Clinical Case Management - Locally Advanced Rectal Cancer

[evilbooyaa]

In the interest of discussing some topics that are things besides the job market and optimism/pessimism, based on a (IMO) good suggestion from an SDN user, I'm going to start a series of threads on general diagnoses and encourage people to discuss how these are managed clinically in your practice/residency/dreams, whatever. Judicious (not 80 links, but like 1-5) use of studies when relevant to the point at hand are encouraged but not mandatory.

If you have other ideas in this vein I'm open to other people starting threads as well. And so help me God, if I see a single post about the job market or other off-topic nonsense without any significant corollary to the topic in question in here I'm warning/deleting. For example, saying "We do long-course chemoRT b/c it pays better in the current era but we may see more SCRT with 5Gy x 5 in the future" is allowed.

OK, so let's talk about LARC.

How are folks managing this? Everybody getting MRI, ERUS, or both?

I imagine most are doing RT in some way. Short-Course or Long-Course? What dose? Boost volume? What chemo? Does this change based on whether patient needs LAR or APR?

Are all patients getting surgery? Anybody have a robust watchful waiting process? If so, how are those patients surveilled? How do you think it works out for those patients?

What about chemotherapy? After surgery? Before surgery? If before surgery (total neoadjuvant therapy) how are you sequencing?

Anybody doing CRT followed by transanal excision?

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[Gfunk6]

All things being equal for T3 or N+ rectal cancers, all our patients receive neoadjuvant CRT with capectiabine. We have adopted a dose-painting IMRT schema where the gross disease gets 50 Gy in 25 fractions and at risk nodal areas receive 45 Gy in 25 fractions. We have pretty much abandoned sequential boost and 3DCRT except in unique cases.

Patients then receive APR/LAR as indicated with TME technique. Outback they get 5FU poly-chemotherapy x4 cycles (as I recall).

Occasionally patients will show up in the ER with acute obstruction in which case surgery is done first but we try to avoid that to the extent possible.

Historically, we used to do EUS for T/N staging but this has been completely supplanted by 3T MRI which our Radiologists feel is comparable without being invasive.

Don't typically see T1N0 or T2N0 but if possible, our colorectal surgeons try for transanal excision followed by close observation.

 

[Lamount]

During my training, we spent time at two hospitals, one of which had much more beam time available than the other. At the former, we did long course with concurrent Xeloda, regardless of tumor location/size (45 to elective nodes + 5.4 to conedown). At the other, we did short course for proximal T3 tumors where down-staging wasn't needed for an LAR, and CRT for distal/T4 disease.

MRI vs. EUS was dependent on the referring surgeon (some did their own EUS). I personally preferred MRI because I thought it better staged the mesorectum.

 

[medgator]

EUS for staging in our practice. If T3N+, traditional 50.4/28 IMRT with concurrent 5-fu or xeloda followed by TME/LAR followed by chemo. We are moving towards TNT (total neoadjuvant therapy) though in patients who aren't symptomatic from their primary. If really bad, we divert first and then start Tx

 

[deleted1002574]

MRI for staging. It's better.
Same dose scheme as GFunktastic.
Would also like to transition to TNT, like the Alligator.

I like 5 x 5 Gy. But, a week or two weeks after treatment, it kicks their butt - abdominal pain, cramping, stabbing. Not pleasant. I don't see this documented in the studies, but every institution that uses it seems to mention it at their talks.

I don't do WW off study and I strongly recommend surgery if they aren't going to be on study, but a lot of patients don't listen. Most have done well. One met'd out in PA node and we SBRT'd that.

 

[evilbooyaa]

For the folks doing IMRT for LARC where it's either non-T4 or doesn't require inguinal coverage (like if it's low-lying with anal invasion) how often are you getting IMRT approved? If you have to do a P2P what data are you referencing to get IMRT approved?

 

[deleted1002574]

95% of the time gets approved.
Mayo data.

(I do want to say, this is part of reason why Mayo AZ shouldn't be included as a new/bad program. Good faculty, actual research / protocols (not just from mothership), teaching, protons, peds, etc. If you're starting a new program, do it like this one. Actually, don't start any new ones).

 

[FrostyHammer]

For the folks doing IMRT for LARC where it's either non-T4 or doesn't require inguinal coverage (like if it's low-lying with anal invasion) how often are you getting IMRT approved? If you have to do a P2P what data are you referencing to get IMRT approved?

Another neat trick I learned when starting in practice was to label the diagnosis code as "cancer of the anorectum" - which for insurance companies is more palatable to allow IMRT than just "rectum".

 

[elementaryschooleconomics]

Another neat trick I learned when starting in practice was to label the diagnosis code as "cancer of the anorectum" - which for insurance companies is more palatable to allow IMRT than just "rectum".

So I watched a Cardiologist do something similar when ordering an echo for a family member of mine. He threw in a ton of diagnosis codes and was like "hopefully insurance is happy with one of these".

Slightly different than what you're talking about, but in our EMR when I order something like a PET or an MRI, I slap about 18 different codes on it to "help it go through".

Does it actually work? I dunno.

Do I have Evicore saved as a "Favorite Contact" and wish I didn't? Yup.

 

[Mandelin Rain]

EUS + MRI typically.
More and more total neoadjuvant. Convinced to do CRT first based on results of recent study showing increased pCR rate with CRT then FOLFOX vs opposite.
50.4 Gy in 28 fx. 25 to pelvis. 3 to GTV +margin. Usually IMRT unless prone.
We have observed a handful of elderly patients or those who initially refuse APR. Alternate MRI and sigmoids +/- biopsy. I'm not crazy about bx unless suspected progression, but they do it anyway.
I have treated local excisions post op if indicated.

 

[deleted1002574]

EUS + MRI typically.
More and more total neoadjuvant. Convinced to do CRT first based on results of recent study showing increased pCR rate with CRT then FOLFOX vs opposite.
50.4 Gy in 28 fx. 25 to pelvis. 3 to GTV +margin. Usually IMRT unless prone.
We have observed a handful of elderly patients or those who initially refuse APR. Alternate MRI and sigmoids +/- biopsy. I'm not crazy about bx unless suspected progression, but they do it anyway.
I have treated local excisions post op if indicated.

GTV + 3mm is boost? Interesting. That's way smaller then what I do.

For CTV, do GTV+1cm and include mesorectum all the way into sacral hollow. Then 0.5ish for PTV. Majority of recurrences in MRE and presacral space, historically. Is this small volume boost thing based on something new? (I don't know my elbow from my a**hole anymore)

 

[Mandelin Rain]

GTV + 3mm is boost? Interesting. That's way smaller then what I do.

For CTV, do GTV+1cm and include mesorectum all the way into sacral hollow. Then 0.5ish for PTV. Majority of recurrences in MRE and presacral space, historically. Is this small volume boost thing based on something new? (I don't know my elbow from my a**hole anymore)

I meant 3 fractions to GTV + margin. Margin is usually 1.5 cm or entire surrounding mesorectum if adjacent nodes. so pretty much what you do.

 

[medgator]

For the folks doing IMRT for LARC where it's either non-T4 or doesn't require inguinal coverage (like if it's low-lying with anal invasion) how often are you getting IMRT approved? If you have to do a P2P what data are you referencing to get IMRT approved?

Do a plan comparison and submit, some insurance companies will approve if imrt shows a 20% improvement in small bowel dose. Much easier to treat patients supine with imrt than trying to do prone 3D with a belly board

 

[deleted1002574]

I meant 3 fractions to GTV + margin. Margin is usually 1.5 cm or entire surrounding mesorectum if adjacent nodes. so pretty much what you do.

Oops
Misread

 

[ramsesthenice]

I do a lot of short course with delayed surgery. I have never seen the delayed toxicity mentioned above. As in not even once. I don’t use IMRT regularly. Just 3 field with a non-divergent anterior border. Not sure why our experiences are so different but that’s how it goes some times.

We are doing a lot of TNT and watch and wait. Anyone who will probably/might need an APR gets TNT with long-course to try to maximize clinical responses and convert if possible. Our experience with watch and wait is exactly what has been published: only a few local failures. Only one presented with distant disease so far and she had two lung Mets. Treated her with chemo, wedged them out, and she is doing ok so far. The surprising thing is the watch and wait has been surgeon driven. I love our surgeons. They are very stringent defining cCR (negative MRI and flex dig repeated q2 months).

 

[evilbooyaa]

Anyone does escalating to more than 50-50.4 in attempt to get more sustained cCR in patients being considered for watch and wait? I remember reading this study a while ago but does not seem to have gained any popularity:

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00120-5/fulltext

I thought 40/51 (78%) rate of cCR was pretty exciting, given that pCR is generally about 50% of cCR rate.

 

[deleted1002574]

It’s logical to dose escalate, if you know you aren’t operating, but agree it hasn’t taken off. Our guys aren’t doing it.

 

[ramsesthenice]

Anyone does escalating to more than 50-50.4 in attempt to get more sustained cCR in patients being considered for watch and wait? I remember reading this study a while ago but does not seem to have gained any popularity:

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00120-5/fulltext

I thought 40/51 (78%) rate of cCR was pretty exciting, given that pCR is generally about 50% of cCR rate.

i don’t. That’s not much better than you get with TNT and FOLFOX (which the patients need anyway). I’ll want to see longer toxicity data. The whole point of watch and wait is to preserve organ function and avoid toxicity. Might pan out, but not something I am currently doing.

 

[deleted774703]

Great thread! Thx for the teaching

 

[scarbrtj]

Re: biopsy... Can definitely biopsy "too soon" after chemoRT if one is relying on pCR for whether or not to countenance organ preservation.

 

[w00tz]

Typically MRI for staging.
Typically do neoadjuvant chemoradiation, but have done a few short courses for various reasons.
Getting IMRT approved has not been too difficult.
TNT - depends on the med onc. Some are super gung-ho about it and others stick with standard chemorads.

Want to get thoughts on this:
80 year old female, KPS 70, with cT1N0 rectal adeno 3 cm from AV. Gets local excision and ends up being a T2 with negative margins. Surgeon says he always worries about recurrences in pT2, despite negative margins, and doesn't want to do a more extensive surgery and wants to know if we could sprinkle a little radiation to reduce that risk. Thoughts?

 

[ramsesthenice]

Typically MRI for staging.
Typically do neoadjuvant chemoradiation, but have done a few short courses for various reasons.
Getting IMRT approved has not been too difficult.
TNT - depends on the med onc. Some are super gung-ho about it and others stick with standard chemorads.

Want to get thoughts on this:
80 year old female, KPS 70, with cT1N0 rectal adeno 3 cm from AV. Gets local excision and ends up being a T2 with negative margins. Surgeon says he always worries about recurrences in pT2, despite negative margins, and doesn't want to do a more extensive surgery and wants to know if we could sprinkle a little radiation to reduce that risk. Thoughts?

Don’t say it on your boards but surgeon concern counts for something to me. I think radiation would be reasonable mainly because of the location. If they recur and you can’t get a CR you may risk needing an APR in an elderly patient.

boards answer: observe. It’s reasonable in real life too. Talk to the patient and see what scares them more, recurrence or radiation.

 

[ramsesthenice]

Re: biopsy... Can definitely biopsy "too soon" after chemoRT if one is relying on pCR for whether or not to countenance organ preservation.

we don’t biopsy. Too worried about healing. I personally think it’s scope and MRI is enough. These are salvageable when they recur. Also, how long does it take for tumor to completely regress? Patients who have minimal residual disease 6-8 weeks after CRT maybe on their way to a complete response with more time. If that’s the case, would identifying minimal disease on biopsy be a contraindication to organ preservation? We just don’t know yet. But I think the Brazilian data supports this idea. They were super liberal defining cCR and sure, they had a good number of recurrences (30%) but that was still lower than I would have expected and again, they were salvageable.

 

[RickyScott]

Anyone does escalating to more than 50-50.4 in attempt to get more sustained cCR in patients being considered for watch and wait? I remember reading this study a while ago but does not seem to have gained any popularity:

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00120-5/fulltext

I thought 40/51 (78%) rate of cCR was pretty exciting, given that pCR is generally about 50% of cCR rate.

I go to 60 Gy for definitive treatments.

 

[thecarbonionangle]

I do a lot of short course with delayed surgery. I have never seen the delayed toxicity mentioned above. As in not even once. I don’t use IMRT regularly. Just 3 field with a non-divergent anterior border. Not sure why our experiences are so different but that’s how it goes some times.

We are doing a lot of TNT and watch and wait. Anyone who will probably/might need an APR gets TNT with long-course to try to maximize clinical responses and convert if possible. Our experience with watch and wait is exactly what has been published: only a few local failures. Only one presented with distant disease so far and she had two lung Mets. Treated her with chemo, wedged them out, and she is doing ok so far. The surprising thing is the watch and wait has been surgeon driven. I love our surgeons. They are very stringent defining cCR (negative MRI and flex dig repeated q2 months).

im interested in learning more about the WW approach. How do you pick these patients? How do you pick if short course vs long course CRT? All get TNT? How long do you wait after surgery? Only monitor with MRI/Scope q2months? How long would you give residual disease to regress before you do surgery?

 

[seper]

What's the best evidence supporting "TNT approach" (I presume, you mean neoadjuvant chemo for many months prior to LAR). Naturally, I'd worry about losing out on local control for poor respondents.

 

[deleted1002574]

What's the best evidence supporting "TNT approach" (I presume, you mean neoadjuvant chemo for many months prior to LAR). Naturally, I'd worry about losing out on local control for poor respondents.

The way most centers do it is
Chemo RT -> Chemo -> surgery

The benefit is you are treating locally with RT, the chemo is easier to tolerate, and if the patient decides to skip surgery, they still have a good chance at CR.

60 Gy is a nice definitive dose. Toxicity seem reasonable?

 

[RickyScott]

im interested in learning more about the WW approach. How do you pick these patients? How do you pick if short course vs long course CRT? All get TNT? How long do you wait after surgery? Only monitor with MRI/Scope q2months? How long would you give residual disease to regress before you do surgery?

I have been in the community and academics and this approach historically is very rare. Typically, pt flat out refuses surgery or simply not a surgical candidate, and then historically went to 60 Gy based on old joint center data. If tumor was really close to sphincter, in the northeast, there were several surgeons who specialized in microexcision approaches to spare sphincter.

 

[evilbooyaa]

i don’t. That’s not much better than you get with TNT and FOLFOX (which the patients need anyway). I’ll want to see longer toxicity data. The whole point of watch and wait is to preserve organ function and avoid toxicity. Might pan out, but not something I am currently doing.

You're seeing 70% cCR rates with just 50.4 and FOLFOX? That seems higher than most published data, no?

we don’t biopsy. Too worried about healing. I personally think it’s scope and MRI is enough. These are salvageable when they recur. Also, how long does it take for tumor to completely regress? Patients who have minimal residual disease 6-8 weeks after CRT maybe on their way to a complete response with more time. If that’s the case, would identifying minimal disease on biopsy be a contraindication to organ preservation? We just don’t know yet. But I think the Brazilian data supports this idea. They were super liberal defining cCR and sure, they had a good number of recurrences (30%) but that was still lower than I would have expected and again, they were salvageable.

I wonder if eventually we'll transition to an anal cancer-like thought process about giving sufficient time for resolution and as long as things aren't growing, leave it the heck alone. We, right now, are scoping and biopsying suspicious scars at 2-3 months post treatment and I just think that's too early if the mass is not obviously growing.

What's the best evidence supporting "TNT approach" (I presume, you mean neoadjuvant chemo for many months prior to LAR). Naturally, I'd worry about losing out on local control for poor respondents.

Greater tolerance of chemotherapy (50-70% vs 90-95%+) and no effect on oncologic outcomes.

People say ADORE trial was positive when other trials failed because of a 90%+ adherence to adjuvant chemotherapy: https://ascopubs.org/doi/full/10.1200/JCO.19.00016

Sloan kettering retrospective and a phase II trial from them are good data:

Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer

This study compares preoperative chemoradiation followed by postoperative adjuvant chemotherapy vs total neoadjuvant therapy for treatment of locally advanced rectal cancer.

jamanetwork.com

Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial - PubMed

National Institutes of Health National Cancer Institute.

www.ncbi.nlm.nih.gov

GCR-3 shows similar oncologic outcomes with less toxicity with total neoadjuvant: Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Sp... - PubMed - NCBI

All that being said, it's being analyzed in an ongoing phase III by the Germans based on randomized phase II data they recently published trying to determine which sequence (chemo then CRT vs CRT then chemo) is 'best' based on pCR: https://ascopubs.org/doi/full/10.1200/JCO.19.00308

I go to 60 Gy for definitive treatments.

I think this sounds very reasonable. In 30 Fx or SIB at 2.4Gy/fx in 25 fractions?

 

[ramsesthenice]

The way most centers do it is
Chemo RT -> Chemo -> surgery

I don't know that that is true. The stanford WashU approach is exactly this but the Brown data was FOLFOX -> CRT -> surgery. That is what was done in GI002 as well. Most med Oncs I know prefer to start with chemo so we can assess the response mid-point. If you do RT first you may blast it down and not know how it is responding to chemo. Personally, I think it doesn't really matter how you order it. Like all solid tumors, I doubt starting chemo a couple months earlier is any better for micrometastatic disease. All of the breast and H&N literature and rectal (ala Spanish trial) tell me that if patients are going to respond to chemo they will do it now or in two months. But I see their point and we generally do chemo first unless they are symptomatic etc.

 

[deleted1002574]

There was a study showing ChemoRT upfront was better, I thought? I swear I saw that reported somewhere and most places switched.

 

[ramsesthenice]

I have been in the community and academics and this approach historically is very rare.

This has to be adopted by surgery. If they don't feel comfortable doing it off trial it simply won't happen. I think there is sufficient data to do it but I concede there are legitimate questions about how to define a cCR and what follow up is adequate and when to pull the trigger on surgery. I really think it should be done at high volume centers and surgeons that have experience with it and feel comfortable with management. There is a lot of potential to go wrong here.

 

[Palex80]

How are folks managing this? Everybody getting MRI, ERUS, or both?

Most patients get EUS at diagnosis and MRI during workup. I find modern MRI is pushing EUS aside more and more...

I imagine most are doing RT in some way. Short-Course or Long-Course? What dose? Boost volume? What chemo? Does this change based on whether patient needs LAR or APR?

We use long course for >T3a disease and for all tumors in the lower rectum.
Short course is rarely used for the seldom small T3a cases in the middle rectum.
We don't give preoperative RT for tumors in the proximal rectum, since resection works well then. One exception would be large nodes that are not well resectable.

Are all patients getting surgery? Anybody have a robust watchful waiting process? If so, how are those patients surveilled? How do you think it works out for those patients?

We don't have an established RT-only alghorithm, although we have done it in a number of patients with low lying tumors, who would have needed an APR and didn't want it. When surveillance is used we mainly do an endoscopy at 8 weeks + an MRI. If MRI is clear we basically keep on doing endoscopy, no biopsies, unless suspicion of progression.

What about chemotherapy? After surgery? Before surgery? If before surgery (total neoadjuvant therapy) how are you sequencing?

5FU/Capecitabine with RT.
XELOX given after surgery.
We do not perform total neoadjuvant treatment.

Anybody doing CRT followed by transanal excision?

Select T2s in need of APR if the reject APR.

 

[Mandelin Rain]

There was a study showing ChemoRT upfront was better, I thought? I swear I saw that reported somewhere and most places switched.

Better pCR rates

 

[ramsesthenice]

Better pCR rates

What comparison are you making? TNT vs non-TNT? Or sequencing of chemo and chemoRT in TNT? Clearly TNT has better pCR and cCR than non-TNT but I dont think there is any good data that sequencing during TNT matters as it relates to pCR. The stanford/washU experience with near TNT and upfront short course saw a pCR of 27% and the total neoadjuvant experience with upfront chemo was 21% in the control arm of GI002 and 32% in the Brown series.

 

[Mandelin Rain]

Or sequencing of chemo and chemoRT in TNT? Clearly TNT has better pCR and cCR than non-TNT but I dont think there is any good data that sequencing during TNT matters as it relates to pCR.

https://ascopubs.org/doi/abs/10.1200/JCO.19.00308

 

[Grubbe-a-dub-dub]

I just started at my job, and it seems like the trend, here at least, is to do TNT for most locally advanced rectal ca. The approach they take is Chemo first then chemo/RT then surgery.

I brought up the idea of doing chemo-rt first in the paradigm, especially for large bulky or locally invasive tumors, but the surgeons seem to be uncomfortable putting off surgery for months after the RT due to potential complications.

What data or arguments could I use to ease their concerns?

 

[Mandelin Rain]

I just started at my job, and it seems like the trend, here at least, is to do TNT for most locally advanced rectal ca. The approach they take is Chemo first then chemo/RT then surgery.

I brought up the idea of doing chemo-rt first in the paradigm, especially for large bulky or locally invasive tumors, but the surgeons seem to be uncomfortable putting off surgery for months after the RT due to potential complications.

What data or arguments could I use to ease their concerns?

See above. No increase in surgical morbidity in the randomized sequencing trial I posted.

 

[Grubbe-a-dub-dub]

Agree - but that trial used only 3 cycles. Typically it's 6-8 which would be much longer than 90 days to surgery.

I need something juicy I can bring to them - this particular surgeon is a tough nut to crack....

 

[ramsesthenice]

https://ascopubs.org/doi/abs/10.1200/JCO.19.00308

Not compelling. Multiple other experiences with upfront chemo in TNT have shown substantially better pathologic responses than in the induction arm of the trial you cited.

Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer

This study compares preoperative chemoradiation followed by postoperative adjuvant chemotherapy vs total neoadjuvant therapy for treatment of locally advanced rectal cancer.

jamanetwork.com

Complete Neoadjuvant Treatment for Rectal Cancer: The Brown University Oncology Group CONTRE Study - PubMed

CONTRE seems to be a well-tolerated alternative to the current standard treatment sequence. Evaluating its impact on long-term outcomes would require a large randomized trial, but using pathologic response as an endpoint, it could serve as a platform for assessing the addition of novel agents to...

www.ncbi.nlm.nih.gov

Addition of Bevacizumab to XELOX Induction Therapy Plus Concomitant Capecitabine-Based Chemoradiotherapy in Magnetic Resonance Imaging–Defined Poor-Prognosis Locally Advanced Rectal Cancer: The AVACROSS Study

Worth noting, responses are clearly mixed. Others have been more on par with mid teens as well.

Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial† - PubMed

Both treatment approaches yield similar outcomes. Given the lower acute toxicity and improved compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy before CRT and surgery is a promising strategy and should be examined in phase III trials.

www.ncbi.nlm.nih.gov

A prospective phase II study of pre-operative chemotherapy then short-course radiotherapy for high risk rectal cancer: COPERNICUS

There are pretty big differences in protocols so it is hard to know. I will say though, in my experience most people do 8 cycles up front for TNT (the same amount they would get outback) and most of those trials have been in the 20s for pCR. Don't get me wrong, I would more often than not prefer to do upfront chemoradiation since it tends to provide faster symptom relief. I am also completely unconvinced that "earlier" chemo is going to improve long-term outcomes AT ALL. But I would not personally cite a small(ish) randomized phase 2 studies with low(ish) response rates in one of the arms as anything more than hypothesis generating.

Another thing I feel very strongly about...people need to be very careful with what pCR means. Too often (even in RTOG protocols) people make the assumption that a higher pCR rate is going to translate into improved oncologic outcomes. The assumption is generally predicated on the fact pCR is strongly correlated with improved outcomes in trials of patients getting conventional CRT. Applying this logic to different neoadjuvant protocols is inherently flawed. Think about it. How many negative induction compared to outback chemo trials in solid tumors do we need to know that early chemo does not translate into better long-term disease control? Breast. Rectal. H&N. Induction chemo + RT improves clinical and pathologic responses in the primary tumor. But where are the randomized trials showing that upfront chemo improves survival compared to outback? In my opinion, we have mountains of data demonstrating its a biology issue. Adjuvant chemo improves survival because in a subset of patients it will clear their micrometastatic disease regardless of when it is given. The notion that starting chemo earlier will increase this proportion of patients has more or less been proven categorically false. Improving pathologic and clinical response rates in rectal cancer is mot meaningful because it can greatly impact surgical options including candidacy for organ preservation. But IMHO, expecting TNT to provide better long-term disease control than conventional approaches is a recipe for disappointment.

 

[Mandelin Rain]

Sigh. Not sure why we even bother doing randomized trials anymore.

 

[ramsesthenice]

Sigh. Not sure why we even bother doing randomized trials anymore.

The real question is why do people do randomized trials with non-standard therapies? The data for concurrent oxalliplatin with RT is marginal at best and it is not widely adopted. 3 cycles of systemic-dose triplet therapy is also on the wimpy side compared to essentially all other TNT trials. They really don't have a standard arm at all which makes it impossible to know how to fit these results into the broader literature. It suggests upfront CRT might be better with this specific regimen but neither arm looks particularly spectacular when compared to TNT experiences with more standard components (4-6 months of systemic therapy + FU-based CRT or short-course radiation). Had they used something remotely resembling SOC it might be a wholly different conversation. It is entirely possible that optimal sequencing may differ based on the composition of the independent components. So why not go with the ones most commonly used?

 

[Mandelin Rain]

Sure. It'd be best if everyone around the world could decide on a standard regimen to compare to, but that's pie in the sky stuff. This is the one trial that asked, "Does sequencing of TNT matter?" For the only immediately measurable outcome, it appears to. If you escalate systemic therapy, would the difference remain? Maybe. Maybe not. Maybe it'd have been even larger difference, or the complete opposite outcome. That wasn't the trial though.

We have one piece of randomized evidence that examine the question. This points to cancer killing supremacy of CRT then Chemo. We have no evidence to suggest the opposite. I suggest we don't fight it.

 

[ramsesthenice]

I suggest we don't fight it.

Acknowledging blatant scientific and generalizable shortcomings to poorly designed trials is not "fighting it." Its being realistic. Their data is potentially interesting but not practice changing.

 

[ramsesthenice]

Sad update relevant to this discussion. I had a complicated case a while back. The guy had a history of a metastatic duodenal cancer and multiple obstructions managed surgically. He eventually developed a rectal cancer that was more or less observed. It eventually became a little symptomatic and I was asked to radiate. Surgery clearly was not going to happen and his overall disease burden was low so I figured what the hell, lets dose escalate. Took the primary to 60 Gy. At first I was happy. Good response to the primary and we actually saw an abscopal response to some small lung lesions (on no systemic therapy). Unfortunately, about 5 months after we were done he developed severe rectal bleeding from severe radiation proctitis (biopsy proven). He failed everything we tried. Hyperbaric, formalin enemas, etc. This went on for about 6 months. He developed a PE over the weekend and when they tried to anticoagulate him he developed severe blood loss from the rectum and was transferred to the ICU where he subsequently died.

I don't think this is typical. I have done 60 Gy a couple of other times without issues. I wonder if it was related to the fact he was very heavily pretreated with chemo (for his duodenal tumor) before I got to him? Or just innate patient effects? Either way, treatment effects killed him before his cancer and that is never the goal. Makes me a little nervous to regularly do 60 Gy in the absence of good data showing a benefit.

 

[medgator]

Sad update relevant to this discussion. I had a complicated case a while back. The guy had a history of a metastatic duodenal cancer and multiple obstructions managed surgically. He eventually developed a rectal cancer that was more or less observed. It eventually became a little symptomatic and I was asked to radiate. Surgery clearly was not going to happen and his overall disease burden was low so I figured what the hell, lets dose escalate. Took the primary to 60 Gy. At first I was happy. Good response to the primary and we actually saw an abscopal response to some small lung lesions (on no systemic therapy). Unfortunately, about 5 months after we were done he developed severe rectal bleeding from severe radiation proctitis (biopsy proven). He failed everything we tried. Hyperbaric, formalin enemas, etc. This went on for about 6 months. He developed a PE over the weekend and when they tried to anticoagulate him he developed severe blood loss from the rectum and was transferred to the ICU where he subsequently died.

I don't think this is typical. I have done 60 Gy a couple of other times without issues. I wonder if it was related to the fact he was very heavily pretreated with chemo (for his duodenal tumor) before I got to him? Or just innate patient effects? Either way, treatment effects killed him before his cancer and that is never the goal. Makes me a little nervous to regularly do 60 Gy in the absence of good data showing a benefit.

Not sure I would have gone that high in someone with metastatic disease (40/15 or 50/20 is my go to aggressive palliation dose).

Nonetheless, I've done 60-63 before intact and have not seen that. I'm guessing the chemo beforehand had something to do with it or other comorbidities (liver mets can impair function, clotting etc as an example, or renal issues)

 

[ramsesthenice]

Not sure I would have gone that high in someone with metastatic disease (40/15 or 50/20 is my go to aggressive palliation dose).

Nonetheless, I've done 60-63 before intact and have not seen that. I'm guessing the chemo beforehand had something to do with it or other comorbidities (liver mets can impair function, clotting etc as an example, or renal issues)

It was a tough call. He had been off chemo with stable low-burden disease for over a year. The assumption was the stable lung modules were duodenal. I thought it worth a shot given his favorable biology. It sucks, because he was essentially NED when he died.

It makes me think twice in heavily pretreated patients going forward.

 

[RickyScott]

Sad update relevant to this discussion. I had a complicated case a while back. The guy had a history of a metastatic duodenal cancer and multiple obstructions managed surgically. He eventually developed a rectal cancer that was more or less observed. It eventually became a little symptomatic and I was asked to radiate. Surgery clearly was not going to happen and his overall disease burden was low so I figured what the hell, lets dose escalate. Took the primary to 60 Gy. At first I was happy. Good response to the primary and we actually saw an abscopal response to some small lung lesions (on no systemic therapy). Unfortunately, about 5 months after we were done he developed severe rectal bleeding from severe radiation proctitis (biopsy proven). He failed everything we tried. Hyperbaric, formalin enemas, etc. This went on for about 6 months. He developed a PE over the weekend and when they tried to anticoagulate him he developed severe blood loss from the rectum and was transferred to the ICU where he subsequently died.

I don't think this is typical. I have done 60 Gy a couple of other times without issues. I wonder if it was related to the fact he was very heavily pretreated with chemo (for his duodenal tumor) before I got to him? Or just innate patient effects? Either way, treatment effects killed him before his cancer and that is never the goal. Makes me a little nervous to regularly do 60 Gy in the absence of good data showing a benefit.

I would have done exactly what you did. I don’t think there is a lesson to be learned here.

 

[evilbooyaa]

I just started at my job, and it seems like the trend, here at least, is to do TNT for most locally advanced rectal ca. The approach they take is Chemo first then chemo/RT then surgery.

I brought up the idea of doing chemo-rt first in the paradigm, especially for large bulky or locally invasive tumors, but the surgeons seem to be uncomfortable putting off surgery for months after the RT due to potential complications.

What data or arguments could I use to ease their concerns?

Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial - PubMed

National Institutes of Health National Cancer Institute.

www.ncbi.nlm.nih.gov

Increasing amount of consolidation chemo after chemoRT did not increase surgical toxicity rates.

 

[evilbooyaa]

Sad update relevant to this discussion. I had a complicated case a while back. The guy had a history of a metastatic duodenal cancer and multiple obstructions managed surgically. He eventually developed a rectal cancer that was more or less observed. It eventually became a little symptomatic and I was asked to radiate. Surgery clearly was not going to happen and his overall disease burden was low so I figured what the hell, lets dose escalate. Took the primary to 60 Gy. At first I was happy. Good response to the primary and we actually saw an abscopal response to some small lung lesions (on no systemic therapy). Unfortunately, about 5 months after we were done he developed severe rectal bleeding from severe radiation proctitis (biopsy proven). He failed everything we tried. Hyperbaric, formalin enemas, etc. This went on for about 6 months. He developed a PE over the weekend and when they tried to anticoagulate him he developed severe blood loss from the rectum and was transferred to the ICU where he subsequently died.

I don't think this is typical. I have done 60 Gy a couple of other times without issues. I wonder if it was related to the fact he was very heavily pretreated with chemo (for his duodenal tumor) before I got to him? Or just innate patient effects? Either way, treatment effects killed him before his cancer and that is never the goal. Makes me a little nervous to regularly do 60 Gy in the absence of good data showing a benefit.

Consider writing that up or having a resident write it up as a case report on the potential risks in treating people heavily pre-treated with chemotherapy and surgery (if multiple obstructions) with dose escalation. We need more data available from these rare situations to guide folks towards or away from certain treatments.