British Journal of Cancer (1996) 74, 961-963
© 1996 Stockton Press
All rights reserved 0007-0920/96 $12.00
Paclitaxel for malignant pleural mesothelioma: a phase II study of the
EORTC Lung Cancer Cooperative Group
J van Meerbeeck', C Debruyne2, N van Zandwijk3, PE Postmus4, MC Pennucci5,
F van Breukelen6, D Galdermans7, H Groen8, P Pinson9, M van Glabbeke2, E van Marck1 and
'University of Antwerp, Belgium; 2EORTC Data Center, Brussels, Belgium; 3Nederlands Kankerinstituut, Amsterdam, The
Netherlands; 4Free University Hospital, Amsterdam, The Netherlands; SIstituto Nazionale per la Ricerca sul Cancro, Genoa, Italy;
6Spaarne Ziekenhuis, Haarlem, The Netherlands; 7Algemeen Ziekenhuis Middlelheim, Antwerp, Belgium; 8Akademisch Ziekenhuis
Groningen, Groningen, The Netherlands; 9Universitair Ziekenhuis Gent, Ghent, Belgium.
chemotherapy-naive patients with malignant pleural mesothelioma. Paclitaxel was given intravenously at a dose
of 200 mg m-2, as a 3 h infusion every 3 weeks, after standard premedication with corticosteroids and
antihistamines. This regimen was well tolerated, with <4% of cycles resulting in severe toxicity. No major
objective responses were observed and ten patients had stable disease. Median survival time was 39 weeks and
the 1 year survival rate was 30%. In conclusion, paclitaxel at the dose and schedule investigated in this trial
had no major activity in the treatment of malignant pleural mesothelioma.
The EORTC Lung Cancer Cooperative Group undertook a phase II study of paclitaxel in 25
Keywords: paclitaxel; malignant pleural mesothelioma
Malignant mesothelioma is almost invariably a lethal tumour
of the pleura or the peritoneum (ratio 2.5: 1); it is linked to
asbestos exposure and its incidence is steadily increasing (De
Klerk and Armstrong, 1992). Diagnosis requires large biopsy
samples and exclusion of metastatic tumours (Henderson et
al.,1992). Computed tomography (CT)
staging the extent of disease. In most studies, Butchart's
modified staging system
pathological findings; however, recently a TNM classification
has been approved and a conversion table from Butchart's to
the UICC staging system proposed (Langlois and Henderson,
1992; UICC, 1992; Boutin et al., 1993).
Survival of untreated patients is poor with a median of less
12 months, but with sporadic long-term survivors.
Prognosis is influenced by histological subtype, performance
score and disease extent at diagnosis (Boutin et al., 1993;
Pisani, 1988; Calavrezos et al., 1988; van Meerbeeck, 1994).
Surgery and radiotherapy have little impact on survival in
malignant pleural mesothelioma (Rush et al., 1991; Ball and
Cruickshank, 1990). Numerous chemotherapeutic agents have
been tested but results have generally been disappointing.
Literature reviews indicate some activity for anthracyclines
considered the single agent with the highest activity, ranging
from 14% to 40%, resulting in a median survival of 14 months
(Kraruf-Hansen and Hansen, 1991; Musk et al., 1992).
The Lung Cancer Cooperative Group (LCCG) of the
malignant pleural mesothelioma with mitoxantrone, epirubi-
cin and etoposide (van Breukelen et al., 1991; Mattson et al.,
1992; PE Postmus, unpublished results). None of these drugs
obtained more than a 15% response rate.
several tumour types, such as ovarian cancer, breast cancer
and non-small-cell lung cancer (Rowinsky and Donehower,
1995). The mechanisms of action and resistance, toxicity and
(Rowinsky et al., 1993). Here we report the results of a
is used, based on surgical and
or in combination chemotherapy.
a new drug with anti-tumour activity in
paclitaxel in the treatment of chemotherapy-naive patients
with malignant pleural mesothelioma.
II study of the EORTC-LCCG with
Patients and methods
Patients with histologically confirmed malignant mesothelio-
ma of thepleural
cavity who had
chemotherapy were accrued into this study. Pathology was
reviewed centrally. Tumour extension had to be measurable
and classified according to the UICC-TNM atlas (UICC,
1992). Pleural effusion alone was not accepted as evaluable
provided no cytotoxic drugs were applied. Patients had to
be older than 18 years and younger than 75 years, with a life
expectancy of more than 3 months; WHO performance status
count>2 x 109 1 -',
count> I00 x 109 1 '),
(bilirubin level<1.5 times normal), and renal (creatinine
clearance>60 ml min-'
functions were required. At least 4 weeks were to have
elapsed since any prior surgery or radiation therapy. Patients
with symptoms or signs of metastases in the central nervous
system and those with a recent history of cardiac disease or
peripheral polyneuropathy were excluded. Written informed
consent from each patient had to be obtained before patient
All patients were premedicated with oral dexamethasone
20 mg 12 and 6 h before paclitaxel and with diphenhydra-
mine 50 mg and ranitidine 50 mg (or cimetidine 300 mg)
intravenously 30 min before each paclitaxel infusion. A dose
of 200 mg m-2 paclitaxel (Taxolg, Bristol-Myers Squibb,
Brussels, Belgium) was diluted in 1000 ml of 5% dextrose in
water (or normal saline) and administered over 3 h in non-
polyvinylchloride containers with micropore
counts were checked weekly after administration, and ECG
Treatment cycles were repeated every 3 weeks, provided
toxic effects were not prohibitive and there was no clinical
evidence of tumour progression. No dose escalation of
was permitted. Doses
175 mg m-2 in the event of >7 days neutropenia grade 3
or more, febrile neutropenia or thrombocytopenia > grade 3.
or creatinine, 1.5
to be reduced
University Hospital, 1117 de Boelelaan, HV 1081 Amsterdam, The
Received 2 February 1996; revised 10 April 1996; accepted 19 April
Paclitaxel for malignant mesothelioma
J van Meerbeeck et al
Paclitaxel was to be discontinued for more than grade 2
treatment delay of >
continued unless tumour progression, death, patient refusal
or unacceptable toxicity developed, up to a maximum of ten
Tumour response was assessed every three cycles and at
the end of treatment, according to WHO criteria (EORTC,
1994). The use of CT scans was mandatory for evaluation of
intrathoracic target lesions. Toxicity was scored according to
the common toxicity criteria of the NCI completed by the
NCIC (EORTC, 1994). This study was planned according to
the two-stage Gehan design aiming at rejecting a drug with a
response rate below 20%, and evaluating the response rate
with a standard error inferior to 10% (Simon, 1989). The
Kaplan-Meier method was used to estimate overall survival
and duration of stabilisation (Kaplan and Meier, 1958).
Between April and October 1993, 25 patients were registered
into the study from eight institutes in Europe. Of these, one
refused to start treatment and no information was received
and one was ineligible because of lack of measurable disease.
The characteristics of 24 registered patients (excluding the
patient never treated) and their tumours are listed in Table I.
The disease was confined to the ipsilateral pleural cavity in
half of the patients. The response and toxicity analysis is
further restricted to the 23 eligible patients.
A total of 128 cycles of paclitaxel were administered. The
median number of cycles per patient was four (range 2-10),
with ten patients receiving at least six cycles. One patient
received only two cycles because of early death owing to
malignant disease. No dose reductions occurred;
patients one cycle had to be delayed, but this was not drug
related. Paclitaxel at this dose and schedule resulted in only
moderate toxicity. Table
occurred across the cycles. Neutropenia grade 3 or more was
the most frequent severe toxicity, appearing in 4% of cycles.
neutropenia. Median white blood cell (WBC) nadir count
for all cycles was 4.2 x 109 1 -'. Overall, 17 patients (74%)
developed peripheral neuropathy: the grade of neurotoxicity
increased with increasing number of cycles.
occurring after the fourth cycle were always grade >2 and
the cause for treatment discontinuation in one patient. All
severe neurotoxicities lasted for at least 5 months after
treatment discontinuation, or until death. Two-thirds of the
patients developed myalgia and/or
II summarises the toxicities that
because of febrile
neurological toxicity, this side-effect occurred from the first
course and was not cumulative. Alopecia, anorexia and
nausea were common but not severe. The only episode of
oesophagitis. Seven patients developed
reaction, which was never severe. No cardiac toxicity was
All eligible patients were assessable for response. One
patient died due to malignant disease before response could
be evaluated. There
confidence interval 0% -15%).
Because of the rapid accrual into the study,
infeasible to apply the two-step design as planned, and more
patients were entered than actually necessary to exclude a
during chemotherapy, while the remaining 12 (52%) showed
disease progression. The median duration of stabilisation was
30 weeks (range 18-63 weeks). The median survival time was
9 months, and the 12 and 18 month survival rates were 30%
and 10% respectively (not shown).
no major objective
rate 0%; 95%
rate. Ten patients (44%) remained stable
Most published series of malignant pleural mesothelioma
percentage of long-term survivors is <5%, and it is doubtful
whether any treatment alters the natural history of the
disease. Disease extent, performance status and histological
subtype appear to be the most important prognostic factors
in this disease (van Meerbeeck, 1994). For the majority of
patients systemic therapy can be considered at some time. In
a review of published
chemotherapy studies and 9% of combination chemotherapy
regarding the observed activity (Kraruf-Hansen and Han-
sen, 1991). The majority of the pooled results, however, were
inconclusive, as most studies enrolled only a few patients and
the evaluation procedures were not accurate. Because of the
inefficacy of currently available drugs, most authors feel that
clinical studies in malignant mesothelioma should focus on
phase II trials with new drugs (Vogelsang, 1992; Kraruf-
One of the greatest problems in the interpretation of the
efficacy of a treatment in this disease is the adequate evaluation
of response. In many of the older studies, this was done on
conventional chest films. Only sequential use of CT scans or
In this study, no therapeutic activity of paclitaxel against
mesothelioma could be observed at a dosage and schedule
a median survival time of less than
series, only 11%
resonance imaging (MRI) may provide useful
are commonly employed in untreated patients. The
Patient and tumour characteristics in 24 registered and
Median age (range), years
Performance status (WHO)
Toxicities (according to CTC) encountered in 23 eligible
aThe highest CTC grade for each patient is reported. bHSR,
P bkwfo Download full-text
J van Meerbeeck et i
median survival time of 9 months is similar to other phase H
studies in this tumour. In a similar study, preliminary results
reported two partial regressions in 15 malignant mesotheio-
ma patients treated with paclitaxel at a dose of 250 mg m-2
as a 24 h infusion (Vogelsang et al., 1994). The question
arises whether this modest activity is due to the higher dose,
to the 24 h infusion or simply to differences in patients'
characteristics. In refractory ovarian cancer it was observed
that 24 h infusion produced more myelosuppression but did
not yield a higher response. The maximum tolerated dose
(MTD) of pacitaxel recommended for phase H studies, when
administered as a 3 h infusion, is 210 mg m-2, myelosuppres-
sion being dose limiting (Schiller et al., 1994). The MTD of
paclitaxel administration with CSF support is 250 mg m-2,
neurotoxicity being dose limiting (Schiller et al., 1994). The
toxicity findings of the present study are similar to other
studies employing 3 h infusions of pacitaxel. Interestingly, in
this study no severe hypersensitivity reaction or cardiac
Cytoplasmic immunoreactivity for P-170 glycoprotein has
been described in the majority of mesothelioma specimens in
one study (Ramaelet
functions as a drug efflux pump and is associated with the
al., 1992).P-glycoprotein (P-gp)
multidrug-resistance phenotype. Whether this mechanism of
drug resistance contributes to resistance to paclitaxel in
malignant mesothelioma remains speculative. Paclitaxel
however, a substrate of P-glycoprotein and overexpression of
P-gp has been shown to be responsible for resistance to
paclitaxel in mammalian cell lines (Gupta, 1993).
In conclusion, pacitaxel was well tolerated at this dose
pleural mesothelioma. The absence of major
objective responses does not warrant further testing of
pacitaxel in this disease.
This study was partly financially supported by Bristol-Myers
Squibb. Additional investigators who took part in this study are:
Belgium, J Bockaert (Mechelen), M Delanote (Geel), L Dirix
(Edegem), B Ghysen
Moorkens (Antwerp), M Ptazynski (Brussels), A Van Mulders
(Antwerp), W Vanroelen (Temse), B Winograd (Brussels); Italy, C
Oliva, A Ardizzoni (Genoa); The Netherlands, P Baas (Amster-
BALL DL AND CRUICKSHANK DG. (1990). The treatment of
malignant mesothelioma of the pleura: review of a 5-year
experience, with special reference to radiotherapy. Am. J. Clin.
Oncol., 13, 4-9.
BOUTIN C, REY F, GOUVERNET I, VIALLET JR, ASTOUL P AND
mesothelioma: a prospective study of 188 consecutive patients.
Cancer, 72, 394-404.
VAN BREUKELEN IF, MATTSON K, GIACCONE G, VAN ZANDWIJK
N, PLANTEYDT HT, KIRKPATRICK A AND DALESIO 0. (1991).
Mitoxantrone in malignant pleural mesothelioma: a study of the
EORTC Lung Cancer Cooperative Group. Eur. J. Cancer, 27,
CALAVREZOS A, KOSHEL G, HUSSELMANN H, TAYLESSANI A,
HERLMAN HP, FABEL H, SCHMOLL H1, DIETRICH H AND HAIN
Wochenschr, 66, 607-613.
DE KLERK NH AND ARMSTRONG BK. (1992). The epidemiology of
asbestos and mesothelioma. In Malignant Mesothelioma, Hen-
derson DW, Shelkin KB, Langlois SLP and Withalker D. (eds),
pp. 223 -243. Hemisphere Publishing Cooperation: New York.
EORTC. (1994). Evaluation criteria, scoring scales and instruments.
In EORTC: A Practical Guide toEORTC Studies. Vantongelen K.
(ed.) pp. 119-131. EORTC: Brussels.
GUPTA RS. (1993). Taxol resistant mutants of Chinese hamster
ovary cells: genetic, biochemical and cross-resistance studies. J.
Cell Physiol., 114, 137-144.
HENDERSON DW, WHITHAKER D AND SHELKIN KB. (1992). The
differential diagnosis of malignant mesothelioma: a practical
approach to diagnosis during life. In Malignant Mesothelioma,
Henderson DW, Shelkin KB, Langlois SLP and Withaker D.
(eds), pp. 183-1940. Hemisphere Publishing Cooperation: New
KAPLAN GL AND MEIER P. (1958). Nonparametric estimation from
incomplete observation. J. Am. Stat. Assoc., 53, 457-481.
KRARUF-HANSEN A AND HANSEN 1H. (1991). Chemotherapy in
malignant mesothelioma: a review. Cancer Chemother. Pharma-
col., 28, 319-330.
mesothelioma: a commentary and update. Lung Cancer, 11,
LANGLOIS SLP AND HENDERSON DW. (1992).
investigation of mesothelioma.
Henderson DW, Shelkin KB, Langlois SLP and Withakler D.
(eds), pp. 259-276. Hemisphere Publishing Cooperation: New
In Malignant Mesothelioma,
PLANTEYDT HT AND VAN ZANDWIK N. (1992). Epirubicin in
malignant mesothelioma: a phase H study of the EORTC-LCCG.
J. Clin. Oncol., 10, 824- 828.
VAN MEERBEECK JP. (1994). Prognostic factors in malignant
mesothelioma: where do we go from here? Eur. Respir. J., 6,
MUSK AW, BOWMAN RV AND CHRISTMAS TI. (1992). Management
of malignant mesothelioma. In Malignant Mesothelioma, Hen-
derson DW, Shelkin KB, Langlois SLP and Withaker D. (eds),
pp. 292-299. Hemisphere Publishing Cooperation: New York.
PISANI Ri. (1988). Malignant mesothelioma of the pleura. Mayo
Clin. Proc., 63, 1234-1244.
RAMAEL M, BUYSSE C, VAN DEN BOSSCHE J, SEGERS K AND VAN
MARK E. (1992). Immunoreactivity for P-170 glycoprotein in
malignant mesothelioma and non-neoplastic mesothelium with
the JSB-1 monoclonal antibody. J. Pathol., 167, 5-8.
ROWINSKY EK AND DONEHOVVER RC. (1995). Pacitaxel (Taxol).
N. Engl. J. Med., 332, 1004-1014.
ROWINSKY EK, EISENHAUER EA, CHAUDHRY V, ARBUCK SG
AND DONEHOWER RC. (1993). Clinical toxicities encountered
with Paclitaxel (Taxol). Semin. Oncol., 20, 1- 15.
RUSH VW, PLANTADOSI S AND HOLMES EC. (1991). The role of
extrapleural pneumonectomy in malignant pleural mesothelioma.
J. Thorac. Cardiovasc. Surg., 102, 1-9.
SCHILLER JH, STORER B, TUTSCH K, ARZOOMANIAN R, ALBERTI
D, FEIERABEND C AND SPRIGGS D. (1994). Phase I trial of 3-
hour infusion of paclitaxel with or without granulocyte colony-
stimulating factor in patients with advanced cancer. J. Clin.
Oncol., 12, 241 -248.
SIMON R. (1989). Optimal two-stage design for phase II clinical
trials. Controlled Clin. Trials, 10, 1-10.
UICC. (1992). International Union against Cancer: TNM atlas, 3rd
edn. pp. 152-156. Springer Berlin.
VOGELSANG NJ. (1992). Malignant mesothelioma: diagnostic and
management strategies for 1992. Semin. Oncol., 19 (suppl. 11),
VOGELSANG NJ, HERNDON J, CLAMON GH, MAUER AM, COOPER
MR AND GREEN MR_ (1994). Paclitaxel (Taxol) for malignant
mesothelioma: a phase II study of the Cancer and Leukemia
Group B (CALGB 9234). Proc. Am. Soc. Clin. Oncol., 13, 405.
K, GIACCONE G, KIRKPATRICK