How Non-Small Cell Lung Cancer Is Treated

The treatment of non-small cell lung cancer depends on the stage of the disease, as well as the subtype and molecular profile. Early-stage cancers may be treated with surgery or a specialized form of radiation therapy if surgery is not possible. Advanced lung cancers are most often treated with targeted therapies, immunotherapy (checkpoint inhibitors), or chemotherapy. In addition to these treatments, local treatments designed to eradicate the sites of spread (metastasis) are sometimes used.

When you've been diagnosed with non-small cell lung cancer, the most important step you can take to maximize your outcome is to find a good doctor and cancer center. With surgery, studies have shown that outcomes of lung cancer surgery are better at cancer centers that perform large volumes of these surgeries. Once you have met with a lung cancer specialist, it's also very helpful to get a second opinion.

Understanding Treatment Options by Stage

With so many options now available to treat non-small cell lung cancer (NSCLC), it's helpful to break these down into two major approaches, with the primary approach taken depending on the stage of the lung cancer.

Local vs. Systemic vs. Regional Treatments

Treatment options can be broken down into:

• Local therapies: These therapies treat the cancer where it arises, and include treatments such as surgery and stereotactic body radiotherapy (SBRT).
• Regional therapies: Regional treatment like standard radiation therapy or even more recent radiation modalities like proton beam therapy also treat cancer where it arises, but less specifically, so normal cells will be affected too.
• Systemic therapies: Body-wide or systemic therapies treat lung cancer cells wherever they may be in the body, including at distant sites.

With stage I cancers, local therapies may be sufficient to treat the tumor. With stage IV tumors, systemic therapies are the treatment of choice. Stage II and stage III lung cancers are usually treated with a combination of local and systemic therapies.

Adjuvant and Neoadjuvant Therapies

For "in-between" tumors, such as stage II and stage IIIA non-small cell lung cancer, a combination of these treatments may be used. In this case:

• Neoadjuvant therapy: Neoadjuvant therapy refers to the use of systemic therapies such as chemotherapy to shrink a tumor prior to surgery.
• Adjuvant therapy: The use of systemic therapies (and sometimes local treatment with radiation) to treat any cancer cells that may remain after surgery is referred to as adjuvant therapy.

Combination Therapy

If a targeted therapy is not available to treat non-small cell lung cancer, combination therapy is often used. This may include a combination of chemotherapy drugs, a combination of immunotherapy drugs, a combination of immunotherapy and chemotherapy drugs, or a combination of an immunotherapy drug, a chemotherapy drug, and an angiogenesis inhibitor.

Precision Medicine

If you are beginning to learn about non-small cell lung cancer, you'll likely hear about "precision medicine." Precision medicine is the practice of tailoring treatment to fit not only the characteristics of the tumor seen under the microscope, but the specific genetic profile of the tumor.

Surgery

For early-stage non-small cell lung cancers (stage I, stage II, and stage IIIA), surgery may offer a chance for a cure. There are a number of different procedures that may be done, with the best option depending on the size and location of the tumor.

• Wedge resection: This procedure involves removing a wedge-shaped piece of lung tissue containing the tumor and a small area of surrounding tissue.
• Segmental resection: A segmental resection involves removal of a somewhat larger section of tissue than a wedge resection, but a smaller amount of tissue than a lobectomy.
• Lobectomy: A lobectomy involves the removal of a lobe of the lung. The left lung has two lobes and the right lobe has three.
• Pneumonectomy: A pneumonectomy involves the removal of an entire lung.
• Sleeve resection: Somewhat less invasive than a complete pneumonectomy, a sleeve resection is a procedure similar to removing a sleeve from a shirt but preserving some of the shirt.

While an open thoracotomy (large chest incision) was most often used to remove lung tumors in the past, minimally invasive techniques such as video-assisted thoracoscopic surgery (VATS) may be done for many tumors; oftentimes with an easier recovery. VATS cannot be used for all tumors, however, and depend on the location of the tumor.

For early lung cancers (stage I) that are inoperable due to location or if a person is unable to tolerate surgery, stereotactic body radiotherapy (SBRT) may be considered as a curative approach.

Targeted Therapies

Everyone with non-small cell lung cancer (advanced stage) should have gene testing (molecular profiling) on their tumor. While targeted therapies are currently used primarily for stage IV cancers, it's likely that they will be used in earlier stages in the near future as adjuvant therapy.

Targetable Gene Changes

There are now targeted treatments available for a number of different mutations/genetic abnormalities in cancer cells, some that are FDA-approved, and others that are available only in clinical trials or through compassionate drug use or expanded access. According to the International Association for the Study of Lung Cancer, roughly 60% of lung adenocarcinomas have one of these abnormalities that may be treated with targeted therapies. Abnormalities for which FDA approved treatments are available include:

• EGFR Mutations: Drugs available include Tarceva (erlotinib), Gilotrif (afatinib), Iressa (gefitinib), Vizimpro (dacomitinib), Tagrisso (osimertinib), and Rybrevant (amivantamab-vmjw). (Portrazza (necitumumab) is somewhat different and may be used for squamous cell carcinoma of the lungs.)
• ALK Rearrangements: Drugs include Xalkori (crizotinib), Alecensa (alectinib), Alunbrig (brigatinib), Zykadia (ceritinib), and Lobrena (lorlatinib)
• ROS1 Rearrangements: Drugs include Xalkori (crizotinib), Rozlytrek (entrectinib), and Augtyro (repotrectinib) for ROS1+ metastatic non-small cell lung cancer, as well as drugs only available in clinical trials such as Lobrena (lorlatinib).
• BRAF mutations: BRAF V600E mutations may be treated with a combination of Tafinlar (dabrafenib) and Mekinist (tremetinib).
• NTRK gene fusions: The drug Vitrakvi (larotrectinib) was approved in 2018 for people who have tumors with a NTRK gene fusion. Unlike many treatments, Vitrakvi may work with a number of different types of cancer. Rozlytrek (entrectinib) is also approved for NTRK fusion-positive solid tumors.
• KRAS G12C mutation: Lumakras (sotorasib) is approved for patients with this mutation whose cancer ​​is locally advanced or metastatic and who have already received systemic therapy.

Other potentially treatable changes include:

• MET mutations (such as exon 14 skipping mutations) or amplification may be treated with MET inhibitors such as Xalkori (crizotinib) or Cometriq or Cabometyx (cabozantinib).
• RET rearrangements: In 2020, the FDA approved Gavreto (pralsetinib) for the treatment of patients with metastatic, RET fusion-positive non-small cell lung cancer. Medications such as Cometriz (cabozantinib) or others may be considered off-label.
• HER2 mutations (but not amplifications): A combination of Herceptin (trastuzumab) or TDM-1 (ado-trastuzumab emtansine) plus chemotherapy may be considered.

Other potential driver mutations include those in PI3K and DDR2, as well as FGFR1 amplifications. In addition, some mutations for which treatment is not yet available may still provide valuable information about the behavior of the tumor and prognosis.

Resistance

Targeted therapies sometimes have a high success rate in controlling the growth of a non-small cell lung cancer, but in time, resistance to the treatment usually develops. Newer medications are being developed such that a second line or third line of treatment may be available when this occurs, or may replace the earlier drug due to a longer duration of action. Looking for further lines of treatment and understanding resistance is a very active area of research at the current time.

Angiogenesis Inhibitors

Another type of treatment that targets specific pathways in the growth of a cancer includes angiogenesis inhibitors. These drugs inhibit the formation of new blood vessels (angiogenesis) that are needed for tumors to grow, and include drugs such as Avastin (bevacizumab). Angiogenesis inhibitors are most often used along with a chemotherapy and immunotherapy drug.

Immunotherapy

Immunotherapy drugs are treatments that work by essentially boosting the ability of the immune system to fight cancer. They can be used alone or combined with other immunotherapy drugs and chemotherapy.

One category of immunotherapy drugs is checkpoint inhibitors, of which six drugs are currently available for treating non-small cell lung cancer (with different indications):

• Opdivo (nivolumab)
• Keytruda (pembrolizumab)
• Tecentriq (atezolizumab)
• Imfinzi (durvalumab)
• Yervoy (Ipilimumab)
• Imjudo (tremelimumab)

Not everyone responds to immunotherapy, but in some cases, the results can be very dramatic with long-term control of the disease. Unfortunately, there is not yet a tool in place to predict who will respond to these drugs.

Chemotherapy

Chemotherapy was once a mainstay of treatment for advanced non-small cell lung cancer, but is less effective (and more toxic) than targeted therapy and immunotherapy drugs when these can be used. It is still frequently used for people who do not have targetable genetic changes in their tumors and in combination with immunotherapy. (Chemotherapy drugs may result in the breakdown of cancer cells such that immunotherapy drugs are able to work better.)

Radiation Therapy

Radiation therapy can be used in different ways to treat non-small cell lung cancer. With locally advanced cancers (such as stage II and stage III), it is often used as an adjuvant treatment. Proton beam therapy may be used as an alternative and is thought by some to have fewer side effects.

With advanced non-small cell lung cancer, radiation may be used as a palliative therapy (to reduce symptoms but not extend life), such as when pain is present due to bone metastases, a tumor is causing obstruction of the airways, and more.

A specialized form of radiation therapy called stereotactic body radiotherapy (SBRT) may be used to treat metastases when only a few are present, with a curative intent (see below). SBRT involves the delivery of a high dose of radiation to a very localized area of tissue.

Clinical Trials

At the current time, there are many clinical trials in progress looking at treatments that are more effective or have fewer side effects than standard options, and with non-small cell lung cancer, a clinical trial may offer by far the best option for some people.

While many people have fears about clinical trials, it's important to understand that the role of clinical trials in cancer has changed significantly in recent years. In the past, a phase I trial (the first trials done on humans) may have been primarily a "last-ditch" option, with a low likelihood of effectiveness. In contrast, the current phase I trials are often designed looking at precise pathways in the growth of a cancer. In this setting, there is often a very reasonable chance that a drug will be effective, and in some cases, a phase I clinical trial may be the only option that could extend life.

Treatment of Metastases

Treatment of metastatic (stage IV) non-small cell lung cancer usually involves systemic therapy, but metastasis-specific treatment may be considered in some cases. When only a few sites of metastases are present (referred to as "oligometastases"), treating these sites can sometimes improve survival.

• Bone metastases: Additional treatments are often used to treat pain as well as reduce the risk of fractures. Radiation therapy and bone-modifying therapies include drugs that can reduce pain and lessen fracture risk but also have anti-cancer properties.
• Brain metastases: Unfortunately, many systemic treatments for non-small cell lung cancer do not pass through the blood-brain barrier (some targeted therapies do). Since some cancers, such as those that are EGFR-positive or ALK-positive, can be controlled for an extended period of time, treatment of isolated or only a few brain metastases (via surgery or SBRT) has the potential to extend life and improve symptoms.
• Adrenal metastases: Most often, adrenal metastases have no symptoms, but can likewise be considered for treatment.
• Liver metastases: Radiation therapy or SBRT in an attempt to eradicate only a few metastases may be considered.

Choosing Treatments

It is wonderful that there are now so many new options available for treating non-small cell lung cancer, but having numerous options can be confusing. It's important to learn as much as you can about your cancer (and your specific mutation if you have one) and to be an advocate in your own care. Not only does this help people feel more in control of their disease, but in some cases, it may improve outcomes. We've entered an era in which sometimes patients understand the treatment options available for their cancer more than many community oncologists.

An example is the change in survival rate for people who have ALK rearrangements. A decade ago the expected survival rate was less than one year. Now the median survival rate, even with brain metastases, is 6.8 years among those who are receiving specialized care by oncologists on the leading end of research.

A Word From Verywell

The treatment options for non-small cell lung cancer have increased dramatically in even the past few years, and many additional therapies are being evaluated in clinical trials. Instead of treating lung cancer as a single disease, it is now recognized and treated as a condition made up of many diseases. Fortunately, along with advances in treatment have come greater social support. Patient-led groups are now available for many of the common mutations (such as the ROS2ders and EGFR resisters) that also include oncologists, surgeons, pathologists, researchers, and more.