymal organs. These tissues are distributed throughout the body and include various structures such as fibrous tissue, adipose tissue, muscle tissue, vascular tissue and synovial membrane. Soft-tissue sarcoma (STS) is a malignant tumor arising from these tissues, most of which originate from the mesoderm, with the exception of tumors which are peripheral neuroectodermal in origin (1). STS comprises <1.5% of all malignant tumors and is a rare tumor compared with other cancers and malignant neoplasms, and the annual incidence per 100 000 is approximately six cases (1). The population is currently aging all over the world, and the annual rate of increase for oldest-old persons over 80 years of age (3.8%) is approximately twice that of old persons over 60 years of age (1.9%) (2). Japan is regarded as a country with the highest rate of aging in the world, and by 2050, one in three persons over 60 years of age are expected to become a part of its oldest-old population (2). With its aging population, the number of cases involving malignant tumors in the geriatric population is on a rising trend every year, and the country faces problems such as determining the appropriate indication for surgical resection and increasing medical costs (3). Although the geriatric population suffering from STS is relatively small, the number of patients are likewise increasing. Surgical intervention is a major treatment for STS (4). However, less invasive and more conservative treatment strategies are increasingly elected for STS in the geriatric population (5). Even in the analysis of the SEER registry of the USA, it has been reported that the number of patients undergoing surgical treatment for sarcoma is significantly lower for the population over 85 of age (6). The purpose of this study is to clarify the status quo of treatment and clinical outcome of high-grade STS for patients over 80 years of age in Japan, which is faced with the highest rate of aging in the world. Patients and methods The data presented in this work were obtained from the Soft Tissue Tumor Registry in Japan, promoted by the Japanese Orthopaedic Association (JOA) and National Cancer Center, details of which have been described elsewhere (7). Initial registration was carried out within 2 years of the first visit, and the data on prognosis were registered at 2 and 5 years. This study was approved by the Institutional Review Board and Musculoskeletal Tumor Committee of the JOA. Informed consent was waived by the IRB of JOA due to the retrospective nature of this study. From 2006 to 2012, 956 cases of STS in oldest-old patients over 80 years of age were registered under the Soft Tissue Tumor Registry in Japan. Among them, we excluded 173 patients who underwent initial treatment at a different hospital from the hospital where they registered and 159 cases with incomplete data, leaving a study population of 624 cases with STS in oldest-old patients. In addition, low-grade sarcomas such as well-differentiated liposarcoma/atypical lipomatous tumors were excluded from our study, resulting in 451 subjects for inclusion. Based on the information from the registry, we examined the following: age at the first visit, sex, follow-up period, diagnosis, site of occurrence, size, depth, the presence or absence of metastasis at the first visit, treatment method, outcome and survival rate. The follow-up period was regarded as the time from presentation to last follow-up. Overall survival and disease-specific survival curves were obtained by the Kaplan–Meier method. Univariate analyses were performed, comparing patient-, tumor- and treatment-related factors according to two groups (surgical therapy and conservative therapy) using the Mann–Whitney U test for continuous variables and the chi-square test for categorical variables. The factors associated with therapy were analyzed using the multivariate logistic regression analysis, and factors associated with survival were analyzed using the univariate and multivariate Cox proportional hazards model. Statistical analyses were performed using SPSS software version 25 (SPSS, Chicago, IL, USA). In all analyses, P < 0.05 indicated statistical significance. Results The median age at the first visit was 84.0 (80–99) years old. Of 451 cases, 254 cases were under 85 years old and 197 cases were 85 years old or older. Three-hundred and fifty-one cases underwent surgical therapy, and 100 cases underwent conservative therapy other than surgery. Although 73.1% patients aged 85 years or older underwent surgical therapy, the proportion of patients who elected to undergo conservative therapy significantly increased (P = 0.022). Even in cases where no metastasis was observed at the first visit, 76.3% of patients aged 85 years and older underwent surgical therapy; however, the proportion of patients who elected to undergo conservative treatment also significantly increased (P = 0.001). The study population consisted of 231 males and 220 females, and there were no significant differences between genders in terms of their elected treatment (P = 0.475). The median follow-up period was 18.9 (range, 0.2–83.1) months, and the outcome at the last follow-up were 224 cases of tumor-free survival, 117 cases of survival with tumor, 82 cases of death caused by tumor and 28 cases of death by other causes. Ten patients underwent chemotherapy and 111 patients underwent radiation therapy. The proportion of patients who received radiation therapy was significantly higher in the conservative therapy group compared with the surgical treatment group (Table 1). Table 1. Characteristics of patients and therapy Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Age (metastasis free) 0.022* (0.001**)  80–84 years old (metastasis free) 254 (218) 207 (193) 47 (25)  ≥85 years old (metastasis free) 197 (173) 144 (132) 53 (41) Sex 0.475  Male 231 179 52  Female 220 172 48 Chemotherapy 0.160  (+) 10 6 4  (−) 441 345 96 Radiotherapy 0.021*  (+) 111 78 33  (−) 340 273 67 Median follow-up period (months) 18.9 18.9 19.0 0.155 Clinical outcome  Alive without disease 224 224 0  Alive with disease 117 44 73  Died of other disease 28 22 6  Died of disease 82 61 21 Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Age (metastasis free) 0.022* (0.001**)  80–84 years old (metastasis free) 254 (218) 207 (193) 47 (25)  ≥85 years old (metastasis free) 197 (173) 144 (132) 53 (41) Sex 0.475  Male 231 179 52  Female 220 172 48 Chemotherapy 0.160  (+) 10 6 4  (−) 441 345 96 Radiotherapy 0.021*  (+) 111 78 33  (−) 340 273 67 Median follow-up period (months) 18.9 18.9 19.0 0.155 Clinical outcome  Alive without disease 224 224 0  Alive with disease 117 44 73  Died of other disease 28 22 6  Died of disease 82 61 21 *P < 0.05, **P < 0.01, ***P < 0.001. Table 1. Characteristics of patients and therapy Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Age (metastasis free) 0.022* (0.001**)  80–84 years old (metastasis free) 254 (218) 207 (193) 47 (25)  ≥85 years old (metastasis free) 197 (173) 144 (132) 53 (41) Sex 0.475  Male 231 179 52  Female 220 172 48 Chemotherapy 0.160  (+) 10 6 4  (−) 441 345 96 Radiotherapy 0.021*  (+) 111 78 33  (−) 340 273 67 Median follow-up period (months) 18.9 18.9 19.0 0.155 Clinical outcome  Alive without disease 224 224 0  Alive with disease 117 44 73  Died of other disease 28 22 6  Died of disease 82 61 21 Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Age (metastasis free) 0.022* (0.001**)  80–84 years old (metastasis free) 254 (218) 207 (193) 47 (25)  ≥85 years old (metastasis free) 197 (173) 144 (132) 53 (41) Sex 0.475  Male 231 179 52  Female 220 172 48 Chemotherapy 0.160  (+) 10 6 4  (−) 441 345 96 Radiotherapy 0.021*  (+) 111 78 33  (−) 340 273 67 Median follow-up period (months) 18.9 18.9 19.0 0.155 Clinical outcome  Alive without disease 224 224 0  Alive with disease 117 44 73  Died of other disease 28 22 6  Died of disease 82 61 21 *P < 0.05, **P < 0.01, ***P < 0.001. Unlike normal survival curves, the Kaplan–Meier survival curve exhibited a stepped curve with two horizontal segments (Figs 1 and 2). Censoring was concentrated at up to 20 months, around 40 months and 80 months, and there were few events and censoring at the horizontal segments in between the three sections. These periods approximately coincided with the period from the first visit, at first registration, and until prognostic evaluation at 2 and 5 years. The 2-year cumulative overall survival rate was 84.4% and the 5-year cumulative overall survival rate was 41.6%. In addition, the 2-year cumulative disease-specific survival rate was 87.9%, and the 5-year cumulative disease-specific survival rate was 51.6%. Further diagnoses were as follows: undifferentiated pleomorphic sarcoma, 231; liposarcoma, 51; leiomyosarcoma, 46; and myxofibrosarcoma, 35. The site of occurrence were 270 cases in the lower extremities, 123 cases in the trunk of the body and 53 cases in the upper extremities, with the most frequent occurrence found in the lower extremities. There were 282 cases with a maximum tumor diameter of <10 cm and 157 cases with 10 cm or more. A total of 111 cases occurred in the superficial layer, and 335 cases occurred in a layer deeper than the fascia. There were 17 cases with regional lymph node metastasis at the first visit and 52 cases with distant metastasis (with some degree of overlap). The proportion of patients who underwent conservative therapy was significantly higher in cases with tumors >10 cm (P = 0.014), deep-seated tumors (P = 0.003), regional lymph node metastasis (P = 0.000) and distant metastasis (P = 0.000) (Table 2). Figure 1. View largeDownload slide Kaplan–Meier curves showing overall survival. The cumulative overall survival at 2 and 5 years after presentation were 84.4 and 41.6%, respectively. Figure 1. View largeDownload slide Kaplan–Meier curves showing overall survival. The cumulative overall survival at 2 and 5 years after presentation were 84.4 and 41.6%, respectively. Figure 2. View largeDownload slide Kaplan–Meier curves showing disease-specific survival. The cumulative overall survival at 2 and 5 years after presentation were 87.9 and 51.6%, respectively. Figure 2. View largeDownload slide Kaplan–Meier curves showing disease-specific survival. The cumulative overall survival at 2 and 5 years after presentation were 87.9 and 51.6%, respectively. Table 2. Overall tumor characteristics Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Histological type  UPS 231 185 46  Liposarcoma 51 42 9  Leiomyosarcoma 46 40 6  Myxofibrosarcoma 35 31 4  Others 88 53 35 Tumor site  Lower extremity 270 223 47  Upper extremity 53 42 11  Trunk 123 83 43 Tumor size 0.014*  <10 cm 282 230 52  ≥10 cm 157 113 44 Tumor depth 0.003**  Superficial 111 97 14  Deep 335 252 83 Compartment 0.033*  In the compartment 197 163 34  Beyond the compartment 237 176 61 Regional lymph node metastasis 0.000***  (+) 17 8 9  (−) 417 336 81 Distant metastasis 0.000***  (+) 52 22 30  (−) 387 328 59 Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Histological type  UPS 231 185 46  Liposarcoma 51 42 9  Leiomyosarcoma 46 40 6  Myxofibrosarcoma 35 31 4  Others 88 53 35 Tumor site  Lower extremity 270 223 47  Upper extremity 53 42 11  Trunk 123 83 43 Tumor size 0.014*  <10 cm 282 230 52  ≥10 cm 157 113 44 Tumor depth 0.003**  Superficial 111 97 14  Deep 335 252 83 Compartment 0.033*  In the compartment 197 163 34  Beyond the compartment 237 176 61 Regional lymph node metastasis 0.000***  (+) 17 8 9  (−) 417 336 81 Distant metastasis 0.000***  (+) 52 22 30  (−) 387 328 59 *P < 0.05, **P < 0.01, ***P < 0.001. UPS, undifferentiated pleomorphic sarcoma. View Large Table 2. Overall tumor characteristics Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Histological type  UPS 231 185 46  Liposarcoma 51 42 9  Leiomyosarcoma 46 40 6  Myxofibrosarcoma 35 31 4  Others 88 53 35 Tumor site  Lower extremity 270 223 47  Upper extremity 53 42 11  Trunk 123 83 43 Tumor size 0.014*  <10 cm 282 230 52  ≥10 cm 157 113 44 Tumor depth 0.003**  Superficial 111 97 14  Deep 335 252 83 Compartment 0.033*  In the compartment 197 163 34  Beyond the compartment 237 176 61 Regional lymph node metastasis 0.000***  (+) 17 8 9  (−) 417 336 81 Distant metastasis 0.000***  (+) 52 22 30  (−) 387 328 59 Total Surgical therapy Conservative therapy P value n = 451 n = 351 n = 100 Histological type  UPS 231 185 46  Liposarcoma 51 42 9  Leiomyosarcoma 46 40 6  Myxofibrosarcoma 35 31 4  Others 88 53 35 Tumor site  Lower extremity 270 223 47  Upper extremity 53 42 11  Trunk 123 83 43 Tumor size 0.014*  <10 cm 282 230 52  ≥10 cm 157 113 44 Tumor depth 0.003**  Superficial 111 97 14  Deep 335 252 83 Compartment 0.033*  In the compartment 197 163 34  Beyond the compartment 237 176 61 Regional lymph node metastasis 0.000***  (+) 17 8 9  (−) 417 336 81 Distant metastasis 0.000***  (+) 52 22 30  (−) 387 328 59 *P < 0.05, **P < 0.01, ***P < 0.001. UPS, undifferentiated pleomorphic sarcoma. View Large In the multivariate analysis, the proportion of cases undergoing conservative therapy increased in patients aged 85 years old or older (P = 0.036), patients with deep-seated occurrences (P = 0.027) and patients with distant metastases (P = 0.000) (Table 3). Table 3. Multivariate logistic regression analysis for conservative therapy Odds ratio 95% Confidence interval P value Age ≥ 85 years old 1.815 1.040–3.169 0.036* Sex (Female) 1.122 0.664–1.955 0.684 Chemotherapy (+) 1.303 0.281–6.035 0.735 Radiotherapy (+) 1.631 0.896–2.968 0.109 Tumor size > 10 cm 1.262 0.711–2.240 0.427 Tumor depth (deep) 2.483 1.110–5.557 0.027* Beyond the compartment 1.059 0.596–1.882 0.845 Lymph node metastasis (+) 2.680 0.710–10.121 0.146 Distant metastasis (+) 6.621 3.156–13.890 0.000*** Odds ratio 95% Confidence interval P value Age ≥ 85 years old 1.815 1.040–3.169 0.036* Sex (Female) 1.122 0.664–1.955 0.684 Chemotherapy (+) 1.303 0.281–6.035 0.735 Radiotherapy (+) 1.631 0.896–2.968 0.109 Tumor size > 10 cm 1.262 0.711–2.240 0.427 Tumor depth (deep) 2.483 1.110–5.557 0.027* Beyond the compartment 1.059 0.596–1.882 0.845 Lymph node metastasis (+) 2.680 0.710–10.121 0.146 Distant metastasis (+) 6.621 3.156–13.890 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Table 3. Multivariate logistic regression analysis for conservative therapy Odds ratio 95% Confidence interval P value Age ≥ 85 years old 1.815 1.040–3.169 0.036* Sex (Female) 1.122 0.664–1.955 0.684 Chemotherapy (+) 1.303 0.281–6.035 0.735 Radiotherapy (+) 1.631 0.896–2.968 0.109 Tumor size > 10 cm 1.262 0.711–2.240 0.427 Tumor depth (deep) 2.483 1.110–5.557 0.027* Beyond the compartment 1.059 0.596–1.882 0.845 Lymph node metastasis (+) 2.680 0.710–10.121 0.146 Distant metastasis (+) 6.621 3.156–13.890 0.000*** Odds ratio 95% Confidence interval P value Age ≥ 85 years old 1.815 1.040–3.169 0.036* Sex (Female) 1.122 0.664–1.955 0.684 Chemotherapy (+) 1.303 0.281–6.035 0.735 Radiotherapy (+) 1.631 0.896–2.968 0.109 Tumor size > 10 cm 1.262 0.711–2.240 0.427 Tumor depth (deep) 2.483 1.110–5.557 0.027* Beyond the compartment 1.059 0.596–1.882 0.845 Lymph node metastasis (+) 2.680 0.710–10.121 0.146 Distant metastasis (+) 6.621 3.156–13.890 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Significant risk factors for overall survival, according to univariate analysis, were as follows: tumor diameter >10 cm (hazard ratio = 1.610, 95% confidence interval = 1.103–2.353, P = 0.014), extracompartmental tumor progression (hazard ratio = 1.337, 95% confidence interval = 1.094–1.631, P = 0.005) and the presence of distant metastasis (hazard ratio = 3.086, 95% confidence interval = 2.020–4.717, P = 0.000) (Table 4). Multivariate analysis showed that distant metastasis (hazard ratio = 3.289, 95% confidence interval = 1.869–5.814, P = 0.000) and progress outside of the compartment (hazard ratio = 1.773, 95% confidence interval = 0.252–1.828, P = 0.014) were significant risk factors (Table 5). Table 4. Univariate Cox proportional hazards models of overall survival Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.674 0.456–0.994 0.047* Sex (Female) 0.871 0.598–1.269 0.472 Surgery (+) 0.915 0.736–1.138 0.426 Chemotherapy (+) 1.658 1.056–2.604 0.028* Radiotherapy (+) 1.087 0.886–1.333 0.427 Tumor size > 10 cm 1.610 1.103–2.353 0.014* Tumor depth (deep) 1.416 0.878–2.283 0.153 Beyond the compartment 1.337 1.094–1.631 0.005** Lymph node metastasis (+) 1.176 0.478–2.890 0.723 Distant metastasis (+) 3.086 2.020–4.717 0.000*** Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.674 0.456–0.994 0.047* Sex (Female) 0.871 0.598–1.269 0.472 Surgery (+) 0.915 0.736–1.138 0.426 Chemotherapy (+) 1.658 1.056–2.604 0.028* Radiotherapy (+) 1.087 0.886–1.333 0.427 Tumor size > 10 cm 1.610 1.103–2.353 0.014* Tumor depth (deep) 1.416 0.878–2.283 0.153 Beyond the compartment 1.337 1.094–1.631 0.005** Lymph node metastasis (+) 1.176 0.478–2.890 0.723 Distant metastasis (+) 3.086 2.020–4.717 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Table 4. Univariate Cox proportional hazards models of overall survival Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.674 0.456–0.994 0.047* Sex (Female) 0.871 0.598–1.269 0.472 Surgery (+) 0.915 0.736–1.138 0.426 Chemotherapy (+) 1.658 1.056–2.604 0.028* Radiotherapy (+) 1.087 0.886–1.333 0.427 Tumor size > 10 cm 1.610 1.103–2.353 0.014* Tumor depth (deep) 1.416 0.878–2.283 0.153 Beyond the compartment 1.337 1.094–1.631 0.005** Lymph node metastasis (+) 1.176 0.478–2.890 0.723 Distant metastasis (+) 3.086 2.020–4.717 0.000*** Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.674 0.456–0.994 0.047* Sex (Female) 0.871 0.598–1.269 0.472 Surgery (+) 0.915 0.736–1.138 0.426 Chemotherapy (+) 1.658 1.056–2.604 0.028* Radiotherapy (+) 1.087 0.886–1.333 0.427 Tumor size > 10 cm 1.610 1.103–2.353 0.014* Tumor depth (deep) 1.416 0.878–2.283 0.153 Beyond the compartment 1.337 1.094–1.631 0.005** Lymph node metastasis (+) 1.176 0.478–2.890 0.723 Distant metastasis (+) 3.086 2.020–4.717 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Table 5. Multivariate Cox proportional hazards models of overall survival Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.725 0.476–1.104 0.133 Sex (Female) 0.931 0.612–1.418 0.740 Surgery (+) 1.582 0.864–2.899 0.137 Chemotherapy (+) 2.252 0.854–5.917 0.101 Radiotherapy (+) 0.776 0.472–1.276 0.317 Tumor size > 10 cm 1.190 0.765–1.852 0.440 Tumor depth (deep) 1.361 0.794–2.326 0.262 Beyond the compartment 1.773 1.122–2.801 0.014* Lymph node metastasis (+) 0.679 0.252–1.828 0.443 Distant metastasis (+) 3.289 1.869–5.814 0.000*** Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.725 0.476–1.104 0.133 Sex (Female) 0.931 0.612–1.418 0.740 Surgery (+) 1.582 0.864–2.899 0.137 Chemotherapy (+) 2.252 0.854–5.917 0.101 Radiotherapy (+) 0.776 0.472–1.276 0.317 Tumor size > 10 cm 1.190 0.765–1.852 0.440 Tumor depth (deep) 1.361 0.794–2.326 0.262 Beyond the compartment 1.773 1.122–2.801 0.014* Lymph node metastasis (+) 0.679 0.252–1.828 0.443 Distant metastasis (+) 3.289 1.869–5.814 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Table 5. Multivariate Cox proportional hazards models of overall survival Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.725 0.476–1.104 0.133 Sex (Female) 0.931 0.612–1.418 0.740 Surgery (+) 1.582 0.864–2.899 0.137 Chemotherapy (+) 2.252 0.854–5.917 0.101 Radiotherapy (+) 0.776 0.472–1.276 0.317 Tumor size > 10 cm 1.190 0.765–1.852 0.440 Tumor depth (deep) 1.361 0.794–2.326 0.262 Beyond the compartment 1.773 1.122–2.801 0.014* Lymph node metastasis (+) 0.679 0.252–1.828 0.443 Distant metastasis (+) 3.289 1.869–5.814 0.000*** Hazard ratio 95% Confidence interval P value Age ≥ 85 years old 0.725 0.476–1.104 0.133 Sex (Female) 0.931 0.612–1.418 0.740 Surgery (+) 1.582 0.864–2.899 0.137 Chemotherapy (+) 2.252 0.854–5.917 0.101 Radiotherapy (+) 0.776 0.472–1.276 0.317 Tumor size > 10 cm 1.190 0.765–1.852 0.440 Tumor depth (deep) 1.361 0.794–2.326 0.262 Beyond the compartment 1.773 1.122–2.801 0.014* Lymph node metastasis (+) 0.679 0.252–1.828 0.443 Distant metastasis (+) 3.289 1.869–5.814 0.000*** *P < 0.05, **P < 0.01, ***P < 0.001. Discussion Ogura et al. reported on STSs for all ages registered from 2006 to 2012 in the Bone and Soft Tissue Tumor Registry in Japan (8). According to the report, 8288 patients were registered for STSs in 7 years, and among them, geriatric patients over 60 years of age accounted for more than 50% of registered patients, and the percentage of patients have dramatically increased with the aging of the Japanese population. In our current study, we focused on oldest-old patients with STS in Japan who were over 80 years of age, as Japan faces the highest rate of aging in the world. In light of this problem, we examined the status quo of treatment and clinical outcome for high-grade STS. In this study, the survival curves of patients aged 80 years or older exhibited atypical, stepped curves. We believe that this is due to restricting our subjects to the elderly, since Ogura et al. reported normal survival curves in a study across all ages. Moreover, in this study, cases treated at a hospital different from the hospital where they were registered were excluded in order to prevent duplication of cases. As the time periods that showed a concentration of censored data had approximately coincided with the time at the first registration and prognostic evaluation at 2 and 5 years, reasons for our atypical results may have been due to active treatment halted early because of old age that resulted in a transfer from a specialized care facility to a local clinic, discontinuation of clinical consultation or subsequent events that were unreported. Since proportional hazards were not adequately preserved in our results, a statistical comparison with the log-rank test remains difficult, and the results of our Cox regression analysis also requires scrutiny. The Bone and Soft Tissue Tumor Registry in Japan is limited by the anonymity of its aggregated data, which could be a subject of future research. With aging, various functions of the body will deteriorate, including cardiovascular, respiratory, mental, immunologic and urological functions (9). For this reason, surgical treatment for the geriatric population has been reported to induce distinctive perioperative complications such as cardiovascular disease, pneumonia and delirium, and the incidence increases with age (10). Infectious diseases after surgery in the geriatric population is one of the leading causes of complications and increased mortality rate, and the sites with high post-operative infection rates include the urinary tract, respiratory tract and operative wound (11). Post-operative delirium is also a notable complication for the geriatric population (12). Age is a risk factor for delirium (13), and post-operative delirium can be a cause for poor clinical outcome that includes functional deterioration, extended hospital stay, institutionalization, increase in medical costs and increased mortality rate (14). Being older is an independent prognostic factor for STS, which has been reported to be a result of undertreatment for the geriatric population (15), but we believe that the increased incidence of complications is also a contributing factor for undertreatment. The results of this study have revealed that the proportion of patients undergoing conservative therapy in the older population demonstrates a greater level of increase than that of patients in the younger population who are <85 years old. For various types of carcinomas, surgical therapy on malignant tumors can be safely performed regardless of age, and numerous reports have suggested that surgical intervention should be presented as treatment options (5,16–23). However, to the best of our knowledge, there are no reports that compare surgical therapy and conservative therapy such as chemotherapy or radiotherapy, and reports that suggest improved life expectancy with surgical intervention for oldest-old patients are scarce in the literature. Although this is a retrospective study, it is one of the few studies to examine the treatment outcomes for both surgical and conservative therapy of highly malignant STSs in patients 80 years or older. From the results of this study, we were unable to show whether or not surgical intervention improved the long-term vital prognosis of oldest-old patients compared with the conservative therapy. Our results may suggest that the surgical indication for elderly patients in Japan could have been generally correct. However, considering the limited patient background information and characteristics previously mentioned in this paper, we believe that the results should be interpreted with caution, and the surgical indication for elderly patients should likewise receive a close examination. According to a report by Ogura et al., 19.4% of STS cases across all age groups had received radiation therapy (8). In elderly patients aged 80 years and older, 22.2% in the surgical treatment group and 33% in the conservative therapy group received radiation therapy, and the percentage of cases receiving radiation therapy significantly increased in the conservative therapy group. We believe that surgical treatment is not elected for the reasons described above that are particular to the elderly, and that palliative radiotherapy is performed as an alternative treatment option. Although palliative treatment included chemotherapy, chemotherapy was only performed in 2.2% of all patients aged 80 years or older and only 4% of the conservative therapy group. Considering that chemotherapy is performed in 26.1% of patients across all ages (8), the low percentage is likely due to difficulties in safely administering chemotherapy for the elderly. In this study, the 2-year cumulative disease-specific survival rate was 87.9% and the 5-year cumulative disease-specific survival rate was 51.6% in elderly STS patients aged 80 years or older. The 2 and 5-year disease-specific survival rates across all ages are reported to be 86.8 and 77.5%, respectively (8). Even if the aforementioned characteristics of the registry are considered, our results were not dissimilar to that of the past literature, which report that the old age is an independent and poor prognostic factor for STSs (15). There are several limitations in our research. First, because the Bone and Soft Tissue Tumor Registry in Japan is organized by the Japanese Orthopaedic Association, the registry may underestimate sarcomas that originate in the trunk of the body that include the retroperitoneal cavity, which is not only treated by orthopedic surgeons but also surgeons and urologists. Second, the registry does not contain a geriatric assessment that is essential for research on elderly people. Third, since this is a retrospective study using a registry, in addition to the registered data, there are many factors that remain unclear, such as patient lifestyle, family background and motivation for treatment; thus, there are many biases in comparing surgical treatment and conservative therapy. Fourth, since cases treated at other institutions are excluded from our study, there could be insufficient reporting of events. Conclusion Japan faces the highest rate of aging in the world, and in this study, the status quo of treatment and clinical outcome for oldest-old patients over 80 years of age with high-grade STS were examined. The proportion of patients undergoing conservative therapy significantly increased in patients aged 85 years or older, patients with deep-seated occurrences and patients with metastases at the first visit. Extracompartmental tumor progression and the presence of distant metastasis at the first visit were significant risk factors for overall survival. Acknowledgements The data presented in this work was obtained from the Bone and Soft Tissue Tumor Registry in Japan (The Japanese Orthopaedic Association/National Cancer Center). We thank all the hospitals and medical staff participating in this registry. Conflict of interest statement None declared. References 1 Goldblum JR , Folpe AL , Weiss SW , Enzinger FM . Enzinger and Weiss’s soft tissue tumors . 6th edn . 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Journal

Japanese Journal of Clinical OncologyOxford University Press

Published: Oct 1, 2018

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