June 29, 2025 • 37 mins
In our last episode, we laid the foundation for anal cancer management, establishing definitive concurrent chemoradiation as the sphincter-sparing standard of care, thanks to the pioneering work of Dr. Nigro and the pivotal ACT I and EORTC trials. We know why we use chemoradiation. Today, we focus on how to optimize it.Modern chemoradiation for anal cancer is a finely tuned balance of three critical components: the right chemotherapy, the right radiation dose, and the right timing. Getting any of these wrong can compromise cure rates or lead to unnecessary toxicity. Today, we’ll dissect the evidence for each of these pillars. We'll compare the key chemotherapy agents, Mitomycin C versus Cisplatin. We’ll justify modern, risk-adapted radiation dose escalation. And we will stress the crucial importance of completing treatment on schedule, without breaks.
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Episode Transcript
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(00:00):
Welcome back to the Rad on SmartReview GI Cancer series.
Great to be back. So we're picking up right where
we left off, building on that foundational discussion of anal
cancer. Exactly.
Last time we really dug into why.
Why definitive concurrent chemo radiation is, you know, the gold
standard. Right, the whole sphincter
sparing approach, all thanks to Doctor Negro's work and those
(00:21):
big trials, ACT 1, the EORTC trial, we really established the
rationale. Yeah, the groundwork and today
we're shifting gears a bit moving from the why to the, I
guess the really critical how. How to actually do it optimally?
Precisely. It's not just following a
recipe, it's about understandinghow to really fine tune modern
(00:42):
concurrent chemoradiation for squamous cell carcinoma of the
anal canal. And that means, you know, really
looking closely the three absolutely critical components
you've got to have the right chemotherapy.
You need the right radiation dose, the precise dose, and
maybe overlook sometimes the right timing, flawless timing.
Get any one of those wrong? Well, it can really mess things
(01:03):
up. You could jeopardize the cure
rates, obviously, but just as important, you could inflict
unnecessary, avoidable toxicity on patients.
It's it's really a balance, an art and a science.
Definitely sounds like it. So to keep us grounded, let's
bring back our patient case fromlast time.
Miss Jenkins. Ah.
Yes, Miss Jenkins. 64 year old woman.
(01:26):
She has a clinical T2N1A squamous cell carcinoma of the
anal canal. Primary tumor is 4 centimeters.
OK, so upper end of T2. Exactly.
And she has that confirmed 1.5cm, right, inguinal lymph
node. So we've decided definitive
chemo radiation is the way to gofor her, right.
But now the challenge is designing her optimal regimen.
(01:49):
So as we, you know, unpack the evidence today, we'll keep
circling back to Missus Jenkins.How does this apply to her?
That's the perfect way to frame it because as we walk through
the evidence, you know, the big trials, the latest guidelines,
you should really keep Miss Jenkins in mind.
We need answers for her. Like what?
Well, first. What's the absolute best
chemotherapy agent to pair with the radiation?
We'll get into that debate then.What's the precise risk adapted
(02:13):
radiation dose, not just any dose, but the right one for her
4 centimeter T2 tumor that involved inguinal node.
And then, maybe most critically,in practice, how vital is it
that she completes her entire treatment course without any
interruption, even a few days? We'll breakdown the evidence for
each of these pillars. OK, let's do it.
(02:33):
Let's unpack this, starting withmaybe the most fundamental
question, the one that's driven a lot of research and honestly
some debate over the years, which is my TOE, my Cincy versus
cisplatin for concurrent chemo. The classic head to head.
We know the original Negro protocol, the one that really
pioneered this whole concurrent approach, used 5 FU and my toe,
(02:55):
my sin C MMC. That's the one foundational.
But MMC has that well known issue, right, the potential for
significant myelosuppression that can be really tough on
patients. That's a huge point.
Myelosuppression. I mean, for anyone less
familiar, we're talking about severe bone marrow suppression.
Right, low counts. Exactly.
Dramatically lower white blood cells, especially neutrophils.
That leaves patients wide open to potentially life threatening
(03:18):
infections. Hospitalizations.
Antibiotic. All of it, broad spectrum
antibiotics, sometimes growth factor support like GCSF.
Plus you can get severe anemia, needing transfusions, low
platelets, increasing bleeding risk.
It's not just challenging, no. It can fundamentally stop a
patient from staying on schedule.
It impacts their safety. So naturally that toxicity
(03:40):
profile made people wonder, could cisplatin, which is often
seen as less stuff on the bone? Marrow less hematologically
toxic, yeah. Could it be a safer but equally
effective substitute? And that question was really at
the heart of two major cooperative group trials, which
interestingly, initially seemed to give us conflicting results.
OK, so let's. Start with the first one, the
(04:02):
one that probably had the biggest initial impact.
Right. That would have to be RTOG 9811
published back in 2008, big study, 644 patients and
importantly they focused on T2 to T4 anal cancer.
So generally larger, more advanced primary tumors.
They randomized patients into two pretty different arms.
Arm A was the control the standard at the time.
(04:24):
Definitive radiation with concurrent 5 FU and my toe, my
sin C. And the specifics of that?
Regimen Standard Stuff 5 FU at 1000 milligrams per meter
squared per day. Continuous infusion over 96
hours. Four days.
Yeah, four days given during week 1 and week 5 radiation and
the my, my sin C was 10 milligrams per meter squared, 4
bolus on day one and day 29 thatwas the MMC arm.
(04:47):
OK, standard Negro basically, and R&B the cisplatin arm.
R&B got radiation with concurrent 5 FU and cisplatin.
The five FU was similar, same dose, same schedule, weeks one
and five. Cisplatin was given at 75
milligrams per meter squared on day one and day. 29 OK 75.
Wait, let me check that dose actually, apologies.
The cisplatin dose in 9811 was 100 milligrams per meter squared
(05:11):
on day one and day 29. The five FU was indeed 1000
milligrams per meter squared over 4 days in weeks 1:00 and
5:00. 100 milligrams per meter squared.
Yes. Now here's a kicker, the really
crucial part for interpreting this whole thing.
What's that? The cisplatin arm also received
2 cycles of induction chemotherapy before starting
(05:33):
their concurrent chemo radiation.
Ah, induction chemo. With what agents?
Typically 5 FU and cisplatin, the same agents they'd get
concurrently but given upfront. So hold on that induction chemo
and the cisplatin arm, that's a major confounder.
Isn't it huge? Absolutely massive.
It delayed the start of their radiation.
By definition, 2 cycles of induction chemo meant, you know,
(05:55):
several weeks delay before thosepatients even started their main
concurrent treatment. OK.
So that's critical context. What were the results?
The results were, well, pretty stark.
The my toe, my sin C arm came out superior across the board.
Pretty much every endpoint measured.
Like overall survival. Significantly better five year
overall survival, 78% for MMC versus 71% for Cisplat.
(06:16):
That's a 7% absolute difference.Wow.
That's substantial. It is disease free survival also
clearly better. 68% for MMC versus 58% for cisplatin. 10%
difference there. And what about sphincter
preservation? Colostomy rates.
Also significantly better with MMC.
The five year colostomy rate wasmuch lower, 10% in the MMC arm
(06:38):
versus 19% in the cisplatin arm.Almost double.
Almost double so patients are far more likely to keep their
sphincter, avoid a permanent colostomy if they got the MMC
regimen in this trial. OK, so RTOG 9811 on the surface
seems to say MMC is definitivelysuperior, but that induction
chemotherapy hanged over it. Exactly.
(06:59):
That's the elephant in the room.Was it truly that MMC is a
better radiosensitizer, or was it the harm caused by delaying
radiation with that induction chemo that made the difference?
That's a huge question. Did MMC win or did delaying
radiation lose? Precisely that confounder was,
and still is, you know, a major discussion point whenever 9811
(07:19):
comes up. So how did the field try to
answer that specific question? Well, that led directly to the
UK ACT 2 trial. Remember, pronounce it like the
word act. ACT 2 got.
It this trial was meticulously designed to eliminate that
confounding induction chemotherapy to get a clean
comparison. What is similar in size?
Even larger actually 940 patients.
(07:40):
And notably, it included anal cancer of all stages, not just
the T2T4 like 1911. OK.
And the design? It used a clever two by two
factorial design, so 2 randomizations happening.
The first randomization directlyaddressed our question.
It compared chemo radiation withfive FU slash MMC versus 5 FU
slash this platen. Critically, both regiments
(08:01):
started concurrently with radiation from day one.
No induction delay. Apples to apples on the timing.
Perfect. The second randomization we'll
discuss later. Exactly that looked at
maintenance chemo, we'll get there.
But for this comparison, MMC versus cisplatin given
concurrently, what did ACT 2 find?
What were the results of that direct comparison?
(08:22):
In that head to HEAD ACT 2 foundno significant difference.
No difference in what? Incomplete response rates in
progression free survival or in colostomy free survival.
The three-year progression free survival, for instance, was
about 75% in both arms, basically equivalent efficacy.
Wow OK what about toxicity? Did MMC still show more mild
(08:44):
suppression? It did.
The MMC arm had slightly higher rates of grade 3 or higher
hematologic toxicity, about 26% versus 16% for cisplatin.
So confirming that known side effect profile.
Right. But interestingly the overall
non hematologic toxicities were pretty similar between the two
arms. So the main difference was
really that blood count issue. So the interpretation from ACT 2
(09:05):
was pretty clear. When you give them concurrently
without that induction chemo delay, cisplatin appears to be
non inferior to my toe my sensei.
Meaning equally effective. Equally effective, just with a
slightly different, potentially less hematologically toxic.
So now we have RTOG 9811 saying MMC is superior and ACT 2 saying
(09:27):
they're basically equivalent or non inferior.
How do we reconcile this? What's the practical take home
for treating Miss Jenkins today?This is where the clinical
judgement, understanding the nuances really comes in.
The key, as you pointed out, is that induction chemotherapy in
9811. The delay.
That delay in starting radiationfor the cisplatin arm likely
(09:48):
skewed the results. It probably disadvantaged the
cisplatin arm unfairly just by starting definitive therapy
later, right? So while 9811 initially made it
look like MMC was just flat out better, ACT 2 helped us
understand why that might have appeared to be the case.
It helped isolate the pure chemotherapy effect from the
timing effect. OK, so where does that leave us
now? What's the consensus?
(10:08):
Like the Astro guidelines? What did it say?
The current consensus, and this is reflected well in the the
2025 Astro guidelines, is that 5FU slash MMC still remains the
preferred standard of care. Preferred OK despite ACT 2.
Despite ACT 2, I think that overall survival benefit seen in
(10:29):
9811, even with the known confounder, carries a lot of
historical weight. It kind of anchors.
MMC is the default. Clinical inertia maybe, or just
respecting that survival signal?Probably a bit of both, but
crucially, the guidelines also acknowledge cisplatin as a very
reasonable alternative. For whom?
Especially for patients where that risk of mild suppression is
(10:51):
particularly concerning. Maybe someone with poor baseline
counts or pre-existing bone marrow issues, or maybe someone
very frail. OK, so for Miss Jenkins, if
she's got good blood counts, no major contraindications, the
default choice would likely still be 5 FU slash MMC.
We'd lean on that historical. Strength, but if she did have
risk factors for mild suppression.
Then switching to concurrent cisplatin or even capacitabine,
(11:14):
which we'll discuss would be a perfectly valid evidence based
chase offering similar efficacy based on ACT 2.
The key is concurrent administration.
No induction delays. It makes sense understanding the
history and the nuance behind the preferred label.
OK, let's shift gears. We've talked chemo agents.
What about the radiation side? The dose.
(11:35):
Right. Equally critical.
The goal is always maximizing local control, killing the tumor
while minimizing late toxicity, preserving function and quality
of life that balance. It's the perpetual challenge,
isn't it, especially in the pelvis, and the evidence here
strongly points towards a risk adapted approach.
Meaning. Meaning we don't just give
everyone the same dose, we need to tailor it.
(11:57):
Specifically, you need to judiciously escalate the dose
for larger tumors and for any involved lymph nodes.
Why escalate for those? Because they inherently carry a
higher risk. Higher risk of microscopic
spread, maybe more resistant cells.
They just need a higher dose to ensure eradication.
It's definitely not one-size-fits-all.
And the Astro guidelines give specific recommendations here.
(12:17):
They do. The 2025 guidelines are quite
clear, distilling data from manytrials into actionable advice.
OK, walk us through it. Let's start with smaller tumors.
What's the dose range? For clinical T1 to T2 tumors,
the guideline recommends a dose of 45 to 50.4 Gray. 45 to 50.4
(12:39):
and how many fractions? Typically delivered in 25 to 28
fractions. This comes from seeing excellent
results of those foundational trials like RTOG 87 O 4 and 9811
where many T2 patients were cured even with 45 Gray.
So that range is kind of the sweet spot for good control,
acceptable toxicity for smaller tumors.
(13:01):
Exactly. But there's an important caveat
for larger T2 tumors. Like Miss Jenkins, hers is 4
centimeters. Precisely like Miss Jenkins, for
T2 tumors that are 4 centimetersor bigger, the guidelines
suggest that pushing the dose towards the higher end of that
range, say 50.4 grey or maybe even up to 54 grey, might be
reasonable. And the thinking there is.
(13:22):
Just that a larger tumor, even if still stage T2, likely has a
higher burden of disease, maybe more heterogeneity, potentially
more resistant clones. It might just need that extra
bit of radiation punch to ensurecure and minimize recurrence
risk. OK, so for Miss Jenkins we're
already thinking maybe closer to50.4 grey for her primary given
(13:43):
its size. That would be a very reasonable
starting point for discussion, yes.
Now, what about the really big ones?
The T3T4 tumors? Inherently tougher cases.
Right. For those clinical T3 to T4A,
significantly higher dose is recommended.
We're talking 53.2 up to 59.4 grey. 53.2 to 59.4 That's quite
(14:05):
a jump. It is, and it's usually
delivered in slightly more fractions, maybe 28 to 33.
This dose escalation is critical.
Why so critical? What's the evidence?
Well, data from trials like RTOG9811 clearly showed much higher
rates of local failure and consequently higher clocktomy
rates for these larger tumors when they were treated with
lower doses like the 45 grey range.
(14:27):
You have an example. Yeah.
For instance, in the MMC arm of 9811 patients with T4 and 0
disease, they had a five year local regional failure rate of
37%. Wow, 37% failure even with MMC
chemo. Yes, that's really high.
It tells us loud and clear that these bigger, more advanced
(14:48):
tumors simply need more radiation dose to achieve
durable local control. We have to push that dose
response curve carefully, of course.
Carefully managing normal tissuetolerance, especially in the
pelvis. Absolutely, it's a fine line.
OK. So that covers the primary tumor
dose based on T stage. What about the lymph nodes
misses Jenkins? Has that confirmed 1.5cm
(15:10):
inguinal node? Right.
For clinically involved nodes like hers, palpable or seen
clearly on imaging, the recommended dose is 50.4 to 54
Gray. 50.4 to 54, similar to thedose for a larger primary.
Exactly. You need to adequately treat
that gross disease. We wouldn't want to underdose a
known involved node. Makes sense.
And what about elective nodes, the areas at risk but not
(15:32):
obviously involved? For those elective nodal
volumes, think the other inguinal regions, the pelvic
nodes like internal iliac, external iliac obturators, we
treat prophylactically but to a lower dose, typically 36 to 45
grey. 36 to 45, and that's usually in maybe 20 to 30
fractions. Correct.
The idea is to cover those at risk areas, sterilize potential
(15:55):
microscopic disease, but withoutgiving excessive dose to large
volumes of normal tissue, minimizing collateral damage and
long term side effects. OK, so let's try a quick
mnemonic here for the primary tumor doses, maybe 4-5 for
small, 5/3 for large. Like that?
Yeah. So T1T2 think 45 Gray range up
to 50 point. 4T3T4 Think 53 Grayrange up to 59.4. 4-5 for small,
(16:21):
5/3 for large. That's sketchy.
Help simplify it. Good one.
OK. So we've got the chemo agent
choice, we've got the risk adapted radiation dose.
What about adding more or chemo?Does induction chemo before or
maintenance chemo after help? The more is better question.
It comes up in so many cancers. Right.
Does it apply here in anal cancer?
The answer based on good evidence from key trials is a
(16:43):
pretty resounding no, and knowing this is really
important. OK, tell us about induction.
First chemo before chemo RT. The French ACCORD 03 trial
tackled this head on. They took patients with larger
tumors or node positive disease,the higher risk groups and
randomize them to what to eitherget induction chemo first,
typically 2 cycles of five FU and cisplatin, or to go straight
(17:07):
to standard concurrent chemo radiation.
And the rationale for induction was?
The usual thinking shrink the tumor up front, maybe make the
main treatment easier and hit potential micrometastases early.
Plausible ideas? But what did they find They.
Found absolutely no benefit. No improvement in colostomy free
survival, no improvement in progression free survival, no
(17:28):
improvement in any major end point by adding that upfront
induction chemo. No benefit at all.
None, and if anything there was maybe a trend towards more
toxicity without any gain. It just delayed the start of
definitive local therapy, which,as we discussed with 9811, can
be detrimental. So induction is out.
What about maintenance chemo after finishing chemo RT to kind
(17:51):
of mop up? Again, the answer is no, and
this comes from that same UK Act2 trial we discussed earlier.
The second randomization. Exactly.
Remember the two by two design, after patients finish their
concurrent chemo radiation either with MMC or cisplatin,
they were then randomized a second time to either receive 2
(18:11):
cycles of maintenance 5 FU slashcisplatin or to get no further
maintenance chemotherapy, just observation.
And the result? Did the maintenance chemo help?
Nope. Just like induction, there was
no benefit whatsoever. No improvement in progression
free survival, No improvement inany other oncologic outcome by
adding those two extra cycles ofchemo.
(18:31):
It just added toxicity. Pretty much added toxicity at a
burden on the patient, cost, time, all for no measurable gain
and efficacy. So the take home message here
seems crystal clear for anal cancer.
It really is. The chemotherapy needs to be
given concurrently with the radiation.
That's where the magic happens. The synergy, The
radiosensitization. Absolutely.
That's what drives the high curerates and allows for sphincter
(18:54):
preservation. Adding chemo before or after
that concurrent window just doesn't seem to add value in
this disease. OK.
That's a really important principle to grasp.
It is. It leads us directly into the
next point, which is honestly maybe one of the most critical
practical pearls in treating anal cancer day-to-day.
What's that? The absolute criticality of
(19:16):
avoiding treatment breaks. We have to emphasize this.
It's not a minor detail. It can literally determine
whether the treatment works or not.
Wow. OK, Avoiding breaks.
Why is it so important? What's the evidence?
There's really strong evidence. A key piece is a pooled analysis
by Ben Joseph, published back in2010.
What did they pull? Data from two of those big RTOG
(19:37):
trials, 87 O 4 and 9811. They look specifically at the
total treatment duration from day one of radiation to the last
day. And what did they find?
Something quite alarming, actually.
They found that if the total treatment duration stretched
beyond 53 days, 53. Days.
How long is that typically? Well, a standard course is
around six weeks, maybe 6 1/2 with common fractionation.
(19:59):
So 53 days is roughly equivalentto having about a one week
interruption, maybe a bit more baked into the total time.
OK. So if the treatment drags out by
about a week or more. It was significantly associated
with worse local regional failure, meaning the cancer was
more likely to come back in the treated area, and worse failure
free survival overall. Just from a one week delay,
(20:21):
that's a huge impact. It is the thinking the
biological rationale is likely accelerated tumor repopulation.
Meaning the cancer cells start growing back during the break.
Exactly. Radiation stuns them, damages
them, but if you give them a break, the surviving cells can
recover, start dividing rapidly again, potentially even faster
than before. Yeah, you basically lose ground.
(20:42):
Undoing some of the work the radiation did.
Precisely, that's a. Powerful reason to avoid breaks.
What about studies that actuallyplan for breaks?
Maybe thinking it would help with toxicity.
Well, that provides an even starker lesson unfortunately.
Look at the RTOG 9208 trial. This was a dose escalation study
and they actually included a planned two week treatment break
(21:05):
in their protocol design. The hypothesis was maybe this
split course would allow normal tissues to recover, reduce
toxicity without hurting efficacy.
Sounds reasonable on the surface.
What happened? The result, particularly for
organ preservation, was disastrous.
They saw a much higher colostomyrate compared to the historical
controls from RTOG 87 O 4 which use continuous treatment.
(21:28):
How much higher? It jumped from about 6% in 87 O
4 to 23% at one year in 9208. 23% that's almost a four fold
increase in needing a colostomy.Exactly.
It was a dramatic demonstration of the direct detrimental effect
of treatment interruptions on both tumor control and the
patient's quality of life, specifically sphincter
(21:49):
preservation. So for Miss Jenkins, this means
we have to do everything possible to prevent any breaks.
Pull out all the stops. Proactive management is key.
And this evidence is so strong that the Astro guidelines now
formally address it, right? They do.
The 2025 guideline makes a conditional recommendation.
Conditional. Yeah, meaning the evidence is
strong, but maybe not from multiple large randomized trials
(22:11):
directly testing breaks versus no breaks.
But based on the available data,they conditionally recommend
that the overall chemo radiationtreatment time should not be
extended by more than four days.Not more than four days.
That's a very tight window. It is.
It underscores how important it is for improving progression
free survival. It gives us a very concrete
(22:33):
target. Extending beyond that short
buffer is associated with worse outcomes.
Which means, practically speaking, proactive toxicity
management isn't just nice to have, it's absolutely paramount.
It's essential. You can't wait for problems to
happen. You need to anticipate them.
Skin care, pain management, diarrhea management, nutritional
support, start it all early. Counsel the patient on the
(22:55):
importance. Be aggressive with supportive
care to keep them on track. That's the only way.
OK, super important point. Now let's quickly review the
standard concurrent chemotherapyregimens and the specific dosing
people need to know these cold. Absolutely.
Let's start with the classic TheNegro Regimen 5 FU and my My Sin
C. OK.
The doses. Five FU is 1000 milligrams per
(23:17):
meter squared per day. That's given as a continuous
infusion over 96 hours. Well, full days.
Four days and that's typically given during week 1 and then
repeated during week five of theradiation therapy.
Weeks one and five got it and the MMC.
Mitomycin C is 10 milligrams permeter squared, given as an IV
bolus on day one and then again on day 29.
(23:38):
Day one and day 29, so near the start of each of those four Day
5 FU infusions. Generally, yes.
Now, it's worth noting the ACT 2trial actually used a slightly
different MMC schedule, a singledose of 12 milligrams per meter
squared just on day one. OK.
Single dose versus 2 doses, right?
But I'd say the two dose approach, 10 milligrams per
(23:58):
meter squared on day one and day29 is probably more common in US
practice reflecting the originalRTOG protocol.
OK. So that's the standard Negro
five FU infusion weeks, one in five MMC bolus days, one in 29.
Are there common alternatives, especially if the infusion is
difficult for a patient? Yes, definitely.
(24:19):
The main alternative involves switching out the infusional 5
FU for its oral pro drug capetitiveine.
Capacitabine or Xeloda. Right.
So the regimen becomes capacitabine plus my toe, my sin
C. And the capacitabine dosing,
it's typically 800. And 25 milligrams per meter
squared, taken orally twice a day.
Five BID. But here's the critical part.
(24:41):
It's taken only on the days the patient receives radiation
treatment, not on weekends or breaks.
Only on RT treatment days. That's important.
Very important. It's a huge convenience factor.
Obviously avoids the infusion pump.
Central line access, maybe dailyclinic visits for the infusion?
Much easier logistically for many patients.
Absolutely, and the mitomycin C is dosed the same way as with
(25:02):
infusional 5 FU, either the single dose or the two dose
schedule. And is this considered
equivalent? What are the guidelines say?
The Astro guideline strongly recommends capacitabine as a
reasonable alternative to infusional 5 FU.
The evidence suggests similar efficacy and it offers that
flexibility and convenience. So yes, widely accepted.
Great. Good to have that option.
(25:23):
OK, so we've systematically gonethrough the evidence.
We've dug into the trials, clarify chemo choices, radiation
dose principles, the role or lack thereof of induction
maintenance, and the absolute criticality of avoiding bricks.
Covered a lot of ground. Now let's bring it all together
back to Miss Jenkins clinical T2N 1A4 centimeter primary 1.5cm
(25:46):
inguinal node. Let's make some evidence based
decisions for her. Plan.
OK, let's design her optimal regimen, starting with
chemotherapy choice. What's the call for her?
Based on everything we discussed, assuming she has good
baseline blood counts, no specific contraindications like
severe kidney issues for cisplatin or marrow problems,
the standard of care, the preferred choice would be
(26:07):
concurrent 5 FU and MiTo mycin C.
OK, sticking with the preferred standard.
Right, while ACT 2 showed non inferiority for cisplatin, that
overall survival signal from 9811 even with the confounder
still kind of anchors. MMC is the go to for many
centers. Clinical comfort.
(26:27):
Historical weight. But we keep the alternative in
mind if needed. Absolutely, if she had risks for
myelosuppression, concurrent cisplatin or concurrent
capacitor being MMC would be very reasonable equally
effective options based on ACT 2.
But for a standard case like hers appears start with 5F UMMC.
OK. Decision one likely 5F UMMC now
(26:50):
radiation dose 4 centimeter T2 primary involved inguinal node.
What's the prescription? All right.
For her primary tumor, it's AT2,but it's 4 centimeters.
So as per the Astro guidelines, the range is 45 to 50.4 Gray,
but given it's at that upper endof T2 size, potentially behaving
more like AT3, pushing the dose towards the higher end of that
range makes sense. Something like 50.4 Gray and 28
(27:12):
fractions seems very appropriatefor the primary. 50.4 Gray and
28 fractions to the primary and the involved node.
For her clinically involved 1.5cm ingotal node, a dose of
50.4 Gray is also perfectly appropriate.
Maybe even up to 54 Gray could be considered for gross disease,
but 50.4 is certainly well within the recommended range of
(27:33):
50.454 guy. OK, 50.4 to the node as well and
elective nodes. Elective nodes, the pelvis,
bilateral groins not grossly involved would get that lower
prophylactic dose. Typically 45 Gray in 25 or 28
fractions, or maybe even down to36 drives depending on the exact
volumes and philosophy. Let's say 45 grey for standard
(27:54):
coverage. Got it.
So primary and involved node boosted to 50.4 guy, elective
nodes to 45 guy. That's a very standard evidence
based approach for her stage. And finally, maybe the most
critical piece of the discussionwith her treatment timing.
Paramount, absolutely paramount for Missus Jenkins.
We need to sit down with her, maybe even multiple times, and
(28:14):
really emphasize how crucial it is to complete all 28 radiation
treatments and the chemo cycles without interruption if at all
possible. Set expectations about side
effects, but also about the importance of pushing through.
Exactly, and back that up with aggressive proactive toxicity
management from day one. Skin creams, pain meds, anti
(28:34):
diarrheals, nutritional counseling, maybe even
prophylactic antibiotics if needed for skin breakdown.
Don't wait for problems. Because as we saw, even a few
days delay can impact her chances of cure her chances of
keeping her sphincter. Precisely, it affects
progression free survival, colostomy, free survival, local
control. It's a team effort between US
(28:55):
and the patient to stay on trackfor those six weeks.
OK, that feels like a solid personalized evidence based plan
for Miss Jenkins. I think so it addresses all the
key components. All right, great discussion.
Let's pivot now to some clinicalpearls.
These are the absolute highest yield facts, the things you
really need to lock in for exams, for boards and just for
safe, effective practice. The sticky knowledge.
(29:17):
OK, let's crystallize them. Pearl #1 MMC versus cisplatin.
What's the bottom line? RTOG 9811 showed superior
overall survival and disease free survival for 5F UMM C / 5
FU cisplatin, but that was confounded by induction chemo in
the cisplatin. Arm right and ACT 2 without
(29:38):
induction showed non inferiority.
So the take away 5F UMMC remainsthe preferred standard largely
due to that historical OS benefit, but concurrent
cisplatin or capacitabine MMC isa reasonable alternative,
especially if myelosuppression is a major concern.
Pearl #2 radiation therapy dose by T stage.
Use our mnemonic. 4-5 for small,5/3 for large T1E2 tumors
(30:02):
generally get 45 to 50.4 Gray, but for larger T twos like 4
centimeters or more, and certainly for T3T4 tumors, you
must dose escalate up to 59.4 Gray is recommended in the
guidelines for T3T4 dose adapt. #3 no induction or maintenance
chemotherapy. Absolutely critical.
ACCORD 03 showed no benefit for induction.
(30:24):
ACT 2 Second randomization showed no benefit for
maintenance. The chemo must be given
concurrently with radiation for that synergistic effect.
Don't add extra chemo before or after, it doesn't help and just
adds toxicity. Pearl #4 avoid treatment breaks.
This one is huge practically. Cannot emphasize this enough.
Extending the overall treatment time by more than about four
(30:45):
days is strongly associated withworse local control and worse
progression free survival, likely due to tumor
repopulation. Proactive toxicity management is
key to keeping patients on schedule and preserving
outcomes, including sphincter function.
Pearl #5 know your standard chemo dosing.
Classic Negro 5 FU 1000 milligrams per meter squared per
day for four days. Continuous infusion weeks one
(31:08):
and five. My toe, my Sins C10 milligrams
per meter squared. IV Bolus days 1 and 29.
And the alternative? Compositabine 825 milligrams per
meter squared orally twice a day, only on radiation therapy
days with MMC dosed as above. A very reasonable and convenient
alternative. No both options.
Excellent pearls. Now let's briefly touch on
(31:28):
controversies and advances. Sometimes what seems like a
controversy gets settled by trials.
And that itself is an advance, right?
It clarifies our approach. That's a great way to put it.
The whole MMC versus cisplatin debate is a perfect example.
The conflicting initial results from 9811 and ACT 2 created a
lot of discussion, maybe even controversy.
(31:49):
Right, but understanding the confounder, the induction chemo
delay, helps reconcile them. It didn't necessarily lead to
one simple answer, but rather toa more nuanced understanding.
Well MMC remains preferred, influenced by that historical OS
signal, but cisplatin gained ground as a clearly viable non
inferior alternative when given concurrently, especially for
(32:10):
certain patients. So the advance wasn't picking a
single winner, but rather validating a good alternative,
allowing for more personalized, risk adapted chemo choices.
That's progress. And similarly, the questions
around induction and maintenancechemo were effectively settled
controversies, right? Absolutely.
Before ACCORD 03 and ACT 2 it was a legitimate question.
(32:31):
Would more chemo help? These trials provided definitive
negative answers for anal cancer.
So the advance was. The advance was streamlining
treatment, proving that adding chemo outside the concurrent
window was unnecessary, avoided extra toxicity, cost, and
patient burden. It's solidified the paradigm of
concurrent therapy as the essential component.
(32:52):
That clarification is an advancein defining optimal efficient
care. It helps us focus our efforts
where they actually make a difference.
Precisely. It's about ensuring every part
of the treatment plan adds real value.
Looking forward, areas like optimizing treatment for
elderly, frail patients, refining response assessment
with PT scans, maybe de intensification for excellent
responders. OK.
(33:13):
Those are areas of ongoing evolution.
Always more to learn. OK, you ready for a quick board
blitz? Let's do it.
Test the knowledge. Case 155 year old man T3N0 anal
cancer. Primary tumor is 6 centimeters.
He's planned for definitive chemo radiation according to the
2025 Astro guidelines. What's the most appropriate
radiation dose to the primary tumor?
(33:33):
A 45 Gray and 25 fractions. B 50.4 Gray and 28 fractions.
C54 Gray and 30 fractions. D66 Gray and 33 fractions.
OK. T36 centimeters, that's
definitely the large category. So A&B, the 45 and 50.4 GR
ranges are generated for T1T2 tumors.
(33:53):
So they're too low. D66DR is quite high, not
standard and likely to toxic without proven benefit.
C54 Gray in 30 fractions falls right in that recommended range
for T3T4 tumors which is 50.2 to59.4 Gray.
So C is the best answer. Needed dose escalate for this T3
tumor. Excellent reasoning.
C It is case 2 patient being treated per the ACT 2 protocol
(34:16):
asks why they aren't getting more chemo after radiation
finishes. What's the correct explanation?
A Maintenance chemotherapy was found to be too toxic.
B Maintenance chemotherapy was found to provide no benefit in
progression free survival. C Maintenance chemotherapy is
only for patients with an incomplete response.
D The trial is still pending andresults are not yet known.
(34:38):
OK. This relates directly to that
second randomization in AC2. The trial is complete and
published. Maintenance chemo isn't standard
only for incomplete responders. While toxicity is always a
factor, the primary finding was the lack of benefit, so B is the
best answer. The ACT 2 trial clearly showed
no improvement in progression free survival or any other
outcome by adding maintenance 5 pieces flattened.
(34:59):
It simply didn't work. Perfect answer is B Case 3
patient on treatment develops severe perineal dermatitis,
really bad skin reaction and asks for a one week treatment
break to heal. What's the most important reason
to counsel against this break? A.
It will increase the risk of late rectal bleeding.
B. It will make the concurrent
chemotherapy less effective. C It is associated with a higher
(35:22):
risk of local regional failure and worse progression free
survival. D It will increase the final
colostomy rate due to surgical complications.
Tough situation clinically, but the evidence is clear.
While brakes might indirectly affect other things, the most
critical evidence based reason to push against that brake is C.
The pooled analysis, the RTOG 9208 experience, the STO
(35:45):
guideline, they all point to treatment prolongation being
strongly associated with worst local control and worst
progression free survival likelydue to that accelerated tumory
population. That's the biggest hit to their
oncologic outcome. We need to manage the dermatitis
aggressively without stopping treatment if at all possible.
Exactly, C is the most critical oncologic reason.
Fantastic. OK, let's summarize.
(36:06):
Today, we really dove deep into optimizing standard chemo
radiation for anal cancer. We've looked at the evidence to
define the best chemo agent, howto pick the right radiation dose
based on risk factors like T stage and nodes.
And we've really hammered home the importance of timely
completion. Yeah.
For our patient Miss Jenkins, wenow have a much clearer picture
of her optimal plan. We dissected the evidence from
(36:28):
key trials 9811 ACT 2 ACC Ord 03and integrated the latest Astro
guidelines. We know 5 FUMC is preferred but
cisplatin is a good alternative.We know dose needs to be risk
adapted up to 59.4. Way to dry for T3T4?
And critically, we cemented thatneither induction nor
maintenance chemo adds value. It has to be concurrent.
(36:50):
And finally, avoiding treatment breaks is absolutely paramount
for preserving local control, survival and sphincter function.
Proactive supportive care is nonnegotiable.
Couldn't have said it better andtranslating this plan, this
prescription into a safe and effective IMRT plan is the next
logical step. So looking ahead, our next
session will be an IMRT treatment planning workshop
(37:11):
specifically for anal cancer. Sounds practical.
Yeah, we'll do a step by step guide, simulation, contouring,
dose painting, drawing heavily on protocols like RTOGO 529 and
incorporating these new Astro guideline principles we
discussed today. We'll show you exactly how to
put this into practice in the planning system.
That sounds incredibly valuable.Remember, you can sharpen your
(37:33):
skills with practice oral boardsand explore more content at
radonksmartlearn.com. That's RADON ksmartlearn.com.
And definitely subscribe to Radonk Smart Review so you don't
miss that IMRT planning workshop.
Thanks for tuning in everyone. See you next time.
Welcome back to the Rad on SmartReview GI Cancer series.
Great to be back. So we're picking up right where
we left off, building on that foundational discussion of anal
cancer. Exactly.
Last time we really dug into why.
Why definitive concurrent chemo radiation is, you know, the gold
standard. Right, the whole sphincter
sparing approach, all thanks to Doctor Negro's work and those
(00:21):
big trials, ACT 1, the EORTC trial, we really established the
rationale. Yeah, the groundwork and today
we're shifting gears a bit moving from the why to the, I
guess the really critical how. How to actually do it optimally?
Precisely. It's not just following a
recipe, it's about understandinghow to really fine tune modern
(00:42):
concurrent chemoradiation for squamous cell carcinoma of the
anal canal. And that means, you know, really
looking closely the three absolutely critical components
you've got to have the right chemotherapy.
You need the right radiation dose, the precise dose, and
maybe overlook sometimes the right timing, flawless timing.
Get any one of those wrong? Well, it can really mess things
(01:03):
up. You could jeopardize the cure
rates, obviously, but just as important, you could inflict
unnecessary, avoidable toxicity on patients.
It's it's really a balance, an art and a science.
Definitely sounds like it. So to keep us grounded, let's
bring back our patient case fromlast time.
Miss Jenkins. Ah.
Yes, Miss Jenkins. 64 year old woman.
(01:26):
She has a clinical T2N1A squamous cell carcinoma of the
anal canal. Primary tumor is 4 centimeters.
OK, so upper end of T2. Exactly.
And she has that confirmed 1.5cm, right, inguinal lymph
node. So we've decided definitive
chemo radiation is the way to gofor her, right.
But now the challenge is designing her optimal regimen.
(01:49):
So as we, you know, unpack the evidence today, we'll keep
circling back to Missus Jenkins.How does this apply to her?
That's the perfect way to frame it because as we walk through
the evidence, you know, the big trials, the latest guidelines,
you should really keep Miss Jenkins in mind.
We need answers for her. Like what?
Well, first. What's the absolute best
chemotherapy agent to pair with the radiation?
We'll get into that debate then.What's the precise risk adapted
(02:13):
radiation dose, not just any dose, but the right one for her
4 centimeter T2 tumor that involved inguinal node.
And then, maybe most critically,in practice, how vital is it
that she completes her entire treatment course without any
interruption, even a few days? We'll breakdown the evidence for
each of these pillars. OK, let's do it.
(02:33):
Let's unpack this, starting withmaybe the most fundamental
question, the one that's driven a lot of research and honestly
some debate over the years, which is my TOE, my Cincy versus
cisplatin for concurrent chemo. The classic head to head.
We know the original Negro protocol, the one that really
pioneered this whole concurrent approach, used 5 FU and my toe,
(02:55):
my sin C MMC. That's the one foundational.
But MMC has that well known issue, right, the potential for
significant myelosuppression that can be really tough on
patients. That's a huge point.
Myelosuppression. I mean, for anyone less
familiar, we're talking about severe bone marrow suppression.
Right, low counts. Exactly.
Dramatically lower white blood cells, especially neutrophils.
That leaves patients wide open to potentially life threatening
(03:18):
infections. Hospitalizations.
Antibiotic. All of it, broad spectrum
antibiotics, sometimes growth factor support like GCSF.
Plus you can get severe anemia, needing transfusions, low
platelets, increasing bleeding risk.
It's not just challenging, no. It can fundamentally stop a
patient from staying on schedule.
It impacts their safety. So naturally that toxicity
(03:40):
profile made people wonder, could cisplatin, which is often
seen as less stuff on the bone? Marrow less hematologically
toxic, yeah. Could it be a safer but equally
effective substitute? And that question was really at
the heart of two major cooperative group trials, which
interestingly, initially seemed to give us conflicting results.
OK, so let's. Start with the first one, the
(04:02):
one that probably had the biggest initial impact.
Right. That would have to be RTOG 9811
published back in 2008, big study, 644 patients and
importantly they focused on T2 to T4 anal cancer.
So generally larger, more advanced primary tumors.
They randomized patients into two pretty different arms.
Arm A was the control the standard at the time.
(04:24):
Definitive radiation with concurrent 5 FU and my toe, my
sin C. And the specifics of that?
Regimen Standard Stuff 5 FU at 1000 milligrams per meter
squared per day. Continuous infusion over 96
hours. Four days.
Yeah, four days given during week 1 and week 5 radiation and
the my, my sin C was 10 milligrams per meter squared, 4
bolus on day one and day 29 thatwas the MMC arm.
(04:47):
OK, standard Negro basically, and R&B the cisplatin arm.
R&B got radiation with concurrent 5 FU and cisplatin.
The five FU was similar, same dose, same schedule, weeks one
and five. Cisplatin was given at 75
milligrams per meter squared on day one and day. 29 OK 75.
Wait, let me check that dose actually, apologies.
The cisplatin dose in 9811 was 100 milligrams per meter squared
(05:11):
on day one and day 29. The five FU was indeed 1000
milligrams per meter squared over 4 days in weeks 1:00 and
5:00. 100 milligrams per meter squared.
Yes. Now here's a kicker, the really
crucial part for interpreting this whole thing.
What's that? The cisplatin arm also received
2 cycles of induction chemotherapy before starting
(05:33):
their concurrent chemo radiation.
Ah, induction chemo. With what agents?
Typically 5 FU and cisplatin, the same agents they'd get
concurrently but given upfront. So hold on that induction chemo
and the cisplatin arm, that's a major confounder.
Isn't it huge? Absolutely massive.
It delayed the start of their radiation.
By definition, 2 cycles of induction chemo meant, you know,
(05:55):
several weeks delay before thosepatients even started their main
concurrent treatment. OK.
So that's critical context. What were the results?
The results were, well, pretty stark.
The my toe, my sin C arm came out superior across the board.
Pretty much every endpoint measured.
Like overall survival. Significantly better five year
overall survival, 78% for MMC versus 71% for Cisplat.
(06:16):
That's a 7% absolute difference.Wow.
That's substantial. It is disease free survival also
clearly better. 68% for MMC versus 58% for cisplatin. 10%
difference there. And what about sphincter
preservation? Colostomy rates.
Also significantly better with MMC.
The five year colostomy rate wasmuch lower, 10% in the MMC arm
(06:38):
versus 19% in the cisplatin arm.Almost double.
Almost double so patients are far more likely to keep their
sphincter, avoid a permanent colostomy if they got the MMC
regimen in this trial. OK, so RTOG 9811 on the surface
seems to say MMC is definitivelysuperior, but that induction
chemotherapy hanged over it. Exactly.
(06:59):
That's the elephant in the room.Was it truly that MMC is a
better radiosensitizer, or was it the harm caused by delaying
radiation with that induction chemo that made the difference?
That's a huge question. Did MMC win or did delaying
radiation lose? Precisely that confounder was,
and still is, you know, a major discussion point whenever 9811
(07:19):
comes up. So how did the field try to
answer that specific question? Well, that led directly to the
UK ACT 2 trial. Remember, pronounce it like the
word act. ACT 2 got.
It this trial was meticulously designed to eliminate that
confounding induction chemotherapy to get a clean
comparison. What is similar in size?
Even larger actually 940 patients.
(07:40):
And notably, it included anal cancer of all stages, not just
the T2T4 like 1911. OK.
And the design? It used a clever two by two
factorial design, so 2 randomizations happening.
The first randomization directlyaddressed our question.
It compared chemo radiation withfive FU slash MMC versus 5 FU
slash this platen. Critically, both regiments
(08:01):
started concurrently with radiation from day one.
No induction delay. Apples to apples on the timing.
Perfect. The second randomization we'll
discuss later. Exactly that looked at
maintenance chemo, we'll get there.
But for this comparison, MMC versus cisplatin given
concurrently, what did ACT 2 find?
What were the results of that direct comparison?
(08:22):
In that head to HEAD ACT 2 foundno significant difference.
No difference in what? Incomplete response rates in
progression free survival or in colostomy free survival.
The three-year progression free survival, for instance, was
about 75% in both arms, basically equivalent efficacy.
Wow OK what about toxicity? Did MMC still show more mild
(08:44):
suppression? It did.
The MMC arm had slightly higher rates of grade 3 or higher
hematologic toxicity, about 26% versus 16% for cisplatin.
So confirming that known side effect profile.
Right. But interestingly the overall
non hematologic toxicities were pretty similar between the two
arms. So the main difference was
really that blood count issue. So the interpretation from ACT 2
(09:05):
was pretty clear. When you give them concurrently
without that induction chemo delay, cisplatin appears to be
non inferior to my toe my sensei.
Meaning equally effective. Equally effective, just with a
slightly different, potentially less hematologically toxic.
So now we have RTOG 9811 saying MMC is superior and ACT 2 saying
(09:27):
they're basically equivalent or non inferior.
How do we reconcile this? What's the practical take home
for treating Miss Jenkins today?This is where the clinical
judgement, understanding the nuances really comes in.
The key, as you pointed out, is that induction chemotherapy in
9811. The delay.
That delay in starting radiationfor the cisplatin arm likely
(09:48):
skewed the results. It probably disadvantaged the
cisplatin arm unfairly just by starting definitive therapy
later, right? So while 9811 initially made it
look like MMC was just flat out better, ACT 2 helped us
understand why that might have appeared to be the case.
It helped isolate the pure chemotherapy effect from the
timing effect. OK, so where does that leave us
now? What's the consensus?
(10:08):
Like the Astro guidelines? What did it say?
The current consensus, and this is reflected well in the the
2025 Astro guidelines, is that 5FU slash MMC still remains the
preferred standard of care. Preferred OK despite ACT 2.
Despite ACT 2, I think that overall survival benefit seen in
(10:29):
9811, even with the known confounder, carries a lot of
historical weight. It kind of anchors.
MMC is the default. Clinical inertia maybe, or just
respecting that survival signal?Probably a bit of both, but
crucially, the guidelines also acknowledge cisplatin as a very
reasonable alternative. For whom?
Especially for patients where that risk of mild suppression is
(10:51):
particularly concerning. Maybe someone with poor baseline
counts or pre-existing bone marrow issues, or maybe someone
very frail. OK, so for Miss Jenkins, if
she's got good blood counts, no major contraindications, the
default choice would likely still be 5 FU slash MMC.
We'd lean on that historical. Strength, but if she did have
risk factors for mild suppression.
Then switching to concurrent cisplatin or even capacitabine,
(11:14):
which we'll discuss would be a perfectly valid evidence based
chase offering similar efficacy based on ACT 2.
The key is concurrent administration.
No induction delays. It makes sense understanding the
history and the nuance behind the preferred label.
OK, let's shift gears. We've talked chemo agents.
What about the radiation side? The dose.
(11:35):
Right. Equally critical.
The goal is always maximizing local control, killing the tumor
while minimizing late toxicity, preserving function and quality
of life that balance. It's the perpetual challenge,
isn't it, especially in the pelvis, and the evidence here
strongly points towards a risk adapted approach.
Meaning. Meaning we don't just give
everyone the same dose, we need to tailor it.
(11:57):
Specifically, you need to judiciously escalate the dose
for larger tumors and for any involved lymph nodes.
Why escalate for those? Because they inherently carry a
higher risk. Higher risk of microscopic
spread, maybe more resistant cells.
They just need a higher dose to ensure eradication.
It's definitely not one-size-fits-all.
And the Astro guidelines give specific recommendations here.
(12:17):
They do. The 2025 guidelines are quite
clear, distilling data from manytrials into actionable advice.
OK, walk us through it. Let's start with smaller tumors.
What's the dose range? For clinical T1 to T2 tumors,
the guideline recommends a dose of 45 to 50.4 Gray. 45 to 50.4
(12:39):
and how many fractions? Typically delivered in 25 to 28
fractions. This comes from seeing excellent
results of those foundational trials like RTOG 87 O 4 and 9811
where many T2 patients were cured even with 45 Gray.
So that range is kind of the sweet spot for good control,
acceptable toxicity for smaller tumors.
(13:01):
Exactly. But there's an important caveat
for larger T2 tumors. Like Miss Jenkins, hers is 4
centimeters. Precisely like Miss Jenkins, for
T2 tumors that are 4 centimetersor bigger, the guidelines
suggest that pushing the dose towards the higher end of that
range, say 50.4 grey or maybe even up to 54 grey, might be
reasonable. And the thinking there is.
(13:22):
Just that a larger tumor, even if still stage T2, likely has a
higher burden of disease, maybe more heterogeneity, potentially
more resistant clones. It might just need that extra
bit of radiation punch to ensurecure and minimize recurrence
risk. OK, so for Miss Jenkins we're
already thinking maybe closer to50.4 grey for her primary given
(13:43):
its size. That would be a very reasonable
starting point for discussion, yes.
Now, what about the really big ones?
The T3T4 tumors? Inherently tougher cases.
Right. For those clinical T3 to T4A,
significantly higher dose is recommended.
We're talking 53.2 up to 59.4 grey. 53.2 to 59.4 That's quite
(14:05):
a jump. It is, and it's usually
delivered in slightly more fractions, maybe 28 to 33.
This dose escalation is critical.
Why so critical? What's the evidence?
Well, data from trials like RTOG9811 clearly showed much higher
rates of local failure and consequently higher clocktomy
rates for these larger tumors when they were treated with
lower doses like the 45 grey range.
(14:27):
You have an example. Yeah.
For instance, in the MMC arm of 9811 patients with T4 and 0
disease, they had a five year local regional failure rate of
37%. Wow, 37% failure even with MMC
chemo. Yes, that's really high.
It tells us loud and clear that these bigger, more advanced
(14:48):
tumors simply need more radiation dose to achieve
durable local control. We have to push that dose
response curve carefully, of course.
Carefully managing normal tissuetolerance, especially in the
pelvis. Absolutely, it's a fine line.
OK. So that covers the primary tumor
dose based on T stage. What about the lymph nodes
misses Jenkins? Has that confirmed 1.5cm
(15:10):
inguinal node? Right.
For clinically involved nodes like hers, palpable or seen
clearly on imaging, the recommended dose is 50.4 to 54
Gray. 50.4 to 54, similar to thedose for a larger primary.
Exactly. You need to adequately treat
that gross disease. We wouldn't want to underdose a
known involved node. Makes sense.
And what about elective nodes, the areas at risk but not
(15:32):
obviously involved? For those elective nodal
volumes, think the other inguinal regions, the pelvic
nodes like internal iliac, external iliac obturators, we
treat prophylactically but to a lower dose, typically 36 to 45
grey. 36 to 45, and that's usually in maybe 20 to 30
fractions. Correct.
The idea is to cover those at risk areas, sterilize potential
(15:55):
microscopic disease, but withoutgiving excessive dose to large
volumes of normal tissue, minimizing collateral damage and
long term side effects. OK, so let's try a quick
mnemonic here for the primary tumor doses, maybe 4-5 for
small, 5/3 for large. Like that?
Yeah. So T1T2 think 45 Gray range up
to 50 point. 4T3T4 Think 53 Grayrange up to 59.4. 4-5 for small,
(16:21):
5/3 for large. That's sketchy.
Help simplify it. Good one.
OK. So we've got the chemo agent
choice, we've got the risk adapted radiation dose.
What about adding more or chemo?Does induction chemo before or
maintenance chemo after help? The more is better question.
It comes up in so many cancers. Right.
Does it apply here in anal cancer?
The answer based on good evidence from key trials is a
(16:43):
pretty resounding no, and knowing this is really
important. OK, tell us about induction.
First chemo before chemo RT. The French ACCORD 03 trial
tackled this head on. They took patients with larger
tumors or node positive disease,the higher risk groups and
randomize them to what to eitherget induction chemo first,
typically 2 cycles of five FU and cisplatin, or to go straight
(17:07):
to standard concurrent chemo radiation.
And the rationale for induction was?
The usual thinking shrink the tumor up front, maybe make the
main treatment easier and hit potential micrometastases early.
Plausible ideas? But what did they find They.
Found absolutely no benefit. No improvement in colostomy free
survival, no improvement in progression free survival, no
(17:28):
improvement in any major end point by adding that upfront
induction chemo. No benefit at all.
None, and if anything there was maybe a trend towards more
toxicity without any gain. It just delayed the start of
definitive local therapy, which,as we discussed with 9811, can
be detrimental. So induction is out.
What about maintenance chemo after finishing chemo RT to kind
(17:51):
of mop up? Again, the answer is no, and
this comes from that same UK Act2 trial we discussed earlier.
The second randomization. Exactly.
Remember the two by two design, after patients finish their
concurrent chemo radiation either with MMC or cisplatin,
they were then randomized a second time to either receive 2
(18:11):
cycles of maintenance 5 FU slashcisplatin or to get no further
maintenance chemotherapy, just observation.
And the result? Did the maintenance chemo help?
Nope. Just like induction, there was
no benefit whatsoever. No improvement in progression
free survival, No improvement inany other oncologic outcome by
adding those two extra cycles ofchemo.
(18:31):
It just added toxicity. Pretty much added toxicity at a
burden on the patient, cost, time, all for no measurable gain
and efficacy. So the take home message here
seems crystal clear for anal cancer.
It really is. The chemotherapy needs to be
given concurrently with the radiation.
That's where the magic happens. The synergy, The
radiosensitization. Absolutely.
That's what drives the high curerates and allows for sphincter
(18:54):
preservation. Adding chemo before or after
that concurrent window just doesn't seem to add value in
this disease. OK.
That's a really important principle to grasp.
It is. It leads us directly into the
next point, which is honestly maybe one of the most critical
practical pearls in treating anal cancer day-to-day.
What's that? The absolute criticality of
(19:16):
avoiding treatment breaks. We have to emphasize this.
It's not a minor detail. It can literally determine
whether the treatment works or not.
Wow. OK, Avoiding breaks.
Why is it so important? What's the evidence?
There's really strong evidence. A key piece is a pooled analysis
by Ben Joseph, published back in2010.
What did they pull? Data from two of those big RTOG
(19:37):
trials, 87 O 4 and 9811. They look specifically at the
total treatment duration from day one of radiation to the last
day. And what did they find?
Something quite alarming, actually.
They found that if the total treatment duration stretched
beyond 53 days, 53. Days.
How long is that typically? Well, a standard course is
around six weeks, maybe 6 1/2 with common fractionation.
(19:59):
So 53 days is roughly equivalentto having about a one week
interruption, maybe a bit more baked into the total time.
OK. So if the treatment drags out by
about a week or more. It was significantly associated
with worse local regional failure, meaning the cancer was
more likely to come back in the treated area, and worse failure
free survival overall. Just from a one week delay,
(20:21):
that's a huge impact. It is the thinking the
biological rationale is likely accelerated tumor repopulation.
Meaning the cancer cells start growing back during the break.
Exactly. Radiation stuns them, damages
them, but if you give them a break, the surviving cells can
recover, start dividing rapidly again, potentially even faster
than before. Yeah, you basically lose ground.
(20:42):
Undoing some of the work the radiation did.
Precisely, that's a. Powerful reason to avoid breaks.
What about studies that actuallyplan for breaks?
Maybe thinking it would help with toxicity.
Well, that provides an even starker lesson unfortunately.
Look at the RTOG 9208 trial. This was a dose escalation study
and they actually included a planned two week treatment break
(21:05):
in their protocol design. The hypothesis was maybe this
split course would allow normal tissues to recover, reduce
toxicity without hurting efficacy.
Sounds reasonable on the surface.
What happened? The result, particularly for
organ preservation, was disastrous.
They saw a much higher colostomyrate compared to the historical
controls from RTOG 87 O 4 which use continuous treatment.
(21:28):
How much higher? It jumped from about 6% in 87 O
4 to 23% at one year in 9208. 23% that's almost a four fold
increase in needing a colostomy.Exactly.
It was a dramatic demonstration of the direct detrimental effect
of treatment interruptions on both tumor control and the
patient's quality of life, specifically sphincter
(21:49):
preservation. So for Miss Jenkins, this means
we have to do everything possible to prevent any breaks.
Pull out all the stops. Proactive management is key.
And this evidence is so strong that the Astro guidelines now
formally address it, right? They do.
The 2025 guideline makes a conditional recommendation.
Conditional. Yeah, meaning the evidence is
strong, but maybe not from multiple large randomized trials
(22:11):
directly testing breaks versus no breaks.
But based on the available data,they conditionally recommend
that the overall chemo radiationtreatment time should not be
extended by more than four days.Not more than four days.
That's a very tight window. It is.
It underscores how important it is for improving progression
free survival. It gives us a very concrete
(22:33):
target. Extending beyond that short
buffer is associated with worse outcomes.
Which means, practically speaking, proactive toxicity
management isn't just nice to have, it's absolutely paramount.
It's essential. You can't wait for problems to
happen. You need to anticipate them.
Skin care, pain management, diarrhea management, nutritional
support, start it all early. Counsel the patient on the
(22:55):
importance. Be aggressive with supportive
care to keep them on track. That's the only way.
OK, super important point. Now let's quickly review the
standard concurrent chemotherapyregimens and the specific dosing
people need to know these cold. Absolutely.
Let's start with the classic TheNegro Regimen 5 FU and my My Sin
C. OK.
The doses. Five FU is 1000 milligrams per
(23:17):
meter squared per day. That's given as a continuous
infusion over 96 hours. Well, full days.
Four days and that's typically given during week 1 and then
repeated during week five of theradiation therapy.
Weeks one and five got it and the MMC.
Mitomycin C is 10 milligrams permeter squared, given as an IV
bolus on day one and then again on day 29.
(23:38):
Day one and day 29, so near the start of each of those four Day
5 FU infusions. Generally, yes.
Now, it's worth noting the ACT 2trial actually used a slightly
different MMC schedule, a singledose of 12 milligrams per meter
squared just on day one. OK.
Single dose versus 2 doses, right?
But I'd say the two dose approach, 10 milligrams per
(23:58):
meter squared on day one and day29 is probably more common in US
practice reflecting the originalRTOG protocol.
OK. So that's the standard Negro
five FU infusion weeks, one in five MMC bolus days, one in 29.
Are there common alternatives, especially if the infusion is
difficult for a patient? Yes, definitely.
(24:19):
The main alternative involves switching out the infusional 5
FU for its oral pro drug capetitiveine.
Capacitabine or Xeloda. Right.
So the regimen becomes capacitabine plus my toe, my sin
C. And the capacitabine dosing,
it's typically 800. And 25 milligrams per meter
squared, taken orally twice a day.
Five BID. But here's the critical part.
(24:41):
It's taken only on the days the patient receives radiation
treatment, not on weekends or breaks.
Only on RT treatment days. That's important.
Very important. It's a huge convenience factor.
Obviously avoids the infusion pump.
Central line access, maybe dailyclinic visits for the infusion?
Much easier logistically for many patients.
Absolutely, and the mitomycin C is dosed the same way as with
(25:02):
infusional 5 FU, either the single dose or the two dose
schedule. And is this considered
equivalent? What are the guidelines say?
The Astro guideline strongly recommends capacitabine as a
reasonable alternative to infusional 5 FU.
The evidence suggests similar efficacy and it offers that
flexibility and convenience. So yes, widely accepted.
Great. Good to have that option.
(25:23):
OK, so we've systematically gonethrough the evidence.
We've dug into the trials, clarify chemo choices, radiation
dose principles, the role or lack thereof of induction
maintenance, and the absolute criticality of avoiding bricks.
Covered a lot of ground. Now let's bring it all together
back to Miss Jenkins clinical T2N 1A4 centimeter primary 1.5cm
(25:46):
inguinal node. Let's make some evidence based
decisions for her. Plan.
OK, let's design her optimal regimen, starting with
chemotherapy choice. What's the call for her?
Based on everything we discussed, assuming she has good
baseline blood counts, no specific contraindications like
severe kidney issues for cisplatin or marrow problems,
the standard of care, the preferred choice would be
(26:07):
concurrent 5 FU and MiTo mycin C.
OK, sticking with the preferred standard.
Right, while ACT 2 showed non inferiority for cisplatin, that
overall survival signal from 9811 even with the confounder
still kind of anchors. MMC is the go to for many
centers. Clinical comfort.
(26:27):
Historical weight. But we keep the alternative in
mind if needed. Absolutely, if she had risks for
myelosuppression, concurrent cisplatin or concurrent
capacitor being MMC would be very reasonable equally
effective options based on ACT 2.
But for a standard case like hers appears start with 5F UMMC.
OK. Decision one likely 5F UMMC now
(26:50):
radiation dose 4 centimeter T2 primary involved inguinal node.
What's the prescription? All right.
For her primary tumor, it's AT2,but it's 4 centimeters.
So as per the Astro guidelines, the range is 45 to 50.4 Gray,
but given it's at that upper endof T2 size, potentially behaving
more like AT3, pushing the dose towards the higher end of that
range makes sense. Something like 50.4 Gray and 28
(27:12):
fractions seems very appropriatefor the primary. 50.4 Gray and
28 fractions to the primary and the involved node.
For her clinically involved 1.5cm ingotal node, a dose of
50.4 Gray is also perfectly appropriate.
Maybe even up to 54 Gray could be considered for gross disease,
but 50.4 is certainly well within the recommended range of
(27:33):
50.454 guy. OK, 50.4 to the node as well and
elective nodes. Elective nodes, the pelvis,
bilateral groins not grossly involved would get that lower
prophylactic dose. Typically 45 Gray in 25 or 28
fractions, or maybe even down to36 drives depending on the exact
volumes and philosophy. Let's say 45 grey for standard
(27:54):
coverage. Got it.
So primary and involved node boosted to 50.4 guy, elective
nodes to 45 guy. That's a very standard evidence
based approach for her stage. And finally, maybe the most
critical piece of the discussionwith her treatment timing.
Paramount, absolutely paramount for Missus Jenkins.
We need to sit down with her, maybe even multiple times, and
(28:14):
really emphasize how crucial it is to complete all 28 radiation
treatments and the chemo cycles without interruption if at all
possible. Set expectations about side
effects, but also about the importance of pushing through.
Exactly, and back that up with aggressive proactive toxicity
management from day one. Skin creams, pain meds, anti
(28:34):
diarrheals, nutritional counseling, maybe even
prophylactic antibiotics if needed for skin breakdown.
Don't wait for problems. Because as we saw, even a few
days delay can impact her chances of cure her chances of
keeping her sphincter. Precisely, it affects
progression free survival, colostomy, free survival, local
control. It's a team effort between US
(28:55):
and the patient to stay on trackfor those six weeks.
OK, that feels like a solid personalized evidence based plan
for Miss Jenkins. I think so it addresses all the
key components. All right, great discussion.
Let's pivot now to some clinicalpearls.
These are the absolute highest yield facts, the things you
really need to lock in for exams, for boards and just for
safe, effective practice. The sticky knowledge.
(29:17):
OK, let's crystallize them. Pearl #1 MMC versus cisplatin.
What's the bottom line? RTOG 9811 showed superior
overall survival and disease free survival for 5F UMM C / 5
FU cisplatin, but that was confounded by induction chemo in
the cisplatin. Arm right and ACT 2 without
(29:38):
induction showed non inferiority.
So the take away 5F UMMC remainsthe preferred standard largely
due to that historical OS benefit, but concurrent
cisplatin or capacitabine MMC isa reasonable alternative,
especially if myelosuppression is a major concern.
Pearl #2 radiation therapy dose by T stage.
Use our mnemonic. 4-5 for small,5/3 for large T1E2 tumors
(30:02):
generally get 45 to 50.4 Gray, but for larger T twos like 4
centimeters or more, and certainly for T3T4 tumors, you
must dose escalate up to 59.4 Gray is recommended in the
guidelines for T3T4 dose adapt. #3 no induction or maintenance
chemotherapy. Absolutely critical.
ACCORD 03 showed no benefit for induction.
(30:24):
ACT 2 Second randomization showed no benefit for
maintenance. The chemo must be given
concurrently with radiation for that synergistic effect.
Don't add extra chemo before or after, it doesn't help and just
adds toxicity. Pearl #4 avoid treatment breaks.
This one is huge practically. Cannot emphasize this enough.
Extending the overall treatment time by more than about four
(30:45):
days is strongly associated withworse local control and worse
progression free survival, likely due to tumor
repopulation. Proactive toxicity management is
key to keeping patients on schedule and preserving
outcomes, including sphincter function.
Pearl #5 know your standard chemo dosing.
Classic Negro 5 FU 1000 milligrams per meter squared per
day for four days. Continuous infusion weeks one
(31:08):
and five. My toe, my Sins C10 milligrams
per meter squared. IV Bolus days 1 and 29.
And the alternative? Compositabine 825 milligrams per
meter squared orally twice a day, only on radiation therapy
days with MMC dosed as above. A very reasonable and convenient
alternative. No both options.
Excellent pearls. Now let's briefly touch on
(31:28):
controversies and advances. Sometimes what seems like a
controversy gets settled by trials.
And that itself is an advance, right?
It clarifies our approach. That's a great way to put it.
The whole MMC versus cisplatin debate is a perfect example.
The conflicting initial results from 9811 and ACT 2 created a
lot of discussion, maybe even controversy.
(31:49):
Right, but understanding the confounder, the induction chemo
delay, helps reconcile them. It didn't necessarily lead to
one simple answer, but rather toa more nuanced understanding.
Well MMC remains preferred, influenced by that historical OS
signal, but cisplatin gained ground as a clearly viable non
inferior alternative when given concurrently, especially for
(32:10):
certain patients. So the advance wasn't picking a
single winner, but rather validating a good alternative,
allowing for more personalized, risk adapted chemo choices.
That's progress. And similarly, the questions
around induction and maintenancechemo were effectively settled
controversies, right? Absolutely.
Before ACCORD 03 and ACT 2 it was a legitimate question.
(32:31):
Would more chemo help? These trials provided definitive
negative answers for anal cancer.
So the advance was. The advance was streamlining
treatment, proving that adding chemo outside the concurrent
window was unnecessary, avoided extra toxicity, cost, and
patient burden. It's solidified the paradigm of
concurrent therapy as the essential component.
(32:52):
That clarification is an advancein defining optimal efficient
care. It helps us focus our efforts
where they actually make a difference.
Precisely. It's about ensuring every part
of the treatment plan adds real value.
Looking forward, areas like optimizing treatment for
elderly, frail patients, refining response assessment
with PT scans, maybe de intensification for excellent
responders. OK.
(33:13):
Those are areas of ongoing evolution.
Always more to learn. OK, you ready for a quick board
blitz? Let's do it.
Test the knowledge. Case 155 year old man T3N0 anal
cancer. Primary tumor is 6 centimeters.
He's planned for definitive chemo radiation according to the
2025 Astro guidelines. What's the most appropriate
radiation dose to the primary tumor?
(33:33):
A 45 Gray and 25 fractions. B 50.4 Gray and 28 fractions.
C54 Gray and 30 fractions. D66 Gray and 33 fractions.
OK. T36 centimeters, that's
definitely the large category. So A&B, the 45 and 50.4 GR
ranges are generated for T1T2 tumors.
(33:53):
So they're too low. D66DR is quite high, not
standard and likely to toxic without proven benefit.
C54 Gray in 30 fractions falls right in that recommended range
for T3T4 tumors which is 50.2 to59.4 Gray.
So C is the best answer. Needed dose escalate for this T3
tumor. Excellent reasoning.
C It is case 2 patient being treated per the ACT 2 protocol
(34:16):
asks why they aren't getting more chemo after radiation
finishes. What's the correct explanation?
A Maintenance chemotherapy was found to be too toxic.
B Maintenance chemotherapy was found to provide no benefit in
progression free survival. C Maintenance chemotherapy is
only for patients with an incomplete response.
D The trial is still pending andresults are not yet known.
(34:38):
OK. This relates directly to that
second randomization in AC2. The trial is complete and
published. Maintenance chemo isn't standard
only for incomplete responders. While toxicity is always a
factor, the primary finding was the lack of benefit, so B is the
best answer. The ACT 2 trial clearly showed
no improvement in progression free survival or any other
outcome by adding maintenance 5 pieces flattened.
(34:59):
It simply didn't work. Perfect answer is B Case 3
patient on treatment develops severe perineal dermatitis,
really bad skin reaction and asks for a one week treatment
break to heal. What's the most important reason
to counsel against this break? A.
It will increase the risk of late rectal bleeding.
B. It will make the concurrent
chemotherapy less effective. C It is associated with a higher
(35:22):
risk of local regional failure and worse progression free
survival. D It will increase the final
colostomy rate due to surgical complications.
Tough situation clinically, but the evidence is clear.
While brakes might indirectly affect other things, the most
critical evidence based reason to push against that brake is C.
The pooled analysis, the RTOG 9208 experience, the STO
(35:45):
guideline, they all point to treatment prolongation being
strongly associated with worst local control and worst
progression free survival likelydue to that accelerated tumory
population. That's the biggest hit to their
oncologic outcome. We need to manage the dermatitis
aggressively without stopping treatment if at all possible.
Exactly, C is the most critical oncologic reason.
Fantastic. OK, let's summarize.
(36:06):
Today, we really dove deep into optimizing standard chemo
radiation for anal cancer. We've looked at the evidence to
define the best chemo agent, howto pick the right radiation dose
based on risk factors like T stage and nodes.
And we've really hammered home the importance of timely
completion. Yeah.
For our patient Miss Jenkins, wenow have a much clearer picture
of her optimal plan. We dissected the evidence from
(36:28):
key trials 9811 ACT 2 ACC Ord 03and integrated the latest Astro
guidelines. We know 5 FUMC is preferred but
cisplatin is a good alternative.We know dose needs to be risk
adapted up to 59.4. Way to dry for T3T4?
And critically, we cemented thatneither induction nor
maintenance chemo adds value. It has to be concurrent.
(36:50):
And finally, avoiding treatment breaks is absolutely paramount
for preserving local control, survival and sphincter function.
Proactive supportive care is nonnegotiable.
Couldn't have said it better andtranslating this plan, this
prescription into a safe and effective IMRT plan is the next
logical step. So looking ahead, our next
session will be an IMRT treatment planning workshop
(37:11):
specifically for anal cancer. Sounds practical.
Yeah, we'll do a step by step guide, simulation, contouring,
dose painting, drawing heavily on protocols like RTOGO 529 and
incorporating these new Astro guideline principles we
discussed today. We'll show you exactly how to
put this into practice in the planning system.
That sounds incredibly valuable.Remember, you can sharpen your
(37:33):
skills with practice oral boardsand explore more content at
radonksmartlearn.com. That's RADON ksmartlearn.com.
And definitely subscribe to Radonk Smart Review so you don't
miss that IMRT planning workshop.
Thanks for tuning in everyone. See you next time.
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