Targeted therapy of lung cancer

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.

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:

• Inhibitors of Epidermal growth factor receptor (EGFR)
  • tyrosine kinase inhibitors (TKI's):
    • erlotinib (Tarceva)
    • gefitinib (Iressa)
    • osimertinib (Tagrisso)
  • monoclonal antibody against EGFR:
    • cetuximab (Erbitux)
• Inhibitors of vascular endothelial growth factor (VEGF)
  • bevacizumab (Avastin)
• 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, found in some relatively young, never or light smokers with adenocarcinoma.

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.

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 ( non-mucinous bronchioloalveolar carcinoma, and adenocarcinoma with mixed subtypes.

Bevacizumab may improve some measures of survival in both SCLC and non-squamous cell variants of NSCLC.

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.

Bevacizumab is contraindicated in squamous cell carcinoma and its variants.

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.

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.

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

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.

References

References

1. (June 1985). "Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases". [[Human Pathology]].
2. 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. Rossi G, Marchioni A, Sartori1 G, Longo L, Piccinini S, Cavazza A. [http://biblioteca.asmn.re.it/pubblicazioni/Current%20Respiratory%20Medicine%20Reviews%202007.pdf 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. Vincent MD. (August 2009). "Optimizing the management of advanced non-small-cell lung cancer: a personal view". [[Current Oncology]].
5. (January 1995). "Lung cancer". [[Cancer (journal).
6. (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]].
7. (March 2010). "Targeted therapies for non-small cell lung cancer". [[Lung Cancer (Amsterdam, Netherlands)]].
8. (June 2009). "Role of tyrosine kinase inhibitors in lung cancer". [[Anti-Cancer Agents in Medicinal Chemistry]].
9. "Tarceva® (Erlotinib) for MNSCLC & Advanced-Stage Pancreatic Cancer".
10. "AstraZeneca - Research-Based BioPharmaceutical Company".
11. "Metastatic Colorectal Cancer and Head & Neck Cancer Treatments | ERBITUX (Cetuximab)".
12. (2010). "Effectiveness and safety of bevacizumab for unresectable non-small-cell lung cancer: a meta-analysis". [[Clinical Drug Investigation]].
13. "Patient Home Page, from Avastin.com".
14. (2010-06-05). "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday.
15. Richard Pazdur>publisher=FDA's Division of Oncology Drug Products. "FDA Approval for Crizotinib".
16. (July 2010). "The biology and treatment of EML4-ALK non-small cell lung cancer". Eur. J. Cancer.
17. (January 2010). "Lung cancer: progress in diagnosis, staging and therapy". [[Respirology]].
18. Stahel RA. (July 2007). "Adenocarcinoma, a molecular perspective". [[Annals of Oncology]].
19. (June 2006). "The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies". [[Cancer Cell (journal).
20. (January 2006). "Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers". [[International Journal of Cancer]].
21. (December 2006). "Update on epidermal growth factor receptor mutations in non-small cell lung cancer". [[Clinical Cancer Research]].
22. (October 2008). "Epidermal growth factor receptor mutations in small cell lung cancer". [[Clinical Cancer Research]].
23. (November 2007). "Epidermal growth factor receptor mutation status and clinicopathological features of combined small cell carcinoma with adenocarcinoma of the lung". [[Cancer Science]].
24. (July 2006). "EGFR mutations in small-cell lung cancers in patients who have never smoked". [[The New England Journal of Medicine]].
25. (June 2006). "EGFR mutation in gefitinib-responsive small-cell lung cancer". [[Annals of Oncology]].
26. (May 2009). "Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile". [[American Journal of Clinical Pathology]].
27. (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]].
28. (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]].
29. (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]].
30. (December 2008). "Immunohistochemical expression of estrogen and progesterone receptors in primary pulmonary neuroendocrine tumors". [[Archives of Pathology & Laboratory Medicine]].
31. (September 2008). "New targeted therapies and small-cell lung cancer". [[Clinical Lung Cancer]].
32. (January 2009). "Pemetrexed in second line and beyond small cell lung cancer: a Hoosier Oncology Group phase II study". [[Journal of Thoracic Oncology]].
33. (May 2010). "Phase 2 trial of pemetrexed disodium and carboplatin in previously untreated extensive-stage small cell lung cancer, N0423". [[Cancer (journal).
34. (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]].
35. (September 2002). "Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens". [[The American Journal of Surgical Pathology]].
36. "Cancer Facts & Figures 2009". American Cancer Society.
37. "NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer". National Comprehensive Cancer Network.