Abstract
Background/Aim: Most patients with small cell lung cancer (SCLC) experience relapse within one year after first-line treatment. The aim of this study was to describe activity and safety of second-line with epirubicin at 70 mg/m2 followed by paclitaxel at 135 mg/m2 on day 1 every three weeks for a maximum of six cycles. Patients and Methods: This is a retrospective review of all patients with SCLC evaluated for second–line treatment between 2003 and 2013 at our Institution. Results: Sixty-eight patients received the study regimen of epirubicin with paclitaxel. We observed partial response in 19 (30%), stable disease in 22 (34%) and total early failure rate in 23 (36%) patients. Median progression free and overall survival were 21.8 and 26.5 weeks, respectively. Haematological toxicities were as follows: grade 3-4 leukopenia and neutropenia in 18 (31%) and 30 (22%) of patients, respectively; grade 3 anaemia and grade 4 thrombocytopenia were reported in 2 (3%) and 5 (9%) of patients, respectively. Conclusion: Epirubicin with paclitaxel is an active and tolerable second-line regimen in patients with SCLC.
Small cell lung cancer (SCLC) is an aggressive tumour which accounts for 12% to 15% of all lung cancer cases, with decreasing incidence in recent years according to changes in smoking habits (1). Extensive disease at diagnosis represents about 60% to 70% of all cases. Worldwide, the currently accepted standard of care in patients with previously untreated metastatic SCLC is a chemotherapy regimen including platinum plus etoposide, which achieves a response rate (RR) of 60%, and median overall (OS) and progression-free survival (PFS) of approximately 8 and 4 months, respectively (28).
Despite high tumour chemosensitivity, the great majority of patients will experience relapse and die because of disease progression. Previous evidence from studies of second-line treatment suggested better treatment outcome in those patients with a longer disease-free interval (DFI) (1, 3, 12). This evidence led to the currently accepted classification of SCLC into sensitive disease, defined by a response to first-line therapy and a DFI of at least 60-90 days, and resistant disease, when there is no response to first-line treatment or relapse within 60-90 days occurs (2, 34). Treatment options in relapsed or progressive disease include rechallenge with platinum plus etoposide (3, 13, 27, 37), cyclophosphamide doxorubicin and vincristin (CAV) regimen (39), or singleagent topotecan (7, 23, 39), the only approved drug after the first-line treatment of SCLC. Most evidence concerns topotecan as a single agent, which led to RR of 7-24%, time to progression (TTP) of 11-13 weeks, OS of 25-35 weeks, and quality of life and symptom improvement comparable to combination regimens (39), and better than best supportive care (BSC) alone, even in patients with worse prognostic features(23). Topotecan, however, is associated with important haematological toxicity, such as grade (G)3-4 neutropenia, thrombocytopenia and anaemia in more than 60%, 40% and 30% of patients, respectively, thus raising some doubts about the feasibility of this treatment, particularly in patients with poor performance status (PS). Several other agents have been investigated in patients previously treated for SCLC, such as taxanes, vinorelbine, irinotecan or gemcitabine, but the absence of randomized trials and the heterogeneous populations under study do not allow any conclusion to be drawn about the superiority of one drug over another.
Treatment outcome of second-line paclitaxel as a single agent and in combination regimens was investigated in several phase II studies(6, 14, 19, 21, 30, 32). One of the more promising options was carboplatin plus paclitaxel, which was investigated in two studies, with a RR of 25% and 73%, median OS of 28 and 31 weeks, and G3-4 leukopenia and neutropenia in about 30% of the patients (14, 19). The different RRs in the two studies may be explained by the regimen administered in the first-line treatment because the first study included most patients previously treated with platinum plus etoposide, while the second study included mostly platinum-naive patients.
Patient characteristics (N=68).
Other combinations are paclitaxel plus gemcitabine (5, 6) or ifosfamide and cisplatin (21), the first leading to a RR of about 25% and the second a RR of more than 70% but with high haematological toxicity. Anthracyclines represented the backbone of first-line chemotherapy before wide implementation of platinum plus etoposide (2-21), thus different regimens including doxorubicin, epirubicin or amrubicin were investigated in the second-line setting of SCLC (9, 16-18, 22, 24, 32).
A phase II study investigated paclitaxel plus doxorubicin, showing an objective response in 41% of the 46 patients, including three complete remissions; median OS and TTP were 25 and 14 weeks, respectively. Treatment was generally well tolerated; among major toxicities, 63% of the study population developed G4 neutropenia, 11% G3 neurotoxicity, 5% G3 mucositis, one patient G4 myalgia, and one patient G3 cardiotoxicity (32). Congestive heart failure may be considered as the main dose-limiting toxicity of doxorubicin. Epirubicin is characterized by a different metabolic degradation compared to doxorubicin, with a more rapid plasma clearance after intravenous bolus injection and less toxicity at doses producing equivalent antitumor effects (35). Epirubicin has been investigated in combination with ifosfamide as second-line treatment of SCLC in a retrospective study, with a RR of about 20%, and a median OS of approximately four months. Haematological toxicity included G3-4 neutropenia in 71% of the patients, with about 10% of febrile neutropenia. Interestingly, patients who had received a previous combination of platinum plus etoposide had a trend towards longer survival compared with patients who had previously received an anthracycline (17).
Second-line regimens in patients not eligible for Epirubicin/Paclitaxel
Haematological toxicity in patients (N=58) according to Common Terminology Criteria for Adverse Events v 4.0.
On the basis of these data, and considering that most patients with SCLC currently receive platinum plus etoposide as first-line treatment, we considered a taxane-anthracycline combination as a promising non-crossresistant alternative to the standard second line treatment with topotecan. The aim of this study was to describe second-line treatment with epirubicin plus paclitaxel (EPac) in terms of response and disease control rate (DCR), PFS and OS, and safety profile.
Patients and Methods
This is a retrospective review of all patients with SCLC evaluated for second-line treatment between January 2003 and December 2013 at our Institution. Written informed consent for treatment was obtained from all patients before beginning chemotherapy. The study was submitted to and approved by the Institutional Ethics Committee (2014/20). For patients to be eligible for the study treatment, they were required to have Eastern Cooperative Oncology Group (ECOG) PS of 0-2 and to have experienced progressive disease (PD) or relapse after stable disease (SD), partial (PR) or complete response (CR) to first-line treatment, or to have refractory disease. Adequate bone marrow, renal and hepatic function, and left ventricular cardiac functions were required and systematically checked before treatment start. We classified SCLC according to the response to first-line chemotherapy into sensitive and resistant disease according to the previous definition (10, 34).
CONSORT diagram describing patient flow at our Institution between 2003 and 2013.
Haematological toxicity by cycle (N=123) according to CTCAE v 4.0.
Eligible patients received intravenous epirubicin at 70 mg/m2 followed by paclitaxel at 135 mg/m2 on day 1 every three weeks. Treatment continued until disease progression, development of unacceptable toxicity, or a request by the patient or physician to discontinue treatment, or on completion of six chemotherapy cycles. Complete blood cell counts were scheduled weekly during each cycle. Tumour assessment was performed after the third and the sixth cycle; cardiac assessment was repeated during chemotherapy if there was clinical suspicion of heart impairment. Prophylactic granulocyte colony-stimulating factor (G-CSF) was administered to those patients with a risk of febrile neutropenia higher than 20%, such as reduced marrow reserve due to previous radiotherapy (4), or between 10% and 20% with additional clinical risk, according to the guidelines of the Associazione Italiana di Oncologia Medica (AIOM). Erythropoiesis-stimulating agents were administered according to European Clinical Practice Guidelines (29).
Non-haematological toxicity in patients (N=62) according to CTCAE v 4.0.
Toxicity profile by patient and by cycle, during the first four cycles, was reported according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 (36). Response evaluation was reappraised according to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria and responses graded as CR, PR, SD, or PD (8). PFS was assessed from the date of enrolment to the date of disease progression (or relapse) or to the date of death, whichever occurred first. OS was assessed from the date of enrolment to the date of death. Patients were followed-up every two months with a radiological evaluation through a total body compu ted tomographic scan. In cases of suspected clinical progression, radiological confirmation was encouraged. Follow-up data were updated in March 2014.
Progression-free survival of the intent-to-treat population (N =68).
Statistics. PFS and OS curves were designed using the Kaplan–Meier method, and were analysed according to response (PR/SD vs. PD), TTP from the first-line treatment (<3 months vs. ≥3 months), ECOG PS (0-1 vs. 2), and age (≥ or <75 years); the impact of these variables on OS and PFS was evaluated by using a Cox regression proportional hazards model. The impact of subsequent treatment lines on patients prognosis was further analysed. A p-value of less than 0.05 was considered significant.
Results
Between January 2003 and December 2013, 291 patients with SCLC were referred to our Center, 175 (60%) with extensive and 116 (40%) with limited disease. Ninety-nine (34%) patients were eligible for systemic second-line treatment at the time of disease relapse or progression; the other patients were not eligible for various reasons (Figure 1). Among the 99 patients eligible for second-line systemic treatment, 68 (69%) received the study regimen, EPac. Patient characteristics are summarized in Table I.
Among non-eligible patients, 10 did not received EPac due to cardiac comorbidity, and 21 based on their physician's decision. Second-line regimens in 31 patients not included in the study are summarized in supplementary Table II.
Overall survival of the intent-to-treat population (N =68).
According to the DFI after first-line treatment, 43 (63%) patients were considered as having sensitive and 25 (37%) resistant SCLC, with disease in six patients progressing during the first-line chemotherapy. A total of 225 cycles were administered; the median number of cycles was 4 (range=1-6). Tumor assessment was available in 52 patients; 12 patients early interrupted chemotherapy before the third cycle and were considered treatment failures (Figure 1). Among evaluable patients (N=64), we observed 19 (30%) PRs, 22 (34%) SDs, for a DCR of 64%. PD was seen in 11 (17%) patients and early treatment discontinuation in 12 (19%), for a total early failure rate of 36%. The median duration of follow-up was 6.5 months; the median PFS was 21.8 (range=3-47) weeks, and the median OS was 26.5 (range=3-137) weeks (Figures 2 and 3).
Twenty-three patients (34%) received at least one further line of systemic treatment and eight (12%) patients received up to four lines of chemotherapy. At the multivariate analysis, ECOG PS of 0-1 (hazard ratio (HR)=0.331, 95% confidence interval (CI)=0.154-0.710; p=0.005) and the administration of further chemotherapy after the study treatment (HR=0.193, 95% CI=0.096-0.387; p<0.001) were significantly associated with better OS; PFS was not significantly associated with any covariate.
The haematological toxicity profile for 58 evaluable patients is given in Table III. The haematological toxicity by cycle, assessed in the first four cycles, showed G3-4 leukopenia in 20%, G3-4 neutropenia in 32% and G3-4 anemia in 2% of the cycles (Table IV). Six patients received at least one red blood cell transfusion, while one patient received a platelet transfusion. Among those patients who did not experience any grade of neutropenia (N=12; 21%), seven received prophylactic G-CSF. Six (10%) patients received epoetin during the study treatment.
Among patients evaluable for non-haematological toxicity (N=62), two patients exhibited cardiotoxicity: one patient had G1 reduction in systolic function, while cardiac ischemia occurred in a second patient after one cycle of study treatment. Other G3 non-haematological toxicities included fatigue (N=3; 5%), nausea (N=1; 2%) and vomiting (N=1; 2%) (Table V). During study treatment, 21 (36%) patients received a dose reduction because of haematological or non-haematological toxicity.
Discussion
Despite high sensitivity to chemotherapy, and responses to standard first-line treatment in about 50% of patients (15), the great majority of patients with SCLC will experience disease progression within one year.
At the time of progression, most patients are not eligible for further treatments, having a median survival of 2-3 months; second-line chemotherapy is feasible in about 40% of patients with SCLC, the main reasons for non-eligibility being rapidly worsening clinical condition and poor compliance, while PS and sensitivity to previous chemotherapy may be considered as prognostic factors for survival (20, 31). Data on the clinical benefit of second-line treatment are controversial, reporting RR in 7 to 24% of the patients and median survival of 3 to 9 months (11, 25). These data were also confirmed from few randomized clinical trials (7, 16, 18, 23, 26, 39), with heterogeneous chemotherapy regimens and patient features. Our study proves the feasibility of a second-line treatment with EPac in patients with sensitive, resistant or refractory SCLC referred to our Center over a period of 10 years. Within the overall population of 291 patients with SCLC, 34% of them were eligible for second-line chemotherapy, and the main reasons for the non feasibility of chemotherapy were rapid worsening of PS and early death. This is in line with previous data, thus highlighting the importance of patient selection and prognostic score assessment in treatment planning (2, 20, 33).
Higher responses to platinum-based rechallenge have been reported in patients with longer DFI after first-line therapy (11, 12). The concept of DFI as a predictor of better outcome came first from clinical series treated with second-line topotecan, while recently a DFI of 60 days compared with 90 days has been reported as a more reliable temporal criterion to predict response to standard second-line treatment. Other prognostic factors such as PS 2, presence of liver metastasis, and low blood level of albumin have been identified(2). Similarly to previous data, our study identified an ECOG PS 0-1 and the administration of further chemotherapy lines as significant prognostic factors. The main limitation of currently known prognostic factors is the retrospective identification of their value, and the possible different significance according to the second-line regimen. The great majority of randomized second-line studies investigated the role of topotecan, which led to disease control and survival improvement, slower deterioration in quality of life and better symptom control compared with best supportive care (13), and similar efficacy when compared with other chemotherapy regimens (11).
There are no available and reliable data on the different efficacy of single-agent compared with combination second-line chemotherapy; retrospective analysis showed higher RR and DCR, and longer PFS with a combination regimen, without significant difference in terms of OS but with higher grade 3-4 toxicity. Beyond the retrospective nature of the studies and the heterogeneity of patients and disease sensitivity, no criteria for treatment choice were clearly stated, thus rising a bias in interpretation of results(31). Taxanes and anthracyclines have shown activity when administered to patients previously treated for SCLC (14-19, 21-26), but no randomized studies compared the combination of these two agents with standard topotecan in the second-line setting, and recent data showed that monotherapy with amrubicin does not improve survival when compared with topotecan (38).
In the present study, within the group of patients with relapsed SCLC, about 70% of them were eligible for EPac; early interruption and dose reduction because of poor tolerability occurred in 18% and 36% of the patients, respectively. We reported RR and DCR of 30% and 64%, median OS and PFS of 26.5 and 21.8 weeks, respectively. Survival data were comparable to those of other studies where both rechallenge with platinum plus etoposide and potential non cross-resistant regimens were tested. A European survey indicates better results by rechallenge with platinum plus etoposide, but data on quality of life, patient compliance and acceptance of a new platinum-based treatment are lacking (36).
The EPac regimen is a single-day hospital admission with acceptable toxicity profile: G3-4 neutropenia was reported in one-third of the cycles, with only one case of febrile neutropenia and no severe non-haematologicaI toxicity or toxic deaths. To our knowledge, these are the first data on the EPac regimen in pretreated SCLC. Of course, no definitive conclusion may be drawn because of the retrospective nature of the study and lack of a control arm. It is, however, clear from these and previous data, that better treatment options for patients with SCLC which progresses after therapy with platinum plus etoposide are needed. Moreover, an effort to prospectively investigate the best strategy between rechallenge with platinum plus etoposide and potential non cross-resistant regimens in pretreated SCLC should be a priority.
Footnotes
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This article is freely accessible online.
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Conflicts of interest
None
- Received December 24, 2014.
- Revision received February 5, 2015.
- Accepted February 9, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
