Clinical applications of serum markers for lung cancer

Respiratory

Medicine

(1995) 89, 587-597

Topical Review

Clinical applications of serum markers for lung cancer D. FERRIGNO* Department

of Respiratory

AND G. BUCCHERI

Medicine,

Introduction Lung cancer is the most common lethal cancer in men and the sixth most common among women worldwide (1). Its devastating incidence and clinical seriousness have stimulated innumerable researches directed toward any possible approach. One of these approaches was the quest for biological markers capable of helping clinicians in the process of diagnosis, staging, disease monitoring and prognostication. Serum tumour markers (TMs) may be defined as substances produced by tumour cells, indicative of their presence, which are released into the bloodstream where they may be assessed (2). None of the TMs are completely tumour-specific, since almost all can be detected in the tissues or blood of patients with benign disease as well as in normal control subjects. Lung tumour markers fall into several categories including peptide and non-peptide hormones, oncofetal proteins, enzymes, structural proteins and membrane antigens (2,3). Sensitivity and specificity are parameters that give information on the validity of a test. These parameters are calculated correlating the serum concentration of TMs with clinical and radiological findings. Marker values are classified as true (or false) positive if high in presence (or absence) of tumour, and true (or false) negative if they are within the normal range in control subjects (or in patients with cancer). Serum tumour markers may be helpful in screening and early diagnosis of cancer, in the initial assessment of the extent of the disease, and in monitoring the tumour growth (or tumour volume reduction) once cancer has been diagnosed and treatment started. They may also give insight into histogenesis, inter-relationships and biological behaviour of tumours (2). Many TMs can also be evaluated as prognostic factors, either alone or in combination with other histopathological, biochemical and clinical variables (4). *Author to whom correspondence should be addressed at: Department of Respiratory Medicine, A. Carle Hospital, I-12100 Cuneo, Italy. 0954-611 l/95/090587+

11 $12.0010

A. Carle Hospital,

Cuneo, Italy

This paper reviews the serum tumour markers which are most useful in the clinical management of lung cancer, as well as the new, most promising TMs (Table 1). Carcinoembryonic

Antigen

(CEA)

Among the numerous biomarkers known up to now, carcinoembryonic antigen (CEA) has certainly been the most extensively used. Carcinoembryonic antigen is an oncofetal protein normally present during fetal life, which occurs at low concentrations in adults, and circulates in high concentrations in patients with certain malignancies, particularly epithelial tumours (5). Abnormally high CEA levels have been found in 40-80% of non-small cell lung cancer (NSCLC) patients, with lower sensitivity in early stage cancer than in advanced cancer (610). It is clearly marked in patients with adenocarcinoma (11,12). A good relationship between CEA levels and treatment response has been demonstrated both in small cell lung cancer (SCLC) and NSCLC (6,9,13,14). Recently Icard et al. (15) have demonstrated that patients who underwent resection of stage I or II NSCLC with pre-operative CEA levels under 30 ng ml - ’ had significantly longer survival than patients with CEA above 30 ng ml - ‘. Virtually all patients with high CEA levels (> 50 ng ml - ‘) died within 2 yr. Therefore, these patients must be highly

Table

I

List

of reviewed

tumour

markers

in lung

cancer

Carcinoembryonic antigen (CEA) Tissue polypeptide antigen (TPA) Squamous cell carcinoma antigen (SCC-Ag) CYFRA 21-1 Neural cell adhesion molecule (NCAM) Neuron-specific enolase (NSE) Creatine-phosphokinase-BB (CPK-BB) Chromogranin A (ChrA) Soluble interleukin-2 receptor (sIL-2R)

0

1995 W. B. Saunders

Company

Ltd

588

Topical Review

suspected of having metastases even if operative staging indicates a limited disease. Generally, CEA levels vary along with changes of disease status, or may precede their clinical recognition. Persistently elevated post-operative values have been shown to indicate residual disease and poor prognosis (9). In 392 carefully evaluated patients with resected stage I NSCLC, Gail et al. (16) found CEA to be an independent indicator of increased risk of recurrence. Other studies confirmed the correlation between CEA, usually by univariate methods, and survival (6,8,9,13,17,18). Conflicting results were obtained in studies using multivariate methods (8,19,29). Recently, CEA was found to be strongly predictive of the outcome of 360 patients with squamous..,cell lung cancer, but of little or no value when multiple factors were jointly considered (18). Carcinoembryonic antigen only emerged as a significant independent prognostic factor after the artificial exclusion of stage and related variables (18). Tissue Polypeptide

Antigen

(TPA)

The cytoskeleton is a complex filamentous cytoplasmic structure that may influence the cell dynamic morphology in the tissue environment (21). It is composed of different types of filaments with different sites: actin; intermediate filaments; myosine and microtubules. Cytocheratins are the major component of intermediate filaments (22). Following the suggestions by Debus et al. (23), these can be subdivided into 20 different cytocheratins, according to their molecular weight and isoelectric point in twodimensional electrophoresis. The cytocheratin family is expressed by all epithelial cells and appears to be a useful marker of epithelial differentiation (23-26). Tissue polypeptide antigen (TPA) is a chemically well defined substance (27) identified in 1957 (28). Three monoclonal antibodies used in the diagnostic assay identify three antigens corresponding to cytocheratins number 8, 18, and 19 (29). Tissue polypeptide antigen is produced and released by proliferating cells (30-32). Thus, the concentration of the antigens is an indicator of the rate of cell division and tumour aggressiveness, and, consequently, of the host survival (2).Tissue polypeptide antigen can be detected in the serum and urine of patients with a wide variety of tumours (33-38) including bronchial carcinoma (3943). Serum determinations of TPA seem effective in all lung cancer histotypes, and are probably more useful than for any other marker (44,45). In patients with any histotype of bronchial carcinoma, the pretreatment level of TPA has been shown, by our team and other authors, to correlate positively with either

primary tumour characteristics, or the nodal involvement, or the metastatic spread (9,39,41,43,44,46,47). Several studies have also indicated that posttreatment TPA assays tend to vary in accordance with changes in disease status, as assessed by the categories of treatment response (9,44,46,47), and may sometimes precede them (43). Five studies with several hundred patients have clearly shown that this marker is well correlated with the prognosis of lung cancer, and this correlation persists when numerous other prognostic factors are taken into account (9,20,43,44,48). In a recent study (18), TPA was also proved to be an independent and strong prognostic indicator in squamous cell lung cancer. More recently, the yield of TPA in the pre-treatment assessment of NSCLC was determined in comparison with a baseline clinical evaluation and a multi-organ computed tomography (CT) (49). Using appropriate threshold values of TPA, it was possible to predict NSCLC resectability with an accuracy similar to that routinely achieved by CT (Fig. 1). Squamous (SCC-Ag)

Cell Carcinoma-Related

Antigen

Squamous cell carcinoma (SCC)-related antigen, also known as tumour-associated antigen or TA-4, is a protein with a molecular weight of approximately 48 000 daltons originally isolated in 1977 by Kato and Torigoe from squamous cell carcinomas of the cervix (50). Successively, a commercial radioimmunoassay was developed which has proved the utility of this marker in the control of treatment and in the detection of cervical SCC recurrence (51-53). Afterwards, the value of this marker was investigated in SCC of other origins (larinx, esophagus, oral and facial tumours etc.). The first results seem to suggest a moderate clinical usefulness of the marker, particularly in the follow-up of patients, in spite of a low sensitivity (54,55). In lung carcinoma, the picture is not so clear: in fact, the reported true positivity rates of SCC varied enormously, probably due to the policlonal or monoclonal antibody employed in the radioimmunoassay or to the influence of renal failure on SCC-Ag levels (54,56,57). Fischbach and Rink (57) reported a detection rate of 53%, Castelli et al. (58) reported a detection rate of 55%, and Ebert et al. (59) reported a detection rate of 78%. On the contrary, Body et al. (60) and Lorenz et al. (61) reported detection rates of 31-35%. SCC-Ag is not a specific marker for SCC, since elevated values were also found in other cell types of lung carcinoma, particularly in adenocarcinoma and large cell carcinomas

Topical Review

589

90 80 -

70 60 8 5040 30 20 10 0

BE

CT TPA Stage

BE

I-II

CT TPA

Stage

BE

CT TPA

Stage IIIb-IV

IIIa

Fig. I Diagnostic accuracies of the clinical baseline evaluation and computer tomography of brain, thorax, and abdomen, and tissue polypeptide antigen (TPA) (cutoff points: up to 110 U I - ‘, between 11 l-160 U 1~ ‘, above 160 U l- ‘). Values refer to the capability of detecting either full operability (Stages I and II, 1987 UICC classification), possible operability (Stage III) or full inoperability (Stages IIIb and IV). Solid bars, accuracy; 0, C.I. 95% (max); 0, C.I. 95% (min). Source: Buccheri and Ferrigno (49). (62,63). Its levels seem unrelated to tumour size, the extent of lymph node involvement, or the presence of metastases in distant organs; neither are these levels related to tumour cell differentiation (63). On the other hand, the value of pre-treatment SCC-Ag was emphasized as a prognostic factor for patients with a SCC of the lung (11,60,63). CYFRA

21-1

CYFRA 21-1 is a cytoskeleton marker. Cytokeratin 19 (CK 19) has a low molecular weight of 40 kDa. It is present and immunohistochemically detectable in the cytoplasm of epithelial tumour cells, including bronchial cancer cells (24,26), and CK 19 fragments may be released in the serum owing to cell lysis or tumour necrosis. They can be used as a tumour marker for lung cancer, and can be measured by a new immunoradiometric assay, the CYFRA 21-1 (64). Several studies have been made in the last few years indicating a high potential of this marker in NSCLC (6466). It has been demonstrated that the CYFRA 21-1 serum assay is significantly more sensitive for SCC than for all other histological lung cancer subtypes (65,67,68). In the first European multicentre study on CYFRA 21-1, Rastel et al. (68) investigated the serum levels of CYFRA 21-1, CEA, SCC-Ag and TPA. The sensitivity of CYFRA 21-1 for SCLC was 16% (n=74), compared to 41% for NSCLC (n = 547). In histological subgroups, sensitivity was 57% for squamous, 34% for undifferentiated large cell carcinoma, and 27% for adenocarcinoma. In SCC, the sensitivity of TPA, SCC-Ag and CEA was 46%, 30% and 25% respectively. Therefore CYFRA 21-1 appeared to be the best tumour marker

for squamous cell lung cancer. Serum levels of CYFRA 21-1 are related to the tumour mass: the sensitivity for stages IIIa and IIIb is 43% and 79%, respectively (68). High values in asymptomatic Tl/T2NO/Nl patients may indicate the presence of (micro) metastases, and may prompt the clinician to perform further clinical investigations (68). Very recently, Pujol et al. (66) have demonstrated in a prospective study of 165 patients that CYFRA 21-1 has an independent prognostic value and that its serum level helps predict the resectability of NSCLC. Serial determinations of CYFRA 21-1 were useful after surgical treatment of patients with SCC (69). A post-operative recurrence was observed in 9 of 10 patients showing increased CYFRA 21-1 concentrations, while 48 of 54 (89%) patients with normal CYFRA 21-1 showed a stable disease-free status. In multivariate analysis, increased serum levels were found to be significantly associated with higher risk of recurrence (69). These observations are consistent with preliminary data from other authors (70,71), who also found CYFRA 21-1 able to predict both success and failure of therapy, as well as relapses, prior to clinical signs. Recently Van der Gaast et ul. (72) confirmed the usefulness of this marker in monitoring the status of disease during and after chemotherapy of patients with SCC. Neural

Cell Adhesion

Molecule

(NCAM)

Cell surface receptors involved in cellular adhesion have been identified on several cell types, including haematopoietic, muscle and neural tissues (73-75). The largest number of antibodies to SCLC have been found to react with the cluster-l antigen,

590 Topical Review a 145KDa molecule later identified as the neural cell adhesion molecule (NCAM) (76). Neural cell adhesion molecule functions as a homophilic adhesion molecule. Recently NCAM expression in lung tumour cell lines have been proved to be associated with the expression of neuroendocrine markers of differentiation, regardless of the histological type of lung cancer (77). The expression of NCAM was found to be bown-regulated in the rare small cell lung cancer cell lines growing attached to substrate (78). Recently, Komminoth et al. (79) have immunohistochemically examined the expression of sialylated NCAM in a small number of SCLCs and bronchial or gastrointestinal carcinoids. There is increasing evidence that NCAM not only exists in membranebound form but is also released from the cell surface (80). A soluble form of NCAM has been described in conditioned media from neural or muscle cells and in different body fluids (81-83). Positivity for NCAM has been found in tumours of varying origins such as SCLC (84) some NSCLC (SS), neuroblastoma (86) nephroblastoma (87) pheocromocitoma (79) and pituitary tumours (77). Recently Kibbelar et al. (88) demonstrated, using immunohistochemistry methods within a group of radically resected NSCLC tumours, NCAM-positive patients to have a significantly shortened overall survival and disease-free interval in comparison with patients with NCAMnegative tumours. Jacques et al. (89) in a study of 221 patients with SCLC, measured the serum levels of NCAM and NSE. They demonstrated that (1) 113 of 221 (51%) of all patients had NCAM levels higher than 20 U ml- ‘, 75 of 221 patients (34%) had NSE levels higher than 25 ng ml - i; (2) levels of both markers were significantly different in limited and extensive disease patients; (3) patients with pathologic NCAM and NSE levels had significantly shorter survival times; (4) pre-treatment NSE and NCAM levels were positively correlated; and (5) serum marker levels were correlated with clinical status in the follow-up studies of 19 patients. These data are preliminary and have to be validated by larger studies. Neuron-Specific

Enolase (NSE)

Enolase is a glycolytic enzyme that is widely distributed throughout mammalian tissues and is composed of three distinct subunits: a, j3 and y (90,91). Neuron-specific enolase (NSE) was identified as isoenzymes y-y (92). Large amounts of NSE have been detected in neuroendocrine cells (93) and in neurogenic tumours (94-96). Neuron-specific enolase has been found to be a useful marker in patients with

SCLC. An elevated pre-treatment level of serum NSE has been reported in 40-70% of patients with local disease, and in 83-98% of patients with extensive SCLC (97-101). The NSE levels have generally been claimed to change along with the course of disease (97,100,102,103). Neuron-specific enolase is an intracellular enzyme involved in energy production, and therefore serum NSE may be a reflection of the turnover and cell death rate (104). Consecutive daily NSE determinations during chemotherapy have revealed a transient increase immediately after the start of cytotoxic drug administration (tumour lysis syndrome), followed by a decrease to the normal level in complete or partial responders (lOl-103,105). This phenomenon seems to indicate tumour sensitivity to chemotherapy (106). Several reports have addressed the prognostic capability of NSE. A significant inverse correlation between NSE levels and survival has been found in univariate analysis (20,107-l 1 l), whereas more equivocal results were reported by Jorgensen et al. (110) and Gronowitz et al. (20) using multivariate methods. Relatively few studies have been devoted to defining the role of serum NSE in NSCLC. The percentage of patients with elevated NSE levels may be 1141% in NSCLC (100,112-l 14) confirming the hypothesis that all human lung cancers have a common cellular origin and that neuroendocrine differentiation may be found in all histologic subtypes of lung cancer (115). Preliminary data suggest that NSCLC detected by neuroendocrine markers are more sensitive to cytotoxic chemotherapy than non-neuroendocrine NSCLC (116119), but may have a shortened survival (88, 120). In this context it is worthwhile to note that NSE is not a specific marker for neuroendocrine differentiation, and elevated serum NSE levels cannot be taken as conclusive proof of neuroendocrine differentiation (121). The value of serum NSE assay remains, therefore, limited to patients with cytohistologically-proved diagnoses.

Creatine

Phosphokinase-BB

(CPK-BB)

Creatine phosphokinase (CPK) consists of three principal cytoplasmic isoenzymes; MM, MB, and BB (122). Creating phosphokinase is an enzyme that catalyses the transfer of a high energy phosphate from creatine phosphate to adenosine diphosphate. The skeletal muscle contains relatively large amounts of isoenzyme MM (123) the cardiac muscle contains significant amounts of MB, and CPK-BB is found mainly in brain and smooth muscle (123). Increased concentrations of CPK-BB have been reported to

Topical Review occur in the serum of patients with carcinomas of the prostate (124), breast (125) and stomach (126). Coolen and Pragay (127) in 1979 were the first to report elevated levels of CPK-BB isoenzyme in the sera of SCLC patients. CPK-BB was found in high concentration in SCLC tumour specimens and cell lines (128). Other authors examined the correlation between the level of this enzyme and the stage of disease (128,129). Gazdar et al. (128) found that CPK-BB was mainly elevated in advanced stages, and depended on tumour size. Similar results were reported by Carney et al. (129) who reported an increase of CPK-BB in 2% of patients with limited disease and in 41% with extensive disease. These authors also suggested a correlation between the number of metastatic sites and the level of enzyme (19% of all patients with single metastases and 100% with multiple metastases had elevated values of CPKBB). Jacques et al. (108) found levels of CPK-BB above 10 ng ml ~ i in 40 of 129 SCLC patients (32%). A subgroup analysis showed that patients with liver and brain marrow metastases had an elevation of this enzyme. In these patients, the same authors observed a correlation between pre-treatment CPK-BB and response to therapy. As to prognosis, subjects with pathologic levels of the enzyme had shorter survival times than patient with normal levels (108). High concentration of this isoenzyme in cerebrospinal fluid seems to be useful to distinguish between meningeal spread and parenchymal cerebral metastases (130). Chromogranin

A (ChrA)

Chromogranin A (ChrA) was initially described as a protein co-stored and co-released with catecholamines (131,132). It is a 68 000 dalton acidic protein that has been found in the neurosecretory granules of normal endocrine tissues and malignant APUD cells (133-l 37). O’Connor and Deftos (138) observed that measurements of plasma chromogranin A were useful in the evaluation endocrine nature of a neoplasm or in the recognition of the neoplastic nature of endocrine tissues that do not produce any other peptide hormones. Immunohistochemical techniques in SCLC have produced contrasting reports: Nakajama et al. (139) found a positive reaction to chromogranin A in five out of 29 biopsy specimens of SCLC, whilst Said et al. (140) failed to demonstrate any positive histochemical reaction in 12 SCLC cases. Another study (141) postulated the potential value of this marker for the subset of SCLC cell lines: the authors found significant chromogranin A released into the culture medium in three out of five SCLC and in only one out of five NSCLC cell lines. Sobol

591

et al. (142) assayed the sera of 46 SCLC patients: 52% of patients with limited disease (LD) and 72% with extensive disease (ED) had elevated levels of chromogranin A. In the same study, four patients with elevated levels of this substance, originally classified as NSCLC, were eventually found to have a mixed SCLC-NSCLC histology (142). Recent work by Johnson et al. (143) measured serum levels of chromogranin A, NSE, LDH and CEA at presentation and during treatment, remission and relapse of 154 SCLC patients. Like NSE and LDH, chromogranin A was correlated with the stage of disease. The response to therapy was best correlated with the presentation levels of ChrA. The prediction of relapse was mostly reliable with ChrA, since 52% of progressed patients recorded rising levels of this marker before any clinical sign. Soluble Interleukin-2

Receptor (sIL-2R)

Activation of T lymphocytes leads to the expression of interleukin-2 receptors (IL-2R) on the cell surface (144) as well as to the release of soluble IL-2R (sIL-2R) molecules into the circulation (145). T lymphocytes are the predominant IL-2R bearing cells (146) and hence the serum sIL-2R level provides a satisfactory indication of T-cell activation in vivo. Increased sIL-2R levels have been found to be associated with lymphoid cell activation (147-150) lymphoproliferative disorders (15 l), and solid tumours (152). Also in the serum of patients with SCLC and NSCLC, sIL-2R levels have been reported to be elevated (151,153-155). Buccheri et al. found increased concentrations of sIL-2R in 126 lung cancer patients, in comparison with healthy volunteers and patients with pulmonary benign diseases (155). Pre-treatment sIL-2R correlated with neither the extent of disease nor with the histotype. On the contrary, post-treatment levels of the receptor correlated significantly with the status of disease, particularly in non-surgical patients. Also, patients with abnormal levels of sIL-2R were found to have a worse prognosis (155). In patients with adenocarcinoma of the lung, Ginns et al. (153) found that the serum concentration of sIL-2R did not correlate with the extent of the disease, degree of differentiation, or presence of symptoms. Conversely, in SCC patients, the peripheral blood concentration of the soluble receptor appeared to relate inversely to the severity of illness, since the highest levels were found in patients who were asymptomatic for a stage I disease. Recently, Chan et al. (156) confirmed that serum sIL-2R is significantly higher in patients with NSCLC if compared with control subjects. The

592

Topical Review

serum levels of sIL-2R were higher in patients with extensive intrathoracic disease detected at operation

but without distant metastasis, than in patients with localized resectable tumour. However, there was no difference

in patients

with

metastatic

disease com-

pared to those with non-metastatic tumours. Tisi et al. (157) evaluated the influence of changes in sIL-2R serum levels during the peri-operative period on early relapse rate of 60 patients with operable NSCLC. Serum levels were measured before surgery and 7 and 30 days after surgery. The study suggests that the persistence of increased sIL-2R levels in the post-operative period might be associated with a higher early relapse rate. Conflicting reports on sIL-2R implies that there are probably multiple factors influencing the degree of T lymphocyte activations in addition to tumour load, and that further studies will be necessaryfor better defining the role of this marker. Conclusion

The WHO pathologic description of malignant tumours classified lung cancers in SCLC and NSCLC (158). Recently, however, data from TM studies have indicated that overlaps exist between SCLC and NSCLC, supporting the concept that all human lung tumours have a common cellular origin and that neuroendocrine (NE) differentiation may be found in all histologic types of lung cancers (112,113,115). NE differentiation may be an important prognostic feature of NSCLC, with increased response to chemotherapy and improved survival (114). Several TMs associated with lung cancer have been investigated in recent years, yet the issue concerning their clinical role remains partly unanswered. To date, no single marker for the screening of asymptomatic patients has been found. The sensitivity increases using multiple marker analysis but there is a consistent loss in specificity. Therefore it remains very

difficult to detect a lung tumour at an early clinical stage with serum marker measurements. On the contrary, TMs may predict the behaviour

and prognosis

of lung cancer and may be useful to monitor the post-operative course of disease. The determination of TMs will eventually lead to a better understanding of the biological properties of bronchogenic carci-

noma. Biological studies on TMs may represent a promising avenue towards new treatment as well as a promising attempt towards

strategies, secondary

prevention. Acknowledgement

The authors gratefully acknowledge MS Anna Cerchetti for her linguistic help.

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