Original article Treatment of advanced non-small-cell lung cancer patients with

Original article Treatment of advanced non-small-cell lung cancer patients with

Original article
Annals of Oncology 15: 419–426, 2004
DOI: 10.1093/annonc/mdh087
Treatment of advanced non-small-cell lung cancer patients with
ECOG performance status 2: results of an European Experts Panel
C. Gridelli1*, A. Ardizzoni2, T. Le Chevalier3, C. Manegold4, F. Perrone5, N. Thatcher6,
N. van Zandwijk7, M. Di Maio5, O. Martelli8 & F. De Marinis8
1
Division of Medical Oncology, ‘S.G.Moscati’ Hospital, Avellino; 2Department of Medical Oncology, National Institute for Cancer Research, Genoa, Italy;
Department of Medicine, Institute Gustave Roussy, Villejuif, France; 4Department of Medical Oncology, Thoraxklinik, Heidelberg, Germany; 5Clinical Trials Unit,
National Cancer Institute, Naples, Italy; 6Department of Medical Oncology, Christie Hospital, Manchester, UK; 7Department of Thoracic Oncology,
Netherlands Cancer Institute, Amsterdam, The Netherlands; 8Fifth Pulmonary-Oncology Unit, Lung Disease Department, Forlanini Hospital, Rome, Italy
3
Received 1 July 2003; revised 7 October 2003; accepted 27 October 2003
ment for patients with advanced non-small-cell lung cancer (NSCLC), but its benefit seems limited to fit
patients with a performance status (PS) of 0 or 1. For PS2 patients, there is no consensus on standard treatment.
With the aims of reviewing the evidence supporting each of these therapeutic options, possibly reaching a
consensus for treatment of PS2 patients affected by advanced NSCLC in clinical practice, and suggesting the
priorities for clinical research in this field, an European Experts Panel took place in Avellino, Italy in April
2003.
Results and conclusions: On the basis of current evidence, chemotherapy treatment appears justified for
patients with advanced NSCLC and PS2. Single-agent chemotherapy (gemcitabine, vinorelbine, taxanes) could
be the preferred option, although carboplatin-based or low-dose cisplatin-based doublets may represent alternative options. Stronger evidence is expected from new clinical research specifically focused on PS2 patients.
Single-agent chemotherapy should be the standard arm against which experimental treatments are tested in
randomised trials dedicated to PS2 patients. High priority should be given to the evaluation of tolerability and
efficacy of platinum-based combinations, and to the testing of new biological agents. Another research priority
is the improvement of supportive care. Patients strongly need symptomatic improvement: end points such as
symptom relief, clinical benefit and quality of life should have a central position in trials dedicated to PS2
NSCLC patients.
Key words: advanced disease, chemotherapy, consensus, non-small-cell lung cancer, performance status 2
Introduction
Lung cancer is the most common cancer in the world and the leading cause of cancer-related deaths in Europe and in other Western
countries [1–3]. Non-small-cell lung cancer (NSCLC), including
squamous carcinoma, adenonocarcinoma and large-cell carcinoma,
represents ∼80% of all lung cancers. Unfortunately, at the time of
diagnosis, the majority of patients already have metastatic disease
and a systemic, palliative treatment is the only therapeutic option.
Performance status (PS) is a general, rough measure of the
patient’s functional status. It measures the impact of tumour
symptoms, together with other pre-existing medical problems and
co-morbidities, on a patient’s daily function and ability of selfcare. Several PS scales are available for clinical use: among them,
those most commonly used are the Karnofsky’s scale [4], created
at the beginning of chemotherapy era, and the Eastern Cooperative
*Correspondence to: Dr C. Gridelli, Division of Medical Oncology,
‘S.G.Moscati’ Hospital, Via Circumvallazione, 83100 Avellino, Italy.
Tel: +39-0825-203573; Fax +39-0825-203556; E-mail: [email protected]
© 2004 European Society for Medical Oncology
Oncology Group Scale of Performance Status (ECOG PS), a fivepoint scale (worsening from 0 to 5) based on the level of symptoms interference with normal activity and on the proportion of
waking hours spent in bed [5] (Table 1). According to the latter
scale, patients are classified as PS2 if they are restricted in physical activity, still ambulatory and capable of self-care but needing
rest in bed, although for <50% of waking hours. PS2 patients
usually account for a small proportion of patients enrolled in trials
of first-line treatment for advanced disease [6–9] but represent a
significantly higher proportion (up to 30–40%) when populationbased surveys are conducted [10, 11].
In a meta-analysis evaluating the efficacy of chemotherapy in
patients with NSCLC [12], cisplatin-based chemotherapy has
shown a slight but statistically significant survival advantage over
supportive care. According to the evidence that platinum-based
combination chemotherapy can prolong survival, possibly improving quality of life (QoL) and controlling symptoms in these
patients, it is currently recommended as the standard approach for
patients with advanced NSCLC [13, 14]. However, the benefit
achievable seems more evident for fit patients (PS0 or -1) and
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Background: Platinum-based combination chemotherapy is currently recommended as the standard treat-
420
Table 1. Most widely used performance status scales
ECOG performance status [5]
100
Normal with no complaints or
evidence of disease
0
Fully active, able to carry on all pre-disease
performance without restriction.
90
Able to carry on normal activity
but with minor signs of illness present
80
Normal activity but requiring effort.
Signs and symptoms of disease more prominent
1
Restricted in physically strenuous activity but
ambulatory and able to carry out work of a light or
sedentary nature e.g. light house work, office work
70
Able to care for self, but unable to work or
carry on other normal activities
60
Able to care for most needs, but requires
occasional assistance
2
Ambulatory and capable of all self-care but unable
to carry out any work activities. Up and about
>50% of waking hours
50
Considerable assistance and frequent medical
care required; some self-care possible
40
Disabled; requiring special care and assistance
3
Capable of only limited self care, confined to bed or
chair >50% of waking hours
30
Severely disabled; hospitalization required but
death not imminent
20
Extremely ill; supportive treatment and/or
hospitalization required
4
Completely disabled, cannot carry on any self-care.
Totally confined to bed or chair
10
Imminent death
0
Dead
5
Dead
there is no consistent evidence about the real efficacy of platinumbased treatment for PS2 patients [13, 15]. For this latter sub-group,
there is no treatment widely accepted as standard and oncologists
have to choose among several treatment options for which PS2
patients are potential candidates: best supportive care without
chemotherapy; single-agent chemotherapy; non-platinum-based
combination chemotherapy; and platinum-based combination
chemotherapy. With the aims of reviewing the evidence supporting each of these therapeutic options, possibly reaching a consensus for treatment of PS2 patients affected by advanced NSCLC in
clinical practice, and suggesting the priorities for clinical research
in this field, an European Experts Panel took place in Avellino
(Italy) in April 2003. Results and conclusions of that meeting are
presented in this paper.
Materials and methods
The ‘European Experts Panel on the Treatment of Advanced NSCLC Patients
with Performance Status 2’ was held at Avellino (Italy) on 14 April 2003.
Eight oncologists from five European countries (France, Germany, Italy, The
Netherlands and UK), with clinical and research experience in NSCLC,
formed the scientific panel of the meeting.
Evidence available for each of the following six topics in the treatment of
PS2 patients was reviewed: performance status as a prognostic factor; chemotherapy versus best supportive care; single-agent versus combination chemotherapy; non-platinum based versus platinum-based polichemotherapy; possible
role of new biological agents; ongoing trials. Each topic was presented by one
of the panellists and, after the discussion, a consensus was reached both for
clinical practice suggestions and for clinical research priorities. Results and
conclusions of the meeting were presented on 15 and 16 April 2003 to about
200 clinical oncologists coming from all over Italy.
Relevant published papers reporting the results of randomised phase III
clinical trials were obtained by Medline search. In order to obtain the largest
amount of specific information on PS2 patients, some authors were contacted
directly by the panel to obtain some data not available from the published
papers. Abstracts from proceedings of the most important oncology meetings,
not yet published as full papers, were also considered. Some of the data considered by the panellists still lack peer-review quality and are possibly not
definitive.
The greatest part of the evidence analysed in the meeting comes from small
sub-groups of patients with PS2, enrolled in clinical trials usually including
patients with a PS ranging from 0 to 2. The proportion of patients with PS2 in
these trials is often <20% of the whole study population, suggesting the existence of a selection bias determining the exclusion of PS2 patients with worse
general conditions and co-morbidities. Median age of patients enrolled in randomised clinical trials is often significantly lower than that observed in clinical
practice [16, 17], and eligibility criteria request good renal, hepatic and cardiac
function, as well as absence of other significant co-morbidities. Consequently,
it is not surprising that the proportion of PS2 patients in population-based
studies—not biased by inclusion criteria and not restricted by the characteristics
of experimental treatment—is consistently higher than that reported in the
majority of clinical trials [10, 11]. The panellists are aware that sub-group
analysis from randomised clinical trials must be interpreted with caution [18],
but currently there are no published prospective trials specifically dedicated
to PS2 patients, and retrospective information based on sub-group analysis
remains the best level of information on this topic available from the literature
to date.
Another significant limitation of the published data is the lack of information regarding symptom relief and/or health-related quality-of-life benefits in
PS2 patients. Despite the recognised priority to include these end points in
studies for patients with advanced NSCLC our review showed that these data
are hardly available.
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Karnofsky rating scale [4]
421
Notwithstanding the presence of the limitations described above, the panellists aimed for a consensus and to identify priorities for future research because
of the clinical relevance of the issue.
Performance status as a prognostic factor
The role of chemotherapy in PS2 patients
A first point of discussion was the evidence supporting the role of
chemotherapy itself in PS2 patients. The discouraging survival,
the lower compliance to chemotherapy and the fear of a higher
risk of toxicity put a question mark behind chemotherapy administration in this category of patients.
Some of the trials comparing best supportive care plus chemotherapy versus best supportive care alone are summarised in Table
2. In the meta-analysis published in 1995, although overall results
were limited by statistical heterogeneity and evident outcome
differences for the different chemotherapy categories, a significant benefit was demonstrated for cisplatin-based trials, and a
sub-group analysis confirmed this benefit for both good and poorer
PS patients [12]. After 1995, some advantage of chemotherapy
versus supportive care alone has been shown not only with
platinum-based combination chemotherapy [26, 29, 30] but also
with many new cytotoxic agents (e.g. gemcitabine [31], vinorelbine [32], paclitaxel [33] and docetaxel [34]), administered as
single agents. These drugs are usually characterised by a good
tolerability, with a low incidence of severe adverse events. Most
of the studies show some advantage of chemotherapy in terms of
overall survival also in the sub-group of PS2 patients, although
formal statistical comparisons are precluded by the low absolute
number of patients. Disappointingly, data about QoL are scanty.
Nearly all trials showed some benefit in terms of QoL and
symptomatic improvement favouring chemotherapy against supportive care alone, but only one study [29] specifically analysed
QoL in the different PS sub-groups. In that study, a comparison of
mean baseline score with mean score after 6 weeks was planned.
PS2 patients reported the worst scores at baseline assessment.
The drop-out rate in PS2 patients was greater than in the other
PS levels (35% compared with 23% in PS0 and 18% in PS1);
thus, the analysis in this sub-group was limited to 31 patients out
of 48 initially enrolled. Nevertheless, PS2 patients had significant
benefit from chemotherapy and, with the greater potential for
palliation determined by worse baseline condition, showed an
improvement in QoL even higher than PS0 and PS1 patients.
When choosing between chemotherapy and supportive care alone,
patients’ preferences should be taken into account, considering
that most patients are willing to accept chemotherapy for a very
small chance of benefit: patients with cancer are much more likely
to opt for chemotherapy with minimal chance of benefit than
people who do not have cancer, including medical and nursing
professionals [35]. These findings should not be ignored, especially considering the availability of several drugs characterised
by a favourable toxicity profile.
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As in other types of cancer, PS has a clear prognostic role in
advanced NSCLC. In all the retrospective and prospective trials
regarding prognostic factors in this disease, PS has been shown to
be an independent prognostic parameter [19–25]. In a series of
more than 5000 patients with inoperable lung cancer analysed
more than two decades ago to investigate the impact on survival of
50 prognostic factors, performance status, extent of disease and
weight loss were among the most important prognostic factors
[19]. These results have been confirmed by others [20–22, 25].
The survival analysis of 1960 patients with advanced NSCLC
treated with cisplatin-based chemotherapy in five ECOG phase II
or III trials conducted from 1981 to 1994 showed again an independent prognostic role of performance status: median survival
was 9.4, 6.4 and 3.3 months in PS 0, 1 and 2 patients, respectively
[25]. Median overall survival of patients with PS2—whatever
the treatment under investigation—is always substantially shorter
than that of PS0 or PS1 patients, and rarely exceeds 5 months
[25–27], with 1-year survival rates <20%.
A worse PS is characterised by lower response rates to chemotherapy, shorter time to treatment failure and shorter progressionfree survival [27, 28]. Chemotherapy also shows a reduced
efficacy in PS2 patients when these patients receive a number of
courses compared to patients with a better PS [29]. Moreover, it is
a widely held opinion that these unfit patients are at higher risk for
severe toxicity, which would counterbalance the eventual small
benefit expected. The outcome of 64 PS2 patients enrolled in the
clinical trial ECOG 1594 comparing four platinum-based combinations has been analysed in detail, after the accrual of PS2
patients had been stopped because of the perception of an excessive number of adverse events in this sub-group [27]. The study
confirmed a substantial incidence of grade 3 and grade 4 toxicities
in PS2 patients, although not significantly higher than in patients
with better PS. The analysis of toxic deaths showed that only a
part of the events were treatment-related and the remaining were
secondary, at least in part, to the concomitant diseases often
associated with an impaired PS. All these observations, as underlined by the authors, reinforce the perception that PS2 patients
need special consideration when receiving chemotherapy.
Furthermore, the gross categories defined only by PS are inevitably heterogeneous: PS2 may be due to tumour-related symptoms
(e.g. pain, anorexia, fatigue, weight loss), to concomitant diseases
(e.g. smoking-related illnesses such as chronic obstructive pulmonary or cardiovascular disease, osteoarthritis, peripheral vascular
disease, age-related decline in functional status) or both. For example,
a 40-year-old PS2 patient confined to bed for a painful single bone
metastasis is different from an elderly patient confined to bed for
a moderate to severe cardiovascular co-morbidity. Different patients
may have different benefit, different compliance and different
toxicities from the same anti-cancer treatment. According to disease-related symptoms and pre-existing co-morbidities, patients
could be divided in different sub-groups, with the aim of properly
predicting risks and benefits of different therapeutic approaches.
However, at present there is no validated categorisation of this
type or prospective study assessing the real impact of different
symptoms and co-morbidities on the risk/benefit ratio of chemotherapy. To date, the available data from retrospective analyses
are few and heterogeneous, and do not allow any type of subclassification.
422
Table 2. Randomised trials of chemotherapy plus supportive care versus supportive care alone in advanced NSCLC
Reference
Chemotherapy
All patients
PS2 patients
n
Survival
(CT vs. BSC)
QoL gain for CT
n
Survival (CT versus BSC)
QoL gain
for CT
Meta-analysis of
CDDP-based CT
778
HR 0.73
(P <0.0001)
NA
NA
Advantage for CT both in
good and poor PS
NA
Cullen et al. [26];
Billingham and Cullen [29]
MMC + Ifo + CDDP
797
CT > BSC
(P = 0.01)
Yes
159
HR 0.98, NS
Yes
Stephens et al. [30]
CDDP-based
725
HR 0.77
(P = 0.0015)
No
147
Advantage for CT, NS
NA
ELVIS [32]
Vinorelbine
161
HR 0.65
(P = 0.03)
Yes
41
6.4 versus 1.9 monthsa
NA
Roszkowski et al. [34]
Docetaxel
207
CT > BSC
(P = 0.026)
Yes
41
NA
NA
Ranson et al. [33]
Paclitaxel
157
CT > BSC
(P = 0.037)
Yes
26
4.1 versus 2.9 monthsb
NA
Anderson et al. [31]
Gemcitabine
300
5.7 versus
5.9 months
(P = 0.84)
Yes
108
3.2 versus 2.6 monthsb
NA
CT, chemotherapy; BSC, best supportive care; QoL , quality of life; CDDP, cisplatin; MMC, mitomycin; Ifo, ifosfamide; NA, not available; NS, not
statistically significant.
a
C. Gridelli, unpublished data.
b
N. Thatcher, unpublished data.
The role of adding platinum to third generation
single agents in PS2 patients
At present, platinum-based combination chemotherapy is considered the standard treatment for advanced NSCLC, but it is still
unclear if the benefit achieved with this treatment is restricted
only to PS0 and PS1 patients, or also applies to PS2 patients.
The results of a European phase III randomised trial comparing
single-agent vinorelbine, vinorelbine–cisplatin and vindesine–
cisplatin in 612 patients with advanced NSCLC and PS not worse
than 2 were published in 1994 [6]. Cisplatin was administered
at 120 mg/m2 on days 1 and 29, and then every 6 weeks. The combination of cisplatin and vinorelbine was superior in terms of survival to vindesine–cisplatin and to vinorelbine alone. A subgroup
analysis of that trial has been subsequently published, with the aim
of testing interactions between treatments and main prognostic
factors [36]. This secondary analysis showed that the significant
advantage obtained with the combination of cisplatin and vinorelbine is predominantly limited to fit patients: in PS0–1 patients,
median survival was 43, 36 and 33 weeks and 1-year survival was
38%, 34% and 29% for cisplatin–vinorelbine, vinorelbine alone
and cisplatin–vindesine, respectively. In the sub-group of 120 PS2
patients enrolled in the trial (20%), instead, a median survival of
18 weeks, significantly lower than PS0-1 patients, was observed
in all three arms. For PS2 patients, grade 3–4 haematological
toxicity occurred earlier and more frequently in the arm receiving
vinorelbine–cisplatin than in the vinorelbine arm (7 versus 28 days
after the start of treatment, respectively). According to these
results, cisplatin-based combination, with cisplatin doses higher
than 100 mg/m2, is no better than single-agent chemotherapy and
should not be recommended to PS2 patients. Lower doses of
cisplatin could probably be better tolerated, but currently there
are no data supporting this hypothesis in PS2 patients.
As for the role of carboplatin, the results of the CALGB 9730
study, comparing paclitaxel plus carboplatin versus paclitaxel
alone, must be considered [37]. The study enrolled patients with
a PS of between 0 and 2. In the sub-group of PS2 patients (107
patients, 18% of the population), median survival in the group
treated with combination chemotherapy was significantly longer
than with paclitaxel alone (4.7 versus 2.4 months), with 18% and
10% of patients, respectively, alive at 1 year (log-rank, 0.0177;
Wilcoxon, 0.0123). Similar to the benefit observed in the subgroup of elderly patients enrolled in the same trial, these results
should be interpreted with caution, in view of the substantial risk
of selection bias. Moreover, it should be noted that combination
chemotherapy with carboplatin and paclitaxel produced a statistically significant higher incidence of several haematological and
non-haematological severe toxicities (neutropenia, thrombocytopenia, anaemia, nausea and vomiting, any severe toxicity) than
single-agent paclitaxel [37]. These data should of course be kept
in mind when treating PS2 patients, who are at a higher risk of
toxicity.
The role of non-platinum-based third
generation polichemotherapy in PS2 patients
Fear of unacceptable toxicity is one of the major concerns in
treatment decisions for PS2 patients and, from this point of view,
platinum-free combination chemotherapy deserves attention as it
is potentially less toxic than platinum-based treatment. In recent
years, several trials comparing platinum-free combinations con-
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NSCLC group [12]
423
Table 3. Recent randomised trials of platinum-free versus platinum-based combination chemotherapy in advanced NSCLC
Reference
P-based arm
P-free arm
Total No.
of pts
Overall survival
(months) (P-based
versus P-free)
PS2 pts
(% of total pts)
Outcome in PS2
patients(P-based
versus P-free)
Georgoulias et al. [38]
CDDP/Doc
Gem/Doc
406
10 versus 9.5
(P = 0.98)
12
Comparable
survival
Kosmidis et al. [39]
CBDCA/Ptx
Gem/Ptx
479
10.4 versus 9.8
(P = 0.32)
13
Comparable
survival
Giaccone [40]
CDDP/Ptx (A) or
CDDP/Gem (B)
Gem/Ptx
480
8.1 (A), 8.8 (B)
versus 6.9 (P = NA)
12
Comparable
survival
Alberola et al. [41]
CDDP/Gem (A) or
CDDP/Gem/Vin (B)
Gem/Vin followed
by Ifo/Vin
557
9.3 (A), 8.2 (B) versus
8.1 (P = NA)
15
NA
Gridelli et al. [42]
CDDP/Gem or
CDDP/Vin
Gem/Vin
501
8.8 versus 7.4
(P = 0.08)
13
Comparable
survival
P-based, platinum-based chemotherapy; P-free, platinum-free chemotherapy; PS, performance status; pts, patients; CDDP, cisplatin; Doc, docetaxel; Gem,
gemcitabine; CBDCA, carboplatin; Ptx, paclitaxel; Vin, vinorelbine; Ifo, ifosfamide; NA, not available
Role of new targeted agents
In recent years, the rapidly expanding knowledge of cancer pathogenesis at a molecular level has provided new targets for drug
discovery, and a great number of new anti-cancer drugs have been
developed. Many of these biological agents are currently being
tested, at different degrees of clinical development, in NSCLC.
Several features of target-based molecules make these drugs
potentially ideal treatments for unfit patients. First, biological
therapies hold the promise of being more selective and less toxic
for normal tissues, both in terms of haematological and nonhaematological adverse effects. Second, given a cytostatic rather
than cytotoxic mechanism of action, these agents are more likely
to be effective when they are administered continuously rather
than in pulses, and oral formulations are preferred for continuous
dosing schedules, with obvious logistic advantages for patients.
ZD1839, a small-molecule tyrosine-kinase inhibitor targeted
against the epidermal growth factor receptor, is one of the most
promising new biological agents. Its activity as second- or thirdline therapy against NSCLC has been tested in two phase II trials,
showing interesting response rates (from 10% to 20% in heavily
pre-treated patients) and promising results in terms of symptom
improvement (~40%) [43–46]. It is worth noting that this symptomatic improvement is usually obtained in a short time following
the start of treatment and has also documented in PS2 patients.
Unfortunately, however, no data on first-line treatments are
currently available. New biological agents should be considered
as excellent candidates for experimental treatments in clinical
trials dedicated to PS2 patients, but as yet cannot be recommended
in clinical practice.
Consensus on clinical practice
On the basis of current evidence, chemotherapy appears justified
to patients with advanced NSCLC and a PS of 2 (Table 4). Subgroup analysis from several randomised trials suggest that several
new generation cytotoxic drugs are superior to supportive care
alone in this category of patients. Therefore, single-agent chemotherapy with these drugs (e.g. gemcitabine, vinorelbine, taxanes)
could be the preferred option for palliative treatment of these
patients. The choice of the drug should be based on the toxicity
profile of each agent and type of co-morbid conditions. No
data justify the use of platinum-free or high-dose (>100 mg/m2)
cisplatin-based combination chemotherapy instead of singleagent treatment in PS2 patients. Although lacking specific data
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taining new cytotoxic agents versus platinum-based treatment,
enrolling patients with PS between 0 and 2, have been performed
(Table 3) [38–42]. These trials are characterised by a remarkable
heterogeneity among the drugs and schedules studied. As expected,
platinum-based treatment is often associated with a higher occurrence of toxicity [38, 42]. Although a trend of slightly lower efficacy of combination chemotherapy without platinum is reported in
some trials [40, 42], none of the trials show a statistically significant advantage for platinum-containing schedules. No significant
interaction between treatment and PS in terms of overall survival
is described, and platinum-free combination chemotherapy could
represent a reasonable, less toxic option for PS2 patients.
However, there is no consistent evidence that combination
chemotherapy without platinum is better than third generation
drugs given as single agents. An Italian randomised trial compared the combination of gemcitabine and vinorelbine to the two
single drugs in patients >70 years of age [9]. PS2 patients represented 18–19% in each of the three arms of the study. The primary
analysis of the study showed that the combination was more
toxic but it did not show advantage over mono-chemotherapy in
terms of overall survival. Also in the sub-group of PS2 patients
(130 patients), there was no advantage for combination chemotherapy over single agents (1-year survival was 20%, 18% and
22%, for vinorelbine, gemcitabine and the vinorelbine–gemcitabine combination, respectively). The hazard ratio of survival for
combination chemotherapy was 1 when compared with vinorelbine and 0.97 when compared with gemcitabine.
424
Table 4. Consensus on treatment of patients with advanced
NSCLC and ECOG PS2 in clinical practice
Table 5. Research strategies in ECOG PS2 patients with advanced
NSCLC
Preferred option
Hypothesis of experimental arm
Priority
Investigational agent (e.g. pemetrexed,
oral formulations)
Medium
Alternative dose and/or scheduling of
single agents
Medium/high
Carboplatin- or low dose cisplatin-based
combination
High
Biological target-based agent without
chemotherapy
High
Supportive treatment added to chemotherapy
(e.g. haematological growth factors,
antidepressants, analgesics)
Medium
Single-agent chemotherapy with a third generation drug
(e.g. gemcitabine, vinorelbine, taxanes)
Alternative options
Carboplatin-based doublets
Cisplatin-based doublets with attenuated doses of cisplatin
ECOG, Eastern Cooperative Oncology Group; NSCLC, nonsmall-cell lung cancer; PS, performance status.
Consensus on clinical research
All the panellists participating in the meeting agreed that an
important prognostic and predictive help for clinical management
could derive from a proper sub-classification of PS2 patients.
However, it seems undeniable that the definition of prognostic
sub-groups cannot be made in a subjective fashion and the only
way to validate a prognostic score is to encourage and support
prospective data collection.
As for treatment, the analysis of the available literature performed for this panel shows the absolute need for clinical trials
specifically dedicated to PS2 patients. They represent a significant
proportion of the patients that every oncologist has to manage in
daily practice, and clinical decision making could be more strongly
founded on the results of prospective studies. As in clinical
research focused on elderly patients, in order to avoid selection
bias, evidence should be based on clinical trials dedicated to
these patients rather than on sub-group analysis coming from nonspecifically designed trials [47]. The stringent exclusion criteria,
the presence of co-morbidities, together with the subjective ‘feeling’ by the investigator that some PS2 patients could not tolerate
the treatment under study, prevent a complete generalisability of
the results obtained in the selected enrolled sub-group. Out of 43
ongoing phase II/III clinical trials for advanced NSCLC registered
in the National Cancer Institute (NCI) Clinical Trials database at
30 April 2003 [48], information on PS eligibility was available for
37 trials: 18 trials were open to patients with PS from 0 to 2, 14
trials were limited to PS0–1 with the exclusion of PS2 patients,
three trials were dedicated to unfit patients (elderly/poor PS) and
only two were dedicated to PS2. These numbers show that in
the last few years there has been a tendency to limit participation
in randomised trials to fit patients, excluding PS2 patients. Such
patients are eventually enrolled in clinical trials together with
elderly patients and patients affected by major co-morbidities,
under the common label of ‘special patient population’ or ‘patients
unsuitable for platinum-based chemotherapy’. The panellists
strongly disagree with this approach, which mixes together very
different categories, leading to heterogeneous study populations.
Elderly patients have peculiar characteristics related to physiological ageing with progressive reduction of organ functions
and are at risk of unexpected and unpredictable toxicity. In our
opinion, the differentiation of PS2 patients from elderly patients is
mandatory for clear interpretation and to improve generalisability
of trials’ results.
A consensus was reached that single-agent chemotherapy with
one of the new agents (e.g. gemcitabine, vinorelbine or taxanes)
should be the standard arm against which experimental treatments
should be tested in randomised clinical trials dedicated to PS2
patients. There is an acceptable amount of data both in terms of
survival and QoL (Table 2) which justifies the exclusion of best
supportive care alone for further clinical studies in PS2 patients.
Furthermore, there is an undeniable demand for specific treatment
by patients and their relatives: patients are often much more willing to receive intensive treatments, even when clinicians forecast
little benefit, if any [35]. In a descriptive study based on interviews asking for the preferences for chemotherapy in patients
with advanced NSCLC, only 17% of the subjects would have
accepted to be randomised between supportive care and chemotherapy [49].
Table 5 shows the most important research priorities for PS2
patients. High priority should be dedicated to prospective clinical
trials evaluating tolerability and efficacy of platinum-based combinations (carboplatin-based or low-dose cisplatin-based doublets), as
well as to trials testing the new biological target-oriented agents.
Another interesting experimental field for these patients, taking
into account the frequency of tumour-related symptoms, concomitant diseases and treatment side-effects, is the improvement
of supportive care, with the aim to better define the role and the
better schedule of administration of a wide spectrum of drugs (e.g.
antidepressants, analgesics, haematological growth factors, etc.).
Regarding the choice of end points in clinical trials, it should be
considered that symptomatic improvement is strongly requested
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in PS2 patients, the panellists considered combinations with cisplatin at lower doses (≤100 mg/m2) as a possible treatment option.
Taking into account the superiority shown by the carboplatin–
paclitaxel combination compared to paclitaxel alone, even in PS2
patients, in one clinical trial [37], carboplatin-based doublets may
also be considered as an alternative option in a selected sub-group
of patients. Stronger evidence on the latter two points is expected
from new clinical research specifically focused on PS2 patients
affected by NSCLC.
425
by the patients. When patients with advanced NSCLC, who had
already experienced a cisplatin-based chemotherapy, were asked
about the benefit thresholds to accept chemotherapy, only 22% of
patients with advanced NSCLC would have chosen chemotherapy
over best supportive care when a 3-month improvement in
survival was hypothesised, whilst a much larger proportion (68%)
chose chemotherapy if it significantly reduced symptoms, even
though not prolonging survival [49]. Although a substantial
improvement in overall survival should obviously be the ideal aim
of clinical research, considering the very poor prognosis of PS2
patients irrespective of the treatment administered, patient-related
end points other than overall survival (symptom relief, clinical
benefit, health-related QoL) should play a central role in the
planning, conducting and analysing of trials dedicated to PS2
patients.
We thank Eli Lilly for their support of the European Experts
Panel.
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