Stereotactic body radiation therapy in oligometastatic pancreatic cancer: overall survival improvement and SMAD4 as a predictor of progression-free survival.

BACKGROUND: The 5-year overall survival (OS) for stage IV pancreatic cancer is dismal despite aggressive systemic therapy. Stereotactic body radiation therapy (SBRT) involves delivering precise, highly conformal, and biologically effective doses of radiation via a linear accelerator to the tumor region. Clinical trials have shown improvement in OS and progression-free survival (PFS) with SBRT plus standard chemotherapy in oligometastatic (<5 metastatic lesions) solid tumors such as breast, lung, colorectal, and prostate cancers, when compared to chemotherapy alone. Factors predicting response to SBRT need to be further explored in oligometastatic pancreatic cancer (oPC). The study aims to assess the role of SBRT in the management of patients with oPC.

METHODS: We conducted a retrospective cohort study of oPC patients treated at the Mayo Clinic during the period from January 2012 to January 2022, who underwent SBRT to at least one site, including the primary site and/or sites of metastases, received at least 4 months of chemotherapy, and had a minimum of 1-year follow-up. Pertinent data were collected from the electronic health records after institutional review board (IRB) approval. The response rates (RRs) were assessed using the RECIST v1.1 criteria, and the PFS and OS were calculated using the Kaplan-Meier method. Multivariate Cox regression was used to determine a statistically significant correlation between treatment and genomic characteristics with OS and PFS.

RESULTS: Sixty-one patients with oPC were identified, among whom 38% were female. Eighty-seven percent were Caucasian, and 13% were other ethnicities (African American, Hispanic, and Asian). The median age was 66 years. Patients received gemcitabine (gem) or 5-fluorouracil (5-FU) based chemotherapy. Eight-five percent of patients received chemotherapy within 3 months of SBRT and the median follow-up time of 16 months. The RR was 25% in the primary lesion and 17% in metastatic lesions. SBRT to primary pancreas lesion correlated with higher OS [hazard ratio (HR): 0.27, 95% confidence interval (CI): 0.082-0.89, P=0.03] but showed no difference in PFS (HR: 0.97, P=0.95) when compared to SBRT to any other metastatic site. SBRT to liver metastases had no improvement in OS (P=0.92) or PFS (P=0.70) versus SBRT to other metastatic sites. The type of chemotherapy (gem vs. 5-FU based) alongside SBRT within 3 months did not influence OS (P=0.47) or PFS (P=0.62) in these patients. Among 30 patients who underwent circulating tumor deoxyribonucleic acid (ctDNA) testing, SMAD4 gene alteration correlated with significantly higher PFS (HR: 0.23, 95% CI: 0.065-0.87, P=0.03) but had no relation with OS (HR: 0.60, 95% CI: 0.18-2.03, P=0.41) compared to patients with undetectable SMAD4 alteration.

CONCLUSIONS: SBRT plus chemotherapy may have benefits in some patients with oPC. SBRT to primary pancreas lesion led to better OS compared with SBRT to other metastatic sites. SMAD4 alteration in ctDNA testing correlated with higher PFS in oPC patients who received SBRT. This implies a potential role for genomic biomarker-based patient selection in oPC. These findings are currently being studied in a randomized clinical trial evaluating SBRT plus chemotherapy in oPC (NCT04975516).