title: Can Multistate Modeling of Local Recurrence, Distant Metastasis, and Death Improve the Prediction of Outcome in Patients With Soft Tissue Sarcomas?
abstract: BACKGROUND
  Exploration of the complex relationship between prognostic indicators such as tumor grade and size and clinical outcomes such as local recurrence and distant metastasis in patients with cancer is crucial to guide treatment decisions. However, in patients with soft tissue sarcoma, there are many gaps in our understanding of this relationship. Multistate analysis may help us in gaining a comprehensive understanding of risk factor-outcome relationships in soft tissue sarcoma, because this methodology can integrate multiple risk factors and clinical endpoints into a single statistical model. To our knowledge, no study of this kind has been performed before in patients with soft tissue sarcoma.
  
  
  OBJECTIVE
  We implemented a multistate model of localized soft tissue sarcoma to statistically evaluate the relationship among baseline risk factors, recurrence, and death in patients with localized soft tissue sarcoma undergoing curative surgery.
  
  
  METHODS
  Between 1998 and 2015, our center treated 539 patients for localized soft tissue sarcoma with surgery as curative intent. Of those, 96 patients (18%) were not included in this single-center retrospective study owing to missing baseline histopathology data (n = 3), not yet observed followup (n = 80), or because a neoadjuvant treatment approach in the presence of synchronous distant metastasis was used (n = 13), leaving 443 patients (82%) for the current analysis, of which 40 were lost to followup during the first year after surgery. All patients had tumors of the stages I to III according to the American Joint Committee on Cancer Stages. The median age of the patients was 62 years (range, 16-96 years), and 217 patients (49%) were female. Three hundred-forty-six patients (78%) had tumors of high grade (Grades 2 and 3), and 310 (70%) tumors were greater than 5 cm in maximum diameter. Patients who had died during the first year of followup were included in this analysis. Median followup for the 443 study patients was 6 years, with 84%, 52%, and 23% of patients being followed for more than 1, 5, and 10 years, respectively. The 15-year cumulative incidences of local recurrence, distant metastasis, and death from any cause, using a competing risk analysis, were 16% (95% CI, 11%-22%), 21% (95% CI, 17%-26%), and 55% (95% CI, 44%-67%), respectively. Wide resection with a margin of 1 mm was the preferred treatment for all patients, except for those with Grade 1 liposarcoma where a marginal resection was considered adequate. Multistate models were implemented with the mstate library in R.
  
  
  RESULTS
  In multistate analysis, patients who experienced a local recurrence were more likely to have distant metastasis develop (hazard ratio [HR] = 8.4; 95% CI, 4.3-16.5; p < 0.001), and to die (HR = 3.4; 95% CI, 2.1-5.6; p < 0.001). The occurrence of distant metastasis was associated with a strong increase in the risk of death (HR = 12.6; 95% CI, 8.7-18.3; p < 0.001). Distant metastasis occurring after a long tumor-free interval was not associated with a more-favorable prognosis with respect to mortality than distant metastasis occurring early after surgery (estimated relative decrease in the adverse effect of distant metastasis on mortality for 1-year delay in the occurrence of distant metastasis = 0.9; 95% CI, 0.7-1.1; p = 0.28). High-grade histology (Grades 2 and 3) was associated with a higher risk of overall recurrence (defined as a composite of local recurrence and distant metastasis, HR = 3.8; 95% CI, 1.8-7.8; p = 0.0003) and a higher risk of death after recurrence developed (HR = 4.4; 95% CI, 1.1-18.2; p = 0.04). Finally, the multistate model predicted distinct outcome patterns depending on baseline covariates and how long a patient has remained free from recurrence after surgery.
  
  
  CONCLUSIONS
  In patients with localized soft tissue sarcoma undergoing resection, the occurrence of local recurrence and distant metastasis contributes to a dramatically impaired long-term survival outcome. Local recurrences are a substantial risk factor for distant metastasis. Multistate modeling is a very powerful approach for analysis of sarcoma cohorts, and may be used in the future to obtain highly personalized, dynamic predictions of outcomes in patients with localized soft tissue sarcoma.
  
  
  METHODS
  Level III, therapeutic study.
authors.affiliation: Clinical Division of Medical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Posch
authors.affiliation: Department of Orthopedic Surgery, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Leitner
authors.affiliation: Department of Orthopedic Surgery, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria.
authors.forename: Marko
authors.initials: M
authors.lastname: Bergovec
authors.affiliation: Clinical Division of Medical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
authors.forename: Angelika
authors.initials: A
authors.lastname: Bezan
authors.affiliation: Clinical Division of Medical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Stotz
authors.affiliation: Clinical Division of Medical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
authors.forename: Armin
authors.initials: A
authors.lastname: Gerger
authors.affiliation: Clinical Division of Medical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.affiliation: Clinical Division of Medical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Stöger
authors.affiliation: Center for Biomarker Research in Medicine, Medical University of Graz, Graz, Austria.|Institute of Pathology, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Liegl-Atzwanger
authors.affiliation: Department of Orthopedic Surgery, Comprehensive Cancer Center Graz, Medical University of Graz, Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leithner
authors.affiliation: Clinical Division of Medical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria. joanna.szkandera@medunigraz.at.
authors.forename: Joanna
authors.initials: J
authors.lastname: Szkandera
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001317:Austria; D003661:Decision Support Techniques; D018450:Disease Progression; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012509:Sarcoma / Q000401:mortality / Q000556:secondary* / Q000601:surgery*; D012983:Soft Tissue Neoplasms / Q000401:mortality / Q000473:pathology* / Q000601:surgery*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult