Recent clinical studies are providing new insights into the role of radiation therapy in pancreatic cancer treatment, with contrasting findings from two significant investigations highlighting both the promise and limitations of different radiotherapy approaches.
Stereotactic Ablative Radiotherapy Shows Clinical Benefits
A single-institution cohort study from the University of Texas Southwestern Medical Center demonstrated that adding stereotactic ablative radiotherapy (SAbR) to neoadjuvant chemotherapy improved pathologic outcomes for pancreatic cancer patients. The study, published in Clinical Cancer Research, analyzed 181 patients diagnosed between 2012 and 2023, with 133 receiving chemotherapy alone and 48 receiving chemotherapy plus SAbR.
Despite the SAbR group having more advanced baseline disease, researchers found better posttreatment pathology and similar overall survival outcomes. Most notably, locoregional recurrence-free survival was significantly improved with SAbR, showing a hazard ratio of 0.24.
The study revealed particularly striking benefits for patients with arterial involvement. While chemotherapy alone showed increased local failure risk in these cases (hazard ratio 3.37), the addition of SAbR significantly reduced this risk (hazard ratio 0.28).
"Our findings suggest stereotactic ablative radiotherapy, which delivers high-dose radiation with minimal toxicity, may improve clinical outcomes for patients with pancreatic ductal adenocarcinoma by lowering the risk of recurrence -- especially in cancers that invade or encase major arteries," stated lead author Todd Aguilera, M.D., Ph.D., from the University of Texas Southwestern.
Gene set enrichment analysis provided mechanistic insights, showing immune activation with CD8 and NK/NKT cell signatures associated with local control, while regulatory T-cell signatures correlated with worse control outcomes.
Phase 3 Trial Questions Chemoradiation Approach
In contrast, the phase 3 CONKO-007 trial published in Journal of Clinical Oncology presented more sobering results for chemoradiotherapy in unresectable pancreatic cancer. The study enrolled 525 patients with unresectable tumors, with 495 receiving induction chemotherapy consisting of FOLFIRINOX (n=402) or gemcitabine (n=93).
After three months of induction therapy, 336 patients without disease progression were randomized to continue chemotherapy alone (n=167) or receive chemoradiotherapy at 50.4 Gy with concurrent gemcitabine (n=169).
The trial's primary endpoint of overall R0 resection rate showed no statistically significant difference between groups: 25.4% in the chemotherapy/chemoradiotherapy arm versus 18.0% in the chemotherapy alone arm (P = .113). Overall survival outcomes were similarly comparable, with median survival of 15 months versus 14 months respectively (HR, 0.94; 95% CI, 0.747-1.174; P = .57).
However, among patients who underwent surgery, chemoradiotherapy demonstrated clear advantages. The combination yielded significantly higher ratios of R0, R1, and R2 resections (P = .02), improved circumferential resection margin-negative status rates (P = .04), and higher pathologic complete response rates compared to chemotherapy alone (P = .004).
Surgical Outcomes Drive Survival Benefits
Both studies emphasized the critical importance of surgical resection in pancreatic cancer outcomes. In the CONKO-007 trial, 122 of 336 patients in the intent-to-treat population underwent surgery, which correlated with superior survival (HR, 0.53; 95% CI, 0.408-0.676).
The survival advantage was substantial: median survival reached 19 months in surgical patients versus 13 months in non-surgical patients, with 5-year survival rates of 18.7% versus 0% respectively (P <.001). Patients achieving circumferential resection margin-negative resection showed even better outcomes, with median survival of 33 months and 5-year survival rates of 30.4%.
Safety Profile Considerations
The CONKO-007 trial revealed important safety differences between treatment approaches. Significant increases in grade 3/4 hematologic toxicities occurred with chemoradiotherapy, including leukopenia (30% vs 7%; P >.001) and thrombocytopenia (25% vs 8%; P >.001) compared to chemotherapy alone.
Three toxicity-related deaths occurred in the chemotherapy arm due to cytomegalovirus infection, pulmonary embolism, and peripheral arterial disease, while no toxicity-related deaths were reported in the chemoradiotherapy arm.
Clinical Implications
Lead study author Rainer Fietkau, M.D., from Friedrich-Alexander-Universität Erlangen-Nürnberg, concluded that while chemoradiotherapy after induction chemotherapy is feasible, it does not provide survival superiority over chemotherapy alone in unresectable pancreatic cancer.
"CRT improves the ratio of R0/R1/R2 resection in secondary surgery without increasing postsurgical mortality. Induction chemotherapy may enable biological selection of patients with a favorable prognosis who benefit the most from CRT," the authors noted.
These findings suggest that while radiation therapy approaches in pancreatic cancer continue to evolve, patient selection and treatment sequencing remain critical factors in optimizing outcomes. The contrasting results between stereotactic ablative radiotherapy and conventional chemoradiotherapy highlight the need for continued research into personalized treatment strategies for this challenging malignancy.
