Combined phosphorus-32 implantation and chemotherapy: a...

Combined phosphorus-32 implantation and chemotherapy: a comparison with standard therapy using a propensity-score weighted landmark analysis and an assessment of its impact on vascularity in locally advanced pancreatic cancer

Amanda H Lim^1,2, Darshan Nitchingham¹, Jana Bednarz^2,3, Madison Bills⁴, Laxmi Lanka⁵, Berry Allen⁶, Alvin Tan⁶, Rohit Joshi⁷, William Hsieh⁴, Benjamin Crouch⁴, Joshua Zobel¹, John-Edwin Thomson⁸, EuLing Neo⁸, Romina Safaeian¹, Edmund Tse^1,2, Christopher Rayner^1,2, Andrew Ruszkiewicz^2,9,10, Jayden Wong¹¹, Nimit Singhal¹², Dylan Bartholomeusz^1,4, Frank Weilert¹³ and Nam Nguyen^1,2

¹Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia;²University of Adelaide, Adelaide, Australia;³SAHMRI Women and Kids Theme, South Australia Health and Medical Research Institute, Adelaide, Australia;⁴Department of Nuclear Medicine, Royal Adelaide Hospital, Adelaide, Australia;⁵Department of Radiology, Waikato Hospital, Hamilton, New Zealand;⁶Department of Nuclear Medicine, Waikato Hospital, Hamilton, New Zealand;⁷Medical Oncology, Lyell McEwin Hospital, Elizabeth Vale, Australia;⁸Department of Hepatobiliary Surgery, Royal Adelaide Hospital, Adelaide, Australia;⁹Surgical Pathology, SA Pathology, Adelaide, Australia;¹⁰Centre of Cancer Biology, University of South Australia, Adelaide, Australia;¹¹Department of Oncology, Waikato Hospital, Hamilton, New Zealand;¹²Department of Oncology, Royal Adelaide Hospital, Adelaide, Australia;¹³Department of Gastroenterology, Waikato Hospital, Hamilton, New Zealand

Background and Aims: Pancreatic cancer is highly lethal. Poor intra-tumour vascularity contributes to its limited response to chemotherapy. The combination of standard chemotherapy and endoscopic ultrasound (EUS)-guided phophorus-32 (³²P) microparticle intra-tumoural implantation has revealed encouraging results in locally advanced pancreatic cancer (LAPC). However, comparative studies are lacking. Therefore, we compared chemotherapy and ³²P implantation with standard therapy using a propensity-score weighted analysis (PSWA). We also aimed to assess changes in pancreatic tumour vascularity following ³²P implantation, using contrast enhanced-EUS (CE-EUS).

Methods: We conducted a retrospective cohort study comparing LAPC patients with combination therapy at 2 centres with standard therapy patients from a single centre, from August 2017 to January 2023. Landmark analysis was used to address immortal time bias. PSWA was applied to reduce the impact of selection bias. The primary outcome was overall survival at 24 months after first-line treatment initiation, with treatment effect expressed as restricted mean survival time (RMST; average event-free survival time). In a sub-cohort of patients with combined therapy, CE-EUS was performed just prior to, and at 4 and 12 weeks after implantation. Time intensity curve was analysed for 90 seconds after IV contrast bolus to ascertain peak intensity and intensity gain.

Results: 104 patients were considered. The landmark date was designated as 3 months after initiation of first-line chemotherapy. After excluding patients who died before the landmark, 101 patients were included in the PSWA (35 vs. 66 chemotherapy only). The RMST within 24 months after chemotherapy initiation is estimated to be 112 days longer for patients with combination therapy (459 days, 95%CI 393-536) compared to chemotherapy only (347 days, 95%CI 308-392). The restricted mean local progression free time within 24 months is estimated to be 112 days (95%CI 36-187) longer and the probability of downstaging is 22.3% higher (95%CI 5.12-39.5, p=0.03) with combination therapy. Eighteen and fifteen patients continued to have follow-up CE-EUS at 4 weeks and 12 weeks respectively, post-implantation. Baseline (pre-implantation, post-chemotherapy) median intensity gain of contrast enhancement within the tumour increased from 32.15 (IQR 18.08-54.35) to 46.85 (IQR 35.05-76.6; p=0.007) and 66.3 (IQR 54.7-76.3; p=0.001) 4 weeks and 12 weeks post-implantation respectively.

Conclusion: This is the first comparative study between chemotherapy and ³²P implantation and standard therapy in patients with LAPC, demonstrating survival, disease control and downstaging benefits. The increased microvascular flow with combined therapy likely allows more delivery of chemotherapy to the tumour and thus, could explain its encouraging outcomes.