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Targeted Therapies in Metastatic Non-small Cell Lung Cancer

Textbook image of the respiratory system. Credit: Clipart Etc.

Summary by Dr. Vera Hirsh

Lung cancer remains one of the most common cancers worldwide and a leading cause of cancer-related deaths, with an estimated 1.6 million new cases and nearly 1.4 million deaths annually. The majority of patients with non small cell lung cancer (NSCLC) will present with advanced stage disease at diagnosis. But even when diagnosed at an early stage, a large number of patients will eventually experience disease relapse with metastases. Five-year survival rate of lung cancer patients is only 15%. Furthermore, patients with advanced lung cancer may experience debilitating symptoms and toxicities related to their treatments, which can seriously effect their quality of life.

In recent years, the growing knowledge and understanding of the biology of NSCLC, the importance of targeting biomarkers driving the NSCLC carcinogenesis and metastases and the distinction and importance of the histological classification of NSCLC lead to an increased number of options which are now available for the treatment of metastatic NSCLC.

Platinum doublets were the standard treatments for metastatic NSCLC independent of histology. It has changed as we realized that we have certain chemotherapeutic agents, i.e., Pemetrexed, or targeted agents, i.e., Bevacizumab, which give an increased benefit only in non-squamous histology.

We also learned about the importance of EGFR pathways and their activating mutations which drive tumour survival and proliferation. These tumours are very responsive to thyrosin kinase inhibitors of EGFR. Mutations in EGFR domain are most common in never smokers, females, adenocarcinomas, and patients of East Asian origin. Other mutations, i.e., K-RAS, EML 4-ALK, and others are being investigated to choose the optimal treatments for patients, as the options and lines of treatments increase. The understanding of the development of resistance to different therapeutic agents will help us to decide on the sequence i.e., choices for first, second, third, and further lines of treatments. Thus our decisions will not depend only on age, comorbidities, gender, smoking history, racial origin, and performance status of patients but also on tumour characteristics and the toxicity profile of the therapies. The goal of the treatments of advanced NSCLC is only palliative for now, thus quality of life remains a very important factor. Early palliative care, control of symptoms such as pain, nausea, constipation or diarrhea, prevention of cytopenias and bone metastases, enables patients to maintain good performance status and QOL and enables them to receive now available many lines of treatments. Better understanding of prognostic and/or predictive markers also helps our decision regarding the multiple options we can now offer to patients. Thus we can offer a personalized, individualized treatment to our patients with metastatic NSCLC, by which we increase the treatment efficacy, but also decrease its toxicity and improve QOL.

The individualized approach is especially important for maintenance treatments after first-line therapy of patients whose disease did not progress.

More accurate staging with PET/CT scans and MRIs enables us to offer better, more appropriate treatments for patients with NSCLC, earlier, even preventive interventions, some of them being under investigations such as for brain or bone metastases.

The treatments of earlier stages of NSCLC have also evolved over the last years, including different surgical approaches of resectable tumours, prognostic and predictive factors guiding our choices of adjuvant treatments, and who will be the patients benefiting from them.

The accurate staging of NSCLC is especially important for locally advanced, unresectable (stage III) NSCLC. The different doses (fractionation) and schedules of delivered radiotherapy, better definition of radiotherapy field (i.e., with PET scan), concomitant administration of systemic and/or radio-sensitizing agents are now better understood, but much more research still has to be done to deliver an optimal treatment for this stage of NSCLC. It is of the utmost importance to define usefulness of preventive treatments (for brain and bone metastases) in this early stage group of patients on the basis of prognostic and predictive factors.

In order to practice the individualized medicine at every step of our decision, during different stages of NSCLC, and different lines of treatments, we will require adequate tumour tissue to direct our decisions. This will require the education of pneumologists, surgeons, and the interventional radiologists in order to obtain adequate biopsies or adequate surgical specimens. The importance of re-biopsying the tumour after certain line of the treatment to detect possible markers of resistance and making decision for further therapy will have to be explained to the patients.

The management of NSCLC is becoming more complex, but at the same time more effective, driven by our better understanding of NSCLC molecular biology.

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