Dataset Information

Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

ABSTRACT:

Purpose

The effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC.

Patients and methods

Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT.

Results

Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8-2.0 months] and 3.3 months (95% CI, 1.2-6.6 months) in cohort A1; 2.5 months (95% CI, 0.1-3.7 months) and 9.0 months (95% CI, 0.5-18.4 months) in A2; 0.9 months (95% CI, 0.7-2.1 months) and 2.1 months (95% CI, 1.1-4.3 months) in B1; and 2.3 months (95% CI, 1.9-3.4 months) and 4.2 months (95% CI, 2.9-9.3 months) in B2.

Conclusions

The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.

SUBMITTER: Xie C

PROVIDER: S-EPMC8284008 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPain symptoms in the upper abdomen and back are prevalent in 80% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), where the current standard treatment is a systemic therapy consisting of at least doublet-chemotherapy for fit patients. Palliative low-dose radiotherapy is a well-established local treatment option but there is some evidence for a better and longer pain response after a dose-intensified radiotherapy of the primary pancreatic cancer (pPCa). Stereotactic body radiation therapy (SBRT) can deliver high radiation doses in few fractions, therefore reducing chemotherapy-free intervals. However, prospective data on pain control after SBRT of pPCa is very limited. Therefore, we aim to investigate the impact of SBRT on pain control in patients with mPDAC in a prospective trial.MethodsThis is a prospective, double-arm, randomized controlled, international multicenter study testing the added benefit of MR-guided adaptive SBRT of the pPca embedded between standard of care-chemotherapy (SoC-CT) cycles for pain control and prevention of pain in patients with mPDAC. 92 patients with histologically proven mPDAC and at least stable disease after initial 8 weeks of SoC-CT will be eligible for the trial and 1:1 randomized in 3 centers in Germany and Switzerland to either experimental arm A, receiving MR-guided SBRT of the pPCa with 5 × 6.6 Gy at 80% isodose with continuation of SoC-CT thereafter, or control arm B, continuing SoC-CT without SBRT. Daily MR-guided plan adaptation intents to achieve good target coverage, while simultaneously minimizing dose to organs at risk. Patients will be followed up for minimum 6 and maximum of 18 months. The primary endpoint of the study is the "mean cumulative pain index" rated every 4 weeks until death or end of study using numeric rating scale.DiscussionAn adequate long-term control of pain symptoms in patients with mPDAC is an unmet clinical need. Despite improvements in systemic treatment, local complications due to pPCa remain a clinical challenge. We hypothesize that patients with mPDAC will benefit from a local treatment of the pPCa by MR-guided SBRT in terms of a durable pain control with a simultaneously favorable safe toxicity profile translating into an improvement of quality-of-life.Trial registrationGerman Registry for Clinical Trials (DRKS): DRKS00025801. Meanwhile the study is also registered at ClinicalTrials.gov with the Identifier: NCT05114213.

Project description:Purpose/objectivesRetrospective analysis suggests that dose escalation to a biologically effective dose of more than 70 Gy may improve overall survival in patients with pancreatic ductal adenocarcinoma (PDAC), but such treatments in practice are limited by proximity of organs at risk (OARs). We hypothesized that CT-guided online adaptive radiotherapy (OART) can account for interfraction movement of OARs and allow for safe delivery of ablative doses.Materials/methodsThis is a single institution retrospective analysis of patients with PDAC treated with OART on the Ethos platform (Varian Medical Systems, a Siemens Healthineers Company, Palo Alto). All patients were treated to 40 Gy in 5 fractions. PTV overlapping with a 5 mm planning risk volume expansion on the stomach, duodenum and bowel received 25 Gy. Initial treatment plans were created conventionally. For each fraction, PTV and OAR volumes were recontoured with AI assistance after initial cone beam CT (CBCT). The adapted plan was calculated, underwent QA, and then compared to the scheduled plan. A second CBCT was obtained prior to delivery of the selected plan. Total treatment time (first CBCT to end of radiation delivery) and active physician time (first to second CBCT) were recorded. PTV_4000 V95 %, PTV_2500 V9 5%, and D0.03 cc to stomach, duodenum and bowel were reported for scheduled (S) and adapted (A) plans. CTCAEv5.0 toxicities were recorded. Statistical analysis was performed using a two-sided T test and α of 0.05.Results21 patients with unresectable or locally-recurrent PDAC were analyzed, with a total of 105 fractions. Average total time was 29 min and 16 s (16:36-49:40) and average active physician time was 19:41 min (9:25-39:34). All fractions were treated with adapted plans. 97 % of adapted plans met PTV_4000 V95.0 % >95.0 % coverage goal and 100 % of adapted plans met OAR dose constraints. Median follow up was 6.6 months. Only 1 patient experienced acute grade 3+ toxicity directly attributable to radiation. Only 1 patient experienced late grade 3+ toxicity directly attributable to radiation.ConclusionsDaily CT-based OART was associated with significantly reduced dose OARs while achieving superior PTV coverage. Given the relatively quick total treatment time, radiation delivery was generally well tolerated and easily incorporated into the clinic workflow. Our initial clinical experience demonstrates OART allows for safe dose escalation in the treatment of PDAC.