Ann Thorac Surg 2003;76:1001-1008
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
The risk of second primary tumors after resection of Stage I nonsmall cell lung cancer
David Rice, MB, BCha*,
Hyung-Woo Kim, MSd,
Anita Sabichi, MDb,
Scott Lippman, MDb,c,
J. Jack Lee, PhDd,
Brendell Williams, RNd,
Ara Vaporciyan, MDa,
W. Roy Smythe, MDa,
Stephen Swisher, MDa,
Garrett Walsh, MDa,
Joe B. Putnam, Jr, MDa,
Waun Ki Hong, MDc,
Jack Roth, MDa
a department of Thoracic and Cardiovascular Surgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
b department of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
c department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
d department of Biostatistics, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
* Address reprint requests to Dr Rice, Department of Thoracic and Cardiovascular Surgery, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 445, Houston, TX 77030, USA.
e-mail: drice{at}mdanderson.org
Presented at the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31–Feb 2, 2003.
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Abstract
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BACKGROUND: The incidence of second primary lung cancers (SPLC) after resection of nonsmall cell lung cancer (NSCLC) is estimated to be 1% to 4% per patient year. The overall effect of SPLC on survival after resection of stage I NSCLC is unknown. Here we report the incidence, management, and outcome of SPLC in a large prospective cohort of patients who underwent careful follow-up.
METHODS: National Cancer Institute Intergroup Trial NCI #I91-0001 examined the effectiveness of isotretinoin A for chemoprevention of second primary tumors, the primary endpoint in that trial. Prospective data from patients randomly assigned to the placebo arm were analyzed.
RESULTS: Five hundred sixty-nine patients underwent complete resection of pathologic stage I NSCLC. The median follow-up was 5.9 years. Second primary tumors developed in 88 (15%) patients. Of these, 49 (56%) were SPLC (incidence = 1.99/100 patient-years), with a median interval from initial surgery of 4.2 years. Second primary lung cancer never developed in patients who had never smoked (n = 44, p = 0.046; never versus ever smokers). Current smokers had a higher incidence of SPLC than former smokers (hazard ratio = 1.91, p = 0.03). Age, sex, stage, histology, tumor location and initial surgery had no effect on SPLC development. Despite semiannual follow-up with chest radiographs, 12 (24%) patients had metastatic disease at the time of diagnosis of SPLC. Surgical resection was performed in 31 (63%) SPLC patients. Median survival was 4.1 years in those who underwent surgery and 1.4 years in those who did not (p = 0.003). Overall SPLC-related mortality in the original cohort was 3.7%.
CONCLUSIONS: Patients who undergo surgery for SPLC can achieve prolonged survival. Despite close follow-up however many patients with SPLC present with advanced disease. That indicates a need for continued lifelong postoperative surveillance.
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Introduction
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Lung cancer is the leading cause of cancer-related death in the United States and is responsible for more than 157,000 deaths annually [1]. The 5-year survival rates in patients undergoing complete resection of stage I nonsmall cell lung cancer (NSCLC) are 67% for those with pathologic stage T1N0 disease and 57% for those with stage T2N0 [2]. Although most cases of treatment failure are due to tumor recurrence, second primary lung cancers (SPLC) develop in a significant proportion of patients. The incidence of SPLC after resection of NSCLC has been estimated to be 1% to 4% per patient year [3–6]. However few studies have attempted to determine the true incidence of SPLC in a prospective fashion and the overall effect of SPLC on survival after the resection of early-stage NSCLC is unknown. We therefore examined the risk of SPLC in a prospectively observed cohort of patients who had undergone complete resection of pathologic stage I NSCLC. In addition we examined the management of SPLC and its relative contribution to overall mortality in this patient population.
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Patients and methods
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Patients
Patients who had undergone complete resection of Stage I NSCLC were recruited in a multicenter National Cancer Institute intergroup trial (NCI #I91-0001) between December 1992 and April 1997 to examine the effect of postoperative oral isotretinoin versus placebo in preventing the development of second primary tumors [7]. This study population was therefore ideal for the prospective analysis of the risk of SPLC after resection of NSCLC. Although the NCI study revealed that postoperative administration of isotretinoin had no statistically significant effect on the development of SPLC, to avoid any possible confounding influence we analyzed data only from patients in the placebo arm of the study. All patients underwent complete resection of pathologically staged T1N0 or T2N0 NSCLC (according to the 1997 international TNM classification system for lung cancer). Current smokers were defined as active smokers and those who had stopped smoking less than 1 year before registration; former smokers were defined as those who had not smoked for 1 or more years; and never smokers were defined as those who had smoked fewer than 100 cigarettes in their lifetime.
Follow-up evaluation
Postoperative follow-up included clinical examination, chest posteroanterior and lateral radiographs, complete blood count and serum chemistry tests at 3 months, 6 months, and semiannually thereafter or more frequently if clinically indicated. The primary endpoint was the development of a second primary tumor. Recurrence and overall survival were secondary endpoints. All subsequent cancer events were verified histologically and classified as either a second primary or a recurrence. New lung lesions were considered to be SPLCs if they met at least one of the following criteria: (1) different histology from that of the primary tumor; (2) if histology was similar, occurring either in a different lobe than the primary tumor in the contralateral lung; or (3) occurring more than 5 years after the primary tumor. All endpoints were reviewed and confirmed by the Endpoint Review Committee. Five hundred seventy-seven patients were randomly assigned to the placebo arm. All patient records were reviewed to ensure the accuracy of the patients' status. This revealed that 7 had disease other than stage I at the time of their initial treatment and these patients were therefore excluded from further analysis. Another patient was excluded because of synchronous tumors at presentation. Endpoint data from the remaining 569 subjects were entered prospectively until July 2002. The median length of follow-up from the date of surgery was 5.9 years.
Statistical analysis
The time to SPLC or recurrence was measured from the first day of surgery for the first primary tumor until the date of the diagnosis of SPLC or recurrence. Survival was measured from the day of surgery for the first primary, unless otherwise stated, and was estimated using the Kaplan-Meier product limit method. Groups were compared using the log-rank test. Univariate and multivariate proportional hazards models were used to test for prognostic effects in the presence of covariates. For the categorical variables, the differences among cohort groups were tested using Pearson's 
2 test or Fisher's exact test. The association between the histology of the first primary tumor and that of the SPLC was estimated by Kappa statistic, a chance-corrected measure of agreement. Kappa equals 1 when there is perfect agreement and it equals 0 when the agreement occurs by chance alone.
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Results
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The study cohort consisted of 569 patients. There were 322 (57%) male and 247 (43%) female patients. The mean age at the time of treatment for the first primary tumor was 63.4 years. Tumor stage was T1N0 in 303 (53%) patients and T2N0 in 266 (47%). One hundred nineteen (21%) patients suffered recurrence at a median of 24 months (range, 5.5 to 103) after surgery. During the follow-up period second primary tumors occurred in 88 (15%) patients; 49 (56%) of these were SLPC (Table 1).
Patient demographics and the criteria used for the determination of SPLC are outlined in Tables 2 and 3,
respectively.
The median interval between surgery for the first primary tumor and the diagnosis of SPLC was 51 months (range, 7.5 to 108). The overall incidence of SPLC was 1.99 per 100 patient-years, and the cumulative risk of SPLC increased with time from the initial resection (Fig 1). Neither univariate nor multivariate analysis showed the development of SPLC to be associated with age, sex, anatomic versus nonanatomic resection, T stage, tumor location, or histology of the first primary (Table 4).
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Fig 1. Cumulative incidence of second primary lung cancer (SPLC) after resection of initial primary tumor. (Dashed lines = 95% confidence interval.)
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When cigarette use before the initial resection was analyzed it showed that SPLC did not develop in patients who had never smoked (n = 44, p = 0.046; never versus ever smokers; Fig 2).
Furthermore SPLC was more likely to develop in patients who were current smokers at the time of resection of the first primary tumor than in patients who were former smokers (p = 0.03). The incidence of SPLC was 1.77 per 100 patient-years for former smokers and 2.71 per 100 patient-years for current smokers. Multivariate analysis confirmed that smoking status (current versus former) at time of initial surgery, was a statistically significant predictor of the development of SPLC (p = 0.02, hazard ratio = 1.9).
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Fig 2. Effect of smoking status on cumulative incidence of second primary lung cancer (SPLC), p = 0.01. Solid line = current (n = 230); broken line = former (n = 295); dashed line = never (n = 44).
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Second primary tumors were histologically confirmed in 46 (94%) patients. Because of poor physiologic status, diagnosis of SPLC was based on clinical and radiographic features in 3 (6%) patients. The histology of the SPLC was the same as that of the first primary tumor in 24 (52%) patients (Table 5).
When comparing SPLC of squamous and adenocarcinoma histology Kappa statistics revealed an association between the histology of the first and second primary tumors (0.45; 95% confidence interval = 0.12 to 0.77). The agreement was moderate but significantly better than by chance alone, suggesting that patients who develop SPLC are more likely to develop tumors of similar histology to their primary lung cancer. The stage distribution of SPLC was as follows: stage Ia, 19 patients (40%); stage Ib, 4 patients (8%); stage IIa, 5 patients (10%); stage IIb, 4 patients (8%); stage IIIa, 4 patients (8%); and stage IV, 12 patients (25%). Accurate staging information was unavailable in 1 patient. Thirty-two SPLCs (65%) occurred in the contralateral lung and there was no significant difference between the first and second primary tumors in terms of anatomic distribution (Table 6).
Forty patients (82%) were asymptomatic at the time of SPLC diagnosis and showed abnormal findings on follow-up chest radiography. The remainder presented with respiratory symptoms (4 patients), weight loss (2 patients), and hoarseness, bone pain, and a supraclavicular mass (1 patient each).
Thirty-one (63%) patients underwent surgical resection of their SPLC. The surgical procedures performed for SPLC are outlined in Table 7.
Nonanatomic resections including wedge resection and segmentectomy were performed more frequently for SPLC than for the first primary (27% versus 6%, p < 0.001). Operative mortality was 0%. Eighteen patients were managed nonoperatively for the following reasons: known metastatic disease (11 patients), inadequate respiratory reserve or poor performance status (5 patients), and patient refusal (2 patients). Overall median survival was 2.8 years. Median survival was 4.1 years for patients who underwent surgery and 1.4 years for patients who did not (p = 0.003). At the time of the last follow-up 16 (33%) patients were alive without evidence of disease, 3 (6%) patients were alive with disease, 21 (43%) had died of disease, 6 (12%) had died from other causes, and 3 (6%) patients had unknown causes of death. The SPLC-related mortality for the entire 569 patient cohort was 3.7%. In comparison mortality related to primary tumor recurrence was 18% with a median survival after recurrence of 0.8 years (Fig 3).
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Table 7. Surgical Procedures Performed for First and Second Resection in 49 Patients With Second Primary Lung Cancer
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Fig 3. Actuarial survival of 569 patients after resection of stage I nonsmall cell lung cancer, p = 0.0001. Dashed line = others (n = 362); broken line = non–lung second primary tumor (n = 39); solid line = second primary lung cancer (n = 49); dotted line = recurrence (n = 119).
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Comment
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The diagnosis of SPLCs can be challenging. Different histology between primary and secondary tumors is considered a reliable indicator. In the event of similar histology Martini and Melamed [8] proposed the following criteria to establish a metachronous tumor as a separate primary: (1) an interval greater than 2 years between the first and second tumors; and (2) occurrence of the tumor in a different lobe or lung provided that there are no metastases in shared lymph node basins and that there are no extrapulmonary metastases at the time of diagnosis. Other authors maintain that a tumor interval of 3 years is more discriminatory [9]. In the present series 24 of 49 patients had tumors with a similar histology; however 10 of these patients had an interval greater than 5 years between the first and second tumors. Of the remaining 14 patients none of the second tumors were associated with N2 or distant metastatic disease and only 5 patients had a tumor interval of less than 2 years (all pathologic stage I). When the survival of patients after SPLC was analyzed according to tumor interval there was no difference between patients with a tumor interval less than 5 years and patients with an interval greater than 5 years, suggesting that the former group did not include recurrences of the primary tumor. Therefore we believe that the criteria used to differentiate second primaries from recurrent tumors were both rigorous and reliable.
The reported incidence of SPLC varies [3, 9–19]. In the study of Faber and associates [9] of 2,867 patients with resected lung cancer, 114 (4%) patients underwent resection of SPLC. Deschamps and associates [3] identified SPLC in 117 patients (1.2%) of a total of 9,611 patients with NSCLC seen at the Mayo Clinic. Neither study was limited to early-stage patients however, as ours was. In a more recent study Martini and associates [14] reviewed 598 patients with completely resected stage I NSCLC and found SPLC developed in 45 patients, yielding a cumulative incidence of 7.5%, which is similar to the one we observed (8.6%). The overall incidence of SPLC will be underestimated in study populations consisting of only surgically treated patients as many patients diagnosed with SPLC do not undergo a repeat resection. In addition the results of large population-based studies such as those by Levi and associates [20], Teppo and associates [17], and Boice and Fraumeni [18] are often misleading. Because the overall numbers of SPLC's reported in these registry-based series are unusually small it is likely that a significant number of SPLCs were either missed, not reported, or misdiagnosed as primary tumor recurrences. In addition SPLC will be underdiagnosed in the absence of diligent long-term postoperative surveillance and standardized criteria defining what constitutes a second lung primary.
There have been few prospective studies that have specifically examined the incidence of SPLC in patients with early-stage lung cancer. Pairolero and colleagues [4] examined a series of 346 patients with postsurgical pathologic stage I NSCLC who were enrolled in a close surveillance follow-up program at the Mayo Clinic. The incidence of SPLC was 2.6 per 100 patient-years for the first 5 years of observation and 0.8 per 100 patient-years thereafter. The overall incidence was 2.2 per 100 patient-years, which is similar to the rate we report. Thomas and associates [21] analyzed data combined from three Lung Cancer Study Group trials. The patients included those enrolled in a natural history study of T1N0 disease, a limited resection trial, and a bacille Calmette-Guerin (BCG) immunotherapy trial. In total 973 patients all had resected T1N0 disease. In contrast to the Mayo Clinic study, this study found the rate of SPLC was 0.9 per 100 patient-years for the first 5 years and 2.0 per 100 patient-years subsequently. Both studies however showed differences in the rate of SPLC with time. We did not observe this phenomenon in our series; the rate of SPLC was relatively constant. Two other prospective lung cancer chemoprevention studies have also documented the incidence of SPLC. The EUROSCAN trial examined the use of postoperative vitamin A and N-acetylcysteine in 1,023 patients with resected stage I–III NSCLC [10]. Remarkably SPLC developed in only 39 patients. The rate of SPLC in the placebo group was not specifically described however. Pastorino and associates [11] investigated the effectiveness of vitamin A as a chemopreventative agent in 307 patients with resected stage I NSCLC. At a median follow-up of 46 months SPLC had developed in 21 of 157 patients in the control arm (13.3%). The risk per patient year was not reported but has been estimated to be 1.5% to 2% per patient-year [22], similar to the incidence we report.
The association between cigarette smoking and SPLC development was striking. Although only 44 patients who had never smoked were enrolled in the study, SPLC did not develop in any after resection of their primary tumor. In addition it appeared that continued smoking up to the time of surgery significantly increased the risk for SPLC. Unfortunately the amount patients smoked was not documented in this trial although duration of smoking was found not to be a significant risk factor. There have been only a few studies that have evaluated the association between smoking and the development of SPLC after treatment of NSCLC. In one study Abbey Smith and associates [23] evaluated 39 patients with SPLC, all of whom smoked, and compared the findings in them with those in case-matched patients with single primaries. Patients with SPLC smoked significantly more cigarettes per day than patients without SPLC. Tucker and associates [24] have reported similar findings in long-term survivors of small cell lung cancer. Among patients surviving at least 2 years after treatment for small cell lung cancer the risk of SPLC was significantly greater among patients who continued to smoke after the diagnosis of their primary tumor compared with those who quit. Furthermore for patients who quit smoking, the time of smoking cessation appeared to influence the risk of SPLC. Patients who stopped smoking at the time of diagnosis of small cell lung cancer had higher rates of SPLC than patients who had quit before the diagnosis. As we also found, SPLC did not develop in patients who had never smoked.
Most of the SPLCs identified in our series were early-stage tumors and the majority were amenable to salvage therapy. Despite close follow-up, however, 12 patients had distant metastatic disease at the time of diagnosis and 4 patients had N2 metastases (33% of 48 adequately staged patients). Similar proportions of patients with advanced disease have been found in other studies that involved close postoperative surveillance [13, 16]. In our study the median diameter of stage IIIA and IV SPLC was 2.1 cm (mean, 2.7 cm), well within the resolution of conventional chest roentgenography. This was not significantly different from the size of stage I and II SPLC (median, 2.0 cm; mean, 2.5 cm). Although it is likely that more sensitive screening modalities such as computed tomography or positron emission tomography would have been able to detect these lesions earlier in time it is debatable whether this would have altered the natural course of the tumors. In fact there is evidence to suggest within the context of T1 (< 3 cm) lesions that tumor size does not have a significant effect on stage distribution or survival [25]. It may therefore be that postoperative surveillance with higher resolution imaging studies would not significantly affect the overall outcome in patients SPLC. This study was not designed to determine the optimal method of postoperative follow-up for early stage NSCLC and no firm conclusions can be drawn from it in this regard. Further randomized prospective trials will be required to answer this important question.
The majority of the patients in this series (63%) underwent reoperation for SPLC. However the observed survival benefit of surgery is skewed by the fact that most of the patients who underwent nonoperative treatment had metastatic disease. Nevertheless surgery for SPLC resulted in a median survival of 4.1 years and 14 (45%) patients were alive without evidence of disease at a median of 2.7 years (range, 0.9 to 5.6) after resection of SPLC. Furthermore 2 other patients with SPLC treated nonoperatively, 1 with radiation therapy alone and 1 with radiation therapy and chemotherapy, were both alive without recurrent disease after 2.3 and 1.5 years, respectively. These data suggest that intervention for SPLC is feasible and can result in prolonged survival. The potential to improve survival coupled with the fact that most SPLCs are asymptomatic at the time of diagnosis suggest that careful postoperative surveillance of patients with early-stage NSCLC is warranted. Furthermore because 43% of SPLC in this study occurred after 5 years and we found no evidence to suggest that the risk of SPLC diminishes with time, we recommend lifelong screening for patients with a history of smoking who have been cured of their primary NSCLC.
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Acknowledgments
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Supported in part by Public Health Service grants CA45809 and CA16672 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; by the National Institutes of Health Lung Cancer SPORE 2P50CA70970–04; and by the Tobacco Settlement Funds as appropriated by the Texas State Legislature. We thank David Galloway and Nora Rios for their editorial assistance.
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Discussion
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DR L. PENFIELD FABER (Chicago, IL): I would like to congratulate Dr Rice and his coauthors on an excellent presentation and for critically analyzing this cohort of patients that were actually ideal for the evaluation of second primary lung cancer.
We analyzed our results at the Rush-Presbyterian-St. Luke's Medical Center and reported on 114 patients with second primary lung cancers who underwent resection. Our operative mortality was 8.8% and actual survival after the second operation was 33%. This present study emphasizes the importance of thoracic surgeons providing lifetime follow-up of the patients they operate on. This study indicates an annual incidence of 2% for the development of a second primary lung cancer and others report similar incidents. Retrospective studies reveal an overall cumulative incidence of 5%. Ours was 4% in 2,867 prior resections. The authors are to be commended on a 9% operative mortality. Ours was 8.8% and other reports vary from 4% to 8%. However, most other series include all stages of disease at the time of the initial resection and this series only includes stage I resected patients. Our series included 14 patients with a prior pneumonectomy. The authors operated on 31 of 49 patients with a second primary lung cancer. There were 12 wedge resections and only 1 segmentectomy. I would like to emphasize consideration of an anatomic segmental resection if the second lesion is under 3 cm in diameter and regional nodes are negative. We performed 64 segmental resections in our series, and long-term results are comparable. A paper to be presented on this program supports this concept and segmental resection can minimize mortality.
This report strongly suggests that we should reassess how we follow up lung cancer patients after resection. Eighty-two percent of patients were asymptomatic at the time of diagnosis of the second primary and in our series we had 78% of patients asymptomatic. A critical finding in this series was that 12 of 49 patients, or 28%, had stage IV disease at the time of diagnosis of the second primary lesion. Routine follow-up was history, physical examination, and chest radiography at 6-month intervals. The authors suggest in their manuscript that earlier detection may not alter survival of second primary lung cancer patients. However, other series clearly indicate that stage is a predictor of survival and resected stage I patients have improved survival over stage II and III.
The routine use of low radiation dose spiral computed tomography could enhance early detection of the second primary lung cancer. A median survival of 2.7 years was achieved in 45% of the resected second primary lung cancers in this series. Others have reported actuarial survival as high as 44%. In our series actual survival was 33%. Additional reports vary from 23% to 31%. Patients who have a second primary lung cancer without evidence of metastatic disease should undergo surgical resection.
Doctor Rice, three questions. One, do you recommend resecting stage II and stage III lung cancer in patients with a second primary lung cancer? Two, as we advocate segmentectomy for second primary lung cancers to conserve lung tissue and minimize morbidity and mortality, is this type of resection a predictor of survival? Three, 80% of patients are asymptomatic at the time of diagnosis. What follow-up regimen do you now recommend for the future?
DR RICE: Thank you, Dr Faber, for your kind remarks. To answer your first question, whether or not we should perform resection for second primary lung cancers that are stage II and stage III, in our series if you look at the patients who are still alive without any evidence of disease, and albeit the median follow-up of those patients is only 2.7 years, nevertheless, approximately 40% of those patients had stage II disease. There has been no patient who had had a stage IIIa second primary lung cancer who underwent surgery who is a long-term survivor. So knowing that we are dealing with small numbers we would recommend surgery for patients who had adequate pulmonary reserve who had certainly stage I and stage II second primary lung cancers. I think that for stage III it would appear that since there were no long-term survivors, those patients may be better treated with radiation or chemotherapy.
To answer your second question regarding segmentectomy, our policy has been in patients who have adequate pulmonary reserve, at least at M.D. Anderson Cancer Center, we recommend performing a standard anatomic resection if they can tolerate it. I think that a segmentectomy is a good alternative. Unfortunately, the majority of patients have limited pulmonary reserve and a significantly greater proportion of wedge resections and segmentectomies were performed for this second tumor. I think that these patients are at risk of further lung cancers. We had only 1 patient who developed a third primary tumor, although one has to temper that with the knowledge that once patients had developed their second primary lung cancer they were taken off study. So there may be more patients who have developed third primary tumors that we do not know about. But certainly considering the continued risk of requiring a further operation it makes good sense to limit resection for that second tumor and perhaps consider segmentectomy rather than lobectomy.
Regarding the follow-up regimen, this is a very difficult question to answer and I do not think has been adequately addressed either by this study or by other studies in the literature. Truly, one needs a prospective randomized trial comparing intense follow-up versus less intense follow-up. With the advent of low dose CT scanning, certainly one can make a case for incorporating this into the follow-up of these patients. However, there is debate as when you are dealing with a sub-3 cm tumor whether or not tumor size at the time of diagnosis has a significant impact on survival. I think it will be very interesting to await the further data from the early lung cancer screening projects. Perhaps this will help answer the question. And I believe that there is also a proposal put before the American College of Surgeons Oncology Group to examine this question in the setting of a randomized prospective trial. Until then, our recommendation is that at least patients be followed up on a 6-month basis for the first 2 years with a physical examination and chest radiograph and then on at least a yearly basis after that.
Again, I would like to thank Dr Faber for his kind remarks and thank the Society for the opportunity and privilege of presenting these data here today.
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Abstract
Introduction
