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a Division of General Thoracic and Foregut Surgery, University of Minnesota, Minneapolis, Minnesota
b Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
c Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, Minnesota
Accepted for publication April 23, 2010.
* Address correspondence to Dr Maddaus, Department of Surgery, University of Minnesota, Division of General Thoracic and Foregut Surgery, MMC 207, 420 Delaware St SE, Minneapolis, MN 55455 (Email: madda001{at}umn.edu).
Presented at the Forty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 25–27, 2010. Winner of the Geriatric Patient Care Award.
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Abstract |
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Methods: Using the Surveillance Epidemiology and End Results Database (1988 through 2005), we identified patients 50 years old and older who underwent lobectomy for stage I NSCLC. We used competing risks methods to calculate conditional survival rates and to ascertain if there is a point in follow-up where the risk of dying of cancer is equivalent to the risk of dying of cardiovascular disease.
Results: In all, 22,518 patients met our inclusion criteria. The difference in the 5-year conditional probability of dying of cancer and the 5-year conditional probability of dying of cardiovascular disease decreased with time; in the whole cohort, these probabilities were equivalent if patients survived to 7 years after lobectomy (p = 0.11). With increasing age, the probability of dying of cancer and the probability of dying of cardiovascular disease became equivalent at earlier time points. Furthermore, the 5-year probability of dying of cardiovascular disease was significantly greater than the 5-year probability of dying of cancer for patients aged 70 to 79 years who survived to 7 years and for patients aged 80 years and older who survived to 5 years after lobectomy.
Conclusions: For patients undergoing lobectomy for stage I NSCLC, cardiovascular-specific mortality becomes increasingly important over the course of follow-up, especially among elderly patients.
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Introduction |
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To illustrate this point, as shown in a cancer-specific survival curve for patients with early stage (I or II) NSCLC based on data from a large population-based cancer dataset (Fig 1), the risk of death (the slope of the curve) is not constant—it changes throughout the course of follow-up (Fig 1A). For example, the risk of dying of cancer in the subsequent 5 years is much greater for patients at the time of diagnosis than for patients who survive at least 3 years (Fig 1B).
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Based on a number of sources in the literature, we know that most NSCLC patients are older and often have cardiovascular comorbidities. A recent study using The Society of Thoracic Surgeons (STS) database estimated that the median age of patients with primary lung cancer is 67 years. That study also found a relatively high prevalence of cardiovascular comorbidities among lung cancer patients: hypertension (66%), coronary artery disease (26%), peripheral vascular disease (11%), cerebrovascular disease (8%), and congestive heart failure (4%) [13]. Because the risk of cancer-specific mortality decreases over time, patients who undergo lobectomy for stage I NSCLC and who survive to a certain point in follow-up may be as likely to die from cardiovascular disease as from cancer.
Using a large population-based cancer dataset, we sought to (1) compare conditional survival rates for patients who underwent lobectomy for stage I NSCLC with their survival rate at the time of diagnosis, and (2) compare conditional cancer-specific survival rates with conditional cardiovascular-specific survival rates using a competing risks model to ascertain if there is a point in follow-up when patients are as likely to die from cardiovascular disease as they are from cancer.
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Material and Methods |
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Data
The Surveillance, Epidemiology, and End Results (SEER) database is a set of population-based cancer registries that was founded in 1973 by the National Cancer Institute (Bethesda, MD). Currently, 17 US cancer registries, selected to include a diverse sample (about 26%) of the national population, participate in the SEER program. We used the SEER database that was based on the November 2007 submission, which provides data through December 31, 2005 [14]. The SEER registries began collecting American Joint Committee on Cancer (AJCC) staging data in 1988 [15]; therefore, this study represents data collected by the SEER registries from 1988 through 2005. Because of the negative impact of Hurricane Katrina on data collection by the Louisiana SEER registry, we excluded information obtained by that registry in 2005.
We collected information on patient characteristics, primary tumor characteristics, and treatment regimens.
Inclusion Criteria
We selected patients from the SEER database for inclusion in our study using the following International Classification Disease for Oncology, Third Edition (ICD-O-3), topography codes: C34.0 to C34.3, C34.8, and C34.9 [16].
We only included patients 50 years and older who underwent lobectomy (the standard of care) [2] for AJCC (sixth edition) stage I (T1N0M0 and T2N0M0) NSCLC [15]. We limited our study to patients with stage I disease to create a homogeneous study group and to eliminate the confounding influence of different extents of resection, different stages of disease, and use of chemotherapy (which until recently SEER did not collect) and radiation therapy on survival. The following carcinoma histologic subtypes were included in our analysis and were categorized as follows: adenocarcinomas, bronchoalveolar carcinomas, squamous cell carcinomas, and other NSCLC histologies (large cell, epithelial, undifferentiated, anaplastic, pleomorphic, giant cell, mixed cell, clear cell, mucoepidermoid, signet cell, and adenosquamous cell carcinomas; cystadenocarcinomas, and NSCLC not otherwise specified [see Appendix for ICD-O-3 morphology codes]).
Exclusion Criteria
We excluded patients with a prior or subsequent cancer diagnosis. Due to the potential for confounding, we also excluded those patients who were unlikely to have received aggressive cancer treatment based on the following reporting sources: a hospice/nursing home, autopsy, or death certificate.
Statistical Analysis
Data were extracted from the SEER database using SAS version 9.1 (SAS Institute, Cary, NC). The Kaplan-Meier method was used to calculate conditional cancer-specific survival rates. We then used the empirical transition matrix (etm) package, version 0.3-7, in the R system, version 2.8.1 (R Foundation for Statistical Computing, Vienna, Austria) to perform competing risks analyses. At each point in follow-up, the probability of surviving, dying from cancer, dying from cardiovascular disease classified in SEER as follows: heart disease, hypertension, cerebrovascular disease, atherosclerosis, aortic aneurysms and dissection, and other arterial diseases), and dying from other causes was estimated using the Aalen-Johansen estimator with covariance estimated using Greenwood's method [17].
We used Wald's method to compute p values for the difference in the probability of cancer-specific mortality within 5 years and the probability of cardiovascular disease-specific mortality within 5 years conditioned on survival to 0 to 11 years after lobectomy. We had insufficient follow-up to perform a competing risk analyses beyond 11 years after lobectomy. We adjusted for multiple comparisons by using a more conservative two-sided significance level of 0.01, rather than the traditional level of 0.05. Because no available statistical software performs a competing-risks regression analysis while comparing the two conditional probabilities of central interest, we qualitatively assessed the effects of patient characteristics (age, race, and sex) and tumor characteristics (tumor [T] stage and histology) by dividing the population into subgroups and then analyzing those groups separately.
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Results |
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Comment |
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Current National Comprehensive Cancer Network (NCCN) guidelines for postoperative surveillance for stage I NSCLC patients recommend chest computed tomography scans every 4 to 6 months for the first 2 years after lobectomy and annually thereafter [18]. Although the primary utility of posttreatment radiographic surveillance is to assess for locoregional recurrence, SEER registries do not collect information on recurrence, and, therefore, we cannot provide data to support (or refute) this recommendation. However, we did show that the conditional probability of cancer-specific mortality (which is temporally correlated with disease recurrence) was highest in the first 5 to 7 years after lobectomy, suggesting the need to focus the intensity of surveillance early in the course of follow-up [19].
Because the risk of cancer-specific mortality decreases over time, we hypothesized that cardiovascular disease would become an increasingly important cause of mortality over the course of follow-up. Indeed, although the risk of dying of cancer exceeds the risk of dying of cardiovascular disease immediately after lobectomy, the disparity between these risks diminishes with time. For patients who survive 7 years after lobectomy for stage I NSCLC, the risk of dying of cancer is not statistically different than the risk of dying of cardiovascular disease. These findings have important implications for NSCLC survivors. Because cardiovascular-specific mortality becomes an increasingly important cause of mortality over the course of follow-up, health promotion and management of medical comorbidities should be incorporated into the care of stage I NSCLC patients after lobectomy.
We divided patients into subgroups to qualitatively assess the effect of potentially important prognostic factors on our findings. Age had the most profound impact on our results; with increasing age, the risk of dying of cancer becomes equivalent to the risk of dying of cardiovascular disease at earlier time points after lobectomy. Because the risk of both cancer-specific and cardiovascular disease-specific mortality increases with age, this finding is not surprising [5, 6].
Similarly, in other subgroups with a higher risk of death (non-Caucasians, men, T2 tumors, squamous cell carcinomas and other NSCLC histologies [which includes large cell and undifferentiated NSCLC]), the risk of cancer-specific mortality and cardiovascular disease-specific mortality converged earlier in the course of follow-up than in lower risk subgroups [5]. Although our subgroup analysis is largely qualitative, each of its findings is expected (ie, mortality rates are higher for older patients as compared with younger patients). Had there been large discrepancies in the observed and expected outcomes, our competing risks analysis would be brought into question.
We recognize a number of limitations of our study, some of which are inherent limitations of using SEER data. In particular, the SEER cancer registries do not collect information on several important prognostic factors, such as performance status, comorbidities, time to local recurrence, and surgeon and hospital volume. Therefore, we could not determine the effects of these covariates on our findings. Our study is also prone to the inherent potential sources of error of observational studies. Of these, selection bias may be especially important. In particular, because we only included patients who underwent lobectomy, we excluded those patients who lacked sufficient cardiopulmonary reserve to tolerate a lobectomy. Consequently, though our data indicate that the risk of dying of cancer exceeds the risk of dying of cardiovascular disease (regardless of age) at the time of diagnosis, our competing risks analysis cannot be used as a widely generalizable indication for lobectomy. Each patient must be evaluated to ascertain whether or not he or she has sufficient cardiopulmonary and functional reserve to tolerate a lobectomy.
In addition, we limited our analysis to patients with stage I disease who underwent standard of care treatment (eg, lobectomy) to create a homogenous group and eliminate the confounding influence of different extents of resection, different stages of disease, and use radiation and chemotherapy (which until recently SEER registries did not record). Consequently, our results may not be generalizable to NSCLC patients who undergo lesser resections or who have more advanced stages of disease. Because our data encompassed a relatively long period of time (17 years), it is possible that improvements in overall and cancer-specific survival over this time period could confound our results. However, although the life expectancy has increased [20] and the overall mortality rate for lung cancer has declined in the United States [21] over the period of our study, the mortality rate for stage I NSCLC has not changed [5]. Finally, our competing risks model does not allow us to perform a regression analysis to simultaneously adjust our results for a number of potentially confounding covariates. Nonetheless, we were able to evaluate the effect of several patient and tumor characteristics using another well-accepted method of assessing for confounding—stratification.
Despite these limitations, we also recognize a number of strengths of our study. We had a large sample size (22,518 patients) with relatively long period of follow-up (as long as 17 years), which allowed us to conduct a survival analysis that would not be possible with many other sources of data. Because we used population-based data, our results may be more generalizable to the US population than data from tertiary cancer centers. Furthermore, this study is the first in the literature to assess conditional survival rates specifically for patients who underwent lobectomy (the standard of care) for stage I NSCLC. Previous studies included patients with more advanced stages of disease [7, 22], included other histologies (ie, small cell carcinoma [6, 7, 22]), and did not adjust for standard of care treatment for the patients that were included [7, 12, 22]. Although Skuladottir and Olsen [6] examined conditional survival rates for stage I NSCLC patients, they did not adjust for extent of resection. This study is also the first that used competing risks analyses to compare the conditional probability of cancer-specific mortality with the conditional probability of cardiovascular disease-specific mortality (or other chronic diseases).
In conclusion, using a large population-based cancer dataset, we found that the risk of dying of cancer exceeds the risk of dying of cardiovascular disease at the time of lobectomy for stage I NSCLC. However, the difference in the conditional probabilities of these outcomes changes over the course of follow-up. While the risk of dying of cancer decreases over time, the risk of dying of cardiovascular disease becomes an increasingly important cause of death, especially for elderly patients. These findings have potentially important implications for counseling NSCLC patients, posttreatment surveillance, and for risk factor modification for cancer survivors.
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Discussion |
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DR GROTH: Thank you for your comments, Dr Harpole. To answer your first question, one of the goals of randomization in an adequately powered clinical trial is to construct treatment groups that have a similar distribution of both recognized and unrecognized confounding variables. You are correct. Due to either random error or systematic error, the treatment groups in a randomized trial may have significant differences. There are methods that can be used when designing a clinical trial to reduce this risk. In particular, stratification is a procedure that can be used as part of a randomization scheme to ensure that certain variables of particular prognostic interest, such as tumor size or sex, have a similar distribution for each of the treatment groups. Although such schemes are more difficult to implement, stratified randomization would eliminate the risk of unbalanced groups. To address your last comment, overall survival does not differentiate between cancer-related and noncancer-related causes of death. As we found, noncancer-related causes of death likely become an increasingly important cause of death in the course of follow-up. For this reason, cancer-specific survival can be a useful outcome to compare with overall survival to assess if other, noncancer-related causes of death are contributing to an observed survival difference in a clinical trial.
DR MICHAEL P. POULLIS (Liverpool, United Kingdom): Did you look at the effect of aspirin?
DR GROTH: Unfortunately, SEER does not collect information on medication use.
DR POULLIS: We have looked at our data the same way as you. We think there are two reasons for dying. About 30% of people coming for lobectomy are on aspirin in our practice, and they have all the risk factors for dying—previous heart attacks, strokes, CVAs, peripheral vascular disease—and actually they do better. We presented that at the European meeting and it will be out in the next couple of months in the European Journal and will be a basis of a trial we're going to look at on aspirin (www.TheBigATrial.co.uk). Aspirin has COX-2 beneficial effects for the adenocarcinomas as well.
DR MALCOLM M. DECAMP (Chicago, IL): I enjoyed that very much. I think what you are doing is to flesh out in numerical form what our clinical judgment tells us when we are evaluating the physiologic state of our patients and trying to equate that with all the very well-defined parameters that you can get from SEER, for example, about the cancer. I'm wondering if this actually isn't almost an underestimate of the competing risks, because you have a lot of detailed information about the cancer, its therapy and stage, and yet the details for cardiovascular comorbidity aren't quite as elaborate. For example, from SEER, it would be very nice to be able to combine data and be able to match or propensity-match patients from the STS databases or some other very well-defined cardiovascular database to really start to drill down on what the competing (noncancer) risks are. But I think this is a fabulous first approximation at doing what we all typically do in terms of clinical judgment of operative risk and potential overall survival. Thank you.
DR GROTH: Thank you for your comments, Dr DeCamp. Although SEER provides some data on cancer treatment, it doesn't collect any information on risk factors for developing comorbidities or on the treatment of comorbidities. Although we were able to limit our analysis to patients who underwent lobectomy, the standard of care treatment for stage I disease, we have no way of assessing whether or not these patients also received standard of care treatment for cardiovascular disease. Had we been able to stratify our analysis based on the presence or severity of cardiovascular disease risk factors or had we been able to restrict our analysis to patients who also received standard of care treatment for cardiovascular disease, our results may have differed slightly. Unfortunately, the limitations of the SEER dataset prevent us from performing such an analysis. However, we did use a large population-based dataset, and, therefore, our results are likely reflective of the treatment patterns of cardiovascular disease in the United States. To address your last comment, we are considered using other datasets, such as the STS database, for future studies. We appreciate your comments.
DR SUDISH C. MURTHY (Cleveland, OH): Congratulations on a very nice paper. To get back to what Dr Harpole was alluding to, perhaps one of the primary endpoints in future studies of lung cancer should be lung cancer recurrence. We have looked at cancer recurrence in a fairly homogeneous population of stage I lung cancers. You get a good sense of what the risk factors are for cancer recurrence. You then you can then study the competing risk of death or death before recurrence, and at some level, that helps address Dr Harpole's question and might clarify some of these data.
DR GROTH: That's a good point, Dr Murthy. Unfortunately, SEER does not collect information on cancer recurrence, and therefore, we couldn't assess the effect of cancer recurrence on our results.
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1) than for patients 3 years after diagnosis (
