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Greetings, everyone. Welcome to another HPV episode on Behind the Knife. This is your HPV team at the MD Anderson Cancer Center in Houston. I'm Anish, a general surgery resident at Stanford and a former T32 fellow at MD Anderson. I'm excited to be joined again by my mentors, Dr. Tim Newhook, the Associate PD of the HPV Fellowship at MD Anderson, and Dr. Jean-Nicolas Botte, the HPV Section Chief at MD Anderson.
Today, we're going to be discussing the treatment sequencing options for patients with synchronous liver metastasis from rectal cancer. Additionally, we'll review a few articles investigating the use of these approaches in the management of patients with synchronous liver metastasis.
So just to start, you know, amongst patients with colorectal cancer who have synchronous liver metastasis, the subgroup who have a primary cancer in the rectum, it's especially challenging compared to right or left colon cancer. Most of these patients would stage for rectal cancer.
have a locally advanced primary tumor that's at risk for local complications that require pelvic radiation, resection, diversion, and they have a higher risk of anastomotic complications that can lead to delays in systemic therapy. making it extremely challenging for these patients. So right now there's three sequencing approaches to treat these patients who have the synchronous liver metastasis in addition to their rectal cancer. Dr. Newhook, do you think you could just talk about these...
three approaches, the classic, combined, and reverse approach. Yeah, sure. Thanks again for another great episode, Anish. It's good to be here again. Obviously, patients who have synchronous disease... There's two sites of disease, both obviously the primary tumor as well as liver metastases. And a lot of the decision-making that goes into it obviously has to take into account the complexity of both locations, obviously.
The classic approach is also called the primary first approach. It's historically been the one that's been used the most frequently. And these patients addressing the primary tumor. first while leaving the liver metastases alone to be treated at a later date and that's why it's called the classic roach. Skip combine and go go to reverse.
the reverse approach or otherwise called the liver first approach is exactly as it sounds and that's when for at least patients who have an otherwise asymptomatic primary tumor or have been prior to being seen been diverted with some form of an ostomy. Is it an appropriate approach to take where we address the liver metastases first and then consider addressing the primary tumor at a later date? In the combined approach, exactly as it seems, those are patients who have...
both their sites of disease, both the liver metastases and the primary tumor address surgically in the same setting. There's obviously a strategy to take care of these patients and all of these approaches are often used in the clinic. We'll get into a little bit further here. why we prefer one over the other. Thanks for that, Dr. Newhook. So, Dr. Pate, I want to ask you, as a trainee, I often think, why don't we just do the combined approach for everyone? I mean, you can just...
treat the liver tumor and the rectal tumor at the same time. That just makes the most sense to me. The reversed approach doesn't seem as intuitive to me. Could you kind of just talk about why we really like the reversed approach and how it came about since it is relatively newer compared to the other two? The reverse approach came about at a time when we started doing more extensive liver surgery for patients, for instance, for the biological corectal liver metastasis.
or we were doing extended liver resections, and we realized that if we added the primary as a combined approach to the resection of the liver metastasis, we had a lot of complications. And that was not favorable at all in these patients because it's a terrible complication when you have either leak and the patient doesn't recover. So as we do it with two-stage hypotectomy, we leak.
kind of segmenting or doing things in sequence to stay on track and avoid major complication in patients who have stage four cancer because it's a catastrophe. In a patient with stage four cancer, if you have a serious complication, a patient do not do well because they have fistula, they have one infection. and they progress they can't get chemotherapy takes them two to three months to recover and you lose the battle so essentially
Gilles Mantat from Geneva, Switzerland, came with this idea to reverse approach. Initially, in his case, it was a small series published in the British Journal of Surgery, about 15, 20 patients. with rectal cancer in who he decided to do. the liver metastasis, the resection of liver metastasis first, followed by the resection of the rectum and that's where the approach started and at the time also we were very focused.
on long duration radiation. So we thought, everyone thought it was very innovative because you essentially take care of the liver disease, then you can give more chemo, then you can... Focus on the primary with abbreviation followed by resection of the primary. Okay, understood. So for the listeners, I think the big thing that Dr. Votay wants to emphasize is that...
It's a catastrophe if these patients suffer major complications from surgery that disturb their therapy, whether it's systemic or another surgical therapy. And that's the benefit kind of the staged approach is rather than trying to push. Two very complex surgeries together that can result in a large complication. You want to stage these operations, whether it's liver first or primary first.
in order to reduce the complication risk so patients continue to get their systemic therapy. And oftentimes the liver-first approach might be more ideal. But we'll get into that more. Thank you guys for that great explanation. Hey, Behind the Knife listeners, it's Kevin here.
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Give Freed AI a shot to help you with your clinic. BTK listeners get 50% off their first month with code BTK50. That's BTK50. Now back to the show. So the first paper that we want to talk about is from the Annals of Search for Oncology in 2017, titled Individualized Treatment Sequencing Selection Contributes to Optimized Survival in Patients with Rectal Cancer and Synchronous Liver Metastasis.
And it's a retrospective analysis of 268 patients with rectal cancer and synchronous liver-only METs who underwent curative intent multimodality therapy between 1999 and 2014. And survival outcomes in these patients were examined across three time periods, an early time period of 1999 to 2003, a middle time period from 2004 to 2008. and a later time period of 2009 to 2014. And so...
In this study, 150 or 56 tons of patients underwent the classic approach or primary tumor resection first, 44 underwent the combined approach, and... The remaining 74%, 27.6% underwent that liver first or the reverse approach. And patient demographic and characteristics were similar amongst the groups with the exception that those who were selected for this reverse approach.
were more likely to have a primary tumor lower in the rectum, and they had significantly more liver disease based on the number of liver meds. Oftentimes, they had a median of three compared to one in the other two groups. a higher incidence of bilobar liver metastasis and larger liver metastasis diagnosis some The big things that came out of this study were that the total number of patients with rectal cancer and liver mets considered eligible for complete resection of all disease.
actually increased over time from the early to the later time period, which is good. And this was despite the fact that we often would be operating on patients with a greater metastatic burden in the liver. Now, amongst patients who completed their treatment sequencing and had resection of all gross disease, The observed five-year overall survival rate rose from 45% in that early period, 1999 to 2003, to 75% in the more recent 2009 to 2014 time period.
And I believe that's actually close to the five-year overall survival at that time for patients who had stage 3 rectal cancer, which is great considering these are all stage 4 patients. And I should note, though, that the five-year survival rates for... All patients who completed treatment were like highest in those who underwent the combined approach.
compared to those who underwent the classic and reverse approach but we should also note that these you know survival rates in the classic income or reverse approach are like 55, 52, 54%, which is still better than the 6% five-year overall survival rate in patients who didn't have complete resection of all gross disease. And like we mentioned before,
patients in the reverse approach often had significantly greater metastatic burden in the liver. So all in all, a lot of progress in terms of treatment of this disease process. Dr. Newhook, you know, what are your kind of interpretations of these results in this paper? Well, thanks for the great summary. And I think we'll get to a more modern version of this paper here in a little bit. But the bottom line is, is this.
For the 30,000 foot view for me, this really shows the evolution of the management of this complex situation in a multidisciplinary fashion. It definitely shows the historical timeline of the role of a liver surgeon in the management of metastatic disease, particularly for rectal cancer. The complexity of the patients that we are considering for surgery and are asked to evaluate for surgery is certainly increasing daily.
and that was definitely seen in this paper despite this with higher disease burden and a more complex at the time at least sequencing decisions the survival significantly increased over time. Now, obviously, there's some significant chemotherapy changes that came about during these different time eras, which is a separate factor for a different day to talk about.
But the bottom line is that we started to address more of the metastatic disease up front and seemingly got better survival. I think this makes intuitive sense. And I wanted to say this from the last point that you made earlier, that... Patients who address their stage four disease first are ones that are better selected for further therapy. Number one.
But also number two, if they didn't have liver metastases, they wouldn't have stage four cancer, right? So focusing on the primary tumor is leaving what is literally driving all of their survival out in the open and vulnerable to progression. The last thing I wanted to say, and we didn't talk about this here, is that I believe that the rates of major complications after rectal cancer surgery, at least during a lot of the early time points in the study, are very, very high.
and puts the patients at significant risk of not achieving systemic control for disease and thus addressing their stage four metastatic cancer. So the reverse approach really fitted nicely in the trend. uh to attacking more complex stage four cancer and the proof is in the pudding so to speak yeah that's a great that's a great point especially regarding the stage four like that this is driving that this liver disease is driving the fact that these patients are stage four
Dr. Voté, what do you have to add, and what do you think is the big take-home that listeners should take away from this paper? Well, I think it shows a trend. I think it shows what we... over the years realized as we did more and more complex cases spacious with more advanced disease more advanced disease in the palace that we couldn't do it all at the same time and there are definitely also
Some low rectal cancers, for instance, you can't do the liver resection with that or major liver resection. It doesn't make sense. We realize also that patients have comorbidities. high DMIs, and it increases the complexity of these procedures. So you want to be careful with these patients. If you look at the Nesquik data, it's very interesting also. There aren't a lot of patients who get combined resects. and these are mainly patients who undergo
partial heterotectomy, small liver surgery. And that's only a subset of patients that does well with the rectal cancer. So you realize that you have to, as I said before, you do separate. the two, or you could do the classic approach. And we saw what the classic approach is doing in some of these patients. These patients have complications from the rectal sort of in and of itself.
And if there is such a complication, you leave the patients that adopt nuboxib vulnerable to progression of the disease because the patients receive no chemotherapy. Young patients get a low end tear resection. and some wound infection, just a simple wound infection. And you are there packing the wound for six, eight weeks. And the patient is off track because the patient is off chemotherapy.
then you reach the opportunity the liver metastasis progressed and the patient becomes unresectable and the cow is out of the barn so the classic approach was no one solution and that's why we started advocating really for either you know combine when indicated and save or Yeah, thank you for that point, Dr. Ray. That's excellent. I think it makes a good transition into the next paper we want to talk about, which Dr. New kind of alluded to, which is more modern data describing...
treatment sequencing, and even the use of the reverse approach in patients with synchronous liver mets from rectal cancer. And so this paper is also published in the Annals of Surgical Oncology. It's from 2023, and it's titled Hepatectomy Before Primary Tumor Resection.
as preferred approach for synchronous liver metastasis from rectal cancer. And so this is a retrospective analysis of 274 patients with rectal cancer liver mets diagnosed before primary tumor resection who underwent a hepatectomy. between January 2004 and April 2021. 141, or about 51%, of these patients underwent the reverse approach. 73, or 27%, underwent the classic approach. And 60, or 22%, underwent the combined approach.
Similar to the prior study we discussed, patients treated with the reverse approach often had more liver mets, larger liver mets, and more extensive liver resection, which is something that Dr. Butte also alluded to, that a lot of the patients who are undergoing these...
Reverse approaches often have more extensive liver disease or get more extensive liver resections. And additionally, we also found in this study that those patients who underwent the reverse approach often have higher or had they had higher preoperative CEA levels. Now, in this study, though, the median survival time of patients who underwent the classic combined and reverse approach were similar at 4.7 years, 5.6 years, and 4.9 years, respectively.
and furthermore in the reverse approach the median overall survival was actually nearly 14 years in the 91 patients who completed treatment sequencing. Meaning that they underwent both that hepatic resection and then the primary tumor resection. While it was only 2.2 years in the 50 patients who did not complete treatment approach or who did not undergo.
primary tumor section. Now, on multivariate analysis, a RAS TP53 commutation was the only factor associated with a lower completion rate of the reverse approach. And I should also note that Of the 50 patients who did not complete the reverse approach, 41 or 82% actually ultimately never required or underwent any form of colonic diversion that you might have expected.
So Dr. Newhook, once again, what do you think are the key interpretations of these results? Well, I'd like to leave a lot more of the interpretation for...
Dr. Bote to elaborate on because it's a really nice combination of a serious amount of time, work and effort to take care of patients. But in general, again, I think it really shows that For patients who have a higher... clearly a higher degree of metastatic tumor burden, are able to undergo addressing their stage four cancer and achieve similar survival as all the other approaches, number one.
Whereas those patients would be at extreme risk for progression if you dealt with their primary tumor first and not have their liver disease addressed and could risk worse survival. I would also like to point out something between the last paper and this paper is that it seems like the survival may be a little bit higher for the combined approach, but that's clear selection bias.
clear selection bias that these patients are the ones who have a tiny little liver meant solitary low tumor burden in their liver. And I think it also brings into the picture the importance of disease biology, the risk of systemic failure and progression, and the opportunity to keep an organ, the rectum. that otherwise would not impact patient's survival if we had to remove it. So I'll let Dr. Devote finish up a little bit more. So I think it's an approach that's really oncologic.
in the sense that it includes also systemic chemotherapy. And we shouldn't forget that when we talk about it. There's almost universal agreement now that patients with... Sanctuary's disease should get preoperative chemotherapy before there, so on the liver. So this is performed in the context of perioperative. pre-liber surgery, chemotherapy, followed by the liver surgery, followed by work chemotherapy, and followed by the treatment of the primary.
and the radiation can fit in this scheme, short cross radiation, obviously, pretty much any time, because it's short course. And for long-course radiation is done before the resection of the primary. But it's an approach that's really similar to the two-stage haptectomy approach. So you start optimistic.
you see the patients and you're gonna give chemo to start and you don't know whom is gonna you know who is gonna become eventually complete the course And as you see in this series, 65% completed the two resections and 35% just had delivery section. But it has to do also with the biology of the disease. And the best way to engage the biology of the disease is taking sure of time and combined with chemo. And you realize that, you know, this patient will read.
would be a good candidate he's responding you stay on track and when you stop and you haven't i mean you haven't hurt the patient or the whole lot because the patients don't complete most of them in fact never needed any osteostomy and all the downside of the surgery for locally advanced rectal cancer. Yeah, I think that's a great breakdown of this paper that really gives more modern data.
about these approaches and why the reverse approach, I think, is a more oncologic and optimistic approach. As always, we just want to leave our listeners with some key takeaways from the episode. First is that synchronous liver metastasis from rectal cancer are challenging to manage because patients can have complications from rectal surgery and or obstruction from the primary tumor that can derail them or take them off schedule from the systemic...
and or surgical therapy that's pivotal for treating their stage 4 disease. There are currently three common sequencing approaches for treatment, the classic approach, the combined approach, and the reverse approach, all of which we've discussed in this episode.
On paper, the combined approach has the best oncologic outcomes, but it's important to note that this can be attributed to patient selection, since the combined approach is generally only preferred and recommended for patients who have a low burden of liver disease. metastasis, not requiring a major hepatic resection, and those who are at lower risk for post-op complications from the approach.
The reverse approach has steadily become the preferred treatment sequence, especially for patients with increased or more advanced liver metastasis, given that more recent data shows continued improvements in survival over time. It treats the stage 4 disease early via pre-op systemic chemotherapy and hepatic resection, followed by primary rectal tumor resection with the idea of reducing interruptions in treatment that can occur with complications from rectal tumor.
surgery. An added benefit is that this approach also may obviate the need for rectal resection or diversion in some patients. This is different from the classic approach where rectal resection is performed first but may result in severe complications that can preclude patients from receiving the systemic chemo and hepatectomy for their liver mets.
Now, in patients with symptomatic primary tumors, there's still some utility in this approach, and the 2023 ASO article we discussed describes this well and has a nice algorithm outlining when and how to choose between the three approaches. Once again, thanks to everyone for tuning in and as always, dominate the day.
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Whether it's a next step in your studies or taking your career to the next level, Newcastle College University Centre has the degree for you. From business to hospitality, rail to sport, we've over 60 practical degree courses to get you work ready.
You'll love our study and social spaces in the heart of the city. Small class sizes mean more time with our industry-experienced tutors. And our student support is first class. Apply now and study your degree with us this September. Search Newcastle College University. Center online.