Keynote speech on the JAVELIN not going far enough to improve survival
The treatment landscape for metastatic renal-cell carcinoma has changed dramatically with the introduction of immunotherapies. Unfortunately though, we are promoting combinations over single agents without having much idea of added benefit of each drug. This is an important issue because when we combine two drugs, the only thing we are certain of are the added toxicities. PD-1 inhibitor nivolumab had improved OS when given in second line, however nivolumab was tested in combination with ipilimumab (not as a nivolumab monotherapy) in the first line trial. Now, pembrolizumab and avelumab have followed suit, although their combination partner was axitinib – a VEGF inhibitor. The control arm was sunitinib for both of the trials of pembrolizumab plus axitinib (KEYNOTE 426) and avelumab plus axitinib (Javelin 101). This is a little surprising because we are testing A B versus C, where both A and B haven’t been approved for the given setting – axitinib was approved for RCC in second line. Both these combinations improved PFS versus sunitinib but only the pembrolizumab combination has shown improved OS. However, I have doubts about the contribution of axitinib to these results. What would the outcome be if pembrolizumab alone is followed by sunitinib in second line? It is important to note that only one third of patients who discontinued sunitinib received PD-1 inhibitor subsequently in the KEYNOTE 426 trial. The important question for patients and clinicians would be to consider a survival difference had most of these patients received a PD-1 inhibitor subsequently. As for avelumab, the JAVELIN trial hasn’t reached as far as pembrolizumab and nivolumab have reached: The OS benchmark – so let’s reserve this combination until we see that benefit.
Have we successfully landed on the COMET?
We should remember that this combo-mania with PD-1/PD-L1 inhibitors may also backfire. Previously, the RCTs of nivolumab and pembrolizumab combos were halted in multiple myeloma for higher deaths in the combo arms. Another RCT IMblaze 370 also reports that atezolizumab, alone or in combination with cobimetinib, failed to improve survival versus regorafenib in patients with metastatic colorectal cancer. This time again A B failed versus C although C in itself is a drug with very marginal benefits in this setting. Also, I don’t understand testing A plus B combo when both A and B are unapproved for the disease.
A survey of 200 physicians under the age of 35 showed that 56% reported unhappiness with the current state of medicine. That number didn’t seem surprising to me at first. I was not particularly “happy” at the time of reading this survey either.
I’ve aspired to become an
oncologist for as long as I can remember. In oncology, despite my inability to
cure, I can always try to heal. I form connections with patients and their
families as they embark on a journey that is quite often their last. I learn
from my patients as much as, and at times more than, they learn from me.
But all of this is overshadowed by
a sense of heaviness that I frequently encounter as I enter the clinic room. That
sense of heaviness hits when a patient tells me of the time when they were placed
on a “brief hold” for more than half an hour in order to reach someone to get a
prescription refilled or reschedule an appointment. Or when their insurance refused
to cover the drug that I had prescribed to them. It is when I hear that clinic
visits or treatments are not scheduled due to insurance authorization delays. Or
when I’m asked about the cost of drugs and end up having to explain how nobody
By the time I hear these stories,
the “allotted time” for the clinic visit is coming to an end. The emotional
burden and physical symptoms of my patient’s cancer diagnosis or chemotherapy
side effects often not adequately addressed.
In the 20th century, hospitals completed their
transformation from the hospice-like institutions of the Middle Ages, into
large, gleaming centers of advanced medical expertise and technology that save
and improve lives every day. But an unintended consequence of hospitals’
dazzling capabilities is a staggering cost burden that’s proving toxic to the
Today, hospital care accounts for approximately 33% of the US’ $3.5 trillion annual health care expenditures, according to CMS. The drivers of hospital costs are complex and hard to tackle, including (but not limited to) market consolidation that enables price hikes, heavy administrative burdens, expensive technology and patient usage patterns.
In The Innovator’s Prescription, Clayton Christensen et al. explained another important driver of high hospital care costs: conflation under one roof of business models designed to address very different needs—such as the need for diagnosis of unique, complex conditions and experimental treatments, versus that for highly standardized services (for instance, some surgical procedures). This common phenomenon makes optimization of either business model very difficult, and thus drives up overhead costs.
One solution to this seemingly intractable
problem is to make home and community the default locations for care, where in
many circumstances it can be provided less expensively, more conveniently, and
more effectively than in a hospital. Fortunately, business model innovation
toward this end is gaining traction.
Fifteen years ago, as a medical student, I learned a
terrifying lesson about blindly using race-based medicine. I was taking care of
Mr. Smith, a thin man in his late 60s, who entered the hospital with severe
back pain and a fever. As the student on the hospital team, I spent over an
hour interviewing him, asking relevant questions about his medical and social history,
the medications he took, and the details of his symptoms. I learned Mr. Smith
was a veteran who ran into tough times that left him chronically homeless,
uninsured, and suffering from hypertension and diabetes. I performed a complete
physical exam, paying particularly close attention to his back. Upon reviewing
his blood tests and kidney function, I read the computer’s report: “normal.”
I felt confident as I presented Mr. Smith’s treatment plan
to my attending physician: I recommended a CT scan, ibuprofen for pain, blood
pressure lowering medication, and an antibiotic. My attending listened quietly,
reviewed the labs herself, and then firmly corrected every aspect of my
treatment proposal. “His kidney function is NOT
normal. What you want to do for him can further damage his kidneys. The lab
reported his creatinine as ‘normal’ because it has an algorithm that makes
faulty assumptions based on race.” Mr. Smith, according to the medical record,
was African American.
I almost harmed Mr. Smith because I hadn’t realized that the exact same creatinine level (the key metric for kidney function) yields two different reports based on whether you’re African American or not. The logic goes that because black people supposedly have higher muscle mass on average, healthy creatinine levels for those who check the “black” box is different from those who check other boxes. Physicians around the country continue to rely on this metric even when the black patient is thin, like Mr. Smith. This example of race-based creatinine levels to determine kidney function is a symptom of race-based medicine in general: (poorly defined) racial categories are often used as proxies to explain discrepancies in health outcomes by race, which is a potentially dangerous analysis. Mr. Smith’s case forced me to consider why race-based medicine is problematic and where our attention as healthcare providers should be directed instead.
What is certain is that health inequities persist along racial lines. African Americans and Hispanics have higher rates of diabetes, hypertension, and heart disease than other groups (Figure 1). American Indians and Alaskan Natives are 2.1 times as likely to be diagnosed with diabetes as white individuals and the prevalence of obesity in this population is higher than any other group. While it would be convenient to attribute these disparities to genetic difference, this is simply not the case.
In my mid-twenties, I was twice prescribed the common antihistamine
Benadryl for allergies. However, my body’s reaction to the drug was anything
but common. Instead of my hives fading, they erupted all over my body and my
arms filled with extra fluid until they were almost twice normal size. I subsequently
described my experience to a new allergist, who dismissed it as “coincidence.”
When I later became a nurse, I learned that seemingly “harmless” medications often cause harm, and older adults are particularly vulnerable. Every year, Americans over age 65 have preventable “adverse drug events” (ADEs) that lead to 280,000 hospital stays and nearly 5 million outpatient visits. The Lown Institute in Boston draws attention to this underrecognized problem in their recent report, Medication Overload: America’s Other Drug Problem. Policymakers, patients, and health professionals must act, because over the next decade, medication overload is predicted to cause 4.6 million hospitalizations of older Americans and 150,000 premature deaths.
Nearly half of all older adults take at least five
prescription drugs, a 300 percent increase from 25 years ago. The
more drugs we take, the likelier it is that one of them, or some combination,
will cause serious harm. When you add in non-prescription medications,
including over-the-counter drugs like ibuprofen and Tylenol, as well as
vitamins and herbal supplements, the potential for harm only goes up.
I’ve seen this in my
work. It is not unusual for elderly, very ill patients on hospice to have
prescriptions for 20 to 30 drugs. Several of their medications may treat the
same problem, amplifying any serious side effects. Blood pressure medications provide
a good example. As older patients become more debilitated, lose weight, and are
taxed by other health issues, the effect of these medications can intensify,
severely lowering blood pressure, and causing the patients to fall. Indeed, if
I am following up with a hospice patient who has fallen, the first thing I
check is their prescription medications for hypertension.
By SAMYUKTA MULLANGI MD, MBA, DANIEL W. BERLAND MD, and SUSAN DORR GOOLD MD, MHSA, MA
Jenny, a woman in her twenties with morbid obesity (not her real name), had already been through multiple visits with specialists, primary care physicians (PCPs), and the emergency department (ED) for unexplained abdominal pain. A plethora of tests could not explain her suffering. Monthly visits with a consistent primary care physician also had little impact on her ED visits or her pain. Some clinicians had broached the diagnosis of functional abdominal pain related to her central adiposity, and recommended weight loss. This suggestion inevitably led her to become defensive and angry.
our standard screen for safety at home had been completed long ago, I wanted to
probe further, knowing that many patients with obesity, chronic pain and other
chronic conditions have suffered an adverse childhood – or adulthood –
experience (ACE). Yet, I hesitated. Would a busy primary care setting offer enough
latitude for me to ask about a history of trauma when it can occur in so many
forms, in so many ways and at different times of life? Furthermore, suppose she
did report a history of trauma or adverse experience. What then? Would I be
able to help her?
I began: “Jenny, many patients with symptoms like yours have been abused,
either emotionally, physically, or sexually, or neglected in their past.
Sometimes they have suffered loss of a loved one, or experienced or witnessed
violence. Has anything like this ever happened to you?”
yielded our first breakthrough. Yes, she had experienced neglect, with parents
who were separated for much of her childhood, and then later divorced. She had
seen her father physically abuse her mother. With little parental oversight,
she had engaged in drug and alcohol use throughout her teenage years. But, she
wanted to be sure we understood that this was all behind her. She had gotten an
education, was in a committed relationship, and had a stable job as a teacher.
That part of her life was thankfully now closed.
In this episode of Radiology Firing Line Podcast, I speak with Bishal Gyawali MD, PhD. Dr. Gyawali obtained his medical degree from Kathmandu. He received a scholarship to pursue a PhD in Japan. Dr. Gyawali’s work focuses on getting cheap and effective treatment to under developed parts of the world. Dr. Gyawali is an advocate for evidence-based medicine. He has published extensively in many high impact journals. He coined the term “cancer groundshot.” He was a research fellow at PORTAL. He is currently a scientist at the Queen’s University Cancer Research Institute in Kingston, Ontario.
As news of Tom Brokaw’s cancer diagnosis spreads, so does his revelation that his cancer treatments cost nearly $10,000 per day. In spite of this devastating diagnosis, Mr. Brokaw is not taking his financial privilege for granted. He is using his voice to bring attention to the millions of Americans who are unable to afford their cancer treatments.
My patient Phil is among them. At a recent appointment, Phil
mentioned that his wife has asked for divorce. When I inquired, he revealed a
situation so common in oncology, we have a name for it: Financial
Toxicity. This occurs when the burden of medical costs becomes so high,
it worsens health and increases distress.
Phil, at the age of 53, suffers with the same type of bone
cancer as Mr. Brokaw. Phil had to stop working because of treatments and
increasing pain. His wife’s full time job was barely enough to support
them. Even with health insurance, the medical bills were mounting. Many
plans require co-pays of 20 percent or more of total costs, leading to insurmountable
patient debt. Phil’s wife began to panic about their future and her debt
inheritance. In spite of loving her husband, divorce has felt like the only
solution to avoiding financial devastation.
Discouraging headlines remind us daily of the ugly battles between payers and providers. Fighting for their slice of the $3.5 trillion health care pie, these companies often seem to leave the consumer out of the equation. But it is not the case across the board. Our latest research documents that when doctors and health plans drop their guards, align incentives and focus on the mutual goal of delivering the best possible care, patients win.
For example, when SelectHealth in Utah
partnered with obstetricians and refused to pay for medically unnecessary — often
dangerous — early inductions of labor,
procedure rates dropped from 28% to zero, leading to shorter labors, fewer
C-sections and $2.5 million in annual savings for all. When Kaiser Foundation Health
Plan execs collaborated with Permanente doctors around opioid safety, prescriptions
for the often-deadly drugs dropped 40%. And, when Security Health Plan in
Wisconsin enlisted physicians and surgeons to develop a new outpatient surgery
and rehab center, health outcomes improved; patient satisfaction jumped to 98%;
and they saved $4.7 million in the first two years.
Back in the
‘stone ages’ when I (an MIT grad) was an intern, I was called at 4 AM to see
someone else’s gravely ill patient because her IV had infiltrated. I
started a new one and drew some blood work to check on her status. When
the results came back (on paper) I (manually) calculated her anion gap.
This is simple arithmetic but I had been up all night and didn’t do it right.
rounds the attending assured me that there was nothing I could have done anyway
but, of course, in other circumstances it could have made a difference and an
EHR could have easily done this calculation and brought the problematic result
to my attention. My passion for EHRs and FHIR apps to improve them really
traces back to this patient episode I will never forget.
My criticism of the recent Kaiser Health News and Fortune article Death by 1000 Clicks is generally not about what it says but what it doesn’t say and its tone.
The article emphasizes the undeniable fact that EHRs cause
new sources of medical error that can damage patients. It devotes a lot of ink
to documenting some of these in dramatic terms. Yes, with hundreds of vendors
out there, the quality of EHR software is highly variable. Among the major
weaknesses of some EHRs are awkward user interfaces that can lead to errors. In
fact, one of the highlights of my health informatics course is a demonstration
of this by a physician whose patient died at least in part as a result of a
poor EHR presentation of lab test results.
However, the article fails to pay equal attention to the
ways EHRs can, if properly used, help prevent errors. It briefly mentions that
around a 60% majority of physicians using EHRs feel that they improve quality. The
reasons quality is improved deserved more attention. The article also fails to
discuss some of the new, exciting technologies to improve EHR usability through
innovative third party apps and he real progress being made in data sharing
including patient access to their digital records.