In the United Kingdom, 11,700 people were diagnosed and 10,000 people died from pancreatic cancer in 2020 [1]. The incidence of pancreatic cancer is increasing in the United Kingdom and in many other countries worldwide [2-9]. If the trend continues, it is likely to become the third-most common cause of cancer death in the United Kingdom by 2030 [10]. Surgical resection remains the only treatment with the potential for long-term survival and cure. However, only about 10% to 20% (n=~61,203) of patients are suitable for resection [8,11-13]. In people who do not undergo resection, the main options are chemotherapy, chemoradiotherapy, and treatment of symptoms [13-18]. The major symptoms related to pancreatic cancer, particularly in those with unresectable cancers, are pain, cachexia, and jaundice. In this work, we will be looking at the evidence for the management of pain and cachexia.

Pancreatic cancer can cause severe pain. It is estimated that 70% to 80% of people with pancreatic cancer seek medical help for the treatment of abdominal or back pain [19,20]. The 2 major mechanisms of pain are pancreatic ductal obstruction and pancreatic neuropathy (increased activation of pain nerve fibers) [20]. The main treatment options evaluated for pancreatic cancer pain include nonopioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics such as morphine, corticosteroids, neuropathic pain medications such as gabapentin or pregabalin, palliative radiotherapy, thoracoscopic splanchnicectomy (severing the splanchnic nerves), celiac plexus nerve blocks or neurolysis, and other treatments include pancreatic duct stenting, acupuncture, and hypnosis [20-24]. Review 1 is a systematic review focusing on the benefits and harms of the different pain control strategies in people with unresectable pancreatic cancer. There are no previous network meta-analyses (NMA) on the topic. Head-to-head comparison systematic reviews included comparison of celiac plexus nerve block plus analgesics with analgesics alone [23,25,26] and videothoracoscopic splanchnicectomy [27], stereotactic radiotherapy [28], various ablative therapies [29], kanglaite (Chinese medicine) in addition to chemoradiotherapy versus chemoradiotherapy alone [30]. The current clinical guidelines on the management of pain in pancreatic cancer are based on the World Health Organization’s 3-step ladder for cancer pain [31]. The National Institute of Health and Care Excellence (NICE) suggests nonpharmacological treatments such as coeliac plexus blocks when the pharmacological treatment fails or is unacceptable because of adverse events [32], a recommendation that has been questioned [21]. The NICE acknowledged the uncertainty in the recommendation [32].

Cancer cachexia is a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment [33]. An estimated 55% to 85% (n=~170) of people with pancreatic cancer have cachexia [34,35]. The major proposed mechanism for cachexia of pancreatic cancer is decreased appetite, decreased production and increased lysis of lipids, increased protein lysis, decreased liver function, fat malabsorption, and decreased muscle mass due to increased cytokines and tumor-derived factors [34,36,37]. Mechanical intestinal obstruction due to the cancer, pancreatic exocrine insufficiency, and nutritional deficiency because of the combination of the above factors are other potential mechanisms [34,36,37]. Interventions evaluated for the prevention and treatment of cachexia include pancreatic enzyme replacements, increased calorie intake, ketogenic diet, amino acid supplementation, nutritional supplements, appetite stimulants, corticosteroids, NSAIDs, progesterone analogues such as megestrol acetate, cytokine inhibitors such as melatonin, omega-3 fatty acids, and exercises to improve muscle mass [37-39]. Review 2 is a systematic review of the prevention and treatment of cachexia in people with pancreatic cancer. There are no previous NMAs on the topic. The existing systematic reviews on the topic are different from this study because of the types of studies included [40,41], types of interventions included [40-42], risk of bias assessment [40-42], and the type of outcome measures studied [40-42]. The NICE guideline on pancreatic cancer does not recommend anything specific for cachexia [32]; however, only nutritional interventions (for cachexia) were evaluated.

Increased pain decreases the health-related quality of life [43]. Cancer cachexia can lead to decreased health-related quality of life and may increase treatment complications, health care costs, and deaths [44]. Low performance status due to cachexia may preclude patients receiving more toxic but effective treatments such as the combination chemotherapy FOLFIRINOX [45]. The research questions included in this study are among the top 10 research priorities of the James-Lind Alliance Priority Setting Partnership on pancreatic cancer therapy involving people with pancreatic cancer in Germany, their carers, and clinicians treating them [46,47], that is, “How can the best treatment for each individual patient with pancreatic cancer be identified?” and “Does nutrition influence the survival or quality of life of patients with pancreatic cancer?” Furthermore, the use of evidence-based clinical care pathways in the National Health Service (NHS) helps to streamline care and avoid health care inequities and therefore would be beneficial for the management of pain and cachexia in people with pancreatic cancer.

The overarching aim of this study is to answer the following research question: “What is the best treatment and NHS care pathway to decrease pain and cachexia and improve health-related quality of life in people with pancreatic cancer?”

The primary objectives include the following:

The secondary objectives include the following:

We will perform two systematic reviews:

We will register the protocols in PROSPERO (International Prospective Register of Systematic Reviews) and conduct and report the systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and its extension for NMA [48,49] (Table 1).

The choice of outcomes is based on the Core Set of Patient-Reported Outcomes in Pancreatic Cancer (ie COPRAC) study that involved patients with pancreatic cancer and health care professionals involved in their care [50]. We will collect all outcomes at 3 time points: until 3 months from randomization or intervention, 3 to 12 months from randomization or intervention, and beyond 12 months.

The primary outcomes include the following:

The secondary outcomes include the following:

The following electronic databases will be searched to retrieve all eligible studies: The Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (OvidSP); Embase (OvidSP); and Science Citation Index Expanded (Web of Knowledge); Conference Proceedings, from inception to date of search using free text and controlled vocabulary terms; ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform [52], which searches various trial registers, including ISRCTN and ClinicalTrials.gov. The search strategies are provided on the web-based published study registration records on PROSPERO (CRD42022333239 and CRD42022333241).

Additionally, we will search the references of the identified trials and the existing recent major systematic reviews on the topics to identify additional trials for inclusion. We will also contact the study authors to identify further trials and obtain aggregate data from unpublished studies.

The information from work package 1 (both systematic reviews and NMA) will be supplemented by surveys and focus group discussions involving patients, carers, and health care professionals. We aim to engage these key stakeholders in a discussion about the acceptability and feasibility of interventions toward developing an evidence-based clinical care pathway for the management of pain and cachexia in pancreatic cancer.

Two web-based surveys will be performed: one directed to patients or carers and the other to health care professionals. Both surveys will address pain and cachexia symptoms in turn and will precede the focus group discussions. Both surveys will include a question asking respondents whether they would be willing to participate in a focus group to further discuss the acceptability and feasibility of the different treatments toward the development of a care pathway for pancreatic cancer pain and cachexia. In this way, we will recruit members for the subsequent focus group discussions. The surveys will be hosted via a web-based survey platform using REDCap software. We will also offer a word-processing version, as well as paper surveys with stamped return envelopes, to increase participation. There will be an appropriate mix of closed questions to allow for quantitative analysis and open questions enabling free-text, qualitative responses. The survey templates are available from the researchers upon request. We will use the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) when formally reporting the results of the surveys for publication [67].

We will conduct focus group discussions involving patients, their carers, and health care professionals to develop a care pathway using the information from the systematic reviews (work package 1) and the surveys described above. Having a rich, mixed focus group (50% patients and carers and 50% health care professionals) will enable all participants to discuss their respective opinions and comments regarding the acceptability and feasibility of treatments, thereby enabling a consensus to be reached.

We will present the evidence from the systematic reviews and meta-analysis, and acceptability of treatments for each of pain and cachexia in two ways:

Similarly, we will then present the feasibility of treatments in the NHS for each of pain and cachexia in 2 ways:

After the presentation of the results of the surveys, the focus group will begin in-depth discussions to review the findings. The focus group discussions will focus around areas of contention—that is, interventions that are acceptable to patients but not very feasible to deliver in NHS or vice versa, or interventions that are highly acceptable but limited efficacy is found in the systematic review. Additionally, further discussions will take place regarding the most appropriate site of delivery of interventions. The templates for the focus group discussions are available from the researchers on request. We anticipate 2 focus group discussions (involving 8 to 12 participants each) covering each symptom (ie, 2 focus groups for pain interventions and 2 focus groups for cachexia interventions). Each round will be iterative, in that findings from the first focus groups in each symptomology will feed into each of the second focus group discussions. Each focus group’s meeting is expected to last from 60 to 90 minutes. We plan to conduct the focus group meetings in-person; however, we have the flexibility to conduct the meetings on the web via Microsoft Teams or using a hybrid model, if preferable for participants. We will record all focus group discussions and use General Data Protection Regulation–compliant transcription services for transcribing the discussions for analysis. The transcript will not contain any identifiable participant details.

The focus group discussions will be analyzed using the Framework method [68], using a preliminary logic model developed following Phase 1 of the study to inform the development of the analytical framework. This logic model will describe the theory underlying a potential care pathway for the management of pain and cachexia and will use a Situation (pain, cachexia)–Inputs (resources)–Outputs (activities)–Mechanism –Outcomes (short and longer terms) configuration [69,70]. The focus group data will be coded and mapped onto this framework and further themes and subthemes will be developed and used to modify the logic model as required. Regular research team discussions will be held to ensure that the coding scheme reflects the data. We will use the Standards for Reporting Qualitative Research when formally reporting the results of the focus group discussions for publication [71].

We anticipate the development of a proposed care pathway in further iterative communications among the research team and relevant additional health care professionals (depending upon the intervention) identified through National Cancer Research Institute Upper Gastrointestinal Group (Pancreatic cancer Workstream), thus reaching a final agreement via email or teleconferences.

The research team includes a patient representative who was involved in the preparation of the grant project proposal and determined that this research was important to patients. The patient representative will be part of the research oversight committee for the project and will help to facilitate the focus group discussions.

This study was approved by the University College London Research Ethics Committee (Ethics number: 23563/001).

This study will provide comprehensive coverage of all the major interventions for the management of pain in people with pancreatic cancer not suitable for pancreatic resection, and for the prevention and treatment of cachexia in people with pancreatic cancer regardless of whether they are suitable for pancreatic resection. It will also be the first time for network meta-analysis to be used for the systematic review on the management of pain in people with unresectable pancreatic cancer, which has several advantages in terms of evaluating multiple treatment comparisons, and enabling calculation of additive main effects, 2-way interactions, and the full interaction models, which allow us to find out if there are any interactions between different combinations of treatments. However, the main limitation of the study is that sufficient outcome data may not be available from the randomized trials to enable network meta-analysis to be performed.

Nevertheless, this study will identify the gaps in the existing research that cause uncertainty in decision-making in the management of pain and cachexia in people with pancreatic cancer. A further strength is that the study will consult key stakeholders in the development of an evidence-based care pathway for pain and cachexia in pancreatic cancer, ensuring acceptability for patients and carers and feasibility for delivery in the NHS.

The team will disseminate the findings of the research through patients group websites, social media groups, conferences, and publish the findings in peer-reviewed journals.