Treatment of Non-Small Cell Lung Cancer

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In the early stages of NSCLC, surgical removal of the tumour offers a potential cure. Treatment plans at this stage may also include radiation therapy and chemotherapy; these are given before or after surgery to make the operation easier or to prevent the cancer from coming back. Treatment plans for advanced stages of cancer can also include a combination of chemotherapy, radiation therapy, and surgery; or, just one or two of these treatments may be used. The treatment of metastatic cancers usually includes chemotherapy, radiation therapy, and, in select cases, targeted therapy and immunotherapy.


Surgery 

The size and location of the tumour, how well the lungs and heart function, and your general health will dictate if surgery is possible and, if so, the type of surgery. When surgery can be performed in early stages of cancer, it can potentially cure the cancer. More extensive operations (for example, removing the entire lobe rather than a smaller portion of the lobe with the tumour) may have a better chance of curing the cancer. Nearby lymph nodes or tissue samples may also be removed along with the lung tumour to more accurately determine the stage of the cancer. In certain cases, treating the tumour with radiation or chemotherapy drugs before surgery can shrink it and make operating on it easier. After surgery, you may be given chemotherapy or radiation to kill any remaining cancer cells. Surgery is used less frequently to treat locally advanced cancer, and rarely for metastatic cancers.

Types of surgery 

The procedures described below are carried out to remove lung tumours, as well as nearby lymph nodes. Other operations may be performed to confirm a diagnosis, or to relieve symptoms such as shortness of breath caused by an airway blockage or by fluid pressing on the lung.
A wedge resection or segmentectomy is the removal of a part of a lobe. This procedure is performed if the tumour is very small and has not spread, or if removing a larger portion of the lung is not advisable based on PFTs and other evaluations.
A lobectomy is the removal of a complete lobe of the lung. You might recall that the right lung has three lobes and the left lung has two. A bilobectomy is the removal of two of the three lobes of the right lung. If the tumour has grown close to the centre of the chest or affects all lobes of a lung, then a pneumonectomy (or pneumectomy) is done to remove the entire lung.
A sleeve resection removes a tumour from the large airways. If you think of the airway as a shirtsleeve with a spot on it, then this procedure removes the spot by cutting across the sleeve above and below the spot, and sews the cut ends back together. Because this procedure removes only an entire lobe and a part of the bronchus, it preserves more lung function compared to a pneumonectomy.
If the tumour has grown into the diaphragm or chest wall, some structures in the chest may be removed as a whole (or en bloc).
To ensure that all the cancer was removed, the surgeon will also remove some healthy-looking tissue around the edge of the tumour. A pathologist will examine these edges, or margins, to check if they contain any cancer cells. If there are clean, clear, or negative margins, usually no additional surgery is needed. If the margins are close or positive, then you may need more surgery or radiation and/or chemotherapy.

Video-Assisted Thoracic Surgery

Removal of tumours by video-assisted thoracic (or thoracoscopic) surgery (VATS) is less invasive than a thoracotomy. There is usually less pain after the operation and a shorter recovery time. VATS is performed under general anesthetic. The surgeon will insert a thoracoscope through a small incision in the chest wall (smaller than a thoracotomy incision). The thoracoscope has a video camera that lets the surgeon see inside the chest cavity. Sometimes multiple small incisions are made to insert other small surgical tools. Lobectomies and segmentectomies, preferably for tumours growing near the surface and outer edges of the lung, can be performed with this technique. 

Robotic-Assisted Thoracic Surgery

Another minimally invasive surgical technique is robotic-assisted thoracic surgery (RATS). With this technique, the surgeon performs the operation by controlling robotic arms equipped with surgical tools. Robotic surgery is commonly used to carry out lobectomies to treat stage I NSCLC. However, doctors may also use this technique to perform other types of chest surgery and treat more advanced cancers.


Radiation Therapy 

Radiation is the main treatment for early stages of cancer that cannot be surgically removed for reasons such as proximity of the tumour to vital organs, poor general health, or decreased lung or heart function. Chemotherapy may be used at the same time as radiation therapy or afterwards to kill any remaining cancer cells.
Radiation therapy uses high-energy beams of radiation to cause damage to the DNA of cancer cells. This sort of damage either kills the cells or keeps them from making new cancer cells.
Radiation can be used to treat tumours within the lung or in other parts of the body. It can be used before surgery to shrink your tumour and make operating on it easier, or after surgery to improve your chances of recovery by killing any cancer cells that might remain. 
Your oncologist may also recommend radiation if you have other medical problems that make surgery too risky. Radiation treatment is also used palliatively to relieve symptoms, such as cough, shortness of breath, and bone pain. Curative radiation treatments are delivered one of two ways. For small localized cancers, stereotactic body radiation therapy (SBRT) may be appropriate (see below). For larger cancers or cancers that have spread into the lymph nodes, conventional radiation is given in small daily doses over five to six weeks. Often, chemotherapy is given together with radiation to enhance its curative effect.
Radiation used for palliative symptom relief is usually given for a shorter time, between five or ten daily treatments. Radiation can also harm some healthy tissue surrounding the tumour; but the treatments are given in such a way as to minimize this damage. Newer treatments are in development to reduce the damage even further. 

External Beam Radiation Therapy 

As its name suggests, external beam radiation therapy (EBRT) focuses a beam of radiation on the tumour from outside the body. EBRT is a painless procedure, and the treatment itself generally takes only a few minutes. It is like a chest x-ray but uses more powerful radiation.
It will, however, take a bit longer to set up the machine to aim the radiation directly at your tumour. Before you receive radiation therapy, you will have a CT simulation, a planning session in which the radiation oncologist designs your radiation treatment. Certain devices may be used to keep you in position and to ensure that the radiation hits the tumour. The doctor will also place some marks on your skin to help get you in the right position during radiation therapy. You will receive radiation therapy within a few weeks of the simulation. During treatment, you will lie still on a table in the same way you did during simulation. You will be alone in the room during treatment but will be able to communicate with the radiation therapists, technicians who administer the radiation therapy.

Stereotactic Body Radiation Therapy 

Stereotactic body radiation therapy (SBRT) is a specialized form of EBRT in which very large radiation doses are given in a short treatment time (one to eight treatments). It is also known as stereotactic ablative radiotherapy (SABR) or radiosurgery. This method can effectively control the tumour in most cases. The advantage of SBRT is that the very high dose of radiation targets the tumour in such a way that areas surrounding the tumour receive much less radiation and, consequently, less damage is done to normal tissue. Since SBRT can be done over a very short time, it is usually very well tolerated. SBRT is generally used to treat very small lung tumours that are too risky to remove by surgery because of other medical conditions that can complicate an operation. It can also be used to treat small tumours that have spread to the brain, lung, liver, or spine.

Brachytherapy 

In contrast to EBRT, brachytherapy or endobronchial radiation uses internal radiation. Brachytherapy is used to treat tumours that block the airways and cause problems like shortness of breath or coughing up blood (hemoptysis). It may also be done at the site of a tumour after it has been surgically removed. This will ensure that any remaining cancer cells not removed surgically are killed by radiation. In rare cases, brachytherapy may be used as primary treatment if EBRT cannot be done because of poor lung function. The procedure is done using local anesthetic to the upper airways, and performed by a thoracic surgeon or respirologist, and a radiation oncologist. Using a bronchoscope, the doctor will place a catheter (a tiny, hollow tube) where the tumour is located. Then, the radiation oncologist will mark the precise spots to be treated after visualizing the tumour and catheter with an x-ray machine called a fluoroscope. The doctor will then insert radioactive seeds, which deliver an intense dose of radiation, into the catheter and place them near the tumour. In most cases, the radiation treatment is given for several minutes; then, the seeds are removed through the catheter. Less commonly, the seeds are left in the lung, and over time the radiation becomes weaker. Since the radiation from brachytherapy is primarily aimed at the tumour and travels a short distance, the surrounding normal tissue can be spared from unnecessary, high doses of radiation.


Chemotherapy 

Chemotherapy is an option for all stages of NSCLC except for stage IA; and is often used in combination with localized therapies, such as surgery and radiation therapy. In choosing the chemotherapy drugs that will be right for you, the doctor will consider how the chemotherapy will be used, and its place within the treatment plan and the stage of your cancer. For example, is the chemotherapy meant to assist surgery or radiation treatment? Or, is the chemotherapy the primary treatment for an advanced cancer? The type of NSCLC you have also determines the chemotherapy drugs you will receive. For example, the drug pemetrexed is less effective for squamous cell carcinoma. 

How Chemotherapy works

Chemotherapy refers to a group of drugs that disrupt the life cycle of cancer cells and keep new cancer cells from being made. They may damage the DNA or prevent the cells from making new DNA; or, they may interfere with other cellular processes involved in the creation of new cells. To take advantage of the different ways in which these drugs exert their effect, chemotherapy is often given as a combination of two different drugs. A common combination, composed of a platinum-containing chemotherapy drug and a second chemotherapy drug, is known as a platinum doublet. Doublets are often referred to as the backbone of first-line therapy for NSCLC. The platinum-containing drug binds to the DNA of fast-growing cells (like cancer cells) in such a way that the DNA cannot be repaired or used to create new cells; eventually, the cells die from the damage to their DNA. If combination treatment is not tolerable, or if the cancer does not respond to doublet chemotherapy or stops responding and gets worse, a different chemotherapy drug may be tried. These subsequent treatments are usually a single chemotherapy drug. 

Cisplatin or carboplatin are commonly used platinum-containing chemotherapy drugs. Other drugs you may receive include vinorelbine, etoposide, gemcitabine, docetaxel, paclitaxel, and pemetrexed. 


Targeted Therapy 

Targeted therapies are mainly used to treat advanced and metastatic lung cancers. They are generally given alone. Occasionally, targeted therapy is given in combination with chemotherapy, or used as adjuvant therapy after surgery to try and keep the cancer from coming back. The molecular tests of your lung tumour, which check whether your cancer cells express any of the targets of this type of therapy, will determine if you can receive a targeted therapy as your primary therapy. If you have previously received other types of treatments, your doctor may suggest targeted therapy as a subsequent treatment. This chapter discusses the targeted therapies for lung cancers with EGFR, ALK, ROS1, and BRAF mutations, as well as for VEGF. However, new therapies that target mutations in genes such as HER2, cMET, RET, NTRK, and many others are in development. If you are not a candidate for one of the targeted therapies available in the market, you may be eligible for a new therapy being tested in clinical trials. Molecular testing for these new gene targets may be available only as part of a clinical trial, so be sure to discuss the options with your doctor.

How does Targeted therapy work?

These drugs target and disrupt key processes of cancer growth—for example, the formation of new blood vessels that bring nutrients to the tumour, or the action of cellular molecules that cause cancer cells to grow and divide quickly. This interference of cellular processes is known as inhibition. When targeted therapies inhibit their targets, they cause tumours to slow down their growth, stop growing, or shrink. Like chemotherapy, these treatments are systemic—some must be injected into a vein, and others are capsules or tablets that can be taken orally. Unlike standard chemotherapy, these drugs attach to or block targets that appear on the surface of cancer cells or the blood vessels in the tumour. Because they have specific molecular targets, targeted therapies generally affect fewer healthy cells and cause less severe (and different) side effects than chemotherapy. When studied in clinical trials, targeted therapies were also more effective—compared to chemotherapy, they were more likely to shrink tumours and control the cancer for a longer time.

What Targeted therapies are available? 

EGFR Inhibitors 

EGFR stands for epidermal growth factor receptor. These are molecules found on the surface of certain cells in the body, and they transmit signals that tell these cells to grow. Some lung cancer cells contain EGFR molecules with mutations that make them overactive. Mutated EGFR molecules constantly signal the cancer cells to grow and divide, making the tumour larger. EGFR inhibitors block this signal. In Canada, around 14% of adenocarcinomas, a subtype of NSCLC, have EGFR mutations; that is, they are EGFR-positive (EGFR+). EGFR+ adenocarcinomas are more common in women, non-smokers and light smokers, and East Asians. Afatinib (Giotrif®), dacomitinib (Vizimpro®), erlotinib (Tarceva®), gefitinib (Iressa®), and osimertinib (Tagrisso®) are oral EGFR inhibitors that are taken on their own as initial treatment for advanced EGFR+ adenocarcinoma. After treatment with EGFR inhibitors, lung cancers may become resistant to treatment. They can do so by developing resistance mutations to counteract the effect of EGFR inhibitors. Encouragingly, in recent years, new drugs have been— and continue to be—developed to overcome these resistance mutations. Osimertinib (Tagrisso®) is an oral drug that acts on the T790M resistance mutation, which appears in about half of the people treated with an EGFR inhibitor. To find out whether your cancer will respond to osimertinib, you will have to undergo a blood test or another biopsy to check for the T790M mutation. Osimertinib may also be used as initial treatment for EGFR+ lung cancer.  Speak with your doctor about the best initial choice for you. Click here to find out more about Epidermal Growth Factor Receptor (EGFR) mutations and mutation testing.

ALK Inhibitors

ALK stands for anaplastic lymphoma kinase. Some cancer cells contain ALK genes that are mixed or fused with another gene—this is known as an ALK fusion. The rearranged ALK gene produces an altered ALK molecule that promotes the growth and spread of cancer cells. ALK fusions occur in about 3% to 5% of NSCLCs. They are more common in younger people with adenocarcinoma who have never smoked or used to be light smokers. ALK inhibitors block these defective ALK molecules. Alectinib (Alecensaro®), brigatinib (AlunbrigTM), ceritinib (Zykadia®), crizotinib (Xalkori®), lorlatinib (Lorbrena™) are all oral ALK inhibitors. Some are used as first-line treatment whereas others are used after failure of a previous ALK inhibitor.

ROS1 Inhibitors

Some cancer cells contain ROS1 genes that are mixed or fused with another gene— this is known as an ROS1 fusion. This mutation is found in only 1% of NSCLCs; like ALK mutations, it is more common in younger people, non-smokers, and light smokers. Crizotinib (Xalkori®) is the first Health Canada approved ROS1 inhibitor. Crizotinib can be used either as first line therapy or after failure of chemotherapy for patients where ROS1 status wasn’t previously known.  Entrectinib is a newly developed ROS1 inhibitor with promising data in patients who have failed prior crizotinib as well as patients who have not received prior ROS1 treatment.

VEGF Inhibitors

VEGF stands for vascular endothelial growth factor. As its name suggests, VEGF stimulates the growth of blood vessels. Cancer cells grow very fast and need a lot of nutrients to do so. They produce a lot of VEGF to create a dense network of blood vessels that brings them these nutrients. By blocking the action of VEGF, VEGF inhibitors essentially starve the tumour of nutrients. VEGF inhibitors are also known as angiogenesis inhibitors. (Angiogenesis is the medical term for the formation of new blood vessels.) Currently, there are no tests to determine the best candidates for treatment with VEGF inhibitors. However, those who have a tumour in the centre of the chest or are coughing up blood should not receive a VEGF inhibitor. Bevacizumab (Avastin®) is an injectable VEGF inhibitor that is occasionally used to treat lung cancer. VEGF inhibitors are usually given in combination with chemotherapy, but bevacizumab may be given on its own later to maintain a good response after initial treatment. 

BRAF Inhibitors

The BRAF molecule is one of many that control the normal growth of healthy cells. Approximately 1% to 3% of NSCLCs have a BRAF mutation known as V600E. These cancers may be treated with a combination of two oral drugs—the BRAF inhibitor dabrafenib (Tafinlar®) and another oral drug called trametinib (Mekinist®). Trametinib inhibits a molecule called MEK, which works with BRAF to control cell growth.

TRK Inhibitors

Some cancer cells contain NTRK1,2,3 genes that are mixed or fused with another gene—this is known as an TRK fusion. This mutation is found in only 1% of NSCLCs; like ALK mutations, it is more common in younger people, non-smokers, and light smokers. Larotrectinib, a first-generation TRK inhibitor has been approved for the treatment of patients with NTRK fusion-positive cancers. Entrectinib is another TRK inhibitor in development for the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumors.


Immunotherapy 

Immunotherapies are used to treat locally advanced and metastatic NSCLC. Depending on the immunotherapy drug being considered for your treatment plan, you may first need to undergo a diagnostic test to check for the presence of certain molecules on the surface of your cancer cells. The effectiveness of giving immunotherapy after surgery or in combination with chemoradiation (a combination of chemotherapy and radiation), chemotherapy, or other immunotherapies is currently being studied in clinical trials.

How does Immunotherapy work?

Immunotherapy increases the activity of your body’s natural defence system—the immune system—so that it can better find and destroy cancer cells. Because immunotherapy simply enhances the performance of your own immune system, the treatment is generally well tolerated.
Under normal circumstances, the immune system keeps the body clear of infection-causing entities such as viruses and bacteria, and abnormal cells like cancer cells. But first, it must identify whether a cell is foreign or normal. This process of checking whether a cell is foreign or not is controlled by an immune checkpoint. These checkpoints ensure that the immune system does not accidentally attack healthy, normal cells.
Some cancer cells exploit an immune checkpoint process involving two cell surface molecules—PD-L1 and PD-1. They produce lots of PD-L1, which binds to PD-1 on the surface of T cells, a specific type of immune cell. When cancer cells interact with T cells in this way, they trick the immune system into identifying the cancer cells as normal cells.

What Immunotherapy drugs are available?

The four main immunotherapy drugs are atezolizumab (Tecentriq™), durvalumab (Imfinzi™), nivolumab (Opdivo®), and pembrolizumab (Keytruda®). They fall into a category of drugs called immune checkpoint inhibitors or PD-1/PD-L1 checkpoint inhibitors. Immune checkpoint inhibitors prevent the interaction between PD-1 and PD-L1 so that the immune cells can destroy the cancer cells. This mechanism is often described as “taking the brakes off the immune system.” Immunotherapy drugs were initially given after an advanced lung cancer had progressed during or after treatment with chemotherapy. However, pembrolizumab may be given alone as a first-line treatment for advanced cancers with high levels of PD-L1; pembrolizumab can also be given in combination with platinum doublet chemotherapy for patients with any PD-L1 status.  Durvalumab may be given after completion of chemoradiation for the treatment of stage III lung cancer. Immunotherapy treatments are given intravenously every two to four weeks.

Other Immunotherapies

Cancer vaccines and adoptive T cell transfer are active areas of research in immunotherapy clinical trials. Just like regular vaccines, cancer vaccines are used to train the immune system to better recognize molecules found on the surface of cancer cells. In adoptive T cell transfer, some T cells from the body are removed, treated in a lab so that they can identify cancer cells better, and then re-injected into the body.