TA25 Pancreatic cancer - gemcitabine: guidance (html)

NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE

Gemcitabine for the treatment of pancreatic cancer

Issue Date: May 2001
Review Date: April 2004

This document has been circulated to the following:

• Health Authority Chief Executives in England and Wales
• NHS Trust Chief Executives in England and Wales
• PCG Chief Executives
• Local Health Group General Managers
• Medical and Nursing Directors in England and Wales
• Consultant Oncologists in England and Wales
• Chief Pharmacists, Heads of Drug Purchasing, Heads of Drug Information, Pharmaceutical Advisors, GP Prescribing Advisors and Purchase Advisors in England and Wales
• NHS Director Wales
• Chief Executive of the NHS in England
• NHS Executive Regional Directors
• Special Health Authority Chief Executives
• Community Health Councils in England and Wales
• Patient advocacy groups
• Commission for Health Improvement
• NHS Clinical Governance Support Team
• Chief Medical, Nursing Officers and Pharmaceutical Officers in England and Wales
• Medical Director & Head of NHS Quality - National Assembly for Wales
• Clinical Effectiveness Support Unit - Wales
• Representative bodies for health services, professional organisations and statutory bodies, Royal Colleges

This guidance represents the view of the Institute which was arrived at after careful consideration of the available evidence. Health professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.

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Copyright National Institute for Clinical Excellence 2001. All rights reserved. This material may be freely reproduced for educational and not for profit purposes within the NHS. No reproduction by or for commercial organisations is permitted without the express written permission of the Institute.

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This section (Section 1) constitutes the Institute's Guidance on the use of gemcitabine for pancreatic cancer. The remainder of the document is structured in the following way:

2. Clinical Need
3. The Technology
4. Evidence
5. Implications for the NHS
6. Further Research
7. Implementation
8. Review of Guidance
Appendix A: Appraisal Committee
Appendix B: Sources of Evidence
Appendix C: Information for Patients
Appendix D: Karnofsky Performance Score

1. Guidance

1.1 Gemcitabine may be considered as a treatment option for patients with advanced or metastatic adenocarcinoma of the pancreas and a Karnofsky performance score of 50 or more, where first line chemotherapy is to be used.

1.2 Gemcitabine is not recommended for patients who are suitable for potentially curative surgery, or patients with a Karnofsky (see Appendix D) score of less than 50.

1.3 There is insufficient evidence to support the use of gemcitabine as a second line treatment in patients with pancreatic adenocarcinoma.

2. Clinical Need and Practice

2.1 Pancreatic adenocarcinoma is a common cancer with an annual incidence rate of around 12 per 100,000. In 1997 there were an estimated 5,730 people (2,740 men and 2,990 women) diagnosed with pancreatic cancer in England and Wales. Of these 75% (4,320: 1,940 men and 2,380 women) were over 65 years of age.

2.2 The annual mortality rate from pancreatic cancer is almost identical to the incidence rate (11 per 100,000) as the prognosis is extremely poor. The 1-year survival rate is generally low at around 12%, and less than 3% of patients survive to 5 years.

2.3 The symptoms of pancreatic cancer are wide-ranging, including jaundice, nausea, diarrhoea, weight loss, loss of appetite, and severe pain. The vast majority of patients present with advanced disease and symptoms significantly reduce the patients' quality of life.

2.4 Potentially curative surgery is currently a treatment option for around 4% of the overall patient population. As the majority of cases are diagnosed at advanced stages, palliative care will often be the best that can be offered to relieve symptoms and the outcomes remain poor.

2.5 Palliative surgery and endoscopic placement of biliary drainage stents can be used to control complications of the pancreatic cancer such as jaundice and gastric outlet obstruction, thus improving quality of life.

2.6 Alternative treatment options include chemotherapy and radiotherapy. It is estimated that around 10-15% of patients diagnosed with pancreatic cancer currently receive chemotherapy.

2.7 5-fluorouracil (5-FU) has been the standard chemotherapy used in the UK over recent years, with evidence suggesting a small survival advantage and improvements in quality of life (QoL) in a proportion of patients with pancreatic cancer. 5-FU is administered using a variety of doses and schedules but the response rate rarely exceeds 20% and no consistent effect on disease-related symptoms or survival has been demonstrated.

3. The Technology

3.1 Gemcitabine (Gemzar) is a chemotherapeutic drug that exerts its action by inhibiting DNA synthesis. It is a novel nucleoside analogue with a wide spectrum of anti-tumour activity against a variety of solid tumours including pancreatic cancer.

3.2 Gemcitabine is licensed as a first line treatment of adult patients with locally advanced or metastatic adenocarcinoma of the pancreas and as a second line treatment of patients with 5-FU refractory pancreatic cancer.

3.3 Gemcitabine is generally well tolerated but may cause rashes and mild gastrointestinal side effects such as nausea. Bone marrow suppression, influenza-like symptoms, proteinuria/haematuria, peripheral oedema, bronchospasm, and in rare cases, Adult Respiratory Distress Syndrome (ARDS), and potentially irreversible renal failure have been reported.

4. Evidence

4.1 Clinical effectiveness

4.1.1 In the first line setting, five published randomised controlled trials (RCT) were identified. One trial compares gemcitabine with a bolus infusion of 5-FU and another with intra-arterial 5-FU (abstract only). In addition, three trials compare gemcitabine to metallomatrix proteinase inhibitors (two trials involve marimastat and one BAY12 9566).

4.1.2 There is thus only one fully reported single-blind RCT, reported by Burris et al, which compares gemcitabine to treatment with 5-FU as a first line treatment used on patients with a Karnofsky score of 50 or more (n=126). In this trial, patients randomised to gemcitabine had better one-year survival (18% vs 2%, p=0.0002), better median survival (5.6 vs 4.4 months, p=0.0025) and improved median progression free survival (2.3 vs 0.9 months, p=0.0002). However, in this trial the comparator, 5-FU, was given by bolus injection, not the standard current means of administration; and the results of this trial may be prone to bias due to lack of blinding of the investigators. Furthermore, the 12-month survival rate of 2% in 5-FU group is unusually low when compared with other published 5-FU studies.

4.1.3 The trial also evaluated the impact of gemcitabine on quality of life in terms of Clinical Benefit Response (CBR) and demonstrated that the administration of gemcitabine led to more clinical benefit responders compared to 5-FU (24% vs 5%, p=0.0022). However, although it has professional support CBR is not a validated tool and its ability to measure the effectiveness of palliative chemotherapy is still investigational.

4.1.4 No relevant RCTs were identified which examine the effect of gemcitabine as a second line treatment in patients with relapsed disease. One non-randomised Phase II trial, involving exclusively individuals with relapsed disease studied the effect of gemcitabine in 74 patients with metastatic pancreatic cancer that had progressed despite the administration of 5-FU. This study demonstrated a median survival of 4 months, one-year survival of 4% and CBR rate of 27%.

4.1.5 In the Burris trial, both gemcitabine and 5-FU were generally well tolerated. However toxicity was worse for gemcitabine; 26% of patients treated with gemcitabine had Grade 3 or 4 neutropenia compared with 5% in 5-FU group (p<0.01).

4.1.6 The role of gemcitabine in the treatment of pancreatic cancer in comparison with other agents including combination regimens is being investigated in 11 ongoing RCTs and 24 Phase II trials.

4.2 Cost effectiveness

4.2.1 Two published economic evaluations of gemcitabine as first line therapy for pancreatic cancer were identified, one of which was only available in abstract form. An economic evaluation of gemcitabine, in both first and second line treatment, was included in the Eli Lilly submission. ScHARR, on behalf of NICE, has undertaken its own analysis.

4.2.2 All of the economic analyses submitted drew on the effectiveness data from the single RCT by Burris et al. For first line treatment the estimates for cost per life year gained ranged from approximately £7,200 to £18,700 dependent on the 5-FU regimen used as comparator. These figures are very sensitive to reduced estimates of survival benefit over comparators.

4.2.3 Cost effectiveness evidence therefore suggests that gemcitabine provides a reasonably cost-effective alternative in the first-line treatment of pancreatic cancer but this conclusion is based on the results from one clinical trial.

5. Implications for NHS

5.1 Of 6,000 patients diagnosed with pancreatic cancer each year, at least 80% of them (4,800 patients) are estimated to have locally advanced or metastatic disease. Assuming that 25-35% of those will be offered chemotherapy and only half of them are treated, the total number of patients on gemcitabine would be in the range of 600 to 840 patients per year.

5.2 The incremental cost of gemcitabine treatment ranges between £1,360 and £3,550 per patient depending on the type of the 5-FU regimen. If gemcitabine were to be made available for routine NHS use, based on the estimated number of eligible patients above, the total additional cost to the NHS is estimated to be between £816,000 and £3m per annum. This includes the direct costs to the NHS such as drug costs and utilisation of health services.

6 Further Research

6.1 Further good quality studies are needed:

• to confirm the survival benefits, and the impact on QoL of gemcitabine as a first line treatment in comparison to commonly used 5-FU regimens.
• to identify the value of gemcitabine as a second line treatment in pancreatic cancer.
• to assess the cost-effectiveness of gemcitabine as a first and second line treatment in the light of any significant new effectiveness evidence.

7 Implementation

7.1 Clinicians should review their current clinical practice for the management of pancreatic cancer against the guidance set out in section 1.

7.2 Relevant clinical guidelines and protocols should be reviewed in light of this guidance and revised if necessary.

7.3 To enable clinicians to audit their own compliance with this guidance it is recommended that, if not already in place, management plans are recorded for each patient with pancreatic cancer.

7.4 This information should be incorporated into local clinical audit data recording systems and consideration given (if not already in place) to the establishment of appropriate categories in electronic record systems.

7.5 Prospective clinical audit programmes should record the proportion of treatments adhering to the guidance. Such programmes are likely to be more effective in improving patient care when they form part of the organisation's formal clinical governance arrangements and where they are linked to specific post-graduate activities.

8 Review of guidance

8.1 This advice will be reviewed in the light of new evidence in April 2004.

Andrew Dillon
Chief Executive>
May 2001

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APPENDIX A

Appraisal Committee Members

The Appraisal Committee is a statutory committee whose members sit for 3 years. Two meetings are held per month and the majority of members attend one of the other. Declared interest may also exclude a member from individual technology appraisals. The committee are supplemented by technology specific experts as indicated in Appendix B.

Professor R. L. Akehurst
Dean, School of Health Related Research
Sheffield University

Professor David Barnett (Chairman)
Professor of Clinical Pharmacology
University of Leicester

Professor Sir Colin Berry
Professor of Morbid Anatomy
St Bartholomew's and Royal London School of Medicine

Dr Sheila Bird
MRC Biostatistics Unit,
Cambridge

Professor Martin Buxton
Director of Health Economics Research Group
Brunel University

Professor Yvonne Carter
Professor of General Practice and Primary Care
St Bartholomew's and Royal London School of Medicine

Dr Karl Claxton
Lecturer in Economics
University of York

Professor Duncan Colin-Jones
Professor of Gastroenterology
University of Southampton

Professor Sarah Cowley
Professor of Community Practice Development
Kings College, London

Dr Nicky Cullum
Reader in Health Studies
University of York

Mr Chris Evennett
Chief Executive
Mid-Hampshire Primary Care Group

Professor Terry Feest
Clinical Director and Consultant Nephrologist
Richard Bright Renal Unit and Chairman of the UK Renal Registry

Ms Jean Gaffin
Formerly Executive Director
National Council for Hospice and Specialist Palliative Care Service

Mrs Sue Gallagher
Chief Executive
Merton, Sutton and Wandsworth Health Authority

Dr Trevor Gibbs
International Medical Operations Director
GlaxoWellcome R&D Ltd

Mr John Goulston
Director of Finance
The Royal Free Hampstead NHS Trust

Professor Philip Home
Professor of Diabetes Medicine
University of Newcastle

Dr Terry John
General Practitioner
The Firs, London

Dr Diane Ketley
Clinical Governance Programme Leader
Leicester Royal Infirmary

Dr Mayur Lakhani
General Practitioner,
Highgate Surgery, Leicester and Lecturer, University of Leicester

Mr M Mughal
Consultant Surgeon
Chorley and South Ribble NHS Trust

Mr James Partridge
Chief Executive
Changing Faces

Professor Philip Routledge
Professor of Clinical Pharmacology
University of Wales

Professor Andrew Stevens (Vice Chairman)
Professor of Public Health
University of Birmingham

 

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APPENDIX B

1. The following documentation and opinion was made available to the Committee:

a. Assessment Report prepared by The School of Health and Related Research (ScHARR), University of Sheffield (A Review of the Clinical and Cost-Effectiveness of Gemcitabine for the Treatment of Pancreatic Cancer, December 2000)

b. Manufacturer/Sponsor submissions from:

1. Eli Lilly

c. Professional/Specialist Group submissions from:

1. Royal College of General Practitioners
2. Royal College of Physicians and the Royal College of Radiologists

d. Patient Group submissions from:

1. CancerBACUP

e. External expert and patient advocate submissions from:

1. Professor William Steward, Head, Department of Oncology, Leicester Royal Infirmary
2. Ms Judith Brodie, Head of Cancer Support Service, CancerBACUP

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Appendix C

Patient Information

Guidance on the use of gemcitabine for the treatment of pancreatic cancer

The patient information in this appendix has been designed to support the production of your own information leaflets. You can download it from our website at www.nice.org.uk where it is available in English and Welsh. If you would like printed copies of the leaflets please ring the NHS Response Line on 0870 1555 455 and quote reference number 23813 for the English patient leaflet and 23814 for the bi-lingual patient leaflet.

What is NICE Guidance?

The National Institute for Clinical Excellence (NICE) is a part of the NHS. It produces guidance for both the NHS and patients on medicines, medical equipment, diagnostic tests and clinical & surgical procedures and where they should be used.

When the Institute evaluates these things, it is called an appraisal. Each appraisal takes around 12 months to complete and involves the manufacturers of the drug or device, the professional organisations and the groups who represent patients.

NICE was asked to look at the available evidence on gemcitabine and provide guidance that would help the NHS in England and Wales decide where it should be used in the treatment of pancreatic cancer.

What is pancreatic cancer?

Cancer is a disease of the body's cells. Normally, all cells divide and reproduce themselves in an orderly and controlled manner. In cancer, the cells multiply without proper control.

Pancreatic cancer is a disease of the pancreas. The pancreas is a large gland found near the stomach. It produces hormones, including insulin, that are secreted into the blood. Pancreatic cancer affects about 12 people in every 100,000. In 1997 around 5,730 people were diagnosed with this condition, 75 out of 100 of these were over the age of 65. Approximately 12 out of 100 people who are diagnosed with pancreatic cancer survive one year after diagnosis, and about 3 out of 100 survive for 5 years.

People with pancreatic cancer can suffer a range of symptoms. These can include jaundice, feeling sick, diarrhoea, weight loss, loss of appetite and severe pain in their abdomen (tummy). The symptoms of pancreatic cancer can severely reduce a patient's quality of life.

The type of treatment given for a cancer depends on many factors.These include:

• the type of cancer
• where in the body it started
• what the cancer cells look like under the microscope
• how far they have spread, if at all
• the general health of the patient

Chemotherapy is the use of anti-cancer drugs to destroy cancer cells.

Chemotherapy may be used on its own to treat cancer or it may be used with other drugs, with surgery and/or with radiotherapy.

About 4 out of 100 patients undergo surgery that may cure their cancer. However, because pancreatic cancer is not usually diagnosed until it is quite advanced, most patients can only be offered palliative care (supportive care to alleviate symptoms, but not cure the cancer).

In some circumstances a palliative surgical procedure may be carried out to relieve jaundice caused by the cancer blocking the bile ducts. This can improve the patient's quality of life. Other treatments may include chemotherapy and radiotherapy to reduce the size of the cancer. Currently about 10 to 15 out of 100 patients receive chemotherapy for pancreatic cancer.

What is gemcitabine?

Gemcitabine (Gemzar) is a chemotherapy treatment that is toxic to cancer cells. It works by stopping a part of the cancer cell replicating itself. Side effects of gemcitabine are fairly mild, but may include rashes and nausea (feeling sick).

What has NICE recommended about the use of gemcitabine?

NICE has recommended to the NHS that:

• People with advanced or metastatic (when the cancer has spread to other parts of the body) pancreatic cancer may be treated with gemcitabine as a first line treatment if they have a Karnofsky performance score of 50 or more.

  Karnofsky is a measure given by a health professional to a person's ability to perform certain ordinary tasks: 100 = normal, no complaints, 70 = unable to carry on normal activity, 50 = requires considerable assistance, 40 = disabled, 30 =hospitalisation recommended.

• Gemcitabine should not be used for people with pancreatic cancer who are suitable for surgery that may cure their cancer, or those who have a Karnofsky performance score of less than 50.

• Gemcitabine should not be used as a second line treatment for people with pancreatic cancer, because there is insufficient evidence to support this practice.

What should I do?

If you, or someone you care for, has pancreatic cancer then you can discuss this advice with the doctor or nurse at your next appointment.

Will NICE review its guidance?
Yes. The guidance will be reviewed in April 2004.

Further Information: Further information on NICE, and the full guidance issued to the NHS is available on the NICE web site (www.nice.org.uk).

The guidance can also be requested from 0870 555 455, quoting reference 23811.

If you have access to the Internet and would like to find out more about cancer visit the NHS Direct website: www.nhsdirect.nhs.uk.

APPENDIX D

Karnofsky Performance Score

100%	The patient has no complaints and is without evidence of disease
90	The patient has minor signs/symptoms, but is able to carry out his or her normal activities
80	The patient demonstrates some signs/symptoms and requires some effort to carry out normal activities
70	The patient is able to care for self, but is unable to do his or her normal activities or active work
60	The patient is able to care for self, but requires occasional assistance
50	The patient requires medical care and much assistance with self care
40	The patient is disabled and requires special care and assistance
30	The patient is severely disabled and hospitalisation is indicated; Death is not imminent
20	The patient is very ill with hospitalisation and active life-support treatment necessary
10	The patient is moribund with fatal process proceeding rapidly
0	Dead

 

ECOG/WHO/RTOG to KPS (Approximate Conversion System)

E/W/R	Karnofsky	Details
0	90-100%	Normal activity
1	70-80%	Symptoms demonstrated, but the patient remains ambulatory, and able to perform self care
2	50-60%	Ambulatory >50% of the time and requires occasional assistance
3	30-40%	Ambulatory <50% of the time and requires nursing care
4	10-20%	Bedridden
5	0%	Death