Targeted therapy of lung cancer
Targeted therapy of lung cancer refers to using agents specifically designed to selectively target molecular pathways responsible for, or that substantially drive, the malignant phenotype of lung cancer cells, and as a consequence of this (relative) selectivity, cause fewer toxic effects on normal cells.
Most previous chemotherapy drugs for cancer were (relatively) nonselective in their activity. Although their exact mechanisms of action were varied and complex, they generally worked by damaging cells undergoing mitosis, which is usually more common in malignant tumors than in most normal tissues. Targeted agents are designed to be selective in their effects by modulating the activity of proteins necessary and essential for oncogenesis and maintenance of cancer, particularly enzymes driving the uncontrolled growth, angiogenesis, invasiveness, and metastasis characteristic of malignant tumors. The increased differential activity usually results in fewer troubling side effects for cancer patients, particularly less nausea, vomiting, and death of cells in the bone marrow and gastrointestinal tract, and increased effectiveness against tumor cells.
Traditional lung cancer classification and treatment
Lung cancer is an extremely heterogeneous family of malignant neoplasms, with well over 50 different histological variants recognized under the 4th revision of the World Health Organization (WHO) typing system, currently the most widely used lung cancer classification scheme. Because these variants have differing genetic, biological, and clinical properties, including response to treatment, correct classification of lung cancer cases are necessary to assure that lung cancer patients receive optimum management.
Approximately 98% of lung cancers are carcinoma, a term describing malignancies derived from transformed cells exhibiting characteristics of epithelium. About 2% of all lung cancers are non-carcinoma (mainly sarcoma, tumors of hematopoietic origin, or germ cell tumors. These forms of lung cancer are usually treated differently from carcinomas. Because of the ubiquity of lung carcinomas, however, the term "lung cancer" generally refers to carcinomas in everyday clinical practice.
Despite the large number of histological variants of lung carcinoma, oncologists have long tended to favor a dichotomous division into small cell and non-small cell forms, based on differences in clinical behavior and response to treatment. Most small cell lung carcinomas (SCLC's) metastasize to distant organs early on in their course, rendering surgery ineffective in curing the cancer. In contrast, non-small cell lung carcinomas (NSCLC's) are more likely to remain localized to the thorax during development, and are thus more amenable to cure using radical surgical resection. Additionally, SCLC's are typically much more sensitive to chemotherapy and/or radiation therapy than are NSCLC's. Therefore, current traditional treatment guidelines and standards of care recommend, when possible, the use of surgery for NSCLC, and chemotherapy with or without radiotherapy for SCLC.
Targeted lung cancer agents in current use
- Inhibitors of Epidermal growth factor receptor (EGFR)
- Inhibitors of vascular endothelial growth factor (VEGF)
- Inhibitor of EML4-ALK
Non-small cell lung cancer
While there have been no randomized clinical trials of targeted agents in combined small-cell lung carcinoma (c-SCLC), some small case series suggest that some may be useful in c-SCLC. Many targeted agents appear more active in certain NSCLC variants. Given that c-SCLC contains components of NSCLC, and that the chemoradioresistance of NSCLC components impact the effectiveness of c-SCLC treatment, these agents may permit the design of more rational treatment regimens for c-SCLC.
EGFR-TKI's have been found to be active against variants exhibiting certain mutations in the EGFR gene. While EGFR mutations are very rare (<5%) in "pure" SCLC, they are considerably more common (about 15%-20%) in c-SCLC, particularly in non-smoking females whose c-SCLC tumors contain an adenocarcinoma component. These patients are much more likely to have classical EGFR mutations in the small cell component of their tumors as well, and their tumors seem to be more likely to respond to treatment with EGFR-TKI's. EGFR-targeted agents appear particularly effective in papillary adenocarcinoma, non-mucinous bronchioloalveolar carcinoma, and adenocarcinoma with mixed subtypes.
Pemetrexed, although not classified as a targeted agent, has been shown to have improve survival in non-squamous cell NSCLC, and is the first drug to reveal differential survival benefit in large cell lung carcinoma.
C-SCLC appear to express female hormone (i.e. estrogen and/or progesterone) receptors in a high (50%-67%) proportion of cases, similar to breast carcinomas However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC.
Several studies have shown that EGFR-TKI's are particularly active in papillary and non-mucinous bronchioloalveolar carcinoma variants of adenocarcinoma.
Small-cell lung cancer
To date, most clinical trials of newer targeted agents - both alone and in combination with previously tested treatment regimens - have either been less effective, or no more effective, than older platinum-based doublets in SCLC.
Combined small-cell lung cancer
The term "combined small-cell lung carcinoma" (c-SCLC) refers to a multiphasic lung cancer that contains a component of SCLC admixed with one (or more) components of NSCLC. It is currently considered a variant of SCLC under the current World Health Organization lung tumor classification scheme. While the true incidence of c-SCLC is unknown, case series suggest that they may account for as many as 25% to 30% of all cases of SCLC, and for 4% to 6% of all lung cancer cases.
To date, most clinical trials of targeted agents, alone and in combination with previously tested treatment regimens, have either been ineffective in SCLC or no more effective than standard platinum-based doublets.
While there have been no randomized clinical trials of targeted agents in c-SCLC, some small case series suggest that some agents currently in use may be beneficial in c-SCLC. Many targeted agents appear more active in certain NSCLC variants. Given that c-SCLC contains components of NSCLC, and that the chemoradioresistance of NSCLC components impact the effectiveness of c-SCLC treatment, these agents may permit the design of more rational treatment regimens for c-SCLC.
- Roggli VL, Vollmer RT, Greenberg SD, McGavran MH, Spjut HJ, Yesner R (June 1985). "Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases". Human Pathology. 16 (6): 569–79. doi:10.1016/S0046-8177(85)80106-4. PMID 2987102.
- Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press: Lyon 2004.
- Rossi G, Marchioni A, Sartori1 G, Longo L, Piccinini S, Cavazza A. Histotype in non-small cell lung cancer therapy and staging: The emerging role of an old and underrated factor. Curr Resp Med Rev 2007; 3: 69-77.
- Vincent MD (August 2009). "Optimizing the management of advanced non-small-cell lung cancer: a personal view". Current Oncology. 16 (4): 9–21. doi:10.3747/co.v16i4.465. PMC . PMID 19672420.
- Travis WD, Travis LB, Devesa SS (January 1995). "Lung cancer". Cancer. 75 (1 Suppl): 191–202. doi:10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. PMID 8000996.
- Pisters KM, Evans WK, Azzoli CG, Kris MG, Smith CA, Desch CE, Somerfield MR, Brouwers MC, Darling G, Ellis PM, Gaspar LE, Pass HI, Spigel DR, Strawn JR, Ung YC, Shepherd FA (December 2007). "Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline". Journal of Clinical Oncology. 25 (34): 5506–18. doi:10.1200/JCO.2007.14.1226. PMID 17954710.
- Simon GR, Turrisi A (September 2007). "Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition)". Chest. 132 (3 Suppl): 324S–339S. doi:10.1378/chest.07-1385. PMID 17873178.
- Dempke WC, Suto T, Reck M (March 2010). "Targeted therapies for non-small cell lung cancer". Lung Cancer (Amsterdam, Netherlands). 67 (3): 257–74. doi:10.1016/j.lungcan.2009.10.012. PMID 19914732.
- Ansari J, Palmer DH, Rea DW, Hussain SA (June 2009). "Role of tyrosine kinase inhibitors in lung cancer". Anti-Cancer Agents in Medicinal Chemistry. 9 (5): 569–75. doi:10.2174/187152009788451879. PMID 19519298.
- Yang K, Wang YJ, Chen XR, Chen HN (2010). "Effectiveness and safety of bevacizumab for unresectable non-small-cell lung cancer: a meta-analysis". Clinical Drug Investigation. 30 (4): 229–41. doi:10.2165/11532260-000000000-00000. PMID 20225906.
- "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. Retrieved 2010-06-07.
- Richard Pazdur>publisher=FDA's Division of Oncology Drug Products. "FDA Approval for Crizotinib".
- Sasaki T, Rodig SJ, Chirieac LR, Jänne PA (July 2010). "The biology and treatment of EML4-ALK non-small cell lung cancer". Eur. J. Cancer. 46 (10): 1773–80. doi:10.1016/j.ejca.2010.04.002. PMC . PMID 20418096.
- Spiro SG, Tanner NT, Silvestri GA, Janes SM, Lim E, Vansteenkiste JF, Pirker R (January 2010). "Lung cancer: progress in diagnosis, staging and therapy". Respirology (Carlton, Vic.). 15 (1): 44–50. doi:10.1111/j.1440-1843.2009.01674.x. PMID 20199634.
- Stahel RA (July 2007). "Adenocarcinoma, a molecular perspective". Annals of Oncology. 18 (Suppl 9): ix147–9. doi:10.1093/annonc/mdm310. PMID 17631568.
- Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, Mahmood U, Mitchell A, Sun Y, Al-Hashem R, Chirieac LR, Padera R, Bronson RT, Kim W, Jänne PA, Shapiro GI, Tenen D, Johnson BE, Weissleder R, Sharpless NE, Wong KK (June 2006). "The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies". Cancer Cell. 9 (6): 485–95. doi:10.1016/j.ccr.2006.04.022. PMID 16730237.
- Shigematsu H, Gazdar AF (January 2006). "Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers". International Journal of Cancer. 118 (2): 257–62. doi:10.1002/ijc.21496. PMID 16231326.
- Riely GJ, Politi KA, Miller VA, Pao W (December 2006). "Update on epidermal growth factor receptor mutations in non-small cell lung cancer". Clinical Cancer Research. 12 (24): 7232–41. doi:10.1158/1078-0432.CCR-06-0658. PMID 17189394.
- Tatematsu A, Shimizu J, Murakami Y, Horio Y, Nakamura S, Hida T, Mitsudomi T, Yatabe Y (October 2008). "Epidermal growth factor receptor mutations in small cell lung cancer". Clinical Cancer Research. 14 (19): 6092–6. doi:10.1158/1078-0432.CCR-08-0332. PMID 18829487.
- Fukui T, Tsuta K, Furuta K, Watanabe S, Asamura H, Ohe Y, Maeshima AM, Shibata T, Masuda N, Matsuno Y (November 2007). "Epidermal growth factor receptor mutation status and clinicopathological features of combined small cell carcinoma with adenocarcinoma of the lung". Cancer Science. 98 (11): 1714–9. doi:10.1111/j.1349-7006.2007.00600.x. PMID 17784875.
- Zakowski MF, Ladanyi M, Kris MG (July 2006). "EGFR mutations in small-cell lung cancers in patients who have never smoked". The New England Journal of Medicine. 355 (2): 213–5. doi:10.1056/NEJMc053610. PMID 16837691.
- Okamoto I, Araki J, Suto R, Shimada M, Nakagawa K, Fukuoka M (June 2006). "EGFR mutation in gefitinib-responsive small-cell lung cancer". Annals of Oncology. 17 (6): 1028–9. doi:10.1093/annonc/mdj114. PMID 16357019.
- De Oliveira Duarte Achcar R, Nikiforova MN, Yousem SA (May 2009). "Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile". American Journal of Clinical Pathology. 131 (5): 694–700. doi:10.1309/AJCPBS85VJEOBPDO. PMID 19369630.
- Motoi N, Szoke J, Riely GJ, Seshan VE, Kris MG, Rusch VW, Gerald WL, Travis WD (June 2008). "Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis". The American Journal of Surgical Pathology. 32 (6): 810–27. doi:10.1097/PAS.0b013e31815cb162. PMID 18391747.
- Zakowski MF, Hussain S, Pao W, Ladanyi M, Ginsberg MS, Heelan R, Miller VA, Rusch VW, Kris MG (March 2009). "Morphologic features of adenocarcinoma of the lung predictive of response to the epidermal growth factor receptor kinase inhibitors erlotinib and gefitinib". Archives of Pathology & Laboratory Medicine. 133 (3): 470–7. doi:10.1043/1543-2165-133.3.470. PMID 19260752.
- Horn L, Dahlberg SE, Sandler AB, Dowlati A, Moore DF, Murren JR, Schiller JH (December 2009). "Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive-stage small-cell lung cancer: Eastern Cooperative Oncology Group Study E3501". Journal of Clinical Oncology. 27 (35): 6006–11. doi:10.1200/JCO.2009.23.7545. PMC . PMID 19826110.
- Zinner RG, Novello S, Peng G, Herbst R, Obasaju C, Scagliotti G (March 2010). "Comparison of patient outcomes according to histology among pemetrexed-treated patients with stage IIIB/IV non-small-cell lung cancer in two phase II trials". Clinical Lung Cancer. 11 (2): 126–31. doi:10.3816/CLC.2010.n.017. PMID 20199979.
- Sica G, Wagner PL, Altorki N, Port J, Lee PC, Vazquez MF, Saqi A (December 2008). "Immunohistochemical expression of estrogen and progesterone receptors in primary pulmonary neuroendocrine tumors". Archives of Pathology & Laboratory Medicine. 132 (12): 1889–95. doi:10.1043/1543-2165-132.12.1889. PMID 19061285.
- Rossi A, Galetta D, Gridelli C (2009). "Biological prognostic and predictive factors in lung cancer". Oncology. 77 Suppl 1: 90–6. doi:10.1159/000258500. PMID 20130436.
- Rossi A, Maione P, Palazzolo G, Sacco PC, Ferrara ML, Falanga M, Gridelli C (September 2008). "New targeted therapies and small-cell lung cancer". Clinical Lung Cancer. 9 (5): 271–9. doi:10.3816/CLC.2008.n.042. PMID 18824449.
- Jalal S, Ansari R, Govindan R, Bhatia S, Bruetman D, Fisher W, Masters G, White A, Stover D, Yu M, Hanna N (January 2009). "Pemetrexed in second line and beyond small cell lung cancer: a Hoosier Oncology Group phase II study". Journal of Thoracic Oncology. 4 (1): 93–6. doi:10.1097/JTO.0b013e31818de1e6. PMID 19096313.
- Chee CE, Jett JR, Bernath AM, Foster NR, Nelson GD, Molina J, Nikcevich DA, Steen PD, Flynn PJ, Rowland KM (May 2010). "Phase 2 trial of pemetrexed disodium and carboplatin in previously untreated extensive-stage small cell lung cancer, N0423". Cancer. 116 (10): 2382–9. doi:10.1002/cncr.24967. PMID 20209614.
- Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, Blakely J, Serwatowski P, Karaseva NA, Ciuleanu T, Jassem J, Dediu M, Hong S, Visseren-Grul C, Hanauske AR, Obasaju CK, Guba SC, Thatcher N (October 2009). "Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer". Journal of Clinical Oncology. 27 (28): 4787–92. doi:10.1200/JCO.2009.23.1548. PMID 19720897.
- Nicholson SA, Beasley MB, Brambilla E, Hasleton PS, Colby TV, Sheppard MN, Falk R, Travis WD (September 2002). "Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens". The American Journal of Surgical Pathology. 26 (9): 1184–97. doi:10.1097/00000478-200209000-00009. PMID 12218575.
- "Cancer Facts & Figures 2009". American Cancer Society.
- "NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer" (PDF). National Comprehensive Cancer Network. V.1.2010.