Combined small-cell lung carcinoma: An institutional experience

Abstract

Background

The purpose of this study is to determine prognostic factors and survival in patients who present with combined small-cell lung cancer (SCLC).

Methods

A retrospective review of combined SCLC histology in patients treated between1995–2010 was undertaken. Demographics, diagnostic information, disease characteristics, treatment modality, and survival were captured. Survival estimates were performed using Kaplan Meier analysis. Statistical significance was defined as P < 0.05.

Results

Forty-one patients were identified, and 35 records were available for analysis. Median age at diagnosis was 68 (range 50–85). The study included 20 (57%) women and 15 (43%) men; and 94% had a current or former history of smoking. Histology was SCLC/large cell carcinoma not otherwise specified in 28 (80%), and SCLC/adenocarcinoma or SCLC/squamous cell carcinoma in seven (20%). Cardiac or pulmonary comorbidities were present in 80% of patients, and 24 patients had metastatic disease at presentation. Twenty-eight patients received treatment of chemotherapy (n = 24), cranial radiotherapy (n = 5), or thoracic radiotherapy (n = 7). Staging was as follows: stage I-III (n = 11), stage IV (n = 24). Median survival was 15.4 months (range <1–53 months) and 3.4 months (range <1–21.9 months) for American Joint Committee on Cancer (AJCC) stage I-III and stage IV, respectively. Estimated overall six and 12 month survival was 82%, 55%, 37%, and 17% for stage I-III and stage IV, respectively. An improved overall survival rate was found for patients with an Eastern Cooperative Oncology Group performance status of <2, and no weight loss (P < 0.05).

Conclusion

Akin to SCLC, advanced stage combined SCLC portends a poor prognosis. Perhaps novel chemotherapeutic drugs or targeted agents may improve outcomes for future patient populations.

Introduction

Small-cell lung cancer (SCLC) represents 13–15% of newly diagnosed lung cancer per year.^1,2 Incidence decreased from 17% in 1986, to 13% in 2002 as a result of the declining number of smokers.¹ Historically, elderly white men have represented the major demographic, however, the number of cases occurring in women almost doubled from 28% to 50% between 1973–2002 in a Surveillance Epidemiology and End Results (SEER) analysis, and women represented 50.4% of patients in a recent National Cancer Data Base (NCDB) analysis.^1,3 Most patients present with extensive stage disease, with an expected survival of two to four months without treatment.^4,5 Although SCLC is sensitive to chemoradiotherapy, because of high rates of dissemination, five year survival rates of 10–13% in limited-stage SCLC and 1–2% in extensive-stage SCLC disease have been reported.⁶ The World Health Organization (WHO) classification currently recognizes two types of SCLC: pure and combined.⁷ While pure histology is the more prevalent presentation, up to 28% of patients may present with combined SCLC histology.^8–11 The variability in frequency of combined SCLC histology presentation may be a result of the changing classification criteria over the last 20 years and limited specimen size that is common with diagnostic procedures in SCLC.^9,12 While research is evolving, no significant histologic or molecular features have been found to be prognostically useful in predicting survival in SCLC patients. Discovery of somatic mutations currently drive treatment of non-small cell lung cancer (NSCLC), but use of targeted therapies has been less fruitful in SCLC. Given the paucity of literature on combined SCLC histology, the purpose of this paper is to report our experience at the University of Missouri, Columbia.

Materials and methods

This is a single-institution retrospective analysis of combined SCLC histology patients conducted after Institutional Review Board approval was obtained. Approximately 350 cases of SCLC were seen at our institution from 1995–2010. Forty-one patients were diagnosed with combined SCLC histology, and medical records of 35 patients were available for review. Patient and disease characteristics, surgical, chemotherapy and radiation treatment information, and survival outcomes, were captured. Staging usually included computed tomography (CT), positron emission tomography (PET), or PET/CT in patients treated in the modern era. Magnetic resonance imaging (MRI) or CT was utilized to assess brain metastasis in patients who were considered treatment candidates. Staging was classified using the Veteran's Health Administration (VHA) and American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) Version 7, depending on the year of diagnosis. For the purpose of analysis, the VHA system classification of extended and limited-stage was converted to TNM staging, as recommended by the International Association for the Study of Lung Cancer, where limited-stage is equivalent to TNM stages I-III, and extensive-stage is equivalent to TNM stage 4.² All patients had histologic classification of combined SCLC histology at diagnosis by experienced pathologists at our institution.

Statistical analysis

Statistical analysis was performed using SAS software, version 9.3 (SAS Institute, Cary NC). Overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up if the patient survived. Mood's median test, a special case of Pearson's chi-squared test, was used to compare median survival between groups. Estimated survival function was calculated using the Kaplan–Meier method, and compared between groups using a log-rank test.^13,14 A two sided P-value ≤0.05 was considered statistically significant.

Results

Patient demographics

Median age at diagnosis was 68 years (range 50–85). Twenty (57%) patients were women, 15 (43%) men, and 33 (94%) were Caucasian. Thirty-two (91%) were current or former smokers, with three patients denying a smoking history. Two patients presented with a paraneoplastic syndrome of inappropriate antidiuretic hormone (SIADH). Histology at diagnosis was 28 (80%) SCLC/large cell carcinoma not otherwise specified (NOS), six SCLC/adenocarcinoma, and one SCLC/squamous cell carcinoma. Sites of histologic diagnosis were lung (n = 28) and metastatic site (n = 7). Two patients underwent pneumonectomy. Early stage patients had no surgical resection because of the following reasons: underlying lung disease (n = 4), patient preference (n = 3), and unknown (n = 2). Twenty-four patients had metastatic disease at presentation. On cranial MRI or CT, the site of metastasis was parenchymal disease (n = 7), bony metastasis (n = 1), or soft tissue (n = 1). Other sites of metastasis were liver (n = 12), non-cranial bone (n = 8), adrenal (n = 1), and neck nodes (n = 2). Seven (20%) patients had a prior history of malignancy: three of the head and neck, one gastrointestinal, two breast, and one breast & gynecologic. Twenty-eight (80%) patients presented with significant cardiac and/or pulmonary comorbidities. Predominant symptoms at presentation were pulmonary in nature. Weight loss of 10–50 lbs. was reported by 14 (40%) patients within a year prior to diagnosis. Patient and disease characteristics are depicted in Table 1.

Table 1.

Patient and disease characteristics

Variable	n = 35	(100%)
Age
Median (range)	68	(50–85)
Gender
Male	15	(43%)
Female	20	(57%)
ECOG Performance Status
0–1	20	(57%)
≥2	15	(43%)
Stage
1–3	11	(31%)
4	24	(69%)
Histology
Large	28	(80%)
Adenocarcinoma	6	(17%)
Squamous Cell	1	(3%)
Metastatic Sites at Presentation
Brain	7	(20%)
Liver	12	(34%)
Bone (cranial and non-cranial)	9	(26%)
Adrenal	1	(3%)
Other	3	(9%)
Smoking Status
Current or Former	32	(91%)
Never	3	(9%)
Treatment Modality
Chemotherapy	24	(69%)
Cranial RT	5	(14%)
Thoracic RT	7	(20%)
No Treatment	7	(20%)

ECOG, Eastern Cooperative Oncology Group; RT, radiotherapy.

Treatment

Twenty-eight patients (80%) were treated with combination chemotherapy, cranial radiotherapy, thoracic radiotherapy and/or palliative treatment. Chemotherapy was administered to 24 patients: 1 cycle (n = 7), 2 cycles (n = 6), 4–6 cycles (n = 5), numerous regimens with varying cycles (n = 4), and unknown (n = 1). Primary chemotherapeutic agents included platinum salts and etoposide. Patients with survival greater than six months were typically treated with different combination chemotherapy regimens after disease progression was identified on imaging. Five patients had cranial irradiation for metastatic disease. No patients received prophylactic cranial irradiation. Seven patients had palliative or definitive thoracic radiotherapy to a dose of 42–64 Gy. All patients who had thoracic radiotherapy also received systemic chemotherapy. Palliative radiotherapy was given for superior vena cava syndrome (n = 1), and bone and liver metastasis (n = 2).

Survival

Median follow-up was 6.3 months (range <1–53 months) for the entire cohort. Survival for seven patients who did not receive treatment was 31 days (range 12–98 days). One patient expired as a result of surgical complications one week post-pneumonectomy. Median survival for the 33 expired patients was 4.8 months (range <1–53 months), and two patients were alive, one with stable disease, and one with no evidence of disease at 25 and 39 months, respectively. For 11 patients who presented with stage I-III disease, the median survival was 15.4 months (range <1–53 months), and for 24 patients with stage IV, median survival was 3.4 months (range <1–21.8 months) (P = 0.0086), as demonstrated in Figure 1. Kaplan Meier estimates of overall survival by stage are also shown in Figure 1. Kaplan Meier estimates revealed improved OS rates for patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status of <2 (P = 0.0208) and a reported weight loss of 10–50 lbs. over the last year (P = 0.0062) (Figs 2, 3). Median survival in women and men were 8.16 and 4.6 months, respectively (P = 0.3865). For patients with SCLC/adenocarcinoma or squamous cell carcinoma, median overall survival was 14.6 months in comparison to 4.7 months for patients with SCLC/ large cell carcinoma NOS (P = 0.1824). Median survival for patients treated with chemoradiotherapy was 13 months (range 3–53 months) (Fig 4).

Figure 1.

Kaplan–Meier plot of overall survival by stage. , stage 1–3; , stage 4.

Figure 2.

Kaplan–Meier plot of overall survival by performance status. , Eastern Cooperative Oncology Group (ECOG) performance status 0–1; , ECOG performance status 2–4.

Figure 3.

Kaplan–Meier plot of overall survival by weight loss. , weight loss; , no weight loss.

Figure 4.

Kaplan–Meier plot of overall survival by treatment modality. , no treatment; , chemotherapy; , chemoradiotherapy.

Discussion

Patient characteristics

Despite improvements in radiotherapy and the discovery of new systemic agents, the landscape of SCLC has not changed significantly over the last 30 years. While disease extent is the most reproducible prognostic factor, age, female gender, and performance status are significant in various SCLC analyses. However, validation and comparison of these prognostic factors has not led to a consensus prognostic algorithm.¹⁵ SCLC has typically been a disease of elderly men over the age of 70 who smoke, which is similar to the findings of our analysis.² The female predominance in our study is in concert with the trend of increasing female representation of patients with SCLC in both the SEER and NCDB reviews.^1,3 However, improved survival was not significantly associated with female gender, which may be because of our small sample size, as well as the evolving classification of SCLC histology over the last two decades. Our study was consistent with findings of numerous publications that performance status is a significant prognostic factor in SCLC, regardless of the extent of disease.^16,17

Disease related characteristics

There have been revisions and controversies in classification of limited versus extensive stage disease, but it is well accepted that patients with limited disease perform better than those with extensive disease. In a recent NCDB analysis of patients with SCLC from 1992–2002, median survival for patients with limited-stage SCLC and extensive stage SCLC was 6.1 and 12.9 months, respectively.³ Our findings agree with the common theme of the literature, as patients with stage IV disease had significantly poorer survival rates in comparison to their early disease counterparts.

SCLC histology portends poorer prognosis than its non-small cell lung cancer (NSCLC) counterpart, but there are limited reports of survival outcomes in patients with combined SCLC histology in the literature. In a study of 19 patients with SCLC/large cell carcinoma (LCLC), Radice et al. reported a significant difference in the OS of six and 10.5 months for SCLC/LCLC and pure SCLC, respectively (P = 0.008).⁸ In contrast, Nicholson et al. reported no significant histologic or immunohistologic predictors of survival difference in an analysis of 72 pure SCLC and 28 combined SCLC histologies.⁹ Our findings were similar, in that no difference in survival was found between SCLC/adenocarcinoma, SCLC/squamous cell, or SCLC/large cell carcinoma NOS. This may seem counterintuitive, given the different treatment paradigms and survival outcomes of patients with pure SCLC and various pure NSCLC histologies. However, many of the older studies, including ours, relied primarily on morphologic and immunohistochemical identification of combined SCLC1.¹⁶ Some have begun to question morphologic identification as the ideal criteria to diagnose combined cases, and as such, if combined SCLC is a true subtype of SCLC. In an analysis of seven cases of SCLC combined with either adeno, squamous cell, or large cell neuroendocrine carcinoma, Wagner et al. reported shared identical immunophenotype in six cases between the SCLC and non-SCLC components of individual cases. They argue that both histologic components share the same clonal origin, and, therefore, should not be classified as a subtype, but as pure SCLC.¹⁷ It will be interesting for future studies to look at such findings in the context of survival differences in larger samples.

Treatment related potential prognostics

In our study, patients with survival greater than 12 months typically presented with stage I-III disease, were women, had SCLC/adenocarcinoma or SCLC/squamous cell carcinoma histology, and were treated with chemoradiotherapy. Meta analyses of limited-stage SCLC patients have shown that treatment with chemoradiotherapy improves survival.^18,19 This is in accord with our results, as patients with thoracic radiotherapy in combination with chemotherapy had a median survival of 13 months, but did not reach significance when compared to patients who were treated with chemotherapy alone (P = 0.11). Given the survival difference between those with and without a large cell carcinoma NOS component, there may be a role for targeted agents based on specific histologic subtype. Pemetrexed has been shown to be more active in non-squamous NSCLC, but only one patient with SCLC/large cell carcinoma NOS histology in our series was treated with pemetrexed as initial therapy and was alive at two years with stable disease at the time of analysis.²⁰ Additionally, given the poor prognosis associated with a SCLC diagnosis, it may be worthwhile to test for various mutations, such as epidermal growth factor receptor (EGFR), echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK), and KRAS in this population of patients with combined SCLC for targeted therapies.

Median survival for patients without definitive treatment for SCLC is two to four months.⁵ Survival for our population of patients who declined or were not eligible for treatment, was similar. In our study, patients with SCLC/large cell carcinoma NOS had a median survival of 4.7 months compared to 14.6 months for SCLC/adenocarcinoma or squamous cell carcinoma, although this was not statistically significant. One reason for the lack of statistical significance may be that of the large difference in sample size between the SCLC/large cell carcinoma NOS histology (80%) in comparison to the other histologies (20%). Median survival for patients who received any treatment was significant, which is important to consider given that any treatment, even palliative in nature, may provide survival benefit in this population of patients.

Limitations

Limitations of our study include the retrospective analysis and the small sample size. Unlike many urban tertiary medical centers, our patients reside in rural areas, often present with advanced stage disease, defer complete diagnostic workup, and opt for palliative treatment. In a recent NCDB analysis, Gaspar et al. reported an increase in the number of community cancer centers and a decrease in teaching research facilities diagnosing and treating SCLC.³ Given these trends, we anticipate that more patients may present to smaller institutions with pure and combined histologic variants of SCLC. Additionally, the histologic classification of lung cancer has evolved over the last two decades, and comparison of older series to newer reports is difficult. Novel markers for differentiating large cell histology have been introduced, but they did not enter common practice until recently. Therefore, further classification of large cell carcinoma may be possible if older patients were diagnosed using modern criteria.

Conclusion

Combined SCLC histology represents up to 20% of cases of SCLC, although this number might be underrepresented given the limited diagnostic specimen associated with the diagnosis of SCLC. It is important to identify the type of combined histology as it may impact survival outcomes. Perhaps novel chemotherapeutic drugs and targeted agents may impact response rates and survival in this subset of patients in the future.

Disclosure

No authors report any conflict of interest.