Turkish Journal of Cancer Volume 34, No.1, 2004 19 Is the third-line chemotherapy feasible for non-small cell lung cancer? A retrospective study MUSTAFA ÖZDO AN, MUSTAFA SAMUR, HAKAN BOZCUK, ERKAN ÇOBAN, MEHMET ARTAÇ, BURHAN SAVAfi Akdeniz University Faculty of Medicine, Department of Internal Medicine, Division of Medical Oncology, Antalya-Turkey ABSTRACT The purpose of this study was to determine the activity of third-line chemotherapy for non small lung cancer (NSCLC). This retrospective study included patients who had failed after a second-line chemotherapy. A total of 16 patients treated with third line chemotherapy were evaluated. Only one patient had a partial response (6.2%), with an additional 4 patients (24.8%) with disease stabilisation. The median time to progression was 46 days and the median overall survival time was 132 days after the onset of third-line therapy. The overall survival (OAS) after the third-line chemotherapy was linked with the presence of objective response achieved by the first-line treatment (p=0.009). Likewise, the progression free survival (PFS) was related with the presence of clinical benefit (complete + partial response + stable disease) after the first-line chemotherapy (p=0.044). However, other factors evaluated as potential predictors of PFS, or OAS were not found to be of significance. As a conclusion; highly selected patients, who have objective response to the first-line therapy may be offered a third-line chemotherapy regimen, provided that they have a good performance status. [Turk J Cancer 2004;34(1):19-23] KEY WORDS: Third-line chemotherapy, non-small cell lung cancer, survival INTRODUCTION Non-small cell lung cancer (NSCLC) accounts for approximately 75% of lung cancers. More than 60%-65% of patients present with locally advanced (stage IIIB) or metastatic (stage IV) disease and, thus, are not suitable for surgical treatment. The prognosis of patients with stage IIIB and IV disease is disappointing since less than 2% of patients with advanced disease survive 5 years (1). Stage IV non-small cell lung cancer is considered to be incurable with the current available therapies. Therefore, chemotherapy remains a therapeutic option mainly for symptom relief and improving quality of life in this patient population at the present time. However, a secondary aim may be a modest increase in survival (1-2). Current first-line treatment for advanced NSCLC is generally platinum-based combination chemotherapy, which produces 30-40% response rate and an overall median survival time of 8-10 months, with a 1-year survival rate of 30-40%. In a previous study, after a relapse following
20 Third-line Chemotherapy for NSCLC platinum-based chemotherapy, the median survival time for patients receiving best supportive care was only 4.5-5 months. In this cohort of patients, one of the most important prognostic factors that predicts for longer survival in these patients is a good performance status (3-5). The value of second-line chemotherapy in advanced NSCLC has been debated until TAX 317 and TAX 320 provide the required evidence of benefit (6). In these trials, docetaxel significantly improved survival, compared with either best supportive care or control reference regimen. Quality of life was also increased with second line chemotherapy (6,7). The role of third-line chemotherapy for the treatment of patients with NSCLC that have relapsed after or failed to respond to second-line treatment is still unclear. Up to date, the only drug reported to have been used in clinical trials specifically for the third-line treatment of NSCLC is the orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) ZD 1839 (Iressa) (8,9). There are currently, no prospective studies to support the usage of third-line cytotoxic chemotherapy in NSCLC patients with either good or poor performance status. Thus, the purpose of this retrospective study is to review the evidence, in relation with the findings from our retrospective cohort of NSCLC patients who have had third line chemotherapy, and to evaluate the role of third-line chemotherapy in the management of advanced NSCLC patients who progress after second-line chemotherapy. PATIENTS AND METHODS 16 patients treated with third-line chemotherapy at the Akdeniz University Medical Oncology Department from June 1998 to January 2003, were retrospectively evaluated in this study. All patients had histological or cytological confirmation of metastatic NSCLC, and other than the current regimen, all had previously received two chemotherapy regimens, at least one being platinum-based. Baseline demographics including age, gender, performance status, date of diagnosis, disease status and tumor histology were obtained from the medical records of each patient. All treatments, best response, date of progression after the third-line chemotherapy, date of last visit to the cancer clinic or date last seen or date of death were recorded. Statistical analysis Survival curves were constructed, and median survival was calculated according to the Kaplan-Meier method. Response and clinical benefit by different lines of treatment (i.e. in the 1 st, 2 nd and 3 rd line setting) was tested by χ 2 test with linear-by-linear association. Overall survival after the third line treatment was calculated from the date of start of the third line treatment to the date of death or date last seen. Progression-free survival time was calculated from the date of start of the third line treatment to the day of progression or date last seen. Long-rank test was used to compare survival between groups. All p values are two sided and significant if less than 0.05. SPSS (Statistical Package for Social Sciences) v.10.0 was used for the statistical analysis. RESULTS 16 patients treated with third line chemotherapy were evaluated. 7 patients were treated with weekly gemcitabine, 4 with docetaxel or paclitaxel, 3 with weekly vinorelbine, one with cisplatin+gemcitabine and one with docetaxel+vinorelbine. Patient characteristics are detailed in table 1. With the third line chemotherapy, one patient achieved a partial response (PR) (6.2%), four patients achieved stable disease (24.8%) with an overall clinic benefit of 31% (CR+PR+Stable disease). Among our cases, 2 (12.5%) and 8 (50%) had obtained a PR and clinical benefit, respectively, in the second-line, and 6 (37.5%) and 10 (62.5%) had attained a PR and clinical benefit, in the first-line setting. The response and clinical benefit to chemotherapy decreased by subsequent lines of treatment (Figure 1, p=0.024, χ 2 =5.12, df=1). Response to chemotherapy in the third line setting according to the different regimens used is summarized in table 1. The median time to progression was 46 days and the median overall survival time was 132 days after the third line therapy (Figures 2A and 2B). The progression free survival (PFS) after the third-line chemotherapy was linked with the presence of clinical benefit achieved by the first-line treatment (p=0.04). The median PFS in those who achieved a clinical benefit by
Özdo an et al. 21 Table 1 Patient characteristics Response to the third-line regimen General Characteristics Number (%) Min, Median, Max PR* SD** Progression Total 16 (100) Age 36, 51, 68 Sex Male 11 (69) Female 5 (31) Performance status (ECOG) 2 16 (100) Third-line regimens Weekly Gemcitabine 7 (44) 1 (6.2) 6 (37.2) Weekly Vinorelbine 3 (19) 2 (12.4) 1 (6.2) Taxanes 4 (25) 1 (6.2) 3 (18.6) Others 2 (12) 1 (6.2) 1 (6.2) Total 16 (100) 1 (6.2) 4 (24.8) 11 (69) * partial response, ** stable disease Fig 1. The association of line of chemotherapy administration with the response attained the first-line treatment was 62 days as opposed to 41 days in those who failed to achieve a clinical benefit (Figure 2D). However, other factors evaluated as potential predictors of PFS previously were not found to be associated with PFS in this study (Table 2). There was no response or stabilization of disease by the third line chemotherapy in any of the patients who failed to achieve a clinical benefit after the first-line treatment. Similarly, OAS after the third-line chemotherapy was linked with the presence of objective response obtained by the first-line chemotherapy (p=0.009). The median OAS in those who obtained an objective response after the first-line treatment was 168 days, versus 90 days in those who did not obtained an objective response (Figure 2C).
22 Third-line Chemotherapy for NSCLC A C B D Fig 2 (A, B, C, D). Survival after the 3 rd line chemotherapy. (A): Overall survival after the 3 rd line chemotherapy, (B): Progression free survival after the 3 rd line chemotherapy, (C): Overall survival with respect to the presence of partial response to 1 st line chemotherapy, (D): Progression free survival with respect to the presence of clinical benefit by 1 st line chemotherapy Table 2 Factors related with survival after the 3 rd line chemotherapy Progression free survival Overall survival General Features Statistics P Statistics P Age (<52 vs. 52 or elder) 3.53 0.060 0.12 0.725 Gender 2.46 0.117 2.60 0.107 Chemotherapy response to previous regimens Partial response to 1 st line chemotherapy (present vs. absent) 0.38 0.540 6.81 0.009 Clinical benefit by 1 st line chemotherapy (present vs. absent) 4.04 0.044 2.00 0.157 Partial response to 2 nd line chemotherapy (present vs. absent) 0.00 0.998 0.47 0.492 Clinical benefit by 2 nd line chemotherapy (present vs. absent) 0.22 0.638 0.00 0.968 DISCUSSION In this study, we present the results of 16 highly selected NSCLC patients treated with a third line regimen in a fiveyear period. Although there is no level 1 or 2 evidence to offer chemotherapy after the second-line treatment for NSCLC, when retrospectively evaluated, there may be a few patients who specifically ask for it, and subsequently be treated. For each case, the discussion on whether to treat
Özdo an et al. 23 or not was made between the patient and the treating physician, and the selection criteria is out of the scope of this manuscript. The new chemotherapeutic drugs (taxanes, vinorelbine, gemcitabine, and irinotecan) have shown reproducable response rates for the second-line therapy (10). We feel that the possibility of attaining a response with the drugs above may have been the main motivation for both the patients and their physicians for the possible consideration of a third-line chemotherapy in these NSCLC patients. The objective response rate of 6.2% in our cohort is obviously disappointing. Similarly, in the only retrospective analysis available in the literature on the usage of third-line chemotherapy in 43 non-small-cell-lung cancer patients by Massarelli et al. (11) a response rate of 2.3% after the third line treatment and 0% in the fourth-line setting was reported. Our study is important for the fact that we showed a relation between the presence of clinical benefit or objective response provided by the first-line chemotherapy and PFS or OAS after the third-line chemotherapy in NSCLC, respectively. So, the use of a third-line therapy may be desirable in patients who maintain a good performance, and in those who had an objective response to the first-line chemotherapy. Conversely, all patients who progressed on the first-line treatment did not respond to the third line regimen. However, it should be noted that present response rates are lower than those of a single agent, tyrosine kinase inhibitor of the epidermal growth factor receptor; Iressa. CONCLUSION With such low response rates, the usage of the thirdline chemotherapy with present drugs are not justified in NSCLC, in general. However, highly selected patients, who have objective response to the first-line therapy may be offered a third-line chemotherapy regimen, provided that they have a good performance status, and especially if the epidermal growth factor receptor inhibitor is not available. New drugs are urgently needed for the treatment of lung cancer patients. Hence, in our view, the value of the thirdline chemotherapy in NSCLC should be further tested in a prospective clinical trial. References 1. Parker SL, Tong T, Bolden et al. Cancer statistics, 1996. CA Cancer J Clin 1997;47:5-27. 2. Ginsberg RJ, Vokes EE, Rosenzweig K. Cancer of the lung: non-small cell lung cancer. In: DeVita VTJ, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology. 6 th ed. Philadelphia: J.B. Lippincott Co., 2001;925-51. 3. Shepherd FA. Second-line chemotherapy for non-small cell lung cancer: is more better or just simply more? Lung Cancer 2002;36:309-11. 4. Lynch T. Review of two phase III randomized trials of singleagent docetaxel in previously treated advanced non-small cell lung cancer. Semin Oncol 2001;28:5-9. 5. Kris MG. What does chemotherapy have to offer patients with advanced-stage non-small cell lung cancer? Semin Oncol 1998;25:1-4. 6. Shepherd F, Dancey J, Ramlau R, et al. A prospective randomized trial of docetaxel (Taxotere) versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095-103. 7. Fosella VF, Lynch T, Shepherd AF. Second line chemotherapy for NSCLC: establishing a gold standard. Lung Cancer 2002;38:45-50. 8. Fukuoka M, Yano S, Giaccone G, et al. Final results from phase II trial of ZD 1839 (Iressa) for patients with advanced non-small cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol 2002;22:abstr 1188. 9. Kris M, Natale R, Herbst R, et al. A phase II trial of ZD 1839 (Iressa) in advanced non-small cell lung cancer patients who had failed platinum and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol 2002;21:abstr 1166. 10. Georgoulias VA. Second-line chemotherapy in relapsing or refractory patients with non-small cell lung cancer. Lung Cancer 2002;38:3:61-6. 11. Massarelli E, Andre F, Liu DD, et al. A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small-cell lung cancer. Lung Cancer 2003;39:55-61.