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J Thorac Cardiovasc Surg 2001;122:891-899
© 2001 The American Association for Thoracic Surgery
General Thoracic Surgery (GTS) |
From the Cuneo Lung Cancer Study Group (wwww.clucasg.org) at the "S. Croce e Carle" Hospital, Cuneo, Italy.
Received for publication Dec 22, 2000. Revisions requested April 17, 2001. Accepted for publication May 17, 2001. Address for reprints: Gianfranco Buccheri, MD, Divisione di Pneumologia, Ospedale "S. Croce e Carle," Cuneo, I-12100, Italy (E-mail: buccheri{at}culcasg.org
Abstract
Objectives: Copious literature shows that in lung cancer many serum markers, especially the cytokeratin degradation products, correlate with the extent of disease. In 1995, we suggested the possibility of predicting the resectability of non–small cell lung cancer by measuring the plasma level of the tissue polypeptide antigen, a marker of the cytokeratin family. This study was designed (1) to confirm the earlier data in a new prospective evaluation, (2) to comparatively assess another classic biomarker (ie, the carcinoembryonic antigen), and (3) to incorporate their results into the preoperative evaluation of non–small cell lung cancer.
Methods: We analyzed the database of a single institution over a 5-year period (1994-1998) in a community-based hospital and second referral level institution for a province of 500,000 people. The database included 124 consecutive patients (105 men) with pathologically documented lung cancer (50% with adenocarcinoma) accurately staged, clinically judged operable or potentially operable, and eventually operated on. Anthropometric, clinical, and laboratory data (including the carcinoembryonic antigen and tissue polypeptide antigen serum levels) and the results of a complex staging workup were prospectively recorded. Receiver-operating characteristic curves and diagnostic formulas were used for data analysis.
Results: Computed tomography of the thorax, upper part of the abdomen, and brain was the most accurate preoperative method to assess tumor resectability (receiver-operating characteristic area: 0.76, 95% confidence intervals: 0.67-0.86, P = .000; accuracy rate: 77%, confidence intervals: 69%-84%). Tissue polypeptide antigen was also predictive for tumor resectability (receiver-operating characteristic area: 0.62, 95% confidence intervals: 0.51-0.73, P = .035; accuracy rate at a threshold level of 110 U/L: 65%, 95% confidence intervals: 56%-73%). Carcinoembryonic antigen was diagnostic only at the extreme values of its distribution (accuracy rate at a level up to 10 ng/mL: 69%, 95% confidence intervals: 60%-77%). The probability of finding resectable disease at the time of the operation increased from 78% (baseline computed tomography–based probability) to 83% when the concentration of tissue polypeptide antigen was lower than 90 U/L and to 85% when the concentration of carcinoembryonic antigen was below 10 ng/mL. The probability of discovering an advanced disease increased from 68% (baseline computed tomography–based probability) to 89% when tissue polypeptide antigen levels were abnormal and to 100% when carcinoembryonic antigen concentrations were higher than 10 ng/mL. Conversely, the predictability of computed tomography was diminished by contrasting biomarker results, requiring further clinical investigations.
Conclusions: Computed tomography remains the gold standard for the preoperative evaluation of non–small cell lung cancer, although it may significantly underestimate the real tumor extension. The addition of the easy and inexpensive tissue polypeptide antigen test (with or without carcinoembryonic antigen) is capable of correcting this underestimation and helps to decide whether to completely rely on computed tomography or order additional clinical investigations.
See related editorial on page 849.
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1 In oncology practice, serum tumor markers may be helpful in the diagnosis, pathologic classifications, and evaluation of stage of disease and prognosis. When measured serially after a diagnosis is established, they may aid in assessing the response to treatment, monitoring the spontaneous course of the illness, and surveilling for tumor recurrences. 2
Lung cancer is no exception to this rule, and the expression of serum biomarkers in this particular tumor is variable and abundant. 3 Lung tumor markers fall into several categories, including oncofetal proteins, structural proteins, enzymes, cell membrane components, secreted peptides, hormones, and other tumor-associated antigens. 3 In non–small cell lung cancer (NSCLC), cytokeratin-derived molecules and the carcinoembryonic antigen (CEA) are probably the most helpful markers and certainly the most frequently used. 3-5
In 1995, we suggested that it should be possible to predict the resectability of NSCLC by simply measuring the plasma level of tissue polypeptide antigen (TPA), the oldest marker of the cytokeratin family. We were aware that such evidence was preliminary and needed confirmation. However, the possible equivalence of a blind serum test to the more complex, time-consuming, and expensive multiorgan computed tomography (CT) was a truly exciting perspective. Given the importance of the issue, we decided to continue the preoperative biomarker testing in a new confirmatory study.
In this report, we describe the most recent experience of the Cuneo Lung Cancer Study Group (CuLCaSG) with CEA and TPA obtained in subjects with potentially resectable NSCLC. As already mentioned, this study was done mainly to confirm our earlier data. Secondary aims were (1) the comparative assessment of TPA and the "classic" CEA and (2) the incorporation of marker test results into the conventional preoperative evaluation of NSCLC.
Patients and methods
Database and study design
In the fall of 1982, a group of chest physicians decided to devote their professional activity to the study of lung cancer. The group, which later became known as CuLCaSG, is still active at the Department of Pulmonary Medicine of the "A. Carle" Hospital in the city of Cuneo, Piedmont, Italy. The former "A. Carle" Hospital for Chest Diseases merged with the "S. Croce" General Hospital, and the two hospitals, now named "S. Croce e Carle," were then designated as Hospitals of National Importance. They serve the whole Cuneo Province as a second referral institution. Among the first acts of the CuLCaSG was the creation of a clinical database for patients with carcinoma of the lung, effective in January 1983. All patients with lung cancer referred to a physician of the group were managed uniformly. Data regarding 44 variables were collected for each new patient with a cytologically or pathologically documented diagnosis of lung cancer 6 and recorded on a computer. This database included anthropometric and clinical characteristics, routine laboratory tests and serum tumor markers, TNM descriptors, and a computer-derived stage of disease. Since 1983, TNM definitions have changed, radically in 1986 and minimally in 1997, because of two consecutive revisions to the International Staging System for Lung Cancer. 7,8 Therefore, to allow for homogeneous comparisons, we had to review the patients' charts and upgrade their TNM variables. This work was done as soon as the revision of the International Staging System for Lung Cancer was formalized. Every 4 to 5 years, the structure of the database was modified and upgraded to new software, and the number of variables progressively increased to hundreds. However, the core variables of the early database remained unchanged, allowing for careful analyses and time-related comparisons. In particular, of 1296 new patients with lung cancer seen consecutively during the years 1983 to 1998, 1136 underwent a pretreatment CEA test and 1115 had a pretreatment TPA test. A large part of this population has been the object of a number of prior publications concerning mainly TPA. 9-13 Updated descriptive statistics of the entire population were obtained during the preparation of this article. This update confirmed prior data, showing that both CEA and TPA levels increased significantly (CEA Rs = 0.161, P = .000; TPA Rs = 0.322, P = .000), paralleling the stage of disease. 8 In the entire sample of the 1115 patients tested, median values of TPA were 70, 120, 70, 115, 114, 130, and 180 U/L, respectively, for the stages Ia, Ib, IIa, IIb, IIIa, IIIb, and IV. Corresponding median values for CEA were 2 ng/mL for stages Ia to IIa and 3 ng/mL for more advanced stages.
All patients seen in 1994 and afterward were eligible for this study if they had a pathologic diagnosis of NSCLC 6 and had undergone each of the following: (1) complete and accurate evaluation of disease extent that had indicated an almost certain or likely tumor resectability, (2) pretreatment CEA and TPA serum tests, and (3) thoracotomy with curative intent, which had resulted at least in an accurate mediastinal exploration and pathologic confirmation of the T and N status.
Anthropometric and clinical characteristics of the 124 assessable patients are shown inTable 1.
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Plasma measurements were performed with commercially available radioimmunoassays (CEA test; CIS Bio International, Gif-sur-Yvette, France; Prolifigen R, TPA IRMA; AB Sangtec Medical, Bromma, Sweden), following the manufacturers' instructions. Normal reference values for CEA and TPA were up to 5 ng/mL and 90 U/L, respectively.
CT: Technique and reading
All patients included in this report were studied with a CT scan of the thorax, upper part of the abdomen, and brain. Up to October 1998, CT scans were performed on a conventional scanner (GE 9800; General Electric, Milwaukee, Wis); since then, a spiral-CT machine (CT twin flash; Elscint Ltd, Haifa, Israel) has been used. Sections of the brain, 10-mm thick, were obtained at 1-cm intervals during suspended inspiration, as well as sections from the lung apices to the upper part of the abdomen. In selected cases, 5-mm thick sections at 5-mm intervals were acquired through the region of interest. Iodinated intravenous contrast material (150-c3 bolus, plus 100-c3 in slow infusion) was injected before all studies. Appropriate windows were used for viewing both the lungs and soft tissues.
Mediastinal nodes were labeled as abnormal if they were 1.5 cm or larger (transverse diameter). All CT scans were interpreted with no restriction to the clinical information available at the time of the examination.
Other staging procedures
Other diagnostic and staging techniques did not vary considerably during the 5 years of recorded data; furthermore, the frequent coexistence of experimental protocols, aimed to optimize diagnostic and staging procedures, ensured an overall accurate clinical assessment. All patients received a technetium 99m methylene diphosphonate bone scan of the entire body. In addition to this, the baseline clinical evaluation also included a physical examination, routine laboratory tests, bronchoscopy, and functional respiratory tests. In half of the sample, the baseline workup was supplemented by nonroutine imaging studies, such as the anti-CEA monoclonal antibody scintigraphy. 14 Other imaging tests, including radiograms, CT scans, and magnetic resonance imaging of the bones, ultrasonographic studies of the abdomen, and other organ-specific investigations were optional and performed as clinically indicated. Any information obtained in this way was considered part of the final clinical evaluation. The preoperative staging evaluation was particularly reliable in 12 patients (10% of the cohort), who had a pathologic stage assessment made by mediastinoscopy (11 subjects) or CT-guided biopsy of a suspected (and unconfirmed) bone metastasis (1 subject). Because we considered both anti-CEA immunoscintigraphy and the marker assay to be investigative, no clinical decision was made on the sole basis of their results.
All staging tests were obtained within a 3- to 4-week period and no thoracotomy was performed later than 30 days after the first physical examination.
Data analysis and statistical considerations
Diagnostic capabilities were calculated for the final clinical assessment, CT reading, CEA, TPA, and CEA-TPA combined variable (mean of the two marker values expressed in percentage of their reference of 5 ng/mL [CEA] and 90 U/L [TPA]). For CEA, TPA, and CEA-TPA, one or multiple threshold levels were chosen to describe a positive or negative test result. In this study, diagnostic capabilities are not intended to show the presence or absence of disease, but the presence (or absence) of the condition of full resectability, that is, the pathologic postoperative documentation of stage Ia through IIb disease. Accordingly, a marker level below a given threshold or a CT result suggestive of stage Ia-IIb was declared true positive when the actual pathologic stage was Ia to IIb and false positive when the latter was IIIa or more. Markers over the considered threshold or more advanced CT stages were considered true negative or false negative when the corresponding pathologic stage was, respectively, IIIa-IV or Ia-IIb.
Statistical analysis was performed with the use of the SPSS package for Windows, version 9.0 (SPSS, Inc, Chicago, Ill). Continuous variables were described by medians and ranges because in many instances, such as in the case of CEA and TPA, their distribution was not gaussian. 15 Sensitivity, specificity, and accuracy, along with predictive positive and negative values, were obtained by means of standard diagnostic formulas. 16 Diagnostic proportions were given along with their 95% confidence intervals (CI). 17 To compare diagnostic capabilities, we used the receiver-operating characteristic curves, 18 whose circumscribed areas (the area under the curve) give an estimate of the diagnostic efficiency. 19 Correlations and differences were tested for statistical significance by means of the Spearman rank test and the Kruskal-Wallis analysis of variance. 15 All statistical tests were 2-sided.
Results
Descriptive statistics
Table 1
shows the anthropometric and clinical characteristics of the patient population, with descriptive statistics on sex, age, history of weight loss, performance status (Eastern Oncology Group scale 20), and CEA and TPA serum levels. Also reported are tumor cell type, the postoperative pathologic stage of disease, the correlated parameters of disease extension, the type of surgical treatment, the survival duration, and the patients' status at the last follow-up reassessment. As of May 1999, 64 of 124 patients (52%) were still alive after a median follow-up of 19 months (range 1-64 months). Most recruited patients had an early stage of disease and had favorable surgical outcomes. A total of 88 patients had completely operable disease (postoperative stages Ia, Ib, IIa, or IIb), another 18 subjects might have benefited from the operation (stage IIIa), and 18 others had a nonoperative condition (stage IIIb or IV). This resulted in 104 pulmonary resections and 20 exploratory thoracotomies.
Median values (ranges) of CEA and TPA in the postoperative pathologic stage Ia-IIb were, respectively, 2 ng/mL (0-60 ng/mL) and 70 U/L (30-360 U/L). Corresponding values for postoperative stages IIIa-IV were 2.5 ng/mL (1-22 ng/mL) and 100 U/L (40-790 U/L). The correlation between serum levels of TPA and the pathologic stage of disease was statistically significant (Spearman R = 0.3, P = .001), whereas that of CEA did not reach the significance level (Rs = 0.162, P = .072). No significant difference in the distribution of the serum markers' concentration among different histotypes was observed (Kruskal-Wallis statistic).
Diagnosis of postoperative pathologic stage by means of a 3-organ CT and the best clinical assessment
Table 2 shows a cross-tabulation between the 3-organ CT stage and the best clinical assessment on the one hand and the postoperative pathologic stage on the other. On the basis of CT, the preoperative classification was stage Ia-IIb in 105 patients. Stage Ia-IIb disease was confirmed postoperatively in only 88 of them. By contrast, there were 19 patients with CT-diagnosed stage IIIa-IV disease and 36 patients with truly inoperable disease. This means a considerable CT underestimation of the real extent of disease, partially corrected by the completion of the full staging workup. The final and best clinical assessment, however, showed no greater diagnostic accuracy, because of an increased overestimation of the real disease(Table 2).
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). A normal level of TPA was properly associated with resectable disease in 79% of the patients (95% CI: 69%-88%), and a higher level was diagnostic of advanced disease in 41% (95% CI: 27%-55%). TPA was also capable of diagnosing resectability when the T or the N factors alone were taken into consideration(Figure 2). For a CEA level up to 5 ng/mL, sensitivity, specificity, and accuracy rates were, respectively, 82%, 14%, and 62%, whereas the probability of properly diagnosing a condition of resectability was 70% (CI: 61%-79%). The combination of CEA and TPA (CEA-TPA combined variable) was unable to increase the overall diagnostic accuracy of TPA alone(Table 4).
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) identified two different situations. The first was the presence of concordant findings (which increased both positive and negative predictive values of CT); the second was the occurrence of bidirectional discordant data (this lowered CT predictability). The TPA-stratified CT stage was the best possible combination of CT and any one single marker(Table 4). As shown, the presence of a normal TPA level increased the chance, based on CT, of correctly predicting tumor resectability from 78% (CI: 70%-86%) to 83% (CI: 74%-92%). The opposite situation was associated to a diagnostic improvement of 21%, from the 68% rate of negative predictability of a sole CT suggesting nonresectability (CI: 48%-89%) to 89% (CI: 68%-109%). In the area of uncertainty of an abnormal TPA and tumor resectability suggested by CT (or vice versa, conversely, of normal TPA and presence of advanced disease on CT), the CT diagnosis of resectable disease was correct in about 50% to 70% of the cases(Table 4). Discussion
This study aimed to assess, in resectable NSCLC, the exact diagnostic capability of two serum biomarkers, CEA and TPA, that are commonly measured in many European countries 21 but are still ignored by important medical societies. 22,23
CEA is an oncofetal protein found normally in the embryonic and fetal gut, produced sometimes by malignant cells. It was discovered in 1965 by Gold and Freedman 24 in the sera of subjects with adenocarcinoma of the colon. Raised CEA concentrations may be detected in persons who smoke, in patients with benign tumors, and in 15% to 20% of subjects with inflammatory disorders such as ulcerative colitis, pancreatitis, liver disease, and pulmonary infections. 25 Abnormally elevated concentrations of CEA can be found in 30% to 70% of patients with lung cancer. 11,13,26-28 Raised levels of CEA are particularly common in those with adenocarcinoma 28,29; however, they can be present in any histologic type. 26,27 Studies have shown that increased concentrations of CEA occur more frequently in advanced cancers, 12,27 although reported differences are not always statistically significant. 11
Nearly half a century ago, Björklund 30 discovered a new antigen by mixing many different tumors and producing an immune serum against the mixture. He called it TPA. TPA has been subsequently identified as a degradation product of the cytoskeleton, formed by the cytokeratins 8, 18, and 19. 31 The cytoskeleton is a complex network that influences the dynamic structure of all eukaryotic cells in their tissue environment. 32 It is composed of microfilaments (7-9.5 nm in diameter), microtubules (25 nm), and intermediate filaments (10-12 nm). 32 Cytokeratins are the major components of the intermediate filaments. 33 Cytokeratins may be divided into 20 different types, according to molecular weight and isoelectric point. 34 The expression of a single cytokeratin or a combination of certain cytokeratins is typical of a specific tissue. Elevated serum concentrations of TPA (ie, of cytokeratins 8, 18, and 19) have been observed in different types of epithelial cancers. 35 In lung cancer, pretreatment levels of TPA are often elevated, particularly in the later stages of disease. 9-13,36-38
As already mentioned, this is not our first attempt to define a clinical strategy capable of exploiting the widely known correlation between tumor burden and serum marker concentration. In 1995, in this Journal, we 36 reported a study specifically designed to investigate the use of TPA as a common test of preoperative assessment. We considered 104 patients with NSCLC who had undergone thoracotomy, mediastinoscopy, or biopsy of suspected metastatic deposits in addition to an extensive noninvasive evaluation of the stage of disease. We made several retrospective evaluations, but the two most pertinent to this study were those regarding TPA and the readings of a CT of the brain, thorax, and upper portion of the abdomen. Among the 20 threshold values considered, ranging from 45 U/L to 450 U/L, we identified two thresholds for detecting the postoperative stage of disease with the highest rate of success. Then, on the basis of the pathologic reference, we determined the sensitivity, specificity, accuracy, and predictive capabilities of both CT and TPA at the thresholds of 110 U/L and 160 U/L. We found that CT and TPA had a diagnostic accuracy of, respectively, 79% and 68% for stages I and II; 69% and 77% for stage IIIa; and 77% and 76% for stages IIIb and IV (1987 International Union Against Cancer [UICC] classification). Impressed by those results, we postulated the equivalence of TPA and CT in predicting surgical resectability. This study starts from that premise, but it limits the focus to what we think is the most clinically important information. Is the patient under assessment a surgical candidate or does he or she have a condition that is partially or completely inoperable? We can summarize our current findings as follows:
Conclusions
Evidence from this study suggests obtaining a routine TPA test (and possibly a CEA test) in all patients with potentially operable NSCLC. CT remains the gold standard for the preoperative evaluation of NSCLC. However, it may significantly underestimate the real extension of tumor. The TPA test is capable of correcting such an underestimation and helps to determine the next steps. We believe that a 3-organ CT showing a resectable tumor (stage Ia-IIb) and a TPA level up to 90 U/L in an asymptomatic subject are clear indications for immediate operation. On the other hand, a higher TPA value (or a very high level of CEA) associated with CT findings of nonresectability (stage IIIa-IV) virtually eliminates any surgical approach. In case of conflicting data, the patient is still a surgical candidate, but an intensification of the preoperative evaluation is mandatory. This could be obtained by ordering a bone scan or performing a mediastinoscopy, even in the absence of symptoms and signs.
Acknowledgments
We thank Lorena Gribaudo and Anna Merlo, nurses of the outpatient unit, for their help and support.
References
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G. Buccheri and D. Ferrigno Identifying patients at risk of early postoperative recurrence of lung cancer: a new use of the old CEA test Ann. Thorac. Surg., March 1, 2003; 75(3): 973 - 980. [Abstract] [Full Text] [PDF]
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