Targeted therapy of lung cancer

Specialty| oncology

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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.

## Contents

* 1 Traditional lung cancer classification and treatment
* 2 Agents in current use
* 3 Non-small cell lung cancer
* 4 Small-cell lung cancer
* 5 Combined small-cell lung cancer
* 6 References
* 7 External links

## Traditional lung cancer classification and treatment

Lung cancer is an extremely heterogeneous family of malignant neoplasms,[1] 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.[2] 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.[3][4]

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.[5] 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.[citation needed]

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.[6][7]

## Agents in current use

While a very large number of agents targeting various molecular pathways are being developed and tested, the main classes and agents that are now being used in lung cancer treatment include:[8]

* Inhibitors of Epidermal growth factor receptor (EGFR)
* tyrosine kinase inhibitors (TKI's):[9]
* erlotinib (Tarceva)[10][unreliable medical source?]
* gefitinib (Iressa)[11][unreliable medical source?]
* osimertinib (Tagrisso)
* monoclonal antibody against EGFR:
* cetuximab (Erbitux)[12][unreliable medical source?]
* Inhibitors of vascular endothelial growth factor (VEGF)[13]
* bevacizumab (Avastin)[14][unreliable medical source?]
* Inhibitor of EML4-ALK
* crizotinib shows benefit in a subset of non-small cell lung cancer that is characterized by the EML4-ALK fusion oncogene,[15][16] found in some relatively young, never or light smokers with adenocarcinoma.[17]

## Non-small cell lung cancer

Targeted agents are beginning to permit the design of more rational treatment regimens for non-small cell lung cancer (NSCLC), which comprises about 80% to 85% of all lung cancers.[3][4][18]

While there have been no randomized clinical trials of targeted agents in combined small-cell lung carcinoma (c-SCLC),[citation needed] 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.[3][4][18]

EGFR-TKI's have been found to be active against variants exhibiting certain mutations in the EGFR gene.[19][20][21][22] While EGFR mutations are very rare (<5%) in "pure" SCLC, they are considerably more common (about 15–20%) in c-SCLC,[23][24] 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.[24][25][26] EGFR-targeted agents appear particularly effective in papillary adenocarcinoma,[27][28] non-mucinous bronchioloalveolar carcinoma,[29] and adenocarcinoma with mixed subtypes.[28]

Bevacizumab may improve some measures of survival in both SCLC[30] and non-squamous cell variants of NSCLC.[4][18][unreliable medical source?]

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.[4][31]

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[32] 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.[citation needed]

Bevacizumab is contraindicated in squamous cell carcinoma and its variants.[citation needed]

Pemetrexed has been approved for treating non-squamous lung carcinomas, and is the first drug that has been specifically shown to improve survival in large cell carcinoma.[citation needed]

## 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.[33][34][35][36][37][excessive citations]

## 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.[2] 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.[38][39]

Traditionally, c-SCLC have been treated according to guidelines established for "pure" SCLC.[7][40]

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.[citation needed]

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.[citation needed]

## References

1. ↑ "Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases". Human Pathology 16 (6): 569–79. June 1985. doi:10.1016/S0046-8177(85)80106-4. PMID 2987102.
2. ↑ 2.0 2.1 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.
3. ↑ 3.0 3.1 3.2 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 Respir Med Rev 2007; 3: 69-77.
4. ↑ 4.0 4.1 4.2 4.3 4.4 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. PMID 19672420.
5. ↑ "Lung cancer". Cancer 75 (1 Suppl): 191–202. January 1995. doi:10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. PMID 8000996.
6. ↑ "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. December 2007. doi:10.1200/JCO.2007.14.1226. PMID 17954710.
7. ↑ 7.0 7.1 "Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition)". Chest 132 (3 Suppl): 324S–339S. September 2007. doi:10.1378/chest.07-1385. PMID 17873178.
8. ↑ "Targeted therapies for non-small cell lung cancer". Lung Cancer (Amsterdam, Netherlands) 67 (3): 257–74. March 2010. doi:10.1016/j.lungcan.2009.10.012. PMID 19914732.
9. ↑ "Role of tyrosine kinase inhibitors in lung cancer". Anti-Cancer Agents in Medicinal Chemistry 9 (5): 569–75. June 2009. doi:10.2174/187152009788451879. PMID 19519298.
10. ↑ "Tarceva® (Erlotinib) for MNSCLC & Advanced-Stage Pancreatic Cancer". http://www.tarceva.com.
11. ↑ "AstraZeneca - Research-Based BioPharmaceutical Company". http://www.iressa.com/.
12. ↑ "Metastatic Colorectal Cancer and Head & Neck Cancer Treatments | ERBITUX (Cetuximab)". http://www.erbitux.com.
13. ↑ "Effectiveness and safety of bevacizumab for unresectable non-small-cell lung cancer: a meta-analysis". Clinical Drug Investigation 30 (4): 229–41. 2010. doi:10.2165/11532260-000000000-00000. PMID 20225906.
14. ↑ "Patient Home Page, from Avastin.com". http://www.avastin.com/avastin/patient/index.m.
15. ↑ "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. http://www.hemonctoday.com/article.aspx?rid=65251.
16. ↑ Richard Pazdur>publisher=FDA's Division of Oncology Drug Products. "FDA Approval for Crizotinib". http://www.cancer.gov/cancertopics/druginfo/fda-crizotinib.
17. ↑ "The biology and treatment of EML4-ALK non-small cell lung cancer". Eur. J. Cancer 46 (10): 1773–80. July 2010. doi:10.1016/j.ejca.2010.04.002. PMID 20418096.
18. ↑ 18.0 18.1 18.2 "Lung cancer: progress in diagnosis, staging and therapy". Respirology 15 (1): 44–50. January 2010. doi:10.1111/j.1440-1843.2009.01674.x. PMID 20199634.
19. ↑ Stahel RA (July 2007). "Adenocarcinoma, a molecular perspective". Annals of Oncology 18 (Suppl 9): ix147–9. doi:10.1093/annonc/mdm310. PMID 17631568.
20. ↑ "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. June 2006. doi:10.1016/j.ccr.2006.04.022. PMID 16730237.
21. ↑ "Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers". International Journal of Cancer 118 (2): 257–62. January 2006. doi:10.1002/ijc.21496. PMID 16231326.
22. ↑ "Update on epidermal growth factor receptor mutations in non-small cell lung cancer". Clinical Cancer Research 12 (24): 7232–41. December 2006. doi:10.1158/1078-0432.CCR-06-0658. PMID 17189394.
23. ↑ "Epidermal growth factor receptor mutations in small cell lung cancer". Clinical Cancer Research 14 (19): 6092–6. October 2008. doi:10.1158/1078-0432.CCR-08-0332. PMID 18829487.
24. ↑ 24.0 24.1 "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. November 2007. doi:10.1111/j.1349-7006.2007.00600.x. PMID 17784875.
25. ↑ "EGFR mutations in small-cell lung cancers in patients who have never smoked". The New England Journal of Medicine 355 (2): 213–5. July 2006. doi:10.1056/NEJMc053610. PMID 16837691.
26. ↑ "EGFR mutation in gefitinib-responsive small-cell lung cancer". Annals of Oncology 17 (6): 1028–9. June 2006. doi:10.1093/annonc/mdj114. PMID 16357019.
27. ↑ "Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile". American Journal of Clinical Pathology 131 (5): 694–700. May 2009. doi:10.1309/AJCPBS85VJEOBPDO. PMID 19369630.
28. ↑ 28.0 28.1 "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. June 2008. doi:10.1097/PAS.0b013e31815cb162. PMID 18391747.
29. ↑ "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. March 2009. doi:10.5858/133.3.470. PMID 19260752.
30. ↑ "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. December 2009. doi:10.1200/JCO.2009.23.7545. PMID 19826110.
31. ↑ "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. March 2010. doi:10.3816/CLC.2010.n.017. PMID 20199979.
32. ↑ "Immunohistochemical expression of estrogen and progesterone receptors in primary pulmonary neuroendocrine tumors". Archives of Pathology & Laboratory Medicine 132 (12): 1889–95. December 2008. doi:10.5858/132.12.1889. PMID 19061285.
33. ↑ "Biological prognostic and predictive factors in lung cancer". Oncology 77 (Suppl 1): 90–6. 2009. doi:10.1159/000258500. PMID 20130436.
34. ↑ "New targeted therapies and small-cell lung cancer". Clinical Lung Cancer 9 (5): 271–9. September 2008. doi:10.3816/CLC.2008.n.042. PMID 18824449.
35. ↑ "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. January 2009. doi:10.1097/JTO.0b013e31818de1e6. PMID 19096313.
36. ↑ "Phase 2 trial of pemetrexed disodium and carboplatin in previously untreated extensive-stage small cell lung cancer, N0423". Cancer 116 (10): 2382–9. May 2010. doi:10.1002/cncr.24967. PMID 20209614.
37. ↑ "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. October 2009. doi:10.1200/JCO.2009.23.1548. PMID 19720897.
38. ↑ "Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens". The American Journal of Surgical Pathology 26 (9): 1184–97. September 2002. doi:10.1097/00000478-200209000-00009. PMID 12218575.
39. ↑ "Cancer Facts & Figures 2009". American Cancer Society. http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2009.
40. ↑ "NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer". National Comprehensive Cancer Network. http://www.nccn.org/professionals/physician_gls/PDF/sclc.pdf.

## External links

* World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart.
* Lung Cancer page at the National Cancer Institute.

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