(P 165) COMPLETE PERITONEAL CYTOREDUCTIVE SURGERY IN HIGHLY SELECTED PATIENTS WITH AGGRESSIVE METASTATIC SDH-DEFICIENT GIST CAN PROLONG EVENT-FREE SURVIVAL

Objective: Gastrointestinal stromal tumors (GIST) are genetically heterogeneous with approximately 5-10% caused by succinate dehydrogenase deficiency (SDH-def). This subset of GIST is characterized by unique clinical features including young age at presentation (median 29 years old), variable disease biology ranging from indolent to aggressive, and poor response to traditional treatment with tyrosine kinase inhibitors. Moreover, the role of surgical management in these patients has been highly debated. A previous study of GIST patients that lack KIT or PDGFRA mutations (i.e., wild-type) reported no improvement in Event-Free Survival (EFS, freedom from progression or recurrence) with more extensive or serial resections. Meanwhile, a Surveillance, Epidemiology, and End Results study showed that operative management was associated with improved overall survival in patients aged 13-39 years old with metastatic GIST. Additionally, a National Cancer Database study showed that surgery was the principal treatment modality in wild-type GIST. However, no studies have specifically investigated the SDH-def GIST cohort. Thus, the role of cytoreductive surgery (CRS) for patients with SDH-def GIST remains contentious.

Methods: We performed a single-institution retrospective analysis of metastatic SDH-def GIST patients undergoing CRS from 2017 to 2023. Inclusion criteria were immunohistochemical confirmation of SDH-def GIST, prior progression having been well controlled with systemic therapy (FDA-approved or investigational agent), and successful CRS with no residual disease (CC0). The Peritoneal Cancer Index (PCI) quantitates the extent of peritoneal-based disease, and the GIST Metastatectomy Surgical Complexity Score (GM-SCS) evaluates the complexity of the case based on patient factors, intraoperative factors, procedures performed, organs resected, and disease burden. Kaplan-Meier survival analysis was performed to compare EFS (Event-Free Survival) immediately before CRS (EFS1) versus after CRS (EFS2). Pre-CRS events were defined as disease progression by mRECIST 1.1, and post-CRS events were defined as recurrence.

Results: A total of 9 patients with advanced SDH-def GIST met inclusion criteria. Median age at diagnosis was 23 years old (range: 14 – 43), and median age at the time of CRS was 29 years old (range: 17 – 43). Patients had mutations in SDHB (n=4, 44%), SDHA (n=3, 33%), SDHC (n=1, 11%), or an SDHC epimutation (n=1, 11%). Median operative time was 11.3 hours (IQR: 9.4 - 12.1), and median estimated blood loss was 200 mL (IQR: 125 – 250). A median of 22 tumor specimens (IQR: 19 - 31) were resected during each operation, with a median of 81% (IQR: 37% - 84%) being confirmed GIST with viable tumor cells. Five patients (56%) had a mitotic index > 5/mm2. The median cumulative diameter of resected and confirmed GIST was 28.1 cm (IQR: 16.4 - 40.9). Patients had a median PCI of 13 (IQR: 10 - 15) and a median GM-SCS of 19 (IQR: 16 - 28). The median length of hospital stay was 11 days (IQR: 9 - 15 days). One-third of patients had a grade ≥3 complication within 90-days according to Clavien-Dindo classification. There were no deaths. Median EFS1 was 5.0 months (95% CI: 2.9 - unreached) immediately prior to CRS on systemic therapy, compared to EFS2 of 26.1 months (95% CI: 15.2 - unreached) post CRS (p≤0.0001) (Figure 1). Moreover, 5 of 6 patients (83%, 3 censored) had >3-fold prolongation of their EFS 2/1 ratios.

Conclusion: Our novel series of surgical intervention in highly selected patients with aggressive metastatic SDH-def GIST shows that patients who achieved disease control on preoperative systemic therapies and can undergo complete cytoreduction (CC0) may achieve improvement in the natural history of their disease. Future studies with larger cohorts of patients are warranted to further assess the efficacy of this approach. Although acquired in a selected non-randomized cohort, our data provides support to the contention that CRS can be an effective way to treat SDH-def GIST.