In addition, clinicians are now hoping that utilizing real-time magnetic resonance imaging (MRI) guidance for delivery of gene therapy may further help improve outcomes for patients with glioblastoma.
Survival Rates in Patients with Glioblastoma Examined
“We have a long way to go, but I think for the very first time people are really optimistic,” said glioblastoma expert Lisa DeAngelis, MD, Chair of the Department of Neurology at Memorial Sloan-Kettering Cancer Center, New York, NY. “The issue of targeted therapy is very complicated and the initial attempts in glioblastoma have been disappointing. I think bevacizumab can be very helpful. Not everyone responds of course, which is not a surprise, but many people do, and many people have improved quality of life, improved functional status, and improved status on imaging.”
Bevacizumab was approved by the U.S. Food and Drug Administration (FDA) in 2009 for the treatment of recurrent glioblastoma. The approval was based on promising radiographic response data, although there was a lack of strong evidence for improved overall survival (OS) in patients with glioblastoma.
However, researchers at the Mayo Clinic who recently analyzed data on 5,607 adult patients from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database before and after the approval of bevacizumab for the treatment of glioblastoma; results of the analysis found patients are, in fact, living significantly longer following the drug’s approval.1
The researchers also examined the survival rates of glioblastoma patients; this analysis included 1,715 patients who died in 2006; 1,924 patients who died in 2008; and 1,968 patients who died in 2010. The researchers found that the difference in survival between 2008 and 2010 was highly significant and likely unrelated to any advances in supportive care. The median survival was 8 months for patients who died in 2006 and 7 months for patients who died in 2008. However, the median survival was 9 months for patients who died in 2010.
“Bevacizumab is the success story of the targeted therapies [for glioblastoma] to date. Most trials of other targeted agents have been disappointing so far,” said lead study author Derek Johnson, MD, who is a neuro-oncologist at the Mayo Clinic Cancer Center, Rochester, MN.
According to Dr. Johnson, this current study provides the strongest evidence to date that bevacizumab therapy improves survival in this patient population. However, Dr. Johnson also indicated during an interview with ChemotherapyAdvisor.com, “There are patients who respond very well and some who don’t respond at all.” This emphasizes that further study is needed to help define which patients will and won’t benefit from this therapy.
Real-Time MRI-Guided Gene Therapy for Glioblastomas
Neurosurgeons at the University of California, San Diego School of Medicine are now using MRI guidance for delivery of a novel investigational gene therapy for brain tumors called Toca 511 (vocimagene amiretrorepvec), which is a retrovirus engineered to selectively replicate in cancer cells. It produces an enzyme that converts the antifungal drug flucytosine (5-FC) into the anticancer drug 5-fluorouracil (5-FU). After injection of Toca 511, patients are treated with an investigational extended-release oral formulation of 5-FC called Toca FC.
Currently, there are two multicenter trials involving the Toca 511 virus for recurrent malignant gliomas: each trial includes approximately 40 out-patients. With this approach, they are given oral tablets of Toca FC for 6 to 8 days every 4 to 7 weeks.
“The Toca 511 approach uses a live virus that does not kill tumor cells directly. This allows the virus to replicate and spread throughout the tumor with time, providing better distribution. Only when the patient takes the Toca FC tablets do the infected cancerous cells die,” said study investigator David Piccioni, MD, who is a neuro-oncologist at the University of California San Diego Moores Cancer Center, San Diego, CA.
Previous efforts using gene therapy to treat brain cancer have been limited by the ability to deliver the drug into the brain. With this new approach, 5-FC crosses the blood-brain barrier, and provides direct access of Toca 511 into the tumor provides a means to selectively generate chemotherapy within the tumor mass.
“Toca 511 is an exciting new treatment modality currently under investigation,” Dr. Piccioni told ChemotherapyAdvisor.com. “Malignant gliomas are currently incurable cancers that often progress rapidly, and the average survival is less than 2 years. Following years of virtually no progress, we have made improvements in the treatment of gliomas over the last decade.”
Repeat Surgeries May Help Extend Life
In 2010, more than 688,096 people in the United States were living with the diagnosis of a primary brain or central nervous system tumor, according to the American Brain Tumor Association. They estimate that gliomas (e.g., all tumors arising from the gluey or supportive tissue of the brain) represent 30% of all brain tumors and 80% of all malignant tumors. Glioblastomas, which represent an estimated 17% of all primary brain tumors and 54% of all gliomas, return in the majority of cases after tumor-removal surgery, chemotherapy, and/or radiation.2
With recurrence being so common, clinicians have questioned the value of performing second, third, or even fourth operation, especially given the dangers of these types of surgeries. However, researchers at Johns Hopkins University School of Medicine in Baltimore, MD, have found that repeat surgeries are associated with longer survival.3
For this study, the investigators reviewed the records of 578 patients who underwent surgery to remove a glioblastoma between 1997 and 2007 at The Johns Hopkins Hospital. At the last follow-up, 354 patients had one surgical resection, 168 patients had two resections, 41 patients had three resections, and 15 patients had four resections. Data revealed that the median survival for patients who underwent one surgery was 6.8 months; however, it was 15.5 months for patients who underwent two surgeries, 22.4 months for patients who had three surgeries, and 26.6 months for patients who had four surgeries.
“We definitely feel the findings of this study are relevant because it shows that at least some patients can benefit from repeated resections. Patients with glioblastoma can have hope that surgery plays an important role in their care. Obviously, our study was retrospective, so a prospective study would be needed to truly evaluate the effects of repeated resections,” said study investigator Kaisorn Chaichana, MD, a neurosurgery resident at John Hopkins University School of Medicine.
Survival rates are increasing in patients with glioblastomas, but this increase is not overwhelmingly dramatic. Oftentimes, patients are not offered repeat surgeries because it is assumed that the risks will outweigh the benefits, described Dr. Chaichana. However, this study questions that assumption. “There are factors that we as clinicians can do to maximize outcomes, and that includes repeated resections, maximal safe resections without causing deficits, and different types of chemotherapies,” Dr. Chaichana told ChemotherapyAdvisor.com.
In addition to surgery, advances in gene therapy and the use of bevacizumab in certain patients with glioblastoma have the potential to extend survival times and ultimately improve outcomes for individuals who would otherwise have a poor prognosis.
1. Johnson DR, Leeper HE, Uhm JH. Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: A population-based analysis. Cancer. 2013 Jul 18. doi: 10.1002/cncr.28259. [Epub ahead of print]
2. American Brain Tumor Association. Glioblastoma. http://www.abta.org/understanding-brain-tumors/types-of-tumors/glioblastoma.html. Last accessed September 3, 2013.
3. Chaichana KL, Zadnik P, Weingart JD, et al. Multiple resections for patients with glioblastoma: prolonging survival. J Neurosurg. 2013 Apr;118(4):812-20. doi: 10.3171/2012.9.JNS1277. Epub 2012 Oct 19.