Lobar or Sublobar Resection for Peripheral Stage IA Non-Small-Cell Lung Cancer.

BACKGROUND: The increased detection of small-sized peripheral non-small-cell lung cancer (NSCLC) has renewed interest in sublobar resection in lieu of lobectomy. METHODS: We conducted a multicenter, noninferiority, phase 3 trial in which patients with NSCLC clinically staged as T1aN0 (tumor size, ≤2 cm) were randomly assigned to undergo sublobar resection or lobar resection after intraoperative confirmation of node-negative disease. The primary end point was disease-free survival, defined as the time between randomization and disease recurrence or death from any cause. Secondary end points were overall survival, locoregional and systemic recurrence, and pulmonary functions. RESULTS: From June 2007 through March 2017, a total of 697 patients were assigned to undergo sublobar resection (340 patients) or lobar resection (357 patients). After a median follow-up of 7 years, sublobar resection was noninferior to lobar resection for disease-free survival (hazard ratio for disease recurrence or death, 1.01; 90% confidence interval [CI], 0.83 to 1.24). In addition, overall survival after sublobar resection was similar to that after lobar resection (hazard ratio for death, 0.95; 95% CI, 0.72 to 1.26). The 5-year disease-free survival was 63.6% (95% CI, 57.9 to 68.8) after sublobar resection and 64.1% (95% CI, 58.5 to 69.0) after lobar resection. The 5-year overall survival was 80.3% (95% CI, 75.5 to 84.3) after sublobar resection and 78.9% (95% CI, 74.1 to 82.9) after lobar resection. No substantial difference was seen between the two groups in the incidence of locoregional or distant recurrence. At 6 months postoperatively, a between-group difference of 2 percentage points was measured in the median percentage of predicted forced expiratory volume in 1 second, favoring the sublobar-resection group. CONCLUSIONS: In patients with peripheral NSCLC with a tumor size of 2 cm or less and pathologically confirmed node-negative disease in the hilar and mediastinal lymph nodes, sublobar resection was not inferior to lobectomy with respect to disease-free survival. Overall survival was similar with the two procedures. (Funded by the National Cancer Institute and others; CALGB 140503 ClinicalTrials.gov number, NCT00499330.).

Perioperative mortality and morbidity after sublobar versus lobar resection for early-stage non-small-cell lung cancer: post-hoc analysis of an international, randomised, phase 3 trial (CALGB/Alliance 140503).

BACKGROUND: Increased detection of small-sized, peripheral, non-small-cell lung cancer has renewed interest in sublobar resection instead of lobectomy, the traditional standard of care for early-stage lung cancer. We aimed to assess morbidity and mortality associated with lobar and sublobar resection for early-stage lung cancer. METHODS: CALGB/Alliance 140503 is a multicentre, international, non-inferiority, phase 3 trial in patients with peripheral non-small-cell lung cancer clinically staged as T1aN0. Patients were recruited from 69 academic and community-based institutions in Australia, Canada, and the USA. Patients were randomly assigned intraoperatively to either lobar or sublobar resection. The random assignment was based on permuted block randomisation without concealment and was stratified according to radiographic tumour size, histology, and smoking status. The primary endpoint of the trial is disease-free survival; here, we report a post-hoc, exploratory, comparative analysis of perioperative mortality and morbidity associated with lobar and sublobar resection. Perioperative mortality was defined as death from any cause within 30 days and 90 days of surgical intervention and was calculated for all randomised patients. Morbidity was graded using Common Terminology Criteria for Adverse Events version 4.0. All analyses were done on an intention-to-treat basis for randomised patients with data available. This trial is registered with ClinicalTrials.gov, number NCT00499330. FINDINGS: Between June 15, 2007, and March 13, 2017, 697 patients were randomly allocated to either lobar resection (n=357) or sublobar resection (n=340; 59% wedge resection). Six (0·9%) patients died by 30 days, four (1·1%) after lobar resection and two (0·6%) after sublobar resection; by 90 days, ten (1·4%) patients had died, six (1·7%) after lobar resection and four (1·2%) after sublobar resection (difference at 30 days, 0·5%, 95% CI -1·1 to 2·3; difference at 90 days, 0·5%, 95% CI -1·5 to 2·6). An adverse event of any grade occurred in 193 (54%) of 355 patients after lobar resection and 172 (51%) of 337 patients after sublobar resection. Adverse events of grade 3 or worse occurred in 54 (15%) patients assigned lobar resection and in 48 (14%) patients assigned sublobar resection. No differences between surgical approaches were noted in cardiac or pulmonary complications. Grade 3 haemorrhage (requiring transfusion) occurred in six (2%) patients assigned lobar resection and eight (2%) patients assigned sublobar resection. Prolonged air leak occurred in nine (3%) patients after lobar resection and two (1%) patients after sublobar resection. INTERPRETATION: Our post-hoc analysis showed that perioperative mortality and morbidity did not seem to differ between lobar and sublobar resection in physically and functionally fit patients with clinical T1aN0 non-small-cell lung cancer. These data may affect the daily choices made by patients and their doctors in establishing the best treatment approach for stage I lung cancer. FUNDING: National Cancer Institute.

Biopsy first: Lessons learned from Cancer and Leukemia Group B (CALGB) 140503.

OBJECTIVE: Cancer and Leukemia Group B 140503 is an ongoing, multicenter randomized trial assessing whether sublobar resection is equivalent to lobectomy for the treatment of stage I A non-small cell lung cancer (NSCLC) ≤2 cm in diameter. The objective of this report is to determine the reasons precluding intraoperative randomization. METHODS: From June 15, 2007, to March 22, 2013, 637 patients were preregistered to the trial. Three hundred eighty-nine were randomized successfully (61%), and 248 patients were not randomized (39%). We analyzed the reasons for nonrandomization among a subset of the nonrandomized patients (208) for whom additional data were available. RESULTS: Of these 208 patients, undiagnosed benign nodules (n =104, 16% of all registered patients) and understaging of NSCLC (n =45, 7% of all registered patients) were the dominant reasons precluding randomization. Granulomas represent one-quarter of the benign nodules. The understaged patients had unsuspected nodal metastases (n =28) or other more advanced NSCLC. The rate of randomization was significantly greater in those patients who had a preoperative biopsy (P <.001). CONCLUSIONS: In a carefully monitored cohort of patients with suspected small NSCLC ≤2 cm, a substantial number are misdiagnosed (benign nodules) or understaged. These patients may not have benefited from a thoracic surgical procedure. Preoperative biopsy significantly increased the rate of correct diagnosis. Preoperative biopsy of small suspected NSCLC will reduce the number of nontherapeutic or unnecessary thoracic procedures. Accuracy in preoperative diagnosis is increasingly important as more such small nodules are discovered through lung cancer screening.

Detection of Occult Micrometastases in Patients With Clinical Stage I Non-Small-Cell Lung Cancer: A Prospective Analysis of Mature Results of CALGB 9761 (Alliance).

PURPOSE: Outcomes after resection of stage I non-small-cell lung cancer (NSCLC) are variable, potentially due to undetected occult micrometastases (OM). Cancer and Leukemia Group B 9761 was a prospectively designed study aimed at determining the prognostic significance of OM. MATERIALS AND METHODS: Between 1997 and 2002, 502 patients with suspected clinical stage I (T1-2N0M0) NSCLC were prospectively enrolled at 11 institutions. Primary tumor and lymph nodes (LNs) were collected and sent to a central site for molecular analysis. Both were assayed for OM using immunohistochemistry (IHC) for cytokeratin (AE1/AE3) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for carcinoembryonic antigen. RESULTS: Four hundred eighty-nine of the 502 enrolled patients underwent complete surgical staging. Three hundred four patients (61%) had pathologic stage I NSCLC (T1, 58%; T2, 42%) and were included in the final analysis. Fifty-six percent had adenocarcinomas, 34% had squamous cell carcinomas, and 10% had another histology. LNs from 298 patients were analyzed by IHC; 41 (14%) were IHC-positive (42% in N1 position, 58% in N2 position). Neither overall survival (OS) nor disease-free survival was associated with IHC positivity; however, patients who had IHC-positive N2 LNs had statistically significantly worse survival rates (hazard ratio, 2.04, P = .017). LNs from 256 patients were analyzed by RT-PCR; 176 (69%) were PCR-positive (52% in N1 position, 48% in N2 position). Neither OS nor disease-free survival was associated with PCR positivity. CONCLUSION: NSCLC tumor markers can be detected in histologically negative LNs by AE1/AE3 IHC and carcinoembryonic antigen RT-PCR. In this prospective, multi-institutional trial, the presence of OM by IHC staining in N2 LNs of patients with NSCLC correlated with decreased OS. The clinical significance of this warrants further investigation.

VATS lobectomy has better perioperative outcomes than open lobectomy: CALGB 31001, an ancillary analysis of CALGB 140202 (Alliance).

BACKGROUND: The short-term superiority of video-assisted thoracoscopic surgery lobectomy compared with open lobectomy for early-stage lung cancer has been suggested by single-institution studies. Lack of equipoise limits the feasibility of a randomized study to confirm this. The hypothesis of this study (CALGB 31001) was that VATS lobectomy results in shorter length of hospital stay and fewer complications compared with open lobectomy in stages I and II non-small cell lung cancer in a multi-institutional setting. METHODS: Five hundred nineteen patients whose tumors had been collected as part of CALGB 140202 (lung cancer tissue bank) were eligible. Propensity-scoring using age, race, sex, performance status, comorbidities, histology, tumor stage, and size as independent variables was used to create a 1:1 matched group of 175 pairs of patients. McNemar's test for binary variables and Wilcoxon signed-rank test for continuous variables were used to assess differences in length of hospital stay, complications, and discharge dispositions between the groups. Comparison of disease-free and overall survival between the two approaches was done using the log-rank test. Probability values of less than 0.05 were considered significant. RESULTS: The matched data on length of hospital stay, complications, and discharge dispositions significantly favored the video-assisted thoracoscopic surgery group. There was no statistically significant difference in survival between the two approaches. CONCLUSIONS: This multi-institutional study supports the assertion that thoracoscopic lobectomy results in shorter hospital length of stay, fewer perioperative complications, and greater likelihood of independent home discharge compared with open lobectomy for early-stage lung cancer. Survival was comparable between the two groups.

Prospective phase II trial of preresection thoracoscopic mediastinal restaging after neoadjuvant therapy for IIIA (N2) non-small cell lung cancer: results of CALGB Protocol 39803.

OBJECTIVE: Accurate pathologic restaging of N2 stations after neoadjuvant therapy in stage IIIA (N2) non-small cell lung cancer is needed. METHODS: A prospective multi-institutional trial was designed to judge the feasibility of videothoracoscopy to restage the ipsilateral nodes in mediastinoscopy-proven stage IIIA (N2) non-small cell lung cancer after 2 cycles of platinum-based chemotherapy and/or 40 Gy or more of radiotherapy. The goals included biopsy of 3 negative N2 node stations or to identify 1 positive N2 node or pleural carcinomatosis. RESULTS: Ten institutions accrued 68 subjects. Of the 68 subjects, 46 (68%) underwent radiotherapy and 66 (97%) underwent chemotherapy. Videothoracoscopy successfully met the prestudy feasibility in 27 patients (40%): 3 negative stations confirmed at thoracotomy in 7, persistent stage N2 disease in 16, and pleural carcinomatosis in 4. In 20 procedures (29%), no N2 disease was found, 3 stations were not biopsied because of unanticipated nodal obliteration. Thus, 47 videothoracoscopy procedures (69%, 95% confidence interval, 57%-80%) restaged the mediastinum. Videothoracoscopy was unsuccessful in 21 patients (31%) because the procedure had to be aborted (n = 11) or because of false-negative stations (n = 10). Of the 21 failures, 15 were right-sided, and 10 had a positive 4R node. The sensitivity of videothoracoscopy was 67% (95% confidence interval, 47%-83%), and the negative predictive value was 73% (95% confidence interval, 56%-86%) if patients with obliterated nodal tissue were included. The sensitivity was 83% (95% confidence interval, 63%-95%) and the negative predictive value was 64% (95% confidence interval, 31%-89%) if those patients were excluded. The specificity was 100%. One death occurred after thoracotomy. CONCLUSIONS: Videothoracoscopy restaging was "feasible" in this prospective multi-institutional trial and provided pathologic specimens of the ipsilateral nodes. Videothoracoscopy restaging was limited by radiation and the 4R nodal station.

Intraoperative sentinel node mapping with technitium-99 in lung cancer: results of CALGB 140203 multicenter phase II trial.

INTRODUCTION: Sentinel node mapping with radioactive technetium in non-small cell lung cancer has been shown to be feasible in several single institution reports. The Cancer and Leukemia Group B designed a phase II trial to test a standardized method of this technique in a multi-institutional setting. If validated, the technique could provide a more accurate and sensitive way to identify lymph node metastases. METHODS: Patients with clinical stage I non-small cell lung cancer amenable to resection were candidates for this trial. Intraoperatively, tumors were injected with technetium sulfur colloid (0.25 mCi). The tumor and lymph nodes were measured in vivo with a hand held Geiger counter and resection of the tumor and nodes was carried out. Sentinel nodes, all other nodes and the tumor were analyzed with standard histologic assessment. Negative sentinel nodes were also evaluated with immunohistochemistry. RESULTS: In this phase II trial, 8 surgeons participated (1-13 patients enrolled per surgeon), and 46 patients (out of a planned 150) were enrolled. Of these, 43 patients had cancer and an attempted complete resection, and 39 patients underwent sentinel node mapping. One or more sentinel nodes were identified in 24 of the 39 patients (61.5%). The sentinel node(s) were found to be accurate (no other nodes were positive for cancer if the sentinel node was negative) in 20/24 patients (83.3%). In the overall group the sentinel node mapping procedure was found to be accurate in 20/39 patients (51.2%). CONCLUSIONS: Intraoperative sentinel node mapping in lung cancer with radioisotope yielded lower accrual and worse accuracy than expected. The multi-institutional attempt at validating this technique was unsuccessful.

Definitive treatment of poor-risk patients with stage I lung cancer: a single institution experience.

PURPOSE: Lung cancer remains the leading cause of cancer death in both men and women. A substantial number of patients with early stage non-small cell lung cancer (NSCLC) are unfit for standard surgery due to cardiopulmonary dysfunction and/or other comorbidity. The appropriate management for this population has not been defined. METHODS: Retrospective analysis of patients with clinical stage I NSCLC judged to be unsuitable for lobectomy between 1996 and 2005. RESULTS: Ninety-six patients, representing 23% of all patients treated for clinical stage I NSCLC were included in this analysis. The median age was 73 years and most patients were female. Patients underwent limited resection (LR, n = 45), primary radiotherapy (RT, n = 39) or radiofrequency ablation (n = 12). With median follow-up of 30 months, 61 patients remain alive. Actuarial 3-year survival is 65% following LR and 60% after primary RT. Local tumor relapse and distant metastases were observed with approximate equal probability following either LR or RT. CONCLUSION: Medical inoperability does not necessarily correspond to poor survival in patients with early stage NSCLC. A nihilistic approach is not warranted towards this population, and prospective trials are needed to better define optimal treatment strategies.

A phase III study of surgical resection and paclitaxel/carboplatin chemotherapy with or without adjuvant radiation therapy for resected stage III non-small-cell lung cancer: Cancer and Leukemia Group B 9734.

PURPOSE: Patients with completely resected stage IIIA (N2) non-small-cell lung cancer (NSCLC) are at substantial risk for locoregional and systemic recurrence. Adjuvant chemotherapy has recently improved overall control for these patients. We added adjuvant chemotherapy to control presumed micrometastatic disease and then randomized patients to receive radiation therapy (RT) or observation to determine the benefit of local radiation consolidation. PATIENTS AND METHODS: Patient eligibility required histologically documented stage IIIA (radiographically occult N2) NSCLC that was completely resected, with no known residual disease, surgical staging per protocol requirements, Cancer and Leukemia Group B performance status of 0/1, no previous chemotherapy or RT, and minimal laboratory values. All eligible patients received 4 cycles of paclitaxel 200 mg/m2 over 3 hours with carboplatin at an area under the curve of 6 on days 1, 22, 43, and 64 beginning 4-8 weeks after surgery. Two to 4 weeks after chemotherapy, patients were randomized to receive RT as 5000 cGy in 25 fractions over 5 weeks or observation. RESULTS: The study closed after 2 years because of slow accrual. Forty-four patients entered the study; 2 were ineligible, and 5 were not randomized because of progression, adverse reaction, or patient withdrawal. Thirty-seven patients were the basis of this analysis. Median failure-free survival was 16.8 months on the observation arm and 33.7 months on the RT arm, with a 1-year survival rate of 72% on the observation arm and 74% on the RT arm. There were no statistical differences between the observation and RT arms for failure-free survival or overall survival. CONCLUSION: In this small study, consolidation RT after complete resection and adjuvant chemotherapy in stage IIIA NSCLC did not significantly improve outcome for this high-risk population.

Cancer and leukemia group B surgery committee.

Surgeons play a vital role in the Cancer and Leukemia Group B by providing patients and specimens for studies of the common solid tumors, and more recently, by serving as investigators who conduct surgically focused research protocols and contribute to the correlative science studies in the Group. Surgical activities encompass thoracic, gastrointestinal, breast, and genitourinary cancers and melanoma. Surgical quality assurance is also an important focus. This article will describe the development and importance of a robust and vigorous surgical component to a strong cooperative group and highlight the many trials conducted by the Cancer and Leukemia Group B surgeons and their contributions to advancement of the care of the patient with solid organ malignancy.

Poor correspondence between clinical and pathologic staging in stage 1 non-small cell lung cancer: results from CALGB 9761, a prospective trial.

PURPOSE: A major problem with the staging system for non-small cell lung cancer (NSCLC) is clinical underestimation of the extent of disease. Many patients with clinical stage 1 disease do not retain that designation following surgical resection. Herein, we present data from Cancer and Leukemia Group B (CALGB) protocol 9761 evaluating the correspondence between clinical and pathologic analysis in early stage NSCLC. METHODS: Five hundred and two patients with suspected or biopsy-proven NSCLC classified as clinical stage 1 (T1-2, N0) by computed tomography (CT) scan or cervical mediastinoscopy were prospectively enrolled in CALGB 9761. The purpose of CALGB 9761 was to prospectively evaluate molecular markers of micrometastatic disease in stage 1 NSCLC. Enrollment occurred at 11 selected institutions within the CALGB. Patients with clinically suspected resectable early stage lung cancer were eligible for enrollment if they had no evidence of mediastinal or hilar adenopathy on CT scan or if they had CT evidence of potential N2 or N3 disease (lymph node > or =1.0 cm) but with negative mediastinoscopy. No prior chemotherapy or radiotherapy was permitted. RESULTS: Of the 502 patients felt to have clinical stage 1 NSCLC enrolled in CALGB 9761, 489 underwent resection with complete surgical staging and routine histopathologic analysis. From these 489 patients, only 422 (86.3%) turned out to have pathologically documented NSCLC. Of these 422 patients, 302 (71.6%) had pathologic stage 1 disease (173 stage 1A and 129 stage 1B). Despite clinical assessment of stage 1 disease, 59 (14%) patients had pathologic stage 2 disease, 57 (13.5%) had stage 3 disease, and four (0.9%) patients had stage 4 disease. Of the patients undergoing resection for clinical stage 1 NSCLC, 65 patients did not have NSCLC (44 had benign disease and 21 had malignancies other than NSCLC) and two additional patients had dual synchronous primary NSCLC tumors and were not eligible for the study. Overall, only 61.7% (302 of 489) of patients with suspected stage 1 NSCLC disease retained that stage and diagnosis after complete surgical staging, while 38.3% had an inaccurate pre-operative clinical stage or diagnosis. CONCLUSIONS: The results from this prospective trial demonstrate the poor predictive value of current clinical staging techniques in early stage NSCLC. These findings will serve as a benchmark for comparison of future clinical imaging modalities and other tests evaluating early stage NSCLC.

Resection for lung cancer in the elderly patient.

Age is sometimes used as an excuse not to resect lung cancer. Nugent et al [10] noted that, although only 6% of patients younger than 45 years had stage I or II disease, 33% underwent surgical resection. In contrast, of the 33% of elderly patients who had stage I or II disease, only 6% underwent surgical resection. The elderly patients who are carefully selected for lung resection are undoubtedly stronger physiologically than others their same age. Patients with adequate predicted postoperative lung function, no contraindications from other medical problems, good performance status, and social support should be offered standard resection for early-stage NSCLC. Lung cancer resection in elderly patients is justified and has decreasing morbidity and mortality rates. Careful patient selection and operative planning are necessary, however. It is wise to have a diagnosis and staging done before the patient arrives in the operating suite. The surgeon should avoid extended resections when possible. In addition, elderly patients should be ambulated as soon as possible and adequate pain control should be ensured. Finally, the stage of the cancer and occurrence of cardiopulmonary complications are the main determinants of outcome.

Impact of tumor size on survival in stage IA non-small cell lung cancer: a case for subdividing stage IA disease.

PURPOSE: Stage IA (T1N0M0) non-small cell lung cancer (NSCLC) includes all lesions up to 3 cm in diameter. With the use of advanced imaging techniques, smaller pulmonary lesions can be identified. A greater proportion of patients with NSCLC will likely have smaller tumors at presentation in the future. The purpose of this study was to determine the relationship between tumor size, and survival in patients with pathologic stage IA NSCLC. METHODS: We conducted a retrospective review of 246 consecutive, surgically treated patients with pathologic stage IA NSCLC. Eligible patients were identified from the tumor registries and pathology records. Follow-up was obtained from the surgical database and primary physicians' records. RESULTS: Eighty six patients had tumors

Effect of number of lymph nodes sampled on outcome in patients with stage I non-small-cell lung cancer.

PURPOSE: We postulate that surgical sampling and pathologic evaluation of lymph nodes of surgical specimens from patients with stage I non-small-cell lung cancer (NSCLC) can have an effect on the time to recurrence and survival of these patients. PATIENTS AND METHODS: We analyzed data on 442 patients with stage I NSCLC who were treated with surgical resection and some form of lymph node sampling. Associations between total lymph nodes sampled and disease-free survival (DFS) and overall survival (OS) were investigated. The effect of total lymph node stations sampled and the surgical techniques (random lymph node sampling, systematic sampling [SS], or complete mediastinal lymph node dissection [MLND]) on DFS and OS was also studied. Complete MLND and SS were defined as dissection or sampling of levels 4, 7, and 10 for right-sided lesions and levels 5 or 6 and 7 for left-sided lesions. RESULTS: Patients were divided into quartiles on the basis of total number of lymph nodes sampled. Improved DFS and OS were associated with greater number of lymph nodes sampled. SS and MLND were associated with improved survival compared with random lymph node sampling. The total number of lymph nodes sampled maintained strong significance in the multivariate analysis. CONCLUSION: These results indicate that examining a greater number of lymph nodes in patients with stage I NSCLC treated with resection increases the likelihood of proper staging and affects patient outcome. Such information is important not only for therapy and prognosis of individuals but also for identifying those who may benefit from adjuvant therapy.

Lung cancer. Invasive staging: the guidelines.

A variety of invasive staging tests are available, including mediastinoscopy, thoracoscopy (video-assisted thoracoscopic surgery), transbronchial needle aspiration (TBNA), transthoracic needle aspiration (TTNA), and endoscopic ultrasound with fine needle aspiration (EUS-NA). Each of these tests requires specific skills, has particular risks, and has technical considerations making it more or less suitable for masses in particular locations. Therefore, direct comparisons among the tests are not possible, and the issue is to define which procedure is most useful for a particular situation. Invasive staging procedures are sometimes used to confirm the stage of a lung cancer, ie, when radiographic staging is not reliable. However, invasive staging procedures are also often used to confirm the diagnosis (ie, when the radiographic stage is reliable). The first situation requires a test with a low false-negative rate; the latter requires a test with high sensitivity. Clinicians must be clear about the question at hand and how to assess the value of a test when selecting an invasive staging procedure. When confirmation of the diagnosis is the primary issue, TBNA (or EUS-NA, if available) are good choices because of high sensitivity and low morbidity. When the primary issue is to confirm that there is no involvement of mediastinal lymph nodes, mediastinoscopy appears to be best suited to most situations. When the primary goal is to confirm malignant involvement of mediastinal nodes, mediastinoscopy also appears to be best in general, although TBNA, TTNA, and EUS-NA may be reasonable alternatives in certain situations. However, selection of a test will also depend on the local availability of expertise, and patient-specific anatomic and physiologic considerations. Selection of the optimal approach is best achieved through a multidisciplinary discussion so that all aspects can be weighed appropriately.

Molecular staging of lung cancer: real-time polymerase chain reaction estimation of lymph node micrometastatic tumor cell burden in stage I non-small cell lung cancer--preliminary results of Cancer and Leukemia Group B Trial 9761.

OBJECTIVE: The 5-year survival for patients with surgically resected stage I non-small cell lung cancer is only 60% to 70%, probably because of undetected systemic occult micrometastases. Detection of occult micrometastases in lymph nodes by reverse-transcriptase polymerase chain reaction for carcinoembryonic antigen messenger RNA in non-small cell lung cancer has not been reported. Detection of occult micrometastases by standard reverse-transcriptase polymerase chain reaction provides only yes or no answers about their presence, whereas quantitative real-time reverse-transcriptase polymerase chain reaction permits reproducible quantitation of target molecules. This study evaluated the ability of quantitative reverse-transcriptase polymerase chain reaction to quantitate lymph node occult metastases with carcinoembryonic antigen messenger RNA as a tumor marker. METHODS: Standard reverse-transcriptase polymerase chain reaction and quantitative reverse-transcriptase polymerase chain reaction for carcinoembryonic antigen messenger RNA were performed on 232 lymph nodes from 53 patients with stage I disease (node negative according to histologic examination). Quantitative reverse-transcriptase polymerase chain reaction determined carcinoembryonic antigen messenger RNA quantity by detecting fluorescence increase at a threshold polymerase chain reaction cycle. Threshold polymerase chain reaction cycle values were correlated with standard curves created from serially diluted carcinoembryonic antigen-positive HTB-174 tumor cells to estimate the number of micrometastatic tumor cells in a lymph node. RESULTS: Detection rates of occult metastases were similar for standard reverse-transcriptase polymerase chain reaction and quantitative reverse-transcriptase polymerase chain reaction at 38 of 232 (16.4 %) and 59 of 232 (25.4 %), respectively. Upstaging rates among 53 cases of stage I non-small cell lung cancer were also similar for standard reverse-transcriptase polymerase chain reaction and quantitative reverse-transcriptase polymerase chain reaction at 23 of 53 (43.4 %) and 30 of 53 (56.6%), respectively. Comparison of positive lymph node stations according to quantitative reverse-transcriptase polymerase chain reaction (threshold polymerase chain reaction cycle <45) with HTB-174 tumor cell standard curves yielded estimates of metastatic tumor cell burden of 1.07 x 10(3)to 3.24 x 10(5)cells per lymph node station (median 7190 tumor cells per lymph node station). CONCLUSIONS: Standard and quantitative real-time reverse-transcriptase polymerase chain reaction for carcinoembryonic antigen detected occult metastases in patients with stage I non-small cell lung cancer at similar rates; both upstaged about 50% of cases. Quantitative reverse-transcriptase polymerase chain reaction allows estimation of the number of metastatic cells per lymph node, however, which potentially allows greater precision in predicting recurrence risk.