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Imaging surveillance for surgically resected stage I non–small cell lung cancer: Is more always better?

Open ArchivePublished:October 24, 2018DOI:https://doi.org/10.1016/j.jtcvs.2018.09.119

      Abstract

      Objective

      Routine surveillance imaging for patients with resected non–small cell lung cancer is standard for the detection of disease recurrence and new primary lung cancers. However, surveillance intensity varies widely in practice, and its influence on long-term outcomes is poorly understood. We hypothesized that surveillance intensity was not associated with 5-year overall survival in patients with resected stage I non–small cell lung cancer. Additionally, we examined patterns of recurrence and new primary lung cancer development.

      Methods

      Cancer registrars at the Commission on Cancer accredited institutions re-abstracted records to augment National Cancer Database patient data with information on comorbidities, imaging surveillance including intent and result of imaging, and recurrence (2007-2012). Pathologic stage I non–small cell lung cancer patients undergoing computed tomography surveillance were placed into 3 imaging surveillance groups based on clinical practice guidelines: high intensity (3 month), moderate intensity (6 month), and low intensity (annual). Kaplan-Meier analysis and Cox regression were used to compare overall survival among the 3 surveillance groups.

      Results

      Two thousand four hundred forty-two patients were identified, with 805 (33%), 1216 (50%), and 421 (17%) patients in the high, moderate, and low surveillance intensity groups, respectively. Five-year overall survival was similar between intensity groups (P = .547). Surveillance on asymptomatic patients detected 210 (63%) cases of locoregional recurrences and 128 (72%) cases of new primary lung cancer.

      Conclusions

      In a unique national dataset of long-term outcomes for stage I non–small cell lung cancer, surveillance intensity was not associated with 5-year overall survival.

      Key Words

      Abbreviations and Acronyms:

      CoC (Commission on Cancer), CT (computed tomography), NCDB (National Cancer Database), NPLC (new primary lung cancer), NSCLC (non–small cell lung cancer), OS (Overall survival)
      Figure thumbnail fx1
      Patients receiving different intensities of CT surveillance have similar overall survival.
      Surveillance imaging intensity after resection for pathologic stage I non–small cell lung cancer is not associated with long-term overall survival.
      There are limited quality long-term data on postoperative imaging surveillance for patients with resected non–small cell lung cancer. Using a large, nationally representative database containing longitudinal data on surgically resected pathologic stage I non–small cell lung cancer patients, we compared 5-year overall survival among patients undergoing different imaging surveillance intensities.
      See Commentary on page 1218.
      See Editorial page 1194.
      Surveillance after lung resection remains a critical component of survivorship care for patients with stage I non–small cell lung cancer (NSCLC).
      • Mollberg N.M.
      • Ferguson M.K.
      Postoperative surveillance for non–small cell lung cancer resected with curative intent: developing a patient-centered approach.
      • Taylor M.D.
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      • Kozower B.D.
      • Lau C.L.
      • et al.
      Tumor recurrence after complete resection for non-small cell lung cancer.
      Surveillance imaging can allow for the early detection of recurrence or screening for new primary lung cancer (NPLC).
      • Calman L.
      • Beaver K.
      • Hind D.
      • Lorigan P.
      • Roberts C.
      • Lloyd-Jones M.
      Survival benefits from follow-up of patients with lung cancer: a systematic review and meta-analysis.
      • Lou F.
      • Sima C.S.
      • Rusch V.W.
      • Jones D.R.
      • Huang J.
      Differences in patterns of recurrence in early-stage versus locally advanced non-small cell lung cancer.
      For patients whose recurrence or NPLC is detected early, there is a possibility that additional curative intent therapy can be performed.
      • Calman L.
      • Beaver K.
      • Hind D.
      • Lorigan P.
      • Roberts C.
      • Lloyd-Jones M.
      Survival benefits from follow-up of patients with lung cancer: a systematic review and meta-analysis.
      Recommendations regarding surveillance imaging intensity after NSCLC resection vary widely in clinical practice. Existing current guidelines recommend visits as frequent as every 3 months to annual visits during the first 2 years.
      • Rubins J.
      • Unger M.
      • Colice G.L.
      • American College of Chest Physicians
      Follow-up and surveillance of the lung cancer patient following curative intent therapy: ACCP evidence-based clinical practice guideline (2nd edition).
      • Ettinger D.
      • Wood D.
      • Aisner D.
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      • Bauman J.
      • Chirieac L.R.
      • et al.
      Non–small cell lung cancer, version 5.2017. NCCN clinical practice guidelines in oncology.
      • Saunders M.
      • Sculier J.P.
      • Ball D.
      • Capello M.
      • Furuse K.
      • Goldstraw P.
      • et al.
      Consensus: the follow-up of the treated patient.
      The influence of surveillance imaging on long-term survival is poorly understood. The lack of consensus is due to limited quality longitudinal follow-up data on postresection patients.
      • Calman L.
      • Beaver K.
      • Hind D.
      • Lorigan P.
      • Roberts C.
      • Lloyd-Jones M.
      Survival benefits from follow-up of patients with lung cancer: a systematic review and meta-analysis.
      • Colt H.G.
      • Murgu S.D.
      • Korst R.J.
      • Slatore C.G.
      • Unger M.
      • Quadrelli S.
      Follow-up and surveillance of the patient with lung cancer after curative-intent therapy: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      We received support from the Patient Centered Outcomes Research Institute to study postresection cancer surveillance. Specifically, we planned 2 separate analyses focusing on the utility of imaging surveillance after resection of NSCLC. McMurry and colleagues
      • McMurry T.L.
      • Stukenborg G.J.
      • Kessler L.G.
      • Colditz G.A.
      • Wong M.L.
      • Francescatti A.B.
      • et al.
      More frequent surveillance following lung cancer resection is not associated with improved survival: a nationally representative cohort study.
      published the first analysis, which studied the influence of imaging surveillance intensity on overall and postrecurrence survival in surgically resected stage I to III NSCLC. Given anticipated stage-specific differences in surveillance practices, recurrence risk and survival, and the paucity of published stage-specific surveillance data, we performed a second planned analysis using independent study design and statistical methodology to examine imaging surveillance intensity in resected stage I NSCLC patients. Additionally, we describe the risk of development of recurrence and NPLC, method of detection of recurrent tumors, and postrecurrence treatment for this population.
      We performed a retrospective cohort study using supplemented data from the National Cancer Database (NCDB) to compare imaging surveillance in patients with pathologic stage I NSCLC. Our primary aim was to determine whether the intensity of surveillance with computed tomography (CT) was associated with 5-year overall survival (OS). We hypothesized that surveillance intensity was not associated with OS. Additionally, we performed descriptive analyses of disease recurrence (locoregional and distant), and development of NPLC.

      Methods

       Study Population and Cohort Selection

      Using the special study mechanism (described in the next section), we identified patients who underwent resection for pathologic stage I NSCLC. Patients were required to have undergone postoperative imaging surveillance. We only analyzed CT scans (as opposed to chest radiographs) based on published level I evidence advocating for CT imaging as standard of care in lung cancer screening.
      • Aberle D.R.
      • Adams A.M.
      • Berg C.D.
      • Black W.C.
      • Clapp J.D.
      • Fagerstrom R.M.
      • et al.
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      The National Lung Screening Trial randomized high-risk patients to receive low-dose CTs or standard chest radiograph.
      • Aberle D.R.
      • Adams A.M.
      • Berg C.D.
      • Black W.C.
      • Clapp J.D.
      • Fagerstrom R.M.
      • et al.
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      • Church T.R.
      • Black W.C.
      • Aberle D.R.
      • Berg C.D.
      • Clingan K.L.
      • Duan F.
      • et al.
      Results of initial low-dose computed tomographic screening for lung cancer.
      The trial found that CT scanning was associated with significantly higher detection of NSCLC and lower mortality. Given this level I evidence suggesting the superiority of CT imaging, only CT scans were considered for analyses. We a priori constructed surveillance intensity cohorts (high intensity, moderate intensity, and low intensity) based on current guidelines. We created visit windows to assign patients into these cohorts based on days from surgery to first surveillance CT. These visit windows included 60 to 150 days (3 months), 151 to 300 days (6 months), and 301 to 450 days (1 year) which corresponded to the high-, moderate-, and low-intensity cohorts, respectively.

       Data Abstraction

      To obtain the detailed level of information required for this study, registrars at Commission on Cancer (CoC) accredited institutions abstracted comorbidity, surveillance, and cancer recurrence/NPLC information utilizing the special study mechanism of the CoC, which supplemented data that already reside in the NCDB.
      Up to 10 NSCLC patients were randomly selected from each institution for further abstraction. These patients underwent surgery for clinical stage I to III NSCLC (January 2006-December 2007), were alive 90 days postsurgery, and had available medical records. Patients with unknown recurrence status were excluded without replacement from the same institution. Patients were followed for 5 years postdiagnosis or until death.
      Registrars obtained information on comorbidities, locoregional and distant recurrence, and development of NPLC for 5 years following surgery. Differentiation between disease recurrence and NPLC was based on original documentation by the treating clinician in the medical record. Locoregional recurrence was defined as tumor recurrence in the ipsilateral and/or regional lymph nodes, whereas distant recurrence was defined as tumor recurrence in the contralateral lung/lymph nodes or nonlung site.
      Detailed information on postoperative imaging, date, and indication for imaging were recorded. Indications included surveillance in absence of a new sign/symptom, follow-up for new sign/symptom, follow-up for suspicious finding on other imaging, imaging performed in response to newly detected malignancy, not cancer related, or unable to determine. Registrars used radiology reports as the primary source to obtain symptom status. They also had access to outpatient records, including clinic and consult notes from visits that preceded the scan and made mention of intent to order imaging as a consequence of a new sign or symptom. These notes were from primary care providers, medical oncologists, radiation oncologists, surgeons, or other relevant providers. When available, information was collected on whether or not a patient underwent treatment (eg, surgery, chemotherapy, radiation, or combination therapy) for recurrent disease. Registrars were trained by weekly webinars to standardize the abstraction process. Study data were merged with existing NCDB data by the CoC, de-identified, and provided to the study team. Data collection was completed in 2015. Data were deemed not human subjects research and were exempted from institutional review board review.

       Inclusion and Exclusion Criteria

      We restricted our study inclusion to patients with pathologic stage I cancer who underwent surgical resection and had their first surveillance imaging CT scan between 60 and 450 days after surgical resection. Additionally, patients must have been asymptomatic at the time of the first postoperative CT. We excluded patients who underwent chemoradiation therapy, had positive surgical margins, or for whom the indication for first surveillance CT was unknown (Figure E1).

       Descriptive and Inferential Statistics

      Descriptive statistics were reported using mean ± standard deviation for those variables that were approximately normally distributed, median (quartile 1-quartile 3) for highly skewed variables, and count (%) for categorical variables. Continuous variables were compared between the 3 cohorts using Kruskal-Wallis tests, whereas categorical data were assessed with χ2 or Fisher exact tests where appropriate. All P values were 2-tailed. For each treatment cohort, the median number of asymptomatic surveillance images per person-year were calculated. Person-years were defined as follow-up time until death, loss to follow-up, or first onset of recurrence/NPLC. Median numbers of surveillance images were reported for 2 person-years because the majority of existing practice guidelines are framed within the first 2 years of patient follow-up.
      • Rubins J.
      • Unger M.
      • Colice G.L.
      • American College of Chest Physicians
      Follow-up and surveillance of the lung cancer patient following curative intent therapy: ACCP evidence-based clinical practice guideline (2nd edition).
      • Ettinger D.
      • Wood D.
      • Aisner D.
      • Akerley W.
      • Bauman J.
      • Chirieac L.R.
      • et al.
      Non–small cell lung cancer, version 5.2017. NCCN clinical practice guidelines in oncology.
      • Saunders M.
      • Sculier J.P.
      • Ball D.
      • Capello M.
      • Furuse K.
      • Goldstraw P.
      • et al.
      Consensus: the follow-up of the treated patient.
      Cumulative incidences of locoregional/distant recurrence were estimated using competing risks analysis, with death or other recurrence/NPLC treated as competing risks. Covariates included in the disease recurrence competing risk models were determined a priori based on clinical experience and literature review and included pathologic stage, lymph nodes sampled, tumor size, tumor histology, tumor grade, and surgical procedure. The final model included the variables with P < .10, where group, pathologic stage, and number of lymph nodes were forced into the model. Overall survival for all 3 cohorts was modeled using univariate and multivariable Cox proportional hazards regression analysis, and covariate effects are presented as hazard ratios with 95% confidence ratios. The proportionality assumption was tested by adding a time-dependent covariate for each variable. When the test indicated nonproportional hazards over time, models were divided into 2 time periods, and the maximized partial likelihood method was used to find the most appropriate breakpoint and the proportionality assumptions were further tested. Interested covariates in Cox proportional hazard modeling were also determined a priori based on literature and clinical significance and included age, gender, race, surveillance intensity group, chronic obstructive pulmonary disease, congestive heart failure, coronary artery disease, diabetes, psychiatric disease, pathologic stage, tumor size, tumor grade, lymph nodes sampled, tumor histology, and surgical procedure. The final model was built through the stepwise selection, where group, pathologic stage, and number of lymph nodes were forced into the model. Kaplan-Meier survival curves were also constructed to compare OS among surveillance cohorts.
      Missing covariate data were ≤1% in all demographic variables: 4 patients were missing tumor histology, and 1 patient was missing gender status. Given the low number of patients with missing data, missing covariate information was reported in descriptive statistics, but was not included in regression analyses. Data that were reported as unknown or indeterminate were handled as separate categorical variables for analyses. All analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC).

      Results

      We identified 4340 patients with pathologic stage I NSCLC who underwent postoperative CT imaging. When examining indication for the first CT scan, 3170 patients (73%) were asymptomatic and eligible for inclusion as true surveillance imaging. Two thousand five hundred sixty-five patients received their first scan within 60 to 450 days from surgery. We excluded 123 patients who underwent chemoradiation therapy or had positive surgical margins, leaving 2442 patients in our study cohort that met inclusion criteria. Of included patients, 805 (33%), 1216 (50%), and 421 (17%) patients were placed in the high-intensity, moderate-intensity, and low-intensity cohorts, respectively (Figure E1). When calculating the median number of asymptomatic surveillance images, high-intensity, moderate-intensity, and low-intensity groups received 4.67 (median Q1-Q3, 2.43-15.02), 3.65 (median Q1-Q3, 1.97-12.54), and 2.96 (median Q1-Q3, 1.71-10.27) images per 2 person-years, respectively. This confirmed that our predefined surveillance intensity cohorts, which were based on time from surgery to time to first surveillance scan, corresponded to differing frequencies of imaging. The cohorts demonstrated similarity across most patient, tumor, and treatment-related variables (Table 1).
      Table 1Patient and tumor-related factors, all patients
      VariableAll patients (N = 2442)High intensity (n = 805)Moderate intensity (n = 1216)Low intensity (n = 421)P value
      Patient-related factors
       Age (y)66.2 (9.7)65.7 (9.9)66.4 (9.7)66.6 (9.6).171
       Male sex1106 (45.3)340 (42.3)569 (46.8)197 (46.8).110
       Race.698
      White2198 (90.0)729 (90.6)1096 (90.1)373 (88.6)
      African American176 (7.2)56 (7.0)88 (7.3)32 (7.6)
      Other68 (2.8)20 (2.4)32 (2.6)16 (3.8)
       Charlson/Deyo score.381
      01236 (50.6)414 (51.4)622 (51.2)200 (47.5)
      1890 (36.4)278 (34.5)445 (36.6)167 (39.7)
      2+316 (13.0)113 (14.1)149 (12.2)54 (12.8)
       Comorbidity
      Chronic obstructive pulmonary disease998 (40.9)324 (40.3)485 (39.9)189 (44.9).179
      Congestive heart failure131 (5.4)50 (6.2)60 (4.9)21 (5.0).428
      Coronary artery disease531 (21.7)168 (20.9)260 (21.4)103 (24.5).319
      Diabetes357 (14.6)129 (16.0)170 (14.0)58 (13.8).385
      Peripheral vascular disease224 (9.2)64 (8.0)109 (9.0)51 (12.1).053
      Psychiatric history197 (8.1)76 (9.4)88 (7.2)33 (7.8).201
      Substance abuse124 (5.1)46 (5.7)56 (4.6)22 (5.2).533
      Tumor-related factors
       Surgical resection.478
      Wedge resection353 (14.4)105 (13.0)183 (15.1)65 (15.5)
      Segmentectomy65 (2.7)28 (3.5)26 (2.1)11 (2.6)
      Lobectomy/bilobectomy1980 (81.1)659 (81.9)985 (81.0)336 (79.8)
      Pneumonectomy44 (1.8)13 (1.6)22 (1.8)9 (2.1)
       Tumor size (mm)22 (15-30)22 (15-30)22 (15-30)21 (15-30).819
       No. of lymph nodes sampled1 (1-1)1 (1-1)1 (1-1)1 (1-1).278
       Pathologic stage.904
      1A1497 (61.3)485 (60.2)754 (62.0)258 (61.3)
      1B866 (35.5)292 (36.3)426 (35.0)148 (35.1)
      1–A/B unknown79 (3.2)28 (3.5)36 (3.0)15 (3.6)
       Histology.935
      Adenocarcinoma1161 (47.6)391 (48.6)572 (47.2)198 (47.0)
      Squamous647 (26.5)209 (26.0)324 (26.7)114 (27.1)
      Other489 (20.1)159 (19.7)241 (19.9)89 (21.1)
      Unknown141 (5.8)46 (5.7)75 (6.2)20 (4.8)
       Grade.567
      Well differentiated402 (16.5)136 (16.9)195 (16.0)71 (16.9)
      Moderately differentiated1071 (43.9)345 (42.9)540 (44.4)186 (44.1)
      Poorly differentiated765 (31.3)251 (31.2)379 (31.2)135 (32.1)
      Undifferentiated18 (0.7)8 (1.0)5 (0.4)5 (1.2)
      Indeterminate186 (7.6)65 (8.0)97 (8.0)24 (5.7)
      Values are presented as n (%) or median (interquartile range).

       Surveillance Intensity and Survival Analysis

      Cox proportional hazard modeling showed that surveillance intensity was not associated with OS (P = .302) (Table 2). Factors associated with worse overall survival included age, pathologic stage, male gender, chronic obstructive pulmonary disease, congestive heart failure, psychiatric disease, histologic grade, and nonlobectomy surgical resection (P < .05). Kaplan-Meier analysis also showed similar 5-year OS probability among our surveillance intensity cohorts (70.7% high intensity vs 70.9% moderate intensity vs 73.2% low intensity; P = .547) (Figure 1).
      Table 2Cox proportional hazard model of 5-year overall survival
      CovariateHazard ratio (95% confidence interval)P value
      Age1.03 (1.02-1.04)<.001
      Gender
       MaleReference.036
       Female0.85 (0.73-0.99)
      Comorbidity
       Chronic obstructive pulmonary disease1.27 (1.09-1.48).003
       Congestive heart failure1.57 (1.20-2.05).001
       Psychiatric history1.54 (1.20-1.98).001
      Pathologic stage
       1AReference.024
       1B1.25 (1.06-1.46)
       11.11 (0.73-1.70)
      Histologic grade
       Well differentiatedReference<.001
       Moderately differentiated1.65 (1.26-2.16)
       Poorly differentiated1.76 (1.32-2.35)
       Undifferentiated4.02 (2.03-7.97)
       Unknown1.62 (1.11-2.36)
      Resection type
       Lobectomy/bilobectomyReference.015
       Wedge resection1.32 (1.07-1.63)
       Segmentectomy1.39 (0.93-2.09)
       Pneumonectomy1.48 (0.89-2.46)
      Number of lymph nodes sampled0.97 (0.84-1.12).689
      Surveillance group.302
       Low intensityReference
       Moderate intensity1.13 (0.91-1.39)
       High intensity1.20 (0.95-1.50)
      Boldface indicates statistical significance (P < .05).
      Figure thumbnail gr1
      Figure 1Overall survival by surveillance intensity group.

       Locoregional Disease Recurrence

      Five-year cumulative incidence of locoregional recurrence was similar across surveillance intensity cohorts (high intensity, 0.13; 95% confidence interval [CI], 0.11-0.15; moderate intensity, 0.13; 95% CI, 0.11-0.15; and low intensity, 0.14; 95% CI, 0.11-0.17 [P = .967]) (Figure 2). Variables associated with increased risk of locoregional disease recurrence included tumor size, histology, and nonlobectomy resection type (P < .05) (Table 3). Of those with locoregional disease recurrence, 166 (49.9%), 96 (28.8%), and 66 (19.8%) had evidence of locoregional disease in the same lung, regional lymph nodes, or both lung and lymph nodes, respectively. For 5 patients (1.5%), the location of local recurrence was unable to be determined. When determining how local recurrences were first detected, 210 (63.1%) patients had disease first detected by routine surveillance CT scans and were asymptomatic at the time of imaging (Table E1).
      Figure thumbnail gr2
      Figure 2Risk of locoregional disease recurrence by surveillance intensity.
      Table 3Competing risks model for time to locoregional cancer recurrence
      VariableHazard ratio (95% confidence interval)P value
      Tumor size (mm)1.02 (1.00-1.03).014
      Substance abuse1.67 (1.08-2.58).022
      Resection type
       Wedge resectionReference.005
       Segmentectomy1.30 (0.70-2.42)
       Lobectomy/bilobectomy0.55 (0.35-0.89)
       Pneumonectomy0.77 (0.31-1.91)
      Pathologic stage
       1AReference.901
       1B0.93 (0.68-1.27)
       11.02 (0.56-1.85)
      Histology
       AdenocarcinomaReference.004
       Squamous0.91 (0.70-1.19)
       Other histology0.51 (0.36-0.74)
       Unknown0.82 (0.49-1.37)
      Number of lymph nodes sampled0.68 (0.33-1.42).305
      Surveillance group
       Low intensityReference.944
       Moderate intensity0.98 (0.72-1.35)
       High intensity1.03 (0.74-1.43)
      Boldface indicates statistical significance (P < .05).
      Of those who had locoregional recurrence, 243 patients (73.0%) underwent subsequent treatment after detection of locoregional recurrence (Video 1). Of those who did not undergo subsequent treatment, 24 patients (21.8%), 30 patients (18.4%), and 16 patients (26.7%) belonged to the high-intensity, moderate-intensity, and low-intensity groups, respectively.
      Figure thumbnail fx2

       Distant Recurrence

      Five-year cumulative incidence of distant recurrence was significantly difference across surveillance intensity groups (high intensity, 0.15; 95% CI, 0.13-0.18; moderate intensity, 0.13; 95% CI, 0.11-0.15; and low intensity, 0.10; 95% CI, 0.07-0.13 [P = .024]) (Figure 3). Variables associated with distant recurrence included surveillance intensity, tumor size, tumor grade, and histology (P < .05) (Table 4). Bone metastases were the most common site of distant recurrence in 89 patients (26.6%), followed by contralateral lung and brain metastases in 87 patients (26.0%) and 76 patients (22.8%), respectively. Routine surveillance imaging detected distant recurrence in 122 patients (36.6%), whereas 135 patients (40.5%) had recurrence detected by imaging ordered after new signs or symptoms developed (Table E1). Of those with distant recurrence, 83 patients (24.9%) did not undergo any treatment (Table E2), with 24 patients (19.4%), 43 patients (26.4%), and 16 patients (34.8%) belonging to the high-intensity, moderate-intensity, and low-intensity groups, respectively.
      Figure thumbnail gr3
      Figure 3Risk of distant recurrence by surveillance intensity.
      Table 4Competing risks model for time to distant cancer recurrence
      VariableHazard ratio (95% confidence interval)P value
      Tumor size (mm)1.02 (1.01-1.04).001
      Resection type
       Wedge resectionReference.121
       Segmentectomy1.28 (0.63-2.58)
       Lobectomy/bilobectomy0.91 (0.63-1.30)
       Pneumonectomy1.90 (0.90-4.03)
      Pathologic stage
       1AReference.504
       1B0.88 (0.64-1.21)
       11.26 (0.68-2.32)
      Histology.006
       AdenocarcinomaReference
       Squamous0.62 (0.46-0.83)
       Other histology0.71 (0.49-1.03)
       Unknown1.01 (0.64-1.61)
      Histologic grade.018
       Well differentiatedReference
       Moderately differentiated1.72 (1.13-2.60)
       Poorly differentiated2.01 (1.29-3.13)
       Undifferentiated2.73 (0.84-8.81)
       Unknown2.18 (1.28-3.71)
      Number of lymph nodes sampled1.02 (0.79-1.31).886
      Surveillance group.032
       Low intensityReference
       Moderate intensity1.31 (0.93-1.85)
       High intensity1.59 (1.12-2.27)
      Boldface indicates statistical significance (P < .05).

       Development of NPLC

      Five-year cumulative incidence of NPLC was similar across surveillance intensity groups (high intensity, 0.05; 95% CI, 0.04-0.08; moderate intensity, 0.08; 95% CI, 0.06-0.11; and low intensity, 0.07; 95% CI, 0.06-0.09 [P = .393]). Ninety-seven patients (54.5%) developed an NPLC with lung cancer histology different from their initial tumor. Routine surveillance imaging detected NPLC in 128 cases (71.9%) (Table E1).

      Conclusions

      There are more than 400,000 lung cancer survivors in the United States.
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      • Jett J.R.
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      • et al.
      The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.
      These individuals are at high risk for developing recurrence or NPLC.
      • Mollberg N.M.
      • Ferguson M.K.
      Postoperative surveillance for non–small cell lung cancer resected with curative intent: developing a patient-centered approach.
      • Jaklitsch M.T.
      • Jacobson F.L.
      • Austin J.H.
      • Field J.K.
      • Jett J.R.
      • Keshavjee S.
      • et al.
      The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.
      Despite the need for evidence-based surveillance guidelines, existing guidelines are not uniform and are based on small retrospective studies and expert opinion. Organizations, including the American College of Chest Physicians, the National Comprehensive Cancer Network, and the International Association for the Study of Lung Cancer offer differing recommendations for intervals and modalities for surveillance.
      • Rubins J.
      • Unger M.
      • Colice G.L.
      • American College of Chest Physicians
      Follow-up and surveillance of the lung cancer patient following curative intent therapy: ACCP evidence-based clinical practice guideline (2nd edition).
      • Ettinger D.
      • Wood D.
      • Aisner D.
      • Akerley W.
      • Bauman J.
      • Chirieac L.R.
      • et al.
      Non–small cell lung cancer, version 5.2017. NCCN clinical practice guidelines in oncology.
      • Saunders M.
      • Sculier J.P.
      • Ball D.
      • Capello M.
      • Furuse K.
      • Goldstraw P.
      • et al.
      Consensus: the follow-up of the treated patient.
      Variability of surveillance in clinical practice is even greater, with adherence to guidelines often being quite poor. In a study of adherence to National Comprehensive Cancer Network and American College of Chest Physicians guidelines, Erb and colleagues
      • Erb C.T.
      • Su K.W.
      • Soulos P.R.
      • Tanoue L.T.
      • Gross C.P.
      Surveillance practice patterns after curative intent therapy for stage I non-small-cell lung cancer in the Medicare population.
      utilized the Surveillance, Epidemiology, and End Results-Medicare database and found that only 61.4% of patients with stage I NSCLC received guideline-adherent surveillance during the initial 2 years after treatment.
      • Erb C.T.
      • Su K.W.
      • Soulos P.R.
      • Tanoue L.T.
      • Gross C.P.
      Surveillance practice patterns after curative intent therapy for stage I non-small-cell lung cancer in the Medicare population.
      Poor adherence can be partially explained by the paucity of quality longitudinal data to inform best practice.
      Using a large, nationally representative database containing complete 5-year follow-up data, we found that surveillance intensity was not associated with overall survival in patients with resected stage I NSCLC. Additionally, surveillance intensity was not associated with differences in time to detection of locoregional recurrence, which represents a group that could potentially benefit from subsequent curative therapy.
      Our findings are similar to studies that previously reported on intensity of follow-up. Calman and colleagues
      • Calman L.
      • Beaver K.
      • Hind D.
      • Lorigan P.
      • Roberts C.
      • Lloyd-Jones M.
      Survival benefits from follow-up of patients with lung cancer: a systematic review and meta-analysis.
      published a meta-analysis of 1669 stage I-III NSCLC patients comparing intensity of postoperative follow-up programs.
      • Calman L.
      • Beaver K.
      • Hind D.
      • Lorigan P.
      • Roberts C.
      • Lloyd-Jones M.
      Survival benefits from follow-up of patients with lung cancer: a systematic review and meta-analysis.
      The majority of included studies were small and retrospective, with only 1 randomized controlled trial and 1 prospective study. The authors found no difference in OS for NSCLC patients treated with curative intent who received more intensive follow-up. They too did not find a correlation between intensive follow-up and reduced time to local recurrence detection. However, their analysis used wide inclusion criteria, resulting in significant heterogeneity of included studies, patient populations, and surveillance strategies.
      In the previously published analysis by members of our study group using special study data to examine the association of CT surveillance intensity in patients with resected stage I-III NSCLC, McMurry and colleagues
      • McMurry T.L.
      • Stukenborg G.J.
      • Kessler L.G.
      • Colditz G.A.
      • Wong M.L.
      • Francescatti A.B.
      • et al.
      More frequent surveillance following lung cancer resection is not associated with improved survival: a nationally representative cohort study.
      observed similar findings. They studied 4463 patients and found that CT surveillance intensity was not associated with overall or postrecurrence survival. However, this analysis highlights the importance of performing stage-specific analysis. There are limited published high quality data that have examined stage-specific surveillance. Homogeneity in surveillance practices and long-term outcomes cannot be assumed across all stages of disease. In fact, McMurry and colleagues
      • McMurry T.L.
      • Stukenborg G.J.
      • Kessler L.G.
      • Colditz G.A.
      • Wong M.L.
      • Francescatti A.B.
      • et al.
      More frequent surveillance following lung cancer resection is not associated with improved survival: a nationally representative cohort study.
      observed that patients with higher stage disease were imaged more frequently. This limits the direct conclusions that can be inferred to the influence of surveillance imaging intensity on patients with early stage disease. In this planned analysis, we exclusively studied patients with stage I NSCLC using independent methodology for classifying and grouping patients into surveillance cohorts. This allowed for comparison within a more homogeneous population, and thus allowed for less biased estimates of disease recurrence and survival.
      In addition to our focus on patients with stage I NSCLC, this analysis provides unique information on 5-year development risk of locoregional/distant recurrence as well as NPLC, modes of detection of recurrence, and postrecurrence treatment patterns. Theoretically, detection of asymptomatic recurrence or NPLC could offer a survival advantage because these diseases are more likely to be early stage and amenable to therapy. McMurry and colleagues
      • McMurry T.L.
      • Stukenborg G.J.
      • Kessler L.G.
      • Colditz G.A.
      • Wong M.L.
      • Francescatti A.B.
      • et al.
      More frequent surveillance following lung cancer resection is not associated with improved survival: a nationally representative cohort study.
      found that symptomatic presentation of recurrence was associated with worse postrecurrence survival in patients with stage I-III NSCLC. However, asymptomatic presentation is likely a function of the patient's initial stage of disease. Although our results do not support the aggressive use of CT surveillance, this does not preclude the use of CT surveillance for stage I patients. Our data have shown that recurrence and NPLC in stage I patients are often detected at the asymptomatic period, and many go on to receive subsequent therapy. Sixty-three percent of locoregional recurrences and 72% of NPLC were detected via routine surveillance. Other stage-specific analyses have shown similar findings. Lou and colleagues
      • Lou F.
      • Sima C.S.
      • Rusch V.W.
      • Jones D.R.
      • Huang J.
      Differences in patterns of recurrence in early-stage versus locally advanced non-small cell lung cancer.
      retrospectively reviewed patients who had undergone resection for NSCLC and subsequently underwent CT surveillance every 6 to 12 months. They identified 1294 patients with stage I or II disease, of whom 257 (20%) had recurrence. Similar to our study, surveillance CT detected 61% of asymptomatic recurrences in these patients. Approximately 78% of the recurrences in early stage patients reported by Lou and colleagues
      • Lou F.
      • Sima C.S.
      • Rusch V.W.
      • Jones D.R.
      • Huang J.
      Differences in patterns of recurrence in early-stage versus locally advanced non-small cell lung cancer.
      underwent subsequent therapy, with 12% being offered surgery with or without radiation. Our study identified that 73% of locoregional recurrences underwent subsequent therapy, with at least 7% undergoing surgical treatment.
      The role of surveillance imaging has previously been debated given that the efficacy of postrecurrence therapies has not been consistently demonstrated. However, in a large retrospective study of 9001 patients with stage I or III NSCLC with postresection recurrence, subsequent treatment has been shown to be highly beneficial. Using the same special study, Wong and colleagues
      • Wong M.L.
      • McMurry T.L.
      • Stukenborg G.J.
      • Francescatti A.B.
      • Amato-Martz C.
      • Schumacher J.R.
      • et al.
      Impact of age and comorbidity on treatment of non-small cell lung cancer recurrence following complete resection: a nationally representative cohort study.
      compared postrecurrence survival between those who received active therapy versus supportive care. Similar to our study, a high percentage of patients (79.5%) with locoregional recurrence received some form of treatment. Median survival for these patients was 19.9 months compared with 4.4 months in patients who received supportive care only. This same pattern was observed in distant recurrence. In our study, 69.4% of patients with distant recurrence underwent some form of therapy, and more frequent imaging was associated with higher incidence of detection of distant recurrence. Wong and colleagues
      • Wong M.L.
      • McMurry T.L.
      • Stukenborg G.J.
      • Francescatti A.B.
      • Amato-Martz C.
      • Schumacher J.R.
      • et al.
      Impact of age and comorbidity on treatment of non-small cell lung cancer recurrence following complete resection: a nationally representative cohort study.
      reported that 77.3% of patients with distant metastases underwent treatment, which translated to longer median survival (11.6 months vs 3.0 months).
      There are important study limitations to note. Our study consisted of patients that were diagnosed more than 10 years ago. These patients were used so additional data abstraction on 5-year follow-up data could be performed. Thus, there was a trade-off required to capture complete 5-year follow-up information, including recurrence and surveillance, which are not routinely captured in the NCDB. An additional and important limitation includes our categorization of surveillance intensity cohorts. In the real world, patients and physicians often deviate from interval-based regimens (especially as time from primary treatment increases). Previous studies have documented remarkably low adherence to existing guideline-recommended surveillance regimens, approximating 60%.
      • Erb C.T.
      • Su K.W.
      • Soulos P.R.
      • Tanoue L.T.
      • Gross C.P.
      Surveillance practice patterns after curative intent therapy for stage I non-small-cell lung cancer in the Medicare population.
      Additionally, one must contend with several biases when quantifying surveillance in observational research. First, there is healthy survivor bias—patients who remain on their intended surveillance frequency and do not deviate from their regimens are more likely to be healthy. This would be due to the fact that patients who receive more regimented surveillance scans over time would have to be alive, without recurrence, and without new symptoms or findings on surveillance imaging that prompted a change to more frequent imaging. Alternatively, there is a possibility for an unhealthy survivor bias. Patients with a recurrence, NPLC, or new signs or symptoms could be subject to more frequent imaging, resulting in a higher number of scans. Due to these challenges, there is no perfect method to measuring surveillance intensity in observational studies. Thus, we created our cohorts a priori based on how surveillance initially happened, using time from surgery to first surveillance scan as a proxy. As expected, we found that patients in the dataset did not adhere to strict regimens of surveillance imaging throughout their follow-up. However, the median numbers of scans per person year in each cohort were significantly different between the cohorts. An additional limitation is that our analysis is confined to the variables captured in the NCDB. We observed a trend toward lower-intensity surveillance in patients who did not undergo any therapy for locoregional/distant recurrence. It is possible that clinicians who survey less aggressively tend to not pursue treatment for patients who recur, representing a treatment selection bias that could lead to worse OS. However, our analysis found no difference in OS between the surveillance intensity cohorts. Alternatively, it is possible that these patients had concerning factors that were not captured in our dataset. Factors, including functional status, pulmonary function, margin distance, and presence of lymphovascular invasion are not included in the special study dataset.
      Despite these limitations, our study exhibits several strengths. Our study utilized high quality, longitudinal data from reabstracted NCDB records that contain complete 5-year recurrence and survival information. The dataset also includes surveillance imaging indications that are critical to distinguish true surveillance from imaging ordered to investigate a new sign or symptom. Additionally, because the NCDB includes 70% of new lung cancers in the United States, these data are broadly representative and our conclusions are generalizable.
      • Stewart A.K.
      • Bland K.I.
      • McGinnis L.S.
      • Morrow M.
      • Eyre H.J.
      Clinical highlights from the national cancer data base, 2000.
      Surveillance intensity was not associated with OS for these patients with stage I disease, suggesting that surveillance is not a 1-size-fits-all approach. Necessary considerations when determining the optimal utilization of any surveillance test include factors such as accuracy, cost and reimbursement for diagnostic studies, the invasiveness of diagnostic procedures, and the emotional stress from fear of recurrence.
      • Mollberg N.M.
      • Ferguson M.K.
      Postoperative surveillance for non–small cell lung cancer resected with curative intent: developing a patient-centered approach.
      • Calman L.
      • Beaver K.
      • Hind D.
      • Lorigan P.
      • Roberts C.
      • Lloyd-Jones M.
      Survival benefits from follow-up of patients with lung cancer: a systematic review and meta-analysis.
      An optimal, patient-centered approach to surveillance should be driven by knowledge of tumor biology, patient history, patient preference, and candidacy for subsequent treatment. Additional high-quality longitudinal studies are needed to determine how surveillance intensity best fits into this comprehensive approach.

       Conflict of Interest Statement

      Authors have nothing to disclose with regard to commercial support.

      Appendix

      Figure thumbnail fx3
      Figure E1Inclusion/exclusion criteria and selection of study cohort. NPLC, New primary lung cancer; CT, computed tomography.
      Table E1Method of detection: Recurrence and new primary lung cancer (NPLC)
      Method of detectionLocoregional recurrence (n = 333)Distant recurrence (n = 333)NPLC (n = 178)
      Finding detected on nonroutine clinician visit, prompted by patient-detected sign/symptom65 (19.5)135 (40.5)45 (25.3)
      Finding detected on routine visit, physician-detected new sign20 (6.0)10 (3.0)
      Finding detected on routine surveillance imaging, patient asymptomatic210 (63.1)122 (36.6)128 (71.9)
      Finding detected as part of workup for other local/distant/NPLC disease22 (6.6)45 (13.5)
      Finding incidentally detected for unrelated/other imaging3 (0.9)15 (4.5)
      Unable to determine13 (3.9)6 (1.8)5 (2.8)
      Values are presented as n (%). NPLC, New primary lung cancer.
      Table E2Subsequent treatment of locoregional/distant recurrence
      TreatmentLocoregional recurrence (n = 333)Distant recurrence (n = 333)
      No treatment70 (21.0)83 (24.9)
      Surgery only21 (6.3)14 (4.2)
      Chemotherapy only88 (26.4)79 (23.7)
      Radiation therapy only52 (15.6)70 (21.0)
      Combination therapy82 (24.6)68 (20.4)
      Unable to determine20 (6.0)19 (5.7)
      Values are presented as n (%).

      Supplementary Data

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