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Long-Term Survival of Patients with Metastatic Non-Small-Cell Lung Cancer over Five Decades

Long-Term Survival of Patients with Metastatic Non-Small-Cell Lung Cancer over Five Decades Hindawi Journal of Oncology Volume 2021, Article ID 7836264, 10 pages https://doi.org/10.1155/2021/7836264 Research Article Long-Term Survival of Patients with Metastatic Non-Small-Cell Lung Cancer over Five Decades 1,2 1,2 3 3 4 1,2 Jair Bar , Damien Urban , Uri Amit, Sarit Appel , Amir Onn, Ofer Margalit , 1 1 2,3,5 Tamar Beller, Teodor Kuznetsov, and Yaacov Lawrence Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 5262000, Israel Affiliated with Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel Department of Radiation Oncology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 5262000, Israel Pulmonology Institute, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 5262000, Israel Department of Radiation Oncology, Sidney Kimmel Medical College at /omas Jefferson University, Philadelphia, PA, USA Correspondence should be addressed to Jair Bar; yair.bar@sheba.health.gov.il Received 14 July 2020; Revised 5 December 2020; Accepted 14 December 2020; Published 13 January 2021 Academic Editor: Xiaosheng Wang Copyright©2021JairBaretal.'isisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. Novel therapeutics and supportive care improved outcomes for metastatic non-small-cell lung cancer (mNSCLC) patients. Major advances over the past five decades include the introduction of combination chemotherapy, small molecules targeting mutant proteins, especially EGFR, and more recently immunotherapy. We aim to document real-world long-term survival over the past five decades. Methods. Survival statistics were extracted from the Survival, Epidemiology, and End Results (SEER) database for mNSCLC patients during 1973–2015. Two- and five-year survival (2yS and 5yS) were analyzed using Kaplan–Meier and proportional hazard models. Results. 'e study population consisted of 280,655mNSCLC patients diagnosed during 1973–2015. Longer survival was seen in younger, female, married, Asian/Pacific Islander race, adenocarcinoma, lower grade, more recent diagnosis, higher income, and chemotherapy-treated patients. 2yS increased during the study period from 2.6% to 12.9%, and 5yS increased from 0.7% to 3.2%. 2yS of patients<50 years of age rose from 2.1% to 22.8%, and their 5yS rose from 0.7% to 6.2%. 2yS of adenocarcinoma patients improved from 2.7% to 16.2%, and their improved 5yS from 1.1% to 3.9%. Conclusions. Between 1973 and 2015, there was a dramatic improvement in long-term survival, with an approximately five-fold increase in both 2yS and 5yS. Nonetheless, absolute numbers of long-term survivors remained low, with less than 4% living 5 years. 'is provides a baseline to compare long-term outcomes seen in the current generation of clinical trials. in supportive care [7], more recently targeted agents [8], and 1. Introduction immunotherapy [9]. Modern treatments have achieved Lungcancer is thenumber one cause of cancer-related death long-term survival, for instance, EGFR-mutant metastatic worldwide, inflicting about 1.6 million deaths annually [1]. lungadenocarcinomatreatedwitherlotiniborgefitinibhasa In 2016, 158,080 lung cancer patients died in the USA alone 14.6% five-year survival, and immunotherapy has achieved [2].Lung cancer patients are diagnosed as metastatic disease 13.4% five-year survival amongst patients with mixed levels in 40–50% of the cases [3, 4], with a median survival of less of programmed death ligand-1 (PD-L1) expression [10]. than nine months [3, 5].'e most common type of lung Remarkably, metastatic anaplastic lymphoma kinase- cancer is non-small-cell lung cancer (NSCLC), comprising (ALK-) positive NSCLC patients were reported to have a 85–89% of lung cancers. Significant advances in the care of median overall survival (mOS) of around4–5 years [11]. 'e metastatic NSCLC (mNSCLC) patients over the recent European Society of Medical Oncology (ESMO) Magnitude decades include the advent of palliative chemotherapy [5], of Clinical Benefit Scale suggests a treatment that increases histology-directed chemotherapy agents [6], improvements the two-year survival of patients who should receive 2 Journal of Oncology maximal support from the Oncologist community [12]. Inclusion criteria were mNSCLC diagnosed between However, long-term survival of mNSCLC is rarely reported 1973and2015.Primarylungcancerwasidentifiedaccording in studies and is not the focus of most retrospective database to the ICD-0-3 codes: C34.0 (main bronchus), C34.1 (upper analyses. lobe, lung), C34.2 (right middle lobe, lung), C34.3 (lower 'e critical evaluation of reports of long-term survival lobe,lung),C34.8(overlappinglesionofthelung),andC34.9 rates of patients with novel therapies requires valid com- (lung, NOS). Identified cases were divided into histology parators; real-world data collected prior to the immuno- groups based on the World Health Organization classifi- therapy era can serve this purpose. 'e Surveillance, cation [25]. Exclusion criteria were unknown stage, non- Epidemiology, and End Results (SEER) registry has been metastatic disease, sarcomas, carcinoid histology, unknown collecting data on cancer across the United States since histology, nonspecified malignant histology, rare or un- 1973.Overtime,theareacoveredhassubstantiallyincreased, specific histologies (WHO ICD-O-3 morphological codes presently including 28% of the U.S. population. 'e pop- [26] 8000, 8001, 8002, 8003, 8004, 8011, 8022, 8030, 8031, ulation covered by the SEER registry is comparable to the 8032, 8033, 8035, 8245, 8490, 8982, 8982, and 9133), or those general U.S. population with regard to measures of income diagnosed only at autopsy. Data extracted included patient and education, but has a higher proportion of foreign-born demographics, tumor grade, primary site, treatment cate- persons compared to the general U.S. population [13].Some gory, year of diagnosis, and survival until death or last previous reports of lung cancer in the SEER database focus follow-up as of December 31, 2015. Treatments are reported on incidence trends [14, 15]. A more recent publication intheSEERdatabaseas‘chemotherapy’,‘radiotherapy,’both reports also on survival, however in an aggregate manner, of these, or none; of note, the SEER database does not including all types of lung cancer (small cell and NSCLC), as differentiate between ‘unknown’ and ‘did not receive’ for well as all stages [16]. Other reports focused on survival and these modalities. Use of oral drugs such as tyrosine kinase treatment costs of squamous cell NSCLC [17] or older inhibitors is not registered in the SEER database. Social NSCLC patients [18]. A mathematical model predicting status was estimated by the median income at 2010 of the survival was suggested, including all stages of lung cancer, county of each patient. Patients’ missing data for a covariate wereincludedinthestudy,asidefromanalysesthatincluded andwaslimitedtopatientsdiagnosedin1998–2001[19].'e impact of tumor size on the outcome of early stage cancer that particular covariate. was analyzed in another report [20]. 'e influence of For the purposes of descriptive (but not survival) treatments on short-term (one year) survival [21] or on analysis, continuous variables (e.g., age, year of diagnosis, median survival [18] of mNSCLC was reported. Other re- and regional income) were converted into categorical var- ports focus on the factors impacting chosen treatments [22]. iables. Statistical analyses were performed using the Stata Another study of the SEER database queried the prognostic statistical package, version IC 11.1 (Stata, College Station, role of race on lung cancer survival [23], and another ex- TX). Chi-square tests were used to assess associations be- amined age [24], both including all stages of disease. tween categorical variables. 'e primary endpoint was Unlike previous studies, we aimed to focus on advanced survival,definedfromthetimeofinitialdiagnosistothedate NSCLC, the largest group of lung cancer patients, where of death, and was calculated using the Kaplan–Meier dramatic changes have occurred recently regarding the method. mOS was calculated for each year separately, or for standard of care systemic therapy. Accordingly, we wanted periods, as relevant for the presented analyses. Landmark to describe the changes in the relevant prognostic param- analyses were conducted regarding two-year survival (2yS) eters and outcome along the 40 years leading to the current and five-year survival (5yS). Since the current SEER data are era. For this goal, we utilized the SEER database to inves- updated till 2015, the most recent 5yS data were from pa- tigate long-term survival of mNSCLC prior to the immu- tients diagnosed during 2010. To ensure that those who did notherapy era. Trends over time and the impact of potential not survive a full month after diagnosis were included in the prognostic factors, including pathologic grade and subtypes, analysis, patients coded in the SEER data set as having a socioeconomic and social parameters, and treatments ad- survival time of zero were assigned a survival time of half a ministered, were studied in a comprehensive manner. We month. 'e effects of demographic, pathologic, and treat- report of one of the largest cohorts of lung cancer patients, ment variables on survival were tested with a Cox univariate focusing on the less well-documented long-term survival. analysis. Multivariate analysis was performed with a Cox 'e data presented herein can serve as a basis of comparison proportional hazard model. All p values were 2 sided, and a when evaluating long-term survivor rates of mNSCLC pa- p<0.05 was considered statistically significant. tients treated with immunotherapy and other novel agents. 3. Results 2. Materials and Methods 3.1. Patient Characteristics. A consort diagram detailing the 'e study utilized data from the 18 registries that comprise selected population is presented in Supplementary Figure 1. the SEER database (Atlanta, Connecticut, Detroit, Hawaii, A total of 280,655 subjects with mNSCLC were included in Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget the analysis; the median age was 67 years, and 58% were Sound, and Utah Alaska, San Jose-Monterey, Los Angeles, male. Demographic characteristics changed significantly Rural Georgia, Greater California, Kentucky, Louisiana, from 1973 to 2015 (summarized by decades in Supple- New Jersey, and Greater Georgia). mentary Table 1): the percentage of females increased from Journal of Oncology 3 15 Race was a significant prognostic factor, with black patients demonstrating a better 2yS than white patients and Asian or Pacific Islanders showing better 2yS and 5yS compared to white and black patients (Tables 1 and 2). Asian/Pacific Islanders had the clearest advantage compared towhites.'enumbersofAmericanIndianorAlaskaNative patients were small in earlier periods, resulting in highly unstable survival rates when comparing different years. 'erefore, only data from 2000 onwards are presented for this group of patients (Supplementary Figure 4, left lower panel).Over time, improvement in outcome is seen amongst all ethnic groups in 2yS. However, only for the Asian/Pacific 1970 1980 1990 2000 2010 Islanders, the 5yS gets to 5% (5.2% for the 2010 cohort, 95% Year of diagnosis CI 3.9–6.8). 'e group of ‘unknown/other’ race demon- strated better outcome but will not be discussed further due 2 years to the small number of patients. 5 years Figure 1: Changes in overall survival of metastatic lung cancer patients, 1973–2015. Trends in proportion of patients surviving 2 3.4. Pathologic Factors. We noted an increase in adeno- and 5 years, as a function of year of diagnosis. Both two- and five- carcinomas (from 29% in 1973 to 66% in 2015, p<0.001) year overall survival have improved over time (both p<0.001, and a decrease in the proportion with squamous cell lung extended Wilcoxon rank-sum test). cancers (from 27.2% to 19.8%, p<0.001). 'ere was no consistent trend of change regarding the proportion of patients with non-other specified (NOS) NSCLC or with 25%in1973to46%in2015,medianageincreasedfrom62to SCLC. Regarding outcome, the improvement in 2yS is the 68years, proportion of white subjects decreased (from about most noticeable in the adenocarcinoma subgroup of pa- 86%to78%),andproportionofmarrieddecreasedfrom73% tients, from 1995 and onward (Figure 3). However, the 5yS to 51% (all statistically significant; supplementary Table 1). remains below 5% for all histologic groups. 'e median income in 2010 at the county of residence of Aiming to identify subgroups with better outcome in an each patient decreased throughout the study period, prob- exploratory manner, we combined some of the favorable ably reflecting the addition of counties with a lower median histologic and demographic factors. Females younger than income to the SEER database. 50 years with adenocarcinoma diagnosed from 2000 on- wards had a 5yS of 6.8% (95% CI 6.0–7.8; number at risk at five years: 172). 3.2. Changes in Overall Survival. 'e mOS for the entire Pathological-grade data were missing for 58% of the cohort (N �280,655) was 4 months (survival data in the study cohort (these patients were, nonetheless, included in SEER database are rounded to full months). Over time, the theanalysisof other covariates).Amongthe121,583 patients mOS has improved from two months in 1973 to five months with grade data, a significant impact of this factor can be in 2015. Regarding long-term survival, a clear rise in 2yS is demonstrated, with 5yS of 6.3% for the well-differentiated noted, increasing from 2.6% in 1973 to 12.9% in 2013 (latest tumors subgroup considering the entire study cohort (i.e., year of which 2yS data can be calculated; Figure 1 and years of diagnosis: 1973 till 2010; Table 2). In patients with Tables 1 and 2), occurring mostly after the mid-1990s. A well-differentiated tumors, the 2yS reached 30.5% and 5yS more modest increase is seen in the 5yS, from 0.7% in 1973 reached 10.6% at the end of the analyzed period (95% CI to 3.2% in 2010 (latest year of which 5yS data can be cal- 7.4–14.4). culated), also seen mostly after the mid-1990s. 3.5. /e Role of Treatment Modalities. Dataabout treatments 3.3. Demographic Factors’ Impact on Survival. A clear sur- entered in the SEER database include general chemo- vival advantage was seen in favor of the younger patients therapy and radiotherapy categories. 'e proportion of (Tables 1 and 2). For instance, amongst patients of 49years patients listed as receiving chemotherapy increased from or below, the 2yS has increased from 2.1% to 22.8% (Fig- 28% in 1973 to 52% in 2015 (Supplementary Table 1). As ure 2) and the 5yS has increased from 0.7% to 6.2%. Pro- can be seen in Figure 4, the improvement in 2yS is sig- portionally similar rises can be seen in the older age groups nificant in patients that received either chemotherapy or and are significant for the 2yS; however, the numerical combined chemotherapy and radiotherapy. 5yS also im- improvements in the 5yS are minimal. Regarding sex, im- proved, but at best reaches 4.6% (95% CI 4.1–5.1).'e provements in both 2yS and 5yS have been more profound groups that received only radiotherapy had similar low amongst women (Supplementary Figure 2). Married people outcomes as those receiving no therapy. We were unable to haveabettersurvivalthanunmarried,andthedifferenceand demonstrate that any particular histologic subtype espe- the improvement with time are seen mostly in the 2yS cially benefited from chemotherapy. (Supplementary Figure 3). Percent surviving (%) 4 Journal of Oncology Table1:Univariateandmultivariateanalysisofvariablesassociatedwithoverallsurvivalinmetastaticlungcancerpatients,1973–2015,Cox model.'emultivariateanalysisincorporatedfollowingvariables:age,sex,race,maritalstatus,histology,grade,yearofdiagnosis,treatment modality (of note regarding treatment, for each modality the database doses not differentiate between ‘treatment not given’ and ‘unknown whethergiven’),andincome(relatingtocountymedianincome,2010,in10,000$).Patientswithmissingdataforanyoneofthesecovariates were excluded from the multivariate analysis. Univariate analysis Multivariate analysis Variable HR 95% C.I. p value HR 95% C.I. p value Age 1.013 (1.013, 1.013) <0.001 1.007 (1.006, 1.008) <0.001 Sex (female vs. male) 0.852 (0.839, 0.852) <0.001 0.840 (0.825, 0.849) <0.001 Race White 1.000 (comparator group) Black 0.989 (0.978, 1.001) 0.063 0.979 (0.960, 0.999) 0.045 Am. Indian/Alaska 1.011 (0.952, 1.074) NS (0.72) 1.143 (0.986, 1.325) 0.076 Asian/Pacific Islander 0.753 (0.742, 0.765) <0.001 0.832 (0.808, 0.856) <0.001 Unknown/other 0.602 (0.524, 0.693) <0.001 0.638 (0.475, 0.858) 0.003 Married 0.880 (0.873, 0.887) <0.001 0.906 (0.893, 0.919) <0.001 Histology Lung carcinoma NOS 1.000 (comparator group) Adenocarcinoma 0.736 (0.729, 0.742) <0.001 0.860 (0.844, 0.875) <0.001 Squamous cell ca. 0.866 (0.856, 0.875) <0.001 0.910 (0.892, 0.929) <0.001 Small cell carcinoma 0.858 (0.849, 0.866) <0.001 1.029 (1.008, 1.05) 0.007 Grade Well diff. 1.000 (comparator group) Moderately diff. 1.173 (1.138, 1.209) <0.001 1.190 (1.149, 1.233) <0.001 Poorly diff. 1.512 (1.470, 1.554) <0.001 1.484 (1.436, 1.535) <0.001 Undifferentiated 1.781 (1.725, 1.840) <0.001 1.484 (1.425, 1.545) <0.001 Year of diagnosis 1973–9 1.000 (comparator group) 1980–9 0.948 (0.928, 0.968) <0.001 0.952 (0.918, 0.987) 0.008 1990–9 0.906 (0.889, 0.924) <0.001 0.935 (0.903, 0.969) <0.001 2000–9 0.773 (0.759, 0.787) <0.001 0.821 (0.793, 0.850) <0.001 2010–5 0.663 (0.651, 0.676) <0.001 0.739 (0.712, 0.766) <0.001 Treatment No treatment 1.00 (comparator group) Chemotherapy only 0.423 (0.418, 0.428) <0.001 0.488 (0.478, 0.498) <0.001 Radiotherapy only 0.766 (0.759, 0.774) <0.001 0.772 (0.758, 0.787) <0.001 Chemo+radio 0.445 (0.440, 0.449) <0.001 0.517 (0.507, 0.527) <0.001 Income 0.977 (0.974, 0.980) <0.001 0.979 (0.974, 0.985) <0.001 HR: hazard ratio. CI: confidence interval. Am: American. NOS: non-other specified. Ca: carcinoma. Diff: differentiated. Chemo: chemotherapy. Radio: radiotherapy. Missing values: grade: 207,149 patients. Marital status: 12,727 patients. Treatment: 10,881 patients. Age: 3 patients. Income: 73,156 patients. 2010 yearly median county income (per 10,000 dollars). stage IVB and 5yS of 10% of stage IVA and 0% for stage IVB 4. Discussion th (clinical stage according the 8 staging edition) [27]. 'e We have described the 2yS and 5yS of lung cancer patients distinction between stage IVA and IVB is not available over a period of 43 years, with improvement seen mostly in within the SEER database. However, our general conclusion the later fifteen years. Better outcomes are most pronounced that even among mNSCLC patients, specific subgroups have among younger, married patients (Figure 2 and Supple- demonstrated nonnegligible long-term survival during the mentary Figure 3), in those bearing adenocarcinoma his- preimmunotherapy period is supported by the IASCLC tology (Figure 3) and lower-grade tumors. Better outcome is study. Recently, Howlader et al. linked death certificate data seen in patients that have received chemotherapy (Figure 4). to the SEER database in order to study changes in NSCLC Race impacted survival, with a generally better outcome for incidence and mortality over the period 2001–2016, and nonwhite patients. 'e latest years analyzed here were 2013 their study was not confined to metastatic disease. Similar to regarding 2yS and 2010 regarding 5yS, before immuno- ourfindings,theydemonstratedmarkedimprovementsin2- therapy entered the arena of lung cancer treatments. An- year mortality amongst both men and women [28]. other large study from the preimmunotherapy period, of the 'e subgroup that stands out with a long 5yS is the International Association for the Study of Lung Cancer younger patients, with age being a significant prognostic (IASLC), summarized world-wide data of more than 90,000 factor, as reported previously [29, 30]. Among the younger lung cancer patients diagnosed between 1999 and 2010. In patients, the improvement in outcome over the years is the that report, 2yS of 23% is reported for stage IVA and 6% for most striking. Multiple factors probably contribute to this Journal of Oncology 5 Table 2: Percentage survival at two and five years by prognostic earlier[31].'egroupof‘AsianorPacificIslanders’hasbeen factors. reported to have a relatively low incidence of lung cancer [32], comprising 6.7% of all lung cancer patients in our 2yOS 5yOS cohort. 'is is a complex group consisting, among others, of % 95% CI % 95% CI patients originated from eastern Asia, possibly including a Entire cohort 8.0 (7.9–8.2) 2.1 (2.0–2.1) higher proportion of EGFR mutation-positive patients. Age However, as discussed for the younger patients and as seen <67 9.5 (9.3–9.6) 2.7 (2.6–2.7) for the entire cohort, the improvement can be seen prior to ≧67 6.6 (6.5–6.7) 1.5 (1.5–1.6) the emergence of EGFR inhibitors or other targeted agents. Sex Our findings resonate with other observations suggesting Male 6.3 (6.1–6.4) 1.6 (1.5–1.7) better outcome of Asian lung cancer patients compared to Female 10.5 (10.3–10.7) 2.8 (2.7–2.9) patients from the Western Hemisphere [33]. Race A recurrent observation is the prognostic value of so- White 7.5 (7.4–7.7) 2 (1.9–2.0) cioeconomic status [34, 35] and, more interestingly, of Black 7.2 (6.9–7.5) 1.8 (1.7–2.0) marital status. Marital status has been found to predict lung American Indian/Alaska 8.6 (7.0–10.4) 1.5 (0.8–2.6) cancer survival for NSCLC [35], as well as SCLC [36], al- native though not in all reports [29]. Being married correlates with Asian/Pacific Islander 15.1 (14.5–15.6) 4.1 (3.7–4.4) better survival for cancer patients in general [37], with di- Unk/oth 23.1 (17.6–29.1) 15.1 (9.8–21.5) verse possible explanations, including better social support Marital status systems for married patients and better socioeconomic Single 7.0 (6.9–7.2) 1.8 (1.7–1.9) Married 8.7 (8.6–8.9) 2.3 (2.2–2.4) status, as well as selection bias; individuals who marry are more likely to be healthier than those that do not marry Histology Adenocarcinoma 10.8 (10.6–11) 2.7 (2.6–2.8) [38].'e impact of being married, as well as the significant Lung carcinoma NOS 5.1 (5.0–5.3) 1.3 (1.3–1.4) impact of the patients’ social status, stresses the importance Squamous cell carcinoma 6.2 (6.0–6.4) 1.8 (1.7–1.9) of providing comprehensive support to cancer patients, Small-cell carcinoma 4.4 (4.3–4.6) 1.3 (1.2–1.4) above and beyond the provision of the medical care. Grade A significant and strong prognostic factor in our cohort Well differentiated 18.6 (17.6–19.7) 6.3 (5.6–7.0) is the pathologic grade of the tumor, as reported previously Moderately differentiated 13.2 (12.8–13.7) 3.8 (3.5–4.1) in smaller data sets [30, 39, 40]. Tumor grade was available Poorly differentiated 7.1 (6.9–7.3) 2.0 (1.9–2.1) only for 43% of the study cohort, thus reducing the validity Undifferentiated 4.5 (4.1–4.8) 1.3 (1.1–1.5) of this observation. Lack of clear definitions for pathologic Year of diagnosis grading of lung cancer impedes the inclusion of this im- 1973–79 3.1 (2.9–3.4) 0.7 (0.6–0.9) portant factor in a standardized manner in pathologic re- 1980–89 3.5 (3.3–3.7) 0.9 (0.8–1.0) ports and in the staging system. It should be noted that only 1990–99 4.5 (4.3–4.7) 1.1 (1.0–1.2) 5% of the patients in our cohort had well-differentiated 2000–09 8.4 (8.3–8.6) 2.1 (2.0–2.2) tumors, and even moderately differentiated tumors con- 2010–15 12.6 (12.3–12.9) 3.7 (3.5–3.9) stituted only 20.6% of the cohort. However, the better Treatment differentiated tumors have a markedly better prognosis. We, None 4.5 (4.3–4.6) 1.6 (1.5–1.7) therefore, suggest that grade should be clearly identified in Chemotherapy only 14.9 (14.6–15.2) 3.3 (3.1–3.5) routine pathologic assessments of lung cancer specimens, as Radiotherapy (RT) only 4.0 (3.9–4.2) 1.0 (1.0–1.1) Chemotherapy+RT 11.7 (11.5–12) 2.9 (2.8–3.1) well as in clinical trials. 'e reasons for the OS improvement seen along the Income <median 7.2 (7.0–7.4) 1.9 (1.8–2.0) years are most likely multifactorial. Conceivably, some of ≧median 8.5 (8.4–8.7) 2.2 (2.1–2.3) the improvement are the result of improved systemic 2yOS: two-year overall survival. 5yOS: five-year overall survival. CI: con- treatments. 'is is supported by the correlation between fidence interval. NOS: non-other specified. Ca: carcinoma. Annual county chemotherapytreatments andimprovedoutcomealongthe median in 2010 of $52,595. years (Figure 4). Clearly a selection bias exists in this analysis, as chemotherapy administration is usually limited to patients with relatively good performance status, a phenomenon, including better performance status, less recognized prognostic factor by itself [2]. Regarding NSCLC, the use of chemotherapy vs. supportive care alone comorbidities, anda higher rate of targetablemutations. 'e improvement in the younger patients is seen starting from gradually gained support during the 1990s [15], which is the mid-90s, similar to the rest of our cohort, prior to the also the period when the survival curves start to rise. addition of the targeted agents to the treatment options. Tailoring of chemotherapy drugs to tumor histology [6] Race is well known to correlate with cancer incidence and addition of anti-VEGF for nonsquamous NSCLC [41] and outcome [19]. Regarding 5yS, black patients had a are the major changes in chemotherapy choices that en- similar outcome to white patients in our data, as reported in tered practice during 2000–2010; each of these had been demonstrated to improve median survival of clinical trial other publications [29]. A markedly better outcome was found in our study for Asian or Pacific Islanders, as reported patients. 6 Journal of Oncology 1970 1980 1990 2000 2010 1970 1980 1990 2000 2010 Year of diagnosis Year of diagnosis Age ≤ 49 years Age 70−84 years Age ≤ 49 years Age 70–84 years Age 50−69 years Age ≥ 85 years Age ≥ 85 years Age 50−69 years (a) (b) Figure2:(a)Changesintheproportionofmetastaticlungcancerpatientssurvivingtwoyearsasafunctionofageandyearofdiagnosis.'e symbolsrepresentdataforaspecificyear,andthelinesindicateatrendline.(b)Changesintheproportionofmetastaticlungcancerpatients surviving five years as a function of age and year of diagnosis. 'e symbols represent data for a specific year, and the lines indicate a trend line. Adenocarcinoma Squamous cell carcinoma Lung carcinoma NOS 1970 1980 1990 2000 2010 1970 1980 1990 2000 2010 1970 1980 1990 2000 2010 Year of diagnosis 2 year OS 5 year OS Figure 3: Trends in two-year and five-year survival 1973–2015 in different histologic subgroups. Yearly data are presented for each group. 'e next breakthrough in the care of NSCLC was [45, 46]. However, the EGFR mutation testing and ap- targeted agents, initially the drugs targeting the EGFR propriate therapy entered practice only in 2009 [4], thus, receptor. Since the entrance of targeted agents, survival has may be, affecting our latest 2yS data and minimally the extended for patients harboring the relevant genetic ab- most recent 5yS data. ALK rearrangement occurs in only errations. Young, female, and adenocarcinoma are the 3–5% of NSCLC [47] and, hence, unlikely to impact the groups where most of the improvement was seen in our survival results of our study cohort. Importantly, the cohort, and these are also the characteristics of patients identification of tumors bearing ALK translocations as harboring most of the driver mutations [42, 43]. 'e candidatesforALKinhibitortherapyoccurredin2010[48], predictive power of EGFR mutations (representing 17% of and the FDA approval of crizotinib for this indication the adenocarcinoma patients [44]) was discovered in 2004 occurred in 2011. Percent surviving 2 years (%) Percent surviving (%) Percent surviving 5 years (%) Journal of Oncology 7 2-year overall survival 5-year overall survival 1970 1980 1990 2000 2010 1970 1980 1990 2000 2010 Year of diagnosis No treatment Chemotherapy only Radiation only Chemotherapy and radiation Figure 4: Proportion of metastatic lung cancer patients surviving two or five years according to treatment modality. Yearly data are presented for each subgroup, separated by the designated treatment modalities. An additional potential explanation for improved mOS regarding systemic treatments administered. In addition, along the years is an overall more aggressive, less nihilistic only a surrogate for socioeconomic status was captured, approach to metastatic lung cancer, with a higher rate of probably misclassifying many patients regarding this im- portant prognostic parameter. Methods of staging have patients receiving chemotherapy. A special example of ag- gressive therapy is the approach to oligometastatic disease changed along the years as noted earlier, and these data are [49, 50] with the use of locally ablative strategies, whether not captured in our data. As for any retrospective study, we surgical,radiosurgical,or other.However,it shouldbenoted cannot assign causative roles to the prognostic factors we that, when looking at the entire population, no correlation have identified. was found in our study between the use of radiotherapy and improved survival. Another relevant and related improve- 5. Conclusions ment that occurred along the years is the development of We have demonstrated substantial improvements over the supportive care, recently demonstrated to prolong survival last decades in the long-term survival of patients with of lung cancer patients [7, 51].As a result of improved metastatic lung cancer, mostly since the mid-90s. Most supportive care, more aggressive treatments can be ad- significant improvements were seen in younger, married ministered to less robust patients, potentially improving patients, females, adenocarcinoma, low-grade tumors, and survival of some of these patients. those receiving chemotherapy. While 2yS has bypassed 10% 'e increase of mOS might be related also to Will in recent years, 5yS is still in the range of 3–4%, stressing the Roger’sphenomenon,i.e., theincreasedlikelihoodwith time need for further progress. Importantly, even prior to the era to correctly classify minimally metastatic patients, whereas of immunotherapy and mostly before the emergence of in the past such tumors may have been understaged. Such targeted agents, subgroupsm NSCLC patients had long-term improved staging would include metastatic patients with a survival. 'e characteristics of these patients point to im- low burden of disease within the metastatic patient cohort, portant prognostic factors, details of which should be col- thus improving the median survival of the cohort. 'e in- lected and reported in current clinical trials. creased use of CT-PET, mediastinoscopy, and brain MRI for staging of patients [52] is likely to have an impact on the Data Availability overall results of this study. 'e strengths of our study include the large size of the 'e raw data are freely available from the website of the database and the inclusion of patients excluded from clinical NCI’s Surveillance, Epidemiology, and End Results (SEER) trials due to comorbidities and/or poor performance status. Program https://seer.cancer.gov/mortality/. Furthermore, this is a well-validated and reliable data set with long-term follow-up [13, 53]. 'e shortcomings of our Ethical Approval study include its retrospective nature, lack of basic clinical data such as performance status and weight loss, lack of data 'is study was exempt from ethics approval since it is based regarding molecular subtypes (especially EGFR mutation upon a publicly available anonymized database. A ‘Data-Use status and other driver mutations), and lack of details Agreement’ with SEER was signed. Percent surviving (%) 8 Journal of Oncology New England Journal of Medicine, vol.363,no.8,pp.733–742, Conflicts of Interest [8] W. Pao and N. Girard, “New driver mutations in non-small- JB reports grants and personal fees from Merck Sharp and cell lung cancer,” /e Lancet Oncology, vol. 12, no. 2, Dohme (MSD), Abbvie, AstraZeneca, Pfizer, Takeda, and pp. 175–180, 2011. Roche, grants from Bristol Myers Squibb (BMS), and per- [9] P. Sharma, K. Wagner, J. D. Wolchok, and J. P. Allison, sonal fees from Boehringer Ingelheim (BI), VBL, Novartis, “Novel cancer immunotherapy agents with survival benefit: Bayer, and Lilly. AO is a consultant and member of the recent successes and next steps,” Nature Reviews Cancer, advisory board to Astra Zeneca, MSD, Roche, and Boeh- vol. 11, 2011. ringer Ingelheim. DU reports personal fees from Merck [10] S. Gettinger, L. Horn, D. Jackman et al., “Five-year follow-up Sharp and Dohme, Bristol Myers Squibb, Boehringer of nivolumab in previously treated advanced non-small-cell Ingelheim, Roche, Takeda, and AstraZeneca. 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Long-Term Survival of Patients with Metastatic Non-Small-Cell Lung Cancer over Five Decades

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Copyright © 2021 Jair Bar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Journal of Oncology Volume 2021, Article ID 7836264, 10 pages https://doi.org/10.1155/2021/7836264 Research Article Long-Term Survival of Patients with Metastatic Non-Small-Cell Lung Cancer over Five Decades 1,2 1,2 3 3 4 1,2 Jair Bar , Damien Urban , Uri Amit, Sarit Appel , Amir Onn, Ofer Margalit , 1 1 2,3,5 Tamar Beller, Teodor Kuznetsov, and Yaacov Lawrence Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 5262000, Israel Affiliated with Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel Department of Radiation Oncology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 5262000, Israel Pulmonology Institute, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 5262000, Israel Department of Radiation Oncology, Sidney Kimmel Medical College at /omas Jefferson University, Philadelphia, PA, USA Correspondence should be addressed to Jair Bar; yair.bar@sheba.health.gov.il Received 14 July 2020; Revised 5 December 2020; Accepted 14 December 2020; Published 13 January 2021 Academic Editor: Xiaosheng Wang Copyright©2021JairBaretal.'isisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. Novel therapeutics and supportive care improved outcomes for metastatic non-small-cell lung cancer (mNSCLC) patients. Major advances over the past five decades include the introduction of combination chemotherapy, small molecules targeting mutant proteins, especially EGFR, and more recently immunotherapy. We aim to document real-world long-term survival over the past five decades. Methods. Survival statistics were extracted from the Survival, Epidemiology, and End Results (SEER) database for mNSCLC patients during 1973–2015. Two- and five-year survival (2yS and 5yS) were analyzed using Kaplan–Meier and proportional hazard models. Results. 'e study population consisted of 280,655mNSCLC patients diagnosed during 1973–2015. Longer survival was seen in younger, female, married, Asian/Pacific Islander race, adenocarcinoma, lower grade, more recent diagnosis, higher income, and chemotherapy-treated patients. 2yS increased during the study period from 2.6% to 12.9%, and 5yS increased from 0.7% to 3.2%. 2yS of patients<50 years of age rose from 2.1% to 22.8%, and their 5yS rose from 0.7% to 6.2%. 2yS of adenocarcinoma patients improved from 2.7% to 16.2%, and their improved 5yS from 1.1% to 3.9%. Conclusions. Between 1973 and 2015, there was a dramatic improvement in long-term survival, with an approximately five-fold increase in both 2yS and 5yS. Nonetheless, absolute numbers of long-term survivors remained low, with less than 4% living 5 years. 'is provides a baseline to compare long-term outcomes seen in the current generation of clinical trials. in supportive care [7], more recently targeted agents [8], and 1. Introduction immunotherapy [9]. Modern treatments have achieved Lungcancer is thenumber one cause of cancer-related death long-term survival, for instance, EGFR-mutant metastatic worldwide, inflicting about 1.6 million deaths annually [1]. lungadenocarcinomatreatedwitherlotiniborgefitinibhasa In 2016, 158,080 lung cancer patients died in the USA alone 14.6% five-year survival, and immunotherapy has achieved [2].Lung cancer patients are diagnosed as metastatic disease 13.4% five-year survival amongst patients with mixed levels in 40–50% of the cases [3, 4], with a median survival of less of programmed death ligand-1 (PD-L1) expression [10]. than nine months [3, 5].'e most common type of lung Remarkably, metastatic anaplastic lymphoma kinase- cancer is non-small-cell lung cancer (NSCLC), comprising (ALK-) positive NSCLC patients were reported to have a 85–89% of lung cancers. Significant advances in the care of median overall survival (mOS) of around4–5 years [11]. 'e metastatic NSCLC (mNSCLC) patients over the recent European Society of Medical Oncology (ESMO) Magnitude decades include the advent of palliative chemotherapy [5], of Clinical Benefit Scale suggests a treatment that increases histology-directed chemotherapy agents [6], improvements the two-year survival of patients who should receive 2 Journal of Oncology maximal support from the Oncologist community [12]. Inclusion criteria were mNSCLC diagnosed between However, long-term survival of mNSCLC is rarely reported 1973and2015.Primarylungcancerwasidentifiedaccording in studies and is not the focus of most retrospective database to the ICD-0-3 codes: C34.0 (main bronchus), C34.1 (upper analyses. lobe, lung), C34.2 (right middle lobe, lung), C34.3 (lower 'e critical evaluation of reports of long-term survival lobe,lung),C34.8(overlappinglesionofthelung),andC34.9 rates of patients with novel therapies requires valid com- (lung, NOS). Identified cases were divided into histology parators; real-world data collected prior to the immuno- groups based on the World Health Organization classifi- therapy era can serve this purpose. 'e Surveillance, cation [25]. Exclusion criteria were unknown stage, non- Epidemiology, and End Results (SEER) registry has been metastatic disease, sarcomas, carcinoid histology, unknown collecting data on cancer across the United States since histology, nonspecified malignant histology, rare or un- 1973.Overtime,theareacoveredhassubstantiallyincreased, specific histologies (WHO ICD-O-3 morphological codes presently including 28% of the U.S. population. 'e pop- [26] 8000, 8001, 8002, 8003, 8004, 8011, 8022, 8030, 8031, ulation covered by the SEER registry is comparable to the 8032, 8033, 8035, 8245, 8490, 8982, 8982, and 9133), or those general U.S. population with regard to measures of income diagnosed only at autopsy. Data extracted included patient and education, but has a higher proportion of foreign-born demographics, tumor grade, primary site, treatment cate- persons compared to the general U.S. population [13].Some gory, year of diagnosis, and survival until death or last previous reports of lung cancer in the SEER database focus follow-up as of December 31, 2015. Treatments are reported on incidence trends [14, 15]. A more recent publication intheSEERdatabaseas‘chemotherapy’,‘radiotherapy,’both reports also on survival, however in an aggregate manner, of these, or none; of note, the SEER database does not including all types of lung cancer (small cell and NSCLC), as differentiate between ‘unknown’ and ‘did not receive’ for well as all stages [16]. Other reports focused on survival and these modalities. Use of oral drugs such as tyrosine kinase treatment costs of squamous cell NSCLC [17] or older inhibitors is not registered in the SEER database. Social NSCLC patients [18]. A mathematical model predicting status was estimated by the median income at 2010 of the survival was suggested, including all stages of lung cancer, county of each patient. Patients’ missing data for a covariate wereincludedinthestudy,asidefromanalysesthatincluded andwaslimitedtopatientsdiagnosedin1998–2001[19].'e impact of tumor size on the outcome of early stage cancer that particular covariate. was analyzed in another report [20]. 'e influence of For the purposes of descriptive (but not survival) treatments on short-term (one year) survival [21] or on analysis, continuous variables (e.g., age, year of diagnosis, median survival [18] of mNSCLC was reported. Other re- and regional income) were converted into categorical var- ports focus on the factors impacting chosen treatments [22]. iables. Statistical analyses were performed using the Stata Another study of the SEER database queried the prognostic statistical package, version IC 11.1 (Stata, College Station, role of race on lung cancer survival [23], and another ex- TX). Chi-square tests were used to assess associations be- amined age [24], both including all stages of disease. tween categorical variables. 'e primary endpoint was Unlike previous studies, we aimed to focus on advanced survival,definedfromthetimeofinitialdiagnosistothedate NSCLC, the largest group of lung cancer patients, where of death, and was calculated using the Kaplan–Meier dramatic changes have occurred recently regarding the method. mOS was calculated for each year separately, or for standard of care systemic therapy. Accordingly, we wanted periods, as relevant for the presented analyses. Landmark to describe the changes in the relevant prognostic param- analyses were conducted regarding two-year survival (2yS) eters and outcome along the 40 years leading to the current and five-year survival (5yS). Since the current SEER data are era. For this goal, we utilized the SEER database to inves- updated till 2015, the most recent 5yS data were from pa- tigate long-term survival of mNSCLC prior to the immu- tients diagnosed during 2010. To ensure that those who did notherapy era. Trends over time and the impact of potential not survive a full month after diagnosis were included in the prognostic factors, including pathologic grade and subtypes, analysis, patients coded in the SEER data set as having a socioeconomic and social parameters, and treatments ad- survival time of zero were assigned a survival time of half a ministered, were studied in a comprehensive manner. We month. 'e effects of demographic, pathologic, and treat- report of one of the largest cohorts of lung cancer patients, ment variables on survival were tested with a Cox univariate focusing on the less well-documented long-term survival. analysis. Multivariate analysis was performed with a Cox 'e data presented herein can serve as a basis of comparison proportional hazard model. All p values were 2 sided, and a when evaluating long-term survivor rates of mNSCLC pa- p<0.05 was considered statistically significant. tients treated with immunotherapy and other novel agents. 3. Results 2. Materials and Methods 3.1. Patient Characteristics. A consort diagram detailing the 'e study utilized data from the 18 registries that comprise selected population is presented in Supplementary Figure 1. the SEER database (Atlanta, Connecticut, Detroit, Hawaii, A total of 280,655 subjects with mNSCLC were included in Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget the analysis; the median age was 67 years, and 58% were Sound, and Utah Alaska, San Jose-Monterey, Los Angeles, male. Demographic characteristics changed significantly Rural Georgia, Greater California, Kentucky, Louisiana, from 1973 to 2015 (summarized by decades in Supple- New Jersey, and Greater Georgia). mentary Table 1): the percentage of females increased from Journal of Oncology 3 15 Race was a significant prognostic factor, with black patients demonstrating a better 2yS than white patients and Asian or Pacific Islanders showing better 2yS and 5yS compared to white and black patients (Tables 1 and 2). Asian/Pacific Islanders had the clearest advantage compared towhites.'enumbersofAmericanIndianorAlaskaNative patients were small in earlier periods, resulting in highly unstable survival rates when comparing different years. 'erefore, only data from 2000 onwards are presented for this group of patients (Supplementary Figure 4, left lower panel).Over time, improvement in outcome is seen amongst all ethnic groups in 2yS. However, only for the Asian/Pacific 1970 1980 1990 2000 2010 Islanders, the 5yS gets to 5% (5.2% for the 2010 cohort, 95% Year of diagnosis CI 3.9–6.8). 'e group of ‘unknown/other’ race demon- strated better outcome but will not be discussed further due 2 years to the small number of patients. 5 years Figure 1: Changes in overall survival of metastatic lung cancer patients, 1973–2015. Trends in proportion of patients surviving 2 3.4. Pathologic Factors. We noted an increase in adeno- and 5 years, as a function of year of diagnosis. Both two- and five- carcinomas (from 29% in 1973 to 66% in 2015, p<0.001) year overall survival have improved over time (both p<0.001, and a decrease in the proportion with squamous cell lung extended Wilcoxon rank-sum test). cancers (from 27.2% to 19.8%, p<0.001). 'ere was no consistent trend of change regarding the proportion of patients with non-other specified (NOS) NSCLC or with 25%in1973to46%in2015,medianageincreasedfrom62to SCLC. Regarding outcome, the improvement in 2yS is the 68years, proportion of white subjects decreased (from about most noticeable in the adenocarcinoma subgroup of pa- 86%to78%),andproportionofmarrieddecreasedfrom73% tients, from 1995 and onward (Figure 3). However, the 5yS to 51% (all statistically significant; supplementary Table 1). remains below 5% for all histologic groups. 'e median income in 2010 at the county of residence of Aiming to identify subgroups with better outcome in an each patient decreased throughout the study period, prob- exploratory manner, we combined some of the favorable ably reflecting the addition of counties with a lower median histologic and demographic factors. Females younger than income to the SEER database. 50 years with adenocarcinoma diagnosed from 2000 on- wards had a 5yS of 6.8% (95% CI 6.0–7.8; number at risk at five years: 172). 3.2. Changes in Overall Survival. 'e mOS for the entire Pathological-grade data were missing for 58% of the cohort (N �280,655) was 4 months (survival data in the study cohort (these patients were, nonetheless, included in SEER database are rounded to full months). Over time, the theanalysisof other covariates).Amongthe121,583 patients mOS has improved from two months in 1973 to five months with grade data, a significant impact of this factor can be in 2015. Regarding long-term survival, a clear rise in 2yS is demonstrated, with 5yS of 6.3% for the well-differentiated noted, increasing from 2.6% in 1973 to 12.9% in 2013 (latest tumors subgroup considering the entire study cohort (i.e., year of which 2yS data can be calculated; Figure 1 and years of diagnosis: 1973 till 2010; Table 2). In patients with Tables 1 and 2), occurring mostly after the mid-1990s. A well-differentiated tumors, the 2yS reached 30.5% and 5yS more modest increase is seen in the 5yS, from 0.7% in 1973 reached 10.6% at the end of the analyzed period (95% CI to 3.2% in 2010 (latest year of which 5yS data can be cal- 7.4–14.4). culated), also seen mostly after the mid-1990s. 3.5. /e Role of Treatment Modalities. Dataabout treatments 3.3. Demographic Factors’ Impact on Survival. A clear sur- entered in the SEER database include general chemo- vival advantage was seen in favor of the younger patients therapy and radiotherapy categories. 'e proportion of (Tables 1 and 2). For instance, amongst patients of 49years patients listed as receiving chemotherapy increased from or below, the 2yS has increased from 2.1% to 22.8% (Fig- 28% in 1973 to 52% in 2015 (Supplementary Table 1). As ure 2) and the 5yS has increased from 0.7% to 6.2%. Pro- can be seen in Figure 4, the improvement in 2yS is sig- portionally similar rises can be seen in the older age groups nificant in patients that received either chemotherapy or and are significant for the 2yS; however, the numerical combined chemotherapy and radiotherapy. 5yS also im- improvements in the 5yS are minimal. Regarding sex, im- proved, but at best reaches 4.6% (95% CI 4.1–5.1).'e provements in both 2yS and 5yS have been more profound groups that received only radiotherapy had similar low amongst women (Supplementary Figure 2). Married people outcomes as those receiving no therapy. We were unable to haveabettersurvivalthanunmarried,andthedifferenceand demonstrate that any particular histologic subtype espe- the improvement with time are seen mostly in the 2yS cially benefited from chemotherapy. (Supplementary Figure 3). Percent surviving (%) 4 Journal of Oncology Table1:Univariateandmultivariateanalysisofvariablesassociatedwithoverallsurvivalinmetastaticlungcancerpatients,1973–2015,Cox model.'emultivariateanalysisincorporatedfollowingvariables:age,sex,race,maritalstatus,histology,grade,yearofdiagnosis,treatment modality (of note regarding treatment, for each modality the database doses not differentiate between ‘treatment not given’ and ‘unknown whethergiven’),andincome(relatingtocountymedianincome,2010,in10,000$).Patientswithmissingdataforanyoneofthesecovariates were excluded from the multivariate analysis. Univariate analysis Multivariate analysis Variable HR 95% C.I. p value HR 95% C.I. p value Age 1.013 (1.013, 1.013) <0.001 1.007 (1.006, 1.008) <0.001 Sex (female vs. male) 0.852 (0.839, 0.852) <0.001 0.840 (0.825, 0.849) <0.001 Race White 1.000 (comparator group) Black 0.989 (0.978, 1.001) 0.063 0.979 (0.960, 0.999) 0.045 Am. Indian/Alaska 1.011 (0.952, 1.074) NS (0.72) 1.143 (0.986, 1.325) 0.076 Asian/Pacific Islander 0.753 (0.742, 0.765) <0.001 0.832 (0.808, 0.856) <0.001 Unknown/other 0.602 (0.524, 0.693) <0.001 0.638 (0.475, 0.858) 0.003 Married 0.880 (0.873, 0.887) <0.001 0.906 (0.893, 0.919) <0.001 Histology Lung carcinoma NOS 1.000 (comparator group) Adenocarcinoma 0.736 (0.729, 0.742) <0.001 0.860 (0.844, 0.875) <0.001 Squamous cell ca. 0.866 (0.856, 0.875) <0.001 0.910 (0.892, 0.929) <0.001 Small cell carcinoma 0.858 (0.849, 0.866) <0.001 1.029 (1.008, 1.05) 0.007 Grade Well diff. 1.000 (comparator group) Moderately diff. 1.173 (1.138, 1.209) <0.001 1.190 (1.149, 1.233) <0.001 Poorly diff. 1.512 (1.470, 1.554) <0.001 1.484 (1.436, 1.535) <0.001 Undifferentiated 1.781 (1.725, 1.840) <0.001 1.484 (1.425, 1.545) <0.001 Year of diagnosis 1973–9 1.000 (comparator group) 1980–9 0.948 (0.928, 0.968) <0.001 0.952 (0.918, 0.987) 0.008 1990–9 0.906 (0.889, 0.924) <0.001 0.935 (0.903, 0.969) <0.001 2000–9 0.773 (0.759, 0.787) <0.001 0.821 (0.793, 0.850) <0.001 2010–5 0.663 (0.651, 0.676) <0.001 0.739 (0.712, 0.766) <0.001 Treatment No treatment 1.00 (comparator group) Chemotherapy only 0.423 (0.418, 0.428) <0.001 0.488 (0.478, 0.498) <0.001 Radiotherapy only 0.766 (0.759, 0.774) <0.001 0.772 (0.758, 0.787) <0.001 Chemo+radio 0.445 (0.440, 0.449) <0.001 0.517 (0.507, 0.527) <0.001 Income 0.977 (0.974, 0.980) <0.001 0.979 (0.974, 0.985) <0.001 HR: hazard ratio. CI: confidence interval. Am: American. NOS: non-other specified. Ca: carcinoma. Diff: differentiated. Chemo: chemotherapy. Radio: radiotherapy. Missing values: grade: 207,149 patients. Marital status: 12,727 patients. Treatment: 10,881 patients. Age: 3 patients. Income: 73,156 patients. 2010 yearly median county income (per 10,000 dollars). stage IVB and 5yS of 10% of stage IVA and 0% for stage IVB 4. Discussion th (clinical stage according the 8 staging edition) [27]. 'e We have described the 2yS and 5yS of lung cancer patients distinction between stage IVA and IVB is not available over a period of 43 years, with improvement seen mostly in within the SEER database. However, our general conclusion the later fifteen years. Better outcomes are most pronounced that even among mNSCLC patients, specific subgroups have among younger, married patients (Figure 2 and Supple- demonstrated nonnegligible long-term survival during the mentary Figure 3), in those bearing adenocarcinoma his- preimmunotherapy period is supported by the IASCLC tology (Figure 3) and lower-grade tumors. Better outcome is study. Recently, Howlader et al. linked death certificate data seen in patients that have received chemotherapy (Figure 4). to the SEER database in order to study changes in NSCLC Race impacted survival, with a generally better outcome for incidence and mortality over the period 2001–2016, and nonwhite patients. 'e latest years analyzed here were 2013 their study was not confined to metastatic disease. Similar to regarding 2yS and 2010 regarding 5yS, before immuno- ourfindings,theydemonstratedmarkedimprovementsin2- therapy entered the arena of lung cancer treatments. An- year mortality amongst both men and women [28]. other large study from the preimmunotherapy period, of the 'e subgroup that stands out with a long 5yS is the International Association for the Study of Lung Cancer younger patients, with age being a significant prognostic (IASLC), summarized world-wide data of more than 90,000 factor, as reported previously [29, 30]. Among the younger lung cancer patients diagnosed between 1999 and 2010. In patients, the improvement in outcome over the years is the that report, 2yS of 23% is reported for stage IVA and 6% for most striking. Multiple factors probably contribute to this Journal of Oncology 5 Table 2: Percentage survival at two and five years by prognostic earlier[31].'egroupof‘AsianorPacificIslanders’hasbeen factors. reported to have a relatively low incidence of lung cancer [32], comprising 6.7% of all lung cancer patients in our 2yOS 5yOS cohort. 'is is a complex group consisting, among others, of % 95% CI % 95% CI patients originated from eastern Asia, possibly including a Entire cohort 8.0 (7.9–8.2) 2.1 (2.0–2.1) higher proportion of EGFR mutation-positive patients. Age However, as discussed for the younger patients and as seen <67 9.5 (9.3–9.6) 2.7 (2.6–2.7) for the entire cohort, the improvement can be seen prior to ≧67 6.6 (6.5–6.7) 1.5 (1.5–1.6) the emergence of EGFR inhibitors or other targeted agents. Sex Our findings resonate with other observations suggesting Male 6.3 (6.1–6.4) 1.6 (1.5–1.7) better outcome of Asian lung cancer patients compared to Female 10.5 (10.3–10.7) 2.8 (2.7–2.9) patients from the Western Hemisphere [33]. Race A recurrent observation is the prognostic value of so- White 7.5 (7.4–7.7) 2 (1.9–2.0) cioeconomic status [34, 35] and, more interestingly, of Black 7.2 (6.9–7.5) 1.8 (1.7–2.0) marital status. Marital status has been found to predict lung American Indian/Alaska 8.6 (7.0–10.4) 1.5 (0.8–2.6) cancer survival for NSCLC [35], as well as SCLC [36], al- native though not in all reports [29]. Being married correlates with Asian/Pacific Islander 15.1 (14.5–15.6) 4.1 (3.7–4.4) better survival for cancer patients in general [37], with di- Unk/oth 23.1 (17.6–29.1) 15.1 (9.8–21.5) verse possible explanations, including better social support Marital status systems for married patients and better socioeconomic Single 7.0 (6.9–7.2) 1.8 (1.7–1.9) Married 8.7 (8.6–8.9) 2.3 (2.2–2.4) status, as well as selection bias; individuals who marry are more likely to be healthier than those that do not marry Histology Adenocarcinoma 10.8 (10.6–11) 2.7 (2.6–2.8) [38].'e impact of being married, as well as the significant Lung carcinoma NOS 5.1 (5.0–5.3) 1.3 (1.3–1.4) impact of the patients’ social status, stresses the importance Squamous cell carcinoma 6.2 (6.0–6.4) 1.8 (1.7–1.9) of providing comprehensive support to cancer patients, Small-cell carcinoma 4.4 (4.3–4.6) 1.3 (1.2–1.4) above and beyond the provision of the medical care. Grade A significant and strong prognostic factor in our cohort Well differentiated 18.6 (17.6–19.7) 6.3 (5.6–7.0) is the pathologic grade of the tumor, as reported previously Moderately differentiated 13.2 (12.8–13.7) 3.8 (3.5–4.1) in smaller data sets [30, 39, 40]. Tumor grade was available Poorly differentiated 7.1 (6.9–7.3) 2.0 (1.9–2.1) only for 43% of the study cohort, thus reducing the validity Undifferentiated 4.5 (4.1–4.8) 1.3 (1.1–1.5) of this observation. Lack of clear definitions for pathologic Year of diagnosis grading of lung cancer impedes the inclusion of this im- 1973–79 3.1 (2.9–3.4) 0.7 (0.6–0.9) portant factor in a standardized manner in pathologic re- 1980–89 3.5 (3.3–3.7) 0.9 (0.8–1.0) ports and in the staging system. It should be noted that only 1990–99 4.5 (4.3–4.7) 1.1 (1.0–1.2) 5% of the patients in our cohort had well-differentiated 2000–09 8.4 (8.3–8.6) 2.1 (2.0–2.2) tumors, and even moderately differentiated tumors con- 2010–15 12.6 (12.3–12.9) 3.7 (3.5–3.9) stituted only 20.6% of the cohort. However, the better Treatment differentiated tumors have a markedly better prognosis. We, None 4.5 (4.3–4.6) 1.6 (1.5–1.7) therefore, suggest that grade should be clearly identified in Chemotherapy only 14.9 (14.6–15.2) 3.3 (3.1–3.5) routine pathologic assessments of lung cancer specimens, as Radiotherapy (RT) only 4.0 (3.9–4.2) 1.0 (1.0–1.1) Chemotherapy+RT 11.7 (11.5–12) 2.9 (2.8–3.1) well as in clinical trials. 'e reasons for the OS improvement seen along the Income <median 7.2 (7.0–7.4) 1.9 (1.8–2.0) years are most likely multifactorial. Conceivably, some of ≧median 8.5 (8.4–8.7) 2.2 (2.1–2.3) the improvement are the result of improved systemic 2yOS: two-year overall survival. 5yOS: five-year overall survival. CI: con- treatments. 'is is supported by the correlation between fidence interval. NOS: non-other specified. Ca: carcinoma. Annual county chemotherapytreatments andimprovedoutcomealongthe median in 2010 of $52,595. years (Figure 4). Clearly a selection bias exists in this analysis, as chemotherapy administration is usually limited to patients with relatively good performance status, a phenomenon, including better performance status, less recognized prognostic factor by itself [2]. Regarding NSCLC, the use of chemotherapy vs. supportive care alone comorbidities, anda higher rate of targetablemutations. 'e improvement in the younger patients is seen starting from gradually gained support during the 1990s [15], which is the mid-90s, similar to the rest of our cohort, prior to the also the period when the survival curves start to rise. addition of the targeted agents to the treatment options. Tailoring of chemotherapy drugs to tumor histology [6] Race is well known to correlate with cancer incidence and addition of anti-VEGF for nonsquamous NSCLC [41] and outcome [19]. Regarding 5yS, black patients had a are the major changes in chemotherapy choices that en- similar outcome to white patients in our data, as reported in tered practice during 2000–2010; each of these had been demonstrated to improve median survival of clinical trial other publications [29]. A markedly better outcome was found in our study for Asian or Pacific Islanders, as reported patients. 6 Journal of Oncology 1970 1980 1990 2000 2010 1970 1980 1990 2000 2010 Year of diagnosis Year of diagnosis Age ≤ 49 years Age 70−84 years Age ≤ 49 years Age 70–84 years Age 50−69 years Age ≥ 85 years Age ≥ 85 years Age 50−69 years (a) (b) Figure2:(a)Changesintheproportionofmetastaticlungcancerpatientssurvivingtwoyearsasafunctionofageandyearofdiagnosis.'e symbolsrepresentdataforaspecificyear,andthelinesindicateatrendline.(b)Changesintheproportionofmetastaticlungcancerpatients surviving five years as a function of age and year of diagnosis. 'e symbols represent data for a specific year, and the lines indicate a trend line. Adenocarcinoma Squamous cell carcinoma Lung carcinoma NOS 1970 1980 1990 2000 2010 1970 1980 1990 2000 2010 1970 1980 1990 2000 2010 Year of diagnosis 2 year OS 5 year OS Figure 3: Trends in two-year and five-year survival 1973–2015 in different histologic subgroups. Yearly data are presented for each group. 'e next breakthrough in the care of NSCLC was [45, 46]. However, the EGFR mutation testing and ap- targeted agents, initially the drugs targeting the EGFR propriate therapy entered practice only in 2009 [4], thus, receptor. Since the entrance of targeted agents, survival has may be, affecting our latest 2yS data and minimally the extended for patients harboring the relevant genetic ab- most recent 5yS data. ALK rearrangement occurs in only errations. Young, female, and adenocarcinoma are the 3–5% of NSCLC [47] and, hence, unlikely to impact the groups where most of the improvement was seen in our survival results of our study cohort. Importantly, the cohort, and these are also the characteristics of patients identification of tumors bearing ALK translocations as harboring most of the driver mutations [42, 43]. 'e candidatesforALKinhibitortherapyoccurredin2010[48], predictive power of EGFR mutations (representing 17% of and the FDA approval of crizotinib for this indication the adenocarcinoma patients [44]) was discovered in 2004 occurred in 2011. Percent surviving 2 years (%) Percent surviving (%) Percent surviving 5 years (%) Journal of Oncology 7 2-year overall survival 5-year overall survival 1970 1980 1990 2000 2010 1970 1980 1990 2000 2010 Year of diagnosis No treatment Chemotherapy only Radiation only Chemotherapy and radiation Figure 4: Proportion of metastatic lung cancer patients surviving two or five years according to treatment modality. Yearly data are presented for each subgroup, separated by the designated treatment modalities. An additional potential explanation for improved mOS regarding systemic treatments administered. In addition, along the years is an overall more aggressive, less nihilistic only a surrogate for socioeconomic status was captured, approach to metastatic lung cancer, with a higher rate of probably misclassifying many patients regarding this im- portant prognostic parameter. Methods of staging have patients receiving chemotherapy. A special example of ag- gressive therapy is the approach to oligometastatic disease changed along the years as noted earlier, and these data are [49, 50] with the use of locally ablative strategies, whether not captured in our data. As for any retrospective study, we surgical,radiosurgical,or other.However,it shouldbenoted cannot assign causative roles to the prognostic factors we that, when looking at the entire population, no correlation have identified. was found in our study between the use of radiotherapy and improved survival. Another relevant and related improve- 5. Conclusions ment that occurred along the years is the development of We have demonstrated substantial improvements over the supportive care, recently demonstrated to prolong survival last decades in the long-term survival of patients with of lung cancer patients [7, 51].As a result of improved metastatic lung cancer, mostly since the mid-90s. Most supportive care, more aggressive treatments can be ad- significant improvements were seen in younger, married ministered to less robust patients, potentially improving patients, females, adenocarcinoma, low-grade tumors, and survival of some of these patients. those receiving chemotherapy. While 2yS has bypassed 10% 'e increase of mOS might be related also to Will in recent years, 5yS is still in the range of 3–4%, stressing the Roger’sphenomenon,i.e., theincreasedlikelihoodwith time need for further progress. Importantly, even prior to the era to correctly classify minimally metastatic patients, whereas of immunotherapy and mostly before the emergence of in the past such tumors may have been understaged. Such targeted agents, subgroupsm NSCLC patients had long-term improved staging would include metastatic patients with a survival. 'e characteristics of these patients point to im- low burden of disease within the metastatic patient cohort, portant prognostic factors, details of which should be col- thus improving the median survival of the cohort. 'e in- lected and reported in current clinical trials. creased use of CT-PET, mediastinoscopy, and brain MRI for staging of patients [52] is likely to have an impact on the Data Availability overall results of this study. 'e strengths of our study include the large size of the 'e raw data are freely available from the website of the database and the inclusion of patients excluded from clinical NCI’s Surveillance, Epidemiology, and End Results (SEER) trials due to comorbidities and/or poor performance status. Program https://seer.cancer.gov/mortality/. Furthermore, this is a well-validated and reliable data set with long-term follow-up [13, 53]. 'e shortcomings of our Ethical Approval study include its retrospective nature, lack of basic clinical data such as performance status and weight loss, lack of data 'is study was exempt from ethics approval since it is based regarding molecular subtypes (especially EGFR mutation upon a publicly available anonymized database. A ‘Data-Use status and other driver mutations), and lack of details Agreement’ with SEER was signed. Percent surviving (%) 8 Journal of Oncology New England Journal of Medicine, vol.363,no.8,pp.733–742, Conflicts of Interest [8] W. Pao and N. Girard, “New driver mutations in non-small- JB reports grants and personal fees from Merck Sharp and cell lung cancer,” /e Lancet Oncology, vol. 12, no. 2, Dohme (MSD), Abbvie, AstraZeneca, Pfizer, Takeda, and pp. 175–180, 2011. Roche, grants from Bristol Myers Squibb (BMS), and per- [9] P. Sharma, K. Wagner, J. D. Wolchok, and J. P. Allison, sonal fees from Boehringer Ingelheim (BI), VBL, Novartis, “Novel cancer immunotherapy agents with survival benefit: Bayer, and Lilly. AO is a consultant and member of the recent successes and next steps,” Nature Reviews Cancer, advisory board to Astra Zeneca, MSD, Roche, and Boeh- vol. 11, 2011. ringer Ingelheim. DU reports personal fees from Merck [10] S. Gettinger, L. Horn, D. Jackman et al., “Five-year follow-up Sharp and Dohme, Bristol Myers Squibb, Boehringer of nivolumab in previously treated advanced non-small-cell Ingelheim, Roche, Takeda, and AstraZeneca. YL reports lung cancer: results from the ca209-003 study,” Journal of research funding from Karyopharm 'erapeutics, Check- Clinical Oncology, vol. 36, no. 17, pp. 1675–1684, 2017. mate Pharmaceuticals, Bristol-Myers Squibb, and pending [11] S.Gettinger,H.Borghaei,J.Brahmeretal.,“OA1404five-year from Merck Serono and honoria/consultancy fees from outcomes from the randomized, phase 3 trials CheckMate Bristol-Myers Squibb, Clinigen Group and Roche Genetech. 017/057: nivolumab vs docetaxel in previously treated NSCLC,” Journal of /oracic Oncology, vol. 14, no. 10, Supplementary Materials pp. S244–S245, 2019. [12] R. S. Herbst, I. Monnet, S. Novello et al., “LBA63Long-term Figure S1: consort diagram of patients participating in this survival in patients (pts) with advanced NSCLC in the study. 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Journal of OncologyHindawi Publishing Corporation

Published: Jan 13, 2021

References