Non small cell lung cancer patients with ECOG PS2: unsolved questions and lessons from clinical trials
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Annals of Oncology16 (Supplement 4): iv123 – iv131, 2005
doi:10.1093/annonc/mdi921
Non small cell lung cancer patients with ECOG PS2: unsolved
questions and lessons from clinical trials
V. Gebbia1*, D. Galetta2 & F. De Marinis3
1
Department of Experimental Oncology and Clinical Applications, University of Palermo, Medical Oncology Unit, La Maddalena Clinic for Cancer, Palermo;
2
Experimental Oncology Unit, Istituto Tumori, Bari; 35th Unit Pulmonary Oncology, Forlanini Hospital, Rome, Italy
Key words: lung cancer, performance status 2, chemotherapy, best supportive care
Introduction seven EORTC trials showed that, after disease extent, PS was
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the most important determinant of outcome [6]. In all studies
In the last two decades the results of medical treatment
a better outcome was also associated to less disease extent,
of advanced non-small cell lung cancer (NSCLC) have
presence of less than 1 metastatic lesion, absence of liver, skin
constantly improved even if they are still far from being
or bone metastases, basal haemoglobin levels >11 gr%, normal
considered satisfactory. Today systemic cisplatin-based
LDH and alkaline phosphatase levels, absence of symptoms
chemotherapy (CT) is able to increase survival and improve
due to metastatic disease, and a preserved appetite. Recently
cancer-related symptoms in patients with advanced ‘wet’ stage
an analysis of 1436 patients treated with third-generation
III and metastatic stage IV NSCLC, but it not clear if the ben-
doublet regimens (ECOG E5592 and E1594 trials) allowed the
efits of CT also apply to patients with poor performance status
identification of six independent poor prognostic factors
(PS) [1, 2].
including PS2, presence of skin or liver metastases, loss of
PS is the most powerful independent prognostic factor in appetite, presence of less than four metastatic sites, and no
advanced NSCLC since it is a reliable measure of functional prior surgical treatment. A normogram using these six pre-
independence, ability to perform daily activities and work, treatment prognostic factors was elaborated and validated to
and a strong predictor of survival and adverse events as well predict 1-and 2-year survival in CT-naı̈ve patients. This prog-
[3]. The vast majority of prospective phase III trials had been nostic model could be potentially useful in clinical decision
conducted stratifying patients according to stage (III versus making and research planning [7].
IV) and PS (PS 0–1 versus 2). In a retrospective analysis by Despite the negative influence of poor PS on survival
the Veteran Administration Lung Group including more than parameters, the relationship between PS score and control of
5000 patients, PS recorded according to the Karnofsky Index cancer-related symptoms deserves some comments. A signifi-
was the strongest prognostic factor followed by extent of cant proportion of patients with PS2 treated with CT may
disease and weigh loss [3]. The same conclusion has been experience an improvement in tumor-related symptoms even
reached by more recent large trials using new regimens. The if a better PS is associated with better control. A study on
survival analysis of 1960 patients treated with cisplatin-based nearly 300 patients showed that 48% of PS2 patients and even
CT in five ECOG trials showed a median survival of 3.3 30% PS3 ones may experience an improvement of cancer-
months for PS2 patients as compared to 9.4 months and 6.4 related symptoms. However a better PS was a strong prognos-
months recorded for PS0 and PS1 patients, respectively [4]. A tic factor for higher symptomatic response [8]. Only one study
similar analysis of 2531 patients included in fourteen SWOG specifically analysed quality of life (QoL) in the different PS
trials also showed that a poor PS was the strongest indepen- sub-groups [9]. Patients with PS2 reported the worst scores at
dent predictor of shorter median survival (PS 0–1: 6.4 baseline assessment. The drop-out rate in PS2 patients was
months; PS > _ 2. 3.3 months) and lower 1-year survival rate greater than in the other PS levels (PS2 35% versus PS1 23%
(20% versus 9%; P < _ 0.01) [5]. These data were confirmed in a versus PS0 18%). Nevertheless, PS2 pts had significant benefit
subset of 904 patients treated with third-generation regimens from CT and, with the greater potential for palliation deter-
where the median survival of patients with PS 0–1 was 6.7 mined by worse baseline condition, showed an improvement
months while that of patients with PS > _ 2 was 3.8 months. in QoL even higher than that of patients with PS 0–1.
Data from 1052 patients treated with cisplatin-based CT in Overall, median survival of PS2 patients is substantially
shorter than that of PS 0– 1 patients, being usually <
_ 5 months
with a 1-year survival rate lower than 20% independently of
*Correspondence to: Dr Vittorio Gebbia, Via Alessandro Paternostro
n. 48, 90133 Palermo, Italy. Tel. +39-0916806906; Fax: +39-0916806906; the type of regimen employed [2]. This poor outcome had–and
E-mail: vittorio.gebbia@tin.it probably still has–a negative influence on the management of
q 2005 European Society for Medical Oncologyiv124
patients with poor PS. In fact PS2 patients have been poorly phenomenon may negatively influence conduction and con-
included or completely excluded from clinical trials. They are clusions of clinical investigations [19]. In a dedicated study
not even referred to oncology centres and offered any anti-neo- perception and evaluation of PS by patients was the worse,
plastic treatment because of expected short survival and poor while oncologists reported a better PS than that scored by
tolerance. However, in daily practice oncologists are frequently nurses and patients. However, physicians’ assessments of PS
faced with PS2 patients which may represent up to 30 –40% of best correlated with survival as compared to patients’ self-
cases with advanced NSCLC even if the exact prevalence is estimation [20]. Any medical scale employed for categorizing
still not certain [10, 11]. Unfortunately clinical data PS2 PS may carry a certain degree of un-precision due to patients
patients are quite scarce and treatment recommendations or heterogeneity even in the same subgroup, and carries in itself
guidelines are largely lacking [12, 13]. the risk of considering homogeneous patients who are hetero-
Recently the development of new active drugs with a geneous in their clinical characteristics. Therefore the ECOG
favourable therapeutic index (i.e. vinorelbine, gemcitabine and PS2 category encompasses various patient populations which
taxanes) has renewed and reinforced the need for an adequate differ for tumor burden, age, amount and degree of co-morbid
treatment of poor PS patients. A recent consensus meeting has medical conditions. Patients in fact may be classified as PS2
stated that clinical evidence is accumulating showing that because of significant tumour-related symptoms– such as dys-
treatment of PS2 patients is needed especially for symptoms pnoea, fatigue. anorexia, weight loss, and pain –or because of
control, but dedicated studies with an accurate evaluation of co-morbidities often related to concomitant smoking-related
co-morbidities and QoL must be carried out in order to define diseases and/or decreased functional status which progres-
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treatment guidelines and clearly establish the role of new sively characterize aging. Tumour-related symptoms and
drugs [12]. co-morbidity-related ones may quantitatively contribute in a
very variable fashion to the definition of poor PS and func-
tional status. In daily clinical practice oncologists may be
Who is a NSCLC patient with advanced faced with patients with low burden of tumour-related symp-
disease and ECOG PS2 ? toms but with severe co-morbidities or with patients without
co-morbid conditions but bedridden because of cancer-related
To date this apparently simple question still represents a real symptoms such as pain, fatigue or dyspnoea. As a conse-
challenge for most clinical oncologists since no clear guide- quence the administration of systemic CT may be relevant in
lines exist for defining, identifying and treating properly reducing symptoms due to cancer, but may have a negligible
patients with poor PS [12, 13]. Treatment of such patients has effect or being potentially harmful in patients with severe co-
been mainly ‘guided’ by physicians’ beliefs and personal morbidities. In most cases and particularly in elderly patients,
experience. Reliable recognition of PS2 patients and appro- functional status as well as type and degree of co-morbidities
priate evaluation of co-morbid diseases play a pivotal role in influence the medical management including CT. Poly-
establishing a therapeutic strategy [14]. pharmacy may also be a matter of concern in the whole
Several scales exist for rating PS, but the most widely patient populations and in older patients particularly.
employed are the Karnosfy Index (KI) and the ECOG Scale In conclusion the PS2 category encompasses different sub-
[15, 16]. Both instruments are used on a routinely basis to groups of patients with different risk-benefit ratios and prog-
evaluate the patients’ functional status, to standardize eligi- nosis which may deserve more tailored treatments. At present
bility for clinical trials, and to predict prognosis. The two data concerning the relative impact of specific tumour-related
scales are different since the former categorizes patients symptoms and concomitant illnesses on the therapeutic choice
according to a percentage ranging from 100% to 0, while the and patients’ outcome in order to establish a more detailed
latter employs only five scores based on the impact of cancer- categorization of PS2 patients are lacking. This heterogeneity
related symptoms on daily activities and proportion of hours of PS2 patients contributes significantly to the difficulties in
spent walking or resting. Generally KI has less ability than the development of a unique strategy and in conducting dedi-
ECOG to discriminate patients with different prognosis, and cated clinical trials. Therefore the ECOG scale may be not
in the last decade the latter has been preferred in most large entirely appropriated to define the PS2 category.
clinical trials due to the lower rate of inter-observer variability
and its greater easy of administration [10]. Both scales are
subjected to a certain degree of intra- and inter-observer varia- Role of chemotherapy in PS2 patients: data
bility due to subjective evaluation even if administered by
from controlled clinical trials
healthcare professionals [17]. Conversions between the two
scales are possible but changes from KI to ECOG are gener- Overall, CT-naı̈ve patients with PS2 show lower objective
ally approximated, often uneasy, and may led to under- or overall response rate (ORR) to systemic CT, shorter median
overestimation of PS [18]. The PS2 category is roughly equi- time to progression (TTP), progression-free survival, 1-year
valent to a KI score of 60% or 70%, but conversion errors are survival rate (SR), and overall survival (OS) as compared to
quite frequent since some caregivers include also a 50% score patients with PS 0–1. Since late nineties, prospective clinical
[10]. Scientific evidence of discrepancies in PS evaluation trials had shown a superiority of systemic CT over best sup-
between oncologists, nurses and patients exists. Such portive care (BSC) in terms of OS and QoL [21, 22]. In 1995iv125
data from a very large meta-analysis showed a statistically analysis of PS2 patients subgroup was later reported showing
significant benefit for cisplatin-based regimens, and a sub- an slight advantage for the GEM arm over BSC one (3.2
group analysis demonstrated the persistence of this benefit for versus 2.6 months) (12). To date the treatment of PS2 must
both good and poor PS patients despite heterogeneity of treat- take into account the underlying concomitant diseases and
ments analyzed [23]. QoL issues [30].
Mono-chemotherapy Mono- versus poly-chemotherapy
The meta-analysis did not include data achieved with the new The meta-analysis published in 1995 demonstrated that the
third-generation drugs such as vinorelbine (VNR), gemcita- ORR obtained with poly-CT was two times greater than that
bine (GEM), docetaxel (DCT) and paclitaxel (PTX) [23]. achieved with single-agent CT with only a most gain in survi-
When give a s single-agent, these drugs have shown a fairly val [23]. Subset analysis showed that this difference is lost if
good therapeutic index which render them suitable for the very active agents, such as VNR or cisplatin (CDDP), were
treatment of poor PS patients [24]. Most of the trials with employed as mono-CT [23, 31].
these agents compared to BSC showed an advantage in survi- Recently it has been published a retrospective analysis of a
val parameters and QoL for mono-CT which persisted also for pivotal, large European phase III trial comparing single-agent
PS2 patients. However these data should be interpreted with VNR to CDDP/VNR and CDDP/vindesine in more than 600
caution since these trials were not specifically designed for patients carried out a decade ago [32, 33]. The regimen used
in this trial employed CDDP at 120 mg/m2, a dosage not con-
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PS2 patients and included small populations of PS2 patients
which may render the results of subgroups analysis uncertain. sidered anymore as a standard therapy. The outcome of the
Four randomised trials of BSC versus single-agent drugs 120 patients with PS2 treated with CDDP-based doublets was
suggested a possible use of CT in patients with PS2. The no better than those receiving single-agent VNR [33].
ELVIS trial randomised 154 elderly patients –including 41 The CALGB carried out a randomised phase III study
patients with PS2 (24%) –to receive BSC plus VNR (CALGB 9730) comparing single-agent PTX to the combi-
(30 mg/m2 i.v. on day 1 and 8 every 3 weeks) or BSC alone nation of PTX and carboplatin (CBDCA) in patients with
[25]. Patients treated with VNR showed both a longer median advanced NSCLC stratified by stage (IIIB vs. IV), age (_ 70 years) and PS (0 –1 versus 2). Among a total of
sus 21 weeks, and 32% versus 14%, P = 0.03). This advantage 561 eligible patients, 99 patients with PS2 were enrolled
persisted also when only PS2 patients were analysed, i.e. 6.4 (18%), the largest number ever accrued to a cooperative group
months for VNR versus 1.9 months for BSC [12, 25]. phase III trial [34]. PS2 patients had a median OS of 3 months
A second trial compared single-agent PTX (200 mg/m2 and a 1-year SR of 14% as compared to PS 0– 1 patients
every 3 weeks) to BSC in a series of 157 patients (17% PS2) which had an OS of 8.8 months and a 1-year SR of 38%.
showing a better OS for the CT arm (6.8 versus 4.8 months, Patients with PS2 treated with combination CT had a higher
P = 0.037) with a small benefit in the functional activity ORR (24% versus 10%), a longer median OS (4.7 versus 2.4
domain of QoL recorded according the Rotterdam Symptoms months, P = 0.01) and better 1-year SR than those who receive
Checklist [26]. The advantage for CT over BSC persisted also mono-CT (18% versus 10%). The difference was statistically
when only PS2 patients were analysed (4.1 versus 2.9 months) significant and indeed of greater magnitude than that observed
[12]. between the two arms in patients with PS 0–1. Analysis of
DCT 100 mg/m2 every 3 weeks was also compared to BSC QoL parameters showed no detrimental effect for PS2 patients
in a series of 207 patients of whom 41 had PS2 [27]. Although treated with the combination regimen.
median OS was similar in both arms, both 1-year and 2-year The MILES study enrolled nearly 700 patients older than
SR as well as QoL were in favour of DCT. However no sub- 69 years of whom 19% has PS2 [35]. Patients were rando-
groups analysis for PS2 patients has been published so far. mised to receive single-agent VNR 30 mg/m2, single-agent
Recently weekly DCT alone or in combination with GEM has GEM 1000 mg/m2, or VNR (25 mg/m2) plus GEM
been employed in a small series of elderly and poor PS (1000 mg/m2) on day 1 and 8 every 3 weeks. Median OS as
patients with interesting results [28]. well as QoL analysis (EORTC QlQ-C30, and LC13) did not
Another prospective trial randomised 300 patients –inclu- differ significantly among the three arms even when subgroup
ding 108 patients with PS2 –to receive BSC or GEM analysis for PS patients was performed.
1000 mg/m2 on day 1, 8, and 15 every 4 weeks [29]. The pri- The issue of mono- versus poly-CT has been recently
mary endpoint was patients’ assessment of symptoms employ- addressed by the Hellenic Co-Operative Oncology Group who
ing the SS14 score system. GEM was associated with a higher carried out a prospective randomised phase II trial of single-
rate of sustained (>_ 4 weeks) improvement >
_ 25% in the SS14 agent GEM (1250 mg/m2 q 14 days every 4 weeks) and GEM
score as compared to BSC alone (22% versus 9%; (1250 mg/m2) plus CBDCA (AUC3 q 14 days every 4 weeks)
P = 0.0014). Moreover, cough, pain, fatigue, emotional state with clinical benefit as primary endpoint [36]. Out of 51
and cognitive function were also improved in the CT arm. OS patients enrolled in each arm with a median age > _ 70 years,
was not different in the two arms –5.7 and 5.9 months for 25% of patients treated with GEM and 35% had response
GEM and BSC respectively (P = 0.84). However survival or stable disease with a TTP of 2.98 and 4.07 monthsiv126
respectively. Median OS was 4.8 and 6.7 months with 17.8% PS but without statistical significance. Review of toxic deaths
and 20% 1-year SR. None of these differences reached a stat- showed that only a part of the events were treatment-related
istical significance. Grade 3–4 neutropenia, thrombocytopenia and the remaining were secondary, at least in part, to the
and anaemia were significantly more frequent in the poly-CT concomitant diseases often associated with an impaired PS.
arm. However, the percentage of general feeling improvement The Spanish Lung Cancer Group carried out a phase III
(64% versus 65%) and that of patients with at least one symp- trial where 557 patients were randomised to receive GEM and
tom improved (71% versus 67%), but were not different VNR followed by VNR and ifosfamide, GEM/CDDP or a
between the two groups. The authors concluded that triplet of GEM, VNR and CDDP [39]. Overall, 16.5% of
GEM/CBDCA was not superior to GEM alone in terms of patients had PS2. No difference in OS among the three arms
clinical benefit, median TTP and OS, while the two drug regi- was detected, but the non-platinum sequential treatment and
mens was significantly more toxic. the triplet regimen were associated with significantly more
toxicity than the GEM/CDDP doublet which was considered
Polychemotherapy as the standard regimen. Although results were not analysed
for subgroups, however median OS of PS2 patients was
Data concerning the outcome of PS2 patients treated with 4.7 months as compared to 9.4 months of PS 0–1 patients
poly-CT stem from retrospective subgroup analysis of large (P = 0.0001). Similar conclusions were reached by an Italian
prospective trials aimed to find the most active doublet, to Lung Cancer Project which retrospectively showed that in PS2
establish if triplet regimens were more active than doublets, patients RR, TTP, OS were significantly lower than those of
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and if CDDP could be omitted. In these studies the vast PS 0–1 patients [40, 41].
majority of enrolled patients had a good PS of 0–1, while
As shown in Figure 1, a retrospective review of all prospec-
generally only less than 20% of enrolled patients had PS2.
tive trials carried out by the Gruppo Oncologico dell’Italia
However, recently the number of ongoing trials specifically
Meridionale [42–47] has confirmed that 203 PS2 patients out
designed for poor PS patients has rapidly increased.
of 1108 patients suitable for CDDP-based doublets with new
The ECOG study E1594 included 64 evaluable PS2 patients drugs have a poorer outcome than patients with PS 0–1 (9
randomised to receive PTX/CDDP, GEM/CDDP, DCT/CDDP versus 5.5 months, P = 0.001; 1-year SR 30% versus 13%)
or PTX/CBDCA [37, 38]. Globally, the ORR was 14%, (VG, personal communication). The relationship between age,
median TTP was 1.7 months, median OS according to an
number of co-morbid disorders and survival have been ana-
intent-to-treat analysis was 4.1 months with a 1-year SR of
lysed as shown in Figure 2. The relationship between age and
19%. There were no significant differences among the 4 treat-
survival was not statistically significant (r2 = 0.0148,
ment arms in terms of ORR and TTP. The only significant
P = 0.083), while a statistically significant correlation was
difference was a higher median OS in the PTX/CDDP arm
observed between number of co-morbidities and survival
(7 months) as compared to the DCT/CDDP arm (2.3 months).
(r2 = 0.02; P = 0.044).
The clinical outcome of PS2 patients was significantly inferior
The Hellenic Cooperative Oncology Group randomised 509
to that of PS 0–1 patients with the exception of ORR which
patients to GEM/PTX versus PTX/CBDCA [48]. Nearly 60
was similar to that reported for good PS patients. Patients in
patients had PS2 and showed lower ORR (11% versus 34%)
the GEM/CDDP arm had the highest ORR and best median
and shorter median OS than PS 0–1 counterparts (5.9 versus
OS, but suffered of the worst toxicity probably related to the
11.1 months; P = 0.0001), while toxicity was very similar. The
use of high-dose CDDP. The PTX/CBDCA arm showed the
EORTC study compared GEM/CDDP to PTX/CDDP or
best tolerance with the exception of peripheral neuropathy.
Accrual of PS2 patients was stopped because an interim analy-
sis of toxicity had shown a higher ‘incidence of serious Overall Survival
adverse events’ including a 7.35% death rate (5 patients) as 100
compared to PS 0–1 patients. However, a subsequent more 90 PS 0-1 median OS 9 months
accurate analysis showed that the overall toxicity experienced 80
PS 2 median OS 5.5 months
Percent surviving
by PS2 patients was not significantly different from that 70
p=0.001; HR 1.95
experienced by PS 0–1 patients. The reported treatment- 60
related death rate in PS2 patients was only 3% (2 patients) as
50
compared to 4% in PS 0–1 ones. The other deaths were con-
sidered to be due to tumour progression. The high incidence 40 30%
of side-effects that caused accrual of PS2 was not only CT- 30
related but also due to rapidly progressive disease and co-mor- 20 13%
bid conditions. The conclusion was that these regimens with 10
these schedules were not considered as a standard treatment 0
for PS2 patients and that new regimens with attenuated doses 0 2 4 6 8 10 12 14 16 18 20 22 24
had to be tested in this particular subset of patients. Analysis Months since registration
of toxicity confirmed a relatively higher rate of grade 3 –4 Figure 1. Outcome of patients as compared to that with PS0-1 in GOIM
side-effects in PS2 patients as compared to those with better trials.iv127
80 Age Comorbidities was 12%, median TTP 3.7 months, OS 6 months with a
5
1-year SR of 28%. The most important grade 3–4 side-effects
4 were neutropenia (10%) and fatigue (10%), nausea (8%),
N. of comorbidies
70 dehydration (7%), and vomiting (5%). A Canadian group
Age (years)
3 reported a multi-centre phase II study with a sequential treat-
60 ment of VNR (30 mg/m2 day 1 + 8 q 3 weeks) followed by
2 GEM (1000 mg/m2 day 1 + 8 q 3 weeks) in a series of 44
patients [53]. A partial response was achieved in 28% of
50
1 patients with a median TTP of 3.5 months and a median survi-
val slightly over 6 months and a 1-year SR of 18%. Toxicity
40 0 was mild with no case of grade 3– 4 side-effects. However
patients with PS or elderly with co-morbid diseases were
0 2 4 6 8 10 12 14 16 18 20
Survival (months from registration)
included in the same trial and no subgroup analysis is avail-
able at present.
Figure 2. Relationship between age, co-morbidities, and survival in PS2
patients (GOIM trials). The perception that palliation of cancer-related symptoms
plays a pivotal role in PS2 patients because of their poor out-
PTX/GEM in a series of 480 patients. A trend in favour of the come has been explored in a phase II trial employing a combi-
GEM/CDDP regimen was found, while PS2 was reported to nation of DCT and GEM [51, 54]. In a series of 30 patients a
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be the only poor prognostic factor across arms. 33% ORR was recorded with a median survival of 4.1 months
[54]. A recent trial analyzed the efficacy and tolerability of
Recently, investigators of the ECOG reported the first ran-
DCT given at 75 mg/m2 every 3 weeks or on a weekly sche-
domised phase II trial (ECOG 1599) specifically carried out to
dule at the dose of 30 mg/m2 in a series of 42 patients with
test the effectiveness of two platinum-based regimens in PS2
PS2 [55]. Tolerability of both schedules was similar with a
patients [49, 50]. The authors employed ‘attenuated doses’ of
very slight trend toward longer survival in patients treated
the GEM/CDDP regimen (GEM 1000 mg/m2 on day 1 + 8,
with the weekly schedule. The SWOG treated 44 patients with
CDDP 60 mg/m2 on day 1 q 3 weeks) and the PTX/CBDCA
PS2 with a sequential regimen of single-agent VNR 25 mg/m2
one (PTX 200 mg/m2, CBDCA AUC 6 both on day 1 q 3
on day 1 and 8 every 3 weeks followed by DCT 35 mg/m2 on
weeks). These two regimens had been shown to be respect-
day 1,8 and 15 every 4 weeks [56]. The ORR was 10% with a
ively the most active and the best tolerated ones in PS2
median OS of 4 months and a 14% 1-year SR. Tolerability of
patients in the retrospective analysis of the previous ECOG
CT was acceptable.
1594 trial. The study was designed to accrue 99 patients in
order to detect a 10% absolute improvement in 1-year SR as
compared to historical controls including data from the ECOG
1594 trial. An interim analysis of tolerability did not show an New investigational drugs
excess of toxicity with only one grade 5 CT-induced-related New biologically targeted drugs are widely investigated for
event in the PTX/CBDCA arm. The GEM/CDDP regimen their possible role in the management of advanced NSCLC
yielded a 25% ORR as compared to 16% recorded in the due to their good therapeutic index. Recently gefinitib
PTX/CBDCA arm. Disease control rates were more than 50% (ZD1839), a small molecule which inhibits tyrosine kinase,
in both arms. TTP was 4.2 and 4.8 months and median OS was given at the dose of 250 mg/day until progression to a
was 6.1 and 6.8 for the GEM/CDDP arm and the group of 25 previously untreated patients with PS2– 3 [57].
PTX/CBDCA one respectively. The 1-year SR was 25% and No partial responses were seen, but 61% of patients had stable
19% respectively. The survival figures were longer than disease and 32% had an improvement in symptoms as evalu-
expected from data derived from previous ECOG 1594 and ated by the Lung Cancer Symptom Scale (LCSS) and the
CALGB 9730 studies. As expected haematological side- FACT-L. Gefinitib was well tolerated with no grade 3–4 side-
effects, thrombocytopenia in particular, nausea/vomiting and effects. Although the impact on survival is difficult to ascer-
mild renal toxicity were more frequent in the GEM/CDDP tain, however, gefinitb seems safe and active in patients with
arm while the incidence of peripheral neurotoxicity and myal- PS2–3. A retrospective analysis of 84 patients with PS2 trea-
gias/arthralgias was higher in the PTX/CBDCA arm. ted with gefinitib achieved a median survival of 2 months and
The widespread concern that PS2 patients can experience a 1-year SR of 15.6% [58]. A similar ORR of 14% was
severe toxicity if challenged with full dose CDDP-based doub- recorded in the IDEAL trials which included patients treated
let regimens has led to investigations aimed to explore the with gefinitb after failure of at least two different CT regimens
role of non-platinum doublets. To date this issue has not been [59].
addressed in PS2 patients by any prospective randomised trial, CT-2103 (i.e. paclitaxel poliglutamex) is a novel paclitaxel
but data from phase II studies are suggestive [51–54]. conjugate that is currently undergoing investigation in patients
Weissmann et al. [52] carried out a phase II trial of weekly with poor PS [50, 60]. The phase II trials in PS2 patients
DCT/CBDCA (35 mg/m2 and AUC2 on day 1, 8, and 15 q 4 reported a median OS of 5.4 months with a favourable toxicity
weeks) in 59 patients younger than 65 years with PS2. ORR profile mainly represented by less haematological toxicity,iv128
neurotoxicity, and alopecia as compared to taxanes. Based on diseases tend to increase with aging, vary significantly in
the these results the Selective Targeting for Efficacy in Lung severity, and may affect many organs and systems often sim-
Cancer, Lower Adverse Reactions trials (STELLAR) 3 and 4 ultaneously [62]. This complex variable is poorly correlated to
have been recently carried out. The STELLAR 3 is a phase III PS, at least in elderly patients, and deeply influences phys-
trial comparing CT-2103 210 mg/m2 and CBDCA to standard icians’ treatment choice in clinical practice since they suggest
PTX 225 mg/m2 plus CBDCA in chemotherapy-naı̈ve PS2 particular caution in drug choice [63]. The obvious great
patients with stage IIIB ‘wet’ and stage IV NSCLC. variability of possible clinical pictures makes a decision-mak-
The STELLAR 4 trial compares a lower dose (175 mg/m2) of ing algorithm very difficult to build and validate [11]. The
CT-2103 with single-agent VNR or GEM in a similar popu- relationship between number and severity of co-morbidities
lation. Final results of both trials are awaited with interest. and aging is another complex issue [64]. In elderly patients,
three factors play a fundamental role in managing cancer: the
functional status, the presence of co-morbid illnesses, and
Are PS2 patients enrolled in clinical trials ageing-specific phenomena as depression, alteration in mental
representative of the ‘real’ patient status, reduced nutritional status, and lower social support.
population? The precise definition of the relative weight of co-morbi-
The answer is no. Patients with significant or multiple co-mor- dities in patients with poor PS play a pivotal role in designing
bidities have usually been not enrolled in large clinical trials and conducting committed trials as well as establishing treat-
because the impact of co-morbid disease on clinical outcome ment guidelines. The Cumulative Illness Rating Scale for
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is quite difficult to ascertain without specifically committed Geriatrics (CIRS-G) is a useful instrument to define the effects
studies. Moreover, in the last two decades CT has been con- of multiple concomitant diseases. The CIRS-G assesses
sidered poorly useful, if not detrimental, in patients with PS 13–14 organ systems and grades the severity from 0 to 4. The
>
_ 2. Potential gains have been considered to be overcome by CIRS-G score has been shown to be a powerful independent
risks and side-effects. Moreover the management of PS2 prognostic factor in patients with locally advanced NSCLC
patients undergoing CT is certainly much more complex than undergoing RT [65]. An other validated instrument is the
that of more ‘fit’ patients. Therefore patients with PS2 encoun- Charlson scale which evaluates 19 different diseases associ-
tered in clinical practice are quite different from those ated with a higher 1-year mortality in internal medicine. The
enrolled in clinical trials. An other important issue regards Charlson score has been found to be strongly associated with
poor PS patient referral to the oncology centres. As many as OS, tolerance to CT, and therapy discontinuation rate in
60% of patients with advanced NSCLC may not be evaluated elderly patients with advanced NSCLC. When the two scales
for a potentially useful palliative chemotherapeutic treatment. are used in the same population, the CIRS-G scale identified
Committed studies to evaluate the size and the clinical charac- as >90% prevalence of co-morbidities with the Charlson only
teristics of PS2 patient population are strongly needed. 36%. Recently, the Comprehensive Geriatric Assessment has
been shown to add useful clinical information on the func-
tional status of patients evaluated for PS according to the
Do co-morbidities influence treatment choice? ECOG scale [66]. In fact there is evidence that ECOG PS
Several different approaches have been used in the therapeutic scoring system is not precisely related to functional capacity
strategy for PS2 patients. Third-generation doublets have been in patients with advanced NSCLC [67]. Future trials com-
employed with ‘attenuated doses’ of CDDP, while in other mitted to poor PS patients need to include this type of evalu-
instances CBDCA substituted for CDDP when oncologists felt ation to establish the most appropriate treatment strategy and
the patients unfit for CDDP and wanted to avoid CDDP- to better evaluate the possible benefits of anti-neoplastic
related morbidity. Another approach has been represented by treatments.
the use of single-agents with highest possible therapeutic Evaluation of PS, functional status and co-morbidities
index, such as GEM, VNR and taxanes, and more recently should be paralleled by the analysis of cancer-related symp-
erlotinib or gefinitib. The current recommendation by the toms relief and QoL. This issue is particularly important
American Society of Clinical Oncology and the National especially in PS2 patients whose life expectancy as well as
Comprehensive Cancer Network suggest single-agent CT for survival gain by CT are limited. Clinical data support that the
the treatment of PS2 patients. However, this variability of possible improvement in symptoms control in PS2 patients
treatment approaches in clinical practice mostly reflects the may be even greater than in patients with better PS. Therefore
significant clinical heterogeneity of PS2 patients [61]. the skilled use of LSCS would be extremely useful in this set-
As stated above, both cancer-related symptoms and co- ting. QoL has been shown to have a definite prognostic value
morbid medical illnesses may variously contribute to patients’ as concern response to treatment and survival. The ECOG
PS, individual tolerance to CT, and potential gains in terms of trial 5592 showed that an high basal score of the FACT-L sub-
survival and QoL. While CT-induced side-effects are well scales were powerful predictors of response to CT with a
categorized and cancer-related symptoms are easily sized reduced risk of progressive disease and death [68].
using appropriate instruments, co-morbidities represent a Another important issue is optimization of BSC. For
significant multidimensional clinical variable. Co-morbid instance, correct and prompt use of erythropoiesis stimulatingiv129
agents to control anemia is most important since mild to mod- 5. Albain KS, Crowley JJ, LeBlanc M et al. Survival determinants in
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patients with lung cancer and concurrent pulmonary and/or 6. Paesmans M, Sculier JP, Libert P et al. Prognostic factors for survival
in advanced non small- cell lung cancer: univariate and multivariate
cardiovascular diseases is crucial to QoL. A direct relationship
analyses including recursive partitioning and amalgamation algor-
exists between decline in QoL and anemia independent of
ithms in 1,052 patients. The European Lung Cancer Working Party.
objective response to CT [69]. J Clin Oncol 1995; 13: 1221–1230.
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Conclusions
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CT with new generation cytotoxic agents such as GEM, VNR liative chemotherapy in non-small cell lung cancer extends to the
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