Download Review of pemetrexed in the treatment of malignant pleural

A Review of pemetrexed in
the treatment of malignant
pleural mesothelioma (MPM):
The effectiveness, safety, cost
effectiveness, impact on quality of life
and identification of possible
alternative cost effective pharmaceutical
therapies
October 2009
Author: Fiona Conlon
Important Note
This evidence-based review summarises information on pemetrexed and
other pharmaceutical treatments for malignant pleural mesothelioma. It
is not intended to replace clinical judgement, or be used as a clinical
protocol. A reasonable attempt has been made to find and review papers
relevant to the focus of this report. It does not claim to be exhaustive.
This document has been prepared by staff of the ACC, Evidence Based
Healthcare Advisory Group. The content does not necessarily represent
the official view of ACC or represent ACC policy.
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Executive Summary
Background: In 2004 an ACC review of pemetrexed in the treatment of malignant
pleural mesothelioma (MPM) concluded that pemetrexed 500mg/m² in combination
with cisplatin 75mg/m² given in 21 day cycles appears to be effective in extending life
expectancy by an average of 2.8 months. Pemetrexed plus cisplatin should be given
in combination with folic acid and vitamin B12 to reduce the toxicity of the drugs.
In May 2005 the Purchasing Guidance Advisory Group (PGAG) recommended the
purchase of pemetrexed by ACC using good practice guidelines developed by Dr
Richard Sullivan, Clinical Director of Oncology, Auckland DHB Oncology Services.
This evidence based healthcare review was undertaken to provide an update on the
effectiveness, safety, cost effectiveness of pemetrexed and the resulting quality of life
provided. The evidence for any alternative effective treatment for MPM was also
investigated; raltitrexed was identified as a possible alternative.
Search strategy: A systematic search of major literature databases (Ovid Medline,
Embase, EBM reviews, Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR,
HTA and NHSEED) was performed from the date of the last search in 2004 up to 29
August 2008. Key words were used to search for studies.
Selection criteria: Systematic reviews, randomised controlled trials, case-control
studies and case series which examined the effectiveness, safety, cost effectiveness
of pemetrexed and raltitrexed and the resulting quality of life provided, in the
treatment of MPM, were included. Papers written in a language other than English,
phase I trials and expert opinion were excluded. Studies were appraised and graded
for methodological quality using the Scottish Intercollegiate Guidelines Network
(SIGN) criteria.
Main results: Two systematic reviews were found, one of pemetrexed and the other of
various chemotherapy treatments for MPM including pemetrexed and raltitrexed. The
National Institute for Health and Clinical Excellence (NICE) technology appraisal
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guidance was derived from the systematic review of pemetrexed and is included in
this review.
Two well designed randomised controlled trials were included, one on pemetrexed
plus cisplatin and the other on raltitrexed and cisplatin. The quality of the other
studies included was poor by evidence based standards and no studies were directly
comparable because of different drug combinations, patient characteristics and
measurement of outcomes.
Conclusions: The main outcome reported in the literature was survival, an outcome
not influenced by selection and/or detection bias. Other outcome measures
(response rate, time to progression, time to treatment failure, toxicity reporting and
quality of life) are less reliable.
This review aimed to report on the effectiveness, safety, cost effectiveness and
added quality of life of pemetrexed as well as identifying any potential alternatives to
pemetrexed in the treatment of MPM

Two systematic reviews and one randomised controlled trial showed good
evidence (that was statistically significant) for the effectiveness of pemetrexed
and cisplatin in extending survival to 12.1 months compared to 9.3 months
when cisplatin was used alone. Response rates (41% versus 17%), time to
disease progression (5.7 versus 3.9 months) and survival (12.1 versus 9.3
months) all favoured the combination treatment. Two quality of life indices
(dyspnoea and pain) assessed using the Lung Cancer Symptom Scale were
both significantly improved with pemetrexed and cisplatin after six cycles of
treatment. However the RCT, on which the systematic review is largely based,
did have some design flaws.

One systematic review and one randomised controlled trial showed good
evidence for the effectiveness of raltitrexed and cisplatin (that was statistically
significant) in extending survival to 11.4 months compared to 8.8 months when
cisplatin was used alone. This trial also showed a higher response rate (23.6%
versus 13.6%) and longer progression free survival (5.3 versus 4 months),
although these latter measures did not achieve conventional statistical
significance.
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
The National Institute for Health and Clinical Excellence (NICE) has
recommended the use of pemetrexed for MPM only in people with a World
Health Organisation (WHO) performance status of 0 or 1.
In July 2007 the Committee to Evaluate Drugs (CED) of the Ministry of Health and
Long Term Care in Ontario, Canada recommended not funding pemetrexed through
Cancer care Ontario’s New Drug Funding Programme, on the basis that it does not
provide value for money compared with existing alternatives on the Formulary. The
Committee believed that pemetrexed and raltitrexed had similar clinical benefits for
the treatment of MPM. Raltitrexed was already listed on the Formulary and given that
the cost of raltitrexed was approximately 15% of the cost of pemetrexed, the
Committee concluded that pemetrexed did not demonstrate good value for money.
As an effective alternative was available on the New Drug Funding Programme
(NDFP) Formulary, the Committee recommended that pemetrexed not be approved
for funding.
There is good evidence based on limited studies that pemetrexed and raltitrexed both
offer a survival benefit to patients with MPM. And based on the evidence available
raltitrexed would be a more cost effective option. However there is currently no
available evidence or information from Ontario regarding the efficacy and safety of
raltitrexed in the treatment of MPM. This information would be critical for future
decision making and enquiries are ongoing to find data on raltitrexed.
Further studies or trials of both of these chemotherapy drugs would be desirable.
It is suggested that ACC should follow the guidance provided by The National
Institute for Health and Clinical Excellence (NICE) technology appraisal guidance
which stated that pemetrexed be recommended as a treatment option for malignant
pleural mesothelioma only in people who have a World Health Organisation (WHO)
performance status of 0 or 1, who are considered to have advanced disease and for
whom surgical resection is considered inappropriate. Patients currently receiving
pemetrexed who do not fall into this category should have the option to continue
therapy until they and their clinicians consider it appropriate to stop.
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Peer Review
ACC appreciates external peer review for this report which has been provided by a
Consultant Medical Oncologist and a Clinical Oncology Pharmacist.
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Glossary of Terms
ASC – Active Symptom Control
AUC – Area under the plasma concentration versus time curve which has units of
concentration times time. This is a measure of how much of a drug reaches the
bloodstream in a set period of time, usually 24 hours
BSC – Best Supportive Care
Complete Response (CR) - The disappearance of all signs of cancer in response
to treatment. This does not always mean the cancer has been cured.
Chemotherapy naïve – have not previously received chemotherapy treatment
EAP – Extended Access Programme
First line treatment – the first course of treatment given once diagnosed with
cancer.
Fully supplemented – Patients who receive folic acid 350 - 1,000 µg orally daily
beginning 1-3 weeks before the first chemotherapy doses and continued throughout
study therapy. Vitamin B12 1,000 µg also given intramuscularly 1 to 3 weeks before
the first dose of study therapy and repeated every 9 weeks while a patient received
study therapy.
Karnofsky Performance Status – Runs from 100 – 0, where 100 denotes perfect
health and 0 denotes death. See Appendix 2.
Leucopenia - a decrease in the number of white blood cells (leukocytes) found in
the blood, which places individuals at increased risk of infection.
Median Survival - The time from either diagnosis or treatment at which half of the
patients with a given disease are found to be, or expected to be, still alive. In a
clinical trial, median survival time is one way to measure how effective a treatment is.
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MPM – Malignant Pleural Mesothelioma
Mucositis - the painful inflammation and ulceration of the mucous membranes lining
the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy
treatment for cancer.
Neutropenia - is a hematological disorder characterized by an abnormally low
number of neutrophils, the most important type of white blood cell, in the blood.
Neutrophils usually make up 50-70% of circulating white blood cells and serve as the
primary defense against infections by destroying bacteria in the blood. Hence,
patients with neutropenia are more susceptible to bacterial infections.
Partial response (PR) – A decrease in the size of a tumour or in the extent of
cancer in the body, in response to treatment.
Pre-treated – Have previously received some form of chemotherapy treatment.
Quality Adjusted Life Year (QALY) - A measure of the outcome of actions
(either individual or treatment interventions) in terms of their health impact. If an
action gives a person an extra year of healthy life expectancy, that counts as one
QALY. If an action gives a person an extra year of unhealthy life expectancy (partly
disabled or in some distress), it has a value of less than one. Death is rated at zero.
RECIST – Response Evaluation Criteria in solid Tumours. See Appendix 3.
Response rate (RR) - The percentage of patients in whom cancer shrinks or
disappears after treatment.
Second line treatment – the treatment given if the first line of treatment does not
work or id the cancer comes back after a period of time.
Stable Disease (SD) - Cancer that is neither decreasing nor increasing in extent
or severity.
WHO/ECOG/Zubrod performance status – Runs from 0 – 5, 0 denoting perfect
health and 5 denoting death. See Appendix 1
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List of Tables
Table 1. Summary of pemetrexed
studies…………………………………………30
Table 2. Summary of raltitrexed
studies…………………………………………..71
Table 3. Comparison between pemetrexed and
raltitrexed …………….……….85
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Table of Contents
Executive Summary…...……………………………………………………………...iii
Background:……………………………………………………………………...iii
Search strategy:…………………………………………………………………..iii
Selection criteria:…………...…………………………………………………....iii
Main results:……………………………………………………………………. iii
Conclusions:……………………………………………………………………. iv
Peer review………………………………………………………………………….. .vi
Glossary of Terms…………………………………………………………………....vii
List of Tables………………………………………………………………………….ix
Table of Contents……………………………………………………………………...x
1. Background………………………………………………………………………..14
2. Objectives………………………………………………………………………….17
3. Methodology……………………………………………………………………….18
3.1
Criteria for selecting studies for this
review………………………………18
Types of Studies:………………………………………………………………...18
Types of Participants:…………………………………………………………...18
3.2 Search Strategy and information
sources…………………………………18
3.3
Methods of the review……………………………………………………..18
3.4
Description of studies……………………………………………………...20
4. Pemetrexed……………………….………………………………………………..18
4.1
Health Technology…………………………………………………………18
4.2
Results……………………………………………………………………...19
4.2.1
Evidence regarding effectiveness of
pemetrexed…...………………..19
4.2.2 Safety…………………………………………………………….…….31
4.2.3
Cost effectiveness…………………………………………………..….34
4.2.4
4.3
Quality of Life…………………………………………………..……..37
Discussion…………………………………………………………………..39
4.3.1
Methodological
quality………………………………………….…....39
Study Design…………………………………………………………..39
Intervention…………………………………………………………...40
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Sample size and statistical
analyses…………………………………..40
Randomisation and blinded
method………………………………....41
Study population, inclusion and exclusion
criteria………………….42
Follow up and study
period…………………………………………..42
4.3 ........2
Outcome measures…………………………………………….……….42
4.3.3
Effectiveness……………………………………………….……..…...43
4.3.4
Safety and adverse
effects………………………………………………...45
4.3.5
Cost
effectiveness…………………………………………………….......46
4.3.6
Quality of
life……………………………………………………………..46
4.4 Summary of
evidence…………………………………………………………..47
5. Raltitrexed………………………………………………………………….………......48
5.1
Health
Technology………………………………………………………….......48
5.2
Results……………………………………………………………………… .....49
5.2.1
Evidence for effectiveness of
raltitrexed……………………………….....49
5.2.2
Safety………………………………………………………………….….. .53
5.2.3
Cost
effectiveness………………………………………………………......54
5.2.4
Quality of
Life……………………………………………………………....54
5.3
Discussion…………………………………………………………………….....56
5.3.1
Methodological
quality…………………………………………………....56
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Study Design……………………………………………………………....
56
Intervention……………………………………………………………... ..56
Sample size and statistical
analyses……………………………………….56
Randomisation and blinded
method……………………………………...57
Study population, inclusion and exclusion
criteria……………………....57
Follow up and study
period…………………………………………..…...57
5.3 .2
Outcome measures……………………………………………………..…..58
5.3.3
Effectiveness………………………………………………………………..58
5.3.4
Safety and adverse
effects…………………………………………………. 58
5.3.5
Cost
effectiveness…………………………………………………………..59
5.4 Summary of
evidence…………………………………………………………….59
6.Conclusions………………………………………………………………………….....…59
7. References………………………………………………………………………………..63
8. Limitations of
review……………………………………………………………….…..67
Appendix 1: WHO performance status………………………………………………..…68
Appendix 2: Karnofsky performance status scale and comparison of WHO and
Karnofsky performance scales……………………………………………..69
Appendix 3. Response evaluation criteria in solid tumours
(RECIST)………………….70
Appendix 4. Pemetrexed prescribe checklist - ACC……………………………………….72
Appendix 5. Pemetrexed literature search…………………………………………………..74
Appendix 6. Evidence tables for pemetrexed……………………………………………….76.
Appendix 7. Evidence tables for raltitrexed………………………………………………....96
Appendix 8. Studies excluded from the review…………………………………………….102
Appendix 9. Stages of pleural mesothelioma………………………………………………104
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Appendix 10. Definitions of phases of pharmaceutical trials………………………………105
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1 Background
Incidence
Malignant Pleural Mesothelioma (MPM) is a rare and aggressive type of cancer,
usually linked to previous exposure to asbestos which does not develop until 10-60
years after exposure to asbestos (median time: 40 years). Two thirds of MPM
patients are aged between 50 and 70 years of age1. Between 1962 and 1971
eighteen new cases of malignant mesothelioma were registered in New Zealand (1.8
cases per year. 25 years later, between 1987 and 1996, 330 new cases were
registered (33 cases per year), an eighteen-fold increase. 83% have their primary site
located in the pleura (9% in the lung, 4% in the peritoneum, 1% in the pericardium
and 1% in the testis and other male genitalia)2. Based on these figures the authors
estimated a doubling of the New Zealand Malignant mesothelioma rate by 2010. The
incidence of mesothelioma notified to the National Asbestos Medical Panel for 19922005 is 164 cases (only 12 cases a year)3.
Maori appear to under represented, particularly as they are likely to have been over
represented in manual occupations with potential asbestos exposure. Diagnosis is
problematic and MPM is frequently not diagnosed until two or three months after the
onset of symptoms or incidentally on a routine chest x-ray. Symptoms are typically
chest pain, shortness of breath and associated pleural effusion. The disease spreads
locally in sheets across the pleural surface and then compresses or invades the local
structures usually leading to death in approximately 9-13 months4.
History
Before 1940 virtually all asbestos products were imported into New Zealand. After
this raw asbestos was also imported and manufactured into asbestos-containing
products (mainly cladding and pipes). Imports of raw asbestos peaked at around
12,500 tonnes in 1974, although as recently as 1983, 3,000 tonnes were imported 5.
The import of raw amphibole (blue and brown) asbestos into New Zealand was
banned in 1984 and chrysotile (white) asbestos was banned in 2002. Workforce
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regulations to protect employees were drafted in 1978 and in 1983 employers were
obliged to inform workers of the particular dangers of smoking in asbestos workers.
In New Zealand asbestos exposure in the workplace was highest between the 1940s1980s and, with a median latency period of 40 years, cases are expected to continue
to occur up to 2020.
Management
A small proportion of patients (1-5%) are suitable for surgical management which
may consist of either partial pleurectomy with pleurodesis (drainage of fluid from the
pleural cavity followed by the insertion of TALC to prevent further fluid accumulation),
or thorascopy with pleurodesis.
Where, for the majority of patients, surgery is not indicated, radiotherapy may be an
option, but is not widely used because the large volumes required for pleural
coverage result in high toxicity and fail to affect survival. A systematic review to
assess the effectiveness and safety of radiotherapy on patients with malignant
pleural mesothelioma in any stage of the disease did not find any RCTs that showed
radiotherapy to be an effective option for MPM6. However the review did identify
some evidence for using radiotherapy for treating incision sites after invasive
diagnostic or therapeutic studies to prevent chest wall implantation.
For many patients treatment is limited to best supportive care (BSC), also known as
active symptom control (ASC) which is treatment or procedures aimed at relieving
symptoms and making the patient more comfortable. It includes the use of steroids,
analgesics, appetite stimulants and/or palliative radiotherapy.
Chemotherapy – the use of pemetrexed
Pemetrexed (brand name ALIMTA®) was registered in New Zealand in August 2004
for the treatment of MPM in combination with cisplatin. The ACC report ‘The
Effectiveness of Pemetrexed in the Treatment of Mesothelioma’ was produced in
October 2004. The ACC Purchasing Guidance Advisory Group (PGAG) considered
purchase of pemetrexed in May 2005.
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Purchase of pemetrexed was recommended using specific criteria (recommended by
Dr Richard Sullivan, Clinical Director, Medical Oncology, Regional Cancer and Blood
Service, Auckland Hospital) to select patients who would receive initial cycles of
pemetrexed. A prescriber checklist is currently used to assess whether a claimant
may be eligible for an ACC contribution to the cost of pemetrexed. The checklist
includes a proven diagnosis of mesothelioma, with radiological and histological
assessments and certain standards regarding patient performance status, organ
function and brain metastases. See Appendix 4. Following this review the prescriber
checklist may need to be reviewed.
Further guidelines were developed to manage the continued funding of pemetrexed
once initial funding was approved. When funding is approved by ACC, the first two
cycles are approved and the third is approved in principle. A report from the treating
specialist is required after the assessment following the second cycle before further
funding is considered. The report needs to detail clinical benefits, quality of life
improvements, tumour status and recommendation whether further treatment should
be carried out. Funding is normally given for six cycles of pemetrexed, however
applications beyond six cycles may be considered.
The cost of pemetrexed to ACC in the year June05/06 was $580,327, the year 06/07
was $720,816 and for 07/08 was $633,337. Funding for pemetrexed represents 10%
of ACC’s pharmaceutical budget.
An evidence based healthcare review update was requested by Sunita Goyal,
Pharmaceutical Advisor, to investigate the effectiveness of pemetrexed in the
treatment of MPM, together with cost effectiveness and related quality of life
outcomes. Also to be included in the review were any cost effective alternatives to
pemetrexed, namely raltitrexed, which was identified early in the review. Raltitrexed
is considered to be a cost effective alternative to pemetrexed and is used in Ontario,
Canada for the treatment of MPM.
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2 Objectives

To evaluate the effectiveness and safety of pemetrexed in the treatment of
MPM in order to update and formalise the clinical criteria and protocols for
treatment.

To report on the cost effectiveness of pemetrexed.

To report on the health related quality of life gain from pemetrexed.

Identify any possible alternative pharmaceutical treatments.
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3 Methodology
3.1 Criteria for selecting studies for this review
Types of Studies:
Clinical studies or trials about pemetrexed or raltitrexed or any study type published
since 1966 to the present were considered for the review, excluding expert opinion
and phase I clinical trials.
Types of Participants:
Patients with malignant pleural mesothelioma. One study included patients who had
MPM with the perineum as the primary site of the mesothelioma.
3.2 Search Strategy and information sources
For this review the search looked for literature published since the last search in 2004
up to the present (2 September 2008) and utilised the following databases: Ovid
MEDLINE(R) 1996 - August week 3 2008, EMBASE 1996 – 2008 Week 35, Ovid
MEDLINE(R) In-Process & Other Non-Indexed Citations August 29, 2008 (PreMedline), all EBM Reviews – Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR,
HTA and NHSEED (“All EBM”). See Appendix 5. The key words and terms used
were “pemetrexed”, “raltitrexed” and “mesothelioma”. The earlier search for literature
published up to 6 September 2004 was repeated for “raltitrexed”.
3.3 Methods of the review
The relevant studies were critically appraised by considering experimental design,
intervention, randomisation and blinding method, inclusion/exclusion criteria for the
study population, follow up, study period and outcomes reported. The quality of
evidence in each study included in the review was graded according to the SIGN
criteria below. The details of included studies were summarised in evidence tables
which are supplied in Appendix 6. The grading for each of the studies included is in
Table 1, Summary of pemetrexed studies, and Table 2, Summary of raltitrexed
studies.
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Levels of evidence
1++ High quality meta analyses, systematic reviews of RCTs, or RCTs
with a very low risk of bias
1+ Well conducted meta analyses, systematic reviews of RCTs, or RCTs
with a low risk of bias
1 - Meta analyses, systematic reviews of RCTs, or RCTs with a high
risk of bias
2++ High quality systematic reviews of case-control or cohort studies
High quality case-control or cohort studies with a very low risk of
confounding, bias, or chance and a high probability that the
relationship is causal
2+ Well conducted case control or cohort studies with a low risk of
confounding, bias, or chance and a moderate probability that the
relationship is causal
2 - Case control or cohort studies with a high risk of confounding, bias,
or chance and a significant risk that the relationship is not causal
3
Non-analytic studies, e.g. case reports, case series
4
Expert opinion
Grades of recommendation
A
At least one meta analysis, systematic review, or RCT rated as 1++,
and directly applicable to the target population; or
A systematic review of RCTs or a body of evidence consisting
principally of studies rated as 1+, directly applicable to the target
population, and demonstrating overall consistency of results
B
A body of evidence including studies rated as 2++, directly
applicable to the target population, and demonstrating overall
consistency of results; or
Extrapolated evidence from studies rated as 1++ or 1+
C
A body of evidence including studies rated as 2+, directly
applicable to the target population and demonstrating overall
consistency of results; or
Extrapolated evidence from studies rated as 2++
D Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+
Good practice points
 Recommended best practice based on the clinical experience of the
guideline development group
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3.4 Description of studies
The literature search yielded almost 300 abstracts which were screened for relevant
inclusion criteria. This was reduced to 54 references and the full articles were
retrieved. The bibliographies of the articles also identified additional relevant material
which was also retrieved. Of those selected the reviews were removed and a total of
23 articles were selected for final critical appraisal. Of these 2 were systematic
reviews and 4 were randomised controlled trials; 5 were case series relating to the
‘Extended Access Programme’ (the EAP followed patients in different studies
subsequent to one of the randomised controlled trials reviewed); and the other 12
articles were case series studies or trials.
The primary outcomes reported were survival, response rate, time to disease
progression, toxicity, cost effectiveness and health related quality of life. Further
detail about the characteristics of the included studies is provided in the results
section.
4 Pemetrexed
4.1 Health Technology
Pemetrexed (trade name ALIMTA®, manufactured by Eli Lilly and Company) was
registered in New Zealand in August 2004 for the treatment of malignant pleural
mesothelioma. It is a multi-targeted folate antagonist that inhibits DNA replication and
is taken up into cells primarily through the reduced folate carrier. It undergoes
extensive intracellular polyglutamation by folypoly-gamma-glutamate synthetase,
which enhances its cytotoxic effect by increasing cellular retention and affinity for
specific folate-dependent enzymes. However, unlike raltitrexed, this drug targets
multiple folate dependent enzymes.
Pemetrexed has demonstrated useful activity against both non-small cell lung cancer
and MPM. However, it is currently only indicated for use in treatment of MPM in New
Zealand. This drug is not currently included on the PHARMAC schedule.
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In order to reduce toxicity, patients treated with pemetrexed must receive folic acid
and vitamin B12 supplementation. To reduce the incidence and severity of skin
reactions, patients are pre-medicated with a corticosteroid.
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4.2 Results
4.2.1 Evidence regarding effectiveness of pemetrexed
A. Systematic reviews
There were 2 systematic reviews.
1. Dundar et al, 20077
In a systematic review of the clinical effectiveness and cost effectiveness of
pemetrexed plus cisplatin Dundar et al7 found only one RCT that met the inclusion
criteria, the EMPHACIS trial8, which demonstrated that pemetrexed in combination
with cisplatin improves survival compared with cisplatin alone.
The review noted, in its critique of the RCT, that approximately 52% of the trial
population were WHO performance status zero, representing only minimal
impairment of activity level at trial entry, which is a considerably higher proportion
than would normally present to clinicians. They also noted that only 67% of the
randomised and treated patients had the pathological diagnosis of MPM confirmed by
independent review. Response, which is usually based on computed tomography
scan measurement, is complicated by the site and mode of spread of mesothelioma
which is in sheets of cells rather than well defined lesions. Therefore the review
suggests the response rates and time to progression should be interpreted with
caution.
The review also looked at 7 other uncontrolled studies of pemetrexed but did not
include them. There was no comparison of any form of chemotherapy for
mesothelioma with ASC/BSC found in their literature search. In terms of clinical
effectiveness they found that for extension of life expectancy and palliation, as
measured by time to progression of disease and other end-points, the absolute
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benefit was small. They concluded limited benefit at the expense of considerable
toxicity to patients.
Concerning cost effectiveness, Dundar et al7 included 2 economic evaluations to
determine cost effectiveness (see section 4.2.3). Their inclusion criteria for the
review were studies that compared pemetrexed plus cisplatin with other cytotoxic
agents or supportive care. This review was of good quality but illustrated the limited
availability of RCTs and evidence based research regarding pemetrexed, as the
review drew conclusions from only one RCT.
National Institute for Health and Clinical Excellence9
The Appraisal Committee considered a number of sources of information including
the systematic review by Dundar et al; the manufacturer of pemetrexed, Eli Lilly and
Company; professional/specialist and patient/carer groups; commentator
organisations and a number of clinical specialists and patient advocate nominations.
The guidance stated:
“1.1 Pemetrexed is recommended as a treatment option for malignant pleural
mesothelioma only in people who have a World Health Organisation (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. Ellis et al, 200610
A systematic review and practice guideline by Ellis et al10 addressed two questions:
(1) Does chemotherapy improve survival, QOL, or symptom control, compared to
best supportive care (BSC)?
(2) Which chemotherapeutic agents (or combinations of agents) have shown the
highest response rates in patients with advanced MPM?
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A wide range of studies were included (119 in all): systematic reviews, meta-analyses,
RCTs, abstracts, practice guidelines and phase II clinical trials. The review also
included studies with patients who had peritoneal as well as pleural mesothelioma.
The quality of the studies included was not always clear and the number of
randomised trials was limited to eight. No studies comparing chemotherapy to BSC
for patients with MPM were identified. Therefore they concluded that there is no
evidence whether chemotherapy improves survival or QOL, compared to BSC.
The systematic review included the EMPHACIS randomised controlled trial8. The
reviewers noted that 118 patients signed informed consent but were not randomised
and the reason for excluding these patients was unclear. They note that this could
limit the generalisability of the results. Also the trial design was modified after 70
patients were enrolled, to allow all patients to receive vitamin supplements because
of concerns about excess toxicity in the pemetrexed/cisplatin combination arm. As a
result the original sample size was increased to compensate for that modification.
The review included a large amount of research, the criteria for inclusion was not
clear and levels of evidence vague. Rather than comparing different types of studies
the review compared different treatment regimes and their response rates. The
review illustrates the lack of evidence to evaluate effectiveness for many
chemotherapy options which have only phase II trials.
Randomised Controlled Trials
There were two randomised controlled trials
1. Vogelzang et al, 20038 – pemetrexed + cisplatin vs cisplatin, in chemotherapy
naive
The EMPHACIS trial (Evaluation of mesothelioma in a phase III trial of pemetrexed
with cisplatin) by Vogelzang et al8 investigated the effectiveness of pemetrexed in
combination with cisplatin versus cisplatin alone in patients with MPM. This was a
multi centre single blind trial of 448 patients and the primary end point was survival.
Those in the intervention arm that were given pemetrexed 500mg/m² plus cisplatin
75mg/m² had a median survival time of 12.1 months compared to 9.3 months in the
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control arm (cisplatin only), a difference of 2.8 months that was statistically significant.
In the fully supplemented patients in the intervention group, median survival was 13.3
months compared to 10 months in the control group. Fully supplemented patients
with advanced disease had a median survival of 13.2 months in the intervention
group and 8.4 months in the control group. The partial response rate in the
intervention group was 41% compared to 16.7% in the control group. Median time to
progression of disease was greater in the intervention group (5.7 months) compared
to the control group (3.9 months). Severe toxicity in the intervention group led to the
introduction of folic acid and vitamin B12 part way through the trial and resulted in a
significant reduction of toxicity.
The results of the EMPHACIS trial suggest that pemetrexed plus cisplatin confers a
survival benefit of approximately 3 months compared with cisplatin monotherapy. The
combination treatment also appears to demonstrate advantages in terms of 1-year
survival, median time to disease progression, tumour response rate and quality of life.
The EMPHACIS study was a single blind trial where the participants were blinded to
the nature of the treatment they received but the outcome assessors were not blind.
This was justified in the study design as necessary to allow clinicians to treat severe
toxicities. However the lack of a double blind trial possibly introduces bias to the
study. The inconsistencies in response rate assessments among investigators,
reviewers and the United States Food and Drug Administration reflect the difficulty of
using response rate as an outcome measure.
As noted by Dundar7 and Ellis10:

Approximately 50% of the EMPHACIS trial patients were WHO performance
status zero, and therefore had only minimal impairment of activity level at trial
entry. This is potentially a higher proportion than would normally present to
clinicians. The EMPHACIS study treated 448 patients but 118 patients signed
informed consent but were not randomised. The reasons for excluding these
patients are not clear and this could limit the generalisability of the results.

In the EMPHACIS trial only 67% of the randomised and treated patients had
the pathological diagnosis confirmed by independent review11 and the
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reported response rates in the experimental arm were higher than in many
published phase II studies. Additionally only 50% of the response rates were
confirmed by independent review12.

The site and mode of spread of mesothelioma, in sheets of cells lining the
pleura rather than well-circumscribed lesions, complicates the assessment of
response,
which
is
usually
based
on
computed
tomography
scan
measurement. Hence claims of response rates and time to progression need
to be interpreted with caution7.
2. Jassem et al, 200813 - second line pemetrexed + BSC vs BSC
A randomised controlled trial by Jassem et al13 of 243 patients from 45 institutions
worldwide with relapsed MPM after first-line chemotherapy, compared overall survival
of second line treatment with pemetrexed plus best supportive care versus best
supportive care alone. BSC was intended to maximise quality of life without a specific
antineoplastic regimen. The study found the median survival time in the intervention
group (BSC plus 2nd line pemetrexed) was 8.4 months versus 9.7 months in the
control group (BSC) but had better outcomes in terms of response rate (18.7%
versus 1.7%), progression free survival (3.6 months versus 1.5), time to tumour
progression (3.7 months versus 1.5) and time to treatment failure (3.6 months versus
1.5). The study suggests that second line pemetrexed is more likely to yield a clinical
benefit among patients who responded to first line chemotherapy. However the
survival figures were not statistically significant and therefore the weight of evidence
is not strong.
Case Series Studies from Extended Access Programme
There were five studies from the Extended Access Programme (EAP)
After completion of the EMPHACIS phase III trial8 an EAP, initiated by Eli Lilly and
Company, included patients enrolled between the end of the trial in May 2002 up to
Federal Drug Association (FDA) approval of pemetrexed in February 2004. The
phase III EMPHACIS trial exclusively included patients who were chemotherapy
naïve, and at the commencement of the EAP in May 2002, only chemotherapy naïve
patients were included. However, in January 2003, the study protocol was amended
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to provide pemetrexed access to patients with MPM who had been previously treated.
The EAP programme included patients with pleural or peritoneal mesothelioma and
enrolled a total of 1056 patients.
The International Extended Access Programme provided more than 3000
mesothelioma patients with access to single-agent pemetrexed or pemetrexed in
combination with either cisplatin or carboplatin in 13 countries outside the USA. The
latter 3 studies reported here are from the International EAP.
1. Janne et al, 200614 - pemetrexed + cisplatin vs cisplatin, in pre-treated patients
As part of the Extended Access Programme, Janne et al14 conducted a nonrandomised open label study to gather additional information on the efficacy and
safety of pemetrexed plus cisplatin and pemetrexed monotherapy in patients who
had received previous systemic chemotherapy. The study included 187 patients with
MPM who had been previously treated with at least one dose of the study drug. The
study found a complete response in 2.5% of those on pemetrexed plus cisplatin (0%
in cisplatin alone), partial response in 30% (5.5% in cisplatin alone), stable disease in
36.6 % (41.1% in cisplatin alone) and progressive disease in 31.3% (53.4% in
cisplatin alone). Median survival for those receiving pemetrexed plus cisplatin was
7.6 months compared to 4.1 months for those on cisplatin alone. While pemetrexed
plus cisplatin is an established first line chemotherapy regime for MPM, this EAP trial
provides some evidence of the effectiveness of this combination in the second line
setting.
2. Obasaju et al, 200715
- pemetrexed + cisplatin and cisplatin alone in
chemotherapy naive
In a non-randomised open label study Obasaju et al15 followed up 728 patients with
MPM in the EAP who were chemotherapy naïve at commencement. Of these
patients, 709 received pemetrexed plus cisplatin, while only 19 were treated with
pemetrexed alone (these were older patients with a median age of 79 years versus
70 years in the pemetrexed/cisplatin group). The overall response rate was 20.5%:
2.5% a complete response and 18.55% a partial response. An additional 47.2% had
stable disease. Median survival was 10.8 months and one year survival 45.4%. 113
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patients discontinued treatment in this study, the most common reason being patient
or physician decision (37.2%).
3. Santoro et al, 200816 - pemetrexed + cisplatin and pemetrexed + carboplatin
Santoro et al16 in a non-randomised multi-centre open label study under the
International Extended Access Programme looked at 1,704 chemotherapy naïve
patients who were given either pemetrexed plus cisplatin (only 745 out of 843 were
evaluable) or pemetrexed plus carboplatin (only 752 out of 861 were evaluable)16.
The first patient was enrolled in November 2002 and the last patient treated in
October 2006. The overall response rate was 26.3% for the pemetrexed/cisplatin arm
and 21.7% for the pemetrexed/carboplatin arm. 1 year survival was 63.1% and 64%
respectively and median time to progressive disease 7 months and 6.9 months
respectively. They concluded that pemetrexed with either carboplatin or cisplatin
resulted in similar efficacy and tolerability.
Although the EMPHACIS trial reported by Vogelzang8 demonstrated promising
results for pemetrexed plus cisplatin, there were many patients who were not eligible
for platinum containing regimens because of co morbidities, age and performance
status and therefore pemetrexed alone was explored in the following two studies.
4. Manegold et al, 200717 - pemetrexed in chemotherapy naive
Manegold et al17 reported on 319 chemotherapy naive patients in the international
EAP who were considered unsuitable for combination chemotherapy and therefore
received single-agent pemetrexed. Although the overall response rate appeared
lower for chemotherapy naive patients who received single-agent therapy, it was
noted that the 1-year survival rates were more similar for patients treated with single
agent pemetrexed (58.6%) versus 63.1 and 64% for patients receiving combination
therapy.
5. Taylor et al, 200818 - pemetrexed in chemotherapy naïve and pre-treated
Taylor et al18
in a non randomised open label study of outcomes from the
International Extended Access Programme (EAP) looked at outcomes for two groups
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of patients, chemotherapy naïve and pre-treated, in a trial of the single agent
pemetrexed. Pemetrexed as a single agent demonstrated a response rate of 10.5%
in chemotherapy naïve patients compared to 12.1% in the pre-treated patients, a
median time to progression of 6 months and 4.9 months, and one year survival rate
of 58.6% and 54.7% respectively. The median survival in the chemotherapy naïve
group was 14.1 months but was not estimable in the pre-treated group due to high
censoring.
Taylor’s study had weaknesses in terms of the pre-treated group being of a lower
mean age and having a greater proportion of patients with a higher Karnofsky
performance score than those in the chemotherapy naïve group 18.
Other Case Series Studies
There were seven other case control studies.
1. Castagneto et al, 200819 - pemetrexed + carboplatin in chemotherapy naive
Castagneto et al19 in a multicentre phase II case series clinical drug trial of 76
patients evaluated the activity and toxicity of the combination of pemetrexed and
carboplatin as first line chemotherapy to treat patients with measurable advanced
MPM, including mostly patients with stage 3 or 4 disease. Complete response was
noted in 4%, partial response in 21% and stable disease in 38%. The median overall
survival was estimated at 14 months and median time to progression was 8 months.
2. Ceresoli et al, 200620 - pemetrexed + carboplatin in chemotherapy naive
Ceresoli et al20 in a multi-centre phase II clinical case series looked at a trial of
combination treatment of pemetrexed and carboplatin in chemotherapy naïve
patients with MPM. Between November 2002 and March 2005 102 patients were
enrolled prospectively from 8 Italian institutions. Response rate was reported as
18.6%, median time to progression was 6.5 months and median survival time 12.7
months but both time to progression and survival time were significantly related to
good performance score in patients. The pemetrexed and carboplatin combination
was well tolerated and showed a low incidence of nausea, vomiting and fatigue than
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in the cisplatin/pemetrexed trial8. However this was a small trial with no control and
therefore does not represent strong evidence.
3. Ceresoli et al, 200821 - pemetrexed + carboplatin in ≥70 years and <70 years
Ceresoli et al21 in a retrospective analysis of patient data pooled from 2 phase II trials
reported on 178 patients who had received the same treatment schedule of
pemetrexed and carboplatin. The study compared the efficacy, toxicity and survival
outcomes for elderly (≥70 years of age) versus younger patients (<70 years of age).
The difference in response rate between the two groups was not significant, 14.6% in
the ≥70 group and 23.8% in the <70 group. The median time to progression was 7.2
months for the ≥70 group and 7.5 months for the <70 group and the median overall
survival was 10.7 months and 13.9 months respectively.
4. Scagliotti et al, 200322
- pemetrexed single agent in chemotherapy naïve
supplemented and non-supplemented
Scagliotti et al22 in a phase II multi centre case series looked at the efficacy of
pemetrexed as a single agent in chemotherapy naïve patients with advanced MPM.
43 patients received pemetrexed with full supplementation with folic acid and vitamin
B12. 21 received pemetrexed but were non-supplemented (i.e. received folic acid and
vitamin B12 supplementation for part of the trial or never received either). They found
that pemetrexed demonstrated moderate activity as a single agent and was well
tolerated, particularly in patients who received low-dose folic acid and vitamin B12
supplementation. The response rate in the fully supplemented was 16.3% and in the
non-supplemented it was 9.6%. However there was conflicting opinion on the tumour
response analysis between investigators and independent reviewers, the latter
reporting a higher response rate for the fully supplemented than the former. The
median survival in the fully supplemented was 13 months and in the nonsupplemented it was 8 months. Median time to progression was 4.8 months and 3
months respectively.
In this single agent trial the incidence of grade 3/4 neutropenia among fully
supplemented patients was 9.3% and in the non-supplemented it was 52.4%. There
were 23 reports of serious adverse events during the study: 13 in the supplemented
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(fever being the most common) and 10 in the non-supplemented (fever and
leucopenia). Five of the seven patients who withdrew from the study due to an
adverse event were non-supplemented.
5. Sorensen et al, 200723 - pemetrexed + carboplatin and pemetrexed single agent
as second line treatment
Sorensen et al23 reported on a case series to evaluate pemetrexed as second line
chemotherapy in MPM patients not previously exposed to pemetrexed. Thirty nine
patients, who had disease progression after previous platinum based regimens
without pemetrexed, received pemetrexed alone or pemetrexed plus carboplatin. The
partial response rate was 21% for the pemetrexed group and 18% for the
pemetrexed pus carboplatin group, while time to progression was 21 weeks and 32
weeks and median survival 42 weeks and 39 weeks respectively. Although the study
had a small number of subjects they concluded that pemetrexed was generally well
tolerated and could be considered for second-line treatment.
6. Janne et al, 200824 - pemetrexed + gemcitabine in chemotherapy naive
Janne et al24 conducted an open label phase II trial of two different treatment
schedules of pemetrexed and gemcitabine(an inhibitor of ribonucleotide reductase
and DNA synthesis)24. The first group received pemetrexed on day eight and
gemcitabine on day one and eight. The second group received pemetrexed on day
one and gemcitabine on day one and eight. Both schedules were part of a 21 day
cycle. The combination of pemetrexed and gemcitabine resulted in moderate clinical
activity in MPM. The median survival times, 8.08 months for group one and 10.12
months for group two, were similar to those with single agent pemetrexed and inferior
to outcomes observed with cisplatin in combination with either pemetrexed or
raltitrexed.
7. Van de Bogaert et al, 200625 - single agent pemetrexed as maintenance therapy
in those who had previously received 6 cycles of pemetrexed
In van de Bogaert’s case series study25 to investigate the toxicity and effectiveness of
pemetrexed maintenance therapy (PMT) in patients with MPM25, 27 patients with
stable disease were included. These participants had already received 6 prior cycles
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of pemetrexed. One group (13) went on to have further cycles of pemetrexed and the
other group (14) did not receive any further treatment with pemetrexed. Of the group
who continued on PMT 23% achieved a partial response This group also had an
almost threefold longer time to disease progression (8.5 months versus 3.4 months)
and overall survival (17.9 months versus 6 months) than those who did not receive
PMT. The study lacks power due to the low number of patients included and also the
intervention group had a lower mean age which may have biased the outcome in
their favour. However the study gives support to the hypothesis that prolonged
pemetrexed exposure and an increase in the total administered dose leads to a
further improvement in tumour response.
Table 1. Summary of pemetrexed studies
Reference
Number
in study
SYSTEMATIC REVIEWS
Dundar et
N/A
al, 2007 7
Outcome
measures
NICE
grading
Drugs
administered
Effectiveness
Clinical
effectiveness,
cost effectiveness
1+
Pemetrexed +
cisplatin
Ellis et al,
2006 10
N/A
Survival,
response rate,
time to
progression,
toxicity
1-
Pemetrexed +
cisplatin and
raltitrexed +
cisplatin
Limited benefit at cost
of considerable toxicity.
Not cost effective by
conventional UK
standards
Evidence for use of
pemetrexed + cisplatin
stronger due to nonsignificant RR and
progression free
survival rates for
raltitrexed + cisplatin.
However the latter
gives significant better
survival and is
recommended if
pemetrexed is not
available
456
Survival,
response rate,
time to
progression, time
to treatment
failure, toxicity,
quality of life
Survival,
response rate,
time to
progression,
progression free
1+
Pemetrexed +
cisplatin vs
cisplatin in
chemotherapy
naive
Survival 12.1 vs 9.3
months. Response rate
41% vs 16.7%. TTP
5.7 vs 3.9 months
1-
Pemetrexed +
BSC vs BSC as
second line
treatment
Survival 8.4 vs 9.7
months. Response rate
18.7% vs 1.7%.
RCTs
Vogelzang
et al 20038
Jassem et
al, 200813
243
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survival, time to
treatment failure,
toxicity
Quality of life
Muers it al,
409
1200826
CASE SERIES AND CASE CONROL STUDIES
Janne et al,
187
Survival,
3
200614
response rate
Chemotherapy +
ASC vs ASC
No difference found
between quality of life
Pemetrexed +
cisplatin vs
cisplatin in pretreated
Pemetrexed +
cisplatin vs
cisplatin in
chemotherapy
naive
Pemetrexed +
cisplatin and
pemetrexed +
carboplatin
Survival 7.6 vs 4.1
months. Response rate
32.5% vs 5.5%
2+/2-
Pemetrexed in
chemotherapy
naive
One year survival
58.6%. Response rate
10.5%
3-
Pemetrexed in
chemotherapy
naïve and pretreated
3-
Pemetrexed +
carboplatin in
chemotherapy
naive
Survival 14.1 months
vs inestimable due to
high censoring.
Response rate 10.5%
and 12.1%
Survival 14 months.
Response rate 25%
3-
Pemetrexed +
carboplatin in
chemotherapy
naive
Survival 12.7 months.
Response rate 18.6%
3
Pemetrexed +
carboplatin in
≥70 year and <70
years
Survival 10.7 and 13.9
months. Response rate
14.6% and 23.8% (not
significant)
3
Pemetrexed in
chemotherapy
naïve –
supplemented
and nonsupplemented
Pemetrexed +
carboplatin and
pemetrexed
alone as second
line treatment
Pemetrexed +
Survival 13 and 8
months. Response rate
16.3% and 9.6%.
Obasaju et
al, 200715
709
Survival,
response rate,
toxicity
2+/2-
Santoro et
al, 200816
1,704
2+/2-
Manegold et
al, 200717
319
Taylor et al,
200818
813
Castagneto
et al, 200819
76
Ceresoli et
al, 200620
102
Ceresoli et
al, 200821
178
Scagliotti et
al, 200322
70
Sorensen et
al, 200723
39
Survival,
response rate,
time to
progression,
toxicity
Survival,
response rate,
time to
progression,
toxicity
Survival,
response rate,
time to
progression,
toxicity
Survival,
response rate,
time to
progression,
toxicity
Survival,
response rate,
time to
progression,
toxicity
Survival,
response rate,
time to
progression,
toxicity
Survival,
response rate,
time to
progression, time
to treatment
failure, toxicity
Survival,
response rate,
time to
progression
Janne et al,
108
Survival,
3
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Survival 10.9 months.
Response rate 20.5%
One year survival
63.1% and 64%.
Response rate 26.3%
and 21.7%
Survival 39 and 42
weeks. Response rate
18% and 21%.
Survival 8.08 and
Evidence Based Brief Report
200824
response rate,
time to
progression
Survival,
response rate,
time to
progression,
toxicity
gemcitabine in
chemotherapy
naive
Pemetrexed
continued in
those who
previously had 6
cycles of
pemetrexed.
Trade off
between survival
benefit of
chemotherapy
and toxicity
Van den
Bogaert et
al, 200625
27
3-
Silvestri,
Pritchard
and Welch,
199827
81
Quality of life,
survival threshold
for receiving
chemotherapy
3-
Cordony et
al, 200828
456
Cost
effectiveness
N/A
Pemetrexed +
cisplatin vs
cisplatin
10.12 months.
Response rate 26%
and 17.1%
Survival 17.9 and 6
months. Response rate
23% and 0%.
22% chose
chemotherapy for
survival benefit of 3
months and 68%
chose chemotherapy if
it substantially reduced
symptoms without
prolonging life.
Can be considered
cost effective
4.2.2 Safety
The toxicity profile of pemetrexed (mucositis, neutropenia and leucopenia) does not
overlap with that of cisplatin (gastrointestinal, neurological and renal) thus supporting
their use in combination. Patients who receive vitamin B12 and folic acid
supplementation have a notable reduction in hematologic toxicity, specifically grade
3/4 neutropenia and leukopenia29. In the EMPHACIS trial by Vogelzang et al8, of
those in the pemetrexed/cisplatin treatment arm, 27.9% experienced grade 3/4
neutropenia as opposed to 2.3% in the cisplatin arm, 17.7% and 0.9% respectively
experienced leucopenia, 14.6% and 6.3% nausea, 10.2% and 8.6% fatigue, 13.3%
and 3.6% vomiting, diarrhoea 4.4% and 0%.
In the pemetrexed/cisplatin patients there was a noted difference in toxicities
between those who were fully supplemented and those who received no
supplementation: 23.2% of the fully supplemented experienced neutropenia
compared to 37.5% among those never supplemented, leucopenia 14.9% and 34.4%
respectively, nausea 11.9% and 31.3%, fatigue 10.1% and15.6%, vomiting 10.7%
and 31.3%, diarrhoea 3.6% and 9.4%. Therefore grade 3 and 4 toxicities of
combined therapy are improved by the addition of vitamin B12 and folic acid and full
supplementation is necessary to reduce toxicity to an acceptable level8.
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Jassem et al13 noted that for patients receiving second line pemetrexed (with
supplementation) plus BSC grade 3 and 4 toxicities were primarily hematologic
(occurring in 4-7% of patients) whereas no hematologic toxicities occurred among the
BSC patients. The greatest toxicity differences between the arms were fatigue:
15.7% and 10.8%, and chest pain, 14% and 8.3% respectively.
In the Extended Access Programme, serious adverse events (SAEs) were reported
for all patients who had either peritoneal or pleural disease and therefore those with
MPM were not differentiated in the results. The chemotherapy naïve and the pretreated were also not differentiated in the records of SAEs. The most commonly
investigator-reported haematological SAEs in the EAP were: anaemia (2.3%), and
thrombocytopenia (1.3%). Neutropenia was reported in <1% of patients in the EAP.
The most commonly reported non-haematological SAEs included dehydration (7.2%),
nausea (5.2%), vomiting (4.9%), dyspnoea (3.8%) and pulmonary embolism (2.4%) 14
15.
This reporting in the EAP relied on investigator reported SAEs and therefore the
true rate of toxicity among patients was potentially greater than that reported.
The International Extended Access Programme reported on toxicities for three
groups of patients: those receiving pemetrexed plus cisplatin, pemetrexed plus
carboplatin and pemetrexed alone. Grade 3/4 neutropenia occurred in 23.9% of the
pemetrexed plus cisplatin group, 36.1% of the pemetrexed plus carboplatin group
and 17.3% of the pemetrexed alone group. Grade 3/4 leucopenia occurred in 13.1%,
21% and 14.7% respectively16
17.
However chemotherapy naïve patients in the
International EAP treated with pemetrexed plus carboplatin had a poorer clinical
status, a median age of 66 (compared to 62 in the pemetrexed/cisplatin group) and
were possibly those who were unsuitable to receive pemetrexed plus cisplatin16.
In the study by Taylor et al, greater toxicity was observed in the chemotherapy naïve
patients rather that the pre-treated, even though they had a lower response rate:
grade 3/4 neutropenia occurred in 17.3% of the chemotherapy naïve group and
15.6% of the pre-treated group. Similarly grade 3/4 leucopenia occurred in 14.7% of
the chemotherapy naïve and 13.9% of the pre-treated patients18.
In light of the potential toxicity of cisplatin, both Castagneto and Ceresoli looked at
carboplatin as a potential alternative in combination with pemetrexed. The reported
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toxicities vary between the studies, possibly because Castagneto’s study participants
received a median 8 cycles of treatment (the median number of cycles in Ceresoli’s
study was 6 cycles) and, although Castagneto’s study claimed to have patients with
poor
performance,
the
staging
according
to
the
tumour-node-metastases
international staging system showed 82.8% and 81% being stage III or IV in both
studies19 20. The study characteristics of the participants are similar in both studies.
Grade 3/4 neutropenia was reported as 32.6% in Castagneto’s study and 19.65 in
Ceresoli’s study, thrombocytopenia 13.1% and 7.8%, anaemia 11.7% and 7.8%, and
vomiting 1% and 11.8% respectively.
In a study that compared the efficacy, toxicity and survival outcomes for elderly (≥70
years of age) versus younger patients (<70 years of age) receiving pemetrexed plus
carboplatin, grade 3/4 neutropenia was slightly worse in the elderly patient group
(25% versus 13.8%) as well as thrombocytopenia (14.6% versus 8.5%). Severe
anaemia was significantly more frequent in the older age group as a cumulative
toxicity of 20.8% versus 6.9%21.
Scagliotti et al, looked at pemetrexed as a single agent in chemotherapy naïve
patients22, both with and without supplementation with folic acid and vitamin B 12.
Grade 3/4 neutropenia among non–supplemented patients was 52.4% versus 9.3%
for the fully supplemented. There were 23 reports of serious adverse events: 13 in
the supplemented (fever being the most common) and 10 in the non-supplemented
(fever and leucopenia). Five of the seven patients who withdrew from the study due
to an adverse event were non-supplemented.
When pemetrexed was given as second line chemotherapy in MPM, either with or
without carboplatin, grade 3/4 leucopenia occurred in 14% of the pemetrexed group
and 9% of the pemetrexed plus carboplatin group, thrombocytopenia in 7% and 18%
and nausea in 4% and 0% respectively23.
In van de Bogaert’s small case series study25 to investigate the toxicity and
effectiveness of pemetrexed maintenance therapy (PMT) after an initial 6 courses, no
grade 4 toxicities were observed in the PMT group but grade 3 toxicities were
neutropenia 15%, leucopenia 8%, anaemia 8% and fatigue 15%. However these only
occurred in the subgroup of patients who had been treated with pemetrexed plus
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carboplatin as an induction regime. The only non haematological grade 3 toxicity was
fatigue 15%.
4.2.3 Cost effectiveness
Pemetrexed plus cisplatin chemotherapy involves a substantial additional cost
compared with cisplatin alone, as the price of pemetrexed is approximately 20 times
that of cisplatin. The economic question is whether the high additional cost of
treatment with pemetrexed is justified by the modest survival gains and the potential
small benefits in terms of quality of life.
Cordony et al, 200828
Using the results of the EMPHACIS phase III trial8 of survival outcomes for
pemetrexed/cisplatin supplemented with folic acid and B 12 compared with cisplatin
monotherapy in patients with MPM (which reported a clear survival gain for all
patients in the former group), Cordony et al28 conducted a cost effectiveness analysis.
NHS direct medical costs were used and no indirect or social costs were incorporated.
The time horizon was 29 months, in line with the follow up time in the phase III trial.
The total incremental cost associated with pemetrexed/cisplatin treatment in the RCT
ranged from £8779 to £9020. Quality adjusted mean survival for all groups returned
values in the range from 0.13 to 0.20 quality-adjusted life-years. The incremental
“cost per quality-adjusted life years gained” ratio ranged from £44,950 to £68,598.
The estimated cost-effectiveness results by the authors were as follows:

FS (fully supplemented) population: incremental cost-effectiveness ratio (ICER)
per quality-adjusted life year (QALY) gained = £68,599.

FS with AD (advanced disease) population: ICER per QALY = £53,314.

FS with performance status 0/1 population: ICER per QALY = £45,454.

FS with performance status 0/1 and AD population: ICER per QALY = £44,950.
Cordony et al, state that these ratios could be considered cost effective by the UK
reimbursement authority (National Institute for Health and Clinical Excellence)
because they reflect survival gains as well as therapeutic gains in quality of life.
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Towse et al (2002)30 have suggested that the ‘threshold’ cost per quality adjusted life
year gained implicit in NICE’s decisions is between £20,000 and £30,000;
technologies with incremental cost effectiveness ratios above this level seem more
likely, but not certain, to be rejected. Analysis by Appleby et al (2007)31 suggests that
NICE does not accept or reject health care technologies on cost effectiveness
grounds alone, although it is a major deciding factor, but analysis suggests that
NICE’s threshold is in practice more generous than admitted, being closer to £45,000.
Dundar et al, 20077
A systematic review of the clinical effectiveness and cost effectiveness of
pemetrexed plus cisplatin by Dundar et al7 found no published full economic reports.
In considering cost-effectiveness one conference abstract/presentation by Davey et
al (2004)32 was evaluated as well as two models submitted by Eli Lilly, the
manufacturers of pemetrexed. The conference abstract/presentation presented a
mean ICER of A$73,470 per life year saved, a figure that led to the Australian
Pharmaceutical Benefits Advisory Committee (PBAC) in 2005 rejecting the listing of
pemetrexed for use in combination with cisplatin for the treatment of patients with
MPM on the basis of unfavourable cost-effectiveness. However the PBAC changed
its conclusion, in 2007, to fund pemetrexed in combination with cisplatin for the
treatment of mesothelioma after Eli Lilly presented data showing pemetrexed was
well tolerated in most patients and because Eli Lilly reduced the price by 10% and
offered the drug in a smaller 50mg dose as compared to the traditional dose of
100mg to reduce wastage of the drug.
Dundar et al concluded that Davey’s study was insufficient to evaluate the economic
value of pemetrexed plus cisplatin versus cisplatin alone due to the poor quality of
the study: no subgroup analysis or sensitivity analysis was presented.
The two models submitted by Eli Lilly and Company lacked credibility to the
reviewers, who reformulated one of the models which included data from EMPHACIS
study8. However they were unable to access individual patient data (IPD) and
therefore acknowledge limitations in their conclusions.
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With regard to cost effectiveness they considered that pemetrexed was not cost
effective at conventionally accepted thresholds in the UK, because of the high cost of
pemetrexed compared with cisplatin, for all patients. Cost effectiveness was better for
some patient subgroups, particularly fully supplemented (FS) patients with good
performance status (0/1) and advanced disease (AD).
The estimated cost-effectiveness results by Dundar et al were as follows:

FS population: incremental cost-effectiveness ratio (ICER) per quality-adjusted
life year (QALY) gained = £59,600.

FS with AD population: ICER per QALY = £47,600.

FS with performance status 0/1 population: ICER per QALY = £49,800.

FS with performance status 0/1 and AD population: ICER per QALY = £36,700.
This suggests that pemetrexed is not cost-effective at conventional thresholds for all
patients.
The authors noted that there is no research or evidence to look at the cost of
standard clinical practice (which may be doing nothing) and that this should be one
of the alternatives compared with the cost of pemetrexed. The cost effectiveness
evaluation was based on UK costing and therefore may have limited usefulness to
the New Zealand context.
Pharmac received an application from Eli Lilly for the listing of pemetrexed in Part V
of Section H of the Pharmaceutical Schedule for the treatment of MPM in 2004. The
Cancer Treatments sub-committee considered that there was relatively good
evidence of a small benefit in terms of overall survival, but with some toxicity. The
subcommittee noted that in addition to the acquisition cost of the pharmaceutical,
there would be additional resource implications for the health sector in terms of
management of adverse effects of treatment. The sub-committee recommended
that pemetrexed be listed on the Pharmaceutical Schedule for MPM. The subcommittee accorded the recommendation a low priority, given the limited overall
benefit. At the time of consideration, the sub-committee considered that if listed,
about 30-40 patients per year might seek and be eligible for treatment.
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Evidence Based Brief Report
Cost of pemetrexed (ALIMTA ®) in New Zealand
ACC pays NZ$5,294 for 2 X 500mg vials from Eli Lilly
Treatment is 500mg/m² per cycle.
If compounded by Baxter Healthcare (Midcentral, Blenheim and Wairau) ACC is only
billed for the amount used.
(Source: Tracy Loader, Case Co-ordinator Asbestos Team)
Total Cost to ACC:
July 05 – June 06 - $580,327
July 06 – June 07 - $720,816
July 07 – June 08 - $633,337
(Source: ACC Data)
4.2.4 Quality of life
Accurate determination of the impact of treatment on quality of life (QOL) requires
reliable, valid and practical instruments for the measurement of quality of life prior to,
during and after treatment. Currently there is no mesothelioma specific instrument
available for QOL assessment.
MPM is similar in its symptoms to lung cancer. The Lung Cancer Symptom Scale
(LCSS) has been identified as potentially suitable for this patient population. LCSS is
a site-specific instrument used to assess QOL in patients with lung cancer. It focuses
primarily on the physical and functional dimensions of QOL, with other dimensions
captured in less depth through summary items. The six symptoms captured in LCSS
are appetite loss, fatigue, cough, dyspnoea, haemoptysis and pain. With the
exception of haemoptysis, all of these symptoms were considered relevant to
patients with MPM. The patient form also includes three summation items:
symptomatic distress, interference with activity level and global quality of life.
Hollen et al33 tested a modified version of the LCSS (known as the LCSS-Meso) and
reported the good feasibility, reliability and validity of this instrument for patients with
pleural mesothelioma. The modified LCSS was used in the EMPHACIS phase III
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randomised single blind trial8 (N=448) and also Scagliotti’s phase II single arm trial of
pemetrexed monotherapy22 (N=64) and these two datasets were combined for
Hollen’s study because of the similarity in inclusion and exclusion criteria between
the trials as well as the methods for the administration of the modified LCSS. The
modified LCSS consisted of a nine-item, patient reported and a six item, observer
reported instrument and was incorporated into the two trials.
In Scagliotti’s study22 patients who responded to therapy also experienced increases
in lung volume and motility. These patients also reported improvements in QOL
parameters including dyspnoea, pain, symptom distress and functional capacity.
Similarly the EMPHACIS study reported that dyspnoea and pain were significantly
improved for patients receiving pemetrexed/cisplatin after 6 cycles of treatment when
compared to cisplatin alone.
Silvestri et al, 199827
Silvestri et al27 in a descriptive study looked at how patients with lung cancer value
the trade off between the survival benefit of chemotherapy and its toxicities. Scripted
interviews with 81 patients previously treated with cisplatinum-based chemotherapy
revealed a median survival threshold for accepting chemotherapy at 4.5 months for
mild toxicity and 9 months for severe toxicity. Elderly patients tended to demand
greater benefit before accepting chemotherapy and patients self reporting lower
quality of life during chemotherapy had higher thresholds for accepting chemotherapy.
When given the choice between supportive care and chemotherapy only 18 (22%)
chose chemotherapy for a survival benefit of 3 months. 55 (68%) chose
chemotherapy if it substantially reduced symptoms without prolonging life.
Some patients simply do not want chemotherapy, as confirmed by a study in Leeds
by Chapman et al34 which audited all referred mesothelioma cases between 2002
and 2005: of 54 patients who were fit for, and offered, chemotherapy, 28 (52%)
declined it. Some patients receiving ASC can have good symptom control and avoid
the toxic effects related to chemotherapy, resulting in overall quality of life which was
very comparable to that of patients receiving chemotherapy.
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Muers et al, 200826
Other studies, not directly related to the use of pemetrexed have shown that ASC
has been effective in enhancing quality of life for patients.
Muers et al26 in a multi-centre RCT enrolled 409 chemotherapy naïve patients from
76 centres in the UK and 2 in Australia, to investigate whether the addition of
chemotherapy to active symptom control (ASC) improved survival and quality of life.
Patients were randomly assigned to ASC alone; ASC plus mitomycin, vinblastine and
cisplatin (MVP); or to ASC plus vinorelbine. Because of the difficulty in recruiting
patients to the ASC group, the chemotherapy groups were combined for analysis.
The trial did not find a statistically significant survival benefit in the addition of
chemotherapy and found that median survival in the ASC group was 7.6 months
compared with 8.5 months in the ASC plus chemotherapy group but no difference
between quality of life between the groups. The results were potentially biased by the
small sample and methodology of the trial.
4.3 Discussion
4.3.1 Methodological Quality
Study design:
There were 2 systematic reviews included in this review. Dundar’s review7 was of
good quality but drew conclusions from only one RCT which met the inclusion criteria.
In contrast the review by Ellis10 included a large number of studies (119) including
eight RCTs looking at a wide range of chemotherapy regimes for MPM patients. The
criteria for selecting reviewed studies were unclear and the quality of the studies
included was not examined and therefore the review is not of good quality.
There were 3 RCTs of varied quality which were not comparable; one looked at
pemetrexed plus cisplatin versus cisplatin alone; another looked at active symptom
control (ASC) versus ASC alone in the chemotherapy naïve, and finally best
supportive care (BSC) versus pemetrexed as second line treatment. The terms ASC
and BSC are defined for the individual studies but are not comparable. There is no
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definitive definition for these in the literature. The remaining studies were either follow
up trials in the EAP or case series studies of low quality by evidence based
healthcare standards.
Intervention:
Pemetrexed in all the studies was administered intravenously at a dose of 500mg/m².
When cisplatin was given it was administered 30 minutes later at a dose of 75mg/m².
Carboplatin was delivered to an area under the curve (AUC) of 5 over 30 min on day
one. Gemcitabine was given at 1,250mg/m².
Treatment cycles were repeated every 21 days. The studies covered different
permutations of treatment regimes for pemetrexed including pemetrexed alone,
pemetrexed
plus
cisplatin,
pemetrexed
plus
carboplatin,
pemetrexed
plus
gemcitabine, pemetrexed as first line and second line treatment and also treatment
with pemetrexed in relapsed patients after chemotherapy. Because of this the studies
were not directly comparable but rather gave a fuller picture of the effects of
pemetrexed on different populations and in different combinations.
Many studies had dose reductions if haematological toxicities occurred and in some
studies treatment cycles were delayed for similar reasons. Because of toxicities and
withdrawals from treatment due to patient of physician choice, the median number of
treatment cycles within studies varied for different drug regimes, for example, in the
EMPHACIS trial the pemetrexed + cisplatin intervention group received a median
number of cycles of 6 (range 1-12) and the cisplatin group received a median of 4
cycles (range 1-9) which makes direct comparison unreliable. Also the number of
treatment cycles varied between studies making comparisons unreliable.
Sample size and statistical analysis:
The number of patients in the studies varied from 27 to 1,704. In the RCTs the study
sample was between 243 and 456. Many of the studies had very low numbers of
patients in the studies and therefore the results are of limited power.
Because of the rarity of MPM, for many studies, patients were recruited from different
centres in
different countries.
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measurement of outcomes in the various studies is impacted by this type of study
design.
Trials that incorporate an ASC group are difficult to recruit to and it is unlikely that any
trial will be conducted to evaluate the effectiveness of pemetrexed versus ASC/BSC.
Originally Muer’s study aimed to recruit 840 patients with MPM in a three group trial
to asses the value of both MVP and vinorelbine compared with ASC but recruitment
was slower than required26. This was due to the availability of pemetrexed as part of
the EAP after its effects were known and also some patients not wanting to receive
chemotherapy. The trial design was changed to two groups and the researchers
acknowledged that 420 patients were required to achieve 76% power. The study only
recruited 409 patients.
Most studies analysed by intention to treat. Given the natural rapid progression of
MPM, with most patients dying within one year of diagnosis, the time to follow up was
usually to time of disease progression or death from MPM. Survival and the
distribution of time to event were estimated using the Kaplan-Meier method.
Response rates and other proportions were compared using x² test or Fischer’s exact
test. Because of the short relative time to death after diagnosis, there was difficulty
with follow up in HRQOL studies because of patients getting too sick to complete
questionnaires.
Randomisation and blinded method:
Two of the RCTs regarding pemetrexed were randomised but the methods were not
clearly explained and they did not use double blinding. Jassem’s open label trial used
“central randomisation” but this was not explained13 and Muer’s study was
randomised by minimisation with stratification for WHO performance status, histology
and centre26.
Because of the relative scarcity of MPM and the need to recruit patients across a
number of treatment centres and often countries, randomisation and blinding is
problematic. However blinding is not necessary for primary outcome of survival
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Study population, inclusion and exclusion criteria:
The majority of studies included patients who

had MPM that was measurable, either histologically or radiologically and
measurable either uni- or bi-dimensionably;

patients that were over the age of 18 years;

had a life expectancy of ≥12 weeks;

had a Karnofsky performance score ≥70 (which equates to an ECOG - WHO
score of 0-2);

were not candidates for surgical treatment; and

had adequate bone marrow, hepatic and renal function.
Patients that were excluded from trials included those with serious co-morbidities;
those with documented brain metastases or other malignancies; those unable to
interrupt NSAIDs and pregnant patients.
Some studies used specific patient groups, for example older patients with MPM21,
and although most studies looked at patients that were chemotherapy naïve, some
looked at patients who had received previous chemotherapy13 14 18 23 25 27.
Follow-up and study period:
Because of the nature of MPM and the short life expectancy for patients once they
were diagnosed, trials of different drugs usually continued until one of the following
outcomes occurred: death, progression of disease, unacceptable toxicity,
discontinuation at the choice of either the patient or their physician.
4.3.2 Outcome measures:
The primary outcome for the majority of studies was survival and the secondary
outcomes were response rate, time to disease progression or treatment failure and
toxicity.
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Ryan and colleagues35 also commented that, because of the diffuse nature of this
tumour, response was difficult to measure, and choosing regimens on the basis of
response rates might not be the best surrogate for survival benefit.
The growth pattern of MPM makes the use of RECIST (response evaluation criteria
in solid tumours) response criteria difficult36. Malignant mesothelioma most
commonly grows in diffuse sheets rather than spherical configurations complicating
accurate
bi-dimensional or uni-dimensional radiographic assessment. In patients
with extensive lobulated disease, selection of appropriate lesions to follow may be
difficult due to lack of well demarcated margins. Therefore the tumour burden may
not be accurately represented by the lesions selected at baseline. The RECIST
criteria specify the use of uni-dimensional measurements, with partial response (PR)
defined as a 30% decrease in the sum of the longest diameter for all target lesions.
However the selection of measurement sites in mesothelioma is difficult and the
RECIST criteria can be applied differently by various investigators. Using modified
RECIST criteria measuring tumour thickness perpendicular to the fixed structures of
the chest wall, Byrne and Nowak’s study found that these criteria for tumour
response correlated with survival and measures of lung function and can be used to
measure outcome in MPM36.
In the USA the Federal Drug Agency (FDA) approved pemetrexed in combination
with cisplatin in February 2004. Approval was based on a demonstration of survival
improvement from one RCT8. Response rates and time to tumour progression were
not included on the product labelling because of inconsistencies in assessments
between the investigators, independent radiological reviewers and the FDA. In the
EMPHACIS trial, of the 94 patients in the combination treatment arm for which the
study claimed an objective tumour response, the FDA only confirmed 4711. However,
although specific response rates could not be accurately assessed, tumour
responses appeared more frequent in the pemetrexed plus cisplatin treatment group
than the single agent cisplatin treatment.
4.3.3 Effectiveness
The principle outcome reported for the effectiveness of pemetrexed was survival and
secondary outcomes were response rate, time to progressive disease and toxicity,
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the former being the least susceptible to bias. The paucity of evidence based
healthcare research means that the effectiveness of pemetrexed, either in
combination or as monotherapy, is not well supported by evidence.
The best available evidence for survival using pemetrexed plus cisplatin is 12.1
months compared to cisplatin alone of 9.3 months8. A weaker study reported survival
at 10.8 months for pemetrexed plus cisplatin but with no comparison group15.
For pemetrexed monotherapy survival for the chemotherapy naïve was reported as
14.1 months18 but in those who had previously received chemotherapy, survival time
varied between three different studies. The first reported survival as 4.1 months14 but
with no comparison group; the second reported survival at 42 weeks (10.5 months)23
compared to 39 weeks for those receiving pemetrexed plus carboplatin; and the third
study reported survival at 17.9 months25 compared to 6 months in the group not
receiving any chemotherapy. These three studies however were of weak quality.
Survival for pemetrexed plus carboplatin was reported as 12.7 months 20 and 14
months19 in the chemotherapy naïve and at 39 weeks (9.75 months)23 in those who
had previously received chemotherapy but these studies were of low quality.
When BSC alone was compared to pemetrexed plus best supportive care, the former
gave a slightly longer survival of 9.7 months compared to 8.4 months (however this
was in patients who had received previous chemotherapy)13.
When active symptom control alone was compared to active symptom control plus
chemotherapy (not pemetrexed) the survival was greater for the ASC plus chemo
group at 8.5 months versus 7.6 months (this was in chemotherapy naïve patients) 26.
The above two studies of ASC and BSC show little gain from chemotherapy in
increasing survival but are low quality studies.
In comparing the one year survival rate for pemetrexed combinations or pemetrexed
monotherapy further evidence is weak: the one year survival for pemetrexed alone is
58.6%, pemetrexed plus cisplatin is 63.1% and pemetrexed plus carboplatin is 64% 16
17.
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In terms of response rates to different permutations of pemetrexed there was
disparity in the quality and results of studies. The response rate for pemetrexed alone
varied from 10.5%18 to 16.3%22 (and 12.1% in those who had previously received
chemotherapy18), neither result being strongly evidence based. The response rate for
pemetrexed plus cisplatin ranged from 26.3%16 to 41%8. In the EMPHACIS trial, of
those who responded to treatment with pemetrexed and cisplatin, 87% had done so
within four cycles.
For pemetrexed and carboplatin the response rate was reported at 21.7% 16 but also
reported as 14.6% for those aged 70 and over and 23.8% for those aged less than
7021. For cisplatin alone the response rate was reported as 16.7%8.
4.3.4 Safety and adverse effects
There was greater toxicity noted in the combination treatment of pemetrexed/cisplatin
than when cisplatin was used alone.
Supplementation with vitamin B12 and folic acid is necessary to reduce toxicity to an
acceptable level in treatment with pemetrexed and cisplatin. Grade 3/4 neutropenia
was noted in 37.5% of those patients never supplemented as opposed to 23.2% in
those fully supplemented8.
Combination pemetrexed/carboplatin toxicity, which was mainly haematological, was
explored in three studies of low quality. Grade 3/4 neutropenia being most frequent,
followed by thrombocytopaenia and anemia19
20.
For older patients ≥70 years
neutropenia was found to be slightly worse (25%) than in those <70 years (13.8%)
and anaemia was much worse in the elderly as a cumulative toxicity at 20.8% versus
6.9% respectively21. However those in the EAP receiving pemetrexed/carboplatin
had a poorer clinical status and a median age of 66 (compared with 62 in the
pemetrexed/cisplatin arm) and were possibly those who were unsuitable to receive
pemetrexed/cisplatin16.
When pemetrexed or pemetrexed/carboplatin was used as second line treatment
leucopenia occurred in 14% of the pemetrexed group and 9% of
the
pemetrexed/carboplatin23.
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When pemetrexed was used alone, supplementation made a significant difference:
neutropenia occurring in 52.4% of the non-supplemented as opposed to 9.4% in the
fully supplemented and 38.1% and 9.3% respectively for occurrence of leukopenia 22.
Continuing pemetrexed therapy after initial treatment with this drug (6 treatments)
resulted in grade 3 neutropenia in 15% and leucopenia in 8%25.
The international EAP reported the most common toxicity as neutropenia which
occurred
in
23%
of
the
pemetrexed/cisplatin
group,
36.1%
of
the
pemetrexed/carboplatin group and 17.3% in the pemetrexed monotherapy group.
Grade 3/4 leucopenia occurred in 13.1%, 21% and 14.7% respectively17 16.
With many of the studies relying on investigator reported SAEs, including the EAP, it
is likely that that the true rate of toxicity among patients is greater than that reported.
The EAP central database did not distinguish between pleural and peritoneal
mesothelioma and therefore it is unclear in which group the SAEs occurred 15. In most
studies grade 3/4 toxicity was managed by dose reduction or dose delay.
4.3.5 Cost effectiveness
Pemetrexed offers a modest survival gain to patients with MPM. An analysis of the
cost effectiveness of this drug based on UK direct medical costs was considered cost
effective by the authors using the NICE suggested threshold cost per quality adjusted
life year gained28.
A model based on the EMPHACIS trial concluded that pemetrexed was not cost
effective at conventionally accepted thresholds in the UK but cost effectiveness is
better in some patient subgroups, particularly for fully supplemented patients with
good performance status (0/1) and advanced disease (stage III or IV)7.
4.3.6 Quality of life
Quality of life includes a trade off between survival benefit of chemotherapy versus
the toxic effects of chemotherapy. When given the choice between supportive care
and chemotherapy 22% chose chemotherapy for a survival benefit of 3 months but
68% chose chemotherapy if it substantially reduced symptoms without prolonging
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life27. Active symptom control which avoids the toxicities and side effects associated
with chemotherapy could offer overall quality of life and a survival benefit comparable
to those patients receiving chemotherapy26.
The EMPHACIS trial used the modified Lung Cancer Symptom Scale (LCSS) and
patients treated with pemetrexed plus cisplatin demonstrated statistically significant
improvements in dyspnoea and pain compared to those treated with cisplatin alone8.
4.4 Summary of evidence
Two systematic reviews and one randomised controlled trial present good evidence
for the effectiveness of pemetrexed and cisplatin, when used with folic acid and
vitamin B12 supplementation, in extending survival to 12.1 months as compared to
9.3 months when cisplatin is used alone. Pemetrexed and cisplatin offer
improvements in life quality in terms of reduced dyspnoea and pain.
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5. Raltitrexed
It was noted at the start of this review that as well as being used for the treatment of
colorectal cancer, raltitrexed is used for the management of MPM in Ontario, Canada
and therefore this drug was included in the review. In July 2007 the Committee to
Evaluate Drugs (CED) of Ontario’s Ministry of Health and Long Term Care
recommended not to fund pemetrexed (Alimta) through Cancer Care Ontario’s New
Drug Funding Programme, on the basis that it did not provide value for money
compared with existing alternatives on the Formulary. The Committee believed that
pemetrexed and raltitrexed had similar clinical benefits in the treatment of MPM.
Raltitrexed is listed on Ontario’s Formulary. Given that the cost of raltitrexed was
approximately 15% of the cost of pemetrexed, the Committee concluded that
pemetrexed did not demonstrate good value-for-money. The CED funding decision
regarding pemetrexed for MPM was informed by a evidence-based report and
guideline developed by the Lung Disease Site Group of Cancer Care Ontario’s
Program in Evidence-based Care (PEBC).
Although raltitrexed is not approved by Health Canada for MPM, it is a recommended
therapy for MPM in Ontario according to Cancer Care Ontario’s (CCO) Program in
Evidence Based Care guideline.
5.1 Health technology
Raltitrexed (trade name Tomudex, manufactured by AstraZenica) is a specific
inhibitor of the enzyme thymidylate synthase (TS). It is a specific inhibitor of the
enzyme thymidylate synthase (TS) and as such it will inhibit the formation of
thymidine nucleotides and its effects will primarily be due to inhibition of DNA
synthesis. The sensitivity of cells to treatment with this drug may be expected to vary
depending on the level of expression of thymidine synthase enzymes in cells.
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5.2 Results
5.2.1 Evidence regarding effectiveness of raltitrexed
Systematic reviews
There was one systematic review
1. Ellis et al, 200610
A systematic review and practice guideline by Ellis et al10 (also discussed in section
4.2.1 – number 2.) addressed two questions: (1) Does chemotherapy improve
survival, QOL, or symptom control, compared to best supportive care (BSC)? (2)
Which chemotherapeutic agents (or combinations of agents) have shown the highest
response rates in patients with advanced MPM?
The review reported on two RCTs8 37, one of pemetrexed plus cisplatin and one of
raltitrexed plus cisplatin, which were compared for median survival, response rate
and progression free survival. These 2 RCTs showed significantly improved survival
with combination chemotherapy and the review concluded that evidence supporting
the use of cisplatin and pemetrexed was stronger, based on the fact that, although
raltitrexed and cisplatin demonstrated superior survival, the improvements in
response rate and survival free progression were non-significant. However, the
review suggested it was reasonable to consider the use of raltitrexed 3mg/m² and
cisplatin 80mg/m² every 3 weeks, if pemetrexed was not available.
Randomised Controlled Trials
There was one randomised controlled trial
1. Van Meerbeeck et al, 200337 - raltitrexed + cisplatin versus cisplatin in
chemotherapy naive
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Van Meerbeeck et al37 in an intergroup study of the European Organisation for
Research and Treatment of Cancer (EORTC) Lung Cancer Group and the National
Cancer Institute of Canada (NCI) conducted a phase III randomised controlled trial to
determine whether raltitrexed plus cisplatin improved overall survival compared with
cisplatin monotherapy in chemotherapy naïve patients with MPM. This was a
multicentre (24 sites) trial of 250 patients recruited between March 2000 and January
2003. Those in the intervention group received raltitrexed intravenously at 3mg/m² in
15 minutes preceded by cisplatin at 80mg/m² in one to two hours. The control group
received only cisplatin. There was no vitamin supplementation.
For those on raltitrexed plus cisplatin there was a borderline significant increase in
median survival: 11.4 months versus 8.8 months in the control group. Median
response rate was 23.6% and 13.6% and time to progression was 5.3 months and
4.0 months respectively. Overall survival was significantly different between the poor
and the good prognosis group of patients as defined by Curran et al38 (the five factors
important for survival were: performance status, white blood cell count, certainty of
the histological diagnosis, gender and histology). Median and 1 year survival were
12.4 months and 51.1% in the good prognosis group and 8.1 months and 35.3% in
the poor prognosis group.
Van Meerbeeck’s sample size of 240 participants gave 80% power to detect a 50%
increase in median duration of survival with cisplatin plus raltitrexed over cisplatin
monotherapy37. The trial could have yielded even more striking results if accrual had
been extended to increase the study size to 340 to detect a 40% increase in overall
median survival, as recommended by an Independent Data Monitoring Committee
after the second interim analyses, but lack of funding prevented it39.
In van Meerbeeck’s study patients were randomly assigned to either of the treatment
protocols (although the process for this is not clear) and then stratified for institution,
performance status and white blood cell count. The two treatment groups were well
balanced for age, gender, histological subtype and stage, and prognostic category.
Allocation concealment and blinding again is not clear but because of the relative
scarcity of MPM and the need to recruit participants to studies from divergent centres
and countries, the issues of randomisation and blinding are difficult to adequately
address. The results for different sites were not compared for consistency and the
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study protocols may have been inconsistent across various sites. Blinding of
assessors was not done and therefore time to progression may be overestimated.
Blinding however does not effect the measurement of the outcome of survival.
Case Series Studies
There were two case series studies
1. Fizazi et al, 200340 - Raltitrexed + oxaliplatin in chemotherapy naïve and those
pre-treated with cisplatin
Fizazi et al40 in an open label case control study of 70 patients over 2 centres
evaluated the activity of raltitrexed and oxaliplatin (a platinum derivative that inhibits
DNA replication) combination therapy in patients who were either chemotherapy
naïve (55 patients) or pre-treated with cisplatin (15 patients). Although the patients all
had diffuse MPM, either the pleura or the peritoneum was the primary site. Both
groups received raltitrexed 3mg/m² as a 15 minute IV infusion followed 45 minutes
later by oxaliplatin 130mg/m² as a 2 hour infusion and the treatment cycle was
repeated every 3 weeks. In terms of response there was no difference between the
chemotherapy naïve and the pre-treated patients with a partial response in 14
patients (20%), stable disease in 32 patients (46%) and progressive disease in 22
patients (31%). The median survival was 32 weeks (31 weeks in the chemotherapy
naïve and 44 weeks in the pre-treated). Median time to disease progression again
favoured the pre-treated with 17 weeks in the chemotherapy naïve and 27 weeks in
the pre-treated.
Fizazi’s small study of 72 patients had an uneven split in the sample groups with 55
in the chemotherapy naïve group and only 15 in the group pre-treated with cisplatin.
This produced large confidence intervals for the reported response rate and there
were different sub groups within the analyses with the primary site of the
mesothelioma being either peritoneal or pleura – these were not differentiated in the
analyses and the methods of statistical analysis were not reported40.
2. Baas et al, 200341 - raltitrexed single agent in chemotherapy naive
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Baas et al41 in an open case series study over 5 European institutes evaluated the
activity and toxicity of raltitrexed as a single agent in the treatment of malignant
pleural mesothelioma. 24 patients received raltitrexed 3.0 mg/m² in a 15 minute IV
infusion on day 1 of a 3 week cycle. Patients received a median of 3 cycles of
treatment and received a minimum of 2 cycles before evaluation by CT scan. The
median survival was 7 months and tumour response using modified RECIST criteria
revealed a partial response in 5 patients (20.8%), stable disease in 8 patients and
progressive disease in 8 patients.
Baas’ case series of single agent raltitrexed41 was a very small study of only 25
participants over 5 different institutions and thus provides a low level of evidence.
Table 2. Summary of Raltitrexed studies
Reference
Number
in study
SYSTEMATIC REVIEWS
Ellis et al,
N/A
200610
RCTs
Van
Meerbeeck
et al, 200537
Outcome
measures
NICE
grading
Drugs
Administered
Effectiveness
Survival, response
rate, time to
progression,
toxicity
1-
Pemetrexed +
cisplatin and
raltitrexed + cisplatin
Evidence for
pemetrexed + cisplatin
stronger due to nonsignificant RR and
progression free
survival rates for
raltitrexed + cisplatin.
However latter give
significant better
survival and is
recommended if
pemetrexed is not
available
Raltitrexed +
cisplatin vs cisplatin
in chemotherapy
naive
Survival 11.4 vs 8.8
months. Response rate
23.6% vs 13.6%
Raltitrexed+ cisplatin
in chemotherapy
naïve and those pretreated with cisplatin
Survival 31 weeks and
44 weeks. Response
rate no difference
between groups
Raltitrexed in
chemotherapy naive
Raltitrexed +
cisplatin vs cisplatin
Survival 7 months.
Response rate 20.8%
Patients who received
raltitrexed + cisplatin
250
Survival, response
1+
rate, progression
free survival,
toxicity, health
related quality of
life
CASE SERIES AND CASE CONTROL STUDIES
Fizazi et al,
70
Survival, response
3
200340
rate, time to
progression,
toxicity, self
reported symptoms
Baas et al,
25
Survival, response
3
200341
rate, toxicity
Bottomley et
229
Quality of life,
3al, 200742
prognostic value of
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reported patient
symptoms
had improvements in
dyspnoea from cycle 2
onwards.
5.2.2 Safety
In van Meerbeeck’s study grade 3/4 neutropenia occurred in 16% of the
raltitrexed/cisplatin group, that is, twice as often as in the cisplatin treatment arm.
Fatigue, nausea and vomiting were also observed in this group and toxicity was the
reason for stopping treatment in 30% of patients in the combined treatment arm
compared to 23% of patients in the cisplatin only arm37.
In Fizazi’s study 20 patients (16 chemotherapy naïve and 4 pre-treated) withdrew
from the treatment because of adverse events. Four cases of grade 4 serious
adverse events were reported; one each of asthenia, dysphagia, dehydration and
heart failure (which was not related to therapy). Grade 3 neutropenia, leucopenia and
anaemia were reported by five (6.9%), four (5.6%) and three (4.2%) patients
respectively40.
Raltitrexed as a single agent resulted in only one grade 4 toxicity (anorexia), but this
may have been due to disease progression. Grade 3 toxicities include neutropenia
13%, leucopenia 4% and fatigue 8%41.
It has been noted that raltitrexed has been studied in the treatment of colorectal
cancer and in some clinical trials resulted in a high death rate43
44.
In one study45 to
compare three chemotherapy regimes an increase in treatment related deaths (due
to combined gastrointestinal and haematological toxicity) was seen in the raltitrexed
regime. However some protocol violations were noted by the authors as well as
appropriate dose reductions not being made and it was suggested that folic acid
supplementation may be helpful. Assessment of renal function before each and every
treatment, dosage adjustment in the presence of renal impairment and close
monitoring with prompt treatment of toxicities has been recommended46.
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5.2.3 Cost effectiveness
There have been no studies investigating the cost effectiveness of raltitrexed.
Cost of Raltitrexed (TOMUDEX ®) in Australia
Raltitrexed is manufactured by AstraZenica but distributed by Hospira.
Raltitrexed 1 X 2mg vial powder for injection costs AU$299 (incl. GST)
Treatment is 3mg/m² and the average size person is between 0.7 and 1.3m² therefore treatment would cost between AU$299 and AU$598.
(Source: Hospira, Melbourne, Australia)
5.2.4 Quality of life
The QLQ-C30 is a validated, patient-rated core questionnaire for cancer patients in
clinical trials and covers the domains of global health and physical, emotional, role,
social, and cognitive function. Symptoms of fatigue, nausea and vomiting, pain,
dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties
are also assessed.
The QLQ-LC13 is a 13-item lung cancer-specific questionnaire that includes multiitem and single-item measures of lung cancer symptoms and treatment-associated
toxicities.
Van Meerbeeck’s phase III study of cisplatin with or without raltitrexed37 in patients
with MPM assessed health related quality of life (HRQOL) with the EORTC QLQ-C30
version 3.0 and QLQ-LC13.
Nowak et al (2004)47 in a study to assess the feasibility and validity of using the
EORTC QLQ-C30 and QLQ-LC13 looked at 53 patients receiving combination
chemotherapy for pleural mesothelioma. At baseline, role function and social function
were the most impaired domains and the worst related symptoms were fatigue,
dyspnoea, pain, insomnia, appetite loss, and cough. Dyspnoea, pain, insomnia and
cough improved with chemotherapy, although functional domains and chemotherapy
related symptoms deteriorated. Fatigue remained unchanged. Functional domains
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and symptoms scales from the QLQ-C30 demonstrated predictive validity for survival.
Dyspnoea scores were correlated strongly with lung function as measured by forced
vital capacity. The study supports the validity of the EORTC QLQ-C30 and QLQLC13 as outcome measures for trials of chemotherapy in mesothelioma.
In van Meerbeeck’s study there was no observed change or deterioration in overall
health status/QOL scale from adding raltitrexed to cisplatin. None of the scales and
items showed any significant or clinically meaningful difference at any time point
during treatment. Both arms of the study demonstrated impairment in baseline scores
for all the scales compared with the normative population and this level of impairment
remained consistent throughout the treatment period. Although nausea and vomiting
increased equally from baseline levels in both arms this did not impact on the QOL
scales over time. Therefore quality of life was not impacted by treatment with
raltitrexed/cisplatin.
Bottomley et al, 200742
Bottomley et al42 evaluated the prognostic value of patient reported symptoms and
HRQOL using the data from van Meerbeeck’s randomised controlled trial using the
EORTC QLQ-C30 version 3.0 and QLQ-LC13. At baseline, compared to the
normative population, both arms had impaired HRQOL. Over the course of treatment
both arms experienced increases in fatigue, nausea and vomiting but patients in the
cisplatin/raltitrexed arm had significant clinically meaningful improvements of
dyspnoea during treatment from cycle two onwards compared to baseline scores.
There were no significant survival differences between the two treatment groups on
any HRQOL scale but both pain and appetite loss were found to be independent
prognostic indicators of survival.
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5.3 Discussion
5.3.1 Methodological quality
Study design
One RCT of raltitrexed and cisplatin versus cisplatin was of low power but otherwise
good quality. The trial could have yielded even more striking results if accrual had
been extended, as recommended by an Independent Data Monitoring Committee
after two interim analyses, but lack of funding prevented it.
While the raltitrexed/cisplatin versus cisplatin trial37 was of good evidence based
quality, the other two studies which investigated raltitrexed, a case control study of
raltitrexed and oxaliplatin40 and a case series of single agent raltitrexed41, both
provided low levels of evidence.
Intervention
Raltitrexed was administered intravenously at 3mg/m² in 15 minutes and where it was
given with cisplatin, it was given first. Cisplatin was administered intravenously at
80mg/m² in 1 to 2 hours. Oxaliplatin when administered was given 45 minutes after
raltitrexed at 130mg/m² as a two hour infusion. Cycles of treatment were repeated
every 21 days for all studies and the median number of cycles in the studies ranged
between 3 and 5.
All studies had dose delays or reductions in the instance of haematological toxicities
and the median number of cycles of treatment for each study varied due to this factor.
Sample size and statistical analyses
In van Meerbeeck’s study overall survival and progression free survival were
estimated on all patients using the Kaplan-Meier method and compared using the
two-sided log-rank test, based on intention to treat analysis.
The methods of statistical analysis were not reported in Fizazi’s study.
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Baas’, in a very small case series used Fleming’s one stage testing procedure
whereby if there were ≤4 responders, the drug was to be considered ineffective and if
there were >4 responders, further investigation was indicated.
Randomisation and blinded method
Van Meerbeeck’s study was randomised with stratification to balance the intervention
and control groups but there was no blinding of assessors. Blinding of participants
was not reported.
Fizazi conducted an open label, non-comparative, two centre study of patients with
diffuse MPM and Baas’ study was a multicentre case series.
Study population, inclusion and exclusion criteria
Meerbeeck’s study included patients with histologically diagnosed advanced MPM
who were not candidates for surgery, had a WHO performance status of 0-2, aged
≥18 with adequate hepatic and renal function and bone marrow reserve 37. The study
excluded those who had had prior chemotherapy, brain metastases, uncontrolled
infections and other malignancies. In this study 24% in the cisplatin group and 25% in
the raltitrexed/cisplatin group were WHO performance status 0, 63% and 61% were
status 1 and 13% and 14% were status 2 respectively. Fizazi and Baas criteria for
inclusion were very similar. However in Baas’ study, although the responders to
raltitrexed were reviewed by two independent radiologists there were problems
confirming initial diagnosis of MPM: out of 21 centrally reviewed cases 18 were
confirmed as being ‘definitive’ or ‘probable’.
Follow up and study period
In van Meerbeeck’s study follow up was 6 weekly and treatment continued until
disease progression, toxicity or patient refusal. Survival was measured from the time
of randomisation to death and a total of 195 deaths were reported before the final
analysis was done. This aimed to give 80% power to detect a 50% increase in
median duration of survival in the combination arm 37. However the recommendation
of the Independent Data Monitoring Committee was that the trial should increase its
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accrual to observe 278 deaths of a total of 340 patients to detect a 40% increase in
the median overall survival with the same power.
Fizazi’s trial included more frequent follow up before each cycle of treatment and
follow up of 57 out of the original 70 patients who received more than 3 cycles of
treatment. In Baas’ study the end points were response rate and toxicity and patients
were evaluated every 2 cycles. The final analysis was done after all the patients had
terminated the treatment protocol.
5.3.2 Outcome measures
Survival was the primary outcome for two of the studies 37
40
but in the open study of
the single agent raltitrexed41 toxicity and tumour response were the main outcomes.
In the measurement of response rate the study used the RECIST response criteria
[discussed in section 4.3.2]
5.3.3 Effectiveness
The principle outcome reported for the effectiveness of raltitrexed was survival.
Secondary outcomes were response rate, toxicity, time to progression and health
related quality of life. One RCT provided evidence for the efficacy of raltitrexed:
survival of 11.4 months for raltitrexed plus cisplatin compared to 8.8 months for
cisplatin alone37. When raltitrexed was given with oxaliplatin survival in the
chemotherapy naïve was 31 weeks (4.75 months) and 44 weeks (11 months) in
those previously treated with cisplatin40. Treatment with raltitrexed monotherapy gave
a median survival of 7 months41.
The response rate with raltitrexed and cisplatin was 23.6% and cisplatin alone 13.6%.
When raltitrexed was combined with oxaliplatin the response rate was 20% in both
the chemotherapy naïve and those pre-treated with cisplatin40. Raltitrexed
monotherapy had a response rate of 20.8%41.
5.3.4 Safety and adverse effects
There was greater toxicity noted in the combination treatment raltitrexed/cisplatin
than when cisplatin was used alone. Grade 3/4 neutropenia was reported twice as
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often in the combination treatment group. Fatigue, nausea and vomiting were also
more common in the combination arm37. When raltitrexed was used alone there was
no grade 4 neutropenia and grade 3 affected only 13% of participants, leucopenia
4% and fatigue 8%41. When raltitrexed was used with oxaliplatin 20 patients out of 70
withdrew from treatment due to adverse events. Although neutropenia, leucopenia
and anaemia were reported at low levels as grade 3 toxicities, the grade 4 toxicities
were asthenia, dysphagia, dehydration and heart failure, toxicities not seen when
raltitrexed was used with cisplatin or as monotherapy40.
5.3.5 Cost effectiveness
There were no studies identified that investigated the cost effectiveness of raltitrexed.
5.4 Summary of evidence
One systematic review and one randomised controlled trial show good evidence for
the effectiveness of raltitrexed and cisplatin in extending survival to 11.4 months as
compared to 8.8 months when cisplatin is used alone.
6. Conclusions
The 2004 ACC review, ‘The Effectiveness of Pemetrexed in the Treatment of
Mesothelioma’ resulted in the purchasing of pemetrexed with cisplatin for the
treatment of MPM and peritoneal mesothelioma. Clinical criteria were developed for
deciding applications to ACC for funding of the cost of pemetrexed (see appendix 4).
Where funding was approved by ACC, the first two cycles of pemetrexed were
funded and the third cycle was approved in principle. A report was required after the
assessment following the second cycle before further funding would be considered.
This review aimed to review the effectiveness, safety, cost effectiveness and added
quality of life of pemetrexed as well as identifying any potential alternatives to
pemetrexed in the treatment of MPM
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
Two systematic reviews and one randomised controlled trial show good
evidence for the effectiveness of pemetrexed and cisplatin in extending
survival to 12.1 months as compared to 9.3 months when cisplatin is used
alone. Response rates (41% versus 17%); time to progression (5.7 versus 3.9
months) and survival (12.1 versus 9.3 months) all favoured the combination
treatment. Two quality of life indices (dyspnoea and pain) assessed using the
Lung Cancer Symptom Scale were significantly improved with pemetrexed
and cisplatin after six cycles of treatment.

One systematic review and one randomised controlled trial show good
evidence for the effectiveness of raltitrexed and cisplatin in extending survival
to 11.4 months as compared to 8.8 months when cisplatin is used alone. This
trial also showed a higher response rate (23.6% versus 13.6%) and longer
progression free survival (5.3 versus 4 months), although these differences did
not achieve conventional statistical significance.
Table 3. Comparison between Pemetrexed and
Raltitrexed RCTs
EMPHACIS Pemetrexed
Trial (Vogelzang)
Pemetrexed
Cisplatin
and cisplatin
Number of patients
Response rate
Median Survival
1 year survival
Progression free
survival
Quality of life
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41.3%
222
16.7%
(p=0.001)
12.1 months
9.3
months
(p=0.020)
55.1%
40.9%
5.7 months
3.9
months
(p=0.001)
dyspnoea and pain were
significantly improved
63
Raltitrexed Trial ()
Raltitrexed Cisplatin
and
cisplatin
125
122
24%
14%
(p=0.056)
11.4
8.8 months
months
(p=0.0483)
46.2%
39.6%
5.3 months 4 months
(p=0.058)
Baseline impairment
scores remained
Evidence Based Brief Report
Toxicity:
Neutropenia
Leucopenia
Haemoglobin
Platelets/thrombocyte
count
Nausea
Vomiting
Fatigue
Measurement of
response
WHO performance
status
Percentage of
patients with Stage
III/IV disease
Median number of
treatment cycles and
range
Cost
for patients receiving
pemetrexed/cisplatin
after 6 cycles of
treatment
consistent throughout
the treatment period.
Although nausea and
vomiting increased
equally from baseline
levels in both arms this
did not impact on the
QOL scales over time.
27.9%
17.7%
4.8%
5.8%
16%
7%
3%
2%
8%
6%
2%
0%
14%
13%
12%
RECIST
10%
7%
6%
2.3%
0.9%
0%
0%
14.6%
6.3%
13.3%
3.6%
10.2%
8.6%
Modified RECIST
51.8% performance
25% performance
level – 0**
level – 0**
49.3% performance level 61% performance
-1
level – 1
14% performance level 2
77.5%
79.1%
85%
79%
6 (1-12)
4 (1-9)
NZ$5,294.25
for 2 X
500mls
(need
500mg/m²)*
* Average sized person is between 0.7 and 1.3m²
5 (1-10)
4 (1-9)
AU$598
for 2 X
2mg (need
3mg/m²)*
**0 - Asymptomatic (Fully active, able to carry on all predisease activities without restriction)
1 - Symptomatic but completely ambulatory (Restricted in physically strenuous activity but
ambulatory and able to carry out work of a light or sedentary nature. For example, light
housework, office work)
2 - Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care but
unable to carry out any work activities. Up and about more than 50% of waking hours)
Patients with minimal impairment of activity level
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It is concluded that there is good evidence based on limited studies that pemetrexed
and raltitrexed both offer a survival benefit to patients with MPM. Although the weight
of evidence for raltitrexed is not as significant as for pemetrexed, comparison of
survival times (an independent indicator not likely to be subject to bias) demonstrates
that raltitrexed offers a similar survival time to pemetrexed.
Although raltitrexed is currently being used in Ontario, Canada for the treatment of
MPM there is no data currently available on its safety, efficacy and outcomes
although enquiries are ongoing. It may be possible to further acquire information on
raltitrexed to inform future decision making.
Quality of life includes a trade off between the survival benefit of chemotherapy
versus its toxic effects. For patients making choices between improved survival and
quality of life, a significant percentage elect not to have chemotherapy when it is
offered. Further studies comparing active symptom control or best supportive care
with either pemetrexed or raltitrexed would be warranted.
Based on the limited evidence available raltitrexed could be a more cost effective
option. Further studies or trials of both pemetrexed and raltitrexed are desirable. ACC
is in contact with Cancer Care Ontario to obtain further data on raltitrexed.
Until further evidence becomes available on the efficacy and safety of raltitrexed in
the treatment of MPM, it is concluded that ACC should continue to purchase
pemetrexed. Following the decision of NICE, purchase should be restricted to those
patients with a WHO performance status of 0 or 1, who have advanced disease and
for whom surgical resection is considered inappropriate.
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treatment of patients with malignant pleural mesothelioma (MS01):
a multicentre randomised trial. The Lancet 2008;371(9625):16851694.
27. Silvestri G, Pritchard R, Welch HG. Preferences for chemotherapy in
patients with advanced non-small cell lung cancer: descriptive
study based on scripted interviews. BMJ 1998;317(September):771-5.
28. Cordony A, Le Reun C, Smala A, Symanowski JT, Watkins J. Costeffectiveness of pemetrexed plus cisplatin: malignant pleural
mesothelioma treatment in UK clinical practice. Value in Health
2008;11(1):4-12.
29. Niyikiza C, Baker SD, Seitz DE. Homoscysteine and methylmalonic
acid: Markers to predict and avoid toxicity from pemetrexed
therapy. Mol Cancer Ther 2002;1:545-552.
30. Towse A. What is NICE's threshold? An external view. Chapter 2 in :
Cost effectiveness thresholds: economic and ethical issues: London:
King's Fund/Office for health Economics, 2002.
31. Appleby J, Devlin N, Parkin D. NICE's cost effectiveness threshold. BMJ
2007;335(August):358-359.
32. Davey P, Cordony A, Rajan N, Arora B, Pavlakis N. Value for money of
pemetrexed plus cisplatin versus cisplatin alone in the treatment of
MPM. Presented at the International Society for Pharmacoeconomics
and Outcomes Research (ISPOR) Conference 2004.
33. Hollen PJ, Gralla RJ, Liepa AM, Symanowski JT, Rusthoven JJ.
Measuring quality of life in patients with pleural mesothelioma
using a modified version of the Lung Cancer Symptom Scale (LCSS):
psychometric properties of the LCSS-Meso. Supportive Care in
Cancer 2006;14(1):11-21.
34. Chapman A, Mulrennan S, Ladd B, Muers MF. Population based
epidemiology and prognosis of mesothelioma in Leeds, UK. Thorax
2008;63(5):435-439.
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35. Ryan CW, Herndon J, Vogelzang NJ. A review of chemotherapy trials
for malignant mesothelioma. Chest 1998(113):665-735.
36. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of
response in malignant pleural mesothelioma. Annals of Oncology
2004(15):257-260.
37. van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck
EA, Vincent M, et al. Randomized phase III study of cisplatin with or
without raltitrexed in patients with malignant pleural
mesothelioma: an intergroup study of the European Organisation
for Research and Treatment of Cancer Lung Cancer Group and the
National Cancer Institute of Canada. Journal of Clinical Oncology
2005;23(28):6881-9.
38. Curran D, Sahmoud T, Therasse P, Meerbeeck Jv, Postmus PE,
Giaccone G. Prognostic Factors in Patients with Pleural
Mesothelioma: The European Organisation for Research and
Treatment of Cancer Experience. Journal of Clinical Oncology
1998;16(1):145-152.
39. Porta C. Adding raltitrexed to cisplatin improves overall survival in
people with malignant pleural mesothelioma. Cancer Treatment
Reviews 2006;32(3):229-233.
40. Fizazi K, Doubre H, Chevalier TL, Riviere A, Viala J, Daniel C, et al.
Combination of Raltitrexed and Oxaliplatin is an active regimen in
malignant mesothelioma:: Results of a phase II study. Journal of
Clinical Oncology 2003;21(2):349-354.
41. Baas P, Ardizzoni A, Grossi F, Nackaerts K, Numico G, Marck EV, et al.
The activity of raltitrexed (Tomudex) in malignant pleural
mesothelioma: an EORTC phase II study. European Journal of Cancer
2003;39:353-357.
42. Bottomley A, Coens C, Efficace F, Gaafar R, Manegold C, Burgers S, et
al. Symptoms and patient-reported well-being: do they predict
survival in malignant pleural mesothelioma? A prognostic factor
analysis of EORTC-NCIC 08983: randomized phase III study of
cisplatin with or without raltitrexed in patients with malignant
pleural mesothelioma. Journal of Clinical Oncology
2007;25(36):5770-6.
43. Hind D, Tappenden P, Tumur I, Eggington S, Sutcliffe P, Ryan A. The
use of irinotecan, oxaliplatin and raltitrexed for the treatment of
advanced colorectal cancer: systematic review and economic
evaluation. Health Technology Assessment 2008;12(15).
44. Hale JP, Cohen DR, Maughan TS, Stephens RJ. Costs and consequences
of different chemotherapy regimens in metastaic colorectal cancer.
British Journal of Cancer 2002;86:1684-1690.
45. Maughan TS, James RD, Kerr DJ, Ledermann JA, McArdle C, Seymour
MT, et al. Comparison of survival, palliation, and quality of life with
three chemotherapy regimens in metastatic colorectal cancer: a
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multicentre randomised trial. The Lancet 2002;359(May 4):15551563.
46. Gebbia V, Verdarame F, Ferrau F, Bordonaro R, Callari A, Caruso M, et
al. Raltitrexed plus levofolinic acid and bolus/continuous infusion
5-fluoroucil on a biweekly schedule for elderly patients with
advanced colorectal carcinomas. Annals of Oncology
2006;17(Supplement 7).
47. Nowak AK, Stockler MR, Byrne MJ. Assessing Quality of Life during
chemotherapy for pleural mesothelioma: feasibility, validity, and
results of using the European Organisation for Research and
Treatment of Cancer core Quality of Life questionnaire and Lung
cancer Module. Journal of Clinical Oncology 2004;22(15):3172-3180.
48. Edelman MJ, Sekine I, Tamura T, Saijo N. Geographic variation in the
second-line treatment of non-small cell lung cancer. Seminars in
Oncology 2006;33(SUPPL. 1):S39-S44.
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8. Limitations of the review

The findings of this evidence based review are considerably limited by the
paucity of good quality studies and particularly by the lack of a RCT to
compare
pemetrexed
and
raltitrexed.
The
two
RCTs
investigating
pemetrexed/cisplatin and raltitrexed/cisplatin both provide evidence of
improved survival but are both limited by methodological weakness.

Because MPM is a rare condition, recruitment of participants to trials is difficult
and most studies included patients from multiple sites or countries. The
chance of bias in the measurement of outcomes, particularly in non-blinded
trials, reduces the quality of these studies.

The measurement of response rate was not consistent across, and even
within, studies. The varying methods for measuring response either uni- or bidimensionably, using RECIST or modified RECIST methods, and potential
investigator bias all contribute to the unreliability of this outcome measure.

There is under reporting of MPM among Maori although they are over
represented in jobs that may have increased exposure to asbestos2. Also the
benefits and risks of anticancer agents may differ between populations. Ethnic
differences may be surrogates for differences in genetic aspects of drug
metabolism or potential differences in tumour susceptibility48. None of the
studies in this review involve New Zealand participants.

There are differences in the mechanism of action of pemetrexed and
raltitrexed and it is likely that tissues of different histology type will respond
differently to these drugs
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ACC
XXX
Appendix 1: WHO/ECOG/Zubrod Performance Status
WHO PERFORMANCE STATUS*
Grade ECOG
0
Asymptomatic (Fully active, able to carry on all predisease activities without
restriction)
1
Symptomatic but completely ambulatory (Restricted in physically strenuous activity
but ambulatory and able to carry out work of a light or sedentary nature. For
example, light housework, office work)
2
Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care
but unable to carry out any work activities. Up and about more than 50% of waking
hours)
3
Symptomatic, >50% in bed, but not bed bound (Capable of only limited self-care,
confined to bed or chair 50% or more of waking hours)
4
Bed bound (Completely disabled. Cannot carry on any self-care. Totally confined to
bed or chair)
5
Death
The WHO or Zubrod score (after C. Gordon Zubrod) was published as the ECOG score by
Oken et al in 1982.
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Appendix 2: Karnofsky performance status scale
Score
Description
100
Normal no complaints
90
Able to carry on normal activities. Minor symptoms of disease
80
Normal activity with effort
70
Cares for self. Unable to carry on normal activity or to do active
work
60
Requires occasional assistance, but able t care for most of own
needs
50
Requires considerable assistance and frequent medical care
40
Disabled. Requires special care and assistance
30
Severely disabled. Hospitalisation indicated though death not
imminent
20
Very sick. Hospitalisation necessary. Active supportive
treatment necessary
10
Moribund, rapidly progressive fatal disease processes
0
Death
Comparison of WHO and Karnofsky performance scores

WHO 0 equals Karnofsky 100; 90-100

WHO 1 equals Karnofsky 80-90; 70-80

WHO 2 equals Karnofsky 60-70; 50-60

WHO 3 equals Karnofsky 40-50; 30-40

WHO 4 equals Karnofsky 20-30;10-20
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
WHO 5 equals Karnofsky 0
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Appendix 3: Response Evaluation Criteria in Solid Tumours
(RECIST)
Measurement
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total measured
at baseline. Lesions selected on the basis of their size (lesions with the longest diameter) and
their suitability for accurate repeated measurements. The sum of the longest diameter for all
target lesions is calculated.
Tumour response
1. Complete response (CR): Disappearance of all target lesions.
2. Partial response (PR): At lease a 30% decrease in the sum of the longest diameter of
target lesions, taking as reference the baseline sum longest diameter.
3. Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for progressive disease, taking as reference the smallest sum longest diameter
since the treatment started.
4. Progressive disease: At least a 20% increase in the sum of the longest diameter of the
target lesions, taking as a reference the smallest sum longest diameter recorded since
the treatment started or the appearance of one or more new lesions.
Modified RECIST criteria
Measurement
Tumour measurements performed on transverse cuts on thoracic CT scans at three separate
anatomically reproducible levels on the study entry CT scan and at the same levels on
subsequent scans. Where possible bidimensional lesions are measured using the longest
dimension and the length perpendicular to the longest measurement. Where unidimensional
measures are used the thickness of pleural tumour was measured at two separate sites on each
of e three levels and the six measurements totalled to produce a total measurement.
Tumour response
1. Complete response (CR): disappearance of all known disease, determined by two
observations not less than 4 weeks apart.
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2. Partial response (PR): a ≥50% decrease in the sum of the products of perpendicular
diameters of bidimensionally measured lesions on two occasions not less than 4 weeks
apart, or a ≥ 30% decrease in the sum of linear tumour measurements on two
observations not less than 4 weeks apart.
3. No change: a decrease in bidimensional tumour area of <50% or an increase of <25%, or
a decrease in the sum of uni-dimensional measurements of <30% or an increase of
<25%, provided no new lesions have appeared.
4. Progressive disease: a ≥25% increase in the size of the tumour being measured (unidimensional or bidimensional) or the appearance of new lesions.
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Appendix 4: Pemetrexed Prescriber Checklist: to
Determine Eligibility for ACC Contribution to Cost
Prescriber groups who may use this form: Medical Oncologists registered in New Zealand.
In order to promote the safe and appropriate use of pharmaceuticals and achieve optimal
health and rehabilitation outcomes for Claimant’s, ACC is using evidence based criteria to
determine when it should contribute to the cost of pharmaceuticals.
Prescribers should use this checklist to self-assess whether a Claimant may be eligible for
ACC contribution to the cost of Pemetrexed.
PART 1: Claimants Details
Name:
Date of Birth:
Date of diagnosis:
NHI Number:
Injury for which this pharmaceutical is being prescribed:
PART 2: Complete and send request for funding to ACC
Does the Claimant have a proven diagnosis of mesothelioma of the pleura or
peritoneum (this should include both histological and radiological assessments)
Please attach histological and radiological reports.
Has the Claimant got a performance status of 2 or better on the WHO scale
(after any palliative measures including pleural drainage)?
Current state performance status………………………..
Does the Claimant have a renal-calculated creatine clearance >45mls/min?
State Renal Creatine …………………………………………………………
Yes
No
Yes
No
Yes
No
Does the Claimant have adequate bone marrow reserve-absolute neutral count
>1.5 x 109/L, - platelets >100 x 109 /L, - Haemoglobin >90g/dcl?
Please attach laboratory report showing heamatology profile
Yes
Does the Claimant have hepatic, bilirubin ≤ 1.5 mg/dL, ALP≤AST ALT≤ 3x upper limit or normal
(ALP, AST, ALT ≤ 5x upper limit of normal is acceptable if there is tumour involvement)?
Please attach liver function test report
Have any brain metastases been adequately treated and stabilised?
Yes
No
Yes
No
No
NA
Attach any other information supporting the use of Pemetrexed
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Conditions for payment relating to Pemetrexed drug selection:
If funding of Pemetrexed is approved by ACC, the first two cycles will be approved and the third will be approved in principle. A
report is required after the assessment following the second cycle before further funding is considered. The reports need to
detail clinical benefits, quality of life improvements, tumour status and recommendation whether further treatment should be
carried out. Note, ACC will not normally contribute to the cost of more than six cycles of Pemetrexed, however any
applications beyond six cycles maybe considered.
PART 3: Prescriber
Responsibilities
 Pemetrexed is being used for the treatment of Malignant Pleural Mesothelioma, which is covered by ACC
 The use of the drug is regularly reviewed by the prescriber and reported to ACC by the specified review dates prior to
further subsidy being agreed by ACC.
 If no clear benefit after two treatment cycles then treatment should be withdrawn
 Organ function is regularly monitored for Claimants at high risk of developing adverse reactions.
 Vitamin B12 and folic acid supplementation should be given as appropriate
 All adverse reactions are reported to the Centre for Adverse Reactions Monitoring, P O Box 913 Dunedin.

Patient records should be available for clinical audit when requested by ACC.
PART 4: MEDICAL SPECIALIST DECLARATION

I have considered the rehabilitation outcomes from the pharmaceuticals used to date.

I agree that use of the unapproved pharmaceutical or pharmaceutical use for an unapproved indication is to facilitate
treatment and is reasonably required for this claimant.
Specialist’s signature:
ACC provider no.
Date:
OR complete name, address and vocational registration type below.
Specialist’s name:
Address:
Vocational registration type:
Reference:
EBHC report and considered judgement form under resources.
Please send all initial requests and ongoing reports to:
Tracey Loader, Case Co-ordinator, Asbestos Team: Fax (03) 962 9301
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Appendix 5: Pemetrexed literature searches, updated 2
September 2008.
Ovid MEDLINE(R) 1996 to August Week 3 2008:
1. exp MESOTHELIOMA/ or exp PLEURA MESOTHELIOMA/ or exp MALIGNANT
MESOTHELIOMA/
2. mesothelioma$.mp.
3. exp PEMETREXED/ or exp raltitrexed/
4. (pemetrexed or alimta or raltitrexed or tomudex).af.
5. (1 or 2) and (3 or 4)
6. limit 5 to (human and english language)
7. limit 6 to ed=20040906-20080902
EMBASE 1996 to 2008 Week 35:
1. exp MESOTHELIOMA/ or exp PLEURA MESOTHELIOMA/ or exp MALIGNANT
MESOTHELIOMA/
2. mesothelioma$.mp.
3. exp PEMETREXED/ or exp raltitrexed/
4. (pemetrexed or alimta or raltitrexed or tomudex).af.
5. (1 or 2) and (3 or 4)
6. limit 5 to (human and english language)
7. 6 and (2008$ or 2007$ or 2006$ or 2005$ or 20045$ or 20044$ or "200439" or
"200438" or "200437" or "200436").em.
Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations August 29, 2008 (“PreMedline”):
1. mesothelioma$.mp.
2. (pemetrexed or alimta or raltitrexed or tomudex).af.
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3. 1 and 2
All EBM Reviews - Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR, HTA, and
NHSEED (“All EBM”)
1. 1. mesothelioma$.mp.
2. 2. (pemetrexed or alimta or raltitrexed or tomudex).af.
3. 3. 1 and 2
4. 4. limit 3 to english language
4 5. limit 4 to yr="2004 - 2008"
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Appendix 6: Evidence tables for pemetrexed
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Study
Study
inclusion/
exclusion
criteria
Exposure/
comparison
treatment
(number of
studies
included)
Common outcomes among
studies
Results
Validity/ Applicability
Yes
No NA
N/S
Conclusions
Dundar et
al, 2007
Systematic
review of
clinical
effectiveness
and costeffectiveness
of
pemetrexed
plus cisplatin
in
unresectable
pleural
mesotheliom
a in
chemotherap
y naïve
patients
Clinical
effectiveness –
Clinical effectiveness:
Extension life expectancy and
palliation as measured by time to
progression of disease and other
end-points
RCT of 448
patients showed
pemetrexed in
combination with
cisplatin showed
a 2.8 month gain
in median
survival
Focused question
Y
Thorough search strategy
Y
Conclusions drawn from
limited research available.
May over stress effect
because of limited studies.
Search terms defined
Y
Appropriate
inclusion/exclusion criteria
Y
Economic
evaluation
conducted by the
study (and that
submitted by the
manufacturer)
suggest
pemetrexed is
not considered
cost effective at
conventionally
accepted
thresholds in UK,
because of high
cost of
pemetrexed
compared with
cisplatin
Two reviewers – selection
study validity rated
Y
Two reviewers -validity
Y
Valid combination of
studies
N/A
1 RCT met
inclusion criteria
Cost
effectiveness –
No published full
economic
reports found. 1
conference
abstract/present
ation found.
Absolute benefit is small
Limited benefit at expense of
considerable toxicity to patients
Cost effectiveness:
Suggest it is not cost effective at
conventional thresholds for all
patients
Cost effectiveness better for some
patient subgroups, especially
patients with good performance
status and with advanced disease.
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Economic evaluation is
based on UK economics. ?
applies to NZ
Y
Appropriate analysis
All important outcomes
considered
Balance between benefit
and harms
1+
Y
Y
Y
Fair conclusions from
evidence
Evidence Based Brief Report
Study
Study
inclusion/
exclusion
criteria
Exposure
/
comparis
on
treatmen
t
(number
of
studies
included)
Common
outcomes
among studies
Results
Validity/
Applicability
Yes
No
NA
N/S
Conclusions
Ellis et
al, 2006
Clinical practice
guideline based on
a systematic review
to address 2
questions:
(1) Does
chemotherapy
improve survival,
QOL, or symptom
control, compared
to best supportive
care (BSC)?
119 studies
included:
8 RCTs
Response rate
Focused question
N
111 noncomparative
studies –
these were
organised into
sub-groups,
based on the
type of
chemotherapy
to allow and
exploratory
comparison of
response
rates between
different
chemotherapy
agents.
Acknowledges
that these are
weaker
evidence
Time to progression
No studies comparing
chemotherapy to BSC for
patients with MPM were
identified. Therefore no
evidence on whether BSC of
chemo improves survival or
QOL.
RCTs of pemetrexed and
cisplatin (Vogelzang) and
raltitrexed and cisplatin (van
Meerbeeck) were compared for
median survival, response rate
and progression free survival.
Also compares toxicities
between trials.
Thorough search
strategy
N
Search terms defined
Y
Clearly illustrates the lack of RCTs
comparing BSC and chemotherapy
in terms of survival and quality of
life.
Also shows lack of evidence of
many drug regimes which have
phase II trials only with which to
evaluate the evidence.
Appropriate
inclusion/exclusion
criteria
N
These 2 RCTs showed
significantly improved survival
with combination chemotherapy.
Two reviewers validity
(2) Which
chemotherapeutic
agents (or
combinations of
agents) have
shown the highest
response rates in
patients with
advanced MPM?
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Survival
Toxicities
Two reviewers –
selection study
validity rated
Y
Because of large number of studies
included, the quality of the studies
was not clear and levels of
evidence not clear.
Y
Valid combination of
studies
Concludes that “evidence
supporting the use of cisplatin
and pemetrexed is stronger.
However, it is reasonable to
consider the use of raltitrexed
3mg/m² and cisplatin 80mg/m²
83
Y
N
Included studies of patients with
both pleural and peritoneal
malignant mesotheliomas.
Appropriate analysis
All important
outcomes considered
Evidence Based Brief Report
N
Evidence presented under different
treatment regimes but not oucomes
every 3 weeks, if pemetrexed is
not available.
Balance between
benefit and harms
Fair conclusions
from evidence
Y
Y
1-
Evidence Based Healthcare Table
Reference: Vogelzang N J et al, 2003
Design
Description
Participants
RCT
Description:
Multicentre and singleblind trial
Bibliographic Number:
Intervention
Outcome Measures:
456 patients with malignant pleural mesothelioma who were not eligible for
curative surgery and chemotherapy naïve.
Mean age 60.5
81% male
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Intervention Group
Pemetrexed 500mg/m² IV
over 10 minutes, then 30
minutes later Cisplatin
75mg/m² IV over 2 hours.
Repeated every 21 days
Age range 19-85
Funded by Eli Lilly and
Company
Outcomes
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Evidence Based Brief Report
Survival
Secondary end points included:
Time to progressive disease
Time to treatment failure
Tumour response rate
Toxicities
Quality of life
Median follow up was 10 months.
118 patients had signed informed consent but were not randomised – reason
unclear.
Median treatment cycles 6 (112)
8 patients were withdrawn from the trial before receiving treatment.
Control Group
Biases/weaknesses:
Group 1 Pemetrexed plus
cisplatin
No. in Group: 226
Mean Age: 61 (29-85)
Group 2 Cisplatin monotherapy
No. in Group: 222
Mean Age: 60 (19-84)
Saline IV over 10 minutes,
then, 30 minutes later
Cisplatin 75mg/m² IV over 2
hours. Repeated every 21
days.
Median treatment cycles 4 (19).
Inclusions:
Uni or bi-dimensionally measurable disease
Age ≥18 years
Life expectancy ≥12 weeks
Karnofsky performance status ≥70
Severe toxicity in intervention
group led to addition of folic
acid and vitamin B12 to both
groups. 331 of commenced
treatment after these were
introduced
Exclusions:
Prior chemotherapy
Second primary malignancy
Brain metastases
Unable to interrupt NSAIDs
Results:
Median survival in intervention group 12.1 months
versus control group 9.3 months (p=<0.020)
1 year survival – 50.3% in intervention group versus
38%
Median time to disease progression in intervention
group 5.7 months versus control group 3.9 months
(p=0.001)
Median
partial (decrease of at least 30% of tumour mass)
response rate in intervention group 41.3% versus
control group 16.7%.(p<0.001)
Toxicity
Incidence of grade 3/4 adverse events more frequent in
intervention group compared with controls: neutropenia
27.9% (2.3%), leukopenia 17.7% (0.9%), nausea
14.6% (6.3%) and vomiting 14.6% (3.6%).
Methodological Score: 1+
Evidence Based Healthcare Table
Reference: Jassem et al, 2008
Bibliographic Number:
Design Description
Participants
Intervention
Outcomes
Randomised controlled
trial to compare overall
survival of second-line
pemetrexed plus best
supportive care versus
best supportive care
alone in patients with
malignant pleural
Description:
Intervention group:
Outcome Measures:
243 patients from 45 institutions worldwide with relapsed malignant pleural
mesothelioma after first-line chemotherapy
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Primary outcome measure – overall survival
Pemetrexed 500mg/m² over
10 minutes. Repeated every
21 days.
Secondary end points:
Response rate
Also administered folic acid
(350 to 1,000 µm daily) and
Vitamin B12 (1000µ
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Evidence Based Brief Report
Progression free survival (PFS)
mesothelioma
intramuscular injection) 1-2
weeks prior to pemetrexed
and every 9 weeks thereafter.
Funded by Eli Lilly and
Co.
Time to treatment failure (TTF)
Toxicity
Group 1: Pemetrexed with Best
Supportive Care
No. in Group: 123
Median Age: 60
Group 2 Best Supportive
Care
Control group:
Results:
Received treatment
administered with intent to
maximise quality of life
without a specific
antineoplastic regimen.
Included antibiotics,
analgesics, antiemetics,
thoracentesis, pleurodesis,
blood transfusions, nutritional
support and focal externalbeam radiation for control of
pain, cough, dyspnoea or
hemoptysis
No. in Group: 120
Median Age: 61
Biases/weaknesses:
Open label – no blinding
Time to tumour progression (TTP)
Inclusions:
Age ≥18 years
Histologically diagnosed advanced MPM
Uni and/or bidimensionally measurable disease
One prior systemic chemotherapy regimen (excluding pemetrexed)
Karnofsky performance score ≥70
Adequate bone marrow reserve
Creatinine clearance ≥45 mL/min
Estimated life expectance ≥8 weeks
Median survival time in intervention group was 8.4
months versus 9.7 months in the control group
(p= .7434).
Median PFS in intervention group was 3.6 months
versus 1.5 in the control group (p= .0148).
Median TTP in intervention group was 3.7 months
versus 1.5 in the control group (p= .0001).
Median TTF in intervention group was 3.6 months
versus 1.5 in the control group (p= < .0001)
Methodological Score:
Grading 1-
Evidence Based Healthcare Table
Reference: Muers et al, 2008
Bibliographic Number:
Design Description
Participants
Multi-centre RCT
Description:
Intervention
Outcome Measures:
409 patients enrolled from 76 centres in UK and 2 in
Australia.
Survival
ASC alone:
Biases/weaknesses:
Did not use more established drug
pemetrexed/cisplatin – unsuccessfully
approached company to use this drug.
Median age – 65 years (46-85)
Difficultly recruiting people to ASC group
Group 2 & 3 chemotherapy groups combined because of
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Outcomes
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Included regular follow up,
structured physical, psych
and social assessments at
every visit, involvement of
other specialists, parallel
Evidence Based Brief Report
Quality of life: physical functioning, pain, dyspnoea
and global health status (using EORTC quality of life
questionnaire – QLQ-C30 and the lung cancer
module LC13)
which meant trial numbers low.
slow accrual to the trial
nursing support, steroids,
analgesic drugs,
bronchodilators, palliative
radiotherapy.
Trial design changed due to low accrual of
ASC group.
ASC + MVP:
Clinicians were allowed to provide nonprotocol treatment at any stage but this
was not documented.
Group
1:
ASC
76 different centres – difficult to maintain
consistency across assessors.
For response (acknowledging difficulty of
assessing this), they asked the clinicians
for their opinion – subjective.
Group 2: ASC + MVP
No. in Group: 137
Group 3: ASC +
vinorelbine
No. in Group: 136
No. in
Group:
136
Results:
4 cycles of MVP (mitomycin
6 mg/m², vinblastine 6 mg/m²
[max 10mg], and cisplatin
50mg/m²). Given on day 1 of
21 day cycle in addition to
ASC.
Median survival in ASC group – 7.6 months
Median survival in ASC + chemotherapy – 8.5
months
(p = 0.29).
ASC+ Vinorelbine:
Inclusions:
Chemotherapy naïve
Only 64% of ASC = MVP received 4
cycles.
In ASC + Vinorelbine group – only 50%
received 10-12 injections
One injection of vinorelbine
every week for 12 weeks
(30mg/m² [max 60mg]) in
addition to ASC with 2 week
gap between injections 6
and 7.
WHO performance status 0-2
Normal blood counts
Median survival in ASC + vinorelbine – 9.5 months (p
= 0.08)
Median survival in ASC + MVP – no evidence of a
survival benefit
Exclusions:
Quality of life – no difference between groups
Other disease or malignancy
Methodological Score: 1Evidence Based Healthcare Table
Reference: Jänne et al, 2006
Design Description
Accident Compensation Corporation
Bibliographic Number:
Participants
Intervention
87
Outcomes
Evidence Based Brief Report
Description:
Clinical study to gather additional
information on efficacy and safety of
pemetrexed and cisplatin or
pemetrexed alone in patients who
have received previous
chemotherapy.
Outcome Measures:
From 1056 patients with malignant mesothelioma in Eli
and Lilly Expanded Access Programme (EAP) 187
patients with malignant pleural mesothelioma (MPM) who
had been previously treated with at least one dose of the
study drug were included in the study.
Funded by Eli Lilly & Co
Group 1:
pemetrexed and
cisplatin
Biases/weaknesses:
No. in Group: 96
Range: 39-84
Pemetrexed 500mg/m² alone
or in combination with
cisplatin 75mg/m² once every
21 days for 6 cycles or until
disease progression. Folic
acid 350 to 600 µg, Vitamin
B12 1000µg and
dexamethasone.
Group 2: pemetrexed only
No. in Group: 91
Range: 27-87
Patients who had been
previously treated with
cisplatin-based regime, who
had responded for ≥6
months.
Inclusions:
Number of previously received
treatments was not collected.
? Accuracy of response rate due to
difficulties measuring tumour size.
Toxicity may be under-reported as
reporting relied on investigator
reporting.
Results:
Response data only available for 153 patients
CR= Complete Response – disappearance of all known
Pemetrexed and cisplatin
Open label study.
No control group
Objective tumour response (using RECIST – Response
Evaluation Criteria in Solid Tumours)
Histological or cytology diagnosis of malignant
mesothelioma not amenable to surgical treatment
≥18 years
Life expectancy ≥70 on Karnofsky scale
Median no of cycles
completed = 4 (range 1-10)
disease in target and non-target (confirmed by 2 obs not more
that 4 weeks apart):
Pemetrexed plus cisplatin 2 (2.5%)
Pemetrexed alone
0
PR= Partial Response – 30% reduction from baseline in
diameters of target lesion and no progress in non-targeted:
Pemetrexed plus cisplatin 24 (30%)
Pemetrexed alone
4 (5.5%)
SD= Stable Disease – do not meet criteria of PR or PD:
Adequate bone marrow reserve, hepatic function and
renal function
Pemetrexed only
Stable brain metastases not requiring corticosteroids.
Reported discontinuation number
for all patients but not for each
treatment arm.
Pemetrexed plus cisplatin 29 (36.3%)
Pemetrexed alone
30 (41.1%)
Patients who had received
prior chemotherapy.
PD= Progressive Disease – development of any new lesions
Median number of cycles
completed = 3. (range 1-13)
of increase of 20% in diameter of target lesions:
Pemetrexed plus cisplatin 25 (31.3%)
Pemetrexed alone
39 (53.4%)
Methodological Score: 3
Evidence Based Healthcare Table
Reference: Jänne et al, 2006
Design Description
Accident Compensation Corporation
Bibliographic Number:
Participants
Intervention
88
Outcomes
Evidence Based Brief Report
Description:
Clinical study to gather additional
information on efficacy and safety of
pemetrexed and cisplatin or
pemetrexed alone in patients who
have received previous
chemotherapy.
Outcome Measures:
From 1056 patients with malignant mesothelioma in Eli
and Lilly Expanded Access Programme (EAP) 187
patients with malignant pleural mesothelioma (MPM) who
had been previously treated with at least one dose of the
study drug were included in the study.
Funded by Eli Lilly & Co
Group 1:
pemetrexed and
cisplatin
Biases/weaknesses:
No. in Group: 96
Range: 39-84
Pemetrexed 500mg/m² alone
or in combination with
cisplatin 75mg/m² once every
21 days for 6 cycles or until
disease progression. Folic
acid 350 to 600 µg, Vitamin
B12 1000µg and
dexamethasone.
Group 2: pemetrexed only
No. in Group: 91
Range: 27-87
Pemetrexed and cisplatin
Open label study.
Patients who had been
previously treated with
cisplatin-based regime, who
had responded for ≥6
months.
Inclusions:
No control group
Histological or cytology diagnosis of malignant
mesothelioma not amenable to surgical treatment
Number of previously received
treatments was not collected.
≥18 years
? Accuracy of response rate due to
difficulties measuring tumour size.
Toxicity may be under-reported as
reporting relied on investigator
reporting.
Reported discontinuation number
for all patients but not for each
treatment arm.
Life expectancy ≥70 on Karnofsky scale
Adequate bone marrow reserve, hepatic function and
renal function
Response data only available for 153 patients
CR= Complete Response – disappearance of all known
disease in target and non-target (confirmed by 2 obs not more
that 4 weeks apart):
Pemetrexed plus cisplatin 2 (2.5%)
Pemetrexed alone
0
PR= Partial Response – 30% reduction from baseline in
diameters of target lesion and no progress in non-targeted:
Pemetrexed plus cisplatin 24 (30%)
Pemetrexed alone
4 (5.5%)
SD= Stable Disease – do not meet criteria of PR or PD:
Pemetrexed only
Pemetrexed plus cisplatin 29 (36.3%)
Pemetrexed alone
30 (41.1%)
Exclusions:
Median number of cycles
completed = 3. (range 1-13)
Pregnant women
Results:
Median no of cycles
completed = 4 (range 1-10)
Patients who had received
prior chemotherapy.
Stable brain metastases not requiring corticosteroids.
Objective tumour response (using RECIST – Response
Evaluation Criteria in Solid Tumours)
PD= Progressive Disease – development of any new lesions
of increase of 20% in diameter of target lesions:
Pemetrexed plus cisplatin 25 (31.3%)
Pemetrexed alone
39 (53.4%)
Methodological Score: 3
Evidence Based Healthcare Table
Reference: Santoro et al, 2008
Design Description
Bibliographic Number:
Participants
Accident Compensation Corporation
Intervention
89
Outcomes
Evidence Based Brief Report
Description:
Non-randomised multicentre open label study of
International Extended
Access Programme
(EAP)
Outcome Measures:
While pemetrexed was under review by regulatory agencies 1704
chemotherapy naïve patients with histological confirmed MPM were
given either pemetrexed plus ciplatin or pemetrexed plus carboplatin.
First patient enrolled 6 Nov 2002 and last patient treated on 19 Oct
2006. 235 study centres in 13 countries [See Manegold et al,
2007 for patients in trial who received pemetrexed
alone]
Biases/weaknesses:
Not randomised
Response rate
Pemetrexed and cisplatin
Survival
500mg/m² as a 10 minute
intravenous infusion,
diluted in 100 m. saline. 30
minutes later cisplatin IV at
75mg/m² over 2 hours.
Given on day 1 of a 21 day
cycle
Time to progression
Toxicity
Results:
Patients treated with
pemetrexed + carboplatin
had poorer clinical status,
median age of 66 (compared
with 62 in pemetrexed +
cisplatin) and possibly were
not suitable to receive
pemetrexed + cisplatin.
Group: 1 Pemetrexed and
cisplatin
Group 2: Pemetrexed and
carboplatin
No. in Group: 843 (of which
only 745 were evaluable)
Mean Age: 62 (24-78)
No. in Group: 861 (of which only 752
were evaluable)
Mean Age: 66 (35-89)
Allowed physician
interpretation in evaluating
response
Not candidate for curative surgery
SAEs reported by
investigators to Eli Lilly
research physician.
≥ 70 on Karnofsky scale
Pemetrexed and
carboplatin
Inclusions:
Overall response rate:
pemetrexed/cisplatin – 26.3%
pemetrexed/carboplatin – 21.7%
1 year survival:
pemetrexed/cisplatin – 63.1%
pemetrexed/carboplatin – 64%
Histologically proven diagnosis of MPM
500mg/m² as a 10 minute
intravenous infusion,
diluted in 100 m. saline. 30
minutes later carboplatin
AUC 5 was given IV over
30 minutes. Given on day
1 of a 21 day cycle.
≥ 18 years
Adequate bone marrow and normal renal function
Exclusions:
Folic acid, vitamin B12 and
dexamethasone also given
to each group.
Pregnant women
Serious concomitant disorders
(Median survival not estimable due to high censoring)
Median time to progressive disease:
pemetrexed/cisplatin – 7 months pemetrexed/carboplatin –
6.9 months
Toxicity
Grade 3/4 neutopenia:
pemetrexed/cisplatin – 23.9%
pemetrexed/carboplatin – 36.1%
Grade 3/4 leucopenia:
pemetrexed/cisplatin – 13.1%
pemetrexed/carboplatin – 21%
Methodological Score: 2+/2-
Evidence Based Healthcare Table
Reference: Manegold et al, 2007 (from abstract)
Design
Description
Bibliographic Number:
Participants
Accident Compensation Corporation
Intervention
90
Evidence Based Brief Report
Outcomes
Non randomised multi
centre open label study
of International
Extended Access
Programme (EAP)
Description:
Outcome Measures:
While pemetrexed was under review by regulatory agencies 1074
chemotherapy naïve patients with histologically confirmed MPM were given
either: (1) Pemetrexed plus cisplatin (2) pemetrexed plus carboplatin or (3)
Pemetrexed alone [Santoro et al, 2008 report on first 2
groups]
Response rate
Pemetrexed 500mg/m² as a
10 minute intravenous
infusion, diluted in 100 m.
saline.
Survival
Time to progression
Biases/weaknesses:
Patients received ≥ 1 dose of
pemetrexed.
Not random.
Allowed physician
interpretation in
evaluating response.
SAEs reported by
investigators to Eli Lilly
research physician.
Toxicity
Pemetrexed monotherapy:
Results:
No. in Group: 319 (of which 247
were evaluable)
Mean Age: 69 (39-87)
RR – 10.5%
Inclusions:
Median time to progressive disease – 6 months
One year survival – 58.6%
Histologically proven diagnosis of MPM
Toxicity:
% of patients with
Karnofsky ≥ 80 was
71.6% in pemetrexed
only group whereas in
the pemetrexed +
cisplatin and
pemetrexed +
carboplatin groups
86.8%and 85.8
respectively.
Not candidate for curative surgery
Grade 3/4 Neutropenia – 17.3%
≥ 18 years
Grade 3/4 leukopenia – 14.7%
≥ 70 on Karnofsky scale
Methodological Score: 2+/2Adequate bone marrow and normal renal function
Exclusions:
Pregnant women
Serious concomitant disorders
Evidence Based Healthcare Table
Reference: Taylor et al, 2008
Design Description
Accident Compensation Corporation
Bibliographic Number:
Participants
Intervention
91
Evidence Based Brief Report
Outcomes
Non randomised open label study of
outcome from Extended Access
Programme (EAP) after
completion of EMPHACIS Phase III
trial (Vogelzang et al, 2003)
Biases/weaknesses:
Patients who had received
pemetrexed previously were
admitted to the trial only if they had
had a response – increases number
of likely responders to the drug in
the trial.
Use old RECIST criteria, WHO or
Southwest Oncology group criteria –
no consistency.
Description:
812 patients (both chemotherapy naive and pre-treated) received
treatment with single-agent pemetrexed in the EAP. Although the
randomised study demonstrated promising results for pemetrexed plus
cisplatin, many patients may not be eligible for platinum containing
regimens because of co morbidities, age and performance status.
Therefore the aim of the study was to see the effect of the single agent
pemetrexed.
Group 1: chemo
naive
No. in Group: 319
(247 evaluated –
77%))
Pemetrexed
500mg/m² IV over
10 minutes on day
1 of a 21 day cycle.
Outcome Measures:
Folic acid, vitamin
B12 and
dexamethasone.
Median survival
Median time to progressive disease (MTTP)
Toxicity
Group 2: pre-treated
Results:
No. in Group: 493
(396 evaluated – 80%)
Response rate:
Chemo naïve – 10.1%
Pre-treated – 12.1%
MTTP:
Chemo naïve – 6.0 months
Pre-treated – 4.9 months
Median Survival:
Chemo naïve – 14.1 months
Pre-treated – not estimable due to high censoring
1 year survival rate:
Chemo naïve – 58.6%
Pre-treated – 54.7%
Mean Age: 63 (31-85)
Dose adjustments
and delays due to
toxicities.
Mean Age: 69 (39-87)
Inclusions:
Pre-treated patients had a lower
mean age and greater proportion in
higher KPS (43% with values of 100
or 90 vs 33% in chemonaive
group) – slight bias
Response rate (Using RECIST criteria)
Histologically proven MPM and not candidates for surgery
≥ 18 years of age
If previously treated with pemetrexed, must have had a tumour response
≥ 70 on Karnofsky performance status scale (KPS)
Adequate bone marrow reserve, hepatic function, and renal function.
Median no. of
cycles in both
groups was 4
cycles:
Exclusions:
Unstable brain metastases requiring NSAIDS
Pregnant women
Toxicity:
Most common G3/4 were neutropenia (17.3% in the
chemo naïve and 15.6% in the pretreated) and
leukopenia (14.7% in the chemo naïve and 13.9% in the
pretreated
Methodological Score: 3Active infections
Serious concomitant disorders
Evidence Based Healthcare Table
Reference: Castagneto et al, 2008
Design
Description
Bibliographic Number:
Participants
Accident Compensation Corporation
Intervention
92
Evidence Based Brief Report
Outcomes
Description:
Multicentre phase II
clinical drug trial – case
series
76 patients - study to evaluate the activity and toxicity of the combination of
pemetrexed and carboplatin as first-line chemotherapy to treat patients
affected by advanced MPM, including patients with poor performance.
54 males and 22 females.
Median age 65 (40-75)
Carboplatin delivered to an
area under the curve (AUC)
of 5 over 30 min on day 1
and permetrexed was diluted
in 100ml of normal saline and
administered at a dose of
500mg/m² i.v. > 10 min on
day 1. Cycles repeated every
21 days.
Outcome Measures:
Folic acid and B12
supplementation and
dexamethasone.
toxicity
A total of 537 cycles
administered – median
8 cycles per patient
Not amenable to surgery
ECOG performance score of 0-2
time to progression (TtP)
Partial response: 16 (21%)
Stable disease: 29 (38%)
Progressive disease: 28 (37%)
Life expectancy > 3 months
Median overall survival estimated at 14 months
Younger than 75 years
Median TtP was 8 months.
Adequate bone marrow, hepatic and renal function
Toxicity:
36 (47%) reported grade III neutropenia and
thrombocytopenia and 5 (6.5%) grade IV.
Grade III gastrointestinal toxicity in 6 (11.8%).
Exclusions:
Small number in trial
overall survival (OS)
Response :
Complete response: 3 (4%)
Histological diagnosis of MPM
No control group
Secondary end points were:
Results:
Inclusions:
Biases/weaknesses:
Evaluation of activity in terms of tumour response rate
(RR).
Systemic chemotherapy or radiotherapy
Other malignancies
Evidence of heart failure or infections
Methodological Score: 3-
Evidence Based Healthcare Table
Reference: Ceresoli et al, 2006
Design
Description
Bibliographic Number:
Participants
Accident Compensation Corporation
Intervention
93
Outcomes
Evidence Based Brief Report
Description:
Multicentre phase II
clinical study – case
series
Treatment:
Trial of combination of pemetrexed and carboplatin as front line treatment in
patients with MPM
Between Nov 2002 and Mar 2005 102 patients enrolled prospectively from 8
Italian institutions.
76 males and 26 females
Median age 65 (38-79)
Outcome Measures:
Primary end point:
Every 21 days:
Pemetrexed IV
500mg/m² over 10
minutes, followed 30
minutes later by
carboplatin as 30 min
IV infusion at an AUC
5mg/mL/min.
-
Tumour response rate (RR)
Secondary end points:
-
Toxicity
Time to Progression (TTP)
Overall Survival (OS)
32 patients > 70 years old
Biases/weaknesses:
Small number in trial
Group 1
Group 2
No. in Group:
Mean Age:
No. in Group:
Mean Age:
Vitamin B12 and folic
acid supplementation
Results:
RR – 18.6%
Stable disease (SD) – 65.7%
Inclusions:
No control group
Patients received a
median of 6 cycles.
79 patients (77%)
completed at least 4
cycles
Histologically proven MPM
Not candidates for curative surgery
Uni or bi-dimensionally measurable disease
Age > 18 years old
ECOG performance score ≥ 2
Life expectancy ≥ 12 weeks
Adequate bone marrow and blood counts
Toxicity: Haematological toxicity mild and mostly neutropenia
or anemia. Non haematological toxicity mild and mostly
nausea, vomiting, fatigue and diarrhoea.
Median TTP – 6.5 months and significantly related to good
performance score (PS) – p=.047
Exclusions:
Median survival time – 12.7 months and significantly related to
PS – p=.04
Prior systematic or intracavitary chemotherapy
Brain metastases
Serious co-morbidities or other malignancies
Unable to discontinue NSAIDs
Methodological Score: 3-
Evidence Based Healthcare Table
Reference: Ceresoli et al, 2008
Design Description
Accident Compensation Corporation
Bibliographic Number:
Participants
Intervention
94
Evidence Based Brief Report
Outcomes
Pooled retrospective analysis of
patient data from 2 phase II trials
that included young (under 70)
and elderly (70 or over) patients
treated with the same treatment
schedule of carboplatin and
pemetrexed
Description:
Both groups received:
178 patients chemotherapy naïve patients with histologically
proven MPM who were not candidates for surgery who had been
included in prospective phase II studies conducted between Nov
2002 and July 2005 trials with pemetrexed plus carboplatin.
Biases/weaknesses:
Retrospective subgroup analysis
Small number of patients in trial
and only 11 over 75 years of age.
Group 1: ≥70 years
Group 2: <70 years
No. in Group: 48
Mean Age:
No. in Group: 130
Mean Age:
Tumour response rate (TRR)
Pemetrexed intravenously at
a dose of 500mg/m² over 10
minutes followed by
carboplatin, administered by
a 30 minute intravenous
infusion at an AUC of 5mg
mlˉ1 minˉ1. Given every 21
days. Folic acid and vitamin
B12 suplementation plus
steroid prophylaxis and
standard antiemetic therapy.
Inclusions:
ECOG performance status les or equal to 2
Median 6 cycles in both
groups
Life expectance ≥12 weeks
Using elderly patients with no comorbidities introduces bias of
possibly more healthy elderly
being included
Outcome Measures: (In both trials)
Secondary end points:
Toxicity
Time to progressive disease (TTP)
Overall survival (OS)
Results:
TRR did not differ significantly between the two age
groups (p=0.15):
TRR in ≥70 – 14.6% (no patients had a completer
response but 7 had a partial response)
TRR in <70 – 23.8% (5 patients had a complete
response and 26 had a partial response).
Stable disease – 45.8% in ≥70 and 43.1% in <70
TTP median for ≥70 – 7.2 months
TTP median for <70 - 7.5 months (p= 0.42)
Uni and/or bidimensionally measurable disease
Exclusions:
OS median for ≥70 - 10.7 months
OS median for <70 – 13.9 months (p= 0.12)
Systemic or intracavitary chemotherapy
Documented brain metastases
Serious co-morbidities
Other malignancies
Toxicity:
Grade 3 – 4 neutropenia, was slightly worse in elderly
patients: 25% in ≥70 and 13.8% in <70 (p=0.11)
Severe anemia was significantly more frequent in
elderly: 20.8% in ≥70 and 6.9% in <70 (p= 0.01)
Only 48 patients were ≥70 which
is small sample of this age group
Methodological Score: 3
Evidence Based Healthcare Table
Reference: Scagliotti et al, 2003
Accident Compensation Corporation
Bibliographic Number:
95
Evidence Based Brief Report
Design Description
Participants
Intervention
Outcomes
Phase II multi centre case
series study
Description:
Fully supplemented:
Outcome Measures:
70 patients in 10 centres over 4 countries were either fully
supplemented or non-supplemented with vitamin B12 and folic acid to
determine the efficacy of pemetrexed as a single agent in
chemotherapy naïve patients with advanced MPM. Only 64 were
eligible to enter the study
Pemetrexed 500mg/m²
diluted in 100mL of normal
saline IV for 10 minutes.
Repeated at 3 week intervals.
Tumour response.
Biases/weaknesses:
Non supplemented patients
had a higher median age of 68
compare to 63 in the
supplemented group. The
supplemented group had a
higher percentage of females
(23.3% compared to 4.8% in
the non supplemented group)
Conflicting tumour response
rate analysis between
investigator assessment
(higher for non supplemented
patients) and independent
reviewer (higher for
supplemented patients)
Different criteria were used to
measure response rate
between uni-dimensionably, bidimensionably measureable
lesions
Survival
Folic acid and vitamin B12
throughout.
Median cycles: 6 (range 1-20
cycles)
Time to progressive disease
Time to treatment failure
Non supplemented:
Group 1: fully
supplemented
No. in Group: 43
Mean Age: 63 (39-80)
Pemetrexed 500mg/m²
diluted in 100mL of normal
saline IV for 10 minutes.
Repeated at 3 week intervals.
Group 2: Non supplemented
No. in Group: 21
Mean Age: 68 (54-74)
Inclusions:
Histologically proven diagnosis of MPM
Not candidates for curative surgery
uni or bidimensionally measurable lesions
Performance status ≥ 70 on Karnofsky performance status scale
Life expectance ≥ 12 weeks
Adequate bone marrow reserve and creatinine clearance
Either did not receive folic
acid and B12
supplementation or for only
part of the trial.
Median cycles: 2 (range 1-16
cycles.
There were 23 reports of
serious adverse events and 7
patient withdrew from the
study due to these
Exclusions:
Previous systemic chemotherapy
Second primary malignancy
Brain metastases or inability to interrupt NSAIDS
Evidence Based Healthcare Table
Reference: Sorensen et al, 2007
Accident Compensation Corporation
Duration of response
Bibliographic Number:
96
Evidence Based Brief Report
Results:
Response rate:
Supplemented – 16.3%
Non supplemented – 9.6%
Median survival:
Supplemented – 13.0 months
Non supplemented – 8.0 months
Median time to progression:
Supplemented – 4.8 months
Nnon supplemented – 3.0 months
Grade 3/4 neutropenia
Supplemented – 9.4%
Non-supplemented – 52.4%
Grade 3/4 leukopenia:
Supplemented – 2.3%
Non-supplemented – 38.1%
Methodological Score: 3
Design
Description
Participants
Intervention
Outcomes
Case series to evaluate
pemetrexed as second
line chemotherapy in
MPM patients not
previously exposed to
pemetrexed
Description:
Pemetrexed
Outcome Measures:
39 patients with disease progression of MPM after previous
platinum-based regimens without pemetrexed were given
pemetrexed to evaluate its activity in second-line treatment.
500mg/m² as a 10 minute infusion
every 3 weeks
Biases/weaknesses:
Small number of
patients
Partial response rate (PRR) – measured with modified
RECIST criteria
Median time to progression (TTP)
First line treatment received was Vinorelbine +cisplatin (21),
Vinorelbine+carboplatin (2), Gemcitabine+carboplatin (5) and
Gemcitabine + caelyx +carboplatin (11)
Median survival
Group 1: pemetrexed
Group 2: pemetrexed
and carboplatin
Pemetrexed and carboplatin
No. in Group: 28 Danes
Mean Age: 62 (30-73)
No. in Group: 11
Norwegians
Mean Age: 62 (43-77)
500mg/m² as a 10 minute infusion
every 3 weeks plus carboplatin
area under the curve (AUC) 5
(pemetrexed plus carboplatin)
both administered day 1 every 3
weeks
No control group
Inclusions:
Difference in treatment
received between
Danish and Norwegian
patients
Histologically proven MPM and measurable disease
Progression after platinum based combination chemotherapy
ECOG performance status of 0-2
Estimated survival ≥ 3 months
≥ 18 years of age
Adequate organ function
3 of the Danish patients
received pemetrexed
as third line treatment.
Exclusions:
Previous exposure to pemetrexed
Significant medical or psychiatric co morbidity
Central nervous metastases
Pregnant or lactating women
History of cancers in last 5 years or breast cancer ever.
Dose delays and reductions due to
toxicities
Median number of cycles for both
groups was 6 cycles (range: 1-23)
PRR:
Pemetrexed 21%
pemetrexed plus carboplatin 18%
TTP:
Pemetrexed – 21 weeks
pemetrexed plus carboplatin – 32 weeks
Median survival:
pemetrexed – 42 weeks
pemetrexed plus carboplatin – 39 weeks
1 year survival::
36% for both groups
Toxicity:
Grade 3/4 leukopenia – 14% with pemetrexed and 9% with
pemetrexed plus carboplatin
Thrombocytopenia – 7% with pemetrexed and 18% with
pemetrexed plus carbopatin.
Nausea – 4% with pemetrexed and 0% with pemetrexed and
arboplatin
Methodological Score: 3
Evidence Based Healthcare Table
Reference: Janne et al, 2008
Accident Compensation Corporation
Bibliographic Number:
97
Evidence Based Brief Report
Design
Description
Participants
Intervention
Outcomes
Open label phase II trial
Description:
Group 1: pemetrexed
Outcome Measures:
108 patients with MPM were enrolled to explore two different schedules of
pemetrexed and gemcitabine. Initially patients entering the trial were treated
as per group 1 but the study protocol was amended to include a second
group and these patients were recruited subsequent to the first group.
500mg/m² administered on
day 8 and gemcitabine
1,250mg/m² administered on
day 1 and immediately after
pemetrexed on day 8.
Treatment repeated every 21
days for 6 cycles or until
progressive disease.
Response rate according to SWOG criteria
Biases/weaknesses:
No controls and no
randomisation.
Complete response
Partial response
Stable disease
Survival
Median cycles – 4 (1-11)
16 patients did not
undergo response
assessment.
Surger: prior to the
study 62.5% of group 1
and 44.2% of group 2
had received prior
surgery.
Stage of disease:
71.4% of grop 1 were
stage IV of disease but
only 57.7% of group 2.
Time to progression
Group 1: gemcitabine day 1 & 8
+ pemetrexed day 8
Group 2: gemcitabine day 1 & 8 +
pemetrexed day 1
No. in Group: 56
Median age: 69 (36-88)
No. in Group: 52
Median age: 71 (47-86)
Results:
Group 2: pemetrexed
500mg/m² administered on
day 1 and gemcitabine
1,250mg/m² administered
immediately after pemetrexed
on day 1 and on day 8.
Treatment repeated evry 21
days for 6 cycles or until
progressive disease.
Inclusions:
Histological or cytological diagnosis of MPM
Chemotherapy naïve
≥ 18 years of age
Life expectancy ≥ 12 weeks
ECOG performance score 0-2
Adequate organ and bone marrow function
Median cycles – 3 (1-16)
Exclusions:
Prior systemic chemotherapy
Brain metastases
Pregnant women
:
Response rate:
Group 1: 26%
Group 2: 17.1%
Median survival:
Group 1: 8.08 months
Group 2: 10.12 months
Toxicity:
Group 1: grade 4 neutropenia – 25%, grade 4
thrombocytopenia – 14.3%, grade 3 or 4 fatigue –
23.2%.
Group 2: grade 4 neutropenia – 29.4%,
thrombocytopenia – 3.9%, grade 3 or 4 fatigue –
15.6%.
Methodological Score: 3
Evidence Based Healthcare Table
Reference: van den Bogaert et al, 2006
Accident Compensation Corporation
Bibliographic Number:
98
Evidence Based Brief Report
Design
Description
Participants
Intervention
Outcomes
Non-randomised
feasibility study
Description:
Pemetrexed 500mg/m² given
IV in 10 minutes on day 1 of
a 21 day cycle.
Outcome Measures:
If applicable this was followed
30 minutes later by
carboplatin AUC 5,
administered IV over 30
minutes
Secondary outputs:
Study of 27 patients to investigate the toxicity and effectiveness of
pemetrexed maintenance therapy (PMT) in patients with MPM in whom no
disease progression was observed during six courses of pemetrexed
containing induction therapy.
Best response: partial response (PR), stable disease
(SD) and progressive disease (PD).
Survival
Time to disease progression (TTP)
Toxicity
Biases/weaknesses:
Small number of
patients in trial and four
sub-groups – low
power of study.
Group 1: maintenance group –
continued to receive
pemetrexed after 6 courses
No. in Group: 13
Group 2: non maintenance
group – did not continue to
Maintenance group
who continued to
receive either
pemetrexed or
pemetrexed plus
cisplatin had a lower
mean age which may
have biased response
in their favour
receive pemetrexed after 6
courses
No in group: 14
(a)previously received pemetrexed and
carboplatin (no = 8, mean age = 64)
(b) previously received pemetrexed (no
= 5, mean age = 54)
(a)previously received pemetrexed and
carboplatin (no = 5, mean age = 66)
(b) previously received pemetrexed (no
= 9, mean age = 63)
Folic acid, vitamin B12 and
dexamethasone given
according to institutional
practice.
Median courses = 4 (2 - 14)
Reasons for stopping PMT:
Results:
PR: 23% (3 out of 13) of those with stable disease after
induction therapy achieved a partial response.
TTP: 8.5 months in PMT versus 3.4 in non
maintenance group
Survival: 17.9 months in PMT versus 6 months in non
maintenance group (p=0.0001)
Toxicity – 23%
Grade III toxicities:
Inclusions:
Disease progression – 69%
Histologically proven diagnosis of MPM not amenable to surgery
WHO performance status 0-2
≥ 18 years of age
Adequate hepatic and renal function and bone marrow reserve
Adequately treated and stable brain metastases not requiring NSAIDs
Exclusions:
Irradiation within 2 weeks before start of therapy
Inability to interrupt NSAIDs
Malnutrition or more that 10% weight loss in preceding 6 weeks
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Patient’s best interest – 8%
Neutropenia – 15%
Leucopenia – 8%
Anemia – 8%
Fatigue – 15%
Methodological Score: 3-
99
Evidence Based Brief Report
Evidence Based Healthcare Table
Reference: Silvestri G, Pritchard R, Gilbert Welch H.
Design
Description
Participants
Descriptive study to
determine howpatinets
with lung cancer value
the tade off between
the survival benefit of
chemotherapy and its
toxicities
Description:
Bibliographic Number:
Intervention
Outcomes
Outcome Measures:
81 patients previously treated with cisplatinum based chemotherapy for
advanced non-small cell lung cancer
Group 1
Group 2
Biases/weaknesses:
No. in Group: N/A
Mean Age:
No. in Group: N/A
Mean Age:
Asking about behaviour
- ? better to observe
Inclusions:
treatment choices.
Stage III or IV non-small cell lung cancer histologically diagnosed
Too many confounders
and biases
Had received at lease one cycle of cis-platinum based chemotherapy
Survival threshold for receiving chemotherapy
Scripted interviews about
their own experiences and
given 2 scenarios in which to
choose minimum survival
benefit and 1 scenario to
choose between supported
care or chemotherapy
Results:
Median survival threshold for accepting chemotherapy
was 4.5 months for mild toxicity and 9 months for
severe toxicity. (Elderly patients tended to demand
greater benefit before accepting chemotherapy and
patients self reporting lower quality of life during
chemotherapy had higher thresholds for accepting
chemotherapy)
Exclusions:
Great variety in
threshold for accepting
chemotherapy: varied
from 1 week to 24
months
Known or suspected brain metastases
When given choice between supportive care and
chemotherapy only 18 (22%) chose chemotherapy for
a survival benefit of 3 months.
Recruitment of patients
not described
55 (68%) chose chemotherapy if it substantially
reduced symptoms without prolonging life.
Selection Notes:
Methodological Score:
3Evidence Based Healthcare Table
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Reference: Cordony A et al, 2008
Design Description
Bibliographic Number:
Participants
Intervention
Description:
Cost effectiveness analysis to
model best survival outcome
over time.
Outcomes
Outcome Measures:
All participants in RCT (Vogelzang N J et al, 2003) - 456
patients with unresectable malignant pleural mesothelioma
Survival
Pemetrexed plus
cisplatin versus
cisplatn
monotherapy
QALYs
Cost
Funded by Eli Lilly and Co.
Biases/weaknesses:
Used direct medical costs
associated with MPM
treatment. No indirect or social
costs were included.
Costs from UK NHS costs may
not be applicable to NZ. Do not
provide cost of individual drug
treatment
Group 1
Group 2
Results:
No. in Group:
Mean Age:
No. in Group:
Mean Age:
Quality adjusted mean survival for all groups in the pemetrexed/cisplatin
group ranged from 0.13 to 0.20 quality adjusted years. The direct (UK)
costs of both therapies were calculated. The mean incremental cost
per life-year gained ratios with the study treatment were given for sub
groups of the pemetrexed plus cisplatin group:
- fully supplemented with folic acid and B12 - (FS) – £68,599
- fully supplemented with advanced disease (stage III or IV) – (FSAD) £53,314
----fully supplemented with performance status (PS) of 0/1- (FSPS) £45,454
---fully supplemented with advanced disease plus PS of 0/1 – (FSADPS) £44,950
Inclusions:
chemotherapy naïve and not eligible for curative therapy
Uni or bi-dimensionally measurable disease
age ≥18 years
life expectancy ≥ 12 weeks
Karnofsky performance status ≥70
Exclusions:
Prior chemotherapy
Calculated dose in size of vials
500mg used in UK. ? same in
NZ
Methodological Score:
Second primary malignancy
N/A. Well conducted study.
Brain metastases
Does not measure quality of life
beyond survival.
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Unable to interrupt NSAIDs
101
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5 Appendix 7: Evidence tables for raltitrexed
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Study
Study
inclusion/
exclusion
criteria
Exposure/
comparison
treatment
(number of
studies
included)
Common outcomes among
studies
Results
Validity/ Applicability
Yes
No NA
N/S
Conclusions
Dundar et
al, 2007
Systematic
review of
clinical
effectiveness
and costeffectiveness
of
pemetrexed
plus cisplatin
in
unresectable
pleural
mesotheliom
a in
chemotherap
y naïve
patients
Clinical
effectiveness –
Clinical effectiveness:
Extension life expectancy and
palliation as measured by time to
progression of disease and other
end-points
RCT of 448
patients showed
pemetrexed in
combination with
cisplatin showed
a 2.8 month gain
in median
survival
Focused question
Y
Thorough search strategy
Y
Conclusions drawn from
limited research available.
May over stress effect
because of limited studies.
Search terms defined
Y
Appropriate
inclusion/exclusion criteria
Y
Economic
evaluation
conducted by the
study (and that
submitted by the
manufacturer)
suggest
pemetrexed is
not considered
cost effective at
conventionally
accepted
thresholds in UK,
because of high
cost of
pemetrexed
compared with
cisplatin
Two reviewers – selection
study validity rated
Y
Two reviewers -validity
Y
Valid combination of
studies
N/A
1 RCT met
inclusion criteria
Cost
effectiveness –
No published full
economic
reports found. 1
conference
abstract/present
ation found.
Absolute benefit is small
Limited benefit at expense of
considerable toxicity to patients
Cost effectiveness:
Suggest it is not cost effective at
conventional thresholds for all
patients
Cost effectiveness better for some
patient subgroups, especially
patients with good performance
status and with advanced disease.
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103
Economic evaluation is
based on UK economics. ?
applies to NZ
Y
Appropriate analysis
All important outcomes
considered
Balance between benefit
and harms
1+
Y
Y
Y
Fair conclusions from
evidence
Evidence Based Brief Report
Evidence Based Healthcare Table
Reference: van Meerbeeck et al, 2005
Bibliographic Number:
Design
Description
Participants
Intervention
Outcomes
Phase III RCT stratified
multicentre (24 centres)
Description:
Intervention group:
Outcome Measures:
250 patients (80% male) with MPM in study to compare treatment with
raltitrexed and cisplatin with cisplatin alone. Patients recruited between March
2000 and January 2003
Cisplatn intravenously at
80mg/m² in 1 to 2 hours.
Raltitrexed was administered
IV at 3mg/m² in 15 minutes,
preceeding cisplatin. Both
drugs given on day 1 of each
cycle and repeated every 3
weeks until progression,
severe toxicity or patient
refusal.
Overall survival
Supported by
AstaZenica and NCI
Canada
Biases/weaknesses:
No blinding – time to
progression may be
over-estimated.
Study carried out at 24
sites (3 sites accounted
for over half of
subjects). Results for
different sites not
compared for
consistency.
Smaller size than
recommended –
therefore reduced
power. As mentioned in
article if the magnitude
of clinical effect on
survival is similar to the
EMPHACIS study – an
increase in sample size
may have resulted in a
more significant result.
Group 1: Raltitexed and
cisplatin
Group 2: cisplatin only
No. in Group: 126
Mean Age: 59 (19-80)
No. in Group: 124
Mean Age: 58 (29-76)
Progression free survival
Toxicity
Health Related Quality of Life (HRQOL)
Results:
Inclusions:
MPM histologically diagnosed
Not candidate for surgery
WHO performance status 0-2
Age ≥18
Adequate hepatic and renal function and bone marrow reserve
Chemotherapy naive
Median cycles 5 (range: 110)
Median survival in intervention group was 11.4 months
and 8.8 months in the control group (p= 0.048)
Dose adjustments of
raltitrexed were made in
subsequent cycles for any
combination of diarrhoea and
haematological toxicity.
Median progression free survival in the intervention
group was 5.3 months and 4.0 in the control group (p=
0.58)
Response rate in intervention group was 23.6% and
13.6% in control group
Control group:
Cisplatin intravenously at
80mg/m² in 1 to 2 hours.
Given on day 1 of each cycle
and repeated every 3 weeks
until progression, severe
toxicity or patient refusal.
Exclusions:
Prior chemotherapy
CNS metatastases
Uncontrolled infections
Median cycles 4 (range: 1-9)
There was no vitamin
supplementation.
Other malignancies
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Response rate
104
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Toxicity:
Grade 3/4 toxicity neutropenia and vomiting reported
twice as often in the combination treatment arm.
HRQOL: no statistically or clinically significant
difference between the two arms
Methodological Score: 1+/1-
Evidence Based Healthcare Table
Reference: Fizazi et al, 2003
Bibliographic Number:
Design
Description
Participants
Intervention
Outcomes
Case control study
phase II open label
study
Description:
Raltitrexed 3mg/m² as 15
minute IV infusion followed
45 minutes later by oxaliplatin
130mg/m² as a 2 hour
infusion. Treatment cycle
repeated every 3 weeks.
Outcome Measures:
Phase II study over 2 centres to evaluate the activity of raltitrexed and
oxaliplatin combination therapy in patients with diffuse malignant pleural
mesothelioma. 72 patients recruited of which 70 were eligible:
Primary site:
Pleural – 64 (91%)
Response rate
Time to progression
Survival
Self reported symptoms (especially pain)
Biases/weaknesses:
Large confidence
interval for response
rate.
Very small group of
pretreated to compare
to chemotherapy naïve.
Pleural and peritoneal
results not separated
Peritoneum – 6 (9%)
Median cycles – 4.6
Mean age for 70 patients: 60 (43-74)
Group 1: chemotherapy naive
Group 2: Pretreated with cisplatin
No. in Group: 55
Mean Age: Not provided
No. in Group: 15
Mean Age: not provided
Inclusions:
Histologically proven MPM of pleura or peritoneum
≥ 18 years of age
WHO performance status 0-2
At least 1 measurable lesion (bi-dimensionable ≥2cm or uni-dimensionable
>0.5cm
Exclusions:
19(26%) raltitrexed and 21
(29%) oxaliplatin required
dose reduction.
20 patients (16 chemo naïve
and 4 pretreated) withdrew
from the treatment because
of adverse events.
:
Other malignancies
Measurement of
lesions not consistent –
some uni and some bidimensionable
Uncontrolled infections or serious illness
Peripheral neuropathy
Results:
Response rate overall:
PR - 14 patients (20%)
SD – 32 patients (46%)
PD – 22 patients (31%)
No
difference between chemotherapy naïve and
pretreated.
Median time to disease progression – 18 weeks
(chemo naïve – 17 weeks and pretreated – 27 weeks).
Median survival – 32 weeks (chemo naïve – 31 weeks
and pretreated – 44 weeks).
Median 1 year survival – 26% (chemonaive – 22% and
pretreated 40%).
Toxicity:
Grade IV – 1 patient with asthenia
Grade III – 19.4% asthenia, 12.5% anorexia, 11.1%
ALT increase.
Methodological Score: 3
Abnormal haematological parameters
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Evidence Based Healthcare Table
Reference: Baas et al, 2003
Design
Description
Participants
Case series - Multi
centre phase II open
study of single agent
raltitrexed
Description:
Bibliographic Number:
Intervention
Outcomes
Outcome Measures:
Open study in 5 European institutes. Patients enroled from November 1999June 2001 to evaluate the activity and toxicity of raltitrexed as a single agent
in the treatment of malignant pleural mesothelioma.
Raltitrexed 3.0 mg/m² on day
one – 15 minute IV infusion
every 3 weeks.
Tumour response (using modified RECIST
measurement and IMIG for tumour extension.
Responders were reviewed by 2 independent
radiologists)
25 patients registered for study.
Biases/weaknesses:
Group 1:
Group 2
No. in Group: 24 included in study
Mean Age: 63 (34-75)
No. in Group:
Mean Age:
Results:
Patients received a minimum
of 2 cycles before evaluation.
SD – 8 patients
No controls
Median: 3 cycles (range 2-8
cycles)
Inclusions:
Biopsy proven and confirmed MPM
Problems confirming
diagnosis: out of 21
centrally reviewed
cases 18 were
confirmed as being
‘definitive’ or ‘probable’.
PR - 5 patients (20.8%)
Evaluation every 2 cycles by
CT scan.
Chemotherapy naïve
≥ 18 years of age
PD – 8 patients
Median survival – 7 months
Toxicity:
Reasons for stopping
treatment:
ECOG-WHO performance scale 0-2
At least one target lesion mesurable in one dimension
No grade IV toxicities except one anorexia but this may
have beeen due to disease progression
11 patients – disease
progression
Grade III tosicities:
3 patients – toxicity
Leucopenia 4%
1 patient - refusal
Neutropenia 13%
Good WBC count
Small number in trial
and large confidence
interval for median.
Exclusions:
Pleurodesis with cytotoxic drugs
Brain metastases
Fatigue 8%
Selection Notes:
Methodological Score:
3
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Evidence Based Healthcare Table
Reference: Bottomley et al, 2007
Bibliographic Number:
Design
Description
Participants
Intervention
Outcomes
Prognostic factor
analysis
Description:
EORTC QLQ-C30 measures
5 functional scales: physical,
role, emotional, cognitive and
social; 3 symptom scales:
fatigue, nausea and vomiting,
and pain; 6 single item
scales: dyspnoea, sleep
disturbance, appetite loss,
constipation, diarrhea and
financial impact; and the
overall health and global
QOL scale.
Outcome Measures:
An evaluation of the prognostic value of patient reported symptoms or health
related quality of life (HRQOL) using data gathered from a recent RCT study
of cisplatin with or without raltitrexed in patients with malignant pleural
mesothelioma.
Group 1
Group 2
No. in Group:
Mean Age:
No. in Group:
Mean Age:
Biases/weaknesses:
Inclusions:
229 patients had a HRQOL assessment
Did not include all of
250 in original trial.
The QLQ-LC13 includes 13
items assessing associated
lung cancer symptoms,
treatment related adverse
effects, and pain medication.
Exclusions:
Appetite loss may be a
symptom of and reflect
developing disease.
21 patients from the phase III study were not included in this analysis
because they did not have a valid HRQOL assessment
EORTC procedures were
used to scale and score the
measured items.
Assessments performed at
baseline, before start of each
up to cycle 5 because of
attrition due to death (only
156 completed
questionnaires up to this
point
Small size of study.
Short term results only
to 5th cycle of treatment
Selection Notes:
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Prognostic value of reported patient symptoms
Results:
The 229 patients had a median survival time of 10.1
months. There were no significant survival differences
between the two treatment groups on any HRQOL
scale.
Patients who received raltitrexed plus cisplatin
had significant clinically meaningful
improvements of dyspnoea during treatment
from cycle 2 onwards compared to baseline
scores
Pain (p < .0001) and appetite loss (p<= .0100) were
independent prognostic indicators of survival.
Methodological Score:
3-
Appendix 8: Studies excluded from this review
Author
Title
Reason for exclusion
Prescribe international
article
Pleural Mesothelioma: a first encouraging trial.
Prescribe International 2005; 14(80):212-14
Summary information
Adjei A.
Clinical studies of pemetrexed and gemcitabine
combinations. Annals of Oncology 2006; 17
Suppl 5:v29-32
Toxicity stage II study
Beck A K et al
Ranpirnase as a potential antitumour
ribonuclease treatment for mesothelioma and
other malignancies. Future Oncology
2008;4(3):341-349
Ranpirnase – another drug
Belmunt J et al
Clinical activity of vinflunine in transitional cell
carcinoma of the urothelium and other solid
tumours. Seminars in Oncology 2008;35(SUPPL
3):S34-S43
Vinflunine review of available evidence – to
another article req: Talbot
Bottomley A and
Aaronson N K.
International perspectives on health related
quality of life research in cancer clinical trials:
The European Organisation for Research and
Treatment of cancer experience. Journal of
Clinical Oncology 2007;25(32):5082-5086
Comment on importance of HRQOL
Budde L S and Hanna N
H.
Antimetabolites in the management of non-small
cell lung cancer. Current Treatment Options in
Oncology 2005;6(1):83-93.
About NSCLC generally
Carbone M et al
Eighth International Mesothelioma Interest
Group. Oncogene 2007;26(49):6959-6967
Review of Eighth international mesothelioma
interest group
Favaretto A.
Overview on ongoing or planned clinical trials in
Europe. Lung Cancer 2005;49 Suppl 1:S117-21
Overview of research.
Felip E and Rosell R.
Pemetrexed as second-line therapy for
advanced non-small-cell lung cancer (NSCLC).
Therapeutics and Clinical Risk Management
2008;4(3):579-585
NSCLC
Ferraldeschi R, Thatcher
N and Lorigan P.
Pemetrexed in small-cell lung cancer:
background and review of the ongoing GALES
pivotal trial. Expert Review of Anticancer
Therapy 2007;7(5):635-40
Small cell lung cnacer
Goeminne H and van
Meerbeeck J P.
Pemetrexed in thoracic cancer. Expert Opinion
on Pharmacotherapy 2006;7(7):917-28
Review
Hahn C E.
Mesothelioma research as a social issue.
Inhalation Toxicology 2006;18(12):991-994
Social impact article
Ismael-Khan R et al
Malignant pleural mesothelioma: A
comprehensive review. Cancer Control
2006;13(4):255-263
Review of general treatment
Janne P A et al
Open-label study of pemetrexed alone or in
combination with cisplatin for the treatment of
patients with peritoneal mesothelioma:
outcomes of an expanded access program.
Clinical Lung Cancer 2005;7(1):40-6
Peritoneal mesothelioma only covered.
Krug L M et al
Potential role of histone deacetylase inhibitors in
mesothelioma: clinical experience with
suberoylanilide hydroxamic acid. Clinical Lung
Cancer 2006;7(4):257-61
Phase I trial
Kulkarni P M et al
Efficacy and safety of pemetrexed in elderly
cancer patients: Results of an integrated
Integrated analysis of safety of pem from 3
different disease types
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analysis. Critical Reviews in
Oncology/Hematology 2008;67(1):64-70
Nikolinakos P and
Heymach J V.
The tyrosine kinase inhibitor cediranib for nonsmall cell lung cancer and other thoracic
malignancies. Journal of Thoracic Oncology
2008;3(6 SUPPL 2):S131-S134
NSCLC drug
Okuno S H et al
A phase 2 study of gemcitabine and epirubicin
for the treatment of pleural mesothelioma: A
north central cancer treatment study, N0021.
Cancer 2008;112(8):1772-1779
Phase II trial of gemcitabine and epirubicin –
minimal effect.
Pavlakis N and Vogelzang
N J.
An antitumour ribonuclease: Its potential role in
malignant mesothelioma. Expert Opinion on
Biological Therapy 2006;6(4):391-399
Expert opinion
Porta C et al
Raltitrexed-Oxaliplatin combination
chemotherapy is inactive as second-line
treatment for malignant pleural mesothelioma
patients
Second line treatment with Raltitrexed, phase
II and unsuccessful – trial closed due to no
response
Razak A R A et al
Retreatment with pemetrexed-based
chemotherapy in malignant pleural
mesothelioma (MPM): A second line treatment
option. Lung Cancer 2008;60(2):294-297
4 case series, second line treatement.
Scagliotti G V and
Selvaggi G.
Emerging drugs for mesothelioma. Expert
Opinion on Emerging Drugs 2007;12(1):127-37
Review and expert opinion
Simon G R et al
Pemetrexed plus gemcitabine as first-line
chemotherapy for patients with peritoneal
mesothelioma: final report of a phase II trial.
Journal of Clinical Oncology 2008;26(21):356772
About peritoneal mesothelioma
Sorensen J B et al
Cisplatin and vinorelbine first-line chemotherapy
in non-resectable malignant pleural
mesothelioma. British Journal of Cancer
2008;99(1):44-50
About cisplatin and vinorelbine – phase 11
study
Steele J P C and Klabatsa
A.
Chemotherapy options and new advances in
malignant pleural mesothelioma.[see comment].
Annals of Oncology 2005;16(3):345-51
review
Yip A Y S, Ong E Y Y and
Chow L W C.
Vinflunine: Clinical perspective of an emerging
anticancer agent. Expert Opinion on
Investigational Drugs 2008;17(4):583-591
About NSCLC
Zhang Y and Trissel L A.
Physical instability of frozen pemetrexed
solutions in PVC bags. Annals of
Pharmacotherapy 2006;40(7-8):1289-1292
About storage of pemetrexed
Zuchali P A et al
Gemcitabine and vinorelbine in pemetrexedpretreated patients with malignant pleural
mesothelioma. Cancer 2008;112(7):1555-61
Second line treatment with gemcitabine and
vinorelbine after disease progression in pts
treated with pemetrexed
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Appendix 9: Stages of Pleural Mesothelioma
Stage I – mesothelioma is present in the right or left pleura and may also
involve the diaphragm on the same side. Specifically, growth of the mass has
been restricted to only one side of the body.
Stage II – mesothelioma has spread to both of the lungs or the chest wall. In
many cases of Stage II mesothelioma, the presence of the primary mass will have
extended into the oesophagus, heart or the lymph nodes located in the chest.
Stage III – mesothelioma has penetrated the bonds of the diaphragm and has
reached the peritoneum or abdominal cavity. The cancer may have spread to the
lymph nodes outside the chest.
Stage IV – mesothelioma has spread via the blood stream to other organs in the
body such as the liver, brain or bone or to lymph nodes on the other side of the
chest.
(Ref : Butchart System)
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Appendix 10: Definitions of the phases of pharmaceutical trials
Phase 1 Clinical Drug Trial: Phase 1 clinical drug trial represents the
first test of a drug in a human population (only animal and in vitro
data are available). Phase 1 trials are designed to determine toxicity,
absorption, metabolism and safe dosage range and are limited to
relatively few subjects (20-80). Although healthy volunteers are
sometimes used, for obvious ethical reasons, Phase 1 testing is more
properly done in patients. For example, cancer chemotherapy subjects
in a Phase 1 trial have exhausted all alternative treatments and enrol
in the study hoping for therapeutic benefit. The study often involves
dose escalation until the maximum tolerated dose is established. This
means the dose is increased until toxicity occurs. Obviously, subjects
in a Phase 1 clinical trial of a toxic chemotherapeutic agent incur the
risk of death from toxicity. Although a subject may receive therapeutic
benefit from participating in a Phase 1 study, the objective in
conducting the study is primarily pharmacological in nature.
Phase 2 Clinical Drug Trial: A Phase 2 clinical drug trial is a
controlled clinical trial involving a limited number of subjects (200300). It is designed to test efficacy and obtain additional data on the
safety of the drug.
Phase 3 Clinical Drug Trial: A Phase 3 clinical drug trial is an
expanded trial (several hundred subjects) which is designed to gain
additional evidence of efficacy.
Phase 4 Clinical Drug Trial: A Phase 4 clinical drug trial is a postmarketing study of an FDA-approved drug in order to gain more
information, e.g., elucidate the incidence of a specific adverse reaction
or determine the long-term effects of the drug on morbidity and
mortality.
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