Unresectable Stage 3 Non-Small Cell Lung Cancer

New Treatment Options for Locally Advanced NSCLC

In This Article

After years of few advances in the treatment of unresectable (inoperable) stage 3 non-small cell lung cancer (NSCLC), a new option is available for some people that may improve survival. While some stage 3 tumors may be removed with surgery (resected), roughly 20% of all people diagnosed with lung cancer today have what is referred to as unresectable stage 3 disease. A combination of chemotherapy and radiation therapy can extend life, but unfortunately, recurrence and progression of the disease is common. The immunotherapy drug (a checkpoint inhibitor) Imfinzi (durvalumab) was approved in February of 2018 to be used after chemotherapy and radiation, and has been found to significantly improve both overall and progression-free survival with stage 3 non-small cell lung cancer.

Let's look at what can make a stage 3 lung cancer inoperable, the treatment options currently available, and the benefits and risks of these therapies.

Definition

Stage 3 non-small cell lung cancer comprises a diverse group of tumors. Considered "locally advanced lung cancer," it is often broken down based on the size of the tumor, number of lymph nodes involved, and more into:

  • Stage 3A non-small cell lung cancer: This includes tumors that are large and have spread to nearby lymph nodes, or tumors that are any size but have spread to lymph nodes further away (but still on the same side of the body as the original cancer).
  • Stage 3B non-small cell lung cancer: This includes tumors of any size that have spread to distant lymph nodes or have invaded structures in the chest such as the heart and esophagus (but have not spread to distant regions such as the brain, bones, liver, or adrenal glands). Stage 3B lung cancer is often lumped together with stage 4 lung cancer as "advanced lung cancer."

In general, stage 3A lung cancers may sometimes be treated with surgery whereas most stage 3B tumors cannot, but there are exceptions. Stage 3A lung cancer may also be considered inoperable at times due to the location of the tumor and more. Similarly, sometimes people with stage 3B non-small cell lung cancer may be candidates for surgery, usually after neoadjuvant (before surgery) treatment with chemotherapy and radiation.

Inoperable (Unresectable) Lung Cancer

There are a number of reasons why a lung cancer may be considered unresectable, but what the term "unresectable" really means is that surgery is not the best treatment option for the lung cancer. In other words, treatments other than surgery are likely to be more effective in extending life and improving quality of life.

To understand the differences, treatment options are broken down into two types:

  • Local treatments: These treatments treat cancer only at the location where the treatment is directed and include surgery, radiation therapy, and ablative treatments.
  • Systemic treatments: These treatments treat cancer cells wherever they happen to be in the body, and include chemotherapy, targeted therapies, and immunotherapy.

A tumor may be unresectable due to:

  • The stage: Tumors that have spread to distant regions of the body are usually inoperable. (There are some exceptions, for example, with ovarian cancer where removing as much of the tumor is possible may be beneficial, but this is not usually the case with lung cancer.)
  • The type: Unlike non-small cell lung cancer, small cell lung cancer is usually not treated with surgery as these tumors tend to spread early.
  • The location of the tumor: In some cases, the location of the tumor could make surgery dangerous if not impossible. For example, tumors that occur near the heart and other regions.
  • Lung function: If a person's lung function is poor, removing lung tissue via surgery could make it worse.
  • General health: Lung cancer surgery is a major surgery, and health conditions such as heart disease or other lung diseases could make surgery a poor option.

Treatment Options

Until recently, surgery, chemotherapy, and/or radiation therapy were the mainstay of treatment for stage 3 non-small cell lung cancer, and treatment hadn't changed significantly in a decade despite advances in the treatment of metastatic (stage 4) lung cancer. But this is changing. Treatment options incude:

Surgery

In some cases, surgery for stage 3 non-small cell lung cancer can be effective and offers a chance of long-term control, especially for those with tumors classified as T3N1M0 and T4N0M0 based on lung cancer TNM staging. That said, for many people with stage 3 lung cancer, surgery has not been found to increase survival over the use of chemotherapy and radiation alone.

Chemotherapy and Radiation

For many people with stage 3 non-small cell lung cancer, a combination of chemotherapy and radiation therapy has been the best option. The two treatments are usually given at the same time, as combination therapy appears to improve survival more than if chemotherapy and radiation are used sequentially (one after the other).

Chemotherapy for lung cancer usually involves using a combination of a platinum drug (such as Platinol (cisplatin) or Paraplatin (carboplatin)) plus Ve Pesid or Etopophos (etoposide) given in four to six cycles.

A number of studies have looked at ways to improve the effectiveness of this combination, including adding in Alimta (pemetrexed) or Erbitux (cetuximab), adding more chemotherapy cycles, or increasing the dose of radiation, but thus far these have not been found to improve survival.

Unfortunately, even though many people respond to chemotherapy and radiation, the cancer eventually spreads to other regions of the body (becomes stage 4 lung cancer) in roughly half of the people who are treated.

Immunotherapy (Immune Checkpoint Inhibitors)

The use of checkpoint inhibitors for non-small cell lung cancer (a type of immunotherapy) has been found to improve overall survival and sometimes results in long-term responses ("durable response") for a subset of people with stage 4 non-small cell lung cancer. Knowing this, researchers are now looking at the use of these drugs in people with earlier stages of the disease.

For people with unresectable stage 3 non-small cell lung cancer who responded well to chemotherapy and radiation (their cancer did not progress during treatment), researchers designed a trial in which one group received the immunotherapy drug Imfinzi (durvalumab) and another group received a placebo.

Imfinzi is a medication that appears to work by enhancing a person's own immune system's ability to fight a tumor. When radiation is before or with immunotherapy, it may sometimes further enhance this effect (the abscopal effect).

Imfinzi was given as an infusion (intravenously) of 10 mg/kg every two weeks for up to 12 months, and was started one day to 42 days after people completed chemotherapy and radiation.

Progression-Free Survival: The progression-free survival (amount of time during which people were alive and their tumor did not progress) was 17.2 months for the group treated with Imfinzi and 5.6 months for those treated with the placebo. The median time to distant metastases or death (the amount of time at which 50% of people developed distant metastases or died and 50% were alive and their tumor had not spread to distant organs) was 28.3 months for those treated with Imfinzi and 16.2 months for those treated with the placebo. This was seen whether people were smokers or non-smokers and regardless of the tissue type of the tumor.

Overall Survival: Overall survival was also greater in the group treated with Imfinzi, with a 2-year survival rate of 66.3% vs. 55.6% (an absolute difference of 10.7%).

Side Effects: Fortunately, improvement in survival came without major side effects for many people. Adverse reactions occurred in 30.5% of people in the Imfinzi group and 26.1% of people in the placebo group. Common adverse effects from checkpoint inhibitors include inflammation of the lungs and other regions.

It's not yet known how some issues seen with immunotherapy for stage 4 lung cancer may affect treatment of stage 3 lung cancer. For example, pseudoprogression, or the appearance of progression on an X-ray despite actual improvement of a cancer is sometimes seen with stage 4 disease. In a small number of people, rather than responding or resulting in long-term control, immunotherapy may actually lead to more rapid worsening of a cancer, a concept referred to as hyperprogression.

Since the studies are young, it's also not yet known if some people treated with Imfinzi will become long-term survivors, has been seen for some people with stage 4 lung cancer treated with checkpoint inhibitors.

Clinical Trials

Clinical trials are currently in place looking at other treatment options for stage 3 non-small cell lung cancer. For example, targeted therapies (such as EGFR, ALK, ROS1, BRAF inhibitors etc.) are often used with stage 4 lung cancer and can sometimes control the growth of a tumor for an extended period of time. Researchers are now considering whether testing tumors for genomic alterations (such as mutations) and treating these when found may play a role in earlier stages of the disease as well, including tumors that can be treated with surgery.

Another new treatment advance that may be of interest to those who have stage 3 lung cancer has been the treatment of "oligometastatic" disease, that is, treatment of single or only a few areas to which a stage 4 lung cancer has spread. It has been found that, in some cases, doing so may improve survival. Whether this may be an option in people who have stage 3 lung cancer that spreads is unknown at this time.

Choosing the Best Treatment

Advances in the treatment of lung cancer now provides more options, but along with this comes the need for people to weigh the potential risks and benefits and choose the option that best meets their needs. One of the best first steps is finding a physician who specializes or takes an active interest in lung cancer.

Being your own advocate and asking a lot of questions can empower you and may sometimes even affect your outcome. Becoming involved in the lung cancer community is priceless, and many people find this a source of not only support, but a way to stay abreast of the latest research. Many lung cancer survivors are now attending the large lung cancer conferences and returning to share new findings on social media.

Weighing Risks and Benefits

When looking at medication options, some people find it helpful to list both the potential benefits and potential risks and side effects of the various options. This is important as different people may be more bothered by particular side effects than others, and it can be a very personal decision about what you choose to tolerate.

The risk of side effects (adverse reactions) is a concern for many people when considering whether or not to choose a treatment for lung cancer, but there is a caveat as these decisions do not always compare apples to apples. In other words, instead of only looking at potential side effects a treatment may confer, this needs to be weighed against symptoms you may experience if you choose not to have the treatment and your cancer progresses. The progression and spread of cancer can cause symptoms as well.

Involving Your Family

Lung cancer is rarely a disease experienced in isolation, and family members suffer as well and often want to take an active part in the decisions you make. This can be wonderful, and having a friend or family member with you at appointments (and sometimes doing their own research) is priceless.

That said, the choice you make about your treatment may differ from that another family member would choose, and this can sometimes lead to conflict. It's important to listen to your loved ones and thank them for their input, but ultimately, the decisions you make should be those that are best for you alone.

A Word From Verywell

Unresectable stage 3 lung cancer has been challenging to treat, with few advances until recently despite the significant advances in the treatment of stage 4 disease. Fortunately, this is changing with the addition of immunotherapy now for stage 3 tumors that initially respond to chemotherapy and radiation. Unfortunately, statistics don't tell us how individual people will do with a particular treatment, and talking to your oncologist about your wishes and hopes as well as side effects you would like to avoid is more important than ever before.

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Article Sources

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