summarize this "The final and perhaps most important tool in our anticancer arsenal is early,
aggressive screening. This remains a controversial topic, but the evidence is
overwhelming that catching cancer early is almost always net beneficial.
Unfortunately, the same problem that I encountered in residency applies
today: too many cancers are detected too late, after they’ve grown and spread
via metastasis. Very few treatments work against these advanced cancers; in
most cases, outside of the few cancers that respond to immunotherapies, the
best we can hope for is to delay death slightly. The ten-year survival rate for
patients with metastatic cancer is virtually the same now as it was fifty years
ago: zero. We need to do more than hope for novel therapies.
When cancers are detected early, in stage I, survival rates skyrocket. This
is partly because of simple math: these earlier-stage cancers comprise fewer
total cancerous cells, with fewer mutations, and thus are more vulnerable to
treatment with the drugs that we do have, including some immunotherapies. I
would go so far as to argue that early detection is our best hope for radically
reducing cancer mortality.
This claim makes intuitive sense, but it is supported by even a cursory
look at data comparing success rates at treating specific cancers in the
metastatic versus adjuvant (i.e., postsurgical) setting. Let’s look at colon
cancer first. A patient with metastatic colon cancer, which means the cancer
has spread past their colon and adjacent lymph nodes to another part of the
body, such as the liver, will typically be treated with a combination of three
drugs known as the FOLFOX regimen. This treatment yields a median
survival time of about 31.5 months,
[*5] meaning about half of patients live
longer than this, and half do not. Regardless, virtually none of these patients
will be alive in ten years. If a patient undergoes successful surgery for stage
III colon cancer, which means all the cancer was removed and there was no
visible spread to distant organs, then the follow-up care is treatment with the
exact same FOLFOX treatment regimen. But in this scenario, fully 78.5
percent of these patients will survive for another six years—more than twice
as long as median survival for the metastatic patients—and 67 percent of
them will still be alive ten years after surgery. That’s an impressive difference.
So what explains it? The difference has to do with the overall burden of
cancer cells in each patient. In advanced, metastatic cancer there are tens if
not hundreds of billions of cancer cells in need of treatment. In less advanced
cancers, while there are undoubtedly still millions, if not billions, of cancer
cells that have escaped the surgeon’s scalpel, the far lower population means
they will also have fewer mutations and thus less resistance to the treatment.
It’s a similar story for patients with breast cancer. Patients with HER2-
positive metastatic breast cancer
[*6] can expect a median survival time of just
under five years, with standard treatment consisting of three chemotherapy
drugs. But if our patient has a smaller (< 3 cm), localized, HER2+ tumor that
is removed surgically, plus adjuvant treatment with just two of these chemo
drugs, she will have a 93 percent chance of living for at least another seven
years without disease. The lower a patient’s overall tumor burden, the more
effective our drugs tend to be—and the greater the patient’s odds of survival.
Again, just as with immunotherapy treatment, it’s a numbers game: the fewer
cancerous cells we have, the greater our likelihood of success.
The problem is that we’re still not very good at detecting cancer in these
early stages—yet. Out of dozens of different types of cancers, we have
agreed-upon, reliable screening methods for only five: lung (for smokers),
breast, prostate, colorectal, and cervical. Even so, mainstream guidelines have
been waving people away from some types of early screening, such as
mammography in women and blood testing for PSA, prostate-specific
antigen, in men. In part this has to do with cost, and in part this has to do
with the risk of false positives that may lead to unnecessary or even
dangerous treatment (entailing further costs). Both are valid issues, but let’s
set aside the cost issue and focus on the false-positive problem.
Medicine 2.0 says that because there are significant false positives with
certain tests, we shouldn’t do these tests on most people, period. But if we put
on our Medicine 3.0 glasses, we see it differently: these tests are potentially
useful, and they’re just about all we have. So how can we make them more
useful and accurate?
With all diagnostic tests, there is a trade-off between sensitivity, or the
ability of the test to detect an existing condition (i.e., its true positive rate,
expressed as a percentage), and specificity, which is the ability to determine
that someone does not have that condition (i.e., true negative rate). Together,
these represent the test’s overall accuracy. In addition, however, we have to
consider the prevalence of the disease in our target population. How likely is
it that the person we are testing actually has this condition? Mammography
has a sensitivity in the mideighties and a specificity in the low nineties. But if
we are examining a relatively low-risk population, perhaps 1 percent of whom
actually have breast cancer, then even a test with decent sensitivity is going to
generate a fairly large number of false positives. In fact, in this low-risk
group, the “positive predictive value” of mammography is only about 10
percent—meaning that if you do test positive, there is only about a one-in-ten
chance that you actually have breast cancer. In other populations, with greater
overall prevalence (and risk), the test performs much better.
The situation with mammography illustrates why we need to be very
strategic about who we are testing and what their risk profile might be, and to
understand what our test can and can’t tell us. No single diagnostic test, for
anything, is 100 percent accurate. So it is foolish to rely on just one test, not
only for breast cancer but in many other areas as well. We need to think in
terms of stacking test modalities—incorporating ultrasound and MRI in
addition to mammography, for example, when looking for breast cancer.
With multiple tests, our resolution improves and fewer unnecessary
procedures will be performed.
In short, the problem is not the tests themselves but how we use them.
Prostate cancer screening provides an even better example. It’s no longer as
simple as “Your PSA number is X or higher, and therefore we must biopsy
your prostate, a painful procedure with many unpleasant possible side
effects.” Now we know to look at other parameters, such as PSA velocity (the
speed at which PSA has been changing over time), PSA density (PSA value
normalized to the volume of the prostate gland), and free PSA (comparing
the amount of PSA that is bound versus unbound to carrier proteins in the
blood). When those factors are taken into account, PSA becomes a much
better indicator of prostate cancer risk.
Then there are other tests, such as the 4K blood test, which looks for
specific proteins that might give us a better idea of how aggressive and
potentially dangerous the patient’s prostate cancer might be. The key question
we want to answer is, Will our patient die with prostate cancer, as many men
do, or will he die from it? We’d rather not disrupt his life, and potentially do
him harm, in the course of finding out. Combining these blood tests I’ve just
described with the techniques of multiparametric MRI imaging means that
the likelihood of performing an unnecessary biopsy or surgery is now very
low.
There is a similar but quieter controversy around screening for colorectal
cancer (CRC), which has long been a rite of passage for those in middle age.
[*7] The purpose of the colonoscopy is to look not only for full-fledged tumors
but also for polyps, which are growths that form in the lining of the colon.
Most polyps remain small and harmless and never become cancerous, but
some have the potential to become malignant and invade the wall of the
colon. Not all polyps become cancer, but all colon cancers came from polyps.
This is what makes a colonoscopy such a powerful tool. The endoscopist is
able not only to spot potentially cancerous growths before they become
dangerous but also to intervene on the spot, using instruments on the
colonoscope to remove polyps for later examination. It combines screening
and surgery into one procedure. It’s an amazing tool.
Traditional guidelines have recommended colorectal cancer screenings for
average-risk people ages fifty to seventy-five. These preventive screenings are
fully covered under the Affordable Care Act, and if no polyps are found and
the patient is of average risk, the procedure needs to be repeated only every
ten years, according to consensus guidelines. But there is ample evidence out
there that age fifty may be too old for a first screening, even in patients with
average risk factors (that is, no family history of colon cancer and no personal
history of inflammatory bowel disease). About 70 percent of people who are
diagnosed with CRC before the age of fifty have no family history or
hereditary conditions linked to the disease. In 2020, some 3,640 Americans
died from colorectal cancer before they turned fifty—and given the slowmoving nature of the disease, it’s likely that many of those who died later
than that already had the disease on their fiftieth birthday. This is why the
American Cancer Society updated its guidelines in 2018, lowering the age to
forty-five for people at average risk.
In my practice, we go further, typically encouraging average-risk
individuals to get a colonoscopy by age forty—and even sooner if anything in
their history suggests they may be at higher risk. We then repeat the
procedure as often as every two to three years, depending on the findings
from the previous colonoscopy. If a sessile (flat) polyp is found, for example,
we’re inclined to do it sooner than if the endoscopist finds nothing at all. Two
or three years might seem like a very short window of time to repeat such an
involved procedure, but colon cancer has been documented to appear within
the span of as little as six months to two years after a normal colonoscopy.
Better safe than sorry.
[*8]
Why do I generally recommend a colonoscopy before the guidelines do?
Mostly because, of all the major cancers, colorectal cancer is one of the
easiest to detect, with the greatest payoff in terms of risk reduction. It
remains one of the top five deadliest cancers in the United States, behind lung
(#1) and breast/prostate (#2 for women/men), and just ahead of pancreas
(#4) and liver (#5) cancers. Of these five, though, CRC is the one we have the
best shot at catching early. As it grows in a relatively accessible location, the
colon, we can see it without any need for imaging techniques or a surgical
biopsy. Because it is so easily observed, we understand its progression from
normal tissue to polyp to tumor. Finding it early makes a huge difference,
since we can effectively eliminate polyps or growths on the spot. If only we
could do that with arterial plaques.
My bottom line is that it is far better to screen early than risk doing it too
late. Think asymmetric risk: It’s possible that not screening early and
frequently enough is the most dangerous option.
[*9]
Other cancers that are relatively easy to spot on visual examination
include skin cancer and melanomas. The pap smear for cervical cancer is
another well-established, minimally invasive test that I recommend my
patients do yearly. When we’re talking about cancers that develop inside the
body, in our internal organs, things get trickier. We can’t see them directly, so
we must rely on imaging technologies such as low-dose CT scans for lung
cancer. These scans are currently recommended in smokers and former
smokers, but (as always) I think they should be used more widely, because
about 15 percent of lung cancers are diagnosed in people who have never
smoked. Lung cancer is the #1 cause of cancer deaths overall, but lung cancer
in never-smokers ranks seventh, all by itself.
MRI has a distinct advantage over CT in that it does not produce any
ionizing radiation but still provides good resolution. One newer technique that
can enhance the ability of a screening MRI to differentiate between a cancer
and noncancer is something called diffusion-weighted imaging with
background subtraction, or DWI for short. The idea behind DWI is to look at
water movement in and around tissue, at different points in time very close to
each other (between ten and fifty microseconds, typically). If the water is held
or trapped, then it could indicate the presence of a tightly packed cluster of
cells, a possible tumor. So the higher the density of cells, the brighter the
signal on the DWI phase of MRI, making DWI functionally a radiographic
“lump detector.” Right now, DWI works best in the brain because it suffers
least from movement artifacts.
I remain optimistic that this technique can be improved over time, with
optimization of software and standardization of technique. Despite all this,
even something as advanced as the best DWI MRI is not without problems, if
used in isolation. While the sensitivity of this test is very high (meaning it’s
very good at finding cancer if cancer is there, hence very few false negatives),
the specificity is relatively low (which means it’s not as good at telling you
when you don’t have cancer, hence a lot of false positives). This is the
inevitable trade-off, the yin and yang if you will, between sensitivity and
specificity. The more you increase one, the more you decrease the other.
[*10]
I tell patients, if you’re going to have a whole-body screening MRI, there
is a good chance we’ll be chasing down an insignificant thyroid (or other)
nodule in exchange for getting such a good look at your other organs. As a
result of this, about a quarter of my patients, understandably, elect not to
undergo such screening. Which brings me to the next tool in the cancer
screening tool kit, a tool that can complement the high sensitivity / low
specificity problem of imaging tests.
I am cautiously optimistic about the emergence of so-called “liquid
biopsies” that seek to detect the presence of cancers via a blood test.
[*11]
These are used in two settings: to detect recurrences of cancer in patients
following treatment and to screen for cancers in otherwise healthy patients, a
fast-moving and exciting field called multicancer early detection.
Max Diehn, one of my med school classmates and now an oncology
professor at Stanford, has been on the forefront of this research since 2012.
Max and his colleagues set out to ask a seemingly simple question initially.
After a patient with lung cancer has had a resection of their tumor, is there
any way a blood test can be used to screen the patient for signs of tumor
recurrence?"