Although MPM aetiology is well known, therapeutic success with this disease has been
unsatisfactory. Standard malignant pleural mesothelioma (MPM) therapy is still deficient,
and decisions for surgical, radiotherapy or multimodal procedures are made on a case-by-case
basis. In the majority of cases, a palliative treatment approach remains the only
choice. The possibilities to resect MPM curatively are rare and only given in early-stage
disease. Yet even at this point, resection is a matter of dispute because of historically
high morbidity and mortality rates, relapse tendencies and disappointing long-term
survival rates (Rusch and Venkatraman, 1996; Boutin et al, 1998). Irradiation for
MPM assists in repelling tumour growth and temporarily relieving pain, but not attaining
appreciably lengthened overall survival time (Kutcher et al, 1987; Soubra et al, 1990;
Bissett et al, 1991). There is also no clear evidence that multimodality protocols
involving surgery, radiotherapy and chemotherapy can improve survival (Antman et al,
1980; Hilaris et al, 1984; Linden et al, 1996). Although success in MPM chemotherapy
has been limited, it now gives rise to promise by the use of an established and standardised
staging system, with consideration given to prognostic factors and development of
novel cytostatic agents.
ROLE OF CHEMOTHERAPY
Chemotherapy for MPM continues to be challenging. A multitude of cytotoxic drugs have
been tested both as single agents and in combination chemotherapy regimens. The rates
of objective tumour regression have only been between 10 and 30% with cytotoxic monotherapy,
having no significant impact on median survival. Combination chemotherapy has shown
no clear advantage over single-agent therapy (Linden et al, 1996).
The evaluation of systemic chemotherapy in MPM has been problematic for several reasons.
Owing to the rarity of this disease, only a few randomised studies based on large
numbers of participants have been implemented to provide statistically significant
statements regarding response to a particular therapy.
Furthermore, inadequate imaging procedures and nonuniform staging systems have complicated
data interpretation. As performed in early studies, restaging by means of chest radiography
failed to determine response to a given therapy accurately. Response rates have been
more reliable since CT scanning has been recognised as a diagnostic tool. In 1995,
the International Mesothelioma Interest Group (IMIG) proposed a novel TNM staging
system, which was designed to record data concerning the natural history of the disease
and was validated in two large surgical series of mesothelioma patients (Rusch and
Venkatraman, 1996; Pass et al, 1998). The universal application of this system has
ever since allowed for a more prudent evaluation of results emerging from clinical
studies (Pass et al, 1998; Steele and Rudd, 2000).
Early clinical trials of MPM patients included heterogeneous groups of patients with
divergent risk factors and were therefore often not powerful enough in assessing therapeutic
efficacy of a particular treatment. In 1998, the European Organization for Research
and Treatment of Cancer (EORTC) identified several prognostic variables for the course
of the disease. In a multivariate analysis of the EORTC, poor prognosis was associated
with the sarcomatous histologic subtype, male gender, poor performance status and
a high white blood cell count (Curran et al, 1998). Likewise, the Cancer and Leukemia
Group B (CALGB) analysed several pretreatment factors pooled from seven phase II studies
that were predictive of poor survival and defined six prognostic groups. Poor prognosis
was seen in patients with the following criteria: age older than 75 years, poor performance
status, chest pain, dyspnoea, weight loss, high white blood cell count, elevated platelet
count, low haemoglobin, elevated serum lactate dehydrogenase levels, pleural effusion
and nonepithelial histology.
Owing to the establishment of prognostic scoring systems, identification of risk groups
facilitated improved study design by evaluating more homogeneous patient groups or
risk-group stratification in the course of randomisation (Curran et al, 1998).
The following sections summarise conventional single-agent and combination chemotherapy
strategies. Results emerging from recent clinical studies with novel cytotoxic agents
and their combinations are then presented, which have been published since the last
review of chemotherapy in MPM.
Tables 1
Table 1
Series of ⩾15 patients with MPM treated with single-agent chemotherapy since 1995
Single agent
First author (year)
No. of patients
Responders
95% confidence interval (%)
Median survival (months)
No
%
Anthracyclines and related compounds
Liposomal doxorubicin
Baas (2000)
32
2
6
0–20
13
Liposomal doxorubicin
Oh (2000)
24
0
0
na
9.3
Liposomal danaurubicin
Steele (1998)
11
0
0
na
6.1
Platinum compounds
ZD0473
Giaccone (2001)
10
Two regressions of evaluable disease
na
na
Alkylating agents
Ifosfamide
Andersen (1999)
26
1
4
0–11
10
Etoposide i.v.
Sahmoud (1997)
49
2
4
1–15
7.3
Etoposide p.o.
Sahmoud (1997)
45
3
7
2–20
9.5
Topoisomerase interactive agents
Campthotecin analogues
Irinotecan
Kindler (2000)
28
0
0
10–55
7.9
Topotecan
Maksymiuk (1998)
22
0
0
na
8
Antimicrotubule agents
Vinca alcaloids
Vinorelbine
Steele (2000)
64
12
21
10–44
13.4
Vincristine
Martensson (1989)
23
0
0
0–14
7
Vinblastine
Cowan (1988)
20
0
0
0–16
3
Taxanes
Docetaxel
Belani (1999)
19
1
5
0–26
na
Docetaxel
Vorobiof (2000)
22
3
14
7–46
12
Paclitaxel
v. Meerbeck (1996)
25
0
0
0–15
9.8
Paclitaxel
Vogelzang (1999)
35
Three regressions of evaluable disease
2–10
5
Antimetabolites
Edatrexate
Kindler (1999)
20
5
25
9–49
9.6
Edatrexate+LV-rescue
Kindler (1999)
38
6
16
6–31
6.6
Gemcitabine
Kindler (2001)
17
0
0
3–13
4.1
Gemcitabine
van Meerbeck (1999)
27
2
7
1–24
8
Gemcitabine
Bischoff (1998)
16
5
31
na
na
Pemetrexed
Scagliotti (2001)
62
9
6
na
10.7
na=not applicable.
2
Table 2
Series of ⩾15 patients with MPM treated with combination chemotherapy since 1995
Agent
First author (year)
No. of patients
Responders
95% confidence interval (%)
Median survival
No.
%
Doxorubicin-containing combinations
Doxorubicin+cisplatin+mitomycin
Pennucci (1997)
23
5
21
7 – 42
11
Doxorubicin+cisplatin+mitomycin+bleomycin
Breau (1991)
25
11
44
27 – 63
na
Cisplatin-containing combinations
Cisplatin+DHAC
Samuels (1998)
29
5
17
5 – 30
6.4
Cisplatin+etoposide
Eisenhauer (1988)
26
3
12
4 – 30
na
Cisplatin+gemcitabine
Byrne (1999)
21
10
48
26 – 69
10.3
Cisplatin+gemcitabine
Novak (2002)
52
17
33
20 – 46
11.2
Cisplatin+gemcitabine
Van Haarst (2000)
22
4
15
na
10
Cisplatin+Irinotecan
Nakano (1999)
15
4
27
8 – 55
7.1
Cisplatin+mitomycin+vinblastine
Middleton (1998)
39
8
20
na
6
Cisplatin+pemetrexed (phase I)
Thodtman (1999)
11
5
45
na
na
Cisplatin+paclitaxel
Fizazi (2000)
18
1
6
0 – 24
12
Other combinations
Methotrexate+mitoxantrone+mitomycin
Pinto (2001)
22
6
32
12 – 51
13.5
Carboplatin+gemcitabine
Aversa (1998)
18
3
16
na
8.6
Carboplatin+pemetrexed (phase I)
Hughes (2002)
25
8
32
na
15
Oxaliplatin+raltitrexed
Fizazi (2000)
30
9
30
15 – 49
na
Oxaliplatin+vinorelbine
Steele (2000)
17
2
12
na
na
Docetaxel+irinotecan
Knuuttila (2000)
15
0
0
2 – 45
8.5
na=not applicable.
and
3
Table 3
Series of randomized phase II – III studies in patients with MPM treated with chemotherapy
Agent
First author (year)
No. of patients
Responders
95% confidence interval (%)
Median survival (months)
No.
%
Doxorubicin vs cyclophosphamide
Sorensen (1985)
32
0
0
0–19
na
0
0
0–19
Doxorubicin+cyclophosphamide vs doxorubicin+cyclophosphamide+DTIC
Samson (1987)
76
4
11
6–21
7.5
5
13
6–21
6.3
Cisplatin+doxorubicin vs cisplatin+mitomycin
Chahinian (1993)
70
5
14
5–30
5
26
12–43
7.7
Cisplatin+etoposide vs carboplatin
White SC (2000)
25
1
8
na
4.7
0
0
5.4
Onconase vs doxorubicin
Vogelzang (2000)
154
na
na
na
7.7
8.2
Cisplatin vs cisplatin+pemetrexed
Vogelzang (2002)
456
na*
na*
na*
na*
Ongoing trials agent
No. of patients planned
Doxorubicin vs doxorubicin+onconase
300
Cisplatin vs cisplatin+raltitrexed
240
Pemetrexed vs best supportive care
240
Vinorelbine vs MVP vs best supportive care
840
Cisplatin+gemcitabine vs cisplatin+gemcitabine+bevacizumab
106
*
Vogelzang N.: http://www.asco.org/asco/ascoMainConstructor/1,47468,_12|002351,00.asp?cat=General+Oncology.
na=not applicable.
summarise phase II–III single-agent and combination chemotherapy trials for MPM including
more than 15 patients, which have been conducted since 1995.
Single-agent chemotherapy
Doxorubicin is the most frequently investigated chemotherapeutic agent in the treatment
of MPM. Studies have failed to corroborate evidence, however, for encouraging response
rates to doxorubicin of up to 20% that had been reported in earlier studies (Aisner
and Wiernik, 1981; Antman and Corson, 1985). Likewise, newer anthracyclines such as
epirubicin, detorubicin, pirarubicin and mitoxantrone have shown low levels of efficacy
and have offered no clinically relevant advantage over doxorubicin (Colbert et al,
1985; Eisenhauer et al, 1986; Sridhar et al, 1989; Kaukel et al, 1990; Magri et al,
1991; van Breukelen et al, 1991; Mattson et al, 1992; Magri et al, 1992). In summary,
the overall response rate produced by anthracyclines applied in MPM appears to be
no higher than 15% and median survival does not exceed 8 months.
Apart from anthracyclines, several studies have investigated the platinum compounds,
cisplatin and carboplatin. Single-agent cisplatin resulted in a response rate of merely
14.3% and a median survival of 7.5 months (Zidar et al, 1988). Studies using the newer
compound carboplatin resulted in similar response rates ranging between 6 and 16%
(Mbidde et al, 1986; Raghavan et al, 1990; Vogelzang et al, 1990).
The alkylating agents cyclophosphamide and mitomycin have shown low-level activity
in MPM therapy (Bajorin et al, 1987; Sorensen et al, 1985). Promising results initially
arising from high-dose ifosfamide therapy (Alberts et al, 1988) could not be confirmed
by subsequent studies (Falkson et al, 1992; Zidar et al, 1992; Icli et al, 1996; Krarup-Hansen,
1996; Andersen et al, 1999).
The older vinca alkaloids vinblastine, vincristine and vindesine have demonstrated
no activity in the treatment of MPM (Kelsen et al, 1983; Boutin et al, 1987; Cowan
et al, 1988; Martensson & Sorenson, 1989). Likewise, poor results were shown with
oral as well as IV etoposide (Tammilehto et al, 1994; Sahmoud et al, 1997).
The antifolates methotrexate and edatrexate have been the only single agents to produce
comparatively better results. A Norwegian study reported a satisfactory response rate
of 37% for high-dose methotrexate and a median survival of 11 months, for trial subjects
with an epithelial subtype drawing a particular benefit from this chemotherapy option
(Solheim et al, 1992). Sequential multicentre phase II studies conducted by the CALGB
have evaluated the activity of the folate antagonist edatrexate, with and without
leucovorin rescue. Edatrexate produced 25% overall response rates but proved to be
relatively toxic. Leucovorin rescue in the control arm led to decreased toxicities,
but may also have reduced the agent's efficacy (Kindler et al, 1999). Other antimetabolites
like fluorouracil, dihydro-5-azacytidine (DHAC), dideazafolic acid and trimetrexate
have shown minor or no activity in the treatment of MPM (Harvey et al, 1984; Vogelzang
et al, 1994; Vogelzang et al, 1997; Samuels et al, 1998).
Combination chemotherapy
Doxorubicin-based regimens
Doxorubicin is the anthracycline most frequently included in chemotherapeutic regimens.
Initially encouraging response rates experienced with the doxorubicin–cisplatin combination
in two phase II studies carried out in Germany (RR: 46%) and Italy (RR: 25%) (Henss
et al, 1988; Ardizzoni et al, 1991) failed to be confirmed by a subsequent, randomised
CALGB study of doxorubicin–cisplatin vs mitomycin–cisplatin treatment (Chahinian et
al, 1993). The doxorubicin-cisplatin doublet was only able to produce a 14% response
rate and proved inferior to the mitomycin–cisplatin combination (RR: 26%). Median
survival duration from study entry was 7.7 and 8.8 months, respectively, with no significant
differences between treatments. An Italian group administered the triplet doxorubicin–cisplatin–mitomycin
to 24 MPM patients and reported a response rate of 20.9%. Thus, the observed level
of activity was similar to that obtained with the respective doublets (Pennucci et
al, 1997).
The combination of doxorubicin, cisplatin and cyclophosphamide was tested by another
prospective trial and produced a similar rate of response (Shin et al, 1995). A multi–institutional
randomised study was designed to compare the activity of doxorubicin-cyclophosphamide
with a triplet consisting of these agents in addition to dacarbazine. With a response
rate of 13%, the triplet did not prove superior to the doublet (RR: 11%) (Samson et
al, 1987).
The combination of doxorubicin and ifosfamide has also been investigated within two
studies. One study giving doxorubicin and ifosfamide every 3 weeks achieved a response
rate of 12.5% (Carmichael et al, 1989). Based on the same trial design, another group
applied dose-escalated doxorubicin at 75 mg m−2, with a 32% response rate (Dirix et
al, 1994). However, the 7-month median survival was poor and toxicity high, limiting
the value of this schedule in the treatment of MPM.
Disappointing response rates have also been shown by the anthracyclines epirubicin
and rubidazone as combined with ifosfamide and dacarbazine (Zidar et al, 1983; Magri
et al, 1992).
Cisplatin-based regimens
Apart from combinations with anthracyclines, cisplatin has also been tested in numerous
other chemotherapy regimens. Three trials evaluated cisplatin combined with etoposide,
showing response rates from 12 to 24% (Eisenhauer et al, 1988; Planting et al, 1995;
White et al, 2000). The doublet combination of cisplatin and DHAC attained an insufficient
response rate of 17.3% (Samuels et al, 1998). Moderate antitumour activity (RR: 25%)
was achieved by the doublet cisplatin–mitomycin in one arm of CALGB 8435, but median
survival was poor (7.7 months) (Chahinian et al, 1993). A 25% response rate and a
13-month mean duration of response have been indicated for the cisplatin–vinblastine
combination (Tsavaris et al, 1994). The cisplatin–mitomycin-C–vinblastine triplet
did not prove to be superior to the doublets (RR: 23%), yet produced a symptomatic
benefit for 63% of the patients with particularly good response for pain (Middleton
et al, 1998).
Likewise, other treatments combining such conventional cytotoxics as methotrexate
with vincristine and mitomycin with vindesine have failed to prove effective (Dimitrov
et al, 1982; Gridelli et al, 1992).
NOVEL CYTOTOXICS
Anthracyclines
Liposomal anthracyclines
Liposomal doxorubicin. Within a phase II study, the EORTC treated 35 patients with
liposomal doxorubicin (Caelyx®) at a dosage of 45 mg m−2 every 4 weeks (Baas et al,
2000). The drug was well tolerated, but the results were disappointing. Only two of
the 31 patients (6%) showed a partial response and the median survival was 13 months.
Similar results were reported by Oh et al, who administered 50 mg m−2 of liposomal
doxorubicin (Doxil®) every 4 weeks to 24 patients with pleural mesothelioma (Oh et
al, 2000). With no objective responses and a median survival of only 37 weeks, the
drug was considered inactive in this indication.
Liposomal daunorubicin. Liposomal daunorubicin (LD) was given to 13 patients at 120 mg m−2
every 3 weeks, but no responses were produced (Steele et al, 2001).
Platinum compounds
ZD0473
A phase II trial (Giaccone et al, 2001) assessed the efficacy of the new generation
platinum compound ZD0473 at 120 mg m−2 on day 1 of a 21-day cycle in mesothelioma
patients that had relapsed after previous platinum-based chemotherapy. Two of 10 (20%)
patients, experienced tumour shrinkage and five of 10 (50%) subjects had stable disease.
Topoisomerase interactive agents
Camptothecin analogues
Irinotecan
The activity of single-agent irinotecan (125 mg m−2 given weekly for 4 weeks, every
6 weeks) in malignant mesothelioma was investigated by the CALGB (Kindler et al, 2000).
In 28 patients evaluable for analysis, no complete or partial responses were observed
and the median overall survival was 7.9 months, indicating that irinotecan, at least
in this dose and schedule, had no antitumor activity and considerable toxicity (leucopenia,
neutropenia, diarrhoea).
Furthermore, the combination of irinotecan and cisplatin was evaluated by a Japanese
group (Nakano et al, 1999). A total of 15 chemonaive MPM patients were treated with
irinotecan at 60 mgmg−2 on days 1, 8 and 15 and cisplatin at 60 mg m−2 on day 1, repeated
every 28 days. A response rate of 26.7% (four partial responses) was observed and
the median survival after chemotherapy was 28.3 weeks. In contrast to the trial conducted
by the CALGB, Nakano et al,reported definite activity with only mild toxicity of this
combination regimen and concluded that it warrants further clinical evaluation.
Recently, Verschraegen et al, (2001) published retrospective data of the same combination
in 10 patients with peritoneal mesothelioma. Six courses of irinotecan 50 mg m−2 (day
1, 8 and 15) and cisplatin 50 mg m−2 (day 1) were administered every 4 weeks, either
intraperitoneally or intravenously, and were well tolerated. The authors reported
that 70% of the patients improved on treatment. Owing to the observed clinical benefit,
a phase II trial is currently planned.
Topotecan. In order to evaluate the efficacy and toxicity of the camptothecin analogue
topotecan in the treatment of MPM, the North Central Cancer Treatment Group treated
22 MPM patients with topotecan 1.5 mg m−2 daily for 5 days at 3-week intervals. 18
patients (86%) experienced grade 3 or 4 neutropenia. There were no objective responses
seen and the median survival for all patients was 230 days (Maksymiuk et al, 1998).
Antimicrotubule agents
Vinca alcaloids
Vinorelbine. Steele et al, (2000) administered vinorelbine to 64 patients with MPM
at a weekly 30 mg m−2 dose for 6 weeks. A response rate of 21% (12 out of 64 patients)
was observed and 63% of patients experienced disease stabilisation. Furthermore, the
patients' quality of life was increased with respect to lung-related symptoms and
physical well-being in general.
The same study group conducted a trial to evaluate the activity of vinorelbine at
30 mg m−2 on days 1 and 8 and oxaliplatin 130 mg m−2 on day 1 every 3 weeks in 21
MPM patients (Steele et al, 2000). Only two partial responses had been observed and
toxicity had been significant. These inferior results could perhaps result from the
large number of stage IV patients, the higher proportion of less favorable subtypes,
and the inclusion of several participants showing a low performance status. At any
rate, the addition of oxaliplatin to vinorelbine seems to bring no advantage, thus
discouraging further studies in this doublet.
Recently, a British randomised phase III study has been initiated, comparing the efficacy
of single-agent vinorelbine (30 mg m−2 up to 60 mg m−2) vs MPV (mitomycin 8 mg m−2,
vinblastin 6 mg m−2, cisplatin 50 mg m−2) vs active best supportive care alone.
Taxanes
Paclitaxel. A total of 25 patients with MPM were given paclitaxel intravenously at
a dose of 200 mg m−2 as a 3 h infusion every 3 weeks in a phase II study conducted
by the EORTC Lung Cancer Cooperative Group (van Meerbeeck et al, 1996). No major objective
responses were seen and the median survival time was only 39 weeks.
These disappointing results were confirmed by the CALGB, which administered paclitaxel
at a slightly higher dose of 250 mg m−2, given as a 24-hour infusion every 3 weeks
plus filgastrim (G-CSF) support to 35 patients with MPM (Vogelzang et al, 1999). Only
three (9%) regressions of evaluable disease were observed and the median survival
was 5 months.
Fizazi et al, (2000) conducted a phase II study of paclitaxel (200 mg m−2) and cisplatin
(100 mg m−2), given to 18 patients on day 1 every 3 weeks. With only one partial response
and a response rate of 6%, the paclitaxel–cisplatin doublet was considered ineffective
and the trial was stopped early.
Bednar (1999) evaluated the combination of paclitaxel at 175 mg m−2 and carboplatin
at an AUC of 5–6 in seven patients with malignant mesothelioma and reported more encouraging
results. One patient with peritoneal malignant mesothelioma had a pathologically proven
CR for a duration of 20 months. The overall median survival was 15 months from diagnosis
and 12 months from the onset of treatment.
Docetaxel. The Eastern Cooperative Oncology Group assigned 19 patients with malignant
mesothelioma to a phase II study of docetaxel 100 mg m−2, administered every 21 days.
Only one patient achieved a partial response, with an overall response rate of 5%.
The study group thus concluded that docetaxel was not effec-tive in the treatment
of malignant mesothelioma (Belani et al, 1999).
Vorobiof et al, (2000), who also evaluated the activity of docetaxel using the same
treatment schedule, reported only three partial remissions and six minor responses
(25% or less reduction in tumour burden) in 22 MPM patients with median survival barely
exceeding 12 months.
A clinical study further tested docetaxel at 60 mg m−2 in combination with irinotecan
at 190 mg m−2 on day 1 of a 3-weekly cycle in 15 MPM patients (Knuuttila et al, 2000).
No objective responses were achieved, and median survival was 8.5 months only. The
study was finally discontinued owing to high toxicity and deficient activity levels.
Antimetabolites
Antifolates
Raltitrexed. The EORTC has recently completed a phase II study of the quinazoline
antifolate raltitrexed (ZD1694, Tomudex) at 3 mg m−2 as a single agent in the treatment
of malignant mesothelioma, which is now in final analysis.
From 1999 to 2000, the Institut Gustave Roussy has treated 70 patients with a combination
of raltitrexed (3 mg m−2) and oxaliplatin (130 mg m−2). Preliminary results show an
encouraging response rate of 25% (14 of 57 patients evaluable for efficacy) and acceptable
toxicity (Fizazi et al, 2000).
Based on these promising results, the EORTC initiated a randomised phase III study,
evaluating the efficacy of the doublet raltitrexed (3 mg m−2)– cisplatin (80 mg m−2)
vs cisplatin (80 mg m−2) alone.
Pemetrexed. A phase I study conducted in 1999 first investigated the activity of the
multitargeted antifolate pemetrexed (LY231514, ALIMTA®) combined with cisplatin in
patients presenting with solid tumours (Thodtmann et al, 1999). Of 11 mesothelioma
patients evaluable for analysis, five experienced a partial remission (RR: 45%).
These promising data resulted in the largest phase III study ever conducted in patients
with MPM, which was initiated in March 1999. The results of this single-blind trial
were first presented at the ASCO annual meeting in May 2002. A total of 456 patients
were randomised to receive either cisplatin–pemetrexed (cisplatin 75 mg m−2 and pemetrexed
500 mg m−2 on day 1, every 21 days) or cisplatin monotherapy in the control group.
The combination of pemetrexed–cisplatin resulted in superior median overall survival,
response rate, lung function and subjective quality-of-life measures (Vogelzang N
http://www.asco.org/asco/ascoMainConstructor/1,47468,_12|002351,00.asp?cat=General+Oncology).
The principal investigator concluded that based on these very promising data, pemetrexed–cisplatin
should now be considered standard front–line therapy for patients with MPM.
Another phase I pemetrexed study demonstrated clinical activity in combination with
carboplatin. A total of 27 patients were treated with various dose levels of pemetrexed
and carboplatin on day 1 of a 21-day schedule (Hughes et al, 2002). In 25 evaluable
patients, eight (32%) achieved a partial remmission and 14 experienced stable disease
at various dose levels. Furthermore, a symptomatic improvement was documented in 19
cases.
A two-stage phase II trial has just been completed by Scagliotti and collaborators,
investigating single-agent pemetrexed in the treatment of MPM. A total of 62 patients
were given pemetrexed at 500 mg m−2 on day 1, every 3 weeks. Scagliotti et al, (2001)
reported a response rate of 14.5% and a median survival of 10.7 months.
Furthermore, a randomised phase III trial comparing pemetrexed plus best supportive
care vs best supportive care alone in previously treated patients with MPM is currently
ongoing.
Nucleoside Analogues
Gemcitabine. The activity of single-agent gemcitabine at 1250 mg m−2 on days 1, 8
and 15 on a 28-day schedule was evaluated by the EORTC-Lung Cancer Group in 27 chemotherapy-naive
subjects with MPM (van Meerbeeck et al, 1999). Two partial responses were achieved
for an overall response rate of 7%. An additional 56% experienced disease stabilisation
and overall median survival was 8 months.
The CALGB administered high-dose gemcitabine at 1500 mg m−2 on days 1, 8 and 15 in
a 28-day cycle to 17 participants (Kindler et al, 2001). Only one minor regression
and six cases of stable disease were reported in 13 assessable patients, with an overall
median survival of 4.1 months. In contrast to these data, Bischoff et al, (1998) reported
an encouraging response rate of 31% (5/16) with the same dose and schedule as the
van Meerbeck study (gemcitabine 1250 mg m−2 on days 1, 8 and 15, every 28 days). Furthermore,
seven additional patients reported a symptom relief via decreased pain or dyspnoea.
An Australian study group evaluated the doublet gemcitabine–cisplatin in 21 patients
presenting with advanced MPM (Byrne et al, 1999). The subjects received gemcitabine
at 1000 mg m−2 on day 1, 8 and 15 and cisplatin at 100 mg m−2 on day 1 of a 28-day
cycle. This combination chemotherapy produced an encouraging response rate of 47.6%
and an overall survival of 41 weeks. Furthermore, nine of 10 responding patients experienced
significant relief of chest pain and dyspnoea. Subsequently, a multicentre study was
initiated, evaluating the same chemotherapy regimen in 53 MPM patients (Novak et al,
2002). A response rate of 33% was achieved and the median survival time was 11.2 months.
Response to treatment was accompanied by significantly improved global quality of
life and respiratory function.
Contrary to the Australian trials, however, only four (15%) of 22 assessable subjects
experienced a partial response within a European multicentre phase II study (Van Haarst
et al, 2000) of gemcitabine at 1250 mg m−2 on days 1 and 8, in addition to cisplatin
at 80 mg m−2 on day 1. The discrepancy between these studies may possibly result from
the different treatment schedules, patient selection criteria and methodology applied
in treatment evaluation.
In turn, Aversa et al, (1998) on evaluated the activity of the gemcitabine–carboplatin
combination. A total of 20 patients were given gemcitabine at 1000 mg m−2 on days
1, 8 and 15 and carboplatin (AUC=5) on day 1, every 28 days for a median of 4.5 cycles.
In 18 assessable subjects, a response rate of 16% and an 8.6-month median survival
rate was achieved.
Recently, investigators at the University of Chicago have initiated a multicenter,
randomised phase II trial of cisplatin–gemcitabine and the vascular endothelial growth
factor (VEGF) inhibitor bevacizumab, which has shown preliminary evidence of activity
in MPM.
CONCLUSION
With rates of objective tumour regression ranging from 10 to 30% for cytotoxic monotherapy,
diffuse pleural mesothelioma was considered to date to be widely chemoresistant. The
most favourable responses to conventional chemotherapeutic agents were reported by
the antimetabolites methotrexate and edatrexate.
In the past few years, a number of novel cytotoxic agents have been introduced into
clinical oncology, the activity of which has also been tested in MPM therapy. Initial
results produced by monotherapy based on new antimetabolites, along with platin combinations,
provide encouragement. Preliminary results of the raltitrexed–oxaliplatin combination
have shown promising activity. Single-agent gemcitabine and the drug combined with
cisplatin appear to decrease symptoms associated with tumor load. In particular, pemetrexed
with cisplatin has demonstrated superior median overall survival, response rate, lung
function and quality-of-life measures in the largest randomised trial in MPM. These
promising data suggest that finally effective chemotherapy exists for this aggressive
disease and that pemetrexed–cisplatin will become a new systemic therapy standard.