Rectal T3N1 TNT (Total Neoadj Therapy) sequencing question...

[OTN]

I trained at a place that does 5x5. Now I do long course as it's what's the local medoncs and surgeons want. In fact, the surgeons generally hate short course, though perhaps less so if proximal. In any case, I've really stopped caring about this question beyond the aims of the opra trial, which, oddly enough, is being run by surgeons.

This is really the correct answer. I did short course in training because it's what the surgeons wanted. I now do long course because it's what the surgeons like.

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[deleted1111261]

This is really the correct answer. I did short course in training because it's what the surgeons wanted. I now do long course because it's what the surgeons like.

Agree!!

 

[BobbyHeenan]

This is really the correct answer. I did short course in training because it's what the surgeons wanted. I now do long course because it's what the surgeons like.

I have multiple good surg oncs/GI docs I work with. Some of them don't care about pre op xrt regmin, but one has explicitly said "don't do the short course again, it felt different in there."

Don't have to tell me twice, buddy.

 

[medgator]

I have multiple good surg oncs/GI docs I work with. Some of them don't care about pre op xrt regmin, but one has explicitly said "don't do the short course again, it felt different in there."

Don't have to tell me twice, buddy.

Is there an ideal interval of time to do SC before surgery? Any issues with more fibrosis or scarring beyond a certain time interval?

 

[Palex80]

Is there an ideal interval of time to do SC before surgery? Any issues with more fibrosis or scarring beyond a certain time interval?

The Stockholm III study

 

[BobbyHeenan]

Is there an ideal interval of time to do SC before surgery? Any issues with more fibrosis or scarring beyond a certain time interval?

This was a number of years ago when we were doing short course then surgery pretty quickly afterward like the original trials. So he said the bowel/rectum/mesorectum felt edematous/"boggy" and he didnt' like it.

NOt sure about late scarring but I've had other surgeons tell me they didn't notice a big difference.

 

[ramsesthenice]

I do a lot of both. Surgeons haven’t noted much of a difference as long as they wait long enough (which they always do). With OR restrictions (ie staff shortages) the days of immediate surgery after SC are gone.

Toxicity wise, there are important differences between SC and LC which you might predict (assuming you delay surgery). With SC, the acute rectal toxicities hit a higher peak (1-2 weeks after RT) but they don’t last as long as with LC. It’s a trade off. Both usually go ok.

 

[deleted1111261]

I would bet if the surgeons were blinded they would not be able to tell the difference with P<0.10. I don’t think it’s a thing. They all say something when it’s brought up. The data doesn’t support it and surgeons are even more resistant to change than we are. But, the acute dissension / bloating - when it occurs often enough, I see why people stick with long course.

 

[elementaryschooleconomics]

https://doi.org/10.1200/JCO.21.01667

Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR)

“TNT was associated with an approximately twofold rate of grade 3-plus toxicity compared with CRT (26.5% v 12.6%; P , .001).”

Short-course TNT vs long-course German style (CRT-surgery-chemo)?

That's an apples-to-orange comparison...I say today, in 2022. I guess it's because this trial was probably written in 2013/2014 to enroll patients in 2015.

Regardless, with PRODIGE23, OPRA, and CAO/ARO/AIO-12: I'm sticking with long-course CRT followed by chemo followed by TME (or WW) until something comes along and shows 5x5 to be clearly superior.

(although, as others have said: I'll do what the surgeons want, or if the patient needs short-course for reasons specific to their case)

 

[Radonc90]

@Palex80,
The Stockholm III study you linked above, the math in the "Findings" section is messed up where it matters the most.
I discussed this with the primary author (Dr. J. Erlandsson et al) back in 2017, he agreed that the math is messed up and said he will try to issue an erratum, I have not seen the erratum yet.

@elementaryschooleconomics,
I agree with your approach, I am currently using long-course chemoRT ---> chemo ---> surgery (vs W&W depending on pt)...

 

[heartisinradonc]

I have barely found any patient who could stand 6+ months of systemic therapy. One site in my area has had apparently quoted ~70% clinical/pathological response for long course RT with radiosensitising chemo using watch and wait for low rectal with no recurrences at 5 years. I personally would never recommendTNT mainly because I think systemic therapy should be minimised at all times. Not a fan of RAPIDO.

 

[jondunn]

mainly because I think systemic therapy should be minimised at all times.

what a wild take. what the actual....

 

[heartisinradonc]

what a wild take. what the actual....

Just my take. Do you prefer to maximise systemic therapy when you can achieve improved control with less toxicity? Organ preservation can be achieved without killing a patient from toxicities. I didn't think my take would be considered controversial at all. I personally have not seen good tolerance to TNT. I've recently seen a patient RIP from 2 cycles of TPF when the patient should have had upfront RT. My faith in systemic therapy is low. Perhaps it is different in the US because the med oncs control so much of the process?

 

[jondunn]

Good luck with rectal preservation without the intensive chemo. Don’t know that You’re not gonna be watching or waiting on much.

 

[heartisinradonc]

Good luck with organ preservation without the intensive chemo. Don’t know that You’re not gonna be watching or waiting on much.

I did say standard of care here would be long course followed by surgery and quoted one regional unit that somehow got 70% complete response after watch and wait with long course for their low rectals which was impressive. The lesser of 2 evils is surgery. I've seen too many disasters with 'induction'/'adjuvant'/'neoadjuvant' systemic therapy in any malignancy to prefer it it to a standard course using conventional RT. Maybe it's different in the US? Looks like the med oncs there are completely out of control.

 

[ramsesthenice]

I have barely found any patient who could stand 6+ months of systemic therapy. One site in my area has had apparently quoted ~70% clinical/pathological response for long course RT with radiosensitising chemo using watch and wait for low rectal with no recurrences at 5 years. I personally would never recommendTNT mainly because I think systemic therapy should be minimised at all times. Not a fan of RAPIDO.

70% cCR with chemoRT alone is an extreme outlier. Even bringing that up shows a fairly willful disregard of a mountain of randomized data from thousands of patients.

Are you suggesting you recommend neoadjuvant CRT, then surgery, and no adjuvant FOLFOX for locally advanced rectal cancers? Because that is very far outside of SOC and excluding a therapy with an OS benefit. This is not H&N where neoadjuvant is giving folks super toxic chemo they wouldn’t otherwise get. It’s a question of sequence only and in most people experience (definitely mine) the 4 months of FOLFOX is tolerated better before surgery than after.

 

[evilbooyaa]

70% cCR with chemoRT alone is an extreme outlier. Even bringing that up shows a fairly willful disregard of a mountain of randomized data from thousands of patients.

Are you suggesting you recommend neoadjuvant CRT, then surgery, and no adjuvant FOLFOX for locally advanced rectal cancers? Because that is very far outside of SOC and excluding a therapy with an OS benefit. This is not H&N where neoadjuvant is giving folks super toxic chemo they wouldn’t otherwise get. It’s a question of sequence only and in most people experience (definitely mine) the 4 months of FOLFOX is tolerated better before surgery than after.

Well, actually, isn't the data on adjuvant chemo in RECTAL Ca like super mixed? Like there's one trial out of like 4 or 5 that actually showed a OS benefit to it? Like yeah we all do it but it's really not as slam dunk of an answer as people make it out to be? And the main reason NCCN recommends it is as an extrapolation of colon cancer?

And that really the best data for it (despite the fact it was done forever) was the ADORE trial, publisehd in 2018, which didn't actually compared to NO adjuvant chemotherapy, but rather did FOLFOX vs FL (similar in concept to the TPF vs PF induction trials in H&N)

UpToDate - From Chris Willett

"The benefit of postoperative chemotherapy following preoperative chemoradiotherapy for rectal cancer has been directly addressed in four randomized phase III trials, all of which are flawed, and a meta-analysis of all four trials. In our view and that of others, the available data from these four trials are insufficient to conclude that there is no benefit for postoperative chemotherapy in this setting [6]. In addition, data on the benefit of an oxaliplatin-containing chemotherapy regimen are also available from the randomized phase III ADORE trial."


All that being said, I would not recommend W&W without some form of chemotherapy on board, as per OPRA. 70% cCR without some form of chemo would be an outlier that even Habr-Gama would maybe be skeptical of.

 

[Palex80]

Indeed, adjuvant chemotherapy after neoadjuvant radiochemotherapy + surgery is a topic of continuing debate.
Adherence to adjuvant chemotherapy after neoadjuvant radiochemotherapy + surgery is one major cause for the conflicting data. The trials may have been underpowered since a lot of patients never received the full planned course of adjuvant treatment.

 

[heartisinradonc]

Indeed, adjuvant chemotherapy after neoadjuvant radiochemotherapy + surgery is a topic of continuing debate.
Adherence to adjuvant chemotherapy after neoadjuvant radiochemotherapy + surgery is one major cause for the conflicting data. The trials may have been underpowered since a lot of patients never received the full planned course of adjuvant treatment.

Exactly my point. I did say earlier than the 70% quote is an absolute outlier. Just my personal belief that having surgery instead of further systemic is the lesser of 2 evils. I've seen too many toxicities with systemic therapy.

"Are you suggesting you recommend neoadjuvant CRT, then surgery, and no adjuvant FOLFOX for locally advanced rectal cancers? Because that is very far outside of SOC and excluding a therapy with an OS benefit"

That is a very contentious statement because the time lag post RT in some of these trials to surgery is likely the reason for the different OS results, and not because of benefit from systemic therapy. FOLFOX isn't an easy regimen you can hand out like candy. A lot of these patients struggle mightily with it/Capetcitabine.

 

[SriRam Chandran]

I am a Hospitalist in California seeking help. My cousin is diagnosed with T4aN2M1 rectal cancer with liver metastasis. She would like to get treatment at MD Anderson or Memorial Sloan Kettering or Dana Farber. She currently lives in India. Which of these centers is the best? Also could anyone working at these centers be able to guide me as to who the best Medical Oncologist, Surgical Oncologist, Colorectal Surgeon and Radiation Oncologist would be at each of these centers?

Time is of essence and I would greatly appreciate your help.

 

[ramsesthenice]

I am a Hospitalist in California seeking help. My cousin is diagnosed with T4aN2M1 rectal cancer with liver metastasis. She would like to get treatment at MD Anderson or Memorial Sloan Kettering or Dana Farber. She currently lives in India. Which of these centers is the best? Also could anyone working at these centers be able to guide me as to who the best Medical Oncologist, Surgical Oncologist, Colorectal Surgeon and Radiation Oncologist would be at each of these centers?

Time is of essence and I would greatly appreciate your help.

Sorry to hear about your cousin. Those are all good centers and they here is no need to worry about finding the best anything. They are all really good and will probably take a similar approach. The first step is to determine if the liver disease is potentially resectable and there are good surgeons at all of those places. Regardless of the answer to that question, they are going to give chemo (or immuno if the tumor by some chance is MSI high) and then restage again. In the best case scenario, her liver is potentially resectable and they can try to do preop pelvic radiation followed by combined pelvic and hepatic resection as a potentially curative approach.

The main value of going to one of the centers you listed is they are high volume and they may have some trials or approaches that others don’t (like IRE for metastases hugging a main hepatic vessel). They maybe a little better equipped to push the envelope for borderline cases. But you are right, time is of the essence. They are all good. Just pick one and get things going.

 

[SriRam Chandran]

Thank you for your help. We are trying to do what we can to beat the odds.

 

[ramsesthenice]

Thank you for your help. We are trying to do what we can to beat the odds.

Good luck. It obviously depends on a lot of details we don’t have here, but colorectal liver metastases are not the same as most other distant metastases for other cancers. Long term survival/cure can approach 30% in favorable scenarios. There is a reason I could rattle off the general approach right off the top of my head. The best case is if their tumor is microsatellite unstable mutated (MSI high). Those tumors have exceptional high response rates to immune therapy (+\- chemo). Still beatable without it, just requires more intense chemo and response rates are not quite as good.

 

[SriRam Chandran]

Good luck. It obviously depends on a lot of details we don’t have here, but colorectal liver metastases are not the same as most other distant metastases for other cancers. Long term survival/cure can approach 30% in favorable scenarios. There is a reason I could rattle off the general approach right off the top of my head. The best case is if their tumor is microsatellite unstable mutated (MSI high). Those tumors have exceptional high response rates to immune therapy (+\- chemo). Still beatable without it, just requires more intense chemo and response rates are not quite as good.

She is a 63 yo F w PMH of HTN with a colonoscopy that revealed 10-20 cm annular growth. Histopath showed moderately differentiated adenocarcinoma grade 2 on biopsy. She has involvement of mesorectal, presacral and promontorial nodes and multiple liver deposits (8) and a 3 mm nodule in the RLL that is indeterminate on FDG. The good thing is there is no bone involvement or involvement of pelvic floor. no biliary obstruction of portal vein thrombosis.

I think it may be worth it for them to fly to the US for treatment. My fear was if she got really sick and was land locked in the US away from friends/family. That would be terrible if she had a limited time. But without the risk there cannot be a reward as well. I guess its worth the second opinion to see what options are available.

Thank you so much for your help!

 

[SriRam Chandran]

Good luck. It obviously depends on a lot of details we don’t have here, but colorectal liver metastases are not the same as most other distant metastases for other cancers. Long term survival/cure can approach 30% in favorable scenarios. There is a reason I could rattle off the general approach right off the top of my head. The best case is if their tumor is microsatellite unstable mutated (MSI high). Those tumors have exceptional high response rates to immune therapy (+\- chemo). Still beatable without it, just requires more intense chemo and response rates are not quite as good.

Any idea how to get the histopathology slides from India to MD Anderson?

Is there a digital system in place to enable this?

 

[jondunn]

I am sure MDACC faces this quite often. If they need slide review, they will get them.

 

[Palex80]

I am not sure, if this was mentioned in one of the previous posts, but the Germans are conducting the MOTHER OF ALL TNT TRIALS, which will hopefully answer all open questions.

ClinicalTrials.gov

clinicaltrials.gov

short course RT with 5x5 Gy --> FOLFOX/CAPOX
vs.
long course CRT (pelvis 25x1.8+ boost 5x1.8 Gy with Capecitabine&Oxaliplatin) -->FOLFOX/CAPOX

+

deferring surgery in case of (near)cCR.


Accrual is running well, 265/702 patients (March 2022) are already registered.

 

[evilbooyaa]

Why are they doing XelOx concurrently with chemoRT again?? They'll go "look, CRT is more TOXIC" and justify SCRT winning. XelOx concurrently with RT is a LOSER!

Godamnit, germany!

 

[Palex80]

Why are they doing XelOx concurrently with chemoRT again?? They'll go "look, CRT is more TOXIC" and justify SCRT winning. XelOx concurrently with RT is a LOSER!

Godamnit, germany!

The Germans love XELOX. The only trial that came back positive for the addition of oxaliplatin during CRT was the German trial.
All the other ones failed (including the French and the Italian trials).

The Germans are truly convinced it has to do with their fact that their schedule was superior.
It's like asking a German if he thinks a Volkswagen is a better car than a Renault or a Fiat. You will always get the same answer.

 

[ramsesthenice]

It's like asking a German if he thinks a Volkswagen is a better car than a Renault or a Fiat. You will always get the same answer.

They come up with good code to cheat the emissions tests?

 

[evilbooyaa]

The Germans love XELOX. The only trial that came back positive for the addition of oxaliplatin during CRT was the German trial.
All the other ones failed (including the French and the Italian trials).

The Germans are truly convinced it has to do with their fact that their schedule was superior.
It's like asking a German if he thinks a Volkswagen is a better car than a Renault or a Fiat. You will always get the same answer.

I am convinced that addition of Oxaliplatin on 0822 is the entire reason that trial went negative for improving toxicity and thus has made getting IMRT approval for rectal cancer in the US to be such a pain in the ass, due to the diarrhea inherent to Oxaliplatin administration