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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. Accident Compensation Corporation ii Evidence Based Brief Report 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 Accident Compensation Corporation iii Evidence Based Brief Report 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. Accident Compensation Corporation iv Evidence Based Brief Report 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. Accident Compensation Corporation v Evidence Based Brief Report Peer Review ACC appreciates external peer review for this report which has been provided by a Consultant Medical Oncologist and a Clinical Oncology Pharmacist. Accident Compensation Corporation vi Evidence Based Brief Report 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. Accident Compensation Corporation vii Evidence Based Brief Report 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 Accident Compensation Corporation viii Evidence Based Brief Report 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 Accident Compensation Corporation ix Evidence Based Brief Report 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 Accident Compensation Corporation x Evidence Based Brief Report 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 Accident Compensation Corporation xi Evidence Based Brief Report 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 Accident Compensation Corporation xii Evidence Based Brief Report Appendix 10. Definitions of phases of pharmaceutical trials………………………………105 Accident Compensation Corporation xiii Evidence Based Brief Report 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 Accident Compensation Corporation 14 Evidence Based Brief Report 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. Accident Compensation Corporation 15 Evidence Based Brief Report 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. Accident Compensation Corporation 16 Evidence Based Brief Report 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. Accident Compensation Corporation 17 Evidence Based Brief Report 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. Accident Compensation Corporation 18 Evidence Based Brief Report 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 Accident Compensation Corporation 19 Evidence Based Brief Report 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. Accident Compensation Corporation 20 Evidence Based Brief Report 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. Accident Compensation Corporation 21 Evidence Based Brief Report 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 Accident Compensation Corporation 22 Evidence Based Brief Report 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? Accident Compensation Corporation 23 Evidence Based Brief Report 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 Accident Compensation Corporation 24 Evidence Based Brief Report 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 Accident Compensation Corporation 25 Evidence Based Brief Report 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 Accident Compensation Corporation 26 Evidence Based Brief Report 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 Accident Compensation Corporation 27 Evidence Based Brief Report 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 Accident Compensation Corporation 28 Evidence Based Brief Report 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 Accident Compensation Corporation 29 Evidence Based Brief Report 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 Accident Compensation Corporation 30 Evidence Based Brief Report (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 Accident Compensation Corporation 31 Evidence Based Brief Report 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 Accident Compensation Corporation 32 Evidence Based Brief Report 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 Accident Compensation Corporation 3 33 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. Accident Compensation Corporation 34 Evidence Based Brief Report 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 Accident Compensation Corporation 35 Evidence Based Brief Report 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 Accident Compensation Corporation 36 Evidence Based Brief Report 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. Accident Compensation Corporation 37 Evidence Based Brief Report 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. Accident Compensation Corporation 38 Evidence Based Brief Report 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. Accident Compensation Corporation 39 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 Accident Compensation Corporation 40 Evidence Based Brief Report 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. Accident Compensation Corporation 41 Evidence Based Brief Report 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 Accident Compensation Corporation 42 Evidence Based Brief Report 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. Accident Compensation Corporation Consistency of 43 assessment, treatment and Evidence Based Brief Report 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 Accident Compensation Corporation 44 Evidence Based Brief Report 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. Accident Compensation Corporation 45 Evidence Based Brief Report 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, Accident Compensation Corporation 46 Evidence Based Brief Report 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. Accident Compensation Corporation 47 Evidence Based Brief Report 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. Accident Compensation Corporation 48 Evidence Based Brief Report 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 Accident Compensation Corporation 49 Evidence Based Brief Report 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. Accident Compensation Corporation 50 Evidence Based Brief Report 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. Accident Compensation Corporation 51 Evidence Based Brief Report 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 Accident Compensation Corporation 52 Evidence Based Brief Report 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 Accident Compensation Corporation 53 Evidence Based Brief Report 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 Accident Compensation Corporation 54 Evidence Based Brief Report 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 Accident Compensation Corporation 55 Evidence Based Brief Report 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. Accident Compensation Corporation 56 Evidence Based Brief Report 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 Accident Compensation Corporation 57 Evidence Based Brief Report 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. Accident Compensation Corporation 58 Evidence Based Brief Report 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. Accident Compensation Corporation 59 Evidence Based Brief Report 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 Accident Compensation Corporation 60 Evidence Based Brief Report 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 Accident Compensation Corporation 61 Evidence Based Brief Report 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 Accident Compensation Corporation 62 Evidence Based Brief Report 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 Accident Compensation Corporation 226 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 Accident Compensation Corporation 64 Evidence Based Brief Report 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. Accident Compensation Corporation 65 Evidence Based Brief Report 7 References 1. Hughes RS. Malignant pleural mesothelioma. American Journal of the Medical Sciences 2005(329):29-44. 2. Kjellstrom T. Increased mesothelioma incidence in New Zealand: the asbestos-cancer epidemic has started. New Zealand Medical Journal 2000;113(1122):485-490. 3. Department of Labour. Asbestos Exposure in New Zealand 1992-2005. Wellington, 2006. 4. Robinson BWS, Musk AW, Lake RA. Malignant Mesothelioma. Lancet 2005(366):397-408. 5. Kjellstrom T, Smartt P. Increased mesothelioma incidence in New Zealand: the asbestos-cancer epidemic has started. NZ Med J 2000;113:485-90. 6. Chapman E, Berenstein EG, Dieguez M, Ortiz Z. Radiotherapy for malignant pleural mesothelioma [Systematic Review]. Cochrane Database of Systematic Reviews 2008;2:2. 7. Dundar Y, Bagust A, Dickson R, Dodd S, Green J, Haycox A, et al. Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation. Health Technology Assessment (Winchester, England) 2007;11(1):1-90. 8. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III Study of Pemetrexed in combination with Cisplatin versus Cisplatin alone in patients with Malignant Pleural Mesothelioma. Journal of Clinical Oncology 2003;21(14):2636-2644. 9. National Institute for Health and Clinical Excellence. Pemetrexed for the treatment of malignant pleural mesothelioma. NICE technology appraisal guidance 135. London, 2008. 10. Ellis P, Davies AM, Evans WK, Haynes AE, Lloyd NS, Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidencebased C. The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 2006;1(6):591-601. 11. Hazarika M, White RM, Jr., Booth BP, Wang Y-C, Ham DYL, Liang CY, et al. Pemetrexed in malignant pleural mesothelioma. Clinical Cancer Research 2005;11(3):982-92. 12. Hazarika M, White RM, Johnson JR, Pazdur R. FDA drug approval summaries: pemetrexed (Alimta). Oncologist 2004;9(5):482-8. 13. Jassem J, Ramlau R, Santoro A, Schuette W, Chemaissani A, Hong S, et al. Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. Journal of Clinical Oncology 2008;26(10):1698-704. Accident Compensation Corporation 66 Evidence Based Brief Report 14. Janne PA, Wozniak AJ, Belani CP, Keohan M-L, Ross HJ, Polikoff JA, et al. Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program.[erratum appears in J Thorac Oncol. 2006 Sep;1(7):621]. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 2006;1(6):506-12. 15. Obasaju CK, Ye Z, Wozniak AJ, Belani CP, Keohan M-L, Ross HJ, et al. Single-arm, open label study of pemetrexed plus cisplatin in chemotherapy naive patients with malignant pleural mesothelioma: outcomes of an expanded access program. Lung Cancer 2007;55(2):187-94. 16. Santoro A, O'Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 2008;3(7):756-63. 17. Manegold C, Santoro A, O'Brien ME, Stahel RA, Nackaerts KB, Bass P, et al. Open-label study of pemetrexed alone or in combination with a platinum in chemonaive patients (pts) with malignant pleural mesothelioma (MPM): Results for the International Expanded Access Program (EAP). J Thoracic Oncol 2007;2(8 Suppl 4):S371. 18. Taylor P, Castagneto B, Dark G, Marangolo M, Scagliotti GV, van Klaveren RJ, et al. Single-agent pemetrexed for chemonaive and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 2008;3(7):764-71. 19. Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Annals of Oncology 2008;19(2):370-3. 20. Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. Journal of Clinical Oncology 2006;24(9):1443-8. 21. Ceresoli GL, Castagneto B, Zucali PA, Favaretto A, Mencoboni M, Grossi F, et al. Pemetrexed plus carboplatin in elderly patients with malignant pleural mesothelioma: combined analysis of two phase II trials. British Journal of Cancer 2008;99(1):51-6. 22. Scagliotti GV, Shin DM, Kindler HL, Vasconcelles MJ, Keppler U, Manegold C, et al. Phase II study of pemetrexed with and without folic acid and vitamin B <sub>12</sub> as front-line therapy in malignant pleural mesothelioma. Journal of Clinical Oncology 2003;21(8):1556-1561. Accident Compensation Corporation 67 Evidence Based Brief Report 23. Sorensen JB, Sundstrom S, Perell K, Thielsen A-K. Pemetrexed as second-line treatment in malignant pleural mesothelioma after platinum-based first-line treatment. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 2007;2(2):147-52. 24. Janne PA, Simon GR, Langer CJ, Taub RN, Dowlati A, Fidias P, et al. Phase II trial of pemetrexed and gemcitabine in chemotherapynaive malignant pleural mesothelioma. Journal of Clinical Oncology 2008;26(9):1465-71. 25. van den Bogaert DPM, Pouw EM, van Wijhe G, Vernhout RM, Surmont VFM, Hoogsteden HC, et al. Pemetrexed maintenance therapy in patients with malignant pleural mesothelioma. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 2006;1(1):25-30. 26. Muers MF, Stephens RJ, Fisher P, Darlison L, Higgs CM, Lowry E, et al. Active symptom control with or without chemotherapy in the 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. Accident Compensation Corporation 68 Evidence Based Brief Report 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 Accident Compensation Corporation 69 Evidence Based Brief Report 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. Accident Compensation Corporation 70 Evidence Based Brief Report 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 Accident Compensation Corporation 71 Evidence Based Brief Report 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. Accident Compensation Corporation 72 Evidence Based Brief Report 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 Accident Compensation Corporation 73 Evidence Based Brief Report WHO 5 equals Karnofsky 0 Accident Compensation Corporation 74 Evidence Based Brief Report 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. Accident Compensation Corporation 75 Evidence Based Brief Report 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. Accident Compensation Corporation 76 Evidence Based Brief Report 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 Accident Compensation Corporation 77 Evidence Based Brief Report 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 Accident Compensation Corporation 78 Evidence Based Brief Report 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$.mp. 2. (pemetrexed or alimta or raltitrexed or tomudex).af. Accident Compensation Corporation 79 Evidence Based Brief Report 3. 1 and 2 All EBM Reviews - Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR, HTA, and NHSEED (“All EBM”) 1. 1. mesothelioma$.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" Accident Compensation Corporation 80 Evidence Based Brief Report Appendix 6: Evidence tables for pemetrexed Accident Compensation Corporation 81 Evidence Based Brief Report 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. Accident Compensation Corporation 82 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? Accident Compensation Corporation 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 Accident Compensation Corporation 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 84 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 Accident Compensation Corporation 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 85 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 Accident Compensation Corporation Outcomes 86 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 Accident Compensation Corporation 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 Accident Compensation Corporation 100 Evidence Based Brief Report 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. Accident Compensation Corporation Unable to interrupt NSAIDs 101 Evidence Based Brief Report 5 Appendix 7: Evidence tables for raltitrexed Accident Compensation Corporation 102 Evidence Based Brief Report 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. Accident Compensation Corporation 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 Accident Compensation Corporation Response rate 104 Evidence Based Brief Report 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 Accident Compensation Corporation 105 Evidence Based Brief Report 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 Accident Compensation Corporation 106 Evidence Based Brief Report 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: Accident Compensation Corporation 107 Evidence Based Brief Report 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 Accident Compensation Corporation 108 Evidence Based Brief Report 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 Accident Compensation Corporation 109 Evidence Based Brief Report 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) Accident Compensation Corporation 110 Evidence Based Brief Report 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. Accident Compensation Corporation 111 Evidence Based Brief Report Accident Compensation Corporation 112 Evidence Based Brief Report