Even considering these factors, these earlier studies may have underestimated current rates of treatment for advanced NSCLC. First, these studies used Medicare-linked Surveillance, Epidemiology, and End Results (SEER) data and therefore included only patients aged 65 years and older.^6–8 In the United States, more than 30% of individuals with lung cancer are younger than 65 years.¹⁰ Second, most of these studies reported data from the 1990s, a time frame that may not reflect contemporary practice patterns. Over the past 10 years, advances in diagnosis, treatment, and supportive care may have expanded the patient population considered for cancer-directed therapy. For example, increased use of positron emission tomography scans has resulted in earlier detection of extrathoracic disease, conceivably leading to diagnosis of advanced-stage NSCLC earlier in the clinical course, when patients may be more medically fit to receive chemotherapy.¹¹ In addition, the number of therapies for NSCLC has grown in recent years, including relatively well-tolerated agents such as erlotinib and pemetrexed. Administration of these and other therapies has been enhanced by improved antiemetics and more convenient formulations of hematopoietic growth factors.

Given these considerable changes to the clinical care of patients with NSCLC, as well as the absence of data on the substantial proportion of individuals younger than 65 years, we performed a single-institution study encompassing a diverse population diagnosed with stage IV NSCLC from 2000 to 2007. Based on the considerations described above, we hypothesized that this cohort would have higher rates of chemotherapy administration than those previously reported.

Whether the higher rate of chemotherapy administration in this cohort reflects the inclusion of all patient ages, the contemporary era of the study, the particular practice patterns of clinicians at our institution, or other factors is not clear. The mean age in our study sample was 60 years, a full decade younger than the mean age of NSCLC diagnosis in the United States. That stated, more than 40% of patients aged 65 years and older received chemotherapy, a rate still considerably higher than that reported in prior studies. Because tumor registry data at UT Southwestern is limited before 2000, the impact of study era on our findings is not readily determined.

Although higher than previously reported, the 49% treatment rate in this series of patients with advanced NSCLC is still lower than treatment rates for other common malignancies. For example, a recent population-based study in Canada found that 63% of patients with metastatic colon cancer receive chemotherapy¹³; at least 70 to 80% of patients with breast and prostate cancer receive systemic therapy.¹⁴ Several factors may explain the lower likelihood of lung cancer patients receiving treatment. With a median age at diagnosis of 71 years, they are older than patients with breast (median 61 years) and prostate (median 68 years) cancer.¹⁰ In contrast to breast and prostate cancer, there are no hormonal therapeutic options, which are generally more easily administered and better tolerated than conventional cytotoxic chemotherapy. Furthermore, many physicians may not be aware of the growing evidence in support of chemotherapy for advanced NSCLC. Wassenaar et al.⁹ found that primary care physicians are less likely to refer patients with advanced lung cancer to an oncologist, compared with patients with advanced breast cancer. In that study, only 31% of primary care physicians were aware that chemotherapy improves survival in advanced lung cancer. Once NSCLC patients are referred to cancer specialists for treatment, relatively low response rates may limit recommendations for chemotherapy. In two landmark phase III trials comparing various chemotherapy regimens for advanced NSCLC, the highest response rates ranged from 22 to 35%.^15,16 In analogous trials for other malignancies, chemotherapy response rates were 61 to 74% for breast cancer^17–19 and 45 to 53% for colon cancer.^20–23

In this study, chemotherapy administration was significantly associated with patient age and insurance type. Forty-one percent of patients aged 65 years and older received chemotherapy, compared with 53% of patients younger than 65 years. When one considers that older patients are more likely to have comorbidities and/or poor performance status, this finding is not surprising. Indeed, it was recently shown that older patients with advanced NSCLC are more likely to suffer chemotherapy-associated adverse events, despite a lower likelihood of receiving (potentially more toxic) platinum-based regimens.²⁴

To our knowledge, the lower rate of chemotherapy receipt among underinsured patients with advanced NSCLC has not been previously reported but is consistent with a number of earlier observations in this disease. It has been shown that insured patients with NSCLC are more likely to be diagnosed with early-stage disease,²⁵ to have surgery for early-stage disease,²⁶ and to receive timely treatment after diagnosis.²⁷ Furthermore, patients with stages I to IIIA NSCLC who were dually eligible for Medicare and Medicaid (a socioeconomically disadvantaged group) had inferior survival compared with patients with Medicare.²⁸ Thus, socioeconomic status can have far-reaching effects throughout the disease course of patients with NSCLC, a finding also noted in other malignancies, including breast and colorectal cancer.^29,30

In our cohort, explanations for this association are not clear. Although we previously reported longer diagnostic and treatment intervals for stage I to III NSCLC in our safety-net medical system, these intervals were not associated with clinical outcomes.²⁷ Indeed, it seems unlikely that treatment selection would differ by medical facility within our institution, because the same clinicians care for lung cancer patients at all sites. Furthermore, the various facilities have similar treatment options, including state-of-the art chemotherapy, biologic agents, and supportive medications, and these are available to patients regardless of insurance status through safety-net medical programs. However, as we have previously reported,²⁷ other aspects of care, such as treatment delays, do differ among UT Southwestern-associated facilities, and these factors may ultimately impact the administration of chemotherapy. It has also been shown that there are wide variations in attitudes toward chemotherapy among patients with NSCLC, although the association between these attitudes and demographic characteristics such as socioeconomic status remains unclear.³¹

Although we presumed that treatment of advanced NSCLC may be increasing over time, within the time period of our study, chemotherapy administration was not significantly associated with the year of diagnosis. Nevertheless, as shown in Figure 1, 2 of the 3 years in which chemotherapy was given to more than 50% of patients were the last 2 years of the study period (2006 and 2007), which may suggest a recent upward trend. The last 10 years have seen substantial advances in the medical management of advanced NSCLC. In the area of supportive care, darbepoetin (Food and Drug Administration approved in 2001) and PEG-filgrastim (approved in 2002) have markedly simplified the administration of hematopoietic growth factors, and aprepitant (approved in 2003) has improved prevention of nausea and vomiting. Since 2004, the anticancer therapies bevacizumab, erlotinib, and pemetrexed have been approved for advanced NSCLC, drugs notable for their relative tolerability. Indeed, from 1997 to 2002, chemotherapy administration for patients aged 65 years and older with advanced NSCLC increased from 28 to 36%.³² Whether the developments in the 2000s will lead to a further increase in treatment rates is not yet known.

Median survival in this study was 5.0 months, and receipt of chemotherapy was the only factor associated with survival in multivariate analysis. The median survival for patients treated with chemotherapy was 9.2 months, similar to other studies.^5,16 However, at 2.3 months, median survival for the 51% of patients who did not receive chemotherapy was considerably lower than that in previous reports. In pivotal phase III clinical trials demonstrating the benefit of chemotherapy for advanced NSCLC, the median survival of patients randomized to best supportive care alone ranged from 4.0 to 5.7 months.^1,3 Our observational, nonrandomized study permits no conclusions to be drawn about the effectiveness of chemotherapy, because the patients who did and did not receive chemotherapy differed in several measured and unmeasured ways.

Nevertheless, our outcome data may provide insight into reasons why patients did not receive chemotherapy. That overall survival among chemotherapy-treated patients in our series approximates survival reported in prospective clinical trials suggests that the performance status and organ function of these individuals may be roughly similar to those of trial participants. By contrast, the particularly poor survival among untreated patients in our cohort suggests that these individuals differ from patients who were eligible for the trials of chemotherapy versus supportive care; they are likely to have a worse performance status, more comorbidities, and impaired organ function. Thus, although there are several reasons why patients may not receive chemotherapy, including patient preference, access to care, and provider preference, it seems reasonable to conclude that insufficient medical fitness was a driving factor in our study. Accordingly, it is possible that insurance type, a widely used socioeconomic marker, is also serving as a surrogate for overall medical condition. Separately, the finding that overall survival seems shorter in multivariate analysis for younger patients in this cohort (hazard ratio for death = 1.23; p = 0.06) merits comment. Although this study offers no certain explanation, we believe that this observation may reflect the characteristics of our particular lung cancer patient population in which younger individuals are more likely to come from socioeconomically disadvantaged groups.²⁷

This study has a number of limitations. Perhaps most importantly, the patient sample is drawn from a single academic medical center, limiting the generalizability of our findings. That stated, because of our geographic setting and the variety of UT Southwestern-associated clinical facilities, our patient cohort is racially and socioeconomically diverse. Second, this is a retrospective analysis and therefore subject to bias from incomplete data availability. However, as evidenced by follow-up through death for more than 95% of patients in the cohort, it seems that the tumor registries have successfully captured the clinical and therapeutic course of these patients. As mentioned, this study does not provide specific reasons why chemotherapy was not administered to half of all patients, and this remains a critical question for lung cancer clinicians and researchers alike. In addition, we do not have data on which treatments were administered. Finally, because of the process by which cases are coded by the tumor registries, our cohort does not include patients with recurrent, metastatic disease after treatment for early-stage NSCLC or patients with malignant pleural effusions, who are typically treated with an advanced disease paradigm but until recently were categorized as stage IIIB.