Treatment of Advanced Non-Small-Cell Lung Cancer Patients with ECOG Performance Status 2: Results of a European Experts Panel

Abstract & Commentary

Synopsis: 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.

Source: Gridelli C, et al. Ann Oncol. 2004;15:419-426.

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. Non-small-cell lung cancer (NSCLC) represents approximately 80% of all lung cancers. The majority of patients have metastatic disease at the time of diagnosis. Palliative treatment is the only therapeutic option. Performance status (PS) is a global, but rough measure of the patient’s functional status. Several PS scales are available for clinical use: among them, those most commonly used are the Karnofsky’s scale and the Eastern Cooperative Oncology Group Scale of Performance Status (ECOG PS). ECOG PS is 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. According to the latter scale, patients are classified as PS 2 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. PS 2 patients usually account for a very small proportion of patients enrolled in trials of first-line treatment for advanced disease but represent a significantly higher proportion (up to 30 40%) when population-based surveys are conducted.1-3 In a meta-analysis evaluating chemotherapy in patients with NSCLC, cisplatin based chemotherapy has shown a slight survival advantage over best supportive care. Chemotherapy can improve quality of life and can control symptoms. It is recommended as the standard approach for patients with advanced disease. The benefit is almost entirely limited to patients with performance status 0 or 1. The benefit of chemotherapy in performance status 2 patients is marginal.4 For this later group there is no consistent standard and oncologists choose among several treatment options including best supportive care without chemotherapy; single-agent chemotherapy; non-platinum-based combination chemotherapy; and platinum-based combination chemotherapy. An European Experts Panel took place in April 2003 with the aims of reviewing the evidence supporting each of these therapeutic options, possibly reaching a consensus for treatment of PS 2 patients affected by advanced NSCLC in clinical practice, and suggesting the priorities for clinical research in this field. The paper reviews their findings.

Comment by Stuart M. Lichtman, MD

Evidence available for each of the following six topics in the treatment of PS 2 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 polychemotherapy; possible role of new biological agents; ongoing trials. Relevant published papers reporting the results of randomized phase III clinical trials were obtained by Medline search in addition to abstracts from important oncology meetings and some authors were contacted directly to obtain data from papers not yet published. The greatest part of the evidence analyzed in the meeting comes from small sub-groups of patients with PS 2, enrolled in clinical trials usually including patients with a PS ranging from 0 to 2. The proportion of patients with PS 2 in these trials is often < 20% of the whole study population, suggesting the existence of a selection bias determining the exclusion of PS 2 patients with worse general conditions and co-morbidities. Median age of patients enrolled in randomized clinical trials is often significantly lower than that observed in clinical practice, 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 PS 2 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. Another significant limitation of the published data is the lack of information regarding symptom relief and/or health-related quality-of-life benefits in PS 2 patients.

Performance status has a clear prognostic role in advanced NSCLC. The survival analysis of 1960 patients with advanced disease treated with cisplatin based chemotherapy in 5 ECOG phase II or III trials conducted fro 1981 to 1994 showed an independent prognostic role of performance status: median survival was 9.4, 6.4, and 3.3 months in PS 0, 1 and 2 patients respectively. PS 2 patients have median overall survival that rarely exceeds 5 months with 1-year survival rates < 20%. The poor performance status is characterized by lower response rates to chemotherapy, shorter time to treatment failure and shorter progression free survival. A number of trials have shown the benefit of chemotherapy to best supportive care. There is a suggestion that patients with PS 2 have a small benefit to chemotherapy, particularly single agent therapy. A formal analysis of benefit has been limited by the small number of these patients on clinical trials. These patients often have a greater potential for palliation due to worse baseline conditions.

At present, platinum based combination chemotherapy is considered the standard treatment for advanced NSCLC. However, its benefit is usually restricted to PS 0-1 patients. In a randomized European phase II trial comparing vinorelbine, vinorelbine-cisplatin and vindesine-cisplatin, the vinorelbine-cisplatin arm was superior.6,7 The advantage was predominantly limited to fit patients: in PS 0-1 the median survival was 43% and 1-year survival was 38%. For PS 2 patients, grade 3-4 hematological toxicity occurred earlier and more frequently. Lower doses of cisplatin could probably be better tolerated, but there are no current data supporting this hypothesis. In a study evaluating the comparison of paclitaxel alone vs. carboplatin and paclitaxel the median survival in the group treated with combination chemotherapy was significantly longer than paclitaxel alone (4.7 vs 2.4 months).8 Cisplatin free regimens are currently being evaluated and may represent a reasonable, less toxic option for PS 2 patients. There is no consistent evidence that combination chemotherapy without platinum is better than third generation drugs given as a single agent.9 There is the emerging role of target agents which have less toxicity. ZD1839, a small molecular tyrosine-kinase inhibitor targeted again the epidermal growth factor receptor is one such drug. It has clinical benefit in pretreated patients.10

The consensus of the panel was that chemotherapy appears justified in patients with advanced NSCLC and PS 2. Several trials show that many cytotoxic agents are superior to supportive care alone. Single agent therapy with these drugs (eg, gemcitabine, vinorelbine, taxanes) could be the preferred option for palliative treatment. The drug of choice should be based on toxicity and the type of comorbidity present. Cisplatin combinations should use the drug at lower doses (< 100 mg/mg2). Research priorities should include investigational agents (e.g. pemetrexed), alternative dose and/or scheduling of single agents, carboplatin or low dose cisplatin combinations, biological target-based agents without chemotherapy and supportive treatment added to chemotherapy.

References

1. Gridelli C, et al. J Natl Cancer Inst. 2003;95:362-372.

2. Schiller JH, et al. N Engl J Med. 2002;346:92-98.

3. Radzikowska E, et al. Ann Oncol. 2002;13:1087-1093.

4. Bunn PA. J Clin Oncol. 2002;20:23s-33s.

5. Gridelli C, et al. Ann Oncol. 2004;15:419-426.

6. LeChevalier T, et al. J Clin Oncol. 1994;12:360-367.

7. Soria JC, et al. Ann Oncol. 2001;12:1667-1670.

8. Lilenbaum RC, et al. Proc Annu Meet Am Soc Clin Oncol. 2002;21:2a.

9. Gridelli C, et al. J Clin Oncol. 2003;21:3025-3034.

10. Fukuoka M, et al. J Clin Oncol. 2003;21:2237-2246.

Stuart M. Lichtman, MD, FACP, Associate Professor of Medicine, NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY, is on the Editorial Board of Clinical Oncology Alert.