Single-Agent Doxorubicin Adjuvant Chemotherapy for Resectable Grade 2/3 Soft Tissue Sarcomas: A Retrospective Study

Introduction

Soft tissue sarcoma (STS) is an aggressive malignant tumor that accounts for 1% and 25% of all cancers in adults and children, respectively.^1,2 It is an umbrella diagnosis with more than 50 histological subtypes.^2,3 In Taiwan, the age-standardized incidence rate of STS is 5.62 per 100,000 person-years.⁴ Owing to the variety and relative rarity of the condition, there is limited clinical evidence regarding the best approach to care. Nonetheless, surgery with or without radiotherapy remains the standard first-line treatment for localized STS regardless of pathological subtype.² Distant recurrence or metastasis can occur in patients with unfavorable prognostic factors, including high-grade tumors, large tumor size, tumor depth, or certain histological subtypes such as leiomyosarcoma or synovial sarcoma.^5,6 

The utilization of adjuvant chemotherapy for STS in patients with unfavorable risk factors remains controversial in the literature.^{1,7, 8} In addition, limited research distinctly outlines the characteristics of patients with high-grade STS who would benefit from adjuvant chemotherapy. A previous study reported that the prognosis of STS varies significantly by tumor stage and subtype, highlighting the complexity and need for tailored treatment approaches.⁹ According to an annual report covering patients with STS from 2003 to 2011 at our institution, the 3-year distant failure rate markedly increased to 62% for grade 3 tumors of 8 cm or more. Accordingly, despite inconclusive data in the literature, our institution provides adjuvant chemotherapy with single-agent doxorubicin for these patients.

Therefore, this study aimed to determine whether adjuvant chemotherapy using single-agent doxorubicin provides a significant oncological advantage over observation alone in patients with resectable grade 2 and 3 STS, potentially guiding future treatment strategies for this high-risk group.

Methods

Study Design and Patient Selection

We performed a retrospective chart review of adult patients with biopsy-proven STS of the extremities and trunk between January 2004 and March 2020 at a tertiary center in Taiwan. The inclusion criteria were as follows: (1) grade 2 or 3 tumors based on the Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) histologic grading system; (2) tumor size of more than 8 cm; (3) tumor status of initial M0; and (4) previously received neoadjuvant chemotherapy. Grade 2 tumors were included in this study because they are considered intermediate grade under the FNCLCC system. Still, they may exhibit aggressive behavior when accompanied by high-risk features such as large size or deep location. Given this potential, their inclusion allows exploration of whether select intermediate-grade tumors may also benefit from adjuvant chemotherapy. Patients who had received neoadjuvant chemotherapy previously were excluded to minimize treatment heterogeneity and focus solely on the effect of postoperative (adjuvant) chemotherapy. At our institution, adjuvant chemotherapy was considered for patients with tumors measuring 8 cm or more, classified as FNCLCC grade 2 or 3, and with no evidence of metastasis at diagnosis (M0). Final decisions regarding adjuvant chemotherapy were made based on multidisciplinary tumor board recommendations, taking into account the patient’s performance status, comorbidities, and willingness to undergo treatment.

Ethics Statement

The investigators are committed to conducting this study in strict adherence to the current revision of the Declaration of Helsinki or in accordance with the regulations and guidelines of Good Clinical Practice, whichever provides greater protection to the participant. The study protocol was submitted to the Institutional Review Board of Chang Gung Memorial Hospital. Because this research involved a retrospective analysis of medical records, with no direct patient involvement and deidentification maintained throughout the process, the ethics committee of Chang Gung Memorial Hospital waived further approval and the requirement for patients’ informed consent.

Treatment Protocol

All patients underwent surgical resection, with or without adjuvant radiotherapy. Adjuvant radiotherapy was administered in cases of marginal surgery, microscopically incomplete resection, no further surgical options, or local recurrence. Adjuvant chemotherapy with single-agent doxorubicin was administered at a dose of more than 75 mg/m² for 3 to 6 cycles. The cumulative doxorubicin dose ranged from 225 to 450 mg/m², depending on the number of cycles completed, which was determined by the treating oncologist based on patient tolerance, comorbidities, and treatment response. Dose intensity was consistent with National Comprehensive Cancer Network (NCCN) guideline recommendations.

Study Variables and Outcome Measures

Patients’ characteristics, including sex, age, and adjuvant radiotherapy, were collected from medical charts. The histopathological subtype, surgical margins, grade, size, and depth of the tumors were obtained from pathology reports evaluated by pathologists with expertise in STS. Outcomes measured included distant metastasis–free survival (DMFS) and overall survival (OS). DMFS was calculated from the date of surgery to the date of the first distant metastasis diagnosed or censored at the date of the last follow-up assessment.

Statistical Analysis

Continuous data with a normal distribution were analyzed using Student’s t-test and are presented as the mean plus or minus standard deviation; continuous data without a normal distribution are presented as median (IQR) and were analyzed using the Wilcoxon rank-sum test. The normal distribution of variables was tested using the Shapiro-Wilk method. Categorical data were analyzed using the X² test or Fisher’s exact test as appropriate and are presented as n (%). HRs and 95% CIs were calculated using the Cox proportional hazards model to assess the associations among DMFS, OS, and treatment modality. Multivariable regression was adjusted for related variables of P value less than .10 in the univariate analysis. Kaplan-Meier analysis was performed using the log-rank test to compare OS and DMFS between the adjuvant chemotherapy and observation groups. Statistical significance was defined as a 2-sided P value of less than .05. All statistical analyses were performed using the SPSS software (version 22.0; IBM Corp; Armonk,
New York).

Results

Characteristics of the Patients

The patient demographics, tumor-related information, and outcomes are summarized in Table 1. Sixty-two patients were enrolled in this study; 8 were in the adjuvant chemotherapy and 54 were in the observation-only group, respectively. The mean age of patients in the adjuvant chemotherapy group was 45.4 years, and 62.5% were women. The mean age of the observation-only group was 58.2 years, and 35.2% of the patients were women (Table 1).

Patients who underwent adjuvant chemotherapy had lower mortality rates (0.0% vs 38.9%, P = .043) and distant metastasis (12.5% vs 51.9%, P = .057) than those in the observation-only group. The proportion of patients who received adjuvant radiotherapy was similar between groups (87.5% in the adjuvant chemotherapy group and 88.9% in the observation group, P = .910). (Table 1).

OS and DMFS

The OS and DMFS rates of patients with and without adjuvant chemotherapy are shown in Figures 1 and 2, respectively. The 3-year OS rate was 100% in the adjuvant chemotherapy group and 60% in the observation group (log-rank test, P = .064) (Figure 1). The 3-year DMFS rate was 75% for the adjuvant chemotherapy group and 45% for the observation-only group (log-rank test, P = .078) (Figure 2).

Associations Among Adjuvant Chemotherapy, OS, and DMFS

Table 2 shows the univariate and multivariable Cox regression analysis of the factors associated with OS and DMFS. Only covariates with a P value less than .10 in the univariate analysis were entered into the multivariable analysis.

Both univariate and multivariable analyses showed a tendency toward improved DMFS with adjuvant chemotherapy vs the observation-only group (HR, 0.20; 95% CI, 0.03-1.46, P = .113; adjusted HR, 0.17; 95% CI, 0.02-1.29, P = .087), although the difference did not reach statistical significance. In univariate analysis, adjuvant radiotherapy was not significantly associated with either OS or DMFS and was thus not included in multivariable models (Table 3).

Adjuvant Chemotherapy and DMFS in Node-Negative Patients

To further investigate the effect of treatment modality on DMFS, a subgroup analysis was conducted in patients who were node negative. Although, a similar trend favoring adjuvant chemotherapy was observed, the difference did not reach statistical significance (Table 3).

Discussion

In this retrospective study, patients with grade 2 and 3 STS (≥ 8 cm) who received single-agent doxorubicin as adjuvant chemotherapy appeared to have improved trends in OS and DMFS compared with those managed with observation alone; however, these differences did not reach statistical significance. A similar, nonsignificant trend was also observed in the subgroup of patients who were node negative, suggesting a potential, though unconfirmed, benefit of adjuvant single-agent doxorubicin in reducing distant metastasis among select high-risk individuals. Given the study’s retrospective nature and small sample size—particularly the limited number of patients who received adjuvant chemotherapy—these findings should be interpreted with caution. They are intended to be hypothesis-generating rather than conclusive, underscoring the need for larger, prospective studies to more definitively assess the role of adjuvant chemotherapy in this population.

STS is a rare, aggressive malignant tumor with more than 50 histological subtypes.^1-3 Despite the complexity of this disease, surgery with or without radiotherapy is the standard first-line treatment for localized disease, regardless of pathological subtype.² This is in contrast to Ewing sarcoma and rhabdomyosarcoma, for which chemotherapy remains essential.¹⁰ Patients with unfavorable risk factors may experience distant recurrence, and the mortality rate can reach 50%.^5,6 These risk factors were explored by Baldini et al, and they identified high-grade tumors, large tumor size, and certain histologic subtypes such as vascular tumors, leiomyosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors. These findings are consistent with those of Byun et al, with the addition of tumors located deep in the investing fascia as another factor.⁶

The use of chemotherapy in patients with distant recurrence and its role in improving survival rates in high-grade STS remains controversial in the literature. With the exception of Ewing sarcoma and rhabdomyosarcoma, for which perioperative chemotherapy is a necessary component of the standard of care, adjuvant chemotherapy is not routinely implemented.⁵ Randomized controlled trials and meta-analyses in the current literature have suggested that adjuvant chemotherapy may provide an advantage compared with surgery alone.^1,6 The advantages include superior locoregional outcomes, minimizing prospective functional loss of the affected limb, and decreasing the risk of amputation.⁶ Baldini et al suggested that adjuvant chemotherapy is reasonable for patients with STS tumors that are intermediate or high grade, with a size of 5 cm or more.⁵

However, the use of adjuvant chemotherapy in patients with resectable STS remains controversial. The data are diverse, and interpretation is confounded by issues that include the small size of individual trials, identification of a suitable high-risk population, the chemotherapy regimen, and heterogeneity with respect to the chemosensitivity of the tumor types included in different studies. The Sarcoma Meta-Analysis Collaboration systematically analyzed data on adjuvant doxorubicin-based chemotherapy regimen for localized STS and showed that adjuvant chemotherapy significantly improved local (HR, 0.73; 95% CI, 0.56-0.94, P = .016) and distant (HR, 0.70; 95% CI, 0.57-0.85, P = .0003) recurrence-free intervals.¹¹ However, there were no significant differences in OS.¹¹ The limitations of that study included strong heterogeneity and weak chemotherapy strength (doxorubicin dose 50-70 mg/m²) because granulocyte colony-stimulating factor was not used.^1,12 The European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group performed the largest single study to date involving 351 patients randomly assigned to no chemotherapy or adjuvant chemotherapy (5 cycles of doxorubicin at 75 mg/m² plus ifosfamide at 5 g/m²).¹² The study demonstrated no benefits of adjuvant chemotherapy in relapse-free survival (HR, 0.91; 95% CI, 0.67-1.22, P = .51) or OS (HR, 0.94; 95% CI, 0.68-1.31, P = .72) compared with no chemotherapy. A similar 5-year OS rate (66.5% vs 67.8%) was observed between the adjuvant chemotherapy and no chemotherapy groups.¹² Similar to our study, there was a trend toward better OS in the adjuvant chemotherapy group, but the difference was not statistically significant.

Patients who underwent neoadjuvant chemotherapy were excluded from the current study. The potential goals of neoadjuvant chemotherapy include reducing the local recurrence rate of marginally resectable tumors, decreasing distant recurrence and mortality, and reducing radiation exposure.^5,13 The advantages of neoadjuvant chemotherapy include a lower overall radiation dose, reduced treatment volume, and increased tissue sparing compared with the adjuvant approach.⁶ The only randomized clinical trial comparing surgery and preoperative neoadjuvant chemotherapy with doxorubicin and ifosfamide indicated no superiority of neoadjuvant chemotherapy to non-neoadjuvant chemotherapy (5-year DFS, 52% for no chemotherapy and 56% for chemotherapy, P = .3548; 5-year OS, 64% and 65%, respectively, P = .220).¹⁴

Although previous studies have demonstrated higher response rates to chemotherapy using a combination regimen compared with a single ifosfamide regimen,¹⁵ these studies failed to demonstrate any survival benefit.¹⁶ A combination of greater than 75 mg/m² doxorubicin plus greater than 9 g/m² ifosfamide is the generally accepted regimen for neoadjuvant chemotherapy.⁵ This was further reinforced by the recommended regimen for neoadjuvant and adjuvant chemotherapy for STS according to the latest guidelines proposed by the NCCN, version 2.2021.¹⁷

Doxorubicin remains one of the most effective agents for the treatment of STS.¹⁸ A doxorubicin dose of 75 mg/m² has been identified as the most appropriate dose for otherwise healthy patients, both as a single agent and in combination therapy.¹⁹ Higher doses of doxorubicin have been described, but results regarding the efficacy of doses higher than 75 mg/m² are equivocal.²⁰ Higher doses are rarely used because of the increased risk of toxicity and lack of demonstrated benefits.¹⁹ Similarly, ifosfamide has been used to treat sarcomas. However, its widespread use is limited by the incidence of hemorrhagic cystitis and renal dysfunction. Mesna, a compound that detoxifies the acrolein metabolite of ifosfamide and prevents bladder toxicity, was later discovered and allowed for additional studies and subsequent widespread use of the drug.²⁰ 

In 2012, the EORTC conducted a large randomized study comparing the outcomes of doxorubicin 75 mg/m² with those of doxorubicin 75 mg/m² plus ifosfamide 10 g/m² as the first-line treatment for metastatic or unresectable STS.²¹ Response rates were 26% and 14% in combination therapy and single-agent doxorubicin arms, respectively. Progression-free survival (PFS) was significantly improved in the combination arm (7.4 months vs 4.6 months). OS was better in the combination arm (12.8 months vs 14.3 months); however, the difference was not statistically significant (P = .076).²² The results of that study seem to support and oppose the use of single-agent doxorubicin over combination therapy. Viewpoints in favor of single-agent treatment included decreased toxicity to the patient and the absence of a statistically significant improvement in OS. In contrast, viewpoints in favor of combination therapy indicate improved PFS and response rates. Given that doxorubicin is readily available and commonly used as the standard treatment for STS at our institution, and considering our priority to minimize toxicity, especially for patients with high comorbidity burdens or low performance status, single-agent doxorubicin was chosen as the adjuvant chemotherapy regimen in this study.

Strengths and Limitations

Despite the small sample size, this study offers some exploratory insights into the use of single-agent doxorubicin in a high-risk STS population. First, it focuses on patients with resectable grade 2 and 3 STS measuring 8 cm or more—a high-risk group that remains understudied despite their increased likelihood of distant metastasis and poor prognosis. By specifically evaluating single-agent doxorubicin as adjuvant chemotherapy in an Asian population, this study provides valuable regional data, addressing the gap in evidence for non-Western cohorts where treatment responses and tolerability may differ due to genetic and environmental factors. Second, the study leverages real-world clinical data from a tertiary center with a long study period (2004-2020), ensuring that outcomes reflect contemporary treatment practices. Lastly, by focusing on single-agent doxorubicin, this study isolates the effect of a widely used but debated treatment regimen, contributing to the ongoing discussion regarding optimal adjuvant chemotherapy strategies for these patients.

This study has several limitations that should be considered when interpreting the findings. First, the single-institution setting may limit the generalizability of the results, as treatment protocols, patient selection, and institutional expertise may differ across centers. Second, the small sample size—particularly in the adjuvant chemotherapy group—reduces statistical power. With only 8 patients receiving single-agent doxorubicin, the ability to detect significant differences in OS and DMFS is limited. Third, there was a notable age difference between groups, with patients in the adjuvant chemotherapy group being, on average, 13 years younger than those in the observation group. Age is a known prognostic factor in STS, with younger patients generally experiencing better outcomes. Although age was not statistically significant in our multivariable analysis, the limited sample size may have reduced the power to detect its effect, and the observed survival benefit may be partially attributable to this imbalance. Fourth, the retrospective design introduces inherent biases, including potential selection and information bias. Treatment decisions were not randomized but influenced by clinician judgment, patient preference, and institutional protocols, and the reliance on medical records may have resulted in incomplete or inconsistent data. Additionally, the 8-cm cutoff was chosen based on retrospective data from our institution, which demonstrated a notable increase in distant recurrence rates among patients with tumors 8 cm or greater. However, we acknowledge that other trials, such as those by Gronchi et al,²³ have used a 5-cm cutoff. Future studies using broader inclusion criteria may help to validate and extend our findings. In addition, the classification of tumor grade evolved over the study period. Prior to 2010, some pathology reports used the designation “high grade, not otherwise specified” rather than FNCLCC grades 1 to 3. This could suggest that patients in the observation group were treated earlier in the study period compared with those in the adjuvant chemotherapy group, introducing potential era-related confounding factors such as advances in imaging, surgical techniques, and supportive care. This temporal heterogeneity may have influenced oncologic outcomes. Another limitation is the absence of toxicity data, including cardiotoxicity, which is particularly relevant given the use of doxorubicin. Due to the retrospective nature of this study and limited documentation in medical records, comprehensive data on adverse events, including left ventricular ejection fraction monitoring and symptomatic heart failure, were unavailable. Finally, the study lacks long-term follow-up beyond the reported 3-year survival outcomes. Extended observation is necessary to evaluate the durability of treatment effects, capture late recurrences, and assess potential long-term adverse effects of chemotherapy.

In the future, prospective randomized controlled trials or balanced cohorts will be essential to minimize bias and establish a clear causal relationship between adjuvant chemotherapy and oncologic outcomes in high-grade STS, alongside comprehensive monitoring of adverse events. Additionally, molecular profiling may help refine personalized treatment strategies and improve patient selection.

Conclusions

This single-center retrospective study suggests a potential trend favoring adjuvant chemotherapy with single-agent doxorubicin to improve OS and DMFS among patients with high-grade STS greater than 8 cm. In addition, adjuvant chemotherapy may have potential benefits in improving DMFS among node-negative patients. Further well-designed prospective studies with larger sample sizes are warranted before a consensus can be reached regarding the integration of this chemotherapy protocol in these patients.

References

1. Tanaka K, Ozaki T. Adjuvant and neoadjuvant chemotherapy for soft tissue sarcomas: JCOG Bone and Soft Tissue Tumor Study Group. Jpn J Clin Oncol. 2021;51(2):180-184. doi:10.1093/jjco/hyaa231
2. Du XH, Wei H, Zhang P, Yao WT, Cai QQ. Heterogeneity of soft tissue sarcomas and its implications in targeted therapy. Front Oncol. 2020;10:564852. doi:10.3389/fonc.2020.564852
3. WHO Classification of Tumours Editorial Board, eds. Soft Tissue and Bone Tumours. 5th ed. International Agency for Research on Cancer; 2020. WHO Classification of Tumours, vol 3.
4. Hung GY, Horng JL, Chen PC, et al. Incidence of soft tissue sarcoma in Taiwan: A nationwide population-based study (2007-2013). Cancer Epidemiol. 2019;60:185-192. doi:10.1016/j.canep.2019.04.007
5. Baldini EH, Le Cesne A, Trent JC. Neoadjuvant chemotherapy, concurrent chemoradiation, and adjuvant chemotherapy for high-risk extremity soft tissue sarcoma. Am Soc Clin Oncol Educ Book. 2018;38:910-915. doi:10.1200/EDBK_201421
6. Byun DJ, Katz LM, Xiao J, et al. Modern management of high-risk soft tissue sarcoma with neoadjuvant chemoradiation: a single-center experience. Am J Clin Oncol. 2021;44(1):24-31. doi:10.1097/COC.0000000000000772
7. Zaidi MY, Ethun CG, Tran TB, et al. Assessing the role of neoadjuvant chemotherapy in primary high-risk truncal/extremity soft tissue sarcomas: an analysis of the multi-institutional U.S. Sarcoma Collaborative. Ann Surg Oncol. 2019;26(11):3542-3549. doi:10.1245/s10434-019-07639-7
8. Li XF, Ma RQ, Wu X, Gan L, Peng ZY, Qian J. Adjuvant therapy for orbital non-rhabdomyosarcoma soft tissue sarcoma: comparison of long-term outcome between radiotherapy and chemotherapy. Int J Ophthalmol. 2023;16(3):402-410. doi:10.18240/ijo.2023.03.11
9. Liu H, Zhang H, Zhang C, et al. Pan-soft tissue sarcoma analysis of the incidence, survival, and metastasis: a population-based study focusing on distant metastasis and lymph node metastasis. Front Oncol. 2022;12:890040. doi:10.3389/fonc.2022.890040
10. Le Cesne A, Ouali M, Leahy MG, et al. Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials. Ann Oncol. 2014;25(12):2425-2432. doi:10.1093/annonc/mdu460
11. Sarcoma Meta-Analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet. 1997;350(9092):1647-1654.
12. Woll PJ, Reichardt P, Le Cesne A, et al; EORTC Soft Tissue and Bone Sarcoma Group and the NCIC Clinical Trials Group Sarcoma Disease Site Committee. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol. 2012;13(10):1045-1054. doi:10.1016/S1470-2045(12)70346-7
13. Tanaka K, Mizusawa J, Fukuda H, et al. Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities (JCOG0304). Jpn J Clin Oncol. 2015;45(6):555-561. doi:10.1093/jjco/hyv042
14. Gortzak E, Azzarelli A, Buesa J, et al; E.O.R.T.C. Soft Tissue Bone Sarcoma Group and the National Cancer Institute of Canada Clinical Trials Group/Canadian Sarcoma Group. A randomised phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer. 2001;37(9):1096-1103. doi:10.1016/s0959-8049(01)00083-1
15. Borden EC, Amato DA, Rosenbaum C, et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol. 1987;5(6):840-850. doi:10.1200/JCO.1987.5.6.840
16. Edmonson JH, Ryan LM, Blum RH, et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993;11(7):1269-1275. doi:10.1200/JCO.1993.11.7.1269
17. NCCN. Clinical Practice Guidelines in Oncology. Soft tissue sarcoma, version 2.2021. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
18. O’Bryan RM, Baker LH, Gottlieb JE, et al. Dose response evaluation of adriamycin in human neoplasia. Cancer. 1977;39(5):1940-1948. doi:10.1002/1097-0142(197705)39:5<1940::aid-cncr2820390505>3.0.co;2-0
19. Ratan R, Patel SR. Chemotherapy for soft tissue sarcoma. Cancer. 2016;122(19):2952-2960. doi:10.1002/cncr.30191
20. Benjamin RS, Legha SS, Patel SR, Nicaise C. Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M.D. Anderson experience. Cancer Chemother Pharmacol. 1993;31(suppl 2):S174-S179.
21. Judson I, Verweij J, Gelderblom H, et al; European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415-423. doi:10.1016/S1470-2045(14)70063-4
22. Gronchi A, Palmerini E, Quagliuolo V, et al. Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: final results of a randomized trial from Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups. J Clin Oncol. 2020;38(19):2178-2186. doi:10.1200/JCO.19.03289

Consent for Publication

All authors have reviewed the manuscript and consent to its publication.

Data Availability

The data sets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Funding

None

Competing Interests

The authors have declared that no competing interests exist.

Authors’ Contributions

Shiny Chih-Hsuan Wu: Conception and design; acquisition of data; analysis and interpretation of data; supervision

Yao-Yu Wu: Acquisition of data; critical revision of the manuscript; final approval of the manuscript; drafting of the manuscript; literature research

Chi-Ting Liau: Analysis and interpretation of data; final approval of the manuscript; literature research

Chih‑Hsiang Chang: Acquisition of data; final approval of the manuscript; drafting of the manuscript; drafting of the manuscript; clinical studies

Shih-Chiang Huang: Acquisition of data; critical revision of the manuscript; final approval of the manuscript; definition of intellectual content

Hsin‑Nung Shih: Conception and design; critical revision of the manuscript; final approval of the manuscript

Chun-Chieh Chen: Conception and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript; final approval of the manuscript; statistical analysis; clinical studies

Corresponding author

Chun-Chieh Chen

Address: New Taipei Municipal TuCheng Hospital (Built and Operated by Chang Gung Medical Foundation), No. 6, Sec. 2, Jincheng Road, Tucheng District, New Taipei City 236, Taiwan

Telephone: 886-2-22630588, ext. 6179

Fax: 886-2-82731845

Email: ms8614@gmail.com