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An analysis of 14 Small Cell Lung Cancer (SCLC) trials was performed to improve our understanding of potential prognostic factors for overall survival (OS) and progression-free survival (PFS) in limited-stage (LD-SCLC) and extensive disease (ED-SCLC) groups separately.
Data on 688 pts with LD-SCLC and 910 pts with ED-SCLC disease were included. Clinical and laboratory factors were tested for prognostic significance using Cox regression models, stratified by protocol. A recursive partitioning and amalgamation (RPA) analyses was used for identification of prognostic subgroups.
Poorer PS led to worse OS and PFS within ED-SCLC, but not within LD-SCLC. The prognostic impact of PS was strong in males, but weak in females within ED-SCLC (interaction p-value < 0.012 for OS, PFS). Other negative prognostic factors included increased age and male sex for LD-SCLC, and increased age, male sex, increased number of metastatic sites at baseline, and increased creatinine levels for ED-SCLC. For ED-SCLC patients, the RPA analyses identified 5 subgroups with different prognosis: based on baseline PS, creatinine levels, sex, and number of metastatic sites.
This pooled analysis identified baseline creatinine levels and the number of metastatic sites as important prognostic factors within ED-SCLC, in addition to the well established factors of sex, age, and PS. There was a significant interaction between sex and PS within ED-SCLC, suggesting that PS is highly prognostic in males, with no significant impact in females. Within LD-SCLC, only age and sex were important prognostic factors. The RPA analyses confirmed many of these findings.
In 2008, lung cancer was expected to cause 161,840 deaths within the United States.1 About 16% of these lung cancer patients are expected to have small cell lung cancer (SCLC).2 Without treatment, SCLC is considered to be the most aggressive of the lung tumors with a median survival ranging from 2 to 4 months.3 The long-term prognosis for SCLC patients is relatively poor with only 5–10% expected to live at least 5 years from diagnosis.4–6
At the time of diagnosis, about 30% of SCLC patients will have a tumor that is confined to the following areas: hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes.3 The patients with disease limited to these areas and encompassable within reasonable RT fields have limited-stage small cell lung cancer (LD-SCLC).3 With currently available treatments, the median survival for patients with LD-SCLC ranges from 16 to 26 months.7–9 Patients with tumors that have metastasized beyond the supraclavicular areas have extensive-stage SCLC (ED-SCLC).3 With currently available treatment options, the median survival varies from 6 to 12 months for patients with ED-SCLC.3
It has previously been demonstrated that good performance status (PS), young age, female sex, and limited-stage disease are associated with improved prognosis.6, 10–15 In addition, other variables including elevated lactate dehydrogenase (LDH) serum levels, liver metastases, low albumin levels, and low sodium levels have been associated with poor prognosis.6, 10–14 Risk categories including stage, performance status and several laboratory tests like LDH, alkaline phosphatase, and sodium level have also been developed.11, 14 In addition, a recursive partitioning and amalgamation (RPA) analyses was used to establish 4 prognostic subgroups based on stage, PS, age, and sex using a large database of SCLC patients.13
We set out to investigate and improve our understanding of the impact of several baseline patient and tumor characteristics on overall survival (OS) and progression-free survival (PFS) within LD-SCLC and ED-SCLC separately. Specifically, we investigated the impact of several pretreatment factors, above and beyond the previously explored factors of age, sex, and PS. A large pooled analysis, such as this, allows one to assess the consistency of such relationships between the prognostic factors and outcome across a large number of trials, rather than from one or two large studies.
Individual patient data were pooled from 14 NCCTG first-line SCLC therapy trials that opened between 1987 and 2001. Of these 14 SCLC trials, 9 enrolled ED-SCLC patients only, 3 enrolled LD-SCLC patients only, and 2 enrolled both ED-SCLC and LD-SCLC patients. All patients who received no study treatment or were ineligible for trial participation were excluded from these analyses. In addition, if a patient was enrolled in more than 1 trial, only data from the first trial was kept for that patient. This analysis includes a total of 910 patients with ED-SCLC and 688 patients with LD-SCLC. See Tables I–II for a detailed listing of the individual trial characteristics.
All analyses were performed within limited disease (LD-SCLC) and extensive disease (ED-SCLC) separately. OS was defined as the time from registration to death due to any cause. PFS was defined as the time from registration to the first of either death from any cause or disease progression. OS and PFS endpoints were censored at 5 years for analysis. The Cox Proportional Hazards model16 was used for both the univariate and the multivariate analyses. Score and likelihood-ratio p-values were reported for the univariate and multivariate models, respectively. The models were stratified by protocol and analyses were carried out on the data available based on the selected covariates for the respective endpoint. An RPA analyses, with tenfold cross-validation, was used to identify different prognostic subgroups for OS and PFS.
As a general guide, sample sizes of 688 and 910 patients provides at least 80% and 90% power, respectively, to detect an effect reflected by a Hazard Ratio (HR) of 1.25 for a two-level factor with a prevalence of 40% vs. 60% (2-sided log rank test, alpha level=0.05) using the actual accrual rates from 1987–2005 and assuming exponential survival with 2 years of minimum follow-up on each patient.
The pretreatment variables we identified at the time of analysis included factors collected across most trials that were either previously reported as prognostic in the literature for SCLC or were included in our previous NCCTG led pooled analysis in non-small cell lung cancer.17 The following pretreatment factors were assessed in univariate models and were considered for inclusion in multivariate models: Age, sex, performance status (PS), body mass index (BMI), creatinine levels (mg/dL), hemoglobin levels (HGB; g/dL), white blood cell counts (WBC; ×109 /L), platelet counts (PLT; ×109 /L), total bilirubin levels (mg/dL), and the number of metastatic sites at baseline for ED-SCLC. Since the goal of this study was to identify additional prognostic factors for OS and PFS above and beyond the known clinical factors of age, sex, and PS, we explored 2 different multivariate models for each endpoint (OS, PFS) and stage. The first model was considered the base clinical model, which only included age, sex, and PS. The second model included the base model, along with additional factors that were found to be potential predictors in the univariate setting (p < 0.20). For the factors included in the multivariate models, all two-way interactions were assessed using stepwise regression modeling techniques.
Those continuous factors that were found to deviate substantially from linearity were modeled using clinically meaningful cut-points. The factors included in the multivariate models were tested for the appropriateness of the proportional hazards (PH) assumption18 and for between-trial heterogeneity. Model discrimination (i.e., ability to discriminate patients with different survival times) was evaluated using the concordance index19 (C-Index). This is a measure of predictive accuracy for time to event data that contains censored observations. All tests were 2-sided, with p-values <0.05 for main effects and p-values <0.02 for two-way interaction terms denoting statistical significance. In addition, HRs and the associated 95% confidence intervals (CI) are reported for the univariate and multivariate results.
Data were frozen on November 19, 2007, and included a total of 1598 eligible patients that received first-line treatment, 688 with LD-SCLC and 910 with ED-SCLC. Data are complete with 98% of patients followed until death within ED-SCLC and 81% followed until death within LD-SCLC. Median OS ranges from 17.2 to 26.4 months for LD-SCLC trials and from 2.6 to 12.3 months for ED-SCLC trials. The median PFS ranges from 10.9 to 18.2 months for LD-SCLC trials and from 1.1 to 8.4 months for ED-SCLC trials. Across all patients, stage was highly prognostic for both OS and PFS, with ED-SCLC patients having a worse prognosis (p<0.0001).
Table III gives a description of the patient characteristics for the full cohort of patients. LD-SCLC and ED-SCLC cohorts had similar patient characteristics, except for PS. Fifty-two patients (8%) with LD-SCLC had a PS of 2, while 222 patients (24%) with ED-SCLC had a PS of 2. The patient characteristics for the full cohort of 910 ED-SCLC patients was similar to the 716 patient cohort used in the multivariate models (data not shown). Likewise, the full 688 patient cohort for LD-SCLC was similar to the 574 patient cohort used in the multivariate models (data not shown).
For LD-SCLC, total bilirubin, creatinine, sex, and age were promising for OS (p < 0.20) and total bilirubin, sex, and age were potential prognostic factors for PFS (p< 0.20). Although PS was not significant univariately, it was nevertheless explored in the multivariate models based on its prognostic importance from previous studies6, 10–15. See Table IV for the univariate results for LD-SCLC.
For ED-SCLC, possible predictors for OS and PFS included age, PS, WBC, sex, creatinine level, and the number of metastatic sites at baseline (all p < 0.20). See Table V for the univariate results for ED-SCLC.
For LD-SCLC, age and sex were highly prognostic for OS and PFS in both the base model (age, sex, PS) and the full model (age, sex, PS, total bilirubin, creatinine), with increased age and male sex having a worse prognosis. See table VI for the multivariate results in LD-SCLC. The RPA analyses validated age as a strong predictor within LD-SCLC for both OS and PFS. No other factors were found to be important.
For ED-SCLC, age, sex, and PS were highly prognostic for OS in both the base (age, sex, PS) and full models (age, sex, PS, WBC, creatinine level, number of metastatic sites at baseline). Specifically, patients with increased age, male sex, and PS > 0 had significantly worse OS. In addition, the number of metastatic sites at baseline and creatinine level were also significant prognostic factors for OS. Specifically, patients with 2 or more metastatic sites at baseline had a significantly worse OS (HR = 1.27 (95% CI: 1.09, 1.48), p = 0.002); and patients with increased creatinine levels at baseline (above upper normal limit (UNL)) had a significantly worse OS (HR = 1.33 (95% CI: 1.03, 1.71), p = 0.04). In the case of PFS, male sex, PS > 0, and increased number of metastatic sites at baseline were found to be significantly associated with worse outcome. See table VII for the multivariate results in ED-SCLC.
The RPA analyses for OS within ED-SCLC, identified the number of metastatic sites at baseline as the most important predictor, with patients having 2 or more metastatic sites having an increased risk of poor outcome. Additional factors that were found to be important included sex, PS, and creatinine levels at baseline. Five groups with differing prognoses were identified (see Figure I): group 1 (median OS 10.6 months): 0,1 metastatic sites at baseline and creatinine value ≤ UNL; group 2 (median OS 9.7 months): females with 2 or more metastatic sites at baseline; group 3 (median OS 8.8 months): males with 2 or more metastatic sites at baseline and PS of 0 or 1; group 4 (median OS 7.5 months): 0,1 metastatic sites at baseline and creatinine value > UNL; and group 5 (median OS 5.8 months): males with 2 or more metastatic sites at baseline and PS of 2. Except age, the RPA analyses identified the same significant prognostic factors as the Cox model for OS. For PFS within ED-SCLC, the RPA analyses only identified the number of metastatic sites at baseline as an important prognostic factor.
No two-way interactions were found to be significant for LD-SCLC. Within ED-SCLC, the interaction between sex and PS was significant for both OS and PFS (p < 0.012; Figures II, III), suggesting that the effect of PS on outcome differed by sex. Among males, for both OS and PFS, patients with a PS of 0 had the best prognosis, patients with a PS of 2 had the worst prognosis, and patients with a PS of 1 were in the middle (p < 0.0001). For females, PS was not significantly associated with OS (p=0.12) or PFS (p=.21).
All continuous factors met the linearity assumption, except creatinine within ED-SCLC. The creatinine was grouped using clinically meaningful cut-points for males: > 1.3 mg/dL (upper normal limit (UNL)) vs. ≤ 1.3 mg/dL and for females: > 1.1 mg/dL (UNL) vs. ≤ 1.1 mg/dL. These UNL values were taken from the Mayo Clinic 2008 calendar which contains the 2008 Mayo Clinic Normal Values by sex. All factors met the PH assumption. In the case of the homogeneity assumptions, the minor deviations were quantitative with the hazard ratios for each factor and study mostly in the same direction as the overall effect. For factors and studies that showed the reverse effect, the individual confidence intervals contained 1 (suggesting a non-significant effect).
The additional factors added to the base model for LD-SCLC did not result in an increase in the C-Index. For OS within ED-SCLC, the full multivariate model had a 3.4% increase in the C-Index as compared to the base model (increased from 0.58 to 0.60). For PFS, the full model had a 3.6% increase in the C-Index as compared to the base model (increased from 0.56 to 0.58). Including the significant PS by sex interaction in the full ED-SCLC models increased the C-Index by an additional 2% for OS and PFS (increased from 0.60 to 0.61 for OS and 0.58 to 0.59 for PFS).
There has been little progress in the treatment of SCLC in the last decade. This disease is generally chemosensitive and multi-agent chemotherapy has been effective in increasing OS.10 In both LD-SCLC and ED-SCLC, patients who respond to systemic therapy appear to benefit in terms of OS with the addition of prophylactic cranial irradiation (PCI). 20,21 In addition, there is strong evidence that thoracic radiation therapy (RT) improves the OS of patients with LD-SCLC and select patients with ED-SCLC who respond very favorably to the initial chemotherapy.22–24 In spite of these therapeutic findings associated with improved OS, the vast majority of patients with SCLC do succumb from their disease.
This pooled analysis identified baseline creatinine levels and number of metastatic sites as important prognostic factors within ED-SCLC, in addition to the well established factors of sex, age, and PS. In addition, there was a significant sex by PS interaction within ED-SCLC. Specifically, among females, there was no significant differences in outcomes by PS, whereas for males, PS = 0 patients had the best prognosis; followed by patients with PS = 1 and patients with PS = 2. The RPA analyses further identified 5 subgroups of ED-SCLC patients with different prognosis: based on baseline PS, creatinine levels, sex, and number of metastatic sites. Within LD-SCLC, only age and sex were identified as important prognostic factors, where age was also confirmed in the RPA analyses.
Increased patient age and male sex were found to be associated with significantly worse outcome within both ED-SCLC and LD-SCLC patients. This is consistent with previous reports.10, 13, 15 PS was also a significant prognostic factor in our ED-SCLC patients (p < 0.01 for OS and PFS), but only of borderline importance within LD-SCLC (p=0.053 for OS and p=0.17 for PFS). This later finding may be partially due to the lack of PS 2 patients within the LD-SCLC series due to the eligibility criteria used in these trials and probably the hesitation on the part of treating oncologists to enroll PS 2 patients in the aggressive multi-modality trials. PS being a prognostic factor is also consistent with the literature.6, 10–15
For ED-SCLC patients, an increased number of metastatic sites at baseline was also a significant adverse prognostic factor. This is also consistent with some previous studies.6, 10 In addition, baseline creatinine levels were found to be prognostic for OS (independent of age), where patients with increased creatinine levels (> UNL) had a significantly worse OS compared to patients with lower levels (≤ UNL). One possible reason for this is that patients with impaired renal function may have poorer tolerance to chemotherapy. These patients would have poorer renal clearance of the drug and decreased renal production of erythropoietin, both of which could cause more marrow suppression. To evaluate this hypothesis, we assessed the relationship between the amount of chemotherapy administered and renal function and found that those with compromised renal function (creatinine > UNL) at baseline received significantly fewer chemotherapy treatment cycles than those with normal renal function within the ED-SCLC population (p<0.001), but not within the LD-SCLC population (p=0.73). This may be a reason why increased creatinine was only found to be an adverse prognostic factor within the ED-SCLC population. However, this observation should be verified in future studies.
The RPA analyses for OS within ED-SCLC patients confirmed that increased number of metastatic sites at baseline yielded worse outcomes; and so did male sex, poorer PS and elevated creatinine levels. Five subgroups with different prognosis were identified based on these factors. One limitation of this pooled analysis was that not all factors were consistently collected at baseline across all 14 trials. In addition, factors such as serum albumin and lactate dehydrogenase (LDH), that have been shown to be of prognostic importance in previous analyses, were not collected in these trials and, hence, not evaluated.
Future progress will require better therapy. This will likely include improvements in systemic therapy (e.g. targeted agents, immunotherapy) based on better molecular understanding of this disease, better methods of irradiating patients, and possibly adding other treatment modalities. In each case, novel therapeutic combinations will need to be piloted and compared to standard therapies. Historical data becomes critical for these comparisons, thus making appropriate study design vital to answer these scientific questions. Proper study design in turn requires a clear understanding of the clinical factors associated with outcome. Without proper stratification for these prognostic factors, trial results can be misleading due to biases and imbalances within treatment arms. We have reviewed our recent experience treating SCLC in an attempt to further clarify these factors so that our future trials can yield useful data, and historical data can be put in perspective. In addition to the well established prognostic factors of age, sex, and PS, this study has shown that it may also be critical to stratify or adjust for baseline creatinine levels and the number of metastatic sites at baseline for ED-SCLC patients.
A pooled analysis of 14 small-cell lung cancer (SCLC) studies identified baseline creatinine levels and the number of metastatic sites at baseline as important prognostic factors within ED-SCLC, in addition to the well established factors of sex, age, and PS. Within LD-SCLC, only age and sex were identified as important prognostic factors.
Financial Disclosures: none to disclose.