Glioblastoma Recurrence: Treatment Options and Coping

Treatments, Clinical Trials, and Life Expectancy

Glioblastoma recurrence is, unfortunately, the rule rather than the exception. Even when it appears a tumor has been eliminated with treatment, there is a high chance it will return. Sadly, there have also been relatively few treatment options when these cancers come back. Several newer treatments have been approved or are in clinical trials, but since these are so new, it can be hard to navigate the information to even find early results.

We will take a look at the statistics on glioblastoma recurrence and why the disease is so challenging to treat relative to many other cancers. We will also explore some of the potential treatment options including immunotherapy, tumor treating fields, angiogenesis inhibitors, and the latest information looking at how diet (such as the ketogenic diet) may play a role in treatment as well. Due to the complexity of glioblastoma, treatment has been most effective using a combination of modalities, and it's important to understand the rationale of some of these so that you can personally weigh the potential benefits and risks to you as an individual.

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Glioblastoma Recurrence

Unfortunately, even when glioblastoma is discovered and treated aggressively, it almost always recurs. It is this very high recurrence rate that is the reason there are so few long term survivors of the disease.

Statistics

Without treatment, the median survival with glioblastoma is only a few months, but even with treatment, survival is frequently only around one year. The five-year survival rate from the disease is roughly 5.0%. For people who have surgery to remove as much of the tumor as possible along with radiation and chemotherapy, the overall median survival (the time after which 50% of people have died and 50% are still alive) is only 14 months.

Even when the tumor appears to have been eliminated, the median time to recurrence (the time where the cancer has come back for half of the people and has still not appeared for the other half) is 9.5 months.

For children, the numbers are slightly more optimistic, with a five-year survival rate for pediatric glioblastoma of 17%.

These numbers reinforce the need to look carefully at new therapies for both initial and recurrent glioblastoma, especially in light of recent advances in the treatments of some other cancers.

Challenges in Treating Glioblastoma

As we hear of advances in the treatment of other aggressive cancers such as metastatic melanoma or lung cancer, it's easy to wonder why similar progress hasn't been seen with glioblastoma. To understand this, as well as the challenges when evaluating treatment, it's helpful to look at how glioblastoma differs from some other cancers with regard to both the initial treatment and treatment after recurrence.

  • Rate of growth: The growth rate of glioblastoma far exceeds that of many other cancers. In one study, the growth rate of untreated glioblastomas was 1.4% per day with an equivalent doubling time of 49.6 days. In comparison, the doubling time for breast cancer averages at least 50 to 200 days.
  • Tendency to spread early: Unlike many tumors that grow like a ball of yarn, glioblastoma spreads along white matter tracts in the brain and it can be difficult to determine how far the tumor has actually spread.
  • Disability: Unlike some cancers, the brain or large amounts of the brain can't simply be removed to treat a tumor.
  • Heterogeneity: Advances have been made in targeted therapy for some advanced cancers such as some lung cancers. In these cancers, the growth of the cancer is often "driven" by a particular gene mutation or other genomic alteration. In contrast, the growth of glioblastoma is often driven by several abnormal genes in the cancer cells such that blocking one pathway is ineffective in controlling growth (it can be bypassed by another pathway so that the tumor continues to grow).
  • Discordance: There is also a high degree of what is called discordance in glioblastomas, meaning that the molecular appearance of the original tumor is often very different from that present when the tumor recurs. Tumors continually develop new mutations that can affect their growth and response to treatment, and how an initial tumor responded to a treatment may differ greatly from how it will respond after a recurrence.
  • Diagnosing recurrence: Scar tissue in the brain from surgery or radiation can sometimes be difficult to discriminate from tumor recurrence. That said, newer techniques such as perfusion magnetic resonance (MRI)-based fractional tumor volume can be helpful in making this distinction. These techniques, however, are not available at all medical centers.
  • The blood-brain barrier: The blood-brain barrier is a tightly knit network of capillaries that is helpful in preventing toxins from reaching the brain. This same network, however, can make it difficult or impossible for many chemotherapy drugs to reach the brain when given intravenously.

Treatment Options

There are treatment options for recurrent glioblastoma, though as noted by looking at survival statistics, few of these have led to long-term survival with the disease. Some treatments do improve survival, and several can improve quality of life. That said, many of these newer treatments have only recently been evaluated in humans, and it's too soon to know what the potential long-term benefit may be. Without offering false hope, it is important that, while very uncommon, some of these treatments (such as tumor treating fields and a few immunotherapy options), have been associated with long-term survival for at least a few people.

Surgery (Reoperation)

Repeating surgery for glioblastoma has been linked to better overall survival as well as survival after progression of glioblastoma, but it's thought that this benefit may be overestimated.

That said, repeat surgery can sometimes be very helpful for relieving symptoms caused by the tumor. It's very important with cancer in general, but especially with cancers such as glioblastoma, to consider the effect of a treatment on quality of life as well as survival. If a therapy allows a person to lead a more comfortable and fulfilling life, it may be priceless even if it doesn't affect survival rates.

Surgery Following Immunotherapy (Checkpoint Inhibition)

For people with recurrent glioblastoma who receive a checkpoint inhibitor (a type of immunotherapy) prior to surgery, the combination was linked to significantly improved survival in a 2019 study. In this small study of only 35 patients, people were treated with the immunotherapy drug Keytruda (pembrolizumab) prior to surgery. Those who received both Keytruda and surgery lived much longer (overall survival of 13.7 months) compared with those who only had surgery (7.5 months).

The combination of Keytruda and surgery almost doubled survival relative to surgery alone.

While this may not seem to be a large amount of time, it is very significant with a tumor that has been so challenging to treat and is so rapidly fatal without treatment. In the future, adding additional therapies (such as an oncolytic virus or other treatment) to these treatments will likely be considered.

Tumor Treating Fields

Tumor treating fields (Optune) were approved for treating recurrent glioblastoma in 2011 (and have more recently been approved for newly diagnosed glioblastoma as well). The treatment uses low-intensity, intermediate frequency, alternating electric fields to interfere with cell division in cancer cells. The treatment, fortunately, has very little effect on normal, healthy brain cells. Optune was initially approved because it has fewer side effects than other treatments that offered similar improvements in survival. Since that time, Optune has been found to have a benefit on survival as well.

With recurrent glioblastoma, studies have found that people treated with tumor treating fields have more than double the one-year and two-year survival rates of those who do not receive the treatment. Despite this, not everyone who has recurrent glioblastoma is aware of this option.

Tumor treating fields doubled one-year and two-year survival with recurrent glioblastoma with few side effects.

With Optune, small transducers are applied to the scalp and attached to a battery pack. While the device must be worn most of the time (at least 18 hours each day) to be effective, it is usually well-tolerated. Tumor treating fields may be used for tumors in the upper part of the brain (supratentorial) but not for tumors in the back of the brain (the cerebellum).

In some cases (roughly 15% of people), the tumor may appear to initially worsen before responding to tumor treating fields, and this has been seen even in people who have had a "durable response" (were alive seven years after the treatment was started).

Immunotherapy

Immunotherapy is a type of treatment that uses the immune system, or principles of the immune system, to treat cancer. There are, however, many different types of immunotherapy with a few options offering hope in treating recurrent glioblastoma.

Checkpoint Inhibition

As noted above under surgery, combining one type of immunotherapy (a checkpoint inhibitor) before surgery has a significant benefit on survival rate with recurrent glioblastoma. However, the kind of responses sometimes seen with melanoma and lung cancer to these drugs have yet to be seen with glioblastoma. It's thought that part of the reason is that glioblastomas have fewer of a type of immune cells known as T cells in the tumor.

That said, the possibility of combining checkpoint inhibitors with other treatments (for example, oncolytic virus therapy or IL-12) offers hope.

Oncolytic Viruses

One of the more optimistic therapies being studied for recurrent glioblastoma is that of oncolytic viruses. There are several viruses that have been considered and/or evaluated in the lab or in clinical trials on humans, and while some effectiveness has been seen, larger clinical trials are needed. Some of these include DNX-2401 (a recombinant adenovirus), a polio-rhinovirus chimera, parvovirus H-1, Toca 511, dentritic cell vaccines, and more.

Poliovirus: A genetically engineered combination of poliovirus and rhinovirus (polio-rhinovirus chimera) was designed as the poliovirus infects cells that bind to a protein commonly found on glioblastoma cells. In the lab, it was found to lead to the death of cancer cells by stimulating immunity against the tumor, with relatively few side effects (people do not develop polio). A phase I trial (in newly diagnosed patients) in which the virus was injected directly into tumors found that the treatment improved two-year and three-year survival beyond what would be expected with conventional therapy, and two patients were alive more than five years later.

DNX-2401 (tasadenoturev): A clinical trial using a different oncolytic adenovirus (DNX-2401) in people with recurrent glioblastoma also offered promising results, though the study was primarily done to test safety. In this study, 20% of the people treated were alive after three years, and 12% had a reduction of 95% or more of their tumor.

A current phase II trial (CAPTIVE/KEYNOTE-192) is now looking at the combination of DNX-2401 with Keytruda (pembrolizumab).

Other Immunotherapy Options

Several other types of immunotherapy have either been studied to some degree or may be evaluated in the near future. One example is CAR T cell therapy, a treatment that uses a person's own T cells (that are collected and modified) to fight cancer.

While only recently studied in humans, immunotherapy options such as oncolytic viruses offer hope.

Radiation

Re-treating with radiation may sometimes be helpful in improving both survival and quality of life with recurrent glioblastoma. Stereotactic body radiotherapy (SBRT or Cyberknife) is a type of high-dose radiation delivered to a small area of tissue and may offer benefit with less radiation exposure.

Chemotherapy

Chemotherapy may be used for recurrent glioblastoma. When chemotherapy has been previously used, either different drugs or higher doses of the previous drugs are often used. The drug TNZ (temozolomide) is most often used, with drugs such as Cytoxan (cyclophosphamide) and CCNU/CuuNu/Gleostine (lomustine) being studied in clinical trials, but thus far, studies have found significant benefits from other chemotherapy drugs studied.

Angiogenesis Inhibitors

In order for tumors to grow, they need to recruit new blood vessels to supply the tumor with nutrients; a process called angiogenesis. Angiogenesis inhibitors (such as Avastin) have been used along with chemotherapy with some benefit.

Avastin (bevacizumab) was approved in December of 2017 for recurrent glioblastoma, and unlike the severe side effects (such as bleeding) seen in using it to treat some other types of cancer, it seems to have fewer side effects with glioblastoma. Thus far, while it does appear to improve progression-free survival, an effect on overall survival has not yet been seen. That said, for people who received the drug after a first or second recurrence roughly 8% of people were classified as achieving "long term survival."

Endostatin (recombinant human endostatin) is a very strong angiogenesis inhibitor that is also being investigated along with chemotherapy.

Other Targeted Therapies

While the exception, some glioblastomas contain targetable mutations that may be addressed with currently available drugs, and when properly identified and treated, may have a large impact on survival, at least short term. DNA sequencing (DNA and RNA) can identify these anomalies.

DNA sequencing (DNA and RNA) of a glioblastoma tumor may identify people who could benefit from targeted therapies.

Other Treatments

A number of other therapies are also being evaluated in clinical trials including boron neutron therapy, the targeted therapy anlotinib, the STAT3 inhibitor WP1066, Toca 511, exportin inhibitors, and more. Some of the approaches are quite novel, such as targeting glioblastoma stem cells by disrupting the circadian rhythm of cancer cells. A gene found in the Ebola virus has even recently helped researchers uncover a weakness in glioblastoma cells.

Complementary Alternative Therapies

When faced with a cancer that has few treatment options, many people wonder about the option of complementary/alternative therapies. In talking about research in this area, it's important to note that these alternative therapies are not used as a substitute for conventional medical care, but rather as an adjunct to help symptoms and possibly improve the effectiveness of conventional treatments. In fact, a 2018 study found that people who refused standard care to use alternative remedies were more than twice as likely to die from their disease.

Fortunately, recent research looking specifically at glioblastoma suggests that some of these options may play a role in treatment (but only with the very careful guidance of a physician) when combined with standard care.

Intermittent Fasting and the Ketogenic Diet

Intermittent fasting takes many forms, but the type usually considered with cancer is prolonged nighttime fasting, or limiting the consumption of food to a period of roughly eight hours each day. The theory behind intermittent fasting and cancer is that healthy cells adapt much better to changes (such as a decrease in calories) than cancer cells. In laboratory and animal studies, fasting appeared to increase the response of glioma cells to radiation and chemotherapy.

The ketogenic diet, or "ketogenic metabolic therapy" (KMT) likewise has been found to have effects on glioblastoma cells in the lab and animal studies significant enough to have some researchers asking whether ketogenic metabolic therapy should become standard of care for glioblastoma. The diet both reduces the amount of glucose available in the brain (to "feed" the cancer) and produces ketone bodies that seem to have a protective effect on the brain.

Since laboratory and animal studies don't necessarily translate into effects on humans, it's important to look at the few human trials to date. The purpose of these early studies is primarily to address safety and tolerability issues (feasability studies).

In a small 2019 in adults with glioblastoma, there were no adverse effects among those who used the ketogenic diet in combination with chemotherapy and radiation.  A different 2019 study looked at the use of the ketogenic diet in children with recurrent pontine glioblastoma. It found that side effects were only mild and transient.

Cannabinoids

A discussion of the potential treatment options for recurrent glioblastoma would not be complete without mentioning cannabinoids. It is the studies on glioblastoma cells in the lab and animals, in fact, that have given rise to some of the public opinion that "weed might fight cancer." Both laboratory and animal studies have demonstrated cannabinoids to have some effectiveness in treating glioma, and this is consistent with the possible mechanisms of action. While human research is lacking, a phase II study does suggest that cannabinoids may have a positive role on survival, and should be studied more thoroughly in the future.

For those who are using cannabis (under the guidance of their oncologist) for other reasons such as to improve appetite or help with nausea, this research may be reassuring.

Life Expectancy/Prognosis

It's difficult to talk about "average" life expectancy for recurrent glioblastoma for many reasons, but one good reason is that new treatments are being studied, and it's still too early to know if these will change the prognosis.

There are several factors that affect prognosis, including:

  • Age at diagnosis (children tend to have a better prognosis than adults, especially older adults)
  • Performance status (how well a person is able to carry on normal daily activities)
  • Tumor volume (how big and how extensive the tumor)
  • The location of the tumor in the brain
  • The specific treatments used
  • The amount of tumor that could be surgically removed
  • MBMT (O-methylguanine-DNA methyltransferase) promoter methylation
  • IDH1 status
  • Timing of recurrence (earlier recurrence may have a poorer prognosis)

Even with these factors, however, it's important to realize that every person and every tumor is different. Some people do very well despite having a very poor prognosis, and vice versa.

Coping

Coping with a tumor that has the statistics of glioblastoma can be incredibly lonely. Cancer is a lonely disease to begin with, but with glioblastoma, even talking to survivors of other types of cancer may leave you feeling isolated.

Support is Essential

Some people have found immense support via support groups. Since glioblastoma is less common than some other cancers, and the treatments so different, many people with the disease prefer an online support community composed of others coping specifically with glioblastoma. Not only are these groups a source of support, but they can be educational. It's now become relatively common for people to learn about new therapies and clinical trials through their connections with other survivors. After all, it is often people living with the disease who are most motivated to learn about the latest research.

Clinical Trials with Recurrent Glioblastoma

With glioblastoma, it's also important for people to understand the purpose, potential risks, and potential benefits of clinical trials. Many of the newer treatments that are being used for glioblastoma are only being used in clinical trials at the current time.

While the term clinical trial can be frightening, these studies have changed significantly in the recent past. While phase I trials in the past were mostly studies that could benefit other people in the future (and had almost no chance of helping the person in the study), these earliest of human trials can now sometimes make a difference in the survival of the person participating; in some cases this has been dramatic. In other cases (as seen originally with tumor treating fields), a treatment may not obviously improve survival more than other treatments, but may have much fewer side effects.

The reason for this is precision medicine. Instead of randomly studying a compound to see what might happen in people who have cancer, most of the treatments being evaluated today have been carefully designed in pre-clinical studies to target specific pathways in the growth of cancer.

Second Opinions

Getting a second opinion, preferably at one of the larger National Cancer Institute designated cancer centers is something to consider. A 2020 study found that people with glioblastoma who were treated at centers that saw larger volumes of patients with glioblastoma had better outcomes.

Difficult Discussions and Decisions

Talking about the chance that nothing will help is difficult, but these conversations are very important for people with cancer and their families alike. What are your wishes? The language surrounding cancer has done a disservice to many people living with the disease. Cancer isn't a fight that either you or the cancer wins; even when a cancer progresses you are still a winner. You win with how you live your life while you are here.

Courage does not mean receiving treatments that drastically reduce your quality of life with little potential benefit. Sometimes it takes the greatest courage to forego some of these efforts. Most importantly, your cancer is your journey, not that of someone else. In whatever choices you make, whether regarding treatment or how to spend these days, make sure you honor your own heart.

A Word From Verywell

If you have or are worried that you have experienced a recurrence of glioblastoma, you are probably feeling more than frightened. Looking at statistics alone can leave you with a sense that there are few choices. Without tossing out false hope or minimizing your fears, we mention some of the studies above (though we know it can be totally overwhelming) so that you can see that research is in progress. Not only research in a dish in the lab or in mice, but early results of clinical trials in humans looking at immunotherapy, tumor treating fields, and other options that are showing promise. That said, and for now, it's likely that the "ideal" treatment will remain a combination of therapies rather than any single drug or treatment.

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