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National Academy of Clinical Biochemistry Guidelines for the Use of Tumor Markers in Lung Cancer

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NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
1
National Academy of Clinical Biochemistry Guidelines for the Use of Tumor Markers in
Lung Cancer
Petra Stieber
1*
, Rudolf Hatz
2
, Stefan Holdenrieder
1
, Rafael Molina
4
, Marius Nap
5
, Joachim
von Pawel
6
, Andreas Schalhorn
3
, Joachim Schneider
7
, Ken Yamaguchi
8
1
Departments of Clinical Chemistry,
2
Surgery and
3
Medicine, Klinikum der Universität
München - Großhadern-Marchioninistr., München, Germany;
4
Department of Clinical
Biochemistry, Hospital Clin, Barcelona, Spain;
5
Department of Pathology, Atrium Medical
Centre, Heerlen, Netherlands;
6
Asklepios Fachklinik für Pneumologie, Gauting, Germany;
7
Institute for Social Medicine, Justus-Liebig-Universitat Giessen, Giessen, Germany:
8
National Cancer Center Research Institute, Tokyo, Japan.
*Sub-Committee Chair, to whom all comments should be addressed via e-mail to
Petra.Stieber@med.uni-muenchen.de, with copies to C.Sturgeon@ed.ac.uk and
ediamandis@mtsinai.on.ca
Key words: CEA, CYFRA 21.1, guidelines, lung cancer, neuron specific enolase, non-small
cell lung cancer, ProGRP, SCCA, small cell lung cancer, tumor markers
Abbreviations: AUC, area under the curve; LDH, lactate dehydrogenase; NSCLC, non-
small cell lung cancer; NSE, neuron specific enolase; progastrin-releasing peptide, ProGRP;
SCC, squamous cell carcinoma; SCCA, squamous cell carcinoma antigen
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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Introduction
Lung cancer is the most frequent cancer in the world, both in terms of incidence (1.2
million new cases or 12.3% of the world total) and mortality (1.1 million deaths or 17.8% of
the total). Trends in lung cancer incidence and mortality reflect smoking habits and/or
exposure to other environmental or occupational carcinogens. The incidence rate in men is
34.9 per 100,000 with highest rates observed in more developed countries although in
countries in which male tobacco consumption has declined, incidence and mortality are now
slowly decreasing. In women, incidence rates are lower (11.1 per 100.000) with the highest
rates found in North America and Northeastern Europe, but there is a rising trend in
incidence and mortality (1-3).
Reflecting different clinical behaviour and sensitivity to chemo- and radiotherapy, lung
cancers can be grouped in two major histological types, i.e. non-small cell and small cell lung
cancer (NSCLC and SCLC respectively). NSCLC accounts for 75-85% of lung cancer
patients and consists of several subtypes, predominantly squamous cell carcinomas,
adenocarcinomas and large cell carcinomas, which are treated in the same manner. Small
cell lung cancer accounts for 15-25% of lung cancer patients, often has neuroendocrine
components, and is primarily treated with chemotherapy and/or radiotherapy. Many lung
cancers constitute histologically mixed tumor types consisting of non-small cell and small cell
components (4-6). Histological differentiation and staging of lung cancer is mandatory for
therapeutic stratification.
Patients with lung cancer often do not exhibit specific symptoms, particularly in early stage
disease. Dyspnoea, cough and thoracic pain are early signs, while hemoptysis often
indicates advanced disease. Relapsing infectious diseases of the respiratory system in
combination with a smoking history suggest a need for further diagnostic investigations,
including medical history and physical examination, laboratory tests, chest radiography,
thoracic CT or MRI, bronchoscopy and biopsy. For staging according to UICC criteria,
additional CT or MRI of the abdomen and the brain, bone scan, and eventually positron
emission tomography are used (5,6). Serum tumor marker measurements also potentially
have an important role in both diagnosis and staging.
For patients with NSCLC, particularly those with early stage disease (Stages I to IIIA),
surgery is the mainstay of treatment. The additional application of adjuvant radio- or
chemotherapy after tumor resection has previously been shown to have only limited benefit.
However, more recent data indicate a considerable improvement in overall survival when
modern adjuvant chemotherapies are applied (7,8). The use of neoadjuvant systemic
therapies prior to surgery to provoke tumor shrinkage and early eradication of systemic
micrometastases is still under discussion (4,5). Five-year-survival rates depend strongly on
tumor stage, with 60%-70% five-year survival reported for patients with Stage I disease,
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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40%-50% for Stage II and 15-30% for Stage IIIA (4,9). Currently, few patients with non-
resectable NSCLC in advanced stages (IIIB and IV) will be cured. Median survival for Stage
IV disease patients has been stable for years at 8 to 10 months. Although response rates for
chemo- and radiotherapy are low, several studies have demonstrated moderate beneficial
effects concerning survival, time to disease progression, and quality of life, as compared with
best supportive care (4).
Small cell lung cancer is characterized by its rapid doubling time and propensity for early
metastases. In clinical practice only two stages of SCLC are distinguished: limited stage
disease with tumor confined to one hemithorax only and extensive stage disease with
metastases in the contralateral chest or at distant sites. Approximately 20 to 25% of patients
have limited disease, treatable with curative intent. However 5-year survival rates are still low
(15-25%, compared with <5% in extensive disease). In these patients, multimodal
approaches of chemo- and radiotherapy are recommended followed by prophylactic cranial
irradiation to prevent cerebral metastases. Optimal timing, dose and fractionation of
radiotherapy treatment have yet to be defined (4-6). For extensive SCLC, the treatment of
choice is combination chemotherapy, usually cis- or carboplatin and etoposide. Current
approaches also include new drugs such as topoisomerase I inhibitors and taxans (4-6).
The intensive search for new therapeutic drugs in advanced lung cancer is highlighted in
the 2003 ASCO guidelines for the treatment of NSCLC, which for patients with good
performance score suggest second and third-line therapies that were not available when
previous recommendations were made in 1997 (10).
With the prospect of more effective therapeutic options for advanced stage disease,
current follow-up procedures for lung cancer should perhaps be reviewed. Tumor marker
measurements, which potentially provide sensitive and cost-effective early detection of
recurrence, may become increasingly important in assessing the efficacy of therapy. The aim
of this article is to assess the current state of knowledge of the clinical use of serum-based
tumor markers in lung cancer and to present new National Academy of Clinical Biochemistry
(NACB) recommendations. Guidelines published by other Expert Panels on this topic are
also summarised.
Currently Available Markers for Lung Cancer
Table 1 lists the mostly widely investigated tissue-based and serum-based tumors markers
for lung cancer. Also listed is the phase of development of each marker as well as the level
of evidence (LOE) for its clinical use. The levels of evidence grading system used is based
on that described by Hayes et al (11) [see Section 1].
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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Tumor Markers in Lung Cancer: NACB Recommendations
Table 2 presents a summary of recommendations from various Expert Panels on the use of
tumor markers in lung cancer. This table also summarises the NACB guidelines for the use
of markers in this malignancy.
Neuron specific enolase (NSE)
Screening and diagnosis. NSE does ot have the sensitivity or specificity necessary for use in
screening, but numerous studies support its use as an aid in the diagnosis of small cell lung
cancer. High serum levels of NSE (>100 μg/L) in patients with suspicion of malignancy
suggest the presence of SCLC with high probability, with the differential diagnoses including
neuroendocrine tumors of other localisations, liver cancer, lymphoma and seminoma.
Moderate elevations of NSE are also found in patients with benign lung diseases as well as
in some pancreatic, gastric, colorectal and breast cancers. Several groups have reported
improved diagnostic discrimination when NSE is combined with measurement of prograstrin
releasing peptide (ProGRP) (12-19).
Prognosis and monitoring. The prognostic value of NSE has been demonstrated in
multivariate trials for both SCLC (15,20-23) and NSCLC (19,24-29). NSE has shown
considerable potential for the monitoring of post-treatment SCLC (13,15,16,30-32) as well as
for the detection of recurrent disease of SCLC after primary therapy (13,16).
Analytical concerns: As NSE is present in erythrocytes, plasma cells and platelets, serum or
plasma must be separated from red cells within 60 minutes of venipuncture to avoid
spuriously high results. Serum samples should be stored at +4°C (short term) and at -70°C
(long term).
Carcinoembryonic antigen (CEA)
Screening and diagnosis. CEA concentrations are particularly high in adenocarcinoma and
large cell lung cancer, but the elevated concentrations also found in various benign
pathologies and other malignancies preclude its use in screening and limit its diagnostic use.
However, CEA may be helpful in the differential diagnosis of non-small cell lung cancer,
preferably in combination with CYFRA 21-1 (12,16,19,33,34).
Prognosis and monitoring. CEA may provide prognostic information in NSCLC, particularly in
adenocarcinoma of the lung (19,29,34-42). Further it may have a role in monitoring therapy
in advanced stages (16,43,44), and detecting recurrent disease of non-small cell
adenocarcinoma (16,45).
Analytical concerns: Slightly higher CEA results may be observed in smokers.
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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Cytokeratin-19 fragments (CYFRA 21-1)
Screening and diagnosis. CYFRA 21-1 is the most sensitive tumor marker for NSCLC,
particularly squamous cell tumors. Since CYFRA 21-1 determines only fragments of
cytokeratin 19, the test shows a higher specificity than tissue polypeptide antigen (TPA),
which determines a mixture of cytokeratins 8, 18 and 19. It is also elevated in urological,
gastrointestinal and gynaecological cancers and in lower amounts in various benign diseases
(34,46-48), precluding its use in screening and limiting its use in diagnosis. However, its
measurement may be helpful in the differential diagnosis of suspicious lung masses,
particularly if biopsy is not possible. Although a metaanalysis has not yet been performed,
numerous authors have reported that in certain circumstances CYFRA 21-1 can aid in
diagnosis (12,14,16,19,27,29,34,46,49,50).
Prognosis and monitoring. A recent analysis of pooled data from nine centers demonstrated
CYFRA 21-1 to be an independent prognostic factor in both early and late stages of NSCLC
(51), confirming earlier multivariate studies demonstrating its prognostic relevance
(27,34,37,38,51-60). Other reports have suggested CYFRA 21-1 may also have prognostic
value in SCLC (61-63).
CYFRA 21-1 has considerable potential for monitoring treatment of NSCLC in advanced
disease (16,49,54,64-69) as well as for the detection of recurrent disease after primary
therapy, particularly in squamous cell lung cancer (16,45,67,70-72). Recent reports suggest
that in patients with advanced stages of NSCLC undergoing chemotherapy, trends in CYFRA
21-1 during the initial treatment phase predict the response to subsequent therapy
(60,67,69).
Analytical concerns: When frozen samples are thawed for cytokeratin analysis, vigorous
mixing of samples should be avoided, as cytokeratins may adhere to tube walls after extreme
agitation. CYFRA 21-1 values may be significantly influenced by renal failure, in which higher
results may be observed.
Progastrin-releasing peptide (ProGRP)
Screening and diagnosis. ProGRP is a reliable marker for SCLC, with good specificity and
sensitivity (73-76), although in view of the incidence of SCLC in the general population these
are not high enough to allow its use in screening. However it is rarely elevated in other
malignancies, and if so, generally only mildly. Renal disease may cause elevations up to 300
ng/L, but raised concentrations are not seen in other benign diseases. ProGRP
concentrations >200 ng/L are highly suspicious for lung cancer, and concentrations >300
ng/L for SCLC if renal function is not impaired (73,75-77).
ProGRP has shown to be helpful in differential diagnosis, particularly in distinguishing
SCLC from other lung cancers. When used as a single marker, it is superior to NSE, while
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Lung Cancer (Section 3P)
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combining both markers provides additional information. ProGRP is released in measurable
amounts in early stage SCLC and does not correlate with tumor extent (14,16,18,73,75-81).
Prognosis and monitoring. Only one report supports the use of ProGRP in prognosis. (82).
However, several studies suggest it may be useful in monitoring SCLC
(16,32,73,78,79,82,83) or detecting recurrent disease after primary therapy (16,82-84).
Analytical concerns. Because of the instability of GRP in serum, the more stable recombinant
ProGRP [31-98] was developed as serum parameter. ProGRP values may also be
significantly elevated due to renal failure.
Squamous cell carcinoma antigen (SCCA)
Screening and diagnosis. Although significantly less sensitive in NSCLC than CYFRA 21-1,
and not suitable for use in screening, SCCA has superior specificity for squamous cell cancer
and can be used for histological subtyping. However it may be significantly raised in
squamous tumors of the cervix, oesophagus, head, neck and lung, as well as in
dermatological diseases. SCCA may be used in the differential diagnosis of NSCLC,
particularly for squamous cell cancer, preferably in combination with CEA and CYFRA 21-1
(12,19,85,86).
Prognosis and monitoring. Potential prognostic utility of SCCA in NSCLC has been reported
(34,87-89).
Analytical concerns. Preanalytical contamination (e.g. with skin or saliva) can result in
significant elevations of SCCA, as can renal failure.
Role of Tumor Markers for Early Detection of Lung Cancer
Screening There are no reports demonstrating the usefulness of single markers or
combinations of markers for the early diagnosis of lung cancer in asymptomatic populations
or in specific high-risk groups such as smokers.
Diagnosis Tumor markers have considerable potential for differential diagnosis and
histological subtyping, particularly in lung tumors of unknown origin. Despite the overlap with
healthy controls and patients with benign diseases, highly elevated concentrations of CEA,
CYFRA 21-1, NSE, SCCA, and ProGRP are suggestive of malignancy. Within the marker
profile, the leading markers suggest the most probable histologies, as follows: in
adenocarcinoma CEA; in squamous cell carcinoma CYFRA 21-1 and SCC; in large cell
cancer CYFRA 21-1 and NSE; and in small cell lung cancer NSE and ProGRP. Most
markers including CYFRA 21-1, CEA, NSE and SCC correlate clearly with tumor burden.
Only ProGRP can reach high levels even in limited SCLC disease. However normal or only
slightly increased marker concentrations never exclude any kind of tumor disease or
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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progression. Despite these limitations, the determination of tumor markers at the time of
primary diagnosis may be helpful for the following reasons:
The pattern of tumor marker release points to the histological background of the tumor
and can reveal mixed histological components.
Tumor markers expressed and released at the time of primary diagnosis are likely to be
the most relevant markers for follow-up monitoring.
CYFRA 21-1, CEA, NSE and lactate dehydrogenase (LDH) are independent prognostic
factors of high significance in NSCLC, as are NSE, LDH, and CYFRA 21-1 in SCLC.
The rate and extent of decrease of preoperatively released markers after surgery provide
useful information about remaining tumor burden and the effectiveness of therapy.
ProGRP at high levels reaches 100% specificity for small cell lung cancer and serves as
valuable diagnostic tool for therapeutic stratification.
Determination of carcinoembryonic antigen (CEA), CYFRA 21.1, NSE, ProGRP and
SCCA at the time of primary diagnosis may be performed as suggested in Table 3.
In all types of NSCLC including the squamous cancer cell subtype, highest diagnostic
sensitivity has been reported for CYFRA 21-1 in a number of studies
(12,19,27,30,33,46,49,54,76,86). Although SCCA had a lower sensitivity than CYFRA 21-1,
its high specificity for squamous cell cancer is valuable for differential diagnosis. SCC
concentrations >2 μg/L are associated with a 95% probability of having NSCLC and 80%
probability of having a squamous tumor (19). If CEA is >10 μg/L and CA125 >100 U/mL, the
presence of adenocarcinoma or large cell carcinoma is very likely (19). Due to the additive
diagnostic sensitivity of CEA and CYFRA 21-1, the combined use of both markers may be
helpful in NSCLC.
In SCLC, NSE and ProGRP are superior to CEA and CYFRA 21-1 concerning tumor and
organ specificity (12). The diagnostic sensitivity of ProGRP was found to be higher than
(15,76) or comparable to NSE (14,18). Because of the different pathophysiologic
background, both markers show additive sensitivity and play a complementary role in the
diagnosis of SCLC (14,18,76). As ProGRP reaches high levels already in limited stages of
disease and as mildly elevated concentrations are observed only rarely in other benign and
malignant diseases, ProGRP >500 ng/L is considered to be a diagnostic tool for SCLC. In
receiver operating characteristic (ROC) comparisons of histological discrimination between
NSCLC and SCLC, ProGRP reaches an area under the curve (AUC) of 0.85-0.97 and NSE
an AUC of 0.81-0.95 (18,81).
Concerning the differentiation of suspicious lung masses, computed algorithms of marker
combinations provide an additional increase in diagnostic sensitivity: by 10% compared with
CYFRA 21-1 as best single marker when using a multiple regression analysis, and by 20%
when using a fuzzy-logic based classification system (90,91).
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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Role of Tumor Markers for Prognosis
Numerous studies report the prognostic value of one or several tumor markers in
conjunction with clinical and/or laboratory parameters. However, comparing these studies is
frequently difficult due to a) the heterogeneity of the study populations (mixture of early and
advanced stages, mixture of various histological types), b) the use of univariate and
multivariate analyses, c) failure to compare single (often new) parameters with established
prognostic parameters, particularly clinical variables, d) failure to define how ”optimized“ cut
off levels were chosen and even occasionally using different methods to select cut off values
within the same investigation, as well as other pitfalls. It would be highly desirable to
compare all potential prognostic factors parameters in a single set of patients in order to
identify the most useful ones (92,93).
Of those markers evaluated in NSCLC, CYFRA 21-1 appears to be the best prognostic
marker in NSCLC patients, both in patients with early operable disease and in those with
advanced disease, as recently demonstrated by a analysis of pooled data (51). In addition to
CYFRA 21-1, LDH, albumin, calcium, NSE, CEA, CA125, TPS and DNA have shown
independent prognostic value in various studies and should be integrated in future prognostic
trials (24-29,35-42,51-55,57-59,71,88,89,94-96).
In SCLC, LDH, sodium, albumin and NSE have shown prognostic relevance in
multivariate analyses (97). Recent work suggests that CYFRA 21-1 and Chromogranin A
(62) and CYFRA 21-1 and NSE (63) may also be strong prognostic indicators.
Role of Tumor Markers for Patient Surveillance
Postoperative follow-up care, control of therapy efficacy and detection of recurrent
disease are the main indications for tumor marker determinations in lung cancer.
Post-surgery follow up care The velocity and the completeness of tumor marker decrease
after surgery is indicative of the further outcome of the patients. After a short-term increase
immediately after therapeutic intervention, due to marker release from operatively damaged
normal and tumor tissue, the decline depends on both biological marker half-life and residual
tumor cells (98-100). Following curative resection, the levels of CYFRA 21-1, TPA, and SCC
(half life 1.5-3 hours) are expected to decrease rapidly reaching the range of healthy persons
within 1-2 days whereas CEA decrease occurs with some delay depending on the initial
marker level [half life 1-4 days (98-102)]. If renal or liver dysfunction which can prolong the
half life of tumor markers considerably (75,103,104) are excluded, a slowed marker
clearance and/or an elevated plateau is indicative for the presence of residual tumor cells
and predict early the recurrence of disease (98).
Control of systemic therapy When monitoring the efficacy of chemo- or radiotherapy by tumor
markers, a substantial decrease often correlates with response to therapy whereas an
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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increase or an insufficient decrease are generally associated with progressive disease. In
NSCLC, CYFRA 21-1 had the best concordance with tumor response [59% to 75%;
(54,64,68)]. In the detection of progressive disease, specificity was 100% and sensitivity 52%
respectively (54,68), whereas the concordance with remission was lower (42%). Early
CYFRA 21-1 changes after one course of chemotherapy have been reported to be predictive
for the further outcome (60,69), although another group did not observe this effect (67).
In SCLC, NSE and ProGRP reflect the clinical course and the response to therapy
(32,83,105). During chemotherapy, their levels may increase temporarily 24 to 72 hours after
therapy application as a result of tumor cytolysis (106) but then decrease rapidly to the
individual baseline values (107). In contrast, failure of therapy is associated with persistently
elevated or insufficiently decreasing marker concentrations. In cases with simultaneously
elevated NSE and ProGPR, the combined determinations provide additional information (83).
Detection of recurrent disease
In the post-therapeutic surveillance situation tumor markers are sensitive indicators for
recurrence of disease, often with a lead-time of several months as compared to imaging
methods. In NSCLC, CYFRA 21-1 showed a sensitivity of 79% which increased further to
100% in patients with preoperative CYFRA 21-1 levels >3.3 μg/L. The lead-time was 2 to 15
months (108). As well as CYFRA 21-1 (70,107), TPS (109) and SCCA (110) have been
reported to be potentially useful for the detection of recurrent disease in the squamous
cancer cell subtype, while TPS and CEA were the best markers in adenocarcinoma (111).
In SCLC, NSE, ProGRP and CEA are relevant markers for detecting recurrent disease
(83). Among them, ProGRP revealed the highest detection rate with a sensitivity of 67% (cf
NSE, 20% and CEA, 38%), but there was a clear additive effect up to 79% sensitivity when
ProGRP and NSE were combined. The median lead-time was 35 days for ProGRP, with no
lead-time found for NSE (84). Similarly to the diagnostic approach, computed algorithms of
marker combinations such as the fuzzy-logic based classification system provide an
increased sensitivity for the detection of recurrent disease (32).
An absolute prerequisite for any kind of monitoring investigations is the maintainance of
the same methods for tumor marker determinations. Changing methods should include one
to two serial measurements with both methods in parallel.
Final Comments on the NACB Recommendation in Lung Cancer
The National Academy of Clinical Biochemistry, in making the recommendations for the use
of serum tumor markers in lung cancer summarized in Tables 2 and 3, recognises that the
routine use of these markers may, quite reasonably, not be widely implemented for clinical
and/or financial reasons in the near future. However, in those centers already chosing to use
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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tumor markers in lung cancer patients, it is highly desirable that the appropriate markers are
selected. It is for this reason that these early NACB recommendations have been developed.
While none of the tumor marker studies reviewed approach the highest level of evidence
(11), the use of these markers in clinical practice is likely to increase as improved treatments
become available. Future trials concerning prognosis, therapy monitoring and prediction of
therapy response should be rigorous and should ideally be undertaken as part of prospective
and randomized intervention trials. However, for diagnostic and differential diagnostic
purposes, results from large retrospective or prospective studies conducted according to the
current state of the art (112) do appear to demonstrate the value of specific markers or
marker combinations.
Based on these pragmatic considerations the following recommendations can be made
regarding the use of serum tumor markers in lung cancer:
1. Currently, single tumor markers, such as CYFRA 21-1, CEA, NSE, and ProGRP should
not be used for screening purposes either in asymptomatic populations or in those at
high risk for lung cancer (e.g. smokers).
2. Depending on histology, determination of CYFRA 21-1, CEA, NSE and/or ProGRP may
be helpful in lung cancer patients prior to the first therapy. Where no histology can be
obtained before surgery, measurement of all four markers is necessary to identify the
leading marker (usually that present in highest concentration).
3. Where inoperable lung cancer is suspected but no histology is available, raised serum
NSE and especially ProGRP are highly suggestive of small cell lung cancer while
raised serum SCCA is suggestive of squamous cell cancer.
4. Follow-up of asymptomatic patients after primary therapy of lung cancer is
controversial. However serial determinations of the appropriate tumor marker may help
assess the completeness of tumor removal and provide early indication of recurrence.
5. CEA and CYFRA 21-1 can be measured during systemic treatment of non-small cell
lung cancer, NSE and ProGRP during systemic treatment of small cell lung cancer to
reflect response to therapy and to document progressive disease. Reliable criteria for
“biochemical progression” are still required to initiate tumor marker-based intervention
trials in future.
6. Careful attention to pre-analytical factors is essential. Specimens for NSE
determination should be separated from the clot within 60 minutes of collection, and
haemolysed samples should not be assayed. Vigorous mixing of serum samples after
thawing should be avoided for cytokeratin measurements. Contamination of samples
with skin or saliva must be avoided for SCCA measurements. Samples may be stored
at +4°C (short term) and at -70°C (long term).
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7. Serial measurements should be performed using the same tumour marker test, which
should be indicated on the laboratory report and documented in the patient’s medical
records.
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Table 1. Useful and potentially useful markers for lung cancer.
Cancer Marker
Proposed Use/Uses
Phase of Development LOE
1
Ref
NSE
Differential diagnosis of lung masses when biopsy is not
available: in high levels high specificity for small cell
carcinoma; in SCLC, additive information to ProGRP
In clinical use, but value not validated
in a high-level evidence study
III 12-19
Assessing prognosis. High levels predict adverse outcome
in SCLC
In clinical use, but value not validated
in a high-level evidence study
II-III 15,20-23
Assessing prognosis. High levels predict adverse outcome
in NSCLC
In clinical use, but value not validated
in a high-level evidence study
II-III 19,24-29
Monitoring therapy in SCLC
In clinical use, but value not validated
in a high-level evidence study
III 13,15,16,30-32
Monitoring therapy in advanced disease (NSCLC) Not in clinical use IV-V 44
Detection of recurrent disease. Increasing kinetics indicate
progressive disease in SCLC
In clinical use, but value not validated
in a high-level evidence study
IV 13,16
CEA
Differential diagnosis of lung masses when biopsy is not
available; in high levels high specificity for
adenocarcinoma; in NSCLC, additive information to
CYFRA 21-1
In clinical use, but value not validated
in a high-level evidence study.
III 12,16,19,33,34
Assessing prognosis. High levels predict adverse outcome
in early and advanced stage NSCLC
Not in clinical use III-IV 19,29,34-42
Monitoring therapy in advanced disease (NSCLC and
SCLC)
Not in clinical use IV 16,43,44
Detection of recurrent disease. Increasing kinetics indicate
progressive disease in NSCLC, part. in adeno cancer.
Not in clinical use III-IV 16,45
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CYFRA 21-1
Differential diagnosis of lung masses when biopsy is not
available: in high levels high specificity for squamous cell
carcinoma; best marker for NSCLC
In clinical use, but value not validated
in a high-level evidence study.
III 12,14,16,19,27,29,34,46,49,50
Assessing prognosis. High levels predict adverse outcome
in early and advanced NSCLC
Recommended for clinical use I-II 27,34,37,38,51-60
Assessing prognosis. High levels predict adverse outcome
in SCLC
Not in clinical use III 61,62
Monitoring therapy in advanced disease (NSCLC)
In clinical use, but value not validated
in a high-level evidence study.
II-III 16,49,54,64-69
Early prediction of therapy response in advanced disease
(NSCLC)
Not in clinical use yet, undergoing
further validation
II-III 60,67,69
Detection of recurrent disease. Increasing kinetics indicate
progressive disease in NSCLC, part in squamous cell
cancer.
In clinical use, but value not validated
in a high-level evidence study.
III 16,45,67,70-72
ProGRP
Differential diagnosis of lung masses when biopsy is not
available: in high levels high specificity for small cell
carcinoma; best marker for SCLC; additive information to
NSE
In clinical use, but value not validated
in a high-level evidence study.
III 14,16,18,73,75-81
Assessing prognosis. High levels predict adverse outcome
in SCLC
Not in clinical use IV 82
Monitoring therapy in SCLC
In clinical use, but value not validated
in a high-level evidence study.
III 16,32,73,78,79,82,83
Detection of recurrent disease. Increasing kinetics indicate
progressive disease in SCLC.
In clinical use, but value not validated
in a high-level evidence study.
III 16,82-84
SCCA
Differential diagnosis of lung masses when biopsy is not
available: in high levels high specificity for squamous cell
carcinoma; in SQC additive information to CYFRA 21-1
Abnormal levels are associated with a high probability of
NSCLC, mainly squamous tumors
In clinical use, but value not validated
in a high-level evidence study.
III 12,19,85,86
Assessing prognosis. High levels predict adverse outcome
in NSCLC
Not in clinical use III-IV 34,87-89
CA 125
Differential diagnosis of lung masses when biopsy is not
available; in high levels relative specificity for
Not in clinical use III 19
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adenocarcinoma, large cell carcinoma
Assessing prognosis in NSCLC. High levels predict
adverse outcome in NSCLC
Not in clinical use IV 35,59,94,113
Monitoring therapy in advanced disease (NSCLC) Not in clinical use IV 43
Early prediction of therapy response in advanced disease
(NSCLC)
Not in clinical use IV 94
Chromogranin A
Differential diagnosis of lung masses when biopsy is not
available; particularly for neuroendocrine tumors
In clinical use, but value not validated
in a high-level evidence study.
III 81,114-116
Assessing prognosis. High levels predict adverse outcome
in SCLC and in neuroendocrine tumors
Not in clinical use III-IV 62,117
Monitoring therapy in neuroendocrine tumors Not in clinical use IV 116
HER2-neu Not appropriate for differential diagnosis Not in clinical use III 118,119
Assessing prognosis. High levels predict adverse outcome
in advanced NSCLC: conflicting data
Not in clinical use IV 119,120
Monitoring therapy in NSCLC not possible Not in clinical use IV 120
DNA fragments Assessing diagnosis; correlation with stage
Not in clinical use yet, undergoing
further validation
III 95,121,122
Assessing prognosis. High levels predict adverse outcome
Not in clinical use yet, undergoing
further validation
II-IV 95,96
Monitoring therapy in advanced disease (NSCLC)
Not in clinical use yet, undergoing
further validation
II-IV 69,95
Early prediction of therapy response in advanced disease
(NSCLC)
Not in clinical use yet, undergoing
further validation
II-III 69
Detection of recurrent disease. Increasing kinetics indicate
progressive disease in NSCLC
Not in clinical use III 121,122
TPA
Differential diagnosis of lung masses when biopsy is not
available
Not in clinical use, undergoing further
validation
III 50,57
Assessing prognosis. High preoperative levels predict
adverse outcome in NSCLC
Not in clinical use III-IV 34,56,88
TPS
Assessing diagnosis (inferior to CYFRA 21-1 and TPA);
correlation with stage
Not in clinical use IV 54,57,123-125
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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Assessing prognosis. High levels predict adverse outcome
in NSCLC
Not in clinical use III-IV 34,54,57
Assessing prognosis. High levels predict adverse outcome
in SCLC
III-IV 53,61
Monitoring therapy in advanced disease (NSCLC) Not in clinical use III 54
Early prediction of therapy response in SCLC Not in clinical use III-IV 53
Detection of recurrent disease. Increasing kinetics indicate
progressive disease in NSCLC.
Not in clinical use III 109,111
TU M2-PK Assessing diagnosis; inconsistent data are available Not in clinical use IV 126,127
Monitoring therapy in NSCLC and SCLC Not in clinical use IV 128
Detection of recurrent disease. Increasing kinetics indicate
progressive disease in NSCLC and SCLC
Not in clinical use IV 128
CEA, carcinoembryonic antigen; CYFRA 21-1, cytokeratin 19 fragments; HER2-neu; shed form of Her2-receptor; LOE, level of evidence; NSE, neuron specific enolase; ProGRP,
progastrin-releasing peptide; SCCA; squamous cancer cell antigen; TPA, tissue polypeptide antigen, cytokeratin fragments 8, 18, and 19; TPS, tissue polypeptide specific-antigen;
cytokeratin fragments 18; TU M2-PK, tumor M2 pyruvate kinase;
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
16
Table 2. Recommendations for use of markers in lung cancer by different expert groups.* [See Final Comments, p.9 for
discussion of caveats relating to the recommendations in this Table.]
Marker Application EGTM 1999
NACB 2005
NSE For differential diagnosis Yes, for SCLC Yes, for SCLC
For prognosis
None published
None published
For post-operative surveillance Yes, in SCLC Yes, in SCLC
For monitoring therapy in advanced disease Yes, in SCLC Yes, in SCLC
For detection of recurrent disease Yes, in SCLC Yes, in SCLC
CEA For differential diagnosis Yes, for NSCLC Yes, for NSCLC
For prognosis
None published
None published
For post-operative surveillance Yes, in adenocarcinoma Yes, in NSCLC
For monitoring therapy in advanced disease Yes, in adenocarcinoma Yes, in NSCLC
For detection of recurrent disease Yes, in adenocarcinoma Yes, in NSCLC
CYFRA 21-1 For differential diagnosis Yes, for NSCLC Yes, for NSCLC
For prognosis None published Yes, in NSCLC
For post-operative surveillance Yes, in all NSCLC and SCLC Yes, in NSCLC
For monitoring therapy in advanced disease Yes, in all NSCLC and SCLC Yes, in NSCLC
For detection of recurrent disease Yes, in all NSCLC and SCLC Yes, in NSCLC
ProGRP For differential diagnosis
None published
Yes, for SCLC
For prognosis
None published
None published
For post-operative surveillance
None published
Yes, in SCLC
For monitoring therapy in advanced disease
None published
Yes, in SCLC
For detection of recurrent disease None published Yes, in SCLC
*The American Cancer Society (ACS) and the American Society of Clinical Oncology (ASCO) have not as yet published recommendations relating to the use of
tumor markers in lung cancer.
NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
Lung Cancer (Section 3P)
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Abbreviations: EGTM, European Group on Tumor Markers; NACB, National Academy of Clinical Biochemistry; NSE, neuron specific enolase; CEA,
carcinoembryonic antigen; CYFRA 21-1, cytokeratin 19 fragments; ProGRP, progastrin-releasing peptide; SCLC; small cell lung cancer; NSCLC; non-small cell
lung cancer
.
18
lines And Recommendations For Use Of Tumor Markers In The Clinic
g Cancer (Section 3P)
Table 3. Recommendations for use of markers according to histologies of lung cancer and application forms.
Histology Before therapy Post-therapy follow-up
Unknown CYFRA 21-1, CEA, NSE, ProGRP
A
fter surgery: following histology
In advanced disease: using the leading marker
Adenocarcinoma CYFRA 21-1 and CEA CYFRA 21-1 and/or CEA
Squamous cell carcinoma CYFRA 21-1 and CEA (and SCCA) CYFRA 21-1 and/or CEA (and/or SCCA)
Large cell carcinoma CYFRA 21-1 and CEA CYFRA 21-1 and/or CEA
Small cell carcinoma NSE and ProGRP NSE and/or ProGRP
CEA, carcino embryonic antigen; CYFRA 21-1, cytokeratin 19 fragments; NSE, neuron specific enolase; ProGRP, progastrin-releasing peptide;
SCCA, squamous cell carcinoma antigen
NACB: Practice Guide
Lun
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... 80,81 Immunohistochemistry of gammaenolase is regularly used for differential diagnosis of small-cell lung cancer (SCLC) from other lung cancer histological subtypes (Table 1). 82,83 Gammaenolase increased expression was observed also in other tumours, including breast cancer, with increased staining in lymph node metastases compared to primary breast tumours 84 or in glioblastomas, with higher levels in advanced stage tumours, which were related to shorter patient survival. 50 Nevertheless, immunostaining of gamma-enolase in tumour tissue has limited diagnostic or prognostic utility, since many clinical studies provided contradictory results. ...
... 80 Levels of gamma-enolase are elevated in sera from patients with various cancers, however, its appearance in extracellular fluids without any apparent cellular damage is not clear. 1,88 After stroke, brain injury or cardiac arrest, gamma-enolase is released into the cerebrospinal fluid and eventually into the bloodstream due to damage or death of neuronal cells or impairment of the blood-brain barrier in- [82,83] Other neuroendocrine tumours (neuroblastoma, endocrine pancreatic tumours, seminoma, medullary thyroid carcinoma, phaeochromocytoma, ect.) ...
... Diagnosis or detection of neuroendocrine differentiation of tumour Yes [80,81,95,96] Serum SCLC Differential diagnosis from other lung cancer subtypes when biopsy is not possible Yes EGTM, NACB [82,83] Prognosis Unknown [82,83,97] Post-operative surveillance Yes EGTM, NACB [82,83] Monitoring efficacy of therapy Yes EGTM, NACB [82,83] Detection of recurrent disease after primary surgery Yes NACB [82,83] NSCLC Monitoring therapy in advanced disease No [83] Prognosis Unknown [83] Testicular cancer (seminoma) Diagnosis Experimental EGTM [98] Carcinoids Diagnosis Unknown [96,99] Monitoring efficacy of therapy Yes EGTM [8,39] Detection of early relapse Yes [8,39,96] Medullary thyroid carcinomas Monitoring efficacy of therapy Yes EGTM [8,39] Detection of early relapse Yes [8,39] Phaeochromocytoma Monitoring efficacy of therapy Yes EGTM [8,39] Detection of early relapse Yes [8,39] Endocrine pancreatic tumours Diagnosis Yes [95,96] Monitoring efficacy of therapy Yes EGTM [8,39] Detection of early relapse Unknown [8,39,99] Paraganglioma Diagnosis Unknown [99] Neuroblastoma Differential diagnosis Unknown [8] Prognosis Yes ACS [100] Monitoring efficacy of therapy Yes EGTM [8,100] Detection of recurrent disease Yes [97] ACS = American Cancer Society; EGTM = European Group for Tumour Markers; NACB = National Academy of Clinical Biochemistry; NSCLC = non-small-cell lung cancer; SCLC = small-cell lung cancer tegrity. For instance, levels of gamma-enolase in cerebrospinal fluid and serum have been used as a biomarker of cerebral injury and for the assessment of neurological disorders. ...
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Gamma-enolase, known also as neuron-specific enolase (NSE), is an enzyme of the glycolytic pathway, which is expressed predominantly in neurons and cells of the neuroendocrine system. As a tumour marker it is used in diagnosis and prognosis of cancer; however, the mechanisms enrolling it in malignant progression remain elusive. As a cytoplasmic enzyme gamma-enolase is involved in increased aerobic glycolysis, the main source of energy in cancer cells, supporting cell proliferation. However, different cellular localisation at pathophysiological conditions, proposes other cellular engagements. The C-terminal part of the molecule, which is not related to glycolytic pathway, was shown to promote survival of neuronal cells by regulating neuronal growth factor receptor dependent signalling pathways, resulting also in extensive actin cytoskeleton remodelling. This additional function could be important also in cancer cells either to protect cells from stressful conditions and therapeutic agents or to promote tumour cell migration and invasion. Gamma-enolase might therefore have a multifunctional role in cancer progression: it supports increased tumour cell metabolic demands, protects tumour cells from stressful conditions and promotes their invasion and migration.
... According to published studies, serum tumor markers (STMs) can aid in the diagnosis of clinically suspected cancer and cancer of an unknown primary site [22,23]. They may also play a significant role in cancer prognosis and treatment, as well as follow-up surveillance [23]. ...
... According to published studies, serum tumor markers (STMs) can aid in the diagnosis of clinically suspected cancer and cancer of an unknown primary site [22,23]. They may also play a significant role in cancer prognosis and treatment, as well as follow-up surveillance [23]. Clinical studies have demonstrated that currently, carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), neuron-specific enolase (NSE), and soluble fragment of cytokeratin 19 (CYFRA 21-1) are the best tumor markers available for the management of lung cancer [23]. ...
... They may also play a significant role in cancer prognosis and treatment, as well as follow-up surveillance [23]. Clinical studies have demonstrated that currently, carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), neuron-specific enolase (NSE), and soluble fragment of cytokeratin 19 (CYFRA 21-1) are the best tumor markers available for the management of lung cancer [23]. In addition, carbohydrate antigen (CA) 125 can differentially diagnose lung masses when biopsy is not available and has been shown to be elevated in ADC and large cell carcinoma [23,24]. ...
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Purpose: The role of serum tumor markers (STMs) in the modern management of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations in lung cancer remains poorly described. In this study, we investigated whether STMs could be a valuable noninvasive tool to predict EGFR mutations and ALK positivity in non-small-cell lung cancer (NSCLC) patients. Experimental design: We retrospectively reviewed and included 1089 NSCLC patients who underwent EGFR or ALK mutation testing and STMs measurement prior to treatment. The differences in several clinical characteristics and STMs between the subgroups were analyzed. Multivariate logistic regression analysis was performed to identify predictors of EGFR mutations and ALK positivity. Results: EGFR mutations were found more frequently in females (63.11%), never-smokers (59.69%), and those with lung adenocarcinoma (ADC) (53.87%). Negative carbohydrate antigen (CA) 125, ferritin (FERR), squamous cell carcinoma antigen (SCC), and soluble fragment of cytokeratin 19 (CYFRA 21-1) levels were significantly associated with EGFR mutations (p < 0.05). Multivariate analysis demonstrated that ADC, never-smoker status, and negative CA 125 and SCC results were predictors of EGFR mutations (p < 0.05). The receiver operating characteristic (ROC) curve yielded an area under the curve (AUC) of 0.715 (95% confidence interval [CI]: 0.673-0.758) for the combination of the four factors. Positive ALK expression was found more frequently in younger patients (median age: 49 years), females (8.40%), never-smokers (8.82%), and those negative for carcinoembryonic antigen (CEA) (8.02%). Multivariate analysis demonstrated that younger age and never-smoker status were the only independent predictors of ALK positivity (p < 0.05). The ROC curve yielded an AUC of 0.760 (95% CI: 0.677-0.844) for the combination of these two factors. Conclusion: STMs are associated with mutant EGFR status and could be integrated with other clinical factors to enhance the ability to distinguish EGFR mutation status among NSCLC patients. For ALK-positive patients, younger age and never-smoker status could predict the mutation status, whereas STMs could not.
... However, the utility of single biomarkers in the diagnosis of lung cancer is limited because they lack sufficient sensitivity and specificity, while at the same time, elevated levels of these biomarkers are often seen in patients with certain benign pulmonary diseases (5). The American Society of Clinical Oncology, the European Group on Tumor Markers (EGTM), and the National Academy of Clinical Biochemistry (NACB) recommend different combinations of these biomarkers to improve detection sensitivity and specificity (6,7). The combination of CYFRA21-1, NSE, and CEA is recommended for the detection of lung cancer by the EGTM. ...
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Background: Folate-receptor alpha (FRα) is overexpressed in lung carcinoma. The FR-positive circulating tumor cell (FR+ CTC) has been established to be a non-invasive biomarker for lung cancer diagnosis. In this study, we sought to examine the value of FR+ CTC in the histological diagnosis of suspicious space-occupying pulmonary lesions. Methods: A total of 538 patients with suspicious space-occupying pulmonary lesions were enrolled in this study. FR+ CTCs were detected before treatment initiation using negative enrichment and ligand-targeted polymerase chain reaction assays. The enrolled patients concurrently received serum biomarker tests. Results: A total of 282 lung cancer patients [163 with adenocarcinoma (ADC), 71 with squamous cell carcinoma (SCC), and 48 with small cell lung cancer (SCLC)], and 256 patients with benign disease who concurrently received FR+ CTC and serum biomarker tests were randomly assigned to a training set and a validation set. The FR+ CTC levels of patients with lung cancer were significantly higher than those of patients with benign disease (P<0.001). Compared to serum tumor biomarkers alone, the model combining FR+ CTC and serum biomarkers had the highest area under the receiver operating characteristic curve in the diagnosis of NSCLC, ADC, SCC, and SCLC. Conclusions: Diagnostic models that include both FR+ CTC and serum biomarkers could increase the efficiency of distinguishing between different histological types of lung cancer and benign space-occupying pulmonary diseases.
... It is also used for survey of treatment in advance, postoperative surveillance of SCLC patients and also in the detection of reoccurrence of disease. [9,10] Temporary increase in gamma-enolase serum during chemotherapy, due to cytolysis of tumour cells, disappears in case of regular treatment. Persistent increase in gamma-enolase level shows the failure of the treatment. ...
... We then compared the cut-off value-related data for the 2 conditions, and a high specificity (94.4%) was observed in the inpatient group, indicating miRNA-30a testing may be a potential candidate in lung cancer differential diagnosis for inpatients. Many studies [24][25][26][27][28][29][30][31] have revealed a positive correlation between levels of the most common tumor markers (such as CEA, CYFRA21-1, NSE, and SCC) and clinical stage of NSCLC patients. These may indicate falsenegative results in early diagnosis, causing insufficient detection or diagnosis at an early stage. ...
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Background MicroRNA (miRNA) is a small, non-coding RNA molecule which plays a role in the carcinogenesis and progression of cancers. Abnormal expression of miRNA in plasma has been found in some patients with malignant tumors. Material/Methods This study was conducted to investigate the expression of miRNA-30a in plasma of patients with non-small cell lung cancer (NSCLC). The plasma miRNA-30a in 87 patients with NSCLC, 20 patients with benign lung diseases, and 76 healthy subjects were measured by real-time PCR. The diagnostic value of miRNA-30a in NSCLC was evaluated via the ROC curve method. Results Plasma miRNA-30a level was significantly higher in the NSCLC group compared with benign control and healthy control groups (P<0.01). No statistically significant difference was found in the expression level of miRNA-30a among various clinical pathologic features in NSCLC. ROC curve analysis showed that the specificity and sensitivity cut-off points were at 61.0% and 84.3% for NSCLC. The specificity and sensitivity values were 54.9% and 94.4%, respectively, in the analysis based on in-patients only. Conclusions All these results suggest that plasma miRNA-30a measurement may be a novel and noninvasive method for NSCLC preliminary screening and differential diagnosis.
... Regarding small cell lung cancer, this occurs less frequent (15-25%) and is related to neuroendocrine components. Nonetheless, recent published data shown an improvement in overall survival when modern and alternative therapy is applied67891011. Nanomedicine became a new tool in medicine signaling and drug delivery, which deals with the small materials having size range less than 100nm [12]. ...
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Owing to their radical scavenging nanoparticles (CeO2-NPs) are currently used for various applications, including drug delivery or alternative chemotherapy agents. In this paper, the cellular uptake and cytotoxicity caused by small size CeO2-NPs (20-nm) on cultured human lung cancer cells was evaluated. The MTT assay was used to assess cell viability after 24h exposure to 0 to 250 μg/ml of CeO2-NPs. The results showed a dose dependent and exposure time decreased of cell viability. Cellular uptake was confirmed by the conjugation of CeO2-NPs with a fluorescent dye rhodamine- 6G using confocal microscopy.
... However, no marker has been found that would characterize specificity in relation to lung cancer. According to the recommendations of the National Academy of Clinical Biochemistry [5], multiple tumor markers combined can improve the diagnostic value. Depending on histology, determination of CEA, NSE and CYFRA 21-1 may be helpful in lung cancer patients prior to the first therapy. ...
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Detection of tumor marker is an effective and low cost means in the early diagnosis of lung cancer, especially multiple tumor markers combined can improve the diagnostic value. In this paper, a chemiluminescence immunoassay using bio-functionlized magnetic nanocomposites (BFMNs) was proposed for simultaneous detection of multiple tumor markers. Carcinoembryonic antigen (CEA), neuron specific enolase (NSE) and cytokeratin 19 fragment (CYFRA21-1) were chose as the detection models. BFMNs were prepared in advance by loading different antibodies to magnetic beads containing Fe2O3 nanoparticles, and characterized using a scanning electron microscope. The BFMNs could specifically capture the corresponding antigen and its HRP labeled antibodies based on a sandwich-type immunoreaction. The immunocomplex further reacts with chemiluminescent substrate and the produced chemiluminescences were detected by a homemade three-channel luminometer. Preliminary results show that there is a good linear relationship between the chemiluminescence intensity and the CEA concentration in the range from 5 to 200 ng/mL, as well as with similar results for the detection of NSE and CYFRA21-1. The whole detection process, including the immune response, the washing and the optical signal detection steps, could be performed to carry out simultaneous detection of three tumor markers within 35 min. The proposed method offers a simple, noninvasive and rapid tool for detection of multiple tumor markers and has potential application in clinical testing.
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Background The trends in usage of tumor markers, including CEA, SCC, NSE, Cyfra21‐1, and ProGRP, in Chinese lung cancer patients in the real‐world setting are not fully investigated. Methods A retrospective descriptive study was conducted using the database of Qilu Hospital of Shandong University, China between January 2013 and December 2017, involving patients primarily diagnosed with NSCLC or SCLC. Utilization trends by first discharge year, utilization rates within different durations before and after first discharge date, and combined utilization patterns of multiple tumor markers were analyzed. Results The utilization of all these tumor markers showed increased from 2013 to 2017. CEA, Cyfra21‐1, and NSE were the most frequently detected, which increased slightly from around 50% in 2013 to around 78% in 2017 in NSCLC and from around 70% in 2013 to around 92% in 2017 in SCLC. CEA, Cyfra21‐1, and NSE were the most commonly measured within 3 months before first diagnosis with approximately 65% in NSCLC and 80% in SCLC, and ProGRP had the lowest utilization (around 30%). CEA, NSE, and Cyfra21‐1 had the highest utilization rates after first diagnosis with both around 80% in NSCLC or SCLC. Combined usage of five tumor markers was ranked the first pattern in combined utilization. Conclusions This study suggests CEA, Cyfra21‐1, and NSE are the most frequently detected before or after first diagnosis of NSCLC or SCLC. However, SCC and ProGRP tests appeared to have relatively low usages. The utilization pattern was consistent with recommendations of guideline, but underutilization still existed.
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Untargeted mass spectrometry-based metabolomic profiling is a powerful analytical methods used for broad-spectrum identification and quantification of metabolites in biofluids in human health and disease states. In this study, we exploit metabolomic profiling for cancer biomarker discovery for diagnosis of malignant pleural effusions. We envisage the result will be clinical useful since currently there are no cancer biomarkers that are accurate enough for the diagnosis of malignant pleural effusions. Metabolomes of 32 malignant pleural effusions from lung cancer patients and 18 benign effusions from patients with pulmonary tuberculosis were analyzed using reversed-phase LC-MS/MS using AB SCIEX TripleTOF 5600. MS spectra were analyzed using XCMS, PeakView and LipidView. Metabolome-Wide Association Study (MWAS) was performed by Receiver Operating Characteristic Curve Explorer & Tester (ROCCET). Insignificant markers were filtered out using a metabolome-wide significance level (MWSL) with p-value < 2 × 10-5 for t-test. Only compounds in Human Metabolome Database (HMDB) will be used as cancer biomarkers. ROCCET analysis of ESI-positive and negative MS spectra revealed free fatty acid (FFA) 18:1 (oleic acid) had the largest area-under-ROC of 0.96 (95% CI: 0.87 - 1.00) in malignant pleural effusions. Using a ratio of FFA 18:1-to-ceramide (d18:1/16:0), the area-under-ROC was further increased to 0.99 (95% CI: 0.91 - 1.00) with sensitivity 93.8% and specificity 100.0%. Using untargeted metabolomic profiling, diagnostic cancer biomarker with the largest area-under-ROC can be determined objectively. This lipogenic phenotype could be explained by overexpression of fatty acid synthase (FASN) in cancer cells. The diagnostic performance of FFA 18:1-to-ceramide (d18:1/16:0) ratio supports its use for diagnosis of malignant pleural effusions.
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Distribution of CEA, SCC, TPS and CYFRA 21-1 serum levels and incidence of their elevated levels were studied in 50 uremic patients before starling dialysis and compared to those in 85 patients with benign lung diseases (BLD) as well as to 60 patients with non-small lung cancer (NSCLC). CEA and TPS showed significantly higher levels in NSCLC as compared to uremia (CEA, p = 0.03; TPS, p = 0.02). Oppositely, SCC and CYFRA 21-1 levels were higher in uremic patients, although only for SCC the difference between these two groups was significant (p < 0.001). CEA was found to be elevated in 16%, SCC in 52%, TPS in 18% and CYFRA 21-1 in 52% of patients with uremia. Between tumor markers themselves a moderate correlation was found only between SCC and CYFRA 21-1 (r=0.51, p=0.002). It is concluded that SCC and CYFRA 21-1 may have a limited value in uremia due to the high incidence of false positive results. Elevated tumor marker serum levels do not indicate malignancy, unless renal failure is excluded.
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Pancreatic cancer remains a vexing treatment challenge, with a cure rate that remains just 7%. Two effective regimens-gemcitabine/nab-paclitaxel and FOLFIRINOX-have improved outcomes and are being used earlier in the disease. However, meaningful differences in outcomes may not be realized without novel strategies. Targeting of the immune system is an active area of research. Copyright © 2015 by the National Comprehensive Cancer Network.
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We have evaluated the prognostic value of 22 pretreatment attributes in 436 small cell lung cancer (SCLC) patients included in a prospective multicenter study with a minimum 5-year follow-up. Pretreatment clinical and laboratory parameters were registered. Possible prognostic factors were evaluated by univariate analysis (log rank test) and by the Cox multivariate regression model. In the univariate analysis of all patients, only age, nodal metastasis, and skin metastasis were not associated with survival. The multivariate Cox model identified gender, extent of disease, performance status (PS), weight loss, platelet count, LDH, and NSE as independent prognostic factors. In subset multivariate analyses according to extent of disease, we found haemoglobin level, PS, NSE, and total WBC as significant prognostic indicators for survival in limited-stage disease (LD-SCLC), while PS, weight loss, LDH, number of metastases, liver metastases, and brain metastases were identified as independent prognostic factors in extensive-stage disease (ED-SCLC). There was a significant correlation between serum LDH and NSE levels. In conclusion, gender, extent of disease, PS, weight loss, haemoglobin, WBC count, platelet count, LDH, and NSE were all found to be independent prognostic factors for SCLC survival. However, the prognostic value of these factors depends highly on whether all or subsets of SCLC patients are studied.
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The diagnostic value of a new tumor marker, c-erbB-2, was studied in the sera of 50 controls, 112 patients with benign diseases and 534 patients with malignancies. Using 15 U/ml as the cutoff, no healthy subjects, patients with benign diseases (excluding liver cirrhosis) or patients with no evidence of disease (45 patients) had serum levels higher than this limit. Abnormal c-erbB-2 levels were found in 38.5% (10 of 26) of the patients with liver cirrhosis and in 26.7% (8 of 30) of those patients with primary liver cancer. No differences were found between the c-erbB-2 serum concentrations in liver cirrhosis or primary liver cancer, suggesting the possible catabolism of this antigen in the liver. Abnormal levels of this antigen were found in 20% (56 of 278) of the patients with breast carcinoma (lo-coregional 7%, metastases 41.5%), in 21 % (6 of 28) of ovarian carcinomas (stage I-II 0%, stage III-IV 42.8%), in 21% (3 of 14) of the colorectal tumors (locoregional 0%, metastases 30%), and in 13.3% (11 of 83) of the patients with lung cancer (locoregional 11.5%, metastases 16%). C-erbB-2 sensitivity in other patients with advanced disease was: 25% (9 of 36) in prostatic cancer; 22% (2 of 9) in gastric cancer, and 11% (1 of 9) in vesical tumors. When patients with liver metastases were excluded, abnormal c-erbB-2 serum levels were only found in breast, lung, prostatic and ovarian carcinomas. C-erbB-2 sensitivity in patients with lung cancer was related to tumor histology with significantly higher values in non-small cell lung cancer (mainly adenocarcinomas) than in patients with small cell lung cancer (p
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CYFRA 21-1 is a new tumor marker using two different monoclonal antibodies which recognize the divergent epitope on the N- or C-terminal region of domain 2 of cytokeratin 19 fragment, respectively. In this study, we investigated the relationship between levels of CYFRA 21-1 and survival duration, as well as the efficacy of chemotherapy associated with changes in CYFRA 21-1. Serum samples were obtained from 87 patients with nonoperable lung cancer (35 cases with squamous-cell carcinoma, 33 with adenocarcinoma, 3 with large-cell carcinoma, and 16 with small-cell carcinoma). The cutoff point was set at 3.5 ng/ml. In a CYFRA 21-1 assay, significantly more patients with squamous-cell carcinoma and adenocarcinoma were positive compared to patients with small-cell and large-cell carcinomas (p = 0.0017). Following chemotherapy, blood levels of CYFRA 21-1 decreased significantly in responders versus nonresponders (p = 0.0246). A significant correlation was noted between survival periods and pretreatment levels of CYFRA 21-1 (p = 0.0036). The present study suggests that CYFRA 21-1 might be useful as a possible indicator of survival and therapeutic effect for lung cancer.
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HER-2/neu tissue overexpression is found in nearly 15% of patients with nonsmall cell lung carcinoma and is reported to affect prognosis adversely in surgical series. However, the prognostic role of serum HER-2/neu oncoprotein, particularly in patients with advanced lung carcinoma, remains unknown. This study was designed to assess the potential value of measuring serum levels of HER-2/neu oncoprotein in predicting response to treatment and survival in patients with locally advanced and metastatic nonsmall cell lung carcinoma. Baseline serum HER-2/neu levels (fm/mL) were studied using an enzyme-linked immunosorbent assay method in 84 patients with newly diagnosed, advanced nonsmall cell lung carcinoma who underwent chemotherapy. The patients enrolled in the study included 76 males and 8 females, with a median age of 62 years (range, 36-73 years) and a median performance status of 1. Fifty patients (59.5%) had nonsquamous histology, and 34 patients (40.5%) had squamous cell carcinoma. Thirty-four patients (40.5%) had Stage III disease, and 50 patients (59.5%) had Stage IV disease. The mean baseline value of HER-2/neu in the whole series was 56.1 fm/mL (range, 13.0-103.8 fm/mL). HER2 immunohistochemistry on paraffin embedded tissue was performed in 18 patients. HER-2/neu tissue overexpression was found in only one patient, who also showed high serum levels (102 fm/mL). No correlation was observed between protein serum quantitation and gender, age, histology, stage, performance status, leukocyte count, or smoking. Nonresponding and responding patients exhibited similar oncoprotein levels (median, 57.6 fm/mL vs. 51.9 fm/mL, respectively). The overall survival rate was 42.5% at 1 year and 12% at 2 years, with a median survival duration of 10 months. At univariate analysis, high HER-2/neu serum levels were associated with an unfavorable survival outcome. Using a cut-off point for HER-2/neu of 73.0 fm/mL (corresponding to the 80th percentile of protein concentration), the survival of patients who had higher serum levels of HER-2/neu was significantly worse compared with patients who had lower serum levels (median, 7.1 months vs. 10.9 months; P = 0.004). Multivariate analysis confirmed the independent predictive value of serum HER-2/neu concentration as a negative prognostic factor (P = 0.02). High pretreatment levels of HER-2/neu oncoprotein are associated with an adverse prognostic impact on survival in patients with locally advanced or metastatic nonsmall cell lung carcinoma.
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We have reviewed the biomedical literature published over the last 25 years in order to try to establish which of four frequently evaluated laboratory parameters (i.e. serum, or plasma, NSE, LDH, sodium or albumin) might, alone or in combination, give the "best" pretreatment prognostic information in small-cell lung cancer (SCLC) patients, independent of the usual radiological and clinical parameters. From the 45 studies included in this review, the only clear conclusion that can be derived is that it has not yet been clearly demonstrated that the "new" tests (NSE or other tumor markers) are superior to the "old" tests (LDH, sodium, albumin etc.). From the only seven studies that used the same powerful statistical methodologies (Cox's models in association with recursive partitioning and amalgamation procedure (RECPAM) analysis) it could be concluded that LDH and albumin might have independent prognostic significance in SCLC and in advanced SCLC respectively. Provided that, in the future, both laboratory and statistical expertises are clearly guaranteed in the primary studies in this field, it might become possible to propose laboratory parameters as additional staging parameters in SCLC.
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Progastrin-releasing peptide (proGRP) is a specific tumor marker in patients with small cell lung carcinoma (SCLC). It has been reported that serum proGRP levels rarely are elevated in patients with nonsmall cell lung carcinoma (NSCLC); the reported frequency is <3%. The purpose of this study was to examine the clinicopathologic features of NSCLC patients with high serum proGRP levels. The authors measured serum proGRP levels with a TND-4 kit, a newly developed enzyme-linked immunoadsorbent assay, in 544 NSCLC and 206 SCLC patients. Pathologic features were examined using conventional hematoxylin and eosin staining and histochemical and immunohistochemical staining using polyclonal antibodies to proGRP, chromogranin A, calcitonin, and monoclonal antibody to the neural cell adhesion molecule (NCC-Lu-243). The serum proGRP levels were elevated in 140 SCLC patients (68.0%) and in 23 NSCLC patients (4.2%). Seven of these 23 NSCLC patients had serum proGRP levels > or = 100 pg/mL. They included two patients with renal dysfunction, one patient diagnosed cytologically with adenocarcinoma without undergoing precise pathologic examination, two patients diagnosed histologically with squamous cell carcinoma with foci of small cell elements, and two patients diagnosed with large cell neuroendocrine carcinoma and poorly differentiated adenocarcinoma, respectively, which showed neuroendocrine differentiation on immunohistologic analysis. The remaining 16 NSCLC patients had serum proGRP levels < 70 pg/mL. Nearly all NSCLC patients had serum proGRP levels < 100 pg/mL. However, if an NSCLC patient presents with a proGRP level > or = 100 pg/mL, the clinicopathologic features must be examined with regard to the small cell component, neuroendocrine differentiation, and renal dysfunction.