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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 4  |  Page : 764-770

Post-progression survival is strongly linked to overall survival in refractory small-cell lung cancer patients who received amrubicin


1 Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ohta, Gunma 373-8550; Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
2 Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
3 Clinical Research Support Center, Shizuoka Cancer Center, Shizuoka 411-8777, Japan
4 Division of Pharmacy, Gunma Prefectural Cancer Center, Ohta, Gunma 373-8550, Japan
5 Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan

Date of Submission19-Oct-2016
Date of Decision14-Aug-2017
Date of Acceptance24-Feb-2018
Date of Web Publication24-Oct-2018

Correspondence Address:
Hisao Imai
Division of Respiratory Medicine, Gunma Prefectural Cancer Center, 617-1, Takahayashinishi, Ohta, Gunma 373-8550
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1170_16

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 > Abstract 


Background: The benefits of second-line chemotherapy on the overall survival (OS) of small-cell lung cancer (SCLC) patients might be confounded by subsequent therapies. In this study, we aimed to determine the influence of progression-free survival (PFS) and postprogression survival (PPS) on OS after second-line chemotherapy in patients with refractory SCLC treated with amrubicin monotherapy.
Materials and Methods: We analyzed the data of 35 patients with refractory SCLC who were treated with amrubicin monotherapy as second-line chemotherapy between July 2005 and December 2015. The correlations of PFS and PPS with OS were statistically analyzed at the individual level using Spearman's rank correlation and linear regression analyses.
Results: The correlation between PPS and OS was strong (r = 0.88, P < 0.05, R2 = 0.87), while that between PFS and OS was weak (r = 0.60, P < 0.05, R2 = 0.15). The number of regimens administered after disease progression postsecond-line chemotherapy was significantly associated with PPS (P = 0.003).
Conclusions:OS is more strongly linked to PPS than to PFS in refractory SCLC patients who undergo amrubicin monotherapy as a second-line treatment. These results suggest that treatments administered after second-line chemotherapy affect the OS of refractory SCLC patients treated with amrubicin monotherapy.

Keywords: Amrubicin, overall survival, postprogression survival, progression-free survival, second-line chemotherapy, small-cell lung cancer


How to cite this article:
Imai H, Kaira K, Mori K, Watase N, Hisada T, Yamada M, Minato K. Post-progression survival is strongly linked to overall survival in refractory small-cell lung cancer patients who received amrubicin. J Can Res Ther 2020;16:764-70

How to cite this URL:
Imai H, Kaira K, Mori K, Watase N, Hisada T, Yamada M, Minato K. Post-progression survival is strongly linked to overall survival in refractory small-cell lung cancer patients who received amrubicin. J Can Res Ther [serial online] 2020 [cited 2020 Sep 23];16:764-70. Available from: http://www.cancerjournal.net/text.asp?2020/16/4/764/243472




 > Introduction Top


Lung carcinoma is the leading cause of cancer-related deaths worldwide,[1] and small-cell lung cancer (SCLC) accounts for almost 13% of all new cases.[2] Although most SCLC patients respond to initial treatment, long-term survival is low, as disease progression or relapse occurs in almost all advanced-stage SCLC patients and in the majority of early-stage SCLC patients.[3],[4],[5],[6],[7] SCLCs are rapidly proliferating tumors that are highly sensitive to chemotherapy. However, the rapid emergence of clinical drug resistance results in poor prognosis, with almost all such patients die within 2 years of the initial diagnosis.[8] For refractory SCLC patients, overall survival (OS) is shorter and options for subsequent chemotherapy are limited. Response to subsequent chemotherapy depends on sensitivity to previous induction chemotherapy as well as the interval between cessation of initial therapy and disease progression.[9],[10] The second-line treatment of choice in refractory SCLC patients with a good performance status (PS) and without interstitial lung disease and poor risk is amrubicin monotherapy.[11],[12]

Progression-free survival (PFS) and OS are two common end points used in cancer trials. OS is usually preferred because it is reliable and precise, and it can be easily documented by noting the date of death. However, the effect of first-line treatments on OS might be confounded by subsequent lines of therapy.[13] In contrast, PFS may be easier to assess than OS because it is faster and more convenient.[14] If there is a strong correlation between PFS and OS, PFS may be a surrogate end point for OS. Conversely, a longer PFS does not necessarily mean a longer OS in non-SCLC (NSCLC);[15] however, postprogression survival (PPS) is strongly associated with OS after first-, second-, and third-line chemotherapy for advanced NSCLC at the clinical trial level.[16],[17],[18] Furthermore, OS can be approximated as the sum of PPS and PFS.[13] Previous studies demonstrated a strong correlation between PPS and OS after first-line chemotherapy in nonelderly extensive disease (ED)-SCLC patients using individual-level data.[19],[20] However, in refractory SCLC patients treated with amrubicin monotherapy, the relationship between PPS and OS is unknown. Although many Phase III trials have been performed for previously treated patients with ED-SCLC, no reports of studies on PPS are available for this group at an individual level. The significance of PPS in refractory SCLC patients treated with amrubicin monotherapy also remains unclear.

Therefore, we aimed to determine the relationships between OS and each of PFS and PPS after second-line chemotherapy for refractory SCLC patients treated with amrubicin monotherapy using individual-level data. We examined second-line amrubicin monotherapy because it is considered one of the standard second-line chemotherapy regimens used in refractory SCLC patients;[11] patients recruited for this study had only limited options for subsequent-line chemotherapy. We also explored the prognostic implications of baseline and tumor characteristics for PPS.


 > Materials and Methods Top


Patients

Between July 2005 and December 2015, 35 patients with refractory SCLC were treated with amrubicin monotherapy as second-line chemotherapy at our institution. These patients, who were refractory to treatment with previous platinum-based chemotherapy regimens, were retrospectively enrolled in this study. The evaluation and resection procedures for these tumors have been described previously.[20] Refractory disease was defined as no response to previous chemotherapy, disease progression on chemotherapy, or disease progression <90 days after completing previous chemotherapy after a complete response (CR) or partial response (PR) had been confirmed. At our institution, patients without interstitial lung disease are usually administered amrubicin monotherapy as subsequent-line treatment. The inclusion criteria were as follows: histologically or cytologically confirmed SCLC, ≤74 years of age at the time of chemotherapy, Eastern Cooperative Oncology Group PS of 0–3 at the beginning of the second-line treatment, and disease progression after second-line treatment. For this type of study, formal consent was not required.

Treatments

The patients were treated with amrubicin (35–40 mg/m2/ day on days 1, 2, and 3, followed by a pause of 21 days). This cycle was repeated every 3–4 weeks until disease progression, intolerable toxicity, or patient refusal. The first- and third-line chemotherapy regimens were determined by the treating physicians.

Assessment of treatment efficacy

The best overall tumor response was recorded. Radiographic tumor responses were evaluated according to the Response Evaluation Criteria In Solid Tumors, ver. 1.1,[21] as follows: CR, disappearance of all target lesions; PR ≤30% decrease in the sum of the target lesion diameters with the summed baseline diameters as a reference; progressive disease (PD), ≥20% increase in the sum of the target lesion diameters above the smallest sum observed during the study; and stable disease (SD), insufficient shrinkage to qualify as PR and insufficient expansion to qualify as PD. PFS was calculated from the start of second-line treatment to the date of PD or death from any cause. OS was recorded from the 1st day of second-line treatment until death or was censored on the date of the last follow-up consultation. PPS was recorded as the time from tumor progression after second-line treatment until death or was censored on the date of the last follow-up consultation.

Statistical analyses

We used Spearman's rank correlation and linear regression analyses to examine whether PFS or PPS was correlated with OS. To identify possible prognostic factors for PPS, a proportional hazards model with a step-wise regression procedure was applied. Hazard ratios (HRs) and 95% confidence intervals were estimated using this model. Because the HR is defined for a 1 unit difference, some factors were converted to an appropriately scaled unit. PPS values were compared using the log-rank test. P ≤0.05 was considered statistically significant for all tests. The two-tailed significance level was also set at 0.05. All statistical analyses were performed using JMP version 11.0 for Windows (SAS Institute, Cary, NC, USA).


 > Results Top


Patient characteristics and treatment efficacy

Thirty-two of the 35 patients included in the analyses died; the median follow-up time was 12.0 months (range, 4.7–31.0 months). [Table 1] shows the characteristics of the 35 patients (median age, 68 years; range, 53–74 years) at the start of second-line treatment. Target lesions were evaluated in all except three cases. Zero, 9, 8, and 18 patients showed CR, PR, SD, and PD, respectively. The response rate was 25.7% and the disease control rate was 48.5%.
Table 1: Baseline patient characteristics at the beginning of second-line treatment

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Of the 35 patients who exhibited relapse after the second-line chemotherapy, 24 did not undergo additional chemotherapy. The remaining 11 patients received subsequent chemotherapy. Among all patients, the median number of follow-up therapeutic regimens was 0 (range, 0–1 regimens). [Table 2] shows the chemotherapy regimens employed for first- and third-line treatments. Carboplatin plus etoposide was the most common first-line chemotherapeutic agent, whereas carboplatin plus irinotecan was the most common third-line agent. The median PFS and OS were 3.4 and 5.7 months, respectively [Figure 1].
Table 2: Chemotherapy regimens employed for first-line and third-line treatment

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Figure 1: (a) Kaplan–Meier plots showing progression-free survival. Median progression-free survival: 3.4 months. (b) Kaplan–Meier plots showing overall survival. Median overall survival: 5.7 months

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Relationships between overall survival and each of progression-free survival and postprogression survival

The relationships between OS and each of PFS and PPS are shown in [Figure 2]a and [Figure 2]b, respectively. Spearman's rank correlation coefficient and linear regression revealed that PPS was strongly associated with OS (r = 0.88, P < 0.05, R2 = 0.87), whereas PFS was weakly correlated with OS (r = 0.60, P < 0.05, R2 = 0.15). The PFS and PPS of the entire population are shown in [Figure 3].
Figure 2: (a) Correlation between overall survival and progression-free survival. (b) Correlation between overall survival and postprogression survival

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Figure 3: Progression-free survival and postprogression survival in the overall population. Censored cases are denoted by an asterisk (*)

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Factors affecting postprogression survival

As PPS was correlated with OS, the associations between PPS and various clinical factors were assessed. On univariate analysis [Table 3], PS at both the beginning and the end of second-line treatment as well as the best response at third-line treatment, first-line chemotherapy regimen (cisplatin based/carboplatin based), and the number of regimens administered following relapse after the second-line chemotherapy were all found to be associated with PPS (P < 0.05). Next, multivariate analysis revealed that the number of regimens administered following disease progression after the second-line chemotherapy was significantly associated with increased PPS (P = 0.003; log-rank test) [Table 4]. The median PPS for those who were not administered additional regimens was 1.4 months; for those who received one additional regimen, the median PPS was 8.4 months [log-rank test, P < 0.001; [Figure 4]. These results remained consistent after adjustment using the Cox proportional hazard models [Table 4].
Table 3: Univariate Cox regression analysis of baseline patient characteristics for post-progression survival

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Table 4: Multivariate Cox regression analysis of post-progression survival according to PS at the beginning of second-line treatment, first-line chemotherapy regimen, and the number of regimens after progression beyond second-line chemotherapy

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Figure 4: Kaplan–Meier plots showing postprogression survival according to the number of regimens after progression. No further regimen: median = 1.4 months; 1 regimen: median = 8.4 months

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 > Discussion Top


We examined the relationships between OS and each of PFS and PPS at the individual level in refractory SCLC patients treated with amrubicin monotherapy as a second-line treatment and found that PPS was strongly associated with OS, whereas the correlation between OS and PFS was weak. Moreover, the number of regimens employed following disease progression after the second-line chemotherapy independently affected PPS. To the best of our knowledge, we are the first to describe individual-level factors that affect PPS in refractory SCLC patients after second-line amrubicin monotherapy.

On reviewing previous Phase II studies, amrubicin showed activity in patients with refractory SCLC, with response rates of 17%–50%, median PFS of 2.6–3.5 months, and OS of 5.3–10.3 months.[11],[22],[23] Meanwhile, the response rate was 25.7% in our study, whereas the median PFS and OS were 3.4 and 5.7 months, respectively. The response rate, PFS, and OS in the present study were consistent with those observed in the previous studies.

The validity of surrogate endpoints has been previously determined through meta-analyses.[24],[25] In recent years, biostatisticians have proposed various measures for validating surrogate end points.[26],[27] Although PFS is a potential surrogate end point for OS in ED-SCLC,[28],[29] its suitability remains controversial. Broglio and Berry recently reported that the duration of PPS, which they termed survival postprogression (defined as OS minus PFS), is important for determining the applicability of OS as a measure of patient outcomes.[13] Some recent studies showed that PPS was strongly associated with OS after first-line chemotherapy for advanced NSCLC at the clinical trial level;[16],[17] similarly, another study found PPS to be strongly associated with OS after second- or third-line chemotherapy for advanced NSCLC at the clinical trial level.[18] Furthermore, we have previously reported the significance of PPS in advanced NSCLC patients in first- and second-line settings, as well as for ED-SCLC patients in the first-line setting, based on analyses of individual patients.[19],[20],[30],[31],[32]

Herein, we found that PFS did not adequately reflect OS in the second-line setting, whereas PPS was closely related to OS in a linear fashion [Figure 2]a and b]. The fact that PPS corresponded to a majority of the OS suggests that the employed chemotherapeutic regimen did not sufficiently influence PFS to be a significant component of OS. In a disease with a dismal prognosis like refractory SCLC, there is no doubt that OS should remain the primary end point for determining efficacy, both in first- and subsequent-line treatments. From the standpoint of refractory SCLC, analyzing the correlations of PFS and PPS with OS is not as relevant as it would be for other solid tumor patients with longer life expectancies and a larger number of available effective lines of treatment when designing clinical trials. Thus, in clinical trials where patients are expected to have a short PFS after second-line chemotherapy (e.g. those with refractory SCLC as in our case), factors that affect PPS ought to be considered.

Trial-level data for advanced NSCLC in the second- or third-line setting suggest that PPS is associated with the induction rate of subsequent chemotherapy.[18] Studies of advanced NSCLC patients who underwent second-line treatment revealed that PPS was associated with the best response at third-line treatment as well as the number of regimens employed after progression beyond second-line chemotherapy.[32] To date, however, no predictive factors for PPS in refractory SCLC cases treated with amrubicin monotherapy have been identified. We studied the prognostic value of baseline factors for PPS in individual refractory SCLC patients and found that the number of regimens administered following disease progression after the second-line chemotherapy were strongly associated with PPS in those settings. Moreover, we confirmed the significance of these relationships using log-rank tests. However, given that this study was retrospectively conducted, it is expected that patients who had longer PPS could receive more lines of treatment because of the indolent nature of tumor. Therefore, it might be a natural result that number of treatment line was associated with PPS.

This study has several limitations. First, the sample size was relatively small. However, because relatively few refractory SCLC patients are treated with second-line amrubicin at our institution, this limitation is difficult to overcome, particularly when patients with similar background characteristics are preferred for such studies. Nevertheless, our institution treats a relatively large number of such cases, and the treatment policy is largely uniform despite the bias inherent in being a single institution. In a future study, we intend to include a larger patient cohort and conduct a more detailed examination. Second, we could not thoroughly evaluate treatments following disease progression after the third-line chemotherapy, although only a few patients received subsequent chemotherapy. Third, since different treating physicians documented patient responses, the timing of evaluation of PFS and tumor response rates may have been less accurate than if only a single physician had documented all responses. Fourth, some survival data were censored; however, this did not influence our outcomes. Furthermore, our reported PPS and OS are based on extended follow-up periods.


 > Conclusions Top


PPS has a greater impact on OS than PFS in refractory SCLC patients who have received second-line amrubicin monotherapy. These results suggest that treatments administered after second-line chemotherapy affect the OS of refractory SCLC patients treated with amrubicin monotherapy. However, larger multicenter studies are required to validate these conclusions in other patient populations and clinical settings.

Acknowledgments

We wish to thank Ms. Mayumi Hashimoto, Mr. Takanori Ohshima, Drs. Sakae Fujimoto, Yosuke Miura, Toshifumi Kazama, Kuniaki Suzuki, Koji Sato, Reiko Sakurai, Go Kobayashi, Shinichi Ishihara, and Yoshikazu Takei, for their assistance in preparing this manuscript.

We would like to thank Editage (www.editage.jp) for English language editing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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