1 Division of Medical Oncology, S.G.Moscati Hospital, Avellino; 2 Department of Medical Oncology, National Institute for Cancer Research, Genoa, Italy; 3 Department of Medicine, Institute Gustave Roussy, Villejuif, France; 4 Department of Medical Oncology, Thoraxklinik, Heidelberg, Germany; 5 Clinical Trials Unit, National Cancer Institute, Naples, Italy; 6 Department of Medical Oncology, Christie Hospital, Manchester, UK; 7 Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands; 8 Fifth Pulmonary-Oncology Unit, Lung Disease Department, Forlanini Hospital, Rome, Italy
Received 1 July 2003; revised 7 October 2003; accepted 27 October 2003
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ABSTRACT |
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Platinum-based combination chemotherapy is currently recommended as the standard treatment 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
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Introduction |
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Performance status (PS) is a general, rough measure of the patients functional status. It measures the impact of tumour symptoms, together with other pre-existing medical problems and co-morbidities, on a patients daily function and ability of self-care. Several PS scales are available for clinical use: among them, those most commonly used are the Karnofskys scale [4], created at the beginning of chemotherapy era, and the Eastern Cooperative Oncology Group Scale of Performance Status (ECOG PS), a five-point 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 [69] but represent a significantly higher proportion (up to 3040%) when population-based surveys are conducted [10, 11].
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Materials and methods |
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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 studiesnot biased by inclusion criteria and not restricted by the characteristics of experimental treatmentis 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.
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.
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Performance status as a prognostic factor |
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A worse PS is characterised by lower response rates to chemotherapy, shorter time to treatment failure and shorter progression-free 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.
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The role of chemotherapy in PS2 patients |
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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.
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The role of adding platinum to third generation single agents in PS2 patients |
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The results of a European phase III randomised trial comparing single-agent vinorelbine, vinorelbinecisplatin and vindesinecisplatin 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 vindesinecisplatin 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 PS01 patients, median survival was 43, 36 and 33 weeks and 1-year survival was 38%, 34% and 29% for cisplatinvinorelbine, vinorelbine alone and cisplatinvindesine, 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 34 haematological toxicity occurred earlier and more frequently in the arm receiving vinorelbinecisplatin 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 sub-group 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.
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The role of non-platinum-based third generation polichemotherapy in PS2 patients |
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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 1819% 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 vinorelbinegemcitabine combination, respectively). The hazard ratio of survival for combination chemotherapy was 1 when compared with vinorelbine and 0.97 when compared with gemcitabine.
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Role of new targeted agents |
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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 non-haematological 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 third-line 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%) [4346]. 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.
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Consensus on clinical practice |
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Consensus on clinical research |
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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 non-specifically 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 PS01 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.).
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Acknowledgement |
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FOOTNOTES |
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