Soft-tissue Sarcomas in the Asia-Pacific Region : A Systematic Review

Soft-tissue sarcomas (STS) are a heterogeneous group of rare tumours. More than 50 STS histotypes have been identified, with most having unique clinical, prognostic, and therapeutic features. Although less than 1% of all adult malignant tumours are STS (Fletcher et al., 2002a), their treatment and management is complex because many tumour-related (eg, histotype, site, size, depth, grade, primary vs recurrent) (Singer et al., 1994; 2000; Pisters et al., 1996) and treatment-related (eg, surgical margins, use of adjuvant therapy) (Singer et al., 2000) factors influence patient outcomes. Because these factors are inherently variable and because STS is rare, the management of patients with STS is best undertaken by an experienced multidisciplinary team in specialist centres to minimise recurrence, maximise survival, and preserve functionality and quality of life (Ray-Coquard et al., 2004; Luis et al., 2010; National Comprehensive Cancer Network, 2012). The standard primary treatment for STS is surgical


Introduction
Soft-tissue sarcomas (STS) are a heterogeneous group of rare tumours.More than 50 STS histotypes have been identified, with most having unique clinical, prognostic, and therapeutic features.Although less than 1% of all adult malignant tumours are STS (Fletcher et al., 2002a), their treatment and management is complex because many tumour-related (eg, histotype, site, size, depth, grade, primary vs recurrent) (Singer et al., 1994;2000;Pisters et al., 1996) and treatment-related (eg, surgical margins, use of adjuvant therapy) (Singer et al., 2000) factors influence patient outcomes.Because these factors are inherently variable and because STS is rare, the management of patients with STS is best undertaken by an experienced multidisciplinary team in specialist centres to minimise recurrence, maximise survival, and preserve functionality and quality of life (Ray-Coquard et al., 2004;Luis et al., 2010;National Comprehensive Cancer Network, 2012).
The standard primary treatment for STS is surgical

Materials and Methods
Database search strategy MEDLINE via PubMed was searched on October 20, 2011, using the search strategy: (((#1 OR #2) AND #3) NOT #4) OR (((#1 OR #2) AND #3) OR #5), where the numbers represent the following search terms: 1) sarcoma OR sarcomas; 2) (neoplasm OR neoplasms OR tumor OR tumour OR tumors OR tumours OR cancer OR cancers) AND "soft tissue"; 3) Australia OR "Hong Kong" OR Indonesia OR Korea OR Malaysia OR "New Zealand" OR Philippines OR Singapore OR Taiwan OR Thailand; 4) bone neoplasm; and 5) extraskeletal OR "extra skeletal" OR extra-skeletal OR extraosseous OR "extra osseous" OR extra-osseous OR chondroosseous OR "chondro osseous" OR chondro-osseous.This search strategy was used to retrieve publications describing STS, including extra-skeletal, extra-osseous, and chondro-osseous STS not located in the bones or the joints, and to exclude publications of bone tumours.The search was restricted to publications from October 20, 2001, to October 20, 2011, and to publications of human patients.There were no restrictions on publication language.

Publication selection
The abstracts of the retrieved publications were screened for possible full text review using prespecified inclusion and exclusion criteria.These criteria were also applied during the full text review of selected publications.Publications (systematic reviews, randomised or nonrandomised controlled trials, uncontrolled trials, or observational studies) of human (male or female) patients with STS that reported tumour characteristics, treatment patterns, efficacy outcomes, or safety outcomes were selected for review.Publications were excluded if subjects were nonhuman; all patients were younger than 18 years; the study had 10 or fewer patients, was done in countries other than Australia, Hong Kong, Indonesia, Korea, Malaysia, New Zealand, Philippines, Singapore, Taiwan, and Thailand, or was a multicountry study of non-Asian and Asia-Pacific countries that did not include a subanalysis of data from the Asia-Pacific country; the STS was located in the bones or joints, was gastrointestinal stromal tumour or Kaposi's sarcoma, or the proportion of patients with benign soft-tissue tumours was greater than 20%; or no relevant tumour attributes or efficacy or safety outcomes were reported.Publications were included if the study involved patients younger than 18 years but the mean or median age was 18 years or older.The bibliographies of relevant reviews were searched for any additional articles that should be assessed.

Data extraction
A spreadsheet was developed for data collection and refined as data were extracted.Data were extracted by a researcher (Julie Monk, ProScribe Medical Communications) and reviewed by all authors.Data collected from each publication included publication and study information (study design, publication type, study period, follow-up duration, and study country), patient information (number, age, sex, ethnicity, and comorbidities), STS characteristics (histotype, site, grade, and stage), treatment patterns (surgery, radiotherapy, chemotherapy, and combinations thereof), efficacy and effectiveness outcomes [complete, partial, or stable response; progressive disease; death; local recurrence; disease-free, relapse-free, progression-free, or overall survival (OS)], and safety and tolerability outcomes (complications arising from surgery; adverse events; drugrelated adverse events).As per the current World Health Organization guidelines for STS classification (Fletcher The search was restricted to studies of human patients with soft-tissue sarcoma that were published from October 20, 2001, to October 20, 2011.There were no restrictions on publication language.a Studies of sarcomas located in the bones or joints, gastrointestinal stromal tumour, or Kaposi's sarcoma, and studies where the proportion of patients with benign soft-tissue tumours was greater than 20% were excluded from review; b Studies from the following Asia-Pacific countries included in this review were Australia, Hong Kong, Indonesia, Korea, Malaysia, New Zealand, Philippines, Singapore, Taiwan, and Thailand DOI:http://dx.doi.org/10.7314/APJCP.2013.14.11.6821 Soft-tissue Sarcoma in the Asia-Pacific Region: A Systematic Review et al., 2002b), pleomorphic sarcoma has been used throughout this review to describe sarcomas classified as malignant fibrous histiocytoma.Not all data collected from the publications are reported in this review.Publications were sorted and analysed according to whether patients had primary or recurrent disease, and local or metastatic disease, because of the different treatment strategies required and different survival outcomes for these stages of disease.Percentages were calculated, when possible, if they were not provided in the original publication.

Literature search results
A total of 1,822 abstracts were retrieved from MEDLINE and screened for inclusion (Figure 1).Overall, 1,787 publications were excluded, mostly because they were of studies of 10 or fewer patients (n=687), nonhuman subjects (n=437), or diseases other than STS (n=429).The remaining 35 publications (all English language) were included for analysis.Most publications (83%, 29/35) were from Australia, Korea, and Taiwan, with none from Indonesia, New Zealand, or Philippines.As 4 publications (Huang et al., 2006;2008;2010;Lin et al., 2006) reported data from one group of patients over time, only data from the most recent publication (Huang et al., 2010) were reviewed.Thus, we examined the findings of 32 studies.

Studies of primary soft-tissue sarcoma
In the 8 studies of primary STS, disease was local (5 studies), local and metastatic (1 study), or not specified (2 studies; Table 2).The predominant STS histotypes were pleomorphic sarcoma and liposarcoma (7 of 8 studies).Sarcoma site was specific (retroperitoneum, extremities, uterus, or sinonasal) in 7 studies and was not reported in 1 study.
Treatment included surgery only (3 studies), surgery and radiotherapy (1 study), and surgery, radiotherapy, and chemotherapy (4 studies).Nearly all patients were treated with surgery: 100% in 5 studies and 86%, 92%, and 99% in the other 3 studies (Table 2).The remaining patients were not treated with surgery because it was not indicated (Wang et al., 2009), the surgery was biopsy only (An et al., 2007), or distant metastases were detected during restaging studies (eg, magnetic resonance imaging of primary tumour site) done after preoperative radiotherapy (Hui et al., 2006).Only 5 patients from 2 studies had amputations (Table 2).In 1 study, complications arising from surgery (minor or major dehiscence, infection, delayed healing, haematoma/ seroma, flap necrosis, and wound edge necrosis) affected 27 (41%) patients (Hui et al., 2006).Few patients (14%, 1 study) had preoperative chemotherapy, whereas 1% (1 study) and 100% (1 study) of patients had preoperative   (Huang et al., 2006;Lin et al., 2006;Huang et al., 2008;Huang et al., 2010) report data from a single group of patients over time, only data from the most recent publication (Huang et al., 2010) were reviewed; k Follow-up data were available for 74 of the 78 patients; l Of the 20 patients, 15 died of causes related to soft-tissue sarcoma and 5 died of other causes radiotherapy.A mixed proportion of patients had postoperative radiotherapy (6-52%; 4 studies) and postoperative chemotherapy (5-40%; 4 studies).

Studies of primary and recurrent soft-tissue sarcoma
In the 5 studies of primary and recurrent STS, disease was local (1 study), local or metastatic (1 study), or not specified (3 studies; Table 3).The predominant STS histotypes were pleomorphic sarcoma, liposarcoma, or leiomyosarcoma.Sarcoma site was specific in 3 studies (retroperitoneum, extremities, or uterus) and varied in 2 studies.
The mean/median follow-up time (reported in 4 studies) varied from 25 to 36 months (Table 3).Survival rates (OS or DSS; 4 studies) differed and were lowest (58%; 5-year OS) for extremity, head, neck, and trunk sarcoma (19% grade 3) (Hsieh et al., 2003) and highest (75%; actuarial 5-year DSS) for retroperitoneal sarcoma (81% FNCLCC grade 2/3) (Cho et al., 2011), despite the rate of local recurrence and/or distant metastases in this study being 70% (median follow-up time=15.9months).In the 4 other studies, the rate of local recurrence and/or distant metastases varied and was as low as 39% in a study of extremity, trunk, pelvic, and retroperitoneal sarcoma (43% grade III) (Miki et al., 2010).Adverse events were reported in only 1 study (complications arising from isolated limb infusion).

Studies of soft-tissue sarcoma: primary or recurrent status not specified
In the 19 studies that did not specify whether STS was primary or recurrent, disease was local (9 studies), local or metastatic (5 studies), or not specified (5 studies; Table 4).The predominant STS histotypes were pleomorphic sarcoma and liposarcoma (11 studies).Sarcoma site was specific in 6 studies (retroperitoneum, extremities, uterus, adductor compartment, or endometrium) or varied in 13 studies, in which the extremities were the predominant site (50-96%; 12 studies).

Local disease
In the 9 studies of patients with local disease, treatment included surgery and radiotherapy (4 studies), and surgery, radiotherapy, and chemotherapy (5 studies; Table 4).All patients were treated with surgery, among whom only 9 patients from 3 studies had amputations.In 1 study (Rudiger et al., 2009), major complications arising from surgery (infection, wound breakdown necessitating debridement and re-closure, giant haematoma, severe permanent lymphoedema, intra-operative catheterisation for femoral artery spasm) were reported for 7 (26%) patients (80% of all patients had received preoperative radiotherapy).Few patients (3%, 1 study) had preoperative chemotherapy, whereas most patients (80% and 100%) in 2 studies had preoperative radiotherapy (Table 4).A mixed proportion of patients had postoperative radiotherapy (8-88%; 8 studies).In 4 studies, 8% to 27% of patients had postoperative chemotherapy.Pre-and postoperative chemotherapy was given to 26% of patients in 1 study.

Local and metastatic disease status unknown
In the 5 studies of patients whose local or metastatic disease status was unknown, treatment included surgery (2 studies), surgery and radiotherapy (1 study), and surgery, radiotherapy, and chemotherapy (2 studies; Table 4).Nearly all patients were treated with surgery: 100% in 4 studies and 89% in the other study.The remaining patients were not treated with surgery because it was not indicated; however, they were treated with radiotherapy (Wong et al., 2004).In 1 study of extremity sarcomas (Wang and Tan, 2010), 6% of patients had amputations, and an overall wound infection rate of 9.8% was reported.No patients had preoperative radiotherapy or chemotherapy.A low proportion of patients had postoperative radiotherapy (9-30%; 3 studies) or chemotherapy (13% and 18%; 2 studies).In 1 study, 50% of patients had postoperative external beam radiotherapy and brachytherapy (Wong et al., 2004).

Discussion
This is the first systematic review of publications reporting findings on patients with STS in the Asia-Pacific region.This review highlights the scarcity of published data about STS treatment, management, and survival outcomes in this region.The strength of evidence of the included studies was limited; most studies were from 3 of the 10 study countries, there were no prospective controlled studies, patient numbers were small, and study periods dated back to the 1980s.Patients with STS require tailored and multidisciplinary treatment and management; however, this approach, and the resources needed to study and publish treatment practices, may be lacking in parts of the Asia-Pacific region.Further, differences in healthcare systems throughout the region (Chongsuvivatwong et al., 2011) may have contributed to the variability in reported outcomes.Overall, these findings emphasise the need for a comprehensive assessment of STS treatment, management, and outcomes in the Asia Pacific and are a critical first step towards developing clinical and research collaborations in the region.
All but a few patients in the included studies were treated with surgery, either alone or with adjuvant radiotherapy and/or chemotherapy.This finding aligns with current guidelines for STS treatment (Casali et al., 2010;National Comprehensive Cancer Network, 2012).Adjuvant radiotherapy has been shown to improve local control but not survival (Pisters et al., 2007), and its use depends on several factors, such as tumour size and location, the preferences of the treating physician and institution, and the resection margins (eg, involved, close, or clear).Adjuvant radiotherapy was administered to some patients, either preoperatively (1-100%) or postoperatively (6-88%), in 24 of the included studies.Preoperative radiotherapy, which may allow for the use of smaller field sizes and lower radiation doses and have lower long-term morbidity than postoperative radiotherapy (Pisters et al., 2007), seemed to be the standard of care at an Australian study centre (Choong et al., 2003;Hui et al., 2006;Rudiger et al., 2009;Miki et al., 2010), despite the potential for acute postoperative wound complications (Hui et al., 2006;Rudiger et al., 2009).Although the use of adjuvant chemotherapy may help local control, its marginal, if any, survival benefit (Pervaiz et al., 2008;Woll et al., 2012) has generally restricted its use to treatment of metastatic disease (Casali et al., 2010;National Comprehensive Cancer Network, 2012).Adjuvant chemotherapy was administered to some patients, either preoperatively (3-67%) or postoperatively (5-40%), in 17 of the included studies.However, the treatment patterns described do not necessarily reflect current practice because the study periods for many studies date back to the late 1970s or 1980s.The standard of care for sarcoma has changed substantially since then, from radical resection and amputation to definitive surgery and the use of adjuvant radiotherapy, where indicated (Colombo et al., 2012).In contrast, the use of adjuvant chemotherapy has become less frequent, especially in recent years, with successive studies failing to demonstrate a significant survival advantage (Pervaiz et al., 2008;Woll et al., 2012).
Survival outcomes and recurrence, when reported, varied among the included studies, which may be attributed to several factors.One factor is the range of sarcoma histotypes, sites, grades, and stages of disease assessed, which all influence patient prognosis.In this review, for example, the 5-year OS rate was about 50% for retroperitoneal liposarcoma (33% FNCLCC grade 3) (Lee et al., 2011), whereas the 53-month OS rate was 93% for extremity liposarcoma (11% high grade) (Ng and Tan, 2009).The quality of surgery also plays a key role in survival outcomes (Stojadinovic et al., 2002;Gronchi et al., 2005) and may have differed across, and possibly within, the centres of the included studies.In addition, access to radiotherapy or chemotherapy agents may have been limited in some of the study countries; however, most publications were from countries (Australia, Korea, and Taiwan) where access to these treatments is unlikely to be a major issue.Although survival outcomes in some studies may have been favourably skewed because they included patients with benign tumours, we limited this variable by excluding publications in which more than 20% of patients had benign tumours.
Pleomorphic sarcoma and liposarcoma were the predominant histotypes described in the included studies, and most sarcomas were located in the extremities.These findings are consistent with what has been reported worldwide (Fletcher et al., 2002a;Clark et al., 2005;Mankin and Hornicek, 2005).Interestingly, some of the sarcomas in the included studies were documented to have known or suspected causes, such as post-irradiated sinonasal pleomorphic sarcoma situated within the radiation field for previous nasopharyngeal carcinoma (Wang et al., 2009).However, most STS arise without an apparent cause (Fletcher et al., 2002a) and most included studies did not document causative factors.
Although we searched for studies from 10 representative Asia-Pacific countries, most of the studies included for review were from Australia, Korea, and Taiwan.As such, our findings may not be applicable to the entire Asia-Pacific region.A potential reason for this imbalance may include differences among countries in the availability of, or patient access to, specialist facilities that detect, diagnose, and treat STS (Sankaranarayanan and Swaminathan, 2011).Other demands on health resources, such as health tourism and the trade of health workers (Acuin et al., 2011), may influence the availability of these facilities.Also, patients in countries poorly resourced to treat STS may opt to go to another country, if possible, for treatment (Ng and Tan, 2009) or seek treatment from private providers.Another potential reason is that because sarcoma is rare, some countries may simply lack sufficient cases to publish meaningful findings on the outcomes of treating sarcoma.In addition, they may lack resources, infrastructure, and academically focused clinicians to conduct research and publish findings.Until such data become available, it is difficult to accurately comment on the quality of care delivered in those countries.
We acknowledge that there are several limitations with our study.First, as with any systematic review, relevant publications may have been inadvertently excluded despite a comprehensive literature search.Second, data from the included studies cannot be pooled for analysis because of the varied reporting of survival outcomes.In addition, the reported sarcoma grade and diagnosis may not be accurate because some studies reassessed pathology slides to confirm or reclassify diagnosis, whereas other studies simply reviewed patient records.Third, the strength of evidence was limited because all included studies had an observational study design with only 1 prospective study and because more than half of the studies had fewer than 50 patients even though studies with 10 or fewer patients were excluded.Last, few studies (5 of 32) reported safety outcomes and those that did mostly reported complications arising from surgery.With the increasing use of adjuvants, such as chemotherapy agents, for sarcoma treatment, monitoring and reporting safety outcomes is paramount.
Our review indicates that data about the treatment and management of patients with STS and their outcomes in the Asia-Pacific region are lacking.Among the included studies, survival outcomes and recurrence, when reported, differed and few reported safety outcomes.The treatment and management of STS requires a multidisciplinary approach; however, healthcare systems within and among Asia-Pacific countries are in various states of evolution (Chongsuvivatwong et al., 2011).This may have adverse consequences for patients by limiting the availability of, or access to, facilities that detect, diagnose, and treat STS.As such, we need to continually invest in collaborative efforts to better understand how STS affects patients within the Asia-Pacific region.By doing so, we will be able to better manage patients from diagnosis to follow-up and help improve survival outcomes and quality of life.

Figure 1 .
Figure 1.Flow Diagram of Literature Search Results. FIGO

Table 3 . Studies Reporting Findings from Patients with Primary and Recurrent Soft-tissue Sarcoma
Of the 24 patients, 21 died of causes related to soft-tissue sarcoma and 3 died of other causes *Abbreviations: AJCC, American Joint Committee on Cancer for STS staging system, 6 th edn; CT, chemotherapy; D, dead; DM, distant metastases; DSS, disease-specific survival; ext., extremities; FIGO, International Federation of Gynecology and Obstetrics for endometrial carcinoma, Vol 19; FNCLCC, Fédération Nationale des Centres de Lutte Contre le Cancer (National Federation of French Cancer Centres) grading system; ILI, isolated limb infusion; LR, local recurrence; max, maximum; min, minimum; NR, not reported; NS, not specified; OS, overall survival; PNST, peripheral nerve sheath tumour; po, postoperative; preop, preoperative; RT, radiotherapy; a Of the 27 patients, 25 died of causes related to soft-tissue sarcoma and 2 died of other causes; b Cytotoxic drugs used for ILI were melphalan 5-10 mg/L of tissue and actinomycin D 50-100 μg/L of tissue.From 1994 to 1996, 1 patient had melphalan and actinomycin D, 3 patients had mitomycin C at 5-20 mg in addition to melphalan, and 1 patient had mitomycin (10 mg), doxorubicin (25 mg), and cisplatin (50 mg).Seven patients had ILI only for either an inoperable recurrence or for palliation; c Of the 3 patients who had pelvic radiotherapy, 1 patient had an intravaginal boost using Ir-192 source; d Patients had combination chemotherapy consisting of dacarbazine, doxorubicin, cyclophosphamide and/or etoposide; e Chemotherapy agent not specified; f

Table 4 (continued). Studies Reporting Findings from Patients with Soft-tissue Sarcoma (primary or recurrent not specified)
*Abbreviations: AJCC, American Joint Committee on Cancer for STS staging system, 6th edn; BT, brachytherapy; CI, confidence interval; CT, chemotherapy; D, dead; DM, distant metastases; DSS, disease-specific survival; EBRT, external beam radiotherapy; ESS, endometrial stromal sarcoma; ext., extremities; FIGO, International Federation of Gynecology and Obstetrics for endometrial carcinoma, Vol 19; FNCLCC, Fédération Nationale des Centres de Lutte Contre le Cancer (National Federation of French Cancer Centres) grading system; LR, local recurrence; max, maximum; min, minimum; ND, not determined; NR, not reported; NS, not specified; OS, overall survival; PNST, peripheral nerve sheath tumour; po, postoperative; preop, preoperative; RT, radiotherapy; WHO, World Health Organization; a Chemotherapy agent not specified; b Follow-up data were available for 22 of the 25 patients; c Of the 16 patients, 14 died of causes related to soft-tissue sarcoma and 2 died of other causes; d Chemotherapy agents given were doxorubicin and ifosfamide; e One patient had etoposide, ifosfamide, cisplatin and 3 patients had doxorubicin, ifosfamide, cisplatin; f Chemotherapy agents were ifosfamide or a combination of vincristine, doxorubicin, cyclophosphamide, etopside, and ifosfamide or doxorubicin, ifosfamide, and cisplatin; g One patient was lost to follow up; h Patient died of causes unrelated to soft-tissue sarcoma; i Chemotherapy agents given were combinations of doxorubicin plus cisplatin/ doxorubicin plus ifosfamide; etoposide, adriamycin, and cyclophosphamide; ifosafamide, adriamycin, and cyclophosphamide; or adriamycin and cisplatin; j Because 4 publications