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.
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.
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.
Well, you might not have noticed that my blogs were missing for the last three months but anyways, its good to be back. I was having a little time off blogs and social media as I was transitioning in my career but now I am back. Sometimes, it is very difficult to manage time for things that you must do versus things you enjoy doing, especially when these two don’t intersect. For me, these last few months the things I had to do were all bureaucratic while I couldn’t find the time for things I enjoy doing like writing these blogs. But now that we are back, let’s recap what has happened in the oncology world in the year 2019 so far. I can’t cover all of them, but will try to summarise the major events in oncology.
Hundred Foxes’ Howl versus One LION’s Roar
In my country, there is a saying that goes somewhat like the roar of one lion will scare hundreds of howling foxes away. In medicine, I guess, it translates as one good RCT trumps the results from hundreds of observational studies. For patients with advanced ovarian cancer, primary surgery to achieve complete resection is the most important treatment and prognostic factor. However, what to do with the lymph nodes is a question that has troubled the oncology community for a long time. Logically, it makes sense to remove the lymph nodes too because they are the sanctuary sites for cancer cells. However, lymph node dissection carries high morbidity. Although multiple observational studies suggested a survival benefit with lymph node dissection, the LION trial, now published in the NEJM, shows that for women with macroscopic complete resection of primary tumour, lymph node dissection increases morbidity (postoperative complications) and post-operative mortality rates but doesn’t improve survival. I am glad that this trial was carried out and these results will now save many women with ovarian cancer worldwide from unnecessary harmful procedures, but I am also sad that we didn’t answer this question until now and thus, many patients suffered unnecessarily. I hope this LION’s roar scares us from jumping to conclusions based on logic or observational data alone and without RCT evidence in future. Another lesson here is the importance of public funds in supporting RCTs like these.
I’m going to show you the Match rate and mean Step 1 score for three groups of residency applicants. These are real data, compiled from the National Resident Matching Program’s (NRMP) Charting Outcomes in the Match reports.
U.S. Allopathic Seniors: 92% match rate; Step 1 232.3
U.S. Osteopathic Seniors: 83% match rate; Step 1 225.8
International Medical Graduates, or IMGs (both U.S. and non-U.S. citizen: 53% match rate; Step 1 223.6
Now. What do you conclude when you look at these numbers?
In the debate over the U.S. Medical Licensing Examination’s (USMLE) score reporting policy, there’s one objection that comes up time and time again: that graduates from less-prestigious medical schools (especially IMGs) need a scored USMLE Step 1 to compete in the match with applicants from “top tier” medical schools.
In fact, this concern was recently expressed by the president of the National Board of Medical Examiners (NBME) in an article inAcademic Medicine (quoted here, with my emphasis added).
“Students and U.S. medical graduates (USMGs) from elite medical schools may feel that their school’s reputation assures their successful competition in the residency application process, and thus may perceive no benefit from USMLE scores. However, USMGs from the newest medical schools or schools that do not rank highly across various indices may feel that they cannot rely upon their school’s reputation, and have expressed concern in various settings that they could be disadvantaged if forced to compete without a quantitative Step 1 score. This concern may apply even more for graduates of international medical schools (IMGs) that are lesser known, regardless of any quality indicator.”
The funny thing is, when I look at the data above, I’m not sure why we would conclude that IMGs are gaining advantage from a scored Step 1. In fact, we might conclude just the opposite – that a scored Step 1 is a key reason why IMGs have a lower match rate.
Say you want to know which baseball players provide the most value for the big dollars they’re being paid. A Google search quickly yields analytics. But suppose your primary care physician just diagnosed you with cancer. What will a search for a “high value” cancer doctor tell you?
Public concern over bloated and unintelligible medical bills has prompted pushback ranging from an exposé by a satirical TV show to a government edict that hospitals list their prices online. But despite widespread agreement about the importance of high-value care, information about the clinical outcomes of individual physicians, which can put cost into perspective, is scarce. Even when information about quality of care is available, it’s often unreliable, outdated, or limited in scope.
For those who are sick and scared, posting health care price tags isn’t good enough. The glaring information gap about the quality of care must be eliminated.
“When people are comparison shopping, knowing the price of something is not enough,” notes Eric Schneider, a primary care physician and senior vice president of policy and research at the Commonwealth Fund. “People want to know the quality of the goods and services they’re buying.”