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Statistics of soft-tissue sarcoma in Japan: Report from the Bone and Soft Tissue Tumor Registry in Japan
Journal of Orthopaedic Science 22 (2017) 755e764
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Original Article
Statistics of soft-tissue sarcoma in Japan: Report from the Bone and Soft Tissue Tumor Registry in Japan Koichi Ogura a, Takahiro Higashi b, Akira Kawai a, * a
Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan Division of Health Services Research, Center for Cancer Control and Information Services, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 January 2017 Received in revised form 21 March 2017 Accepted 23 March 2017
Background: No previous reports to date have characterized the national profiles of soft-tissue sarcomas (STSs). In the present study, we reviewed current practice for STSs in Japan using data from a nationwide organ-specific cancer registry for bone and soft-tissue tumors in Japan, the Bone and Soft Tissue Tumor (BSTT) Registry. Methods: In the registry, we identified 8228 patients with STSs during the period 2006e2012, and extracted data on patient demographics, treatment, and outcome at the last follow-up for each patient. Disease-specific survival was analyzed using the Cox proportional hazards model. Results: STSs showed a slight male predilection. The age distribution had a single peak in the seventh decade, the proportion of elderly patients aged >60 years being approximately 53%. For most of the histologic subtypes, the most frequent tumor location was the lower extremity, whereas it was the trunk in patients with malignant peripheral nerve sheath tumor, dedifferentiated liposarcoma, and primitive neuroectodermal tumor. Based on data for 2432 patients with STSs, we found significant associations between disease-specific survival and age, sex, histologic subtype, tumor size, tumor depth, tumor location, additional surgery, limb salvage status, and surgical margin; elderly patients showed the poorest disease-specific survival. Conclusions: Using the BSTT Registry, this study has clarified the epidemiology, treatment, and prognosis of patients with STSs in Japan. Our experiences with the BSTT Registry will be of help to other countries where aging of the population is occurring. Continuous accumulation of clinical data in the BSTT Registry should provide more informative data on STSs, thus improving both the level of medical care offered by clinicians and the outcomes for patients through sharing of such data and promotion of clinical research. © 2017 The Authors. Published by Elsevier B.V. on behalf of The Japanese Orthopaedic Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
1. Introduction Soft-tissue sarcomas (STSs) are heterogeneous neoplasms originating from mesenchymal cells, comprising more than 50 histological subtypes. They can arise at any anatomic site, resulting in a large variety of combinations of histology and primary site [1]. Against this biological background, the rarity of STSs inevitably hinders accurate diagnosis and appropriate treatment. This makes it difficult to accumulate a sufficient number of cases of STS at a single institution for statistical analysis.
* Corresponding author. Fax: þ81 3 3542 3815. E-mail address: [email protected] (A. Kawai).
In order to improve clinical practice for STSs, understanding the current status is essential. Although there have been a few previous reports focusing on the epidemiology of some histologic subtypes using the Surveillance, Epidemiology, and End Results (SEER) database in the United States [2e5], to our knowledge, no attempt has yet been made to characterize the overall profiles of STS at the national level, including data such as patient age and sex distribution, details of the tumors (size, site, histologic subtype, etc.), treatment modalities, and prognostic factors on the basis of a large nationwide cohort [2e5]. In the present study, we investigated current practice nationwide for STSs in Japan using data from a nationwide organ-specific cancer registry for bone and soft-tissue tumors in Japan, the Bone and Soft Tissue Tumor (BSTT) Registry. Previously, we have
http://dx.doi.org/10.1016/j.jos.2017.03.017 0949-2658/© 2017 The Authors. Published by Elsevier B.V. on behalf of The Japanese Orthopaedic Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
reported the statistics for bone sarcoma in Japan [6], and to our knowledge, the present study is the first to have analyzed STSs using the BSTT Registry since it became available for the purpose of clinical research in 2014.
IBM SPSS version 19.0 (IBM SPSS, Armonk, NY, USA) and Stata 13 (StataCorp LP, College Station, TX, USA).
2. Patients and methods
3.1. Clinical characteristics of the patients
2.1. Data source
We identified BSTT-registered 44,709 patients for the period 2006e2012. Of these, we extracted the records of 8288 patients with STSs who had been treated at 130 hospitals. The numbers of hospitals and patients registered as having STS per year gradually increased: from 825 cases at 69 hospitals in 2006 to 1138 cases at 71 hospitals in 2009, and 1597 cases at 85 hospitals in 2012 (Fig. 1). Table 1 shows the clinical and demographic characteristics in relation to the major histologic diagnoses. Further details of the diagnosis are summarized in Appendix 1 (Supplementary Material). There was a slight male predilection for cases of STS. The age distribution had a single peak in the seventh decade with mean age of 58.3 years overall. Among the major histologic subtypes, undifferentiated pleomorphic sarcoma (UPS), well differentiated liposarcoma (WDLS), leiomyosarcoma (LMS), myxofibrosarcoma (MFS), malignant peripheral nerve sheath tumor (MPNST), and dedifferentiated liposarcoma (DDLS) had a peak in the elderly, whereas myxoid/round cell liposarcoma (MRLS), synovial sarcoma, primitive neuroectodermal tumor (PNET), and rhabdomyosarcoma (RMS) had a peak in children and young adults aged <40 years. Most of the patients received treatment at the first hospitals with expertise, or were referred to such hospitals before surgery. The mean tumor size in the patients overall was 10.2 cm. The most frequent site of involvement was the lower extremity in patients with UPS, WDLS, MRLS, LMS, MFS, synovial sarcoma, and RMS, whereas it was the trunk in patients with MPNST, DDLS, and PNET. Further details of tumor location are summarized in Appendix 2 (Supplementary Material).
For this study, we utilized the BSTT Registry, details of which have been described elsewhere [6]. Briefly, it is a nationwide organspecific cancer registry for bone and soft tissue tumors that was launched in the 1950s, being organized and funded by the Japanese Orthopaedic Association (JOA) and promoted by the National Cancer Center. All the JOA-certified hospitals for musculoskeletal oncology (N ¼ 89) [7] are obliged to participate in the registry, but participation by other hospitals is voluntary. The database includes the following data: 1) basic data on the patient: hospital, sex, age, date of diagnosis, and status at the first visit, etc.; 2) information on the tumor: origin of the tumor (bone, soft tissue, or metastatic bone tumor), histologic details (malignant or benign, and diagnosis), tumor depth and location, and the data required for TNM (AJCC Cancer Staging Manual 6th edition) [8] and Enneking staging (tumor size, nodal or distant metastasis, and histologic grade), etc.; 3) information on surgery: date of definitive surgery, type of surgery, reconstruction details, and additional surgery for complications, etc.; 4) information on treatment other than surgery: details of chemotherapy, radiotherapy, and hyperthermia; and 5) information on several outcomes at the time of the latest follow-up, such as local recurrence, distant metastasis, oncologic outcome, limb salvage status, and functional outcome (ISOLS/MSTS rating scale [9]). Use of the BSTT Registry for the purposes of clinical research was initiated in 2014 after approval from the Musculoskeletal Tumor Committee of the JOA. The Institutional Review Board of the JOA approved the present study protocol. Because the database is de-identified, informed consent was not mandated by the Ethics Guidelines for Human Subject Medical Research, and was waived by the IRB. 2.2. Data extraction Data were obtained from the BSTT Registry during 2006e2012. In this analysis, we focused on primary malignant soft-tissue tumors (STSs). Patients with STS were defined as patients whose diagnosis was “malignant” and origin of the tumor was “soft-tissue”. Patients with intermediate grade malignancy such as desmoid tumor or dermatofibrosarcoma protuberans were not included in STS in this study. For each patient, we extracted the following data: year of registration, sex, age, status at first visit, tumor size, tumor depth and location, histologic diagnosis and grade of the tumor, TNM (AJCC Cancer Staging Manual 6th edition) [8] and Enneking stage, details of treatment (surgical and non-surgical), postoperative complications, and outcome at the last follow-up (no evidence of disease, alive with disease, dead of disease, or dead due to other causes). Cases with insufficient data were excluded.
3. Results
3.2. Surgical treatment Table 2 summarizes the statistics of surgery according to histologic subtype. Overall, 6680 patients (80.6%) underwent surgical treatment. The proportion of patients who underwent definitive surgery was relatively low for PNET (63.4%) and RMS (60.2%), perhaps because of the radiosensitivity of these histologic subtypes and the tendency of PNET to arise in the trunk. The amputation rate was 4.7% (313/6680) overall, which was lower than that for bone sarcoma (10.6%) [6]. Status of surgical margin was wide in 70.4%, marginal in 23.1%, and intralesional in 5.6%. In surgical cases, bone
2.3. Statistical analyses Disease-specific survival (DSS) was defined as the period between the date of diagnosis and tumor-related death. Patients who died of causes other than STS were considered as censored at the time of death. The KaplaneMeier method was used for estimation of DSS. The factors associated with survival were analyzed using the Cox proportional hazards models. The threshold for statistical significance was P < 0.05. All statistical analyses were conducted using
Fig. 1. Annual transition of the numbers of hospitals and patients registered as having STS.
Table 1 Characteristics of the study population according to histologic subtype. No. of patients
Overall (N ¼ 8288)
UPS (N ¼ 1613)
%
%
MRLS (N ¼ 775)
%
LMS (N ¼ 539)
%
MFS (N ¼ 488)
%
Synovial sarcoma (N ¼ 479)
%
MPNST (N ¼ 373)
%
DDLS (N ¼ 333)
%
PNET (N ¼ 161)
%
RMS (N ¼ 211)
%
High grade sarcoma (others) (N ¼ 1174)
Low grade sarcoma (others) (N ¼ 548)
%
%
%
943 58.5 884 55.5 425 54.8 260 48.2 272 55.7 230 48.0 198 53.1 214 64.3 80 49.7 120 56.9 658 56.0 297 54.2 670 41.5 710 44.5 350 45.2 279 51.8 216 44.3 249 52.0 175 46.9 119 35.7 81 50.3 91 43.1 516 44.0 251 45.8 68.1 [13.8] 62.5 [13.2] 50.6 [16.3] 62.7 [15.5] 67.2 [13.3] 39.4 [18.7] 52.7 [20.2] 64.7 [13.3] 33.7 [18.2] 33.8 [26.1] 54.6 [20.6] 54.9 [18.9] 2 2 22 44 107 229 437 483 262 25
0.1 0.1 1.4 2.7 6.6 14.2 27.1 29.9 16.2 1.5
0 5 15 87 182 340 493 370 96 6
0.0 0.3 0.9 5.5 11.4 21.3 30.9 23.2 6.0 0.4
1 14 67 167 148 142 133 87 15 1
0.1 1.8 8.6 21.5 19.1 18.3 17.2 11.2 1.9 0.1
0 6 16 38 43 120 141 115 58 2
0.0 1.1 3.0 7.1 8.0 22.3 26.2 21.3 10.8 0.4
1 0 5 15 34 74 136 155 65 3
0.2 0.0 1.0 3.1 7.0 15.2 27.9 31.8 13.3 0.6
17 67 92 98 61 63 48 27 6 0
3.5 14.0 19.2 20.5 12.7 13.2 10.0 5.6 1.3 0.0
2 25 39 48 50 53 72 60 22 2
0.5 6.7 10.5 12.9 13.4 14.2 19.3 16.1 5.9 0.5
0 2 0 11 41 62 96 87 33 1
0.0 0.6 0.0 3.3 12.3 18.6 28.8 26.1 9.9 0.3
9 32 41 34 17 11 12 4 1 0
5.6 19.9 25.5 21.1 10.6 6.8 7.5 2.5 0.6 0.0
43 55 23 17 10 16 24 13 9 1
20.4 26.1 10.9 8.1 4.7 7.6 11.4 6.2 4.3 0.5
17 46 126 144 142 156 243 205 85 10
1.4 3.9 10.7 12.3 12.1 13.3 20.7 17.5 7.2 0.9
6 21 39 67 84 107 104 79 38 3
1.1 3.8 7.1 12.2 15.3 19.5 19.0 14.4 6.9 0.5
1239 76 107 67 113 11 9.2 [6.3]
76.8 4.7 6.6 4.2 7.0 0.7
1418 33 10 24 106 3 14.2 [7.1]
89.0 2.1 0.6 1.5 6.6 0.2
630 48 25 18 51 3 10.7 [6.7]
81.3 6.2 3.2 2.3 6.6 0.4
365 54 37 34 45 4 8.0 [5.2]
67.7 10.0 6.9 6.3 8.3 0.7
372 24 38 24 27 3 8.5 [6.4]
76.2 4.9 7.8 4.9 5.5 0.6
352 39 24 18 41 5 7.2 [4.6]
73.5 8.1 5.0 3.8 8.6 1.0
276 21 11 17 47 1 9.3 [5.3]
74.0 5.6 2.9 4.6 12.6 0.3
231 8 9 14 68 3 14.6 [8.4]
69.4 2.4 2.7 4.2 20.4 0.9
115 9 9 8 16 4 9.3 [5.3]
71.4 5.6 5.6 5.0 9.9 2.5
183 2 4 6 13 3 8.4 [5.5]
86.7 0.9 1.9 2.8 6.2 1.4
891 53 47 46 124 13 8.8 [6.1]
75.9 4.5 4.0 3.9 10.6 1.1
418 33 33 20 43 1 7.9 [6.9]
76.3 6.0 6.0 3.6 7.8 0.2
426 615 283 112 50 127
26.4 38.1 17.5 6.9 3.1 7.9
120 465 383 331 244 51
7.5 29.2 24.0 20.8 15.3 3.2
133 308 175 67 48 44
17.2 39.7 22.6 8.6 6.2 5.7
179 207 61 25 13 54
33.2 38.4 11.3 4.6 2.4 10.0
164 181 72 21 20 30
33.6 37.1 14.8 4.3 4.1 6.1
184 155 60 15 5 60
38.4 32.4 12.5 3.1 1.0 12.5
92 150 61 34 11 25
24.7 40.2 16.4 9.1 2.9 6.7
36 85 76 72 50 14
10.8 25.5 22.8 21.6 15.0 4.2
39 54 35 13 3 17
24.2 33.5 21.7 8.1 1.9 10.6
68 85 26 13 6 13
32.2 40.3 12.3 6.2 2.8 6.2
346 434 173 82 30 109
29.5 37.0 14.7 7.0 2.6 9.3
224 185 58 19 28 34
40.9 33.8 10.6 3.5 5.1 6.2
225 857 487 26 18
13.9 53.1 30.2 1.6 1.1
121 1033 387 39 14
7.6 64.8 24.3 2.4 0.9
42 579 138 3 13
5.4 74.7 17.8 0.4 1.7
54 275 184 10 16
10.0 51.0 34.1 1.9 3.0
83 278 120 6 1
17.0 57.0 24.6 1.2 0.2
75 239 137 22 6
15.7 49.9 28.6 4.6 1.3
48 131 149 26 19
12.9 35.1 39.9 7.0 5.1
13 124 185 1 10
3.9 37.2 55.6 0.3 3.0
13 49 80 14 5
8.1 30.4 49.7 8.7 3.1
40 69 55 32 15
19.0 32.7 26.1 15.2 7.1
167 508 398 38 63
14.2 43.3 33.9 3.2 5.4
80 238 209 14 7
14.6 43.4 38.1 2.6 1.3
501 1066 46
31.1 229 66.1 1334 2.9 31
14.4 162 83.7 593 1.9 20
20.9 166 76.5 358 2.6 15
30.8 177 66.4 303 2.8 8
36.3 62 62.1 393 1.6 24
12.9 96 82.0 259 5.0 18
25.7 35 69.4 295 4.8 3
10.5 21 88.6 134 0.9 6
13.0 24 83.2 182 3.7 5
11.4 264 86.3 862 2.4 48
22.5 204 73.4 329 4.1 15
37.2 60.0 2.7
0 0 362 180 663 190 218
0.0 0.0 22.4 11.2 41.1 11.8 13.5
103 1353 4 2 9 4 119
6.5 84.9 0.3 0.1 0.6 0.3 7.5
11.0 32.8 5.4 4.6 31.0 7.9 7.4
2.8 3.3 26.5 7.1 33.8 13.5 13.0
77 110 80 34 139 9 39
15.8 22.5 16.4 7.0 28.5 1.8 8.0
1.5 1.3 33.6 1.9 31.3 13.2 17.3
16 28 51 33 130 52 63
4.3 7.5 13.7 8.8 34.9 13.9 16.9
5 17 23 22 203 36 27
1.5 5.1 6.9 6.6 61.0 10.8 8.1
0 0 34 7 52 46 22
0.0 0.0 21.1 4.3 32.3 28.6 13.7
0 2 39 5 65 82 18
0.0 0.9 18.5 2.4 30.8 38.9 8.5
0 0 252 66 375 308 173
0.0 0.0 21.5 5.6 31.9 26.2 14.7
211 267 0 0 0 22 48
38.5 48.7 0.0 0.0 0.0 4.0 8.8
0 0
0.0 0.0
949 500
59.5 226 31.4 123
4.5 2.2
124 71
25.4 10 14.5 3
2.1 0.6
31 11
8.3 2.9
10 10
3.0 3.0
0 0
0.0 0.0
1 1
0.5 0.5
0 0
0.0 0.0
300 176
54.7 32.1
85 254 42 36 240 61 57
15 18 143 38 182 73 70
29.2 24 15.9 12
7 6 161 9 150 63 83
757
(continued on next page)
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
Sex Male 4581 55.3 Female 3707 44.7 Age (years), 58.3 [18.9] mean [SD] 0e10 98 1.2 11e20 275 3.3 21e30 485 5.9 31e40 770 9.3 41e50 919 11.1 51e60 1373 16.6 61e70 1939 23.4 71e80 1685 20.3 81e90 690 8.3 91e 54 0.7 a Status at first visit 1 6490 78.3 2 400 4.8 3 354 4.3 4 296 3.6 5 694 8.4 6 54 0.7 Tumor size (cm), 10.2 [6.8] mean [SD] 5 2011 24.3 5.1e10 2924 35.3 10.1e15 1463 17.7 15.1e20 804 9.7 20.1e 508 6.1 Unknown 578 7.0 Tumor location Upper extremity 961 11.6 Lower extremity 4380 52.8 Trunk 2529 30.5 Head and neck 231 2.8 Multiple disease 187 2.3 Depth Superficial 1941 23.4 Deep 6108 73.7 Unknown 239 2.9 TNM stage Stage IA 519 6.3 Stage IB 2055 24.8 Stage IIA 1191 14.4 Stage IIB 432 5.2 Stage III 2208 26.6 Stage IV 946 11.4 Unknown 937 11.3 Enneking stage Stage IA 1675 20.2 Stage IB 907 10.9
WDLS (N ¼ 1594)
SD: standard deviation. UPS: undifferentiated pleomorphic sarcoma, WDLS: well-differentiated liposarcoma, MRLS: myxoid/round cell liposarcoma, LMS: leiomyosarcoma, MFS: myxofibrosarcoma, MPNST: malignant peripheral nerve sheath tumor, DDLS: dedifferentiated liposarcoma, PNET: primitive neuroectodermal tumor, RMS: rhabdomyosarcoma. a Each number refers to the following status; 1: First visit/After preoperative therapy, 2: NED after resection at the previous hospital, 3: With microscopic residual tumor after resection at the previous hospital, 4: With macroscopic residual tumor after resection at the previous hospital, 5: Local or metastatic recurrence, 6: Others.
%
0 0 26 46 %
30.3 29.0 30.7 9.9 356 341 361 116
%
31.8 28.4 34.1 4.7 67 60 72 10
%
23.6 34.2 31.1 11.2 38 55 50 18
%
29.4 41.1 15.0 8.4 98 137 50 28
%
27.1 29.8 17.2 14.7 101 111 64 55
%
33.0 33.2 17.7 13.4 158 159 85 64
%
27.7 22.3 3.1 7.0 135 109 15 34
%
38.4 30.2 16.1 8.5 207 163 87 46
% %
0.7 0.3 0.4 7.7 Stage IIA Stage IIB Stage III Unknown
1953 1879 1100 774
23.6 22.7 13.3 9.3
613 604 213 183
11 5 6 123 %
38.0 37.4 13.2 11.3
%
169 135 71 51
21.8 17.4 9.2 6.6
High grade sarcoma (others) (N ¼ 1174) RMS (N ¼ 211) PNET (N ¼ 161) DDLS (N ¼ 333) MPNST (N ¼ 373) Synovial sarcoma (N ¼ 479) MFS (N ¼ 488) LMS (N ¼ 539) MRLS (N ¼ 775) WDLS (N ¼ 1594) UPS (N ¼ 1613) Overall (N ¼ 8288) No. of patients
Table 1 (continued )
0.0 0.0 4.7 8.4
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
Low grade sarcoma (others) (N ¼ 548)
758
reconstruction was performed less frequently (229/6680; 3.4%) than for bone sarcoma (59.5%). The most frequent methods of bone reconstruction were the use of an autograft (137/6680; 2.1%) and a prosthesis (77/6680; 1.2%). Soft tissue reconstruction was performed in 22.6% of the surgical cases (1512/6680). The most frequent methods of soft tissue reconstruction were the use of a pedicled myocutaneous flap (680/6680; 10.2%) and a skin graft (671/6680; 10.0%). Other forms of reconstruction involved mainly in situ preparation, reconstruction of the tendon (e.g. Achilles tendon or patellar tendon), ligament, or capsule, and reconstruction of the chest wall or abdominal wall. The rate of complications requiring additional surgical procedures (672/6680; 10.1%) was lower than that for bone sarcoma (15.1%) [6]. The rate of wound complications (delayed wound healing (192/6680; 2.9%) and infection (146/6680; 2.2%)) was lower for STS than for bone sarcoma (3.6% and 5.3%, respectively), whereas surgery for local recurrence was more frequent for STS (178/6680; 2.7%) than for bone sarcoma (1.9%) [6]. Additional surgery for other reasons included removal of postoperative hematoma, additional resection resulting from a change in the histologic diagnosis or an inadequate surgical margin after evaluation of the surgical specimen, surgery for lymphedema such as lymphaticovenular anastomosis, internal fixation for postoperative fracture, and implant removal. The rate of additional surgery was highest for patients with MPNST (60/301; 19.9%). 3.3. Treatments other than surgery Table 3 shows a summary of patients who underwent nonsurgical treatment. Overall, 2167 (26.1%) of 8288 patients underwent chemotherapy, which was much lower than the rate for bone sarcoma [6]. This included the majority of patients with synovial sarcoma (304/479; 63.5%), PNET (142/161; 88.2%), and RMS (155/ 211; 73.5%), whereas few patients with WDLS (8/1594; 0.5%) and MFS (52/488; 10.7%) underwent chemotherapy. Adjuvant chemotherapy before and/or after surgery accounted for 83.6% (254/304) of the chemotherapy in patients with synovial sarcoma. The most frequently used agents were adriamycin (ADR), ifosfamide (IFO), and etoposide (VP16). Overall, 1604 (19.4%) of the 8288 patients received radiotherapy. Patients with PNET and RMS received radiotherapy more frequently than patients with other histologic subtypes. Radiotherapy in a radical setting was performed mostly for patients with PNET (19/ 61; 31.1%) and RMS (44/106; 41.5%). The high proportion of radiotherapy in a radical setting for these histologic subtypes may have been attributable to their radiosensitivity, in addition for the tendency of PNET to arise in the trunk. In fact, among the 19 patients with PNET who underwent radical radiotherapy, the primary tumor was located in the trunk, or the head and neck, in 15 (78.9%). 3.4. Prognosis During the study period, we identified the records of 3826 patients from 79 hospitals whose prognostic data at 2 or 5 years after initial registration were available. The outcome at 2 and 5 years was evaluable for 52.5% (1022 patients) and 42.9% (834 patients) of 1946 patients whose first registrations had been conducted in 2006 and 2007, respectively. The mean follow-up period for these patients was 34.2 months (range, 2e83 months). The cumulative DSS at 2 and 5 years after treatment was 86.8% and 77.5%, respectively (Fig. 2). The unadjusted associations of various factors with the DSS rate estimated using the KaplaneMeier method are shown in Fig. 3AeL. Table 4 shows the unadjusted and adjusted hazard ratios obtained from the Cox proportional hazards models for DSS based on
Table 2 Statistics of surgery according to histologic subtype. UPS (N ¼ 1613)
Low grade sarcoma (others) (N ¼ 548)
1330
82.5
1351
84.8
666
85.9
420
77.9
433
88.7
377
78.7
301
80.7
258
77.5
102
63.4
127
60.2
860
73.3
455
83.0
5792 552 313 23
86.7 8.3 4.7 0.3
1111 148 69 2
83.5 11.1 5.2 0.2
1323 14 13 1
97.9 1.0 1.0 0.1
592 54 18 2
88.9 8.1 2.7 0.3
333 64 20 3
79.3 15.2 4.8 0.7
364 53 16 0
84.1 12.2 3.7 0.0
300 50 25 2
79.6 13.3 6.6 0.5
257 25 13 6
85.4 8.3 4.3 2.0
237 8 13 0
91.9 3.1 5.0 0.0
90 9 3 0
88.2 8.8 2.9 0.0
111 5 9 2
87.4 3.9 7.1 1.6
684 75 98 3
79.5 8.7 11.4 0.3
390 47 16 2
85.7 10.3 3.5 0.4
4704 1542 371 63 229 137 66 45 99 30 11 8 1 77 8 1512 671 680 312 110 24 136 672
70.4 23.1 5.6 0.9 3.4 2.1 1.0 0.7 1.5 0.4 0.2 0.1 0.0 1.2 0.1 22.6 10.0 10.2 4.7 1.6 0.4 2.0 10.1
1107 142 74 7 58 35 19 12 19 6 1 3 0 22 0 448 218 207 90 13 2 32 162
83.2 10.7 5.6 0.5 4.4 2.6 1.4 0.9 1.4 0.5 0.1 0.2 0.0 1.7 0.0 33.7 16.4 15.6 6.8 1.0 0.2 2.4 12.2
464 831 51 5 11 9 9 8 8 8 0 0 0 2 0 23 6 16 2 0 0 2 38
34.3 61.5 3.8 0.4 0.8 0.7 0.7 0.6 0.6 0.6 0.0 0.0 0.0 0.1 0.0 1.7 0.4 1.2 0.1 0.0 0.0 0.1 2.8
561 90 14 1 15 8 4 3 7 3 0 1 1 5 0 111 46 46 18 14 0 8 59
84.2 13.5 2.1 0.2 2.3 1.2 0.6 0.5 1.1 0.5 0.0 0.2 0.2 0.8 0.0 16.7 6.9 6.9 2.7 2.1 0.0 1.2 8.9
344 52 10 14 13 7 4 2 6 2 2 0 0 5 0 122 55 48 17 21 0 13 45
81.9 12.4 2.4 3.3 3.1 1.7 1.0 0.5 1.4 0.5 0.5 0.0 0.0 1.2 0.0 29.0 13.1 11.4 4.0 5.0 0.0 3.1 10.7
350 44 37 2 10 8 1 1 7 0 1 0 0 1 0 170 99 59 38 1 2 7 57
80.8 10.2 8.5 0.5 2.3 1.8 0.2 0.2 1.6 0.0 0.2 0.0 0.0 0.2 0.0 39.3 22.9 13.6 8.8 0.2 0.5 1.6 13.2
318 38 17 4 31 18 6 2 13 1 2 2 0 12 2 117 29 51 38 26 9 17 44
84.4 10.1 4.5 1.1 8.2 4.8 1.6 0.5 3.4 0.3 0.5 0.5 0.0 3.2 0.5 31.0 7.7 13.5 10.1 6.9 2.4 4.5 11.7
203 63 29 6 17 9 4 5 8 4 1 0 0 1 6 88 31 43 19 7 8 9 60
67.4 20.9 9.6 2.0 5.6 3.0 1.3 1.7 2.7 1.3 0.3 0.0 0.0 0.3 2.0 29.2 10.3 14.3 6.3 2.3 2.7 3.0 19.9
148 65 42 3 4 3 2 0 3 0 0 0 0 1 0 41 20 18 5 5 0 5 37
57.4 25.2 16.3 1.2 1.6 1.2 0.8 0.0 1.2 0.0 0.0 0.0 0.0 0.4 0.0 15.9 7.8 7.0 1.9 1.9 0.0 1.9 14.3
77 15 9 1 9 5 1 1 5 1 1 0 0 3 0 20 5 10 6 2 0 6 10
75.5 14.7 8.8 1.0 8.8 4.9 1.0 1.0 4.9 1.0 1.0 0.0 0.0 2.9 0.0 19.6 4.9 9.8 5.9 2.0 0.0 5.9 9.8
95 20 8 4 10 8 3 3 3 0 0 0 0 4 0 27 8 14 6 2 0 2 13
74.8 15.7 6.3 3.1 7.9 6.3 2.4 2.4 2.4 0.0 0.0 0.0 0.0 3.1 0.0 21.3 6.3 11.0 4.7 1.6 0.0 1.6 10.2
687 95 63 15 38 19 8 5 13 3 1 1 0 18 0 238 108 109 55 17 2 25 113
79.9 11.0 7.3 1.7 4.4 2.2 0.9 0.6 1.5 0.3 0.1 0.1 0.0 2.1 0.0 27.7 12.6 12.7 6.4 2.0 0.2 2.9 13.1
350 87 17 1 13 8 5 3 7 2 2 1 0 3 0 107 46 59 18 2 1 10 34
76.9 19.1 3.7 0.2 2.9 1.8 1.1 0.7 1.5 0.4 0.4 0.2 0.0 0.7 0.0 23.5 10.1 13.0 4.0 0.4 0.2 2.2 7.5
525 108 39
7.9 1.6 0.6
119 35 8
8.9 2.6 0.6
38 0 0
2.8 0.0 0.0
53 5 1
8.0 0.8 0.2
32 10 3
7.6 2.4 0.7
46 10 1
10.6 2.3 0.2
32 8 4
8.5 2.1 1.1
44 9 7
14.6 3.0 2.3
31 4 2
12.0 1.6 0.8
7 3 0
6.9 2.9 0.0
9 4 0
7.1 3.1 0.0
86 15 12
10.0 1.7 1.4
28 5 1
6.2 1.1 0.2
178 146 47 5 2 192 163
2.7 2.2 0.7 0.1 0.0 2.9 2.4
50 34 13 1 0 50 32
11 11 1 0 0 12 5
0.8 0.8 0.1 0.0 0.0 0.9 0.4
8 19 7 0 1 18 9
1.2 2.9 1.1 0.0 0.2 2.7 1.4
14 8 1 2 0 15 10
3.3 1.9 0.2 0.5 0.0 3.6
14 7 5 0 0 20 17
3.2 1.6 1.2 0.0 0.0 4.6 3.9
7 9 7 1 0 12 15
1.9 2.4 1.9 0.3 0.0 3.2 4.0
17 13 3 1 0 12 20
5.6 4.3 1.0 0.3 0.0 4.0 6.6
14 9 2 0 0 9 8
5.4 3.5 0.8 0.0 0.0 3.5 3.1
2 5 0 0 0 2 1
2.0 4.9 0.0 0.0 0.0 2.0 1.0
2 5 0 0 0 5 3
1.6 3.9 0.0 0.0 0.0 3.9 2.4
31 21 5 0 1 30 29
3.6 2.4 0.6 0.0 0.1 3.5 3.4
8 5 3 0 0 7 14
1.8 1.1 0.7 0.0 0.0 1.5 3.1
%
%
%
%
%
%
%
%
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
3.8 2.6 1.0 0.1 0.0 3.8 2.4
%
Synovial sarcoma (N ¼ 479)
High grade sarcoma (others) (N ¼ 1174)
80.6
%
MFS (N ¼ 488)
RMS (N ¼ 211)
6680
%
LMS (N ¼ 539)
PNET (N ¼ 161)
Surgery Type of surgery Resection Additional resection Amputation Others Surgical margin Wide Marginal Intralesional Unknown Bony reconstruction Autograft Free autograft Vascularized autograft Devitalized autograft Other autograft Artificial bone graft Allograft Bone lengthening Prosthesis Spinal reconstruction Soft tissue reconstruction Skin graft Pedicled myocutaneous flap Free myocutaneous flap Vascular reconstruction Nerve reconstruction Other reconstruction Additional surgery for complications No. of additional surgery 1 2 3Cause of the additional surgery Local recurrence Infection Circulatory deficit Nerve disorder Prosthetic failure Delay of wound healing Other causes
%
MRLS (N ¼ 775)
DDLS (N ¼ 333)
Overall (N ¼ 8288)
%
WDLS (N ¼ 1594)
MPNST (N ¼ 373)
No. of patients
UPS: undifferentiated pleomorphic sarcoma, WDLS: well-differentiated liposarcoma, MRLS: myxoid/round cell liposarcoma, LMS: leiomyosarcoma, MFS: myxofibrosarcoma, MPNST: malignant peripheral nerve sheath tumor, DDLS: dedifferentiated liposarcoma, PNET: primitive neuroectodermal tumor, RMS: rhabdomyosarcoma. 759
760
Table 3 Statistics of treatment other than surgery according to histologic subtype. No. of patients
Overall (N ¼ 8288)
UPS (N ¼ 1613)
%
%
MRLS (N ¼ 775)
%
LMS (N ¼ 539)
%
MFS (N ¼ 488)
%
Synovial sarcoma (N ¼ 479)
%
MPNST (N ¼ 373)
%
DDLS (N ¼ 333)
%
PNET (N ¼ 161)
%
RMS (N ¼ 211)
%
High grade sarcoma (others) (N ¼ 1174)
%
Low grade sarcoma (others) (N ¼ 548)
%
%
26.1
406
25.2
8
0.5
215
27.7
170
31.5
52
10.7
304
63.5
126
33.8
90
27.0
142
88.2
155
73.5
459
39.1
40
7.3
66.3 28.9 4.8
283 106 17
69.7 26.1 4.2
5 3 0
62.5 37.5 0.0
165 41 9
76.7 19.1 4.2
98 62 10
57.6 36.5 5.9
40 10 2
76.9 19.2 3.8
254 42 8
83.6 13.8 2.6
66 51 9
52.4 40.5 7.1
47 40 3
52.2 44.4 3.3
103 34 5
72.5 23.9 3.5
99 42 14
63.9 27.1 9.0
249 185 25
54.2 40.3 5.4
27 10 3
67.5 25.0 7.5
79.2 75.2 22.6 16.8 15.2 13.5 7.6 0.6 20.6 19.4
329 305 74 54 7 25 39 2 65 378
81.0 75.1 18.2 13.3 1.7 6.2 9.6 0.5 16.0 23.4
7 7 1 1 0 0 0 0 0 27
87.5 87.5 12.5 12.5 0.0 0.0 0.0 0.0 0.0 1.7
193 178 40 32 17 15 24 0 22 197
89.8 82.8 18.6 14.9 7.9 7.0 11.2 0.0 10.2 25.4
134 120 21 22 3 3 13 0 35 90
78.8 70.6 12.4 12.9 1.8 1.8 7.6 0.0 20.6 16.7
40 42 10 1 2 2 5 0 12 101
76.9 80.8 19.2 1.9 3.8 3.8 9.6 0.0 23.1 20.7
266 277 45 35 23 22 17 2 32 108
87.5 91.1 14.8 11.5 7.6 7.2 5.6 0.7 10.5 22.5
93 93 34 14 11 9 9 1 28 98
73.8 73.8 27.0 11.1 8.7 7.1 7.1 0.8 22.2 26.3
70 68 13 14 3 2 8 0 22 89
77.8 75.6 14.4 15.6 3.3 2.2 8.9 0.0 24.4 26.7
126 119 99 15 114 92 8 2 34 61
88.7 83.8 69.7 10.6 80.3 64.8 5.6 1.4 23.9 37.9
79 82 51 34 105 86 5 2 63 106
51.0 52.9 32.9 21.9 67.7 55.5 3.2 1.3 40.6 50.2
352 310 93 129 42 33 36 4 122 295
76.7 67.5 20.3 28.1 9.2 7.2 7.8 0.9 26.6 25.1
28 28 8 12 3 3 1 0 12 54
70.0 70.0 20.0 30.0 7.5 7.5 2.5 0.0 30.0 9.9
61.0 14.9 20.2 3.9 0.5
253 49 60 16 9
66.9 13.0 15.9 4.2 0.6
24 0 3 0 1
88.9 0.0 11.1 0.0 0.1
155 15 21 6 15
78.7 7.6 10.7 3.0 1.9
42 23 21 4 2
46.7 25.6 23.3 4.4 0.4
76 2 20 3 0
75.2 2.0 19.8 3.0 0.0
69 8 24 7 4
63.9 7.4 22.2 6.5 0.8
50 23 19 6 3
51.0 23.5 19.4 6.1 0.8
52 19 15 3 0
58.4 21.3 16.9 3.4 0.0
27 11 19 4 0
44.3 18.0 31.1 6.6 0.0
46 15 44 1 1
43.4 14.2 41.5 0.9 0.5
148 69 66 12 5
50.2 23.4 22.4 4.1 0.4
37 5 12 0 0
68.5 9.3 22.2 0.0 0.0
70.0 15.0 10.0 5.0
6 0 2 1
66.7 0.0 22.2 11.1
1 0 0 0
100.0 0.0 0.0 0.0
14 0 1 0
93.3 0.0 6.7 0.0
0 2 0 0
0.0 100.0 0.0 0.0
0 0 0 0
0.0 0.0 0.0 0.0
4 0 0 0
100.0 0.0 0.0 0.0
0 2 0 1
0.0 66.7 0.0 33.3
0 0 0 0
0.0 0.0 0.0 0.0
0 0 0 0
0.0 0.0 0.0 0.0
0 0 1 0
0.0 0.0 100.0 0.0
3 2 0 0
60.0 40.0 0.0 0.0
0 0 0 0
0.0 0.0 0.0 0.0
UPS: undifferentiated pleomorphic sarcoma, WDLS: well-differentiated liposarcoma, MRLS: myxoid/round cell liposarcoma, LMS: leiomyosarcoma, MFS: myxofibrosarcoma, MPNST: malignant peripheral nerve sheath tumor, DDLS: dedifferentiated liposarcoma, PNET: primitive neuroectodermal tumor, RMS: rhabdomyosarcoma. ADR ¼ adriamycin, IFO ¼ ifosfamide, CDDP ¼ cisplatin, MTX ¼ methotrexate, VP16 ¼ etoposide, VCR ¼ vincristine, CPM ¼ cyclophosphamide, DTIC ¼ dacarbazine.
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
Chemotherapy 2167 Setting of chemotherapy Adjuvant 1436 Palliative 626 Unknown 105 Chemotherapeutic agent ADR 1717 IFO 1629 VP16 489 CDDP 363 VCR 330 CPM 292 DTIC 165 MTX 13 Others 447 Radiotherapy 1604 Setting of radiotherapy Adjuvant 979 Palliative 239 Radical 324 Unknown 62 Hyperthermia 40 Setting of hyperthermia Adjuvant 28 Palliative 6 Radical 4 Unknown 2
WDLS (N ¼ 1594)
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
761
4. Discussion
Fig. 2. KaplaneMeier curves showing DSS for all of the 3826 patients. The cumulative DSS at 2 and 5 years after treatment was 86.8% and 77.5%.
2432 cases with no missing data for age, sex, status at first visit, histologic subtype, depth and location of the tumor, additional surgery, and surgical margin. Statistical testing by proportional hazards assumption demonstrated no evidence of violation with respect to any of the variables included (P ¼ 0.242). Patients aged 75 years had a significantly worse DSS than those aged 30e69 years (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.02e1.82; P ¼ 0.035). Female patients had a significantly better DSS than male patients (HR: 0.75; 95% CI, 0.59e0.96; P ¼ 0.021). Taking the UPS as the reference, poorer DSS was observed for MPNST (HR: 1.56; 95% CI, 1.05e2.33; P ¼ 0.028), PNET (HR: 2.23; 95% CI, 1.28e3.89; P ¼ 0.005), and RMS (HR: 2.15; 95% CI, 1.16e3.97; P ¼ 0.015), whereas significantly better DSS was seen for WDLS (HR: 0.01; 95% CI, 0.00e0.05; P < 0.001), MRLS (HR: 0.36; 95% CI, 0.23e0.57; P < 0.001), and MFS (HR: 0.47; 95% CI, 0.27e0.79; P ¼ 0.005). Patients with tumors >5 cm and 10 cm in diameter and >10 cm in diameter had a significantly poorer DSS than those with tumors 5 cm in diameter (HR: 2.02; 95% CI, 1.38e2.96; P < 0.001 and HR: 3.27; 95% CI, 2.19e4.86; P < 0.001, respectively). A deep tumor location (HR: 2.05; 95% CI, 1.41e2.99; P < 0.001) was associated with a significantly poorer DSS than a superficial tumor location. Tumor location in the trunk (HR: 1.76; 95% CI, 1.08e2.86; P ¼ 0.022) or the head and neck (HR: 2.49; 95% CI, 1.22e5.10; P ¼ 0.013) was associated with a significantly poorer DSS than a tumor location in the upper extremity. Local recurrence had a tendency toward poor DSS, but not significant (P ¼ 0.060). Patients undergoing amputation had a significantly poorer DSS than those undergoing limb salvage surgery (HR: 1.69; 95% CI, 1.15e2.49; P ¼ 0.008). Status of surgical margin (wide/marginal versus intralesional) was significantly associated with DSS (HR: 1.73; 95% CI, 1.19e2.53; P ¼ 0.004). We performed additional analysis focusing on the association between DSS and tumor size and depth (Table 5). Our results based on this large patient cohort showed that while a tumor size of >10 cm did not increase the risk of disease-specific death compared with a tumor size of >5 cm and 10 cm in patients with a superficial tumor location, a large tumor size had a stronger impact on disease-specific death in patients with deep-seated tumors.
Our present study has clarified the national profiles of the characteristics and treatments of 8228 patients with STSs entered in the BSTT Registry between 2006 and 2012. We further provided an overview of the prognosis and significant factors affecting DSS for 2432 patients with STS. We believe that the present study is valuable for the following reasons. First, the BSTT Registry is a nationwide organ-specific registry for bone and soft tissue tumors in Japan that contains detailed data on epidemiology, treatment, and oncologic, surgical and functional outcomes. Such a large sarcoma database is rare in other countries. Second, the data presented here reflect the current statistics and outcomes of modern multidisciplinary treatments performed in JOA-certified hospitals, the surgical treatment aiming at accomplishing a sufficient margin and appropriate methods of chemotherapy and radiotherapy. Because these treatment strategies are considered to be standard treatments internationally, the present data reflect not only the national profiles in Japan but also provide the best evidence of what can be expected from modern multidisciplinary treatment in a worldwide context. In addition, these data are based on patients treated during a recent short period (2006e2012) and therefore exclude any historical changes in statistics or treatment outcomes. The elderly population is growing rapidly worldwide, and Japan is now facing a “super-aging society” ahead of most other countries, those aged 65 years accounting for 25% of the population in 2013, representing the highest proportion in the world [10]. Consequently, we expect that the number of elderly patients diagnosed with STS will increase accordingly. Our data demonstrated a single peak of age distribution for STS patients, with a peak in the seventh decade. Also, the proportion of elderly patients aged over 60 years exceeded 50%. We demonstrated that the age distribution of STS has changed in the last two decades as the population of Japan rapidly ages, the proportion of patients aged >60 years in particular showing a dramatic increase (Fig. 4) [11]. We also demonstrated that STS in elderly patients aged 75 years had a significantly worse DSS than in younger patients after adjustment for patient background characteristics. As this trend is expected to continue in the next few decades, it will be necessary to establish a treatment standard for older patients with STS, who usually have decreased performance status and several comorbidities. Furthermore, it is anticipated that documenting our experiences using the BSTT Registry will be of help to other countries that are also experiencing aging of the population. Because tumor size and depth are considered to be major factors affecting oncologic outcome, the T stage of STS in the AJCC staging system is based on tumor size and depth: the cut-off tumor size between stages T1 and T2 is set at 5 cm, and the difference between T1a/T2a and T1b/T2b is defined as tumor depth being shallower than the superficial fascia without invasion [12]. However, a deep tumor location is frequently associated with a larger tumor size, as was found in the present series: tumor diameter was 5 cm in 50% of the patients with superficial tumors and >5 cm in 84% of those with deep-seated tumors. In addition, quantitative data regarding the effects of various combinations of these factors on survival have been lacking. The data presented here reveal that a large tumor size and a deep tumor location together greatly increase the risk of disease-specific death, and this quantitative evidence will assist physicians with accurate prognostication and provide a more informative explanation for patients with STS. One of the unique advantages of the BSTT Registry over the SEER is that we can obtain data regarding surgical outcomes including details about postoperative complications and reoperation. The surgical outcomes revealed in the present study provide solid
762
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
Fig. 3. KaplaneMeier survival plots stratified by predictor variables for DSS: (A) age (Child, 14 years; AYA, 15e29 years; Adult, 30e74 years; Elderly, 75 years), (B) sex, (C) status at first visit (1: First visit/After preoperative therapy, 2: NED after resection at the previous hospital, 3: With microscopic residual tumor after resection at the previous hospital, 4: With macroscopic residual tumor after resection at the previous hospital, 5: Local or metastatic recurrence, 6: Others), (D) histologic grade, (E) histologic subtype, (F) tumor size, (G) tumor depth, (H) tumor location, (I) presence or absence of additional surgery for complications, (J) limb salvage status, (K) surgical margin, and (L) presence or absence of local recurrence.
evidence for the commonly accepted notion that STS surgery is associated with lower rates of postoperative complications and reoperation (10.1%) than is the case for bone sarcoma surgery (15.1%) [6]. Furthermore, this information should help physicians to give more accurate explanations to their patients based on clinical evidence, as such nationwide data have not been available hitherto. Several limitations of this study should be mentioned, as was the case for our previous study of bone sarcoma [6]. First, the time and effort required to collect some of the items in the BSTT Registry
resulted in their exclusion from our analysis; for example, the Enneking stage, which sometimes requires re-checking of imaging data, and functional outcome, which may necessitate patient examination, had relatively more missing values than the other items. Second, we were unable to completely exclude the possibility of duplicate reporting if a patient had received care at more than one hospital, although the BSTT Registry was devised to automatically exclude cases with “Second opinion/Observation only after treatment in the previous hospital” in the “Status at the first visit”
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
763
Table 4 Cox proportional hazards models for DSS (N ¼ 2432). No. of patients
5-year survival (%)
Univariate analysis
P value
Hazard ratio (95% CI) Age Child (14 years) AYA (15e29 years) Adult (30e74 years) Elderly (75 years) Sex Male Female Status at the first visita 1e3 4, 5 Histologic subtypes UPS WDLS MRLS LMS MFS Synovial sarcoma MPNST DDLS PNET RMS Tumor size 5 cm >5 cm and 10 cm >10 cm Unknown Depth Superficial Deep Location Upper extremity Lower extremity Trunk Head and neck Local recurrence No Yes Limb salvage status Limb salvage Amputation Unknown Surgical margin Wide or marginal Intralesional
1557 42 351 482
71.8 73.1 80.3 75.7
1.29 (0.57e2.92) 1.26 (0.92e1.73) Reference 1.70 (1.28e2.25)
1325 1107
75.5 79.9
2187 245
Multivariate analysis
P value
Hazard ratio (95% CI) 0.538 0.150 <0.001
0.76 (0.32e1.80) 0.85 (0.60e1.21) Reference 1.36 (1.02e1.82)
0.529 0.371
Reference 0.68 (0.54e0.86)
0.001
Reference 0.75 (0.59e0.96)
0.021
78.7 71.5
Reference 1.18 (0.82e1.68)
0.377
Reference 1.07 (0.73e1.57)
0.718
574 602 354 193 202 172 141 93 53 48
72.5 99.5 85.3 72.2 87.2 71.5 62.1 66.9 58.3 48.0
Reference 0.01 (0.00e0.07) 0.35 (0.23e0.55) 1.15 (0.79e1.67) 0.42 (0.25e0.71) 0.75 (0.49e1.15) 1.65 (1.13e2.39) 1.31 (0.82e2.09) 1.95 (1.17e3.26) 1.81 (1.04e3.17)
<0.001 <0.001 0.476 0.001 0.186 0.009 0.269 0.011 0.037
0.01 0.36 1.35 0.47 0.96 1.56 0.73 2.23 2.15
(0.00e0.05) (0.23e0.57) (0.92e1.97) (0.27e0.79) (0.60e1.55) (1.05e2.33) (0.45e1.20) (1.28e3.89) (1.16e3.97)
<0.001 <0.001 0.126 0.005 0.872 0.028 0.216 0.005 0.015
564 906 853 109
86.6 76.9 70.5
Reference 2.11 (1.46e3.04) 2.61 (1.82e3.74) 1.10 (0.51e2.35)
<0.001 <0.001 0.810
Reference 2.02 (1.38e2.96) 3.27 (2.19e4.86) 0.83 (0.38e1.80)
<0.001 <0.001 0.657
602 1830
89.5 74.1
Reference 2.53 (1.78e3.60)
<0.001
Reference 2.05 (1.41e2.99)
<0.001
281 1391 704 56
85.8 81.4 71.5 68.7
Reference 1.38 (0.87e2.18) 2.41 (1.52e3.84) 3.79 (1.93e7.45)
0.172 <0.001 <0.001
Reference 1.45 (0.91e2.33) 1.76 (1.08e2.86) 2.49 (1.22e5.10)
0.120 0.022 0.013
2286 146
84.1 67.6
Reference 2.16 (1.54e3.03)
<0.001
Reference 1.42 (0.99e2.04)
0.060
2173 91 168
81.7 48.7
Reference 4.16 (2.90e5.96) 2.07 (1.45e2.96)
<0.001 <0.001
Reference 1.69 (1.15e2.49) 1.29 (0.87e1.92)
0.008 0.209
2291 141
82.9 64.2
Reference 2.69 (1.89e3.83)
<0.001
Reference 1.73 (1.19e2.53)
0.004
0.035
CI: confidence interval, UPS: undifferentiated pleomorphic sarcoma, WDLS: well-differentiated liposarcoma, MRLS: myxoid/round cell liposarcoma, LMS: leiomyosarcoma, MFS: myxofibrosarcoma, MPNST: malignant peripheral nerve sheath tumor, DDLS: dedifferentiated liposarcoma, PNET: primitive neuroectodermal tumor, RMS: rhabdomyosarcoma. a Each number refers to the following status; 1: First visit/After preoperative therapy, 2: NED after resection at the previous hospital, 3: With microscopic residual tumor after resection at the previous hospital, 4: With macroscopic residual tumor after resection at the previous hospital, 5: Local or metastatic recurrence.
Table 5 The 5-year DSS and hazard ratio stratified by size and depth of the tumor (N ¼ 2432). Tumor size
5 cm >5 cm and 10 cm >10 cm
Depth Superficial
Deep
91% (Reference) 92% (HR, 1.38; P ¼ 0.391) 91% (HR, 1.49; P ¼ 0.441)
87% (HR, 1.46; P ¼ 0.255) 81% (HR, 2.97; P < 0.001) 76% (HR, 3.38; P < 0.001)
section of the database. Third, the detailed data regarding chemotherapy and radiotherapy were unavailable from the BSTT Registry. Although setting of chemotherapy (preoperative, postoperative, or palliative) or chemotherapeutic agents and setting of radiotherapy (preoperative, postoperative, or palliative) were available, we were not able to know the more detailed data such as protocol of chemotherapy or dose, fraction, and protocol of radiotherapy. Fourth, the mean follow-up period was relatively short (34.2
Fig. 4. Proportion of patients with STS by age diagnosed during 1985e1994 and 2006e2012.
764
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
months). Fifth, the number of soft-tissue sarcoma originating from retroperitoneum, peritoneum, or uterine represented by leiomyosarcoma should be underestimated in the BSTT Registry because this registry has been operated by JOA and data have been collected by orthopaedic surgeons. Finally, participation in the registry is not mandatory for non-JOA-certified hospitals. Although we expect that the majority of STS cases would have been treated at specialist centers certified by the JOA, there is still a possibility that some would have been treated at non-specialist hospitals due to patient preference or other reasons. In conclusion, this study has provided an overview of the statistics for STS, including epidemiology, clinical features, treatment, and prognosis in Japan, based on the large cohort entered in the BSTT Registry. The study is the first to have analyzed data for STS from the BSTT Registry and should offer a valuable basis for future clinical studies aimed at determining the best therapeutic strategies for management of STS patients. We anticipate that continuous accumulation of clinical data in the BSTT Registry will provide more informative data on STS, thus improving both the level of medical care offered by clinicians and the outcomes for patients through sharing of such data and promotion of clinical research. Conflict of interest Each author certifies that he or she has no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/ licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. Acknowledgments This study was funded by a Grant-in-Aid for Scientific Research from the Ministry of Education and Science, Japan (B, No. 22390296), and by the National Cancer Center Research and Development Fund (23-A-10; 28-A-16). We thank all the hospitals and medical staff participating in the BSTT Registry, and all the patients whose data were recorded, without whom the registry would have not been established. We would also like to
acknowledge Ms. Misuzu Mori and Ms. Rie Nakano for their administrative support with the registry.
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.jos.2017.03.017.
References [1] Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F. WHO classification of tumours of soft tissue and bone. Lyon: IARC Press; 2013. [2] Wang H, Jacobson A, Harmon DC, Choy E, Hornicek FJ, Raskin KA, Chebib IA, DeLaney TF, Chen YL. Prognostic factors in alveolar soft part sarcoma: a SEER analysis. J Surg Oncol 2016 Apr;113(5):581e6. [3] Shen W, Sakamoto N, Yang L. Model to predict the survival benefit of radiation for patients with rhabdomyosarcoma after surgery: a population-based study. Int J Oncol 2014 Aug;45(2):549e57. [4] Ng VY, Scharschmidt TJ, Mayerson JL, Fisher JL. Incidence and survival in sarcoma in the United States: a focus on musculoskeletal lesions. Anticancer Res 2013 June;33(6):2597e604. [5] Jawad MU, Extein J, Min ES, Scully SP. Prognostic factors for survival in patients with epithelioid sarcoma: 441 cases from the SEER database. Clin Orthop Relat Res 2009 Nov;467(11):2939e48. [6] 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 Jan;22(1): 133e43. [7] Ogura K, Yasunaga H, Horiguchi H, Fushimi K, Tanaka S, Kawano H. Nomogram predicting severe adverse events after musculoskeletal tumor surgery: analysis of a national administrative database. Ann Surg Oncol 2014 Oct;21(11):3564e71. [8] Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, Morrow M. AJCC cancer staging manual. 6th ed. New York, NY: Springer; 2002. [9] Enneking WF, Dunham W, Gebhardt MC, Malawar M, Pritchard DJ. A system for the functional evaluation of reconstructive procedures after surgical treatment of tumors of the musculoskeletal system. Clin Orthop Relat Res 1993 Jan;286:241e6. [10] Arai H, Ouchi Y, Toba K, Endo T, Shimokado K, Tsubota K, Matsuo S, Mori H, Yumura W, Yokode M, Rakugi H, Ohshima S. Japan as the front-runner of super-aged societies: perspectives from medicine and medical care in Japan. Geriatr Gerontol Int 2015 Jun;15(6):673e87. [11] Japanese Orthopaedic Association Musculoskeletal Tumor Committee. Bone and soft tissue tumor registry in Japan. Tokyo: National Cancer Center; 2013. [12] Edge SB, Byrd DR, Compton CC, Fritz AG, Greeme FL, Trotti A. AJCC cancer staging manual. 7th ed. New York, NY: Springer; 2010.
Contents lists available at ScienceDirect
Journal of Orthopaedic Science journal homepage: http://www.elsevier.com/locate/jos
Original Article
Statistics of soft-tissue sarcoma in Japan: Report from the Bone and Soft Tissue Tumor Registry in Japan Koichi Ogura a, Takahiro Higashi b, Akira Kawai a, * a
Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan Division of Health Services Research, Center for Cancer Control and Information Services, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 January 2017 Received in revised form 21 March 2017 Accepted 23 March 2017
Background: No previous reports to date have characterized the national profiles of soft-tissue sarcomas (STSs). In the present study, we reviewed current practice for STSs in Japan using data from a nationwide organ-specific cancer registry for bone and soft-tissue tumors in Japan, the Bone and Soft Tissue Tumor (BSTT) Registry. Methods: In the registry, we identified 8228 patients with STSs during the period 2006e2012, and extracted data on patient demographics, treatment, and outcome at the last follow-up for each patient. Disease-specific survival was analyzed using the Cox proportional hazards model. Results: STSs showed a slight male predilection. The age distribution had a single peak in the seventh decade, the proportion of elderly patients aged >60 years being approximately 53%. For most of the histologic subtypes, the most frequent tumor location was the lower extremity, whereas it was the trunk in patients with malignant peripheral nerve sheath tumor, dedifferentiated liposarcoma, and primitive neuroectodermal tumor. Based on data for 2432 patients with STSs, we found significant associations between disease-specific survival and age, sex, histologic subtype, tumor size, tumor depth, tumor location, additional surgery, limb salvage status, and surgical margin; elderly patients showed the poorest disease-specific survival. Conclusions: Using the BSTT Registry, this study has clarified the epidemiology, treatment, and prognosis of patients with STSs in Japan. Our experiences with the BSTT Registry will be of help to other countries where aging of the population is occurring. Continuous accumulation of clinical data in the BSTT Registry should provide more informative data on STSs, thus improving both the level of medical care offered by clinicians and the outcomes for patients through sharing of such data and promotion of clinical research. © 2017 The Authors. Published by Elsevier B.V. on behalf of The Japanese Orthopaedic Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
1. Introduction Soft-tissue sarcomas (STSs) are heterogeneous neoplasms originating from mesenchymal cells, comprising more than 50 histological subtypes. They can arise at any anatomic site, resulting in a large variety of combinations of histology and primary site [1]. Against this biological background, the rarity of STSs inevitably hinders accurate diagnosis and appropriate treatment. This makes it difficult to accumulate a sufficient number of cases of STS at a single institution for statistical analysis.
* Corresponding author. Fax: þ81 3 3542 3815. E-mail address: [email protected] (A. Kawai).
In order to improve clinical practice for STSs, understanding the current status is essential. Although there have been a few previous reports focusing on the epidemiology of some histologic subtypes using the Surveillance, Epidemiology, and End Results (SEER) database in the United States [2e5], to our knowledge, no attempt has yet been made to characterize the overall profiles of STS at the national level, including data such as patient age and sex distribution, details of the tumors (size, site, histologic subtype, etc.), treatment modalities, and prognostic factors on the basis of a large nationwide cohort [2e5]. In the present study, we investigated current practice nationwide for STSs in Japan using data from a nationwide organ-specific cancer registry for bone and soft-tissue tumors in Japan, the Bone and Soft Tissue Tumor (BSTT) Registry. Previously, we have
http://dx.doi.org/10.1016/j.jos.2017.03.017 0949-2658/© 2017 The Authors. Published by Elsevier B.V. on behalf of The Japanese Orthopaedic Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
reported the statistics for bone sarcoma in Japan [6], and to our knowledge, the present study is the first to have analyzed STSs using the BSTT Registry since it became available for the purpose of clinical research in 2014.
IBM SPSS version 19.0 (IBM SPSS, Armonk, NY, USA) and Stata 13 (StataCorp LP, College Station, TX, USA).
2. Patients and methods
3.1. Clinical characteristics of the patients
2.1. Data source
We identified BSTT-registered 44,709 patients for the period 2006e2012. Of these, we extracted the records of 8288 patients with STSs who had been treated at 130 hospitals. The numbers of hospitals and patients registered as having STS per year gradually increased: from 825 cases at 69 hospitals in 2006 to 1138 cases at 71 hospitals in 2009, and 1597 cases at 85 hospitals in 2012 (Fig. 1). Table 1 shows the clinical and demographic characteristics in relation to the major histologic diagnoses. Further details of the diagnosis are summarized in Appendix 1 (Supplementary Material). There was a slight male predilection for cases of STS. The age distribution had a single peak in the seventh decade with mean age of 58.3 years overall. Among the major histologic subtypes, undifferentiated pleomorphic sarcoma (UPS), well differentiated liposarcoma (WDLS), leiomyosarcoma (LMS), myxofibrosarcoma (MFS), malignant peripheral nerve sheath tumor (MPNST), and dedifferentiated liposarcoma (DDLS) had a peak in the elderly, whereas myxoid/round cell liposarcoma (MRLS), synovial sarcoma, primitive neuroectodermal tumor (PNET), and rhabdomyosarcoma (RMS) had a peak in children and young adults aged <40 years. Most of the patients received treatment at the first hospitals with expertise, or were referred to such hospitals before surgery. The mean tumor size in the patients overall was 10.2 cm. The most frequent site of involvement was the lower extremity in patients with UPS, WDLS, MRLS, LMS, MFS, synovial sarcoma, and RMS, whereas it was the trunk in patients with MPNST, DDLS, and PNET. Further details of tumor location are summarized in Appendix 2 (Supplementary Material).
For this study, we utilized the BSTT Registry, details of which have been described elsewhere [6]. Briefly, it is a nationwide organspecific cancer registry for bone and soft tissue tumors that was launched in the 1950s, being organized and funded by the Japanese Orthopaedic Association (JOA) and promoted by the National Cancer Center. All the JOA-certified hospitals for musculoskeletal oncology (N ¼ 89) [7] are obliged to participate in the registry, but participation by other hospitals is voluntary. The database includes the following data: 1) basic data on the patient: hospital, sex, age, date of diagnosis, and status at the first visit, etc.; 2) information on the tumor: origin of the tumor (bone, soft tissue, or metastatic bone tumor), histologic details (malignant or benign, and diagnosis), tumor depth and location, and the data required for TNM (AJCC Cancer Staging Manual 6th edition) [8] and Enneking staging (tumor size, nodal or distant metastasis, and histologic grade), etc.; 3) information on surgery: date of definitive surgery, type of surgery, reconstruction details, and additional surgery for complications, etc.; 4) information on treatment other than surgery: details of chemotherapy, radiotherapy, and hyperthermia; and 5) information on several outcomes at the time of the latest follow-up, such as local recurrence, distant metastasis, oncologic outcome, limb salvage status, and functional outcome (ISOLS/MSTS rating scale [9]). Use of the BSTT Registry for the purposes of clinical research was initiated in 2014 after approval from the Musculoskeletal Tumor Committee of the JOA. The Institutional Review Board of the JOA approved the present study protocol. Because the database is de-identified, informed consent was not mandated by the Ethics Guidelines for Human Subject Medical Research, and was waived by the IRB. 2.2. Data extraction Data were obtained from the BSTT Registry during 2006e2012. In this analysis, we focused on primary malignant soft-tissue tumors (STSs). Patients with STS were defined as patients whose diagnosis was “malignant” and origin of the tumor was “soft-tissue”. Patients with intermediate grade malignancy such as desmoid tumor or dermatofibrosarcoma protuberans were not included in STS in this study. For each patient, we extracted the following data: year of registration, sex, age, status at first visit, tumor size, tumor depth and location, histologic diagnosis and grade of the tumor, TNM (AJCC Cancer Staging Manual 6th edition) [8] and Enneking stage, details of treatment (surgical and non-surgical), postoperative complications, and outcome at the last follow-up (no evidence of disease, alive with disease, dead of disease, or dead due to other causes). Cases with insufficient data were excluded.
3. Results
3.2. Surgical treatment Table 2 summarizes the statistics of surgery according to histologic subtype. Overall, 6680 patients (80.6%) underwent surgical treatment. The proportion of patients who underwent definitive surgery was relatively low for PNET (63.4%) and RMS (60.2%), perhaps because of the radiosensitivity of these histologic subtypes and the tendency of PNET to arise in the trunk. The amputation rate was 4.7% (313/6680) overall, which was lower than that for bone sarcoma (10.6%) [6]. Status of surgical margin was wide in 70.4%, marginal in 23.1%, and intralesional in 5.6%. In surgical cases, bone
2.3. Statistical analyses Disease-specific survival (DSS) was defined as the period between the date of diagnosis and tumor-related death. Patients who died of causes other than STS were considered as censored at the time of death. The KaplaneMeier method was used for estimation of DSS. The factors associated with survival were analyzed using the Cox proportional hazards models. The threshold for statistical significance was P < 0.05. All statistical analyses were conducted using
Fig. 1. Annual transition of the numbers of hospitals and patients registered as having STS.
Table 1 Characteristics of the study population according to histologic subtype. No. of patients
Overall (N ¼ 8288)
UPS (N ¼ 1613)
%
%
MRLS (N ¼ 775)
%
LMS (N ¼ 539)
%
MFS (N ¼ 488)
%
Synovial sarcoma (N ¼ 479)
%
MPNST (N ¼ 373)
%
DDLS (N ¼ 333)
%
PNET (N ¼ 161)
%
RMS (N ¼ 211)
%
High grade sarcoma (others) (N ¼ 1174)
Low grade sarcoma (others) (N ¼ 548)
%
%
%
943 58.5 884 55.5 425 54.8 260 48.2 272 55.7 230 48.0 198 53.1 214 64.3 80 49.7 120 56.9 658 56.0 297 54.2 670 41.5 710 44.5 350 45.2 279 51.8 216 44.3 249 52.0 175 46.9 119 35.7 81 50.3 91 43.1 516 44.0 251 45.8 68.1 [13.8] 62.5 [13.2] 50.6 [16.3] 62.7 [15.5] 67.2 [13.3] 39.4 [18.7] 52.7 [20.2] 64.7 [13.3] 33.7 [18.2] 33.8 [26.1] 54.6 [20.6] 54.9 [18.9] 2 2 22 44 107 229 437 483 262 25
0.1 0.1 1.4 2.7 6.6 14.2 27.1 29.9 16.2 1.5
0 5 15 87 182 340 493 370 96 6
0.0 0.3 0.9 5.5 11.4 21.3 30.9 23.2 6.0 0.4
1 14 67 167 148 142 133 87 15 1
0.1 1.8 8.6 21.5 19.1 18.3 17.2 11.2 1.9 0.1
0 6 16 38 43 120 141 115 58 2
0.0 1.1 3.0 7.1 8.0 22.3 26.2 21.3 10.8 0.4
1 0 5 15 34 74 136 155 65 3
0.2 0.0 1.0 3.1 7.0 15.2 27.9 31.8 13.3 0.6
17 67 92 98 61 63 48 27 6 0
3.5 14.0 19.2 20.5 12.7 13.2 10.0 5.6 1.3 0.0
2 25 39 48 50 53 72 60 22 2
0.5 6.7 10.5 12.9 13.4 14.2 19.3 16.1 5.9 0.5
0 2 0 11 41 62 96 87 33 1
0.0 0.6 0.0 3.3 12.3 18.6 28.8 26.1 9.9 0.3
9 32 41 34 17 11 12 4 1 0
5.6 19.9 25.5 21.1 10.6 6.8 7.5 2.5 0.6 0.0
43 55 23 17 10 16 24 13 9 1
20.4 26.1 10.9 8.1 4.7 7.6 11.4 6.2 4.3 0.5
17 46 126 144 142 156 243 205 85 10
1.4 3.9 10.7 12.3 12.1 13.3 20.7 17.5 7.2 0.9
6 21 39 67 84 107 104 79 38 3
1.1 3.8 7.1 12.2 15.3 19.5 19.0 14.4 6.9 0.5
1239 76 107 67 113 11 9.2 [6.3]
76.8 4.7 6.6 4.2 7.0 0.7
1418 33 10 24 106 3 14.2 [7.1]
89.0 2.1 0.6 1.5 6.6 0.2
630 48 25 18 51 3 10.7 [6.7]
81.3 6.2 3.2 2.3 6.6 0.4
365 54 37 34 45 4 8.0 [5.2]
67.7 10.0 6.9 6.3 8.3 0.7
372 24 38 24 27 3 8.5 [6.4]
76.2 4.9 7.8 4.9 5.5 0.6
352 39 24 18 41 5 7.2 [4.6]
73.5 8.1 5.0 3.8 8.6 1.0
276 21 11 17 47 1 9.3 [5.3]
74.0 5.6 2.9 4.6 12.6 0.3
231 8 9 14 68 3 14.6 [8.4]
69.4 2.4 2.7 4.2 20.4 0.9
115 9 9 8 16 4 9.3 [5.3]
71.4 5.6 5.6 5.0 9.9 2.5
183 2 4 6 13 3 8.4 [5.5]
86.7 0.9 1.9 2.8 6.2 1.4
891 53 47 46 124 13 8.8 [6.1]
75.9 4.5 4.0 3.9 10.6 1.1
418 33 33 20 43 1 7.9 [6.9]
76.3 6.0 6.0 3.6 7.8 0.2
426 615 283 112 50 127
26.4 38.1 17.5 6.9 3.1 7.9
120 465 383 331 244 51
7.5 29.2 24.0 20.8 15.3 3.2
133 308 175 67 48 44
17.2 39.7 22.6 8.6 6.2 5.7
179 207 61 25 13 54
33.2 38.4 11.3 4.6 2.4 10.0
164 181 72 21 20 30
33.6 37.1 14.8 4.3 4.1 6.1
184 155 60 15 5 60
38.4 32.4 12.5 3.1 1.0 12.5
92 150 61 34 11 25
24.7 40.2 16.4 9.1 2.9 6.7
36 85 76 72 50 14
10.8 25.5 22.8 21.6 15.0 4.2
39 54 35 13 3 17
24.2 33.5 21.7 8.1 1.9 10.6
68 85 26 13 6 13
32.2 40.3 12.3 6.2 2.8 6.2
346 434 173 82 30 109
29.5 37.0 14.7 7.0 2.6 9.3
224 185 58 19 28 34
40.9 33.8 10.6 3.5 5.1 6.2
225 857 487 26 18
13.9 53.1 30.2 1.6 1.1
121 1033 387 39 14
7.6 64.8 24.3 2.4 0.9
42 579 138 3 13
5.4 74.7 17.8 0.4 1.7
54 275 184 10 16
10.0 51.0 34.1 1.9 3.0
83 278 120 6 1
17.0 57.0 24.6 1.2 0.2
75 239 137 22 6
15.7 49.9 28.6 4.6 1.3
48 131 149 26 19
12.9 35.1 39.9 7.0 5.1
13 124 185 1 10
3.9 37.2 55.6 0.3 3.0
13 49 80 14 5
8.1 30.4 49.7 8.7 3.1
40 69 55 32 15
19.0 32.7 26.1 15.2 7.1
167 508 398 38 63
14.2 43.3 33.9 3.2 5.4
80 238 209 14 7
14.6 43.4 38.1 2.6 1.3
501 1066 46
31.1 229 66.1 1334 2.9 31
14.4 162 83.7 593 1.9 20
20.9 166 76.5 358 2.6 15
30.8 177 66.4 303 2.8 8
36.3 62 62.1 393 1.6 24
12.9 96 82.0 259 5.0 18
25.7 35 69.4 295 4.8 3
10.5 21 88.6 134 0.9 6
13.0 24 83.2 182 3.7 5
11.4 264 86.3 862 2.4 48
22.5 204 73.4 329 4.1 15
37.2 60.0 2.7
0 0 362 180 663 190 218
0.0 0.0 22.4 11.2 41.1 11.8 13.5
103 1353 4 2 9 4 119
6.5 84.9 0.3 0.1 0.6 0.3 7.5
11.0 32.8 5.4 4.6 31.0 7.9 7.4
2.8 3.3 26.5 7.1 33.8 13.5 13.0
77 110 80 34 139 9 39
15.8 22.5 16.4 7.0 28.5 1.8 8.0
1.5 1.3 33.6 1.9 31.3 13.2 17.3
16 28 51 33 130 52 63
4.3 7.5 13.7 8.8 34.9 13.9 16.9
5 17 23 22 203 36 27
1.5 5.1 6.9 6.6 61.0 10.8 8.1
0 0 34 7 52 46 22
0.0 0.0 21.1 4.3 32.3 28.6 13.7
0 2 39 5 65 82 18
0.0 0.9 18.5 2.4 30.8 38.9 8.5
0 0 252 66 375 308 173
0.0 0.0 21.5 5.6 31.9 26.2 14.7
211 267 0 0 0 22 48
38.5 48.7 0.0 0.0 0.0 4.0 8.8
0 0
0.0 0.0
949 500
59.5 226 31.4 123
4.5 2.2
124 71
25.4 10 14.5 3
2.1 0.6
31 11
8.3 2.9
10 10
3.0 3.0
0 0
0.0 0.0
1 1
0.5 0.5
0 0
0.0 0.0
300 176
54.7 32.1
85 254 42 36 240 61 57
15 18 143 38 182 73 70
29.2 24 15.9 12
7 6 161 9 150 63 83
757
(continued on next page)
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
Sex Male 4581 55.3 Female 3707 44.7 Age (years), 58.3 [18.9] mean [SD] 0e10 98 1.2 11e20 275 3.3 21e30 485 5.9 31e40 770 9.3 41e50 919 11.1 51e60 1373 16.6 61e70 1939 23.4 71e80 1685 20.3 81e90 690 8.3 91e 54 0.7 a Status at first visit 1 6490 78.3 2 400 4.8 3 354 4.3 4 296 3.6 5 694 8.4 6 54 0.7 Tumor size (cm), 10.2 [6.8] mean [SD] 5 2011 24.3 5.1e10 2924 35.3 10.1e15 1463 17.7 15.1e20 804 9.7 20.1e 508 6.1 Unknown 578 7.0 Tumor location Upper extremity 961 11.6 Lower extremity 4380 52.8 Trunk 2529 30.5 Head and neck 231 2.8 Multiple disease 187 2.3 Depth Superficial 1941 23.4 Deep 6108 73.7 Unknown 239 2.9 TNM stage Stage IA 519 6.3 Stage IB 2055 24.8 Stage IIA 1191 14.4 Stage IIB 432 5.2 Stage III 2208 26.6 Stage IV 946 11.4 Unknown 937 11.3 Enneking stage Stage IA 1675 20.2 Stage IB 907 10.9
WDLS (N ¼ 1594)
SD: standard deviation. UPS: undifferentiated pleomorphic sarcoma, WDLS: well-differentiated liposarcoma, MRLS: myxoid/round cell liposarcoma, LMS: leiomyosarcoma, MFS: myxofibrosarcoma, MPNST: malignant peripheral nerve sheath tumor, DDLS: dedifferentiated liposarcoma, PNET: primitive neuroectodermal tumor, RMS: rhabdomyosarcoma. a Each number refers to the following status; 1: First visit/After preoperative therapy, 2: NED after resection at the previous hospital, 3: With microscopic residual tumor after resection at the previous hospital, 4: With macroscopic residual tumor after resection at the previous hospital, 5: Local or metastatic recurrence, 6: Others.
%
0 0 26 46 %
30.3 29.0 30.7 9.9 356 341 361 116
%
31.8 28.4 34.1 4.7 67 60 72 10
%
23.6 34.2 31.1 11.2 38 55 50 18
%
29.4 41.1 15.0 8.4 98 137 50 28
%
27.1 29.8 17.2 14.7 101 111 64 55
%
33.0 33.2 17.7 13.4 158 159 85 64
%
27.7 22.3 3.1 7.0 135 109 15 34
%
38.4 30.2 16.1 8.5 207 163 87 46
% %
0.7 0.3 0.4 7.7 Stage IIA Stage IIB Stage III Unknown
1953 1879 1100 774
23.6 22.7 13.3 9.3
613 604 213 183
11 5 6 123 %
38.0 37.4 13.2 11.3
%
169 135 71 51
21.8 17.4 9.2 6.6
High grade sarcoma (others) (N ¼ 1174) RMS (N ¼ 211) PNET (N ¼ 161) DDLS (N ¼ 333) MPNST (N ¼ 373) Synovial sarcoma (N ¼ 479) MFS (N ¼ 488) LMS (N ¼ 539) MRLS (N ¼ 775) WDLS (N ¼ 1594) UPS (N ¼ 1613) Overall (N ¼ 8288) No. of patients
Table 1 (continued )
0.0 0.0 4.7 8.4
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
Low grade sarcoma (others) (N ¼ 548)
758
reconstruction was performed less frequently (229/6680; 3.4%) than for bone sarcoma (59.5%). The most frequent methods of bone reconstruction were the use of an autograft (137/6680; 2.1%) and a prosthesis (77/6680; 1.2%). Soft tissue reconstruction was performed in 22.6% of the surgical cases (1512/6680). The most frequent methods of soft tissue reconstruction were the use of a pedicled myocutaneous flap (680/6680; 10.2%) and a skin graft (671/6680; 10.0%). Other forms of reconstruction involved mainly in situ preparation, reconstruction of the tendon (e.g. Achilles tendon or patellar tendon), ligament, or capsule, and reconstruction of the chest wall or abdominal wall. The rate of complications requiring additional surgical procedures (672/6680; 10.1%) was lower than that for bone sarcoma (15.1%) [6]. The rate of wound complications (delayed wound healing (192/6680; 2.9%) and infection (146/6680; 2.2%)) was lower for STS than for bone sarcoma (3.6% and 5.3%, respectively), whereas surgery for local recurrence was more frequent for STS (178/6680; 2.7%) than for bone sarcoma (1.9%) [6]. Additional surgery for other reasons included removal of postoperative hematoma, additional resection resulting from a change in the histologic diagnosis or an inadequate surgical margin after evaluation of the surgical specimen, surgery for lymphedema such as lymphaticovenular anastomosis, internal fixation for postoperative fracture, and implant removal. The rate of additional surgery was highest for patients with MPNST (60/301; 19.9%). 3.3. Treatments other than surgery Table 3 shows a summary of patients who underwent nonsurgical treatment. Overall, 2167 (26.1%) of 8288 patients underwent chemotherapy, which was much lower than the rate for bone sarcoma [6]. This included the majority of patients with synovial sarcoma (304/479; 63.5%), PNET (142/161; 88.2%), and RMS (155/ 211; 73.5%), whereas few patients with WDLS (8/1594; 0.5%) and MFS (52/488; 10.7%) underwent chemotherapy. Adjuvant chemotherapy before and/or after surgery accounted for 83.6% (254/304) of the chemotherapy in patients with synovial sarcoma. The most frequently used agents were adriamycin (ADR), ifosfamide (IFO), and etoposide (VP16). Overall, 1604 (19.4%) of the 8288 patients received radiotherapy. Patients with PNET and RMS received radiotherapy more frequently than patients with other histologic subtypes. Radiotherapy in a radical setting was performed mostly for patients with PNET (19/ 61; 31.1%) and RMS (44/106; 41.5%). The high proportion of radiotherapy in a radical setting for these histologic subtypes may have been attributable to their radiosensitivity, in addition for the tendency of PNET to arise in the trunk. In fact, among the 19 patients with PNET who underwent radical radiotherapy, the primary tumor was located in the trunk, or the head and neck, in 15 (78.9%). 3.4. Prognosis During the study period, we identified the records of 3826 patients from 79 hospitals whose prognostic data at 2 or 5 years after initial registration were available. The outcome at 2 and 5 years was evaluable for 52.5% (1022 patients) and 42.9% (834 patients) of 1946 patients whose first registrations had been conducted in 2006 and 2007, respectively. The mean follow-up period for these patients was 34.2 months (range, 2e83 months). The cumulative DSS at 2 and 5 years after treatment was 86.8% and 77.5%, respectively (Fig. 2). The unadjusted associations of various factors with the DSS rate estimated using the KaplaneMeier method are shown in Fig. 3AeL. Table 4 shows the unadjusted and adjusted hazard ratios obtained from the Cox proportional hazards models for DSS based on
Table 2 Statistics of surgery according to histologic subtype. UPS (N ¼ 1613)
Low grade sarcoma (others) (N ¼ 548)
1330
82.5
1351
84.8
666
85.9
420
77.9
433
88.7
377
78.7
301
80.7
258
77.5
102
63.4
127
60.2
860
73.3
455
83.0
5792 552 313 23
86.7 8.3 4.7 0.3
1111 148 69 2
83.5 11.1 5.2 0.2
1323 14 13 1
97.9 1.0 1.0 0.1
592 54 18 2
88.9 8.1 2.7 0.3
333 64 20 3
79.3 15.2 4.8 0.7
364 53 16 0
84.1 12.2 3.7 0.0
300 50 25 2
79.6 13.3 6.6 0.5
257 25 13 6
85.4 8.3 4.3 2.0
237 8 13 0
91.9 3.1 5.0 0.0
90 9 3 0
88.2 8.8 2.9 0.0
111 5 9 2
87.4 3.9 7.1 1.6
684 75 98 3
79.5 8.7 11.4 0.3
390 47 16 2
85.7 10.3 3.5 0.4
4704 1542 371 63 229 137 66 45 99 30 11 8 1 77 8 1512 671 680 312 110 24 136 672
70.4 23.1 5.6 0.9 3.4 2.1 1.0 0.7 1.5 0.4 0.2 0.1 0.0 1.2 0.1 22.6 10.0 10.2 4.7 1.6 0.4 2.0 10.1
1107 142 74 7 58 35 19 12 19 6 1 3 0 22 0 448 218 207 90 13 2 32 162
83.2 10.7 5.6 0.5 4.4 2.6 1.4 0.9 1.4 0.5 0.1 0.2 0.0 1.7 0.0 33.7 16.4 15.6 6.8 1.0 0.2 2.4 12.2
464 831 51 5 11 9 9 8 8 8 0 0 0 2 0 23 6 16 2 0 0 2 38
34.3 61.5 3.8 0.4 0.8 0.7 0.7 0.6 0.6 0.6 0.0 0.0 0.0 0.1 0.0 1.7 0.4 1.2 0.1 0.0 0.0 0.1 2.8
561 90 14 1 15 8 4 3 7 3 0 1 1 5 0 111 46 46 18 14 0 8 59
84.2 13.5 2.1 0.2 2.3 1.2 0.6 0.5 1.1 0.5 0.0 0.2 0.2 0.8 0.0 16.7 6.9 6.9 2.7 2.1 0.0 1.2 8.9
344 52 10 14 13 7 4 2 6 2 2 0 0 5 0 122 55 48 17 21 0 13 45
81.9 12.4 2.4 3.3 3.1 1.7 1.0 0.5 1.4 0.5 0.5 0.0 0.0 1.2 0.0 29.0 13.1 11.4 4.0 5.0 0.0 3.1 10.7
350 44 37 2 10 8 1 1 7 0 1 0 0 1 0 170 99 59 38 1 2 7 57
80.8 10.2 8.5 0.5 2.3 1.8 0.2 0.2 1.6 0.0 0.2 0.0 0.0 0.2 0.0 39.3 22.9 13.6 8.8 0.2 0.5 1.6 13.2
318 38 17 4 31 18 6 2 13 1 2 2 0 12 2 117 29 51 38 26 9 17 44
84.4 10.1 4.5 1.1 8.2 4.8 1.6 0.5 3.4 0.3 0.5 0.5 0.0 3.2 0.5 31.0 7.7 13.5 10.1 6.9 2.4 4.5 11.7
203 63 29 6 17 9 4 5 8 4 1 0 0 1 6 88 31 43 19 7 8 9 60
67.4 20.9 9.6 2.0 5.6 3.0 1.3 1.7 2.7 1.3 0.3 0.0 0.0 0.3 2.0 29.2 10.3 14.3 6.3 2.3 2.7 3.0 19.9
148 65 42 3 4 3 2 0 3 0 0 0 0 1 0 41 20 18 5 5 0 5 37
57.4 25.2 16.3 1.2 1.6 1.2 0.8 0.0 1.2 0.0 0.0 0.0 0.0 0.4 0.0 15.9 7.8 7.0 1.9 1.9 0.0 1.9 14.3
77 15 9 1 9 5 1 1 5 1 1 0 0 3 0 20 5 10 6 2 0 6 10
75.5 14.7 8.8 1.0 8.8 4.9 1.0 1.0 4.9 1.0 1.0 0.0 0.0 2.9 0.0 19.6 4.9 9.8 5.9 2.0 0.0 5.9 9.8
95 20 8 4 10 8 3 3 3 0 0 0 0 4 0 27 8 14 6 2 0 2 13
74.8 15.7 6.3 3.1 7.9 6.3 2.4 2.4 2.4 0.0 0.0 0.0 0.0 3.1 0.0 21.3 6.3 11.0 4.7 1.6 0.0 1.6 10.2
687 95 63 15 38 19 8 5 13 3 1 1 0 18 0 238 108 109 55 17 2 25 113
79.9 11.0 7.3 1.7 4.4 2.2 0.9 0.6 1.5 0.3 0.1 0.1 0.0 2.1 0.0 27.7 12.6 12.7 6.4 2.0 0.2 2.9 13.1
350 87 17 1 13 8 5 3 7 2 2 1 0 3 0 107 46 59 18 2 1 10 34
76.9 19.1 3.7 0.2 2.9 1.8 1.1 0.7 1.5 0.4 0.4 0.2 0.0 0.7 0.0 23.5 10.1 13.0 4.0 0.4 0.2 2.2 7.5
525 108 39
7.9 1.6 0.6
119 35 8
8.9 2.6 0.6
38 0 0
2.8 0.0 0.0
53 5 1
8.0 0.8 0.2
32 10 3
7.6 2.4 0.7
46 10 1
10.6 2.3 0.2
32 8 4
8.5 2.1 1.1
44 9 7
14.6 3.0 2.3
31 4 2
12.0 1.6 0.8
7 3 0
6.9 2.9 0.0
9 4 0
7.1 3.1 0.0
86 15 12
10.0 1.7 1.4
28 5 1
6.2 1.1 0.2
178 146 47 5 2 192 163
2.7 2.2 0.7 0.1 0.0 2.9 2.4
50 34 13 1 0 50 32
11 11 1 0 0 12 5
0.8 0.8 0.1 0.0 0.0 0.9 0.4
8 19 7 0 1 18 9
1.2 2.9 1.1 0.0 0.2 2.7 1.4
14 8 1 2 0 15 10
3.3 1.9 0.2 0.5 0.0 3.6
14 7 5 0 0 20 17
3.2 1.6 1.2 0.0 0.0 4.6 3.9
7 9 7 1 0 12 15
1.9 2.4 1.9 0.3 0.0 3.2 4.0
17 13 3 1 0 12 20
5.6 4.3 1.0 0.3 0.0 4.0 6.6
14 9 2 0 0 9 8
5.4 3.5 0.8 0.0 0.0 3.5 3.1
2 5 0 0 0 2 1
2.0 4.9 0.0 0.0 0.0 2.0 1.0
2 5 0 0 0 5 3
1.6 3.9 0.0 0.0 0.0 3.9 2.4
31 21 5 0 1 30 29
3.6 2.4 0.6 0.0 0.1 3.5 3.4
8 5 3 0 0 7 14
1.8 1.1 0.7 0.0 0.0 1.5 3.1
%
%
%
%
%
%
%
%
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
3.8 2.6 1.0 0.1 0.0 3.8 2.4
%
Synovial sarcoma (N ¼ 479)
High grade sarcoma (others) (N ¼ 1174)
80.6
%
MFS (N ¼ 488)
RMS (N ¼ 211)
6680
%
LMS (N ¼ 539)
PNET (N ¼ 161)
Surgery Type of surgery Resection Additional resection Amputation Others Surgical margin Wide Marginal Intralesional Unknown Bony reconstruction Autograft Free autograft Vascularized autograft Devitalized autograft Other autograft Artificial bone graft Allograft Bone lengthening Prosthesis Spinal reconstruction Soft tissue reconstruction Skin graft Pedicled myocutaneous flap Free myocutaneous flap Vascular reconstruction Nerve reconstruction Other reconstruction Additional surgery for complications No. of additional surgery 1 2 3Cause of the additional surgery Local recurrence Infection Circulatory deficit Nerve disorder Prosthetic failure Delay of wound healing Other causes
%
MRLS (N ¼ 775)
DDLS (N ¼ 333)
Overall (N ¼ 8288)
%
WDLS (N ¼ 1594)
MPNST (N ¼ 373)
No. of patients
UPS: undifferentiated pleomorphic sarcoma, WDLS: well-differentiated liposarcoma, MRLS: myxoid/round cell liposarcoma, LMS: leiomyosarcoma, MFS: myxofibrosarcoma, MPNST: malignant peripheral nerve sheath tumor, DDLS: dedifferentiated liposarcoma, PNET: primitive neuroectodermal tumor, RMS: rhabdomyosarcoma. 759
760
Table 3 Statistics of treatment other than surgery according to histologic subtype. No. of patients
Overall (N ¼ 8288)
UPS (N ¼ 1613)
%
%
MRLS (N ¼ 775)
%
LMS (N ¼ 539)
%
MFS (N ¼ 488)
%
Synovial sarcoma (N ¼ 479)
%
MPNST (N ¼ 373)
%
DDLS (N ¼ 333)
%
PNET (N ¼ 161)
%
RMS (N ¼ 211)
%
High grade sarcoma (others) (N ¼ 1174)
%
Low grade sarcoma (others) (N ¼ 548)
%
%
26.1
406
25.2
8
0.5
215
27.7
170
31.5
52
10.7
304
63.5
126
33.8
90
27.0
142
88.2
155
73.5
459
39.1
40
7.3
66.3 28.9 4.8
283 106 17
69.7 26.1 4.2
5 3 0
62.5 37.5 0.0
165 41 9
76.7 19.1 4.2
98 62 10
57.6 36.5 5.9
40 10 2
76.9 19.2 3.8
254 42 8
83.6 13.8 2.6
66 51 9
52.4 40.5 7.1
47 40 3
52.2 44.4 3.3
103 34 5
72.5 23.9 3.5
99 42 14
63.9 27.1 9.0
249 185 25
54.2 40.3 5.4
27 10 3
67.5 25.0 7.5
79.2 75.2 22.6 16.8 15.2 13.5 7.6 0.6 20.6 19.4
329 305 74 54 7 25 39 2 65 378
81.0 75.1 18.2 13.3 1.7 6.2 9.6 0.5 16.0 23.4
7 7 1 1 0 0 0 0 0 27
87.5 87.5 12.5 12.5 0.0 0.0 0.0 0.0 0.0 1.7
193 178 40 32 17 15 24 0 22 197
89.8 82.8 18.6 14.9 7.9 7.0 11.2 0.0 10.2 25.4
134 120 21 22 3 3 13 0 35 90
78.8 70.6 12.4 12.9 1.8 1.8 7.6 0.0 20.6 16.7
40 42 10 1 2 2 5 0 12 101
76.9 80.8 19.2 1.9 3.8 3.8 9.6 0.0 23.1 20.7
266 277 45 35 23 22 17 2 32 108
87.5 91.1 14.8 11.5 7.6 7.2 5.6 0.7 10.5 22.5
93 93 34 14 11 9 9 1 28 98
73.8 73.8 27.0 11.1 8.7 7.1 7.1 0.8 22.2 26.3
70 68 13 14 3 2 8 0 22 89
77.8 75.6 14.4 15.6 3.3 2.2 8.9 0.0 24.4 26.7
126 119 99 15 114 92 8 2 34 61
88.7 83.8 69.7 10.6 80.3 64.8 5.6 1.4 23.9 37.9
79 82 51 34 105 86 5 2 63 106
51.0 52.9 32.9 21.9 67.7 55.5 3.2 1.3 40.6 50.2
352 310 93 129 42 33 36 4 122 295
76.7 67.5 20.3 28.1 9.2 7.2 7.8 0.9 26.6 25.1
28 28 8 12 3 3 1 0 12 54
70.0 70.0 20.0 30.0 7.5 7.5 2.5 0.0 30.0 9.9
61.0 14.9 20.2 3.9 0.5
253 49 60 16 9
66.9 13.0 15.9 4.2 0.6
24 0 3 0 1
88.9 0.0 11.1 0.0 0.1
155 15 21 6 15
78.7 7.6 10.7 3.0 1.9
42 23 21 4 2
46.7 25.6 23.3 4.4 0.4
76 2 20 3 0
75.2 2.0 19.8 3.0 0.0
69 8 24 7 4
63.9 7.4 22.2 6.5 0.8
50 23 19 6 3
51.0 23.5 19.4 6.1 0.8
52 19 15 3 0
58.4 21.3 16.9 3.4 0.0
27 11 19 4 0
44.3 18.0 31.1 6.6 0.0
46 15 44 1 1
43.4 14.2 41.5 0.9 0.5
148 69 66 12 5
50.2 23.4 22.4 4.1 0.4
37 5 12 0 0
68.5 9.3 22.2 0.0 0.0
70.0 15.0 10.0 5.0
6 0 2 1
66.7 0.0 22.2 11.1
1 0 0 0
100.0 0.0 0.0 0.0
14 0 1 0
93.3 0.0 6.7 0.0
0 2 0 0
0.0 100.0 0.0 0.0
0 0 0 0
0.0 0.0 0.0 0.0
4 0 0 0
100.0 0.0 0.0 0.0
0 2 0 1
0.0 66.7 0.0 33.3
0 0 0 0
0.0 0.0 0.0 0.0
0 0 0 0
0.0 0.0 0.0 0.0
0 0 1 0
0.0 0.0 100.0 0.0
3 2 0 0
60.0 40.0 0.0 0.0
0 0 0 0
0.0 0.0 0.0 0.0
UPS: undifferentiated pleomorphic sarcoma, WDLS: well-differentiated liposarcoma, MRLS: myxoid/round cell liposarcoma, LMS: leiomyosarcoma, MFS: myxofibrosarcoma, MPNST: malignant peripheral nerve sheath tumor, DDLS: dedifferentiated liposarcoma, PNET: primitive neuroectodermal tumor, RMS: rhabdomyosarcoma. ADR ¼ adriamycin, IFO ¼ ifosfamide, CDDP ¼ cisplatin, MTX ¼ methotrexate, VP16 ¼ etoposide, VCR ¼ vincristine, CPM ¼ cyclophosphamide, DTIC ¼ dacarbazine.
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
Chemotherapy 2167 Setting of chemotherapy Adjuvant 1436 Palliative 626 Unknown 105 Chemotherapeutic agent ADR 1717 IFO 1629 VP16 489 CDDP 363 VCR 330 CPM 292 DTIC 165 MTX 13 Others 447 Radiotherapy 1604 Setting of radiotherapy Adjuvant 979 Palliative 239 Radical 324 Unknown 62 Hyperthermia 40 Setting of hyperthermia Adjuvant 28 Palliative 6 Radical 4 Unknown 2
WDLS (N ¼ 1594)
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
761
4. Discussion
Fig. 2. KaplaneMeier curves showing DSS for all of the 3826 patients. The cumulative DSS at 2 and 5 years after treatment was 86.8% and 77.5%.
2432 cases with no missing data for age, sex, status at first visit, histologic subtype, depth and location of the tumor, additional surgery, and surgical margin. Statistical testing by proportional hazards assumption demonstrated no evidence of violation with respect to any of the variables included (P ¼ 0.242). Patients aged 75 years had a significantly worse DSS than those aged 30e69 years (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.02e1.82; P ¼ 0.035). Female patients had a significantly better DSS than male patients (HR: 0.75; 95% CI, 0.59e0.96; P ¼ 0.021). Taking the UPS as the reference, poorer DSS was observed for MPNST (HR: 1.56; 95% CI, 1.05e2.33; P ¼ 0.028), PNET (HR: 2.23; 95% CI, 1.28e3.89; P ¼ 0.005), and RMS (HR: 2.15; 95% CI, 1.16e3.97; P ¼ 0.015), whereas significantly better DSS was seen for WDLS (HR: 0.01; 95% CI, 0.00e0.05; P < 0.001), MRLS (HR: 0.36; 95% CI, 0.23e0.57; P < 0.001), and MFS (HR: 0.47; 95% CI, 0.27e0.79; P ¼ 0.005). Patients with tumors >5 cm and 10 cm in diameter and >10 cm in diameter had a significantly poorer DSS than those with tumors 5 cm in diameter (HR: 2.02; 95% CI, 1.38e2.96; P < 0.001 and HR: 3.27; 95% CI, 2.19e4.86; P < 0.001, respectively). A deep tumor location (HR: 2.05; 95% CI, 1.41e2.99; P < 0.001) was associated with a significantly poorer DSS than a superficial tumor location. Tumor location in the trunk (HR: 1.76; 95% CI, 1.08e2.86; P ¼ 0.022) or the head and neck (HR: 2.49; 95% CI, 1.22e5.10; P ¼ 0.013) was associated with a significantly poorer DSS than a tumor location in the upper extremity. Local recurrence had a tendency toward poor DSS, but not significant (P ¼ 0.060). Patients undergoing amputation had a significantly poorer DSS than those undergoing limb salvage surgery (HR: 1.69; 95% CI, 1.15e2.49; P ¼ 0.008). Status of surgical margin (wide/marginal versus intralesional) was significantly associated with DSS (HR: 1.73; 95% CI, 1.19e2.53; P ¼ 0.004). We performed additional analysis focusing on the association between DSS and tumor size and depth (Table 5). Our results based on this large patient cohort showed that while a tumor size of >10 cm did not increase the risk of disease-specific death compared with a tumor size of >5 cm and 10 cm in patients with a superficial tumor location, a large tumor size had a stronger impact on disease-specific death in patients with deep-seated tumors.
Our present study has clarified the national profiles of the characteristics and treatments of 8228 patients with STSs entered in the BSTT Registry between 2006 and 2012. We further provided an overview of the prognosis and significant factors affecting DSS for 2432 patients with STS. We believe that the present study is valuable for the following reasons. First, the BSTT Registry is a nationwide organ-specific registry for bone and soft tissue tumors in Japan that contains detailed data on epidemiology, treatment, and oncologic, surgical and functional outcomes. Such a large sarcoma database is rare in other countries. Second, the data presented here reflect the current statistics and outcomes of modern multidisciplinary treatments performed in JOA-certified hospitals, the surgical treatment aiming at accomplishing a sufficient margin and appropriate methods of chemotherapy and radiotherapy. Because these treatment strategies are considered to be standard treatments internationally, the present data reflect not only the national profiles in Japan but also provide the best evidence of what can be expected from modern multidisciplinary treatment in a worldwide context. In addition, these data are based on patients treated during a recent short period (2006e2012) and therefore exclude any historical changes in statistics or treatment outcomes. The elderly population is growing rapidly worldwide, and Japan is now facing a “super-aging society” ahead of most other countries, those aged 65 years accounting for 25% of the population in 2013, representing the highest proportion in the world [10]. Consequently, we expect that the number of elderly patients diagnosed with STS will increase accordingly. Our data demonstrated a single peak of age distribution for STS patients, with a peak in the seventh decade. Also, the proportion of elderly patients aged over 60 years exceeded 50%. We demonstrated that the age distribution of STS has changed in the last two decades as the population of Japan rapidly ages, the proportion of patients aged >60 years in particular showing a dramatic increase (Fig. 4) [11]. We also demonstrated that STS in elderly patients aged 75 years had a significantly worse DSS than in younger patients after adjustment for patient background characteristics. As this trend is expected to continue in the next few decades, it will be necessary to establish a treatment standard for older patients with STS, who usually have decreased performance status and several comorbidities. Furthermore, it is anticipated that documenting our experiences using the BSTT Registry will be of help to other countries that are also experiencing aging of the population. Because tumor size and depth are considered to be major factors affecting oncologic outcome, the T stage of STS in the AJCC staging system is based on tumor size and depth: the cut-off tumor size between stages T1 and T2 is set at 5 cm, and the difference between T1a/T2a and T1b/T2b is defined as tumor depth being shallower than the superficial fascia without invasion [12]. However, a deep tumor location is frequently associated with a larger tumor size, as was found in the present series: tumor diameter was 5 cm in 50% of the patients with superficial tumors and >5 cm in 84% of those with deep-seated tumors. In addition, quantitative data regarding the effects of various combinations of these factors on survival have been lacking. The data presented here reveal that a large tumor size and a deep tumor location together greatly increase the risk of disease-specific death, and this quantitative evidence will assist physicians with accurate prognostication and provide a more informative explanation for patients with STS. One of the unique advantages of the BSTT Registry over the SEER is that we can obtain data regarding surgical outcomes including details about postoperative complications and reoperation. The surgical outcomes revealed in the present study provide solid
762
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
Fig. 3. KaplaneMeier survival plots stratified by predictor variables for DSS: (A) age (Child, 14 years; AYA, 15e29 years; Adult, 30e74 years; Elderly, 75 years), (B) sex, (C) status at first visit (1: First visit/After preoperative therapy, 2: NED after resection at the previous hospital, 3: With microscopic residual tumor after resection at the previous hospital, 4: With macroscopic residual tumor after resection at the previous hospital, 5: Local or metastatic recurrence, 6: Others), (D) histologic grade, (E) histologic subtype, (F) tumor size, (G) tumor depth, (H) tumor location, (I) presence or absence of additional surgery for complications, (J) limb salvage status, (K) surgical margin, and (L) presence or absence of local recurrence.
evidence for the commonly accepted notion that STS surgery is associated with lower rates of postoperative complications and reoperation (10.1%) than is the case for bone sarcoma surgery (15.1%) [6]. Furthermore, this information should help physicians to give more accurate explanations to their patients based on clinical evidence, as such nationwide data have not been available hitherto. Several limitations of this study should be mentioned, as was the case for our previous study of bone sarcoma [6]. First, the time and effort required to collect some of the items in the BSTT Registry
resulted in their exclusion from our analysis; for example, the Enneking stage, which sometimes requires re-checking of imaging data, and functional outcome, which may necessitate patient examination, had relatively more missing values than the other items. Second, we were unable to completely exclude the possibility of duplicate reporting if a patient had received care at more than one hospital, although the BSTT Registry was devised to automatically exclude cases with “Second opinion/Observation only after treatment in the previous hospital” in the “Status at the first visit”
K. Ogura et al. / Journal of Orthopaedic Science 22 (2017) 755e764
763
Table 4 Cox proportional hazards models for DSS (N ¼ 2432). No. of patients
5-year survival (%)
Univariate analysis
P value
Hazard ratio (95% CI) Age Child (14 years) AYA (15e29 years) Adult (30e74 years) Elderly (75 years) Sex Male Female Status at the first visita 1e3 4, 5 Histologic subtypes UPS WDLS MRLS LMS MFS Synovial sarcoma MPNST DDLS PNET RMS Tumor size 5 cm >5 cm and 10 cm >10 cm Unknown Depth Superficial Deep Location Upper extremity Lower extremity Trunk Head and neck Local recurrence No Yes Limb salvage status Limb salvage Amputation Unknown Surgical margin Wide or marginal Intralesional
1557 42 351 482
71.8 73.1 80.3 75.7
1.29 (0.57e2.92) 1.26 (0.92e1.73) Reference 1.70 (1.28e2.25)
1325 1107
75.5 79.9
2187 245
Multivariate analysis
P value
Hazard ratio (95% CI) 0.538 0.150 <0.001
0.76 (0.32e1.80) 0.85 (0.60e1.21) Reference 1.36 (1.02e1.82)
0.529 0.371
Reference 0.68 (0.54e0.86)
0.001
Reference 0.75 (0.59e0.96)
0.021
78.7 71.5
Reference 1.18 (0.82e1.68)
0.377
Reference 1.07 (0.73e1.57)
0.718
574 602 354 193 202 172 141 93 53 48
72.5 99.5 85.3 72.2 87.2 71.5 62.1 66.9 58.3 48.0
Reference 0.01 (0.00e0.07) 0.35 (0.23e0.55) 1.15 (0.79e1.67) 0.42 (0.25e0.71) 0.75 (0.49e1.15) 1.65 (1.13e2.39) 1.31 (0.82e2.09) 1.95 (1.17e3.26) 1.81 (1.04e3.17)
<0.001 <0.001 0.476 0.001 0.186 0.009 0.269 0.011 0.037
0.01 0.36 1.35 0.47 0.96 1.56 0.73 2.23 2.15
(0.00e0.05) (0.23e0.57) (0.92e1.97) (0.27e0.79) (0.60e1.55) (1.05e2.33) (0.45e1.20) (1.28e3.89) (1.16e3.97)
<0.001 <0.001 0.126 0.005 0.872 0.028 0.216 0.005 0.015
564 906 853 109
86.6 76.9 70.5
Reference 2.11 (1.46e3.04) 2.61 (1.82e3.74) 1.10 (0.51e2.35)
<0.001 <0.001 0.810
Reference 2.02 (1.38e2.96) 3.27 (2.19e4.86) 0.83 (0.38e1.80)
<0.001 <0.001 0.657
602 1830
89.5 74.1
Reference 2.53 (1.78e3.60)
<0.001
Reference 2.05 (1.41e2.99)
<0.001
281 1391 704 56
85.8 81.4 71.5 68.7
Reference 1.38 (0.87e2.18) 2.41 (1.52e3.84) 3.79 (1.93e7.45)
0.172 <0.001 <0.001
Reference 1.45 (0.91e2.33) 1.76 (1.08e2.86) 2.49 (1.22e5.10)
0.120 0.022 0.013
2286 146
84.1 67.6
Reference 2.16 (1.54e3.03)
<0.001
Reference 1.42 (0.99e2.04)
0.060
2173 91 168
81.7 48.7
Reference 4.16 (2.90e5.96) 2.07 (1.45e2.96)
<0.001 <0.001
Reference 1.69 (1.15e2.49) 1.29 (0.87e1.92)
0.008 0.209
2291 141
82.9 64.2
Reference 2.69 (1.89e3.83)
<0.001
Reference 1.73 (1.19e2.53)
0.004
0.035
CI: confidence interval, UPS: undifferentiated pleomorphic sarcoma, WDLS: well-differentiated liposarcoma, MRLS: myxoid/round cell liposarcoma, LMS: leiomyosarcoma, MFS: myxofibrosarcoma, MPNST: malignant peripheral nerve sheath tumor, DDLS: dedifferentiated liposarcoma, PNET: primitive neuroectodermal tumor, RMS: rhabdomyosarcoma. a Each number refers to the following status; 1: First visit/After preoperative therapy, 2: NED after resection at the previous hospital, 3: With microscopic residual tumor after resection at the previous hospital, 4: With macroscopic residual tumor after resection at the previous hospital, 5: Local or metastatic recurrence.
Table 5 The 5-year DSS and hazard ratio stratified by size and depth of the tumor (N ¼ 2432). Tumor size
5 cm >5 cm and 10 cm >10 cm
Depth Superficial
Deep
91% (Reference) 92% (HR, 1.38; P ¼ 0.391) 91% (HR, 1.49; P ¼ 0.441)
87% (HR, 1.46; P ¼ 0.255) 81% (HR, 2.97; P < 0.001) 76% (HR, 3.38; P < 0.001)
section of the database. Third, the detailed data regarding chemotherapy and radiotherapy were unavailable from the BSTT Registry. Although setting of chemotherapy (preoperative, postoperative, or palliative) or chemotherapeutic agents and setting of radiotherapy (preoperative, postoperative, or palliative) were available, we were not able to know the more detailed data such as protocol of chemotherapy or dose, fraction, and protocol of radiotherapy. Fourth, the mean follow-up period was relatively short (34.2
Fig. 4. Proportion of patients with STS by age diagnosed during 1985e1994 and 2006e2012.
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months). Fifth, the number of soft-tissue sarcoma originating from retroperitoneum, peritoneum, or uterine represented by leiomyosarcoma should be underestimated in the BSTT Registry because this registry has been operated by JOA and data have been collected by orthopaedic surgeons. Finally, participation in the registry is not mandatory for non-JOA-certified hospitals. Although we expect that the majority of STS cases would have been treated at specialist centers certified by the JOA, there is still a possibility that some would have been treated at non-specialist hospitals due to patient preference or other reasons. In conclusion, this study has provided an overview of the statistics for STS, including epidemiology, clinical features, treatment, and prognosis in Japan, based on the large cohort entered in the BSTT Registry. The study is the first to have analyzed data for STS from the BSTT Registry and should offer a valuable basis for future clinical studies aimed at determining the best therapeutic strategies for management of STS patients. We anticipate that continuous accumulation of clinical data in the BSTT Registry will provide more informative data on STS, thus improving both the level of medical care offered by clinicians and the outcomes for patients through sharing of such data and promotion of clinical research. Conflict of interest Each author certifies that he or she has no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/ licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. Acknowledgments This study was funded by a Grant-in-Aid for Scientific Research from the Ministry of Education and Science, Japan (B, No. 22390296), and by the National Cancer Center Research and Development Fund (23-A-10; 28-A-16). We thank all the hospitals and medical staff participating in the BSTT Registry, and all the patients whose data were recorded, without whom the registry would have not been established. We would also like to
acknowledge Ms. Misuzu Mori and Ms. Rie Nakano for their administrative support with the registry.
Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.jos.2017.03.017.
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