|Year : 2015 | Volume
| Issue : 3 | Page : 606-611
Clinical impact of postprogression survival for overall survival in elderly patients (aged 75 years or older) with advanced nonsmall cell lung cancer
Reiko Yoshino1, Hisao Imai2, Keita Mori3, Yoshio Tomizawa1, Kosuke Takei1, Mai Tomizawa1, Kyoichi Kaira4, Akihiro Yoshii1, Satoru Watanabe1, Ryusei Saito1, Masanobu Yamada2
1 Department of Respiratory Medicine, National Hospital Organization Nishigunma Hospital, 2854 Kanai, Shibukawa, Gunma 377-8511, Japan
2 Department of Medicine and Molecular Science, University Graduate School of Medicine, 3-39-15 Showa machi, Maebashi, Gunma 371-8511, Japan
3 Clinical Trial Coordination Office, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Suntou-gun, Shizuoka 411-8777, Japan
4 Oncology Clinical Development, University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan
|Date of Web Publication||9-Oct-2015|
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511
Source of Support: None, Conflict of Interest: None
Introduction: The effects of first-line single-agent chemotherapy on overall survival (OS) might be confounded by subsequent treatments in elderly patients with nonsmall cell lung cancer (NSCLC). We, therefore, aimed to evaluate whether progression-free survival (PFS), postprogression survival (PPS), or tumor response might be a valid surrogate endpoint for OS in this patient population.
Patients and Methods: We retrospectively reviewed the clinical data of 58 elderly patients with advanced NSCLC, who received first-line single-agent cytotoxic chemotherapy at our institution between October 2003 and November 2013. The relationships of PFS, PPS, and tumor response with OS were individually analyzed.
Results: The study cohort included 46 men and 12 women with a median age of 79 years (range: 75-87 years). There were 30 adenocarcinomas, 22 squamous cell carcinomas, and 6 other histologic types with 1 stage IIIA, 9 IIIB, and 48 IV cases. The performance status (PS) scores were 0, 1, and 2 in 18, 35, and 5 patients, respectively. The median PFS and OS were 2.8 and 5.4 months, respectively. Our analyses revealed a strong correlation of PPS and PFS with OS, whereas that between tumor shrinkage and OS was weak. Tumor stage and PS after initial treatment were significantly associated with PPS. Individual analysis indicated that PPS might serve as a surrogate for OS in elderly patients with advanced NSCLC receiving first-line single-agent chemotherapy.
Conclusion: Our findings suggested that the disease course after progression following first-line single-agent chemotherapy might influence the OS of elderly patients with advanced NSCLC.
Keywords: Elderly, nonsmall cell lung cancer, overall survival, postprogression survival, progression-free survival, tumor response
|How to cite this article:|
Yoshino R, Imai H, Mori K, Tomizawa Y, Takei K, Tomizawa M, Kaira K, Yoshii A, Watanabe S, Saito R, Yamada M. Clinical impact of postprogression survival for overall survival in elderly patients (aged 75 years or older) with advanced nonsmall cell lung cancer. J Can Res Ther 2015;11:606-11
|How to cite this URL:|
Yoshino R, Imai H, Mori K, Tomizawa Y, Takei K, Tomizawa M, Kaira K, Yoshii A, Watanabe S, Saito R, Yamada M. Clinical impact of postprogression survival for overall survival in elderly patients (aged 75 years or older) with advanced nonsmall cell lung cancer. J Can Res Ther [serial online] 2015 [cited 2019 Jul 19];11:606-11. Available from: http://www.cancerjournal.net/text.asp?2015/11/3/606/163683
| > Introduction|| |
Lung cancer is the most common cause of cancer-related mortality worldwide, with nonsmall cell lung cancer (NSCLC) accounting for approximately 85% of all cases.  Overall survival (OS) is considered as the most reliable endpoint in cancer studies, and when any studies can be conducted to adequately assess survival, it is usually the preferred endpoint.  This endpoint is precise, easy to measure, and can be documented by the date of death. Surrogate endpoints, such as tumor response and progression-free survival (PFS), are also useful in phase II oncology clinical trials because they can be measured earlier and more conveniently as well as more frequently detected than the main endpoints of interest, which are referred to as the true endpoints.
As the number of drugs and their combinations for the treatment of NSCLC rapidly increases, the effects of first-line chemotherapy on OS might be confounded by subsequent therapies.  Indeed, PFS improvement does not necessarily result in an improved OS, as shown by recent randomized trials involving NSCLC patients.  In recent years, a growing number of active compounds are available for second- or third-line chemotherapy for advanced NSCLC, as in cases of breast, ovarian, and colorectal cancers. ,, Although PFS following first-line chemotherapy has not been validated as a surrogate endpoint for OS, postprogression survival (PPS) has been shown to strongly associate with OS after first-line chemotherapy in advanced NSCLC, , especially with the development of molecular targeted agents such as gefitinib and erlotinib during the last decade (2002-2012). , The evaluation of PPS using a simple method was first reported in 2009,  in which, OS was expressed as the sum of PFS and PPS.
The effect of therapies administered after disease progression on individual survival is of particular interest. A recent report suggests that PPS could be used as a surrogate for OS in advanced nonsquamous NSCLC patients with unknown oncogenic driver mutations, and thus having limited options for subsequent chemotherapy.  However, it is unclear whether this finding is applicable to elderly patients with advanced NSCLC, who receive first-line single-agent chemotherapy. Therefore, it may be of clinical importance whether PFS, PPS, or tumor response is valid surrogate endpoints for OS after first-line single-agent chemotherapy in elderly patients with advanced NSCLC.
A marked increase in life expectancy and the association between lung cancer frequency and aging have resulted in a considerable rise of the disease incidence in the elderly. Nowadays, more than half of lung cancer cases are diagnosed in patients aged more than 65 years, which is usually the limit for defining elderly people, at least in epidemiological studies.  NSCLC accounts for 85% of all lung cancer cases in the elderly,  which is quite similar to what is observed in their younger counterparts. However, within NSCLC, squamous cell carcinoma is more common in elderly patients, whereas adenocarcinoma is the predominant subtype in those of younger age.  Although platinum-based doublets involving newer agents such as docetaxel, paclitaxel, gemcitabine, vinorelbine, and irinotecan are standard first-line chemotherapy for most patients with advanced NSCLC, the use of these regimens in elderly patients remains controversial.  The main reasons for withholding standard platinum-based doublet regimens from elderly patients include age-related impairment of organ function, the presence of potentially complicating comorbid conditions, and possibly lower tolerance for potential toxicity from combination chemotherapy than younger patients. The European Society for Medical Oncology Clinical Practice Guidelines suggest platinum-based chemotherapy as the preferred option for elderly patients with advanced NSCLC, who present with a performance status (PS) of 0-1 and adequate organ function, whereas a single-agent approach might be the recommended treatment for elderly unfit or comorbid patients, who are more likely to develop treatment-related adverse events.  The 2004 American Society of Clinical Oncology guidelines recommend monotherapy for elderly patients with advanced NSCLC.  Currently, the most frequently studied agents are vinorelbine and gemcitabine with similar reported outcomes. In a Japanese study comparing docetaxel and vinorelbine,  despite a trend toward longer survival with docetaxel, the difference was not significant. Although many patients initially achieve clinical response or disease control with first-line chemotherapy, they most subsequently experience disease progression and eventually die of advanced NSCLC. We examined first-line single-agent cytotoxic chemotherapy because this treatment is considered standard first-line chemotherapy for elderly advanced NSCLC. , In the present study, we analyzed the relationships of PFS, PPS, and tumor response with OS after first-line single-agent chemotherapy in elderly patients with advanced NSCLC at the individual level. We also explored the prognostic value of baseline and tumor characteristics for PPS.
| > Patients and methods|| |
Between October 2003 and November 2013, 60 elderly patients with advanced NSCLC, who received first-line single-agent chemotherapy, were enrolled in this study. The eligibility criteria were as follows: Histologically or cytologically proven NSCLC, unresectable stage IIIA/IIIB/IV disease, age 75 years or older, and receiving first-line single-agent cytotoxic chemotherapy. PFS data were censored in two patients who were excluded from the analyses to unify patient background. Thus, data from 58 patients were retrospectively analyzed. The study protocol was approved by the Institutional Review Board of National Hospital Organization Nishigunma Hospital. Written informed consent was not required because this study was retrospective. As first-line treatment, patients received single-agent chemotherapy. The best overall response and maximum tumor shrinkage were recorded as tumor responses. Radiographic tumor responses were evaluated according to the response evaluation criteria in solid tumors  as follows: Complete response (CR) - disappearance of all target lesions; partial response (PR) - a minimal 30% decrease in the sum of all target lesion diameters with the summed baseline diameters as the reference; progressive disease (PD) - a minimal 20% increase in the sum of all target lesion diameters with the smallest sum observed during the study period as the reference; and stable disease (SD) - insufficient shrinkage to qualify as PR and insufficient expansion to qualify as PD. PFS was calculated from the date of treatment initiation to that of PD or death from any cause. OS was recorded from the 1 st day of treatment until death or censored on the date of the last follow-up consultation. PPS was recorded as the time from tumor progression until death or censored on the date of the last follow-up consultation.
To examine whether PFS, PPS, or tumor shrinkage correlated with OS, Spearman rank correlation analysis and linear regression analysis were performed. To explore prognostic factors for PPS, the proportional hazards model with a stepwise regression procedure was applied. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the model. Because HR was defined for 1-unit difference, some factors were converted to an appropriate scale unit. PPS values were compared using the log-rank test. A P ≤ 0.05 was considered as statistically significant for all tests. The two-tailed significance level was also set at 0.05. All statistical analyses were performed using JMP version 9.0 for Windows (SAS Institute, Cary, NC, USA).
| > Results|| |
Patient characteristics and treatment efficacy
All 58 patients included in the analyses died during a median follow-up period of 10.4 months (range: 0.5-67.2 months). The characteristics of these patients (median age: 79 years; range: 75-87 years) are shown in [Table 1]. Target lesions were not evaluated in one patient.
Of the enrolled patients, 1, 13, 32, and 12 showed CR, PR, SD, and PD, respectively. The response rate was 24.1%, and the disease control rate was 79.3%.
When disease progressed following first-line treatment, 34 of the 58 patients did not receive postprogression chemotherapy. The other 24 patients received subsequent chemotherapy after completing their first-line treatment. The median number of follow-up therapeutic regimens for all 58 patients was 0 (range: 0-3 regimens). The chemotherapy regimens employed at disease progression after first-line chemotherapy are shown in [Table 2]. Erlotinib was the most common second-line chemotherapy, whereas gefitinib was most frequently used after second-line chemotherapy. The median PFS and OS were 2.8 and 5.4 months, respectively [Figure 1].
|Figure 1: (a) Kaplan-Meier curve for progression-free survival (median: 2.8 months); (b) Kaplan-Meier curve for overall survival (median: 5.4 months) during a median follow-up period of 10.4 months|
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|Table 2: Chemotherapy regimens employed after progression following first-line chemotherapy|
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Relationship between overall survival and progression-free survival, postprogression survival, and tumor shrinkage
The relationship between OS and PFS, PPS, and tumor shrinkage is shown in [Figure 2]a-c, respectively. PPS and PFS strongly correlated with OS (r = 0.73; P < 0.05; R2 = 0.76 and r = 0.72; P < 0.05; R2 = 0.41, respectively) according to the calculated Spearman's rank correlation coefficient and linear regression, whereas a weak correlation was observed between tumor shrinkage and OS (r = 0.49; P < 0.05; R2 = 0.12).
|Figure 2: (a) Correlation between overall survival and progression-free survival (*r: Spearman's rank correlation coefficient, ** R2: linear regression); (b) correlation between overall survival and postprogression survival (*r: Spearman's rank correlation coefficient, ** R2: linear regression); (c) correlation between overall survival and tumor shrinkage (*r: Spearman's rank correlation coefficient, ** R2: linear regression)|
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Factors affecting postprogression survival
PPS was strongly associated with OS. Thus, the association between PPS and various clinical factors was assessed. In the univariate analysis [Table 3], clinical stage, best response at first-line treatment (PR/non-PR), PS at the end of first-line treatment, and the number of regimens administered after progression beyond first-line chemotherapy were found to be associated with PPS (P < 0.05). Next, a multivariate analysis for PPS was conducted to identify which clinical factors might affect PPS [Table 4]. The clinical stage and PS at the end of first-line treatment were significantly associated with PPS (P < 0.05).
|Table 3: Univariate Cox regression analysis of baseline patient characteristics for PPS|
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|Table 4: Multivariate Cox regression analysis of clinical stage, best response at first-line treatment, PS at the end of first-line treatment, and number of regimens employed after progression beyond first-line chemotherapy for PPS|
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Log-rank tests confirmed that PPS differences were observed in patients according to their clinical stage and PS at the end of first-line treatment. In terms of PS at the end of first-line treatment, the PPS was 10.7 months for those with a PS score of 0, 2.2 months for PS score of 1, 1.6 months for PS score of 2, 1.2 months for PS score of 3, and 0.3 month for PS score of 4 (log-rank, P < 0.05). These results remained valid after adjustments in the Cox proportional hazards models [Table 4].
| > Discussion|| |
In the present study, we examined the relationships of OS with PFS, PPS, and tumor shrinkage at the individual level for elderly patients. Spearman rank correlation analysis and linear regression analysis revealed that PPS and PFS strongly correlated with OS, whereas a weak correlation was observed between tumor shrinkage and OS. Also, the factors significantly associated with PPS were clinical stage and PS at the end of first-line treatment.
The validity of surrogate endpoints has been previously determined through meta-analysis. , In recent years, biostatisticians have proposed a wide variety of measures for validating surrogate endpoints. , Although tumor response and PFS are potential surrogate endpoints for OS in extensive-stage small cell lung cancer,  their validity is controversial in advanced NSCLC.  Broglio and Berry recently studied PPS which they termed survival postprogression and defined as OS minus PFS in a hypothetical clinical trial setting under the assumption that treatment affected PFS but not PPS.  In addition, PPS was found to be strongly associated with OS after first-line chemotherapy for advanced NSCLC in clinical trials. ,
Our results were not in agreement with some previous reports, which indicated that tumor response and PFS were surrogate endpoints for OS in advanced NSCLC. , We analyzed our data pertaining to first-line chemotherapy in elderly patients with advanced NSCLC, who received first-line single-agent chemotherapy, and the results suggested that PFS and tumor response did not reflect OS in such settings. We found that PPS was more closely related to OS than PFS with a linear PPS-OS relationship [Figure 2]a and b owing to a large R2 value. The fact that PPS accounted for part of OS suggested that the administered chemotherapy was insufficient for PFS to prolong OS. Thus, in clinical trials with elderly patients expected to have a short PFS after first-line chemotherapy, as the cases in our study, factors impacting PPS need to be well controlled.
According to trial data for advanced NSCLC, prolonged PPS was associated with good PS and the use of first-line monotherapy and a molecular targeted agent.  However, to date, factors affecting PPS based on individual data of elderly patients with advanced NSCLC are unidentified. We attempted to explore the prognostic value of baseline factors for PPS and found that PS at the end of first-line treatment was strongly related to PPS. Moreover, we confirmed such a relationship by log-rank tests. The Eastern Cooperative Oncology Group PS is not only a major prognostic factor for survival in lung cancer but also an indicator for the most appropriate treatment of advanced NSCLC cancer. Although PS also has a prognostic impact in elderly patients, independently of comorbidities, it is not a sufficient appraisal of the real situation, and geriatric indexes may add certain important information.  To the best of our knowledge, this study is the first to report on individual factors affecting PPS in elderly patients with advanced NSCLC. Our findings suggested that a good PS at the end of first-line treatment might affect the disease course after progression following first-line chemotherapy. However, PPS was unaffected even when subsequent chemotherapy was administered. A possible reason for failing to detect a significant difference was that subsequent second-line chemotherapy was administered in only 41.3% of patients. Another reason might have been the small sample size of this study. A previous report indicated that in elderly patients with advanced NSCLC, platinum-based doublet chemotherapy with carboplatin and weekly paclitaxel yielded better results in terms of OS, PFS, and response rates than monotherapy with either vinorelbine or gemcitabine.  Thus, the paradigm of treatment for elderly patients aged 70 years or older and having a PS score of 0-2 should probably be modified to favor the combination of carboplatin and weekly paclitaxel. Whether, other carboplatin-based doublets might provide the same benefit remains to be evaluated. If platinum-based doublet chemotherapy is administered as first-line treatment for elderly patients, the outcomes might differ. There are no specific salvage therapy trials dedicated to elderly patients. The only available data are a subgroup analysis of 86 patients aged 70 years or older among the 571 included in a phase III study comparing pemetrexed and docetaxel as second-line therapy.  Such an analysis reported similar outcomes for patients aged <70 years and those aged 70 years or older. In addition, the number of patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors was relatively small as EGFR mutation status was undetermined in most patients and was not commonly examined previously.
This study has several limitations. First, the sample size was small. However, because the number of elderly patients with advanced NSCLC, who received first-line single-agent chemotherapy, was limited at a single institution, such a limitation was difficult to overcome, especially when the purpose of this study was to analyze patients with similar background. Nevertheless, at our institution, we arguably treated the largest number of such cases, and the practice policy was mostly unified. There was inevitable bias, but understanding the nature of such bias ensured meaningful results. In a future study, we hope to include a larger patient cohort, and more detailed examination is warranted. Second, we could not thoroughly evaluate treatments after progression following second-line chemotherapy. However, we consider the results of the present investigation worthwhile because there were few patients receiving third-line or subsequent chemotherapy. Finally, the date on which a response was recorded was individually decided by the attending physicians, which might have introduced variances in PFS and tumor response rate.
| > Conclusion|| |
Our results based on individual data suggested that PFS and tumor response might not be ideal surrogates for OS in elderly patients with advanced NSCLC. In these patients, PPS might be associated with OS, but a PFS advantage was not associated with an OS advantage owing to the increasing influence of PPS on OS. Also, clinical stage and the PS at the end of first-line treatment were identified as prognostic factors for PPS. Thus, our findings suggested that the disease course after progression following first-line chemotherapy markedly influenced OS. We believe that these results should be validated with regard to their generalizability to other larger populations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]