Non small cell lung cancer patients with ECOG PS2: unsolved questions and lessons from clinical trials

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1 Annals of Oncology16 (Supplement 4): iv123 iv131, 2005 doi: /annonc/mdi921 Non small cell lung cancer patients with ECOG PS2: unsolved questions and lessons from clinical trials V. Gebbia 1 *, D. Galetta 2 & F. De Marinis 3 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; 3 5 th Unit Pulmonary Oncology, Forlanini Hospital, Rome, Italy Key words: lung cancer, performance status 2, chemotherapy, best supportive care Introduction In the last two decades the results of medical treatment of advanced non-small cell lung cancer (NSCLC) have constantly improved even if they are still far from being considered satisfactory. Today systemic cisplatin-based chemotherapy (CT) is able to increase survival and improve cancer-related symptoms in patients with advanced wet stage III and metastatic stage IV NSCLC, but it not clear if the benefits of CT also apply to patients with poor performance status (PS) [1, 2]. PS is the most powerful independent prognostic factor in advanced NSCLC since it is a reliable measure of functional independence, ability to perform daily activities and work, and a strong predictor of survival and adverse events as well [3]. The vast majority of prospective phase III trials had been conducted stratifying patients according to stage (III versus IV) and PS (PS 0 1 versus 2). In a retrospective analysis by the Veteran Administration Lung Group including more than 5000 patients, PS recorded according to the Karnofsky Index was the strongest prognostic factor followed by extent of disease and weigh loss [3]. The same conclusion has been reached by more recent large trials using new regimens. The survival analysis of 1960 patients treated with cisplatin-based CT in five ECOG trials showed a median survival of 3.3 months for PS2 patients as compared to 9.4 months and 6.4 months recorded for PS0 and PS1 patients, respectively [4]. A similar analysis of 2531 patients included in fourteen SWOG trials also showed that a poor PS was the strongest independent predictor of shorter median survival (PS 0 1: 6.4 months; PS >_ months) and lower 1-year survival rate (20% versus 9%; P <_0.01) [5]. These data were confirmed in a subset of 904 patients treated with third-generation regimens where the median survival of patients with PS 0 1 was 6.7 months while that of patients with PS >_ 2 was 3.8 months. Data from 1052 patients treated with cisplatin-based CT in *Correspondence to: Dr Vittorio Gebbia, Via Alessandro Paternostro n. 48, Palermo, Italy. Tel ; Fax: ; vittorio.gebbia@tin.it seven EORTC trials showed that, after disease extent, PS was the most important determinant of outcome [6]. In all studies a better outcome was also associated to less disease extent, presence of less than 1 metastatic lesion, absence of liver, skin or bone metastases, basal haemoglobin levels >11 gr%, normal LDH and alkaline phosphatase levels, absence of symptoms due to metastatic disease, and a preserved appetite. Recently an analysis of 1436 patients treated with third-generation doublet regimens (ECOG E5592 and E1594 trials) allowed the identification of six independent poor prognostic factors including PS2, presence of skin or liver metastases, loss of appetite, presence of less than four metastatic sites, and no prior surgical treatment. A normogram using these six pretreatment prognostic factors was elaborated and validated to predict 1-and 2-year survival in CT-naïve patients. This prognostic model could be potentially useful in clinical decision making and research planning [7]. Despite the negative influence of poor PS on survival parameters, the relationship between PS score and control of cancer-related symptoms deserves some comments. A significant proportion of patients with PS2 treated with CT may experience an improvement in tumor-related symptoms even if a better PS is associated with better control. A study on nearly 300 patients showed that 48% of PS2 patients and even 30% PS3 ones may experience an improvement of cancerrelated symptoms. However a better PS was a strong prognostic factor for higher symptomatic response [8]. Only one study specifically analysed quality of life (QoL) in the different PS sub-groups [9]. Patients with PS2 reported the worst scores at baseline assessment. The drop-out rate in PS2 patients was greater than in the other PS levels (PS2 35% versus PS1 23% versus PS0 18%). Nevertheless, PS2 pts had significant benefit from CT and, with the greater potential for palliation determined by worse baseline condition, showed an improvement in QoL even higher than that of patients with PS 0 1. 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 the type of regimen employed [2]. This poor outcome had and probably still has a negative influence on the management of q 2005 European Society for Medical Oncology

2 iv124 patients with poor PS. In fact PS2 patients have been poorly included or completely excluded from clinical trials. They are not even referred to oncology centres and offered any anti-neoplastic treatment because of expected short survival and poor tolerance. However, in daily practice oncologists are frequently faced with PS2 patients which may represent up to 30 40% of cases with advanced NSCLC even if the exact prevalence is still not certain [10, 11]. Unfortunately clinical data PS2 patients are quite scarce and treatment recommendations or guidelines are largely lacking [12, 13]. Recently the development of new active drugs with a favourable therapeutic index (i.e. vinorelbine, gemcitabine and taxanes) has renewed and reinforced the need for an adequate treatment of poor PS patients. A recent consensus meeting has stated that clinical evidence is accumulating showing that treatment of PS2 patients is needed especially for symptoms control, but dedicated studies with an accurate evaluation of co-morbidities and QoL must be carried out in order to define treatment guidelines and clearly establish the role of new drugs [12]. Who is a NSCLC patient with advanced disease and ECOG PS2? To date this apparently simple question still represents a real challenge for most clinical oncologists since no clear guidelines exist for defining, identifying and treating properly patients with poor PS [12, 13]. Treatment of such patients has been mainly guided by physicians beliefs and personal experience. Reliable recognition of PS2 patients and appropriate evaluation of co-morbid diseases play a pivotal role in establishing a therapeutic strategy [14]. Several scales exist for rating PS, but the most widely employed are the Karnosfy Index (KI) and the ECOG Scale [15, 16]. Both instruments are used on a routinely basis to evaluate the patients functional status, to standardize eligibility for clinical trials, and to predict prognosis. The two scales are different since the former categorizes patients according to a percentage ranging from 100% to 0, while the latter employs only five scores based on the impact of cancerrelated symptoms on daily activities and proportion of hours spent walking or resting. Generally KI has less ability than ECOG to discriminate patients with different prognosis, and in the last decade the latter has been preferred in most large 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 variability due to subjective evaluation even if administered by healthcare professionals [17]. Conversions between the two scales are possible but changes from KI to ECOG are generally approximated, often uneasy, and may led to under- or overestimation of PS [18]. The PS2 category is roughly equivalent to a KI score of 60% or 70%, but conversion errors are quite frequent since some caregivers include also a 50% score [10]. Scientific evidence of discrepancies in PS evaluation between oncologists, nurses and patients exists. Such phenomenon may negatively influence conduction and conclusions of clinical investigations [19]. In a dedicated study perception and evaluation of PS by patients was the worse, while oncologists reported a better PS than that scored by nurses and patients. However, physicians assessments of PS best correlated with survival as compared to patients selfestimation [20]. Any medical scale employed for categorizing PS may carry a certain degree of un-precision due to patients heterogeneity even in the same subgroup, and carries in itself the risk of considering homogeneous patients who are heterogeneous in their clinical characteristics. Therefore the ECOG PS2 category encompasses various patient populations which differ for tumor burden, age, amount and degree of co-morbid medical conditions. Patients in fact may be classified as PS2 because of significant tumour-related symptoms such as dyspnoea, fatigue. anorexia, weight loss, and pain or because of co-morbidities often related to concomitant smoking-related diseases and/or decreased functional status which progressively characterize aging. Tumour-related symptoms and co-morbidity-related ones may quantitatively contribute in a very variable fashion to the definition of poor PS and functional status. In daily clinical practice oncologists may be faced with patients with low burden of tumour-related symptoms but with severe co-morbidities or with patients without co-morbid conditions but bedridden because of cancer-related symptoms such as pain, fatigue or dyspnoea. As a consequence the administration of systemic CT may be relevant in reducing symptoms due to cancer, but may have a negligible effect or being potentially harmful in patients with severe comorbidities. In most cases and particularly in elderly patients, functional status as well as type and degree of co-morbidities influence the medical management including CT. Polypharmacy may also be a matter of concern in the whole patient populations and in older patients particularly. In conclusion the PS2 category encompasses different subgroups of patients with different risk-benefit ratios and prognosis which may deserve more tailored treatments. At present data concerning the relative impact of specific tumour-related symptoms and concomitant illnesses on the therapeutic choice and patients outcome in order to establish a more detailed categorization of PS2 patients are lacking. This heterogeneity of PS2 patients contributes significantly to the difficulties in the development of a unique strategy and in conducting dedicated clinical trials. Therefore the ECOG scale may be not entirely appropriated to define the PS2 category. Role of chemotherapy in PS2 patients: data from controlled clinical trials Overall, CT-naïve patients with PS2 show lower objective overall response rate (ORR) to systemic CT, shorter median time to progression (TTP), progression-free survival, 1-year survival rate (SR), and overall survival (OS) as compared to patients with PS 0 1. Since late nineties, prospective clinical trials had shown a superiority of systemic CT over best supportive care (BSC) in terms of OS and QoL [21, 22]. In 1995

3 iv125 data from a very large meta-analysis showed a statistically significant benefit for cisplatin-based regimens, and a subgroup analysis demonstrated the persistence of this benefit for both good and poor PS patients despite heterogeneity of treatments analyzed [23]. Mono-chemotherapy The meta-analysis did not include data achieved with the new third-generation drugs such as vinorelbine (VNR), gemcitabine (GEM), docetaxel (DCT) and paclitaxel (PTX) [23]. When give a s single-agent, these drugs have shown a fairly good therapeutic index which render them suitable for the treatment of poor PS patients [24]. Most of the trials with these agents compared to BSC showed an advantage in survival parameters and QoL for mono-ct which persisted also for PS2 patients. However these data should be interpreted with caution since these trials were not specifically designed for PS2 patients and included small populations of PS2 patients which may render the results of subgroups analysis uncertain. Four randomised trials of BSC versus single-agent drugs suggested a possible use of CT in patients with PS2. The ELVIS trial randomised 154 elderly patients including 41 patients with PS2 (24%) to receive BSC plus VNR (30 mg/m 2 i.v. on day 1 and 8 every 3 weeks) or BSC alone [25]. Patients treated with VNR showed both a longer median OS and higher 1-year SR as compared to BSC alone (28 versus 21 weeks, and 32% versus 14%, P = 0.03). This advantage persisted also when only PS2 patients were analysed, i.e. 6.4 months for VNR versus 1.9 months for BSC [12, 25]. A second trial compared single-agent PTX (200 mg/m 2 every 3 weeks) to BSC in a series of 157 patients (17% PS2) showing a better OS for the CT arm (6.8 versus 4.8 months, P = 0.037) with a small benefit in the functional activity domain of QoL recorded according the Rotterdam Symptoms Checklist [26]. The advantage for CT over BSC persisted also when only PS2 patients were analysed (4.1 versus 2.9 months) [12]. DCT 100 mg/m 2 every 3 weeks was also compared to BSC in a series of 207 patients of whom 41 had PS2 [27]. Although median OS was similar in both arms, both 1-year and 2-year SR as well as QoL were in favour of DCT. However no subgroups analysis for PS2 patients has been published so far. Recently weekly DCT alone or in combination with GEM has been employed in a small series of elderly and poor PS patients with interesting results [28]. Another prospective trial randomised 300 patients including 108 patients with PS2 to receive BSC or GEM 1000 mg/m 2 on day 1, 8, and 15 every 4 weeks [29]. The primary endpoint was patients assessment of symptoms employing the SS14 score system. GEM was associated with a higher rate of sustained (>_4 weeks) improvement >_25% in the SS14 score as compared to BSC alone (22% versus 9%; P = ). Moreover, cough, pain, fatigue, emotional state and cognitive function were also improved in the CT arm. OS was not different in the two arms 5.7 and 5.9 months for GEM and BSC respectively (P = 0.84). However survival analysis of PS2 patients subgroup was later reported showing an slight advantage for the GEM arm over BSC one (3.2 versus 2.6 months) (12). To date the treatment of PS2 must take into account the underlying concomitant diseases and QoL issues [30]. Mono- versus poly-chemotherapy The meta-analysis published in 1995 demonstrated that the ORR obtained with poly-ct was two times greater than that achieved with single-agent CT with only a most gain in survival [23]. Subset analysis showed that this difference is lost if very active agents, such as VNR or cisplatin (CDDP), were employed as mono-ct [23, 31]. Recently it has been published a retrospective analysis of a pivotal, large European phase III trial comparing single-agent VNR to CDDP/VNR and CDDP/vindesine in more than 600 patients carried out a decade ago [32, 33]. The regimen used in this trial employed CDDP at 120 mg/m 2, a dosage not considered anymore as a standard therapy. The outcome of the 120 patients with PS2 treated with CDDP-based doublets was no better than those receiving single-agent VNR [33]. The CALGB carried out a randomised phase III study (CALGB 9730) comparing single-agent PTX to the combination of PTX and carboplatin (CBDCA) in patients with advanced NSCLC stratified by stage (IIIB vs. IV), age (<70 years vs. >_70 years) and PS (0 1 versus 2). Among a total of 561 eligible patients, 99 patients with PS2 were enrolled (18%), the largest number ever accrued to a cooperative group phase III trial [34]. PS2 patients had a median OS of 3 months and a 1-year SR of 14% as compared to PS 0 1 patients which had an OS of 8.8 months and a 1-year SR of 38%. Patients with PS2 treated with combination CT had a higher ORR (24% versus 10%), a longer median OS (4.7 versus 2.4 months, P = 0.01) and better 1-year SR than those who receive mono-ct (18% versus 10%). The difference was statistically significant and indeed of greater magnitude than that observed between the two arms in patients with PS 0 1. Analysis of QoL parameters showed no detrimental effect for PS2 patients treated with the combination regimen. The MILES study enrolled nearly 700 patients older than 69 years of whom 19% has PS2 [35]. Patients were randomised to receive single-agent VNR 30 mg/m 2, single-agent GEM 1000 mg/m 2, or VNR (25 mg/m 2 ) plus GEM (1000 mg/m 2 ) on day 1 and 8 every 3 weeks. Median OS as well as QoL analysis (EORTC QlQ-C30, and LC13) did not differ significantly among the three arms even when subgroup analysis for PS patients was performed. The issue of mono- versus poly-ct has been recently addressed by the Hellenic Co-Operative Oncology Group who carried out a prospective randomised phase II trial of singleagent GEM (1250 mg/m 2 q 14 days every 4 weeks) and GEM (1250 mg/m 2 ) plus CBDCA (AUC3 q 14 days every 4 weeks) with clinical benefit as primary endpoint [36]. Out of 51 patients enrolled in each arm with a median age >_70 years, 25% of patients treated with GEM and 35% had response or stable disease with a TTP of 2.98 and 4.07 months

4 iv126 respectively. Median OS was 4.8 and 6.7 months with 17.8% and 20% 1-year SR. None of these differences reached a statistical significance. Grade 3 4 neutropenia, thrombocytopenia and anaemia were significantly more frequent in the poly-ct arm. However, the percentage of general feeling improvement (64% versus 65%) and that of patients with at least one symptom improved (71% versus 67%), but were not different between the two groups. The authors concluded that GEM/CBDCA was not superior to GEM alone in terms of clinical benefit, median TTP and OS, while the two drug regimens was significantly more toxic. Polychemotherapy Data concerning the outcome of PS2 patients treated with poly-ct stem from retrospective subgroup analysis of large prospective trials aimed to find the most active doublet, to establish if triplet regimens were more active than doublets, and if CDDP could be omitted. In these studies the vast majority of enrolled patients had a good PS of 0 1, while generally only less than 20% of enrolled patients had PS2. However, recently the number of ongoing trials specifically designed for poor PS patients has rapidly increased. The ECOG study E1594 included 64 evaluable PS2 patients randomised to receive PTX/CDDP, GEM/CDDP, DCT/CDDP or PTX/CBDCA [37, 38]. Globally, the ORR was 14%, median TTP was 1.7 months, median OS according to an intent-to-treat analysis was 4.1 months with a 1-year SR of 19%. There were no significant differences among the 4 treatment arms in terms of ORR and TTP. The only significant difference was a higher median OS in the PTX/CDDP arm (7 months) as compared to the DCT/CDDP arm (2.3 months). The clinical outcome of PS2 patients was significantly inferior to that of PS 0 1 patients with the exception of ORR which was similar to that reported for good PS patients. Patients in the GEM/CDDP arm had the highest ORR and best median OS, but suffered of the worst toxicity probably related to the use of high-dose CDDP. The PTX/CBDCA arm showed the best tolerance with the exception of peripheral neuropathy. Accrual of PS2 patients was stopped because an interim analysis of toxicity had shown a higher incidence of serious adverse events including a 7.35% death rate (5 patients) as compared to PS 0 1 patients. However, a subsequent more accurate analysis showed that the overall toxicity experienced by PS2 patients was not significantly different from that experienced by PS 0 1 patients. The reported treatmentrelated death rate in PS2 patients was only 3% (2 patients) as compared to 4% in PS 0 1 ones. The other deaths were considered to be due to tumour progression. The high incidence of side-effects that caused accrual of PS2 was not only CTrelated but also due to rapidly progressive disease and co-morbid conditions. The conclusion was that these regimens with these schedules were not considered as a standard treatment for PS2 patients and that new regimens with attenuated doses had to be tested in this particular subset of patients. Analysis of toxicity confirmed a relatively higher rate of grade 3 4 side-effects in PS2 patients as compared to those with better PS but without statistical significance. Review 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. The Spanish Lung Cancer Group carried out a phase III trial where 557 patients were randomised to receive GEM and VNR followed by VNR and ifosfamide, GEM/CDDP or a triplet of GEM, VNR and CDDP [39]. Overall, 16.5% of patients had PS2. No difference in OS among the three arms was detected, but the non-platinum sequential treatment and the triplet regimen were associated with significantly more toxicity than the GEM/CDDP doublet which was considered as the standard regimen. Although results were not analysed for subgroups, however median OS of PS2 patients was 4.7 months as compared to 9.4 months of PS 0 1 patients (P = ). Similar conclusions were reached by an Italian Lung Cancer Project which retrospectively showed that in PS2 patients RR, TTP, OS were significantly lower than those of PS 0 1 patients [40, 41]. As shown in Figure 1, a retrospective review of all prospective trials carried out by the Gruppo Oncologico dell Italia Meridionale [42 47] has confirmed that 203 PS2 patients out of 1108 patients suitable for CDDP-based doublets with new drugs have a poorer outcome than patients with PS 0 1 (9 versus 5.5 months, P = 0.001; 1-year SR 30% versus 13%) (VG, personal communication). The relationship between age, number of co-morbid disorders and survival have been analysed as shown in Figure 2. The relationship between age and survival was not statistically significant (r 2 = , P = 0.083), while a statistically significant correlation was observed between number of co-morbidities and survival (r 2 = 0.02; P = 0.044). The Hellenic Cooperative Oncology Group randomised 509 patients to GEM/PTX versus PTX/CBDCA [48]. Nearly 60 patients had PS2 and showed lower ORR (11% versus 34%) and shorter median OS than PS 0 1 counterparts (5.9 versus 11.1 months; P = ), while toxicity was very similar. The EORTC study compared GEM/CDDP to PTX/CDDP or Percent surviving Overall Survival 13% PS 0-1 median OS 9 months PS 2 median OS 5.5 months p=0.001; HR % Months since registration Figure 1. Outcome of patients as compared to that with PS0-1 in GOIM trials.

5 iv127 Age (years) 80 Age Comorbidities Survival (months from registration) Figure 2. Relationship between age, co-morbidities, and survival in PS2 patients (GOIM trials). PTX/GEM in a series of 480 patients. A trend in favour of the GEM/CDDP regimen was found, while PS2 was reported to be the only poor prognostic factor across arms. Recently, investigators of the ECOG reported the first randomised phase II trial (ECOG 1599) specifically carried out to test the effectiveness of two platinum-based regimens in PS2 patients [49, 50]. The authors employed attenuated doses of the GEM/CDDP regimen (GEM 1000 mg/m 2 on day 1 + 8, CDDP 60 mg/m 2 on day 1 q 3 weeks) and the PTX/CBDCA one (PTX 200 mg/m 2, CBDCA AUC 6 both on day 1 q 3 weeks). These two regimens had been shown to be respectively the most active and the best tolerated ones in PS2 patients in the retrospective analysis of the previous ECOG 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 excess of toxicity with only one grade 5 CT-induced-related event in the PTX/CBDCA arm. The GEM/CDDP regimen yielded a 25% ORR as compared to 16% recorded in the PTX/CBDCA arm. Disease control rates were more than 50% in both arms. TTP was 4.2 and 4.8 months and median OS was 6.1 and 6.8 for the GEM/CDDP arm and the PTX/CBDCA one respectively. The 1-year SR was 25% and 19% respectively. The survival figures were longer than expected from data derived from previous ECOG 1594 and CALGB 9730 studies. As expected haematological sideeffects, thrombocytopenia in particular, nausea/vomiting and mild renal toxicity were more frequent in the GEM/CDDP arm while the incidence of peripheral neurotoxicity and myalgias/arthralgias was higher in the PTX/CBDCA arm. The widespread concern that PS2 patients can experience severe toxicity if challenged with full dose CDDP-based doublet regimens has led to investigations aimed to explore the role of non-platinum doublets. To date this issue has not been addressed in PS2 patients by any prospective randomised trial, but data from phase II studies are suggestive [51 54]. Weissmann et al. [52] carried out a phase II trial of weekly DCT/CBDCA (35 mg/m 2 and AUC2 on day 1, 8, and 15 q 4 weeks) in 59 patients younger than 65 years with PS2. ORR N. of comorbidies was 12%, median TTP 3.7 months, OS 6 months with a 1-year SR of 28%. The most important grade 3 4 side-effects were neutropenia (10%) and fatigue (10%), nausea (8%), dehydration (7%), and vomiting (5%). A Canadian group reported a multi-centre phase II study with a sequential treatment of VNR (30 mg/m 2 day q 3 weeks) followed by GEM (1000 mg/m 2 day q 3 weeks) in a series of 44 patients [53]. A partial response was achieved in 28% of patients with a median TTP of 3.5 months and a median survival slightly over 6 months and a 1-year SR of 18%. Toxicity was mild with no case of grade 3 4 side-effects. However patients with PS or elderly with co-morbid diseases were included in the same trial and no subgroup analysis is available at present. The perception that palliation of cancer-related symptoms plays a pivotal role in PS2 patients because of their poor outcome has been explored in a phase II trial employing a combination of DCT and GEM [51, 54]. In a series of 30 patients a 33% ORR was recorded with a median survival of 4.1 months [54]. A recent trial analyzed the efficacy and tolerability of DCT given at 75 mg/m 2 every 3 weeks or on a weekly schedule at the dose of 30 mg/m 2 in a series of 42 patients with PS2 [55]. Tolerability of both schedules was similar with a very slight trend toward longer survival in patients treated with the weekly schedule. The SWOG treated 44 patients with PS2 with a sequential regimen of single-agent VNR 25 mg/m 2 on day 1 and 8 every 3 weeks followed by DCT 35 mg/m 2 on day 1,8 and 15 every 4 weeks [56]. The ORR was 10% with a median OS of 4 months and a 14% 1-year SR. Tolerability of CT was acceptable. New investigational drugs New biologically targeted drugs are widely investigated for their possible role in the management of advanced NSCLC due to their good therapeutic index. Recently gefinitib (ZD1839), a small molecule which inhibits tyrosine kinase, was given at the dose of 250 mg/day until progression to a group of 25 previously untreated patients with PS2 3 [57]. No partial responses were seen, but 61% of patients had stable disease and 32% had an improvement in symptoms as evaluated by the Lung Cancer Symptom Scale (LCSS) and the FACT-L. Gefinitib was well tolerated with no grade 3 4 sideeffects. Although the impact on survival is difficult to ascertain, however, gefinitb seems safe and active in patients with PS2 3. A retrospective analysis of 84 patients with PS2 treated with gefinitib achieved a median survival of 2 months and a 1-year SR of 15.6% [58]. A similar ORR of 14% was recorded in the IDEAL trials which included patients treated with gefinitb after failure of at least two different CT regimens [59]. CT-2103 (i.e. paclitaxel poliglutamex) is a novel paclitaxel conjugate that is currently undergoing investigation in patients with poor PS [50, 60]. The phase II trials in PS2 patients reported a median OS of 5.4 months with a favourable toxicity profile mainly represented by less haematological toxicity,

6 iv128 neurotoxicity, and alopecia as compared to taxanes. Based on the these results the Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reactions trials (STELLAR) 3 and 4 have been recently carried out. The STELLAR 3 is a phase III trial comparing CT mg/m 2 and CBDCA to standard PTX 225 mg/m 2 plus CBDCA in chemotherapy-naïve PS2 patients with stage IIIB wet and stage IV NSCLC. The STELLAR 4 trial compares a lower dose (175 mg/m 2 )of CT-2103 with single-agent VNR or GEM in a similar population. Final results of both trials are awaited with interest. Are PS2 patients enrolled in clinical trials representative of the real patient population? The answer is no. Patients with significant or multiple co-morbidities have usually been not enrolled in large clinical trials because the impact of co-morbid disease on clinical outcome is quite difficult to ascertain without specifically committed studies. Moreover, in the last two decades CT has been considered poorly useful, if not detrimental, in patients with PS >_2. Potential gains have been considered to be overcome by risks and side-effects. Moreover the management of PS2 patients undergoing CT is certainly much more complex than that of more fit patients. Therefore patients with PS2 encountered in clinical practice are quite different from those enrolled in clinical trials. An other important issue regards poor PS patient referral to the oncology centres. As many as 60% of patients with advanced NSCLC may not be evaluated for a potentially useful palliative chemotherapeutic treatment. Committed studies to evaluate the size and the clinical characteristics of PS2 patient population are strongly needed. Do co-morbidities influence treatment choice? Several different approaches have been used in the therapeutic strategy for PS2 patients. Third-generation doublets have been employed with attenuated doses of CDDP, while in other instances CBDCA substituted for CDDP when oncologists felt the patients unfit for CDDP and wanted to avoid CDDPrelated morbidity. Another approach has been represented by the use of single-agents with highest possible therapeutic index, such as GEM, VNR and taxanes, and more recently erlotinib or gefinitib. The current recommendation by the American Society of Clinical Oncology and the National Comprehensive Cancer Network suggest single-agent CT for the treatment of PS2 patients. However, this variability of treatment approaches in clinical practice mostly reflects the significant clinical heterogeneity of PS2 patients [61]. As stated above, both cancer-related symptoms and comorbid medical illnesses may variously contribute to patients PS, individual tolerance to CT, and potential gains in terms of survival and QoL. While CT-induced side-effects are well categorized and cancer-related symptoms are easily sized using appropriate instruments, co-morbidities represent a significant multidimensional clinical variable. Co-morbid diseases tend to increase with aging, vary significantly in severity, and may affect many organs and systems often simultaneously [62]. This complex variable is poorly correlated to PS, at least in elderly patients, and deeply influences physicians treatment choice in clinical practice since they suggest particular caution in drug choice [63]. The obvious great variability of possible clinical pictures makes a decision-making algorithm very difficult to build and validate [11]. The relationship between number and severity of co-morbidities 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 ageing-specific phenomena as depression, alteration in mental status, reduced nutritional status, and lower social support. The precise definition of the relative weight of co-morbidities in patients with poor PS play a pivotal role in designing and conducting committed trials as well as establishing treatment guidelines. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) is a useful instrument to define the effects of multiple concomitant diseases. The CIRS-G assesses organ systems and grades the severity from 0 to 4. The CIRS-G score has been shown to be a powerful independent prognostic factor in patients with locally advanced NSCLC undergoing RT [65]. An other validated instrument is the Charlson scale which evaluates 19 different diseases associated with a higher 1-year mortality in internal medicine. The Charlson score has been found to be strongly associated with OS, tolerance to CT, and therapy discontinuation rate in elderly patients with advanced NSCLC. When the two scales are used in the same population, the CIRS-G scale identified as >90% prevalence of co-morbidities with the Charlson only 36%. Recently, the Comprehensive Geriatric Assessment has been shown to add useful clinical information on the functional status of patients evaluated for PS according to the ECOG scale [66]. In fact there is evidence that ECOG PS scoring system is not precisely related to functional capacity in patients with advanced NSCLC [67]. Future trials committed to poor PS patients need to include this type of evaluation to establish the most appropriate treatment strategy and to better evaluate the possible benefits of anti-neoplastic treatments. Evaluation of PS, functional status and co-morbidities should be paralleled by the analysis of cancer-related symptoms relief and QoL. This issue is particularly important especially in PS2 patients whose life expectancy as well as survival gain by CT are limited. Clinical data support that the possible improvement in symptoms control in PS2 patients may be even greater than in patients with better PS. Therefore the skilled use of LSCS would be extremely useful in this setting. QoL has been shown to have a definite prognostic value as concern response to treatment and survival. The ECOG trial 5592 showed that an high basal score of the FACT-L subscales were powerful predictors of response to CT with a reduced risk of progressive disease and death [68]. Another important issue is optimization of BSC. For instance, correct and prompt use of erythropoiesis stimulating

7 iv129 agents to control anemia is most important since mild to moderate anaemia develops in up to 2/3 of NSCLC patients undergoing CT. Maintenance of adequate hemoglobin levels in patients with lung cancer and concurrent pulmonary and/or cardiovascular diseases is crucial to QoL. A direct relationship exists between decline in QoL and anemia independent of objective response to CT [69]. Conclusions As stated in a recent consensus meeting [12], to date mono- CT with new generation cytotoxic agents such as GEM, VNR and taxane may be considered a reasonable choice for the palliative treatment of PS2 patients with advanced stage NSCLC. Although formal prospective comparison is not available, current evidence suggests that these cytotoxic agents are roughly equiactive in PS2 patients and therefore the drug choice should be based on expected toxicity, number and type of co-morbid conditions, convenience of administration, and also the oncologist s confidence with chosen therapy. Data from retrospective analysis suggest that carboplatin-based doublets with a new generation, non-platinum, agent may be a valid therapeutic option at least in some subgroups of patients. The role of cisplatin-based regimens is still not cleared even if some evidence suggests the possible role of attenuated dose regimens. Patients with PS2 enrolled in clinical trial not specifically committed to poor PS patients are not representative of the whole population seen in clinical practice. The number and severity of co-morbidities as well as symptoms relief probably should be carefully assessed in poor PS patients with advanced NSCLC. Oncologists should also consider patients willingness to accept CT even if the expected amount of benefit is not high. It must be taken into account the whole patients clinical picture and evaluation of co-morbid medical conditions should be accurate. 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