Overview of Second-Line Treatment for Cancer

Second-line treatment is treatment for a disease or condition after the initial treatment (first-line treatment) has failed, stopped working, or has side effects that aren't tolerated. It's important to understand "lines of treatment" and how they differ from first line treatment and can play a role in clinical trials. Learn more about second line therapies and questions you should ask if your oncologist recommends this.

Person in hospital, focus on IV in foreground
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Lines of Treatment

When oncologist talk about "lines of treatment" they are referring to different approaches to treating cancer at different times. This can be confusing, and example is likely the best way to describe how this works.

The initial treatment used to treat a cancer after diagnosis is referred to as first-line treatment or first-line therapy. First line treatment can include more than one treatment method. For example, if a woman has surgery followed by chemotherapy and radiation for breast cancer, the combination of therapies is still considered first line therapy.

Second-line or further lines of therapy (third-line, fourth-line, seventh-line, etc.) may be used for a few different reasons:

  • The first-line treatment doesn't work
  • The first-line treatment worked but has since stopped working
  • The first-line treatment has side effects that are not tolerated
  • A new treatment becomes available that appears to be more effective than the present treatment.

With survival rates improving for many cancers, and the number of available treatments increase, some people receive many lines of therapy.


Since discussing second-line treatment usually means that first-line treatment failed, you are likely feeling a whole host of cancer emotions, similar to when you were first diagnosed. Some people say that it feels like starting all over—but with less energy this time. Usually, first-line treatments are chosen because they have the greatest benefit and/or the fewest side effects. Yet all people are different and respond in different ways to different treatments. While statistically a person is less likely to respond (or respond for as long) to a second line treatment, people aren't statistics. In some cases a person will have a better response to a second line therapy than they did to first line treatment.

Second-line treatments are available for most cancers, but the likelihood of effective options can vary with the type and stage of your cancer. In general, the chance of a good result with a second-line treatment is often lower—and is the reason that you and your oncologist began your treatment with a first-line treatment. Still, advances are continually taking place in medicine, and many second-line, and even third-line and fourth-line treatments are improving.

The Option of Clinical Trials

Understanding line of treatment becomes very important when looking at clinical trials for cancer. Some clinical trials require that people have no previous treatments, whereas others are designed for people who have had inadequate results with a previous treatment. For example, one clinical trial may require the treatment to be used as a first line therapy, whereas another may only be entered if a person has "failed" first line or second line treatment.

For those who are considering second line treatments, the option of clinical trials should be considered. While this thought may be frightening at first (especially for those who have heard too many guinea pig jokes), it might be helpful to learn about how clinical trials have changed in recent years.

In the past, many clinical trials (especially phase 1 clinical trials) were often considered a "last ditch" effort. Today, many of the medications being evaluated in these trials have been designed to target specific molecular abnormalities in cancer cells. For this reason, they often have fewer side effects than traditional chemotherapy drugs, but are also more likely to be effective for a person participating in a clinical trial.

Another helpful thought to consider is that every currently available treatment for cancer was once studied in a clinical trial. In some cases, a treatment option offered in a clinical trial may be the only option available that may extend life.

Trying to navigate clinical trials can be daunting, but fortunately there are now matching services through which a trained healthcare professional can help match your particular cancer (and specifics such as molecular profile) to clinical trials anywhere in the world.

Questions to Ask About Second-Line Treatments

Since the failure of a first treatment can leave you feeling overwhelmed and anxious, having a list of questions to ask your healthcare provider (as well as a friend to attend the visit with you) can be very helpful.

  • How effective is the second-line treatment, and how does it compare to the treatment you had previously?
  • What are the possible side effects of the treatment?
  • What has been your oncologist's experience with other patient's given this treatment?
  • What other options are available for second-line treatment?
  • Are there treatments offered at different cancer centers that you should consider?
  • What is the goal of treatment? (Unfortunately, patients and oncologists often have different goals in mind when selecting treatment options.)
  • Would it make a difference to wait awhile before beginning a new treatment?
  • What options lay beyond second-line treatment—3rd-line and 4th-line treatments? (Many people find it very helpful to have some idea what options are available down the road if the second line treatment is ineffective or has side effects that you don't tolerate.)
  • Are there any clinical trials that would be appropriate for your particular type and stage of cancer?
  • What is your prognosis if you receive this second-line treatment?


An example of the importance of defining lines of treatment is a 2019 study that compared different second-line treatments for lung cancer. Since there are a number of different options, and many studies look at the effectiveness of first line therapies, this can give important information to oncologists. For example, the second line chemotherapy drug Taxotere (docetaxel) was often used alone as a second line therapy. In the study (which looked at 30 different studies using 17 different drug combinations), it was demonstrated that in general, and based on lab and genetic tests, other combinations worked better. The combination of Taxotere with either Cyramza (ramucirumab) or Ofev (nintedanib) worked better than Taxotere alone with lung adenocarcinoma. The tyrosine kinase inhibitors Tarceva (erlotinib) or Iressa (gefitinib) worked better than Tarceva in people with EGFR positive lung cancer, and people who had tumors with high PD-L1 expression did better when treated with Opdivo (nivolumab).


Thinking about and making decisions about second-line treatment can be heartwrenching. It's hard enough the first time around, but at this point many people are exhausted and it's easy to get discouraged. Reach out to people in your support network, and don't be afraid to share your fears. Certainly, not every friend will be comfortable with this, but choose at least a friend or two with who you can be open and vulnerable about your fears and worries.

Connecting with cancer communities can be priceless in this situation in a few ways. First of all, there is something special about being able to share and receive support from others who truly know what you're going through. Yet other patients are sometimes a tremendous resource in learning about new treatment options, especially those only available in clinical trials. It's become relatively common for patients to know more about available clinical trials for a particular cancer than many community oncologists. And it makes a lot of sense. There is a lot of motivation to learn when the option is the progression of cancer.

In some cases you may find support groups for your particular cancer type in your community, but online support communities offer much that can't be found near home, especially if you have an uncommon type of cancer, or a cancer with a specific mutation that is relatively uncommon. You may find some of these communities online by googling, but an excellent way to find others asking the same questions you are is to go on twitter and use hashtags. For example, the hashtag #LCSM (standing for lung cancer social media) or #BCSM (for breast cancer social media) will help you find the kind of posts that may pertain to your specific situation. More specific hashtags, such as #BRAF (for melanoma or lung cancer with a BRAF mutation) can help you fine-tune your searches.

A Word From Verywell

If you're learning about second-line treatments, you or a loved one might be feeling discouraged that your first line therapies were ineffective or had too many side effects. Fortunately, there are many new treatments for cancer, and multiple lines of therapy are sometimes available. As new treatments are approved or being studied in clinical trials, some of these treatments may actually be more effective or have fewer side effects. Don't hesitate to ask a lot of questions or get a second (or third or fourth) opinion. If your oncologist were in the same situation she would likely do so herself.

1 Source
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Vickers AD, Winfree KB, Cuyan Carter G. Relative efficacy of interventions in the treatment of second-line non-small cell lung cancer: a systematic review and network meta-analysis. BMC Cancer. 2019. 19(1):353. doi:10.1186/s12885-019-5569-5

Additional Reading

By Lynne Eldridge, MD
 Lynne Eldrige, MD, is a lung cancer physician, patient advocate, and award-winning author of "Avoiding Cancer One Day at a Time."