A Q&A with Martin Brown D.Phil, FASTRO, Emeritus Professor, and Lawrence Recht, MD, Professor, at Stanford University’s Department of Neurology
Q: The treatment of glioblastoma multiforme (GBM) is a serious challenge. Recurrence after initial surgery is common and subsequent treatment almost always unsuccessful. Just as “an army marches on its stomach,” GBM growth depends on blood supply. Successful use of the FDA-approved drug plerixafor (Mozobil) combined with irradiation for mouse model gliomas some years ago has lead to clinical trials in human GBM.
What is the current status of these investigations, and how could our readers help the effort?
A: A little over ten years ago, Dr. Brown began a series of preclinical studies to test the possibility that an important contributor to the recurrence of malignant brain tumors after radiation therapy was reconstitution of the tumor vasculature. Specifically, he hypothesized that this reconstitution stemmed at least in part from circulating pro-angiogenic cells not in the tumor at the time of radiation—a phenomenon known as “vasculogenesis.” In agreement with this concept, a finding common to all of the tumor models he tested was a major influx into the irradiated tumors of bone marrow-derived cells, most of which were macrophages, that correlated with when tumors began to grow two to three weeks after completion of radiation. Further, he demonstrated that the mechanism for this influx was a radiation-induced hypoxia that triggered a cascade that led to the secretion of stromal cell-derived factor-1 (SDF-1), which was instrumental in attracting these cells. The apparent importance of excluding these cells’ entry into tumors post-irradiation suggests a new treatment strategy, which we call macrophage exclusion radiation therapy (MERT). Continue reading…
“Instructing the immune system to recognize and kill tumours, an approach termed cancer immunotherapy, has transformed the clinical treatment of certain types of malignancy. Prominent among these therapies are immune-checkpoint inhibitors, which block the action of proteins that dampen immune-cell responses against tumours. For example, antibodies can be used to interfere with the inhibitory protein PD-1, which is present on T cells, a type of immune cell that attacks tumours. Immune-checkpoint inhibitors have been most successfully used to treat cancers, such as melanomas, that are well infiltrated by T cells and have a large number of genetic mutations. A subset of these mutations might generate neoantigens — altered protein sequences that are uniquely produced in cancer cells and are recognized as foreign by the immune system.”
“A new study from Helsinki University Hospital, University of Helsinki and the Finnish Cancer Registry shows that survival after glioblastoma has improved since the millennium. The improvement in survival was, however, modest in elderly patients, raising concerns whether current treatment strategies are optimal for this patient group.
“Glioblastoma is the most common brain cancer, and one of the deadliest cancers known. Unfortunately, there is no cure for these rapidly progressing tumors.”
In the summer of 2016, Sheena’s father called her from the emergency room. Her mother Shobha, a fitness trainer in the Bay Area, had experienced a seizure, and the doctors suspected a brain tumor. “I packed and moved back home from the east coast the next day,” Sheena says.
Shobha later had surgery to remove the tumor and received a diagnosis of glioblastoma (GBM). Her oncologist prescribed a standard GBM treatment of radiation and chemotherapy, but she had a bad reaction to the chemotherapy drug Temodar, and had to stop the medication.
“That threw us off completely because there are very few treatment options for GBM,” says Sheena, who has a master’s degree in public health and had previously worked in an oncology department. Shobha’s doctor advised that she wait and watch for tumor growth, but she and her family weren’t comfortable with inaction.
“I’ve had my own medical challenges and learned over the years how to advocate for myself,” Sheena says. “People assume that you should do whatever the doctor says, which is a good place to start, but I’ve found that you shouldn’t stop there.”
The family began looking into other treatment options for Shobha. “Every night, we researched clinical trials on ClinicalTrials.gov, and called the medical centers with trials in the morning,” Sheena says.
Meanwhile, they sought guidance from ASK Cancer Commons’ Emma Shtivelman and from previously featured Super Advocate Stephen Western. Emma and Stephen helped Shobha’s family sort through the many complex enrollment requirements for each trial, and narrow the options to trials with potentially more promising treatments.
“They were really our brainstorming partners through all of this because we didn’t know who else to talk to,” Sheena says. “It was a huge comfort to have them available as we navigated this new, scary territory.”
Shobha ended up receiving treatment with an immunotherapy drug and a device called Optune. She also tried a number of other therapies, and worked with oncology nutritionist Patrice Surley, to incorporate dietary changes and supplements. It wasn’t an easy transition, but improving the odds for her was the main focus.
Meanwhile, although she couldn’t do many of the exercises herself, she continued teaching fitness classes out of her home studio as she had for 15 years, while Sheena and her father worked from home.
“She would teach while sitting with her cane, and her clients said that her workouts got a lot more difficult now that she didn’t do the exercises with them,” Sheena says. “They love her. Working also focused her mind on something positive and off the difficult diagnosis and treatments.”
A year later, Shobha’s symptoms gradually returned, and her family pushed for an MRI, which revealed that the tumor had regrown. To their dismay, the size of the tumor disqualified her from participating in a particularly promising clinical trial that involved surgery plus injection of MDNA55, a toxin that targets glioblastoma cells.
At this point, Shobha had started travelling to Los Angeles regularly to receive second opinions from Santosh Kesari, MD, PhD, a neuro-oncologist recommended by glioblastoma survivor and patient advocate Greg Cantwell.
“Dr. Kesari really, really fought for my mother,” Sheena says. After battling paperwork, back-and-forth calls, and a rollercoaster of promise and disappointment, Dr. Kesari, her neurosurgeon Dr. Achrol, and their team were able to arrange for Shobha to receive the MDNA55 treatment through the U.S. Food and Drug Administration (FDA)’s compassionate use program.
The treatment worked well for Shobha for a year, though she experienced some side effects. She is currently undergoing treatment in Los Angeles for a different trial.
Lessons for Caregivers
Brain tumors are incredibly challenging on the patient and patient’s family due to any number of unexpected symptoms that can show up depending on the tumor location, and medication side effects, including physical limitations such as walking or using the bathroom to cognitive decline, memory and speech issues, vision issues, and extreme personality changes. For this reason, it is also one of the most financially difficult diseases on the patient and family. Professional caregivers can be hired but are usually not covered by insurance.
Through all of this, Sheena and her father have learned some key aspects of being caregivers. They recommend that families prepare for a lot of emotional ups and downs, which can come with any difficult diagnosis. Everyone deals with such news differently, so they urge families to try to be kind to one another as they adjust to the word “cancer.”
From a practical standpoint, after every scan, Sheena suggests getting multiple copies of the cd so that it’s ready to quickly mail out to brain tumor centers, if needed. It’s helpful to keep an updated Word/Excel file of all the latest results, labs, scans etc., so that precious time isn’t wasted collecting that data, in case it is needed for clinical trials and new physician appointments. She also says she wishes she had registered her mother as a patient in more hospitals when she was feeling well, so that they could easily get appointments and more opinions later on when they needed them urgently.
For seeking out information on treatment and other aspects of the glioblastoma experience, Sheena recommends online support groups (such as those found at Inspire and Facebook), as well as services like ASK Cancer Commons and people like Stephen and Greg.
She suggests connecting with the hospital social worker early to help pursue options, such as disability benefits, paid family leave, unemployment benefits, or other government programs, should they be needed. On the same note, it may be helpful to connect with close family, friends, a pastor or priest, and other key people who can help. “Many people are very willing to help, they often just don’t know how,” Sheena says. “So, it’s okay to ask for specific help.”
Crucially, she emphasizes the importance of finding doctors who are a good fit. “It really has to feel like they’re on your team and you can be very open with them.”
And lastly, Sheena advises always advocating for the best possible care. “So often, we put the responsibility on the doctor and just assume that’s the way it is. But it really is your own responsibility,” she says. “It’s an attitude shift. We have to be proactive in the process, and always remember that there is hope.”
Super Patients are cancer survivors who learned to be more engaged in their own care. Cancer Commons believes every patient can be a Super Patient or benefit from a Super Caregiver or Super Advocate. We hope these stories will provide inspiration and hope for your or your loved one’s own treatment journey.
“Magnetic resonance imaging-guided laser interstitial thermal therapy (LITT) appears to be safe and effective for glioblastomas in select patients and may add an average of 2 months to life expectancy compared with the current standard of care, according to a new report published in the journal Neurosurgery.
” ‘We showed that the procedure is well tolerated and that recurrent patients had a meaningful clinical benefit that seems to be better when compared with previously published data on the current standard of care,’ said Eric Leuthardt, MD, senior study author and a professor of neurosurgery, neuroscience, biomedical engineering, and mechanical engineering & applied science at Washington University School of Medicine in St. Louis, Missouri.”
A Q&A with Al Musella, DPM, President, Musella Foundation For Brain Tumor Research & Information, Inc., Hewlett, NY; email: firstname.lastname@example.org, phone: 888-295-4740
Q: You direct an established foundation that supports research and information about brain tumors. What would you do if you yourself were diagnosed with a glioblastoma multiforme (GBM)?
A: Now that GBMs are in the news again, I would like to discuss what I would do if it happened to me—a newly diagnosed GBM in an adult in otherwise good shape. There are several choices.
Standard of care: Surgery, radiation, Temozolomide. Chance of 5 year survival is about 5%.
Standard of care PLUS Optune. Bumps my chance of 5 year survival up to 24.9% (if used over 90% of the time) with no added toxicity.
Phase 3 Clinical trials: There are now about nine phase 3 trials for newly diagnosed GBM. Some have impressive phase 1 and phase 2 data. By the time a treatment gets to phase 3, it has shown enough promise in earlier trials that the sponsor is willing to risk a lot of money to test in a phase 3 trial. Most have two big downsides: 1) Most have a control group of patients who receive the old standard of care so that some of the participants do not get the experimental treatment. 2) Most do not allow you to use Optune, so you are trading a known benefit for a chance at an unknown benefit.
Phase 1 or 2 trials: There are about 75 of these trials in the USA. There are many interesting choices here, but we do not have enough data to make an informed decision on which one to try. We do have early results from some phase 1 trials, which are much better than those seen with standard therapies, but it is not likely that any one of these alone will make a big difference in survival for most patients. We do not (under the current system) have the ongoing results of these trials—we only get the results a few months after the trial is over. And while inside the trial, we cannot combine them with other treatments.
Off label use of drugs approved for other diseases. There are many choices here and a rational approach might be to select a “cocktail of drugs” based on a genomic analysis of my tumor.
Cocktail approach involving experimental and approved treatments. Right now, this is impossible or very difficult to obtain. However, if it were possible, this would be my approach. Especially if we had a registry of all of the patients, the treatments tried, and the outcomes so we can learn from every patient.
“The first patient has been dosed in a phase I/II open-label, multicenter trial investigating a novel immunotherapy combination in patients with newly diagnosed glioblastoma (GBM). Fifty patients have been accrued in the trial, as of May 31, 2018, which will be conducted at 25 sites across the nation.
“This study aims to investigate the efficacy of INO-5401, a T-cell activating immunotherapy agent encoding multiple antigens in GBM, and INO-9012, an immune activator encoding IL-12, in combination with the PD-1 inhibitor cemiplimab (REGN2810).”
“A genetically modified poliovirus may help some patients fight a deadly form of brain cancer, researchers report.
“The experimental treatment seems to have extended survival in a small group of patients with glioblastoma who faced a grim prognosis because standard treatments had failed, Duke University researchers say.
” ‘I’ve been doing this for 50 years and I’ve never seen results like this,’ says Dr. Darell Bigner, the director emeritus of the The Preston Robert Tisch Brain Tumor Center at the Duke Cancer Institute, who is helping develop the treatment.”
“A new way of treating glioblastoma — the deadly brain tumor currently ailing Arizona Sen. John McCain — with a personalized vaccine is giving some patients in a clinical trial more time.
“The vaccination, called DCVax-L, is made out of a patient’s own cells and uses them to jumpstart the immune system and attack the tumor. In the trial, some patients survived for more than 36 months — more than a year and a half longer than current life expectancy after glioblastoma diagnosis.”