June 29, 2025 • 25 mins
We've arrived at our final primary site in the lower GI tract: anal cancer. In many ways, this disease is the ultimate success story for radiation oncology. It is one of the few solid tumors where we have moved from a paradigm of radical, mutilating surgery to a non-operative, organ-preserving standard of care, with definitive chemoradiation as the backbone. Today, we'll trace the history of this remarkable shift. We’ll start with the fundamentals of anatomy and staging that make anal cancer unique. Then we'll cover the revolutionary Nigro protocol that started it all, and finally, dive deep into the pivotal trials that fine-tuned this approach, answering the key questions of which chemotherapy drugs to use and for how long.
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(00:00):
Welcome everyone to the Radon Smart Review GI Cancer series.
Today we're kicking off something really important.
Actually, it's a well A2 part journey into anal cancer.
Yeah, absolutely. Part 1 today.
Part 1 focusing on the foundations, you know, the
basics and also the story of theNegro Revolution, which is just
fascinating. It really is.
(00:20):
You might initially think of anal cancer alongside rectal
cancer. They're anatomically.
Close, right? Very close.
People often group them. But we're going to unpack today
just how how different anal squamous cell carcinoma is
biologically, anatomically, and crucially, how we treat it.
It's a story of huge progress. Yeah, that's a great way to
think about it. And you know, it's interesting
(00:41):
because anal cancer, while it's relatively rare, it's actually
highly curable for most people. Right.
Highly curable. And maybe more than that, it's,
well, it's one of radiation oncology's biggest success
stories, really. It showcases this massive
paradigm shift. Paradigm shift?
How so? Well, we moved entirely from,
you know, these really radical life altering surgeries to a non
(01:05):
operative approach, an approach that preserves organ function,
preserves quality of life. It's it's really quite
remarkable, it. Sounds a a testament to research
I guess. Absolutely.
Clinical research. Innovation, Persistence, it all
came together here. So yeah, the story's really
about organ preservation, a truemedical revolution, like you
(01:26):
said. Exactly.
So today our plan is to really build that solid foundation.
We'll start with the anatomy, the bits that really dictate our
radiation fields. Absolutely key.
Then we'll get into the modern staging it's size base, which is
interesting. Right, different from rec.
Goal. We'll walk through the whole
workup, what you need to do fromthe start, and then then we dive
into the history, the Negro protocol, how that changed
(01:48):
everything. Yeah, that story is incredible.
It wasn't even the original intention.
Exactly. That accidental discovery
element is amazing. And then finally we have to talk
about the big trials, the ones that proved chemo radiation
wasn't just an option, it was necessary.
Level 1. Evidence.
Level 1 evidence absolutely showing that adding chemo to
radiation was superior. Understanding this history, I
(02:10):
mean it genuinely impacts how wetreat patients every single day
in the clinic. Couldn't agree more.
OK, let's let's dive in then. Clinical context first.
Epidemiology. You said it's rare.
How rare are we talking in the US?
Well, rare is relative in oncology, right?
But yeah, it's on the rarer sidefor GI cancers.
We see about 8600 new cases diagnosed each year in the
(02:35):
United States, give or take. 8600 OK and as a slice of the GI
cancer Π. It's small, only about 2% of all
gastrointestinal cancers. Wow, just 2% and compared to say
rectal cancer, which people might confuse it with.
Yeah, good comparison. It's roughly five times less
common than rectal cancer. So while they're neighbors
anatomically, epidemiologically they're quite different beasts.
(02:59):
Five times less common, but but you mentioned something
interesting earlier. The incidence is increasing.
Yes, that's a really important point.
Despite its rarity, we've seen this steady, kind of concerning
increase in the number of cases over the last few decades.
Any idea why? Better detection or something
else changing? That's the $1,000,000 question
really. It's likely multi factorial,
(03:20):
maybe some improved detection, sure.
More awareness, maybe. But a big driver is almost
certainly related to changes in the prevalence of its main risk
factor, which we'll definitely get into.
And you know, the population is aging and it tends to affect
older adults more often, so thatplays a role too.
But the bottom line is, while it's rare, it's becoming more
(03:40):
common in our practices. Residents starting out now,
we'll likely see more cases thanthose who trained, say, 20 years
ago. That's a really practical point.
OK, so demographically, who tends to get anal cancer?
Any patterns with sex or age? There are definitely patterns.
It's about twice as common in females as it is in males.
Twice as common in women. OK.
Yeah, that's a pretty significant difference.
(04:00):
And age wise, the average age ofdiagnosis tends to be in the
early 60s, you know, maybe 5264,somewhere around there.
So the typical patient, if thereis one, might be a woman in her
early 60s. That's often the picture, yes,
But, and this is important, we see it across a wider age range
and particularly in younger folks, it's often more strongly
(04:23):
tied to specific risk factors like immunosuppression, for
instance. Right.
OK. So when someone like that comes
into the clinic, what are they usually complaining of?
What symptoms bring them in? The symptoms can be tricky
because they often overlap with much more common benign things
like hemorrhoids. OK, which can delay things I
imagine. Exactly, that delay can be a
(04:43):
real problem. The most common things people
report are bleeding, usually intermittent rectal bleeding.
They might notice on the toilet paper, dismiss it in this, or
they might feel a lump, you know, a palpable mass down there
or just a sensation of a lump. Sometimes it's a non healing
sore or ulcer that just doesn't seem to go away.
Itching discharge can happen too.
(05:05):
OK. Any other symptoms?
Less commonly, if the tumor getsreally large and starts
impacting the sphincter muscles,you might see fecal
incontinence, but thankfully that's not usually the initial
presentation. OK.
And when they do present, what'sthe typical stage?
How much spread has usually happened?
Well, in terms of local spread, we find that about 30 to 40% of
(05:26):
patients already have positive lymph nodes in the region when
they're first diagnosed. 30 to 40% with positive nodes.
OK. Yeah.
So regional spread is fairly common at diagnosis, but the
good news is that distant metastatic disease, cancer
spreading to far off organs is much less common.
Less than 10% of patients present with Mets.
And if they do have Mets, where does it typically go?
(05:48):
Most commonly to the liver and the lungs.
That's pretty typical for many GL cancers.
OK. So let's get into those risk
factors you mentioned. What's the absolute main driver
here? You hinted at it.
Yeah, the number one major risk factor, and you really can't
emphasize this enough, is human papilloma virus HPD.
HPV, like with cervical cancer. It's exactly like with cervical
(06:08):
cancer and oropharyngeal cancer too.
HPV is the dominant driver. We think something like 80 to
90% of all anal squamous cell carcinomas are HPV driven. 80 to
90%, that's huge. It is, and specifically, it's
usually HPV 16. That subtype is responsible for
the lion's share of cases. We can actually confirm this
(06:30):
link on the pathology report using something called P16
staining. It's a surrogate marker for that
oncogenic HPV activity. So P16 positive usually means
HPV driven. Got it.
What else increases risk besidesHPV itself?
Well, anything that compromises the immune system is a big one.
Immunosuppression like HIV. Exactly.
Patients with HIV, even if it's well controlled with medication,
(06:53):
have a significantly higher risk.
Also organ transplant recipientsbecause they're on chronic
immunosuppressive drugs, their immune system just can't keep
the virus in check as effectively.
Makes sense. Also having a history of other
HPV related cancers like cervical or vulvar cancer put
some at a higher risk. It's just maybe a broader
susceptibility. Lifestyle factors matter too.
(07:14):
Multiple sexual partners increases risk again because it
increases the chance of acquiring HPV.
And maybe surprisingly for some,smoking is a definite
independent risk factor. Smoking too.
How does that work? Well, the thinking is that
smoking might suppress the localimmune response in the area, and
the carcinogens in smoke might also just create a more
(07:36):
favorable environment for cancerto develop, even separate from
the HPV effect. Fascinating.
So HPV is king, but immunosuppression, other HPV
cancers, sexual history and smoking all play a role.
Precisely and understanding these is key for prevention,
right? The HPV vaccine is a huge tool
here for the future. Absolutely.
OK, this is a great overview. To really make this concrete,
(07:57):
let's introduce our case for today.
We'll call her Mrs. Jenkins. Can you set the scene for us?
What's her story? Sure.
Mrs. Jenkins is a 64 year old woman.
She came in because for about 3 months she'd been having some
intermittent rectal bleeding andalso feeling like there was a
lump. Persistent sensation down there.
OK, classic symptoms we just discussed.
Exactly so. On examination, the doctor found
a firm ulcerative mass. It measured about 4 centimeters,
(08:20):
located right in the anal canal.And importantly, it extended
down to the dentate line. We'll circle back to why that
landmark is so crucial. 4 centimeters reaching the dentate
line. Got it.
Anything else on exam? Yes, two key things.
First, her sphincter tone was assessed and noted to be good.
That's really important information when we start
(08:41):
thinking about treatment goals like organ preservation.
Good sphincter tone. OK.
And the second thing. The second thing was concerning.
There is a palpable lymph node in her right groin, measuring
about 1.5 centimeters. Felt firm.
Suspicious for involvement? OK, a suspicious inquinal node.
So Miss Jenkins sounds like a very representative case.
(09:01):
Very much so. She gives us a perfect
foundation to build on. As we talk through the work up,
the anatomy, staging and how we decide on her treatment, we'll
keep referring back to her. Perfect.
So let's do that with Miss Jenkins in mind.
What's the comprehensive work up?
What are the essential steps when someone presents like this,
right? It's a very systematic process.
You don't want to miss anything.It starts, as always, with a
(09:22):
really thorough history and physical exam.
Beyond the basics. Well, the digital rectal exam,
the DRV is absolutely critical here.
You're not just feeling for the tumor, you're carefully
assessing its size, its exact location, how close it is to the
sphincter muscles, confirming that good sphincter function we
mentioned for Miss Jenkins. And palpating for nodes too.
Exactly feeling for any other suspicious nodes locally and re
(09:45):
evaluating that palpable right inguinal node she has.
That finding from the physical exam is a major flag.
OK, what else in the physical? Critically, for any female
patient like Misses Jenkins, a full gynecologic exam including
cervical screening is mandatory.Non negotiable.
Because of the HPV connection. Precisely because of that strong
(10:06):
HPV link, you have to check for a synchronous or related HPV
driven lesions elsewhere in the pelvis.
You'd be surprised how often something might be found.
Good point. OK, so history and physical are
done. How do we get that definitive
tissue diagnosis? That comes from anoscopy and
biopsy, usually done by a colorectal surgeon or maybe AGI
specialist. Anoscopy that's with a scope.
(10:28):
Yeah, a small scope inserted into the anal canal.
It allows direct visualization. You can see the mass, assess its
extent visually, and most importantly, take biopsies.
Get that tissue sample. And for Miss Jenkins, this
confirmed. Confirmed squamous cell
carcinoma, which is, you know, by far the most common Histology
we see in anal cancer. You absolutely need that path
(10:49):
confirmation before you even think about starting treatment.
Right path is proof. OK, so diagnosis confirmed
locally. Now we need to stage her figure
out the full extent of the disease.
Systemic staging first. Yep.
Standard of care for systemic staging is a computed tomography
scan. ACT scan of the chest, abdomen
and pelvis and you need intravenous contrast.
(11:09):
What's that looking for? That's our survey tool.
It looks for distance spread primarily to the lungs and liver
as we mentioned. It also gives us a look at lymph
nodes higher up in the abdomen and pelvis that might be
involved. OK.
CTCT key with contrast. What about getting a really
detailed look locally at the primary tumor itself?
For that, particularly for defining the precise local
(11:30):
extent of the tumor and its relationship to surrounding
structures like the sphincter orsay, the vagina, a pelvic
magnetic resonance imaging scan and MRI is really crucial.
MRI better than CT for local detail.
Much better, especially if you suspect a more advanced tumor
like AP3 or T4. The soft tissue detail on MRI is
(11:50):
just far superior for seeing exactly how far the tumor
extends and if it's invading adjacent structures.
CT can be a bit fuzzy for that level of detail right in the
pelvis. OK.
So it's CT for the big picture, MRI for the local details.
Now what about PT scans? You hear a lot about PCT, is
that standard here? It's not strictly mandatory by
all guidelines, but it is highlyrecommended.
(12:11):
I would argue it's become almostessential for optimal staging in
anal cancer. APTT.
Pronounced pet. CT.
Why is it so important? Was it add?
It adds functional information, it shows metabolic activity, and
studies have clearly shown that PECT can find involved lymph
nodes that look normal on a standard CT scan.
It actually upstages nodal disease, finds more disease than
(12:32):
expected in about 30% of patients compared to CT alone.
30%, that's significant. Is huge.
Think about Miss Jenkins with her palpable inguinal node.
APCT is critical for her first to confirm if that node is FDG
avid, meaning it lights up indicating active cancer cells.
OK, confirm the suspicious node.Right.
But just as importantly, the PCTscans the whole body.
(12:56):
It might pick up other involved nodes, maybe in the pelvis or
even higher up, that weren't suspected, or it could rarely
find distant metastatic disease we didn't know about.
It gives you the most accurate picture of the disease burden
before you commit to a treatmentplan.
It's a real game changer for precision staging.
OK so CTMRI and highly recommendPTCD.
What about blood work? Any specific labs needed?
(13:17):
Standard labs, of course. CBC, kidney function, liver
function. But given the strong link to
immunosuppression, HIV testing should be routinely offered and
performed for all anal cancer patients.
HIV testing for everyone. Got it.
Yep, and also for any patients who could potentially become
pregnant. You absolutely need a pregnancy
(13:37):
test before starting treatment, and just as important is
fertility counseling. Our treatments, both chemo and
radiation, can definitely impactfuture fertility, so that
discussion needs to happen up front.
Right. Fertility preservation is Q OK,
that's a very thorough workout plan.
Let's switch gears now to something absolutely fundamental
for treatment planning, the anatomy.
(13:58):
You mentioned the dentate line earlier.
Let's unpack the key anatomical distinctions here.
First, anal canal versus anal margin.
Absolutely critical distinction.They're close but different.
The anal canal is the inner tube.
Basically, it's about 4 to 6 centimeters long, a muscular
tube lined mostly with squamous cells sitting just inside the
anal verge, which is the external opening.
So the canal is the inside passage.
(14:19):
Right. The anal margin, on the other
hand, is the outside skin. It's the hair bearing karyanal
skin that surrounds the anal verge.
We usually define it as the skinwithin about a 5 centimeter
radius of that opening. OK.
Inside tube versus outside skin?Why does this difference matter
so much? It matters for staging, for how
the tumor behaves, and cruciallyfor lymphatic drainage where the
(14:41):
cancer is likely to spread. First tumor starting in the
canal versus the margin can drain to different lymph node
groups. Ah.
OK. Lymphatic drainage.
That brings us back to that landmark you mentioned the
dentate line. Tell us about that.
What is it and why is it the critical landmark?
The dentate line, sometimes called the pectinate line, is
probably the single most important anatomical landmark
(15:04):
for us in this region. Think of it as a sort of
internal dividing line. It's located roughly halfway up
the anal canal, maybe about 2cm in from the anal verge.
Halfway up the canal and anatomically, what is it?
It's where different tissue types meet.
It marks the transition from thecolumnar mucosa, the glandular
lining coming down from the rectum, to the squamous
epithelium, the skin like liningof the lower anal canal.
(15:27):
It's a biological junction. OK.
A tissue transition zone. But clinically it's big
importance is. Lymphatics.
It acts as a lymphatic watershed, like a continental
divide for lymph flow. Where the lymph drains depends
crucially on whether the tumor is above or below this line.
A lymphatic watershed. I like that analogy.
OK, so spell it out for us. How does this watershed work?
(15:47):
Where does lymph drain from above versus below?
It sounds like prime board blitzmaterial.
It absolutely is. This is a core concept.
You have to know cold for exams and for safe clinical practice
to avoid missing critical targets.
Here's the rule. The clinical Pearl tumors with
their epicenter above the dentate line higher up in the
canal. They primarily drain upwards and
(16:08):
sideways, basically following the roots, similar to a low
rectal cancer. OK, above the dentate drains
like low rectum. Which nodes are those?
Those are the pelvic nodes, specifically the mesorectal
nodes, the presacral nodes, and the internal iliac nodes, all
deep inside the pelvis. Pelvic nodes.
Got it. Now what if the tumor epicenter
(16:29):
is at or below the dentate line?If it's at or below the dentate
line, the drainage pattern shifts dramatically downwards
towards the groin through. The groin.
OK, which nodes specifically? Those are the inguinal nodes,
the femoral nodes right near them, and the external iliac
nodes which are a bit higher butstill part of that groin lower
pelvic drainage system. OK, this is super clear and
super important. So the mnemonic we should burn
(16:52):
into our brains is above the dentate it drains to the pelvis.
Below the dentate it goes to thegroin.
Exactly it Nail that down. And the important corollary,
what if the tumor is right at the dentate line or crosses it
like Miss Jenkins, whose tumor extended to the dentate line?
Good question. I assume you have to cover both
pathways then, pelvis and groin.You absolutely have to.
(17:13):
If it's sitting on the fence, orif there's any ambiguity about
its exact epicenter relative to the line, you must assume it has
access to both drainage routes. So your elective radiation
volume, the area you treat even if you don't see involved nodes,
has to comprehensively cover both the pelvic nodes and the
groin nodes. No cutting corners there.
(17:33):
Cover both if in doubt or at theline.
Got it. This anatomical precision
directly translates into defining our radiation target
volumes. Precisely, it's fundamental to
everything we do in treatment planning for anal cancer.
OK, fantastic. Now that we've got the anatomy
and lymphatics down, let's talk staging.
We use the AJCC 9th edition. You mentioned earlier that T
(17:54):
staging is different from rectalcancer.
How so? Yes, this is a key point that
often trips people up. Unlike rectal cancer, where T
stage depends on how deeply the tumor invades through the bowel
wall layers, Aim Cancer T staging is based purely on the
tumors size, its largest dimension.
Size, not depth like breast cancer.
Exactly like breast cancer or mini skin cancers.
(18:15):
It's simpler in a way. T1 is defined as 2cm or smaller.
T12 centimeters. Or less, right?
T2 is greater than 2cm up to andincluding five centimeters.
T2 more than two up to 5 centimeter.
Correct. And T3 is any tumor greater than
5 centimeters. T3 bigger than 5 centimeters.
Pretty straightforward size cut off.
They are. It reflects how these squamous
(18:35):
cell cancers tend to grow. OK, what about T4?
When does it become T4? T4 is defined by invasion into
adjacent organs, specifically invasion into the vagina, the
urethra, or the bladder. Vagina, urethra, bladder.
OK, now what's the common pitfall here?
What does not count as T4, even if it seems like extensive local
(18:57):
invasion? This is a really important
distinction for accurate staging.
Direct invasion of the rectal wall itself, or spread onto the
perianal skin, or even direct invasion into the sphincter
muscles. None of those make it AT4 tumor.
Even sphincter invasion isn't T4.
Nope. While those certainly indicate
locally advanced disease and affect prognosis and function,
(19:17):
they don't meet the specific AJCC definition of T4, which is
reserved for those specific adjacent organs.
It's a nuance, but crucial for correct staging.
Good to clarify. OK, let's move to end staging
the nodes. You said it's based on location,
not number. That's right, another key
difference from many other cancers.
For anal cancer nodes, it's all about where the positive nodes
(19:38):
are located, tying back directlyto those drainage pathways we
discussed. So how are the N categories
defined? We have N1A N 1B and N1C N1.
Erich means metastases are foundin the inguinal nodes or the
mesorectal nodes or the internaliliac nodes, basically the groin
nodes or the deep pelvic nodes we talked about earlier.
(19:58):
N1A, inguinal, mesorectal, or internal iliac.
N1B specifically refers to metastases in the external iliac
lymph nodes. These are a bit higher up in the
pelvis, closer to the common iliacs.
N1B external iliac nodes only. Right.
And then N1C is when you have metastases in both the external
iliac nodes, the N1B location and any of the N1A locations
(20:20):
inguinal, mesorectal or internaliliac.
N1C both external iliac and N1A nerds involved, so it reflects
more extensive regional spread. Exactly.
It's about the geography of the nodal spread.
OK, and M staging for distant myths.
Is there a specific nodal group that automatically bumps a
patient up to M1 even though it's technically still lymph
nodes? Yes there is.
(20:42):
This is the classic board question.
Favorite metastases to the common iliac lymph nodes, which
are located above the external iliacs, are considered M1
disease. Common iliac nodes equal M1.
Got it. Because they're outside the
defined regional basins. Precisely, they signify disease
has spread beyond the expected regional drainage and is
behaving more like systemic disease.
(21:03):
OK, let's tie this back to Miss Jenkins.
Remind us of her findings. She had a 4 centimeter primary
tumor in the anal canal extending to the dentate line
and she had that suspicious 1.5cm palpable right inguinal
lymph node. Right.
So based on the AJCC 9th edition, how do we stage her
clinically? OK.
Let's break it down. A4 centimeter primary tumor fits
(21:25):
into the greater than two up to 5 centimeters category.
So that makes her a clinical T2.T2 based on size.
Right and the suspicious right angle node falls into the N1A
category is inguinal nodes are listed under N1A.
N1A based on inguinal node. Correct.
So putting it together, Miss Jenkins would be staged as
clinical T2 and 1A, assuming herPECT and other staging scans
(21:48):
don't show anything else furtherafield.
Clinical T2 and 1A perfect. That staging is obviously
obviously fundamental for deciding her treatment.
Absolutely. It dictates everything that
follows. Which brings us perfectly to the
next major topic, the treatment itself, and specifically the
historical revolution that got us here.
Let's talk about the Negro revolution.
Before this, say pre 1970s, whatwas life like for an anal cancer
(22:12):
patient? What was the standard treatment?
Life for an anal cancer patient back then was, well, pretty
bleak honestly. The standard, and really the
only widely accepted curative intent treatment was an
abdominoperineal resection, an APR.
The APR, that's the radical surgery we mentioned.
The most radical it involved removing the entire rectum, the
anus, the anals, extinctors, often some surrounding tissue
(22:33):
and sometimes part of the colon,and the inevitable consequence
was a permanent colostomy, a bagfor life.
Wow, that was a standard for everyone, even early stages.
Pretty much, yes. Even for someone like Miss
Jenkins with potentially curablelocalized disease, it was
incredibly invasive, disfiguring, and had a massive
impact on quality of life. And despite how radical it was,
(22:56):
how are the outcomes? That's the kicker, they weren't
great. Even with this huge surgery,
five year overall survival rateswere only hovering around 50%.
Only 50% survival. Yeah.
And local recurrence rates, the cancer coming back in the pelvis
or perineum were distressingly high.
So patients endured this massiveoperation, the permanent
colostomy, and still had a significant chance of the cancer
(23:19):
returning locally. It's a really tough situation.
That paints a very stark pictureindeed.
OK, so something had to change. Enter Doctor Norman Negro at
Wayne State University in the early 70s.
What was his initial idea? What was he trying to achieve?
Right. So Doctor Negro published this
preliminary report in 1974 That really change the world for
(23:39):
these patients, even though thatwasn't his initial grand plan.
Not the plan. What was he trying to do?
His goal was actually more modest, maybe more pragmatic.
At the time, he wasn't trying toreplace the APR, he was trying
to improve it. He wanted to develop a
neoadjuvant chemo radiation regimen treatment given before
surgery to see if it could shrink the tumor, maybe kill off
microscopic cancer cells around the edges, and ultimately make
(24:01):
the APR surgery more successful,leading to better survival and
lower recurrence rates. So a preoperative treatment to
make the existing surgery work better.
Exactly. Enhance the surgery, not
eliminate it. That was the initial concept.
OK, So what did this original Negro protocol actually involve?
What was the recipe? It was, in retrospect,
(24:21):
remarkably simple but potent. The radiation part was actually
quite a modest dose by today's standards. 30 Gray delivered in
15 fractions over 3 weeks. 30 Gray OK And where was the
radiation aimed? Critically, it was aimed at the
pelvis and the inguinal lymph node regions.
So even back then, based on anatomical understanding, he
(24:42):
knew those were the key areas needing treatment.
He basically established the standard target volumes we still
build on today. Pelvis and inguinos and the
chemotherapy. Concurrent chemotherapy given
alongside the radiation. It consisted of two drugs, 5
floricil or five FU, spoken as five FU, which was given as a
continuous infusion over 4 days,and then a single bolus
(25:05):
injection of mitomycin C or mitomycin C right on day one of
the treatment. Five FU infusion and a bolus of
mitomycin C That combination sound familiar?
It should. It's essentially the backbone
that was tested and proven in those later landmark trials
we'll discuss. But again, the doses and intent
here were originally neoadjuvant.
OK, so patients got this 30 greyradiation with concurrent 5 FU
(25:28):
and mitomycin C The plan was then for them to proceed to.
The plan was for them to recoverfor about 6 weeks and then head
to the operating room for their scheduled APR, the big surgery.
And this is where the story takes its amazing turn right
What happened when those first few patients actually went to
surgery? This is the incredible part, the
serendipity of science. When the surgeons operated on
(25:49):
those first few patients who hadreceived the Negro protocol
preoperatively, and the pathologists examined the
specimens that were removed, they found something stunning.
Which was? No cancer, or rather a
pathologic complete response. APCR.
The tumor, which had been biopsied and confirmed before
treatment, had completely vanished.
All that was left was scar tissue in many cases.
(26:11):
Wow, so the pretreatment had completely eradicated the tumor
before the planned surgery even happened?
In those initial patients, yes. Imagine the shock, the
excitement. They went in, expected to do
this massive resection for residual cancer, and instead
they found the treatment had already seemingly cured the
patient locally. That must have been a light bulb
moment. A huge one.
Absolutely. Doctor Negro and his team
(26:32):
immediately recognized the profound implications.
They realized this combined chemo radiation was so
effective, so cytotoxic to the tumor, that maybe, just maybe,
the radical APR surgery wasn't necessary at all for the
majority of patients. So the attempt to improve
surgery accidentally led to the potential to avoid surgery
altogether. That's like that analogy you use
(26:54):
stumbling onto a paved Hwy. whenyou're hacking through the
jungle. That's a perfect way to put it.
It wasn't just a detour, it was a completely new, vastly better
route. This discovery fundamentally
birthed the new paradigm for anal cancer treatment.
The paradigm of definitive chemoradiation.
Exactly. Definitive chemo radiation
became the primary standard of care approach and the APR that
(27:17):
one standard mutilating operation was relegated to a
salvage role, only used if the chemo radiation didn't work
initially or if the cancer came back later.
A true revolution then, establishing one of the very
first truly successful organ preservation strategies in all
of oncology. Without a doubt it had ripple
effects inspiring similar organ sparing approaches and other
cancers like bladder, larynx, breast.
(27:40):
It taught the entire field that challenging surgical dogma with
combined modality therapy could yield incredible benefits for
patients, not just in survival, but profounding quality of life.
Preserving normal function became a real therapeutic goal.
What an amazing story, and a huge win for patients.
OK, so Negro showed chemo radiation could work
spectacularly well, in fact. But the critical scientific
(28:02):
question remained was the chemotherapy part actually
essential? Could radiation alone achieve
similar results, maybe with lesstoxicity?
Precisely that was the next logical, crucial question.
Negro showed The combination waspotent, but was it the chemo,
the radiation, or the synergy ofboth?
This needed rigorous testing in large clinical trials.
(28:22):
Which brings us to those landmark European trials you
mentioned. Let's start with the first big
one, the UKCCCR Act One trial. That's UKCCCRA CT1.
The ACT One trial published backin 1996.
This is a really important largestudy.
They enrolled over 580 patients with anal cancer and
significantly, they excluded only the very earliest stage,
(28:45):
the T1 N 0 tumors, focusing on the majority of patients who
present with more advanced disease.
Over 580 patients. And what was the core
comparison? How did they test the chemo
question? It was a straightforward,
elegant design. Patients were randomly assigned
to one of two groups. Group One got radiation therapy
alone. The standard dose back then was
(29:06):
typically 45 grey, sometimes with an optional boost to the
tumor bed. OK, radiation alone arm.
Group 2 got the exact same radiation therapy, same dose,
same fields, but with the addition of concurrent
chemotherapy. 5 FU and muttomycin C given in the
standard Negro like schedule during the radiation.
So radiation alone versus radiation plus chemo.
(29:28):
A direct head to head test. Exactly isolating the effect of
adding those two chemotherapy drugs.
And the results? Did the chemo make a difference?
The results are absolutely striking, unequivocal and in the
chemotherapy made a massive difference in outcomes.
The headline finding was local control.
The three-year rate of controlling the cancer in the
pelvis and anus was 54% in the chemo radiation group. 64% local
(29:51):
control with chemo RT. OK, what about radiation?
Alone only 41%. Wow, 41 versus 64%, that's a
huge gap, huge over a 20% absolute improvement in local
control just by adding the chemotherapy and that had major
downstream consequences Like what?
Like significantly better colostomy free survival.
(30:11):
Because the cancer was controlled locally much more
often, far fewer patients in thechemoradiation arm ended up
needing a salvage APR and a permanent colostomy later on.
They kept their sphincters, kepttheir normal function.
Better local control, fewer colostomies?
Did it impact survival too? Yes, it also led to a
statistically significant reduction in cancer specific
deaths. So more cures, better local
(30:34):
control, and better quality of life.
The conclusion was crystal clear.
Which was? Adding concurrent 5 FU and
mitomycin C to radiation is definitively superior to
radiation alone for treating anal cancer in terms of both
controlling the disease and preserving the sphincter.
Incredibly strong evidence from ACT 1.
Was this finding replicated? Did other trials confirm it?
(30:55):
Yes, it was robustly confirmed by another major European trial
run by the EORTC, that's the European Organization for
Research and Treatment of Cancer.
Their trial number was 22861, published just a year after ACT
One in 1997. EOR TC-22861 OK, did it look at
(31:15):
a similar patient population? Slightly different actually.
This trial focused specifically on patients with higher risk,
more locally advanced disease, so T3 or T4 tumors or any node
positive patients, about 110 patients in total.
Higher risk group and the designsame comparison.
Same fundamental comparison, Yeah, Radiation therapy alone
versus the same radiation therapy with concurrent 5 FU and
(31:38):
mite MYCIN C. And the results in this higher
risk group, did chemo still add benefit?
Absolutely. The results were remarkably
consistent with ACT 1, even in this tougher to treat
population. The five year local control rate
was 70% with chemo radiation compared to only 50% with
radiation alone. 70 versus 50% local control at five years,
still a 20% gap. Exactly.
(31:59):
And again this translated directly into significantly
better five year colostomy free survival, 70% for the chemo
radiation group versus just 40% for the radiation alone group.
70 versus 40% chance of avoidingA colostomy.
That's a massive difference for patients.
Huge. So the EORTC trial strongly
reinforced the message, even, perhaps especially in patients
(32:20):
with more advanced disease, adding the chemotherapy provides
a major, undeniable benefit. So these two trials together,
UKCCCRA CT1 and EOTC 22861, theyreally cemented it.
They provided that definitive Level 1 evidence.
They absolutely did. They effectively closed the door
on radiation alone as a standardprimary treatment for the vast
majority of anal cancer patients.
(32:42):
Concurrent chemo radiation became and remains the
undisputed gold standard thanks to this rigorous evidence.
OK, this is fantastic. We've covered the epidemiology,
the anatomy, the staging, the history and the pivotal trials.
Now let's synthesize all of this.
Let's apply it directly to our patient, Misses Jenkins.
Remind us again, 64 years old clinical T2N1A squamous cell
(33:05):
carcinoma of the anal canal. Based on everything we've
discussed, what is the clear evidence based treatment
recommendation for her? Right, putting it all together
from his Jenkins given her clinical T2N1A squamous cell
carcinoma, the standard of care without question is definitive
concurrent chemo radiation. OK.
Why specifically chemo radiation?
(33:26):
Just to summarize the rationale.Because of the foundational work
by Negro showing it could achieve complete responses, and
crucially because of the level 1evidence from ACT 1 and EO or
TC22A61 which proved that addingconcurrent 5 FU and mitomycin C
to radiation significantly improves local control and
colostomy free survival comparedto radiation alone.
It offers her the best chance ofcure, preserving her sphincter
(33:48):
function. And surgery.
The AP? Where does that fit in now for
her? Surgery.
The APR is reserved strictly forsalvage, meaning if
unfortunately the chemoradiationdoesn't completely eradicate her
cancer or if it were to recur locally sometime down the road,
that an APR might be considered,but it's absolutely not the
upfront treatment anymore. OK.
What about just cutting the tumor out?
(34:10):
Local excision? Is that ever an option for
someone like Missus Jenkins T2N1A in the canal?
Absolutely not. This is a really important point
for residents to grasp. Local excision is an extremely
selective option in anal cancer.The current Astro guidelines,
for example, state it's only considered for highly selected,
very small clinical T1N0 tumors that are located on the anal
(34:32):
margin, the outside skin and have favorable pathology
features like no lymphovascular invasion.
So only tiny superficial skin tumors on the outside basically.
Essentially yes, misses Jenkins tumors T2 it's in the anal canal
and she has nodal involvement N1A all of those are absolute
contraindications local excisionas primary therapy it would be
completely inadequate treatment for her virtually guaranteeing
(34:53):
failure very. And just to reiterate, what if
someone proposed just radiation alone for her?
Maybe to avoid chemo side effects?
That would be substandard care based on the ACT 1 and EO core
TC trials. Choosing radiation alone for
Miss Jenkins would significantlycompromise her chances.
Her risk of local recurrence would be much higher, and her
(35:14):
likelihood of meeting a colostomy eventually would
increase substantially. It's simply not an equivalent
option. So the definitive, unambiguous
recommendation for Miss Jenkins is concurrent chemo radiation,
aiming for cure with organ preservation.
That's precisely it. It's a testament to how far the
field has come, offering her an excellent chance of cure while
(35:34):
maintaining her quality of life,something unimaginable 50 years
ago. It really is remarkable.
Now we know the Negro protocol established the what and where
to treat chemo radiation to the pelvis and inguinals.
How do we actually deliver that radiation in modern practice?
You mentioned advanced techniques.
Right. While the fundamental principles
of what volumes need to be treated haven't changed
drastically since Negro pelvis and groin based on anatomy and
(35:57):
state trade, the how we deliver that radiation has evolved
tremendously. To be more precise.
Exactly. We now use highly sophisticated
techniques like Intensity Modulated radiation therapy or
IMRT, and Volumetric modulated arc therapy, or VMAT.
IMRT and VMAT, what do they allow us to do?
(36:17):
They allow us to sculpt the radiation dose with incredible
precision. We can shape the high dose
radiation cloud very tightly around the target volumes, the
tumor itself, any involved nodes, and those elective nodal
regions we need to cover, while simultaneously minimizing the
dose delivered to nearby healthyorgans.
Organs like. Like the small bowel, the
bladder, the femoral heads, the tops of the thigh bones, the
(36:39):
external genitalia and even uninvolved parts of the anal
sphincter complex. By sparing these normal tissues
better, we can significantly reduce both acute side effects
during treatment like diarrhea and skin reaction and also long
term toxicities while still delivering the necessary
curative dose to the cancer. So better targeting, less
collateral damage. That's the goal.
We won't get into the physics weeds of IMRT and VMAT today,
(37:02):
but it's important to know that these advanced technologies are
what allow us to safely and effectively implement the
principles established by Negro and those landmark trials.
They optimize the therapeutic ratio, maximizing cure while
minimizing harm. Makes perfect sense.
OK, let's lock this all in time for our board blitz.
Ready to test your recall on these key concepts?
Let's do it. Fire away.
(37:23):
All right, question one scenario.
A 65 year old woman presents. She has a 1.5 centimeter well
differentiated squamous cell carcinoma found on the anal
margin. She undergoes a wide local
excision pathology, shows 2cm clear margins and crucially, no
lymphovascular invasion, no perineural invasion.
What is the most appropriate next step in her management?
(37:45):
Is it a adjuvant chemo radiationto 50.4 Gray B adjuvant
radiation alone to 45 Gray C observation with close
surveillance or D abdomenoperenial resection?
OK. Thinking through the criteria,
small tumor, 1.5cm of T1 in a margin location, wide negative
margins, no high risk features like LDI or PNI.
(38:07):
This fits those very selective criteria we discussed.
So the answer should be C observation with close
surveillance. And the rationale?
The rationale is that for this very specific subset of
patients, clinical T1 and zero anal margin completely excised
with wide margins and no adversefeatures.
The cure rates with surgery alone are excellent.
According to Astro and other guidelines, adjuvant therapy,
(38:29):
chemo or radiation is generally not recommended as it likely
adds toxicity without significantly improving
outcomes. In this highly favorable
situation, close follow up is key, but further immediate
treatment isn't needed. Perfect.
Highlights the importance of knowing those narrow exceptions.
Question 2. Scenario A patient is diagnosed
with A4 centimeter squamous cellcarcinoma of the anal canal.
(38:49):
Imaging confirms the epicenter of the tumor is located right at
the dentate line. Question Which nodal basins are
considered at risk and must be included in the elective
radiation volume? A Inguinal and external iliac
nodes only. B Mesorectal and internal iliac
nodes only. C Both pelvic, mesorectal,
internal iliac and groin, groin inguinal, external iliac nodes
(39:10):
or D para aortic nodes only. The dentate line question, OK, 4
centimeter tumor, so T2 epicenter right of the dentate
line. Our mnemonic was above the
dentate drains to pelvis, below the dentate goes to groin if
it's at the line. It has access to both pathways.
Exactly. It has access to both superior
drainage pelvis and inferior drainage groin.
(39:31):
Therefore, you absolutely must cover both sets of regional
nodes electively. That means the answer is C Both
pelvic mesorectal internal iliacand groin inguinal external
iliac nodes must be included in the target volume.
Treating only one would be a geographic mess.
Excellent. That watershed concept is
critical. Final question.
Question three Scenario A juniorresident is presenting a patient
(39:52):
with AT3 and one anal canal cancer.
The attending asks the resident why concurrent chemotherapy is
the standard of care for this patient.
Which of the following trials provides the best level 1
evidence to support this practice?
A. The original Negro protocol
report BRTO G9811 spoken as RTO G9811CU KCCCRA CT1 or D, The
(40:15):
Stockholm. The third trial.
OK T3 and one disease definitelyneeds definitive treatment.
Why chemo with the radiation? We have the trial that directly
compared chemo RT versus RT alone.
The Negro protocol showed feasibility but wasn't a
randomized comparison. RTOG 9811 compared different
chemo regimens with RT. Stockholm the 3rd is a rectal
cancer trial that leaves. BTCCCRA CT1.
Exactly the answer is CUKCCCRA CT1 along with ER3 RTC 22861
(40:42):
provide the definitive level 1 evidence from randomized
controlled trial showing that adding concurrent 5 FU and
mitamycin C to radiation significantly improved local
control and colostomy free survival compared to radiation
alone. That's the evidence that
mandates chemo radiation as the standard for this T3 and one
patient. Perfect reasoning that nails
down the core evidence base. OK, let's zoom out again
(41:03):
briefly. Controversies and advances.
We spent a lot of time today rightfully celebrating the huge
advance of the Negro protocol, and the subsequent trials
represented that massive shift from APR to definitive chemo
radiation. It truly was foundational.
Absolutely. It's hard to overstate how
transformative that was. It fundamentally changed the
prognosis and quality of life for countless patients.
(41:24):
It really set the stage for everything that followed in anal
Cancer Research. So building on that foundation,
what are some of the areas wherethe field is still evolving or
where there's ongoing research? You mentioned optimizing chemo
earlier, right? While five a few Mitomycin C is
the proven standard based on ACT1 and EOTC, there's been an
ongoing research like the RTOG 9811 trial comparing it to five
(41:47):
if you cisplatin. The results were complex,
suggesting maybe similar efficacy but different toxicity
profiles. So, choosing the optimal chemo
regimen, especially considering individual patient factors and
comorbidities, is still an area of discussion and refinement.
OK, Chemo optimization. What else?
There's interest in treatment deescalation for very favorable
early stage HPV positive tumors.Can we perhaps reduce the
(42:10):
radiation dose or intensity of chemotherapy for these patients
to minimize long term side effects without compromising the
excellent cure rates that's an active area?
De intensification for low risk?What about the other end?
High risk? For more advanced or bulky
tumors, there's investigation into neoadjuvant or induction
chemotherapy, giving chemo before the chemo radiation
starts to try and shrink the tumor 1st and potentially
(42:32):
improve outcomes. The evidence for that is still
evolving, and like everywhere else in oncology, immunotherapy
is being explored, particularly for metastatic or recurrent
disease leveraging that HPV connection.
Lots of directions for future progress, and this foundational
understanding we've built today really prepares us for diving
into those nuances, which leads perfectly into our next session,
Anal Cancer Part 2. What can listeners expect us to
(42:54):
cover them? In Part 2, we'll get much more
into the practical weeds of optimizing treatment.
We'll do a detailed comparison of mitomycin C versus cisplatin
based chemotherapy regimens. We'll talk about how we tailor
radiation doses based on the initial TNN stage.
It's not one-size-fits-all, and critically, we'll emphasize the
huge importance of avoiding treatment breaks during chemo
(43:15):
radiation, explaining the data behind why completing treatment
on schedule is so vital for success.
It'll be focused on refining theapplication of today's
principles. Sounds essential.
OK, let's quickly recap the absolute must know takeaways
from today's foundational session.
First, anal cancer distinct, mostly HPV driven and its
incidences rising. 2nd staging based on tumor size, T stage and
(43:38):
nodal location end stage, not depth of invasion like rectal
cancer. 3rd anatomy is destiny, especially that dentate line,
the lymphatic watershed dictating pelvic versus groin
drainage. Remember, above the dentate to
the pelvis, below the dentate tothe groin. 4th The Negro
protocol was revolutionary, shifting the paradigm from
(43:59):
radical APR surgery to sphincterpreserving definitive chemo
radiation. 5th, the UKCCCRA CT1 and ER or TC-22861 trials
provided the level 1 evidence proving concurrent 5F
humidamycin C plus radiation is superior to radiation alone.
Chemo is necessary. 6th A comprehensive workup including
(44:20):
history, physical, an oscopapsy CT, pelvic MRI and ideally a PET
CT PET CT is crucial for accurate staging.
And finally, local excision is avery niche option only for
highly select T1 and zero anal margin tumors with favorable
features. For almost everyone else, like
Mrs. Jenkins, definitive chemo radiation is the standard.
That covers the core foundationsperfectly.
(44:42):
Excellent. For more detailed notes on all
of this and to test yourself with practice oral board
scenarios, you can visit radoncsmartlearn.com.
That's radoncsmartlearn.com. And definitely subscribe to
Radon Smart Review so you don't miss Part 2, where we'll really
get into optimizing that chemoradiation regimen.
Thanks so much for joining us for this deep dive into the
foundations of anal cancer treatment.
(45:02):
Thanks for listening. We'll talk to you next time.
Welcome everyone to the Radon Smart Review GI Cancer series.
Today we're kicking off something really important.
Actually, it's a well A2 part journey into anal cancer.
Yeah, absolutely. Part 1 today.
Part 1 focusing on the foundations, you know, the
basics and also the story of theNegro Revolution, which is just
fascinating. It really is.
(00:20):
You might initially think of anal cancer alongside rectal
cancer. They're anatomically.
Close, right? Very close.
People often group them. But we're going to unpack today
just how how different anal squamous cell carcinoma is
biologically, anatomically, and crucially, how we treat it.
It's a story of huge progress. Yeah, that's a great way to
think about it. And you know, it's interesting
(00:41):
because anal cancer, while it's relatively rare, it's actually
highly curable for most people. Right.
Highly curable. And maybe more than that, it's,
well, it's one of radiation oncology's biggest success
stories, really. It showcases this massive
paradigm shift. Paradigm shift?
How so? Well, we moved entirely from,
you know, these really radical life altering surgeries to a non
(01:05):
operative approach, an approach that preserves organ function,
preserves quality of life. It's it's really quite
remarkable, it. Sounds a a testament to research
I guess. Absolutely.
Clinical research. Innovation, Persistence, it all
came together here. So yeah, the story's really
about organ preservation, a truemedical revolution, like you
(01:26):
said. Exactly.
So today our plan is to really build that solid foundation.
We'll start with the anatomy, the bits that really dictate our
radiation fields. Absolutely key.
Then we'll get into the modern staging it's size base, which is
interesting. Right, different from rec.
Goal. We'll walk through the whole
workup, what you need to do fromthe start, and then then we dive
into the history, the Negro protocol, how that changed
(01:48):
everything. Yeah, that story is incredible.
It wasn't even the original intention.
Exactly. That accidental discovery
element is amazing. And then finally we have to talk
about the big trials, the ones that proved chemo radiation
wasn't just an option, it was necessary.
Level 1. Evidence.
Level 1 evidence absolutely showing that adding chemo to
radiation was superior. Understanding this history, I
(02:10):
mean it genuinely impacts how wetreat patients every single day
in the clinic. Couldn't agree more.
OK, let's let's dive in then. Clinical context first.
Epidemiology. You said it's rare.
How rare are we talking in the US?
Well, rare is relative in oncology, right?
But yeah, it's on the rarer sidefor GI cancers.
We see about 8600 new cases diagnosed each year in the
(02:35):
United States, give or take. 8600 OK and as a slice of the GI
cancer Π. It's small, only about 2% of all
gastrointestinal cancers. Wow, just 2% and compared to say
rectal cancer, which people might confuse it with.
Yeah, good comparison. It's roughly five times less
common than rectal cancer. So while they're neighbors
anatomically, epidemiologically they're quite different beasts.
(02:59):
Five times less common, but but you mentioned something
interesting earlier. The incidence is increasing.
Yes, that's a really important point.
Despite its rarity, we've seen this steady, kind of concerning
increase in the number of cases over the last few decades.
Any idea why? Better detection or something
else changing? That's the $1,000,000 question
really. It's likely multi factorial,
(03:20):
maybe some improved detection, sure.
More awareness, maybe. But a big driver is almost
certainly related to changes in the prevalence of its main risk
factor, which we'll definitely get into.
And you know, the population is aging and it tends to affect
older adults more often, so thatplays a role too.
But the bottom line is, while it's rare, it's becoming more
(03:40):
common in our practices. Residents starting out now,
we'll likely see more cases thanthose who trained, say, 20 years
ago. That's a really practical point.
OK, so demographically, who tends to get anal cancer?
Any patterns with sex or age? There are definitely patterns.
It's about twice as common in females as it is in males.
Twice as common in women. OK.
Yeah, that's a pretty significant difference.
(04:00):
And age wise, the average age ofdiagnosis tends to be in the
early 60s, you know, maybe 5264,somewhere around there.
So the typical patient, if thereis one, might be a woman in her
early 60s. That's often the picture, yes,
But, and this is important, we see it across a wider age range
and particularly in younger folks, it's often more strongly
(04:23):
tied to specific risk factors like immunosuppression, for
instance. Right.
OK. So when someone like that comes
into the clinic, what are they usually complaining of?
What symptoms bring them in? The symptoms can be tricky
because they often overlap with much more common benign things
like hemorrhoids. OK, which can delay things I
imagine. Exactly, that delay can be a
(04:43):
real problem. The most common things people
report are bleeding, usually intermittent rectal bleeding.
They might notice on the toilet paper, dismiss it in this, or
they might feel a lump, you know, a palpable mass down there
or just a sensation of a lump. Sometimes it's a non healing
sore or ulcer that just doesn't seem to go away.
Itching discharge can happen too.
(05:05):
OK. Any other symptoms?
Less commonly, if the tumor getsreally large and starts
impacting the sphincter muscles,you might see fecal
incontinence, but thankfully that's not usually the initial
presentation. OK.
And when they do present, what'sthe typical stage?
How much spread has usually happened?
Well, in terms of local spread, we find that about 30 to 40% of
(05:26):
patients already have positive lymph nodes in the region when
they're first diagnosed. 30 to 40% with positive nodes.
OK. Yeah.
So regional spread is fairly common at diagnosis, but the
good news is that distant metastatic disease, cancer
spreading to far off organs is much less common.
Less than 10% of patients present with Mets.
And if they do have Mets, where does it typically go?
(05:48):
Most commonly to the liver and the lungs.
That's pretty typical for many GL cancers.
OK. So let's get into those risk
factors you mentioned. What's the absolute main driver
here? You hinted at it.
Yeah, the number one major risk factor, and you really can't
emphasize this enough, is human papilloma virus HPD.
HPV, like with cervical cancer. It's exactly like with cervical
(06:08):
cancer and oropharyngeal cancer too.
HPV is the dominant driver. We think something like 80 to
90% of all anal squamous cell carcinomas are HPV driven. 80 to
90%, that's huge. It is, and specifically, it's
usually HPV 16. That subtype is responsible for
the lion's share of cases. We can actually confirm this
(06:30):
link on the pathology report using something called P16
staining. It's a surrogate marker for that
oncogenic HPV activity. So P16 positive usually means
HPV driven. Got it.
What else increases risk besidesHPV itself?
Well, anything that compromises the immune system is a big one.
Immunosuppression like HIV. Exactly.
Patients with HIV, even if it's well controlled with medication,
(06:53):
have a significantly higher risk.
Also organ transplant recipientsbecause they're on chronic
immunosuppressive drugs, their immune system just can't keep
the virus in check as effectively.
Makes sense. Also having a history of other
HPV related cancers like cervical or vulvar cancer put
some at a higher risk. It's just maybe a broader
susceptibility. Lifestyle factors matter too.
(07:14):
Multiple sexual partners increases risk again because it
increases the chance of acquiring HPV.
And maybe surprisingly for some,smoking is a definite
independent risk factor. Smoking too.
How does that work? Well, the thinking is that
smoking might suppress the localimmune response in the area, and
the carcinogens in smoke might also just create a more
(07:36):
favorable environment for cancerto develop, even separate from
the HPV effect. Fascinating.
So HPV is king, but immunosuppression, other HPV
cancers, sexual history and smoking all play a role.
Precisely and understanding these is key for prevention,
right? The HPV vaccine is a huge tool
here for the future. Absolutely.
OK, this is a great overview. To really make this concrete,
(07:57):
let's introduce our case for today.
We'll call her Mrs. Jenkins. Can you set the scene for us?
What's her story? Sure.
Mrs. Jenkins is a 64 year old woman.
She came in because for about 3 months she'd been having some
intermittent rectal bleeding andalso feeling like there was a
lump. Persistent sensation down there.
OK, classic symptoms we just discussed.
Exactly so. On examination, the doctor found
a firm ulcerative mass. It measured about 4 centimeters,
(08:20):
located right in the anal canal.And importantly, it extended
down to the dentate line. We'll circle back to why that
landmark is so crucial. 4 centimeters reaching the dentate
line. Got it.
Anything else on exam? Yes, two key things.
First, her sphincter tone was assessed and noted to be good.
That's really important information when we start
(08:41):
thinking about treatment goals like organ preservation.
Good sphincter tone. OK.
And the second thing. The second thing was concerning.
There is a palpable lymph node in her right groin, measuring
about 1.5 centimeters. Felt firm.
Suspicious for involvement? OK, a suspicious inquinal node.
So Miss Jenkins sounds like a very representative case.
(09:01):
Very much so. She gives us a perfect
foundation to build on. As we talk through the work up,
the anatomy, staging and how we decide on her treatment, we'll
keep referring back to her. Perfect.
So let's do that with Miss Jenkins in mind.
What's the comprehensive work up?
What are the essential steps when someone presents like this,
right? It's a very systematic process.
You don't want to miss anything.It starts, as always, with a
(09:22):
really thorough history and physical exam.
Beyond the basics. Well, the digital rectal exam,
the DRV is absolutely critical here.
You're not just feeling for the tumor, you're carefully
assessing its size, its exact location, how close it is to the
sphincter muscles, confirming that good sphincter function we
mentioned for Miss Jenkins. And palpating for nodes too.
Exactly feeling for any other suspicious nodes locally and re
(09:45):
evaluating that palpable right inguinal node she has.
That finding from the physical exam is a major flag.
OK, what else in the physical? Critically, for any female
patient like Misses Jenkins, a full gynecologic exam including
cervical screening is mandatory.Non negotiable.
Because of the HPV connection. Precisely because of that strong
(10:06):
HPV link, you have to check for a synchronous or related HPV
driven lesions elsewhere in the pelvis.
You'd be surprised how often something might be found.
Good point. OK, so history and physical are
done. How do we get that definitive
tissue diagnosis? That comes from anoscopy and
biopsy, usually done by a colorectal surgeon or maybe AGI
specialist. Anoscopy that's with a scope.
(10:28):
Yeah, a small scope inserted into the anal canal.
It allows direct visualization. You can see the mass, assess its
extent visually, and most importantly, take biopsies.
Get that tissue sample. And for Miss Jenkins, this
confirmed. Confirmed squamous cell
carcinoma, which is, you know, by far the most common Histology
we see in anal cancer. You absolutely need that path
(10:49):
confirmation before you even think about starting treatment.
Right path is proof. OK, so diagnosis confirmed
locally. Now we need to stage her figure
out the full extent of the disease.
Systemic staging first. Yep.
Standard of care for systemic staging is a computed tomography
scan. ACT scan of the chest, abdomen
and pelvis and you need intravenous contrast.
(11:09):
What's that looking for? That's our survey tool.
It looks for distance spread primarily to the lungs and liver
as we mentioned. It also gives us a look at lymph
nodes higher up in the abdomen and pelvis that might be
involved. OK.
CTCT key with contrast. What about getting a really
detailed look locally at the primary tumor itself?
For that, particularly for defining the precise local
(11:30):
extent of the tumor and its relationship to surrounding
structures like the sphincter orsay, the vagina, a pelvic
magnetic resonance imaging scan and MRI is really crucial.
MRI better than CT for local detail.
Much better, especially if you suspect a more advanced tumor
like AP3 or T4. The soft tissue detail on MRI is
(11:50):
just far superior for seeing exactly how far the tumor
extends and if it's invading adjacent structures.
CT can be a bit fuzzy for that level of detail right in the
pelvis. OK.
So it's CT for the big picture, MRI for the local details.
Now what about PT scans? You hear a lot about PCT, is
that standard here? It's not strictly mandatory by
all guidelines, but it is highlyrecommended.
(12:11):
I would argue it's become almostessential for optimal staging in
anal cancer. APTT.
Pronounced pet. CT.
Why is it so important? Was it add?
It adds functional information, it shows metabolic activity, and
studies have clearly shown that PECT can find involved lymph
nodes that look normal on a standard CT scan.
It actually upstages nodal disease, finds more disease than
(12:32):
expected in about 30% of patients compared to CT alone.
30%, that's significant. Is huge.
Think about Miss Jenkins with her palpable inguinal node.
APCT is critical for her first to confirm if that node is FDG
avid, meaning it lights up indicating active cancer cells.
OK, confirm the suspicious node.Right.
But just as importantly, the PCTscans the whole body.
(12:56):
It might pick up other involved nodes, maybe in the pelvis or
even higher up, that weren't suspected, or it could rarely
find distant metastatic disease we didn't know about.
It gives you the most accurate picture of the disease burden
before you commit to a treatmentplan.
It's a real game changer for precision staging.
OK so CTMRI and highly recommendPTCD.
What about blood work? Any specific labs needed?
(13:17):
Standard labs, of course. CBC, kidney function, liver
function. But given the strong link to
immunosuppression, HIV testing should be routinely offered and
performed for all anal cancer patients.
HIV testing for everyone. Got it.
Yep, and also for any patients who could potentially become
pregnant. You absolutely need a pregnancy
(13:37):
test before starting treatment, and just as important is
fertility counseling. Our treatments, both chemo and
radiation, can definitely impactfuture fertility, so that
discussion needs to happen up front.
Right. Fertility preservation is Q OK,
that's a very thorough workout plan.
Let's switch gears now to something absolutely fundamental
for treatment planning, the anatomy.
(13:58):
You mentioned the dentate line earlier.
Let's unpack the key anatomical distinctions here.
First, anal canal versus anal margin.
Absolutely critical distinction.They're close but different.
The anal canal is the inner tube.
Basically, it's about 4 to 6 centimeters long, a muscular
tube lined mostly with squamous cells sitting just inside the
anal verge, which is the external opening.
So the canal is the inside passage.
(14:19):
Right. The anal margin, on the other
hand, is the outside skin. It's the hair bearing karyanal
skin that surrounds the anal verge.
We usually define it as the skinwithin about a 5 centimeter
radius of that opening. OK.
Inside tube versus outside skin?Why does this difference matter
so much? It matters for staging, for how
the tumor behaves, and cruciallyfor lymphatic drainage where the
(14:41):
cancer is likely to spread. First tumor starting in the
canal versus the margin can drain to different lymph node
groups. Ah.
OK. Lymphatic drainage.
That brings us back to that landmark you mentioned the
dentate line. Tell us about that.
What is it and why is it the critical landmark?
The dentate line, sometimes called the pectinate line, is
probably the single most important anatomical landmark
(15:04):
for us in this region. Think of it as a sort of
internal dividing line. It's located roughly halfway up
the anal canal, maybe about 2cm in from the anal verge.
Halfway up the canal and anatomically, what is it?
It's where different tissue types meet.
It marks the transition from thecolumnar mucosa, the glandular
lining coming down from the rectum, to the squamous
epithelium, the skin like liningof the lower anal canal.
(15:27):
It's a biological junction. OK.
A tissue transition zone. But clinically it's big
importance is. Lymphatics.
It acts as a lymphatic watershed, like a continental
divide for lymph flow. Where the lymph drains depends
crucially on whether the tumor is above or below this line.
A lymphatic watershed. I like that analogy.
OK, so spell it out for us. How does this watershed work?
(15:47):
Where does lymph drain from above versus below?
It sounds like prime board blitzmaterial.
It absolutely is. This is a core concept.
You have to know cold for exams and for safe clinical practice
to avoid missing critical targets.
Here's the rule. The clinical Pearl tumors with
their epicenter above the dentate line higher up in the
canal. They primarily drain upwards and
(16:08):
sideways, basically following the roots, similar to a low
rectal cancer. OK, above the dentate drains
like low rectum. Which nodes are those?
Those are the pelvic nodes, specifically the mesorectal
nodes, the presacral nodes, and the internal iliac nodes, all
deep inside the pelvis. Pelvic nodes.
Got it. Now what if the tumor epicenter
(16:29):
is at or below the dentate line?If it's at or below the dentate
line, the drainage pattern shifts dramatically downwards
towards the groin through. The groin.
OK, which nodes specifically? Those are the inguinal nodes,
the femoral nodes right near them, and the external iliac
nodes which are a bit higher butstill part of that groin lower
pelvic drainage system. OK, this is super clear and
super important. So the mnemonic we should burn
(16:52):
into our brains is above the dentate it drains to the pelvis.
Below the dentate it goes to thegroin.
Exactly it Nail that down. And the important corollary,
what if the tumor is right at the dentate line or crosses it
like Miss Jenkins, whose tumor extended to the dentate line?
Good question. I assume you have to cover both
pathways then, pelvis and groin.You absolutely have to.
(17:13):
If it's sitting on the fence, orif there's any ambiguity about
its exact epicenter relative to the line, you must assume it has
access to both drainage routes. So your elective radiation
volume, the area you treat even if you don't see involved nodes,
has to comprehensively cover both the pelvic nodes and the
groin nodes. No cutting corners there.
(17:33):
Cover both if in doubt or at theline.
Got it. This anatomical precision
directly translates into defining our radiation target
volumes. Precisely, it's fundamental to
everything we do in treatment planning for anal cancer.
OK, fantastic. Now that we've got the anatomy
and lymphatics down, let's talk staging.
We use the AJCC 9th edition. You mentioned earlier that T
(17:54):
staging is different from rectalcancer.
How so? Yes, this is a key point that
often trips people up. Unlike rectal cancer, where T
stage depends on how deeply the tumor invades through the bowel
wall layers, Aim Cancer T staging is based purely on the
tumors size, its largest dimension.
Size, not depth like breast cancer.
Exactly like breast cancer or mini skin cancers.
(18:15):
It's simpler in a way. T1 is defined as 2cm or smaller.
T12 centimeters. Or less, right?
T2 is greater than 2cm up to andincluding five centimeters.
T2 more than two up to 5 centimeter.
Correct. And T3 is any tumor greater than
5 centimeters. T3 bigger than 5 centimeters.
Pretty straightforward size cut off.
They are. It reflects how these squamous
(18:35):
cell cancers tend to grow. OK, what about T4?
When does it become T4? T4 is defined by invasion into
adjacent organs, specifically invasion into the vagina, the
urethra, or the bladder. Vagina, urethra, bladder.
OK, now what's the common pitfall here?
What does not count as T4, even if it seems like extensive local
(18:57):
invasion? This is a really important
distinction for accurate staging.
Direct invasion of the rectal wall itself, or spread onto the
perianal skin, or even direct invasion into the sphincter
muscles. None of those make it AT4 tumor.
Even sphincter invasion isn't T4.
Nope. While those certainly indicate
locally advanced disease and affect prognosis and function,
(19:17):
they don't meet the specific AJCC definition of T4, which is
reserved for those specific adjacent organs.
It's a nuance, but crucial for correct staging.
Good to clarify. OK, let's move to end staging
the nodes. You said it's based on location,
not number. That's right, another key
difference from many other cancers.
For anal cancer nodes, it's all about where the positive nodes
(19:38):
are located, tying back directlyto those drainage pathways we
discussed. So how are the N categories
defined? We have N1A N 1B and N1C N1.
Erich means metastases are foundin the inguinal nodes or the
mesorectal nodes or the internaliliac nodes, basically the groin
nodes or the deep pelvic nodes we talked about earlier.
(19:58):
N1A, inguinal, mesorectal, or internal iliac.
N1B specifically refers to metastases in the external iliac
lymph nodes. These are a bit higher up in the
pelvis, closer to the common iliacs.
N1B external iliac nodes only. Right.
And then N1C is when you have metastases in both the external
iliac nodes, the N1B location and any of the N1A locations
(20:20):
inguinal, mesorectal or internaliliac.
N1C both external iliac and N1A nerds involved, so it reflects
more extensive regional spread. Exactly.
It's about the geography of the nodal spread.
OK, and M staging for distant myths.
Is there a specific nodal group that automatically bumps a
patient up to M1 even though it's technically still lymph
nodes? Yes there is.
(20:42):
This is the classic board question.
Favorite metastases to the common iliac lymph nodes, which
are located above the external iliacs, are considered M1
disease. Common iliac nodes equal M1.
Got it. Because they're outside the
defined regional basins. Precisely, they signify disease
has spread beyond the expected regional drainage and is
behaving more like systemic disease.
(21:03):
OK, let's tie this back to Miss Jenkins.
Remind us of her findings. She had a 4 centimeter primary
tumor in the anal canal extending to the dentate line
and she had that suspicious 1.5cm palpable right inguinal
lymph node. Right.
So based on the AJCC 9th edition, how do we stage her
clinically? OK.
Let's break it down. A4 centimeter primary tumor fits
(21:25):
into the greater than two up to 5 centimeters category.
So that makes her a clinical T2.T2 based on size.
Right and the suspicious right angle node falls into the N1A
category is inguinal nodes are listed under N1A.
N1A based on inguinal node. Correct.
So putting it together, Miss Jenkins would be staged as
clinical T2 and 1A, assuming herPECT and other staging scans
(21:48):
don't show anything else furtherafield.
Clinical T2 and 1A perfect. That staging is obviously
obviously fundamental for deciding her treatment.
Absolutely. It dictates everything that
follows. Which brings us perfectly to the
next major topic, the treatment itself, and specifically the
historical revolution that got us here.
Let's talk about the Negro revolution.
Before this, say pre 1970s, whatwas life like for an anal cancer
(22:12):
patient? What was the standard treatment?
Life for an anal cancer patient back then was, well, pretty
bleak honestly. The standard, and really the
only widely accepted curative intent treatment was an
abdominoperineal resection, an APR.
The APR, that's the radical surgery we mentioned.
The most radical it involved removing the entire rectum, the
anus, the anals, extinctors, often some surrounding tissue
(22:33):
and sometimes part of the colon,and the inevitable consequence
was a permanent colostomy, a bagfor life.
Wow, that was a standard for everyone, even early stages.
Pretty much, yes. Even for someone like Miss
Jenkins with potentially curablelocalized disease, it was
incredibly invasive, disfiguring, and had a massive
impact on quality of life. And despite how radical it was,
(22:56):
how are the outcomes? That's the kicker, they weren't
great. Even with this huge surgery,
five year overall survival rateswere only hovering around 50%.
Only 50% survival. Yeah.
And local recurrence rates, the cancer coming back in the pelvis
or perineum were distressingly high.
So patients endured this massiveoperation, the permanent
colostomy, and still had a significant chance of the cancer
(23:19):
returning locally. It's a really tough situation.
That paints a very stark pictureindeed.
OK, so something had to change. Enter Doctor Norman Negro at
Wayne State University in the early 70s.
What was his initial idea? What was he trying to achieve?
Right. So Doctor Negro published this
preliminary report in 1974 That really change the world for
(23:39):
these patients, even though thatwasn't his initial grand plan.
Not the plan. What was he trying to do?
His goal was actually more modest, maybe more pragmatic.
At the time, he wasn't trying toreplace the APR, he was trying
to improve it. He wanted to develop a
neoadjuvant chemo radiation regimen treatment given before
surgery to see if it could shrink the tumor, maybe kill off
microscopic cancer cells around the edges, and ultimately make
(24:01):
the APR surgery more successful,leading to better survival and
lower recurrence rates. So a preoperative treatment to
make the existing surgery work better.
Exactly. Enhance the surgery, not
eliminate it. That was the initial concept.
OK, So what did this original Negro protocol actually involve?
What was the recipe? It was, in retrospect,
(24:21):
remarkably simple but potent. The radiation part was actually
quite a modest dose by today's standards. 30 Gray delivered in
15 fractions over 3 weeks. 30 Gray OK And where was the
radiation aimed? Critically, it was aimed at the
pelvis and the inguinal lymph node regions.
So even back then, based on anatomical understanding, he
(24:42):
knew those were the key areas needing treatment.
He basically established the standard target volumes we still
build on today. Pelvis and inguinos and the
chemotherapy. Concurrent chemotherapy given
alongside the radiation. It consisted of two drugs, 5
floricil or five FU, spoken as five FU, which was given as a
continuous infusion over 4 days,and then a single bolus
(25:05):
injection of mitomycin C or mitomycin C right on day one of
the treatment. Five FU infusion and a bolus of
mitomycin C That combination sound familiar?
It should. It's essentially the backbone
that was tested and proven in those later landmark trials
we'll discuss. But again, the doses and intent
here were originally neoadjuvant.
OK, so patients got this 30 greyradiation with concurrent 5 FU
(25:28):
and mitomycin C The plan was then for them to proceed to.
The plan was for them to recoverfor about 6 weeks and then head
to the operating room for their scheduled APR, the big surgery.
And this is where the story takes its amazing turn right
What happened when those first few patients actually went to
surgery? This is the incredible part, the
serendipity of science. When the surgeons operated on
(25:49):
those first few patients who hadreceived the Negro protocol
preoperatively, and the pathologists examined the
specimens that were removed, they found something stunning.
Which was? No cancer, or rather a
pathologic complete response. APCR.
The tumor, which had been biopsied and confirmed before
treatment, had completely vanished.
All that was left was scar tissue in many cases.
(26:11):
Wow, so the pretreatment had completely eradicated the tumor
before the planned surgery even happened?
In those initial patients, yes. Imagine the shock, the
excitement. They went in, expected to do
this massive resection for residual cancer, and instead
they found the treatment had already seemingly cured the
patient locally. That must have been a light bulb
moment. A huge one.
Absolutely. Doctor Negro and his team
(26:32):
immediately recognized the profound implications.
They realized this combined chemo radiation was so
effective, so cytotoxic to the tumor, that maybe, just maybe,
the radical APR surgery wasn't necessary at all for the
majority of patients. So the attempt to improve
surgery accidentally led to the potential to avoid surgery
altogether. That's like that analogy you use
(26:54):
stumbling onto a paved Hwy. whenyou're hacking through the
jungle. That's a perfect way to put it.
It wasn't just a detour, it was a completely new, vastly better
route. This discovery fundamentally
birthed the new paradigm for anal cancer treatment.
The paradigm of definitive chemoradiation.
Exactly. Definitive chemo radiation
became the primary standard of care approach and the APR that
(27:17):
one standard mutilating operation was relegated to a
salvage role, only used if the chemo radiation didn't work
initially or if the cancer came back later.
A true revolution then, establishing one of the very
first truly successful organ preservation strategies in all
of oncology. Without a doubt it had ripple
effects inspiring similar organ sparing approaches and other
cancers like bladder, larynx, breast.
(27:40):
It taught the entire field that challenging surgical dogma with
combined modality therapy could yield incredible benefits for
patients, not just in survival, but profounding quality of life.
Preserving normal function became a real therapeutic goal.
What an amazing story, and a huge win for patients.
OK, so Negro showed chemo radiation could work
spectacularly well, in fact. But the critical scientific
(28:02):
question remained was the chemotherapy part actually
essential? Could radiation alone achieve
similar results, maybe with lesstoxicity?
Precisely that was the next logical, crucial question.
Negro showed The combination waspotent, but was it the chemo,
the radiation, or the synergy ofboth?
This needed rigorous testing in large clinical trials.
(28:22):
Which brings us to those landmark European trials you
mentioned. Let's start with the first big
one, the UKCCCR Act One trial. That's UKCCCRA CT1.
The ACT One trial published backin 1996.
This is a really important largestudy.
They enrolled over 580 patients with anal cancer and
significantly, they excluded only the very earliest stage,
(28:45):
the T1 N 0 tumors, focusing on the majority of patients who
present with more advanced disease.
Over 580 patients. And what was the core
comparison? How did they test the chemo
question? It was a straightforward,
elegant design. Patients were randomly assigned
to one of two groups. Group One got radiation therapy
alone. The standard dose back then was
(29:06):
typically 45 grey, sometimes with an optional boost to the
tumor bed. OK, radiation alone arm.
Group 2 got the exact same radiation therapy, same dose,
same fields, but with the addition of concurrent
chemotherapy. 5 FU and muttomycin C given in the
standard Negro like schedule during the radiation.
So radiation alone versus radiation plus chemo.
(29:28):
A direct head to head test. Exactly isolating the effect of
adding those two chemotherapy drugs.
And the results? Did the chemo make a difference?
The results are absolutely striking, unequivocal and in the
chemotherapy made a massive difference in outcomes.
The headline finding was local control.
The three-year rate of controlling the cancer in the
pelvis and anus was 54% in the chemo radiation group. 64% local
(29:51):
control with chemo RT. OK, what about radiation?
Alone only 41%. Wow, 41 versus 64%, that's a
huge gap, huge over a 20% absolute improvement in local
control just by adding the chemotherapy and that had major
downstream consequences Like what?
Like significantly better colostomy free survival.
(30:11):
Because the cancer was controlled locally much more
often, far fewer patients in thechemoradiation arm ended up
needing a salvage APR and a permanent colostomy later on.
They kept their sphincters, kepttheir normal function.
Better local control, fewer colostomies?
Did it impact survival too? Yes, it also led to a
statistically significant reduction in cancer specific
deaths. So more cures, better local
(30:34):
control, and better quality of life.
The conclusion was crystal clear.
Which was? Adding concurrent 5 FU and
mitomycin C to radiation is definitively superior to
radiation alone for treating anal cancer in terms of both
controlling the disease and preserving the sphincter.
Incredibly strong evidence from ACT 1.
Was this finding replicated? Did other trials confirm it?
(30:55):
Yes, it was robustly confirmed by another major European trial
run by the EORTC, that's the European Organization for
Research and Treatment of Cancer.
Their trial number was 22861, published just a year after ACT
One in 1997. EOR TC-22861 OK, did it look at
(31:15):
a similar patient population? Slightly different actually.
This trial focused specifically on patients with higher risk,
more locally advanced disease, so T3 or T4 tumors or any node
positive patients, about 110 patients in total.
Higher risk group and the designsame comparison.
Same fundamental comparison, Yeah, Radiation therapy alone
versus the same radiation therapy with concurrent 5 FU and
(31:38):
mite MYCIN C. And the results in this higher
risk group, did chemo still add benefit?
Absolutely. The results were remarkably
consistent with ACT 1, even in this tougher to treat
population. The five year local control rate
was 70% with chemo radiation compared to only 50% with
radiation alone. 70 versus 50% local control at five years,
still a 20% gap. Exactly.
(31:59):
And again this translated directly into significantly
better five year colostomy free survival, 70% for the chemo
radiation group versus just 40% for the radiation alone group.
70 versus 40% chance of avoidingA colostomy.
That's a massive difference for patients.
Huge. So the EORTC trial strongly
reinforced the message, even, perhaps especially in patients
(32:20):
with more advanced disease, adding the chemotherapy provides
a major, undeniable benefit. So these two trials together,
UKCCCRA CT1 and EOTC 22861, theyreally cemented it.
They provided that definitive Level 1 evidence.
They absolutely did. They effectively closed the door
on radiation alone as a standardprimary treatment for the vast
majority of anal cancer patients.
(32:42):
Concurrent chemo radiation became and remains the
undisputed gold standard thanks to this rigorous evidence.
OK, this is fantastic. We've covered the epidemiology,
the anatomy, the staging, the history and the pivotal trials.
Now let's synthesize all of this.
Let's apply it directly to our patient, Misses Jenkins.
Remind us again, 64 years old clinical T2N1A squamous cell
(33:05):
carcinoma of the anal canal. Based on everything we've
discussed, what is the clear evidence based treatment
recommendation for her? Right, putting it all together
from his Jenkins given her clinical T2N1A squamous cell
carcinoma, the standard of care without question is definitive
concurrent chemo radiation. OK.
Why specifically chemo radiation?
(33:26):
Just to summarize the rationale.Because of the foundational work
by Negro showing it could achieve complete responses, and
crucially because of the level 1evidence from ACT 1 and EO or
TC22A61 which proved that addingconcurrent 5 FU and mitomycin C
to radiation significantly improves local control and
colostomy free survival comparedto radiation alone.
It offers her the best chance ofcure, preserving her sphincter
(33:48):
function. And surgery.
The AP? Where does that fit in now for
her? Surgery.
The APR is reserved strictly forsalvage, meaning if
unfortunately the chemoradiationdoesn't completely eradicate her
cancer or if it were to recur locally sometime down the road,
that an APR might be considered,but it's absolutely not the
upfront treatment anymore. OK.
What about just cutting the tumor out?
(34:10):
Local excision? Is that ever an option for
someone like Missus Jenkins T2N1A in the canal?
Absolutely not. This is a really important point
for residents to grasp. Local excision is an extremely
selective option in anal cancer.The current Astro guidelines,
for example, state it's only considered for highly selected,
very small clinical T1N0 tumors that are located on the anal
(34:32):
margin, the outside skin and have favorable pathology
features like no lymphovascular invasion.
So only tiny superficial skin tumors on the outside basically.
Essentially yes, misses Jenkins tumors T2 it's in the anal canal
and she has nodal involvement N1A all of those are absolute
contraindications local excisionas primary therapy it would be
completely inadequate treatment for her virtually guaranteeing
(34:53):
failure very. And just to reiterate, what if
someone proposed just radiation alone for her?
Maybe to avoid chemo side effects?
That would be substandard care based on the ACT 1 and EO core
TC trials. Choosing radiation alone for
Miss Jenkins would significantlycompromise her chances.
Her risk of local recurrence would be much higher, and her
(35:14):
likelihood of meeting a colostomy eventually would
increase substantially. It's simply not an equivalent
option. So the definitive, unambiguous
recommendation for Miss Jenkins is concurrent chemo radiation,
aiming for cure with organ preservation.
That's precisely it. It's a testament to how far the
field has come, offering her an excellent chance of cure while
(35:34):
maintaining her quality of life,something unimaginable 50 years
ago. It really is remarkable.
Now we know the Negro protocol established the what and where
to treat chemo radiation to the pelvis and inguinals.
How do we actually deliver that radiation in modern practice?
You mentioned advanced techniques.
Right. While the fundamental principles
of what volumes need to be treated haven't changed
drastically since Negro pelvis and groin based on anatomy and
(35:57):
state trade, the how we deliver that radiation has evolved
tremendously. To be more precise.
Exactly. We now use highly sophisticated
techniques like Intensity Modulated radiation therapy or
IMRT, and Volumetric modulated arc therapy, or VMAT.
IMRT and VMAT, what do they allow us to do?
(36:17):
They allow us to sculpt the radiation dose with incredible
precision. We can shape the high dose
radiation cloud very tightly around the target volumes, the
tumor itself, any involved nodes, and those elective nodal
regions we need to cover, while simultaneously minimizing the
dose delivered to nearby healthyorgans.
Organs like. Like the small bowel, the
bladder, the femoral heads, the tops of the thigh bones, the
(36:39):
external genitalia and even uninvolved parts of the anal
sphincter complex. By sparing these normal tissues
better, we can significantly reduce both acute side effects
during treatment like diarrhea and skin reaction and also long
term toxicities while still delivering the necessary
curative dose to the cancer. So better targeting, less
collateral damage. That's the goal.
We won't get into the physics weeds of IMRT and VMAT today,
(37:02):
but it's important to know that these advanced technologies are
what allow us to safely and effectively implement the
principles established by Negro and those landmark trials.
They optimize the therapeutic ratio, maximizing cure while
minimizing harm. Makes perfect sense.
OK, let's lock this all in time for our board blitz.
Ready to test your recall on these key concepts?
Let's do it. Fire away.
(37:23):
All right, question one scenario.
A 65 year old woman presents. She has a 1.5 centimeter well
differentiated squamous cell carcinoma found on the anal
margin. She undergoes a wide local
excision pathology, shows 2cm clear margins and crucially, no
lymphovascular invasion, no perineural invasion.
What is the most appropriate next step in her management?
(37:45):
Is it a adjuvant chemo radiationto 50.4 Gray B adjuvant
radiation alone to 45 Gray C observation with close
surveillance or D abdomenoperenial resection?
OK. Thinking through the criteria,
small tumor, 1.5cm of T1 in a margin location, wide negative
margins, no high risk features like LDI or PNI.
(38:07):
This fits those very selective criteria we discussed.
So the answer should be C observation with close
surveillance. And the rationale?
The rationale is that for this very specific subset of
patients, clinical T1 and zero anal margin completely excised
with wide margins and no adversefeatures.
The cure rates with surgery alone are excellent.
According to Astro and other guidelines, adjuvant therapy,
(38:29):
chemo or radiation is generally not recommended as it likely
adds toxicity without significantly improving
outcomes. In this highly favorable
situation, close follow up is key, but further immediate
treatment isn't needed. Perfect.
Highlights the importance of knowing those narrow exceptions.
Question 2. Scenario A patient is diagnosed
with A4 centimeter squamous cellcarcinoma of the anal canal.
(38:49):
Imaging confirms the epicenter of the tumor is located right at
the dentate line. Question Which nodal basins are
considered at risk and must be included in the elective
radiation volume? A Inguinal and external iliac
nodes only. B Mesorectal and internal iliac
nodes only. C Both pelvic, mesorectal,
internal iliac and groin, groin inguinal, external iliac nodes
(39:10):
or D para aortic nodes only. The dentate line question, OK, 4
centimeter tumor, so T2 epicenter right of the dentate
line. Our mnemonic was above the
dentate drains to pelvis, below the dentate goes to groin if
it's at the line. It has access to both pathways.
Exactly. It has access to both superior
drainage pelvis and inferior drainage groin.
(39:31):
Therefore, you absolutely must cover both sets of regional
nodes electively. That means the answer is C Both
pelvic mesorectal internal iliacand groin inguinal external
iliac nodes must be included in the target volume.
Treating only one would be a geographic mess.
Excellent. That watershed concept is
critical. Final question.
Question three Scenario A juniorresident is presenting a patient
(39:52):
with AT3 and one anal canal cancer.
The attending asks the resident why concurrent chemotherapy is
the standard of care for this patient.
Which of the following trials provides the best level 1
evidence to support this practice?
A. The original Negro protocol
report BRTO G9811 spoken as RTO G9811CU KCCCRA CT1 or D, The
(40:15):
Stockholm. The third trial.
OK T3 and one disease definitelyneeds definitive treatment.
Why chemo with the radiation? We have the trial that directly
compared chemo RT versus RT alone.
The Negro protocol showed feasibility but wasn't a
randomized comparison. RTOG 9811 compared different
chemo regimens with RT. Stockholm the 3rd is a rectal
cancer trial that leaves. BTCCCRA CT1.
Exactly the answer is CUKCCCRA CT1 along with ER3 RTC 22861
(40:42):
provide the definitive level 1 evidence from randomized
controlled trial showing that adding concurrent 5 FU and
mitamycin C to radiation significantly improved local
control and colostomy free survival compared to radiation
alone. That's the evidence that
mandates chemo radiation as the standard for this T3 and one
patient. Perfect reasoning that nails
down the core evidence base. OK, let's zoom out again
(41:03):
briefly. Controversies and advances.
We spent a lot of time today rightfully celebrating the huge
advance of the Negro protocol, and the subsequent trials
represented that massive shift from APR to definitive chemo
radiation. It truly was foundational.
Absolutely. It's hard to overstate how
transformative that was. It fundamentally changed the
prognosis and quality of life for countless patients.
(41:24):
It really set the stage for everything that followed in anal
Cancer Research. So building on that foundation,
what are some of the areas wherethe field is still evolving or
where there's ongoing research? You mentioned optimizing chemo
earlier, right? While five a few Mitomycin C is
the proven standard based on ACT1 and EOTC, there's been an
ongoing research like the RTOG 9811 trial comparing it to five
(41:47):
if you cisplatin. The results were complex,
suggesting maybe similar efficacy but different toxicity
profiles. So, choosing the optimal chemo
regimen, especially considering individual patient factors and
comorbidities, is still an area of discussion and refinement.
OK, Chemo optimization. What else?
There's interest in treatment deescalation for very favorable
early stage HPV positive tumors.Can we perhaps reduce the
(42:10):
radiation dose or intensity of chemotherapy for these patients
to minimize long term side effects without compromising the
excellent cure rates that's an active area?
De intensification for low risk?What about the other end?
High risk? For more advanced or bulky
tumors, there's investigation into neoadjuvant or induction
chemotherapy, giving chemo before the chemo radiation
starts to try and shrink the tumor 1st and potentially
(42:32):
improve outcomes. The evidence for that is still
evolving, and like everywhere else in oncology, immunotherapy
is being explored, particularly for metastatic or recurrent
disease leveraging that HPV connection.
Lots of directions for future progress, and this foundational
understanding we've built today really prepares us for diving
into those nuances, which leads perfectly into our next session,
Anal Cancer Part 2. What can listeners expect us to
(42:54):
cover them? In Part 2, we'll get much more
into the practical weeds of optimizing treatment.
We'll do a detailed comparison of mitomycin C versus cisplatin
based chemotherapy regimens. We'll talk about how we tailor
radiation doses based on the initial TNN stage.
It's not one-size-fits-all, and critically, we'll emphasize the
huge importance of avoiding treatment breaks during chemo
(43:15):
radiation, explaining the data behind why completing treatment
on schedule is so vital for success.
It'll be focused on refining theapplication of today's
principles. Sounds essential.
OK, let's quickly recap the absolute must know takeaways
from today's foundational session.
First, anal cancer distinct, mostly HPV driven and its
incidences rising. 2nd staging based on tumor size, T stage and
(43:38):
nodal location end stage, not depth of invasion like rectal
cancer. 3rd anatomy is destiny, especially that dentate line,
the lymphatic watershed dictating pelvic versus groin
drainage. Remember, above the dentate to
the pelvis, below the dentate tothe groin. 4th The Negro
protocol was revolutionary, shifting the paradigm from
(43:59):
radical APR surgery to sphincterpreserving definitive chemo
radiation. 5th, the UKCCCRA CT1 and ER or TC-22861 trials
provided the level 1 evidence proving concurrent 5F
humidamycin C plus radiation is superior to radiation alone.
Chemo is necessary. 6th A comprehensive workup including
(44:20):
history, physical, an oscopapsy CT, pelvic MRI and ideally a PET
CT PET CT is crucial for accurate staging.
And finally, local excision is avery niche option only for
highly select T1 and zero anal margin tumors with favorable
features. For almost everyone else, like
Mrs. Jenkins, definitive chemo radiation is the standard.
That covers the core foundationsperfectly.
(44:42):
Excellent. For more detailed notes on all
of this and to test yourself with practice oral board
scenarios, you can visit radoncsmartlearn.com.
That's radoncsmartlearn.com. And definitely subscribe to
Radon Smart Review so you don't miss Part 2, where we'll really
get into optimizing that chemoradiation regimen.
Thanks so much for joining us for this deep dive into the
foundations of anal cancer treatment.
(45:02):
Thanks for listening. We'll talk to you next time.
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