Locally Advanced Pancreatic Cancer After Systemic Therapy: Ablative MR-guided Radiotherapy

Rationale: About 40% of patients with pancreatic cancer are diagnosed with locally advanced pancreatic cancer (LAPC). Recommended treatment consists of chemotherapy to prevent disease dissemination and prolong survival. Nevertheless, local tumor growth often causes severe morbidity, including pain, gastrointestinal obstruction, and malnutrition. This has a substantial negative impact on health-related quality of life (HRQoL). Eventually, one-third of patients die due to local tumor growth rather than from systemic disease spread. For palliation of symptoms and improved local tumor control, potentially prolonging survival, minimally-invasive ablative therapies may be effective. Online adaptive stereotactic Magnetic Resonance-guided radiotherapy (MRgRT) is an innovative treatment modality that enables high-precision ablative radiotherapy for pancreatic tumors. This potentially improves RT efficacy without increasing the risk of RT-related toxicity. Consequently, MRgRT holds promise for the treatment of pancreatic cancer.

Objective: To investigate the efficacy of stereotactic MRgRT on HRQoL deterioration-free survival, including death as an event, in patients with LAPC after systemic chemotherapy.

Study design: Nationwide randomized controlled trial (1:1 randomization).

Study population: Patients with LAPC according to Dutch Pancreatic Cancer Group (DPCG) criteria who are not eligible for tumor resection after at least two months of chemotherapy (sample size 150 patients). Also, patients with LAPC who are eligible but choose to refrain from chemotherapy and/or surgery can participate in this trial.

Intervention: Patients in the intervention arm receive 50Gy MRgRT in five fractions over two weeks in one of the four Consortium Centers, followed by standard care, either consisting of continuation of chemotherapy or best supportive care. Patients in the control arm continue standard care without ablative MRgRT.

Main study endpoints: The primary outcome is HRQoL deterioration-free survival from the time of randomization, defined as the Time Until Definitive Deterioration (TUDD) including death as an event. HRQoL is evaluated using the EORTC QLQ-C30 Summary Score. The TUDD is defined as a 10-point minimal clinically important difference compared to baseline, with no further improvement of ≥10 points afterwards. All patients will be offered home monitoring using the Trial@home platform to decrease the burden of trial participation.

• Overall survival [Time frame: From the date of LAPC diagnosis untill either death from any cause or last follow-up, whichever came first, assessed up to 18 months]
• Patient reported Quality of Life EORTC QLQ-PAN26 [Time frame: At baseline and at 2,4, weeks and subsequently every 2 months. Assessed through study completion, up to 18 months]
• Patient reported Quality of Life EORTC QLQ-C30 [Time frame: At baseline and at 2,4, weeks and subsequently every 2 months. Assessed through study completion, up to 18 months]
• Patient reported Quality of Life EQ5D-5L [Time frame: At baseline and at 2,4, weeks and subsequently every 2 months. Assessed through study completion, up to 18 months]
• The need of subsequent treatments [Time frame: Through study completion, an average of 18 months]
• Treatment response assessed on CT-imaging (graded according to RECIST guidelines) [Time frame: with available imaging during 18 months follow-up]
• CA 19.9 response [Time frame: Through study completion, an average of 18 months]
• Trial@home monitoring related outcome: feasibility Withings Steel HR smartwatch [Time frame: Through study completion, an average of 18 months]
• Trial@home monitoring related outcome: feasibility Body+ scale [Time frame: Through study completion, an average of 18 months]
• Trial@home monitoring related outcome: feasibility Whitings Sleep [Time frame: Through study completion, an average of 18 months]
• Trial@home monitoring related outcome: feasibility ePRO application [Time frame: Through study completion, an average of 18 months]
• Trial@home monitoring related outcome: digital biomarkers [Time frame: Through study completion, an average of 18 months]