- Email: [email protected]
Prognostic factors for patients with non-small cell lung cancer
10. PROGNOSTIC FACTORS FOR PATIENTS WITH NON-SMALL CELL LUNG CANCER Elizabeth Rosvold, MD
CLINICAL FACTORS Many clinical, pathologic, and molecular factors have been recognized as important determinants of survival of patients with n o n small cell lung cancer (NSCLC). The three most powerful prognostic factors are performance status, extent of disease (ie, stage), and weight loss. In studies of advanced and localized disease, these three factors are dominant, even w h e n tumor size, histologic type, and treatment are accounted for. 1"3 In advanced disease, age has not been shown to be a significant prognostic factor, except in one study. 4 Sex does influence survival of patients with advanced disease, with women faring better than men. 46 Patients with distant sites of metastatic disease have poor survival, and those with a single site fare better than those with multiple sites? The presence of skin metastasis has been shown to be a powerful negative prognostic factor in two studies. 5'7 Elevation of the serum lactate dehydrogenase level has been shown by some to be associated with poorer s u r v i v a l , 4.6.8,9 a s has elevation of the white blood cell count 2,s.8 and elevation of the neutrophil count? Histologic subtype is not of prognostic importance for advanced disease. 2.5,6.9Another independent predictor of survival in a retrospective study was cisplatin treatment 4 and objective response to chemotherapy was associated with longer median survival in another retrospective study? For resectable NSCLC, several prognostic factors have been identified in addition to performance status, stage, and weight loss. Tumor size (T1 versus T2) has been shown to be important in several studies of patients with stage I or II disease, 1~ with long-tern~ survival rates of 9% to 22% lower for those with T2 lesions. Histologic subtype is important for patients with resectable disease; squamous cell carcinoma has a more favorable prognosis than adenocarcinoma, and large cell carcinoma is the least favorable subtype. 1~ The subtype of adenocarcinoma is also important, because the bronchoalveolar cell, acinar, and papillary types have significantly better survivorship 272
Curr Probl Cancer, July/August 1996
than the solid carcinomas with mucus formation) 7,~aOther negative prognostic determinants include lack of tumor differentiation, 13'~9lymphatic vessel invasion in patients with disease-negative lymph nodes, 2~ blood vessel i n v a s i o n , 19'21'22high mitotic index, 1~ loss or alteration of the expression of blood group antigens on the tumor c e l l s , 2a.24 and the presence of tumor-associated carbohydrate antigens, including H/Le(y)/ Le(b), 25sialyl Lewis(X), and sialyl Lewis(a). 22.26 Flow-cytometry analysis has been used to determine prognoses for patients with a variety of cancers. Analysis of DNA content or ploidy in NSCLC tumor cells has yielded conflicting results. Several studies have demonstrated that diploid tumors have significantly better long-term survivals than aneuploid t u m o r s , 27"33 but other studies have shown no correlation between ploidy and survival, a4"38A high fraction of tumor cells in S phase was shown to correlate with poorer outcome in one study, 27 but not in two others. 37"38 Proliferating cell nuclear antigen (PCNA) is a nuclear protein associated with DNA replication. The presence of this protein is a marker for the proliferative activity of tumors. In one study, PCNA-positive tumors had a significantly worse prognosis than PCNAonegative tumors. 39 Several serine proteases, including urokinase and plasminogen activator inhibitor, may play a role in cancer invasion. Elevated levels of these enzymes have been associated with shortened survival/~ and they may represent a novel target for intervention. The degree of angiogenesis is an important determinant of survival. A high microvessel count correlated with recurrence of disease after resection in two studies. 43.44Another marker of metastatic potential is the ability to establish in vitro cell lines, which has been correlated with poor prognosis for potentially curable patients. 45 GENETIC FACTORS Molecular genetic changes important in the pathogenesis of NSCLC have also been found to be useful determinants of survival. Mutations in KRAS have an adverse effect on survival of patients with adenocarcinomas 48 or other types of NSCLC. 47 Overexpression of the p2 1 protein of the KRAS gene also negatively affects survival of NSCLC patients. 48 Overexpression of the ERBB2 protein has been associated with significantly shorter survival, although only for those with adenocarcinomas? 9-51The combination of KRAS mutation and ERBB2 overexpression had an additive negative impact on survival in one study of adenocarcinomas. 51 The effect of alterations in the P53 gene on prognosis has been studied extensively. P53 protein expression has been associated with decreased survival in several studies5255; however, three studies were unable to demonstrate a difference in survival between those with Curr Probl Cance~ July/August 1996
273
p53-positive and p53-negative tumors, 5658 and two studies demonstrated that p53 expression was a positive prognostic f a c t o r . 59'G~ Mutations of the P53 gene have been studied as well. Mutations were associated with decreased survival in patients with stages I through IIIA NSCLC in one study, 61 but this association held only for those with advanced disease in another trial, with no significant difference found in survival for those with stage I or II disease32 Mutations in P53 were not a prognostic factor in a third study? 3 The reasons for the inconsistencies in these studies are unclear. It is known that some mutations in P53 are not correlated with positive protein staining and that not all mutant proteins are inactive. The best method of evaluating P53 remains unknown, and the role of the P53 gene in NSCLC awaits determination. RB1 protein expression has been associated with a significantly better prognosis than lack of expression (32 versus 18 months), and combined evaluation of RB1 and p53 proteins was better at predicting survival than evaluating either one. 55 Expression of the BCL2 oncogene has been associated with improved survival of patients with squamous cell cancers in one study 63 and of those with all histologic types in another. 64 Which combination of these molecular and clinical factors is best for predicting relapse and disease progression remains to be determined. A prospective evaluation of several of these markers, including KRAS mutations, P53 mutations, blood group antigens, neuroendocrine markers, and others, is currently being performed in patients with stage II or IIIA NSCLC treated by surgical resection. This and similar prospective studies will help to determine which patients are most at risk for recurrence and may therefore benefit from adjuvant treatment.
1. 2. 3. 4. 5.
6.
274
REFERENCES Zelen M. Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 1973;4:31-42. Stanley KE. Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst 1980;65:25-32. Pater JL, Loeb M. Nonanatomic prognostic factors in carcinoma of the lung: a multivariate analysis. Cancer 1982;50:326-31. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991;9:1618-26. Paesmans M, Sculier JP, Libert P, et al. Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analysis including recursive partitioning and amalgamation algorithms in 1,052 patients. J Clin Oncol 1995;13:1221-30. O'Connell JP, Kris MG, Gralla RJ, et al. Frequency and prognostic importance of pre-treatment clinical characteristics in patients with advanced nonsmall-cell lung cancer treated with combination chemotherapy. J Clin Oncol 1986;4:1604-14. Curr Prabl Cancer, July/August 1996
7. Ruckdeschel JC, Finklestein DM, Ettinger DS, et al. A randomized trial of four,most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol 1986;14:14-22: 8. Sorensen JB, Badsberg JH, Olsen J. Prognostic factors in inoperable adenocarcinoma of the lung: a multivariate regression analysis in 259 patients. Cancer Res 1989;49:5748-54. 9. Luedke DW, Einhorn L, Omura GA, et al. Randomized comparison of two combination regimens versus minimal chemotherapy in non-small cell lung cancer: a Southeastern Cancer Study Group trial. J Clin Oncol 1990;8:88691. 10. Gall M, Eagan RT, Feld R, et al. Prognostic factors in patients with resected stage I NSCLC: a report from the Lung Cancer Study Group. Cancer 1984;54:1802-13. 11. Mountain CE A new international staging system for lung cancer. Chest 1986;89:2255-335. 12. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1988;96:440-7. 13. Lipford EH, Eggleston JC, Lillemoe KD, et al. Prognostic factors in surgically resected limited-stage, nonsmall cell carcinoma of the lung. Am J Surg Pathol 1984;8:357-65. 14. Treasure T, Belcher JR. Prognosis of peripheral lung tumours related to size of the primary. Thorax 1981;36:5-8. 15. Thomas PA, Piantadosi S. Postoperative TIN0 non-small cell lung cancer: squamous versus nonsquamous recurrences. J Thorac Cardiovasc Surg 1987;94:349-54. 16. Mountain C, Lukeman J, Hammer S, et al. Lung cancer classification: the relationship of disease extent and cell type to survival in a clinical trials population. J Surg Oncol 1987;35:147-56. 17. Sorenson JB, Badsberg JH. Prognostic factors in resected stage I and II adenocarcinoma of the lung. J Thorac Cardiovasc Surg 1990;99:218-26. 18. Sorensen JB, Olsen JE. Prognostic implications of histopathologic subtyping in patients with surgically treated stage I or II adenocarcinoma of the lung. J Thorac Cardiovasc Surg 1989;97:245-51. 19. Takise A, Kodama T, Shimosato Y, et al. Histopathologic prognostic factors in adenocarcinomas of the peripheral lung less than 2 cm in diameter. Cancer 1988;61:2083-8. 20. Shields TW. Prognostic significance of parenchymal lymphatic vessel and blood vessel invasion in carcinoma of the lung. Surg Gynecol Obstet 1983;157:185-90. 21. Macchiarini P, Fantanini G, Hardin MJ, et al. Blood vessel invasion by tumor cells predicts recurrence in completely resected TINOM0 non-small cell lung cancer. J Thorac Cardiovasc Surg 1993;106:80-9. 22. Ogawa J, Tsurumi T, Yamada S, et al. Blood vessel invasion and expression of sialyl lewis(X) and proliferating cell nuclear antigen in stage I non-small cell lung cancer. Relation to postoperative recurrence. Cancer 1994;73:117783. 23. Lee JS, Ro J'Y,Sahin AA, et al. Expression of blood-group antigen A: a favorable prognostic factor in non-small cell lung cancer. N Engl J Med 1991;324:108490. 24. Matsumoto H, Muramatsu H, Shimotakahara T, et al. Correlation of expression of ABH blood group carbohydrate antigens with metastatic potential in human lung carcinomas. Cancer 1993;72:75-81. Curr Probl Cancer, July/August 1996
275
25. Miyake M, Take T, Hitomi S, Hakomori S. Correlation of expression of H/ Le(y)/Le[b] antigens with survival in patients with carcinoma of tile lung. N Engl J Med 1992;327:14-8. 26. Ogawa J, Sano A, Koide S, Shohtsu A. Relation between recurrence and expression of proliferating cell nuclear antigen, sialyl lewis(X}, and sialyl lewis(a} in lung cancer. J Thorac Cardiovasc Surg 1994;108:329-36. 27. Volm M, Hahn EW, Mattern J, et al. Five-year follow-up study of independent clinical and flow cytometric prognostic factors for the survival of patients with non-small cell lung carcinoma. Cancer Res 1988;48:2923-8. 28. Zimmerman PV, Bint MH, Hawson GAT, Parsons, PG. Ploidy as a prognostic determinant in surgically treated lung cancer. Lancet 1987;2:530-3. 29. Tirindelli-Danesi D, Teodori L, Maruo E et al. Prognostic significance of flow cytometry in lung cancer: a 5-year study. Cancer 1987;60:844-51. 30. Salvati F, Teodori L, Gagliardi L, et al. DNA flow cytometry of 66 human lung tumors analyzed before treatment: prognostic implications. Chest 1989;96:1092-8. 31. Sahin AA, Ro JA, E1-Naggar AK, et al. Flow cytometric analysis of the DNA content of non-small cell lung cancer: ploidy as a significant prognostic indicator in squamous cell carcinoma of tile lung. Cancer 1990;65:530-7. 32. Isobe H, Miyamoto H, Shimizu T, et al. Prognostic and therapeutic significance of the flow cytometric nuclear DNA content in non-small cell lung cancer. Cancer 1990;65:1391-5. 33. Tanaka I, Masuda R, Furuhata Y, et al. Flow cytometric analysis of the DNA content of adenocarcinoma of the lung, especially for patients with stage 1 disease with long term follow-up. Cancer 1995;75:2461-5. 34. Van Bodegom PC, Baak JPA, Van Galen CS, et al. The percentage of aneuploid cell is significantly correlated with survival in accurately staged patients with stage 1 resected squamous cell lung cancer and long-term follow up. Cancer 1989;63:143-7. 35. Cibas ES, Melamed MR, Zaman MB, Kimmel M. The effect of tumor size and tumor cell DNA content on the survival of patients with stage 1 adenocarcinoma of the lung. Cancer 1989;63:1552-6. 36. Carp NZ, Ellison DD, Brophy PE et al. DNA content in correlation with postsurgical stage in non-small cell lung cancer. Ann Thorac Surg 1992;53:6803. 37. Schmidt RA, Rusch VW, Piantadosi S. A flow cytometric study of non-small cell lung cancer classified as T1N0. Cancer 1992;69:78-85. 38. Rice TW, Bauer TW, Gephart GN, et al. Prognostic significance of flow cytometry in non-small cell lung cancer. J Thorac Cardiovasc Surg 1993;106:210-7. 39. Ishida T, Kaneko S, Akazawa K, et al. Proliferating cell nuclear antigen expression and argyrophilic nucleolar organizer regions as factors influencing prognosis of surgically treated lung cancer patients. Cancer Res 1993;53:5000-3. 40. Pederson H, Grondahl-Hansen 1, Francis D, et al. Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma. Cancer Res 1994;54:120-3. 41. Pedersen H, Brunner N, Francis D, et al. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994;54:4671-5. 42. Nagayama M, Sato S, Hayakawa H, et al. Plasminogen activator inhibitor associated with tumor dissemination. Cancer 1994;73:1398-405. 276
Curr Probl Cancer, July/August 1996
43. Macchiarini P, Fontanini G, Hardin MJ, et al. Relation of neovascularisation to metastasis of non-small cell lung cancer. Lancet 1992;340:145-6. 44. Yamazaki K, Abe S, Takekawa H, eL al. Tumor angiogenesis in human lung adenocarcinoma. Cancer 1994;74:2245-50. 45. Stevenson H, Gazdar AF, Phelps RS. Tumor cell lines established in vitro: an independent prognostic factor for survival in non-small-cell lung cancer. Ann Intern Med 1990;113:764-70. 46. Slebos RJ, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic m a r k e r in a d e n o c a r c i n o m a of the lung. N Engl J Med 1990;323:561-5. 47. Mitsudomi T, Steinberg SM, Oie H, et al. Ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent. Cancer Res 1991;51:4999-5002. 48. Harada M, Dosaka-Akita H, Miyamoto H, et al. Prognostic significance of the expression of ras oncogene product in non-small cell lung cancer. Cancer 1992;69:72-7. 49. Kern JA, Schwartz DA, Nordberg JE, et al. P185(neu) expression in human hmg adenocarcinomas predicts shortened survival. Cancer Res 1990;50: 5184-91. 50. Tateishi M, Ishida T, Mitsodomi T, et al. Prognostic value of c-erb-2 protein expression in human lung adenocarcinoma and squamous cell carcinoma. Eur J Cancer 1991;27:1372-5. 51. Kern J, Slebos R, Top B, et al. C-erbB-2 expression and .codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas. J Clin Invest 1994;93:516-20. 52. Quinlan DC, Davidson AG, Summers CL, et al. Accumulation of p53 protein correlates with a poor prognosis in h u m a n lung cancer. Cancer Res 1992;52:4828-31. 53. Carbone DP, Mitsudomi T, Chiba I, et al. P53 immunostaining positivity is associated with reduced survival and is imperfectly correlated with gene mutations in resected non-small cell lung cancer. A preliminary report of LCSG 871. Chest 1994;106:$377-81. 54. Ebina M, Steinberg SM, Mulshine JL, Linnoila RI. Relationship of p53 overexpression and upregulation of proliferating cell nuclear antigen with the clinical course of non-small cell lung cancer. Cancer Res 1994;54:2496-503. 55. Xu H-J, Quinlan DC, Davidson AG. Altered retinoblastoma protein expression and prognosis in early-stage non-small-cell lung carcinoma. J Natl Caner Inst 1994;86:692-9. 56. McLaren R, Kuzu I, Dunnill M, et al. The relationship of p53 immunostaining to survival in carcinoma of the lung. Br J Cancer 1992;66:735-8. 57. Brambilla E, Gazzeri S, Moro D, et al. Immunohistochemical study of p53 in human lung carcinomas. Am J Pathol 1993;143:199-220. 58. Morkve O, Halvorsen OJ, Skjaerven R, et al. Prognostic significance of p53 protein expression and DNA ploidy in surgically treated non-small cell lung carcinomas. Anticancer Res 1993;13:571-8. 59. Passlick B, Izbicki JR, Riethmuller G, Pantel K. P53 in non-small cell lung cancer. J Natl Cancer Inst 1994;86:801-3. 60. Lee JS, Yoon A, Kalapurakal SK, et al. Expression of p53 oncoprotein in non-small-cell lung cancer: a favorable prognostic factor. J Clin Oncol 1995;13:1893-903. 61. Horio Y, Takahashi T, Kurosishi T, et al. Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res 1993;53:1-4. C u r t P r o b l Cancer, July/August 1996
277
62. Mitsudomi T, Omaya T, Knsano T, et al. Mutation of the p53 gene as a predictor of poor prognosis in patients with non-small cell lung cancer. J Natl Cancer Inst 1993;85:2018-23. 63. Pezzella E Turley H, Kuzu I, et al. Bcl-2 protein in non-small cell lung carcinoma. N Engl J Med 1993;329:690-4. 64. Fontanini G, Vignati S, Bigini D, et al. Bcl-2 protein: a prognostic factor inversely correlated to p53 in non-small-cell lung cancer. Br J Cancer 1995;71:1003-7.
278
Curr Probl Cancer, July/August 1996
Corey J. Langer, MD, is board certified in medical oncology. He graduated from the combined liberal arts and medicine program of Boston University in 1981. He completed his medical residency at the Graduate Hospital of the University of Pennsylvania and h& fellowship in medical oncology and hematology at Presbyterian University of Pennsylvania Medical Center and the American Oncologic Hospital of Fox Chase Cancer Center, and since 1993 he has been codirector of thoracic oncology. He is a Fellow of the American College of Physicians and a member of the American Society of Clinical Oncology, the American Association for Cancer Research, and the International Association for the Study of Lung Cancer. His specific h~terests include combined-modality therapy for locally advanced non-small cell lung carcinoma and the investigation of new systemic agents. Elizabeth Rosvold received her MD degree from the Milton S. Hershey Medical Center in 1985. She completed training in internal medicine and oncology at Temple University and the Fox Chase Cancer Center in Philadelphia. She has been on staff at the Fox Chase Cancer Center since 1992. Her interests are in the genetic predisposition to and treatment of lung cancer. Curr Probl Cancer,
July/August 1996
279
CLINICAL FACTORS Many clinical, pathologic, and molecular factors have been recognized as important determinants of survival of patients with n o n small cell lung cancer (NSCLC). The three most powerful prognostic factors are performance status, extent of disease (ie, stage), and weight loss. In studies of advanced and localized disease, these three factors are dominant, even w h e n tumor size, histologic type, and treatment are accounted for. 1"3 In advanced disease, age has not been shown to be a significant prognostic factor, except in one study. 4 Sex does influence survival of patients with advanced disease, with women faring better than men. 46 Patients with distant sites of metastatic disease have poor survival, and those with a single site fare better than those with multiple sites? The presence of skin metastasis has been shown to be a powerful negative prognostic factor in two studies. 5'7 Elevation of the serum lactate dehydrogenase level has been shown by some to be associated with poorer s u r v i v a l , 4.6.8,9 a s has elevation of the white blood cell count 2,s.8 and elevation of the neutrophil count? Histologic subtype is not of prognostic importance for advanced disease. 2.5,6.9Another independent predictor of survival in a retrospective study was cisplatin treatment 4 and objective response to chemotherapy was associated with longer median survival in another retrospective study? For resectable NSCLC, several prognostic factors have been identified in addition to performance status, stage, and weight loss. Tumor size (T1 versus T2) has been shown to be important in several studies of patients with stage I or II disease, 1~ with long-tern~ survival rates of 9% to 22% lower for those with T2 lesions. Histologic subtype is important for patients with resectable disease; squamous cell carcinoma has a more favorable prognosis than adenocarcinoma, and large cell carcinoma is the least favorable subtype. 1~ The subtype of adenocarcinoma is also important, because the bronchoalveolar cell, acinar, and papillary types have significantly better survivorship 272
Curr Probl Cancer, July/August 1996
than the solid carcinomas with mucus formation) 7,~aOther negative prognostic determinants include lack of tumor differentiation, 13'~9lymphatic vessel invasion in patients with disease-negative lymph nodes, 2~ blood vessel i n v a s i o n , 19'21'22high mitotic index, 1~ loss or alteration of the expression of blood group antigens on the tumor c e l l s , 2a.24 and the presence of tumor-associated carbohydrate antigens, including H/Le(y)/ Le(b), 25sialyl Lewis(X), and sialyl Lewis(a). 22.26 Flow-cytometry analysis has been used to determine prognoses for patients with a variety of cancers. Analysis of DNA content or ploidy in NSCLC tumor cells has yielded conflicting results. Several studies have demonstrated that diploid tumors have significantly better long-term survivals than aneuploid t u m o r s , 27"33 but other studies have shown no correlation between ploidy and survival, a4"38A high fraction of tumor cells in S phase was shown to correlate with poorer outcome in one study, 27 but not in two others. 37"38 Proliferating cell nuclear antigen (PCNA) is a nuclear protein associated with DNA replication. The presence of this protein is a marker for the proliferative activity of tumors. In one study, PCNA-positive tumors had a significantly worse prognosis than PCNAonegative tumors. 39 Several serine proteases, including urokinase and plasminogen activator inhibitor, may play a role in cancer invasion. Elevated levels of these enzymes have been associated with shortened survival/~ and they may represent a novel target for intervention. The degree of angiogenesis is an important determinant of survival. A high microvessel count correlated with recurrence of disease after resection in two studies. 43.44Another marker of metastatic potential is the ability to establish in vitro cell lines, which has been correlated with poor prognosis for potentially curable patients. 45 GENETIC FACTORS Molecular genetic changes important in the pathogenesis of NSCLC have also been found to be useful determinants of survival. Mutations in KRAS have an adverse effect on survival of patients with adenocarcinomas 48 or other types of NSCLC. 47 Overexpression of the p2 1 protein of the KRAS gene also negatively affects survival of NSCLC patients. 48 Overexpression of the ERBB2 protein has been associated with significantly shorter survival, although only for those with adenocarcinomas? 9-51The combination of KRAS mutation and ERBB2 overexpression had an additive negative impact on survival in one study of adenocarcinomas. 51 The effect of alterations in the P53 gene on prognosis has been studied extensively. P53 protein expression has been associated with decreased survival in several studies5255; however, three studies were unable to demonstrate a difference in survival between those with Curr Probl Cance~ July/August 1996
273
p53-positive and p53-negative tumors, 5658 and two studies demonstrated that p53 expression was a positive prognostic f a c t o r . 59'G~ Mutations of the P53 gene have been studied as well. Mutations were associated with decreased survival in patients with stages I through IIIA NSCLC in one study, 61 but this association held only for those with advanced disease in another trial, with no significant difference found in survival for those with stage I or II disease32 Mutations in P53 were not a prognostic factor in a third study? 3 The reasons for the inconsistencies in these studies are unclear. It is known that some mutations in P53 are not correlated with positive protein staining and that not all mutant proteins are inactive. The best method of evaluating P53 remains unknown, and the role of the P53 gene in NSCLC awaits determination. RB1 protein expression has been associated with a significantly better prognosis than lack of expression (32 versus 18 months), and combined evaluation of RB1 and p53 proteins was better at predicting survival than evaluating either one. 55 Expression of the BCL2 oncogene has been associated with improved survival of patients with squamous cell cancers in one study 63 and of those with all histologic types in another. 64 Which combination of these molecular and clinical factors is best for predicting relapse and disease progression remains to be determined. A prospective evaluation of several of these markers, including KRAS mutations, P53 mutations, blood group antigens, neuroendocrine markers, and others, is currently being performed in patients with stage II or IIIA NSCLC treated by surgical resection. This and similar prospective studies will help to determine which patients are most at risk for recurrence and may therefore benefit from adjuvant treatment.
1. 2. 3. 4. 5.
6.
274
REFERENCES Zelen M. Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 1973;4:31-42. Stanley KE. Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst 1980;65:25-32. Pater JL, Loeb M. Nonanatomic prognostic factors in carcinoma of the lung: a multivariate analysis. Cancer 1982;50:326-31. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991;9:1618-26. Paesmans M, Sculier JP, Libert P, et al. Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analysis including recursive partitioning and amalgamation algorithms in 1,052 patients. J Clin Oncol 1995;13:1221-30. O'Connell JP, Kris MG, Gralla RJ, et al. Frequency and prognostic importance of pre-treatment clinical characteristics in patients with advanced nonsmall-cell lung cancer treated with combination chemotherapy. J Clin Oncol 1986;4:1604-14. Curr Prabl Cancer, July/August 1996
7. Ruckdeschel JC, Finklestein DM, Ettinger DS, et al. A randomized trial of four,most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol 1986;14:14-22: 8. Sorensen JB, Badsberg JH, Olsen J. Prognostic factors in inoperable adenocarcinoma of the lung: a multivariate regression analysis in 259 patients. Cancer Res 1989;49:5748-54. 9. Luedke DW, Einhorn L, Omura GA, et al. Randomized comparison of two combination regimens versus minimal chemotherapy in non-small cell lung cancer: a Southeastern Cancer Study Group trial. J Clin Oncol 1990;8:88691. 10. Gall M, Eagan RT, Feld R, et al. Prognostic factors in patients with resected stage I NSCLC: a report from the Lung Cancer Study Group. Cancer 1984;54:1802-13. 11. Mountain CE A new international staging system for lung cancer. Chest 1986;89:2255-335. 12. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1988;96:440-7. 13. Lipford EH, Eggleston JC, Lillemoe KD, et al. Prognostic factors in surgically resected limited-stage, nonsmall cell carcinoma of the lung. Am J Surg Pathol 1984;8:357-65. 14. Treasure T, Belcher JR. Prognosis of peripheral lung tumours related to size of the primary. Thorax 1981;36:5-8. 15. Thomas PA, Piantadosi S. Postoperative TIN0 non-small cell lung cancer: squamous versus nonsquamous recurrences. J Thorac Cardiovasc Surg 1987;94:349-54. 16. Mountain C, Lukeman J, Hammer S, et al. Lung cancer classification: the relationship of disease extent and cell type to survival in a clinical trials population. J Surg Oncol 1987;35:147-56. 17. Sorenson JB, Badsberg JH. Prognostic factors in resected stage I and II adenocarcinoma of the lung. J Thorac Cardiovasc Surg 1990;99:218-26. 18. Sorensen JB, Olsen JE. Prognostic implications of histopathologic subtyping in patients with surgically treated stage I or II adenocarcinoma of the lung. J Thorac Cardiovasc Surg 1989;97:245-51. 19. Takise A, Kodama T, Shimosato Y, et al. Histopathologic prognostic factors in adenocarcinomas of the peripheral lung less than 2 cm in diameter. Cancer 1988;61:2083-8. 20. Shields TW. Prognostic significance of parenchymal lymphatic vessel and blood vessel invasion in carcinoma of the lung. Surg Gynecol Obstet 1983;157:185-90. 21. Macchiarini P, Fantanini G, Hardin MJ, et al. Blood vessel invasion by tumor cells predicts recurrence in completely resected TINOM0 non-small cell lung cancer. J Thorac Cardiovasc Surg 1993;106:80-9. 22. Ogawa J, Tsurumi T, Yamada S, et al. Blood vessel invasion and expression of sialyl lewis(X) and proliferating cell nuclear antigen in stage I non-small cell lung cancer. Relation to postoperative recurrence. Cancer 1994;73:117783. 23. Lee JS, Ro J'Y,Sahin AA, et al. Expression of blood-group antigen A: a favorable prognostic factor in non-small cell lung cancer. N Engl J Med 1991;324:108490. 24. Matsumoto H, Muramatsu H, Shimotakahara T, et al. Correlation of expression of ABH blood group carbohydrate antigens with metastatic potential in human lung carcinomas. Cancer 1993;72:75-81. Curr Probl Cancer, July/August 1996
275
25. Miyake M, Take T, Hitomi S, Hakomori S. Correlation of expression of H/ Le(y)/Le[b] antigens with survival in patients with carcinoma of tile lung. N Engl J Med 1992;327:14-8. 26. Ogawa J, Sano A, Koide S, Shohtsu A. Relation between recurrence and expression of proliferating cell nuclear antigen, sialyl lewis(X}, and sialyl lewis(a} in lung cancer. J Thorac Cardiovasc Surg 1994;108:329-36. 27. Volm M, Hahn EW, Mattern J, et al. Five-year follow-up study of independent clinical and flow cytometric prognostic factors for the survival of patients with non-small cell lung carcinoma. Cancer Res 1988;48:2923-8. 28. Zimmerman PV, Bint MH, Hawson GAT, Parsons, PG. Ploidy as a prognostic determinant in surgically treated lung cancer. Lancet 1987;2:530-3. 29. Tirindelli-Danesi D, Teodori L, Maruo E et al. Prognostic significance of flow cytometry in lung cancer: a 5-year study. Cancer 1987;60:844-51. 30. Salvati F, Teodori L, Gagliardi L, et al. DNA flow cytometry of 66 human lung tumors analyzed before treatment: prognostic implications. Chest 1989;96:1092-8. 31. Sahin AA, Ro JA, E1-Naggar AK, et al. Flow cytometric analysis of the DNA content of non-small cell lung cancer: ploidy as a significant prognostic indicator in squamous cell carcinoma of tile lung. Cancer 1990;65:530-7. 32. Isobe H, Miyamoto H, Shimizu T, et al. Prognostic and therapeutic significance of the flow cytometric nuclear DNA content in non-small cell lung cancer. Cancer 1990;65:1391-5. 33. Tanaka I, Masuda R, Furuhata Y, et al. Flow cytometric analysis of the DNA content of adenocarcinoma of the lung, especially for patients with stage 1 disease with long term follow-up. Cancer 1995;75:2461-5. 34. Van Bodegom PC, Baak JPA, Van Galen CS, et al. The percentage of aneuploid cell is significantly correlated with survival in accurately staged patients with stage 1 resected squamous cell lung cancer and long-term follow up. Cancer 1989;63:143-7. 35. Cibas ES, Melamed MR, Zaman MB, Kimmel M. The effect of tumor size and tumor cell DNA content on the survival of patients with stage 1 adenocarcinoma of the lung. Cancer 1989;63:1552-6. 36. Carp NZ, Ellison DD, Brophy PE et al. DNA content in correlation with postsurgical stage in non-small cell lung cancer. Ann Thorac Surg 1992;53:6803. 37. Schmidt RA, Rusch VW, Piantadosi S. A flow cytometric study of non-small cell lung cancer classified as T1N0. Cancer 1992;69:78-85. 38. Rice TW, Bauer TW, Gephart GN, et al. Prognostic significance of flow cytometry in non-small cell lung cancer. J Thorac Cardiovasc Surg 1993;106:210-7. 39. Ishida T, Kaneko S, Akazawa K, et al. Proliferating cell nuclear antigen expression and argyrophilic nucleolar organizer regions as factors influencing prognosis of surgically treated lung cancer patients. Cancer Res 1993;53:5000-3. 40. Pederson H, Grondahl-Hansen 1, Francis D, et al. Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma. Cancer Res 1994;54:120-3. 41. Pedersen H, Brunner N, Francis D, et al. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994;54:4671-5. 42. Nagayama M, Sato S, Hayakawa H, et al. Plasminogen activator inhibitor associated with tumor dissemination. Cancer 1994;73:1398-405. 276
Curr Probl Cancer, July/August 1996
43. Macchiarini P, Fontanini G, Hardin MJ, et al. Relation of neovascularisation to metastasis of non-small cell lung cancer. Lancet 1992;340:145-6. 44. Yamazaki K, Abe S, Takekawa H, eL al. Tumor angiogenesis in human lung adenocarcinoma. Cancer 1994;74:2245-50. 45. Stevenson H, Gazdar AF, Phelps RS. Tumor cell lines established in vitro: an independent prognostic factor for survival in non-small-cell lung cancer. Ann Intern Med 1990;113:764-70. 46. Slebos RJ, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic m a r k e r in a d e n o c a r c i n o m a of the lung. N Engl J Med 1990;323:561-5. 47. Mitsudomi T, Steinberg SM, Oie H, et al. Ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent. Cancer Res 1991;51:4999-5002. 48. Harada M, Dosaka-Akita H, Miyamoto H, et al. Prognostic significance of the expression of ras oncogene product in non-small cell lung cancer. Cancer 1992;69:72-7. 49. Kern JA, Schwartz DA, Nordberg JE, et al. P185(neu) expression in human hmg adenocarcinomas predicts shortened survival. Cancer Res 1990;50: 5184-91. 50. Tateishi M, Ishida T, Mitsodomi T, et al. Prognostic value of c-erb-2 protein expression in human lung adenocarcinoma and squamous cell carcinoma. Eur J Cancer 1991;27:1372-5. 51. Kern J, Slebos R, Top B, et al. C-erbB-2 expression and .codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas. J Clin Invest 1994;93:516-20. 52. Quinlan DC, Davidson AG, Summers CL, et al. Accumulation of p53 protein correlates with a poor prognosis in h u m a n lung cancer. Cancer Res 1992;52:4828-31. 53. Carbone DP, Mitsudomi T, Chiba I, et al. P53 immunostaining positivity is associated with reduced survival and is imperfectly correlated with gene mutations in resected non-small cell lung cancer. A preliminary report of LCSG 871. Chest 1994;106:$377-81. 54. Ebina M, Steinberg SM, Mulshine JL, Linnoila RI. Relationship of p53 overexpression and upregulation of proliferating cell nuclear antigen with the clinical course of non-small cell lung cancer. Cancer Res 1994;54:2496-503. 55. Xu H-J, Quinlan DC, Davidson AG. Altered retinoblastoma protein expression and prognosis in early-stage non-small-cell lung carcinoma. J Natl Caner Inst 1994;86:692-9. 56. McLaren R, Kuzu I, Dunnill M, et al. The relationship of p53 immunostaining to survival in carcinoma of the lung. Br J Cancer 1992;66:735-8. 57. Brambilla E, Gazzeri S, Moro D, et al. Immunohistochemical study of p53 in human lung carcinomas. Am J Pathol 1993;143:199-220. 58. Morkve O, Halvorsen OJ, Skjaerven R, et al. Prognostic significance of p53 protein expression and DNA ploidy in surgically treated non-small cell lung carcinomas. Anticancer Res 1993;13:571-8. 59. Passlick B, Izbicki JR, Riethmuller G, Pantel K. P53 in non-small cell lung cancer. J Natl Cancer Inst 1994;86:801-3. 60. Lee JS, Yoon A, Kalapurakal SK, et al. Expression of p53 oncoprotein in non-small-cell lung cancer: a favorable prognostic factor. J Clin Oncol 1995;13:1893-903. 61. Horio Y, Takahashi T, Kurosishi T, et al. Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res 1993;53:1-4. C u r t P r o b l Cancer, July/August 1996
277
62. Mitsudomi T, Omaya T, Knsano T, et al. Mutation of the p53 gene as a predictor of poor prognosis in patients with non-small cell lung cancer. J Natl Cancer Inst 1993;85:2018-23. 63. Pezzella E Turley H, Kuzu I, et al. Bcl-2 protein in non-small cell lung carcinoma. N Engl J Med 1993;329:690-4. 64. Fontanini G, Vignati S, Bigini D, et al. Bcl-2 protein: a prognostic factor inversely correlated to p53 in non-small-cell lung cancer. Br J Cancer 1995;71:1003-7.
278
Curr Probl Cancer, July/August 1996
Corey J. Langer, MD, is board certified in medical oncology. He graduated from the combined liberal arts and medicine program of Boston University in 1981. He completed his medical residency at the Graduate Hospital of the University of Pennsylvania and h& fellowship in medical oncology and hematology at Presbyterian University of Pennsylvania Medical Center and the American Oncologic Hospital of Fox Chase Cancer Center, and since 1993 he has been codirector of thoracic oncology. He is a Fellow of the American College of Physicians and a member of the American Society of Clinical Oncology, the American Association for Cancer Research, and the International Association for the Study of Lung Cancer. His specific h~terests include combined-modality therapy for locally advanced non-small cell lung carcinoma and the investigation of new systemic agents. Elizabeth Rosvold received her MD degree from the Milton S. Hershey Medical Center in 1985. She completed training in internal medicine and oncology at Temple University and the Fox Chase Cancer Center in Philadelphia. She has been on staff at the Fox Chase Cancer Center since 1992. Her interests are in the genetic predisposition to and treatment of lung cancer. Curr Probl Cancer,
July/August 1996
279