Background: Following curative surgery for non-small cell lung carcinoma (NSCLC), patients remain at risk for recurrence or for development of second primary lung cancer (SPLC). While regular surveillance imaging may detect early stage recurrence or SPLC, its effectiveness has not been established, and current practice guidelines conflict in terms of optimal frequency and modalities of surveillance. The purpose of this study is to evaluate the effectiveness of surveillance following curative surgery for NSCLC in comparison with usual care.

Methods: Electronic databases (MEDLINE, Embase, CINAHL, and Cochrane Library) were searched for pertinent studies published between 1990 and 2010. Major search concepts included non-small cell lung carcinoma, surveillance, curative resection, recurrence, and second primary lung cancer. Baseline data and results were pooled. Outcomes examined included rate of detection of recurrence, presence of symptoms at recurrence, and site of recurrence.

Results: 18 studies were included in this analysis. No randomized controlled trials were identified. A total of 699 recurrences and 88 second primary lung cancers were detected among 2716 patients. Of these, 53.1% of cases were detected by surveillance protocol. The majority of patients were symptomatic at detection (65.1%). Distant recurrence was more frequent than local recurrence (67% vs. 33%). Only 109 patients (13.9%) were offered a repeat surgery, primarily for SPLC.

Edwards TQH, Kuo YF, Sharma G (2013) Surveillance Following Lung Cancer Resection. Clin Res Pulmonol 1: 1001.

•    Lung cancer
•    Surveillance
•    Non-small cell lung cancer
•    Outcomes
•    CT chest

ACCP: American College of Chest Physicians; CINAHL: Cumulative Index to Nursing and Allied Health Literature; CT: Computed Tomography; MeSH: Medical Subject Headings; MRI: Magnetic Resonance Imaging; NCCN: National Comprehensive Cancer Network; NSCLC: Non-Small Cell Lung Carcinoma; PET: Positron Emission Tomography; PRISMA: Preferred Reporting Items for Systematic Reviews and MetaAnalyses; RCT: Randomized Controlled Trial; SPLC: Second Primary Lung Cancer; TNM: Tumor-Node-Metastasis; US: United States

Lung cancer is the leading cause of cancer death among men and women in the U.S. Non-small cell lung cancer (NSCLC) comprises about 80% of primary lung cancers. An estimated 219,440 NSCLC cases were diagnosed in the U.S. in 2009 [1]. Curative-intent surgeries offer the best chance for survival in these patients. However, only 15% of patients have localized disease amenable to complete surgical resection at time of diagnosis [2].

Following curative surgery, patients remain at risk for recurrence or for development of second primary lung cancer (SPLC) [3]. Approximately 30%, 65%, and 80%, of patients undergoing resection for Tumor-Node-Metastasis (TNM) stage I, II, and III cancers, respectively, will have recurrence within 5 years [4-6]. Few of these recurrences are amenable to a subsequent curative resection. Second primary lung cancers will develop in approximately 2-3% of these patients each year, a risk that remains relatively constant in the first 5 years after primary resection [5,6-8].

Surveillance regimens following curative treatment for NSCLC generally consist of some combination of physical examination, laboratory studies, and imaging. No single modality is simultaneously sensitive, specific, safe, convenient, and costeffective. Thus, combining strategies is preferred so as to optimize detection of recurrence or SPLC, with the goal of facilitating potentially curative treatment or early palliation.

To date, no published prospective, randomized trials have evaluated surveillance in asymptomatic patients following curative resection for NSCLC. Likewise, no consensus among national guidelines exists for modes or frequency of surveillance.

The American Society of Clinical Oncology recommends posttreatment surveillance with history and physical exam alone. In contrast, the American College of Chest Physicians (ACCP), and American College of Radiologists recommend the use of chest X-ray and the National Comprehensive Cancer Network (NCCN) recommends use of computed tomography (CT) for surveillance [9,10]. None of these recommendations are based on level 1 evidence.

While periodic surveillance may benefit NSCLC survivors by detecting early stage recurrence or SPLC, it bears the potential harm inherent in disease screening. It has not been established if post-surgical surveillance affects cancer-related or overall mortality. Any perceived benefit may be attributable to leadtime bias. Additionally, the risk of adverse outcomes related to treatment of benign nodules is not insignificant. Furthermore, the cost of surveillance studies and associated treatments must be considered.

The purpose of this systematic review is to evaluate whether the use of surveillance following curative surgery for NSCLC is effective in diagnosing recurrent NSCLC or SPLC in asymptomatic patients, in comparison to usual care defined as symptom triggered workup for reoccurrence. This study aims to compare patterns of surveillance testing after curative surgical resection for NSCLC, and to examine the relationship between surveillance imaging and disease-free survival, overall survival, and cost.

The PRISMA guidelines for systematic reviews were used for this study [11,12]. Electronic databases (MEDLINE, EMBASE, CINAHL, and Cochrane Library) were searched for pertinent studies published between 1990-2010. Other sources of data included meeting abstracts, completed studies, and references cited in the studies were identified. Major search concepts included non-small cell lung cancer, surveillance, curative resection, recurrence, second primary lung cancer, CT, and chest X-Ray. These concepts and their synonyms were exploded to include all Medical Subject Headings (MeSH) Subheadings. No other search filters were used. Non-English results were included in the screening.

Cohort and case-control studies were examined. Surveillance modalities of interest included chest x-ray, physical exam, CT, and positron emission tomography (PET). The types of outcome measures studied included detection of recurrent NSCLC, detection of second primary lung cancer, site of recurrence or second primary, rates of asymptomatic presentation, and rates of second curative-intent resection.

All pertinent studies were retrieved and independently screened. Data from each study were extracted by the primary investigator. The Cochrane Collaboration’s tool for assessing risk of bias was used to evaluate each study. Although this tool was designed to aid assessment of randomized controlled trials, many aspects of the tool remained applicable. Individual studies were evaluated on the basis of generalizability, sample size, dropout rate, and statistical methodology. No studies were excluded on the basis of quality. Baseline data and results from the individual studies were pooled. Due to study heterogeneity, a formal metaanalysis could not be performed.

A flow diagram of the search strategy is shown in Figure 1. The initial database search generated 64 records. An additional 5 records were identified during review of meeting abstracts, unpublished studies, and cited references. After duplicates were removed, 61 unique records were screened. Because they did not meet the study criteria, 31 records were excluded. The remaining 30 full-text articles were assessed for eligibility. Four case studies, 2 editorials, 2 review articles, and 2 survey-based studies were excluded. One article employing computer-based economic modeling and 1 clinical trial design was also excluded. The 18 remaining original studies were included in the qualitative analysis. Characteristics, including study date, design, sample size, demographics, primary tumor characteristics, primary treatment, and rate of recurrence are shown in Table 1.

Baseline characteristics

Baseline characteristics of the study population are summarized in Table 2. Not all data were available for every patient. In total, 4119 patients were involved in these 18 studies. The median age of the study population was 63.3 years, and most male. Information on primary tumor histology was available for 3669 patients. The primary NSCLCs included 46.8% adenocarcinoma and 40% squamous cell carcinoma. Postresection stage information was available for 3776 patients. The stage distribution included 54.2% stage I, 18.9% stage II, 25.9% stage III tumors, and 0.4% stage IV tumors. Information on primary surgical treatment was available for 2243 patients. The most common surgical procedures were lobectomy (71.8%), followed by pneumonectomy (22.3%), and wedge resection (5.5%). Approximatly one quarter of the patients underwent adjuvant chemotherapy following their primary surgery.

Surveillance protocols

Reported surveillance protocols are summarized in Table 3. Although no 2 protocols were identical, there were notable trends. The most commonly employed modalities were physical exam, chest x-ray, and CT of the chest. Many protocols included physical exam and chest x-ray at every visit, with more advanced radiological modalities being used at less frequent intervals (e.g., every other visit) or as confirmatory studies. There was a trend toward more frequent monitoring in the first 2 years after surgery, with surveillance tapering thereafter. The majority of follow-up post resection was performed by thoracic surgeons.

Detection of recurrent NSCLC or second primary lung cancer

Patient data from the studies were pooled for analysis. Not all data of interest were available for each patient. Summary measures are shown in Table 4. A total of 699 recurrences (25.7%) and 88 SPLCs (3.2%) were detected among 2716 patients. Information on mode of detection was available for 392 cases. Of those, 208 (53.1%) were detected by surveillance protocol and 184 (46.9%) were detected by usual care (p=0.2195). Presence or absence of symptoms was available for 625 patients with recurrence or SPLC. Among those 625 patients, 407 (65.1%) were symptomatic at the time of detection and 218 (34.9%) were asymptomatic (p<0.001). Site of recurrence was available for 699 cases. Of those, 231 (33%) were local, 399 (57.1%) were distant, and 69 (9.9%) were both (p<0.001). Notably, of the 787 recurrences and SPLCs, only 109 (13.9%) were offered a second surgery. The majority of these surgeries (77%) were for SPLC.

Disease-free interval

Younes and colleagues found no difference in disease-free interval between patients monitored via a surveillance protocol and those given usual care [18]. In a series of 239 patients with recurrent NSCLC or SPLC, Egermann and colleagues found no correlation between disease-free interval and duration of survival after the second curative surgery [22]. In contrast, Walsh and colleagues determined that a disease-free interval greater than 12 months was the most important predictor of survival after recurrence.

Survival

Associations between surveillance protocols, mode of presentation (asymptomatic or symptomatic), site of recurrence, and overall survival were conflicting. In a retrospective analysis of 182 patients, Virgo and colleagues found that patients intensively followed after primary resection survived an average of 192 days longer than those without intensive follow-up [14]. Walsh and colleagues found that mode of presentation and site of recurrence did not significantly affect survival in a series of 358 patients. Egermann and colleagues found no significant difference in survival between patients who underwent a second curative-intent resection for recurrent NSCLC or SPLC and those who did not [22].

Cost-effectiveness

Egermann and colleagues examined the cost associated with surveillance and second curative-intent treatment for a series of 563 patients [22]. A total of 239 cases of recurrence and SPLC were detected, with over 70% of the cases occurring in the first year after primary surgery. Only 23 patients were eligible for a second curative resection. Of these, 21 cases were identified as SPLC, and 15 were detected by surveillance. Taken together, the 23 patients gained a calculated benefit of 17 additional life-years. The associated cost per life-year gained was approximately 56,000 US dollars. Based on these cost estimates, the authors recommended a strategy consisting solely of chest X-ray every 6 months for the first 5 years after primary surgery.

Using Medicare fee schedules, Korst et al. compared the cost of surveillance CT scans and associated care in a cohort of 213 patients with a hypothetically identical cohort not subjected to surveillance scans [26]. The authors estimated that the cost in the surveillance group would be 16.6% higher than for the hypothetical usual care group.

Prognostic indicators

Nakamura and colleagues conducted the largest retrospective review to date, with a population of 1,398 patients treated between 1980-2008 [30]. Using univariate and multivariate analyses, they concluded that age less than 65 years, female sex, early stage disease (TNM stage I or II), lack of adjuvant therapy, and a Charlson Index score of 0-1 were all positive prognostic factors for survival. Similarly, Westeel and colleagues identified asymptomatic recurrence, female sex, performance status of 2 or less, and age 61 years or younger as favorable prognostic indicators [20]. In contrast, Gilbert and colleagues sought to identify factors that negatively impacted survival [19]. In their study of 245 patients with initial early stage NSCLC, negative prognostic factors included a disease-free interval of less than 12 months, advanced tumor stage at time of recurrence or SPLC, and presence of symptoms at detection of recurrence.

No current practice guidelines exist for surveillance following curative-intent surgery for NSCLC based on high-grade evidence. As a result, wide variation exists in both the type and frequency of surveillance investigations employed. Nonetheless, trends in results were noted both within studies and with the pooled data. Rates of recurrence and detection of SPLC are high. Evidence from these studies suggests that surveillance protocols do not appear significantly better at detecting these recurrences than usual care. This is supported by the finding that many patients are already symptomatic at presentation for work-up. Furthermore, recurrences are more likely to be distant. This may represent a failure of surveillance strategies that focus on lung alone, and do not take into account common sites of distant disease, such as bone. Alternatively, this may imply that many early “recurrences” actually represent progression of micrometastases undetected at time of primary staging and treatment.

Only 1 study found a survival difference between patients under surveillance and those who received usual care. Several studies reported no significant difference in survival with active surveillance. These findings further argue against the utility of surveillance protocols. Any perceived benefit of active surveillance may be related to lead-time bias, without an associated survival advantage.

Additionally, the costs of surveillance tests and associated work-up are significantly higher than the cost of usual care. Even when a modest survival benefit of surveillance is assumed, the costs per life-year gained remain high. Given the prevalence of NSCLC, the cumulative cost of surveillance care represents a sizable expenditure.

Nonetheless, some nuances of the physician-patient relationship are not highlighted by these studies, which may influence the use of surveillance imaging. First, there is a gap between what a patient may want to know about disease progression or recurrence and what a physician is capable of treating or curing. Poor understanding of the prognosis associated with recurrence or SPLC may unduly increase the use of surveillance. Secondly, physicians may be motivated to apply surveillance strategies to improve patient satisfaction, for medicolegal purposes, or simply to assess the outcomes of the care they are providing.

Novel treatment strategies have improved survival in earlier stage NSCLC [31]. Adjuvant therapy with cisplatin-based chemotherapy agents have been shown to improve cure rates [32]. Similarly, concurrent chemoradiation therapy has been shown to improve survival, with increased benefit over radiation alone [33]. In addition, growing interest in genotyping and personalized medicine has led to the identification of genetic variants associated with response to treatment and with survival [34]. Given these advances beyond the mainstay of surgical resection, the role of surveillance imaging may be evolving and could be significant.

It is important to note that only 5 of the studies examined in this review involved the use of PET scans, and only 2 incorporated PET scans at regular intervals. PET scans have traditionally been utilized for secondary investigation of suspicious lesions, but as their availability has grown, so has their routine use. Since the majority of recurrent lung cancers are extrapulmonary, PET scans have become an attractive and viable option for whole body imaging in post-treatment surveillance. Nonetheless, the effectiveness of PET scans as a surveillance tool in comparison to x-ray and CT remains unclear. More studies using PET scans as a primary surveillance tool are needed to address this issue.

Taken alone, these studies argue against surveillance as efficacious and cost-effective in detecting recurrence following curative-intent surgery for primary NSCLC. However, this systematic review is limited by the strength of evidence currently available. The included studies were all cohort or case-control studies, mostly reflective of various institutions’ anecdotal experience. Data for all study patients were incomplete, limiting the strength of the statistical analysis.

The recently published results of the large National Lung Screening Trial suggest a mortality benefit in high-risk patients screened annually with low-dose CT [35]. Although this study was focused on screening prior to diagnosis of a primary lung carcinoma, it calls into question again the potential benefit of surveillance following treatment for lung cancer. With routine screening, most patients will be diagnosed at an early stage potentially amenable to curative surgery increasing the number of patients in the surveillance pool. Evidence from randomized, controlled trials (RCTs) would be most useful in determining best practice guidelines for this area. One large RCT, currently underway in France, is expected to conclude in 2014, with 10 years of data to be collected [36]. While we await these results, we must continue to weigh the risks and benefits of routine surveillance in the context of patient-centered care, and to strive towards advances in the treatment of NSCLC.

Tu-Quynh H. Edwards, MD, MS has no conflicts of interest to disclose.

Yong-Fang Kuo, PhD has no conflicts of interest to disclose.

Gulshan Sharma, MD, MPH has no conflicts of interest to disclose.

The authors have reported no potential conflicts of interest exist with any organizations whose services may be discussed in this article.

The authors thank Sarah Toombs Smith PhD for help in preparation of the manuscript.

Dr. Edwards was a student in the UTMB Clinical Science Graduate Program, which is supported in part by a Clinical and Translational Science Award (UL1RR029876) from the National Center for Research Resources, National Institutes of Health, at the time this research was conducted.

Dr. Edwards is a junior co-investigator member of the Comparative Effectiveness Research on Cancer in Texas (CERCIT) consortium, which is funded by the Cancer Prevention and Research Institute of Texas (CPRIT) [Grant RP101207]. Dr. Sharma is supported by K08-AG31583 mentored career development award from the NIA.

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