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

Radonc90

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    At tumor board today, 65 yo man with T3N1 rectal cancer.
    Low-lying tumor encroaching on the sphincter.

    Colorectal surgeon argues for 1) ChemoRT ---> Chemo ---> Surg.
    I am used to 2) Chemo ---> ChemoRT (wait 6-8 wks) ---> Surg.

    The CR surgeons claim that Annals of Surgery article says #1 is better bc of higher pCR in that cohort "about 11% more pCR in approach #1"...blah blah blah.

    They pointed me to this article in Annals of Surg (BTW, primary author is a colorectal surg fellow, no radonc
    authors in the paper, and this is the usual "infamous" NCDB study).

    Primary author is Goffredo, Paolo et al (Division of Colon & Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis, MN)...

    I have never done #1 bc of long interval between RT and Surg and risks of increased fibrosis.
    I do not have access to Annals of Surg.
    Does anyone know the pros and cons (any data on the observation study) for approach #1?

    Thanks...

    PS: Maybe the surgeons quoted the wrong paper but he mentioned Annals of Surg a few months ago.
     
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    jondunn

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      lol you are so lucky to have this conversation with your surgeons

      some surgeons ask you if you're referring to Bugs Bunny when you bring up TNT!
       
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      communitydoc13

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        This is quite like the OPRA protocol from MSKCC. Better pCr and higher likelihood of organ preservation. If your surgeons are comfortable go for it. F/u should be strictly protocolized with sigmoidoscopy and MRI between chemorads and chemo, after chemo and at scheduled intervals. (Some recurrences/residuals are appreciated on MRI not exam).

        I would follow OPRA protocol schedule and you can dose escalate within reason to primary tumor.
         
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        ramsesthenice

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          At tumor board today, 65 yo man with T3N1 rectal cancer.
          Low-lying tumor encroaching on the sphincter.

          Colorectal surgeon argues for 1) ChemoRT ---> Chemo ---> Surg.
          I am used to 2) Chemo ---> ChemoRT (wait 6-8 wks) ---> Surg.

          The CR surgeons claim that Annals of Surgery article says #1 is better bc of higher pCR in that cohort "about 11% more pCR in approach #1"...blah blah blah.

          They pointed me to this article in Annals of Surg (BTW, primary author is a colorectal surg fellow, no radonc
          authors in the paper, and this is the usual "infamous" NCDB study).

          Primary author is Goffredo, Paolo et al (Division of Colon & Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis, MN)...

          I have never done #1 bc of long interval between RT and Surg and risks of increased fibrosis.
          I do not have access to Annals of Surg.
          Does anyone know the pros and cons (any data on the observation study) for approach #1?

          Thanks...

          PS: Maybe the surgeons quoted the wrong paper but he mentioned Annals of Surg a few months ago.
          The better data is the prelim data from the OPRA trial presented last year at ASCO. Organ preservation was better in the upfront CRT arm than the upfront chemo arm. If the goal is organ preservation it’s the preferred sequence now. We do it all the time. No worse surgical complications waiting. And don’t forget the RAPIDO trial. It was SC but still shows radiation followed by chemo is a fine sequence.
           
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          Radonc90

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            Thanks for all the replies...

            Do you have link to OPRA data of the 2 approaches #1 and #2.
            Or the data from ASCO last year?

            PS: Haha...I am on equal footing with the surgeons bc I trained them.
             
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            TheWallnerus

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              At tumor board today, 65 yo man with T3N1 rectal cancer.
              Low-lying tumor encroaching on the sphincter.

              Colorectal surgeon argues for 1) ChemoRT ---> Chemo ---> Surg.
              I am used to 2) Chemo ---> ChemoRT (wait 6-8 wks) ---> Surg.

              The CR surgeons claim that Annals of Surgery article says #1 is better bc of higher pCR in that cohort "about 11% more pCR in approach #1"...blah blah blah.

              They pointed me to this article in Annals of Surg (BTW, primary author is a colorectal surg fellow, no radonc
              authors in the paper, and this is the usual "infamous" NCDB study).

              Primary author is Goffredo, Paolo et al (Division of Colon & Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis, MN)...

              I have never done #1 bc of long interval between RT and Surg and risks of increased fibrosis.
              I do not have access to Annals of Surg.
              Does anyone know the pros and cons (any data on the observation study) for approach #1?

              Thanks...

              PS: Maybe the surgeons quoted the wrong paper but he mentioned Annals of Surg a few months ago.
              Option "1" is the "top line" (FWIW) NCCN rec now, and it is broadly what the best arm in RAPIDO followed I think. I kind of like option "1" versus getting them after the chemo. But no one TRULY knows if option 1 or 2 is best. (In RAPIDO, pCR rate was better vs *chemoRT* then surgery). But if I tried to perfectly follow RAPIDO style, that's more #1.

              zK88oLk.png
               
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              Radonc90

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                I work with different medonc's, and very often I get the pts after the medonc's have given the chemo.
                This happens bc the surgeons usually refer to medonc first.
                 
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                TheWallnerus

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                  I work with different medonc's, and very often I get the pts after the medonc's have given the chemo.
                  This happens bc the surgeons usually refer to medonc first.
                  Me too. Then your hands are tied. And usually "Hey, you know you should have done this differently" doesn't go over the greatest
                   
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                  medgator

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                    I work with different medonc's, and very often I get the pts after the medonc's have given the chemo.
                    This happens bc the surgeons usually refer to medonc first.
                    We will sometimes start with the chemoRT first if pt has a bulky/symptomatic tumor. Med oncs are usually pretty reasonable about it
                     

                    ramsesthenice

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                      Option "1" is the "top line" (FWIW) NCCN rec now, and it is broadly what the best arm in RAPIDO followed I think. I kind of like option "1" versus getting them after the chemo. But no one TRULY knows if option 1 or 2 is best. (In RAPIDO, pCR rate was better vs *chemoRT* then surgery). But if I tried to perfectly follow RAPIDO style, that's more #1.

                      zK88oLk.png
                      The results are still maturing but OPRA was a trial randomizing people to TNT with upfront chemoRT vs upfront chemo. It was literally a sequencing trial. cCR and OP were higher with upfront chemorads than upfront chemo. There actually is equipoise supporting this particular sequence.


                      I agree that RAPIDO does not help with sequencing. But it does show that delaying surgery for chemo after RT is feasible.
                       
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                      CaesarRO

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                        There was an interesting discussion (I think on Twitter) suggesting that the reason we don't see fibrosis after CRT up front and Surgery is because of the intervening chemo. Implication being the usual time-from-RT-to-surgery concerns don't apply.

                        Found the actual multi-institution Phase 2 data showing this concept: Study

                        Findings from this trial show that delivering systemic chemotherapy after chemoradiation and delaying total mesorectal excision to up to 20 weeks after completion of chemoradiation does not increase the surgical technical difficulty or the risk of surgical complications—a concern that, to the best of our knowledge, has not been addressed in a prospective manner until this point.32,33
                         
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                        ramsesthenice

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                          I work with different medonc's, and very often I get the pts after the medonc's have given the chemo.
                          This happens bc the surgeons usually refer to medonc first.
                          And this is precisely why they send them to me first. They trust me not to go rogue and not to start treating someone until we have all seen them and discussed the case.

                          Our surgeons are 100% in on w/w for low and mid rectal tumors achieving a cCR. They are still hesitant to consider organ preservation for rectosigmoid tumors because they are worried that local recurrences may not be anatomically confined like a true rectal cancer and they worry they will lose salvage.

                          Our practice is to do TNT for pretty much everyone. Upfront RT for most low vs and mid tumors. If they have a high tumor with a lot of nodes we usually go with chemo first. Since the only apparent benefit is preservation rates, sequence probably doesn’t matter much for high tumors (assuming w/w is off the table).
                           
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                          ramsesthenice

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                            Next time I have to have this argument in tumor board I'm just going to print off this thread as a handout.
                            Data can be a beautiful thing. You could make logical arguments to support upfront chemo or upfront chemoradiation but at the end of the day only one can be right (for the general population at least). Compare the nature of this discussion with say the Protons CMS thread which is up to page 13 or something crazy like that.
                             
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                            ramsesthenice

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                              Feels like with N1 disease vs N0, the whole body is at higher risk for harboring subclinical mets, which in turn, makes starting with chemo more reasonable in my mind. Unless the patient is symptomatic.
                              Except that the randomized evidence we have suggests starting chemo now vs 8 weeks from now (after CRT) has no effect on MFS. This was the exact argument that oncology use to use to suggest we should always do upfront chemo. Overall the data suggests that TNT may improve distant disease control compared to outback chemo (conventional sequencing) but there is no evidence that starting chemo sooner within the context of TNT has any impact on distant disease control. If there is a plan to attempt organ preservation, should consider upfront chemoradiation.

                              Now this is not to say that the micrometastatic disease control issue is settled. Just suggesting getting to FOLFOX right away appears to have limited return. Clearly need to do better for some folks. The data for FOLFOXIRI for high risk people is looking pretty good and it is recommended for T4N+ disease by the most recent guidelines. Im betting before long we are doing TNT with FOLFOXIRI instead of FOLFOX for most fit patients (at least with N2 disease).
                               
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                              evilbooyaa

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                                If doing FOLFOXIRI (reasonable IMO based on PRODIGE data), do chemo first because that's how the trial supporting its use did it and we don't know if long course chemoRT affects ability to receive full dose FOLFOXIRI - DEFINE_ME

                                If doing FOLFOX/XelOx, then would do CRT first MOST of the time as per OPRA showing improvement in organ preservation with equivanelt MFS/OS in patients receiving CRT followed by chemotherapy: https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.4008

                                The German Rectal cancer group (yes the same one who gave us 13% vs 8%) also suggest from their new randomized phase II that CRT --> Chemo has a numerically higher rate of pCR than Chemo --> CRT, so in their phase III that will compare TNT to CRT --> Surgery --> Chemo, they will be doing CRT --> Chemo: https://ascopubs.org/doi/10.1200/JCO.19.00308?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed

                                So CRT --> Chemo has better organ preservation rates (important in this patient with tumor extending to sphincter) per OPRA and better pCR as per German Rectal Cancer group in resected patients, with equivalent MFS and OS.

                                Only times I would advocate for chemo first in rectal cancer as part of TNT in someone receiving FOLFOX is if the patient had N2 disease, or had nodal disease extending to say the high external/internal iliac LNs or the common iliac LNs. While I think the OPRA data is compelling, some others do not.
                                 
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                                Radonc90

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                                  Anyway, hot off the press (JAMA Oncology).
                                  I have to laugh when I saw this "Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant
                                  therapy in both groups".

                                  With many pts on the research protocol, how the heck did they manage to do the TME exactly on day 123? German precision!!!

                                  Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer
                                  Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial


                                   
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                                  Radonc90

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                                    Does anyone here have access to JAMA Oncology?
                                    I could not find the exact pCR in each arm bc I do not have access to JAMA Oncology.

                                    Also, does anyone know the permanent colostomy or APR rates in each arm?

                                    OTOH, what you see is a difference in pCR, which is kind of a "feel-good" factor...you have a pCR in the specimen (TME)
                                    that yuou removed. But the BIG picture (local recurrence, OS and DFS) is the same for both arms.

                                    So, why do we care about pCR? Just a philosophical question...
                                     

                                    jondunn

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                                      I agree, it doesn’t really matter. It must just be a result of longer time from radiation to surgery in the radiation first arm.

                                      There may be other data supporting radiation first in the sequence but the higher pcr rates here aren’t really a reason to favor it, IMO
                                       

                                      BobbyHeenan

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                                        Does anyone here have access to JAMA Oncology?
                                        I could not find the exact pCR in each arm bc I do not have access to JAMA Oncology.

                                        Also, does anyone know the permanent colostomy or APR rates in each arm?

                                        OTOH, what you see is a difference in pCR, which is kind of a "feel-good" factor...you have a pCR in the specimen (TME)
                                        that yuou removed. But the BIG picture (local recurrence, OS and DFS) is the same for both arms.

                                        So, why do we care about pCR? Just a philosophical question...

                                        I think if you have the potential for watch and wait (and consider avoiding surgery), then pCR is a reasonable variable to look at. At our rectal program we have a very progressive surg onc who is open to omitting surgery with an established watch and wait paradigm (this has actually been a surgeon led initiative. We have ACS Rectal Center of Excellence designation), so in theory a higher pCR may mean more successful non operative mgmt. Though this is certainly not definitive with the data from these trials, it's something to consider.

                                        If everyone 100% of the time goes to surgery then I think you're correct, if DFS and OS are the same, it's dealer's choice.
                                         
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                                        SubserviantToABR

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                                          Anyway, hot off the press (JAMA Oncology).
                                          I have to laugh when I saw this "Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant
                                          therapy in both groups".

                                          With many pts on the research protocol, how the heck did they manage to do the TME exactly on day 123? German precision!!!

                                          Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer
                                          Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial



                                          I did a quick skim (may have missed it), but the authors mention, repeatedly, that the pCR rate was reported in their initial paper (reference 10), referenced by EB in post 18. I did not see an updated pCR number.
                                          1637760444400.png
                                           

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                                          Mandelin Rain

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                                            I did a quick skim (may have missed it), but the authors mention, repeatedly, that the pCR rate was reported in their initial paper (reference 10), referenced by EB in post 18. I did not see an updated pCR number.
                                            View attachment 346070
                                            The pCR rate is the pCR rate. It can't really be updated.
                                             
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                                            evilbooyaa

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                                              Does anyone here have access to JAMA Oncology?
                                              I could not find the exact pCR in each arm bc I do not have access to JAMA Oncology.

                                              Also, does anyone know the permanent colostomy or APR rates in each arm?

                                              OTOH, what you see is a difference in pCR, which is kind of a "feel-good" factor...you have a pCR in the specimen (TME)
                                              that yuou removed. But the BIG picture (local recurrence, OS and DFS) is the same for both arms.

                                              So, why do we care about pCR? Just a philosophical question...

                                              Because the goal is to move to a scenario where people don't need surgery, and something that improves pCR is likely to improve outcomes in the CCR data.

                                              Although not 100% at the normal surgical timeline, because as we all know for anal cancer, up to 26 weeks of no touchy as long as it's still shrinking. That's why cCR is ~50% and ~80% of those can avoid surgery at 2 years with W&W, that works out to essentially a 40% 'pCR' rate with TNT, higher than what any trial will report.
                                               

                                              jondunn

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                                                something that improves pCR is likely to improve outcomes in the CCR data.

                                                all things being equal, yes of course

                                                however, if it is because radiation came first in the sequence, and thus there was more time before surgery, and thus more time for tumor kill, then this trial does not really answer the question nor support the notion that chemoRT should come before chemo in a watch and wait situation.
                                                 

                                                Radonc90

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                                                  I finally had the manuscript of JAMA Oncology.
                                                  The pCR rates were not mentioned in the 2021 article bc they were already reported in this link from 2019:

                                                  "...A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B (P < .001), but not group A (P = .210), fulfilled the predefined statistical hypothesis..."

                                                  So, approx. 8% difference in pCR rates between 2 arms.

                                                  As others said above, this is only important if the pt refuses surgery and pursues observation approach.

                                                  PS: On a related note, a small portion of these pts do not require systemic chemo, such as pure T3N0, I wonder if the usual
                                                  time of 6-8 wks between the completion of ChemoRT (or RT alone à la Swedish 5 fractions thingy) and surgery is good enough.
                                                  Maybe there is increased pCR rate if the surgeon waits longer such as 12-16 weeks???
                                                   
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                                                  Palex80

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                                                    PS: On a related note, a small portion of these pts do not require systemic chemo, such as pure T3N0, I wonder if the usual
                                                    time of 6-8 wks between the completion of ChemoRT (or RT alone à la Swedish 5 fractions thingy) and surgery is good enough.
                                                    Maybe there is increased pCR rate if the surgeon waits longer such as 12-16 weeks???
                                                    This is indeed a matter of debate and I think we have discussed here in the past. Retrospective series seem to point out that this may be truth but there's also a randomized French trial which was negative.
                                                     

                                                    Krukenberg

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                                                      I finally had the manuscript of JAMA Oncology.
                                                      The pCR rates were not mentioned in the 2021 article bc they were already reported in this link from 2019:

                                                      "...A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B (P < .001), but not group A (P = .210), fulfilled the predefined statistical hypothesis..."

                                                      So, approx. 8% difference in pCR rates between 2 arms.

                                                      As others said above, this is only important if the pt refuses surgery and pursues observation approach.
                                                      this. Unless the patient wants to do watch and wait, I’d rather the chemo go first. I like to get a post-chemo MRI to shrink boost volumes.
                                                       

                                                      jondunn

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                                                        this. Unless the patient wants to do watch and wait, I’d rather the chemo go first. I like to get a post-chemo MRI to shrink boost volumes.
                                                        chemo first has a lot of advantages. starts immediately. by the time the patient comes to you for chemoRT, they already have gotten symptomatic relief from the chemo from their tumor in some cases (if they had symptoms to begin with)

                                                        again -in my opinion this should be the same thing with watch and wait. we do not know that radiation first is better for organ preservation. the radiation first arm had more time to work before surgery than when given closer to surgery in the chemo first arm. it should not be surprising that there are higher pcr rates when radiation comes first.
                                                         
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