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Early Stage Non–Small-Cell Lung Cancer in Octogenarian and Older Patients: A SEER Database Analysis
Accepted Manuscript Early stage non-small cell lung cancer in octogenarian and older patients: a SEER database analysis Apar Kishor Ganti, Valerie Shostrom, Mohamed Elorabi, Weining (Ken) Zhen, Alissa S. Marr, Karin Trujillo, KM Monirul Islam, Rudy P. Lackner, Anne Kessinger PII:
S1525-7304(15)00278-8
DOI:
10.1016/j.cllc.2015.11.014
Reference:
CLLC 431
To appear in:
Clinical Lung Cancer
Received Date: 13 August 2015 Revised Date:
19 November 2015
Accepted Date: 23 November 2015
Please cite this article as: Ganti AK, Shostrom V, Elorabi M, Zhen W(K), Marr AS, Trujillo K, Islam KM, Lackner RP, Kessinger A, Early stage non-small cell lung cancer in octogenarian and older patients: a SEER database analysis, Clinical Lung Cancer (2015), doi: 10.1016/j.cllc.2015.11.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Early stage non-small cell lung cancer in octogenarian and older patients: a SEER database analysis
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Apar Kishor Ganti1,2, Valerie Shostrom3, Mohamed Elorabi4, Weining (Ken) Zhen5, Alissa S. Marr2, Karin Trujillo6,7, KM Monirul Islam8, Rudy P. Lackner6,7, Anne Kessinger2. From:
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Department of Internal Medicine, VA Nebraska Western Iowa Health Care System, Omaha, NE Department of Internal Medicine, Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE Department of Clinical Oncology, Ain Shams University Hospitals, Cairo, Egypt. Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE Department of Surgery, Division of Cardiothoracic Surgery, University of Nebraska Medical Center, Omaha, NE Department of Surgery, VA Nebraska Western Iowa Health Care System, Omaha, NE Department of Epidemiology, University of Nebraska Medical Center, Omaha, NE
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Funding: This work was partly funded by Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727) and a VA Career Development Award (AG)
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Corresponding Author: Apar Kishor Ganti, MD, MS, FACP. Division of Oncology-Hematology Department of Internal Medicine University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198-7680. Tel. No.: 402-559-6210. Fax No.: 402-559-6520. E-mail: [email protected]
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Abstract Background The median age at diagnosis of lung cancer is 70 years. However, the evidence guiding the
younger patients and may not be appropriate. Methods
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management of octogenarians and older patients with NSCLC, is based on data derived from
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Patients ≥80 years diagnosed with clinical stages I and II NSCLC, between 1988 and 2007, were identified from the SEER database. Patients were classified according to treatments received: no
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treatment, surgery only, radiation only and surgery + radiation. Factors associated with survival were assessed using the Cox proportional hazards model. Results
There were 1338 cases of early stage NSCLC in octogenarians. Surgery was the most
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common treatment modality. The median overall survival was 3.8 years for patients who had surgery, compared to 1.6 years, 1.6 years and 0.9 years for those who received surgery + radiation, radiation alone and no treatment, respectively (p<0.0001). Factors significantly
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associated with worse overall survival following surgery included increasing age [hazard ratio (HR) – 1.08; p=0.0005], male gender (HR – 1.33; p=0.01), stage II (HR – 2.21; p<0.0001) and
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squamous histology (HR – 1.36; p=0.01). Conclusion
Surgical resection is associated with long-term survival outcomes in a substantial
proportion of octogenarian and older patients with early stage lung cancer and should not be withheld on the basis of age alone.
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Microabstract Evidence guiding the management of octogenarian and older patients with NSCLC, is based on data derived from younger patients. This SEER database analysis demonstrated a
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median overall survival was 3.8 years for patients who had surgery. Surgical resection is associated with long-term survival in a substantial proportion of octogenarian and older patients
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with early stage lung cancer and should not be withheld on the basis of age alone.
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Introduction Lung cancer is the most common cause of cancer related deaths in the United States.1 The median age of patients at the time of diagnosis is 70 years.2 As the population ages, the number
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of older patients with non-small cell lung cancer (NSCLC) is likely to increase. The evidence guiding the management older patients with NSCLC, particularly octogenarians, is based on data derived from younger patients and may not be appropriate.3, 4
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Surgical resection is the standard of care for patients with early stage NSCLC. Approximately 18% of patients beyond the age of 75 years present with localized disease
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(Source: Surveillance Epidemiology and End Results). However the only data suggesting a role for surgery in older patients are based on retrospective single-institution analyses.5-14 While most of these series suggest that properly selected octogenarian patients with early stage NSCLC tolerate surgical resection well, at least two series recommend resection without mediastinal
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lymph node dissection for older patients.12, 13 Although some opine that octogenarians may be at an increased risk for complications
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, perioperative mortality and overall survival appear
similar to those of younger individuals. 6, 13
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These outcomes are reported by large centers, and may not reflect the experience of smaller, low-volume centers. A recent prediction model using the data from the Rotterdam and
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Thames Cancer registries found that the post-operative mortality increased with age; 1.7% for patients <60 years vs. 9.4% for patients ≥80 years.16 A comparison of the outcomes of octogenarian patients with early stage NSCLC after surgery and non-surgical management in a well-defined US population, included in the SEER database was conducted to help define the best treatment options for this cohort.
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Patients and methods Data source This retrospective cohort study used data from the Surveillance, Epidemiology and End
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Results (SEER) registry of the National Cancer Institute. The SEER program collects information on cancer incidence, prevalence, mortality, population-based variables, primary tumor characteristics, and treatment excluding chemotherapy in 17 US geographical areas.
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Study population
The SEER database between 1988 and 2007 was examined using the SEER*Stat
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software. Patients with stage I-II NSCLC, who were at least 80 years of age at diagnosis, were included in this analysis. Tumor staging was based on the American Joint Committee on Cancer (AJCC-6th Edition) criteria; T1-2N0M0 for stage I and T1-2N1M0 or T3N0M0 for stage II (2). The following information was obtained for each patient: year of diagnosis, demographic
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information (age, ethnic group and gender), histological type of the tumor, treatment received, survival information and cause of death. Study outcome
Statistical analysis:
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The primary outcome of this study was overall survival (OS) by stage and treatment.
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Patients were classified according to the following treatments received: no treatment,
surgery only, radiation only and surgery + radiation (primary resection followed by postoperative radiation). Each treatment group was divided into 5 year intervals based on date of diagnosis. For every treatment group, the frequency and percentage of patient and tumor characteristics were calculated. Survival was defined from the time of diagnosis to the date of death or last contact, at which point the survival information was censored. A Cox Proportional Hazards model including terms for age (continuous), cancer stage, race, gender, histology, and 5
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year of diagnosis was fit for all subjects in this cohort to evaluate the effect of the different covariates on overall survival. Kaplan-Meier analysis with the log-rank test was used to plot survival curves for comparisons between patients in each stage and the received treatment. All
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statistical analyses were made using SAS version 9.2 (SAS Institute, Cary, NC). Statistical
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significance was defined as P <0.05.
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Results The SEER database identified 1338 cases of early stage NSCLC in octogenarians. The majority had stage I (1116 patients). Demographic data of these patients are shown in Table 1.
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Most cases were diagnosed between 2003 and 2007 and the most were Caucasian. Surgery was the most common treatment modality in all treatment periods, but there was an increasing trend for surgical resection in the latter time periods. Most patients who treated with radiation alone
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were males (64.7%).
Of the 1116 stage I patients, 291 had no treatment while 518 were resected, 276 had
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radiation and 31 patients were treated surgery + radiation. Adenocarcinoma was the most common histologic subtype comprising 51.9% of patients who had a resection, 30.8% of patients who underwent radiation and 35.5% of patients who underwent surgery + radiation. The histologic subtype in patients who did not receive treatment included adenocarcinoma (27.8%),
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squamous cell carcinoma (17.2%) or other NSCLC histology (55%). Of the 222 stage II patients, 52 patients did not receive any treatment, while 76, 70 and 24 patients received surgery, radiation and surgery + radiation, respectively. Similar to stage I
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patients, adenocarcinoma (48.7%) was the most common pathological subtype in patients who had a surgical resection. In contrast, squamous cell carcinoma was more common among those
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who received radiation (38.6%) or surgery + radiation (41.7%). A little more than half of the patients (55.8%), with no treatment had other NSCLC histology. Patients with stage I and II disease, who were treated with surgery, had a better overall
survival (Table 2). For all patients with early stage NSCLC, median overall survival was 3.8 years for patients who had surgery, compared to 1.6 years, 1.6 years and 0.9 years for those who received surgery + radiation, radiation alone and no treatment, respectively (p<0.0001). One year
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overall survival was 79.6%, 68.1%, 62.4% and 45.6% for patients who received surgery, surgery + radiation, radiation and no treatment respectively. Two year overall survival for patients who had surgery, surgery + radiation, radiation and no treatment was 68.5%, 40.5%, 34.8% and 25%
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respectively.
For stage I patients median overall survival for the surgery group was 4.4 years as compared to 1.9 years, 1.8 years and 1 year in the surgery + RT, RT alone and no treatment
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groups (p<0.0001) (Figure 1). One and two year overall survival for stage I patients was higher for patients who received surgery alone (Table 2). Similar findings were observed in patients
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with stage II NSCLC. Median overall survival for the patients treated with surgery only was 1.9 years as compared to 1.2 years, 0.9 years and 0.5 years in the surgery + RT, RT alone and no treatment groups (p<0.0001) (Figure 2). As in patients with stage I disease, 1- and 2-year overall survival for stage II patients was higher in patients who received surgery alone.
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A multivariate analysis of factors affecting outcomes in this cohort revealed that increasing age, male gender, increasing stage (II vs. I), non-adenocarcinoma histology and nonsurgical therapy were associated with an increased risk of death (Table 3). Race did not affect
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outcomes; compared to whites, blacks had a 3% decreased risk of mortality, while others had a 6% decreased risk of mortality, neither of which reached statistical significance. When year of
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diagnosis was evaluated, a diagnosis after 1998 was associated with better outcomes. When patients who had a surgical resection with or without radiation (n=649) were
analyzed (n=649) to identify potential factors that could predict for outcomes, one and 5-year overall survival for patients with stage I disease was 82% and 43% respectively, while the corresponding values for patients with stage II disease were 61% and 13%. On multivariate analysis, factors significantly associated with worse overall survival included increasing age
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[hazard ratio (HR) – 1.08; p=0.0005], male gender (HR – 1.33; p=0.01), stage II (HR – 2.21; p<0.0001) and squamous histology (HR – 1.36; p=0.01). (Table 4) There was a significant change in the proportion of patients undergoing various treatment
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modalities over time (p=0.02). Of the patients diagnosed in 1988-1992, 40.3% underwent surgery. This number increased to 42.3% in 1993-1997 and 49.3% in 1998-2002, but decreased to 43.6% between 2003 and 2007. The proportion of patients receiving radiation therapy
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decreased from 34.5% in 1988-1992 to 25.6% in 1993-1997, but increased slightly to 27.2% and 27.4% in 1998-2002 and 2003-2007 respectively. The proportion of patients who received no
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treatment was the lowest in 1988-1992 (18.4%), but increased to 25.6%, 27.2% and 26.2% in the subsequent time periods. The use of surgery followed by radiation showed a consistent decline over the time period studied from 6.7% in 1988-1992 to 6.0%, 4.1% and 3.1% in the subsequent
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periods.
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Discussion This analysis includes a larger cohort of octogenarian and older patients with early stage NSCLC than has been previously reported. Octogenarians treated with surgery for stage I and II
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NSCLC had the best outcomes as compared to other treatment modalities, while not surprisingly, untreated patients had the worst outcomes. Increasing age, male gender, higher stage and nonadenocarcinoma histology were associated with a worse overall survival.
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Patients treated with surgery had a median survival of 3.8 years and a 2 year OS of 68.5% in this analysis. Forty-three percent of patients with stage I disease treated with surgery were
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alive 5 years after diagnosis. While this is lower than the median life expectancy for octogenarians in the United States of 8.4 years between 1999 and 200117, it nonetheless is longer than that seen for patients treated with other modalities.
There was a consistent decrease in the use of post-operative radiation during the period
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analyzed. This is most likely the result of the findings of the PORT meta-analysis that showed a detrimental effect of post-operative radiation therapy on outcomes, especially in stage I/II patients18. However this trend is likely to be reversed with the publication of new data that
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suggest that selected patients who undergo incomplete resection may actually benefit from postoperative radiation19. An interesting finding of this analysis is the increasing number of patients
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who are opting for no treatment. Future studies should analyze the reasons behind this phenomenon.
Multiple single-institution reports of outcomes following surgical resection of early stage
NSCLC in octogenarians are available. In one of the earliest reports, Naunheim et al. analyzed 40 patients and found a complication rate of 45% and a mortality rate of 16%; increasing age predicted for worse overall survival.20 One and 3-year overall survival was 55% and 40%. Osaki et al. found a 5-year survival of 32% and an operative mortality rate of 3% in their series of 33 10
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surgically treated NSCLC patients.21 The only factor affecting survival in this analysis was the development of perioperative cardiorespiratory complications. Similar results were noted in a series of 54 patients, who for the most part, underwent at least a lobectomy for NSCLC, with 1-
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and 5-year survival rates of 85% and 41%.5 Aoki et al reported no surgical mortality and a 60% complication rate in their series of 35 patients treated between 1981 and 1998.9 Brock et al. presented results of 69 patients, 80 years of age or older, with stage I NSCLC treated between
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1980 and 2002.8 The thirty day mortality was 8.8%, and the overall survival at 1, and 5 years was 73% and 34%. Patients with advanced tumor stage (stage IB vs. IA), lower American Society of
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Anesthesiology (ASA) physical status, and low pre-operative FEV1 had a worse long-term survival. In the largest analysis of octogenarians thus far, Dominguez-Ventura et al reported outcomes of 379 NSCLC patients treated with resection over a 20 year period from 1985-2004.22 Almost half the patients (48%) had significant perioperative morbidity (atrial fibrillation,
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pneumonia and retained secretions needing a bronchoscopy), with male gender, hemoptysis and a previous stroke predicting for development of these morbidities. They noted an operative mortality of 6.3% with congestive heart failure and prior myocardial infarction predicting for
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death post-operatively.
In a more recent series, Hino et al reported outcomes of 94 octogenarians treated with
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surgery for early stage NSCLC.23 Five-year overall survival in this cohort was 57.5%. Male gender and non-adenocarcinoma histology were significant risk factors for poor prognosis. Ito et al reported a series of 65 octogenarians who underwent curative resection for clinical stage I NSCLC and noted an actuarial survival rate was 68.6% at 5 years, with the median survival of 109.2 months.24 On multivariate analysis, male sex and sub-lobar resection were independent risk factors for survival. These findings are similar to the present cohort. In an Italian series of 73
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patients ≥80 years of age, who underwent intended curative lung resection for lung cancer the overall survival at 1, 3 and 5 years was 96, 83 and 60%.25 However in contrast to the above studies, only a low-respiratory reserve was associated with a poor outcome, while age, gender
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and histology were not.
While the present analysis does not include data on post-operative morbidity and mortality, the survival results are similar to those seen in these smaller, highly selected single
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institution series (43% compared to 32-68.5%). More importantly, the present analysis includes a
with single institution studies.
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large number of patients treated at many institutions, thereby eliminating any biases associated
Stereotactic ablative body radiation (SABR) is commonly used in patients with early stage NSCLC, who are not candidates for surgical resection, but data on such treatment for octogenarians are sparse. One series of 109 patients with T1-2N0M0 NSCLC treated with SBRT,
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reported a 3-yr OS and lung cancer-specific survival rates of 53.7% and 70.8%, respectively.26 Of note, 47 of the 109 patients did not have biopsy confirmed NSCLC, which could have influenced the results. In another analysis of 24 patients with stage I NSCLC, the 24-month
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overall survival (OS) was 74%, with no local failure reported during the study period.27 A recent SEER-Medicare study compared lobectomy, sublobar resection and SABR in
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patients >65 years old.28 Although data on octogenarians were not reported separately, the overall analysis showed that lobectomy was associated with better outcomes than sub-lobar resection. SABR was associated with better outcomes than lobectomy in the first six months after diagnosis (HR 0.45; 95%CI, 0.27–0.75), but worse survival later on (HR 1.66; 95%CI, 1.39–1.99). Propensity score matching analysis demonstrated similar overall survival in wellmatched SABR and lobectomy cohorts (HR 1.01; 95%CI, 0.74–1.38).
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Limitations of this study include its retrospective design and absence of adjuvant chemotherapy data for the stage II patients. Patients who received radiation were more likely to have received conventional radiation therapy, since stereotactic radiation was not in use during
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most of the period encompassed by the study. Data regarding the type of surgery performed, post-operative morbidity, performance status and other comorbid conditions are not available in the SEER database and hence were not included in this analysis. Only patients who were deemed
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fit to undergo surgery by the treating team underwent resection and there was no formal treatment algorithm for patient selection; this is likely a source of bias.
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The findings of the present analysis may have implications on the upper age limit for CT scan screening for lung cancer. The NLST included patients between 55 and 74 years of age29, but the United States Preventive Services Task Force (USPSTF) recommends stopping screening at the age of 80 years30, while the American Association of Thoracic Surgery recommends
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screening to the age of 79 years31. It is well recognized that age is a poor surrogate for fitness and ability to tolerate surgery32. The present analysis demonstrates that older patients seem to tolerate and benefit from surgical resection of lung cancer and could potentially impact the
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recommendations for CT screening of lung cancer. In summary, 43% of octogenarians with surgically resected stage I NSCLC and 13% with
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stage II NSCLC, identified in the SEER database, experienced a 5 year survival. Thus, surgical resection is associated with long-term survival in a substantial proportion of octogenarians with early stage lung cancer and should not be withheld on the basis of age alone.
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Clinical Practice Points •
Evidence guiding the management of octogenarians with early stage NSCLC, is based on data derived from younger patients and may not be appropriate. The median overall survival was 3.8 years for patients who had surgery and was
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•
significantly higher than that for patients treated with other modalities (p<0.0001). •
Factors significantly associated with worse overall survival following surgery included
Surgical resection is associated with respectable survival outcomes in octogenarians with
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early stage lung cancer and should not be withheld on the basis of age alone.
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•
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increasing age, male gender, stage II and squamous histology.
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Total 1338
95 172 249 600
24 43 45 110
119 215 294 710
560 556
88 134
648 690
975 66 75
197 11 14
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291 518 276 31
1172 77 89
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296 446 374
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Stage II 222
75 77 70
371 523 444
52 76 70 24
343 594 346 55
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Number Year of diagnosis 1988-1992 1993-1997 1998-2002 2003-2007 Gender Female Male Ethnic group White African-American Others Histology Squamous cell carcinoma Adenocarcinoma Others Treatment No treatment Surgery RT Surgery + RT
Stage I 1116
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Table 1: Patient characteristics
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Table 2: Survival according to treatment Surgery only
Surgery + RT
RT only
No treatment
Stage I
Median (95% CI) (years) Survival 1 yr (95% CI) Survival 2 yrs (95% CI) N
1.9 (1.3 - 4.3)
1.8 (1.5 - 1.9)
1 (0.8 - 1.2)
82.3% (78.6% 85.4%) 71.7% (67.3% 75.6%)
76.1% (56.3% 87.8%) 46.4% (25.6% 64.9%) Stage II
67.2% (61.1% 72.6%) 38.2% (31.8% 44.5%)
48.5% (42.4% 54.3%) 28.9% (23.3% 34.7%)
76
24
70
52
1.9 (1 - 2.4)
1.2 (0.8 - 2.2)
0.9 (0.7 - 1.3)
0.5 (0.3 - 0.9)
61.5% (49.2% 71.6%) 47.5% (35.4% 58.8%)
58.3% (36.4% 75%) 33.3% (15.9% 51.9%) Stage I + II
41.9% (29.3% 54.1%) 21% (11.6% 32.2%)
29.9% (18% 42.8%) 5.1% (1% - 14.7%)
594
55
346
343
3.8 (3.3 - 4.5)
1.6 (1.1 - 2.9)
1.6 (1.3 - 1.8)
0.9 (0.8 - 1.1)
79.6% (76% 82.7%) 68.5% (64.4% 72.3%)
68.1% (53.8% 78.8%) 40.5% (26.6% 54%)
62.4% (56.8% 67.5%) 34.8% (29.3% 40.4%)
45.6% (40.1% 50.9%) 25% (20.1% 30.1%)
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4.4 (3.7- 5)
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Median (95% CI) (years) Survival 1 yr (95% CI) Survival 2 yrs (95% CI)
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N
276
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2-yr OS (95% CI)
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Median (95% CI) (years) 1-yr OS (95% CI)
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N
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Table 3: Multivariate analysis of factors affecting outcomes in octogenarians and older patients
Stage
Histology
Year of diagnosis
1.20 1 1.050 0.698 0.772 1 3.26 2.20 1.34
0.73, 1.29 0.72, 1.21
0.84 0.62
1.16, 1.52
<0.0001
1.44, 2.02
<0.0001
1.25, 1.76
<0.0001
1.02, 1.42
0.0291
0.83, 1.33 0.55, 0.88 0.62, 0.97
0.68 0.0024 0.02
2.70, 3.92 1.85, 2.63 0.95, 1.90
<0.0001 <0.0001 0.09
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Treatment
1.48
P-value 0.0043
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Gender
White AA/Black Other Female Male I II Adenocarcinoma Squamous cell carcinoma Other 1988-1992 1993-1997 1998-2002 2003-2007 Surgery only None RT Surgery/RT
95% CI 1.01, 1.05
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Race
HR 1.03 1 0.97 0.94 1 1.33 1 1.70 1
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Median age (years)
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Table 4: Multivariate analysis of factors affecting outcomes in octogenarians following surgery
Stage Histology
0.42, 1.21 0.68, 1.7
0.21 0.75
1.07, 1.65
0.01
1.71, 2.87
<0.0001
1.07, 1.74 0.98, 1.74 0.83, 1.68 0.67, 1.35 0.61, 1.27
0.01 0.07 0.36 0.78 0.50
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Year of diagnosis
P-value 0.0005
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Gender
White AA/Black Other Female Male I II Adeno Squamous Other 1988-1992 1993-1997 1998-2002 2003-2007
95% CI 1.03, 1.12
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Race
HR 1.08 1 0.71 1.01 1 1.33 1 2.21 1 1.36 1.31 1 1.178 0.951 0.879
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Median age (years)
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Figure Legends Figure 1: Survival outcome for stage I patients
Figure 2: Survival outcome for stage II patients
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The median survival (95% CI) (years) for the patients treated with the different modalities is: Surgery only - 4.4 (3.7- 5), Surgery + RT - 1.9 (1.3 - 4.3), RT only - 1.8 (1.5 - 1.9), No treatment - 1 (0.8 - 1.2)
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The median survival (95% CI) (years) for the patients treated with the different modalities is: Surgery only - 1.9 (1 - 2.4), Surgery + RT - 1.2 (0.8 - 2.2), RT only - 0.9 (0.7 - 1.3), No treatment - 0.5 (0.3 - 0.9)
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Wang EH, Corso CD, Rutter CE, et al. Postoperative Radiation Therapy Is Associated With Improved Overall Survival in Incompletely Resected Stage II and III Non-SmallCell Lung Cancer. J Clin Oncol. 2015;33:2727-2734. Naunheim KS, Kesler KA, D'Orazio SA, Fiore AC, Judd DR. Lung cancer surgery in the octogenarian. Eur J Cardiothorac Surg. 1994;8:453-456. Osaki T, Shirakusa T, Kodate M, Nakanishi R, Mitsudomi T, Ueda H. Surgical treatment of lung cancer in the octogenarian. Ann Thorac Surg. 1994;57:188-192; discussion 192183. Dominguez-Ventura A, Allen MS, Cassivi SD, Nichols FC, 3rd, Deschamps C, Pairolero PC. Lung cancer in octogenarians: factors affecting morbidity and mortality after pulmonary resection. Ann Thorac Surg. 2006;82:1175-1179. Hino H, Murakawa T, Ichinose J, et al. Results of Lung Cancer Surgery for Octogenarians. Ann Thorac Cardiovasc Surg. 2015. Ito H, Nakayama H, Yamada K, Yokose T, Masuda M. Outcomes of lobectomy in 'active' octogenarians with clinical stage I non-small-cell lung cancer. Ann Thorac Cardiovasc Surg. 2015;21:24-30. Dell'Amore A, Monteverde M, Martucci N, et al. Lobar and sub-lobar lung resection in octogenarians with early stage non-small cell lung cancer: factors affecting surgical outcomes and long-term results. General thoracic and cardiovascular surgery. 2015;63:222-230. Takeda A, Sanuki N, Eriguchi T, et al. Stereotactic ablative body radiation therapy for octogenarians with non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2013;86:257-263. von Pawel J, Harvey JH, Spigel DR, et al. Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer. Clin Lung Cancer. 2014;15:188-196 e182. Shirvani SM, Jiang J, Chang JY, et al. Lobectomy, sublobar resection, and stereotactic ablative radiotherapy for early-stage non-small cell lung cancers in the elderly. JAMA surgery. 2014;149:1244-1253. National Lung Screening Trial Research T, Aberle DR, Adams AM, et al. Reduced lungcancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409. Moyer VA, Force USPST. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160:330-338. Jacobson FL, Austin JH, Field JK, et al. Development of The American Association for Thoracic Surgery guidelines for low-dose computed tomography scans to screen for lung cancer in North America: recommendations of The American Association for Thoracic Surgery Task Force for Lung Cancer Screening and Surveillance. J Thorac Cardiovasc Surg. 2012;144:25-32. Field JK, Aberle DR, Altorki N, et al. The International Association Study Lung Cancer (IASLC) Strategic Screening Advisory Committee (SSAC) response to the USPSTF recommendations. J Thorac Oncol. 2014;9:141-143.
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S1525-7304(15)00278-8
DOI:
10.1016/j.cllc.2015.11.014
Reference:
CLLC 431
To appear in:
Clinical Lung Cancer
Received Date: 13 August 2015 Revised Date:
19 November 2015
Accepted Date: 23 November 2015
Please cite this article as: Ganti AK, Shostrom V, Elorabi M, Zhen W(K), Marr AS, Trujillo K, Islam KM, Lackner RP, Kessinger A, Early stage non-small cell lung cancer in octogenarian and older patients: a SEER database analysis, Clinical Lung Cancer (2015), doi: 10.1016/j.cllc.2015.11.014. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Early stage non-small cell lung cancer in octogenarian and older patients: a SEER database analysis
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Apar Kishor Ganti1,2, Valerie Shostrom3, Mohamed Elorabi4, Weining (Ken) Zhen5, Alissa S. Marr2, Karin Trujillo6,7, KM Monirul Islam8, Rudy P. Lackner6,7, Anne Kessinger2. From:
3 4 5 6 7 8
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Department of Internal Medicine, VA Nebraska Western Iowa Health Care System, Omaha, NE Department of Internal Medicine, Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE Department of Clinical Oncology, Ain Shams University Hospitals, Cairo, Egypt. Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE Department of Surgery, Division of Cardiothoracic Surgery, University of Nebraska Medical Center, Omaha, NE Department of Surgery, VA Nebraska Western Iowa Health Care System, Omaha, NE Department of Epidemiology, University of Nebraska Medical Center, Omaha, NE
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Funding: This work was partly funded by Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727) and a VA Career Development Award (AG)
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Corresponding Author: Apar Kishor Ganti, MD, MS, FACP. Division of Oncology-Hematology Department of Internal Medicine University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198-7680. Tel. No.: 402-559-6210. Fax No.: 402-559-6520. E-mail: [email protected]
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Abstract Background The median age at diagnosis of lung cancer is 70 years. However, the evidence guiding the
younger patients and may not be appropriate. Methods
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management of octogenarians and older patients with NSCLC, is based on data derived from
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Patients ≥80 years diagnosed with clinical stages I and II NSCLC, between 1988 and 2007, were identified from the SEER database. Patients were classified according to treatments received: no
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treatment, surgery only, radiation only and surgery + radiation. Factors associated with survival were assessed using the Cox proportional hazards model. Results
There were 1338 cases of early stage NSCLC in octogenarians. Surgery was the most
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common treatment modality. The median overall survival was 3.8 years for patients who had surgery, compared to 1.6 years, 1.6 years and 0.9 years for those who received surgery + radiation, radiation alone and no treatment, respectively (p<0.0001). Factors significantly
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associated with worse overall survival following surgery included increasing age [hazard ratio (HR) – 1.08; p=0.0005], male gender (HR – 1.33; p=0.01), stage II (HR – 2.21; p<0.0001) and
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squamous histology (HR – 1.36; p=0.01). Conclusion
Surgical resection is associated with long-term survival outcomes in a substantial
proportion of octogenarian and older patients with early stage lung cancer and should not be withheld on the basis of age alone.
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Microabstract Evidence guiding the management of octogenarian and older patients with NSCLC, is based on data derived from younger patients. This SEER database analysis demonstrated a
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median overall survival was 3.8 years for patients who had surgery. Surgical resection is associated with long-term survival in a substantial proportion of octogenarian and older patients
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with early stage lung cancer and should not be withheld on the basis of age alone.
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Introduction Lung cancer is the most common cause of cancer related deaths in the United States.1 The median age of patients at the time of diagnosis is 70 years.2 As the population ages, the number
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of older patients with non-small cell lung cancer (NSCLC) is likely to increase. The evidence guiding the management older patients with NSCLC, particularly octogenarians, is based on data derived from younger patients and may not be appropriate.3, 4
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Surgical resection is the standard of care for patients with early stage NSCLC. Approximately 18% of patients beyond the age of 75 years present with localized disease
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(Source: Surveillance Epidemiology and End Results). However the only data suggesting a role for surgery in older patients are based on retrospective single-institution analyses.5-14 While most of these series suggest that properly selected octogenarian patients with early stage NSCLC tolerate surgical resection well, at least two series recommend resection without mediastinal
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lymph node dissection for older patients.12, 13 Although some opine that octogenarians may be at an increased risk for complications
8, 9, 15
, perioperative mortality and overall survival appear
similar to those of younger individuals. 6, 13
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These outcomes are reported by large centers, and may not reflect the experience of smaller, low-volume centers. A recent prediction model using the data from the Rotterdam and
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Thames Cancer registries found that the post-operative mortality increased with age; 1.7% for patients <60 years vs. 9.4% for patients ≥80 years.16 A comparison of the outcomes of octogenarian patients with early stage NSCLC after surgery and non-surgical management in a well-defined US population, included in the SEER database was conducted to help define the best treatment options for this cohort.
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Patients and methods Data source This retrospective cohort study used data from the Surveillance, Epidemiology and End
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Results (SEER) registry of the National Cancer Institute. The SEER program collects information on cancer incidence, prevalence, mortality, population-based variables, primary tumor characteristics, and treatment excluding chemotherapy in 17 US geographical areas.
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Study population
The SEER database between 1988 and 2007 was examined using the SEER*Stat
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software. Patients with stage I-II NSCLC, who were at least 80 years of age at diagnosis, were included in this analysis. Tumor staging was based on the American Joint Committee on Cancer (AJCC-6th Edition) criteria; T1-2N0M0 for stage I and T1-2N1M0 or T3N0M0 for stage II (2). The following information was obtained for each patient: year of diagnosis, demographic
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information (age, ethnic group and gender), histological type of the tumor, treatment received, survival information and cause of death. Study outcome
Statistical analysis:
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The primary outcome of this study was overall survival (OS) by stage and treatment.
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Patients were classified according to the following treatments received: no treatment,
surgery only, radiation only and surgery + radiation (primary resection followed by postoperative radiation). Each treatment group was divided into 5 year intervals based on date of diagnosis. For every treatment group, the frequency and percentage of patient and tumor characteristics were calculated. Survival was defined from the time of diagnosis to the date of death or last contact, at which point the survival information was censored. A Cox Proportional Hazards model including terms for age (continuous), cancer stage, race, gender, histology, and 5
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year of diagnosis was fit for all subjects in this cohort to evaluate the effect of the different covariates on overall survival. Kaplan-Meier analysis with the log-rank test was used to plot survival curves for comparisons between patients in each stage and the received treatment. All
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statistical analyses were made using SAS version 9.2 (SAS Institute, Cary, NC). Statistical
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significance was defined as P <0.05.
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Results The SEER database identified 1338 cases of early stage NSCLC in octogenarians. The majority had stage I (1116 patients). Demographic data of these patients are shown in Table 1.
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Most cases were diagnosed between 2003 and 2007 and the most were Caucasian. Surgery was the most common treatment modality in all treatment periods, but there was an increasing trend for surgical resection in the latter time periods. Most patients who treated with radiation alone
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were males (64.7%).
Of the 1116 stage I patients, 291 had no treatment while 518 were resected, 276 had
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radiation and 31 patients were treated surgery + radiation. Adenocarcinoma was the most common histologic subtype comprising 51.9% of patients who had a resection, 30.8% of patients who underwent radiation and 35.5% of patients who underwent surgery + radiation. The histologic subtype in patients who did not receive treatment included adenocarcinoma (27.8%),
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squamous cell carcinoma (17.2%) or other NSCLC histology (55%). Of the 222 stage II patients, 52 patients did not receive any treatment, while 76, 70 and 24 patients received surgery, radiation and surgery + radiation, respectively. Similar to stage I
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patients, adenocarcinoma (48.7%) was the most common pathological subtype in patients who had a surgical resection. In contrast, squamous cell carcinoma was more common among those
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who received radiation (38.6%) or surgery + radiation (41.7%). A little more than half of the patients (55.8%), with no treatment had other NSCLC histology. Patients with stage I and II disease, who were treated with surgery, had a better overall
survival (Table 2). For all patients with early stage NSCLC, median overall survival was 3.8 years for patients who had surgery, compared to 1.6 years, 1.6 years and 0.9 years for those who received surgery + radiation, radiation alone and no treatment, respectively (p<0.0001). One year
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overall survival was 79.6%, 68.1%, 62.4% and 45.6% for patients who received surgery, surgery + radiation, radiation and no treatment respectively. Two year overall survival for patients who had surgery, surgery + radiation, radiation and no treatment was 68.5%, 40.5%, 34.8% and 25%
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respectively.
For stage I patients median overall survival for the surgery group was 4.4 years as compared to 1.9 years, 1.8 years and 1 year in the surgery + RT, RT alone and no treatment
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groups (p<0.0001) (Figure 1). One and two year overall survival for stage I patients was higher for patients who received surgery alone (Table 2). Similar findings were observed in patients
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with stage II NSCLC. Median overall survival for the patients treated with surgery only was 1.9 years as compared to 1.2 years, 0.9 years and 0.5 years in the surgery + RT, RT alone and no treatment groups (p<0.0001) (Figure 2). As in patients with stage I disease, 1- and 2-year overall survival for stage II patients was higher in patients who received surgery alone.
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A multivariate analysis of factors affecting outcomes in this cohort revealed that increasing age, male gender, increasing stage (II vs. I), non-adenocarcinoma histology and nonsurgical therapy were associated with an increased risk of death (Table 3). Race did not affect
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outcomes; compared to whites, blacks had a 3% decreased risk of mortality, while others had a 6% decreased risk of mortality, neither of which reached statistical significance. When year of
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diagnosis was evaluated, a diagnosis after 1998 was associated with better outcomes. When patients who had a surgical resection with or without radiation (n=649) were
analyzed (n=649) to identify potential factors that could predict for outcomes, one and 5-year overall survival for patients with stage I disease was 82% and 43% respectively, while the corresponding values for patients with stage II disease were 61% and 13%. On multivariate analysis, factors significantly associated with worse overall survival included increasing age
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[hazard ratio (HR) – 1.08; p=0.0005], male gender (HR – 1.33; p=0.01), stage II (HR – 2.21; p<0.0001) and squamous histology (HR – 1.36; p=0.01). (Table 4) There was a significant change in the proportion of patients undergoing various treatment
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modalities over time (p=0.02). Of the patients diagnosed in 1988-1992, 40.3% underwent surgery. This number increased to 42.3% in 1993-1997 and 49.3% in 1998-2002, but decreased to 43.6% between 2003 and 2007. The proportion of patients receiving radiation therapy
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decreased from 34.5% in 1988-1992 to 25.6% in 1993-1997, but increased slightly to 27.2% and 27.4% in 1998-2002 and 2003-2007 respectively. The proportion of patients who received no
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treatment was the lowest in 1988-1992 (18.4%), but increased to 25.6%, 27.2% and 26.2% in the subsequent time periods. The use of surgery followed by radiation showed a consistent decline over the time period studied from 6.7% in 1988-1992 to 6.0%, 4.1% and 3.1% in the subsequent
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periods.
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Discussion This analysis includes a larger cohort of octogenarian and older patients with early stage NSCLC than has been previously reported. Octogenarians treated with surgery for stage I and II
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NSCLC had the best outcomes as compared to other treatment modalities, while not surprisingly, untreated patients had the worst outcomes. Increasing age, male gender, higher stage and nonadenocarcinoma histology were associated with a worse overall survival.
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Patients treated with surgery had a median survival of 3.8 years and a 2 year OS of 68.5% in this analysis. Forty-three percent of patients with stage I disease treated with surgery were
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alive 5 years after diagnosis. While this is lower than the median life expectancy for octogenarians in the United States of 8.4 years between 1999 and 200117, it nonetheless is longer than that seen for patients treated with other modalities.
There was a consistent decrease in the use of post-operative radiation during the period
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analyzed. This is most likely the result of the findings of the PORT meta-analysis that showed a detrimental effect of post-operative radiation therapy on outcomes, especially in stage I/II patients18. However this trend is likely to be reversed with the publication of new data that
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suggest that selected patients who undergo incomplete resection may actually benefit from postoperative radiation19. An interesting finding of this analysis is the increasing number of patients
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who are opting for no treatment. Future studies should analyze the reasons behind this phenomenon.
Multiple single-institution reports of outcomes following surgical resection of early stage
NSCLC in octogenarians are available. In one of the earliest reports, Naunheim et al. analyzed 40 patients and found a complication rate of 45% and a mortality rate of 16%; increasing age predicted for worse overall survival.20 One and 3-year overall survival was 55% and 40%. Osaki et al. found a 5-year survival of 32% and an operative mortality rate of 3% in their series of 33 10
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surgically treated NSCLC patients.21 The only factor affecting survival in this analysis was the development of perioperative cardiorespiratory complications. Similar results were noted in a series of 54 patients, who for the most part, underwent at least a lobectomy for NSCLC, with 1-
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and 5-year survival rates of 85% and 41%.5 Aoki et al reported no surgical mortality and a 60% complication rate in their series of 35 patients treated between 1981 and 1998.9 Brock et al. presented results of 69 patients, 80 years of age or older, with stage I NSCLC treated between
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1980 and 2002.8 The thirty day mortality was 8.8%, and the overall survival at 1, and 5 years was 73% and 34%. Patients with advanced tumor stage (stage IB vs. IA), lower American Society of
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Anesthesiology (ASA) physical status, and low pre-operative FEV1 had a worse long-term survival. In the largest analysis of octogenarians thus far, Dominguez-Ventura et al reported outcomes of 379 NSCLC patients treated with resection over a 20 year period from 1985-2004.22 Almost half the patients (48%) had significant perioperative morbidity (atrial fibrillation,
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pneumonia and retained secretions needing a bronchoscopy), with male gender, hemoptysis and a previous stroke predicting for development of these morbidities. They noted an operative mortality of 6.3% with congestive heart failure and prior myocardial infarction predicting for
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death post-operatively.
In a more recent series, Hino et al reported outcomes of 94 octogenarians treated with
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surgery for early stage NSCLC.23 Five-year overall survival in this cohort was 57.5%. Male gender and non-adenocarcinoma histology were significant risk factors for poor prognosis. Ito et al reported a series of 65 octogenarians who underwent curative resection for clinical stage I NSCLC and noted an actuarial survival rate was 68.6% at 5 years, with the median survival of 109.2 months.24 On multivariate analysis, male sex and sub-lobar resection were independent risk factors for survival. These findings are similar to the present cohort. In an Italian series of 73
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patients ≥80 years of age, who underwent intended curative lung resection for lung cancer the overall survival at 1, 3 and 5 years was 96, 83 and 60%.25 However in contrast to the above studies, only a low-respiratory reserve was associated with a poor outcome, while age, gender
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and histology were not.
While the present analysis does not include data on post-operative morbidity and mortality, the survival results are similar to those seen in these smaller, highly selected single
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institution series (43% compared to 32-68.5%). More importantly, the present analysis includes a
with single institution studies.
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large number of patients treated at many institutions, thereby eliminating any biases associated
Stereotactic ablative body radiation (SABR) is commonly used in patients with early stage NSCLC, who are not candidates for surgical resection, but data on such treatment for octogenarians are sparse. One series of 109 patients with T1-2N0M0 NSCLC treated with SBRT,
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reported a 3-yr OS and lung cancer-specific survival rates of 53.7% and 70.8%, respectively.26 Of note, 47 of the 109 patients did not have biopsy confirmed NSCLC, which could have influenced the results. In another analysis of 24 patients with stage I NSCLC, the 24-month
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overall survival (OS) was 74%, with no local failure reported during the study period.27 A recent SEER-Medicare study compared lobectomy, sublobar resection and SABR in
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patients >65 years old.28 Although data on octogenarians were not reported separately, the overall analysis showed that lobectomy was associated with better outcomes than sub-lobar resection. SABR was associated with better outcomes than lobectomy in the first six months after diagnosis (HR 0.45; 95%CI, 0.27–0.75), but worse survival later on (HR 1.66; 95%CI, 1.39–1.99). Propensity score matching analysis demonstrated similar overall survival in wellmatched SABR and lobectomy cohorts (HR 1.01; 95%CI, 0.74–1.38).
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Limitations of this study include its retrospective design and absence of adjuvant chemotherapy data for the stage II patients. Patients who received radiation were more likely to have received conventional radiation therapy, since stereotactic radiation was not in use during
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most of the period encompassed by the study. Data regarding the type of surgery performed, post-operative morbidity, performance status and other comorbid conditions are not available in the SEER database and hence were not included in this analysis. Only patients who were deemed
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fit to undergo surgery by the treating team underwent resection and there was no formal treatment algorithm for patient selection; this is likely a source of bias.
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The findings of the present analysis may have implications on the upper age limit for CT scan screening for lung cancer. The NLST included patients between 55 and 74 years of age29, but the United States Preventive Services Task Force (USPSTF) recommends stopping screening at the age of 80 years30, while the American Association of Thoracic Surgery recommends
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screening to the age of 79 years31. It is well recognized that age is a poor surrogate for fitness and ability to tolerate surgery32. The present analysis demonstrates that older patients seem to tolerate and benefit from surgical resection of lung cancer and could potentially impact the
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recommendations for CT screening of lung cancer. In summary, 43% of octogenarians with surgically resected stage I NSCLC and 13% with
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stage II NSCLC, identified in the SEER database, experienced a 5 year survival. Thus, surgical resection is associated with long-term survival in a substantial proportion of octogenarians with early stage lung cancer and should not be withheld on the basis of age alone.
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Clinical Practice Points •
Evidence guiding the management of octogenarians with early stage NSCLC, is based on data derived from younger patients and may not be appropriate. The median overall survival was 3.8 years for patients who had surgery and was
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•
significantly higher than that for patients treated with other modalities (p<0.0001). •
Factors significantly associated with worse overall survival following surgery included
Surgical resection is associated with respectable survival outcomes in octogenarians with
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early stage lung cancer and should not be withheld on the basis of age alone.
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•
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increasing age, male gender, stage II and squamous histology.
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Total 1338
95 172 249 600
24 43 45 110
119 215 294 710
560 556
88 134
648 690
975 66 75
197 11 14
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291 518 276 31
1172 77 89
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296 446 374
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Stage II 222
75 77 70
371 523 444
52 76 70 24
343 594 346 55
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Number Year of diagnosis 1988-1992 1993-1997 1998-2002 2003-2007 Gender Female Male Ethnic group White African-American Others Histology Squamous cell carcinoma Adenocarcinoma Others Treatment No treatment Surgery RT Surgery + RT
Stage I 1116
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Table 1: Patient characteristics
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Table 2: Survival according to treatment Surgery only
Surgery + RT
RT only
No treatment
Stage I
Median (95% CI) (years) Survival 1 yr (95% CI) Survival 2 yrs (95% CI) N
1.9 (1.3 - 4.3)
1.8 (1.5 - 1.9)
1 (0.8 - 1.2)
82.3% (78.6% 85.4%) 71.7% (67.3% 75.6%)
76.1% (56.3% 87.8%) 46.4% (25.6% 64.9%) Stage II
67.2% (61.1% 72.6%) 38.2% (31.8% 44.5%)
48.5% (42.4% 54.3%) 28.9% (23.3% 34.7%)
76
24
70
52
1.9 (1 - 2.4)
1.2 (0.8 - 2.2)
0.9 (0.7 - 1.3)
0.5 (0.3 - 0.9)
61.5% (49.2% 71.6%) 47.5% (35.4% 58.8%)
58.3% (36.4% 75%) 33.3% (15.9% 51.9%) Stage I + II
41.9% (29.3% 54.1%) 21% (11.6% 32.2%)
29.9% (18% 42.8%) 5.1% (1% - 14.7%)
594
55
346
343
3.8 (3.3 - 4.5)
1.6 (1.1 - 2.9)
1.6 (1.3 - 1.8)
0.9 (0.8 - 1.1)
79.6% (76% 82.7%) 68.5% (64.4% 72.3%)
68.1% (53.8% 78.8%) 40.5% (26.6% 54%)
62.4% (56.8% 67.5%) 34.8% (29.3% 40.4%)
45.6% (40.1% 50.9%) 25% (20.1% 30.1%)
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4.4 (3.7- 5)
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Median (95% CI) (years) Survival 1 yr (95% CI) Survival 2 yrs (95% CI)
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N
276
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2-yr OS (95% CI)
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Median (95% CI) (years) 1-yr OS (95% CI)
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Table 3: Multivariate analysis of factors affecting outcomes in octogenarians and older patients
Stage
Histology
Year of diagnosis
1.20 1 1.050 0.698 0.772 1 3.26 2.20 1.34
0.73, 1.29 0.72, 1.21
0.84 0.62
1.16, 1.52
<0.0001
1.44, 2.02
<0.0001
1.25, 1.76
<0.0001
1.02, 1.42
0.0291
0.83, 1.33 0.55, 0.88 0.62, 0.97
0.68 0.0024 0.02
2.70, 3.92 1.85, 2.63 0.95, 1.90
<0.0001 <0.0001 0.09
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Treatment
1.48
P-value 0.0043
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Gender
White AA/Black Other Female Male I II Adenocarcinoma Squamous cell carcinoma Other 1988-1992 1993-1997 1998-2002 2003-2007 Surgery only None RT Surgery/RT
95% CI 1.01, 1.05
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Race
HR 1.03 1 0.97 0.94 1 1.33 1 1.70 1
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Median age (years)
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Table 4: Multivariate analysis of factors affecting outcomes in octogenarians following surgery
Stage Histology
0.42, 1.21 0.68, 1.7
0.21 0.75
1.07, 1.65
0.01
1.71, 2.87
<0.0001
1.07, 1.74 0.98, 1.74 0.83, 1.68 0.67, 1.35 0.61, 1.27
0.01 0.07 0.36 0.78 0.50
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Year of diagnosis
P-value 0.0005
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Gender
White AA/Black Other Female Male I II Adeno Squamous Other 1988-1992 1993-1997 1998-2002 2003-2007
95% CI 1.03, 1.12
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Race
HR 1.08 1 0.71 1.01 1 1.33 1 2.21 1 1.36 1.31 1 1.178 0.951 0.879
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Median age (years)
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Figure Legends Figure 1: Survival outcome for stage I patients
Figure 2: Survival outcome for stage II patients
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The median survival (95% CI) (years) for the patients treated with the different modalities is: Surgery only - 4.4 (3.7- 5), Surgery + RT - 1.9 (1.3 - 4.3), RT only - 1.8 (1.5 - 1.9), No treatment - 1 (0.8 - 1.2)
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The median survival (95% CI) (years) for the patients treated with the different modalities is: Surgery only - 1.9 (1 - 2.4), Surgery + RT - 1.2 (0.8 - 2.2), RT only - 0.9 (0.7 - 1.3), No treatment - 0.5 (0.3 - 0.9)
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