|Year : 2015 | Volume
| Issue : 4 | Page : 805-809
Retrospective analysis of third-line chemotherapy in advanced non-small cell lung cancer
Ali Murat Tatli1, Deniz Arslan2, Mukremin Uysal3, Sema Sezgin Goksu4, Seyda Gulenay Gunduz5, Hasan Senol Coskun5, Mustafa Ozdogan6, Burhan Savas5, Hakan Sat Bozcuk5
1 Department of Medical Oncology, Van Training and Research Hospital, Van, Turkey
2 Department of Medical Oncology, Erzurum Training and Research Hoospital, Erzurum, Turkey
3 Department of Medical Oncology, Afyon Kocatepe University, Afyon, Turkey
4 Department of Medical Oncology, Kayseri Training and Research Hospital, Kayseri, Turkey
5 Department of Medical Oncology, Akdeniz University, Antalya, Turkey
6 Department of Medical Oncology, Antalya Medstar Hospital, Antalya, Turkey
|Date of Web Publication||15-Feb-2016|
Ali Murat Tatli
Department of Medical Oncology, Van Training and Research Hospital, Van
Source of Support: None, Conflict of Interest: None
Background: First- and second-line chemotherapies have been demonstrated to be effective in treatment of patients with inoperable, advanced non-small cell lung cancer (NSCLC), although the role of third-line chemotherapy remains unclear. The present investigation assessed treatment outcomes in patients with advanced NSCLC who received third-line and higher chemotherapy.
Patients and Methods: This retrospective study included consecutive patients with advanced NSCLC who received at least three lines of systemic chemotherapy.
Results: A total of 72 patients who had received third-line or higher chemotherapy were included in the analysis. The median age of patients was 49 years (range 41-76), and there were 13 (18.1%) women and 59 (81.9%) men. Estimated median survival was 26 months. Moreover, overall survival was significantly longer in patients for whom disease control was achieved after second-line chemotherapy compared to those with disease progression (34 vs. 17 months, respectively). Survival after third-line treatment was significantly longer in the group with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 at the beginning of third-line therapy compared to patients with a status of 2-3.
Conclusions: In patients with advanced stage NSCLC, administration of third-line and higher systemic chemotherapy may be associated with increase in overall survival. Furthermore, greater increases in overall survival were also observed in patients for whom disease control was achieved after second-line therapy and in those with ECOG performance status of 0-1 before third-line treatment.
Keywords: Advanced stage, non-small cell lung cancer, third-line chemotherapy
|How to cite this article:|
Tatli AM, Arslan D, Uysal M, Goksu SS, Gunduz SG, Coskun HS, Ozdogan M, Savas B, Bozcuk HS. Retrospective analysis of third-line chemotherapy in advanced non-small cell lung cancer. J Can Res Ther 2015;11:805-9
|How to cite this URL:|
Tatli AM, Arslan D, Uysal M, Goksu SS, Gunduz SG, Coskun HS, Ozdogan M, Savas B, Bozcuk HS. Retrospective analysis of third-line chemotherapy in advanced non-small cell lung cancer. J Can Res Ther [serial online] 2015 [cited 2019 Oct 20];11:805-9. Available from: http://www.cancerjournal.net/text.asp?2015/11/4/805/146092
| > Introduction|| |
Every year worldwide, approximately 1.3 million individuals die from lung cancer. , As the majority of patients with advanced stage non-small cell lung cancer (NSCLC) are not eligible for curative treatment, systemic chemotherapy is the standard treatment. The main goals of treatment are to reduce palpable disease and increase both quality of life and survival.  In patients with metastatic NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2, chemotherapy with a cisplatin doublet or a single agent is known to be superior to best supportive care.  In a study comparing cisplatin-based combination chemotherapies as first-line treatment in patients with NSCLC, it was shown that in those with an ECOG PS of 0-1, there is greater control of disease-related symptoms, improvement in the quality of life, and increase in overall survival. 
Although many new agents are available for treatment of lung cancer, response rates achieved in second-line treatment are still around 10%. To date, three agents have been approved for second-line treatment based on randomized phase III studies. These include the cytotoxic agents, docetaxel and pemetrexed, and the targeted agent, erlotinib. These drugs are associated with modest increases in one-year survival, in addition to significant improvement in quality of life and disease-related symptoms. Moreover, erlotinib is the only agent approved for third-line treatment. ,,,
Considering the clinical benefits seen with first- and second-line treatments in patients with lung cancer, the third-line treatments are being increasingly used with time. In fact, started around the year 2000, third-line treatment is now carried out in about 25% of patients. Following this trend, fourth-line treatment rates are now about 10%.  In third-line treatment of patients who have limited benefits from chemotherapy, the aims are to achieve greater disease control, and improve both quality of life and survival, with minimal toxicity. Herein, a retrospective study was performed to identify patients who may benefit the most from third-line chemotherapy.
| > Patients and methods|| |
In this study, clinical charts of patients diagnosed with metastatic NSCLC who had third-line chemotherapy between January 1, 2004 and December 31, 2013 were reviewed. All patients had histologically confirmed disease, and only patients with NSCLC (adenocarcinoma, squamous carcinoma, large-cell carcinoma, not otherwise specified) and stage IV at the beginning of treatment were included. Age, diagnosis, and ECOG PS before treatment were collected from follow-up records. All patients were selected from those who had received at least three lines of chemotherapy. Only patients who received a platinum combination treatment in at least one of the lines were included. Patients with secondary tumors were excluded. All patients experienced progression of disease following second-line treatment, and had sufficient overall health status to receive third-line or higher treatment with a different therapeutic regimen.
Statistical analyses were performed using SPSS (version 18.0; SPSS Inc., Chicago, IL, USA). Descriptive statistics were used for demographic characteristics, while Kaplan-Meier analysis was used for survival. Cox regression analysis was used for univariate and multivariate analyses to evaluate factors associated with survival after first- and third-line treatments. Survival analyses were also compared using the log-rank test. A P value < 0.05 was considered statistically significant.
| > Results|| |
A total of 72 patients, all followed-up at a single center, and who received third-line or higher chemotherapy were included in the study. All patients had previously undergone a platinum doublet chemotherapy regimen in first-line treatment. The median age of patients was 49.0 years (range 41 − 76), and there were 13 (18.1%) women and 59 men (81.9%). Selected demographic and clinicopathological characteristics are shown in [Table 1].
|Table 1: Baseline characteristics of the study population median age 59 (min - max 41 - 76) |
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ECOG performance status, chemotherapy regimens used, and treatment responses seen during third-line treatment are shown in [Table 2]. The objective response rates of patients administered three lines of chemotherapy are shown in [Figure 1]. The objective response rates and disease control rates were 50% and 76.4%, respectively, for first-line chemotherapy, 43.1% and 65.3%, respectively, for second-line chemotherapy, and 20.8% and 51.4%, respectively, for third-line chemotherapy.
|Figure 1: Response data for first-to third-line chemotherapy in patients (NE: Not evaluable, PD: Progressive disease, SD: Stable disease, PR: Partial response)|
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Median survival in the estimated survival analysis for patients undergoing third-line chemotherapy was 26 months after first-line chemotherapy, and 10 months following third-line chemotherapy. [Figure 2] shows the Kaplan-Meier curves for overall survival and for survival after third-line treatment. In the group of patients in whom disease control was achieved during first- and second-line chemotherapy, the overall survival time of 34 months was significantly greater than 17 months seen in the group with progression (HR, 0.41; 95% CI, 0.24 - 0.70; P < 0.001).
|Figure 2: Overall survivals from the initiation of first-line treatment (a) and third-line treatment (b)|
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Univariate analysis of prognostic factors for OS
[Table 3] details the prognostic factors (gender, histopathology, performance status, first- and second-line treatment responses) examined after the start of first- and third-line chemotherapy. In univariate analysis, in the groups with ECOG PS 0-1 and 2-3 at the start of first-line treatment, overall survival was 27 months and 16 months, respectively (HR, 1.90; 95% CI, 1.02-3.55; P = 0.035). Moreover, it was also significantly longer in the group with ECOG PS 0-1 at the start of third-line treatment compared to those with ECOG PS 2-3 (15 and 5 months, respectively; HR, 2.59; 95% CI, 1.49 - 4.50; P < 0.001). In patients achieving disease control after second-line chemotherapy, compared to patients with progression, the overall survival rates were 34 months and 17 months, respectively (HR, 0.27; 95% CI, 0.24 − 0.70; P < 0.001). Survival rates in patients with disease control were also significantly greater after third-line treatment compared to those without disease control (15 vs. 7 months, respectively; HR, 2.04; 95% CI, 1.19−3.50; P = 0.006).
|Table 3: Prognostic factors on overall survival from the initiation of first-line treatment and third-line treatment (Univariate analysis) |
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Multivariate analysis of prognostic factors for OS
[Table 4] shows the prognostic factors (performance status, second-line treatment responses) investigated after the start of first-line and third-line chemotherapy. In multivariate analyses, an ECOG PS 0-1 before the start of third-line treatment was found to be a statistically significant factor for increased survival following therapy (HR, 0.38; 95% CI, 0.22-0.67; P < 0.001). Considering overall survival calculated from the start of first-line treatment, patients who achieved disease control in second-line treatment had better outcomes than those with disease progression (HR, 0.27; 95% CI, 0.15-0.48; P < 0.001). In [Figure 3], the Kaplan-Meier curves of overall survival according to disease control after second- and third-line treatment and before and after third-line treatment according to ECOG PS are shown. Patients with disease control after second-line treatment, and especially those with ECOG PS 0-1 before third-line treatment, had the longest overall survival and the longest survival after third-line treatment.
|Figure 3: Overall survival from the initiation of first-line treatment according to disease control after second-line treatment (a), overall survival from the initiation of third-line treatment, according to performance status before third-line treatment (b)|
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|Table 4: Prognostic factors on overall survival from the initiation of first-line treatment and third-line treatment (multivariate analysis) |
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| > Discussion|| |
Herein, a group of 72 patients with advanced stage NSCLC was retrospectively studied. All patients were followed at a single institution and received third-line or higher chemotherapy. To date, there are no prospective randomized studies on third-line and higher treatments. This retrospective study allowed identification of prognostic factors for patients receiving third-line treatment.
In this analysis, following third-line treatment the objective response rate was 20%, with a disease control rate of 50%. These results are far better than those found in the previous study by Massarelli et al.  in 2003, who reported an objective response rate of 2.3% and a disease control rate of 30% after third-line treatment. It is likely that the large difference in objective response may be related to the availability of new agents, especially the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Indeed, the use of these drugs is becoming more widespread as they are associated with definite clinical benefits and increased rates of disease control. In second- and third-line treatment decisions, tumor histology, age, performance status, comorbidity, previous treatments, molecular profile, and side effects due to previous medications as well as patient preference all play an important role. In second- and third-line therapy, the main goals are to control disease-related symptoms and increase survival. Since there are no chemotherapeutic regimens that are preferred as third-line treatment, the possibility that the patient will benefit from the treatment without unacceptable toxicity should always be kept in mind.
This study examined factors that influence not only overall survival, but survival after third-line treatment. All the patients included in the study received third-line and higher treatment. Before the start of first-line treatment, the vast majority of patients had an ECOG PS of 0-1 (n = 64, 88.9%). It is well known that ECOG PS is one of the most important prognostic factors in NSCLC.  Indeed, in the group with ECOG PS 0-1 survival was higher in both first-line treatment and after third-line treatment. In second-line treatment, survival was significantly higher in patients with disease control.
Two studies similar to the present one have recently been published that are in agreement with the results seen herein. , In both those investigations, there was also a relationship between responses obtained in first- and third-line treatments. In the study by Hajime et al., it was demonstrated that in the first two lines of treatment the group with disease control duration greater than 12 months had better outcomes than the group with disease control lasting less than 12 months. In the study by Nicolas et al., it was reported that survival times following third-line treatment were longer for patients who achieved disease control in the first two lines of treatment. It was also shown that tumor histology and gender were not prognostic factors for third-line treatment. Furthermore, survival was longer in patients with ECOG PS 0-1 and in those who achieved disease control after the second line of treatment. Of note, in that study, prior to third-line chemotherapy 49% of patients had an ECOG PS 2-3, compared to 30% in the present analysis.
One limitation of the present study is its retrospective nature, although it was performed in a single institution and in a highly homogeneous patient group. Clinical charts and computer records were nonetheless examined in detail, and this was complemented by telephoning patients whenever possible. Another limitation of our study is that neither EGFR nor ALK mutational analysis was performed for all patients, and thus it was not possible to make any correlations with survival in the regard.
| > Conclusion|| |
In patients with NSCLC, response rates to third-line treatment are low, and criteria for patient selection are inadequate. In this setting, based on the present results it may be appropriate to consider patients who achieved disease control in the second line of treatment and who have sufficient ECOG PS for third-line treatment. In order to better address these issues, prospective randomized studies on third-line treatments are needed, especially in light of the recent availability of new drugs and associated molecular analyses.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]