Abstract
Background
The aim of this study was to confirm the association between the response to docetaxel combined with platinum as first-line chemotherapy and prognosis and subsequent treatment for patients with non-small cell lung cancer (NSCLC).
Methods
This study enrolled 224 patients with NSCLC diagnosed at our institution between January 2001 and August 2012. All patients received more than two cycles of docetaxel combined with platinum as first-line chemotherapy and were reassessed after two cycles. The association between the response to first-line treatment and prognosis and subsequent treatment were statistically analyzed.
Results
Among the 224 patients, 70 (31.25%) achieved partial response (PR), 90 (40.18%) stable disease (SD), and 64 (28.57%) progressive disease (PD). The overall survival (OS) of NSCLC patients with PR, SD and PR+SD was significantly longer than those with PD (P = 0.043; P = 0.000; P = 0.001). However, no significant difference was observed in OS between patients with PR and SD (P = 0.174). Cox regression analysis found treatment response was an independent prognostic factor (hazard ratio = 1.615, 95% confidence interval: 1.121–2.327). Two independent non-parametric sample tests showed that patients with a good response to first-line treatment had received further treatment cycles and treatment lines (P = 0.000; P = 0.000).
Conclusions
Our study demonstrated that the response to docetaxel in combination with platinum as a first-line chemotherapy was an independent prognostic factor for patients with NSCLC. In addition, patients with a good response to first-line treatment had received further treatment cycles and treatment lines.
Keywords: Chemotherapy, non-small cell lung cancer, prognosis, response
Introduction
The mortality of lung cancer is one of the highest among malignant tumors.1 One major reason for the poor outcome is the fact that the majority of non-small cell lung cancer (NSCLC) patients are diagnosed at advanced stages, and, therefore, systemic combination chemotherapy has become the standard approach in these patients.2–6 The utility of chemotherapy in providing a survival benefit has been a hot research topic in recent times. One meta-analysis showed that median survival time (MST) was significantly associated with both the objective response rate (ORR) and disease control rate (DCR) in first-line chemotherapy in these patients. Patients with advanced NSCLC almost always receive multiple cycles of chemotherapy; however, a subgroup analysis showed no correlation between the ORR and MST in patients receiving molecular-targeted agents as part of the chemotherapy regimen.7 The study by Gebbia et al. evaluated the efficacy of vinorelbine plus cisplatin versus gemcitabine combined with cisplatin in advanced NSCLC patients. The study found that gemcitabine in combination with cisplatin was significantly more efficient than the vinorelbine plus cisplatin treatment, but a significant difference in overall survival (OS) was not observed between the two groups.8 Similar results have been observed in several other studies assessing the efficacy of vinorelbine and gemcitabine in NSCLC patients.9,10 Collectively, these data suggest that the efficacy of chemotherapy in providing a survival benefit is related to the type of chemotherapy drug used.
Docetaxel is a clinically well established anti-mitotic chemotherapeutic that has been widely used for lung cancer chemotherapy. However, the relationship between the response to docetaxel in combination with platinum as a first-line chemotherapy for NSCLC patients is not clear. Therefore, the aim of this study was to confirm this relationship and explore possible mechanisms by assessing the clinical data.
Materials and methods
Patients and treatment evaluation
Two hundred and twenty-four patients with NSCLC diagnosed at our institution between January 2001 and August 2012 were enrolled in this study (Table 1). All final diagnoses were confirmed by pathologic examination. The clinical stages of the enrolled NSCLC patients ranged from stage III to IV based on the guidelines of the tumor node metastasis (TNM) staging system of the Union for International Cancer Control 7th edition.11 The stage assessment was based on computed tomography (CT) scans of the thorax and upper abdomen, magnetic resonance imaging (MRI) scans of the brain, and emission CT scans of the bone. All patients received more than two cycles of standardized docetaxel plus platinum chemotherapy and were reassessed after two cycles of chemotherapy. The rules established by the Response Evaluation Criteria in Solid Tumors (RECIST) were used to evaluate tumor responses to treatment.12 Patients were considered to have achieved disease control (DC) if they had a complete response (CR), a partial response (PR), or stable disease (SD) according to RECIST. Progressive disease (PD) was considered to represent disease progress. If the assessment after two cycles of first-line chemotherapy was PD, then the patients received second line treatment with either a new chemotherapeutic agent or an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). This process continued for each failure. Administration of a chemotherapeutic for 21 days or a one-month treatment of EGFR-TKI was defined as one cycle of treatment. OS was determined for all patients who were censored at the time of last follow-up (31 August 2012). The Medical Ethics Committee of Jinling Hospital approved this study. As this study was retrospective in nature, it did not require informed patient consent.
Table 1.
Non-small cell lung cancer (NSCLC) patient demographics and clinicopathology characteristics
| Characteristic | Value (%) |
|---|---|
| Number of patients | 224 |
| Gender | |
| Male | 151 (67.41) |
| Female | 73 (32.59) |
| Median age, years (range) | 8–85 (61) |
| <65 | 139 (62.54) |
| ≥65 | 85 (37.46) |
| Smoking habits (years) | |
| <20 | 122 (54.46) |
| ≥20 | 102 (45.54) |
| Histology | |
| Adenocarcinoma | 147 (65.63) |
| Squamous | 63 (28.12) |
| Others | 14 (6.25) |
| TNM Stage | |
| III | 75 (33.48) |
| IV | 149 (66.52) |
TNM, tum or node metastasis.
Statistical analyses
All statistical analyses were performed with SPSS 17.0 software. The Kaplan-Meier method was used to calculate survival probability. The log-rank test was performed to assess heterogeneity in survival within each prognostic factor. A Cox regression model was used to analyze independent prognostic risk factors. Two independent sample non-parametric tests were used to evaluate the association between patient response to first-line treatment and the total number of treatment cycles or the total number of treatment lines. A P < 0.05 was considered statistically significant.
Results
The response to first-line chemotherapy and overall survival (OS)
All of the patients were assessed after two cycles of treatment. No patient achieved a CR, 70 (31.25%) achieved a PR, 90 (40.18%) had SD, and 64 (28.57%) patients had PD. The median OS in the 224 NSCLC patients was 450 days (range: 55–3044). The median OS of patients with PR, SD, and PD was 470, 497, and 350 days, respectively. Kaplan-Meier survival analysis showed that the OS of the NSCLC patients with PR and SD was significantly longer than that of the NSCLC patients with PD (log-rank test, P = 0.043 and P = 0.000, respectively). However, there was no significant difference in OS between patients with PR and SD (log-rank test, P = 0.174; Fig 1a).
Figure 1.
Relationship between the response to first-line chemotherapy and overall survival (OS). (a) Kaplan-Meier curves compare partial response (PR) (blue line), stable disease (SD) (green line) and progressive disease (PD) (gray line); (b) Kaplan-Meier curves compare PR+SD (blue line), and PD (green line). (a) 
, PR; 
, SD; 
, PD; 
, PR-censored; 
, SD-censored; 
, PD-censored. (b) 
, PR+SD; 
, PD; 
, PR+SD-censored; 
, PD-censored.
The median OS of patients with PR+SD and PD was 481 and 350 days, respectively. Kaplan-Meier survival analysis showed that the OS of the NSCLC patients with DC was significantly longer than that of the NSCLC patients with PD (log-rank test, P = 0.001; Fig 1b). A Cox regression analysis found that response (P = 0.01, hazard ratio [HR] = 1.615, 95% confidence interval [CI]: 1.121–2.327), gender (P = 0.026, HR = 0.605, 95% CI: 0.388–0.943), and TNM stage (P = 0.008, HR = 1.710, 95% CI: 1.152–2.538) were independent prognostic factors in NSCLC patients (Table 2).
Table 2.
Cox regression analysis of independent risk factors for overall survival (OS) in patients with non-small cell lung cancer (NSCLC)
| P | HR | 95% CI for HR | ||
|---|---|---|---|---|
| Lower | Upper | |||
| Response | 0.010 | 1.615 | 1.121 | 2.327 |
| Gender | 0.026 | 0.605 | 0.388 | 0.943 |
| Age | 0.260 | 1.223 | 0.861 | 1.736 |
| Smoking | 0.994 | 0.998 | 0.656 | 1.520 |
| Histology | 0.746 | 0.953 | 0.712 | 1.275 |
| TNM stage | 0.008 | 1.710 | 1.152 | 2.538 |
CI, confidence interval; HR, hazard ratio; TNM, tumor node metastasis.
The number of cycles in first-line therapy and OS
Of the 224 patients, 145 patients received no less than four cycles of chemotherapy in first-line treatment, and 79 patients received less than four cycles. The median OS of the 145 patients who received no less than four cycles of chemotherapy was 516 days, and that of the 79 patients receiving less than four cycles of chemotherapy was 336 days. Kaplan-Meier survival analysis showed that the OS of the NSCLC patients receiving no less than four cycles of chemotherapy for first-line treatment was significantly longer than that of patients receiving less than four cycles chemotherapy (log-rank test, P = 0.000; Fig 2a).
Figure 2.
Relationship between the number of treatment cycles received as first line therapy and overall survival (OS). (a) Kaplan-Meier curves compare the number of treatment cycles ≥4 (blue line) and <4 (green line); (b) Kaplan-Meier curves compare the number of treatment cycles, four (blue line) and six (green line). (a) , ≥4; 
, <4; 
, ≥4-censored; 
, <4-censored. (b) 
, 4; 
, 6; 
, 4-censored; 
, 6-censored.
Of the 160 patients with DC, the median OS of 69 patients receiving four cycles of chemotherapy was 482 days and the median OS of 61 patients receiving six cycles chemotherapy was 536 days. However, the Kaplan-Meier survival analysis showed there was no significant difference between the two groups (P = 0.228; Fig 2b).
Response to first-line chemotherapy and the total number of treatment cycles
The median total number of treatment cycles was five (range: 2–30). As shown in Figure 3a, the total number of treatment cycles of patients with DC (PR+SD) was six (range: 2–30) and with PD was two (range: 2–7). Two independent sample non-parametric tests showed that the mean rank of the total number of treatment cycles for patients with DC (PR+SD) and PD was 139.69 and 44.52, respectively. Importantly, the total number of treatment cycles between the two groups was significantly different (P = 0.000).
Figure 3.
(a) The total number of treatment cycles of 224 patients stratified by response to first line treatment; (b) The total number of treatment lines of 224 patients stratified by response to first line treatment.
Response to first-line chemotherapy and the total number of treatment lines
The median total number of treatment lines was one (range: 1–4). Figure 3b shows that the median number of treatment lines for patients with DC (PR+SD) and PD was one (range: 1–4) and one (range: 1–3), respectively. Two independent sample non-parametric tests showed that the mean rank of the total number of treatment lines for patients with DC (PR+SD) and PD was 121.50 and 89.99, respectively (P = 0.000).
Discussion
Our study has demonstrated that the response to docetaxel in combination with platinum as a first-line chemotherapy regimen was an independent prognostic factor for patients with advanced or locally advanced NSCLC. The NSCLC patients with DCR (PR+SD) had longer survival compared to patients who did not achieve DCR. These findings were similar to those using single-agent docetaxel in patients with NSCLC, which yielded an ORR of only 6%, even though it provided a significant survival advantage as a second line therapy.13 Moreover, similar results have been observed in other tumors, such as multiple myeloma,14 non-Hodgkin's lymphoma,15 and gastric cancer.16 However, several other studies assessing the efficacy of vinorelbine in combination with gemcitabine for treating NSCLC did not show the same results,8–10 and this observed difference may be related to the type of chemotherapy drug. However, to date, the specific mechanism remains unclear.
We further confirmed these results using a Kaplan-Meier analysis. The Kaplan-Meier survival analysis showed that the OS of NSCLC patients who had received no less than four cycles of chemotherapy as the first-line treatment was significantly longer than that of patients who received less than four cycles of chemotherapy. It is well accepted that most patients with PR or SD after two cycles of treatment would receive at least two more cycles. Conversely, patients with (PD) would receive a second line or other type of treatment, such as radiotherapy. Therefore, the number of treatment cycles for these patients would be less than four, thereby confirming that the response to docetaxel in combination with platinum as a first-line chemotherapy regimen was associated with the prognosis of NSCLC patients. However, the OS was not significantly different between the patients receiving four cycles of chemotherapy and those receiving six cycles (P = 0.228). These results suggest that four cycles was sufficient and that additional cycles would not provide a greater survival benefit. A study by Park et al. had similar findings and showed that patients who received a total of six cycles had a significantly longer progression-free survival than those patients receiving less cycles; however, both groups had the same OS.17
Our study found that both OR (CR+PR) and DCR (CR+PR+SD) were associated with OS in NSCLC patients treated with docetaxel in combination with platinum. The median OS of patients with SD was longer than patients with PR (497 vs. 470 days), although the difference was not statistically significant. These results suggest that DCR may be a good surrogate marker for the efficacy of novel types of anticancer agents used in first line chemotherapy for NSCLC. A previous study found that single-agent docetaxel yielded an ORR of only 6%, and 43% of patients achieved SD, though the drug yielded a significant survival advantage as a second line therapy.13 These findings suggest that not only tumor shrinkage, but also disease stabilization may contribute to the survival benefit in first-line chemotherapy in NSCLC patients. Similarly, a meta-analysis demonstrated that in second line or later settings, the median MST was not associated with the ORR, but was associated with the DCR.7
Our study also explored the reasons for these observations by evaluating the influence of a response to docetaxel in combination with platinum used as a first-line therapy on subsequent treatments. We found that patients with a good response to first-line treatment received a greater number of treatment cycles and treatment lines. Therefore, patients with a good response to first-line chemotherapy had longer survival. However, the reasons for this effect were not clear and will require additional studies for clarification.
Several chemotherapeutics are available as a first-line therapy for advanced NSCLC, and platinum-based two-drug combination chemotherapy has become the standard of care for these patients. In addition, although the efficacy of different chemotherapy drug combinations may be different, this does not always translate into an improvement in OS. The lower ORR did correlate with a decrease in the OS in our study. Treatment of advanced NSCLC is generally palliative chemotherapy to prolong survival and improve the quality of life. Therefore, the extension of survival may be a primary end point in addition to ORR.
There were several limitations to our study. First, this was a retrospective study, and, therefore, a prospective study with a larger cohort may be needed to confirm these findings. Second, the rate of second line treatment was low, and, therefore, this may affect our conclusions to some extent.
Conclusions
Our study demonstrated that the response to docetaxel plus platinum as a first-line regimen was an independent prognostic factor for patients with advanced or locally advanced NSCLC. In addition, NSCLC patients who had a good response (PR+SD) to the first-line treatment had a longer OS, and response to first-line chemotherapy influenced the outcome of subsequent treatments.
Disclosure
No authors report any conflict of interest.
References
- Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29. doi: 10.3322/caac.20138. [DOI] [PubMed] [Google Scholar]
- Molina JR, Yang P, Cassivi SD. Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83:584–594. doi: 10.4065/83.5.584. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wakelee HA, Bernardo P, Johnson DH, Schiller JH. Changes in the natural history of nonsmall cell lung cancer (NSCLC) – comparison of outcomes and characteristics in patients with advanced NSCLC entered in Eastern Cooperative Oncology Group trials before and after 1990. Cancer. 2006;106:2208–2217. doi: 10.1002/cncr.21869. [DOI] [PubMed] [Google Scholar]
- Ramalingam S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist. 2008;13(Suppl 1):5–13. doi: 10.1634/theoncologist.13-S1-5. [DOI] [PubMed] [Google Scholar]
- Fathi AT, Brahmer JR. Chemotherapy for advanced stage non-small cell lung cancer. Semin Thorac Cardiovasc Surg. 2008;20:210–216. doi: 10.1053/j.semtcvs.2008.09.002. [DOI] [PubMed] [Google Scholar]
- Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–98. doi: 10.1056/NEJMoa011954. [DOI] [PubMed] [Google Scholar]
- Hotta K, Fujiwara Y, Kiura K, et al. Relationship between response and survival in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic chemotherapy in 143 phase III trials. J Thorac Oncol. 2007;2:402–407. doi: 10.1097/01.JTO.0000268673.95119.c7. [DOI] [PubMed] [Google Scholar]
- Gebbia V, Galetta D, Caruso M, et al. Gemcitabine and cisplatin versus vinorelbine and cisplatin versus ifosfamide+gemcitabine followed by vinorelbine and cisplatin versus vinorelbine and cisplatin followed by ifosfamide and gemcitabine in stage IIIB-IV non small cell lung carcinoma: a prospective randomized phase III trial of the Gruppo Oncologico Italia Meridionale. Lung Cancer. 2003;39:179–189. doi: 10.1016/s0169-5002(02)00444-0. [DOI] [PubMed] [Google Scholar]
- Laack E, Dickgreber N, Müller T, et al. Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group. J Clin Oncol. 2004;22:2348–2356. doi: 10.1200/JCO.2004.10.576. [DOI] [PubMed] [Google Scholar]
- Alberola V, Camps C, Provencio M, et al. Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol. 2003;21:3207–3213. doi: 10.1200/JCO.2003.12.038. [DOI] [PubMed] [Google Scholar]
- Sobin LH, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumors (UICC International Union Against Cancer) 7th edn. Oxford: Wiley-Blackwell; 2009. [Google Scholar]
- Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026. [DOI] [PubMed] [Google Scholar]
- Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18:2095–2103. doi: 10.1200/JCO.2000.18.10.2095. [DOI] [PubMed] [Google Scholar]
- Riccardi A, Mora O, Tinelli C, et al. Response to first-line chemotherapy and long-term survival in patients with multiple myeloma: results of the MM87 prospective randomised protocol. Eur J Cancer. 2003;39:31–37. doi: 10.1016/s0959-8049(02)00529-4. [DOI] [PubMed] [Google Scholar]
- Alici S, Bavbek S, Basaran M, Onat H. Prognostic factors in patients with aggressive non-Hodgkin's lymphoma without complete response to first-line therapy. Adv Ther. 2006;23:534–542. doi: 10.1007/BF02850042. [DOI] [PubMed] [Google Scholar]
- Ichikawa W, Sasaki Y. Correlation between tumor response to first-line chemotherapy and prognosis in advanced gastric cancer patients. Ann Oncol. 2006;17:1665–1672. doi: 10.1093/annonc/mdl174. [DOI] [PubMed] [Google Scholar]
- Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007;25:5233–5239. doi: 10.1200/JCO.2007.10.8134. [DOI] [PubMed] [Google Scholar]