Pemetrexed for the treatment of malignant pleural

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Pemetrexed for the treatment of malignant pleural ...

Issue date: January 2008

    Review date: September 2010

    Pemetrexed for the

    treatment of malignant

    pleural mesothelioma

NICE technology appraisal guidance 135

    Pemetrexed for the treatment of malignant pleural mesothelioma Ordering information

    You can download the following documents from

    ? The full guidance (this document).

    ? A quick reference guide for healthcare professionals. ? Information for people with malignant pleural mesothelioma and their

    carers (‘Understanding NICE guidance’).

    ? Details of all the evidence that was looked at and other background


    For printed copies of the quick reference guide or ‘Understanding NICE guidance’, phone the NHS Response Line on 0870 1555 455 and quote:

    ? N1454 (quick reference guide)

    ? N1455 (’Understanding NICE guidance’).

    This guidance is written in the following context This guidance represents the view of the Institute, which was arrived at after

    careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement.

    The guidance does not, however, override the individual responsibility of

    healthcare professionals to make decisions appropriate to the circumstances

    of the individual patient, in consultation with the patient and/or guardian or


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? National Institute for Health and Clinical Excellence, 2008. All rights reserved. This material

    may be freely reproduced for educational and not-for-profit purposes. No reproduction by or

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    written permission of the Institute.


    1 Guidance 4 2 Clinical need and practice 4 3 The technology 6 4 Evidence and interpretation 7 5 Implementation 18 6 Recommendation for further research 19 7 Related NICE guidance 19 8 Review of guidance 20 Appendix A: Appraisal Committee members and NICE project team 21 Appendix B: Sources of evidence considered by the Committee 26

1 Guidance

    1.1 Pemetrexed is recommended as a treatment option for malignant pleural

    mesothelioma only in people who have a World Health Organization (WHO)

    performance status of 0 or 1, who are considered to have advanced disease

    and for whom surgical resection is considered inappropriate. 1.2 Patients currently receiving pemetrexed who do not fall into the patient

    population defined in section 1.1 should have the option to continue therapy

    until they and their clinicians consider it appropriate to stop. 2 Clinical need and practice

    2.1 Malignant pleural mesothelioma (MPM) is a type of cancer that occurs in the

    pleura the mesothelium (membranous lining) surrounding the lungs. MPM is

    a rapidly progressive malignancy of insidious onset. 2.2 Approximately 90% of cases of MPM are linked to asbestos exposure. When

    asbestos fibres are inhaled or swallowed, they can cause scarring of the lung

    tissues, cancer of the bronchial tree (lung cancer) and sometimes cancers in

    the pleura and peritoneum. A wide range of occupations, notably shipbuilding,

    railway engineering and asbestos product manufacture, are associated with

    an increased risk of MPM. Family members of people whose work clothes

    were contaminated with asbestos fibres have also developed MPM. The

    condition is significantly more common in men, with a male to female ratio of

    5:1. People with mesothelioma usually present with the disease between the

    ages of 60 and 79 years.

    2.3 MPM usually develops 2050 years after exposure to asbestos. Data from

    2004 suggest that about 1700 people in the UK are diagnosed with MPM

    each year. It is estimated that this figure will increase to a peak of more than

    2000 cases each year between 2011 and 2015, reflecting a lag from the

    highest use of asbestos in the 1970s. An estimated 65,000 cases are NICE technology appraisal guidance 135 4

    expected to occur between 2002 and 2050. The use of asbestos was banned in the UK in 1999.

    2.4 Most people with MPM present with chest pain and dyspnoea and have

    pleural effusions evident on examination. Fatigue, profuse sweating, weight loss, anorexia and difficulty in swallowing become common as the disease progresses. Presentation and diagnosis often occur at an advanced stage and the prognosis for most patients is extremely poor. Median survival from diagnosis varies in studies, with a range of 913 months. Age, tumour

    histology, tumour stage at diagnosis and performance status have been shown to be independent prognostic factors. The most commonly used performance status scoring systems include the Karnofsky performance status (KPS) and the World Health Organization (WHO) scales. KPS is a 10-point scale ranging from 0 to 100, with higher scores representing normal day-to-day activity. The WHO system is a five-point scale with lower scores representing normal day-to-day activity. In general, WHO scores of 0 and 1 are considered equivalent to KPS scores of 70100.

    2.5 There is no standard treatment pathway for MPM in England and Wales. The

    clinical management is multimodal and a patient may receive a combination of treatments. Staging provides prognostic information and can help to determine an appropriate treatment strategy; however, it is complex, and surgical intervention is required to stage the disease fully. There is no universally accepted staging system, but the traditional Butchart system is gradually being replaced with a tumour nodes metastases (TNM) system developed by the International Mesothelioma Interest Group. In clinical practice, MPM is generally staged pragmatically based on whether or not surgical resection is considered an appropriate option. Extrapleural pneumonectomy is an option for the small proportion of patients (15%)

    whose tumours are at stage 1 or 2.

    NICE technology appraisal guidance 135 5

    2.6 Surgery is not indicated for the majority of patients, so treatment aims to

    improve symptoms and maintain quality of life for as long as possible. Often,

    this does not involve treating the tumour with chemotherapy. Treatment that

    does not include a specific anti-cancer therapy is referred to as active

    symptom control (ASC) or best supportive care (BSC). For people with MPM,

    this may include interventions to manage pain and dyspnoea, and to address

    psychosocial problems. Treatments may include draining excess fluid from

    the pleural cavity and applying a talc pleurodesis (the insertion of talc to

    prevent further fluid accumulation), palliative radiotherapy, analgesics,

    steroids, appetite stimulants and bronchodilators.

    2.7 There is no standard chemotherapy treatment for MPM. Pemetrexed in

    combination with cisplatin is the only chemotherapy regimen that is currently

    licensed for this indication. However, a variety of combination and single-

    agent regimens such as the mitomycin C, vinblastine and cisplatin

    combination (MVP) or vinorelbine are used. To date there have been no

    published randomised controlled trials (RCTs) comparing survival and

    symptom control in patients receiving chemotherapy with those receiving ASC.

    3 The technology

    3.1 Pemetrexed (Alimta, Eli Lilly and Company) is licensed, in combination with

    cisplatin, for the treatment of chemotherapy-naive patients with unresectable

    MPM. Pemetrexed is a multi-targeted folate antagonist that inhibits DNA

    replication. Cisplatin is a platinum-based chemotherapeutic agent that has

    anti-tumour activity, either as a single agent or in combination, for a number of

    different cancers. The licensed dose of pemetrexed is 500 mg/m2 body

    surface area, to be administered as a 10-minute intravenous infusion on the

    first day of a 21-day cycle. It is followed approximately 30 minutes later by

    2cisplatin (recommended dose 75 mg/m body surface area) infused over

    2 hours. In order to reduce toxicity, patients treated with pemetrexed must

    receive folic acid and vitamin B supplementation. To reduce the incidence 12

    and severity of skin reactions, patients are pre-medicated with a corticosteroid.

    NICE technology appraisal guidance 135 6

3.2 Adverse effects commonly associated with pemetrexed include nausea,

    vomiting, fatigue and neutropenia. Skin rash, mucositis and liver function

    abnormalities have also been reported. Cisplatin causes nausea and vomiting

    in the majority of patients. This is controllable in 5080% of patients with anti-

    emetic drugs. Serious toxic effects of cisplatin on the kidneys, bone marrow

    and ears are common, and serum electrolyte disturbances, hyperuricaemia,

    allergic reactions and cardiac abnormalities have also been reported. For full

    details of side effects and contraindications, see the summaries of product


    3.3 Pemetrexed costs ?800 for a 500-mg vial (excluding VAT, ‘British national 2, is approximately formulary’ [BNF] 53rd edition). The cost per patient, assuming an average of

    ?8000. Costs may vary in different settings because of negotiated five treatment cycles and a body surface area of 1.8 m

    procurement discounts.

    4 Evidence and interpretation

    The Appraisal Committee (appendix A) considered evidence from a number

    of sources (appendix B).

    4.1 Clinical effectiveness

    4.1.1 A single RCT of pemetrexed in MPM was identified. The EMPHACIS

    (‘Evaluation of mesothelioma in a Phase III trial of pemetrexed with cisplatin’)

    study compared pemetrexed plus cisplatin with cisplatin alone. This was a

    single-blind, international, multicentre trial in 448 patients. To be eligible,

    patients had to be 18 years or older, and were required to have a minimum

    life expectancy of 12 weeks, uni- or bi-dimensionally measurable disease, and

    a KPS of greater than or equal to 70. Patients who had had prior

    chemotherapy, those with a second primary malignancy or brain metastasis,

    and those unable to interrupt non-steroidal anti-inflammatory drugs were


    NICE technology appraisal guidance 135 7

    22 followed 30 minutes later by cisplatin at a dose of 75 mg/m.

    4.1.2 Patients in the intervention arm (n = 226) received pemetrexed at a dose of Patients in the control arm (n = 222) received normal saline followed

    500 mg/m230 minutes later by cisplatin at a dose of 75 mg/m. In both arms, treatment

    was administered on the first day of each 21-day cycle. The median number

    of cycles given was 6 (range 112) in the pemetrexed plus cisplatin arm and

    4 (range 19) in the cisplatin arm. Median length of follow-up was 10 months.

    4.1.3 During the early stages of the trial, incidences of severe toxicity (including

    drug-related death, neutropenia, febrile neutropenia and diarrhoea) were high

    in the combination arm. Folic acid and vitamin B

    supplementation were 12

    therefore added to the trial protocol in both treatment arms to preserve

    blinding. With effect from the date of the protocol change, all patients received

    supplementation, resulting in three patient subgroups defined by

    supplementation status: never supplemented (n = 70), partially supplemented

    (those who started treatment before the protocol change; n = 47) and fully

    supplemented (those who started treatment after the protocol change;

    n = 331). The primary analysis was performed on all patients who were

    randomised and treated (intention-to-treat [ITT] population). A subgroup

    analysis was performed on fully supplemented patients. Further post-hoc

    subgroup analyses were performed on fully supplemented patients with

    advanced disease (stage 3/4) because it was thought that most patients

    presenting to clinicians would fall into this category.

    4.1.4 The primary endpoint of the EMPHACIS trial was survival. A statistically

    significant survival benefit was observed in patients randomised to

    pemetrexed plus cisplatin versus those receiving cisplatin alone. In the ITT

    population, median survival was 12.1 months (95% confidence interval [CI],

    10.0 to 14.4) in the pemetrexed plus cisplatin arm versus 9.3 months (95% CI,

    7.8 to 10.7) in the cisplatin arm (hazard ratio [HR] 0.77; 95% CI, 0.61 to 0.96;

    log rank test p value = 0.02). In fully supplemented patients, median survival

    was 13.3 months (95% CI, 11.4 to 14.9) in the combination arm versus

    NICE technology appraisal guidance 135 8

    10 months (95% CI, 8.4 to 11.9) in the cisplatin arm (HR 0.75; 95% CI, 0.57 to 1.00; log-rank test p value = 0.051). In fully supplemented patients with advanced disease, median survival was 13.2 months (95% CI, 9.3 to 14.9) in the combination arm versus 8.4 months (95% CI, 6.8 to 10.2) in the cisplatin arm (HR 0.63; 95% CI, 0.46 to 0.86; log rank test p value = 0.003).

    4.1.5 Secondary endpoints included 1-year survival, median time to progressive

    disease and tumour response rate. Pemetrexed plus cisplatin demonstrated statistically significant benefits versus cisplatin alone for all of these outcomes in the ITT population and in the subgroups. The results for these endpoints in the ITT population for the pemetrexed plus cisplatin group versus the cisplatin alone group, respectively, were as follows:

    ? 1-year survival: 50.3% versus 38.0% (p = 0.012)

    ? median time to progression: 5.7 months versus 3.9 months (p < 0.001) ? tumour response rate: 41.3% versus 16.7% (p < 0.001).

    4.1.6 Quality of life was evaluated using the Lung Cancer Symptom ScaleMeso

    instrument. Several aspects of quality of life were evaluated, including pain, dyspnoea, fatigue, anorexia and cough. Over 18 weeks, patients treated with pemetrexed plus cisplatin demonstrated statistically significant symptomatic improvements when compared with those who received cisplatin alone. For global quality of life in the ITT population, a least squares mean score of 56 out of 100 was reported for patients randomised to pemetrexed plus cisplatin versus a score of 53 out of 100 for patients in the cisplatin arm (p value for the difference between arms = 0.012). A similar result was observed in the fully supplemented population.

    4.1.7 Severe to life-threatening or disabling adverse events were statistically

    significantly more frequent in patients receiving pemetrexed plus cisplatin than in those receiving cisplatin alone. The most commonly reported of these

    NICE technology appraisal guidance 135 9

    in patients receiving pemetrexed plus cisplatin were: neutropenia (27.9%),

    leukopenia (17.7%), nausea (14.6%) and vomiting (13.3%). Supplementation resulted in a consistent reduction in the severity 12

    with folic acid and vitamin Band incidence of adverse events (except for dehydration) in the pemetrexed

    plus cisplatin arm. The most common severe adverse events in fully

    supplemented patients randomised to pemetrexed plus cisplatin were:

    neutropenia (23.2%), leukopenia (14.9%), nausea (11.9%) and vomiting


    4.1.8 Supplementary documentation on pemetrexed provided by the manufacturer

    indicated that, in the ITT population, 42% (94 of 226) of patients randomised

    to pemetrexed plus cisplatin responded to treatment. Of those who

    experienced a response, 87% (82 of 94) did so within four cycles. Summary of the evidence on clinical effectiveness

    4.1.9 The results of the EMPHACIS trial suggest that pemetrexed plus cisplatin

    confers a survival benefit of approximately 3 months compared with cisplatin

    alone. The combination treatment also appears to demonstrate advantages in

    terms of 1-year survival, median time to progressive disease, tumour

    response rate and quality of life. Pemetrexed plus cisplatin appears to offer

    greater survival benefits than cisplatin alone in patients with advanced


    4.2 Cost effectiveness

    4.2.1 Estimates of cost effectiveness were provided by the manufacturer and by the

    Assessment Group. A review of the published literature identified a single

    cost-effectiveness study. This was a conference presentation/abstract that

    was a forerunner of the manufacturer’s submission.

    4.2.2 Two cost-effectiveness models were submitted by the manufacturer. Model 1

    compared pemetrexed plus cisplatin with cisplatin alone. Model 2 compared

    pemetrexed plus cisplatin with standard care (as defined by the manufacturer NICE technology appraisal guidance 135 10

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