ECOG randomized patients with advanced NSCLC to 1 of 4 new 3 of the 4 regimens used in ECOG docetaxel/cisplatin, paclitaxel/cisplatin. In the ECOG trial, the only direct comparison of similar regimens, response rates and survival times were similar between patients treated with cisplatin. ECOG was chosen as a plenary session presentation because it is an important trial that reflects the state of care in of metastatic NSCLC—the.
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Platinum-based combination chemotherapy is currently recommended as the standard treatment for patients with advanced non-small-cell lung cancer NSCLCbut 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, eckg suggesting the priorities for clinical research in this field, an European Experts Panel took place in Avellino, Italy in April 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 5194 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 edog agents.
Another research priority is the improvement of supportive care. Patients strongly need symptomatic improvement: Lung cancer is the most common cancer in the world and the leading cause of cancer-related deaths in Europe and in other Western countries [ 1 — 3 ]. Unfortunately, at the time of diagnosis, the majority of patients already have metastatic disease and a systemic, palliative treatment is the only therapeutic option. Several PS scales are available for clinical use: In a meta-analysis evaluating the efficacy of chemotherapy in patients with NSCLC [ 12 ], cisplatin-based chemotherapy has shown a slight but statistically significant survival advantage over supportive care.
According to the evidence that platinum-based combination chemotherapy can prolong survival, possibly improving quality of life QoL and controlling symptoms in these patients, it is currently recommended as the standard approach for patients with advanced NSCLC [ 1314 ]. However, the benefit achievable seems more evident for fit patients PS0 or -1 and there is no consistent evidence about the real exog of platinum-based treatment for PS2 patients [ 1315 ].
For this latter sub-group, there is no treatment widely exog as standard and oncologists have to choose among several treatment options for which PS2 patients are potential candidates: 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 Results and conclusions of that meeting are presented in this paper.
Evidence available for each of the following six topics in the treatment of PS2 patients was reviewed: 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 to about 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 dcog 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 1954 from small sub-groups of patients with PS2, enrolled in clinical trials usually including patients with a PS ranging from 0 to 2.
Median age of patients enrolled in randomised clinical trials is often significantly lower than that observed in clinical practice [ 1617 ], and eligibility criteria request good renal, hepatic and cardiac function, as well as absence of other significant co-morbidities. Consequently, it is not surprising that the proportion of PS2 patients in population-based studies—not biased by inclusion criteria and not restricted by the characteristics of experimental treatment—is consistently higher than that reported in the majority of clinical trials [ 1011 ].
The panellists are aware that ecoh 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 1954 remains the best level of information on this topic available from the literature to date. 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. In all the retrospective and prospective trials regarding prognostic factors in this disease, PS has been shown to be an independent prognostic parameter [ 19 — 25 ].
In a series of more than patients with inoperable lung cancer analysed more than two decades eccog to investigate the impact on survival of 50 prognostic factors, performance status, extent of disease and weight loss were among the most important prognostic factors [ 19 ].
Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
These results have been confirmed by others [ 20 — 2225 ]. A worse PS is 194 by lower response rates to chemotherapy, shorter time to treatment failure and shorter progression-free survival [ 2728 ]. 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 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 ]. Efog 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. For example, a 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.
To date, the available data from retrospective analyses are few and heterogeneous, and do not allow any type of subclassification. A first point of discussion was the evidence supporting the role of chemotherapy itself in PS2 patients. The discouraging survival, the lower compliance to chemotherapy and the fear of a higher risk of toxicity put a question mark behind chemotherapy administration in this category of patients. Some of the trials comparing best supportive care plus chemotherapy versus best supportive care alone are summarised in Table 2.
Taxane-Platinum Combinations in Advanced Non-Small Cell Lung Cancer: A Review
In the meta-analysis published inalthough 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 ].
Aftersome advantage of chemotherapy versus supportive care alone has been shown not only with platinum-based combination chemotherapy [ 261159430 ] but also with many new cytotoxic agents e. 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 1549 absolute number of patients.
Disappointingly, data about Eocg 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.
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. These findings should not be ignored, especially considering the availability of several drugs characterised by a favourable toxicity profile. At present, platinum-based combination chemotherapy is considered the standard treatment for advanced NSCLC, but it is still unclear if the benefit achieved with this treatment is restricted only to PS0 and PS1 patients, or rcog applies to PS2 patients.
The results of a European phase III randomised trial comparing single-agent vinorelbine, vinorelbine—cisplatin and vindesine—cisplatin in wcog with advanced NSCLC and PS not worse 1549 2 were published in [ 6 ].
Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
The combination of cisplatin and vinorelbine was superior in terms of survival to vindesine—cisplatin and to vinorelbine alone. A subgroup analysis of that trial has been subsequently published, with the aim of testing interactions between treatments and main prognostic factors [ 36 ]. This secondary analysis showed that the significant advantage obtained with the combination of cisplatin and vinorelbine is predominantly limited to fit patients: For PS2 patients, grade 3—4 haematological toxicity occurred earlier and more ecov in the arm receiving vinorelbine—cisplatin than in the vinorelbine arm 7 versus 28 days after the start of treatment, respectively.
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 study, comparing paclitaxel plus carboplatin versus paclitaxel alone, must be considered [ 37 ]. The study enrolled patients with a PS of between 0 and 2.
Similar to the benefit observed in the sub-group of elderly patients enrolled 5194 the same trial, these results should be interpreted with caution, in view of the substantial risk of ecov 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. Fear eog unacceptable toxicity is one of the major concerns in treatment decisions for PS2 patients and, from this point of view, platinum-free combination chemotherapy deserves attention as it is potentially less toxic than platinum-based treatment.
In recent years, several trials comparing platinum-free combinations containing new cytotoxic agents versus platinum-based treatment, enrolling patients with PS between 0 and 2, have been performed Table 3 [ 38 — 42 ]. Exog trials are characterised by a remarkable heterogeneity among the drugs and schedules studied.
Lung Cancer Highlights
As expected, platinum-based treatment is often associated with a higher occurrence of toxicity [ 3842 ]. Although a trend of slightly lower efficacy of combination chemotherapy without platinum is reported in some trials [ 4042 ], none of the trials show a statistically significant advantage for platinum-containing schedules. No significant interaction between treatment and PS in terms of overall survival is described, and platinum-free combination chemotherapy could represent a reasonable, less toxic option for PS2 patients.
However, there is no consistent evidence that combination chemotherapy without platinum is better than third generation drugs given as single agents. 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.
The hazard ratio of survival for combination chemotherapy was 1 when compared with vinorelbine and 0. In recent years, the rapidly expanding knowledge of cancer pathogenesis at a molecular level has provided new targets for drug discovery, and a great number of new anti-cancer drugs have been developed. Many of these biological agents are currently being tested, at different degrees of clinical development, in NSCLC.
Several features of target-based molecules make these drugs potentially ideal treatments for unfit patients. First, biological therapies hold the promise of being more selective and less toxic for normal tissues, both in terms of haematological and 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. ZD, a small-molecule tyrosine-kinase inhibitor targeted against the epidermal growth factor receptor, is one of the most promising new biological agents.
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.
Sub-group analysis from several randomised trials suggest that several new generation cytotoxic drugs are superior to supportive care alone in this category of patients. Therefore, single-agent chemotherapy with these drugs e. The choice of the drug should be based on the toxicity profile of each agent and type of co-morbid conditions. Taking into account the superiority shown by the carboplatin—paclitaxel combination compared to paclitaxel alone, even in PS2 patients, in one clinical trial [ 37 ], carboplatin-based doublets may also be considered as an alternative option in a selected sub-group of patients.
Stronger evidence on the latter two points is expected from new clinical research specifically focused on PS2 patients affected by NSCLC. All the panellists participating in the meeting agreed that an important prognostic and predictive help for clinical management could derive from a proper sub-classification of PS2 patients. However, it seems undeniable that the definition of prognostic sub-groups cannot be made in a subjective fashion and the only way to validate a prognostic score is to encourage and support prospective data collection.
As for treatment, the analysis of the available literature performed for this panel shows the absolute need for clinical trials specifically dedicated to PS2 patients.
They represent a significant proportion of the patients that every oncologist has to manage in daily practice, and clinical decision making could be more strongly founded on the results of prospective studies.