Considered Judgement Form
This form is a checklist of issues that may be considered by the Purchasing Guidance Advisory Group when making
purchasing recommendations.
Meeting date: 28 October 2009
Topic: Pemetrexed for the treatment of malignant pleural mesothelioma (MPM)
Background and Purpose:
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.
1. Effectiveness, Volume of Evidence, Applicability /Generalisability and Consistency
Comment here on the extent to which the service/product/ procedure achieves the desired outcomes. Specific reference needs to be
made to safety. Report number needed to treat and harm where possible, report any issues concerning the quantity of evidence and its
methodological quality and the extent to which the evidence is directly applicable or generalisable to the New Zealand Population, and
the degree of consistency demonstrated by the available evidence. Where there are conflicting results, indicate how the group formed a
judgement as to the overall direction of the evidence
Two systematic reviews and one randomised controlled trial (EMPHACIS) 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.
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.
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2. Cost
Comment on any economic costs associated with this service, product or procedure
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
Funding for pemetrexed represents 10% of ACC’s pharmaceutical budget.
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)
3. Clinical impact
Comment on the clinical impact e.g. size of population, magnitude of effect, relative benefit over other management options,
resource implications, balance of risk and benefit.
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 age. 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). 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 1992-2005 is 164 cases (only 12
cases a year).
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 MPM. 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.
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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.
Pemetrexed:
Effectiveness - The best available evidence for survival using pemetrexed plus cisplatin is 12.1
months compared to cisplatin alone of 9.3 months from the EMPHACIS RCT. A weaker study reported
survival at 10.8 months for pemetrexed plus cisplatin but with no comparison group15. 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% to 16.3% (and 12.1% in those
who had previously received chemotherapy), neither result being strongly evidence based. The
response rate for pemetrexed plus cisplatin ranged from 26.3% to 41%. In the EMPHACIS RCT trial,
of those who responded to treatment with pemetrexed and cisplatin, 87% had done so within four
cycles.
Safety - 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 supplemented.
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 gained.
A model based on the EMPHACIS RCT 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).
Quality of life - The EMPHACIS RCT 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 alone.
Raltitrexed:
Effectiveness - 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 alone. The response rate with raltitrexed
and cisplatin was 23.6% and cisplatin alone 13.6%. Raltitrexed monotherapy had a response rate of
20.8%.
Safety - 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 often in the combination
treatment group. Fatigue, nausea and vomiting were also more common in the combination arm.
When raltitrexed was used alone there was no grade 4 neutropenia and grade 3 affected only 13% of
participants, leucopenia 4% and fatigue 8%.
Cost effectiveness - There were no studies identified that investigated the cost effectiveness of
raltitrexed.
Quality of life - In the RCT 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
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scales over time. Therefore quality of life was not impacted by treatment with raltitrexed/cisplatin.
4. Equity, Maori Health, Pacific Health, Acceptability
Comment on the extent to which the service, product or procedure reduces disparities in health status (equity of access,
resources, health outcome), is consistent with the treaty of Waitangi and encourages Maori/ Pacific participation in providing
and using service, product and procedures, and is consistent with values and expectations of New Zealanders.
There is under reporting of MPM among Maori although they are over represented in jobs that may
have increased exposure to asbestos. Also the benefits and risks of anticancer agents may differ
between populations. None of the studies in this review involve New Zealand participants.
5. Possible Purchasing Options
List the possible purchasing options.
1. Continue to purchase pemetrexed as currently purchased
2. Follow the guidance provided by the National Institute for Health and Clinical Excellence (NICE)
which states 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.
3. Purchase raltitrexed
6. Evidence Statements
Summarise the advisory group’s synthesis of evidence relating to this service, product or procedure, taking the above factors into
account, and indicate the evidence level that applies.
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’s efficacy and
safety.
7. Purchasing Recommendations
What recommendation(s) does the advisory group draw from this evidence?
Pemetrexed continue to be purchased on a case by case basis using the guidance provided by the
National Institute for Health and Clinical Excellence (NICE), which restricts pemetrexed use to those
patients with MPM 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.
The Evidence Based Healthcare group continue to monitor the use of raltitrexed in Ontario, Canada.
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