Targeted therapy of lung cancer refers to using agents specifically designed to selectively target molecular pathways responsible for, or that substantially drive, the
malignant
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
of
lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...
cells, and as a consequence of this (relative) selectivity, cause fewer
toxic
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
effects on normal cells.
Most previous
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
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
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
and maintenance of cancer, particularly
enzymes driving the uncontrolled growth, angiogenesis, invasiveness, and
metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then ...
characteristic of malignant tumors. The increased differential activity usually results in fewer troubling
side effects
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
for cancer patients, particularly less
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
, 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
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
,
with well over 50 different
histological
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
variants recognized under the 4th revision of the
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
(WHO) typing system, currently the most widely used lung cancer classification scheme.
[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.] 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.
[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.
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
A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal ( connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sar ...
, tumors of
hematopoietic origin, or
germ cell
Germ or germs may refer to:
Science
* Germ (microorganism), an informal word for a pathogen
* Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually
* Germ layer, a primary layer of cells that forms during emb ...
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
The thorax or chest is a part of the anatomy of humans, mammals, and other tetrapod animals located between the neck and the abdomen. In insects, crustaceans, and the extinct trilobites, the thorax is one of the three main divisions of the cre ...
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
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor rece ...
(EGFR)
**
tyrosine kinase inhibitors
A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosp ...
(TKI's):
***
erlotinib
Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) â ...
(Tarceva)
***
gefitinib
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targ ...
(Iressa)
***
osimertinib
Osimertinib, sold under the brand name Tagrisso, is a medication used to treat non-small-cell lung carcinomas with specific mutations. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor.
The most common side eff ...
(Tagrisso)
**monoclonal antibody against EGFR:
***
cetuximab
Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal a ...
(Erbitux)
*Inhibitors of
vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(VEGF)
**
bevacizumab (Avastin)
* Inhibitor of
EML4-ALK
**
crizotinib
Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). It acts as an ALK ( anaplastic lymphoma kinase) and ROS1 ( c-ros oncogene 1) inhibitor.
...
shows benefit in a subset of non-small cell lung cancer that is characterized by the
EML4-ALK fusion
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. ,
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
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...
(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
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
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
Adenocarcinoma in situ (AIS) of the lung —previously included in the category of "bronchioloalveolar carcinoma" (BAC)—is a subtype of lung adenocarcinoma. It tends to arise in the distal bronchioles or alveoli and is defined by a non-invasive ...
,
and
adenocarcinoma with mixed subtypes.
may improve some measures of survival in both SCLC
and non-squamous cell variants of NSCLC.
Pemetrexed
Pemetrexed, sold under the brand name Alimta among others, is a chemotherapy medication for the treatment of pleural mesothelioma and non-small cell lung cancer (NSCLC)..
It is available as a generic medication.
Medical use
In February 2004 ...
, 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 medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...
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
Large-cell carcinoma (LCC, LCLC) is a heterogeneous group of undifferentiated malignant neoplasms that lack the cytologic and architectural features of small cell carcinoma and glandular or squamous differentiation. LCC is categorized as a type of ...
.
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
External links
World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lung Cancer pageat the National Cancer Institute.
{{DEFAULTSORT:Targeted Therapy Of Lung Cancer
Lung cancer
Cancer treatments
Lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...