Introduction
Pain radiating from the lower back to the upper abdomen, often referred to as ‘retroperitoneal pain syndrome’, is commonly observed in patients with advanced pancreatic cancer or retroperitoneal lymphadenopathy [1, 2]. Despite its high intensity, this pain is frequently refractory to systemic analgesics and co-analgesics, leading to uncontrolled pain and adverse effects associated with high doses of non-opioids and opioids, such as constipation, sedation, nausea, and opioid-induced hyperalgesia. These issues significantly impair patients’ quality of life [1, 3]. Although there are several interventional therapeutic approaches, such as celiac nerves radiofrequency, and celiac plexus neurolysis or block, their effectiveness is not always sufficient. Moreover, many patients are not considered as candidates due to the anatomical alterations caused by local invasion of the disease [4–6]. Historically, this has resulted in a substantial number of patients suffering from severe, uncontrolled pain with no further treatment options available. Retrospective studies have suggested that more accessible palliative radiotherapy (RT) may serve as an alternative option. However, the investigated approaches were limited to basic low-dose, tumour-directed RT, unlikely to have ablative effects, and lacking data from prospective studies [4, 7, 8]. Dr. Yaacov Lawrence has hypothesised that merging ‘state-of-the-art’ stereotactic body radiation therapy (SBRT) with a novel concept of organ-at-risk-adapted dose-painting could help to achieve consistently safe delivery of high ablative doses, despite the challenging location and large size of the target volume. The conception of this idea is described in detail in Supplementary 1.
Data from prospective trials
Celiac plexus radioablation (CPR) was initially investigated in a preliminary, proof-of-concept, prospective, single-arm trial (NCT02356406). This study aimed to establish clinical feasibility and refine the method [9]. Eighteen patients were included; initially treated with 45 Gy in 5 fractions, the protocol was later amended to a single 25 Gy fraction. Although fractionation is an appealing strategy to reduce the risk of radiation-induced toxicity, it is important to recognise that this treatment targets a particularly vulnerable and frail patient population suffering from severe uncontrolled pain. For these patients, a 2-week-long SBRT course and 5 radiation procedures may represent an unfeasible burden. Instead, sophisticated RT methods were employed to ensure safety and allow patients to receive treatment during a single RT session. The trial was successful; 3 weeks post-treatment, 13 out of 18 patients experienced meaningful pain relief. The median pain intensity, assessed using the 11-point numerical rating scale (NRS), decreased from 6.2 to 3. Furthermore, none of the patients reported treatment-related adverse events (AEs) of grade 3 or worse [9].
Subsequently, an international phase II clinical trial was conducted to assess the efficacy of single-fraction CPR (NCT03323489) [10]. The trial accrued patients with uncontrolled pain, with an average NRS pain score of ≥ 5 despite use of analgesics and co-analgesics, over the course of pancreatic cancer or other malignancy involving the celiac axis. The primary endpoint was the rate of clinically significant pain relief, defined as ≥ 2 points reduction in the ‘average pain’ domain of the brief pain inventory – short form (BPI-SF) questionnaire at 3 weeks after procedure. Of 149 patients enrolled in the trial, 125 received CPR between 2018 and 2022, and 90 met the pre-defined eligibility criteria for evaluation. Conservatively assuming that non-reporting patients are non-responders, 53.3% and 54.4% achieved clinically significant pain relief at 3 and 6 weeks, respectively. Moreover, patients experienced a significant improvement in pain interference across almost all domains assessed in the BPI-SF, and a decrease in the use of rapid-onset opioid medications. The treatment was well tolerated. In total, 5 serious AEs were classified as possibly treatment-related, all of which are also considered as possible manifestations of the disease progression. A major limitation was a significant subset of patients who did not respond to the treatment, and the authors could not identify strong prognostic factors for treatment response [11].
Development of a practical Polish-language manual
The celiac plexus radioablation was soon included in the National Comprehensive Cancer Network practical guidelines for management of patients with pancreatic adenocarcinoma [12], and mentioned in the Polish guidelines for management of cancer-related pain [6], where CPR was performed for the first time in Europe [13]. However, the therapeutic management of these patients is complicated, and the complex RT planning approach might present a challenge to many clinicians. To facilitate the implementation of CPR in clinical practice, we decided to prepare a comprehensive practical Polish-language manual. The document covers the basics of pharmacotherapy, patient selection, RT planning, peri-procedural management, and finally, the treatment delivery. The description is based on a previously published study protocol [10], but most importantly, it draws on the authors’ expertise gained from treating numerous patients. We hope that through this document we will be able to help clinicians implement CPR in clinical practice and provide treatment access to more patients. The Polish-language manual can be found online attached to the manuscript as Supplementary File 2, along with an English-language translation (Supplementary File 3).
Future directions
Following the analysis of primary outcomes, we are conducting several analyses of the clinical data related to secondary trial aims, as well as detailed imaging data analyses. There remains an open question as to how we can better identify patients who would most benefit from CPR. Additionally, the novel solutions implemented in CPR could result in a steep learning curve. We believe it is beneficial to monitor real-world treatment outcomes to determine if they align with those from the rigorous phase II perspective clinical trial.
To address this, we are currently developing a collaborative, consortium-like, multicentre observational trial aimed at capturing data from patients treated with CPR. Many patients undergoing palliative treatment are not followed up in radiotherapy departments due to their serious disease burden and different immediate needs. We propose using telemedicine solutions, such as email or electronic questionnaires, to collect data. Treatment qualifications and decisions will be at the discretion of the attending physicians, who will obtain informed consent from patients. Outcome data will then be periodically collected using patient-preferred methods. In the future, this collected data could help verify the efficacy of the treatment in a real-world setting and provide additional data on prognostic factors for pain response. An equally important immediate result of the trial would be facilitating experience-sharing among co-investigators, thus improving access to CPR by aiding new centres in performing the first procedures. We encourage readers to contact the corresponding author for further information.
Coda
Retroperitoneal pain syndrome, often caused by the infiltration of the celiac plexus by advanced pancreatic cancer, frequently requires measures beyond conventional pharmacotherapy to control the pain. CPR is a novel treatment method combining state-of-the-art technology with advanced RT planning techniques, designed to improve patients’ access to an interventional treatment method for otherwise uncontrolled pain. In this article, we briefly describe the history of the method’s development and provide a summary of the most important findings from the prospective trials that led to the introduction of CPR into clinical guidelines. Most importantly, we provide readers with a comprehensive practical manual, available online in both Polish and English, to facilitate the introduction of CPR into clinical practice.
