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RICOCHET study supplement

This supplement has been commissioned and funded by Viatris and developed in partnership with Guidelines. See bottom of page for full disclaimer.

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Foreword: Mr Keith Roberts, Consultant pancreatic surgeon, University Hospitals Birmingham; Royal College of Surgeons specialty lead for pancreatic cancer; lead investigator for the RICOCHET Study Group

Pancreatic cancer outcomes can be improved through multidisciplinary care and, importantly, by ensuring that patients receive care and treatments based upon best evidence.1 The 2018 NICE pancreatic cancer guideline provides a guide for how care should look in the UK;2 however, there is much variation and there are concerns that optimal care is not experienced by all patients.3

Following the publication of the NICE guideline, we undertook a national prospective audit of pancreatic cancer care (RICOCHET) in the summer of 2018. Across the UK, 84 hospitals and over 500 collaborators provided data to the largest ever audit of pancreatic cancer care. One of the key aims of the audit was to determine the use of pancreatic enzyme replacement therapy (PERT).4

There is clear evidence of benefit to patients when pancreatic exocrine insufficiency (PEI) is treated with PERT.1,5 PEI is highly prevalent among patients with pancreatic cancer.4–6 It is progressive, is difficult to identify because symptoms overlap with the underlying cancer, and if left untreated leads to weight loss, unpleasant symptoms, and frailty.6 When PEI is treated with PERT, patients maintain their weight, have fewer symptoms, are more likely to receive chemotherapy, and live longer.7 In a recent risk-adjusted analysis of over 1600 patients with pancreatic adenocarcinoma, PERT was associated with increased survival, regardless of the studied sub-group with respect to use of surgery or chemotherapy.8

For patients with unresectable cancer, often the only treatment suitable is best supportive care; among these patients, near the end of life, PERT can improve symptoms and quality of life.7 For patients receiving chemotherapy with or without surgery, PERT will help patients meet their daily nutrition requirements, meaning that they will preserve their strength and are thus more likely to be able to tolerate their anti-cancer treatments.9 Furthermore, with ever increasing complex pathways, such as neoadjuvant therapy and more aggressive chemotherapies such as FOLFIRINOX, ensuring that patients are protected against malnutrition is vital so that they have the best chance of completing their treatments.

For these reasons, the NICE guideline recommends offering PERT to patients with unresectable pancreatic cancers and to consider offering it before and after pancreatic cancer resection.2 Yet, our national audit shows widespread variation and underuse of PERT.4 The data is encouraging as there is increased prescribing when compared to an earlier UK national cohort, but PERT in pancreatic cancer remains a work in progress.

Conflicts of interest

Mr Roberts received an honorarium from Viatris for his work on this supplement and has received honoraria from Viatris and Abbott to speak on PEI/PERT.

References

  1. Roberts K. Br J Surg 2017; 104 (11): 1421–1423.
  2. NICE. Pancreatic cancer in adults: diagnosis and management. NICE Guideline 85. NICE, 2018. Available at: www.nice.org.uk/ng85.
  3. Henson K et al. Br J Cancer 2018; 118 (10): 1382–1390.
  4. The RICOCHET Study Group on behalf of the West Midlands Research Collaborative. Pancreatology 2021; 21 (6): 1127–1134.
  5. Landers A et al. Palliat Care 2019; 12: 1178224218825270.
  6. Sikkens E et al. J Clin Gastroenterol 2014; 48 (5): e43–e46.
  7. de la Iglesia D et al. United European Gastroenterol J 2020; 8 (9): 1115–1125.
  8. Roberts K et al. Pancreatology 2019; 19 (1): 114–121.
  9. Domínguez-Muñoz J et al. BMC Cancer 2018; 18 (1): 534.

A national audit of pancreatic enzyme replacement therapy (PERT) prescribing in patients with pancreatic cancer: The RICOCHET study

Key points

  • NICE guidance recommends offering enteric‑coated pancreatin to patients with unresectable pancreatic cancers
  • NICE guidance recommends considering offering enteric‑coated pancreatin to patients before and after pancreatic cancer resection
  • There are wide variations in PERT prescribing for patients with pancreatic cancer across the UK
  • Specialist surgical centres have higher rates of prescribing than non-surgical hospitals
  • Patients with unresectable pancreatic cancer are disadvantaged by being less likely to be prescribed PERT
  • Contact with a clinical nurse specialist and/or dietitian increases the likelihood of PERT prescribing for patients with pancreatic cancer
  • Strategies are needed to disseminate good prescribing practice and overcome barriers to prescribing.

PEI=pancreatic exocrine insufficiency; PERT=pancreatic enzyme replacement therapy

Pancreatic cancer has a poor prognosis. The five-year survival rate is less than 7% and the UK has one of the worst survival rates in Europe, ranking 29th out of 33 countries. Most people with pancreatic cancer will not receive active treatment, with only around 10% receiving potentially curative surgery and 20% receiving chemotherapy. Early diagnosis enables prompt surgical treatment, with the five-year survival rate increasing to around 30% in patients who have tumours that can be removed surgically and who are given adjuvant chemotherapy.1–4

Since 2001, pancreatic surgical services in the UK have been centralised, with most operations taking place in specialist high-volume surgical hospitals, resulting in improved short-term and long-term outcomes for patients with resectable pancreatic cancer.5,6 Most patients with unresectable pancreatic cancer will be managed in non-surgical hospitals and referred when necessary.6 It is hoped that optimising diagnostic pathways will reduce the time to surgery for patients and that advances in personalised chemotherapy will further improve their outcomes.6–9

In addition to surgery and chemotherapy, healthcare professionals can do much to improve the quality of life of people with pancreatic cancer. NICE guidance highlights the importance of assessing and managing the psychological impact of fatigue, pain, gastrointestinal symptoms, nutrition, anxiety, and depression, as well as the need to manage pain and pancreatic exocrine insufficiency (PEI).2

Pancreatic exocrine insufficiency

PEI is a common complication of pancreatic cancer, in which patients experience malabsorption, causing symptoms such as steatorrhoea, weight loss, and malnutrition, resulting in a reduced quality of life and survival. Approximately half to two-thirds of patients with pancreatic cancer will have PEI at diagnosis, with the prevalence increasing after diagnosis.10,11

Malnutrition increases the burden on patients with pancreatic cancer, contributing to frailty, with cachexia and anorexia limiting their ability to undergo surgery or tolerate chemotherapy.12 Patients may require nutritional supplements and dietary changes alongside treatment for PEI to help them regain weight and rebuild muscle.13 PEI can be treated with pancreatic enzyme replacement therapy (PERT), which improves patients’ absorption and nutritional status. PERT increases the ability of patients with pancreatic cancer and PEI to tolerate treatment, and has been shown to improve their quality of life and increase survival.3,4,8,12,14,15

NICE issued guidance in 2018 that aimed to improve diagnostic pathways and provide faster access to treatment for patients with pancreatic cancer. One of its recommendations was that healthcare professionals should offer enteric-coated pancreatin to patients with unresectable pancreatic cancer, and they should consider offering enteric-coated pancreatin to patients before and after pancreatic cancer resection.2,3

Despite the importance of treating PEI, a population-based observational study published in 2019 found that nearly 80% of 4554 patients who had been diagnosed with pancreatic cancer in England between 1998 and 2015 were not given PERT.12 The reasons for this high level of under-treatment were not clear but the study authors suggested that a lack of clinical awareness and understanding of the potential benefits of addressing malnutrition could be responsible.12

The RICOCHET study

The ReceIpt of Curative resection Or palliative Care for HEpatopancreaticobiliary Tumours (RICOCHET) study was a UK multicentre, prospective, observational audit of patients with pancreatic cancer or malignant biliary obstruction. It aimed to highlight variations in diagnostic and management pathways for patients with pancreatic cancer across the UK and to determine factors associated with these variations and whether these impact patient outcomes.6,7 In May 2021, the RICOCHET Study Group published an analysis of the variation in PERT prescribing among patients with pancreatic cancer.6

Data were collected using the Research Electronic Data Capture platform for a 16‑week period from April to July 2018 at all UK hospitals included in the RICOCHET study. Patients were followed up for 90 days from presentation. Patients who received a diagnosis of pancreatic cancer during this period were included in the RICOCHET study (n=2550). Patients were excluded from the PERT analysis if they:6

  • were aged <16 years
  • had gallbladder or intrahepatic malignant lesions
  • had benign disease
  • died within 14 days of their first multidisciplinary team discussion
  • had missing PERT prescription data.

A total of 1350 patients from 84 NHS hospitals (59 non-surgical and 25 specialist surgical hospitals) suitable for PERT treatment were included in the analysis (Figure 1).6

The primary outcome of the study was the proportion of patients with pancreatic cancer who were prescribed PERT. Secondary outcomes related to factors associated with PERT prescription.6 Multivariable logistic regression was carried out with PERT prescription as the dependent variable for patients with and without resectable cancer.6

Figure 1

Which patients were given PERT?

Just over half of all patients with pancreatic cancer (54.5%; n=736/1350) were prescribed PERT. A larger proportion of those patients diagnosed with potentially resectable cancer were prescribed PERT (74.4%; n=319/429) compared with those with unresectable cancer (45.3%; n=417/921) (Figure 2).6

Figure 2

Potentially resectable cancer

PERT prescribing rates for patients with potentially resectable cancer varied according to their treatment pathway or stage of treatment. PERT was prescribed to:6

  • 96.6% of patients who had had resectional surgery
  • 74.5% of patients planned for surgery but for whom resection could not be carried out
  • 63.7% of patients receiving neoadjuvant therapy
  • 40.5% of patients awaiting surgery.

Table 1

Multivariable analysis (Table 1) showed that patients with potentially resectable cancer were more likely to be prescribed PERT if they:6

  • had a dietitian referral (odds ratio (OR)=3.78, 95% confidence interval (CI)=1.73 to 8.29, p=0.001)
  • were treated in a pancreato-biliary (PB) surgical hospital (OR=5.18, 95% CI=1.50 to 17.80, p=0.009)
  • were treated in a hepato-pancreato-biliary (HPB) surgical hospital (OR=2.07, 95% CI=1.00 to 4.27, p=0.049).

Unresectable cancer

PERT was prescribed to:6

  • 45.3% of patients with unresectable cancer.

Multivariable analysis (Table 1) showed that patients with unresectable cancer were more likely to be prescribed PERT if they had:6

  • a review with a clinical nurse specialist (OR=1.68, 95% CI=1.06 to 2.68, p=0.028)
  • a dietitian referral (OR=3.43, 95% CI=2.14 to 5.50, p<0.001).

Patients with unresectable cancer were less likely to be prescribed PERT if they had:6

  • increasing comorbidity (Carlson comorbidity score >7) (OR=0.36, 95% CI=0.17 to 0.78, p=0.010).

How did prescribing vary across hospitals?

The highest rates of PERT prescribing were found in PB surgical hospitals (84.6%, n=154/182), followed by combined HPB surgical hospitals (55.2%, n=376/681), with the lowest rates in non-surgical hospitals (42.3%, n=206/487). PERT prescribing rates in PB hospitals were higher than in HPB hospitals for both resectable (93.0% vs 76.3%, p<0.001) and unresectable (79.3% vs 40.5%, p<0.001) cancer (Figure 3).6

PERT prescribing rates in surgical hospitals were not associated with corresponding rates in their networked non-surgical referring hospitals.6

Figure 3

Discussion

This study was the first of its kind to examine national prescribing levels of PERT and to include patients with resectable and unresectable cancers who are managed in both surgical and non-surgical hospitals. The study found wide variation in PERT prescribing for patients with pancreatic cancer across the UK, despite NICE guidance recommending PERT treatment.2,3,6

Patients who were treated in surgical hospitals were much more likely to be given PERT, whether or not their cancer was resectable. Organisational factors may be at least partly responsible for the variation across treatment centres. The multidisciplinary teams working at hospitals that provide pancreato-biliary surgery had the highest rates of PERT prescribing but this good practice did not appear to disseminate through to their referring non-surgical hospitals. Figure 4 shows that there was also variation in PERT prescribing across the specialist centres.6

Figure 4

More than two-thirds of patients in the study had unresectable disease. The lower rate of PERT prescribing in patients with unresectable cancer compared with those with resectable cancer indicates that patients who are managed palliatively are less likely to receive optimised treatment.6

The level of PERT prescribing among patients with resectable cancer seems to vary according to where they are along the treatment pathway, with the lowest rate of prescribing found in those waiting for surgery.6

An interesting finding was that having a contact with a clinical nurse specialist or dietitian meant that patients were more likely to be prescribed PERT.6

The RICOCHET authors suggest that the lack of an accurate diagnostic test for PEI could have been a barrier to prescribing PERT for the healthcare professionals in this study.6

The NICE guidelines were published only a few months before data collection was carried out for the RICOCHET study, so it is possible that more time might have been needed for the recommendations to filter out to the healthcare professionals involved in the study before PERT prescribing rates increased.6

Strategies to improve PERT prescribing

The authors suggest some strategies to improve the rate of PERT prescribing for patients with pancreatic cancer:6

  • identify local reasons for poor prescribing practice. While the centralisation of services has improved the delivery of complex surgery in specialist centres,8 it could perhaps lead to deskilling of healthcare professionals in the referring hospitals as they become regarded as ‘non-specialists’ in pancreatic cancer management.
  • ensure that patients in all hospital settings are referred to a dietitian and have input from a clinical nurse specialist as contact with these healthcare professionals increases the likelihood of PERT prescription.
  • specialist surgical centres should work to disseminate best practice to their referring centres. Hub-and-spoke healthcare design which arranges service provision into a central hub (the specialist surgical hospital) and outer spokes (the non-surgical referring hospitals) requires the development of relationships between network establishments to work effectively and reduce variation in practice.7,16

Conclusion

Even though national guidance recommends the use of PERT to treat PEI and improve the quality of life and survival for patients with pancreatic cancer, prescribing levels across the UK vary enormously. Strategies are, therefore, needed urgently to address these disparities in care and ensure that all patients with pancreatic cancer receive optimal treatment.

References

  1. Pancreatic Cancer UK. Pancreatic cancer statistics. www.pancreaticcancer.org.uk/what-we-do/media-centre/pancreatic-cancer-statistics (accessed 4 October 2021).
  2. NICE. Pancreatic cancer in adults: diagnosis and management. NICE Guideline 85. NICE, 2018. Available at: www.nice.org.uk/ng85
  3. NICE. Pancreatic cancer. Quality Standard QS177. NICE, 2018. Available at: www.nice.org.uk/qs177
  4. Landers A, Brown H, Strother M. The effectiveness of pancreatic enzyme replacement therapy for malabsorption in advanced pancreatic cancer, a pilot study. Palliat Care 2019; 12: 1178224218825270.
  5. Ahola R, Siiki A, Vasama K et al. Effect of centralization on long-term survival after resection of pancreatic ductal adenocarcinoma. Br J Surg 2017; 104 (11): 1532–1538.
  6. The RICOCHET Study Group on behalf of the West Midlands Research Collaborative. Pancreatic enzyme replacement therapy in patients with pancreatic cancer: a national prospective study. Pancreatology 2021; 21 (6): 1127–1134.
  7. RICOCHET Study Group, West Midlands Research Collective. Receipt of Curative Resection or Palliative Care for Hepatopancreaticobiliary Tumours (RICOCHET): Protocol for a Nationwide Collaborative Observational Study. JMIR Res Protoc 2019; 8 (7): e13566.
  8. Roberts K. Improving outcomes in patients with resectable pancreatic cancer. Br J Surg 2017; 104 (11): 1421–1423.
  9. Cancer Research UK: Precision-Panc. What is precision medicine?https://www.precisionpanc.org/patients-and-carers/what-is-precision-medicine/  (accessed 4 October 2021).
  10. Sikkens E, Cahen D, de Wit J et al. A prospective assessment of the natural course of the exocrine pancreatic function in patients with a pancreatic head tumor. J Clin Gastroenterol 2014; 48 (5): e43–e46.
  11. Tseng D, Molenaar I, Besselink M et al. Pancreatic exocrine insufficiency in patients with pancreatic or periampullary cancer: a systematic review. Pancreas 2016; 45 (3): 325–330.
  12. Roberts K, Bannister C, Schrem H. Enzyme replacement improves survival among patients with pancreatic cancer: results of a population based study. Pancreatology 2019; 19 (1): 114–121.
  13. Pancreatic Cancer UK. Diet and pancreatic cancer. PCUK, 2020. Available at: https://publications.pancreaticcancer.org.uk/collections/information-about-diet-and-digestion
  14. Roberts K, Schrem H, Hodson J et al. Pancreas exocrine replacement therapy is associated with increased survival following pancreatoduodenectomy for periampullary malignancy. HPB (Oxford) 2017; 19 (10): 859–867.
  15. Seiler C, Izbicki J, Varga-Szabo L et al. Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension. Aliment Pharmacol Ther 2013; 37: 691–702.
  16. Elrod J, Fortenberry Jr J. The hub-and-spoke organization design: an avenue for serving patients well. BMC Health Serv Res 2017; 17 (Suppl 1): 457.

Acknowledgement

Sonia Davies, independent medical writer, helped draft this document.

This supplement has been commissioned and funded by Viatris and developed in partnership with Guidelines. Viatris suggested the topic and foreword author, and carried out full medical approval on all materials to ensure compliance with regulations. The foreword author was paid an honorarium. The views and opinions expressed in this supplement are not necessarily those of Guidelines, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher.

NON-2021-4064

Date of preparation: February 2022