Lung Cancer (2005) 49S1, S113—S116

Clinical trials in malignant pleural mesotheliomain Australasia

Anna K. Nowak ∗

Department of Medical Oncology, University of Western Australia, 4th Floor, G Block, Sir CharlesGairdner Hospital, Hospital Avenue, Nedlands, WA 6009, Australia

KEYWORDSMalignantmesothelioma;

Summary Australasia has a strong record in clinical trials in malignant pleuralmesothelioma (MPM), driven by the relatively high incidence of this disease in theregion. Two current and three proposed trials in mesothelioma in this region are

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discussed, covering the diverse clinical scenarios of diagnosis and staging, health-related quality of life, maintenance therapy, prediction of response and combinedmodality treatment.© 2005 Elsevier Ireland Ltd. All rights reserved.

ustralasia has a strong record in clinical trials inalignant pleural mesothelioma (MPM), driven byhe relatively high incidence of this disease in theegion. Australia was the world’s highest per capitaser of asbestos in the 1950s, mining asbestos forver 100 years, and consequently, has the world’sighest incidence of mesothelioma with more than5 cases per million population per year in 19971]. Western Australia has the highest incidencen the country (53 per million per year in 1997),lthough greater absolute numbers of cases comerom the states of New South Wales and Victoria,ith higher populations. The mining town of Wit-enoom, in the north of Western Australia, was anmportant source of crocidolite asbestos in Aus-ralia, with nearly 7000 employees between 1943nd 1966, and nearly 5000 other residents not di-ectly employed by the mine [2]. The clinical trialsrogram in Perth continues to enrol patients who

lived and worked in this town. The incidence ofmesothelioma is predicted to peak in around 2010in Australia [1].

Synopses of current and proposed trials aregiven, with details of the rationale and aims of eachtrial, the trial design and current status. There areno currently accruing or planned trials in mesothe-lioma prevention in this region, and a further pro-posed chemotherapy protocol is currently confiden-tial.

1. Active current trials

1.1. Diagnosis and staging: ‘‘use of FDG PETin the assessment of tumour extent andtumour response in pleural mesothelioma’’

It is often difficult to define the extent of dis-

* Tel.: +61 8 9346 3841; fax: +61 8 9346 3390.E-mail address: anowak@cyllene.uwa.edu.au.

ease at presentation, especially with small volume,minimally symptomatic disease. Survival may be

169-5002/$ — see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.lungcan.2005.03.021

S114 A.K. Nowak

increased by combined modality treatment in se-lected patients with localised disease [3]. How-ever, many of these patients go on to developdisease outside of the resected area. More sen-sitive and specific staging may help select pa-tients for combined modality treatment by exclud-ing those with undetected contralateral diseaseor distant metastases. Furthermore, chemotherapyfor mesothelioma is effective but toxic. Many clin-icians are reluctant to try chemotherapy in pa-tients with asymptomatic or non-measurable dis-ease, as they cannot gauge if treatment is ef-fective. If we could predict response at an earlytime point using FDG PET scanning, patients couldhave a trial of treatment, which could be stoppedif there was early progression or no response.Also, symptomatic patients might accept treat-ment more readily if response could be pre-dicted after just one or two cycles of chemother-apy.

The trial of PET scanning in MPM has two parts:

Part A: assessment of disease extent using FDG PETscanning in newly diagnosed patients withpleural mesothelioma. The aims of Part Aare:

B, in addition, patients must also be suitable andplanned for treatment with any chemotherapy, re-gardless of whether they have measurable or non-measurable disease. This trial is active at the PerthMesothelioma Centre, Sir Charles Gairdner Hospi-tal, in Western Australia, and has accrued morethan 45 patients to date.

1.2. Quality of life assessment: ‘‘use of FDGpet in the assessment of tumour extent andtumour response in pleuralmesothelioma—–HRQL sub-study’’

There is little published data on health-relatedquality of life (HRQL) in pleural mesotheliomato date. Studies including HRQL questionnaireshave all included patients with advanced dis-ease who are on chemotherapy and are al-ready symptomatic [4—6]. Furthermore, thesestudies have stopped evaluating HRQL or suf-fered from poor compliance once chemother-apy has ceased. Hence, there is little informa-tion on HRQL in patients without measurable dis-ease, with progressive disease, or after comple-tiswsm

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• to define the PET appearance in thosewith masses visible on CAT scan and thosewith effusion only;

• to examine the incidence and extent ofcryptic metastatic disease compared toroutine CAT scanning;

• to assess the relationship of histologicalsubtype and PET appearance;

• to evaluate whether the PET appearanceprovides prognostic information.

Part B: assessment of objective response usingFDG PET scanning patients with pleuralmesothelioma being treated with combi-nation chemotherapy. The aims of Part Bare:• in patients with measurable disease, toassess the sensitivity/specificity of FDGPET scan changes after one cycle ofchemotherapy to predict response, timeto progression (TTP) and overall survival(OS);

• in patients with non-measurable disease,to evaluate changes in FDG PET scan af-ter one cycle of chemotherapy and tocorrelate those changes with TTP afterfour cycles of therapy and OS.

All consenting newly diagnosed patients withpleural mesothelioma, who have not had anti-tumour treatment, and have no contraindication toFDG PET scanning are eligible for Part A. For Part

ion of treatment. Functional status declines dur-ng chemotherapy, despite improvement in someymptoms [5]. It is unclear whether patientsith early disease and few symptoms experienceimilar declines in functional status on treat-ent.The patient disease and treatment assessment

orm (Pt DATA Form) is a novel HRQL tool developedor use in routine clinical practice and clinical trialsy Dr. Martin Stockler (University of Sydney). It hasot previously been used in pleural mesothelioma,ut is a transparent tool, which will allow identifi-ation of individual symptoms of importance in bothndividuals and populations.This study is using the EORTC core quality of life

uestionnaire (QLQ-C30, Version 3.0) and lung can-er module (LC-13, Version 3.0) and the Pt DATAorm to assess HRQL at intervals before, during andfter chemotherapy.The aims of this study are to assess baseline

RQL in patients with MPM from patients with andithout measurable disease at baseline, to com-are baseline HRQL of these two groups; to as-ess change in HRQL during treatment in these tworoups; to validate aspects of the Pt DATA Form inPM, and to further validate the EORTC instrumentsn this disease.This trial is active at the Perth Mesothelioma

entre, Sir Charles Gairdner Hospital, in West-rn Australia, with accrual of more than 45atients.

Mesothelioma trials in Australasia S115

2. Proposed trials

2.1. Maintenance therapy: ‘‘A placebocontrolled randomized phase III study ofthalidomide as maintenance therapy inpatients with malignant pleuralmesothelioma with stable disease orremission after first-line platinum basedchemotherapy’’

There is pre-clinical evidence for both VEGF andb-FGF mediated angiogenesis inhibition by thalido-mide. A modest objective response to thalidomidewas seen in a non-randomised parallel phase II trial(6%), and similar proportions of 1 year survivorsand patients with stable disease for more than6 months were seen with thalidomide alone andwith the combination of thalidomide, cisplatin andgemcitabine (31% versus 39% and 27% versus 35%).Twenty-seven percent of patients on thalidomidehad stable HRQL for more than 6 months, and thedrug was well tolerated [7]. In this proposed trial,patients who have achieved either an objective re-sponse or stable disease on platinum-based com-bination chemotherapy would be randomized in addtttct[tsapm

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identified as unlikely to respond to conventionaltreatment could also be offered clinical trials ofnovel investigational agents as first line therapy.Similar exploratory studies have been performedin breast cancer and other cancers using gene mi-croarray to identify gene sets to predict responseto chemotherapy. Multigene models can predictresponse to neo-adjuvant chemotherapy in earlybreast cancer, and further large trials are currentlyplanned.

This study aims to determine markers to bet-ter predict response to chemotherapy in pleu-ral mesothelioma. It is designed as a multicen-tre, single-arm correlative study collecting clini-cal information and tumour specimens from pa-tients with malignant mesothelioma undergoingstandard or investigational chemotherapy. Patientswith any stage and histological subtype of malig-nant mesothelioma who are planned for treatmentwith chemotherapy will be eligible. Standard as-sessments including clinical examination, imagingand collection of demographic and prognostic datawill be performed and participants would then un-dergo a pre-treatment core biopsy to obtain RNA-preserved tissue for cDNA microarray studies, fol-lcwfttnbppT

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ouble blind fashion to either thalidomide 100mgaily, or an identical placebo, for 1 year or un-il disease progression. The aims of this study areo compare progression free survival between thereatment and control groups. Study endpoints in-lude time to progression; overall survival; objec-ive response (using the Modified RECIST criteria8]); HRQL (using the Modified Lung Cancer Symp-om Scale); lung function tests; serum VEGF anderum IL-6R. One hundred and twenty patients perrm will be accrued in order to detect a 50% im-rovement in time to progression from 5 to 7.5onths. This study is not yet active.

.2. Prediction of response: ‘‘a multicentreustralasian study to identify and evaluatearkers of response to chemotherapy inalignant mesothelioma’’

hilst most patients with mesothelioma will not re-pond to chemotherapy, there is no way of iden-ifying who will benefit without a trial of treat-ent. All commonly used regimens are toxic. Clin-cal and laboratory parameters have been unhelp-ul in predicting response in the limited datasetsvailable. The ability to predict who will respondo treatment may be even more important whene consider treating patients with non-measurableisease, or when chemotherapy is used adjuvantlys part of combined modality treatment. Patients

owed by chemotherapy according to local clini-al practice. Patients on investigational protocolsould also be eligible. Patients would be assessedor response according to the modified RECIST cri-eria [8]. Post-treatment core biopsies would beaken after four treatment cycles or after the fi-al cycle of chemotherapy. All biopsy sites woulde prophylactically irradiated. The proposed sam-le size is 100, with a ‘learning set’ comprising 75atients, and a ‘validation set’ of the remaining 25.his study is not active.

.3. Combined modality therapy: ‘‘aeasibility study of post-operativeadiotherapy for malignant pleuralesothelioma’’

ased on the encouraging results for post-operativeadiotherapy seen in recent studies [9,10], it wasroposed that the Trans Tasman Radiation Oncol-gy Group (TROG) join with an EORTC initiative toffer post-operative mesothelioma patients wholepsilateral thorax radiotherapy in a phase II study.atients would have three cycles of chemother-py with pemetrexed and cisplatin, followed byxtrapleural pneumonectomy. They would then beandomised to IMRT or no post-operative radiother-py. The techniques for this trial are currently beingiloted at Royal Prince Alfred Hospital, Sydney.

S116 A.K. Nowak

3. The Australasian Lung Cancer TrialsGroup (ALTG)

The conduct and planning of clinical trials inmesothelioma in Australia will be greatly facilitatedby the recent formation of the Australasian LungCancer Trials Group (ALTG). The inaugural meetingof the group was in Sydney in February 2004. Fullmembership is open to medical and non-medicalpersons active in and interested in the conduct ofAustralian clinical trials in lung cancer. The missionstatement of the ALTG is to ‘‘reduce the incidence,morbidity and mortality of lung cancer in Australiaand New Zealand through the co-ordination and fa-cilitation of high quality clinical research’’. Thisnew group is likely to play an important role in clin-ical trials in mesothelioma in this region.

References

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[2] Hansen J, de Klerk N, Musk AW, Hobbs MS. Envi-

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[4] Nowak AK, Stockler MR, Byrne MJ. Use of the EORTCQLQ-C30 and LC13 in a study of combination chemother-apy for pleural malignant mesothelioma: feasibility,validity and baseline HRQL. J Clin Oncol 2004;22:3172—80.

[5] Steele JP, Shamash J, Evans MT, Gower NH, TischkowitzMD, Rudd RM. Phase II study of vinorelbine in pa-tients with malignant pleural mesothelioma. J Clin Oncol2000;18:3912—7.

[6] Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C,Kaukel E, Ruffie P, et al. Phase III study of pemetrexedin combination with cisplatin versus cisplatin alone in pa-tients with malignant pleural mesothelioma. J Clin Oncol2003;21:2636—44.

[7] Pavlakis N, Abraham R, Harvie R, Brock C, Bell D,Wheeler H. Thalidomide alone or in combination withcisplatin/gemcitabine in malignant pleural mesothelioma(MM): interim results from a parallel phase II study. LungCancer 2003;41(Suppl. 2):11.

[8] Byrne MJ, Nowak AK. Modified RECIST criteria for assess-ment of response in malignant pleural mesothelioma. AnnOncol 2004;15:257—60.

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