Neoadjuvant Chemotherapy and Stereotactic Body Radiation Therapy in Patients with Early Onset Pancreatic Cancer: Clinical Outcomes and Toxicity

Abstract

<h3>Purpose/Objective(s)</h3> Little is known on optimal management of patients with early onset pancreatic cancer (EOPC), including the role of radiation therapy. As such, we report on a cohort of patients with EOPC (age <55 years) who was treated with neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT). <h3>Materials/Methods</h3> This was a single institution retrospective review of patients with EOPC who were treated with upfront chemotherapy followed by SBRT with or without surgical resection. Endpoints included overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and treatment-related toxicity. Next-generation sequencing (NGS) was performed on select patient tumor specimens. <h3>Results</h3> From 2016-2021, 47 patients met the inclusion criteria. Median age was 50.4 years (range, 36.4 – 54.7 years). Median induction chemotherapy duration was 4 months (range, 2.5 – 9 months). The majority (46/47, 97.9%) of patients received 33 Gy in 5 fractions. Following SBRT, 43 patients (91%) underwent surgical exploration, with extent of vascular involvement on post-SBRT imaging precluding exploration in 4 patients (9%). Gross resection was achieved in 33 patients (70.2%), with intraoperative metastatic disease precluding resection in 8 patients (17%) and intraoperative extent of vascular involvement of the primary tumor precluding resection in 4 patients (9%). Median OS, LPFS, DMFS, and PFS were 14.2 months, 11.6 months, 8.9 months, and 8.1 months respectively. Six-month and 1-year LPFS were 88.3% and 45.4%, respectively. Chemotherapy duration (≥ 4 months) was associated with improved median OS (16.5 vs 10.1 months, p=0.005), LPFS (10.1 vs 4.9 months, p=0.002), DMFS (9.7 vs 5.2 months, p=0.014), and PFS (9.7 vs 5.2 months, p=0.020). Normalization of CA 19-9 (≤ 34 vs > 34 U/ml) after chemotherapy was associated with improved median DMFS (not reached vs 5.6 months, p=0.003) and PFS (11.3 vs 5.6 months, p=0.022). Grade 3+ rates of chemotherapy and radiation-related toxicity were 14.9% and 2.1% respectively. Clavien-Dindo 3b toxicity rate was 3.0%. A total of 15 patients underwent NGS, with mutations being found in <i>KRAS</i> (10/15, 66.7%), <i>TP53</i> (7/15, 46.7%), <i>NOTCH 1/2</i> (3/15, 20%), <i>CDK2NA</i> (2/15, 13.3%), and <i>SMAD4</i> (1/15, 6.7%). <h3>Conclusion</h3> Multi-modality therapy for EOPC was administered with low toxicity, but outcomes remain suboptimal. Induction chemotherapy duration ≥ 4 months and normalization of CA 19-9 after chemotherapy were associated with improved outcomes, suggesting a role for extended durations of systemic therapy titrated to CA 19-9 response before transitioning to local therapy. The high rate of local failure and the low rate of grade 3+ toxicity also suggest a role for intensifying local therapy in this population, such as radiation dose escalation, expansion of the radiation target volume, and more aggressive surgical techniques.