Lung Cancer (2005) 49S1, S49—S52

Prognostic factors in mesothelioma

Jeremy P.C. Steele ∗, Astero Klabatsa, Dean A. Fennell, Arben Pallaska,Mike T. Sheaff, Marie T. Evans, Jonathan Shamash, Robin M. Rudd

Mesothelioma Unit, Department of Medical Oncology, St. Bartholomew’s Hospital and Medical College,London EC1A 7BE, UK

Abstract Prognostic factors can help clinicians and patients when deciding a treat-ment plan. Patients in the best prognostic groups can be considered for more inten-smtbtlcpphcSIbcsr©

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ive or experimental therapy. Alternatively, patients in the best prognostic groupsight prefer a period of observation prior to commencement of therapy. For pa-ients with mesothelioma prognostic factors are potentially especially importantecause of the lack of a widely applicable anatomical staging system. Both the In-ernational Mesothelioma Interest Group (IMIG) and Brigham staging systems are ofimited relevance to patients not undergoing radical debulking surgery. Radiologi-al prediction of IMIG or Brigham stage is of little value. Review of the best-knownrognostic scoring systems from the EORTC and CALGB has shown that the most im-ortant predictors of poor prognosis are: poor performance status; nonepithelioidistology; male gender; low hemoglobin; high platelet count; high white blood cellount; and high lactate dehydrogenase (LDH). The EORTC model was validated att Bartholomew’s Hospital in a group of 145 patients treated in sequential phaseI chemotherapy trials. For 70 patients treated with vinorelbine, those having theest EORTC prognosis had a median survival of 19.2 months [95% C.I. = 14.7—23.7]ompared to 9.9 months [95% C.I. = 8.5—11.3] for those in the worst group. Theuggestion is that all clinical and biological factors relevant to prognosis should beecorded prospectively in mesothelioma patients selected for clinical trials.2005 Published by Elsevier Ireland Ltd.

. Introduction

rognostic factors are biological or physical char-cteristics of a patient or the patient’s cancer thatan be used to predict the outcome for the indi-idual. They are of value for the management of

* Corresponding author. Tel.: +44 207 601 7900;ax: +44 207 601 7577.

E-mail address: jeremy.steele@bartsandthelondon.nhs.ukJ.P.C. Steele).

mesothelioma because they can help the physicianto give patients a prognosis. Patients need this in-formation in order to be able to make informed de-cisions about treatment options. They may assist inthe selection of patients more likely to benefit frommore intensive treatment, especially in the contextof clinical trials [1].Recently, it has become clear that prognostic

factors may have an additional benefit: they maygive insights into the biology of the cancer being

169-5002/$ — see front matter © 2005 Published by Elsevier Ireland Ltd.oi:10.1016/j.lungcan.2005.03.009

S50 J.P.C. Steele et al.

studied, and lead to improved understanding of themolecular pathogenesis [2]. This new role for prog-nostic factors may prove to be the most importantof all.The Cancer and Leukemia Group B (CALGB) and

European Organization for Research and Treatmentof Cancer (EORTC) prognostic scoring systems arethe two most useful currently available for malig-nant mesothelioma [3,4]. These systems rate per-formance status, age, histological subtype, weightloss and hematological parameters as the most im-portant prognostic factors for malignant mesothe-lioma. In the future, molecular biological markersand DNA expression profiles may be able to giveus more insight into mesothelioma and will help inprognostication.

2. The natural history of mesothelioma

Most series have shown that the median survival fora patient with mesothelioma is between 4 and 18months. Three recent phase II chemotherapy trialswith response rates greater than 20% reported me-dian overall survivals of 6.0 months [5], 9.5 months

Survival curves were generated for subgroups de-fined by these putative prognostic factors and sur-vival comparisons were made. Patients were splitinto subgroups using an algorithm that maximizeddifferences in the survival distribution measured bythe log-rank test. A stepwise analysis generated aregression tree with successive stratification intogroups according to prognostic factor with progres-sively decreasing risk ratio.The CALGB prognostic scoring system was able

to derive various factors strongly linked with a pooroutcome for patients with mesothelioma. The mostimportant predictors of a poor prognosis were:poor PS; the presence of chest pain; the presenceof pleural involvement; breathlessness as a majorsymptom; high platelet count; significant weightloss; raised LDH; low Hb; high WBC count; age over75 years; and nonepithelioid histology. The statisti-cal analysis was able to define the best prognosticgroups as that containing patients with excellentperformance status, age less than 49 years and nor-mal hemoglobin level.

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[6] and 10.6 months [7]. The large internationalrandomised phase III trial of chemotherapy, pub-lished recently [8], reported a median survival of12.1 months for the experimental group (treatedwith pemetrexed and cisplatin) and 9.3 months forthe control arm (treated with cisplatin only). Thislarge trial included mainly good performance sta-tus patients: patients seen in a mesothelioma clinicwill have a wider variety of performance status andsome will have a much shorter or longer survivalthan these data suggest.

3. The Cancer and Leukemia Group Bprognostic scoring system

The Cancer and Leukemia Group B examined theindividual and joint effect of various pretreatmentclinical characteristics on the survival of patientswith mesothelioma treated with chemotherapy ina series of sequential phase II trials [3]. Over a 10-year period, 337 untreated patients with malignantmesothelioma were registered in phase II studies of10 different treatment regimens. The median over-all survival for patients in these trials ranged from3.9 months to 9.8 months with 1-year survival fig-ures ranging between 14% and 50%. The investiga-tors then used Cox survival models and exponentialregression trees to examine the prognostic impor-tance of various pretreatment patient characteris-tics.

esearch and Treatment of Cancerrognostic scoring system

he EORTC examined data from 204 adult pa-ients with malignant mesothelioma entered intove consecutive EORTC phase II clinical trials from984 to 1993 [4]. The drugs tested were mitox-ntrone, epirubicin, etoposide and paclitaxel. Theox model was used to assess 13 factors related toiology and disease history with respect to survival.he median survival duration was 8.4 months fromrial entry and 12.6 months measured from diagno-is.In multivariate analysis, poor prognosis was as-ociated with:

. poor performance status (1 or 2);

. high white blood cell count (≥8.3× 109/L);

. low hemoglobin level (<1 g/dL lower than nor-mal);

. probable/possible histological diagnosis ofmesothelioma (i.e. uncertain diagnosis);

. sarcomatoid histology.

Using these five factors, the EORTC classified pa-ients into two groups: a good-prognosis group (with1-year survival rate of 40%) and a poor-prognosisroup (with a 1-year survival rate of 12%). Basedn prognostic score, patients were divided into tworoups: A good-prognosis group with a score≤1.27corresponding to having zero, one or two poor

Prognostic factors in mesothelioma S51

prognostic factors) and a poor-prognosis group witha score >1.27 (corresponding to having three, fouror five poor prognostic factors). Relative to patientsin the low-risk group, the high-risk group had a rela-tive risk of 2.9 [95% C.I. = 2.0—4.1%; p < 0.001]. Themedian survival times were 10.8 months and 5.5months for the low- and high-risk groups, respec-tively. The 1-year survival rates were 40% and 12%respectively.

5. Validation of the CALGB and EORTCprognostic models by other researchgroups

5.1. St. Bartholomew’s Hospital, London,UK

Fennell et al. [9] from the mesothelioma unit of StBartholomew’s Hospital, London, UK, validated theEORTC model in a group of 145 patients treated inthree sequential phase II chemotherapy trials. Forpatients treated with single-agent vinorelbine (70patients) those predicted as having good progno-sis by the EORTC system had a median survival of1pm

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the Cox proportional hazards regression model andshowed that the favorable prognostic factors wereepithelioid subtype; age less than 60 years; and fe-male gender.What is interesting about these studies is the im-

portance of systemic biological measures of diseaseactivity as prognostic factors. Low hemoglobin, highwhite blood cell count, elevated platelets and el-evated LDH were shown to be important by theCALGB and high white blood cell count was impor-tant in the EORTC system. These parameters arelikely to be markers of disease activity and mayprove less subjective than some of the prognos-tic factors described previously such as age andapproximate clinical stage. Specialists treating pa-tients with mesothelioma are aware of the preva-lence of systemic symptoms: weight loss, anorexia,lethargy and night sweats are all frequently seenand refute the common view that mesothelioma is a‘localised’ disease that metastasizes only in the endstages. It is likely that these constitutional symp-toms reflect the cytokine-rich milieu of mesothe-lioma as described by Fitzpatrick [12]. These re-ports may represent real progress in our under-standing of malignant mesothelioma.

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9.2 months [95% C.I. = 14.7—23.7] and those in theoor-prognosis group had a median survival of 9.9onths [95% C.I. = 8.5—11.3].

.2. Glenfield Hospital, Leicester, UK

dwards et al. [10] from Leicester, UK, published aetrospective analysis of a series of 142 mesothe-ioma patients. The authors derived EORTC andALGB prognostic groups, plotted Kaplan—Meierurvival and calculated survival rates from life ta-les to see if these prognostic groups predictedutcome. The prognostic significance of cell type,ow Hb, high WBC, performance status, and gen-er were identified in a multivariate model. Theverall median survival was 5.9 months. Median 1-nd 2-year survival data within prognostic groupsrom Leicester were comparable to the EORTC andALGB series.

. German mesothelioma register

urther observational data has been reported fromhe German mesothelioma register by Neumann etl. [11]. From 1987 to 2000, the German registerecorded 4455 patients with malignant mesothe-iomas. Survival data were only available for 498atients of whom 156 survived for more than twoears. They undertook a multivariate analysis using

. Novel molecular predictors ofrognosis

ecent publications have reported possible bio-ogical correlates with prognosis in mesothelioma.any of these markers are overexpressed in ma-ignant mesothelioma and often there are statisti-al correlations with clinical outcome. The insightsrovided by such recent data are exciting and sug-est real therapeutic progress may not be far away.

.1. Glucose transporter-1 (GLUT-1)

lucose transporter-1 (GLUT-1) is an example ofmolecule which has recently been shown toorrelate with outcome [13]. Mesothelioma isharacterized by resistance to cytotoxic therapyependent in part on defective apoptosis induc-ion [2]. Apoptosis and glycolysis are linked. GLUT-1as measured in 51 archival mesothelioma spec-mens by immunohistochemistry. GLUT-1 intensitynd extent were scored and the impact on responseate, progression-free survival and overall survivalere studied. Comparisons were made with theORTC prognostic score. GLUT-1 was expressed in2 specimens (23%). No association between GLUT-levels and response rate was observed, how-ver, a trend towards shorter progression-free sur-

S52 J.P.C. Steele et al.

vival was observed in GLUT-1 positive patients.GLUT-1 overexpression predicted for poor clinicaloutcome at least as efficiently as the EORTC prog-nostic score 2.Other markers that are associated with clinical

endpoints in mesothelioma include cyclooxygenase-2 (COX-2) [14]; cyclin-dependent kinase inhibitorp27 [15,16]; MIB-1 [17]; angiogenic cytokines [18];glycoprotein 90K [19].

8. Summary

Prognosis in mesothelioma can be predicted bywell-validated parameters based on the EORTC andCALGB scoring systems. These distinct, but closely-related systems, have clarified previous contradic-tory data. The most important poor-prognosis pre-dictors are poor performance status, nonepithe-lial histology, male gender, low hemoglobin, highplatelet count, high white blood cell count andhigh LDH. In addition to prognostic information,these systems have led to insights into the biologyof mesothelioma—–in particular, the possible roleplayed by cytokine networks in the symptoms ex-

[5] Middleton GW, Smith IE, O’Brien ME, Norton A, Hickish T,Priest K, et al. Good symptom relief with palliative MVP(mitomycin-C, vinblastine and cisplatin) chemotherapy inmalignant mesothelioma. Ann Oncol 1998;9:269—73.

[6] Byrne MJ, Davidson JA, Musk AW, Dewar J, van Hazel G, BuckM, et al. Cisplatin and gemcitabine treatment for malignantmesothelioma: a phase II study. J Clin Oncol 1999;17:25—30.

[7] 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.

[8] 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.

[9] Fennell DA, Parmar A, Shamash J, Evans MT, Sheaff MT,Sylvester R, et al. Statistical validation of the EORTCprognostic model for malignant pleural mesotheliomabased on three consecutive phase II trials. Lung Cancer2003;41(Suppl 2):S12.

[10] Edwards JG, Abrams KR, Leverment JN, Spyt TJ, Waller DA,O’Byrne KJ. Prognostic factors for malignant mesotheliomain 142 patients: validation of CALGB and EORTC prognosticscoring systems. Thorax 2000;55:731—5.

[11] Neumann V, Rutten A, Scharmach M, Muller KM, FischerM. Factors influencing long-term survival in mesotheliomapatients-results of the German mesothelioma register. IntArch Occup Environ Health 2004;77:191—9.

[12] Fitzpatrick DR, Peroni DJ, Bielefeldt-Ohmann H. The role of

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perienced by patients.Prognostic factors may, at last, not simply al-

low us to predict outcomes for some patients com-pared to others, but help us understand mesothe-lioma. Numerous molecular markers of prognosisare under investigation. Overexpression of variousproteins has been shown to correlate with clinicaloutcomes in the source patients. Understanding theimportance of these markers in prognosis should al-low targeted treatments to be developed.

References

[1] Steele JP, Rudd RM. Malignant mesothelioma: predictors ofprognosis and clinical trials. Thorax 2000;55:725—6.

[2] Fennell DA, Rudd RM. Defective core-apoptosis signaling indiffuse malignant mesothelioma: opportunities for effec-tive drug development. Lancet Oncol 2004;5:354—62.

[3] Herndon JE, Green MR, Chahinian AP, Corson JM, SuzukiY, Vogelzang NJ. Factors predictive of survival among337 patients with mesothelioma treated between 1984and 1994 by the Cancer and Leukemia Group B. Chest1998;113:723—31.

[4] Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Post-mus PE, Giaccone G. Prognostic factors in patients withpleural mesothelioma: the European Organization for Re-search and Treatment of Cancer Experience. J Clin Oncol1998;16:145—52.

growth factors and cytokines in the tumorigenesis and im-munobiology of malignant mesothelioma. Am J Respir CellMol Biol 1995;12:455—60.

13] Fennell DA, Klabatsa A, Sheaff MT, Steele JP, Evans MT,Strefford JC, et al. Identification of glucose transportertype 1 overexpression as a predictor of survival in pa-tients with malignant pleural mesothelioma. J Clin Oncol2004;22(14S):7199.

14] Edwards JG, Faux SP, Plummer SM, Abrams KR, Walker RA,Waller DA, et al. Cyclooxygenase-2 expression is a novelprognostic factor in malignant mesothelioma. Clin CancerRes 2002;8:1857—62.

15] Beer TW, Shepherd P, Pullinger NC. p27 immunostain-ing is related to prognosis in malignant mesothelioma.Histopathology 2001;38:535—41.

16] Bongiovanni M, Cassoni P, De Giuli P, Viberti L, Cappia S,Ivaldi C, et al. p27(kip1) immunoreactivity correlates withlong-term survival in pleural malignant mesothelioma. Can-cer 2001;92:1245—50.

17] Comin CE, Anichini C, Boddi V, Novelli L, Dini S. MIB-1 prolif-eration index correlates with survival in pleural malignantmesothelioma. Histopathology 2000;36:26—31.

18] Kumar-Singh S, Weyler J, Martin MJ, Vermeulen PB, VanMarck E. Angiogenic cytokines in mesothelioma: a studyof VEGF, FGF-1 and -2, and TGF beta expression. J Pathol1999;189:72—8.

19] Strizzi L, Muraro R, Vianale G, Natoli C, Talone L, CatalanoA, et al. Expression of glycoprotein 90K in human malignantpleural mesothelioma: correlation with patient survival. JPathol 2002;197:218—23.