Targeted therapy of lung cancer

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Targeted therapy of lung cancer
Specialty oncology

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.

Contents

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, [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]

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 ]

Related Research Articles

<span class="mw-page-title-main">Gefitinib</span> Drug used in fighting breast, lung, and other cancers

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 target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.

<span class="mw-page-title-main">Erlotinib</span> EGFR inhibitor for treatment of non-small-cell lung cancer

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) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken by mouth.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Non-small-cell lung cancer</span> Any type of epithelial lung cancer other than small-cell lung carcinoma

Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small-cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both preoperatively and postoperatively.

<span class="mw-page-title-main">KRAS</span> Protein-coding gene in humans

KRAS is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). It is called KRAS because it was first identified as a viral oncogene in the KirstenRAt Sarcoma virus. The oncogene identified was derived from a cellular genome, so KRAS, when found in a cellular genome, is called a proto-oncogene.

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<span class="mw-page-title-main">Adenocarcinoma in situ of the lung</span> Medical condition

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 growth pattern. This small solitary tumor exhibits pure alveolar distribution and lacks any invasion of the surrounding normal lung. If completely removed by surgery, the prognosis is excellent with up to 100% 5-year survival.

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<span class="mw-page-title-main">Afatinib</span> Chemical compound

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<span class="mw-page-title-main">Combined small-cell lung carcinoma</span> Medical condition

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<span class="mw-page-title-main">Adenocarcinoma of the lung</span> Medical condition

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<span class="mw-page-title-main">Crizotinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

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 and ROS1 inhibitor.

<span class="mw-page-title-main">ALK inhibitor</span>

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<span class="mw-page-title-main">Squamous-cell carcinoma of the lung</span> Medical condition

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