Real-World-Time Data and RCT Synergy: Advancing Personalized Medicine and Sarcoma Care through Digital Innovation
Abstract
:Simple Summary
Abstract
1. Introduction
2. Real-World/Time Data/Evidence: Foundations and Future
3. Enhancing Healthcare Insights through Prospective RWTD/E
4. Methodological Advancements in RWTD/E
5. RWTD/E in Informing Healthcare Policy and Practice
6. Case Studies and Practical Applications of RWTD/E
7. Future Directions
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A. The SSN-Minimal Data Set (SSN-MDS) Includes the Basic Parameters of Sarcoma Patient Care, Which Allow Data Harmonization over the Geography and Across Institutions
Institution | free field |
Pat ID | number |
Gender (M/F) | [0] male [1] female |
Date of birth | DD/MM/YY |
Affected tissue | [0] Superficial Soft Tissue [1] Deep Soft Tissue (according to the investing fascia; note that a tumor located superficially but invading the investing fascia should be recorded as deep) [2] Bone |
Site of lesion | [0] Foot [1] Distal lower limb below knee—anterior compartment [2] Distal lower limb below knee—lateral compartment [3] Distal lower limb below knee—posterior compartment [4] Distal lower limb below knee—more than one compartment [5] Popliteal fossa/knee [6] Proximal lower limb at or above knee—anterior compartment [7] Proximal lower limb at or above knee—posterior compartment [8] Proximal lower limb at or above knee—more than one compartment [9] Buttocks and inguinal region [10] Hand [11] Distal upper limb below elbow—ventral compartment [12] Distal upper limb below elbow—dorsal compartment [13] Distal upper limb below elbow—more than one compartment [14] Elbow [15] Proximal upper limb at or above the elbow—ventral compartment [16] Proximal upper limb at or above the elbow—dorsal compartment [17] Proximal upper limb at or above the elbow—more than one compartment [18] Axilla/scapula [19] Head and neck [20] Chest wall [21] Abdominal wall [22] Paraspinal [23] Retroperitoneal [24] Uterus [25] Other visceral [26] Intrathoracic [0] C-spine [27] T-spine [28] L-spine [29] Sacrum [30] Scapula [31] Prox humerus [32] Mid humerus [33] Dist humerus [34] Prox forearm [35] Mid forearm [36] Dist forearm [37] Carpus [38] Hand [39] Clavicle [40] Post pelvis [41] Acetabulum [42] Ant pelvis [43] Prox femur [44] Mid femur [45] Dist femur [46] Prox tibia [47] Mid tibia [48] Dist tibia [49] Fibula [50] Foot |
Disease Status @ diagnosis | [0] Localized disease [1] Oligometastatic disease (5 or less lesions) [2] Polymetastatic disease (6 and more lesions) |
Date of index surgery | DD/MM/YY |
Type of index surgery | [0] Previous inadvertent excision; no re-excision [1] Re-excision after previous primary inadequate resection [2] Primary surgery without soft tissue reconstruction [3] Primary surgery with soft tissue reconstruction [4] Primary surgery without bone reconstruction [5] Primary surgery with bone reconstruction [6] Primary surgery with bone and soft tissue reconstruction |
Margin status | [0] R0 [1] R1 [2] R2 [3] unknown |
Tumor maximal size (cm) | If patients has undergone preoperative Tx, please record the largest diameter either pre or post the preop therapy |
Date of histological diagnosis | DD/MM/YY |
Histological diagnosis | [0] Angiosarcoma of soft tissues [1] Atypical chondromatous tumor [2] Atypical lipomatous tumor/well differentiated liposarcoma [3] Chondrosarcoma [4] Conventional osteosarcoma [5] Dedifferentiated liposarcoma [6] Desmoid-type fibromatosis [7] Ewing sarcoma [8] Giant cell tumor of bone [9] GIST [10] Intramuscular myxoma [incl. variants] [11] Leiomyosarcoma [excluding skin] [12] Myxofibrosarcoma [13] Myxoid liposarcoma [14] Pleomorphic liposarcoma [15] Solitary fibrous tumor [16] Synovial sarcoma [17] Tenosynovial giant cell tumor [18] Undifferentiated/unclassified sarcoma |
If other, please specify | Free text |
Grading (FNCLCC) | [0] Grade 1 (Low grade): Total score 3–5 [1] Grade 2 (Intermediate grade): Total score 6–7 [2] Grade 3 (High grade): Total score 8–9 [3] Unknown [4] None available |
Chemotherapy (index) | [0] No therapy [1] Neoadjuvant (localized disease) [2] Preoperative (metastatic) [3] Adjuvant (localized) [4] Postoperative (metastatic) [5] Palliative intent: treatment pressure |
Radiotherapy (index; type of administration) | [0] Preoperative [1] Postoperative [2] Pre- and postoperative [3] IORT [4] Brachytherapy [5] Preoperative + IORT [6] Preoperative + brachytherapy [7] IORT + postoperative [8] Brachytherapy + postoperative [9] IORT + postoperative [10] Brachytherapy + postoperative operative [11] In combination with hyperthermia [12] None |
Radiotherapy (index; schedule) | [0] Normofractionated 25 × 2 Gy [1] Hypofractionated 15 × 3 Gy [2] Ultrahypofractionated 5 × 5 Gy [3] Other |
Date of 1st local recurrence | DD/MM/YY; otherwise “none” |
Treatment of 1st LR | [0] Surgery [1] Chemotherapty [2] Radiotherapy [3] Surgery + Radiotherapy [4] Surgery + Chemotherapty [5] Surgery + Chemotherapty + Radiotherapy [7] Radiotherapy + Chemotherapty [6] Best supportive care |
Date of 1st LR surgery | DD/MM/YY |
Date of 2nd LR | DD/MM/YY |
Treatment of 2nd LR | [0] Surgery [1] Chemotherapty [2] Radiotherapy [3] Surgery + Radiotherapy [4] Surgery + Chemotherapty [5] Surgery + Chemotherapty + Radiotherapy [7] Radiotherapy + Chemotherapty [6] Best supportive care |
Date of 2nd LR surgery | DD/MM/YY |
Date of pulmonary metastasis | DD/MM/YY; otherwise “none” |
Date of extrapulmonary metastasis | DD/MM/YY; otherwise “none” |
Site of extrapulmonary metastasis | free field |
Treatment of metastasis | [0] Surgery [1] Chemotherapty [2] Radiotherapy [3] Surgery + Radiotherapy [4] Surgery + Chemotherapty [5] Surgery + Chemotherapty + Radiotherapy [7] Radiotherapy + Chemotherapty [6] Best supportive care |
Date of last follow-up | DD/MM/YY |
Status | [0] NED (no evidence of disease) [1] AWD (alive with disease) [2] DOD (dead of disease) [3] DOC (dead of other causes) |
References
- Schmitt-Egenolf, M. The Disruptive Force of Real-World Evidence. J. Clin. Med. 2023, 12, 4026. [Google Scholar] [CrossRef] [PubMed]
- Mahon, P.; Hall, G.; Dekker, A.; Vehreschild, J.; Tonon, G. Harnessing oncology real-world data with AI. Nat. Cancer 2023, 4, 1627–1629. [Google Scholar] [CrossRef] [PubMed]
- Penberthy, L.T.; Rivera, D.R.; Lund, J.L.; Bruno, M.A.; Meyer, A.M. An overview of real-world data sources for oncology and considerations for research. CA Cancer J. Clin. 2022, 72, 287–300. [Google Scholar] [CrossRef] [PubMed]
- Chaturvedi, R.R.; Angrisani, M.; Troxel, W.M.; Gutsche, T.; Ortega, E.; Jain, M.; Boch, A.; Kapteyn, A. American Life in Realtime: A benchmark registry of health data for equitable precision health. Nat. Med. 2023, 29, 283–286. [Google Scholar] [CrossRef] [PubMed]
- Jiang, P.; Sinha, S.; Aldape, K.; Hannenhalli, S.; Sahinalp, C.; Ruppin, E. Big data in basic and translational cancer research. Nat. Rev. Cancer 2022, 22, 625–639. [Google Scholar] [CrossRef] [PubMed]
- Saesen, R.; Lacombe, D.; Huys, I. Real-world data in oncology: A questionnaire-based analysis of the academic research landscape examining the policies and experiences of the cancer cooperative groups. ESMO Open Cancer Horiz. 2023, 8, 100878. [Google Scholar] [CrossRef] [PubMed]
- Saesen, R.; Van Hemelrijck, M.; Bogaerts, J.; Booth, C.M.; Cornelissen, J.J.; Dekker, A.; Eisenhauer, E.A.; Freitas, A.; Gronchi, A.; Hernán, M.A.; et al. Defining the role of real-world data in cancer clinical research: The position of the European Organisation for Research and Treatment of Cancer. Eur. J. Cancer 2023, 186, 52–61. [Google Scholar] [CrossRef]
- Sweeney, S.M.; Hamadeh, H.K.; Abrams, N.; Adam, S.J.; Brenner, S.; Connors, D.E.; Davis, G.J.; Fiore, L.D.; Gawel, S.H.; Grossman, R.L.; et al. Challenges to using big data in cancer. Cancer Res. 2023, 83, 1175–1182. [Google Scholar] [CrossRef]
- Abernethy, A. Time for real-world health data to become routine. Nat. Med. 2023, 29, 1317. [Google Scholar] [CrossRef] [PubMed]
- Booth, C.M.; Karim, S.; Mackillop, W.J. Real-world data: Towards achieving the achievable in cancer care. Nat. Rev. Clin. Oncol. 2019, 16, 312–325. [Google Scholar] [CrossRef]
- Pizzi, L.T.; Willke, R.J. EUreCCA 2025: A Multistakeholder Effort to Further Real-World Evidence in Healthcare Decision Making. Value Health 2023, 26, 1–2. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.G.; Honerlaw, J.P.; Maripuri, M.; Samayamuthu, M.J.; Beaulieu-Jones, B.R.; Baig, H.S.; L’Yi, S.; Ho, Y.L.; Morris, M.; Panickan, V.A.; et al. Potential pitfalls in the use of real-world data for studying long COVID. Nat. Med. 2023, 29, 1040–1043. [Google Scholar] [CrossRef] [PubMed]
- Concato, J.; Corrigan-Curay, J. Real-World Evidence—Where Are We Now? N. Engl. J. Med. 2022, 386, 1680–1682. [Google Scholar] [CrossRef] [PubMed]
- Collins, R.; Bowman, L.; Landray, M.; Peto, R. The Magic of Randomization versus the Myth of Real-World Evidence. N. Engl. J. Med. 2020, 382, 674–678. [Google Scholar] [CrossRef] [PubMed]
- Gebremedhin, L.T. Investment in health data can drive economic growth. Nat. Med. 2022, 28, 2000. [Google Scholar] [CrossRef] [PubMed]
- Boehm, K.M.; Khosravi, P.; Vanguri, R.; Gao, J.; Shah, S.P. Harnessing multimodal data integration to advance precision oncology. Nat. Rev. Cancer 2022, 22, 114–126. [Google Scholar] [CrossRef] [PubMed]
- Jayakrishnan, T.; Aulakh, S.; Baksh, M.; Nguyen, K.; Ailawadhi, M.; Samreen, A.; Parrondo, R.; Sher, T.; Roy, V.; Manochakian, R.; et al. Landmark Cancer Clinical Trials and Real-World Patient Populations: Examining Race and Age Reporting. Cancers 2021, 13, 5770. [Google Scholar] [CrossRef] [PubMed]
- Fuchs, B.; Schelling, G.; Elyes, M.; Studer, G.; Bode-Lesniewska, B.; Scaglioni, M.F.; Giovanoli, P.; Heesen, P.; on behalf of the SwissSarcomaNetwork. Unlocking the Power of Benchmarking: Real-World-Time Data Analysis for Enhanced Sarcoma Patient Outcomes. Cancers 2023, 15, 4395. [Google Scholar] [CrossRef] [PubMed]
- Heesen, P.; Studer, G.; Bode, B.; Windegger, H.; Staeheli, B.; Aliu, P.; Martin-Broto, J.; Gronchi, A.; Blay, J.Y.; Le Cesne, A.; et al. Quality of Sarcoma Care: Longitudinal Real-Time Assessment and Evidence Analytics of Quality Indicators. Cancers 2022, 15, 47. [Google Scholar] [CrossRef]
- Elyes, M.; Heesen, P.; Schelling, G.; Bode-Lesniewska, B.; Studer, G.; Fuchs, B.; Swiss Sarcoma, N. Enhancing Healthcare for Sarcoma Patients: Lessons from a Diagnostic Pathway Efficiency Analysis. Cancers 2023, 15, 4892. [Google Scholar] [CrossRef]
- Scharer, M.; Heesen, P.; Bode-Lesniewska, B.; Studer, G.; Fuchs, B.; Swiss Sarcoma, N. Benchmarking Time-to-Treatment Initiation in Sarcoma Care Using Real-World-Time Data. Cancers 2023, 15, 5849. [Google Scholar] [CrossRef] [PubMed]
- Blay, J.Y.; Hindi, N.; Bollard, J.; Aguiar, S.; Angel, M.; Araya, B.; Badilla, R.; Bernabeu, D.; Campos, F.; Caro-Sánchez, C.H.S.; et al. SELNET clinical practice guidelines for soft tissue sarcoma and GIST. Cancer Treat. Rev. 2022, 102, 102312. [Google Scholar] [CrossRef] [PubMed]
- Blay, J.Y.; Palmerini, E.; Bollard, J.; Aguiar, S.; Angel, M.; Araya, B.; Badilla, R.; Bernabeu, D.; Campos, F.; Chs, C.S.; et al. SELNET Clinical practice guidelines for bone sarcoma. Crit. Rev. Oncol. Hematol. 2022, 174, 103685. [Google Scholar] [CrossRef] [PubMed]
- Fuchs, B.; Studer, G.; Bode, B.; Wellauer, H.; Frei, A.; Theus, C.; Schupfer, G.; Plock, J.; Windegger, H.; Breitenstein, S.; et al. Development of a value-based healthcare delivery model for sarcoma patients. Swiss Med. Wkly. 2021, 151, w30047. [Google Scholar] [CrossRef] [PubMed]
- Fuchs, B.; Bode, B.; Heesen, P.; Kopf, B.; Michelitsch, C.; Odermatt, M.; Giovanoli, P.; Breitenstein, S.; Schneider, P.; Schupfer, G.; et al. Transdisciplinary sarcoma care: A model for sustainable healthcare transformation. Swiss Med. Wkly. 2024, 154, 3473. [Google Scholar] [CrossRef] [PubMed]
- Matthews, A.A.; Danaei, G.; Islam, N.; Kurth, T. Target trial emulation: Applying principles of randomised trials to observational studies. BMJ 2022, 378, e071108. [Google Scholar] [CrossRef]
- Hernan, M.A.; Robins, J.M. Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available. Am. J. Epidemiol. 2016, 183, 758–764. [Google Scholar] [CrossRef] [PubMed]
- Hernan, M.A.; Wang, W.; Leaf, D.E. Target Trial Emulation: A Framework for Causal Inference From Observational Data. JAMA 2022, 328, 2446–2447. [Google Scholar] [CrossRef]
- Friend, S.H.; Ginsburg, G.S.; Picard, R.W. Wearable Digital Health Technology. N. Engl. J. Med. (NEJM) 2023, 389, 2100–2101. [Google Scholar] [CrossRef]
- Kann, B.H.; Hosny, A.; Aerts, H. Artificial intelligence for clinical oncology. Cancer Cell 2021, 39, 916–927. [Google Scholar] [CrossRef]
- Kamel Boulos, M.N.; Zhang, P. Digital Twins: From Personalised Medicine to Precision Public Health. J. Pers. Med. 2021, 11, 745. [Google Scholar] [CrossRef] [PubMed]
- Swanson, K.; Wu, E.; Zhang, A.; Alizadeh, A.A.; Zou, J. From patterns to patients: Advances in clinical machine learning for cancer diagnosis, prognosis, and treatment. Cell 2023, 186, 1772–1791. [Google Scholar] [CrossRef] [PubMed]
- Kufel, J.; Bargieł-Łączek, K.; Kocot, S.; Koźlik, M.; Bartnikowska, W.; Janik, M.; Czogalik, Ł.; Dudek, P.; Magiera, M.; Lis, A.; et al. What Is Machine Learning, Artificial Neural Networks and Deep Learning?—Examples of Practical Applications in Medicine. Diagnostics 2023, 13, 2582. [Google Scholar] [CrossRef] [PubMed]
- Haug, C.J.; Drazen, J.M. Artificial Intelligence and Machine Learning in Clinical Medicine, 2023. N. Engl. J. Med. (NEJM) 2023, 388, 1201–1208. [Google Scholar] [CrossRef] [PubMed]
- Feuerriegel, S.; Frauen, D.; Melnychuk, V.; Schweisthal, J.; Hess, K.; Curth, A.; Bauer, S.; Kilbertus, N.; Kohane, I.S.; van der Schaar, M. Causal machine learning for predicting treatment outcomes. Nat. Med. 2024, 30, 958–968. [Google Scholar] [CrossRef] [PubMed]
- Kalra, S.; Wen, J.; Cresswell, J.C.; Volkovs, M.; Tizhoosh, H.R. Decentralized federated learning through proxy model sharing. Nat. Commun. 2023, 14, 2899. [Google Scholar] [CrossRef] [PubMed]
- Fuchs, B.; Studer, G.; Bode-Lesniewska, B.; Heesen, P. The Next Frontier in Sarcoma Care: Digital Health, AI, and the Quest for Precision Medicine. J. Pers. Med. 2023, 13, 1530. [Google Scholar] [CrossRef] [PubMed]
- Hernandez-Boussard, T.; Macklin, P.; Greenspan, E.J.; Gryshuk, A.L.; Stahlberg, E.; Syeda-Mahmood, T.; Shmulevich, I. Digital twins for predictive oncology will be a paradigm shift for precision cancer care. Nat. Med. 2021, 27, 2065–2066. [Google Scholar] [CrossRef] [PubMed]
- Aerts, A.; Bogdan-Martin, D. Leveraging data and AI to deliver on the promise of digital health. Int. J. Med. Inf. 2021, 150, 104456. [Google Scholar] [CrossRef]
- Harry, A. The Future of Medicine: Harnessing the Power of AI for Revolutionizing Healthcare. Int. J. Multidiscip. Sci. Arts 2023, 2, 36–47. [Google Scholar] [CrossRef]
- Bekbolatova, M.; Mayer, J.; Ong, C.W.; Toma, M. Transformative Potential of AI in Healthcare: Definitions, Applications, and Navigating the Ethical Landscape and Public Perspectives. Healthcare 2024, 12, 125. [Google Scholar] [CrossRef] [PubMed]
- Lipkova, J.; Chen, R.J.; Chen, B.; Lu, M.Y.; Barbieri, M.; Shao, D.; Vaidya, A.J.; Chen, C.; Zhuang, L.; Williamson, D.F.K.; et al. Artificial intelligence for multimodal data integration in oncology. Cancer Cell 2022, 40, 1095–1110. [Google Scholar] [CrossRef] [PubMed]
- Ross, J.S.; Waldstreicher, J.; Krumholz, H.M. Data Sharing—A New Era for Research Funded by the U.S. Government. N. Engl. J. Med. (NEJM) 2023, 389, 2408–2410. [Google Scholar] [CrossRef] [PubMed]
- Perkel, J.M. How to make your scientific data accessible, discoverable and useful. Nature 2023, 618, 1098–1099. [Google Scholar] [CrossRef] [PubMed]
- Sabatello, M.; Martschenko, D.O.; Cho, M.K.; Brothers, K.B. Data sharing and community-engaged research. Science 2022, 378, 141–143. [Google Scholar] [CrossRef] [PubMed]
- Eisenstein, M. In pursuit of data immortality. Nature 2022, 604, 207–208. [Google Scholar] [CrossRef]
- Blumenthal, D. A Step toward Interoperability of Health IT. N. Engl. J. Med. (NEJM) 2022, 387, 2201–2203. [Google Scholar] [CrossRef] [PubMed]
- Barnholtz-Sloan, J.S. Maximizing Cancer Data—The Future of Cancer Is Now. JAMA Oncol. 2022, 8, 1095. [Google Scholar] [CrossRef]
- Saldanha, O.L.; Quirke, P.; West, N.P.; James, J.A.; Loughrey, M.B.; Grabsch, H.I.; Salto-Tellez, M.; Alwers, E.; Cifci, D.; Ghaffari Laleh, N.; et al. Swarm learning for decentralized artificial intelligence in cancer histopathology. Nat. Med. 2022, 28, 1232–1239. [Google Scholar] [CrossRef]
Term | Definition | Source of Data | Timing of Data Collection | Usage Context |
---|---|---|---|---|
Retrospective data | Data collected from past events, often through examination of existing records such as medical charts and billing information | Historical records, medical charts, insurance claims | Collected after all events have occurred, looking back in time | Analyzing past events, to understand outcomes, trends, and areas for future research. Subject to selection biases |
Prospective data | Data collected from the initiation of the study forward, with specific research questions and data collection processes in mind | Direct observations, surveys, clinical assessments. | Collected moving forward from the start of the study | Observing and assessing outcomes following specific exposures or interventions, minimizing recall biases and clarifying temporal relationships |
Randomized controlled trials (RCTs) | Health-related data derived from sources outside traditional clinical trials, including EHRs, registries, and patient generated data | Controlled experimental settings | Prospective, starting at the time of the trial | Establishing causality between interventions and outcomes, minimizing bias through randomization and control |
Real-world data (RWD) | Health-related data derived from sources outside traditional clinical trials, including EHRs, registries, and patient generated data | EHRs, claims, registries, patient devices | Not specific to real time; collected during routine clinical practice | Capturing patient experiences in routine practice to understand healthcare delivery and outcomes in natural settings |
Real-world evidence (RWE) | Clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analyzing RWD | Derived from RWD | Analysis occurs at any time post data collection | Supporting clinical decision-making and health policy by providing evidence from real-life setting beyond controlled trials |
Real-time data (RTD) | Information that is collected and immediately available for use or analysis as events occur, without significant delay | Monitoring devices, clinical care systems | Immediate, as events occur | Required in scenarios requiring immediate action, like critical care monitoring. |
Real-world/time data and evidence (RWTD/E) | Conceptualized as combining real-world context with the immediacy of real-time data collection and analysis | EHRs, patient devices, and real-time monitoring systems | Real-time, as events occur in real-world settings | Enhancing understanding of healthcare interventions in real-world settings with the immediacy of real-time data capture |
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Share and Cite
Heesen, P.; Schelling, G.; Birbaumer, M.; Jäger, R.; Bode, B.; Studer, G.; Fuchs, B., on behalf of the Swiss Sarcoma Network. Real-World-Time Data and RCT Synergy: Advancing Personalized Medicine and Sarcoma Care through Digital Innovation. Cancers 2024, 16, 2516. https://doi.org/10.3390/cancers16142516
Heesen P, Schelling G, Birbaumer M, Jäger R, Bode B, Studer G, Fuchs B on behalf of the Swiss Sarcoma Network. Real-World-Time Data and RCT Synergy: Advancing Personalized Medicine and Sarcoma Care through Digital Innovation. Cancers. 2024; 16(14):2516. https://doi.org/10.3390/cancers16142516
Chicago/Turabian StyleHeesen, Philip, Georg Schelling, Mirko Birbaumer, Ruben Jäger, Beata Bode, Gabriela Studer, and Bruno Fuchs on behalf of the Swiss Sarcoma Network. 2024. "Real-World-Time Data and RCT Synergy: Advancing Personalized Medicine and Sarcoma Care through Digital Innovation" Cancers 16, no. 14: 2516. https://doi.org/10.3390/cancers16142516
APA StyleHeesen, P., Schelling, G., Birbaumer, M., Jäger, R., Bode, B., Studer, G., & Fuchs, B., on behalf of the Swiss Sarcoma Network. (2024). Real-World-Time Data and RCT Synergy: Advancing Personalized Medicine and Sarcoma Care through Digital Innovation. Cancers, 16(14), 2516. https://doi.org/10.3390/cancers16142516