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Ann Thorac Surg 2006;82:424-430
© 2006 The Society of Thoracic Surgeons
a Division of Cardio-Thoracic Surgery, Department of Surgery, University of Alabama at Birmingham (UAB), Birmingham, Alabama
b Department of Epidemiology, UAB School of Public Health, Birmingham, Alabama
Accepted for publication February 27, 2006.
* Address correspondence to Dr Cerfolio, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 1900 University Blvd., THT 712, Birmingham, AL 35294 (Email: rcerfolio{at}uab.edu).
Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons Chicago, IL, Jan 30–Feb 1, 2006. Winner of the Geriatric Patient Care Award.
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Abstract |
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METHODS: A nested case-control study over a 5-year period using an electronic prospective database (n = 6,450) of patients with NSCLC who underwent complete resection. Patients 70 years or older, 75 years or older, and 80 years or older were matched 1:1 to younger controls for stage, pulmonary function, performance status, and type of pulmonary resection.
RESULTS: There were 726 patients: 363 were 70 years of age or older (191 patients were 70 to 74 years old, 121 were 75 to 79, and 51 patients were 80 or older). There were 363 patients younger than 70 years of age. There was no significant difference in length of stay, major morbidity, or operative mortality between any of the elderly groups and the younger controls. However, elderly patients who received neoadjuvant therapy had three times the risk of developing major morbidity (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.14 to 7.41). There was a statistically significant better 5-year survival in elderly patients with stage I NSCLC (78% vs 69%, p = 0.01); however, survival was similar for all other stages.
CONCLUSIONS: Elderly patients with NSCLC should not be denied pulmonary resection based on chronologic age. Their short-term risks and long-term survival are similar to younger patients. Additionally, there seems to be no increased risk in selected octogenarians. However, elderly patients had double the risk for developing major morbidity after resection if they underwent neoadjuvant therapy.
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Introduction |
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Outcomes were hospital length of stay, admission or transfer to the intensive care unit (the ICU was not used routinely after thoracotomy and was reserved for patients with a possible perioperative myocardial infarction or other complications that required more careful monitoring), overall and major morbidity, operative mortality, and 5-year survival rates. Major morbidity was defined in this article based on the complications (such as pneumonia, myocardial infarction, stroke, bleeding, adult respiratory distress, and the need for reintubation) that occurred during the study time frame. Operative mortality was defined as any death within 30 days of operation or prior to dismissal. The 5-year survival was stratified by stage for the elderly group and their younger counterparts. Survival was calculated from the date of resection to the date of death. Patients alive at the end of the study period were censored for purposes of data analysis.
The Institutional Review Board at the University of Alabama at Birmingham approved the electronic prospective database used for this study as well as the study itself. Patients consent was obtained for entry into the prospective database and patients were aware that these data would be used for research purposes.
Staging
Patients were clinically staged by computed tomographic (CT) scan and by dedicated positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG-PET) using specific techniques that have been previously described [5]. Patients were meticulously staged. All suspicious N2, N3, or M1 areas (defined after PET as areas with a maximum standard uptake value [maxSUV] > 2.5) were biopsied prior to pulmonary resection. Mediastinoscopy was used to biopsy suspicious lymph nodes in the paratracheal area (stations 2R, 4R, 2L, 4L, and top of 7) and endoscopic transesophageal ultrasound [EUS} [6] was used to biopsy suspicious posterior aorta-pulmonary window nodes (5), subcarinal nodes (7), periesophageal nodes (8), and inferior pulmonary ligament nodes (9). The techniques used for EUS- fine needle aspiration have been previously described [7].
Patients with suspected M1 disease in the liver, adrenal, or contralateral lung underwent definitive biopsy to prove or disprove M1 cancer. If the bone or brain was suspected to harbor metastases, magnetic resonance imaging was considered the standard reference. If there was no evidence of N2 or higher disease, patients underwent thoracotomy, pulmonary resection, and complete thoracic lymphadenectomy as previously described [8]. Pathologic review was performed by standard techniques and immunohistochemical staining was employed when appropriate. A pathologic stage was generated using the using the tumor, node, metastasis classification system using the international staging system [9].
Statistics
Data were stored using an Excel (Microsoft, Seattle, WA). Analysis was conducted using SAS software 9.0 (SAS Corp, Cary, NC). Continuous data are presented as medians and categoric data are presented as percentages. The Fisher exact test or Pearson 
2 test was used to assess categoric data and the Wilcoxon test to evaluate continuous variables. Log-rank analyses and Cox proportional-hazards regression modeling were used to adjust for major prognostic and stratification factors in the survival analysis. A two-sided p value of less than 0.05 was considered statistically significant and unlikely due to chance. Patients alive at the end of the study period were censored for purposes of data analysis.
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Results |
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Table 1
compares the patient characteristics of the elderly with their younger counterparts. The male to female ratio differs significantly between the two groups. Women were more prevalent in the older age groups than in the younger (p = 0.044) group. The groups were otherwise similar for comorbidities. Although there was no statistically significant difference in the median maxSUV of the primary tumor, there was a trend for the maxSUV of the primary NSCLC to fall as patients aged. As patients increased in age their tumors were more likely to be well-differentiated (66% of those 
70 years had a well or moderately differentiated tumor compared with 59% of those < 70 years), although this difference was not statistically significant (p = 0.62).
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Survival
The overall 5-year survival for the elderly was 51% and for the younger group was 58%; this difference was of borderline significance (p = 0.09). As shown in Figure 1, the elderly had a significantly better 5-year survival for stage I (T1N0M0 and T2N0M0) NSCLC (78% vs 69%, p = 0.02). However, survival for other stages (as shown in Figs 1B and 1C) was not significantly different in the elderly compared with their younger counterparts (5-year survival of 47% vs 54% for stage II and 4-year survival of 23% vs 36% for stage III, respectively). These survival data reflect follow-up data obtained on 649 of the 723 (90%) patients.
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Comment |
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The average age of patients diagnosed with lung cancer is 63 years. Less than 3% of patients who develop lung cancer are 45 years or younger [10]. Given these facts and the increasing age of the population of the United States, more and more elderly Americans will present to their physicians with non-small cell lung cancer.
The purpose of this study was to assess the short and long-term results of elderly patients with NSCLC who underwent complete resection, and to compare these results to a matched cohort of younger patients. Because the definition of "elderly" varies by study, we chose to stratify our elderly group into three age brackets and evaluate each group separately as well as the group as a whole.
Interestingly, we found no difference in the short-term results (morbidity, mortality, length of hospital stay) for the elderly when compared with the younger controls. The elderly did not have a more difficult time with surgery than the younger patients. However, we found a higher morbidity for those elderly patients who received neoadjuvant therapy. Gridelli and colleagues [11], in 2002, also reported that elderly patients tolerated preoperative chemotherapy poorly compared with their younger counterparts [11]. Similarly, other studies have corroborated these results [12]. Thus, short-term results favor surgery in selected elderly patients with NSCLC but avoidance of neoadjuvant therapy may be best.
Similarly, the long-term outcomes also showed little difference between the younger and older patients. In fact, the overall 5-year survival was 58% compared with 51% in the elderly. The 5-year survival was actually better in elderly patients with stage I NSCLC (78% vs 69%, p = 0.01) than it was in the younger matched control patients. These findings are similar to a study by Hanagiri and colleagues [13] in which there was a similar 5-year survival rate between elderly and younger counterparts and Shirakusa and colleagues [14] who reported a cumulative survival of 79% in elderly patients with stage I NSCLC. Other studies, such as a recent one by Mery and colleagues [15] show age to be an independent predictor of survival. However, these authors included all cancer patients in the computation of their median survival, including patients who were not completely resected, most of whom were elderly.
Interestingly we found certain trends as patients get older. The male to female ratio nears one with increasing age. This is of no surprise as men are more likely to die sooner than women from other causes. Because there was a significant difference in gender distribution in the various age groups and because it has been shown that women do better than men, present at an earlier age, have an increased susceptibility to NSCLC, and have an increased survival for almost every stage as compared with men [16–18] we controlled for gender in our survival analysis. Second, the stage of presentation decreases as patients get older. This concept correlates with other findings from this study such as with median maxSUV, which falls with age and with degree of tumor differentiation, as there is a greater percentage of well-differentiated tumors in older age groups. Previous studies have shown the correlation between a lower maxSUV and well-differentiated tumors [19–21]. Perhaps there is an immunopathophysiologic mechanism that explains why elderly patients seem to have less virulent tumors. These interesting data are further supported by the increased survival of elderly patients with stage I cancers. This may due not only to the fact that their tumors are less virulent but also may be attributed to the fact that those with advanced age are a self-selected group to live longer when compared with an average 60 year old patient with NSCLC. Additionally, very young patients with NSCLC are more likely to have developed their malignancy, at least in part, on a genetic basis and these tumors are often very aggressive. Susceptibility may vary between young and old based on the mechanism of injury. For example, while an older and a younger patient may present with the same histologic type of cancer, a younger patient may develop NSCLC due to a DNA sequence mutation that may allow for more aggressive disease progression, whereas an older person may develop NSCLC secondary to damage caused by carcinogens that may result in a slower disease progression.
Our experience has taught us some important lessons in the postoperative care of elderly patients. These lessons are hard to "prove" with statistics or a p value. These suggestions include the following: the careful use or even avoidance of narcotics and epidural analgesia in elderly patients, the need for aggressive physical therapy, the prevention and treatment of constipation, the judicious use of not only neoadjuvant, but adjuvant therapy as well. If the latter is used, the elderly patient may do better with a longer interval between surgery and the start of the adjuvant chemotherapy. Elderly patients are more likely to require a rehabilitation center after surgery because often their spouse at home is also elderly and has health issues of their own. The family of each individual and the their social support structure need to be carefully assessed and postoperative plans made prior to resection. These plans should be clearly discussed with the patient prior to surgery.
There are strengths and limitations to every study. The foremost limitation in this study is our entry criteria. We studied only those patients who underwent pulmonary resection and were completely resected. Obviously these two points need to be carefully considered when the results of this study are interpreted. The entry criteria represent an inherent bias. However, this study was designed to address specifically whether a patient who has an apparent, early resectable lung cancer and is fit for operation should be denied it just because of their advanced age. The strengths of this article include carefully chosen risk factors on which to match controls, the large number of patients in the database from which to select controls, the accuracy of a prospective database used to collect and store the data, a low number of patients lost to follow-up, pathological instead of clinically based staging, and the use of only one surgeon, which minimizes confounders such as different selection criteria for surgery, surgical techniques, and postoperative management.
In conclusion, we have shown that medically fit, elderly patients with early resectable non-small cell lung cancer should not be denied surgical resection based on their chronologic age alone. However, elderly patients did have increased morbidity if they underwent neoadjuvant therapy, when compared with the younger control patients.
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Discussion |
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Unfortunately we're almost preaching to the choir here. This needs to be disseminated to our pulmonary colleagues probably as much as anybody else. So my first question to you is exactly that. Yes, this is a highly selected cohort, probably because these patients, in my experience, self-refer to a thoracic surgeon because their primary care physician and their pulmonologist try to dissuade them from thoracic surgery because they have these unreal expectations of what the true morbidity is. So I wondered if you have a comment on how you are able to overcome that.
Secondly, a lot of the data, if you look in the literature on this, in patients, the octogenarians and older, we tend to do more limited resections as opposed to lobes and so forth, just because with age there's an age adjustment of their expected pulmonary function, and generally these patients tend to be, which is normal for an 85-year-old, at somewhere between 35% and 50% of their predicted FEV1 [percent predicted of forced expiratory volume in 1 second] , and so we tend to do wedges and segments. What is your philosophy on how you decide what resection to do in these people? I enjoyed it very much.
DR CERFOLIO: Thank you very much, Dr Harpole. Your comments are right on the button. I'll start with your second question first. It is true that we are more likely to do a segmentectomy in the elderly. This fact may be because their tumors are smaller, or their FEV1% and(or) DLCO% [percent diffusing capacity of lung for carbon monoxide] was lower, or we're picking patients with smaller tumors, or even perhaps because I am biased and believe local recurrence is less of a problem and thus I am more likely to do a segment instead of a lobe. It may be because their tumor is less biologically aggressive and, hence, smaller. I am not really sure of the reason but the fact is true; we are more likely to do a smaller resection.
As far as your first question concerning overcoming the thinking—there are a few pulmonologists in the Alabama community who are very aggressive and one has even sent me a 98-year-old patient for resection. But I think that you're right, that thinking is out there, and our job is to educate each other as well as medical physicians with clean data that shows that in properly selected patients their risks are no higher. In fact, an 80-year-old who comes into your office is more likely to be alive in 5 years than the 70-year-old; he has already proven that he is a survivor and statistically is more likely to be alive in 5 years.
DR DANIEL J. BOFFA (Cleveland, OH): In looking at the survival curve, did you look at cancer-specific survival? That's my first question. Second of all, you discussed neoadjuvant therapy. Did you compare the use of adjuvant therapy in the two groups, in the younger and the older patients?
DR CERFOLIO: Your first question is about cancer-specific survival. This is a common question and one we often get from reviewers for our papers. The truth is I do not know the best answer. When we have tried to report cancer-specific survival we had one reviewer say, "How do you know that the patient that died in a car accident didn't have a stroke from a metastatic lesion in his brain and really he died from metastatic cancer as opposed to a car accident?" It's hard to argue with that type of reviewer's comment. On the other hand, we have reviewers who say we should look at specific cancer-related deaths. The truth is, if you try to do the latter, most patients' family members don't have that information. You call families and they say, "Oh, yes, my husband died 6 months ago." And when you ask form what, they usually say "I don't know. He died in his sleep; he had an arrhythmia and never got an autopsy." Or, if they state the cancer came back and you ask if it got biopsied the answer is usually no, just some new spots. So in this paper and in most of our work we look at overall deaths. Whether that's more accurate than cancer-related deaths, I don't know. But the data in our database is much more accurate when we use overall survival. Our data for cancer-related deaths is more limited because a lot of these elderly people die and they never get an autopsy and the real cause isn't known.
Your other question was about the use of adjuvant therapy. We are less likely to use adjuvant therapy in these elderly patients, and so the study was not matched for that variable. I'm much less likely to recommend a T2N0 lesion in a 77-year-old for adjuvant chemo than I would be a 67-year-old.
DR DANIEL L. MILLER (Atlanta, GA): Cerf, I enjoyed your paper, and, again, congratulations on the elderly award. You brought up a good point on your summary slide, and I think a lot of times when you do an elderly patient, they will be discharged to a secondary facility, like a nursing home or pulmonary rehab area. You didn't comment on that, but I wish you would comment. Was there a difference between the older and younger patients? And also, you just mentioned briefly about your adjuvant treatment. What is the feeling at UAB in regards to the adjuvant trials? Do you-all actually have a cutoff at 70, 75? I know a lot of places, instead of doing IV [intravenous] therapy, they are actually suggesting some oral, like Tarceva, and so forth.
DR CERFOLIO: The latter question, which I'll start with, is a great question. I think it depends on our oncologists. Often the creatinine clearance in the elderly patient is not high enough for the standard adjuvant chemotherapeutic regimen that one might administer to a younger patient. In general, if they are N0 and T2s, we have watched them. If they have had unrecognized N2 disease, which is pretty uncommon in these patients because we use PET [positron emission tomography] in all and mediastinoscopy and EUS-FNA [endoscopic transesophageal ultrasound-fine needle aspiration] liberally, then we do strongly recommend it. But in general, we don't use adjuvant therapy for complete resections.
Your first question concerns discharge to a nursing home. We get geared up preoperatively with these patients—they are set up to either go home to a younger healthy family member, who hopefully is still going to be friends with them a month later, or to a rehab center, and we let the patients know up front that's where they will most likely have to go. Most are very independent and dread this concept and so we tell them preop, that on POD [postoperative day] 3, 4, or 5, when they go home it is not realistic to think they can always care for themselves, especially because, in my practice, many have an elderly spouse who has health issues of their own. I do not know the numbers as to who went to what facility; I have not collected that data prospectively. I am sorry.
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