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Reference Section Tumour Markers in Lung Cancer a report by R a f a e l M o l i n a , X a v i e r F i l e l l a and J o s e p M A u g é Oncobiology Unit, Laboratory of Biochemistry and Genetics, IDIBAPS Hospital Clinic Survival and treatment of lung cancer is clearly related Pro-gastrin-releasing Peptide to the histological type involved. Non-small cell lung cancer (NSCLC) is comprised of three major Pro-gastrin-releasing peptide (ProGRP) is a histological subtypes: adenocarcinoma, squamous cell precursor of the gastrin-releasing peptide (GRP) carcinoma and large cell carcinoma in which surgery gut hormone, which is the mammalian counterpart is the only chance for cure (stages I–IIIA). SCLC is an of amphibian bombesin. ProGRP specificity is high aggressive neoplasm of rapid growth, with metastatic and only renal failure may produce significantly diseases in regional lymph nodes or distant organs at high serum levels of this tumour marker.7–10 the time of diagnosis, but with high sensitivity to Excluding renal failure, fewer than 5% of patients chemotherapy and radiotherapy.1 Unfortunately, with benign or malignant diseases, except for lung however, the disease is usually diagnosed late in most cancer or neuroendocrine tumours, had ProGRP patients.2 Patients with lung cancer, particularly in the levels higher than 50pg/ml.9–11 ProGRP serum early stages, often do not exhibit specific symptoms: levels are clearly related to the histology of the lung dyspnoea, cough, thoracic pain, symptoms frequently cancer, with significantly higher levels in found in smokers. Radiotherapy is mainly palliative SCLC.3,4,7,10–12 Slightly high ProGRP serum levels and the role of chemotherapy in the therapeutic (95% <150pg/ml) may be found in 5–18% of management of patients with advanced NSCLC is NSCLC, mainly in squamous tumours.7–12 still debatable since only modest improvement in survival has been obtained.2 The sensitivity of ProGRP ranges from 40–60% in intrathoracic SCLC and from 75–85% in Tumour Markers in Lung Cancer extrathoracic SCLC.3–8,10–12 Most publications indicate a higher sensitivity with ProGRP than with The most commonly used tumour markers in lung NSE, mainly in SCLC patients with limited disease cancer are discussed below. (LD). Likewise, the absence of ProGRP false positive results with haemolysis, in addition to the greater Neuron Specific Enolase differences between the normal range and the levels found in SCLC patients with ProGRP than with Neuron specific enolase (NSE) has been the tumour NSE, support ProGRP as marker of choice.10,13–15 marker of choice in SCLC.3–7 NSE is present in However, NSE is a complementary marker for platelets and erythrocytes making it necessary to SCLC, and the combination of the two markers exclude samples with haemolysis. Moderate increases the sensitivity as well as facilitates greater elevations of NSE serum levels are found in about precision in the histological diagnosis, prognosis, 10–20% of NSCLC as well as in a small proportion follow-up and early diagnosis of recurrence.6,7 of patients with benign lung diseases or in malignancies other than in the lung (pancreas, Carcinoembryonic Antigen gastric, breast).4–8 In contrast, NSE levels that are double the cut-off values highly suggest SCLC or Carcinoembryonic antigen (CEA) is a glycoprotein neuroendocrine tumours.4–8 The sensitivity of NSE with a molecular weight of 180kDa. It is one of the in SCLC ranges from 50–80%, in relation to the carcinofoetal antigens produced during embryonal and tumour extension.3–9 foetal development. Slightly high CEA concentrations, habitually lower than 10ng/ml, are found in 5–10% of Different publications have demonstrated NSE smoker patients and in various benign pathologies values to be an independent prognostic factor in both including liver and renal diseases (<20ng/ml).16–21 SCLC and NSCLC.4–12 Likewise, NSE is useful in CEA is a tumour marker used in many solid therapy monitoring as well as in the detection of adenocarcinomas, mainly in gastrointestinal tumours. recurrent disease of SCLC after primary therapy.3–7 The sensitivity of this tumour marker ranges from EUROPEAN ONCOLOGICAL DISEASE 2006 1 Reference Section 40–70% in NSCLC and from 30–65% in important utilities of SCC in lung cancer is its aid in SCLC.8,14,17–20 The highest CEA sensitivity and serum establishing histological diagnosis.7,8,33,17–19,36,37 concentrations are found in adenocarcinomas and large Several articles have reported the potential utility of cell lung cancer with the lowest values being seen in SCC as a prognostic factor in the early diagnosis of squamous tumours. recurrence and in the follow-up of NSCLC, mainly in squamous tumours.8,36,37 CEA may provide prognostic information in NSCLC, particularly in lung adenocarcinomas.8,21–24 Clinical Utility of Tumour Markers Likewise, as with other tumour markers, the utility of CEA in the early diagnosis of recurrence and in Diagnosis and Early Diagnosis therapy monitoring has been clearly established.25,26 There are no reports on the utility of tumour markers Cytokeratin-19 Fragment in the early diagnosis of lung cancer in asymptomatic populations. The sensitivity obtained in the early CYFRA 21-1 is a water soluble cytokeratin-19 stages of lung cancer clearly suggests that tumour fragment. Histopathological studies have demonstrated makers are not useful for these purposes. However, that cytokeratin-19 is abundant in carcinomas of he tumour markers, alone or in combination, show lung.8,18–22,26,27 Abnormal serum levels (>3.3ng/ml) of considerable sensitivity in lung cancer.7–10 In the this tumour marker have been found in several benign authors’ experience, with the use of three tumour diseases, including liver pathologies and renal markers in NSCLC (CEA, CYFRA 21-1 and SCC) failure.7–8 Likewise, CYFRA 21-1 is increased in and in SCLC (ProGRP, NSE and CEA or CYFRA several malignancies other than lung cancer, including 21-1) it is possible to obtain a sensitivity higher than most gynaecological or gastrointestinal tumours, 80% in stage I–III patients or LD and 90% in stage IV mesotheliomas and urological malignancy.8,2 or extensive disease (ED).7,8 It is known than some However, the highest CYFRA 21-1 concentrations benign diseases may produce false positive results in are found in lung cancer, mainly in NSCLC. On this group of patients.7,8,16,21 However, when these comparing different tumour markers, different authors pathologies are excluded, the specificity increases reported that CYFRA 21-1 is the most sensitive significantly (>90%).7–10 In summary, there are no tumour marker in lung cancer, with the highest ideal tumour markers in lung cancer, but the concentrations in squamous tumours. The sensitivity sensitivity and specificity obtained with them is higher of CYFRA ranges from 30–75% in NSCLC and from than that achieved with other tumour markers in 20–60% in SCLC.29 other malignancies, such as prostate serum antigen (PSA) in prostate cancer. Tumour markers in lung Since CYFRA 21-1 determines only fragments of cancer may be useful as an aid in patients suspected of cytokeratin-19, the test shows a higher specificity having this malignancy.4,7–8,17–21,26,38,39 than tissue-polypeptide antigen (TPA), which determines a mixture of cytokeratins 8, 18 and Histological Diagnosis 19.30–32 The utility of CYFRA as an aid in the diagnosis, prognosis (mainly in NSCLC), early The most important point in lung cancer is to diagnosis of recurrence and therapy monitoring has distinguish NSCLC and SCLC. ProGRP and NSE are been clearly indicated.8,19–22,25–28,30,33–35 useful parameters to suggest SCLC.4–11,20 The higher the levels of NSE and/or ProGRP, the higher the Squamous Cell Carcinoma Antigen probability of SCLC (see Table 1). The highest efficiency in the diagnosis of SCLC is obtained using Squamous cell carcinoma antigen (SCC) is a 48kDa both tumour markers simultaneously (see Table 1).4–12,33 protein with strong homology to the serpin family of protease inhibitors. Its main clinical application is There are no specific tumour markers for NSCLC, in squamous tumours of different origin: uterine but some of them show a clear relationship with the cervix, oesophagus, head, neck and lung. The main histological type.20,21 Abnormal SCC serum levels sources of SCC false positive results are renal failure suggest a probability higher than 95% of NSCLC and dermatological disorders in which very high (75% probability, squamous). Significantly higher levels up to 30–40 times higher than the cut-off concentrations of CEA and mucins (CA 15.3 and values may be found.16,21 The sensitivity of SCC in TAG) are found in adenocarcinomas.17,18,24,29,40 It is lung cancer ranges from 25–60% in NSCLC, but is interesting to point out that it is very infrequent to rarely found in SCLC (<5%).7–8,17–18,21,27,32 The find abnormal levels of some tumour markers such as highest sensitivity of this tumour marker is observed CEA or CYFRA 21-1 with normal NSE or in squamous tumours, but it is possible to find ProGRP. Table 2 shows some combinations of abnormal levels in other NSCLC. One of the most tumour markers to help in the histological diagnosis. 2 EUROPEAN ONCOLOGICAL DISEASE 2006 Tumour Markers in Lung Cancer In summary, pathological evaluation is the gold Table 1: Probability of SCLC According to Tumour Stage and NSE and/or standard in diagnosis, but the use of tumour markers ProGRP Serum Levels in 533 Patients with Lung Cancer may be of aid when biopsy is not available or in certain specific situations. Criteria SCLC/total lung LD/total stage I–III ED/total stage IV cancer Prognostic Value NSE > 25ng/ml 98/135 (72.6%) 38/57 (66.7%) 60/78 (76.9%) NSE > 35ng/ml 76/79 (96.2%) 24/24 (100%) 52/55 (94.5%) Numerous studies have been published regarding the NSE > 40ng/ml 68/70 (97.1%) 20/20 (100%) 48/50 (96%) utility of tumour markers in the prognosis, on ProGRP 95/113 (84.1%) 36/44 (81.8%) 59/69 (85.5%) univariate and multivariate analysis, in SCLC (CEA, > 100pg/ml CYFRA 21-1, NSE and ProGRP) as well as in ProGRP 87/95 (91.6%) 31/32 (96.8%) 56/63 (88.9%) NSCLC (CEA, CYFRA 21-1, NSE, SCC, CA > 150pg/ml 125).4–8,17–26,34,35,40,41 The authors’ group compared the ProGRP 82/86 (95.3%) 29/29 (100%) 53/57 (93%) most important clinical and pathological prognostic > 200pg/ml factors and tumour markers in a prospective evaluation NSE > 40ng/ml 109/114 (95.6%) 40/40 (100%) 69/74 (93.2%) of 211 NSCLC patients and, on multivariate analysis, and/or found that some clinical (stage, histology, Karnofsky ProGRP > 200pg/ml Index, thoracic pain), therapeutical (surgery, NSE > 35ng/ml 116/126 (92%) 44/45 (97.8%) 72/81 (87.7%) chemotherapy) and biological (CA 125 or CEA, NSE and/or or LDH and SCC) parameters were independent ProGRP > 150pg/ml prognostic factors. However, as occurs with most prognostic factors, the clinical utility remains to be Table 2: Probability of NSCLC According to Tumour Extension and Tumour demonstrated. Moreover, serum tumour markers have Markers in 384 Patients with Lung Cancer potential advantages, as they are readily performed and can be standardised and quality controlled. Criteria NSCLC/total lung Stage I–III/total lung Stage IV/total cancer cancer Mo lung cancer M1 NSE has also been suggested as a prognostic factor in SCC > 2ng/ml 84/85 (98.8%) 47/48 (97.9%) 36/36 (100%) NSCLC.22,33,42,43 The hypothesis to explain these CEA > 5ng/ml, 157/161 (97.5%) 70/71 (98.6%) 87/90 96.7% results may be that NSE is a predictive factor, NSE < 26ng/ml and selecting the patients with neuroendocrine ProGRP < 50pg/ml differentiation and with higher response to CYFRA > 3.3ng/ml 223/231 (96.5%) 118/121 (97.5%) 105/110 (95.5%) chemotherapy. The use of NSE and other parameters NSE < 36ng/ml such as LDH or chromogranin A as predictive factors PROgrp < 150pg/ml in SCLC has also been suggested.3–10 CA 125 > 100U/ml 76/80 (95%) 22/23 (95.7%) 54/57 (94.7%) NSE < 36ng/ml and Early Diagnosis of Recurrence ProGRP < 150pg/ml Following curative resection, tumour markers, Therapy Monitoring depending on the half-life of each tumour marker, may decrease, reaching normal values within a short The main interest of tumour marker evaluation in period of time. Patients with an elevated plateau or serum is in patient follow-up, mainly in those with with increased tumour marker levels in serial abnormal values.7–15,21,28,34,40–43 Patients in remission determinations are indicative of the presence of usually have a substantial reduction in marker levels, residual tumour cells.44 However, to suspect while those with progressive disease generally have recurrence, possible sources of false positive results increased levels. Tumour markers in patients treated such as in liver diseases or renal failure must be with chemotherapy should be determined before excluded. Tumour marker sensitivity as well as the every chemotherapy course, since certain treatments lead time are related to the tumour marker used. may cause transient increases in serum marker levels. Increasing serial SCC levels have been reported as ProGRP is the most sensitive tumour marker in the first sign of recurrence in 79% of squamous SCLC but the addition of NSE as complementary tumours.26 The sensitivity of CYFRA 21-1 was tumour marker, mainly in patients with LD, provides found to be similar in NSCLC with a lead time of additional information.3–6,15,48 between two and 15 months.26,45,46 CEA and TPS have also been reported as relevant tumour markers The tumour marker used in NSCLC differs for detecting recurrent disease.24,25,45–47 The according to the histological type. CYFRA 21-1 is simultaneous use of ProGRP and NSE is useful in the most sensitive tumour marker in NSCLC and the early diagnosis of recurrence in more than 80% of its use in therapy evaluation, mainly in the patients with SCLC recurrence.3–8,10,15 detection of progression, has been reported.26,32,43,49 EUROPEAN ONCOLOGICAL DISEASE 2006 3 Reference Section In our experience, the best combination of tumour their use are not clear. In this review it is shown markers in disease monitoring is CYFRA 21-1 and that the sensitivity and specificity of tumour CEA in all NSCLC, also including SCC in markers in lung cancer are high or are at least squamous tumours and one mucin (CA 15.3, TAG) similar to the values obtained in other malignancies. in adenocarcinoma or SCLC. The use of tumour markers is closely related to treatment and lung cancer is habitually diagnosed Conclusion late with short curative possibilities. Nevertheless, tumour markers may provide very helpful aid in Tumour markers are not habitually used in patients diagnosis, prognosis, early diagnosis of recurrence with lung cancer because the clinical advantages of and therapy monitoring. ■ References 1. Stupp R, Monnerat C, Turrisi AT, Perry MC, Leyvraz S, “Small cell lung cancer: state of the art and future perspectives”, Lung Cancer (2004);45: pp. 105–117. 2. Spira A, Ettinger DS, “Multidisciplinary management of lung cancer”, N Engl J Med (2004);350: pp. 379–392. 3. Niho S, Nishiwaki Y, Goto K, et al., “Significance of serum pro-gastrin-releasing peptide as a predictor of relapse of small cell lung cancer: comparative evaluation with neuron-specific enolase and carcinoembryonic antigen”, Lung Cancer (2000);27: pp. 159–167. 4. Shibayama T, Ueoka H, NishiiI K, et al., “Complementary roles of pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase (NSE) in diagnosis and prognosis of small cell lung cancer (SCLC)”, Lung Cancer (2001);32: pp. 61–69. 5. Quoix E, Purohit A, Faller-Beau M, et al., “Comparative prognostic value of lactate dehydrogenase and neuron-specific enolase in small-cell lung cancer patients treated with platinum-based chemotherapy”, Lung Cancer (2000);30: pp. 127–134. 6. Lassen U, Osterlind K, Hansen M, et al., “Long-term survival in small-cell lung cancer: post treatment characteristics in patients surviving 5 to 18+ years. An analysis of 1714 consecutive patients”, J Clin Oncol (1995);13: pp. 1215–1220. 7. Molina R, Filella X, Auge JM, “ProGRP: A New Biomarker for Small Cell Lung Cancer”, Clinical Biochem (2004);37: pp. 505–511. 8. Molina R, Filella X, Auge JM, et al., “Tumour markers (CEA, CA125, CYFRA 21-1, SCC and NSE) in patients with Non-Small Cell lung Cancer as aid in histological diagnosis and prognosis: comparison with the main clinical and pathological prognostic factors”, Tumor Biol (2003);24: pp. 209–218. 9. Molina R, Alicarte J, Auge JM, et al., “Pro-gastrin-releasing peptide (ProGRP) in patients with benign and malignant diseases”, Tumor Biol (2004);25: pp. 56–61. 10. Stieber P, Yamaguchi K, “ProGRP enables diagnosis of Small-Cell Lung Cancer”, in Diamandis P, Fritsche HA, Lilja H, Cham DW, Schwartz M (eds.), Tumor Markers. Physiology, Pathobiology, Technology and Clinical Applications (2002), Washington: AACC Press: pp. 517–521. 11. Lamy PJ, Grenier J, Kramar A, Pujol JL, “Pro-gastrin-releasing peptide, neuron specific enolase and chromogranin A as serum markers of small cell lung cancer”, Lung Cancer (2000);29: pp. 197–203. 12. Takada M, Kusunoki Y, Masuda N, et al., “Pro-gastrin-releasing peptide (31-98) as a tumor marker of small-cell lung cancer: comparative evaluation with neuron-specific enolase”, Br J Cancer (1996);73: pp. 1227–1232. 13. Sunaga N, Tsuchiya S, Minato K, et al., “Serum pro-gastrin-releasing peptide is a useful marker for treatment monitoring and survival in small-cell lung cancer”, Oncology (1999);6: pp. 143–148. 14. Stieber P, Dinemann H, Schalhorn A, et al., “Pro-gastrin-releasing Peptide (ProGRP) – a useful marker in small cell lung carcinomas”, Anticancer Res (1999);19: pp. 2673–2678. 15. Okusaka T, Eguchi K, Kasai T, et al., “Serum levels of Pro-Gastrin-releasing peptide for follow-up of patients with small cell lung cancer”, Clinical Cancer Res (1997);3: pp. 123–127. 16. Cases A, Filella X, Molina R, et al., “Tumor markers in chronic renal failure and hemodialysis patients”, Nephron (1991);57: pp. 183–186. 17. Mizushima Y, Hirata H, Izumi S, et al., “Clinical significance of the number of positive markers in assisting the diagnosis of lung cancer with multiple tumor marker assay”, Oncology (1990);47: pp. 43–48. 18. Nisman B, Heching N, Barak V, “Serum tumor markers in resectable and non-resectable non-small cell lung cancer”, J Tumor Marker Oncology (2000);15: pp. 195–207. 19. Foa P, Fornier M, Miceli R, et al., “Tumor markers CEA, NSE, SCC, TPA and CYFRA 21.1 in resectable non- small cell lung cancer”, Anticancer Res (1999);19: pp. 3613–3618. 20. Paone G, De Angelis G, Munno R, et al., “Discriminant analysis on small cell lung cancer and non-small cell lung cancer by means of NSE and CYFRA 21-1”, Eur Respir J (1995);8: pp. 1136–1140. 21. European Group on Tumor Markers, “European Group on Tumor Markers: Consensus recommendations”, Anticancer Res (1999);19: pp. 2785–2820. 4 EUROPEAN ONCOLOGICAL DISEASE 2006 Tumour Markers in Lung Cancer 22. Barlesi F, Gimenez C, Torre JP, et al., “Prognostic value of combination of Cyfra 21-1, CEA and NSE in patients with advanced non-small cell lung cancer”, Respir Med (2004);98: pp. 357–362. 23. Pollan M, Varela G, Torres A, et al., “Clinical value of p53, c-erbB-2, CEA and CA 125 regarding relapse, metastases and death in resectable non-small cell lung cancer”, Int J Cancer (2003);107: pp. 781–790. 24. Sawabata N, Maeda H, Yokota S, et al., “Postoperative serum carcinoembryonic antigen levels in patients with pathologic stage IA non-small cell lung carcinoma: subnormal levels as an indicator of favourable prognosis”, Cancer (2004);101: pp. 803–809. 25. Kao CH, Hsieh JF, Ho YJ, Ding HJ, “Cytokeratin fragment 19 (CYFRA 21-1) and carcinoembryonic antigen for early prediction of recurrence of lung adenocarcinoma”, Lung (1999);177: pp. 707–713. 26. Schalhorn A, Fuerst H, Stieber P, “Tumor markers in lung cancer”, J Lab Med (2001);25: pp. 353–361. 27. Scheulen ME, Klanig H, Wiefelspÿtz JK, et al., “Pre-therapeutic evaluation of cytokeratin fragment 19 (CYFRA 21-1) in 240 patients with lung cancer in comparison to CEA, NSE, SCC-Ag, TPA and TPS”, Tumor Diagn Ther (1997);18: pp. 14–19. 28. Barak V, Goike H, Panaretakis KW, Einarsson R, “Clinical utility of cytokeratins as tumor markers”, Clin Biochem (2004);37: pp. 529–540. 29. Rastel D, Ramaiolo A, Cornillie F, Thirion B, “CYFRA 21-1, a sensitive and specific new tumour marker for Squamous cell lung cancer. Report of the first European multicentre evaluation. CYFRA 21-1 multicentre Study Group”, Cancer (1994);30: pp. 601–606. 30. Pujol JL, Quantin X, Jacot M, et al., “Neuroendocrine and cytokeratin serum markers as prognostic determinants of small cell lung cancer”, Lung Cancer (2003);39: pp. 131–138. 31. Stieber P, Dienemann H, Hasholzner U, et al., “Comparison of CYFRA 21-1, TPA and TPS in lung cancer, urinary bladder cancer and in benign diseases”, Int J Biol Markers (1994);9: pp. 82–88. 32. Nisman B, Lafair J, Heching N, et al., “Evaluation of tissue polypeptide specific antigen, CYFRA 21-1, and CEA in non-small cell lung carcinoma”, Cancer (1998);82: pp. 1850–1859. 33. Kulpa J, Wojcik E, Reinfuss M, Kolodziejski L, “Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21-1, and neuron-specific enolase in squamous cell lung cancer patients”, Clin Chem (2002);48: pp. 1931–1937. 34. Takei Y, Minato K, Tsuchiya S, et al., “CYFRA 21-1: an indicator of survival and therapeutic effect in lung cancer”, Oncology (1997);54: pp. 43–47. 35. Ando S, Suzuki M, Yamamoto N, et al., “The prognostic value of both neuron-specific enolase (NSE) and CYFRA 21- 1 in small cell lung cancer”, Anticancer Res (2004);24: pp. 1914–1916. 36. Takeuchi S, Nonaka M, Kadokura M, Takaba T, “Prognostic significance of serum squamous cell carcinoma antigen in surgically treated lung cancer”, Ann Thorac Cardiovasc Surg (2003);9: pp. 98–104. 37. Hatzakis KD, Froudarakis ME, Bouros D, et al., “Prognostic value of serum tumor markers in patients with lung cancer”, Respiration (2002);69: pp. 25–29. 38. Seeman MD, Beinert T, Furst H, Fink U, “An evaluation of the tumour markers, carcinoembryonic antigen (CEA), cytokeratin marker (CYFRA 21-1) and neuron-specific enolase (NSE) in the differentiation of malignant from benign solitary pulmonary lesions”, Lung Cancer (1999);26: pp. 149–155. 39. Schneider J, Bitterlich N, Velcovsky HG, et al., “Fuzzy logic-based tumor-marker profiles improved sensitivity in the diagnosis of lung cancer”, Int J Clin Oncol (2002);7: pp. 145–151. 40. Rubins JB, Dunitz J, Rubins HB, et al., “Serum carcinoembryonic antigen as an adjunct to preoperative staging of lung cancer”, J Thorac. Cardiovasc Surg (1998);116: pp. 412–416. 41. Bonner JA, Sloan JA, Rowland KM, et al., “Significance of neuron-specific enolase levels before and during therapy for small cell lung cancer”, Clin Cancer Res (2000);6: pp. 597–601. 42. Ferrigno D, Buccheri G, Giordano C, “Neuron specific enolase is an effective tumour marker in non-small cell lung cancer (NSCLC)”, Lung Cancer (2003);41: pp. 311–320. 43. Viñolas N, Molina R, Galan MC, et al., “Tumor markers in response monitoring and prognosis of non-small cell lung cancer: Preliminary report”, Anticancer Res (1998);18: pp. 631–634. 44. Yoshimasu T, Miyoshi S, Maebeya S, et al., “Disappearance curves for tumor markers after resection of intrathoracic malignancies”, Int J Biol Markers (1999);14: pp. 99–105. 45. Sun SS, Hsieh JF, Tsai SC, et al., “Cytokeratin fragment 19 and Squamous cell carcinoma antigen for early prediction of recurrence of Squamous cell lung carcinoma”, AM J Clin Oncol (2000);23: pp. 241–243. 46. Yeh JJ, Liu FY, Hsu WH, et al., “Monitoring cytokeratin fragment 19 (CYFRA 21-1) serum levels for early prediction of recurrence of adenocarcinoma and Squamous cell carcinoma in the lung after surgical resection”, Lung (2002);180: pp. 273–279. 47. Sun SS, Hsieh JF, Tsai SC, Ho YJ, Kao CH, “Tissue polypeptide-specific antigen and carcinoembryonic antigen for early prediction of recurrence in lung adenocarcinoma”, Am J Clin Oncol (2000);23: pp. 605–608. 48. Schneider J, Phillipp M, Salewski L, Velcovsky HG, “Pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase (NSE) in therapy control of patients with small-cell lung cancer”, Clin Lab (2003);49: pp. 35–42. 49. Vollmer RT, Govindan R, Graziano SL, et al., “Serum CYFRA 21-1 in advanced stage non-small cell lung cancer: an early measure of response”, Clin Cancer Res (2003);9: pp. 1728–1733. EUROPEAN ONCOLOGICAL DISEASE 2006 5
"Tumour Markers in Lung Cancer"