Complex Anal Case

[ramsesthenice]

Love to know what others think. Got a lady with extramammary pagets of the perineal area with an associated invasive adenocarcinoma involving the entire anal canal and peri-anal soft tissues with extension to the left labia and multiple 1/5-3 cm bilateral inguinal nodes with no distant disease. These tend to be bad actors. Planning chemo, preop chemorads and APR with plastics for recon. I am curious to know what people would do with the inguinals. This is not your typical SCC of the anal canal. I could try to treat the entire chain to 45-50 and then boost the gross nodes to the mid 60s. My concern is that even with that she would have a high risk of residual viable disease and wound healing with salvage surgery in the groin tends to be disastrous after boost dosing. I am inclined to just stop at 45 and have surgery do a planned inguinal femoral dissection. Med Onc recommended upfront chemo and I was immediately on board because seeing how she responds might help us (myself and surgery) decide. Thoughts?

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[RADONC4285]

Great plan. 45 Gy to inguinals makes sense to minimize risk of complications. These nodes will come out with surgery so no need to boost

 

[RADONC4285]

Great plan. 45 Gyto inguinals makes sense to minimize risk of complications. These nodes will come out with surgery so no need to boost. Would keep a very close eye during chemo. Clearly she has bad dz and don't want it to progress through chemo and extend more. Slightest sign of progression, jump in with RT

 

[seper]

Great plan. 45 Gy to inguinals makes sense to minimize risk of complications. These nodes will come out with surgery so no need to boost

In my experience, colorectal surgeons do not know how to do inguinal nodes and try to avoid them whenever possible. So, I'd boost

 

[evilbooyaa]

In my experience, colorectal surgeons do not know how to do inguinal nodes and try to avoid them whenever possible. So, I'd boost

Might be a joint case with gyn-onc given labial extension, and those folks definitely know how to do inguinofemoral dissection.

I'm somewhat confused as to chemo first in this situation. It's mostly adenocarcinoma right? I suppose yeah you're treating it kinda like TNT for rectal adeno but I'm not really confident it's the same actor given the extramammary paget's. FOLFOX as neoadjuvant chemo?

To me this is like induction chemo for H&N. If she does respond, great, volumes remain the same and doses remain the same - not a huge benefit to the patient. If she doesn't respond, chemoRT just became more toxic and maybe she is now incurable. I get it for like extensive nodal disease (like if she had external/internal iliac LNs or common iliac adenopathy) to try to initially prevent distant mets, I just don't get it for this clinical situation.

I'd try to get some form of imaging in the treatment planning position prior to chemo if feasible, maybe a PET in treatment planning position (frog leg like a vulva case would prob be my preference) b/c if this stuff does shrink you're going to have a rough time trying to identify where peri-anal soft tissue disease stopped, putting you at risk for missing.

I see both arguments but if you can get gyn-onc involved in surgery and get them to definitely do inguionfemoral dissection, then IMO OK to stop at 45. If you can't get commitment to IFLND then you kinda *have* to boost.

 

[ramsesthenice]

In my experience, colorectal surgeons do not know how to do inguinal nodes and try to avoid them whenever possible. So, I'd boost

Totally agree with the thought. Fortunately, our surgeons know their limits and this will be a joint operation with Gyn Onc. Same for me. The inguino-femoral suggestion came from me, not surgery. This is a great case of how as a rad onc we can leverage our general oncology knowledge (since I also do Gyn unlike anyone else in the room). Glad to know at least some people don't think its crazy

To me this is like induction chemo for H&N. If she does respond, great, volumes remain the same and doses remain the same - not a huge benefit to the patient. If she doesn't respond, chemoRT just became more toxic and maybe she is now incurable. I get it for like extensive nodal disease (like if she had external/internal iliac LNs or common iliac adenopathy) to try to initially prevent distant mets, I just don't get it for this clinical situation.

I didn't mention it but she does have pelvic nodes too. I actually don't buy the preventing distant mets argument though. Until someone can show me data in a solid tumor that induction chemo offers better long-term distant control than adjuvant chemo I will continue to believe that its a biology issue. Patients with chemo responsive micrometastatic disease probably respond as well now as they will in a couple months.

I think it could significantly change her care particularly as it pertains to surgery. If she responded very well, I might feel better about boosting and helping her avoid an inguinal dissection. RT alone would be less morbid. Second, downstaging her primary tumor could also be a big deal. This is going to be a very morbid operation depending on the extent of anterior structure involvement (which is unknown at this point). I get what you are saying and 9/10 times I am quick to shoot down evidence-free induction chemo. In this case I am personally ok with it.

 

[evilbooyaa]

I didn't mention it but she does have pelvic nodes too. I actually don't buy the preventing distant mets argument though. Until someone can show me data in a solid tumor that induction chemo offers better long-term distant control than adjuvant chemo I will continue to believe that its a biology issue. Patients with chemo responsive micrometastatic disease probably respond as well now as they will in a couple months.

I think it could significantly change her care particularly as it pertains to surgery. If she responded very well, I might feel better about boosting and helping her avoid an inguinal dissection. RT alone would be less morbid. Second, downstaging her primary tumor could also be a big deal. This is going to be a very morbid operation depending on the extent of anterior structure involvement (which is unknown at this point). I get what you are saying and 9/10 times I am quick to shoot down evidence-free induction chemo. In this case I am personally ok with it.

I suppose I get the boosting argument but I wouldn't let chemo response change whether I boosted a LN to gross disease dose or not... just like we don't turn down the dose in H&N with good response to induction chemo.

I get the benefit of chemo prior to surgery in terms of a less morbid surgical resection. With TNT for rectal cancer (which is basically what you're treating this as given adenocarcinoma histology?) I generally prefer chemoRT first then chemo then surgery as my sequence. However, with pelvic nodes I think chemo first is reasonable - all it takes is one patient to develop metastatic disease during chemoRT for chemo and surgery to then push for chemo first in every. single. patient.

I suppose at end of day we're now reaching a similar conclusion (that chemo first is reasonable in this case) although our justifications for doing so are slightly different.

 

[ramsesthenice]

I suppose I get the boosting argument but I wouldn't let chemo response change whether I boosted a LN to gross disease dose or not... just like we don't turn down the dose in H&N with good response to induction chemo.

Only considering radiation you are right. But in the preoperative setting for most diseases we rarely if ever do substantial boosts to resectable gross nodes. If there is a planned dissection afterwards the relevance to definitive diseases with good local control becomes less relevant. No question if the patient or surgery declined to dissect I would boost the heck out of those things regardless of response to chemo.

 

[scarbrtj]

Love to know what others think. Got a lady with extramammary pagets of the perineal area with an associated invasive adenocarcinoma involving the entire anal canal and peri-anal soft tissues with extension to the left labia and multiple 1/5-3 cm bilateral inguinal nodes with no distant disease. These tend to be bad actors. Planning chemo, preop chemorads and APR with plastics for recon. I am curious to know what people would do with the inguinals. This is not your typical SCC of the anal canal. I could try to treat the entire chain to 45-50 and then boost the gross nodes to the mid 60s. My concern is that even with that she would have a high risk of residual viable disease and wound healing with salvage surgery in the groin tends to be disastrous after boost dosing. I am inclined to just stop at 45 and have surgery do a planned inguinal femoral dissection. Med Onc recommended upfront chemo and I was immediately on board because seeing how she responds might help us (myself and surgery) decide. Thoughts?

Just out of curiosity, what upfront chemo they choosing. And what will be your plan if at 45 Gy the anal adenoCA in the inguinal nodes hasn't responded very much...

 

[ramsesthenice]

Just out of curiosity, what upfront chemo they choosing. And what will be your plan if at 45 Gy the anal adenoCA in the inguinal nodes hasn't responded very much...

Good question. They have not formally decided. FOLFOX would be the typical choice for garden variety adenocarcinomas but also considering carbo/tax given the associated Pagets and different biology.

In my mind not responding much to 45 Gy would make the decision easier. I would send for surgery. Would be hard for me to think giving another 20 Gy would have a high chance of succeeding. I think the opposite situation would require more thought. If they appear to be responding well then I would feel more confident that definitive dosing has a reasonable chance of control with less toxicity than a full dissection. The luxury that I have is that I can make that call. Even if the plan heading into RT is an outback resection if I opted to boost instead of resecting because of a good response I would get surgical buy in. The surgeons where I trained were nice, but there is no way rad onc would be making a call like that.

No doubt this is a bad problem and I think RT all the way or preop with a planned dissection are both reasonable options. I ran this buy the group because I have never recommended a planned IF dissection after RT and I wanted to see if people thought I was crazy. The only thing I know I don't want to do is full dose followed by surgery. Anyone who has ever seen wound healing issues in a previously treated groin knows what I am concerned about.

 

[RadOncDoc21]

Sounds like a very tough case and I agree with your approach. I don’t think there is a wrong choice here as she has very aggressive disease. I do like 45 Gy in this situation because it does leave some room for a possible boost in the future while also taking care of microscopic disease. You have the surgery to back you as well along with the chemo.

Even if it may not be enough, you would have at the very least spared her some toxicity while potentially provide possible durable local control for palliation.

 

[Palex80]

This is a horrible case.

Although the approach you describe is certainly an "all-in" approach and is basically a TNT, I would like to suggest to reverse the sequence and question if she should get all that surgery in any case. I believe you are running a very high risk of maximum toxicity if you do all that. Wound healing, permanent lympedema, lymph fistula, etc...

How about not giving chemo first but doing radiochemotherapy with 5FU/Capecitabine, then going to chemotherapy (FOLFOX) and then considering surgery. And how about pushing the radiation dose as far as you can, hoping to control the macroscopic disease.

We know that sequencing radiochemo before chemo may show a benefit than vice-versa in the context of TNT, based on the MSKCC-trial that was shown on ASCO last year. They demonstrated higher rates of skipping surgery with that sequence. And I presume toxicity may be better, bearing in mind the extensive surgery which you suggested, if there's a longer interval between radiochemotherapy and surgery.

 

[ramsesthenice]

This is a horrible case.

Although the approach you describe is certainly an "all-in" approach and is basically a TNT, I would like to suggest to reverse the sequence and question if she should get all that surgery in any case. I believe you are running a very high risk of maximum toxicity if you do all that. Wound healing, permanent lympedema, lymph fistula, etc...

How about not giving chemo first but doing radiochemotherapy with 5FU/Capecitabine, then going to chemotherapy (FOLFOX) and the considering surgery. And how about pushing the radiation dose as far as you can, hoping to control the macroscopic disease.

We know that sequencing radiochemo before chemo may show a benefit than vice-versa in the context of TNT, based on the MSKCC-trial that was shown on ASCO last year. They demonstrated higher rates of skipping surgery with that sequence. And I presume toxicity may be better, bearing in mind the extensive surgery which you suggested, if there's a longer interval between radiochemotherapy and surgery.

I got a heads up about her from surgery (who first saw her at one of our regional centers) and that was my initial thought as well. Then I got the images and examined her. This thing is huge and her chances of having any meaningful function are slim to none. You could argue to use TNT to try to avoid a huge surgery for morbidity reasons but she would still need a permanent colostomy for functional reasons so I wouldn't look at this from a traditional organ preservation perspective.

In general, I 100% agree with your thoughts on sequencing for TNT and fortunately so do our med oncs now. They actually believe the OPRA study and (finally) our preferred sequence is CRT -> chemo when organ preservation is the goal. It settled a lot of long running debates and it felt good to be on the winning side of that one

I guess I view the toxicity risk for this case as follows: primary CRT (no surgery) < preop RT + planned surgery < maximal radiation + salvage surgery. Option 1 is the best case scenario but if it doesn't pan out you move straight to option 3. Anyone have a good psychic???

 

[FrostyHammer]

No right or wrong answer, but tbh I would treat this as TNT for rectal - Palex, as per usual, is absolutely right on point. Planned surgery obviously, but giving him TNT (chemoRT first vs chemo first - agree with the European trial in JCO and the ASCO trial from MSKCC, but it's still a choice since idk the medical rationale why chemoRT first was better in both those trials) would at least mean earlier delivery of full-dose chemo which is better to address the likely micromets in this patient. 100% agree that organ preservation is not possible, but TNT is worthwhile in nearly all patients because of DFS improvements (for rectal) from earlier delivery of full chemo, not necessarily only for organ preservation. I think a major misconception with med oncs (and rad oncs) that we need to teach others is that TNT is not solely for the purpose of organ preservation, it's about much more than that for the patients whose organs likely won't be preservable.

 

[ramsesthenice]

No right or wrong answer, but tbh I would treat this as TNT for rectal - Palex, as per usual, is absolutely right on point. Planned surgery obviously, but giving him TNT (chemoRT first vs chemo first - agree with the European trial in JCO and the ASCO trial from MSKCC, but it's still a choice since idk the medical rationale why chemoRT first was better in both those trials) would at least mean earlier delivery of full-dose chemo which is better to address the likely micromets in this patient. 100% agree that organ preservation is not possible, but TNT is worthwhile in nearly all patients because of DFS improvements (for rectal) from earlier delivery of full chemo, not necessarily only for organ preservation. I think a major misconception with med oncs (and rad oncs) that we need to teach others is that TNT is not solely for the purpose of organ preservation, it's about much more than that for the patients whose organs likely won't be preservable.

Thanks all. I’m sold on conventional TNT with no crazy boost and planned surgery. It would be nice to be able to avoid surgery but looking at it I just don’t think the chances are great and this approach will probably go better than going through a salvage surgery later when everything is fibrotic. Appreciate everyone’s input.

 

[evilbooyaa]

No right or wrong answer, but tbh I would treat this as TNT for rectal - Palex, as per usual, is absolutely right on point. Planned surgery obviously, but giving him TNT (chemoRT first vs chemo first - agree with the European trial in JCO and the ASCO trial from MSKCC, but it's still a choice since idk the medical rationale why chemoRT first was better in both those trials) would at least mean earlier delivery of full-dose chemo which is better to address the likely micromets in this patient. 100% agree that organ preservation is not possible, but TNT is worthwhile in nearly all patients because of DFS improvements (for rectal) from earlier delivery of full chemo, not necessarily only for organ preservation. I think a major misconception with med oncs (and rad oncs) that we need to teach others is that TNT is not solely for the purpose of organ preservation, it's about much more than that for the patients whose organs likely won't be preservable.

Is there evidence for the bolded in the long-course setting? I'm aware of RAPIDO results but would love to know of evidence for this long-course. I remember the MSKCC series showed earlier ostomy rates but I thought DFS was same between the groups?

 

[RO5231]

Is there evidence for the bolded in the long-course setting? I'm aware of RAPIDO results but would love to know of evidence for this long-course. I remember the MSKCC series showed earlier ostomy rates but I thought DFS was same between the groups?

PRODIGE 23 was presented at ASCO last year and showed improved DFS with TNT (long course chemoRT) vs long course chemoRT with adjuvant chemo.

https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.4007

 

[ramsesthenice]

Is there evidence for the bolded in the long-course setting? I'm aware of RAPIDO results but would love to know of evidence for this long-course. I remember the MSKCC series showed earlier ostomy rates but I thought DFS was same between the groups?

PRODIGE 23 was presented at ASCO last year and showed improved DFS with TNT (long course chemoRT) vs long course chemoRT with adjuvant chemo.

https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.4007

I think the answer is up in the air. As you said, MSKCC experience doesn't support improved survival. PRODIGE and RAPIDO are encouraging but there is also the original Spanish trial which was negative (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). Granted, the latter was nTNT and not full TNT but there wasn't even a whiff of a difference. I think it is still a stretch at this point to say that TNT is definitely associated with improved survival thought it certainly could be. What is not a stretch though is that is is better tolerated and associated with better clinical pathologic responses which, for most cases (not this particular one) could translate into markedly better long term functional outcomes for patients avoiding surgery. Improved survival would be the cherry on top of an already very delectable desert.

 

[evilbooyaa]

PRODIGE 23 was presented at ASCO last year and showed improved DFS with TNT (long course chemoRT) vs long course chemoRT with adjuvant chemo.

https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.4007

With neoadjuvant FOLFIRINOX, which is not SOC in rectal cancer, compared to adjuvant FOLFOX/Xeloda. Also, FOLFIRINOX arm received more scheduled chemotherapy than SOC arm (6 + 3 months vs 6 months). Would love an apples to apples comparison, but this is better than nothing I suppose, thanks.

And ramses, I agree with TNT being my preferred SOC, just looking for additional data that makes it the ONLY option in this clinical scenario to shove down the throat of others who disagree with me.

 

[FrostyHammer]

Is there evidence for the bolded in the long-course setting? I'm aware of RAPIDO results but would love to know of evidence for this long-course. I remember the MSKCC series showed earlier ostomy rates but I thought DFS was same between the groups?

Yes. both RAPIDO and PRODIGE trials. One used short course with FOLFOX, the other with long course and FOLFIRINOX. Both similar conclusions.

 

[FrostyHammer]

I think the answer is up in the air. As you said, MSKCC experience doesn't support improved survival. PRODIGE and RAPIDO are encouraging but there is also the original Spanish trial which was negative (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). Granted, the latter was nTNT and not full TNT but there wasn't even a whiff of a difference. I think it is still a stretch at this point to say that TNT is definitely associated with improved survival thought it certainly could be. What is not a stretch though is that is is better tolerated and associated with better clinical pathologic responses which, for most cases (not this particular one) could translate into markedly better long term functional outcomes for patients avoiding surgery. Improved survival would be the cherry on top of an already very delectable desert.

I do not trust that trial, which was 5-10 times smaller than the 2 new trials. BTW, RAPIDO is published in this month's issue of Lancet or Lancet Oncology.

 

[ramsesthenice]

With neoadjuvant FOLFIRINOX, which is not SOC in rectal cancer, compared to adjuvant FOLFOX/Xeloda. Also, FOLFIRINOX arm received more scheduled chemotherapy than SOC arm (6 + 3 months vs 6 months). Would love an apples to apples comparison, but this is better than nothing I suppose, thanks.

And ramses, I agree with TNT being my preferred SOC, just looking for additional data that makes it the ONLY option in this clinical scenario to shove down the throat of others who disagree with me.

I do not trust that trial, which was 5-10 times smaller than the 2 new trials. BTW, RAPIDO is published in this month's issue of Lancet or Lancet Oncology.

Except that as Evil pointed out its not really clear how to apply PRODIGE to patients getting SOC FOLFOX. Intensified regimens like FLOT and FOLFIRINOX smoke FOLFOX in diseases like esophageal pancreatic adenocarcinomas in terms of distant disease control. Can you really look at PRODIGE and say that we should do TNT with FOLFOX because it improves survival? I personally don't think so. RAPIDO is more relevant and given that there are essentially no differences in oncologic outcomes between standard short and long course RT I don't think the use of short course in that trial is problematic. Again, this is all academic semantics. TNT has a number of clear cut advantages and is a preferred SOC regardless of effects on survival.

FWIW, I also strongly suspect that we will eventually move towards FOLFIRINOX or FLOT type regimens in the TNT setting given their superiority in other GI cancers so I don't think the use of FOLFIRINOX in PRODIGE is in anyway problematic. It lends credence to my long-held suspicion this will be the way to go

 

[FrostyHammer]

Except that as Evil pointed out its not really clear how to apply PRODIGE to patients getting SOC FOLFOX. Intensified regimens like FLOT and FOLFIRINOX smoke FOLFOX in diseases like esophageal pancreatic adenocarcinomas in terms of distant disease control. Can you really look at PRODIGE and say that we should do TNT with FOLFOX because it improves survival? I personally don't think so. RAPIDO is more relevant and given that there are essentially no differences in oncologic outcomes between standard short and long course RT I don't think the use of short course in that trial is problematic. Again, this is all academic semantics. TNT has a number of clear cut advantages and is a preferred SOC regardless of effects on survival.

FWIW, I also strongly suspect that we will eventually move towards FOLFIRINOX or FLOT type regimens in the TNT setting given their superiority in other GI cancers so I don't think the use of FOLFIRINOX in PRODIGE is in anyway problematic. It lends credence to my long-held suspicion this will be the way to go

I agree. There are a lot of moving parts in terms of TNT - what chemotherapy drugs, short vs long course RT, sequencing, etc. But the point still remains that TNT in itself, as a concept and paradigm, should be done. The rest is just details for now with predictable variability for now, but TBD on the details as more data comes out in the future.

 

[Palex80]

FWIW, I also strongly suspect that we will eventually move towards FOLFIRINOX or FLOT type regimens in the TNT setting given their superiority in other GI cancers so I don't think the use of FOLFIRINOX in PRODIGE is in anyway problematic. It lends credence to my long-held suspicion this will be the way to go

There is one issue left open, however:
We will need a "middle way" between 5FU-based CRT and FOLFIRINOX + RT for those patient that should still get some TNT but will no tolerate FOLFIRINOX. FOLFIRINOX is not doable in all patients.

 

[ramsesthenice]

There is one issue left open, however:
We will need a "middle way" between 5FU-based CRT and FOLFIRINOX + RT for those patient that should still get some TNT but will no tolerate FOLFIRINOX. FOLFIRINOX is not doable in all patients.

I think there are a lot of questions. PRODIGE 23 is encouraging in that is shows a survival benefit and lower distant mets but admittedly the improvements (at least with the early data) look far more incremental than they did with pancreatic and gastric cancers. Its not entirely surprising (they are worse diseases) but still these results look far less game changing than I would have hoped to see given how much more intense the regimen is.

The other question is who does TNT help in terms of survival. RAPIDO (the only trial to show a survival benefit using a FOLFOX regimen) was limited to high risk patients. Is there a survival benefit in more standard risk patients? Does that tell us anything about who we should even consider for something like FOLFIRINOX or FLOT?

We are also going to be victims of our own riches to some extent; at least from an academic perspective. Some of these questions are going to be a lot harder to answer going forward. TNT has so rapidly become a preferred approach given that I suspect randomizations to TNT vs not TNT are going to get a lot harder to accrue. I realize this is like complaining about your wallet being to full of money to close but still.

 

[GI_RadOnc]

I agree with @Palex80; my approach would be neoadjuvant chemoradiation with 5FU; and agree with others to help surgeons along for a 'group resection.' But these patients do not do well, that is for sure. One could also use FOLFOX after the chemoradiation and keep watching it shrink/stabilize prior to the surgery.

As others have noted; I think there is a local control challenge with upfront chemotherapy in gastrointestinal cancer; and I think it has even come up in head and neck cancer? (** going above the clavicles is always frightening for me, this may be fake news!)