Renegade Neurosurgeons: Patient Champions or Charlatans?
When Natasha’s life was drawing to an end, she became more dependent on a type of steroid called dexamethasone (Decadron). Dex relieves swelling in the brain but in children it comes at a premium; its side effects can include extreme personality changes, especially depression, muscle wasting, which can limit mobility, and gastritis. In some children, dex can cause such sudden and significant weight gain — especially visible in the face — that they can become virtually unrecognizable.
I was forced to come to terms with the dreadful reality that in the duel between brain tumor and my 12-year-old, the tumor would be the victor. Now I was determined to do anything to maximize her quality of life. I had read about the drug Xerecept that had been tested in a phase I-II clinical trial of dex-dependent pediatric brain tumor patients. Of the 14 children in the trial, 10 had reduced dex by more than 50 percent and five of those 10 had stopped the steroid altogether. “Significant improvements in physical and emotional functioning,” were noted in the drug company’s press release. Great. Where and when could we get it for Natasha, I asked our oncologist.
No response from Bermuda
Our oncologist called the trial’s principal investigator, who directed her to the drug company, Celtic Pharma, located in the surprisingly non Celtic-populated Caribbean islands of Bermuda. Calls were made — many of them. E-mails were sent — many of them. We never did hear from Celtic Pharma, I’m assuming because it was not making the drug available until phase III of the trial, by which time my child would have passed away.
With this experience in mind, I was interested to read about the recent case in which two neurosurgeons have stepped down from their positions at UC Davis (one in June, the other at the end of last month), after offering their terminally ill patients a treatment that, like Xerecept, had not been FDA approved. Unlike Xerecept, it was one that came with substantial risks.
At first blush, the case sounds Mengelean. Dr. J. Paul Muizelaar, former head of neurosurgery, and his colleague Dr. Rudolph Schrot, offered patients with glioblastoma, a highly aggressive brain tumor that is ultimately fatal, a treatment in which bowel bacteria would be surgically implanted behind a bone flap in the skull. When infection developed, antibiotics would be withheld. The theory was that the resulting increase in white blood cells would fight both the infection and malignant cells, buying time for the patient before their inevitable demise.
That theory is substantiated by research, albeit flimsy research. In the journal Neurosurgery, researchers described four cases of malignant brain tumor in which regression co-occurred with infection. In three of those four cases, the bacterium identified from microbial cultures was the same used by the UC Davis neurosurgeons. In another study, also published in Neurosurgery, a “non-definitive” association was found between the longer-term glioblastoma survivors who had an infection and those that did not: 30 months vs. 16 months.
After the treatment, two of the neurosurgeons’ patients died of sepsis weeks later. A third patient lived for a further year, surpassing her prognosis by 10 months. One of the two sepsis patients was administered the treatment before standard radiation and chemotherapy at a time when their prognosis, at Muizelaar’s own estimate, was six to 12 months — facts that undermine the neurosurgeons’ integrity in many people’s eyes. The family of that patient, as well as the daughters of the longer-term surviving patient, have settled claims against the university for six-figure amounts.
Reputations at stake
Muizelaar and Schrot have become lightning rods by medical ethicists, patients’ rights groups and fellow researchers. The doctors did not get approval from the hospital’s internal review board (IRB) or the FDA, tarnishing the reputation of UC Davis and putting Medicare funding in jeopardy, as well as NIH grants for other researchers. The doctors took advantage of vulnerable dying patients. The doctors instilled misplaced trust in the patients and their families.
A few thoughts:
• While Muizelaar and Schrot appeared to have hopped a few fences before administering the controversial treatment, it looks like UC Davis was at least partially complicit. According to the medical journal Nature, Schrot contacted the director of the IRB asking permission to perform the “one-time procedure.” The director said this procedure could be classed as “innovative care,” rather than “research,” thus bypassing the need for both FDA and IRB approval. It wasn’t until Schrot and Muizelaar sought approval to treat an additional five patients, after the initial three, when UC Davis began its internal investigation.
• Dr. Michael Carome, a former top official with the federal Office for Human Research Protections, was quoted in the Sacramento Bee as saying the neurosurgeons took advantage of “highly vulnerable patients who are easily susceptible to suggestions for things that might give them a glimmer of hope.” I’m not convinced that all of these patients were “highly vulnerable,” or at least not in the way that Carome means. The Internet has depolarized the dynamic between cancer patient/caregiver and doctor. A once paternalistic relationship has gradually been replaced by a more egalitarian partnership. As cancer patients or caregivers of cancer patients, many of us seek second and third opinions, share treatment protocols with fellow patients via social media, track clinical trials on the FDA’s website and read peer-reviewed studies on PubMed.
Rabecca Rich, the widow who did not sue and publicly praised both neurosurgeons, suggests that her late husband may have exemplified the patient who made his own medical decisions based on personal preferences and research, rather than blind adherence to a doctor’s suggestion. In a letter published in the Bee, Rich said that her late husband “went into surgery with full knowledge that he might not survive, but potentially would be part of work that would in the future shed light and potential cure to a disease that currently has none.”
• The daughters of the longer-time survivor have blamed the neurosurgeons for winning their trust. “It was the surgeons, they were so believable,” said Janet Bradley in an interview with the Bee. “We trusted everything they did and said.” But the consent form, which Bradley herself read, while not technically valid since the procedure was later determined to be “research” rather than “innovative care,” in no way glossed over the potential for harm, nor did it hint at a positive result. “There is no proof that such treatment might be beneficial, nor are there animal data to support it,” it said. The ensuing infection might cause further harm to the patient, including “paralysis, inability to speak or understand speech, inability to swallow, vegetative state, coma or death.” Bradley said she was also informed that the treatment was not FDA-approved and that the first patient, who had received the treatment weeks ago, might not survive.
What motivated these two neurosurgeons to choose an unorthodox means of treating their patients. Was it compassion, battle fatigue at witnessing their glioblastoma patients decline before their eyes time and time again, or visions of personal glory? Muizelaar and Schrot were banned from performing medical research with human subjects following a six-month internal investigation, which preceded highly critical reviews by an independent body and a federal watchdog agency.
Both neurosurgeons are currently said to be polishing their resumes.