A new framework leveraging observational and randomized controlled trial (RCT) data refines treatment strategies for gastrointestinal stromal tumors (GIST) and soft tissue sarcomas, potentially improving patient outcomes and reducing unnecessary treatments. The framework addresses challenges in patient selection for adjuvant therapies, offering a more personalized approach.
Optimizing Imatinib Use in GIST
Imatinib has dramatically improved survival in advanced GIST, but optimal patient selection for adjuvant imatinib remains controversial. Current criteria may lead to overtreatment of patients who have already achieved cure from surgical resection. Researchers developed an Optimal Policy Tree (OPT) using data from 536 patients who underwent surgery at Memorial Sloan Kettering (MSK) between 1982 and 2017. At a median follow-up of 87 months, 18.6% of patients experienced recurrence. The OPT identified subgroups that benefit most from imatinib, balancing the risks of undertreatment and overtreatment.
The OPT recommended imatinib for patients with a mitotic count equal or greater than 10.5 and for those with tumors of non-gastric sites that were equal or larger than 5.05 cm. It was also recommended for patients with tumors of large size (> 7.15 cm), gastric site, and a mitotic count equal or greater than 1.5. Validation in a cohort of 557 patients from Poland showed the OPT had a sensitivity of 89% (95%CI: 84–93%) and specificity of 70% (95%CI: 65–74%).
Incorporating Genetic Data for Personalized GIST Treatment
The framework was further refined by incorporating genetic data from 293 patients. The OPT recommended against imatinib for patients with tumors harboring PDGFRA D842V or D842I mutations, aligning with current clinical practice guidelines. Adjuvant imatinib was recommended for patients with wild-type PDGFRA tumors and a mitotic count of 6.5 or greater, and for those with a lower mitotic count but tumors of non-gastric sites. Validation in a cohort of 206 patients showed a sensitivity of 88% (95%CI: 79–94%) and specificity of 67% (95%CI: 58–76%).
Refining Radiotherapy Recommendations in Soft Tissue Sarcoma
Adjuvant radiotherapy (RT) reduces local recurrence rates in extremity or truncal sarcomas, but it is unlikely that all patients need treatment. The framework was applied to data from a randomized trial of 164 patients conducted at MSK. The OPT recommended RT for patients older than 60 years, those younger than 60 with lower extremity sarcomas, and those with high-grade liposarcomas. Adjuvant RT was not recommended for patients younger than 60 with truncal or upper extremity sarcomas (with exception to those with high grade non-liposarcomas).
Validation in a cohort of 936 patients who underwent surgery at MSK and did not receive RT showed a sensitivity of 90% (95%CI: 82–95%) and specificity of 14% (95%CI: 12–17%). The OPT can potentially spare around 15% of patients who would not have benefited from adjuvant RT from an unnecessary treatment.
Implications for Precision Medicine
This framework demonstrates the potential of integrating observational data, RCT data, and molecular markers to optimize treatment decisions. By identifying patient subgroups that benefit most from specific therapies, this approach can improve outcomes and reduce unnecessary treatments, advancing the field of precision medicine.
