Veroniek M. van Praag1, Anja J. Rueten-Budde2, Marta Fiocco2, Michiel A.J. van de Sande1 1
Dept. Of Orthopaedic Surgery, Leiden, Leiden University Medical Centre, the Netherlands 2Mathematical Institute, Leiden University, Leiden, the Netherlands
[email protected]
PERSARC Dynamic survival prediction for high-grade STS: Model design and external validation Purpose
Design & internal validation
External validation
Number of patients at risk at each landmark time point
Number of patients at risk at each landmark time point
In the figure above, an overview is given of the number of patients used at each landmark time point. In total 1034 patients died, 143 patients developed a local recurrence (LR), 556 a distant metastasis (DM), and 159 both.
An overview of the number of patients used at each landmark time point is given in the figure above. In total 540 patients died, 270 patients developed LR, 575 DM and 137 developed both.
Develop and externally validate a model with updated predictions of overall survival at different times during follow-up for high-grade soft tissue sarcomas (STS).
Calibration plots The plots on the left, show how well the model fits on the external data. Top plot is for the prediction made two years postop. (C-index 0.80). The bottom plot shows the prediction made 5-years postop. (C-index 0.83).
10.0
Time-varying hazard ratio for surgical margin Blue: R0 margin Red: R1-2 margin (ref)
5.0
271 (14) 93 (4.8) 176 (9.1) 237 (12.2) 24 (1.2) 190 (9.8) 942 (48,7) 340 (17.6) 1593 (82.4) 844 (43.6) 177 (9.2) 912 (47.2) -
2.0
432 (19.4) 167 (7.5) 277 (12.4) 108 (4.8) 492 (22.0) 604 (27.1) 152 (6.8) 274 (12.3) 1890 (84.7) 68 (3.0) 1004 (45) 265 (11.9) 916 (41) 47 (2.1)
1.0
56.01 (17.27) 1039 (53.8) 8.76 (5.98) 1411 (73) 522 (27) -
Hazard ratio
60.86 (18.74) 1203 (53.9) 8.95 (5.85) 1269 (56.9) 551 (24.7) 412 (18.4)
0.5
Age mean (sd) Male (%) Tumour size in cm mean (sd) Tumour depth deep (%) Superficial Unknown Histological type (%) Myxofibrosarcoma MPNST Synovial sarcoma Sarcoma – NOS Spindle cell sarcoma MFH/UPS Other Margin, R1-2 (%) R0 Unknown Radiotherapy, adjuvant (%) Neo-adjuvant No Unknown
MODELLING & EXTERNAL INT. VALIDATION VALIDATION 2232 PATIENTS 1933 PATIENTS
R0
Predictions seem to underestimate survival in general, which is indicated by groups laying mostly above the dotted line (which represents perfect prediction).
R1−2
0.2
PATIENT- AND TUMOUR CHARACTERISTICS
0
1
2
3
4
5
Prediction time in years since surger y
Surgical margin shows a significant time-varying effect. The effect of margin is strongest shortly after surgery and fades slightly over time (see figure directly above).
Discussion Development of local recurrences (LR) and distant metastases (DM) has a strong effect on overall survival: updated predictions must account for this. Other strong predictors are survival time after surgery, histological type, age, tumour depth and surgical margin, in that order. Surgical margin and histological type show a significant time-varying effect on overall survival.
Survival differs between histological types The figures below show the survival curves of two fictive patients. Both developed a distant metastasis. On the left, a 61-year-old patient that had a 9 cm. deep-seated tumour, treated with surgical resection with an R0 margin without radiotherapy.
Between both cohorts duration of follow-up differs. This might explain the underestimation of survival, which is higher in the external validation cohort with shorter follow-up.
Conclusions The high dynamic C-indices indicate a very good discrimination between high-risk and low-risk patients, which is achieved by taking adverse events such as LR and DM at prediction time point into account. Individualised dynamic prognostication for STS patients will be implemented in the new PERSARC model, that will soon be available as a mobile app and through the LUMC website.
PERsonalised SARcoma Care study group PERSARC Dario Callegaro, Alessandro Gronchi, Andrew Hayes, Jay S Wunder, Lee M Jeys, Minna K Laitinen, Rob Pollock, Will Aston, Jos A van der Hage, Peter C Ferguson, Anthony M Griffin, Julie J Willeumier, Emelie Styring, Henry Smith, Dirk Strauss, M. Fiore, Florian Posch, Olga Zaikova, Katja Maretty-Kongstad, Johnny Keller, Andreas Leithner, Maria A Smolle, Rick L Haas, Cees Verhoef, Han Bonekamp, Winan van Houdt, Robert-Jan van Ginkel, PD Sander Dijkstra
On the right, a 45-year-old patient that had a 5 cm. superfiscial tumour, treated with surgical resection with an R0 margin and postoperative radiotherapy.
