Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma

1. The median progression-free survival in the metastasis-directed therapy arm was 10.3 months vs 2.5 months in the control arm with an HR of 0.43 (significant).

2. Baseline CA19-9 level were found to be prognostic, ≥90 U/mL compared to<90 U/mL had an HR 2.96 (significant).

Evidence Rating Level: 1 (Excellent)

Study Rundown: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor outcomes after frontline chemotherapy however for patients with oligometastatic PDAC, some evidence exists for combining chemotherapy with metastasis-directed therapy (MDT) to improve outcomes. This study further explored whether adding MDT to systemic therapy could improve outcomes in these patients. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), time to next-line systemic therapy, time to local failure, time to new lesion formation, toxicity, and quality of life (QoL). There were also some exploratory endpoints which investigated measures of systemic immune response with MDT. Median PFS in the MDT arm was 10.3 months vs 2.5 months in the control arm with an HR 0.43 (p=0.030). PFS rates at 1 year were 42% in the MDT arm and 9% in the control arm. A post hoc analysis found baseline CA19-9 level as prognostic, ≥90 U/mL compared to <90 U/mL, with an HR 2.96 (p=0.004). When analyzed for PFS, MDT for patients with CA19-9 <90 U/mL had an HR 0.33 (p=0.06) compared with CA19-9 ≥90 U/mL with an HR 0.37 (p=0.048). The median time to new lesion recurrence was 14 months in the MDT arm vs 5 months in the control arm with an HR 0.51 (p=0.22). The median time to next-line systemic therapy was 19 months in the MDT arm vs 8 months in the control arm with an HR 0.53 (p=0.24). The median OS for the MDT arm was 12 months vs 10 months in the control arm with an HR 0.58 (p=0.20). QoL comparisons showed no apparent differences. Exploratory endpoints for the systemic immune response of MDT found that proliferative CD8 T cells were greater at follow-up in the MDT arm compared with the control arm (p=0.02), and that some markers of T-cell activated were associated with improved PFS and OS. The strengths of this study included its methodology and the limitations included the sample size. Overall, this study found that adding MDT to systemic therapy had some improved outcomes compared with systemic therapy alone in oligometastatic PDAC.

Click to read the study in JCO

Relevant Reading: Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer The EXTEND Phase 2 Randomized Clinical Trial

In-Depth [randomized controlled trial]: This multicenter phase II basket trial enrolled adults with PDAC with less than 5 sites of metastatic disease amenable to MDT and randomized them (1:1) to MDT with systemic therapy (n = 20) vs systemic therapy alone (n = 21). MDT consisted of definitive local therapy such as stereotactic ablative radiotherapy with the most common prescriptions being 50 Gy in 4 fractions or 70 Gy in 10 fractions. The systemic therapy was chosen by the treating oncologist and the most common therapy was GA-based chemotherapy. Most patients (78%) had 1 or 2 metastases at baseline. Median follow-up of 17.3 months. Median PFS in the MDT arm was 10.3 months (95%CI, 4.6-14.0) vs 2.5 months in the control arm (95%CI, 1.7-5.1) with an HR 0.43 (95%CI, 0.20-0.94, p=0.030). PFS rates at 1 year were 42% (95%CI, 19-64) in the MDT arm and 9% (95%CI, 1-29) in the control arm. A post hoc analysis found baseline CA19-9 level as prognostic, ≥90 U/mL compared to <90 U/mL, with an HR 2.96 (95%CI, 1.40-6.24, p=0.004). When analyzed for PFS, MDT for patients with CA19-9 <90 U/mL had an HR 0.33 (95%CI, 0.11-1.05, p=0.06) compared with CA19-9 ≥90 U/mL with an HR 0.37 (95%CI, 0.14-0.99, p=0.048). The median time to new lesion recurrence was 14 months in the MDT arm (95%CI, 6-NA) vs 5 months in the control arm (95%CI, 3-NA) with an HR 0.51 (95%CI, 0.18-1.49, p=0.22). The median time to next-line systemic therapy was 19 months in the MDT arm (95%CI, 8-NA) vs 8 months in the control arm (95%CI, 3-NA) with an HR 0.53 (95%CI, 0.19-1.51, p=0.24). The median OS for the MDT arm was 12 months (95%CI, 8-23) vs 10 months in the control arm (95%CI, 7-NA) with an HR 0.58 (95%CI, 0.25-1.34, p=0.20). QoL comparisons showed no apparent differences. Exploratory endpoints for the systemic immune response of MDT found that proliferative CD8 T cells were greater at follow-up in the MDT arm compared with the control arm (p=0.02) and that some markers of T-cell activation were associated with improved PFS and OS. Overall, this study found that adding MDT to systemic therapy had some improved outcomes compared with systemic therapy alone in oligometastatic PDAC.

Image: PD

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